Effects of Dapagliflozin on Cardiovascular Outcomes in Patients With Type 2 Diabetes at Risk of Liver Fibrosis

AIMS: The fibrosis-4 (FIB-4) score is used to identify risk of advanced liver fibrosis. This post hoc analysis investigated its prognostic value for cardiovascular (CV) outcomes and its relevance to the effects of dapagliflozin. MATERIALS AND METHODS: DECLARE-TIMI 58 was a randomised, placebo-controlled phase 3 trial investigating dapagliflozin in patients with type 2 diabetes (T2D) and either atherosclerotic cardiovascular disease (ASCVD) or high ASCVD risk. Participants were stratified by baseline FIB-4 scores (< 1.30, 1.30 to < 2.67, and ≥ 2.67). Hazard ratios (HRs) and 95% confidence intervals (CIs) for dapagliflozin versus placebo were calculated for the two primary outcomes (major adverse cardiovascular events MACE and the composite of CV death and hospitalisation for heart failure HHF). RESULTS: Of 17 160 patients enrolled, 16 361 were included (median follow-up of 4.2 years). Distribution across FIB-4 categories was: < 1.30, n = 9084 (55.5%); 1.30 to < 2.67, n = 6556 (40.7%); and ≥ 2.67, n = 621 (3.8%), with similar ASCVD prevalence across groups (40%-43%). In the placebo arm, the ≥ 2.67 FIB-4 group had the highest event rates for MACE, HHF, CV death, and all-cause death. MACE HRs (95% CIs) for dapagliflozin versus placebo were 0.95 (0.83-1.10), 0.92 (0.79-1.08), and 0.61 (0.38-0.97) across ascending FIB-4 groups. For the CV death and HHF composite endpoint, they were 0.81 (0.67-0.98), 0.90 (0.73-1.10), and 0.50 (0.28-0.90). Dapagliflozin reduced aspartate aminotransferase and alanine aminotransferase levels compared with placebo. CONCLUSION: Highest FIB-4 scores were associated with increased CV risk in patients with T2D. Dapagliflozin reduced CV risk across FIB-4 categories without significant interactions.