ORLANDO – The SGLT2 inhibitor empagliflozin reduced the risk of the composite endpoint of hospitalization for heart failure or death due to cardiovascular disease by 34% in patients with type 2 diabetes and prior cardiovascular events in the landmark EMPA-REG OUTCOME trial, Dr. Silvio E. Inzucchi reported at the American Heart Association scientific sessions.
The benefit was consistent regardless of whether or not patients had heart failure at enrollment, added Dr. Inzucchi, professor of medicine and clinical director of the endocrinology section at Yale University in New Haven, Conn.
He presented a prespecified secondary analysis from EMPA-REG OUTCOME that focused on heart failure–related endpoints. He had previously presented the primary outcome in Stockholm at the annual meeting of the European Association for the Study of Diabetes: a 14% relative risk reduction for empagliflozin in the composite of cardiovascular death, MI, or stroke, compared with placebo, driven largely by a 38% relative risk reduction in cardiovascular death.
The phase III, randomized, double-blind study has taken the worlds of cardiology and endocrinology by storm because it has convincingly demonstrated that empagliflozin (Jardiance) is the first glucose-lowering agent that also prevents cardiovascular complications.
“There are 12 different types of medications for lowering blood sugar levels in patients with type 2 diabetes – more than there are for lowering high blood pressure,” he noted. “We have been searching for decades for a diabetes medicine that will not only lower blood sugar but also reduce cardiovascular complications.”
The EMPA-REG OUTCOME trial included 7,020 patients with type 2 diabetes and a history of cardiovascular disease who were followed for a median of 3.1 years. Participants had a high rate of background optimal medical therapy for secondary cardiovascular prevention. They were randomized to empagliflozin at 10 or 25 mg/day or placebo. Results with the two doses of empagliflozin were pooled because the outcomes were so similar.
In addition to the 34% relative risk reduction in the combined endpoint of heart failure hospitalization or heart failure death, the empagliflozin group also experienced a 39% reduction in the composite of heart failure hospitalization or death due to heart failure.
These advantages for empagliflozin held true for all prespecified patient subgroups, including those based upon age, renal function, use of insulin, and background cardioprotective medications, Dr. Inzucchi noted.
Of study participants, 10% already had heart failure at baseline. Their rate of heart failure hospitalization or cardiovascular death was 20.1% on placebo and 16.2% with empagliflozin, a 28% relative risk reduction. In patients without heart failure at enrollment, the rates of this composite endpoint were 7.1% with placebo and 4.5% with the SGLT2 (sodium-glucose transporter 2) inhibitor, for a 37% relative risk reduction.
The only adverse event that occurred more frequently in empagliflozin-treated patients with or without heart failure than in controls was a threefold increase in genital infections. These easily treatable infections are a consequence of empagliflozin’s mechanism of action in reducing blood glucose, which entails increasing urinary excretion, the endocrinologist explained.
Discussant Dr. Allison B. Goldfine called Dr. Inzucchi’s update “really exciting.”
“Up to this time there has been little within the diabetes therapeutic pharmacologic options that has established clear safety, specifically with regard to heart failure. While we may not fully understand the mechanism behind the observed cardiovascular risk reduction, the uniformity of the findings is really remarkably consistent,” said Dr. Goldfine, head of the section of endocrinology at the Joslin Diabetes Center and an endocrinologist at Harvard Medical School, Boston.
“This is very promising,” Dr. David Goff, dean of the Colorado School of Public Health, declared in an interview. “We’ve had a lot of disappointments in the field of cardiovascular disease prevention for patients with diabetes mellitus. I think this medication should change the way we take care of people with diabetes.”
Metformin is widely accepted within endocrinology as the first-line agent for the treatment of type 2 diabetes, Dr. Inzucchi said. But he added that cardiovascular disease is a major problem in patients with diabetes. Heart failure, for example, is present in more than one in five type 2 diabetic patients over age 65.
Asked if he believes the cardiovascular benefits seen with empagliflozin in EMPA-REG OUTCOME are likely to be due to a class effect for SGLT2 inhibitors, Dr. Inzucchi replied that it’s impossible to say, since empagliflozin’s mechanism of cardiovascular benefit is unknown.
“Large randomized trials with hard cardiovascular endpoints are ongoing for the other two SGLT2 inhibitors, canagliflozin and dapagliflozin. Results should be available in 2-3 years. Then we’ll know,” he said.
