Rosiglitazone Revisited: An Updated Meta-analysis of Risk for Myocardial Infarction and Cardiovascular Mortality | Acute Coronary Syndromes | JAMA Internal Medicine | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Nissen  SEWolski  K Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes [published online May 21, 2007].  N Engl J Med 2007;356 (24) 2457- 2471PubMedGoogle ScholarCrossref
 Staff report on GlaxoSmithKline and the diabetes drug Avandia. The United States Senate Committee on Finance Web site. Accessed May 7, 2010
 Benefit-risk assessment of rosiglitazone vs. pioglitazone. The United States Senate Committee on Finance Web site. Accessed May 7, 2010
Home  PDPocock  SJBeck-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 [published online June 6, 2009].  Lancet 2009;373 (9681) 2125- 2135PubMedGoogle ScholarCrossref
Psaty  BMPrentice  RL Variation in event rates in trials of patients with type 2 diabetes.  JAMA 2009;302 (15) 1698- 1700PubMedGoogle ScholarCrossref
Nissen  SE Setting the RECORD straight.  JAMA 2010;303 (12) 1194- 1195PubMedGoogle ScholarCrossref
DeAngelis  CDFontanarosa  PB Ensuring integrity in industry-sponsored research: primum non nocere, revisited.  JAMA 2010;303 (12) 1196- 1198PubMedGoogle ScholarCrossref
Nissen  SE The rise and fall of rosiglitazone.  Eur Heart J 2010;31 (7) 773- 776PubMedGoogle ScholarCrossref
Benbow  AStewart  MYeoman  G Thiazolidinediones for type 2 diabetes: all glitazones may exacerbate heart failure.  BMJ 2001;322 (7280) 236PubMedGoogle ScholarCrossref
Cobitz  AZambanini  ASowell  M A retrospective evaluation of congestive heart failure and myocardial ischemia events in 14,237 patients with type 2 diabetes mellitus enrolled in 42 short-term, double-blind, randomized clinical studies with rosiglitazone.   Pharmacoepidemiol Drug Saf 2008;17 (8) 769- 781PubMedGoogle ScholarCrossref
 Glaxo agrees to post results of drug trials on Web site.  The New York Times Web site. Accessed May 7, 2010Google Scholar
Singh  SLoke  YKFurberg  CD Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis.  JAMA 2007;298 (10) 1189- 1195PubMedGoogle ScholarCrossref
Diamond  GABax  LKaul  S Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death [published online August 6, 2007].  Ann Intern Med 2007;147 (8) 578- 581PubMedGoogle ScholarCrossref
 Briefing document: Division of Metabolism and Endocrine Products and Office of Surveillance and Epidemiology: joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. FDA Web site. Accessed May 7, 2010
Rosen  CJ The rosiglitazone story—lessons from an FDA Advisory Committee meeting [published online August 8, 2007].  N Engl J Med 2007;357 (9) 844- 846PubMedGoogle ScholarCrossref
Nathan  DMBuse  JBDavidson  MB  et al. American Diabetes Association; European Association for Study of Diabetes, Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.  Diabetes Care 2009;32 (1) 193- 203PubMedGoogle ScholarCrossref
Gerstein  HCRatner  RECannon  CP  et al. APPROACH Study Group, Effect of rosiglitazone on progression of coronary atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History trial.  Circulation 2010;121 (10) 1176- 1187PubMedGoogle ScholarCrossref
Gerstein  HCYusuf  SBosch  J  et al. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.  Lancet 2006;368 (9541) 1096- 1105PubMedGoogle ScholarCrossref
Kahn  SEHaffner  SMHeise  MA  et al. ADOPT Study Group, Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy [published online December 4, 2006].  N Engl J Med 2006;355 (23) 2427- 2443PubMedGoogle ScholarCrossref
 Clinical study register. GSK Web site. Accessed May 7, 2010
 Drug approval package: Avandia (rosiglitazone maleate) tablets. FDA Web site. Accessed May 7, 2010
Lebovitz  HEDole  JFPatwardhan  RRappaport  EBFreed  MIRosiglitazone Clinical Trials Study Group, Rosiglitazone monotherapy is effective in patients with type 2 diabetes [published correction appears in J Clin Endocrinol Metab. 2001;86(4):1659 and 2002;2(1):iv].  J Clin Endocrinol Metab 2001;86 (1) 280- 288PubMedGoogle ScholarCrossref
Phillips  LSGrunberger  GMiller  EPatwardhan  RRappaport  EBSalzman  ARosiglitazone Clinical Trials Study Group, Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes [published correction appears in Diabetes Care. 2001;24(5):973].  Diabetes Care 2001;24 (2) 308- 315PubMedGoogle ScholarCrossref
Jones  TASautter  MVan Gaal  LFJones  NP Addition of rosiglitazone to metformin is most effective in obese, insulin-resistant patients with type 2 diabetes.  Diabetes Obes Metab 2003;5 (3) 163- 170PubMedGoogle ScholarCrossref
Fonseca  VRosenstock  JPatwardhan  RSalzman  A Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial [published correction appears in JAMA. 2000;284:1384].  JAMA 2000;283 (13) 1695- 1702PubMedGoogle ScholarCrossref
Bradburn  MJDeeks  JJBerlin  JALocalio  AR Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events.  Stat Med 2007;26 (1) 53- 77PubMedGoogle ScholarCrossref
Sweeting  MJSutton  AJLambert  PC What to add to nothing? use and avoidance of continuity corrections in metaanalysis of sparse data [published correction appears in Stat Med. 2006;25:2700].  Stat Med 2004;23 (9) 1351- 1375PubMedGoogle ScholarCrossref
Sutton  ACooper  NLambert  PJones  DAbrams  KSweeting  M Meta-analysis of rare and adverse event data.  Expert Rev Pharmacoecon Outcomes Res 2002;2367- 369PubMedGoogle ScholarCrossref
Mantel  NHaenszel  W Statistical aspects of the analysis of data from retrospective studies.  J Natl Cancer Inst 1959;22 (4) 719- 748PubMedGoogle Scholar
 Diabetes statistics. American Diabetes Association Web site. Accessed May 7, 2010
 Diabetes facts. World Diabetes Federation Web site. Accessed May 7, 2010
Home  PDPocock  SJBeck-Nielsen  H  et al. RECORD Study Group,  Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis [published online June 5, 2007].  N Engl J Med 2007;357 (1) 28- 38PubMedGoogle ScholarCrossref
Dormandy  JACharbonnel  BEckland  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 (9493) 1279- 1289PubMedGoogle ScholarCrossref
Goldberg  RBKendall  DMDeeg  MA  et al. GLAI Study Investigators, A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia.  Diabetes Care 2005;28 (7) 1547- 1554PubMedGoogle ScholarCrossref
Hsiao  AWorrall  DSOlefsky  JMSubramaniam  S Variance-modeled posterior inference of microarray data: detecting gene-expression changes in 3T3-L1 adipocytes.  Bioinformatics 2004;20 (17) 3108- 3127PubMedGoogle ScholarCrossref
Wilson  KDLi  ZWagner  R  et al.  Transcriptome alteration in the diabetic heart by rosiglitazone: implications for cardiovascular mortality.  PLoS One 2008;3 (7) e2609PubMedGoogle ScholarCrossref
 Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. FDA Web site. Accessed May 7, 2010
June 28, 2010

