What Diabetes Medicine Do I Use When? - UCSF Medical Education · ADA Standards of Medical Care in Diabetes 2017. Glucose-lowering medication in type 2 diabetes: overall approach

Elizabeth J. Murphy, MD, DPhilJune 15, 2020

What Diabetes Medicine Do I Use When?

I have no financial interests or relationships to disclose.

Today• Overview of the advantages and disadvantages of the different classes of drugs (thinking like an internist)

• Review the data (as of now) for cardiovascular and renal outcomes

• Practice critical review of diabetes drug comparator studies• Put some of it together? • Won’t cover:

– Insulins– Role of CGM and insulin pumps

Diabetes Care. Published online Oct 22, 2008

2008 ADA Type 2 Consensus Statement Diabetes Treatment Algorithm

An American Diabetes Association consensus statement represents the authors’ collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion.

Revised Consensus Algorithm - ADA and EASDDiabetes Care 31:173, 2008.

Diabetes Care, Diabetologia. 19 April 2012

Less Well‐Validated Buffet for DM2

ADA Standards of Medical Care in Diabetes 2017

Glucose-lowering medication in type 2 diabetes: overall approach.

Diabetes Care 2020;43:S98-S110

Decision cycle for patient‐centered glycemic management in type 2 diabetes. Davies MJ, D’Alessio

DA, Fradkin J, et al. Diabetes Care 2018;41:2669–2701.

Diabetes Complications in the US

Microvascular• Retinopathy, nephropathy, neuropathy• Leading cause of

– end stage renal disease– blindness – non‐traumatic amputations

Macrovascular• CAD, stroke, PVD • 2 x increase risk for CVD death• 2‐4 x increased risk of stroke• Prevalence of DM in patients

hospitalized for HF > 40% • DM is strongest risk factor for PVD

(OR 2.72)

Managing Complications

• Tight glucose control reduces microvascular complications– The lower you go the better– The earlier in the disease the better– Effects last long after tight control is over

• Tight glucose control early in the disease reduces macrovascular complications many years later

• BP control reduces micro and macrovascular complications• Lipid management reduces macrovascular complications

12

Tight Control Trials 1970s‐1990s

• United Kingdom Prospective Diabetes Study (UKPDS) ‐ Type 2 DM

• Diabetes Control and Complications Trial (DCCT) and follow on Epidemiology of Diabetes Interventions and Complications (EDIC) ‐ Type 1 DM

13

Tight Glucose vs Tight Blood Pressure Control in the UKPDS

StrokeAny Diabetic

EndpointDM

DeathsMicrovascularComplications

-50

-40

-30

-20

-10

0

% R

edu

ctio

n I

n R

elat

ive

Ris

k

Tight Glucose Control

32%

10%12%

5%

+ P < 0.05 compared to conventional rx*P <0.05 compared to glucose control Turner RC, et al. BMJ. 1998;317:703-713.

+

+

Tight BP Control+*

+*

37%

32%

24%

44%

+*+*

7% v. 7.9% A1C

Nathan D for the DCCT/EDIC Research Group Diabetes Care 2014;37:9‐1614

15JAMA 2003;290:2159‐2167.

DCCT/EDIC –T1DMTight Control A1C 7.2 v Usual Care 9.1%

Prevalence and Incidence of Albuminuria

EDIC Both Groups A1C 8%

N Engl J Med 2005;353:2643-2653

DCCT/EDIC ‐ Cumulative Incidence CVD Outcomes42% reduction in CVD risk57% reduction in risk of nonfatal MI, stroke or CVD death

8.0 v 8.1 % A1C[----------------------------------------------]

A1C 7.2 v 9.1%

At 30 y Follow up30% reduction in CVD risk32% reduction in risk of nonfatal MI, stroke or CVD death

1980s

9%

BeforeDCCT,UKPDS

SulfonylureaInsulin

1990s

8%

AfterDCCT

+ Metformin

1997

+ TZD

7%

AfterDCCT,UKPDS

Glycemic Targets Over the Years

Crude and Age-Adjusted Incidence of End-Stage Renal Disease Related to Diabetes Mellitus (ESRD-DM) per 100,000 Diabetic Population, United States,

