First glucose-lowering agent to show CV benefit in outcome trial- Empagliflozin

Empagliflozin is a selective SGLT2 inhibitor that has been approved for T2DM. Empagliflozin also seems to beneficially affect markers of arterial stiffness and vascular resistance, among other effects. Its use has been associated with an increase in LDL and HDL-c.

The EMPA-REG OUTCOME trial evaluated the effect of empagliflozin, as compared with placebo, on CV morbidity and mortality in patients with T2DM at high risk for CV events, who are receiving standard care. 7020 patients were randomised (1:1:1 for empagliflozin 10 mg or 25 mg or placebo once daily) and treated for a median of 2.6 years (median observation time: 3.1 years).
 

• The primary outcome of a composite of death from CV causes, nonfatal myocardial infarction (MI, excluding silent MI), or nonfatal stroke occurred in a significantly lower percentage of patients on empagliflozin (490 of 4687, 10.5%) than in the placebo group (282 of 2333, 12.1%)
• The key secondary outcome of the primary outcome plus hospitalisation for unstable angina also occurred less often in the empagliflozin group (599 of 4687, 12.8%) than in the placebo group (333 of 2333, 14.3%,).
• Risk of CV death was lower with empagliflozin (HR: 0.62, 95%CI: 0.49-0.77, P<0.001), as was all-cause death (HR 0.68, 95%CI: 0.57-0.82, P<0.001) and the risk of hospitalisation for heart failure (HR: 0.65, 95%CI: 0.50-0.85, P=0.002).
• The occurrence of MI or stroke did not differ significantly between treatments (MI: 4.8% vs. 5.4% with placebo, stroke: 3.5% vs. 3.0%).
• Separate analyses of each of the doses yielded very similar but not statistically significant hazard ratios as compared with placebo (primary outcome: 10 mg: HR: 0.85, 95%CI: 0.72-1.01, P=0.07, and 25 mg: HR: 0.86, 95%CI: 0.73-1.02, P=0.009).
• The difference in the glycated haemoglobin level between patients receiving empagliflozin and those on placebo changed from -0.54 % for 10 mg (95%CI: -0.58 to -0.49) and -0.60% for 25 mg, 95%CI: -0.64 to -0.55) at week 12, to -0.24 % for 10 mg (95%CI: -0.40 to -0.08) and -0.36% for 25 mg, 95%CI: -0.51 to -0.20) at week 206.
• The proportions of patients with adverse events (AEs), serious AEs and AEs leading to study drug discontinuation were similar in the treatment groups. Genital infections were more common in the pooled empagliflozin group. While urosepsis was more often reported (0.4 vs. 0.1%) in the empagliflozin-treated patients, there was no imbalance in overall rates of urinary tract infections, complicated urinary tract infection, or pyelonephritis.