Magdy El-Masry

Prof of Cardiology Tanta University

The Triumvirate = triad = trio

Pathogenesis of type 2 diabetes the triumvirate

Insulin resistance in muscle and liver and impaired insulin secretion represent the core defects in type 2 diabetes

1999 The Triumvirate

The ominous octet Multiple defects contribute to the development

of glucose intolerance in type 2 diabetes HGP hepatic glucose production

2008 The ominous octet

Pathophysiological abnormalities targeted by currently available antidiabetic medications DPP4i dipeptidyl peptidase-4 inhibitor GLP1 RA glucagon-like peptide-1 receptor agonist HGP hepatic glucose

production MET metformin SGLT2i sodium glucose co-transporter 2 inhibitor TZD thiazolidinedione

The Ominous Octet How Pathophysiology And Therapy Merge

Cardiologists and diabetes

Managing type 2 diabetes in the primary care setting beyond glucocentricity

Glucocentricity

The irrational belief that lowering blood sugar using

virtually any pharmacological means will produce a

reliable reduction in adverse outcomes

glu-co-cen-tricity |ˈgloōkō senˈtrisitēnoun

Improving Diabetes Outcomes Beyond Glucocentricity

History of diabetes medications

John R W hite Jr Diabetes Spectr 20142782-86

copy2014 by American Diabetes Association

Target organs and action mechanism of antidiabetic drugsNature Reviews Endocrinology 12 337ndash346 (2016)

The mechanism for metformin action remains uncertain metformin might target the liver to reduce gluconeogenesis and skeletal muscles to enhance peripheral glucose utilization with a possible role in the gut to increase levels of glucagon-like peptide 1 (GLP-1) Sulfonylureas and meglitinides increase insulin secretion in the pancreas Thiazolidinediones (TZDs) act as insulin sensitizers in skeletal muscle adipose tissue and the liverGLP-1 receptor (GLP-1R) agonists (GLP-1RA) target the pancreas to increase insulin secretion and reduce glucagon production as well as act in the gut to reduce gastric emptying Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase endogenous incretin levels by blocking the action of DPP-4 Sodiumndashglucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) reduce renal glucose reabsorption

Evolving concepts in the perception of safety issues related to anti-diabetic drugs

(ie research priority and clinical implications )

Primum non nocere is a Latin phrase that means first do no harm

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

The Triumvirate = triad = trio

Pathogenesis of type 2 diabetes the triumvirate

Insulin resistance in muscle and liver and impaired insulin secretion represent the core defects in type 2 diabetes

1999 The Triumvirate

The ominous octet Multiple defects contribute to the development

of glucose intolerance in type 2 diabetes HGP hepatic glucose production

2008 The ominous octet

Pathophysiological abnormalities targeted by currently available antidiabetic medications DPP4i dipeptidyl peptidase-4 inhibitor GLP1 RA glucagon-like peptide-1 receptor agonist HGP hepatic glucose

production MET metformin SGLT2i sodium glucose co-transporter 2 inhibitor TZD thiazolidinedione

The Ominous Octet How Pathophysiology And Therapy Merge

Cardiologists and diabetes

Managing type 2 diabetes in the primary care setting beyond glucocentricity

Glucocentricity

The irrational belief that lowering blood sugar using

virtually any pharmacological means will produce a

reliable reduction in adverse outcomes

glu-co-cen-tricity |ˈgloōkō senˈtrisitēnoun

Improving Diabetes Outcomes Beyond Glucocentricity

History of diabetes medications

John R W hite Jr Diabetes Spectr 20142782-86

copy2014 by American Diabetes Association

Target organs and action mechanism of antidiabetic drugsNature Reviews Endocrinology 12 337ndash346 (2016)

