Cardiovascular outcomes with sodium–glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: A meta-analysis of placebo-controlled randomized trials

Background The impact of sodium–glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular outcomes in patients with type II diabetes mellitus (DM) is not well established. Methods We searched electronic databases from inception through July 2016 for randomized, placebo-controlled trials, involving SGLT-2 inhibitors. Fixed-effects summary odds ratios (OR) were constructed using Peto model. Results Eighty-one trials with a total of 37,195 patients were included. The mean follow-up was 89 weeks. Compared with placebo, SGLT-2 inhibitors were associated with a lower risk of all-cause mortality (OR 0.72; 95% CI 0.59–0.86; P < 0.001), cardiovascular mortality (OR 0.67; 95% CI 0.53–0.84; P = 0.001), and heart failure (OR 0.67; 95% CI 0.51–0.87; P = 0.003), but a similar risk of myocardial infarction (OR 0.89; 95% CI 0.74–1.09; P = 0.29) and stroke/transient ischemic attack (OR 1.09; 95% CI 0.87–1.37; P = 0.47). The reduction in all-cause mortality was noticed with empagliflozin (OR 0.66; 95% CI 0.54–0.81; P < 0.001), but not with other SGLT-2 inhibitors (OR_{dapagliflozin} 1.37; 95% CI 0.71–2.62; P = 0.35; OR_{canagliflozin} 0.82; 95% CI 0.41–1.68; P = 0.59; OR_{luseogliflozin} 4.6; 95% CI 0.07–284.25; P = 0.47; and OR_{ipragliflozin} 4.73; 95% CI 0.08–283.14; P = 0.46) (P_interaction = 0.19). Potential harm was observed with dapagliflozin on cardiovascular mortality (OR 2.15, 95% CI 0.92–5.04, P = 0.08). Conclusions In patients with type II DM, SGLT-2 inhibitors appeared to reduce both all-cause and cardiovascular mortality, primarily due to reduction in the risk of heart failure. The benefit was only seen with empagliflozin. There was suggestion of potential harm with dapagliflozin, thus future trials are needed to ascertain the cardiovascular safety of other agents in this class.