new treatments for type 2 diabetes: implications of ......microvascular complications of t2dm in...

New Treatments for Type 2 Diabetes: Implications of Cardiovascular Outcome Trials

Richard Pratley, M.D.

Samuel Crockett Chair in Diabetes ResearchDirector, Florida Hospital Diabetes Institute

Senior Investigator, Translational Research InstituteAdjunct Professor, Sanford Burnham Prebys Medical Discovery Institute

Orlando, Florida

Neal B et al. N Engl J Med. 2017 Jun 12.

Disclosures

Advisory Board / Consultant: Boehringer-Ingleheim, GSK, Lilly, Merck, Novo Nordisk, Pfizer, Takeda

Research Support: Lexicon, Lilly, Merck, Novo Nordisk, Pfizer, Sanofi, Takeda

All honoraria directed toward a non-profit which supports education and research

Outline

Overview of new classes of diabetes drugs

Rationale for CVOTs in diabetes

Cardiovascular safety of new diabetes drugs: evidence to date Thiazolidinediones

DPP-4 Inhibitors

SGLT-2 Inhibitors

GLP-1 Receptor Agonists

Insulin

Implications of CVOTs for clinical practice

Multiple Metabolic Defects Contribute to Hyperglycemia in T2DM

Islet -cell

ImpairedInsulin Secretion

NeurotransmitterDysfunction

Decreased GlucoseUptake

Islet -cell

IncreasedGlucagon Secretion

IncreasedLipolysis

Increased GlucoseReabsorption

IncreasedHGP

DecreasedIncretin Effect

From DeFronzo, Diabetes: 2009

Prediabetesstate

Normal IGT

Clinical disease

Type 2Diabetes

DisabilityDeath

Complications

Complications

Primary Secondary TertiaryPrevention Prevention Prevention

Type 2 Diabetes: A Progressive Disease

86 million 29 million

CDC National Diabetes Statistics Report, 2014. www.CDC.gov

IGT = impaired glucose tolerance

Microvascular Complications of T2DM

● In 2005-2008, of adults ≥40 years of age with diabetes, 4.2 million (28.5%) had diabetic retinopathy.

655,000 (4.4%) had advanced diabetic retinopathy

● In 2010, about 73,000 non-traumatic lower-limb amputations were performed in adults ≥20 years of age with diabetes.

● About 60% of non-traumatic lower-limb amputations among adults ≥20 years of age are in people with diabetes.

● Diabetes was listed as the primary cause of kidney failure in 44% of all new cases in 2011.

Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and ItsBurden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services; 2014.

Diabetes Doubles the Risk for Vascular Outcomes

HR = hazard ratio; CI = confidence interval; MI = myocardial infarction.Emerging Risk Factors Collaboration. Lancet. 2010;375(9733):2215–2222.

Numberof Cases

Coronary heart disease* 26,505Coronary death 11,556Nonfatal MI 14,741

Stroke subtypes*Ischemic stroke 3,799Hemorrhagic stroke 1,183Unclassified stroke 4,973

Other vascular deaths 3,826

HR (95% CI) I2 (95% CI)

2.00 (1.83–2.19) 64 (54–71)2.31 (2.05–2.60) 41 (24–54)1.82 (1.64–2.03) 37 (19–51)

2.27 (1.95–2.56) 1 (0–20)1.56 (1.19–2.05) 0 (0–26)1.84 (1.59–2.13) 33 (12–48)

1.73 (1.51–1.98) 0 (0–26)

1 2 4

GI = gastrointestinal; GLP-1 = glucagon-like peptide-1; RA = receptor agonist; CHF = congestive heart failure; ARF = acute renal failure; MTC = medullary thyroid carcinoma; DPP-4 = dipeptidyl peptidase-4; SGLT2 = sodium-dependent glucose cotransporter -2.

Adapted from: Nathan DM, et al. Diabetes Care. 2007;30(3):753-759. Nathan DM, et al. Diabetes Care. 2006;29(8):1963-1972. Nathan DM, et al. Diabetes Care. 2009;32(1):193-203. ADA. Diabetes Care. 2008;31:S12-S54. Buse J, et al. Lancet. 2009;374(9683):39-47.

12 Classes of Antihyperglycemic Agents for T2DMClass A1c

ReductionHypo-

glycemiaWeightChange

Dosing(times/day) Other Safety Issues

Metformin 1.5 No Neutral 2 GI, lactic acidosis, B12 deficiency

Basal insulin analog 1.5–2.5 Yes Gain 1, injected Hypoglycemia

Rapid-acting insulin 1.5–2.5 Yes Gain 1-4,injected

Sulfonylureas 1.5 Yes Gain 1 Allergies, secondary failure

Thiazolidinediones 0.5–1.4 No Gain 1 Edema, CHF, bone fractures

Short-acting GLP-1 RAs 0.5–1.0 No Loss 2, injected GI, ? pancreatitis, ARF

Long-acting GLP-1 RAs ~1.5 No Loss 1, injected GI, ? pancreatitis, ?MTC, ?ARF

Repaglinide 1–1.5 Yes Gain 3

Nateglinide 0.5–0.8 Rare Gain 3

Alpha-glucosidase inhibitors 0.5–0.8 No Neutral 3 GI

Amylin mimetics 0.5–1.0 No Loss 3, injected GI

DPP-4 inhibitors 0.6–0.8 No Neutral 1 Pancreatitis

Bile acid sequestrant 0.5 No Neutral 1 or 2 GI

Bromocriptine quick release 0.7 No Neutral 1 GI

SGLT2s 0.8-1.0 No Loss 1 Genital mycotic infections

From DeFronzo, Diabetes: 2009

Complementary Mechanisms of Action of Current Diabetes Medications

Islet -cell

ImpairedInsulin Secretion

NeurotransmitterDysfunction

Decreased GlucoseUptake

Islet -cell

IncreasedGlucagon Secretion

IncreasedLipolysis

Increased GlucoseReabsorption

IncreasedHGP

DecreasedIncretin Effect

InsulinSulfonylureasMegltinides

MetforminBromocryptine

TZDs

GLP-1 RADPP-4 inhibitors

GLP-1 RADPP-4 inhibitors

SGLT-2 inhibitors

Class Mechanism Advantages Disadvantages CostBiguanides(Metformin)