The mechanism for metformin action remains uncertain metformin might target the liver to reduce gluconeogenesis and skeletal muscles to enhance peripheral glucose utilization with a possible role in the gut to increase levels of glucagon-like peptide 1 (GLP-1) Sulfonylureas and meglitinides increase insulin secretion in the pancreas Thiazolidinediones (TZDs) act as insulin sensitizers in skeletal muscle adipose tissue and the liverGLP-1 receptor (GLP-1R) agonists (GLP-1RA) target the pancreas to increase insulin secretion and reduce glucagon production as well as act in the gut to reduce gastric emptying Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase endogenous incretin levels by blocking the action of DPP-4 Sodiumndashglucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) reduce renal glucose reabsorption

Evolving concepts in the perception of safety issues related to anti-diabetic drugs

(ie research priority and clinical implications )

Primum non nocere is a Latin phrase that means first do no harm

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

The ominous octet Multiple defects contribute to the development

of glucose intolerance in type 2 diabetes HGP hepatic glucose production

2008 The ominous octet

Pathophysiological abnormalities targeted by currently available antidiabetic medications DPP4i dipeptidyl peptidase-4 inhibitor GLP1 RA glucagon-like peptide-1 receptor agonist HGP hepatic glucose

production MET metformin SGLT2i sodium glucose co-transporter 2 inhibitor TZD thiazolidinedione

The Ominous Octet How Pathophysiology And Therapy Merge

Cardiologists and diabetes

Managing type 2 diabetes in the primary care setting beyond glucocentricity

Glucocentricity

The irrational belief that lowering blood sugar using

virtually any pharmacological means will produce a

reliable reduction in adverse outcomes

glu-co-cen-tricity |ˈgloōkō senˈtrisitēnoun

Improving Diabetes Outcomes Beyond Glucocentricity

History of diabetes medications

John R W hite Jr Diabetes Spectr 20142782-86

copy2014 by American Diabetes Association

Target organs and action mechanism of antidiabetic drugsNature Reviews Endocrinology 12 337ndash346 (2016)

The mechanism for metformin action remains uncertain metformin might target the liver to reduce gluconeogenesis and skeletal muscles to enhance peripheral glucose utilization with a possible role in the gut to increase levels of glucagon-like peptide 1 (GLP-1) Sulfonylureas and meglitinides increase insulin secretion in the pancreas Thiazolidinediones (TZDs) act as insulin sensitizers in skeletal muscle adipose tissue and the liverGLP-1 receptor (GLP-1R) agonists (GLP-1RA) target the pancreas to increase insulin secretion and reduce glucagon production as well as act in the gut to reduce gastric emptying Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase endogenous incretin levels by blocking the action of DPP-4 Sodiumndashglucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) reduce renal glucose reabsorption

Evolving concepts in the perception of safety issues related to anti-diabetic drugs

(ie research priority and clinical implications )

Primum non nocere is a Latin phrase that means first do no harm

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Pathophysiological abnormalities targeted by currently available antidiabetic medications DPP4i dipeptidyl peptidase-4 inhibitor GLP1 RA glucagon-like peptide-1 receptor agonist HGP hepatic glucose

production MET metformin SGLT2i sodium glucose co-transporter 2 inhibitor TZD thiazolidinedione

The Ominous Octet How Pathophysiology And Therapy Merge

Cardiologists and diabetes

Managing type 2 diabetes in the primary care setting beyond glucocentricity

Glucocentricity

The irrational belief that lowering blood sugar using

virtually any pharmacological means will produce a

reliable reduction in adverse outcomes

glu-co-cen-tricity |ˈgloōkō senˈtrisitēnoun

Improving Diabetes Outcomes Beyond Glucocentricity

History of diabetes medications

John R W hite Jr Diabetes Spectr 20142782-86

copy2014 by American Diabetes Association

Target organs and action mechanism of antidiabetic drugsNature Reviews Endocrinology 12 337ndash346 (2016)

The mechanism for metformin action remains uncertain metformin might target the liver to reduce gluconeogenesis and skeletal muscles to enhance peripheral glucose utilization with a possible role in the gut to increase levels of glucagon-like peptide 1 (GLP-1) Sulfonylureas and meglitinides increase insulin secretion in the pancreas Thiazolidinediones (TZDs) act as insulin sensitizers in skeletal muscle adipose tissue and the liverGLP-1 receptor (GLP-1R) agonists (GLP-1RA) target the pancreas to increase insulin secretion and reduce glucagon production as well as act in the gut to reduce gastric emptying Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase endogenous incretin levels by blocking the action of DPP-4 Sodiumndashglucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) reduce renal glucose reabsorption