1980–2008

http://www.cdc.gov/diabetes/statistics/esrd/fig7.htm

1980s

9%

BeforeDCCT,UKPDS

SulfonylureaInsulin

1990s

8%

AfterDCCT

+ Metformin

1997

+ TZD

7%

AfterDCCT,UKPDS


2006

+ Incretin

? 6% And focus on CVD prevention

1980s

9%

BeforeDCCT,UKPDS

SulfonylureaInsulin

1990s

8%

AfterDCCT

+ Metformin

1997

+ TZD

7%

AfterDCCT,UKPDS


2006

+ Incretin

? 6%

Follow on Effects

• FDA mandated CV outcome trials for safety• Recognition that tight control in established CVD is likely not beneficial

1980s 1990s 1997

9%

BeforeDCCT,UKPDS

SulfonylureaInsulin

8%

AfterDCCT

+ Metformin + TZD

7%

AfterDCCT,UKPDS


2006

+ Incretin

? 6%

7%

AfterACCORD

2008+ Mortality

A1C Goal

Efficacy

ComorbiditiesComplications (CKD, obesity,

HF, CAD)

Adverse EffectsRisks/Hypoglycemia

PatientAcceptance

Cost

CardiovascularBenefit/Harm

A1C Targets• < 7% ‐ is appropriate for many nonpregnant adults. A• < 6.5% ‐might be reasonable for select patients C• < 8% (“less stringent A1C goals”) may be appropriate if: (B)

– h/o severe hypoglycemia– limited life expectancy– advanced micro or macrovascular complications– extensive comorbid conditions– longstanding DM and can’t get to goal despite trying really hard

ADA Diabetes Standards of Care 2020

25

A1C COST

Metformin 1-2% $4 $4Sulfonylurea 1-2% $5 $4Pioglitazone 0.5-1.5% $20 $11Exenatide 0.5-1.5% $450 $728Canagliflozin 0.5-1.0% $330 $520Sitagliptin 0.5-0.8% $320 $475Acarbose 0.5-0.8% $30 $19

Good Rx.com10/2014 6/2020

$498$731

$455

10/2019

Metformin

Advantages• Lowers A1C 1.5‐2%• Weight loss (0‐2 kg)• Lowers TG, LDLc; Increases HDLc• Data supports decrease in CVD

mortality and perhaps all cause mortality

• No hypoglycemia when used alone• Inexpensive

Disadvantages• Majority of patients with GI SE• Minimal risk of lactic acidosis• Impairs B12 absorption• Need to stop when GFR < 30

26

SulfonylureasAdvantages• Lowers A1C 1.5‐2%• Inexpensive

Disadvantages• Weight gain• Hypoglycemia

27

CVD???

MEDPAGE TODAY

Antonios Douros et al. BMJ 2018;362:bmj.k2693

Forest plot summarising the primary analysis and all sensitivity analyses

77,138Metformin Monotherapy Users

25,699Adding or switching to SU

13,217Adding SU

9,800Switching to SU

0.5 2.5 4.5 6.5 8.5

Myocardial InfarctionAdding SUSwitching to SU

Ischemic StrokeAdding SUSwitching to SU

CV DeathAdding SUSwitching to SU

All Cause MortalityAdding SUSwitching to SU

Adjusted HR(95% CI)

Adding a sulfonylurea to metformin does not increase the risk of cardiovascular disease but replacing metformin with a sulfonylurea does

MEDPAGE TODAY

SulfonylureasAdvantages• Lowers A1C 1.5‐2%• Inexpensive

Disadvantages• Weight gain• Hypoglycemia

35

CVD: The Jury’s Still Out

Thiazolidinediones (rosiglitazone, pioglitazone)

(PPAR‐γ Agonists)

Advantages• Lowers A1C 0.5‐1.5%• No hypoglycemia when used alone• Inexpensive• Likely benefit in fatty liver and NASH• Benefit shown in diabetes prevention

Disadvantages• Weight gain (2‐5 kg)• Increased fracture (osteoporosis) and

bladder cancer• Edema (up to 30% of patients)• Contraindicated in HF

36

Notes: ‐ Stop TZDs when insulin is started‐ Effectiveness is very patient dependent, stop if it’s not doing anything

Thiazolidinediones – CVDGood• Benefit post stent/revascularization• Benefit after stroke/TIA in insulin

resistant patients without diabetes1

• Some studies with decreased death, MI, Stroke2

Not So Good• Increases rates of serious HF• Some studies with increased mortality

37

1N Engl J Med 2016; 374:1321‐1331. 2JAMA 2007; 298: 1180‐1188

Preference for pioglitazone

The Incretins

Normal Control Subject

Insulin Response to Oral vs Intravenous Glucose

J Clin Invest 1967; 46:1954-1962

OralIntravenous

60

Insu

lin (

U/m

L)

30

00 60 120 18030 90 150

90

Minutes

GIP, GLP-1, CCK

Reduced in DM2

T1/2 2-5 minutes

Breakdown by DPPIV

DPPIV Inhibitors (gliptins)

Advantages• No hypoglycemia when used alone• ?

