A Randomized Controlled Trial of R-Form Verapamil Added to Ongoing Metformin Therapy in Patients with Type 2 Diabetes

Context: There is a medical need for effective insulin-independent antidiabetic drugs that can promote pancreatic [beta]-cell function and have a low risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients. R-form verapamil (R-Vera), which is able to enhance the survival of [beta]-cells and has higher cardiovascular safety margin compared with racemic verapamil, was developed as a novel approach for T2DM treatment. Objective: This randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of 3 dosages of R-Vera added to ongoing metformin therapy in T2DM patients who had inadequate glycemic control on metformin alone. Methods: Participants were randomly assigned in an equal ratio to receive R-Vera 450, 300, or 150 mg per day, or matching placebo, in combination with metformin. The primary endpoint was change in hemoglobin A1c (HbA1c) after 12 weeks of treatment. Results: A total of 184 eligible participants were randomized to receive either R-Vera or placebo plus metformin. At week 12, significant reductions in HbA1c were observed for R-Vera 300 mg/day (-0.36, P = 0.0373) and 450 mg/day (-0.45, P = 0.0098) compared with placebo. The reduction in HbA1c correlated with decreasing fasting plasma glucose levels and improved HOMA2-[beta] score. Treatment with R-Vera was well tolerated with no hypoglycemic episodes occurring during the trial. Conclusion: Addition of R-Vera twice daily to ongoing metformin therapy significantly improved glycemic control in T2DM patients. The favorable efficacy and safety profile of R-Vera 300 mg/day can be considered as the appropriate dose for clinical practice. Key Words: R-form verapamil, metformin, type 2 diabetes, HbA1c, antidiabetic drug Abbreviations: AE, adverse event; BMI, body mass index; DM, diabetes mellitus; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin A1c; HDL, high-density lipoprotein; HOMA2-[beta], homeostasis model 2 assessment [beta]-cell; HOMA2-IR, homeostasis model 2 assessment of insulin resistance; LDL, low-density lipoprotein; LS, least squares; R-Vera, R-form verapamil; SBP, systolic blood pressure; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TEAE, treatment-emergent adverse event; TXNIP, thioredoxin-interacting protein.