Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes

Abstract

ImportanceIn 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.ObjectiveTo determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes.Design, Setting, and ParticipantsThis 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.InterventionsParticipants 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 MeasuresThe 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.ResultsAmong 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT04233034

Effect of Tight Glycemic Control on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes

“…An independent data and safety monitoring board provided trial oversight. The protocol included a factorial design in which the effect of verapamil vs placebo on beta cell function was also evaluated; the results of which are reported separately …”

Preserving Pancreatic Beta Cell Function in Recent-Onset Type 1 Diabetes

“…In the verapamil group, 95% of participants had a peak C-peptide level of 0.2 pmol/mL or greater at 52 weeks compared with 71% of participants in the placebo group . The factorial randomization design to either intensive diabetes management (automated insulin delivery) or standard diabetes care did not alter the comparison of C-peptide levels between the verapamil and placebo groups.…”

“…The primary outcome was the area under the curve values for C-peptide level, the gold standard measure of beta cell function, after a standardized meal (mixed-meal tolerance test) at 52 weeks. Verapamil treatment resulted in a 30% increase in C-peptide secretion compared with placebo, so verapamil delayed the expected decline in C-peptide production from 3 to 6 months after diagnosis …”

“…In the study by McVean and colleagues, 113 children and adolescents aged 7 years to 17 years were randomized to either automated insulin delivery with intensive follow-up or standard insulin therapy. Of these children and adolescents, the 88 who weighed 30 kg or greater were randomized in a balanced factorial design to either oral extended-release verapamil or placebo within 1 month after diagnosis of type 1 diabetes in the study by Forlenza and colleagues . The primary outcome was the area under the curve values for C-peptide level, the gold standard measure of beta cell function, after a standardized meal (mixed-meal tolerance test) at 52 weeks.…”

“…Hybrid closed-loop therapy determines the basal insulin delivery rate by algorithm, and users give themselves insulin boluses at meals. This is the most advanced automated insulin delivery system commercially available, and it was used in this study …”