This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (155)  • Contact me when this article is cited  Related Content  • Related letters  • Related article  • Similar articles in JAMA  Topic Collections  • Cardiovascular System  • Cardiovascular Disease/ Myocardial Infarction  • Drug Therapy  • Adverse Effects  • Endocrine Diseases  • Diabetes Mellitus  • Congestive Heart Failure/ Cardiomyopathy  • Alert me on articles by topic  Social Bookmarking   What's this?

Steven E. Nissen, MD; Kathy Wolski, MPH; Eric J. Topol, MD

JAMA. 2005;294:2581-2586. Published online October 20, 2005 (doi:10.1001/jama.294.20.joc50147).

Context  Peroxisome proliferator–activated receptors (PPARs) are nuclear transcription factors that modulate gene expression. Therapeutic agents targeting 2 distinct families of PPARs ( and ) have been introduced in the United States. The first dual-PPAR agonist, muraglitazar, was reviewed by a US Food and Drug Administration (FDA) advisory committee on September 9, 2005, resulting in a vote of 8:1 recommending approval for its use in controlling blood glucose levels in patients with type 2 diabetes.

Objective  To evaluate the incidence of death, myocardial infarction (MI), stroke, congestive heart failure (CHF), and transient ischemic attack (TIA) in diabetic patients treated with muraglitazar compared with controls.

Design, Setting, and Participants  The source material for this analysis consisted of documents about phase 2 and 3 clinical trials released under public disclosure laws for the FDA advisory committee meeting. All reviewed trials were prospective, randomized, double-blind, multicenter studies enrolling patients with type 2 diabetes and hemoglobin A_1c levels between 7% and 10%. Patients (N = 3725) were randomized to receive differing doses of muraglitazar, pioglitazone, or placebo as monotherapy or in combination with metformin or glyburide in trials ranging from 24 to 104 weeks.

Main Outcome Measures  The primary outcome was the incidence of death, nonfatal MI, or nonfatal stroke. A more comprehensive composite outcome included these events plus the incidence of CHF and TIA.

Results  In the muraglitazar-treated patients, death, MI, or stroke occurred in 35 of 2374 (1.47%) patients compared with 9 of 1351 (0.67%) patients in the combined placebo and pioglitazone treatment groups (controls) (relative risk [RR], 2.23; 95% confidence interval [CI], 1.07-4.66; P = .03). For the more comprehensive outcome measure that included TIA and CHF, the incidence was 50 of 2374 (2.11%) for muraglitazar compared with 11 of 1351 (0.81%) for controls (RR, 2.62; 95% CI, 1.36-5.05; P = .004). Relative risks for each of the individual components of the composite end point exceeded 2.1 but were not statistically significant. Incidence of adjudicated CHF was 13 of 2374 (0.55%) muraglitazar-treated patients and 1 of 1351 controls (0.07%) (RR, 7.43; 95% CI, 0.97-56.8; P = .053).

Conclusions  Compared with placebo or pioglitazone, muraglitazar was associated with an excess incidence of the composite end point of death, major adverse cardiovascular events (MI, stroke, TIA), and CHF. This agent should not be approved to treat diabetes based on laboratory end points until safety is documented in a dedicated cardiovascular events trial.

Author Affiliations: Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

RELATED LETTERS

Adverse Events Related to Muraglitazar Use in Diabetes
David M. Najman
JAMA. 2006;295(17):1997.
EXTRACT | FULL TEXT  

Adverse Events Related to Muraglitazar Use in Diabetes
David Parra, Cherylyn Beckey, and Thomas Thomas
JAMA. 2006;295(17):1997-1998.
EXTRACT | FULL TEXT  

Adverse Events Related to Muraglitazar Use in Diabetes—Reply
Steven E. Nissen
JAMA. 2006;295(17):1998.
EXTRACT | FULL TEXT  

RELATED ARTICLE

Selling Safety—Lessons From Muraglitazar
James M. Brophy
JAMA. 2005;294(20):2633-2635.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Improving Access to FDA Reviews and Documents
Tuttle et al.
JAMA 2009;302:2204-2204.
FULL TEXT  

