EarlyCombination Therapyand Treatment Escalation for ... · Objective of this Session •This session is not conceived to provide guidance to treatment •This session would like

Early Combination Therapy and Treatment Escalation for Sustained Glycemic Control in T2DMStefano Del PratoSection of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Italy

@SDelprato

Objective of this Session

• This session is not conceived to provide guidance to treatment

• This session would like to discuss available evidence on:

• The relevance of achieving early and durable glycaemic control

• The therapeutic options for achieving such a goal

• The strategies for initial therapeutic strategy selection and escalation

Our First Patient: Please, Meet Anna

Anne is free of symptoms, and much engaged with her family and job

• 54-year-old female• Diagnosed with T2DM 3 months ago• Hypertension • Dyslipidaemia

Not a real patient

Metabolic parameters

• HbA1c: 6.7%• BP: 135/84 mmHg• LDL-C: 71 mg/dl• HDL: 56 mg/dl• Triglycerides: 119 mg/dl

• Tot-C: 158 mg/dl• BMI: 31 kg/m2

• eGFR: 88 ml/min/1.73 m2

• UACR: 15 mg/g


Not a real patient

• Lisinopril/Hydrochlorothiazide 20/12.5 mg qd• Atorvastatin 20 mg qd• Clodronic acic 100mg im every 2 weeks

Medication


Not a real patient

HbA1c target• <6.0%• <6.5%• <7.0%• <7.5%

Which glycaemic target for Anna?

Not a real patient


Time to Treatment Intensification after Monotherapy Failure and Its Association With Subsequent Glycaemic Control

Attaining glycaemic control (HbA1c <7%) after intensification

Time to intensification (months) HR 95% CI P value

Parameters

<12 Reference

12 to <24 0.78 0.76-0.81 <0.0001

24 to < 36 0.76 0.70-0.75 <0.0001

0.5 0.75 1.0 1.25

Desai U et al Diabetes Care 2018 ;41:2096-2104

N= 93,515

10-yr Risk of Complication for Early HbA1c >6.5%

HRs adjusted for year of diagnosis, age at diagnosis, sex, race/ethnicity, BMI, systolic and diastolic blood pressure, total cholesterol, HDL cholesterol, smoking status, HbA1c after each early exposure period, and comorbidity.

Laiteerapong N et al Diabetes Care 2019; ;42:416-426

34,737 managed care newly diagnosed T2DM patients; 10 years of survival (average follow-up 13.0 years)

Mac

rova

scul

arev

ents

Mic

rova

scul

arev

ents

• Lifestyle modification• Metformin• Lifestyle modification + metformin• Lifestyle modification + combination therapy

Which anti-hyperglycemic treatment?

Not a real patient


FIRST-LINE THERAPY IS METFORMIN AND COMPREHENSIVE LIFESTYLE (INCLUDING WEIGHT MANAGEMENT AND PHYSICAL ACTIVITY)

FIRST-LINE THERAPY IS METFORMIN AND COMPREHENSIVE LIFESTYLE (INCLUDING WEIGHT MANAGEMENT AND PHYSICAL ACTIVITY)

Davies MJ et al Diabetologia. 2018;61:2461-2498

Is Disease Progression Predictable? The UKPDS Lesson

Conventional treatment

Glyburide

Chlorpropamide

Metformin

Insulin

ULN=6.2%

9

8

7

6

0

Years after randomisation

2 4 6 8 10

HbA

1c (%

)

HbA1c, glycated haemoglobin; UKPDS, UK Prospective Diabetes Study; ULN, upper limit of normal

UKPDS Group. Lancet. 1998;352:854–65.

% o

f ref

eren

ce c

ateg

ory

NFG IFG Diabetes

100

75

50

25

0

<5.0

5.0-

5.4

5.5-

5.9

6.0-

6.4

6.5-

6.9

7.0-

7.4

7.5-

7.9

8.0-

8.4

8.5-

8.9

≥9.0

Fasting plasma glucose (mM)

1st phase insulin secretion

Ref.

MatsudalSI

InsAUC30/GluAUC30

InsAUC120/GluAUC120

2nd phase insulinsecretion

(N=6414)

Progressive Loss of Insulin Sensitivity and β-cell Function in the Natural History of Type 2 Diabetes

AUC, area under curve; HbA1c, glycated haemoglobin; IFG, impaired fasting glucose; Ins, insulin; NFG, normal fasting glucose; OGTT, oral glucose tolerance test

Stančáková A et al. Diabetes. 2009;58:1212–21.

