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What Do We Now Know? Moderator What Do We Now Know? Moderator

What Do We Now Know? Moderator - PowerPoint Presentation

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What Do We Now Know? Moderator - PPT Presentation

Deepak L Bhatt MD MPH Professor of Medicine Harvard Medical School Executive Director of Interventional Cardiovascular Programs Brigham amp Womens Hospital Heart and Vascular Center Boston Massachusetts ID: 746245

cardiovascular diabetes type patients diabetes cardiovascular patients type risk death study 2007 med heart 2014 nonfatal trial placebo meta

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Slide1

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 T2DSlide2

Panelists

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

Jean-Claude Tardif, MD

Director

Montreal Heart Institute Research Centre

Professor of Medicine

University of Montreal

Montreal, CanadaSlide3

Learning Objectives

Review the latest evidence on PPAR agonists on the management of cardiovascular risk in patients with type 2 diabetesDiscuss the efficacy and safety results seen in the latest cardiovascular outcomes clinical trials evaluating glucose-lowering therapies in patients with type 2 diabetesSlide4

Metabolic Abnormalities Associated With T2D

Insulin resistanceHigh triglycerideLow HDL-cholesterolSlightly elevated LDL-cholesterol

Increased small, dense LDL particle concentration

ObesitySlide5

CV Events With PPAR-gamma Agonists

RosiglitazoneMeta-analysisa

Myocardial infarction (OR

)

Meta-analysis

a

Cardiovascular death (OR

)

Meta-analysis

b

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

PioglitazonePROactivef 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)

1

0

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

] Slide6

Effect of Fibrates

on CV OutcomesA Systematic Review and Meta-analysisJun 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)Overall

0.90 (0.82-1.00); P = .048

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

Excluding VA CO-OP Atherosclerosis0.88 (0.82-0.95); P = .002(I2 = 18.6%, Q = 3.7, P = .298)Slide7

ACCORD 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

+

f

enofibratebetter10

2

Simvastatinalone

better

OverallTriglyceride – HDL-C combination TG ≥ 204 mg/dL + HDL-C ≤ 34 mg/dL All others10.5 (2765)12.4 (485)10.1 (2264)HR(95% CI)P Value forInteraction% of event (no. in group)

.06

Simvastatin

+ placebo

Simvastatin

+ fenofibrate

SubgroupSlide8

Pioglitazone

Safety IssuesSlightly increased risk for bladder cancer

a

Bone

fractures

b

Fluid

retention, edema, risk for decompensation/congestive heart

failure

c

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]Slide9

Pioglitazone Meta-analysisHeart Failure & MI

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

[7]

MI

Death

/

MI

Serious HF

Death/serious HF

Pioglitazone better

1

02Control better

HR (95% CI)

End PointSlide10

Dual PPAR

a/g AgonistsPast Development Programs

Phase of

Investigation

Program Outcome

Reasons for Termination

Tesaglitazar

3

Terminated

May, 2006

Data from ~ 3000 patients

Increased creatinine; uncertain

risk:

benefit

a,b

Muraglitazar3TerminatedMay, 2006Data from 3725 patientsExcess 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] Slide11

AleCardio

Aleglitazar (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 patients

Treatment duration: at least 2.5 years

Placebo (+ SC)

Aleglitazar 150

g (+ SC)

Primary efficacy: Time to 1

st

occurrence of CV death, nonfatal MI, or nonfatal stroke

Secondary efficacy : CV death, MI, stroke, or hospitalization for ACS

Principal 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 ageT2DHospitalization for ACS event and randomization up to 12 weeks after index eventLincoff AM et al. JAMA. 2014;311:1515-1525.[16]Slide12

AleCardio Efficacy and Safety Outcomes

Primary efficacySecondary efficacy

Hospitalization for HF

Gastrointestinal hemorrhage

Bone fracture

Aleglitazar better

1

0

2

Placebo better

HR (95% CI)

End Point

Lincoff

AM et al.

JAMA

. 2014;311:1515-1525.[16]Slide13

Lincoff

AM et al. JAMA. 2014;311:1515-1525.[16]AleCardioGlycemic Control and Lipoprotein Effects

Mean Change From Baseline, %

HbA

1c

HDL-C TG

LDL-CSlide14

Genes 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

478563626

Pioglitazone - 70Rosiglitazone - 140

Troglitazone - 126

Pioglitazone - 52Rosiglitazone - 65

Activated(N = 147)Troglitazone - 122821543810

70Slide15

Older Antidiabetic Drugs and CV Benefit/Harm

SulfonylureasMay facilitate ischemic preconditioning in the diabetic heart (animal data)aClass warning for possible increased CV mortalityb