Rosiglitazone Revisited: An Updated Meta-analysis of Risk for Myocardial Infarction and Cardiovascular Mortality

Author Affiliations

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

Arch Intern Med. 2010;170(14):1191-1201. doi:10.1001/archinternmed.2010.207

Context  Controversy regarding the effects of rosiglitazone therapy on myocardial infarction (MI) and cardiovascular (CV) mortality persists 3 years after a meta-analysis initially raised concerns about the use of this drug.

Objective  To systematically review the effects of rosiglitazone therapy on MI and mortality (CV and all-cause).

Data Sources  We searched MEDLINE, the Web site of the Food and Drug Administration, and the GlaxoSmithKline clinical trials registry for trials published through February 2010.

Study Selection  The study included all randomized controlled trials of rosiglitazone at least 24 weeks in duration that reported CV adverse events.

Data Extraction  Odds ratios (ORs) for MI and mortality were estimated using a fixed-effects meta-analysis of 56 trials, which included 35 531 patients: 19 509 who received rosiglitazone and 16 022 who received control therapy.

Results  Rosiglitazone therapy significantly increased the risk of MI (OR, 1.28; 95% confidence interval [CI], 1.02-1.63; P = .04) but not CV mortality (OR, 1.03; 95% CI, 0.78-1.36; P = .86). Exclusion of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) trial yielded similar results but with more elevated estimates of the OR for MI (OR, 1.39; 95% CI, 1.02-1.89; P = .04) and CV mortality (OR, 1.46; 95% CI, 0.92-2.33; P = .11). An alternative analysis pooling trials according to allocation ratios allowed inclusion of studies with no events, yielding similar results for MI (OR, 1.28; 95% CI, 1.01-1.62; P = .04) and CV mortality (OR 0.99; 95% CI, 0.75-1.32; P = .96).

Conclusions  Eleven years after the introduction of rosiglitazone, the totality of randomized clinical trials continue to demonstrate increased risk for MI although not for CV or all-cause mortality. The current findings suggest an unfavorable benefit to risk ratio for rosiglitazone.