Pioglitazone to Reduce Restenosis After Bare-Metal Stent Placement?
Nissen
J Am Coll Cardiol Intv 2009;2:532-533.
FULL TEXT  

Intensive therapy of type 2 diabetes (ACCORD trial) (OCTOBER 2008)
NAJMAN
Cleveland Clinic Journal of Medicine 2009;76:83-83.
FULL TEXT  

Rosiglitazone and pioglitazone in the treatment of diabetes mellitus
Odom et al.
Am J Health Syst Pharm 2008;65:1846-1850.
FULL TEXT  

The Peroxisome Proliferator-Activated Receptor-{gamma} Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-{alpha}-Dependent Manner In Vitro and In Vivo in Mice
Orasanu et al.
J Am Coll Cardiol 2008;52:869-881.
ABSTRACT | FULL TEXT  

Improvement of glycaemic and lipid profiles with muraglitazar plus metformin in patients with type 2 diabetes: an active-control trial with glimepiride
Rubin et al.
Diabetes and Vascular Disease Research 2008;5:168-176.
ABSTRACT  

A Lesson in Moderation: Applying Pharmacodynamics to Clarify the Relationship Between Thiazolidinediones and Adverse Vascular Outcomes in Type 2 Diabetes
Lehmann and Lohray
J Clin Pharmacol 2008;48:999-1002.
FULL TEXT  

Patient-Important Outcomes in Registered Diabetes Trials
Gandhi et al.
JAMA 2008;299:2543-2549.
ABSTRACT | FULL TEXT  

Selective Activation of Peroxisome Proliferator-Activated Receptor (PPAR){alpha} and PPAR{gamma} Induces Neoangiogenesis Through a Vascular Endothelial Growth Factor-Dependent Mechanism
Biscetti et al.
Diabetes 2008;57:1394-1404.
ABSTRACT | FULL TEXT  

Does PERISCOPE Provide a New Perspective on Diabetic Treatment?
Steg and Marre
JAMA 2008;299:1603-1604.
FULL TEXT  

Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy
Turner et al.
NEJM 2008;358:252-260.
ABSTRACT | FULL TEXT  

Accessing FDA Approval Packages and Briefing Documents
Ohmer et al.
The Annals of Pharmacotherapy 2007;41:2071-2072.
FULL TEXT  

Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Trials
Lincoff et al.
JAMA 2007;298:1180-1188.
ABSTRACT | FULL TEXT  

The Avandia Debate
Bloomgarden
Diabetes Care 2007;30:2401-2408.
FULL TEXT  

High-Density Lipoprotein as a Therapeutic Target: A Systematic Review
Singh et al.
JAMA 2007;298:786-798.
ABSTRACT | FULL TEXT  

Peroxisome Proliferator Activated Receptor {alpha}/{gamma} Dual Agonist Tesaglitazar Attenuates Diabetic Nephropathy in db/db Mice
Cha et al.
Diabetes 2007;56:2036-2045.
ABSTRACT | FULL TEXT  

Rosiglitazone and implications for pharmacovigilance
Kazi
BMJ 2007;334:1233-1234.
FULL TEXT  

Rosiglitazone and Cardiovascular Risk
Psaty and Furberg
NEJM 2007;356:2522-2524.
FULL TEXT  

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes
Nissen and Wolski
NEJM 2007;356:2457-2471.
ABSTRACT | FULL TEXT  

Evolution of Peroxisome Proliferator-Activated Receptor Agonists
Chang et al.
The Annals of Pharmacotherapy 2007;41:973-983.
ABSTRACT | FULL TEXT  

Comment on: Boden et al. (2007) Combined Use of Rosiglitazone and Fenofibrate in Patients with Type 2 Diabetes: Prevention of Fluid Retention: Diabetes 56:248-255
Karalliedde and Viberti
Diabetes 2007;56:e3-e3.
FULL TEXT  

Hypertriglyceridemia: its etiology, effects and treatment
Yuan et al.
CMAJ 2007;176:1113-1120.
ABSTRACT | FULL TEXT  

Effects of a Potent and Selective PPAR-{alpha} Agonist in Patients With Atherogenic Dyslipidemia or Hypercholesterolemia: Two Randomized Controlled Trials
Nissen et al.
JAMA 2007;297:1362-1373.
ABSTRACT | FULL TEXT  

