Association of Baseline HbA_1c With Cardiovascular and Renal Outcomes: Analyses From DECLARE-TIMI 58

OBJECTIVE Current guidelines recommend prescribing SGLT2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA_1c levels. We studied the association of HbA_1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA_1c. RESEARCH DESIGN AND METHODS In the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomly assigned to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA_1c in the overall population and with dapagliflozin versus placebo in HbA_1c subgroups were studied by Cox regression models. RESULTS In the overall population, higher baseline HbA_1c was associated with a higher risk of cardiovascular death or hospitalization for heart failure (HHF); major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarc-tion, and ischemic stroke; and cardiorenal outcomes (adjusted hazard ratios 1.12 [95% CI 1.06–1.19], 1.08 [1.04–1.13], and 1.17 [1.11–1.24] per 1% higher level, respectively). Elevated HbA_1c was associated with a greater increased risk for MACE and cardiorenal outcomes in patients with multiple risk factors (MRF) than in established ASCVD (P-interaction 5 0.0064 and 0.0093, respectively). Compared with placebo, dapagliflozin decreased the risk of cardiovascular death/ HHF, HHF, and cardiorenal outcomes, with no heterogeneity by baseline HbA_1c (P-interaction > 0.05). CONCLUSIONS Higher HbA_1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA_1c, including patients with HbA_1c <7%.