Disadvantages• Poor A1C lowering (0.5‐0.8%)• Expensive• Possibly higher rates of admission for

HF (worse with sitagliptin?), otherwise CV neutral

• Pancreatitis?• Joint pain?

40

Notes: ‐ Weight neutral‐ Stop when insulin is started‐ Don’t start if you are more than 0.8% from your A1C goal

41

CD26• Expressed on the surface of most cell types• T‐cell activation marker• 62 known substrates • Tumor suppressor role• Inhibitors inhibit T‐cell proliferation

• Good or evil: CD26 and HIV infection. J Derm Sci. 2000; 22:152‐60.

• Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. Front Biosci. 2008;13:2299‐310.

• Dipeptidyl peptidase IV (DPPIV), a candidate tumor suppressor gene in melanomas is silenced by promoter methylation. Front Biosci. 2008 13:2435‐43.

/DPPIV

DPPIV Inhibitors (gliptins)

Advantages• No hypoglycemia when used alone• ?

Disadvantages• Poor A1C lowering (0.5‐0.8%)• Expensive• Possibly higher rates of admission for

HF (worse with sitagliptin?), otherwise CV neutral

• Pancreatitis?• Joint pain?

42

Notes: ‐ Weight neutral‐ Stop when insulin is started‐ Don’t start if you are more than 0.8% from your A1C goal

‐ Immune modulating effects (good or bad?)‐ Be cautious in HIV disease

‐Glucosidase Inhibitors (acarbose)Advantages• No hypoglycemia when used alone• Weight loss or weight neutral• Inexpensive• Benefit shown in diabetes prevention

Disadvantages• Poor A1C lowering (0.5‐0.8%)• GI side effects (gas/bloating)

43

Notes: ‐ Limited data shows CVD neutral‐ Don’t start if more than 0.8% from A1C goal‐ Need glucose for hypoglycemia

GLP‐1 AnaloguesAdvantages• Good A1C lowering (0.5‐1.5%)• Excellent weight loss (2‐4 kg)• No hypoglycemia when used alone• Some require only once a week

injection

Disadvantages• GI side effects (nausea, vomiting,

diarrhea, abdominal pain)• Injectable except for oral semilgutide• Expensive• Pancreatitis? • Risk of C‐cell tumors (medullary thyroid

cancer – h/o other thyroid cancers not a contraindication)

44

Heloderma suspectumGila Monster

CVD AND RENAL OUTCOMES?

Liraglutide (Victoza GLP-1): CV outcomes

Marso SP et al. N Engl J Med 2016;375:311-322

CV DeathHR 0.78*


1° OutcomeHR 0.87*

Nonfatal Stroke, NS

Nonfatal MI, NS



Liraglutide (Victoza): CV outcomes

DeathHR 0.85*

HF Hosp, NS

Mann et al. N Engl J Med 2017;377:839

Liraglutide (Victoza): Renal Outcomes

HR 0.78*

GLP‐1 Agonists and Renal Outcomes

• All analyses are secondary analysis and the majority of data is in high CVD risk folks

• Consistently suggest renal protective effect• Across the board 17% RR reduction• Driven primarily by decrease in urinary albumin excretion/new macroalbuminuria

• Need trials with primary endpoint of hard renal outcomes

GLP‐1Agonists Trade Name Indication Cost/month

(Good Rx.com 6 2020)

Abliglutide Tanzeum NA

exenatide Byetta/Bydureon 1. Glucose control $731/$691

dulaglutide Trulicity1. Glucose control2. Reduce risk of major CV events

in patients with established CVD or multiple CV risk factors

$693

liraglutide

(a) Victoza(b) Saxenda

1. Glucose control2. Reduce risk of major

cardiovascular events in patients with established CVD.

