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Dapagliflozin reduced cardiorenal outcomes but not MACE in T2 diabetes with or at risk for atherosclerotic CVD

Question In patients with type 2 diabetes who have, or are at risk for, atherosclerotic cardiovascular disease (CVD), what is the effect of dapagliflozin on CV and renal outcomes? Methods Design Randomized placebo-controlled trial (Dapagliflozin Effect on Cardiovascular Events [DECLARE]TIMI 58 trial). ClinicalTrials.gov NCT01730534. Allocation Concealed.* Blinding Blinded* (patients and all study staff). Follow-up period Median 4.2 years. Setting 882 clinical centers in 33 countries. Patients 17190 adults (mean age 64 y, 63% men) who had type 2 diabetes; established atherosclerotic CVD (age 40 y and 1 of ischemic heart disease, cerebrovascular disease, or peripheral arterial disease) or 2 risk factors for atherosclerotic CVD (age 55 y for men or 60 y for women, plus 1 of dyslipidemia, hypertension, or current tobacco use); hemoglobin A1c 6.5% to 12.0%; creatinine clearance 60 mL/min; and successfully completed a 4- to 8-week placebo run-in period. Intervention Dapagliflozin, 10 mg/d (n =8582), or placebo (n =8578). Outcomes Primary efficacy outcomes were major adverse cardiac events (MACE) and a composite of CV death or hospitalization for heart failure (HF). Secondary efficacy outcomes included a cardiorenal composite, a renal-specific composite, and all-cause mortality. Patient follow-up 99% (intention-to-treat analysis). Main results The main results are in the Table. Conclusion In patients with type 2 diabetes who have, or are at risk for, atherosclerotic CVD, dapagliflozin reduced a composite of CV death or hospitalization for heart failure and cardiorenal outcomes but not major adverse cardiac events. Dapagliflozin (Dap) vs placebo in patients with type 2 diabetes who had, or were at risk for, atherosclerotic cardiovascular (CV) disease Outcomes Event rates At a median 4.2 y Dap Placebo RRR (95% CI) NNT (CI) Major adverse cardiac events (primary outcome) 8.8% 9.4% 7% (3 to 15) NS CV death or hospitalization for HF (primary outcome) 4.9% 5.8% 17% (5 to 26) 104 (66 to 355) Cardiorenal composite 4.3% 5.6% 23% (13 to 32) 77 (56 to 141) Renal-specific composite 1.5% 2.8% 47% (34 to 57) 77 (64 to 107) All-cause mortality 6.2% 6.6% 7% (4 to 17) NS ESRD = end-stage renal disease; HF = heart failure; NS = not significant; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from placebo event rates and hazard ratios in articles. CV death, myocardial infarction, or ischemic stroke. CV death: 2.9% vs 2.9%, NS, hospitalization for HF: 2.5% vs 3.3% (RRR 27%, CI 12 to 39; NNT 114, CI 79 to 257). Sustained confirmed decrease in eGFR by 40% to <60 mL/min/1.73 m2: 1.4% vs 2.6% (RRR 46%, CI 33 to 57; NNT 85, CI 68 to 118), ESRD: 0.1% vs 0.2% (RRR 69%, CI 21 to 87; NNT 725, CI 575 to 2383), CV death, or renal death: 0.1% vs 0.1%, NS. Sustained confirmed decrease in eGFR by 40% to <60 mL/min/1.73 m2, ESRD, or renal death. Commentary The beneficial effects of sodiumglucose cotransporter 2 (SGLT-2) inhibitors on CV outcomes may differ in patients without vs with previous CVD. In the DECLARETIMI 58 trial (CVD prevalence 41%), dapagliflozin did not reduce MACE, CV mortality, or all-cause mortality. This differs from other large SGLT-2 inhibitor CV trials, which showed that MACE and other CV outcomes were reduced in patients with (13) and without (3) CVD. DECLARE-TIMI 58 supports previous evidence that SGLT-2 inhibitors reduce hospitalizations for HF. That this benefit occurred in patients without a history of CVD or HF is clinically important, as it expands the benefit of dapagliflozin to a broader population than previously identified in other large SGLT-2 inhibitor trials (13). A secondary analysis of DECLARE-TIMI 58 by Mosenzon and colleagues showed that, in patients with mostly preserved kidney function with minimal proteinuria, dapagliflozin reduced risk for a cardiorenal composite outcome in patients with and without CVD and baseline kidney dysfunction. The results are only hypothesis-generating but are consistent with previous studies of SGLT-2 inhibitors (13). Baseline kidney disease, albuminuria, and established CVD are the most important indicators of risk for both CV and kidney events and, thus, may also indicate which patients will benefit most from SGLT-2 inhibitors. Studies with definitive kidney outcomes in patients with and without these risk factors are currently under way (ClinicalTrials.gov NCT03036150, NCT03594110).