A landmark study has demonstrated that the sodium–glucose cotransporter 2 inhibitor empagliflozin cuts the risk of cardiovascular (CV) death in people with type 2 diabetes. It is the first of the new glucose-lowering drugs to demonstrate such a benefit.
In the EMPA-REG OUTCOME study, a total of 7020 people with type 2 diabetes and established CV disease were given empagliflozin 10 mg, 25 mg or placebo once daily, in addition to standard care, and were observed for a median of 3.1 years. During this time, the primary outcome, a composite of death from CV causes, non-fatal myocardial infarction (MI) or non-fatal stroke, occurred in 10.5% of participants in the pooled empagliflozin group compared with 12.1% in the placebo group (hazard ratio, 0.86; 95% confidence interval, 0.74–0.99).
The incidence of stroke and MI was similar between the treatment arms; however, empagliflozin recipients had a significantly lower risk of CV death (3.7% vs. 5.9%; relative risk reduction, 38%), hospitalisation for heart failure (2.7% vs. 4.1%; relative risk reduction, 35%), and all-cause death (5.7% vs. 8.3%; relative risk reduction, 32%). As would be expected, empagliflozin was associated with a higher rate of genital infections (6.4% vs. 1.8%); however, the rates of other adverse events were similar between the two treatments.
The authors note that the two doses of empagliflozin were similar in terms of mortality outcomes; however, there were minor differences in metabolic parameters. Regarding glycaemic control, after adjustment for confounders such as baseline HbA1c, compared with placebo, HbA1c was reduced by 6 mmol/mol (0.54%) with empagliflozin 10 mg and by 7 mmol/mol (0.60%) with the 25 mg dose after 12 weeks of treatment. After 206 weeks, the differences had fallen to 3 mmol/mol (0.24%) and 4 mmol/mol (0.36%), respectively. Empagliflozin was associated with small reductions in CV risk factors, including weight, waist circumference, uric acid level and blood pressure, with no significant difference in LDL or HDL cholesterol.
Commenting on the study, which drew rounds of applause as it was presented at the European Association for the Study of Diabetes 2015 Meeting, senior study author Silvio Inzucchi (Yale Diabetes Center, New Haven, CT, USA) said: “Empagliflozin is reducing death, the ultimate outcome. This is a first in my lifetime – a diabetes drug trial that has shown improved outcomes in high-risk cardiovascular patients.”
Professor Inzucchi admits to being surprised by these positive results and is even on record as predicting that the results would be neutral. When asked why he thought the drug had this effect, he said: “A lot of it is speculation and it’s very challenging to come up with an answer… a possibility is maybe, by doing a little of this and a little of that, you do right by patients. Weight goes down a little, blood pressure goes down a little, glucose goes down a little, and [the drug doesn’t] result in hypoglycemia. So maybe the quadruple benefit of lower blood pressure, weight and glucose, without hypoglycemia, can somehow add up and lead to a benefit. We need help from the cardiology community and scientists to really hash through this data.”
These findings were first presented at the 51st European Association for the Study of Diabetes Annual Meeting, and can be read in full in the New England Journal of Medicine here.
