What Do We Now Know?

ModeratorDeepak L. Bhatt, MD, MPHProfessor of Medicine, Harvard Medical SchoolExecutive Director of Interventional Cardiovascular ProgramsBrigham & Women’s Hospital Heart and Vascular CenterBoston, Massachusetts

A Balanced Therapeutic Approach to CV Risk in T2DA Balanced Therapeutic Approach to CV Risk in T2D

PanelistsA. Michael Lincoff, MDDirector, C5Research, Cleveland ClinicCoordinating Center for Clinical ResearchProfessor of MedicineDepartment of Cardiovascular MedicineCleveland Clinic Lerner College of MedicineCleveland, Ohio

Jean-Claude Tardif, MDDirectorMontreal Heart Institute Research CentreProfessor of MedicineUniversity of MontrealMontreal, Canada

Learning ObjectivesLearning Objectives

• Review the latest evidence on PPAR agonists on the management of cardiovascular risk in patients with type 2 diabetes

• Discuss the efficacy and safety results seen in the latest cardiovascular outcomes clinical trials evaluating glucose-lowering therapies in patients with type 2 diabetes

Metabolic Abnormalities Associated With T2DMetabolic Abnormalities Associated With T2D

• Insulin resistance

• High triglyceride

• Low HDL-cholesterol

• Slightly elevated LDL-cholesterol

– Increased small, dense LDL particle concentration

• Obesity

CV Events With PPAR-gamma AgonistsCV Events With PPAR-gamma AgonistsRosiglitazone

Meta-analysisa Myocardial infarction (OR)

Meta-analysisa Cardiovascular death (OR)

Meta-analysisb Myocardial infarction (OR)

Meta-analysis of 42 trialsc Myocardial ischemia (OR)

Data from Nissen and RECORDd Myocardial infarction (OR)

Data from Nissen and RECORDd Cardiovascular death (OR)

Meta-analysise Myocardial infarction (HR)

Better Worse

Hazard ratio/Odds ratio

Pioglitazone

PROactivef Primary end point (HR)

PROactivef MI, stroke, or death (HR)

PROactive MI subgroupg Myocardial infarction (HR)

Meta-analysish MI, stroke, or death (HR)

Meta-analysisc MI, stroke, or death (HR)

10 2

a. Nissen SE, et al. N Engl J Med. 2007;356:2457-2471[1]; b. Krall RL, et al. Lancet. 2007;369:1995-1996[2]; c. US Food and Drug Administration 2007[3]; d. Bracken MB, et al. N Engl J Med. 2007;357:937-938[4]; e. Singh S, et al. JAMA. 2007;298:1189-1195[5]; f. Dormandy JA, et al. Lancet. 2005;366:1279-1289[8]; g. Erdmann E, et al. J Am Coll Cardiol. 2007;49:1772-1780[9]; h. Lincoff AM, et al. JAMA. 2007;298;1180-1188.[7]

Effect of Fibrates on CV OutcomesA Systematic Review and Meta-analysisEffect of Fibrates on CV OutcomesA Systematic Review and Meta-analysis

Jun M, et al. Lancet. 2010;375:1875-1884.[10]

Relative Risk (95% CI)

VA CO-OP Atherosclerosis (1973) 1.35 (0.89-2.07)

VA-HIT (1999) 0.78 (0.68-0.90)

LEADER (2002) 0.94 (0.77-1.15)

FIELD (2005) 0.90 (0.81-0.99)

ACCORD (2010) 0.94 (0.80-1.09)

Overall0.90 (0.82-1.00); P = .048

(I2 = 47.0%, Q = 7.55, P = .110)

Excluding VA CO-OP Atherosclerosis

0.88 (0.82-0.95); P = .002(I2 = 18.6%, Q = 3.7, P = .298)

ACCORD Lipid Hazard Ratios for the Primary OutcomeACCORD Lipid Hazard Ratios for the Primary Outcome

