Cardiovascular, Renal, and Metabolic Outcomes of Dapagliflozin Versus Placebo in a Primary Cardiovascular Prevention Cohort: Analyses From DECLARE-TIMI 58

Aims: International guidelines propose prescribing SGLT-2 inhibitors to patients with type-2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT-2 inhibitors in MRF patients.

Methods: The DECLARE-TIMI 58 trial randomized 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) to dapagliflozin vs. placebo, followed for a median 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction.

Results: Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF; HR 0.84, 95%CI 0.67-1.04) and the renal-specific outcome (HR 0.51, 95%CI 0.37-0.69) did not differ from patients with ASCVD (P_interaction 0.99 and 0.72 respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95%CI 0.46-0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA1c, weight, systolic blood-pressure and urinary albumin:creatinine ratio were lower with dapagliflozin vs. placebo and eGFR was higher (p<0.001).

Conclusion: In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin on important outcomes in a broad primary prevention population.