1b. Chronic weight management

$963

$1288

semaglutide Ozempic(b) Rybelsus

1. Glucose control1b. Glucose control

$808$770

lixisenatide Adlixin 1. Glucose control $645

GLP‐1 Agonists Indications in Adults (with DM2)

SGLT1

(180 L/day) (900 mg/L)=162 g/day

10%

Glucose

No Glucose

S1

S3

Renal Handling of Glucose

SGLT2

90%

Lots of Glucose

Canvas Trial

Neal et al, N Engl J Med 2017; 377:644‐657 DOI: 10.1056/NEJMoa1611925.

SGLT2‐Inhibitors

Advantages• Modest weight loss• Lower blood pressure• No hypoglycemia when used alone

Disadvantages• Modest A1C lowering (0.5‐1%)• Increased fractures• Increase in UTI and genital infections• Decreases GFR• Fournier’s Gangrene?• Euglycemic DKA

52

Laboratory Tests:

UA 3+ glucose, + ketoneshydroxybuterate 10.3 mmol/L Lactate 0.6 ABG: 7.20/23/90Lipase 369.

53

43 yo Hispanic man with history of IDDM, HTN, hyperTG and bumex treated heart failure presents with 2 days of epigastric abdominal pain and 1 day of nausea and vomiting.

138 96 103.5 14 0.72

167

Medications:NPH 50 units BIDAspart 25 units QAC Aspart correction 3:50 > 175Metformin 1 gm bidCanagliflozin 300 mg dailyAtorva 80 mg dailyFenofibrate 160 mg dailyOmega-3 FA 1 gm daily

A1C 8.9%

Laboratory Tests:

UA 3+ glucose, + ketoneshydroxybuterate 10.3 mmol/L Lactate 0.6 ABG: 7.20/23/90Lipase 369.

54


138 96 103.5 14 0.72

167


A1C 8.9%

1997!!

Diabetes Subtypes

• Type 1 Diabetes• Type 2 Diabetes• Ketosis Prone Type 2 Diabetes• LADA: Latent Autoimmune Diabetes in Adults• Post pancreatitis diabetes.

Laboratory Tests:

UA 3+ glucose, + ketoneshydroxybuterate 10.3 mmol/L (0.4-0.5) Lactate 0.6 ABG: 7.20/23/90Lipase 369 Blood Lipemic

57


138 96 103.5 14 0.72

167


TG 8807 mg/dL

A1C 8.9%

Laboratory Tests:

UA 3+ glucose, + ketoneshydroxybuterate 10.3 mmol/L (0.4-0.5) Lactate 0.6 ABG: 7.20/23/90Lipase 369 Blood Lipemic

58


138 96 103.5 14 0.72

167


TG 8807 mg/dL

A1C 8.9%

Euglycemic KetoacidosisWhat we think we know

• Patients at increased risk for DKA are at increased risk of euglycemic ketoacidosis

• Reported precipitants are things that result in relative insulin deficiency OR promote ketones

• Reduction or stopping insulin• Severe acute illness/stress (e.g. surgery)• Dehydration• Extensive exercise• Low carbohydrate diets/poor PO intake/fasting• Excessive alcohol intake

Euglycemic KetoacidosisWhat we think we know

• Ketoacidosis can still occur several days after the SGLT2i is stopped

• Normal urine ketones might be misleading so check plasma ketones if concerned.

• Symptoms are similar to DKA with n/v, lethargy, abdominal pain but the glucose is relatively normal

• Treat with insulin and carbohydrates to correct relative insulin deficiency and dampen glucagon response

• For now would avoid use in hospital• More common in woman

SGLT2‐Inhibitors


Disadvantages• Modest A1C lowering (0.5‐1%)• Increased fractures• Increase in UTI and genital infections

• Decreases GFR• Fournier’s Gangrene?• Euglycemic DKA

61

CVD AND RENAL OUTCOMES?

Zinman B et al. N Engl J Med 2015;373:2117‐2128.

Empagliflozin (SGLT2): CV and Mortality Benefit

Death – HR 0.68*

CV Death HR 0.62*

Hosp HF –HR 0.65*

Primary Outcome–HR 0.86*

V Perkovic et al. N Engl J Med 2019;380:2295‐2306.

