Hernandez et al. performed a systematic review and meta-analysis 1 of placebo-controlled RCTs evaluating the effect of rosiglitazone or pioglitazone (TZD) on investigator-reported heart failure (HF) and edema. 29 trials (n = 20254) were evaluated. TZDs were significantly associated with HF (TZD 360/6807 [5.3%] vs placebo 234/6 328 [3.7%], OR 1.59; 95% CI 1.34, 1.89; p<0.00001): NNH 63 in this patient group. The risk of HF tended to be higher with rosiglitazone than with pioglitazone (2.73 [95% CI 1.46, 5.10] vs 1.51 [1.26, 1.81]; p = 0.06). TZDs were associated with a similar risk of serious/severe HF (OR 1.47; 95% CI 1.16, 1.87; p = 0.002). Use of TZDs was also associated with edema (OR 2.04; 95% CI 1.85, 2.26; p<0.00001). HF and edema risks were consistent using Peto and random effects models. Risks of HF were significantly higher for the subgroups of trials including patients with or at high risk for type 2 DM, and for the subgroup of trials with ≥12 months of follow-up. Meta-regression analysis showed that trials with lower overall baseline risk had higher HF risks.
In placebo-controlled trials of adult patients with or at high risk for type 2 DM, TZD therapy is significantly and consistently associated with a higher risk of HF. The risk of serious/severe HF is also increased with the use of TZDs.
In a multicentre, open-label study 2, Komajda et al. randomized 4447 people with type 2 diabetes on metformin or sulfonylurea monotherapy with a mean HbA1c of 7.9% to add-on rosiglitazone (n. 2220) or to a combination of metformin and sulfonylurea (n . 2227) and followed them over 5.5 years on average.
In the rosiglitazone group, the risk of HF death or hospitalization was doubled: HR 2.10 (95% CI, 1.35-3.27): the excess HF event rate was 2.6 (1.1-4.1) per 1000 person-years. An excess in HF deaths was observed (10 vs. 2), including four HF deaths as first HF events. By contrast, there was no increase in cardiovascular mortality or hospitalization (HR 0.99, 95% CI, 0.85-1.16) or in cardiovascular deaths (60 vs. 71). Independent predictors of HF were rosiglitazone assignment, age, urinary albumin: creatinine ratio,body mass index, and systolic blood pressure at baseline. A history of previous cardiovascular disease was not predictive of HF. Duration of HF hospitalization and rate of HF re-hospitalization were similar in the two groups.
These findings confirm the increased risk of HF events in people treated with rosiglitazone and support the recommendation that this agent should not continue to be used in people developing symptomatic HF while using the medication.
To evaluate the effect of pioglitazone in people with insulin resistance, pre-diabetes and type 2Diabetes, Liao et al. conducted a systematic review and meta-analysis of randomised, controlled trials 3.
Nine trials with 12 026 participants were enrolled in the meta-analysis. Pioglitazone therapy was associated with a lower risk of major adverse cardiac events (MACE) in patients with pre-diabetes or insulin resistance (RR 0.77, 95% CI 0.64 to 0.93), and diabetes (RR 0.83, 95% CI 0.72 to 0.97). Risks of heart failure (RR 1.32; CI 1.14 to 1.54), oedema (RR, 1.63; CI 1.52 to 1.75) and weight gain (RR 1.60; CI 1.50 to 1.72) increased in pioglitazone group.
It was concluded that pioglitazone was associated with reduced risk of MACE in people with insulin resistance, pre-diabetes and diabetes mellitus. However, the risks of heart failure, oedema and weight gain were increased.
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