Rosiglitazone,Myocardial Ischemic Risk,and Recent Regulatory Actions

Abstract

Spanish

French

Objective:

To review the evidence surrounding rosiglitazone and ischemic cardiovascular risk and discuss the Food and Drug Administration (FDA) decision to revise safety information and restrict access to the drug.

Data Sources:

A literature search was conducted through MEDLINE (1950-January 2012), PubMed (1966-January 2012), and International Pharmaceutical Abstracts (1970-December 2011) using the search terms rosiglitazone and cardiovascular risk. Regulatory documents from the FDA and the Center for Drug Evaluation and Research, as well as reference citations from publications identified, were reviewed.

Study Selection and Data Extraction:

All articles in English identified from the data sources were evaluated for inclusion.

Data Synthesis:

Literature regarding rosiglitazone and ischemic cardiovascular risk has shown inconsistent results. Meta-analyses by the FDA, GlaxoSmithKline, and several independent research groups suggest an increased risk for myocardial infarction (MI), while others have not. Long-term, controlled trials not designed to evaluate cardiovascular outcomes did not find a significant increase in cardiovascular events and had low event rates overall. The RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes In Oral Agent Combination Therapy for Type 2 Diabetes) trial is the only prospective randomized trial to date designed to evaluate cardiovascular outcomes of rosiglitazone; the results were limited because of issues with study design and event adjudication. The only direct comparisons between rosiglitazone and pioglitazone are observational studies in which pioglitazone had a more favorable MI risk profile.

Conclusions:

Data involving rosiglitazone and an association with ischemic cardiovascular risk have yielded variable results. The FDA made the decision to restrict access to rosiglitazone in September 2010 by requiring GlaxoSmithKline to submit a risk evaluation and mitigation strategy (REMS). Drug labeling was revised in February 2011, and the rosiglitazone REMS program took full effect in November 2011.

Keywords

cardiovascular risk risk evaluation and mitigation strategy (REMS)rosiglitazone

Get full access to this article

View all access options for this article.

References

Top 200 drugs by sales, www.drugs.com/top200.html (accessed 2011 Jun 8).

Shah

, Mortori

, Krumholz

, Tu

, Alexander

, Jackevicius

. Responding to an FDA warning—geographic variation in the use of rosiglitazone. N Engl J Med 2010;363:2081–4.

European Public Access Reports, www.ema.europa.eu (accessed 2011 Jun 8).

Product information. Avandia (rosiglitazone). Research Triangle Park, NC: GlaxoSmithKline, February 2011.

Kaul

, Boiger

, Herrington

, Giugliano

, Eckel

. Thiazolidinedione drugs and cardiovascular risks. A science advisory from the American Heart Association and American College of Cardiology Foundation. Circulation 2010;121:1868–77.

Khanderia

, Pop-Busui

, Eagle

. Thiazolidinediones in type 2 diabetes: a cardiology perspective. Ann Pharmacother 2008;42:1466–74. DOI 10.1345/aph.1K666

Chiquette

, Ramirez

, DeFronzo

A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med 2004;164:2097–104.

Nest

, Bell

, Bonow

. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation 2003;108:2941–8.

Loke

, Singh

, Furberg

. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 2009;180:32–9.

10.

Zhang

, Zhang

, Kohan

, Nelson

, Gonzalez

, Yang

Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention. Proc Natl Acad Sci U S A 2005;102:9406–11.

11.

Product information. Actos (pioglitazone). Deerfield, IL: Takeda Pharmaceuticals America, Inc., January 2011.

12.

Centers for Disease Control and Prevention. National diabetes fact sheet: complications of diabetes in the United States, 2011. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf (accessed 2011 May 3).

13.

Haffner

, Legto

, Ronnemaa

, Pyorala

, Laakso

Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–34.

14.

Nissen

, Wolski

Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71.

15.

Singh

, Loke

, Furberg

. Long-term risk of cardiovascular events with rosiglitazone. JAMA 2007;298:1189–95.

16.

Diamond

, Bax

, Kaul

Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med 2007;147:578–81.

17.

FDA briefing document: advisory committee meeting July 30th 2007 to discuss cardiovascular ischemic events with Avandia, www.fda.gov.ohrms/dockets/ac/07/briefing/2007-4308b1-02-FDA-backgrounder.pdf (accessed 2011 May 2).

18.

Advisory committee briefing document: cardiovascular safety of rosiglitazone. www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-01-sponsor-backgrounder.pdf (accessed 2011 May 2).

19.

Shuster

, Jones

, Salmon

. Fixed vs random effects meta-analysis in rare event studies: the rosiglitazone link with myocardial infarction and cardiac death. Stat Med 2007;26:4375–85.

20.

Cobitz

, Zambanini

, Sowell

. A retrospective evaluation of congestive heart failure and myocardial ischemia events in 14237 patients with type 2 diabetes mellitus enrolled in 42 short-term, double-blind, randomized clinical studies with rosiglitazone. Pharmacoepidemiol Drug Saf 2008;17:769–81.