• Activates AMP-kinase• Hepatic glucose production

• Extensive experience• No hypoglycemia• Weight neutral• ? CVD events

• Gastrointestinal• Lactic acidosis• B-12 deficiency• Contraindications

Low

SUs / Meglitinides

• Closes KATP channels• Insulin secretion

• Extensive experience• Microvascular risk

• Hypoglycemia• Weight gain• Low durability• ? Ischemic preconditioning

Low

TZDs • Activates PPAR-• Insulin sensitivity

• No hypoglycemia• Durability• TGs, HDL-C • ? CVD events (pio)

• Weight gain• Edema / heart failure• Bone fractures• ? MI (rosi)• ? Bladder ca (pio)

Low

Properties of Established Anti-Hyperglycemic Agents

Diabetes Care 2012;35:1364–1379. Diabetologia 2012;55:1577–1596

The Incretin Defect in T2DM

Substantial impairment – 40% of normal response

Not due to impaired secretion of GLP-1 or GIP

Absent insulinotropic response to GIP Beta-cell GIP receptor down-regulation

Decreased response to GLP-1 Can be overcome by achieving higher than physiologic GLP-1

levels

GLP-1 infusions that achieve higher levels effective at enhancing insulin secretion and suppressing glucagon in a glucose-dependent manner

Nauck et al. Diabetologia. 1986;29:46–52. Laakso et al. Diabetologia. 2008;51:502‐11. Nauck et al. Diabetologia. 2011;54:10‐8.Højberg et al. Diabetologia. 2009;52:199‐207. Vilsbøll et al. Diabetologia. 2002;45:1111–19. Nauck et al. Diabetologia. 1993;36:741–44.

Add GLP-1 analogues with longer half-life:

Incretin effect is impaired in T2DM

Natural GLP-1 has extremely short half-life

InjectablesBlock DPP-4, the enzyme that degrades GLP-1:

• Sitagliptin• Saxagliptin• Linagliptin• Alogliptin

Oral agents

Drucker. Curr Pharm Des. 2001;7(14):1399-1412. Drucker. Mol Endocrinol. 2003;17(2):161-171.

Incretin Therapies to Treat T2DM

Exendin-4 Based:• Exenatide• Exenatide QW

Human GLP-1:• Liraglutide• Albiglutide• Dulagutide

Comparison of DPP-4 InhibitorsSitagliptin Alogliptin Saxagliptin Linagliptin

Usual Phase 3 Dose 25, 50, 100 mg QD 6.25, 12.5 25 mg QD 2.5, 5 mg QD 5 mg QD

Half Life (t1/2) 12.4h 12.5 to 21.1h (25mg) 2.2 to 3.8h 40 h

DPP-4 inhibition at 24h ~80% at 24h ~78% at 24h (25 mg) 5 mg: ~55% at 24h 75% at 24 h

EliminationKidney(mostly

unchanged)

Kidney(mostly unchanged)

Liver and kidneyActive metabolite

Bile (mostly unchanged)

Renal Dose Adjustments Required

Yes Yes Yes No

Selectivity for DPP-4

>2600 fold vs DPP-8 >10,000 fold

vs DPP-9

>10,000 fold vs DPP-8/9

>400 fold vs DPP-8>100 vs DPP-9

>10,000 fold vsDPP-8/9

Potential for DDI Low Low Strong CYP3A4/5 inhibitorsd

Strong CYP3A4/5 inhibitorsd

Food effect No No No No

Efficacy of DPP-4 Inhibitor Therapy Added to Metformin

141. Charbonnel. Diabetes Care. 2006;29:2638‐43. 2. Raz et al. Curr Med Res Opin. 2008;24:537‐50.3. Scott et al. Diabetes Obes Metab. 2008;10:959‐69. 4. DeFronzo et al. Diabetes Care. 2009;32:1649‐55.5. Taskinen et al. Diabetes Obes Metab. 2011;13:65‐74. 6. Nauck et al. Int J Clin Pract. 2009;63:46‐55.

BL

A1C

(%)

8.0

≥7–≤

10

7.7

7.7

7.7

≥7–≤

10

≥7–≤

10

≥7–≤

10

8.1

8.1

≥7–≤

10

n=701

n=190

n=273n=273

n=273

n=743n=743

n=743

n=743

n=701

n=701

n=527

Sitagliptin 100 mgRosiglitazonePlaceboSaxagliptin 2.5 mg

Saxagliptin 5 mgSaxagliptin 10 mgLinagliptin 5 mgAlogliptin 12.5–25 mg

—

Sitagliptin Saxagliptin Linagliptin Alogliptin

DPP-4 Inhibitors vs Sulfonylureas Added to Metformin – 2-Year ResultsDPP-4 Inhibitors vs Sulfonylureas Added to Metformin – 2-Year Results

1. Del Prato et al. Diabetes Obes Metab. 2014;16:1239‐46.2. Gallwitz et al. Lancet. 2012;380:475‐83.3. Göke et al. Int J Clin Pract. 2013;67:307‐16.4. Seck et al. Int J Clin Pract. 2010;64:562‐76.5. Nauck et al. Diabetes Obes Metab. 2007;9:194‐205.

ALO (25 mg)1,a LINA (5 mg)2,b SITA (100 mg)4,d

GLIP1,3,4

SAXA (5 mg)3,c

GLIM2

P = .01

Agent Δ Weight, kg Hypoglycemia, %

DPP-4i SU DPP-4i SUALO1,a −0.9e +1.0 1.4 23.2LINA2,b −1.4e +1.3 7e 36SAXA3,c −1.5 +1.3 3.5 38.4SITA4,d −1.6 +0.7 5 34

Noninferiority vs SU

Ser

Lys

GlnGlu

His Gly Glu Gly Thr Phe Thr Ser Asp Leu

MetGluGluAlaValArgLeuPhe

Ile

Glu

Trp Leu Lys Asn Gly Gly Pro Ser SerGly

Ala

ProProProSer


GLP-1 RA

1. Christensen M, et al. Idrugs. 2009;12:503-513. 2. Ratner RE, et al. Diabet Med. 2010;27:1024-1032. 3. Stewart M, et al. ADA 2008, poster 522-p. 4. Glaesner, et al. Diabetes Metab Res Rev. 2010;26:287-296. 5. Meier JJ. Nat Rev Endocrinol. 2012;8:728-742.