The stepwise approach may often lead to treatment failure with prolonged periods of hyperglycaemia as a consequence of clinical inertia and delays in achieving optimal glycaemic control

OAD, oral antidiabetes drug

Adapted from: Del Prato S et al. Int J Clin Pract. 2005;59:1345–55.

7

6

9

8

10

0

OADmonotherapy

OAD monotherapyuptitration

OAD combination

+

OAD + basal insulin

OAD + multipledaily insulin injections

+

Duration of diabetes (years)

HbA

1c(%

)

+

Present Conservative Strategy to Treat Hyperglycaemia

Diet andExercise


7

0

9

8

10

0

OAD combination

+

OAD + basal insulin


+


HbA

1c(%

)

OADmonotherapy

OAD monotherapyuptitration

+

Diet andExercise




Management of Hyperglycaemia in Type 2 Diabetes 2018 - A Consensus Report by the ADA and EASD

…While there is some support for initial combination therapy due to the greater initial reduction of A1c than can be provided by metformin alone,

there is little evidence that this approach is superior to sequential addition of medications for maintaining glycemic control, or slowing the

progression of diabetes…Davies MJ et al Diabetologia. 2018;61:2461-2498


7

0

9

8

10

0

OAD combination

+

OAD + basal insulin


+


HbA

1c(%

)

Diet andExercise




VariableEarly combinationN=998

Initial monotherapyN=1003

Women 55% 51%

Age (years) 54.1 (9.5) 54.6 (9.2)

T2DM duration (months)* 3.3 (1.0–9.8) 3.4 (0.9–10.4)

HbA1c (%) 6.7 (0.4) 6.7 (0.5)

FPG (mmol/L)* 6.9 (6.1–7.8) 6.9 (6.2–7.9)

BMI (kg/m2) 31.2 (4.8) 31.0 (4.7)

Weight (kg)* 85.0 (72.8–97.3) 84.0 (72.0–97.0)

Normal baseline eGFR (MDRD), mL/min/1.73m2 43.3% 44.3%

Current smoker 15.4% 13.6%Data is presented as mean (SD), unless specified. *Median (IQR). The baseline demographics and clinical characteristics were similar between the treatment arms

VERIFY - Baseline Characteristics

BMI, body mass index; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; MDRD, modification of diet in renal disease; T2DM,type 2 diabetes mellitus

Matthews DR et al. Lancet. 2019; 26;394:1519-1529

Del Prato S et al. Diabet Med. 2014;31:1178–84. Matthews DR et al. Diabetes Obes Metab. 2019;21:2240–47.

RA

ND

OM

ISA

TIO

N Metformin + Vildagliptin

Metformin + Placebo

Early combination

Initial monotherapy

Time to failure

Time to failure is the Primary Outcome

It addresses the first question –Q1: Do those with type 2 diabetes

benefit from having combined therapy at the beginning of their

pharmacological treatment?

Rate of failure is calculated in each

strategy group by an assessment of those

failing as a proportion of all those in that group.

VERIFY Study Design

Patie

nts

with

an

even

t (%

)

Initial monotherapyEarly combination 983 960 862 815 752 671 597 551 509 478 187Patients at risk

989 937 733 661 576 503 434 377 337 299 108

Early combination

Initial monotherapy

Hazard ratio (95% CI): 0·51 (0·45,0·58);p<0·0001

VERIFY - Time to Initial Treatment Failure

CI, confidence interval


Insulin

Insulin

Not failed

Not failed

Failed – move to combination

Failed – stay on combination

Period 3Period 2

RA

ND

OM

ISA

TIO

N Metformin + Vildagliptin

Metformin + Placebo

Combination strategy

Sequential strategy

Period 1

Time to second failure is the Secondary Outcome

It addresses the question –Q2: Do those with type 2

diabetes benefit more from having combined therapy at

the beginning of their pharmacological treatment compared to a sequential

additive strategy?

Rate of failure is calculated in each

strategy group by an assessment of those failing as a proportion

of all those in that group.

No insulin

No insulin

VERIFY Study Design

Del Prato S et al. Diabet Med. 2014;31:1178–84. Matthews DR et al. Diabetes Obes Metab. 2019;21:2240–47.

