Safety and Effectiveness of Bexagliflozin in Patients With Type 2 Diabetes Mellitus and Stage 3a/3b CKD

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/1.73m² 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/1.73m²) and 3b (eGFR, 30-<45mL/min/1.73m²) 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.

Keywords: SGLT2 inhibitor; Type 2 diabetes; albuminuria; bexagliflozin; chronic kidney disease (CKD); estimated glomerular filtration rate (eGFR); glucose-lowering therapy; hemoglobin A(1c) (HbA(1c)); kidney function; randomized controlled trial (RCT); renal impairment.