Human GLP-1 Analogues[4]

Exendin-4 analogues

Liraglutide Albiglutide DulaglutideLixisenatide Exenatide BID Exenatide QW

*Not approved

Lys

His Ala Thr Thr SerPheGlu Gly AspVal

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

Structural modifications confer albumin (liraglutide, albiglutide) or IgG Fc fraction (dulaglutide) binding

Semaglutide*

GLP-1 RA Administration and Devices

1. BYETTA Prescribing Information. 2. Victoza Summary of Product Characteristics. 3. Eperzan Summary of Product Characteristics. 4. Lyxumia Summary of Product Characteristics. 5. BYDUREON Prescribing Information.

DulaglutideAutomatic Injection

Hidden needle

*Not FDA approved

*

Short-Acting vs. Long-acting GLP-1 RAs: Pharmacokinetic Differences

1. Byetta. Summary of Product Characteristics; 2. Lyxumia. Summary of Product Characteristics; 3. Victoza. Summary of Product Characteristics; 4. Barrington et al. Diabetes Obes Metab 2011;13:434–8; 5. Eperzan. Summary of Product Characteristics; 6. Novo Nordisk data on file; 7. Fineman et al. Clin Pharmacokinet 2011;50:65–74

OD, once daily; Tmax, time to reach maximum concentration

Category Agent Half-life Tmax

Short-acting GLP-1 RAsExenatide BID1 2.4 h 2 h

Lixisenatide2 2.7–4.3 h 1.25–2.25 h

Long-acting GLP-1 RAs

Liraglutide3 13 h 8–12 h

Dulaglutide4 90 h 24–48 h

Albiglutide5 5 days 3–5 days

Semaglutide6 ~7 days 1–1.5 days

Exenatide OW7 7–14 days 6–7 weeks

Incr

easi

ng p

rotra

ctio

n

FPG

Short-acting Long-acting

PPG FPG PPG

GLP-1RA Duration Influences FPG, PPG and A1c

FPG, fasting plasma glucose; PPG, postprandial plasma glucose

Fineman MS et al. Diabetes Obes Metab 2012;14:675-688.

Head-to-Head Trials Comparing Efficacy of GLP-1 RAs

a P < .05 between groups.b Noninferiority vs LIRA not met.c DULA noninferior to LIRA, P < .0001.1. Buse JB, et al. Lancet. 2009;374:39-47; 2. Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310; 3. Buse JB, et al. Lancet.

2013;381:117-124; 4. Pratley R, et al. Lancet Diabetes Endocrinol. 2014;2:289-297; 5. Wysham C, et al. Diabetes Care. 2014;37:2159-2167; 6. Dungan K, et al. Lancet. 2014; 384(9951):1349-1357.

a

ab

a,b

DURATION-52LEAD-61 DURATION-63 HARMONY-74 AWARD-15 AWARD-66

ac

EXN BID 10 mcg LIRA 1.8 mg EXN QW 2.0 mg ALBI 50 mg DULA 1.5 mg

Added toMET ± SU

Added toDrug-naïve

or MET ± SU

± TZD

Added toDrug-naïve

or MET ± SU

± TZD

Added toMET ± SU

± TZD

Added toMET ± TZD

Added toMET

Placebo

GLP-1 RAs vs DPP-4 InhibitorsAdded to Metformin

Agent

Δ Weight, kg

Hypoglycemia, % of patients

GLP-1 RA DPP-4i GLP-1

RA DPP-4i

EXENBID1,d −2.8 NA 5 NA

EXENQW2,e −2.3b −0.8 1d 3

LIRA3,f −3.4a -1.0 5d 5

DULA4,g −3.0b −1.5 10d 5

ALBI5,h −0.8c -0.2 24d,j 16j

EXEN BID (10 μg)1,e

EXEN QW (2 mg)2,fDULA (1.5 mg)4,h

P<0.001 P<0.0001

ΔA

1c F

rom

Bas

elin

e, %

LIRA (1.8 mg)3,gALBI (30 or 50 mg)5,i

aP<0.0001 vs DPP-4 inhibitor; bP<0.001 vs DPP-4 inhibitor; cP<0.05 vs DPP-4 inhibitor; dNo statistical analysis performed;eEXEN BID: 30-week study of exenatide twice daily; baseline A1C, 8.2%; fEXEN QW: 26-week trial of exenatide once weekly; baseline A1c, 8.4%; gLIRA: 26-week trial with liraglutide; baseline A1c, 8.5%; hDULA: 52-week trial; baseline A1c, 8.1%; iALBI: 26-week trial of albiglutide; baseline A1c, 8.2%; jAlmost all patients experiencing hypoglycemia were also taking a sulfonylurea. 1. DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100; 2. Bergenstal RM, et al. Lancet. 2010;376:431-439; 3. Pratley RE, et al. Lancet. 2010;375(9724):1447-1456; 4. Nauck M, et al. Diabetes Care. 2014;37(8):2149-2158; 5. Leiter LA, et al. Diabetes Care. 2014;37(10):2723-2730.

SITA

P<0.001

P<0.001

P<0.0001

Na+/Glucose

SGLT-2 InhibitionInsulin-Independent Reversal of Glucotoxicity

Insulin sensitivity in muscle1,2

Insulin sensitivity in liver2

Gluconeogenesis2,3

Improved β-cell function4,5

GLUT-2, glucose transporter 2.1. DeFronzo RA, et al. Diabetes Obes Metab. 2012;14(1):5-14; 2. Merovci A, et al. J Clin Invest. 2014;124(2):509-514; 3. Marsenic O. Am J Kidney Dis. 2009;53(5):875-883; 4. Ferrannini E, et al. J Clin Invest. 2014;124(2):499-508; 5. Polidori D, et al. Diabetologia. 2014;57(5):891-901.