Evolving concepts in the perception of safety issues related to anti-diabetic drugs

(ie research priority and clinical implications )

Primum non nocere is a Latin phrase that means first do no harm

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Cardiologists and diabetes

Managing type 2 diabetes in the primary care setting beyond glucocentricity

Glucocentricity

The irrational belief that lowering blood sugar using

virtually any pharmacological means will produce a

reliable reduction in adverse outcomes

glu-co-cen-tricity |ˈgloōkō senˈtrisitēnoun

Improving Diabetes Outcomes Beyond Glucocentricity

History of diabetes medications

John R W hite Jr Diabetes Spectr 20142782-86

copy2014 by American Diabetes Association

Target organs and action mechanism of antidiabetic drugsNature Reviews Endocrinology 12 337ndash346 (2016)

The mechanism for metformin action remains uncertain metformin might target the liver to reduce gluconeogenesis and skeletal muscles to enhance peripheral glucose utilization with a possible role in the gut to increase levels of glucagon-like peptide 1 (GLP-1) Sulfonylureas and meglitinides increase insulin secretion in the pancreas Thiazolidinediones (TZDs) act as insulin sensitizers in skeletal muscle adipose tissue and the liverGLP-1 receptor (GLP-1R) agonists (GLP-1RA) target the pancreas to increase insulin secretion and reduce glucagon production as well as act in the gut to reduce gastric emptying Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase endogenous incretin levels by blocking the action of DPP-4 Sodiumndashglucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) reduce renal glucose reabsorption

Evolving concepts in the perception of safety issues related to anti-diabetic drugs

(ie research priority and clinical implications )

Primum non nocere is a Latin phrase that means first do no harm

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Managing type 2 diabetes in the primary care setting beyond glucocentricity

Glucocentricity

The irrational belief that lowering blood sugar using

virtually any pharmacological means will produce a

reliable reduction in adverse outcomes

glu-co-cen-tricity |ˈgloōkō senˈtrisitēnoun

Improving Diabetes Outcomes Beyond Glucocentricity

History of diabetes medications

John R W hite Jr Diabetes Spectr 20142782-86

copy2014 by American Diabetes Association

Target organs and action mechanism of antidiabetic drugsNature Reviews Endocrinology 12 337ndash346 (2016)

The mechanism for metformin action remains uncertain metformin might target the liver to reduce gluconeogenesis and skeletal muscles to enhance peripheral glucose utilization with a possible role in the gut to increase levels of glucagon-like peptide 1 (GLP-1) Sulfonylureas and meglitinides increase insulin secretion in the pancreas Thiazolidinediones (TZDs) act as insulin sensitizers in skeletal muscle adipose tissue and the liverGLP-1 receptor (GLP-1R) agonists (GLP-1RA) target the pancreas to increase insulin secretion and reduce glucagon production as well as act in the gut to reduce gastric emptying Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase endogenous incretin levels by blocking the action of DPP-4 Sodiumndashglucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) reduce renal glucose reabsorption

Evolving concepts in the perception of safety issues related to anti-diabetic drugs

(ie research priority and clinical implications )

Primum non nocere is a Latin phrase that means first do no harm

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Glucocentricity

The irrational belief that lowering blood sugar using

virtually any pharmacological means will produce a

reliable reduction in adverse outcomes

glu-co-cen-tricity |ˈgloōkō senˈtrisitēnoun

Improving Diabetes Outcomes Beyond Glucocentricity

History of diabetes medications

John R W hite Jr Diabetes Spectr 20142782-86

copy2014 by American Diabetes Association

Target organs and action mechanism of antidiabetic drugsNature Reviews Endocrinology 12 337ndash346 (2016)

