The safety of thiazolidinediones in older diabetics

December 14, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Toronto Thiazolidinediones (TZDs), a class of diabetes medicines comprising rosiglitizone and pioglitizone, are making headlines again. New research published in the Journal of the American Medical Association (JAMA) has found that older diabetics taking TZDs were at increased risk for heart attack, congestive heart failure, and death.

The safety of the TZDs has been under scrutiny since a meta-analysis published in the New England Journal of Medicine showed a higher rate of cardiovascular death among patients taking rosiglitizone (brand name Avandia). In November, the FDA released an indecisive statement about the coronary disease risk associated with Avandia: “A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared Avandia to placebo, showed Avandia to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 patients), comparing Avandia to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive." (http://www.fda.gov/bbs/topics/NEWS/2007/NEW01743.html) The boxed warning on Avandia now includes a possible increased risk of ischemia or myocardial infarction in patients taking this medicine.  While indecisive, the FDA statement has stressed the need for additional data.

The authors of the JAMA study sought to define the cardiovascular effects of TZDs in elderly patients, and did so by piecing together data from a few different public databases. They linked prescription data from the Ontario Drug Benefit database with hospital visit data from the National Ambulatory Care Reporting System and the Canadian Institute for Health Information Discharge Abstract Database, demographic/death data from the Registered Persons Database, and finally diabetes status from the Ontario Diabetes Database. Cases were defined as those having congestive heart failure, acute myocardial infarction or mortality (all-cause) during the follow-up period. Up to five controls were chosen for each case, matched on age, sex, diabetes duration, and history of cardiovascular disease or history of acute MI or congestive failure.

The final cohort consisted of over 150,000 subjects, with a mean age of 75 and a median follow-up of 4 years. Cases and controls were overall well-matched on baseline characteristics. Cases of death were more likely to be residents of long-term care facilities than were controls, and cases of congestive heart failure had higher Charleson co-morbidity scores. Patients on TZD monotherapy were more likely to have renal disease or cardiovascular disease than subjects on combination oral hypoglycemics or metfomin or a sulfonylurea. Also, given the nature of the Ontario Drug Benefit program, most patients on TZDs had been treated unsuccessfully with other oral hypoglycemics while almost no patients on metformin or sulfonylureas had ever received TZDs.

TZD monotherapy was associated with an increased risk of congetive heart failure (RR 1.6, CI 1.21 to 2.10, p<0.001), myocardial infarction (RR 1.4, CI 1.05 to 1.86, p=0.02), and all-cause mortality (RR 1.29, CI 1.02 to 1.62, p=0.03). TZD combination therapy was also associated with increased risk of congestive heart failure (RR 1.31, CI 1.17 to 1.47, p<0.001) and all-cause mortality (RR 1.24, CI 1.11 to 1.39, p<0.001), but not associated with increased incidence of myocardial infarction (RR 0.96, CI 0.85 to 1.08, p=0.49). Interestingly, when the analyzed the data based on the particular TZD prescribed, this excess risk was only seen in patients taking rosiglitizone. Of note, patients who were started on insulin during the follow-up period also had a higher incidence of congestive heart failure, acute myocardial infaction and death.

This study will certainly fuel the on-going debate about the cardiovascular safety of TZDs, and rosiglitizone in particular. The nature of the Ontario Drug Benefit for TZDs at that time brings a note of caution, as patients on TZDs likely had more difficult to control diabetes in order to qualify for TZD treatment. This study is the first to examine elderly patients taking TZDs, which is a big advance as most clinical trials excluded this patient population.

This study was funded by the Ontario Ministry of Health and Long-term Care

Lipscombe LL, Gomes T, Lévesque LE, Hux JE, Juurlink DN, Alter DA. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. ''JAMA. 2007 Dec 12;298(22):2634-43. ''