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

Chih-Yuan Wang, Kuo-Chin Huang, Chia-Wen Lu, Chih-Hsun Chu, Chien-Ning Huang, Harn-Shen Chen, I-Te Lee, Jung-Fu Chen, Ching-Chu Chen, Chung-Sen Chen, Chang-Hsun Hsieh, Kai-Jen Tien, Hung-Yu Chien, Yu-Yao Huang, Jui-Pao Hsu, Guang-Tzuu Shane, Ai-Ching Chang, Yen-Chieh Wu, Wayne Huey-Herng Sheu, Chih-Yuan Wang, Kuo-Chin Huang, Chia-Wen Lu, Chih-Hsun Chu, Chien-Ning Huang, Harn-Shen Chen, I-Te Lee, Jung-Fu Chen, Ching-Chu Chen, Chung-Sen Chen, Chang-Hsun Hsieh, Kai-Jen Tien, Hung-Yu Chien, Yu-Yao Huang, Jui-Pao Hsu, Guang-Tzuu Shane, Ai-Ching Chang, Yen-Chieh Wu, Wayne Huey-Herng Sheu

Abstract

Context: There is a medical need for effective insulin-independent antidiabetic drugs that can promote pancreatic β-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 β-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-β 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.

Trial registration: ClinicalTrials.gov NCT03317028.

Keywords: HbA1c; R-form verapamil; antidiabetic drug; metformin; type 2 diabetes.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.
Figure 1.
The study design and participant disposition in the 4 treatment groups. Abbreviations: ICF, informed consent form; R-Vera, R-form verapamil.
Figure 2.
Figure 2.
Subgroup analysis of changes in HbA1c after 12 weeks of treatment with R-Vera or placebo plus metformin therapy. When compared with placebo, participants in R-Vera groups with (A) baseline HbA1c ≥ 8.0%; (B) HOMA2-β  130 mg/dL had greater HbA1c reductions from baseline. Abbreviations: Diff, difference; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; HOMA2-β, homeostasis model 2 assessment β-cell; LS-mean, least squares mean; R-Vera, R-form verapamil; SE, standard error.

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