ESPEYB20 8. Type 1 Diabetes Clinical Trials – New Treatments (2 abstracts)
8.1. Effect of Verapamil on pancreatic beta cell function in newly diagnosed pediatric type 1 diabetes: A randomized clinical trial
Forlenza GP , McVean J , Beck RW , Bauza C , Bailey R , Buckingham B , DiMeglio LA , Sherr JL , Clements M , Neyman A , Evans-Molina C , Sims EK , Messer LH , Ekhlaspour L , McDonough R , Van Name M , Rojas D , Beasley S , DuBose S , Kollman C , Moran A & CLVer Study Group
JAMA 2023;329(12):990–999.PMID: 36826844
Brief summary: In this double-blind, randomized clinical trial conducted in 6 US centres, 88 children and adolescents (aged 7–17 years) with newly diagnosed type 1 diabetes (T1D) were randomized to either once-daily oral verapamil or placebo, within 1 month from diagnosis. Treatment with verapamil led to better stimulated C-peptide secretion at 52 weeks post-diagnosis, with levels 30% higher compared to placebo.
Verapamil is a calcium channel blocker, already in use in adults as an anti-hypertensive drug. Of interest, in vitro studies showed that verapamil reduces the expression of thioredoxin-interacting protein, a cellular redox regulator contributing to β-cell apoptosis and death induced by glucotoxicity (1). A previous small study in adults with T1D showed a beneficial effect of verapamil in preserving β-cell function (2).
In this clinical trial, verapamil was tested in a small group (n=88) of children and adolescents with newly diagnosed T1D, with the aim of preserving residual β-cell function. Levels of C-peptide remained stable over time in the verapamil group, whereas declined in the placebo group, leading to 30% higher C-peptide level at 52 weeks in the former group. Treatment with verapamil was safe with similar rates of adverse events than placebo.
These findings could have important clinical implications. There is an ongoing focus on preserving β-cell function by intervening soon after diagnosis of T1D. This is based on the association between residual endogenous insulin production and better long-term glycemic outcomes and less complications (3). Verapamil is a marketed low-cost drug, which can be taken orally, once daily, and with a relatively safe profile. These characteristics make it an ideal treatment, less burdensome than other immunotherapies tested in previous or ongoing clinical trials. However, this will likely be a drug to be used as part of a ‘combination approach’ with other immunomodulatory and immunosuppressive agents, acting directly on the immune system (4). It remains to be clarified whether the effect of verapamil persists and for how long after stopping treatment.
Limitations of the current study are the small sample size, full recruitment was not achieved due to the COVID-19 pandemic, and only children with a weight of at least 30 Kg were included (due to the available verapamil dosing options). Further studies are needed to confirm these findings, expand them to a wider age range, and better define verapamil’s safety profile. In this context, the ongoing ‘Verapamil SR in Adults with Type 1 Diabetes (Ver-A-T1D)’ trial (ClinicalTrial.gov: NCT04545151), assessing the effect of verapamil in adults newly diagnosed with T1D, will provide additional information in future.
References: 1. Borowiec AM, Właszczuk A, Olakowska E, Lewin-Kowalik J. TXNIP inhibition in the treatment of diabetes. Verapamil as a novel therapeutic modality in diabetic patients. Med Pharm Rep. 2022;95(3): 243–250. 2. Ovalle F, Grimes T, Xu G, et al. Verapamil and beta cell function in adults with recent-onset type 1 diabetes. Nat Med. 2018;24(8):1108–1112. 3. Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care. 2003;26(3):832–836. 4. Mathieu C, Martens PJ, Vangoitsenhoven R. One hundred years of insulin therapy. Nat Rev Endocrinol. 2021;17(12):715–725.
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ESPE Yearbook of Paediatric Endocrinology
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