Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes
Author:
Forlenza Gregory P.1, McVean Jennifer23, Beck Roy W.4, Bauza Colleen4, Bailey Ryan4, Buckingham Bruce5, DiMeglio Linda A.6, Sherr Jennifer L.7, Clements Mark8, Neyman Anna6, Evans-Molina Carmella6, Sims Emily K.6, Messer Laurel H.19, Ekhlaspour Laya510, McDonough Ryan8, Van Name Michelle7, Rojas Diana4, Beasley Shannon2, DuBose Stephanie411, Kollman Craig4, Moran Antoinette2, Moran Antoinette12, McVean Jennifer12, Beasley Shannon12, Pappenfus Beth12, Street Anne12, Nelson Brittney12, Leschyshyn Janice12, Kennedy Jane12, Rizky Ihsan12, Forlenza Gregory12, Cobry Erin12, Messer Laurel12, Slover Robert12, Wadwa Paul12, Towers Lindsey12, Karami Angela12, Fivekiller Emily12, Boranian Emily12, Escobar Estella12, Jost Emily12, Lange Samantha12, Berget Cari12, Geiser Luke12, Clements Mark12, Moore Wayne12, McDonough Ryan12, Paprocki Emily12, Halpin Kelsee12, Yan Yun12, Livingston Erica12, Howell Kelsye12, Seuferling Barbara12, Parish Susan12, Orlich Stephen12, Goff Rachel12, Neyman Anna12, DiMeglio Linda12, Woerner Stephanie12, Evans-Molina Carmella12, Sims Emily12, Kirchner Megan12, Chatila Dana12, Buckingham Bruce12, Ekhlasour Laya12, Norlander Lisa12, Frank Eliana12, Suh Bailey12, Morgan Marci12, Kingman Ryan12, Hsu Liana12, Sherr Jennifer12, Weyman Kate12, Tichy Eileen12, Van Name Michelle12, Brei Michelle12, Steffen Amy12, Carria Lori12, Zgorski Melinda12, Bauza Colleen12, Beck Roy12, Bailey Ryan12, Kollman Craig12, DuBose Stephanie12, Rojas Diana12, Cagnina Nicole12, Reese Nicole12, Strayer Heidi12, Smith Emma12, Frey Sarah12, Vyas Shachi12, Rosen Jonathan12, Dutta Sanjoy12, Janicek Robert12, Gabrielson Deanna12, Yu Liping12, Stablein Donald12, Klingensmith Georgeanna12, Rodrigeuz Henry12,
Affiliation:
1. Barbara Davis Center, Anschutz Medical Campus, University of Colorado, Aurora 2. University of Minnesota, Minneapolis 3. now with Medtronic, Northridge, California 4. Jaeb Center for Health Research, Tampa, Florida 5. Stanford University, Stanford, California 6. Indiana University School of Medicine, Indianapolis 7. Yale School of Medicine, Yale University, New Haven, Connecticut 8. Children’s Mercy Hospital, Kansas City, Missouri 9. now with Tandem Diabetes Care, San Diego, California 10. now with University of California, San Francisco 11. now with Emory University, Atlanta, Georgia 12. for the CLVer Study Group
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
Publisher
American Medical Association (AMA)
Cited by
72 articles.
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