Hazard ratio (95% CI): 0·74 (0·63, 0·86);{p<0·0001}

983 966 918 870 830 768 715 644 602 565 221

Patie

nts

with

an

even

t (%

)

Initial monotherapy

Early combination

Patients at risk

989 968 897 821 761 698 643 575 531 490 179

Initial monotherapy

Early combination

VERIFY - Time To Second Failure

CI, confidence interval


Safety EventsEarly combinationN=998, n (%)

Initial monotherapyN=1001, n (%)

Patients with at least one AE 833 (83.5) 833 (83.2)SAE 166 (16.6) 183 (18.3)Drug-related AE 159 (15.9) 143 (14.3)Severe AE 105 (10.5) 106 (10.6)AEs leading to permanent discontinuation of treatment

41 (4.1) 53 (5.3)

Death 13 (1.3) 9 (0.9)Hypoglycaemic events 13 (1.3) 9 (0.9)

AE, adverse event; SAE, serious adverse event


VERIFY - Overall Safety Events

Hazard ratio (95% CI): 0·71 (0·42,1·19);{p=0·19}

Early combination

Initial monotherapy


VERIFY - Time to First Adjudicated Macrovascular Event

Although this is an indicative signal, more dedicated studies are required

10-yr Mortality Risk for Early HbA1c >6.5%34,737 managed care newly diagnosed T2DM patients; 10 years of survival (average follow-up 13.0 years)

HRs adjusted for year of diagnosis, age at diagnosis, sex, race/ethnicity, BMI, systolic and diastolic blood pressure, total cholesterol, HDL cholesterol, smoking status, HbA1c after each early exposure period, and comorbidity.

Laiteerapong N et al Diabetes Care 2019; ;42:416-426

Management of Hyperglycaemia in Type 2 Diabetes ADA-EASD Consensus Report 2018

…While there is some support for initial combination therapy due to the greater initial reduction of A1c than can be provided by metformin alone,

there is little evidence that this approach is superior to sequential addition of medications for maintaining glycemic control, or slowing the

progression of diabetes…

now

2020

Adapted from Davies MJ et al Diabetologia. 2018;61:2461-2498

John attends a follow-up appointment after his stent procedure

• 63-year-old male• Diagnosed with T2D 15 years ago• Dyslipidaemia• Diffuse moderate multi-vessel CAD• NYHA class III

Not a real patient

LAD, left anterior descending

Our Second Patient: Please, Meet Giulio

Meet John

• HbA1c: 8.3%• BP: 143/83 mmHg• Tot-C: 181 mg/dl• LDL-C 97 mg/dl• TG 195 mg/dl

• BMI: 31.3 kg/m2

• eGFR: 52 ml/min/1.73 m2

• UACR: 597 mg/g

Metabolic parameters

Not a real patient


Meet John

• Metformin 1000 mg bid• Sitagliptin 100 mg qd• Atorvastatin 40 mg qd• Telmisartan 20 mg qd• Nifedipine 5 mg qd• ASA 100 mg qd

Medications

Not a real patientNot a real patient


Meet John

Not a real patient

• Poorly Controlled DM?• CKD?• ASCVD?• HF?

Not a real patient

Our Second Patient: Please, Meet GiulioWhat the main clinical problem

Renal Insufficiency And Cardiovascular Events (RIACE)Phenotypic Characteristics Associated with Hypertension in T2DM Patients

Solini A et al Diabetes Care 2012; 35: 143–49.

DKD, diabetic kidney disease; T1D, type 1 diabetes; T2D, type 2 diabetes; IDNT, Irbesartan Type 2 Diabetic Nephropathy Trial; RAAS, renin–angiotensin-aldosterone system; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan.

1Mogensen CE et al. Br Med J (Clin Res Ed) 1982;285:685; 2Parving HH et al. Lancet 1983;1:1175; 3Lewis EJ et al. N Engl J Med 1993;329:1456; 4Lewis EJ et al. N Engl J Med 2001;345:851;6Brenner BM et al. N Engl J Med 2001;345:861

1980 1990 2000

No new DKD-specific treatment after the start of the RAAS blokade

High blood pressure

identified as DKD risk factor

ß-blockers1

Hydralazine2

Captopril3T1D

IDNT4, IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No New DKD-specific Treatment in the last 15 Years

2015

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med. 2016 375:323-34

Proposed Renal Protective Pathways with SGLT2-inhibitors

CREDENCE (Canagliflozin and Renal Events in Diabetes with Established NephropathyClinical Evaluation)