Tubular Lumen

3Na+

2K+ATP

GLUT-2

GlucoseGLUT-1

Glucose

SGLT-2

Glucose

Na+

SGLT-1

ProximalTubule

3Na+

2K+ATP

SGLT2 Inhibitors: FDA-Approved Agents

FDA-approved SGLT2 InhibitorsAgent AdministrationCanagliflozin • Oral, once daily

• Taken before the first meal of the dayDapagliflozin • Oral, once daily

• Taken in the morning with or without food

Empagliflozin

SGLT-2 Inhibitors vs SulfonylureasAdded to Metformin

Agent

Δ Weight, kg

Hypoglycemia, % of patients

SGLT-2Inhibitor SU SGLT-2

Inhibitor SU

CANA1,a −4.0a +0.7 5a 34

DAPA2,b −3.2a +1.4 3a 41

EMPA3,c −3.2a +1.6 2a 24CANA (300 mg)1,b

DAPA (10 mg)2,c

Noninferiorvs SU

ΔA

1c F

rom

Bas

elin

e, %

EMPA (25 mg)3,d

GLIPGLIM

aP<0.0001 vs SU.bCANA: 52-week trial of canagliflozin; baseline A1c, 7.8%; cDAPA: 52-week trial of dapagliflozin; baseline A1c, 7.7%; d EMPA:104-week trial of empagliflozin; baseline A1c, 7.9%. 1. Cefalu WT, et al. Lancet. 2013;382(9896):941-950; 2. Nauck MA, et al. Diabetes Care. 2011;34(9):2015-2022; 3. Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2(9):691-700.

Outline




DPP-4 Inhibitors

SGLT-2 Inhibitors


Insulin


Nissen SE, Wolski K. N Engl J Med 2007;356:2457-2471.

Diabetes and Cardiovascular Disease:The Perfect Storm

2008 FDA Guidance for Industry on Evaluating the Cardiovascular Risk of New Antidiabetic Therapies

For completed studies prior to NDA:● Integrated meta-analysis of phase

2/3 trials to compare CV events in patients randomized to investigational drug vs. control

● Demonstrate new therapy will not result in an unacceptable CV risk Evaluated by Major Adverse

Cardiovascular Events (MACE) Estimated risk ratio for upper bound

of the 2-sided CI for the investigational drug should be <1.8

If upper CI = 1.3 - 1.8, post-marketing CV surveillance trial may be required

Traditional CV Outcome Trials vs Diabetes CV Safety Trials

CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; LDL-C = low density lipoprotein cholesterol. 1.Heart Protection Study Collaborative Group. Lancet. 2002;360:7–22. 2. Heart Protection Study Collaborative Group. Lancet. 2003;361:2005–2016. 3. White WB et al. N Engl J Med. 2013;369:1327–1335. 4. Scirica BM et al. N Engl J Med. 2013;369:1317–1326. 5. Green JB et al. Am Heart J. 2013;166:983–989.e7.

Traditional (eg, LDL-C) CV Outcome Trials

Designed to Demonstrate CV Benefit1,2

Diabetes CV Safety TrialsPrimarily Designed to Demonstrate CV

Safety3–5

Lower CV risk vs Placebo or Active comparator

Difference in LDL-C between treatment and placebo or active comparator

CV benefit of treatment demonstrated by significant reduction in CV outcomes

No adjustmentto maintain

LDL-C levels the same in both groups

No increased CV risk vs Placebo as part of standard care

Small or no difference in HbA1c between treatment and placebo

No increased CV risk (CV safety) of treatment demonstrated by

noninferiority

Adjustmentto maintainHbA1c levels the same in both groups

Initiation of blinded treatment or placebo or active comparator Initiation of blinded treatment or

placebo

Insulin

20192015 20202013 2014 2016 2017 2018 2021

SGLT-2i

EMPA-REG OUTCOME(Empagliflozin, SGLT-2i)

n=7000; duration up to 5 years Q2 2015 - RESULTS

CANVAS(Canagliflozin, SGLT-2i)

n=4418; duration 4+ yearsCompletion Q1 2017

DECLARE-TIMI-58(Forxiga, SGLT-2i)

n=17,276; duration ~6 yearsCompletion Q2 2019

CANVAS-R(Canagliflozin, SGLT-2i)

n=5826; duration ~3 yearsCompletion Q1 2017

VERTIS CV (NCT01986881)(Ertugliflozin, SGLT-2i)

n=8000; duration ~6.3 yearsCompletion Q4 2019

CREDENCE (cardio-renal)(Canagliflozin, SGLT-2i)

n=3700; duration ~5.5 years Completion Q1 2020

DEVOTE(Insulin degludec, insulin)n=7637; duration ~5 yearsQ3 2016 - COMPLETED

GLP-1RA

ELIXA(Lyxumia, GLP-1RA)

n=6000; duration ~4 yearsQ1 2015 – RESULTS

FREEDOM (ITCA 650, GLP-1RA in DUROS)

n=4000; duration ~2 yearsQ2 2016 - COMPLETED

REWIND(Dulaglutide, QW GLP-1RA)n=9622; duration ~6.5 years

Completion Q3 2018

SUSTAIN 6(Semaglutide, GLP-1RA)

n=3297; duration ~2.8 yearsQ3 2016 - RESULTS

LEADER(Victoza, GLP-1RA)

n=9341; duration 3.5–5 yearsQ2 2016 - RESULTS

EXSCEL(Bydureon, QW GLP-1RA)

n=14,000; duration ~7.5 yearsCompletion Q2 2018

HARMONY OUTCOME(Tanzeum, QW GLP-1RA)n~9400; duration ~4 years

Completion Q2 2019

DPP-4i

TECOS(Januvia, DPP-4i)

n=14,000; duration ~4–5 yearsQ4 2014 - RESULTS

SAVOR TIMI-53(Onglyza, DPP-4i)

n=16,492; follow-up ~2 years Q2 2013 – RESULTS

EXAMINE(Nesina, DPP4i) n=5380;

follow-up ~1.5 yearsQ3 2013 – RESULTS

CAROLINA(Tradjenta, DPP-4i vs. SU)n=6000; duration ~8 years

Completion Q1 2019

CARMELINA(Tradjenta, DPP-4i)

n=8000; duration ~4 years Completion Q1 2018

Cardiovascular Outcomes Trials in Diabetes

Boxes with broken lines are for completed CVOTsCVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase 4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; QW, once weekly; SGLT-2i, sodium glucose co‐transporter 2 inhibitor; SU, sulphonylurea

Source: clinicaltrials.gov (October 2016)

2008FDA guidance

T2DM Patients in CV Outcomes Trials

Holman RR et al. Lancet 2014; 383: 2008–17.

