Dapagliflozin in high-risk T2DM reduces hospitalization for HF, but does not reduce death, MI, or stroke (DECLARE-TIMI 58)

Référence

Wiviott SD, Raz I, Bonaca MP, et al, for the DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380(4):347-357.

Sommaire

Dapagliflozin is one of several SGLT2 inhibitors that induce glucosuria to lower blood sugar levels. In the current study, researchers identified patients 40 years or older with T2DM and established cardiovascular disease, or men who were 55 years or older (60 or older for women) with one or more cardiovascular risk factor in addition to age. Patients had to have a hemoglobin A1C level between 6.5% and 12% and creatinine clearance of at least 60 mL/min. After a 4-week to 8-week placebo run-in period, approximately 25% of the patients who were initially enrolled were excluded, largely because they did not meet the laboratory criteria (although the stated purpose of the run-in period in the study protocol document was to identify nonadherent patients). Patients could receive other medications to treat their T2DM at the discretion of their physician. A total of 17,160 patients were randomized to receive dapagliflozin 10 mg or placebo. Groups were balanced, with a mean age of 64 years, a mean body mass index of 32 kg/m2, 41% of patients with cardiovascular disease, and 59% with multiple risk factors. They were contacted regularly and followed up for a median of 4.2 years, and the primary outcome was the composite of cardiovascular death, acute myocardial infarction (MI), or ischemic stroke. There was no difference between groups for the primary outcome, or for secondary individual outcomes of cardiovascular death, all-cause mortality, ischemic stroke, or MI. There were significantly fewer hospitalizations due to heart failure in the intervention group (2.5% vs 3.3%; number needed to treat [NNT] = 125 over 4 years) and fewer patients with progression of renal disease in the intervention group (1.5% vs 2.8%; NNT = 77 over 4 years). The authors highlight the composite outcome of "cardiovascular death or hospitalization for heart failure," an outcome not prespecified in their protocol, and one that makes no sense scientifically as there was no difference in cardiovascular deaths—all of the benefit in this composite outcome was due to fewer heart failure admissions. Nevertheless, this is the featured outcome in the figures and abstract. Patients given dapagliflozin had more genital infections serious enough to discontinue the study medicine or be classified as severe (0.8% vs 0.1%) and more episodes of diabetic ketoacidosis (0.3% vs 0.1%).