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
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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.