乌鸦传媒

STOCKHOLM -- Empagliflozin (Jardiance) became the first type 2 diabetes drug to show a significant cardiovascular benefit in a safety trial, researchers reported here.

The primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke was met by 10.5% of patients on empagliflozin and regular care versus 12.1% of patients in the placebo group (hazard ratio 0.86, 95.02% 0.74-0.99; P=0.04), reported co-author , of Lunenfeld-Tanenbaum Research Institute in Toronto, at the 51st annual meeting of the European Association for the Study of Diabetes. The trial contained more than 7,000 patients.

Of note, the benefit was driven by significant reduction in cardiovascular mortality, overall mortality, and heart failure hospitalizations as there were no differences between the group on the drug, a once-daily sodium-glucose cotransporter 2 (SGLT2) inhibitor used to treat type 2 diabetes, and the control group in terms of rates of myocardial infarction or stroke over the 3 years of the study.

Zinman said treating 39 patients with empagliflozin for 3 years would prevent one cardiovascular death. "That's pretty good."

In the treatment group, the rate of cardiovascular death was 3.7% versus 5.9% in controls, which was a relative risk reduction of 38%. Hospitalization for heart failure was 2.7% versus 4.1% for a relative risk reduction of 35%, and death from any cause was 5.7% versus 8.3%, which worked out to a relative risk reduction of 32%.

The results were simultaneously published in the .

Calling the results dramatic and exciting, Zinman told 乌鸦传媒 "We quite clearly met the safety criteria of non-inferiority."

A secondary composite outcome included the primary outcome, plus hospitalization for unstable angina. There, there was no significant difference between groups (P=0.08). Those in the treatment group experienced an increased risk of genital infection, but there was no risk increase for other adverse events, reported Zinman and colleagues.

The randomized trial of empagliflozin was a post-marketing requirement by the FDA to ensure that it didn't raise the risk of cardiovascular events, and it follows on the heels of other, similar trials but with an important difference: this time there was a clear cardiovascular benefit.

Earlier this year it was reported that lixisenatide (Lyxumia) and saxagliptin (Januvia) neither increased nor decreased cardiovascular risk. EMPA-REG, as the trial of empagliflozin is known, is the first such trial to show cardiovascular superiority, though it's possible that with a long enough follow-up time, other drugs will show a modest benefit, wrote the authors.

Asked about potential guideline changes, Zinman demurred, but did say that he hopes societies will look at the drug and "use the evidence to make guidelines."

, at the University of Copenhagen, said in an interview that it can be frustrating to tell patients, right after they've been diagnosed with diabetes, that they have a condition that increases their risk of cardiovascular disease, only to tell them there are no drugs that can really help decrease the risk.

"This will definitely lift the bar for all glucose-lowering drugs," said Knop.

Patients were treated with either 10 mg or 25 mg of empagliflozin (n=4,687) or with placebo (n=2,333). The primary outcome was calculated by pooling the two groups on different doses of the drug together. Eligible patients in the trial were adults aged 18 or older and had type 2 diabetes and cardiovascular disease, and the trial took place at 590 sites in 42 countries. The trial was designed to continue until the primary event occurred in at least 691 patients.

The patients received no glucose-lowering agents for at least 12 weeks before randomization and had a glycated hemoglobin level of at least 7.0% but no more than 10.0% or were maintained in a range of 7.0% to 10.0% on another agent. All but eight (3%) of the patients were included in the primary analysis, but nearly a quarter of patients on empagliflozin discontinued medication prematurely. The median duration of observation was 3.1 years, and the median duration of treatment was 2.6 years.

The hazard ratios for the primary outcomes were 0.85 (95% CI 0.72-1.01; P=0.07) in the 10 mg group and 0.86 (95% CI 0.73-1.02; P=0.09) for the 25 mg group. "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," since the cardiovascular benefits don't seem to differ significantly between the groups, wrote the authors.

During the oral session, researchers speculated that the CV benefit was probably a class effect, and added that the cardioprotective effects "require explanatory studies."

For 12 weeks -- during which doctors were told not to change glucose-lowering therapy -- the adjusted mean difference in the glycated hemoglobin level between patients receiving empagliflozin and patients receiving placebo was -0.54 percentage points for the 10 mg group (95% CI -0.58 to -0.49) and -0.60 percentage points for the 25 mg group (95% CI -0.64 to -0.55).

"Over the course of the study, empagliflozin, as compared with placebo, was associated with small reductions in weight, waist circumference, uric acid level, and systolic and diastolic blood pressure with no increase in heart rate and small increases in both LDL and HDL cholesterol," wrote the authors.

A higher percentage of patients in the placebo group received additional glucose-lowering medication, anti-hypertensive medication, and anticoagulants during the trial.

The benefits of the drug occurred early in the trial and continued throughout its duration the authors wrote.

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