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The Questions Continue About Thiazolidinediones’ Safety

A new meta-analysis shows an elevated risk for congestive HF but no increase in cardiovascular death rate with either rosiglitazone or pioglitazone

Thiazolidinediones (TZDs) not only improve glycemic control as measured by lowered HbA_1C levels but also have an independently positive cardiometabolic profile. However, none of the trials that established these benefits was designed or powered to detect TZDs’ effects on MI, congestive heart failure, or cardiovascular death rates. In May 2007, a meta-analysis of results from 42 trials (including unpublished as well as published data) uncovered evidence of adverse cardiovascular outcomes with rosiglitazone (Journal Watch Cardiology May 21 2007). A recently published interim analysis of an ongoing phase III trial of rosiglitazone (Journal Watch Cardiology Jun 6 2007) showed low and comparable rates of MI and death, but double the HF incidence seen with other diabetes drugs.

In a new meta-analysis of seven published, randomized, controlled trials that compared TZDs with standard oral antidiabetic drugs or placebo, investigators pooled risk estimates of cardiovascular outcomes in 20,191 patients randomized to either rosiglitazone (14,491) or pioglitazone (5700) who had either prediabetes or type 2 diabetes. Most patients did not have congestive HF or evidence of LV dysfunction at study entry. Trial durations were short (between 12 and 48 months).

Significantly more TZD recipients than controls developed congestive HF (2% vs. 1.4%), and increased HF risk was independent of a wide range of cardiac risk factors. An absence of heterogeneity across studies indicated a class effect. The risk for cardiovascular death was not greater in TZD recipients than in controls.

Comment: These findings suggest that the increased rate of congestive heart failure seen across these studies (1) seems to be a class effect of thiazolidinediones (although considerably less data on pioglitazone than on rosiglitazone were included in the analysis), and (2) was not associated with an increased risk for cardiovascular death. Whether, as the authors suggest, TZD-related fluid retention is a more benign cause of congestive HF than other causes is a questionable hypothesis that cannot be addressed by such short-term trials. This study is also limited by the exclusion of the many unpublished trials that were reported in the earlier meta-analysis, and it confirms once more that trialists continue to err in relying on surrogate instead of patient-important outcomes. As editorialists in three accompanying pieces comment, TZDs’ role in current and future medical practice is doubtful at best.

— Beat J. Meyer, MD

Published in Journal Watch Cardiology September 28, 2007

Citation(s):

Lago RM et al. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: A meta-analysis of randomised clinical trials. Lancet 2007 Sep 29; 370:1129.

• Medline abstract (Free)

Cleland JGF and Atkin SL. Thiazolidinediones, deadly sins, surrogates, and elephants. Lancet 2007 Sep 29; 370:1103.

• Medline abstract (Free)

Montori VM et al. Patient-important outcomes in diabetes — time for consensus. Lancet 2007 Sep 29; 370:1104.

• Medline abstract (Free)

Ensuring drug safety: Lessons from the thiazolidinediones. Lancet 2007 Sep 29; 370:1101.

• Medline abstract (Free)