Percovic V et al. N Engl J Med. 2019;380:2295-2306

Hazard ratio (95% CI) P value

Primary composite outcome 0.70 (0.59–0.82) 0.00001

Doubling of serum creatinine 0.60 (0.48–0.76) <0.001

ESKD 0.68 (0.54–0.86) 0.002

eGFR <15 mL/min/1.73 m2 0.60 (0.45–0.80) –

Dialysis initiated or kidney transplantation 0.74 (0.55–1.00) –

Renal death 0.39 (0.08–2.03) –

CV death 0.78 (0.61–1.00) 0.0502

CV death or hospitalization for heart failure 0.69 (0.57–0.83) <0.001

CV death, MI, or stroke 0.80 (0.67–0.95) 0.01

Hospitalization for heart failure 0.61 (0.47–0.80) <0.001

ESKD, doubling of serum creatinine, or renal death 0.66 (0.53–0.81) <0.001

CREDENCE - Summary of Key Renal and CV Outcomes

Favors Canagliflozin Favors Placebo

0.25 0.5 1.0 2.0 4.0


Declining Renal Function Is Associated with Incident HF

CKD= chronic kidney disease; HF= heart failure; HFpEF= heart failure with preserved ejection fraction; HFrEF= heart failure with reduced ejection fraction.

Nayor M et al. Eur J Heart Fail. 2017;19:615-623

Incidence rates of HF are higher in those with CKD compared to those without

Incidence rates of HF are higher in those with microalbuminuria compared to those without

Cum

ulat

ive

inci

denc

e of

HF

Years

CKD HFrEFCKD HFpEFNo CKD HFrEFNo CKD HFpEF

0 2 4 6 8 10 12

8%

6%

4%

2%

0%

Cum

ulat

ive

inci

denc

eof

HF

Years

Microalbuminuria HFrEFMicroalbuminuria HFpEFNo microalbuminuria HFrEFNo microalbuminuria HFpEF

0 2 4 6 8 10 12

8%

6%

4%

2%

0%

John attends a follow-up appointment after his stent procedure

• 63-year-old male• Diagnosed with T2D 15 years ago• Dyslipidaemia• Diffuse moderate multi-vessel CAD• Recent percutaneous coronary intervention

(stent) due to obstruction at medial LAD• NYHIA class III

Not a real patient

LAD, left anterior descending


CREDENCE - Primary Outcome by Screening eGFR and AlbuminuriaHazard ratio

(95% CI)Interaction

P value

Screening eGFR 0.11

30 to <45 mL/min/1.73 m2 0.75 (0.59–0.95)

45 to <60 mL/min/1.73 m2 0.52 (0.38–0.72)

60 to <90 mL/min/1.73 m2 0.82 (0.60–1.12)

Baseline UACR 0.49

≤1000 mg/g 0.76 (0.55–1.04)

>1000 mg/g 0.67 (0.55–0.81)

Favors Canagliflozin Favors Placebo

0.25 0.5 1.0 2.0 4.0


EMPA-REG CANVAS DECLARE CREDENCE

Drug Empagliflozin Canagliflozin Dapaglifozin Canagliflozin

Doses analysed 10, 25 mg QD 100, 300mg QD 10 mg QD 100 mg QD

Median follow-up, time 3.1 2.4 4.2 2.6

Trial participants 7020 10142 17160 4401

Age, mean 63 63 64 63

Pts with established ASCVD 100% 66% 41% 50%

Women 29% 36% 37% 34%

Pts with history of HF 10% 14% 10% 15%

Pts with eGFR<60ml/min 26% 20% 7% 60%

Primary EP 3P-MACE 3P-MACE 3P-MACE Renal worsening

Secondary EP Renal worsening Renal worsening Renal worsening CV outcomes

Randomized Controlled Phase 3/4 CVOTs of SGLT2Is

Adapted from Zelniker TA et al Lancet. 2019;393:31-39

38373

Meta-Analysis of SGLT2 Inhibitor CVOTs:Renal Worsening, ESRD or Renal Death Composite

Zelniker TA et al Lancet. 2019;393:31-39

By Presence of Baseline eGFR

Meta-Analysis of SGLT2 Inhibitor CVOTs

Hospitalization for Heart Failure and CV DeathBy Presence of Atherosclerotic Cardiovascular Disease

