Elsevier

The Lancet

Volume 370, Issue 9593, 29 September–5 October 2007, Pages 1129-1136
The Lancet

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Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials

https://doi.org/10.1016/S0140-6736(07)61514-1Get rights and content

Summary

Background

The overall clinical benefit of thiazolidinediones (TZDs) as a treatment for hyperglycaemia can be difficult to assess because of the risk of congestive heart failure due to TZD-related fluid retention. Since prediabetic and diabetic patients are at high cardiovascular risk, the outcome and natural history of such risks need to be better understood. We aimed to examine the risk of congestive heart failure and of cardiac death in patients given TZDs.

Methods

We used a search strategy to identify 3048 studies. 3041 were excluded, and we did a systematic review and meta-analysis of the seven remaining randomised double-blind clinical trials of drug-related congestive heart failure in patients given TZDs (either rosiglitazone or pioglitazone). We calculated pooled random-effects estimates of the risk ratios for development of congestive heart failure in patients given TZDs compared with controls. The main outcome measures were development of congestive heart failure and the risk of cardiovascular death.

Findings

360 of 20 191 patients who had either prediabetes or type 2 diabetes had congestive heart failure events (214 with TZDs and 146 with comparators). Results showed no heterogeneity of effects across studies (I2=22·8%; p for interaction=0·26), which indicated a class effect for TZDs. Compared with controls, patients given TZDs had increased risk for development of congestive heart failure across a wide background of cardiac risk (relative risk [RR] 1·72, 95% CI 1·21–2·42, p=0·002). By contrast, the risk of cardiovascular death was not increased with either of the two TZDs (0·93, 0·67–1·29, p=0·68).

Interpretation

Congestive heart failure in patients given TZDs might not carry the risk that is usually associated with congestive heart failure which is caused by progressive systolic or diastolic dysfunction of the left ventricle. Longer follow-up and better characterisation of such patients is needed to determine the effect of TZDs on overall cardiovascular outcome.

Introduction

The prevalence of type 2 diabetes is increasing, and mortality from cardiovascular disease is two-fold to eight-fold higher in people with diabetes than in those without.1 Thiazolidinediones (TZDs) are synthetic selective ligands of the nuclear transcription factor, peroxisome-proliferator-activated receptor γ (PPARγ). TZDs enhance insulin sensitivity2, 3 and are effective agents for control of glycaemia in patients with type 2 diabetes. Both rosiglitazone and pioglitazone have been shown to have a positive cardiometabolic profile that is independent of their effects on glycaemia.4, 5, 6 One trial7 showed that pioglitazone reduced major cardiovascular events in patients with type 2 diabetes; another8 that pioglitazone slowed progression of carotid artery intima-media thickening. However, a recent meta-analysis has questioned the cardiac safety of rosiglitazone.9

The clinical use of TZDs has been limited by the fact that they cause fluid retention, and therefore could potentially lead to development of congestive heart failure in patients with or without pre-existing left ventricular systolic or diastolic dysfunction. However, TZDs do not directly affect left ventricular systolic or diastolic function.10, 11 In 2003, the American Heart Association and American Diabetes Association (AHAADA) issued a consensus statement on the issue of congestive heart failure and provided guidelines for use of TZDs in patients with type 2 diabetes, with or without coexisting cardiovascular disease.12

The overall clinical benefit from use of TZDs in randomised clinical trials might be difficult to gauge because of the risk of congestive heart failure. Moreover, the outcome and natural history of congestive heart failure that is caused by TZD-related fluid retention has not been defined. TZD-related congestive heart failure could either be a drug-related adverse event or a negative outcome that might ultimately affect the survival of patients who receive TZDs. We did a systematic review and meta-analysis of pooled data from randomised trials of TZDs in subjects with prediabetes or type 2 diabetes to assess the risk of development of heart failure and death from cardiovascular causes in patients given TZDs.

Section snippets

Search strategy

Randomised, double-blind, controlled trials of TZDs were eligible for inclusion in our meta-analysis if they reported risk estimates or frequency data for congestive heart failure and cardiovascular death. We excluded non-randomised clinical trials and those in which outcomes were not reported.

We did a systematic review of Embase, MEDLINE, Database of Abstracts of Reviews of Effects (DARE), and the Cochrane Library (from January, 1998, to March, 2007). Figure 1 summarises the flowchart of

Results

We identified 3048 publications from our systematic review. A preliminary review of these studies led us to reject 2387 of them: 634 because they were not original and 1753 because they were not relevant to our aim. Of the 661 remaining studies, 654 were excluded because they either did not randomise patients in their study design (n=394) or did not measure or report outcome data for congestive heart failure or death (n=260). Ultimately, the meta-analysis included seven studies7, 8, 10, 18, 19,

Discussion

In 20 191 patients with prediabetes or type 2 diabetes in seven randomised trials, the risk of congestive heart failure was higher in patients given TZDs than in controls. However, despite the higher incidence of congestive heart failure in patients given TZDs, these patients did not have a higher rate of cardiovascular death. Even with the expected heterogeneity of baseline risk for congestive heart failure in these patients, the final outcome, measured for either congestive heart failure or

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