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Cited by 169Pancreatic function and diabetesDiabetes and associated disordersDiabetes Treatment and Management

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

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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·2023·JAMA
DOI 10.1001/jama.2023.2064PMC PMC9960020
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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 A 1c 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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Research works printed but not linked: 20

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Metadata

Authors
Forlenza, G. P., McVean, J., Beck, R. W., Bauza, C., Bailey, R., Buckingham, B., DiMeglio, L. A., Sherr, J. L., Clements, M., Neyman, A., Evans-Molina, C., Sims, E. K., Messer, L. H., Ekhlaspour, L., McDonough, R., Van Name, M., Rojas, D., Beasley, S., DuBose, S., Kollman, C., Moran, A., CLVer Study Group, Moran, A., McVean, J., Beasley, S., Pappenfus, B., Street, A., Nelson, B., Leschyshyn, J., Kennedy, J., Rizky, I., Forlenza, G., Cobry, E., Messer, L., Slover, R., Wadwa, P., Towers, L., Karami, A., Fivekiller, E., Boranian, E., Escobar, E., Jost, E., Lange, S., Berget, C., Geiser, L., Clements, M., Moore, W., McDonough, R., Paprocki, E., Halpin, K., Yan, Y., Livingston, E., Howell, K., Seuferling, B., Parish, S., Orlich, S., Goff, R., Neyman, A., DiMeglio, L., Woerner, S., Evans-Molina, C., Sims, E., Kirchner, M., Chatila, D., Buckingham, B., Ekhlasour, L., Norlander, L., Frank, E., Suh, B., Morgan, M., Kingman, R., Hsu, L., Sherr, J., Weyman, K., Tichy, E., Van Name, M., Brei, M., Steffen, A., Carria, L., Zgorski, M., Bauza, C., Beck, R., Bailey, R., Kollman, C., DuBose, S., Rojas, D., Cagnina, N., Reese, N., Strayer, H., Smith, E., Frey, S., Vyas, S., Rosen, J., Dutta, S., Janicek, R., Gabrielson, D., Yu, L., Stablein, D., Klingensmith, G., & Rodrigeuz, H.
Affiliations
  • Barbara Davis Center, Anschutz Medical Campus, University of Colorado, Aurora
  • Jaeb Center for Health Research, Tampa, Florida
  • Indiana University School of Medicine, Indianapolis
  • Yale School of Medicine, Yale University, New Haven, Connecticut
  • University of California, San Francisco (US)
  • University of Minnesota (US)
  • for the CLVer Study Group
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2023-03-28
Volume
329
Issue
12
Pages
990
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2023.2064
PMC
PMC9960020
OpenAlex
W4321749334
Cited by
169
References
25
Citations by year
2026: 27 · 2025: 48 · 2024: 56 · 2023: 38
FWCI
45.28
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
Funders
  • National Institutes of Health (UL1TR001863)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK121929, R01DK127308, K23DK121942, P30DK097512, R01DK133881)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
verapamil, type 1 diabetes, pediatric diabetes, newly diagnosed diabetes, beta-cell function, C-peptide, calcium channel blockers, TXNIP, beta-cell apoptosis, glucotoxicity, intensive diabetes management, mixed meal tolerance test, beta-cell preservation, children and adolescents, intensive insulin therapy, islet autoimmunity, HLA-DR4
MeSH terms
Adolescent, C-Peptide, Child, Diabetes Mellitus, Type 1, Double-Blind Method, Female, Humans, Hypoglycemic Agents, Male, Verapamil, Insulin-Secreting Cells

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