Abstract
RATIONALE & OBJECTIVE: Hyperglycemia exacerbates the progression of chronic kidney disease (CKD), but most glucose-lowering therapies do not address morbidities associated with CKD. Sodium/glucose cotransporter 2 (SGLT2) inhibitors offer potential benefits to patients with diabetes and CKD, but their effectiveness may be diminished with decreased kidney function. We aimed to evaluate the safety and effectiveness of bexagliflozin, a novel SGLT2 inhibitor, in patients with type 2 diabetes and CKD. STUDY DESIGN: Phase 3, double-blind, placebo-controlled, multicenter, multinational, randomized trial. SETTING & PARTICIPANTS: 54 sites across 4 countries. Patients with CKD stage 3a or 3b, type 2 diabetes mellitus, and hemoglobin A(1c) level of 7.0% to 10.5% and estimated glomerular filtration rate (eGFR) of 30 to 59mL/min/1.73m(2) who were taking oral hypoglycemic agents for 8 weeks. INTERVENTIONS: Bexagliflozin, 20mg, daily versus placebo for 24 weeks. OUTCOMES: Primary outcome was change in percent hemoglobin A(1c) from baseline to week 24. Secondary end points included changes in body weight, systolic blood pressure, albuminuria, and hemoglobin A(1c) level stratified by CKD stage. RESULTS: 312 patients across 54 sites were analyzed. Bexagliflozin lowered hemoglobin A(1c) levels by 0.37% (95% CI, 0.20%-0.54%); P<0.001 compared to placebo. Patients with CKD stages 3a (eGFR, 45-<60mL/min/1.73m(2)) and 3b (eGFR, 30-<45mL/min/1.73m(2)) experienced reductions in hemoglobin A(1c) levels of 0.31% (P=0.007) and 0.43% (P=0.002), respectively. Bexagliflozin decreased body weight (1.61kg; P<0.001), systolic blood pressure (3.8mm Hg; P=0.02), fasting plasma glucose level (0.76mmol/L; P=0.003), and albuminuria (geometric mean ratio reduction of 20.1%; P=0.03). Urinary tract infection and genital mycotic infections were more common in the bexagliflozin group; otherwise, frequencies of adverse events were comparable between groups. LIMITATIONS: Not designed to evaluate the impact of treatment on long-term kidney disease and cardiovascular outcomes. CONCLUSIONS: Bexagliflozin reduces hemoglobin A(1c) levels in patients with diabetes and stage 3a/3b CKD and appears to be well tolerated. Additional observed benefits included reductions in body weight, systolic blood pressure, and albuminuria. FUNDING: Trial was sponsored by Theracos Sub, LLC.