Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial

Abstract

Importance: In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes.

Objective: To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes.

Design, setting, and participants: This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022.

Interventions: Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care.

Main outcomes and measures: The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes.

Results: Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, -0.3% [95% CI, -1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a nonserious adverse event considered to be related to treatment.

Conclusions and relevance: In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy.

Trial registration: ClinicalTrials.gov Identifier: NCT04233034.

Figure 1.. Recruitment, Randomization, and Follow-up of Participants in a Trial of Verapamil vs Placebo for the Preservation of Beta Cell Function in Children and Adolescents With Newly Diagnosed Type 1 Diabetes

^aRandomization was stratified by site with a permuted block design. Intensive diabetes management included an automated insulin delivery system. ^bHad at least 1 analyzable area under the curve value for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test. One participant in the placebo group who dropped out immediately after randomization before completing the baseline mixed-meal tolerance test was not included in the primary analysis.

Figure 2.. Area Under the Curve Values for 52-Week C-Peptide Level, Area Under the Curve Values for C-Peptide Level at Each Time Point, and Peak C-Peptide Levels at Each Time Point

In A and B, the area under the curve values for the C-peptide levels were obtained from a mixed-meal tolerance test and computed using the trapezoidal rule as a weighted sum of the measurements for C-peptide level at time 0 and after 15, 30, 60, 90, and 120 minutes. In A, for any given C-peptide area under the curve level, the percentage of participants in each treatment group with a value at that level or higher can be determined from the Figure. In B and C, for each box and whisker plot, the blue or orange dot inside the box represents the geometric mean, the horizontal black line represents the median, the ends of the box represent the 25th and 75th percentiles, and the whiskers represent the highest or lowest values within 1.5 × the IQR. The numbers beneath the x-axis reflect the number of participants in each group completing a mixed-meal tolerance test at each time point.