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. 2023 Mar 28;329(12):990-999.
doi: 10.1001/jama.2023.2064.

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

Gregory P Forlenza  1 , Jennifer McVean  2   3 , Roy W Beck  4 , Colleen Bauza  4 , Ryan Bailey  4 , Bruce Buckingham  5 , Linda A DiMeglio  6 , Jennifer L Sherr  7 , Mark Clements  8 , Anna Neyman  6 , Carmella Evans-Molina  6 , Emily K Sims  6 , Laurel H Messer  1   9 , Laya Ekhlaspour  5   10 , Ryan McDonough  8 , Michelle Van Name  7 , Diana Rojas  4 , Shannon Beasley  2 , Stephanie DuBose  4   11 , Craig Kollman  4 , Antoinette Moran  2 ; CLVer Study Group
Collaborators, Affiliations

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

Gregory P Forlenza et al. JAMA. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Forlenza reported serving as a consultant, speaker, or advisory board member for Medtronic, Dexcom, Abbott, Tandem Diabetes Care, Insulet, Lilly, and Beta Bionics and reported that his institution has received funding on his behalf for research grants from Medtronic, Dexcom, Abbott, Tandem Diabetes Care, Insulet, Lilly, and Beta Bionics. Dr McVean reported being an employee of Medtronic. Dr Beck reported that his institution has received funding on his behalf as follows: grant funding and study supplies from Tandem Diabetes Care, Beta Bionics, and Dexcom; grant funding from Bigfoot Biomedical; study supplies from Medtronic, Ascensia, and Roche; consulting fees and study supplies from Lilly and Novo Nordisk; and consulting fees from Insulet and Zucara Therapeutics. Dr Buckingham reported receiving grants, personal fees, and/or nonfinancial support from Medtronic, Tandem Diabetes Care, Insulet, Novo Nordisk, and Lilly and reported his institution has received research funding from Medtronic, Tandem Diabetes Care, Beta Bionics, and Insulet. Dr DiMeglio reported receiving consulting or advisory fees from Abata Therapeutics, MannKind, ProventionBio, and Zealand Pharma and study supplies from Dexcom. Dr Sherr reported receiving speaker honoraria from Lilly, Insulet, Medtronic, and Zealand Pharma; serving on advisory boards for Bigfoot Biomedical, Cecelia Health, Insulet, Medtronic Diabetes, JDRF (formerly the Juvenile Diabetes Research Foundation) T1D Fund, StartUp Health T1D Moonshot, and Vertex Pharmaceuticals; receiving consulting fees from Insulet and Medtronic; and reported that her institution has received research grant support from Medtronic and Insulet. Dr Clements reported receiving personal fees from Glooko Inc and receiving nonfinancial support from Dexcom and Abbott Diabetes Care. Dr Evans-Molina reported serving on advisory boards for ProventionBio, Isla Technologies, MaiCell Therapeutics, Avotres Inc, DiogenX, and Neurodon; receiving in-kind research support from Bristol Myers Squibb and Nimbus Therapeutics; receiving investigator-initiated grants from Lilly and Astellas Pharma; and having a patent for extracellular vesicle RNA cargo as a biomarker of hyperglycemia and type 1 diabetes and a provisional patent for a biomarker of type 1 diabetes (PDIA1 as a biomarker of beta cell stress). Dr Sims reported receiving compensation for educational lectures on type 1 diabetes screening from Medscape and the American Diabetes Association. Dr Messer reported receiving speaking or consulting fees from Dexcom, Tandem Diabetes Care, Capillary Biomedical (now owned by Tandem Diabetes Care), and Lilly; receiving grants from Insulet, Beta Bionics, and Tandem Diabetes Care; and being a current employee of Tandem Diabetes Care. Dr Ekhlaspour reported receiving consulting fees from Tandem Diabetes Care and Ypsomed Holding AG; receiving speaking fees from Insulet; and receiving research support from Medtronic and MannKind. Dr Van Name reported receiving research support from ProventionBio. Dr Kollman reported receiving grants from Dexcom and Tandem Diabetes Care. Dr Moran reported serving on advisory boards for Dompé Farmaceutici SpA, ProventionBio, and Abata Therapeutics; serving on a data and safety monitoring board for Novo Nordisk; and reported that her institution has received grant funding on her behalf from Abbott Diabetes, ProventionBio, Intrexon (now Precigen), and Caladrius Biosciences and study supplies from Novo Nordisk, Medtronic, and Abbott Diabetes. No other disclosures were reported.

Figures

Figure 1.
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.
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.
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