The effect of verapamil on beta cell function in adolescents and adults with cystic fibrosis-related dysglycemia

The National Institute of Diabetes and Digestive and Kidney Diseases, part of the Department of Health and Human Services National Institutes of Health, awarded Rhode Island Hospital $343,940 on August 31, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to conduct a pilot pre/post interventional clinical trial assessing the efficacy and safety of verapamil in adolescents and adults with cystic fibrosis-related dysglycemia.

The trial will enroll 30 adolescents (age >14 years) and adults with cystic fibrosis and abnormal glucose tolerance or early cystic fibrosis-related diabetes not yet requiring insulin therapy. The study will determine whether verapamil, a calcium channel blocker known to downregulate thioredoxin-interacting protein and preserve beta cell function in other diabetes types, improves beta cell function measured by mixed meal tolerance test-stimulated C-peptide area under the curve and reduces dysglycemia assessed via continuous glucose monitoring over a six-month treatment period. The award will also evaluate verapamil's safety and tolerability in this population.

Work is performed in Providence, Rhode Island. The period of performance runs from August 31, 2026, through July 31, 2029. This is a Project Grant, an assistance type supporting extramural biomedical research that advances prevention, diagnosis, and treatment of diabetes and kidney diseases.

Abstract

Cystic fibrosis-related diabetes (cfrd) is increasingly prevalent comorbidity in people with cystic fibrosis (pwcf). Cfrd and its precursor state, abnormal glucose tolerance (AGT), are associated with progressive pulmonary decline and nutritional deterioration. Insulin is the mainstay of treatment for cfrd and is known to improve long-term clinical outcomes. However no therapies, including insulin, currently exist to improve clinical outcomes in AGT, limit beta cell dysfunction, or halt progression from AGT to cfrd. Oxidative stress is known to contribute to both type 1 (T1D) and type 2 diabetes mellitus (T2D). Thioredoxin- interacting protein (txnip), a key regulator of oxidative stress, is upregulated in hyperglycemic states and contributes to beta cell apoptosis and impaired insulin secretion. Verapamil, a widely used calcium channel blocker, downregulates txnip and has shown promise in preserving beta cell function in T1D and T2D. Emerging data implicates oxidative stress as a central component of cystic fibrosis pathology, including within the CF pancreatic islets. Oxidative stress in pwcf is likely exacerbated by chronic inflammation, impaired antioxidant defenses, and cftr-related cellular dysfunction. The effects of verapamil on beta cell function and dysglycemia in people with CF-related dysglycemia are currently unknown. We propose a pilot pre/post interventional clinical trial to assess the efficacy and safety of verapamil in 30 adolescents (>14 years) and adults with CF and AGT or early cfrd (not yet on insulin). Aim 1 will determine whether verapamil (a) improves beta cell function, measured by mixed meal tolerance test (mmtt)-stimulated c-peptide area under the curve (AUC), and (b) reduces dysglycemia, assessed via continuous glucose monitoring (CGM), over a 6-month treatment period. Aim 2 will evaluate the safety, tolerability, and adherence to verapamil in this population. We hypothesize that verapamil will improve beta cell function and glycemic control, while demonstrating a favorable safety profile. This study will address a pressing unmet need in the management of AGT and early cfrd and provide further insight into the mechanism of CF-related dysglycemia. This proposal has the potential to transform the management of AGT and cfrd through a targeted, low risk, low-cost intervention aimed at preserving beta cell function and improving dysglycemia, providing key preliminary data to inform a larger phase 3 trial in this patient population.