Metformin

Potential for risk reduction in MI and death from any cause in overweight

patients

c

Rosiglitazone

Potential increased risk of

MI

d

Class warning for congestive heart

failuree PioglitazonePotential for risk reduction in all-cause mortality, nonfatal MI, or strokefClass warning for congestive heart failurega. 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]Slide16

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 causeDeath from CV causesMIIschemic strokeHospitalization for UAHospitalization for HFHospitalization for coronary revascularizationDoubling of creatinine level, initiation of dialysis, renal transplantation, or creatinine > 6.0 mg/dL (530 μmol/L)Hospitalization for hypoglycemiaHR (95% CI)End Point

0

2

1

Saxagliptin

better

Placebo betterSlide17

Scirica

BM et al. Circulation. 2014 [Epub ahead of print].[26]SAVOR-TIMI 53Hospitalization for Heart Failure Stratified by NT-proBNP Quartiles

Quartiles of NT-proBNP (

pg

/mL)

Saxagliptin

, %

Placebo, %

HR (95% CI)

P

V

alueQ1(5-64)

0.7

0.7

1.04

(0.04-26.30).98Q2(65-141)1.10.41.82(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

)

.02Slide18

Scirica

BM et al. N Engl J Med. 2013;369:1317-26.[25]SAVOR-TIMI 53Safety End Points

End Point

Saxagliptin

N =

8280, %

Placebo

N =

8212, %

P

ValueBone fracture2.92.9

1.00

Cancer

3.9

4.4.15Any pancreatitis0.30.3.77Any liver abnormality0.7

0.8

.

28

Any

hypoglycemia

15.3

13.4

< .001

Major

2.1

1.7

.047

Minor

14.2

12.5

.002Slide19

EXAMINESafety 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 causes Nonfatal MI Nonfatal stroke

Principal secondary end point

Other end pointsDeath from any cause

Death from CV causes Slide20

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)

OutcomeComposite CV outcome Hospitalization for HFComposite of CV death and hospitalization due to HF CV death Hospitalization for HFSlide21

Mechanism of Heart Failure

Fluid retention as evidenced byWeight gain with PPARsReduction in glomerular filtration and creatinine clearance that is reversible on discontinuing PPAR Other as yet unknown mechanismSlide22

Ongoing CVD Outcomes Trials in Type 2 Diabetes

Study

Intervention

Estimated 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

LEADERLiraglutide vs placebo93408/2010–1/2016ELIXALixisenatide vs placebo60006/2010–10/2013

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

12/2009-06/2018Slide23

Clinical Trial Design Considerations

Current trial designsFollow-up not long enough to show CV risk reductionFocus on CV safety and not CV benefitEnrollment of high-risk patients to show occurrence of events quickly to demonstrate noninferiorityFuture 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 diseaseSlide24

AlePrevent

Aleglitazar in Patients With Stable CVD and Glucose AbnormalitiesPhase 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 CVD

Established T2D/evidence of glucose abnormalities

Placebo (+ SC)

Aleglitazar 150

g (+ SC)

Primary: Time to 1

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

st 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] Slide25

Newer Antidiabetic Drugs & CV Risk Reduction

GLP-1 receptor agonistsWeight lossaReduction in blood pressureb

SGLT2

inhibitors

c

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]Slide26

Concluding Remarks

Aggressive lipid management withStatinsNewer agents: PCSK9 inhibitors and CEPT inhibitors Other CV risk factor management

Obesity

Hypertension

Inflammation

Lifestyle modification Slide27

Abbreviations

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 MellitusAlePrevent

=

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 RiskCAROLINA = Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 DiabetesCETP = cholesterylester transfer protein CI = confidence interval CV = cardiovascular CVD = cardiovascular diseaseDPP4 = dipeptidyl peptidase-4Slide28

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 A1cHDL = high-density lipoprotein HF = heart failureHR = hazard ratioLDL = low-density lipoprotein LEADER = Lower Extremity Arterial Disease Event ReductionMI = myocardial infarction NT-proBNP = N-terminal of the prohormone brain natriuretic peptide OR = odds ratioSlide29

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 DiabetesSAVOR-TIMI 53 = Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes Medications- Thrombolysis in Myocardial InfarctionSC = subcutaneous SGLT2 = sodium-glucose co-transporter 2 T2D = type 2 diabetesTECOS = Trial Evaluating Cardiovascular Outcomes With SitagliptinTG = triglycerideUA = unstable angina VA CO-OP = Veterans Administration Cooperative Study GroupVA-HIT = Veterans Affairs High-Density Lipoprotein Intervention TrialSlide30

References

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.Slide31

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.Slide32

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.Slide33

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.Slide34

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.Slide35

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]Slide36

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.Slide37

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.