The mechanism for metformin action remains uncertain metformin might target the liver to reduce gluconeogenesis and skeletal muscles to enhance peripheral glucose utilization with a possible role in the gut to increase levels of glucagon-like peptide 1 (GLP-1) Sulfonylureas and meglitinides increase insulin secretion in the pancreas Thiazolidinediones (TZDs) act as insulin sensitizers in skeletal muscle adipose tissue and the liverGLP-1 receptor (GLP-1R) agonists (GLP-1RA) target the pancreas to increase insulin secretion and reduce glucagon production as well as act in the gut to reduce gastric emptying Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase endogenous incretin levels by blocking the action of DPP-4 Sodiumndashglucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) reduce renal glucose reabsorption

Evolving concepts in the perception of safety issues related to anti-diabetic drugs

(ie research priority and clinical implications )

Primum non nocere is a Latin phrase that means first do no harm

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

History of diabetes medications

John R W hite Jr Diabetes Spectr 20142782-86

copy2014 by American Diabetes Association

Target organs and action mechanism of antidiabetic drugsNature Reviews Endocrinology 12 337ndash346 (2016)

The mechanism for metformin action remains uncertain metformin might target the liver to reduce gluconeogenesis and skeletal muscles to enhance peripheral glucose utilization with a possible role in the gut to increase levels of glucagon-like peptide 1 (GLP-1) Sulfonylureas and meglitinides increase insulin secretion in the pancreas Thiazolidinediones (TZDs) act as insulin sensitizers in skeletal muscle adipose tissue and the liverGLP-1 receptor (GLP-1R) agonists (GLP-1RA) target the pancreas to increase insulin secretion and reduce glucagon production as well as act in the gut to reduce gastric emptying Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase endogenous incretin levels by blocking the action of DPP-4 Sodiumndashglucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) reduce renal glucose reabsorption

Evolving concepts in the perception of safety issues related to anti-diabetic drugs

(ie research priority and clinical implications )

Primum non nocere is a Latin phrase that means first do no harm

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Target organs and action mechanism of antidiabetic drugsNature Reviews Endocrinology 12 337ndash346 (2016)

The mechanism for metformin action remains uncertain metformin might target the liver to reduce gluconeogenesis and skeletal muscles to enhance peripheral glucose utilization with a possible role in the gut to increase levels of glucagon-like peptide 1 (GLP-1) Sulfonylureas and meglitinides increase insulin secretion in the pancreas Thiazolidinediones (TZDs) act as insulin sensitizers in skeletal muscle adipose tissue and the liverGLP-1 receptor (GLP-1R) agonists (GLP-1RA) target the pancreas to increase insulin secretion and reduce glucagon production as well as act in the gut to reduce gastric emptying Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase endogenous incretin levels by blocking the action of DPP-4 Sodiumndashglucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) reduce renal glucose reabsorption

Evolving concepts in the perception of safety issues related to anti-diabetic drugs

(ie research priority and clinical implications )

Primum non nocere is a Latin phrase that means first do no harm

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Evolving concepts in the perception of safety issues related to anti-diabetic drugs

(ie research priority and clinical implications )

Primum non nocere is a Latin phrase that means first do no harm

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Primum non nocere is a Latin phrase that means first do no harm

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

What Do We Know So Far

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Completed and ongoing CVOTs in type 2 diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

3-P MACE 3 - point major adverse cardiac events (composite of cardiovascular death nonfatal stroke and nonfatal myocardial infarction)4-P MACE Composite of 3-P MACE plus unstable angina ACS hospitalization for HF

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Unknown = cardiovascular outcome data is currently unavailable

Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes

Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes

Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

BiguanideMetformin

Cardiovascular Impact Improves Outcomes Metformin

Cardiovascular Outcomes DataA subanalysis of the UKPDS trial found good glycemic control with metformin with about 10 years of use MAY reduce the risk of CV mortality especially in obese patients NNT = 14 [Evidence level A high-quality RCT]

Pooled data demonstrate possible reduced CV mortality with a NNT = 56compared to other DM medications or placebo [Evidence level A high-quality meta-analysis]

