Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials

Background Some glucose-lowering drugs or strategies adversely affect cardiovascular outcomes. We aimed to assess the extent to which glucose lowering by various drugs or strategies increases the risk of heart failure in patients with or at risk for type 2 diabetes, and to establish whether risk is associated with achieved differences in glycaemia or weight control. Methods We searched Ovid Medline, the Cochrane Library, and meeting abstracts up to Feb 20, 2015, for large randomised controlled trials of glucose-lowering drugs or strategies that assessed cardiovascular outcomes. The primary endpoint was incidence of heart failure. We derived pooled risk ratios (RRs) with random-effects models. Findings We included data from 14 trials, with mean duration 4.3 (2.3) years, comprising 95 502 patients, of whom 3907 (4%) patients developed a heart failure event. Glucose-lowering drugs or strategies were associated with a 0.50% (SD 0.33) reduction in HbA(1c) and a 1.7 kg (2.8) weight gain. Overall, glucose-lowering drugs or strategies increased the risk of heart failure compared with standard care (RR 1.14, 95% CI 1.01-1.30; p=0.041). The magnitude of this effect varied dependent on the method of glucose lowering (p for interaction=0.00021). Across drug classes, risk was highest with peroxisome proliferator-activated receptor agonists (RR 1.42, 95% CI 1.15-1.76; six trials), intermediate with dipeptidyl peptidase-4 inhibitors (1.25, 1.08-1.45; two trials), and neutral with insulin glargine (0.90, 0.77-1.05; one trial). Target-based intensive glycaemic control strategies (RR 1.00, 95% CI 0.88-1.13; four trials) and intensive weight loss (0.80, 95% CI 0.62-1.04; one trial) were also not associated with development of heart failure. Meta-regression analysis showed that for every 1.0 kg of weight gain associated with glucose-lowering drugs or strategies, there was a 7.1% (95% CI 1.0-13.6) relative increase in the risk of heart failure compared with standard care (p=0.022). Interpretation Compared with standard care, glycaemic lowering by various drugs or strategies might increase the risk of heart failure, with the magnitude of risk dependent on the method of glucose lowering and, potentially, weight gain.