Zelniker TA et al Lancet. 2019;393:31-39

DAPA-HF: CV Death or hHF or an Urgent HF Visit

2105931096147819172075216322582371Placebo2106121146156020022147222123052373DAPA

32

28

24

20

16

12

8

4

0242115 18129630

No. at Risk Months from Randomization

Cum

ulat

ive

Perc

enta

ge (%

)

36

HR 0.74 (0.65, 0.85)p=0.00001

NNT = 21

DAPA

Placebo26% RRRT2DM at baseline

Yes 0.75 (0.63, 0.90)

No 0.73 (0.60, 0.88)

0.800.50 1.00 1.25 2.00

Placebo BetterDAPA Better

McMurray JJV et al. N Engl J Med. 2019 Sep 19. doi: 10.1056/NEJMoa1911303. [Epub ahead of print]

• SGLT2-inhibitor?

• GLP1 Receptor Agonist?

Not a real patient


Meta-analysis of GLP1-RAs and SGLT2 Inhibitors Trials on Renal End Points

Zelniker TA et al Circulation 2019;139:2022-2031

Meta-analysis of GLP1-RAs and SGLT2 Inhibitors Trials on Renal End PointsExcluding Macroalbuminuria


Management of Hyperglycaemia in Type 2 Diabetes 2018 - A Consensus Report by the ADA and EASD


Choosing Glucose-lowering Medication in Those With Established ASCVD or CKD

HF CKD


• Age: 62• Diagnosed with type 2 diabetes 14 yrs

ago • Good glycemic control maintained for

many years but recently hitting >7.5%• AMI and coronary angioplasty with

stenting 5 years ago• TIAs in the past 4 yrs• Takes multiple medications for

cardiovascular disease• Hypertension• Lives alone, arthritis in both hips

Current medications• Metformin 1000 mg bid• Glibenclamide 10 mg bid • Ramipril 5 mg b.i.d.• Furosemide 25 mg• Atorvastatin 80 mg daily• Glyceryl trinitrate spray 400 µg x 2 as

needed• Propranolol 80 mg b.i.d.• ASA 75 mg daily

Not a real patient

Our Third Patient: Please, Meet Sandra

Clinical chemistry†

FPG: 10.0 mmol/l (180 mg/dl)HbA1c: 7.8% (62 mmol/mol)LDL-cholesterol: 1.1 mmol/l (43 mg/dl)HDL-cholesterol: 1.5 mmol/l (58 mg/dl)Triglycerides: 1.2 mmol/l (106 mg/dl)Creatinine 1.08 mg/mleGFR (CKD-EPI) 55 ml/minBP: 138/77 mmHgBMI: 31 kg/m2

Additional examinations• Foot exam: no abnormalities• Eye exam: initial signs of non-

proliferative retinopathy

Not a real patient


How happy are you with Sandra’s therapy?

• Poorly Controlled DM?• Hypoglycemia?• ASCVD?• Stroke?

Not a real patient


What’s your clinical concern about her?

Antidiabetic Agents and Risk of Hypoglycaemia

1. Henderson JN, et al. Diabet Med. 2003;20:1016; 2. Bolen S, et al. Ann Intern Med. 2007;147:386; 3. Kahn SE, et al. N Engl J Med. 2006;355:2427; 4. Krentz AJ, Bailey CJ. Drugs. 2005;65:385; 5. Prandin® (repaglinide) package insert. Novo Nordisk; June 2006; 6. Kahn SE, et al. N Engl J Med. 2006;355:2427; 7. Cefalu WT. Nature. 2007;81:636; 8. Bolen S, et al. Ann Intern Med. 2007;147:386; 9. DeFronzo RA, et al. Diabetes Care. 2005;28:1092;

10. Stonehouse A. Curr Diabetes Rev 2008;4:101; 11. Aschner P et al. Diabetes Care. 2006; 29:2632; 12. Rosenstock J et al. Diabetes Obes Metab 2008;10:376.

q Metformin6

q a-glucosidase inhibitors7

q Pioglitazone6,8

q GLP-1 agonists9

q DPP-4 inhibitors10-12

q SGLT2-inhibitors13

q Insulin therapy1

q Sulfonylureas2

q Glinides (less than SUs)1,3

q Drug-drug interaction can potentiate hypo-glycemia4,5

High risk Low risk✓

✓

✓

✓

Potential Interactions Between Pioglitazone and Alogliptin

Potential advantages• Synergistic effect• Beta-cell protection• Efficacy on FPG and PPG• Durability• Tolerability in CKD• CV protection

