32-OR: The Bexagliflozin Efficacy and Safety Trial (BEST): A Randomized, Double-Blind, Placebo-Controlled, Phase IIII, Clinical Trial

Bexagliflozin (bexa) is a potent and selective inhibitor of SGLT2. To demonstrate its effects in patients (pts) at increased risk of cardiovascular (CV) events, pts with type 2 diabetes (T2D) ≥40 years old with HbA1c 7.5-11 % and eGFR ≥45 were enrolled in 1 of 3 groups: 1) established atherosclerotic CVD 2) heart failure (HF) or 3) ≥55 years with ≥2 CV risk factors. The primary endpoint was change in HbA1c at wk 24. Secondary endpoints included change in SBP at 24 wks in pts with SBP ≥140 mmHg, weight loss at 48 wks in pts with BMI ≥25 kg/m², and time to hospitalization for HF or CV death. MACE+ (CV death, myocardial infarction, stroke, or unstable angina) was tested in a non-inferiority analysis to demonstrate upper 95% CI <1.8. Pts were randomized 2:1 to bexa 20 mg or placebo qd. Follow-up continued until all pts completed ≥52 wks and when ≥134 subjects had a MACE+ event. CV endpoints and deaths were adjudicated and analyzed using Cox proportional hazards regression. Placebo-corrected changes from baseline in HbA1c, weight and SBP were analyzed using a mixed model repeated measures approach to account for missing data. 1700 pts were enrolled (62.6% Group1, 14.5% Group 2, 22.9% in Group 3) and followed for a median of 30 months. At baseline mean (SD) HbA1c was 8.32 (0.91)%; BMI 32.6 (6.0) kg/m² (92%≥25); SBP 134 (16) mmHg (39% ≥140); eGFR 77.9 (19.5) (19% <60). The primary endpoint showed a placebo-corrected reduction in HbA1c of 0.48% (95% CI -0.56, -0.39), p<0.0001; SBP fell 3.0 mmHg (- 5.5, -0.4), p=0.02; and weight declined 2.7kg (-3.1, -2.2), p<0.0001. CV death or HF hosp. occurred in 48 (4.2%) pts on bexa and 31 (5.5%) on placebo: HR 0.74 (0.47, 1.17). MACE+ occurred in 90/1133 (7.9%) pts on bexa and 57/567 (10.1%) on placebo: HR 0.79 (95%CI 0.56, 1.09). In high-risk T2D pts, bexagliflozin was well tolerated and improved HbA1c, SBP, and weight. Non-inferiority was demonstrated for MACE+, with point-estimates for MACE+ and CV death or HF hosp similar to other SGLT2 inhibitors.