● 25 Trials Ongoing/Completed● 8 classes of medications● >200,000 planned participants

Outline




DPP-4 Inhibitors

SGLT-2 Inhibitors


Insulin


PROactive: Significant Reduction in Secondary Outcome

Dormandy JA et al. Lancet. 2005;366:1279-89.

Events(%)

*Excluding silent MI

060 12 18 24 30 36

Time from randomization (months)

16% RRRHR 0.84 (0.72–0.98)

P = 0.027

5

10

15

25

20

Pioglitazone301 events

Placebo358 events

All-cause mortality, nonfatal MI*, stroke

PROactive: HF Hospitalization and Mortality

Pioglitazonen (%)

Placebon (%) P

HF leading to hospital admission*

Fatal HF

149 (5.7)

25 (0.96)

108 (4.1)

22 (0.84)

0.007

NS

Dormandy JA et al. Lancet. 2005;366:1279-89.

*Non-adjudicated

N = 5238

● 5½-year study● 338 centers● 23 countries in

Europe, Australia, and New Zealand

Home P et al. Lancet. 2009 373(9681):2125-35.

Home P et al. Lancet. 2009 373(9681):2125-35.

NEJM: Published on-line: February 17, 2016 DOI: 10.1056/NEJMoa1506930

IRIS: Pioglitazone for Stroke Prevention

Eligibility: Recent TIA or Ischemic StrokeNon-DiabeticInsulin Resistant (HOMA > 3.0)No CHF

IRIS: Trial Design

RN=3895*

Placebo

Pioglitazone15mg→45 mg

Fatal/non-fatal MIFatal/non-fatal stroke

5 years

5 years

*90% power to detect a 20% RRR from 27% in the placebo group to 22% in the pioglitazone group at an alpha level of 0.05

ClinicalTrials.gov Identifier:NCT00091949Viscoli CM et al. Am Heart J 2014;168:823

IRIS: Primary Outcome

80%

85%

90%

95%

100%

‐ 20 40 60Months in Trial

CumulativeEvent-Free

SurvivalProbability HR 0.76

95% CI, 0.62 to 0.93 P=0.007

Pioglitazone

Placebo

11.8%*

9.0%*

0

Kernan WN et al. N Engl J Med, published on-line Feb 17, 2016 DOI: 10.1056/NEJMoa1506930

*cumulative event rates

Summary: ThiazoladinedioneCardiovascular Outcomes Trials

● No apparent increased risk of MI or MACE

Some benefit apparent with pioglitazone

Cannot assume that this is a class effect

● Increased risk for heart failure

No increased risk for heart failure deaths

● Increased risk for fractures

Outline




DPP-4 Inhibitors

SGLT-2 Inhibitors


Insulin


Cardiovascular Outcomes Trials for DPP-4 Inhibitors

Median Duration of Follow-up

Randomization Year 3Year 2Year 1

SAVOR-TIMI 531 Primary Endpoint Hazard Ratio

CV death,nonfatal MI, or nonfatal stroke

Saxagliptin

Placebo

CVD or CRFsA1c 6.5–12.0%

n=16,492

1.00 (95% CI

0.89, 1.12)p=0.99

Median follow-up2.1 years

EXAMINE2


Alogliptin

Placebo

ACSA1c 6.5–11.0%

n=5,380

Median follow-up1.5 years

0.96(upper boundary

of 1-sided repeated CI 1.16)

p=0.315

TECOS3

CV death,nonfatal MI, or

nonfatal stroke, or UA requiring

hospitalization

Sitagliptin

Placebo

CVDA1c 6.5–8.0%

n=14,735

Median follow-up

3 years

0.98(95% CI 0.88, 1.09)

p=0.645(superiority)

. Scirica BM, et a. NEJM. 2013;369:1317-1326; 2. White W, et al. NEJM. 2013;369:1327-1335; 3. Green JB, et al. NEJM, 2015

0.99(95% CI 0.89, 1.10)

p=0.84(superiority)


Cardiovascular Outcomes Trials for DPP-4 Inhibitors

1. Scirica, BM, et al. New Eng J Med. 2013 Oct 3;369(14):1317-26.2. White WB, et al. N Engl J Med. 2013 Oct 3;369(14):1327-35.3. Green JB, et al. N Engl J Med. 2015 Jul 16;373(3):232-42.

N=16,492

Composite of CV death, MI, or ischemic stroke

0 180 360 540 720 900Days

Patie

nts,

%

14

10

6

20

Saxagliptin

Placebo

Hazard ratio: 1.00 (95% CI: 0.89–1.12)P < 0.001 (noninferiority)

12

8

4

Saxagliptin (SAVOR-TIMI 53 Trial1)

Composite of CV death, nonfatal MI, or nonfatal stroke.

Months0 6 12 18 24 30

24

18

12

6

0

Alogliptin

Placebo

Hazard ratio: 0.96 (upper boundary of one-sided repeated 95% CI: 1.16)

N=5380

Alogliptin (EXAMINE Trial2)

Months

15

10

0

Sitagliptin

Placebo

5

Sitagliptin (TECOS Trial3)

Composite of CV death, nonfatal MI, nonfatal stroke, or

hospitalization for unstable angina

Hazard ratio: 0.98(95% CI: 0.89, 1.08)P=0.65

0 12 2418 3630 42 4884

N=14,671

SAVOR-TIMI 53, EXAMINE, and TECOS: MACE Outcomes

SAVOR-TIMI(saxagliptin vs placebo)

EXAMINE(alogliptin vs placebo)

TECOS(sitagliptin vs placebo)

SAVOR + EXAMINE+ TECOS

613/8280(7.4%)

305/2701(11.3%)

745/7332(10.2%)

1663/18313(9.1%)

Study Drugn/N (%)

609/8212(7.4%)

316/2679(11.8%)

746/7339(10.2%)

1671/18230(9.2%)

Placebon/N (%)

1.00

0.96

0.99

0.99

HazardRatio

0.89, 1.12

NA, 1.16

0.89, 1.10

0.92, 1.06

95%CI

0.99

0.315

0.844

p-Value

0 1 2

Favors Treatment

Favors Placebo

*

Test for heterogeneity for 3 trials:p=0.877, I2=0%

*Lower Confidence Limit not given for EXAMINE trial; MACE = major adverse cardiac events.1. Scirica BM, et al. N Engl J Med. 2013;369:1317–1326. 2. White WB, et al. N Engl J Med. 2013;369:1327–1335. 3. Green JB, et al. N Engl J Med. 2015;373(3):232–242.

