Clinical Question

In patients with type 2 diabetes mellitus and cardiovascular (CV) disease, does the addition of empagliflozin (Jardiance) improve outcomes?

Bottom Line

In patients with established CV disease and type 2 diabetes, the addition of empagliflozin to standard therapy reduces all-cause mortality and CV mortality. This is notable because empagliflozin is the only drug other than metformin to demonstrate a mortality benefit, albeit for a fairly narrow group of patients. A dose of 10 mg appears to provide a similar benefit to the 25-mg dose, but with half the risk of genital infections. It is not appropriate to extend these conclusions to all patients with type 2 diabetes, because they are at lower risk of bad outcomes and are unlikely to benefit to the same degree. (Level of Evidence = 1b)

Synopsis

Empagliflozin decreases reabsorption of glucose in the kidneys, leading to greater urinary excretion. In this industry-sponsored trial, adults with type 2 diabetes and known CV disease were randomized to receive empagliflozin, 10 mg; empagliflozin, 25 mg; or placebo. The 7,028 patients were recruited from 590 sites in 42 countries. The mean age of participants was 63 years, 71% were men, and 5% were black. This was a very high-risk group: 75% had coronary artery disease, 23% had a previous stroke, 20% had peripheral arterial disease, and 25% had a coronary artery bypass graft. The other hypoglycemic medications used by patients included metformin (75%), insulin (53%), or a sulfonylurea (43%). Outcomes were adjudicated by a committee masked to treatment assignment, and analysis was by modified intention to treat for all patients who received at least one dose of the study drug.

The primary outcome was a composite of myocardial infarction, stroke, or CV death. Patients were followed for a median of 3.1 years. Results for the two empagliflozin doses were pooled and compared with placebo. The patients in the intervention groups had lower all-cause mortality (5.7% vs. 8.3%; P < .001; number needed to treat [NNT] = 38 over 3.3 years), CV mortality (3.7% vs. 5.9%; P < .001; NNT = 45 over 3.3 years), and hospitalization for heart failure (2.7% vs. 4.1%; P = .002; NNT = 71 over 3.3 years). There were no differences in other outcomes, including myocardial infarction, stroke, coronary revascularizations, or transient ischemic attacks. The pooled dropout rate due to adverse events was 11.5% for the study drug and 13.0% for placebo. There were more episodes of urosepsis or pyelonephritis in the empagliflozin groups (0.8% vs. 0.5%), and far more genital infections (5.0% vs. 1.5% in men; 10.0% vs. 2.6% in women).

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry

Allocation: Concealed

Setting: Outpatient (any)

Reference: ZinmanBWannerCLachinJMet alEMPA-REG OUTCOME InvestigatorsEmpagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med2015; 373( 22): 2117– 2128.