Are thiazolidinediones associated with an increased risk of heart failure and cardiovascular death?

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SYNOPSISBACKGROUNDThe peroxisome-proliferator-activated receptor γ (PPAR-γ) agonists thiazolidinediones (e.g. pioglitazone and rosiglitazone) are used for glycemic control in patients with type 2 diabetes. Studies have indicated that these agents have a poor cardiovascular safety profile and are reportedly associated with increased fluid retention leading to heart failure (HF).OBJECTIVETo establish whether there is an association between thiazolidinedione use and increased risk of HF and cardiovascular death in patients with prediabetes and type 2 diabetes.DESIGNThis was a meta-analysis of randomized, controlled trials. The authors carried out a search of the MEDLINE and EMBASE databases, the Cochrane Library, the Database of Abstracts of Reviews and Effects, and the databases of the European Society of Cardiology, the AHA, the ACC, and the American Diabetes Association for studies published in English between January 1998 and March 2007. Search terms, used in various combinations, included "congestive heart failure", "CHF", "cardiovascular", "mortality", "cardiac", "heart", "death", "thiazolidinediones", "rosiglitazone", and "pioglitazone". Nonrandomized trials and studies in which outcomes were not reported were excluded. Pooled relative risks [RRs] for cardiovascular death and HF were calculated using the DerSimonian and Laird random effects models.OUTCOME MEASURESThe primary outcome measures were cardiovascular death and development of HF.RESULTSThe database search identified 661 original studies that were relevant to the aim of the meta-analysis, of which 654 were excluded because they did not report on one or both of the outcome measures or because they were not randomized. The final meta-analysis included seven studies, all of which were published between 2005 and 2007. The median trial population size was 4,351 (range 200-5,269), and the mean length of follow-up was 29.7 months (range 12.0-48.0 months). The total meta-analysis population comprised 20,191 patients with prediabetes or type 2 diabetes, 9,360 of whom received thiazolidinediones and 10,831 of whom formed the control group. The mean age of patients was 59.4 years (range 54.7-64.0 years) and the majority of patients were male (64.8%) and white (83.0%). The incidence of HF was higher among patients taking thiazolidinediones than among control patients (2.3% vs 1.4%, RR 1.72, 95% CI 1.21-2.42; P = 0.002). By contrast, there was no significant difference in the RR of cardiovascular death between patients receiving thiazolidinediones and those not receiving this medication (0.7% vs 0.7%, RR 0.93, 95% CI 0.67-1.29; P = 0.68). Analysis of pooled data demonstrated that pioglitazone and rosiglitazone were associated with similarly increased risks of HF.CONCLUSIONThiazolidinedione use (both pioglitazone and rosiglitazone) by patients with prediabetes or type 2 diabetes is associated with an increased risk of HF, but this does not equate to an increased risk of cardiovascular death.

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