SAVOR-TIMI 53, EXAMINE, and TECOS:Hospitalization for Heart Failure

SAVOR-TIMI(saxagliptin vs placebo)

EXAMINE(alogliptin vs placebo)

TECOS(sitagliptin vs placebo)

289/8280(3.5%)

106/2701(3.9%)

228/7332(3.1%)

Study Drugn/N (%)

228/8212(2.8%)

89/2679(3.3%)

229/7339(3.1%)

Placebon/N (%)

1.27

1.19

1.00

HazardRatio

1.07, 1.51

0.89, 1.58

0.83, 1.20

95%CI

0.009*

0.238

0.983

p-Value

0 1 2

Favors Treatment Favors Placebo

*Statistically significant increase in hospitalizations for heart failure associated with saxagliptin use in SAVOR-TIMI.1. Scirica BM, et al. N Engl J Med. 2013;369:1317–1326. 2. White WB, et al. N Engl J Med. 2013;369:1327–1335.

Summary: DPP-4 Inhibitor Cardiovascular Outcomes Trials

● All trials met the primary goal of demonstrating that there is no increased risk of CVD

No benefit is apparent

Cannot assume that this is a class effect

There may be heterogeneity with respect to heart failure

● These large trials have been useful for evaluating other potentially beneficial effects of the drugs

Decreased rates of albuminuria

● More precise estimates of the risk of other rare events

Outline




DPP-4 Inhibitors

SGLT-2 Inhibitors


Insulin


Zinman B,. N Engl J Med. 2015 Nov 26;373(22):2117-28

EMPA-REG Outcomes Trial: Design

Randomised and treated

(n=7020)

Empagliflozin 10 mg(n=2345)

Empagliflozin 25 mg (n=2342)

Placebo (n=2333)

Screening(n=11531)

Key inclusion criteria:• Adults with type 2 diabetes• BMI < 45 kg/m2

• HbA1c 7-10%• Established cardiovascular disease

Key exclusion criteria:• eGFR < 30 mg/min/1.73 m2 (MDRD)

Median treatment duration = 2.6 years

Zinman B,. N Engl J Med. 2015 Nov 26;373(22):2117-28

EMPA-REG Outcomes Trial: Main Results

aCumulative incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.N=7020 patients with T2DM at high risk of cardiovascular events.Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128.

Patie

nts W

ith

Even

t, %

Empagliflozin

P=0.04 for superiorityHazard ratio, 0.86 (95.02% CI, 0.74–0.99)

Placebo20

15

5

10

00 126 18 24 30 36 42 48

Cumulative Incidence of the Primary Outcomea

Patie

nts W

ith

Even

t, %

Empagliflozin

P<0.001Hazard ratio, 0.62 (95% CI, 0.49–0.77)

Placebo9

3

6

00 126 18 24 30 36 42 48

Cumulative Incidence of Death From CV Causes

Patie

nts W

ith

Even

t, %

Empagliflozin

P=0.002Hazard ratio, 0.65 (95% CI, 0.50–0.85)

Placebo76

45

00 126 18 24 30 36 42 48

Month

Hospitalization for Heart Failure

321

Patients with event/analysedEmpagliflozin Placebo HR (95% CI) p-value

3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638

EMPA-REG Outcomes Trial: CV Death, MI and Stroke

51

Favours empagliflozin Favours placeboCox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction*95.02% CI

Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128.

EMPA-REG Outcomes Trial:Renal OutcomesEMPA-REG Outcomes Trial:Renal Outcomes

1. Zinman B, et al. N Engl J Med. 2015;373:2117-2128; 2. Barnett AH, et al. Lancet Diabetes Endocrinol. 2014;2:369-384.

Lower rates of acute renal failure and kidney injury (5.2% vs 6.6% and 1.0% vs 1.6%, respectively; P < .05 vs placebo)1

A1C reduction of –0.52% to –0.68% vs placebo in CKD stage 2-3 (eGFR ≥ 30 to < 90 mL/min/1.73m2), P < .00012

Equivalent adverse event rates as placebo in patients in CKD stage 2-32

Baseline Demographics and Disease History


CANVAS: Primary MACE Outcome


CANVAS: MACE Components and HF

56Neal B et al. N Engl J Med. 2017 Jun 12.

CANVAS: Renal Outcomes


CANVAS: Amputation Risk


Summary: SGLT-2 Inhibitor Cardiovascular Outcomes Trials● Both trials met the primary goal of demonstrating that there is

no increased risk of CVD

MACE benefit with both empagliflozin and canagliflozin

Heart failure benefit for both empagliflozin and canagliflozin

Mortality benefit with empagliflozin but not canagliflozin




Amputation and fracture risk with canagliflozin

Outline




DPP-4 Inhibitors

SGLT-2 Inhibitors


Insulin


ELIXA Study: Lixisenatide vs. Placebo

Bentley-Lewis R et al. AHJ 2015; 169:631-638.e7; Results of ELIXA, oral presentation 3-CT-SY28. Presented at the American Diabetes Association 75th annual scientific sessions, Boston, 8 June 2015

Trial information • Multi-centre• Double-blind• Parallel-group• Event-driven• Randomised

Lixisenatide, 20 μg maximum dose

Placebo

203±1 weeks

End of treatment

Randomisation (1:1)

2 weeks1 week

Placebo

Run-in Titration

Lixisenatide10 μg

Placebo

Run-in period• Patients were trained in self-administration

of daily subcutaneous volume-matched placebo

Titration• Lixisenatide or matching placebo (1:1)