11.3 (2753)

17.3 (456)

10.1 (2284)

ACCORD Study Group, et al. N Engl J Med. 2010;362:1563-1574.[14]

• 31% reduction in events in patients with atherogenic dyslipidemia• 20 with T2D and atherogenic dyslipidemia needed to be treated for 5

years to prevent 1 CV event

Simvastatin +fenofibrate

better

10 2

Simvastatinalonebetter

Overall

Triglyceride – HDL-C combination

TG ≥ 204 mg/dL + HDL-C ≤ 34 mg/dL

All others

10.5 (2765)

12.4 (485)

10.1 (2264)

HR

(95% CI)

P Value for

Interaction

% of event (no. in group)

.06

Simvastatin

+ placebo

Simvastatin

+ fenofibrateSubgroup

Pioglitazone Safety Issues

• Slightly increased risk for bladder cancera

• Bone fracturesb

• Fluid retention, edema, risk for decompensation/congestive heart failurec

Nesto RW, et al. Circulation. 2003;108:2941-2948.a. Ferwana M, et al. Diabet Med. 2013;30:1026-1032[15]; b. Aubert RE, et al. Diabetes Obes Metab. 2010;12:716-721[17]; c. Lincoff AM, et al. JAMA. 2007;298;1180-1188.[7]

Pioglitazone Meta-analysisHeart Failure & MIPioglitazone Meta-analysisHeart Failure & MI

Lincoff AM, et al. JAMA. 2007;298;1180-1188.[7]

MI

Death/MI

Serious HF

Death/serious HF

Pioglitazone better

10 2

Control better

HR (95% CI)End Point

Dual PPAR a/g AgonistsDual PPAR a/g Agonists

Past Development Programs

Phase ofInvestigation

Program Outcome

Reasons for Termination

Tesaglitazar 3

TerminatedMay, 2006

Data from ~ 3000 patients

Increased creatinine; uncertain

risk: benefita,b

Muraglitazar 3

TerminatedMay, 2006

Data from 3725 patients

Excess CV events in pooled trialsc

a. Ratner RE, et al. Diabetes Vasc Dis Res. 2007;4:214-221[18]; b. Hamrén B, et al. J Clin Pharmacol. 2012;52:1317-1327[19]; c. Nissen SE, et al. JAMA. 2005;294:2581-2586.[1]

AleCardioAleglitazar (PPAR a/g Agonist) in Patients With T2D and ACS

AleCardioAleglitazar (PPAR a/g Agonist) in Patients With T2D and ACS

Phase 3, double-blind, parallel, randomized trial in patients with recent ACS and T2D

Enrolled 7226 patientsTreatment duration: at least 2.5 years

Placebo (+ SC) Aleglitazar 150 g (+ SC)

Primary efficacy: Time to 1st occurrence of CV death, nonfatal MI, or nonfatal strokeSecondary efficacy : CV death, MI, stroke, or hospitalization for ACSPrincipal safety: Hospitalization due to heart failure and changes in renal function

Superiority: Event-driven (950 primary end point events)

Inclusion Criteria:Adults > 18 years of age

T2DHospitalization for ACS event and randomization up to 12 weeks after index event

Lincoff AM et al. JAMA. 2014;311:1515-1525.[16]

AleCardio Efficacy and Safety OutcomesAleCardio Efficacy and Safety Outcomes

Primary efficacy

Secondary efficacy

Hospitalization for HF

Gastrointestinal hemorrhage

Bone fracture

Aleglitazar better

10 2

Placebo better

HR (95% CI)End Point

Lincoff AM et al. JAMA. 2014;311:1515-1525.[16]

Lincoff AM et al. JAMA. 2014;311:1515-1525.[16]

AleCardioGlycemic Control and Lipoprotein EffectsAleCardioGlycemic Control and Lipoprotein Effects