Canagliflozin and Renal and Cardiovascular Outcomes

CV Death - HR 0.78* Death – HR 0.83

ESRD- HR 0.68* HD, Tx, Death HR 0.72*

V Perkovic et al. N Engl J Med 2019;380:2295‐2306.

Canagliflozin and Renal Outcomes

• Ejection fraction of 40% or less• 60% of enrolled WITHOUT Diabetes• ACE/ARB/ARNI 94%, beta‐blocker 96%, mineralocorticoid receptor antagonist 71%

McMurray et al., NEJM 2019; 381:1995‐2008

DAPA‐HF

Diabetes Medications and Heart Failure 66DapaHF N Engl J Med 2019; 381:1995‐2008 DOI: 10.1056/NEJMoa1911303

HF Hospitalization HR 0.70*

DeathHR 0.83*CV Death

HR 0.82*

SGLT2‐Inhibitors


• Decreases GFR • Prevents death in patients with

established CVD• Prevents renal failure in patients with

renal disease

Disadvantages• Modest A1C lowering (0.5‐1%)• Increased fractures• Increase in UTI and genital infections• Fournier’s Gangrene?• Euglycemic DKA

67

BIG Advantages

SGLT2 Inhibitors ‐ Indications in Adults with DM2

SGL2 Inhibitors

Trade Name FDA Approved Indications

Cost/mth(Good rx.com

6/2020)

canagliflozin Invokana 1. Glucose control 2. Reduce risk of major CV adverse events in patients with

established CVD3. Reduce risk of ESRD, doubling of creatinine, CV death,

hospitalization for HF ‐ in patients with diabetic nephropathy with albuminuria

$520

dapagliflozin Farxiga*# 1. Glucose control2. Reduce risk of hospitalization for HF in patients with CVD or

CV risk factors$500

empagliflozin Jardiance 1. Glucose control 2. Reduce the risk of CV death in patients with established CVD $504

ertuglifozin Steglatro 1. Glucose control $300

*Forxiga is approved in Europe for DM1#Dapagliflozin now approved for the treatment of HF in patients without DM2

1980s

9%

BeforeDCCT,UKPDS

SulfonylureaInsulin

1990s

8%

AfterDCCT

+ Metformin

1997

+ TZD

7%

AfterDCCT,UKPDS


2006

+ Incretin

? 6%

7%

AfterACCORD

2008+ Mortality

2016

7-8%

After CV trials

+SGLT2

Putting it all Together?

WEIGHT IS A MAJOR ISSUE:‐ Beware with SU/TZD‐ Consider GLP‐1 first (more A1C

lowering and weight loss)‐ Consider SGLT2i second

FAR FROM A1C GOAL‐ Consider SU/TZD first for most effect‐ Avoid DPPIV, BAS, bromocriptine‐ SGLT2i okay for other reasons but not

for A1C lowering

HIGH ASCVD (Established or risk):‐ Consider GLP‐1 (with proven benefit) first

(more A1C lowering and weight loss)‐ Consider SGLT2i second

HIGH RISK FOR HYPOGLYCEMIA:‐ Avoid SU and insulin

HF OR CKD:‐ Consider SGLT2i (with proven benefit) first ‐ Consider GLP‐1 second especially if needed for

A1C lowering/renal benefit‐ Avoid TZD

Metformin

72

A1C COST

Metformin 1-2% $4 $4Sulfonylurea 1-2% $5 $4Pioglitazone 0.5-1.5% $20 $11Exenatide 0.5-1.5% $450 $728Canagliflozin 0.5-0.1% $330 $520Sitagliptin 0.5-0.8% $320 $475Acarbose 0.5-0.8% $30 $19

Good Rx.com10/2014 6/2020

$498$731

$455

10/2019

REFERENCES

ADA 2020 Standards of Care (Readers Digest version for Primary Care) https://clinical.diabetesjournals.org/content/38/1/10

In depth discussion of pharmacologic therapies. 2020https://care.diabetesjournals.org/content/43/Supplement_1/S98.full-text.pdf

Full supplement for ADA 2020 Standards of Carehttps://care.diabetesjournals.org/content/43/Supplement_1

Nice review of the data on renal effects of GLP‐1 Agonistshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136364/#Sec5title

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Documents

What Diabetes Medicine Do I Use When? - UCSF Medical Education · ADA Standards of Medical Care in Diabetes 2017. Glucose-lowering medication in type 2 diabetes: overall approach