• Initial dose 10 μg/day• Down- or up-titration permitted to

maximum of 20 μg/day

• Glucose control was managed by site investigators’ judgement

6,068 subjects with T2DM and recent ACS event randomized to lixisenatide vs placebo

Time to first occurrence of the primary CV event: CV death, non-fatal MI, non-fatal stroke or hospitalisation for unstable angina1

ELIXA Study: Primary Composite Endpoint

CV, cardiovascular; MI, myocardial infarction1. Clinicaltrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT01147250. Accessed May 2015Results of ELIXA, oral presentation 3-CT-SY28. Presented at the American Diabetes Association 75th annual scientific sessions, Boston, 8 June 2015

Patie

nts

with

eve

nt (%

)

0

0 12 24 36

5

10

15

20

Lixisenatide: 406/3034 = 13.4%Placebo: 399/3034 = 13.2%

HR=1.02 (0.89, 1.17)

Months

30343034

27592785

15661558

476484

Number at riskPlacebo

Lixisenatide

ELIXA Study: Lixisenatide vs Placebo

Outcome Lixisenatide n=3034

Placebo n=3034

HR (95% CI)

Primary outcome (CV death, nonfatal MI, nonfatal stroke, or hospitalization for UA)

13.4% 13.2% 1.02 (0.89–1.17)

Primary outcome plus hospitalization for HF 15% 15.5% 0.97 (0.85–1.10)

Hospitalization for HF 4.0% 4.2% 0.96 (0.75–1.23)

All-cause mortality – – 0.94 (0.78–1.13)

ELIXA = Evaluation of Lixisenatide in Acute Coronary Syndrome; ACS = acute coronary syndrome; UA = unstable angina; HF = heart failure.

Trial data presented by Pfeffer, MA et al, ADA Scientific Sessions, June 8 2015, Boston Patients followed for a mean of 2.1 years

LEADER: Liraglutide vs. Placebo Cardiovascular Outcomes Trial

RANDOMISATION

(1:1)

Key inclusion criteria

Adult T2D patients:• HbA1c 7.0%• Antidiabetic drug naïve; or• Treated with one or more OADs;

or• Treated with basal or premix

insulin (alone or in combination with OADs)

• High-risk CV profile

N=9340 Standard of care + liraglutide

(0.6–1.8 mg once daily)

Standard of care + placebo*

3.5–5 year follow-up

Placebo* run-in period of ≥2 weeks

Patients demonstrating ≥50% adherence to

regimen and willingnessto continue with injection protocol for duration of

trial proceeded to randomisation

Marso et al. Am Heart J 2013;166:823–30.e5

*Daily single-blind subcutaneous injection of placeboCV, cardiovascular; OAD, oral antidiabetic drug; T2D, type 2 diabetes

LEADER: Primary and Secondary Outcomes with Liraglutide

aComposite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.N=9340 patients with T2DM and high cardiovascular risk.Marso SP, et al. N Engl J Med. 2016 June 13 [Epub ahead of print].

Months Since Randomization

Patie

nts W

ith E

vent

,%

Liraglutide

Placebo

Hazard ratio, 0.87 (95% CI, 0.78–0.97)P<0.001 for noninferiorityP=0.01 for superiority

20

15

5

10

00 126 18 24 30 36 42 54

Primary Outcomea

48

Hazard ratio, 0.78 (95% CI, 0.66–0.93)P=0.007

0 126 18 24 30 36 42 54

Cardiovascular-Related Death

48

Liraglutide

Placebo

Hazard ratio, 0.85 (95% CI, 0.74–0.97)P=0.02

0 126 18 24 30 36 42 54

Death From Any Cause

48

Liraglutide

Placebo

20

15

5

10

0

20

15

5

10

0

LEADER: Time to First Renal Event

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; ESRD: end-stage renal disease; HR: hazard ratio.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

Macroalbuminuria, doubling of serum creatinine, ESRD, renal death

SUSTAIN 6: Primary and Secondary Outcomes With Semaglutide

Marso et al. NEJM, Oct 2016

Top-line Results from Exscel and Freedom-CVO

Summary: GLP-1 Receptor Agonist Cardiovascular Outcomes Trials

● All trials met the primary goal of demonstrating that there is no increased risk of CVD

● LEADER (liraglutide) and SUSTAIN 6 (semaglutide) demonstrated a benefit on MACE and mortality (liraglutide)

● ELIXA (lixisenatide), EXSCEL (exenatide) and FREEDOM (exenatide) did not demonstrate a CV benefit




No increased rate of pancreatitis

Outline




DPP-4 Inhibitors

SGLT-2 Inhibitors


Insulin


DEVOTE: Trial Design

Insulin degludec once daily (blinded vial) +Standard of care

IGlar U100 once daily (blinded vial) +Standard of care

Randomization

7637 patients

randomized

End of treatment

(633 MACE accrued)

Follow-up period

30 days

Follow-up period

Secondary endpoints • Rate of severe hypoglycemic episodes*‡

• Incidence of severe hypoglycemic episodes*‡

Primary endpoint Time from randomization to first occurrence of a 3-point MACE: cardiovascular death*†, non-fatal myocardial infarction* or non-fatal stroke*

Interim analysis(150 MACE accrued)

Marso S. et al. NEJM, June14, 2017

Insulin degludec IGlar U100Type of insulin

New generation long-acting basal insulin analog

First generation basal insulin analog

Mode of protraction

Forms soluble multihexamers

Precipitates as microcrystals

Half life ~25 hours ~12 hours

Day-to-dayvariability (AUCGIR,0–24h)

Coefficient of variation 20% Coefficient of variation 80%

Study Drugs

AUCGIR, area under the curve for glucose infusion rate; IGlar U100, insulin glargine U100Insulin glargine image data on file; Jonassen et al. Pharm Res. 2012;29:2104–14; Heise et al. Expert Opin Drug Metab Toxicol 2015;11:1193–201; Heise et al. Diabetes Obes Metab 2012;14:859–64

0

2

4

6

8

10

12

0 3 6 9 12 15 18 21 24 27 30

DEVOTE: Time to First 3-point MACE

Full analysis set; Cox regression analysis accounting for treatment. Analysis includes events between randomization date and follow-up date. Patients without an event are censored at the time of last contact (phone or visit)EAC, Event Adjudication Committee; N, number of patients at risk; PYO, patient-years of observation

