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

Abstract

Context There is a medical need for effective insulin-independent antidiabetic drugs that have the capability to 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 to racemic verapamil, was developed as a novel approach for the T2DM treatment. Objective This randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of three doses of R-Vera added to ongoing metformin therapy in T2DM patients who had inadequate glycemic control on metformin alone. Methods Subjects were randomly assigned in an equal ratio to receive R-Vera 450, 300, 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 subjects 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 to 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.

Toward better diabetes care: Exploration and implementation

“…In collaboration with investigators from Japan and South Korea, we collected real-world data from medical records and proved that the use of sodium-glucose cotransporter 2 inhibitors was associated with lower inpatient expenses and emergency room visits compared with dipeptidyl peptidase-4 inhibitors use in routine clinical practice 13 . Recently, we examined a new form of the old drug, R-form verapamil, which could further reduce the level of glycated hemoglobin in addition to metformin therapy in patients with type 2 diabetes in Taiwan 14 .…”

Verapamil chronicles: advances from cardiovascular to pancreatic β-cell protection

“…This randomized, double-blind, placebo-controlled clinical trial showed a significant reduction in Hb1Ac levels in patients with T2D, following treatment with verapamil ( Malayeri et al, 2021 ). It is noteworthy that co-treatment with verapamil and metformin significantly improved the glycemic control in patients with T2D by reducing HbA1c and fasting plasma glucose levels ( Wang et al, 2022 ). Applying to precision medicine, an innovative approach to tailoring disease prevention and treatment would be by taking into account the differences in genes, ethnicity, environment, and lifestyle, in order to provide a more elaborative data regarding efficacy and safety of verapamil in maintaining HbA1c level and general blood glucose management, especially in populations with diverse attributes.…”

MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation: implications for innovative type 2 diabetes mellitus management

“…In the heart and the pancreas, effective pharmacological LTCC blockage can inhibit the expression of pro-apoptotic thioredoxin-interacting protein, a significant contributor to pancreatic β-cell dysfunction and a key gene regulated in response to hyperglycemia, thereby promoting the survival and proper functioning of β-cells and improving glucose homeostasis[ 46 , 48 ]. Verapamil has, thus, the potential not only to enhance β-cell survival and function, but also improve and even prevent overt diabetes of both types[ 48 , 49 ]. In a recent study, verapamil combined with metformin, significantly improved glycemic control in T2DM[ 49 ].…”

“…Verapamil has, thus, the potential not only to enhance β-cell survival and function, but also improve and even prevent overt diabetes of both types[ 48 , 49 ]. In a recent study, verapamil combined with metformin, significantly improved glycemic control in T2DM[ 49 ]. Finally, a drawback in the use of monotherapy as ACEi/ARBs (in conditions that already are associated with low miR-155 Levels) is that they significantly further decrease already reduced miR-155 Levels[ 50 , 51 ].…”