A Balanced Therapeutic
Approach to CV Risk in T2D
What Do We Now Know?
Moderator
Deepak L. Bhatt, MD, MPH
Professor of Medicine, Harvard Medical School
Executive Director of Interventional
Cardiovascular Programs
Brigham & Women’s Hospital Heart and
Vascular Center
Boston, Massachusetts
Panelists
A. Michael Lincoff, MD
Jean-Claude Tardif, MD
Director, C5Research, Cleveland Clinic
Coordinating Center for Clinical Research
Professor of Medicine
Department of Cardiovascular Medicine
Cleveland Clinic Lerner College of
Medicine
Cleveland, Ohio
Director
Montreal Heart Institute Research
Centre
Professor of Medicine
University of Montreal
Montreal, Canada
Learning 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 T2D
• Insulin resistance
• High triglyceride
• Low HDL-cholesterol
• Slightly elevated LDL-cholesterol
– Increased small, dense LDL particle
concentration
• Obesity
CV Events With PPAR-gamma Agonists
Rosiglitazone
Hazard ratio/Odds ratio
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)
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)
0
Better
1
Worse
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 Outcomes
A Systematic Review and Meta-analysis
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
Atherosclerosis
0.88 (0.82-0.95); P = .002
(I2 = 18.6%, Q = 3.7, P = .298)
Jun M, et al. Lancet. 2010;375:1875-1884.[10]
ACCORD Lipid
Hazard Ratios for the Primary Outcome
Simvastatin Simvastatin
Subgroup
+ fenofibrate
+ placebo
HR
P Value for
(95% CI) Interaction
% of event (no. in group)
Overall
10.5 (2765)
11.3 (2753)
.06
Triglyceride – HDL-C combination
TG ≥ 204 mg/dL + HDL-C ≤ 34 mg/dL 12.4 (485)
17.3 (456)
10.1 (2264)
10.1 (2284)
All others
0
Simvastatin +
fenofibrate
better
1
2
Simvastatin
alone
better
• 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
ACCORD Study Group, et al. N Engl J Med. 2010;362:1563-1574.[14]
Pioglitazone
Safety Issues
• Slightly increased risk for bladder
cancera
• Bone fracturesb
• Fluid retention, edema, risk for
decompensation/congestive heart
failurec
a. Ferwana M, et al. Diabet Med. 2013;30:1026-1032[15]; b. Aubert RE, et al. Diabetes Obes Metab.
[7]
RW,
2003;108:2941-2948.
2010;12:716-721[17]; c.Nesto
Lincoff
AM,etetal.al.Circulation.
JAMA. 2007;298;1180-1188.
Pioglitazone Meta-analysis
Heart Failure & MI
End Point
HR (95% CI)
MI
Death/MI
Serious HF
Death/serious HF
0
Pioglitazone better
Lincoff AM, et al. JAMA. 2007;298;1180-1188.[7]
1
2
Control better
Dual PPAR a/g Agonists
Past Development Programs
Phase of
Investigation
Tesaglitazar
Muraglitazar
3
3
Program
Outcome
Reasons for
Termination
Terminated
May, 2006
Increased
creatinine;
uncertain
risk: benefita,b
Data from ~ 3000
patients
Terminated
May, 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]
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
Inclusion Criteria:
Adults > 18 years of age
T2D
Hospitalization for ACS event and randomization up to 12 weeks after index event
Placebo (+ SC)
Aleglitazar 150 g (+ SC)
Superiority: Event-driven (950 primary end point events)
Primary efficacy: Time to 1st 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
Lincoff AM et al. JAMA. 2014;311:1515-1525.[16]
AleCardio
Efficacy and Safety Outcomes
End Point
HR (95% CI)
Primary efficacy
Secondary efficacy
Hospitalization for HF
Gastrointestinal hemorrhage
Bone fracture
0
Aleglitazar better
Lincoff AM et al. JAMA. 2014;311:1515-1525.[16]
1
2
Placebo better
AleCardio
Mean Change From Baseline, %
Glycemic Control and Lipoprotein Effects
30
HbA1c
HDL-C
TG
LDL-C
20
10
0
-10
-20
-30
Lincoff AM et al. JAMA. 2014;311:1515-1525.[16]
Aleglitazar
Placebo
Genes Regulated by Glitazones
Pioglitazone - 52
8
2
4
Activated
(N = 147)
Rosiglitazone - 65 Pioglitazone - 70 Rosiglitazone - 140
38
15
10
5
1
8
56
47
36
70
26
Troglitazone - 122
Troglitazone - 126
Repressed
(N = 179)
The number of genes uniquely regulated by a glitazone is
contained in the nonoverlapping regions of each circle
Sears DD, et al. Biochem Biophys Res Commun. 2007;364:515-521.[21]