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Sulfonylureas ( first generation )

ChlorpropamideTolazamide

Tolbutamide

Cardiovascular ImpactUnknown1048696 Chlorpropamide1048696 Tolazamide

Worsens Outcomes Tolbutamide

Cardiovascular Outcomes DataTolbutamide use has been associated with increased CV mortality compared to diet alone or diet plus insulin

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Sulfonylureas (second generation)

GliclazideGlipizide

GlimepirideGlyburide

Cardiovascular ImpactUnknown1048696 Gliclazide1048696 Glipizide1048696 Glimepiride1048696 Glyburide

Cardiovascular Outcomes DataGlimepiride CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D is ongoing to evaluate the long-term impact of glimepiride on CV morbidity and mortality

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Meglitinides(Glinides)

NateglinideRepaglinide

Cardiovascular Impact Unknown1048696 Nateglinide1048696 Repaglinide

Cardiovascular Outcomes DataNateglinide No outcome data for inpatients with T2D However the NAVIGATOR trial found nateglinide use in patients with impaired glucose tolerance and at high risk for CV events had a neutral effect on cardiovascularoutcomes [Evidence level A high-quality RCT]

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Alpha-glucosidaseinhibitors

Acarbose

Cardiovascular Impact Unknown1048696 Acarbose

Cardiovascular Outcomes Data Acarbose The ACE (Acarbose Cardiovascular Evaluation) trial is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients with impaired glucose tolerance and established CHD or ACS

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Thiazolidinediones( Glitazones )

PioglitazoneRosiglitazone

Cardiovascular Impact Improves OutcomesPioglitazoneNeutral Rosiglitazone

based on CV morbidity and mortality outcomes but note increased risk of heart failure associated with use

Cardiovascular Outcomes DataPioglitazone and Rosiglitazone are known for their associated risk of heart failure with a meta-analysis determining an NNH of approximately 50 patients treatedwith either agent for approximately two years [Evidence level A high-quality meta-analysis]

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Cardiovascular Outcomes DataPioglitazone The primary endpoint in the PROactive trial was not improved with pioglitazone A secondary endpoint found use of pioglitazone for about three years in patients with T2D and macrovascular disease (eg MI stroke PCI) may reduce the risk of all-cause mortality non-fatal MI and stroke (NNT = 50)[Evidence level A high quality RCT]

Subgroup analysis found use of pioglitazone for about three years in patients with T2D and a previous stroke may reduce the risk of recurrent fatal or nonfatal stroke (NNT = 22) [Evidence level A high quality RCT]

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Rosiglitazone The RECORD trial found adding rosiglitazone to metformin or a sulfonylurea for at least five years did not affect overall CV morbidity or mortality[Evidence level A high-quality RCT]

Cardiovascular Outcomes DataPioglitazone The IRIS trial found use of pioglitazone for about five years in patients with prediabetes and a history of stroke (with mild impairment) or TIA may reduce the risk of a future stroke or MI (NNT = 36)[Evidence level A high-quality RCT]

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Dipeptidyl peptidase-4(DPP-4) inhibitors( Incretin enhancers oral ) ldquoGliptinsrdquo

Cardiovascular Impact Worsens Outcomes Alogliptin SaxagliptinNeutralSitagliptinUnknown1048696 Linagliptin

AlogliptinSaxagliptin

Sitagliptin Linagliptin

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Cardiovascular Outcomes Data

Alogliptin The EXAMINE trial found alogliptin use in patients with T2D and a history of a recent ACS did not increase major adverse CV events compared to placebo [Evidence level A high-quality RCT]Alogliptin is associated with an increased risk of heart

failure-related admissions NNH = 167 [Evidence level A high-quality RCT]

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Cardiovascular Outcomes DataSaxagliptin The SAVOR-TIMI 53 found saxagliptin use in patients with T2D at high risk for CV events neither reduced nor increased the risk of CV deathMI or ischemic stroke compared to standard therapy [Evidence level A highquality RCT] Saxagliptin was associated with an increased risk of

heart failure-related admissions NNH = 143 [Evidence level A high-quality RCT]

