Metformin plus R-form verapamil improves glycaemic control in T2D

Combination therapy with metformin plus R-form verapamil (R-Vera) leads to significant improvements in glycaemic control by reducing haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) among patients with type 2 diabetes (T2D), reports a study.

“The favourable efficacy and safety profile of R-Vera 300 mg/day, combined with the potential for beta cell preservation and reduction in high blood pressure, make R-Vera a promising new antidiabetic medication,” the researchers said.

One hundred eighty-four participants were randomized to receive R-Vera 450, 300, or 150 mg per day or matching placebo in combination with metformin. Change in HbA1c after 12 weeks of treatment was the primary endpoint.

HbA1c significantly decreased at week 12 in the R-Vera 300-mg/day (‒0.36; p=0.0373) and 450-mg/day (‒0.45; p=0.0098) groups compared with placebo. The decrease in HbA1c was associated with declining FPG levels and improved HOMA2-β score. [J Clin Endocrinol Metab 2022;107:e4063-e4071]

Treatment with R-Vera was generally well tolerated, and no hypoglycaemic episodes occurred during the trial.

“After 12 weeks of treatment, participants in the R-Vera treatment groups showed a trend of increase in HOMA2-β from baseline compared with participants in the placebo group, despite the fact that participants in the R-Vera treatment groups already had higher HOMA2-β score relative to participants in the placebo group at baseline,” the researchers said.

“Apoptosis is the primary mechanism underlying beta cell death in both type 1 diabetes mellitus and T2DM, and beta cell death may be induced by thioredoxin-interacting protein (TXNIP),” they added. [Diabetes 2005;54(Suppl 2):S97-107]

An oligonucleotide microarray study that assessed the effects of glucose on isolated human pancreatic islets first identified TXNIP as the most upregulated gene. [Endocrinology 2002;143:3695-3698]

TXNIP is a negative regulator of thioredoxin. It applies its proapoptotic effects on beta cells by inhibiting thioredoxin and inducing oxidative stress, which is a vital part of beta cell glucotoxicity and apoptosis. Notably, alterations in blood glucose levels highly regulate TXNIP. [J Biol Chem 2009;284:16898-16905; Endocrinology 2005;146:2397-2405; Cell Metab 2007;5:412-414]

“As a calcium channel blocker, R-Vera was found to inhibit TXNIP expression and may have mediated a TXNIP-lowering effect on beta cells in our preclinical study,” the researchers said. [PLoS One 2021;16:e0255405]

In the current study, the improvement in HOMA2-β score among patients treated with R-Vera was consistent with the report by A. Shalev and colleagues, which showed that the addition of oral verapamil to a standard insulin regimen for 12 months in adult participants with type 1 diabetes exhibited less increase in insulin requirement, fewer hypoglycaemic events, and promotion of endogenous beta cell function relative to placebo. [Nat Med 2018;24:1108-1112]

The present study was limited by its small sample size and restricted treatment duration. In addition, the study groups were not well-balanced with regard to their baseline beta cell function.

“A larger number of participants and longer treatment period (for example, 26 weeks or longer) should be considered in future trials to determine whether the beneficial effects can be sustained with (or without) continuous R-Vera treatment,” the researchers said.