Empagliflozin’s effects independent of CVD risk factors

LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.

The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA_1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

^{Sara Freeman/Frontline Medical News}

Dr. David Fitchett

“EMPA-REG OUTCOME was the first diabetes outcome trial to show a reduction in the primary cardiovascular endpoint,” Dr. Fitchett, a cardiologist on the staff of St. Michael’s Hospital, University of Toronto, said. “It was designed as a safety study, but the statistical analysis allowed for an efficacy analysis once safety had been proven.”

EMPA-REG OUTCOME was an international, multicenter, phase 3, randomized, double-blind, placebo-controlled trial set up to look at the effects of a once-daily dose of empagliflozin (Jardiance) versus placebo on CV events in 7,020 adults with type 2 diabetes with established CV disease. Empagliflozin (10 mg or 25 mg) or placebo was given in addition to the standard of care, with the design stipulating that glucose-lowering treatment should be unchanged for the first 3 months.

The trial continued until an adjudicated primary outcome event, defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, had occurred in at least 691 patients. This three-point major cardiovascular outcome (MACE) occurred in 10.5% of patients treated with empagliflozin and in 12.5% of those who had been given placebo, with a 14% reduction overall (HR, 0.86; 95% CI, 0.74–0.99; P = .04). Almost all of this benefit was due to the reduction in CV deaths, Dr. Fitchett noted, which in turn drove the reduction in all-cause mortality.

The question, then, was how did empagliflozin have this apparent cardiovascular effect? Seeking an answer, the core EMPA-REG OUTCOME investigators looked to see if it could be explained by changes in blood pressure, LDL cholesterol, or HbA_1c level, as small reductions had been seen in the main trial. Cox proportional analyses were performed to see how controlling for each of these might affect the results. In these analyses, control of blood pressure was defined as achieving a systolic value of less than 140 mm Hg and a diastolic value of less than 90 mm Hg; control of LDL cholesterol as a value of less than 100 mg/dL, and control of HbA_{1c level} as a value below 7.5%.

Comparing baseline values to the last recorded values, the proportions of patients who achieved control of HbA_1c with empagliflozin were a respective 26.7% and 46.7% versus 25.5% and 34% for placebo. LDL cholesterol was controlled in 70.6% and 68.7%, respectively, with empagliflozin and in 72.9% and 70% with placebo. The proportions of patients who achieved control of HbA_1c, LDL cholesterol, and blood pressure were 12.6% and 21.8% for empagliflozin and 11.7% and 16.7% for placebo.*

The latest findings “suggest that the mortality reductions in the EMPA-REG OUTCOME trial were not driven by control of these standard cardiovascular risk factors during the trial,” Dr. Fitchett concluded.

In a separate poster presentation at the meeting, EMPA-REG OUTCOME investigators reported that empagliflozin also reduced heart failure outcomes, regardless of blood pressure, LDL cholesterol, or HbA₁c control. Hazard ratios for hospitalization for heart failure with or without CV death were 0.64-0.67 (95% CIs, 0.49–0.87). Other subanalyses from the study showed that neither baseline HbA_1c nor change in HbA_1c predicted the reduction in CV deaths with empagliflozin and that background glucose-lowering treatment – metformin or sulfonylurea use – did not change the results.

The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.

*This article was updated Sept. 28, 2017.