Potential concerns• Fluid retention• Heart failure• Body weight gain• Bone fractures

Meta-Analysis of GLP1-RA and SGLT2i Trials on the Composite of Myocardial Infarction, Stroke, and CV Death (MACE)


Meta-Analysis of GLP1-RA and SGLT2i Trials on Hospitalization for Heart Failure (HHF)


Study Glucose-loweringdrug HR 95% CI

EMPA-REG Empagliflozin 1.24 0.92 – 1.67

CANVAS Canagliflozin 0.90 0.71 – 1.15

DECLARE Dapagliflozin 1.01 0.84 – 1.21

0.6 1 1.4

Favors placeboFavors study drug

Effect of SGLT2 Inhibitors on Nonfatal Stroke

1.60.8 1.2 1.8

Zinman B et al. NEJM 2015;373:2117; Pfeffer MA et al. NEJM 2015;373:2247; Neal B et al. NEJM 2017;377:644; Wiviott SD et al NEJM 2019;380:347

Fatal and Nonfatal Outcomes with GLP1RAs in T2DM: a Systematic Review and Meta-analysis of CVOTs

Kristensen SL et al Lancet Diabetes Endocrinol. 2019 Aug 14. [Epub ahead of print]

SGLT2 Inhibitors and GLP1-RAs: Adverse Effects

SGLT2-Inhibitors GLP1-RAsDehydration Nausea, vomiting

Genitourinary tract infections Pancreatitis (not confirmed)

Euglycemic DKA

Bone fractures (canagliflozin)

Lower limb amputation (canagliflozin?)

Fournier’s gangrene

Presence of cardiovascular disease is compelling indication

Step 1: Assess Cardiovascular Disease

Management of Hyperglycaemia in Type 2 Diabetes 2018 - A Consensus Report by the ADA/EASD


Choosing Glucose-lowering Medication in Those With Established ASCVD or CKD


Integrating Metabolic Control and Organ Damage Prevention

YoungShort DM duration

No micro-macrovascular complications

LongtermGlycemic control

Reduced risk of microvascularcomplications

Improved adherenceReduced clinical inertia

Prefer glucose-lowering agents with low risk of hypoglycaemia

Reduced risk of CV

Epicardial Coronary Arteries and the Full Coronary Circulation

Taqueti, V.R. et al. J Am Coll Cardiol. 2018;72:2625–41

Microvascular Disease and CV Risk in T2DM IndividualsUK Clinical Practice Research Datalink; n=49,027; median follow-up 5.5 yrs

Brownrigg JRW et al Lancet Diabetes Endocrinol 2016;4:588-97

0

10

20

30

HbA1c <7.0%BP <140/90 mmHgLDL <2.5 mmol/L

HbA1c �7.0%BP <140/90 mmHgLDL <2.5 mmol/L

HbA1c �7.0%BP �140/90 mmHgLDL <2.5 mmol/L

HbA1c �7.0%BP �140/90 mmHgLDL �2.5 mmol/L

Risk Factors

Prim

ary O

utcom

e (pe

r 100

0 pers

on-ye

ars)

Numb

er of

Micro

vasc

ular R

isk Fa

ctors

0

1

2

3







Reduced risk of CV



(and ancillary properties?)

CONSIDER COMBINATION

Reduced risk of CKDReduced risk of CV and

Heart Failure

CONSIDER SGLT2-i




and ancillary properties?




Reduced risk of CV and all-cause mortality

SGLT2i(CANVAS, DECLARE, EMPA-REG)

CREDENCE

Impaired kidney function


CONSIDERSGLT2i


Heart Failure










CREDENCE



CONSIDERSGLT2i


Heart Failure










CREDENCE

History of CV disease

ASCVD HF

Metformin(UKPDS34)

Pioglitazone(PROACTIVE, IRIS)SGLT2-I

(CANVAS, EMPA-REG)GLP1RAs

(EXSCEL, HARMONY, LEADER, SUSTAIN 6)

SGLT2i(CANVAS, CVD-REAL,

EMPA-REG, DECLARE)



CONSIDERSGLT2i


Heart Failure

Documents

EarlyCombination Therapyand Treatment Escalation for ... · Objective of this Session •This session is not conceived to provide guidance to treatment •This session would like