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

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