21.

Dormany

, Charbonnel

, Eckland

. 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;366:1279–89.

22.

Goldberg

, Kendall

, Deeg

. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547–54.

23.

Loke

, Kwok

, Singh

Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. BMJ 2011;342:d1309.

24.

Mannucci

, Monami

, Bari

. Cardiac safety profile of rosiglitazone: a comprehensive meta-analysis of randomized clinical trials. Int J Cardiol 2010;143:135–40.

25.

Nissen

, Wolski

Rosiglitazone revisited: an updated meta-analysis on risk for myocardial infarction and cardiovascular mortality. Arch Intern Med 2010;170:1191–201.

26.

FDA briefing information, Avandia (rosiglitazone maleate) tablets, for the July 13-14, 2010 joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf (accessed 2011 May 11).

27.

GlaxoSmithKline briefing information, Avandia (rosiglitazone maleate) tablets, for the July 13-14, 2010 joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm218491.htm (accessed 2011 May 11).

28.

Dargie

, Hildebrandt

, Riegger

GAJ

. A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with NYHA class I or II heart failure. J Am Coll Cardiol 2007;49:1696–704.

29.

Lautamaki

, Airaksinen

, Seppanen

. Rosiglitazone improves myocardial glucose uptake in patients with type 2 diabetes and coronary artery disease: a 16-week randomized, double-blind, placebo-controlled study. Diabetes 2005;54:2787–94.

30.

GlaxoSmithKline clinical trial registry, www.gsk-cMcalstudyregister.com/quick-search-list.jsp?tab=results&phase=All&studyType=All&population=AU&marketing=All&status=All&country=All&item=rosiglitazone&letterrange=Q-U&type=Compound (accessed 2012 Jan 17).

31.

Richter

, Bandeira-Echtler

, Bergerhoff

. Rosiglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007;3:CD006063. DOI 10.1002/14651858.CD006063.pub2

32.

Gerstein

, Yusuf

, Bosch

. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096–105.

33.

Kahn

, Haffner

, Heise

. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427–43.

34.

Home

, Pocock

, Beck-Nielson

. Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med 2007;357:28–38.

35.

Home

, Pocock

, Beck-Nielson

. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009;373:2125–35.

36.

MacDonald

, Petrie

, Home

. Incidence and prevalence of unrecognized myocardial infarction in people with diabetes. Diabetes Care 2011;34:1394–6.

37.

Gelperin

, Zhou

, Graham

. Systematic review of controlled epidemiologic studies of cardiovascular risk in patients treated with rosiglitazone or pioglitazone. OSE RCM #2010-277. June 15, 2010. Presented at the Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, July 13-14, 2010. www.fda.gov/AdvisoryCommittees/Commit-teesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm191113.htm (accessed 2011 Jun 12).

38.

Graham

, Ouellet-Hellstrom

, MacCurdy

. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010;304:411–8.

39.

FDA adds boxed warning for heart-related risks to anti-diabetes drug Avandia. November 14, 2007. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109026.htm (accessed 2011 May 10).

40.

Thiazolidinedione intervention with vitamin D evaluation. Clinical Trials Registry Identifier NCT00879970. http://clinicaltrials.gov/ct2/show/NCT00879970 (accessed 2011 Jun 28).

41.

Lincoff

, Wolski

, Nicholls

, Nissen

Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a metaanalysis of randomized trials. JAMA 2007;298:1180–8.

42.

US Department of Health and Human Services, Food and Drug Administration, and Center for Drug Evaluation and Research. Guidance for industry diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. December 2008.

43.

The TIDE trial investigators. Design, history, and results of the Thiazonlidine Intervention with Vitamin D Evaluation (TIDE) randomised controlled trial. DIabetologia 2012;55:36–45. DOI 10.1007/s00125-011-2357–4.

44.

Medication guide. Avandia (rosiglitazone maleate tablets). GlaxoSmithKline 2011. www.fda.gov/downloads/Drugs/DrugSafety/ucm085922.pdf (accessed 2011 May 17).

45.

Woodcock

Decision on continued marketing of rosiglitazone. September 22, 2010. www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM226959.pdf (accessed 2011 May 10).

46.

EDA drug safety communication: updated Risk Evaluation and Mitigation Strategy (REMS) to restrict access to rosiglitazone-containing medicines including Avandia, Avandamet, and Avandaryl. May 18, 2011. wwwfda.gov/Drugs/DrugSafety/ucm255005.htm (accessed 2011 May 19).

47.

Risk Evaluation and Mitigation Strategy (REMS). NDA 21-071 AVANDIA (rosiglitazone maleate) Tablets, NDA 21-410 AVANDAMET (rosiglitazone maleate and metformin hydrochloride) Tablets, NDA 21-700 AVANDARYL (rosiglitazone maleate and glimepiride) Tablets. Research Triangle Park, NC: GlaxoSmithKline, May 2011.