Older 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 53
Clinical End Points: Saxagliptin (DPP4 Inhibitor) vs
Placebo
End Point
HR (95% CI)
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
Scirica BM et al. N Engl J Med. 2013;369:1317-1326.[25]
0
1
2
Saxagliptin better
Placebo better
SAVOR-TIMI 53
Hospitalization for Heart Failure Stratified
by NT-proBNP Quartiles
Quartiles of NTproBNP (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. Circulation. 2014 [Epub ahead of print].[26]
SAVOR-TIMI 53
Safety End Points
Saxagliptin
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
End Point
Scirica BM et al. N Engl J Med. 2013;369:1317-26.[25]
EXAMINE
Safety End Points: Alogliptin (DPP-4 Inhibitor) vs Placebo
End Point
HR (95% CI)
Primary end point
Components of primary end point
Death from CV causes
Nonfatal MI
Nonfatal stroke
Principal secondary end point
Other end points
Death from any cause
Death from CV causes
• 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
White WB, et al. N Engl J Med. 2013; 369:1327-1335.
EXAMINE
Heart Failure Outcomes
Outcome
HR (95% CI)
Composite CV outcome
Hospitalization for HF
Composite of CV death and
hospitalization due to HF
CV death
Hospitalization for HF
• Composite CV outcome: first occurrence of all-cause mortality, nonfatal MI and
stroke, urgent revascularization due to unstable angina, and hospitalization for HF
Zannad F, et al. J Am Coll Cardiol. 2014;63(12S).
Mechanism 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 Diabetes
Study
Intervention
Estimated
Enrollment Estimated Duration
Exenatide once weekly vs
placebo
9500
6/2010–3/2017
ITCA 650 (exenatide) vs
placebo
2000
03/2013–07/2018
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
Sitagliptin vs placebo
14,000
12/2008–12/2014
Linagliptin vs glimepiride
6000
10/2010–9/2018
Linagliptin vs placebo
Acarbose vs placebo
8300
7500
07/2013–01/2018
02/2009-10/2014
Canagliflozin vs placebo
4335
12/2009-06/2018
EXSCEL
FREEDOMCVO
LEADER
TECOS
CAROLINA
CARMELINA
ACE
CANVAS
Clinical 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
AlePrevent
Aleglitazar in Patients With Stable CVD
and Glucose Abnormalities
Phase 3B, double-blind, parallel, randomized trial in patients with
stable CVD and glucose abnormalities
Target 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 1st occurrence of CV death, nonfatal MI, or nonfatal stroke
Secondary 1: Time to 1st occurrence of CV death, nonfatal MI, or nonfatal
stroke in subgroups with or without evidence of T2D at baseline
Secondary 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
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 Remarks
• Aggressive lipid management with
– Statins
– Newer agents: PCSK9 inhibitors and CEPT
inhibitors
• Other CV risk factor management
– Obesity
– Hypertension
– Inflammation
• Lifestyle modification
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 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)
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)
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
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 MetaAnalysis. Advisory Committee Briefing Document. Cardiovascular Safety of
Rosiglitazone. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-01sponsor-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)
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)
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 longterm 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)
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)
19. Hamrén B, Ohman KP, Svensson MK, Karlsson MO. Pharmacokineticpharmacodynamic 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)
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=310.51
7. 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)
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)
31. Pinelli NR, Hurren KM. Efficacy and safety of long-acting glucagon-like peptide1 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.