Series1

-30

-20

-10

0

10

20

30

AleglitazarPlacebo

Mea

n C

han

ge

Fro

m B

asel

ine,

%

HbA1c HDL-C TG LDL-C

Genes Regulated by GlitazonesGenes Regulated by Glitazones

Sears DD, et al. Biochem Biophys Res Commun. 2007;364:515-521.[21]

The number of genes uniquely regulated by a glitazone is contained in the nonoverlapping regions of each circle

Repressed(N = 179)

5 1 47

856

36

26

Pioglitazone - 70 Rosiglitazone - 140

Troglitazone - 126

Pioglitazone - 52 Rosiglitazone - 65

Activated(N = 147)

Troglitazone - 122

8 2 15

438

10

70

Older Antidiabetic Drugs and CV Benefit/HarmOlder Antidiabetic Drugs and CV Benefit/Harm

• Sulfonylureas– May facilitate ischemic preconditioning in the diabetic heart (animal

data)a

– Class warning for possible increased CV mortalityb

• Metformin– Potential for risk reduction in MI and death from any cause in

overweight patientsc

• Rosiglitazone– Potential increased risk of MId

– Class warning for congestive heart failuree

• Pioglitazone– Potential for risk reduction in all-cause mortality, nonfatal MI, or

strokef

– Class warning for congestive heart failureg

a. Hausenloy DJ, et al. J Cardiovasc Pharmacol Ther. 2013;18:263-269[22]; b. US Food and Drug Administration 2013[23]; c. UK Prospective Diabetes Study. Lancet. 1998;352:854-865[24]; d. Nissen SE, et. N Engl J Med. 2007;356:2457-2471[1]; e. Avandia [package insert][32]; f. Dormandy JA, et al. Lancet. 2005;366:1279-1289[8]; f. Actos® [package insert].[33]

SAVOR-TIMI 53Clinical End Points: Saxagliptin (DPP4 Inhibitor) vs Placebo

SAVOR-TIMI 53Clinical End Points: Saxagliptin (DPP4 Inhibitor) vs Placebo

Scirica BM et al. N Engl J Med. 2013;369:1317-1326.[25]

Primary efficacy: CV death, MI, or stroke

Secondary efficacy: CV death, MI, stroke, hospitalization for UA, HF, or coronary revascularization

Death from any cause

Death from CV causes

MI

Ischemic stroke

Hospitalization for UA

Hospitalization for HF

Hospitalization for coronary revascularization

Doubling of creatinine level, initiation of dialysis, renal transplantation, or creatinine > 6.0 mg/dL (530 μmol/L)

Hospitalization for hypoglycemia

HR (95% CI)End Point

0 21

Saxagliptin better Placebo better

Scirica BM et al. Circulation. 2014 [Epub ahead of print].[26]

SAVOR-TIMI 53Hospitalization for Heart Failure Stratified by NT-proBNP Quartiles

SAVOR-TIMI 53Hospitalization for Heart Failure Stratified by NT-proBNP Quartiles

Quartiles of NT-proBNP (pg/mL) Saxagliptin, % Placebo, % HR (95% CI)

P Value

Q1(5-64) 0.7 0.7 1.04

(0.04-26.30) .98

Q2(65-141) 1.1 0.4 1.82

(0.86-4.09) .12

Q3(1412-333) 2.2 2.0 0.94

(0.57-1.55) .82

Q4(333-46,627) 11.0 8.9 1.31

(1.04-1.66) .02

Scirica BM et al. N Engl J Med. 2013;369:1317-26.[25]

SAVOR-TIMI 53Safety End PointsSAVOR-TIMI 53Safety End Points

End PointSaxagliptin N = 8280, %

Placebo N = 8212, % P Value

Bone fracture 2.9 2.9 1.00

Cancer 3.9 4.4 .15

Any pancreatitis 0.3 0.3 .77

Any liver abnormality 0.7 0.8 .28

Any hypoglycemia 15.3 13.4 < .001

Major 2.1 1.7 .047

Minor 14.2 12.5 .002

EXAMINESafety End Points: Alogliptin (DPP-4 Inhibitor) vs PlaceboEXAMINESafety End Points: Alogliptin (DPP-4 Inhibitor) vs Placebo

White WB, et al. N Engl J Med. 2013; 369:1327-1335.

