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美国Jaeb健康研究中心Roy Beck团队研究了维拉帕米对初诊青少年1型糖尿病患者胰腺β细胞功能的影响。相关论文于2023年2月24日发表在《美国医学会杂志》上。

在临床前研究中，硫氧还蛋白相互作用蛋白过表达诱导胰腺β细胞凋亡，并参与糖毒性诱导的β细胞死亡。钙通道阻滞剂可降低这些影响，并可能有利于1型糖尿病的β细胞保留。

为了探讨维拉帕米对新诊断的1型糖尿病儿童和青少年胰腺β细胞功能的影响，研究组在美国6个中心进行了一项双盲、随机临床试验（2020年7月20日至2021年10月13日）进行，招募7至17岁的儿童和青少年，均新诊断为1型糖尿病，体重30公斤或以上，随访于2022年9月15日完成。

参与者被1:1随机分配，每天口服一次维拉帕米（n = 47）或安慰剂（n = 41）作为析因设计的一部分，其中参与者也被分配接受强化糖尿病管理或标准糖尿病护理。主要结局是在诊断1型糖尿病52周时，通过混合膳食耐受试验刺激的C肽水平（胰腺β细胞功能的测量）曲线下面积。

在88名参与者中（平均年龄12.7岁；36名为女性[41%]；从诊断到随机分组的平均时间为24天），83人（94%）完成了试验。维拉帕米组的平均C肽曲线下面积在基线时为0.66 pmol/mL，52周时为0.65 pmol/mL；而安慰剂组的平均曲线下面积为0.60 pmol/L，52周后为0.44 pmol/mL（经组间差异校正为0.14 pmol/mL）。

这相当于维拉帕米在52周时C肽水平提高30%。维拉帕米组52周C肽峰值水平为0.2 pmol/mL或更高的参与者比例为95%（43名参与者中有41名），安慰剂组为71%（38名参与者中有27名）。52周时，维拉帕米组的血红蛋白A1c为6.6%，安慰剂组为6.9%（校正组间差异为-0.3%）。维拉帕米的8名参与者（17%）和安慰剂组的8名（20%）参与者发生了与治疗相关的非严重不良事件。

研究结果表明，在新诊断为1型糖尿病的儿童和青少年中，与安慰剂相比，维拉帕米在诊断52周时部分保留了刺激的C肽分泌。需要进一步的研究来确定C肽改善的纵向持久性和最佳治疗时间。

附：英文原文

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

Author: Gregory P. Forlenza, Jennifer McVean, Roy W. Beck, Colleen Bauza, Ryan Bailey, Bruce Buckingham, Linda A. DiMeglio, Jennifer L. Sherr, Mark Clements, Anna Neyman, Carmella Evans-Molina, Emily K. Sims, Laurel H. Messer, Laya Ekhlaspour, Ryan McDonough, Michelle Van Name, Diana Rojas, Shannon Beasley, Stephanie DuBose, Craig Kollman, Antoinette Moran, CLVer Study Group, Antoinette Moran, Jennifer McVean, Shannon Beasley, Beth Pappenfus, Anne Street, Brittney Nelson, Janice Leschyshyn, Jane Kennedy, Ihsan Rizky, Gregory Forlenza, Erin Cobry, Laurel Messer, Robert Slover, Paul Wadwa, Lindsey Towers, Angela Karami, Emily Fivekiller, Emily Boranian, Estella Escobar, Emily Jost, Samantha Lange, Cari Berget, Luke Geiser, Mark Clements, Wayne Moore, Ryan McDonough, Emily Paprocki, Kelsee Halpin, Yun Yan, Erica Livingston, Kelsye Howell, Barbara Seuferling, Susan Parish, Stephen Orlich, Rachel Goff, Anna Neyman, Linda DiMeglio, Stephanie Woerner, Carmella Evans-Molina, Emily Sims, Megan Kirchner, Dana Chatila, Bruce Buckingham, Laya Ekhlasour, Lisa Norlander, Eliana Frank, Bailey Suh, Marci Morgan, Ryan Kingman, Liana Hsu, Jennifer Sherr, Kate Weyman

Issue&Volume: 2023-02-24

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.

DOI: 10.1001/jama.2023.2064

Source: https://jamanetwork.com/journals/jama/fullarticle/2801974

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