STOCKHOLM – The combined risk for cardiovascular death, nonfatal MI, and nonfatal stroke was reduced by 14% when empagliflozin was added to standard care for type 2 diabetes in patients at high cardiovascular risk, compared with standard care alone, in the EMPA-REG OUTCOME study.
This primary composite endpoint was reached by 10.5% of the 4,687 patients treated with the antidiabetic drug versus 12.1% of the 2,333 patients given a placebo, with a hazard ratio (HR) of 0.86 and 95% confidence interval (CI) of 0.74 to 0.99 (P = .04 for superiority and P less than .001 for noninferiority).
The results of the EMPA-REG OUTCOME study, which were reported for the first time at the annual meeting of the European Association for the Study of Diabetes, were published simultaneously Sept. 17 online in the New England Journal of Medicine (doi: 10.1056/NEJMoa1504720).
Dr. Silvio Inzucchi, professor of medicine at Yale University, New Haven, Conn., and the study investigator who presented the key outcome findings, said during the Q&A session that this was the first presentation of these data and that of course there had to be a little bit of caution before making any firm recommendations.
“It is really important that the diabetes and cardiology communities digest [these data], to try to understand them, and that we also have to be cautious here. This was a group of patients with 10 years’ duration of diabetes, all of whom had cardiovascular disease, so we can not necessarily ‘cut and paste’ these expectations to the entirety of the diabetes population.”
Putting the results into context ahead of their presentation in detail at the meeting, Dr. Naveed Sattar of the University of Glasgow, Scotland, said in an interview that there had been four other cardiovascular outcomes trials in this high-risk population of patients with type 2 diabetes and cardiovascular disease – three with DPP-4 inhibitors, namely the SAVOR-TIMI 53 trial, the EXAMINEtrial, and the recent TECOS. The fourth such trial involved a GLP-1 antagonist (ELIXA). All of these had shown modest or small additional reductions in blood glucose levels with the tested drugs versus standard of care or placebo control but had “shown unequivocally no benefit in [reducing] cardiovascular events.” Cardiovascular effects had simply been neutral or no cause for concern.
So to now have a trial with a drug that is potentially more potent at lowering blood glucose than the others and is showing a cardiovascular benefit is potentially game changing, said Dr. Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.
Evidence suggests that empagliflozin does more than just lower blood glucose, said Dr. Sattar, who was not involved in the EMPA-REG trial. “Empagliflozin lowers blood pressure, it reduces weight, so is it these added effects that have conferred this benefit or is it something else?” He added: “Most people’s perception is that it is possibly a class effect, but the data need to be seen.”
Dr. Lars Rydén, professor of cardiology at the Karolinska Institute in Stockholm, singled out the EMPA-REG study as one to watch. Speaking in an interview at the annual meeting of the European Society of Cardiology in London, he said that if the cardiovascular risk reduction touted were true it would make empagliflozin “the only modern glucose-lowering drug to have shown such a capacity.”
EMPA-REG OUTCOME was a phase III, international, multicenter, randomized, parallel group, double-blind cardiovascular safety study of empagliflozin, given at an oral dose of 10 mg/day or 25 mg/day compared to the best usual care in patients with type 2 diabetes who were at increased cardiovascular risk due to the presence of established cardiovascular disease. The study was done at 590 sites in 42 countries across six continents and involved more than 7,000 patients observed over a median of 3.1 years.
Looking at the individual components of the primary composite endpoint, there was no significant difference in terms of the relative risk reduction for MI or stroke. However, the unexpected results were that cardiovascular death, hospitalization for heart failure, and all-cause mortality were all reduced by more than one-third, with respective relative risk reductions of 38% (HR, 0.62; 95% CI, 0.49-0.77; P less than .001), 35% (HR, 0.68; 95% CI, 0.57-0.82; P less than .001), and 32% (HR, 0.65; 95% CI, 0.50-0.85; P = .002).
Even when the results were shown separating out the two doses of empagliflozin, the HR remained highly significant for these and the primary composite endpoint.