HR: 0.91[0.78; 1.06]95% CI

Non-inferiority confirmedp<0.001

Patie

nts

with

an

even

t (%

)

Insulin degludec (N) 3818 3765 3721 3699 3611 3563 3504 2851 1767 811 217IGlar U100 (N) 3819 3758 3703 3655 3595 3530 3472 2832 1742 811 205

Time to first EAC-confirmed event (months)

IGlar U100Insulin degludec

356 patients

325 patients

Rate:4.71/100 PYO

Rate:4.29/100 PYO

Marso S. et al. NEJM, June14, 2017

● Glycemic control (insulin degludec vs. IGlar U100):

End of treatment mean HbA1c values 7.55% vs. 7.50%

Change in FPG levels -39.9 mg/dL vs. -34.9 mg/dL

● 27% fewer patients experienced severe hypoglycemia

with insulin degludec

● 40% rate reduction of severe hypoglycemia

● 53% rate reduction of nocturnal severe hypoglycemia

DEVOTE: Glycemic Control and Severe Hypoglycemia

Outline




DPP-4 Inhibitors

SGLT-2 Inhibitors


Insulin


Putting the Mortality Rates From EMPA-REG and LEADER into Perspective

ACE, acetylcholinesterase; ARB, Angiotensin II Receptor Blocker; HF, heart failure; MRA, Mineralocorticoid receptor antagonistaSOLVD Treatment; bCHARM Alternative; cCOPERNICUS and MERIT-HF; dRALES and EMPHASIS-HF, ePARADIGM, fEMPA-REG OUTCOME, gLEADERFitchett DH et al. Eur J Heart Fail 2016;doi: 10.1002/ejhf.633

-40%

-30%

-20%

-10%

0%ARB ACE inhibitor Beta blocker MRA

ARB +Neprilysininhibitor Empagliflozin Liraglutide

% D

ecre

ase

in m

orta

lity

Study duration (months)

38 41 10-12 21-24 27 36 46

a b c d

e

f g

Considerations for Selecting Therapies

● Current HbA1c and magnitude of reduction needed to reach goal

● Potential effects on body weight and BMI

● Potential for hypoglycemia – age, lack of awareness of hypoglycemia, disordered eating habits

● Effects on CVD risk factors – blood pressure and blood lipids

● Comorbidities – CAD, heart failure, CKD, liver dysfunction

● Patient factors – adherence to medications and lifestyle changes, preference for oral vs injected therapy, economic considerations

Inzucchi et al. Diabetes Care 2012; 35:1364‐79.

How Do Comorbidities Affect Anti-Hyperglycemic Therapy in T2DM?

Coronary Disease

Heart Failure

Renal Disease

Liver Dysfunct

ion

Hypo-glycemia

Metformin: CVD benefit (UKPDS)

Avoid hypoglycemia

? SUs & ischemic precondition‐ing

? Pioglitazone & CVD events

Liraglutide Empagliflozin,

Canagliflozin

Metformin: May use unless condition is unstable or severe

Avoid TZDs Avoid

saxagliptin Empagliflozin,

Canagliflozin

↑ risk of hypoglycemia

Metformin & lactic acidosis US: half‐dose @GFR < 45 &stop @GFR < 30

Caution with SUs

DPP4‐Is – dose adjust for most

Avoid exenatide if GFR < 30

SGLT‐2i

Most drugs not tested in advanced liver disease

Pioglitazone may help steatosis

Insulin best option if disease severe

Emerging concernsregardingassociation with increasedmorbidity / mortality

Proper drug selection is key in hypoglycemia prone

DPP‐4i, GLP‐1 RA, SGLT‐2i

Degludec

ADA Glycemic Treatment Recommendations for T2DM

DPP-4i, dipeptidyl peptidase-4 inhibitor; fxs, fractures; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide-1 receptor agonist; GU, genitourinary; HbA1c, glycosylated hemoglobin; HF, heart failure; SU, sulfonylurea; SGLT2-i, sodium-glucose co-transporter 2 inhibitor; TZD, thiazolidinedione. American Diabetes Association. Diabetes Care 2016;39(Suppl. 1):S52-S59.

Healthy eating, weight control, increased physical activity, diabetes education

Not at target HbA1c after ~3 months

Dual therapy

Triple therapy

Combination injectable therapy

Monotherapy

Not at target HbA1c after ~3 months

GLP-1 RASGLT2iDPP-4iTZDSU Insulin (basal)

Metformin

SUTZD

Insulin

SUTZD

DPP-4iInsulin

SUTZD

SGLT2iInsulin

SUDPP-4iSGLT2i

GLP-1 RAInsulin

TZDDPP-4iSGLT2i

GLP-1 RAInsulin

TZDDPP-4iSGLT2i

GLP-1 RA

Metformin + basal insulin + mealtime insulin or GLP-1 RA

Metformin +

+ + + + + +

or

Metformin +SU +

Metformin +TZD +

Metformin +DPP-4i +

or or oror

or

Metformin +SGLT2i +

Metformin +GLP-1 RA +

Metformin +Insulin (basal) +

Not at target HbA1c after ~3 months*

ADA Glycemic Treatment Recommendations for T2DM 2017

Summary

Completed long-term CV safety trials have demonstrated no increased risk of CV events associated with newer antihyperglycemic agents

DPP-4 inhibitors not associated with an increased overall risk

Investigation continues to identify mechanisms and/or factors that may explain the potential for increased HF risk with some DPP-4 inhibitors

The LEADER trial (liraglutide) and SUSTAIN-6 trial (semaglutide) demonstrated some CV benefit, whereas ELIXA (lixisenatide) EXSCEL and FREEDOM (exenatide) did not

The EMPA-REG Outcomes Trial (empagliflozin) and CANVAS (canagliflozin) demonstrated a CV benefit, decreased mortality (empagliflozin) and less heart failure hospitalizations

Label recently updated to reflect this

Guidelines are evolving rapidly to reflect the new evidence

new treatments for type 2 diabetes: implications of ......microvascular complications of t2dm in...

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