Patients with type 2 diabetes and cardiovascular disease (CVD) who took empagliflozin had lower rates of mortality, including from cardiovascular (CV) events, than those on placebo, an industry-funded study found. Rates of the study's primary outcome (a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke) were 10% in intervention patients (who took either 10 mg/d or 25 mg/d empagliflozin) and 12% in the placebo group. The groups had similar rates of adverse events.
The study, known as the EMPA-REG OUTCOME trial, was published in the Nov. 26, 2015, New England Journal of Medicine and summarized in the October 2015 ACP Diabetes Monthly. The following commentary by Paul Shekelle, MD, FACP, was published in the ACP Journal Club section of the Jan. 19 Annals of Internal Medicine.
The EMPA-REG OUTCOME trial is fascinating but not sufficient to change practice—yet. The problem is clinically important: Prevalence of diabetes is almost 10% in many countries and will increase over the next 10 to 20 years.
The main cause of death in patients with diabetes is macrovascular: cardiac disease. Intensive therapy to lower levels of glycemia decreased microvascular complications in type 2 diabetes, but CVD reduction has not been shown conclusively. Thus, the results of the EMPA-REG OUTCOME trial, which showed that empagliflozin reduced both hemoglobin A1c levels and CV deaths, are potentially important.
So what is holding me back from endorsing the addition of empagliflozin to standard care in patients with diabetes and CVD? First, control of blood glucose levels is almost certainly not the main mechanism of action because benefit occurs far earlier than would be expected from glucose control alone. Second, 23% of these high-risk patients were not receiving statins at baseline, and we don't know the dose for those who were. The effect on CVD deaths of adding empagliflozin to standard care vs use of appropriate high-intensity statin therapy in all patients is worth studying. Third, no dose–response gradient was found. Fourth, although safety outcomes seem favorable, some existing drugs for glucose control and CVD reduction have been withdrawn from the market because of severe adverse events.
The results of the EMPA-REG OUTCOME trial should be replicated, preferably by investigators without close financial ties to the manufacturer, before we know whether we are witnessing the dawn of a new paradigm in CVD risk reduction in diabetes.