• Primary end point: death from CV causes, nonfatal MI, or nonfatal stroke

• Secondary end point: death from CV causes, nonfatal MI, nonfatal stroke, or urgent revascularization due to unstable angina within 24 hours after hospital admission

HR (95% CI)End Point

Primary end point

Components of primary end pointDeath from CV causesNonfatal MI

Nonfatal stroke

Principal secondary end point

Other end pointsDeath from any cause

Death from CV causes

EXAMINEHeart Failure Outcomes EXAMINEHeart Failure Outcomes

Zannad F, et al. J Am Coll Cardiol. 2014;63(12S).

• Composite CV outcome: first occurrence of all-cause mortality, nonfatal MI and stroke, urgent revascularization due to unstable angina, and hospitalization for HF

HR (95% CI)Outcome

Composite CV outcome

Hospitalization for HF

Composite of CV death and hospitalization due to HF

CV death

Hospitalization for HF

Mechanism of Heart FailureMechanism of Heart Failure

• Fluid retention as evidenced by

– Weight gain with PPARs

– Reduction in glomerular filtration and creatinine clearance that is reversible on discontinuing PPAR

• Other as yet unknown mechanism

Ongoing CVD Outcomes Trials in Type 2 DiabetesOngoing CVD Outcomes Trials in Type 2 Diabetes

Study InterventionEstimated Enrollment Estimated Duration

EXSCEL Exenatide once weekly vs placebo 9500 6/2010–3/2017

FREEDOM-CVO

ITCA 650 (exenatide) vs placebo 2000 03/2013–07/2018

LEADER Liraglutide vs placebo 9340 8/2010–1/2016

ELIXA Lixisenatide vs placebo 6000 6/2010–10/2013

REWIND Dulaglutide vs placebo 9622 7/2011–4/2019

TECOS Sitagliptin vs placebo 14,000 12/2008–12/2014

CAROLINA Linagliptin vs glimepiride 6000 10/2010–9/2018

CARMELINA Linagliptin vs placebo 8300 07/2013–01/2018

ACE Acarbose vs placebo 7500 02/2009-10/2014

CANVAS Canagliflozin vs placebo 4335 12/2009-06/2018

Clinical Trial Design ConsiderationsClinical Trial Design Considerations

• Current trial designs– Follow-up not long enough to show CV risk reduction– Focus on CV safety and not CV benefit

• Enrollment of high-risk patients to show occurrence of events quickly to demonstrate noninferiority

• Future trial considerations to show CV benefit– Larger trials– Longer follow-up– Population not at high ischemic risk

• No recent ACS• No previous MI• No previous stroke

– Population with early atherosclerotic disease

AlePreventAleglitazar in Patients With Stable CVD and Glucose Abnormalities

AlePreventAleglitazar in Patients With Stable CVD and Glucose Abnormalities

Phase 3B, double-blind, parallel, randomized trial in patients with stable CVD and glucose abnormalitiesTarget sample size = 19,000 patients

Study duration: 5 years

Inclusion Criteria:Adults ≥ 40 years

Stable CVDEstablished T2D/evidence of glucose abnormalities

Placebo (+ SC) Aleglitazar 150 g (+ SC)

Primary: Time to 1st occurrence of CV death, nonfatal MI, or nonfatal strokeSecondary 1: Time to 1st occurrence of CV death, nonfatal MI, or nonfatal

stroke in subgroups with or without evidence of T2D at baselineSecondary 2: Time to 1st occurrence of all-cause mortality, nonfatal MI, or nonfatal stroke in subgroups with or without evidence of T2D at baseline

