For patients with type 2 diabetes who have or are at risk for atherosclerotic cardiovascular disease, do, according to investigators.
A composite measure of major adverse cardiovascular events (MACE), including cardiovascular death, ischemic stroke, or myocardial infarction, was comparable between dapagliflozin and placebo; in contrast, diabetic ketoacidosis occurred more frequently with dapagliflozin, reported lead authorat the American Heart Association scientific sessions.
“As a result of [the] intersection of diabetes, atherosclerotic cardiovascular disease, and heart failure, the importance of determining diabetes therapies that are not only safe but also effective in reducing cardiovascular risk is paramount,” Dr. Wiviott and colleagues wrote in an article published simultaneously in the New England Journal of Medicine.
“Dapagliflozin is a selective inhibitor of sodium–glucose cotransporter (SGLT2) that blocks glucose resorption in the proximal tubule of the kidney and promotes glucosuria,” the investigators wrote. “Other SGLT2 inhibitors have shown favorable cardiovascular effects, including a reduction in the risk of hospitalization for heart failure, predominantly in patients with type 2 diabetes and established cardiovascular disease; they have also been shown to delay the progression of kidney disease.”
The goal of the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) trial was to determine what impact, if any, dapagliflozin has on renal and cardiovascular outcomes in a diverse array of patients with or at risk for atherosclerotic cardiovascular disease. The phase III, double-blind, placebo-controlled, randomized study involved 17,160 adults with type 2 diabetes from 33 countries. Of these, nearly 7,000 patients had atherosclerotic cardiovascular disease and the remaining 10,000 or so patients had multiple risk factors for atherosclerotic cardiovascular disease. Patients were at least 40 years of age, had a creatinine clearance of at least 60 mL/minute, and a HbA1c level between 6.5% and 12.0%. They were randomly assigned to receive either dapagliflozin 10 mg daily or placebo. Every 6 months, patients had laboratory testing with in-person follow-up for safety, clinical response, and adherence; patients were contacted via telephone at the halfway point between appointments (3 months).
The primary safety outcome of the study was major adverse cardiovascular outcomes (MACE: ischemic stroke, myocardial infarction, or cardiovascular death). The trial began with MACE as the sole primary safety outcome, as guided by the Food and Drug Administration, but this changed before completion. “During the trial,” the investigators explained, “compelling external scientific information from thetrial, which evaluated another SGLT2 inhibitor, showed greater benefit with respect to cardiovascular death and hospitalization for heart failure than with respect to MACE.” Therefore, before data were known, the investigators added a second primary outcome: a composite of cardiovascular death or hospitalization for heart failure. The two secondary outcomes were a renal composite (new end-stage renal disease, estimated glomerular filtration rate decrease by at least 40% to less than 60 m/min per 1.73 m2 of body-surface area, or death from renal or cardiovascular disease), and death from any cause.
The primary safety outcome (MACE rate) showed that dapagliflozin was noninferior to placebo (upper boundary of the 95% confidence interval, less than 1.3; P less than .001 for noninferiority). Although the MACE rate was similar between treatment groups (8.8% for dapagliflozin vs 9.4% for placebo; P = .017), the composite rate of cardiovascular death or hospitalization for heart failure was 17% lower for patients receiving dapagliflozin, compared with those who received placebo (4.9% vs 5.8%); this latter finding was attributable mostly to a 27% lower risk of hospitalization, instead of the 2% reduction in cardiovascular death. Seven percent fewer deaths of any kind were observed in the dapagliflozin group (6.2%) than in the placebo group (6.6%). Renal events saw a bigger difference, of 23% (4.3% vs 5.6%).
Statistically significant adverse events seen in more dapagliflozin than placebo patients included diabetic ketoacidosis and genital infection. Dr. Wiviott noted that adverse events favoring hypoglycemia included major hypoglycemia and bladder cancer..
“We did not find that SGLT2 inhibition with dapagliflozin resulted in a lower rate of cardiovascular death or death from any cause than placebo, a finding that contrasts with that in the EMPA-REG OUTCOME trial,” the investigators noted. Apart from possible differences in drugs within the same class, the investigators pointed to more restrictive renal criteria in the DECLARE trial and possible inherent differences between patient populations, among other possible factors.
“…in a broad population of patients with type 2 diabetes [dapagliflozin] did result in a significantly lower rate of cardiovascular death or hospitalization for heart failure than placebo, with additional findings supporting a possible lower rate of adverse renal outcomes,” the investigators concluded.
The DECLARE-TIMI 58 trial was sponsored by AstraZeneca and Bristol-Myers Squibb. Authors reported various financial affiliations with Eisai, Medtronic, Sanofi Aventis, Abbott, Regeneron, and others.
SOURCE: Wiviott et al. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812389