Trials That Matter: Rosiglitazone, Ramipril, and the Prevention of Type 2 Diabetes
Nathan and Berkwits
ANN INTERN MED 2007;146:461-463.
FULL TEXT  

Confidentiality Laws And Secrecy In Medical Research: Improving Public Access To Data On Drug Safety
Kesselheim and Mello
Health Aff (Millwood) 2007;26:483-491.
ABSTRACT | FULL TEXT  

Peroxisome Proliferator Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets
Brown and Plutzky
Circulation 2007;115:518-533.
ABSTRACT | FULL TEXT  

Anti-Inflammatory Effects of Pioglitazone and/or Simvastatin in High Cardiovascular Risk Patients With Elevated High Sensitivity C-Reactive Protein: The PIOSTAT Study
Hanefeld et al.
J Am Coll Cardiol 2007;49:290-297.
ABSTRACT | FULL TEXT  

Comparative effects of pitavastatin and probucol on oxidative stress, Cu/Zn superoxide dismutase, PPAR-{gamma}, and aortic stiffness in hypercholesterolemia
Umeji et al.
Am. J. Physiol. Heart Circ. Physiol. 2006;291:H2522-H2532.
ABSTRACT | FULL TEXT  

Peroxisome Proliferator-Activated Receptors at the Crossroads of Obesity, Diabetes, and Cardiovascular Disease
Gilde et al.
J Am Coll Cardiol 2006;48:A24-A32.
ABSTRACT | FULL TEXT  

The FDA and drug safety: a proposal for sweeping changes.
Furberg et al.
Arch Intern Med 2006;166:1938-1942.
ABSTRACT | FULL TEXT  

Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem.
Hayward et al.
ANN INTERN MED 2006;145:520-530.
ABSTRACT | FULL TEXT  

PPAR-{alpha} and -{gamma} agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse
Calkin et al.
Nephrol Dial Transplant 2006;21:2399-2405.
ABSTRACT | FULL TEXT  

Pharmacological Targeting of Adipocytes/Fat Metabolism for Treatment of Obesity and Diabetes
Pilch and Bergenhem
Mol. Pharmacol. 2006;70:779-785.
ABSTRACT | FULL TEXT  

Adverse events related to muraglitazar use in diabetes.
Najman
JAMA 2006;295:1997-1997.
FULL TEXT  

Adverse events related to muraglitazar use in diabetes.
Parra et al.
JAMA 2006;295:1997-1998.
FULL TEXT  

Peroxisome proliferator-activated receptor gamma agonists in renal disease.
Iglesias and Diez
Eur J Endocrinol 2006;154:613-621.
ABSTRACT | FULL TEXT  

Goodbye glitazars?
Conlon
British Journal of Diabetes & Vascular Disease 2006;6:135-137.
ABSTRACT  

Improvement of Glycemic Control, Triglycerides, and HDL Cholesterol Levels With Muraglitazar, a Dual ({alpha}/{gamma}) Peroxisome Proliferator-Activated Receptor Activator, in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy: A double-blind, randomized, pioglitazone-comparative study
Kendall et al.
Diabetes Care 2006;29:1016-1023.
ABSTRACT | FULL TEXT  

The Changing Face of Dyslipidemia Therapies
Rochester and Cooke
Journal of Pharmacy Practice 2006;19:79-93.
ABSTRACT  

Metabolic risk factors, drugs, and obesity.
Padwal et al.
NEJM 2006;354:974-975.
FULL TEXT  

Emerging Therapies Targeting High-Density Lipoprotein Metabolism and Reverse Cholesterol Transport
Duffy and Rader
Circulation 2006;113:1140-1150.
FULL TEXT  

What's new in the other general journals
Tonks
BMJ 2005;331:1293-1294.
FULL TEXT  

Analysis Suggests Risks of Muraglitazar
Goldfarb
DOC News 2005;2:6-6.
FULL TEXT  

Is Muraglitazar Safe for Patients with Type 2 Diabetes?
JWatch General 2005;2005:3-3.
FULL TEXT  

Selling Safety--Lessons From Muraglitazar
Brophy
JAMA 2005;294:2633-2635.
FULL TEXT