Clinicaltrials.gov. NCT01715818.[29]

Newer Antidiabetic Drugs & CV Risk ReductionNewer Antidiabetic Drugs & CV Risk Reduction

• GLP-1 receptor agonists– Weight lossa

– Reduction in blood pressureb

• SGLT2 inhibitorsc

– Weight loss

– Reduction in blood pressure

a. Pinelli NR, et al. Ann Pharmacother. 2011;45:850-860[31]; b. Wang B, et al. Diabetes Obes Metab. 2013;15:737-749 [34]; c. Kaushal S. N Am J Med Sci. 2014;6:107-113.[30]

Concluding RemarksConcluding Remarks

• Aggressive lipid management with– Statins

– Newer agents: PCSK9 inhibitors and CEPT inhibitors

• Other CV risk factor management– Obesity

– Hypertension

– Inflammation

• Lifestyle modification

AbbreviationsAbbreviations

ACCORD = Action to Control Cardiovascular Risk in Diabetes)

ACS = acute coronary syndromes

AleCardio = Safety and Efficacy Study to Evaluate the Potential of Aleglitazar to Reduce Cardiovascular Risk in Coronary Heart Disease Patients With a Recent Acute Coronary Syndrome Event and Type 2 Diabetes Mellitus

AlePrevent = Aleglitazar in Patients With a Recent Acute Coronary Syndrome and Type 2 Diabetes Mellitus

BNP = brain natriuretic peptide

C = cholesterol

CANVAS = Canagliflozin Cardiovascular Assessment Study

CARMELINA = Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk

CAROLINA = Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes

CETP = cholesterylester transfer protein

CI = confidence interval

CV = cardiovascular

CVD = cardiovascular disease

DPP4 = dipeptidyl peptidase-4

Abbreviations (cont)Abbreviations (cont)

ELIXA = Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 [Lixisenatide]

EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome

EXSCEL = Exenatide Study of Cardiovascular Event Lowering

FIELD = Fenofibrate Intervention and Event Lowering in Diabetes

FREEDOM-CVO = Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease-CVO

GLP-1 = glucagon-like peptide-1

HbA1c = hemoglobin A1c

HDL = high-density lipoprotein

HF = heart failure

HR = hazard ratio

LDL = low-density lipoprotein

LEADER = Lower Extremity Arterial Disease Event Reduction

MI = myocardial infarction

NT-proBNP = N-terminal of the prohormone brain natriuretic peptide

OR = odds ratio

Abbreviations (cont)Abbreviations (cont)

PCSK9 = proprotein convertase subtilisin/kexin type 9

PPAR = peroxisome proliferator-activated receptor

PROactive = Prospective Pioglitazone Clinical Trial in Macrovascular Events

RECORD = Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes

REWIND = Researching Cardiovascular Events With a Weekly Incretin in Diabetes

SAVOR-TIMI 53 = Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes Medications- Thrombolysis in Myocardial Infarction

SC = subcutaneous

SGLT2 = sodium-glucose co-transporter 2

T2D = type 2 diabetes

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin

TG = triglyceride

UA = unstable angina

VA CO-OP = Veterans Administration Cooperative Study Group

VA-HIT = Veterans Affairs High-Density Lipoprotein Intervention Trial

ReferencesReferences

1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471.

2. Krall RL. Cardiovascular safety of rosiglitazone. Lancet. 2007;369:1995-1996.

3. US Food and Drug Administration. NDA 21-071 Supplement 022 FDA Meta-Analysis. Advisory Committee Briefing Document. Cardiovascular Safety of Rosiglitazone. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-01-sponsor-backgrounder.pdf Accessed September 18, 2014.

4. Bracken MB. Rosiglitazone and cardiovascular risk. N Engl J Med. 2007;357:937-938.

5. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA. 2007;298:1189-1195.

