Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes
Authors: Forlenza Gregory P. , McVean Jennifer , Beck Roy W. , Bauza Colleen , Bailey Ryan , Buckingham Bruce , DiMeglio Linda A. , Sherr Jennifer L. , Clements Mark , Neyman Anna , Evans-Molina Carmella , Sims Emily K. , Messer Laurel H. , Ekhlaspour Laya , McDonough Ryan , Van Name Michelle , Rojas Diana , Beasley Shannon , DuBose Stephanie , Kollman Craig , Moran Antoinette ,   CLVer Study Group, Moran Antoinette , McVean Jennifer , Beasley Shannon , Pappenfus Beth , Street Anne , Nelson Brittney , Leschyshyn Janice , Kennedy Jane , Rizky Ihsan , Forlenza Gregory , Cobry Erin , Messer Laurel , Slover Robert , Wadwa Paul , Towers Lindsey , Karami Angela , Fivekiller Emily , Boranian Emily , Escobar Estella , Jost Emily , Lange Samantha , Berget Cari , Geiser Luke , Clements Mark , Moore Wayne , McDonough Ryan , Paprocki Emily , Halpin Kelsee , Yan Yun , Livingston Erica , Howell Kelsye , Seuferling Barbara , Parish Susan , Orlich Stephen , Goff Rachel , Neyman Anna , DiMeglio Linda , Woerner Stephanie , Evans-Molina Carmella , Sims Emily , Kirchner Megan , Chatila Dana , Buckingham Bruce , Ekhlasour Laya , Norlander Lisa , Frank Eliana , Suh Bailey , Morgan Marci , Kingman Ryan , Hsu Liana , Sherr Jennifer , Weyman Kate , Tichy Eileen , Van Name Michelle , Brei Michelle , Steffen Amy , Carria Lori , Zgorski Melinda , Bauza Colleen , Beck Roy , Bailey Ryan , Kollman Craig , DuBose Stephanie , Rojas Diana , Cagnina Nicole , Reese Nicole , Strayer Heidi , Smith Emma , Frey Sarah , Vyas Shachi , Rosen Jonathan , Dutta Sanjoy , Janicek Robert , Gabrielson Deanna , Yu Liping , Stablein Donald , Klingensmith Georgeanna , Rodrigeuz Henry 
Published: February 2023

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