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Sitagliptin The TECOS trial found adding sitagliptin to existing DM therapy did not increase the major adverse CV events hospitalization for heart failure or other adverse events compared to placebo [Evidence level A high-quality RCT]

Linagliptin CAROLINA CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 DM is ongoing to evaluate the long-term impact of linagliptinversus glimepiride on CV morbidity and mortality

Cardiovascular Outcomes Data

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Glucagon-like peptide-1(GLP-1) receptor agonists( Incretin mimeticsinjectable )

Albiglutide Liraglutide LixisenatideDulaglutideExenatide

Cardiovascular ImpactUnknown1048696 Albiglutide1048696 Dulaglutide1048696 ExenatideImproves Outcomes LiraglutideNeutral Lixisenatide

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Cardiovascular Outcomes Data

Albiglutide HARMONY Outcomes is ongoing to evaluate the effects of adding albiglutide to standard blood glucose lowering therapies on MACE

Dulaglutide The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial is ongoing to evaluate if dulaglutide can reduce MACE in patients with T2D

Exenatide The EXSCEL (Exenatide Study of Cardiovascular Events Lowering Trial) trial is ongoing to evaluate if exenatide added to usual care impacts CV outcomes in patients with T2D

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Liraglutide The LEADER trial [Evidence level A high-quality RCT] found adding liraglutide to standard care in patients with T2D with CV disease or at high CV risk over almost four years may reduceDeath from CV causes nonfatal MI or nonfatal stroke NNT = 53Death from CV causes NNT = 77Death from any cause NNT = 71Liraglutide did not reduce the individual rates of MI nonfatal stroke or hospitalization for heart failure

Lixisenatide The ELIXA trial found adding lixisenatide to conventional therapy in T2D patients with a recent ACS had a neutral effect on CV outcomes

Cardiovascular Outcomes Data

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ldquoFlozinsrdquo

Canagliflozin EmpagliflozinDapagliflozin

Cardiovascular ImpactUnknown1048696 Canagliflozin1048696 DapagliflozinImproves Outcomes Empagliflozin

Cardiovascular Outcomes DataCanagliflozin CANVAS (CANagliflozin cardioVascularAssessment Study) is ongoing to evaluate the impact of canagliflozin on CV risk for MACEs

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Dapagliflozin DECLARE-TIMI58 is ongoing to evaluate the impact of adding dapagliflozin to current DM therapy on MI ischemic stroke and CV death

Empagliflozin The EMPAG-REG OUTCOME trial [Evidence level A highquality RCT] found empagliflozin use for about three years when added to standard glucose-lowering therapy in patients with T2D and underlying CV disease may reduce Hospitalization due to heart failure (NNT = 71) CV death rates (NNT = 45) Overall death rates (NNT = 39) Empagliflozin did not reduce the individual rates of MI

or stroke

Cardiovascular Outcomes Data

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

What do the guidelines say

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

L I R A G L U T I D EE M P A G L I F L O Z I N

M E T F O R M I N P I O G L I T A Z O N E

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Metformin if not contraindicated and if tolerated is the

preferred initial pharmacologic agent for the treatment of T2D A

In patients with long-standing suboptimally controlled T2D and

established ASCVD empagliflozin or liraglutide should be

considered as they have been shown to reduce cardiovascular

and all-cause mortality when added to standard care Ongoing

studies are investigating the cardiovascular benefits of other

agents in these drug classes B

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

In patients with symptomatic heart failure thiazolidinedione

treatment should not be used A

In patients with T2D with stable congestive heart failure

metformin may be used if eGFR remains gt30mLmin but

should be avoided in unstable or hospitalized patients with

congestive heart failure B

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes

Recommendations Class Level

Metformin is recommended as first-line therapy if tolerated and not contra-indicated following evaluation of renal function

I B

In patients with type 2 DM and CVD the use of an SGLT2 inhibitor should be considered early in the course of the disease to reduce CV and total mortality

IIa B

Recommendations for management of diabetes