PracticeUpdate Cardiology Best of 2018

CONFERENCE COVERAGE 26

Dapagliflozin Reduces Risk of Cardiovascular Death or Hospitalization for Heart Failure in Diabetes But second primary efficacy outcome of major adverse cardiac events failed to achieve significance. T he SGLT2 inhibitor dapagliflozin reduced the risk of cardiovascular death or hospitalization from heart nor decreased MACE. Dapagliflozin was safe and generally well-tolerated.”

“What we see is a modest reduction in MACE, includingmyocardial infarction, cardi- ovascular death, and stroke, limited to those with known atherosclerotic cardiovascular disease, but no benefit in those withmultiple risk factors,” concluded discussant Javed Butler, MD, of the University of Mississippi in Jackson, during a press conference. “How- ever, heart failure hospitalization and renal protection was robust, and was seen across the entire patient population, including pri- mary and secondary prevention.” Dr. Butler advised that it “stands to reason that for patients similar to those that were studied in the SGLT2 inhibitor trials, these drugs should be used for heart failure risk reduction irrespective of their effects on MACE outcomes.” However, for patients “not studied in these trials, for example those without risk factors or with manifest heart failure, who were not robustly studied, further data are needed.” The DECLARE-TIMI 58 trial was funded by AstraZeneca and Bristol-Myers Squibb. www.practiceupdate.com/c/76137

The DECLARE-TIMI 58 trial enrolled 17,160 patients with type 2 diabetes and fol- lowed them for an average of 4.2 years after random assignment to receive either empagliflozin (10 mg daily) or placebo, in addition to standard therapy. Of these patients, 6974 had cardiovascular disease, and 10,186 had more than one risk factor for cardiovascular disease. The mean age of enrolled patients was 64 years. A total of 37% of patients included were female. “There’s something that we can say now about SGLT2 inhibitors that is relatively consistent,” Dr. Wiviott said. “They have moderate benefits on atherosclerotic MACE that appear confined to those with established disease. But they have robust effects on reducing the risk of heart failure and renal outcomes, which do not appear dependent on baseline factors.” He concluded that these “data extend the benefit of SGLT2 inhibitors to a broader population of patients for primary and sec- ondary prevention.”

failure but failed to reduce rates of major adverse cardiovascular events (MACE) among diabetic patients at risk for athero- sclerotic cardiovascular disease, according to the results of the DECLARE-TIMI 58 trial. Patients who received dapagliflozin expe- rienced MACE at a rate of 8.8%, compared with 9.4% in the placebo group (HR 0.93; 95% CI 0.84−1.03, P = .17 for superiority). The rate of cardiovascular death or hos- pitalization for heart failure was 4.9% for patients who received dapagliflozin, com- pared with 5.8% among patients receiving placebo (HR 0.83; 95% CI 0.73−0.95, P = .005 for superiority). These results constitute a split primary out- come overall for the DECLARE-TIMI 58 trial, as the two primary pre-specified efficacy endpoints for the trial were 1) reduction MACE and 2) a composite of cardiovascular death and hospitalization for heart failure. Notably, there was no difference in cardio- vascular death between groups (HR 0.98; 95%CI 0.82−1.17), implying that the significant outcome observed in the second primary efficacy outcome was driven by reduced rates of hospitalization for heart failure. The safety profile associated with dapag- liflozin in the DECLARE-TIMI 58 trial was encouraging and met pre-specified criteria for non-inferiority in major adverse cardiac events (P < .001 for noninferiority); there was no significantly elevated risk of ampu- tation, stroke, or bladder cancer observed among patients receiving empagliflozin rather than placebo. However, rates of genital infections and diabetic ketoacidosis severe enough to warrant regimen discontinuation were significantly elevated among patients receiving dapagliflozin relative to patients receiving placebo. Study presenter Stephen Wiviott, MD, of BrighamandWomen’s Hospital and Harvard Medical School in Boston, said that the safety signals were not a major concern, given that they are “known side effects of this class of agents,” during a press conference. “To summarize, this is the largest SGLT2 inhibitor trial,” Dr. Wiviott continued. “It had the broadest population of primary and sec- ondary prevention patients. Dapagliflozin reduced cardiovascular death and hospital- ization for heart failure. It neither increased

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