6. Home PD, Pocock SJ, Beck-Nielsen H, et al; RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373:2125-2135.

References (cont)References (cont)

7. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180-1188.

8. Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289.

9. Erdmann E, Dormandy JA, Charbonnel B, et al; PROactive Investigators. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J Am Coll Cardiol. 2007;49:1772-1780.

10. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375:1875-1884.

References (cont)References (cont)

11. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237-1245.

12. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410-418.

13. Keech A, Simes RJ, Barter P, et al; FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849-1861.

14. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563-1574.

References (cont)References (cont)

15. Ferwana M, Firwana B, Hasan R, et al. Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabet Med. 2013;30:1026-1032.

16. Lincoff AM, Tardif JC, Schwartz GG, et al; AleCardio Investigators. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA. 2014;311:1515-1525.

17. Aubert RE, Herrera V, Chen W, et al. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab. 2010;12:716-721.

18. Ratner RE, Parikh S, Tou C; GALLANT 9 Study Group. Efficacy, safety and tolerability of tesaglitazar when added to the therapeutic regimen of poorly controlled insulin-treated patients with type 2 diabetes. Diabetes Vasc Dis Res. 2007;4:214-221.

References (cont)References (cont)

19. Hamrén B, Ohman KP, Svensson MK, Karlsson MO. Pharmacokinetic-pharmacodynamic assessment of the interrelationships between tesaglitazar exposure and renal function in patients with type 2 diabetes mellitus. J Clin Pharmacol. 2012;52:1317-1327.

20. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294:2581-2586.

21. Sears DD, Hsaio A, Ofrecio JM, et al. Selective modulation of promoter recruitment and transcriptional activity of PPAR? Biochem Biophys Res Commun. 2007;364:515-521.

22. Hausenloy DJ, Wynne AM, Mocanu MM, Yellon DM. Glimepiride treatment facilitates ischemic preconditioning in the diabetic heart. J Cardiovasc Pharmacol Ther. 2013;18:263-269.

References (cont)References (cont)

23. US Food and Drug Administration. Code of Federal Regulations Title 21. Labeling for oral hypoglycemic drugs of the sulfonylurea class. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=310.517. Updated April 1, 2013. Accessed September 18, 2014.

24. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.

25. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326.

26. Scirica BM, Braunwald E, Raz I, et al; for the SAVOR-TIMI 53 Steering Committee and Investigators. Heart Failure, Saxagliptin and Diabetes Mellitus: Observations from the SAVOR - TIMI 53 Randomized Trial. Circulation. 2014 Sep 4. pii: CIRCULATIONAHA.114.010389. [Epub ahead of print]

References (cont)References (cont)

27. White WB, Cannon CP, Heller SR, et al; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335.

28. Zannad F, Cannon C, Cushman W, et al. Alogliptin in patients with type 2 diabetes after acute coronary syndromes: heart failure outcomes and cardiovascular safety in heart failure patients. J Am Coll Cardiol. 2014;63(12_S):A117.

29. ClinicalTrials.gov. A Study on The Potential of Aleglitazar to Reduce Cardiovascular Risk in Patients With Stable Cardiovascular Disease and Glucose Abnormalities. NCT01715818. http://www.clinicaltrials.gov/ct2/show/NCT01715818. Accessed September 18, 2014.

30. Kaushal S, Singh H, Thangaraju P, Singh J. Canagliflozin: a novel SGLT2 inhibitor for type 2 diabetes mellitus. N Am J Med Sci. 2014;6:107-113.

References (cont)References (cont)

31. Pinelli NR, Hurren KM. Efficacy and safety of long-acting glucagon-like peptide-1 receptor agonists compared with exenatide twice daily and sitagliptin in type 2 diabetes mellitus: a systematic review and meta-analysis. Ann Pharmacother. 2011;45:850-860.

32. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.

33. Actos [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013.

34. Wang B, Zhong J, Lin H, et al. Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diabetes Obes Metab. 2013;15:737-749.