Principal Findings:

The primary outcome of major adverse cardiac events (MACE) for dapagliflozin vs. placebo: 8.8% vs. 9.4%, hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.84-1.03, p < 0.001 for noninferiority; p = 0.17 for superiority

Secondary outcomes for dapagliflozin vs. placebo:

• Reduction in HbA1c with dapagliflozin: 0.42%
• CV death or heart failure (HF) hospitalization: 4.9% vs. 5.8%, p = 0.005
• HF hospitalization: 2.5% vs. 3.3%, p < 0.005
• All-cause mortality: 6.2% vs. 6.6%, p > 0.05
• >40% decrease in GFR, end-stage renal disease, or death due to renal or CV causes: 4.3% vs. 5.6%, p < 0.05
• Diabetic ketoacidosis: 0.3% vs. 0.1%, p = 0.02
• Genital infections: 0.9% vs. 0.1%, p < 0.001
• Amputation: 1.4% vs. 1.3%, p = 0.53

Based on presence of peripheral artery disease (PAD): PAD was present in 1,025 (6%) of randomized patients, with nearly 75% being asymptomatic or with mild claudication symptoms. MACE and renal events were higher among PAD patients compared with those without PAD. Limb events were also higher (20.3% vs. 2.1% in the placebo arm). No effect modification was noted by PAD status for the effect of dapagliflozin vs. placebo. Limb events were also similar, including major adverse limb events (1.4% vs. 1.2%), urgent revascularization (0.5% vs. 0.6%), and elective revascularization (1.6% vs. 1.5%). Amputation rates were overall similar (1.4% vs. 1.3%). Among patients with PAD, event rates were higher, but rates were similar with dapagliflozin vs. placebo. There was a numerically higher rate of amputations among PAD patients with dapagliflozin (8.4% vs. 5.6%; HR 1.51, 95% CI 0.94-2.42).

Patients with prior myocardial infarction (MI): (n = 3,584). Dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% among patients with prior MI (15.2% vs. 17.8%; HR 0.84, 95% CI 0.72-0.99, p = 0.039), whereas there was no effect in patients without prior MI (7.1% vs. 7.1%; HR 1.00, 95% CI 0.88-1.13, p = 0.97; p-interaction for relative difference 0.11).

Effect of ejection fraction (EF): 3.9% had HF with reduced EF (HFrEF). Dapagliflozin reduced CV death/hospitalization for HF more in patients with HFrEF (HR 0.62, 95% CI 0.45-0.86) than in those without HFrEF (HR 0.88, 95% CI 0.76-1.02; p-interaction 0.046). Dapagliflozin reduced hospitalization for HF both in those with (HR 0.64, 95% CI 0.43-0.95) and without HFrEF (HR 0.76, 95% CI 0.62-0.92); it reduced CV death only in patients with HFrEF (HR 0.55, 95% CI 0.34-0.90) but not in those without HFrEF (HR 1.08, 95% CI 0.89-1.31; p-interaction 0.012). Similar results were noted for all-cause mortality.

Effect on atrial fibrillation (AF): AF/atrial flutter (AFL) events were identified by search of the safety database using the MedDRA Preferred Terms (“atrial fibrillation”, “atrial flutter”). AF/AFL events for dapagliflozin vs. placebo: 7.8 vs. 9.6 events/1,000 patient-years, HR 0.81, 95% CI 0.68-0.95, p = 0.009). Reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (prior AF/AFL: HR 0.79, 95% CI 0.58-1.09, no AF/AFL: HR 0.81, 95% CI 0.67-0.98; p for interaction = 0.89). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 vs. 432; incidence rate ratio 0.77, 95% CI 0.64-0.92, p = 0.005).

Safety and efficacy based on eGFR and urinary albumin-to-creatinine ratio (UACR): 7.4% had eGFR <60, 30.9% had albuminuria (UACR >30 mg/g). Patients were categorized as having no more than chronic kidney disease (CKD) stage 2 (65.1%), at least one marker of CKD (31.7%), or both (3.3%). Patients with more markers of CKD were more likely to be older, male, and have atherosclerotic CVD and HF at baseline. Relative risk for CV death and HF hospitalization for dapagliflozin vs. placebo was similar across the three subgroups (p for interaction = 0.24). Absolute risk difference with dapagliflozin was highest among the subgroup with two markers of CKD (-8.3% vs. -1.0% vs. -0.5%, p for interaction = 0.02). Relative and absolute risk reduction was similar for the MACE endpoint. At 6 months, HbA1c reduction was lowest among patients with lower baseline eGFR (least squares mean difference -0.39 vs. -0.47 vs. -0.7 for eGFR <60, 60-<90 and ≥90, p for interaction < 0.001).

Effects on blood pressure (BP) and baseline hypertension: Effects of dapagliflozin on systolic BP (SBP) were apparent as early as at the first 6 months of trial assessment (least means square difference -3.1 mm Hg, 95% CI -3.5 to -2.7, p < 0.0001). Reductions in SBP with dapagliflozin remained sustained at 48 months of follow-up (least means square difference -2.4 mm Hg, 95% CI -2.9 to -1.9, p < 0.0001). The beneficial effects of dapagliflozin on HF hospitalization and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (p-interactions = 0.28 and 0.52, respectively), including among patients with baseline normotension.

Effect of obesity: Of 17,134 patients, 31.5% were overweight, 32.4% were moderately (BMI 30-<35 kg/m²), 17.2% severely (BMI 35-<40), and 9.8% were very severely (BMI ≥40) obese. Patients with higher BMI had a higher risk of HF hospitalization and AF/AFL. The effect of dapagliflozin compared with placebo was consistent across BMI categories for CV death/HF hospitalization (p for interaction = 0.33), HF hospitalization (p for interaction = 0.20), renal-specific composite outcome (p for interaction = 0.90), and AF/AFL (p for interaction = 0.97). No differences in safety were observed based on BMI either. When dichotomized as obese (BMI ≥30) vs. not, dapagliflozin showed a greater reduction in CV death/HF hospitalization compared with placebo (p for interaction = 0.02) and HF hospitalization (p for interaction = 0.02) among obese patients.