Presentation of results at the European Association for the Study of Diabetes follows the announcement of topline results in August. For years, researchers and pharmaceutical leaders alike wondered if a diabetes therapy would be shown to have a cardioprotective effect.
Patients who took the SGLT2 inhibitor empagliflozin were less likely to die from cardiovascular (CV) causes and had lower mortality rates overall, according to the full results of the first long-term CV outcomes trial to find a cardioprotective effect in a drug for type 2 diabetes (T2D).
Empagliflozin, marketed as Jardiance by Eli Lilly and Company and Boehringer Ingelheim Pharmaceuticals Inc, was shown to reduce CV-related deaths by 38%, hospitalization for heart failure by 35%, and death from any cause by 32% in results that were presented today at the European Association for the Study of Diabetes in Stockholm, Sweden. The results were simultaneously published in the New England Journal of Medicine, although topline results had been announced in August.
“These results are both novel and exciting for the millions of people living with type 2 diabetes at risk of cardiovascular disease. Addressing the burden of cardiovascular events, including death, is at the core of diabetes care, and until now no single diabetes medication has been associated with a reduction in mortality,” said lead investigator Bernard Zinman, MD, director of the Diabetes Centre, Mount Sinai Hospital, in Toronto, Canada, and professor of medicine at the University of Toronto. “In this study, empagliflozin was shown to prevent 1 out of 3 cardiovascular deaths.”
According to a statement from the drug makers, life expectancy for those with T2D and high CV risk is reduced by 12 years on average, with about 50% of deaths caused by CV disease. The effect of empagliflozin for these patients occurred in addition the benefits of therapy they were already receiving, such as blood pressure and cholesterol-lowering medications.
The randomized controlled trial, known as EMPA-REG OUTCOME, involved 7020 patients who were followed for an average of 3.1 years. Patients were randomized to receive either 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key secondary endpoint was the primary outcome plus hospitalization for unstable angina.
Compared with placebo, empagliflozin showed a significantly lower risk of death from CV causes: 490 of 4687, or 10.5% of patients taking the study drug; compared with 282 of 2333, or 12.1% of patients on placebo. The key secondary endpoint, hospitalization for heart disease, occurred in 599 of 4687 patients (12.8%) taking the study drug compared with 333 of 2333 patients (14.3%) taking placebo.
Cardiovascular outcomes trials became an FDA requirement after several embarrassing episodes in the mid-2000s. In a well-publicized saga, the agency was compelled to restrict sales of rosiglitazone (Avandia) after an NEJM study suggested the therapy increased the risk of heart attacks. Since that time, researchers and pharmaceutical companies alike have wondered whether a therapy would finally be shown to both control glycated hemoglobin (A1C) in patients with T2D and offer some measure of protection from heart disease.
The results involving empagliflozin are the first for the new class of sodium glucose cotransporter-2 (SGLT2) inhibitors, which work by helping excrete excess sugar through the urine. The drug class, which includes canagliflozin (Invokana) and dapagliflozin (Farxiga), has also been shown to have positive effects on blood pressure and produce modest weight loss in some patients. It remains to be seen whether the results presented today will be replicated in the rest of the SGLT2 class.
As the researchers noted, the 2 different doses of empagliflozin produced different metabolic responses, but not different CV outcomes. “Thus,” they wrote, “in clinical practice, the choice of the empagliflozin dose will probably depend primarily on the achievement of metabolic targets and the occurrence of adverse events.”
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes [published online September 17, 2015]. N Engl J Med. 2015; doi:10.1056/NEJMoa1504720.