Verapamil Effect in Cystic Fibrosis-related Dysglycemia

Cystic fibrosis-related diabetes (CFRD) is one of the most common non-pulmonary complications of cystic fibrosis (CF) and is associated with reduced pulmonary function, worse nutritional status, earlier mortality, and impaired quality of life. Dysglycemia in CF typically begins with abnormal glucose tolerance (AGT), characterized by impaired first-phase insulin secretion and postprandial hyperglycemia, and may progress over time to CFRD. Insulin therapy is currently the only recommended treatment for CFRD; however, it adds substantial treatment burden to an already medically complex population. At present, there are no approved therapies targeting beta cell dysfunction or aimed at preventing progression from AGT to CFRD in people with CF.

The pathophysiology of CFRD is increasingly recognized as being driven primarily by beta cell dysfunction rather than complete beta cell destruction. Although insulin secretion is impaired in CF, beta cell mass is relatively preserved compared with type 1 diabetes mellitus (T1D), and residual endogenous insulin production often persists for many years after CFRD diagnosis. Mechanisms contributing to beta cell dysfunction in CF are believed to include oxidative stress, inflammation, endoplasmic reticulum stress, impaired antioxidant defenses, and islet immune dysregulation.

Thioredoxin-interacting protein (TXNIP), a key cellular regulator of oxidative stress, has been implicated in beta cell dysfunction and apoptosis in other forms of diabetes mellitus. Verapamil, a calcium channel blocker commonly used for hypertension and arrhythmias, has been shown to reduce TXNIP expression, decrease inflammatory signaling, and promote beta cell survival. Given the known role of oxidative stress in the CF pancreas and the preservation of residual beta cell function in CFRD, verapamil represents a promising candidate therapy for modifying beta cell dysfunction and improving dysglycemia in CF. However, the effects of verapamil on beta cell function and glucose regulation in people with CF have not previously been studied.

This study is a pilot open-label, pre/post interventional trial designed to evaluate the safety, tolerability, and preliminary efficacy of verapamil in adolescents and adults with CF and AGT or early CFRD not currently treated with insulin therapy. Thirty participants aged 14 years and older with genetically confirmed CF, pancreatic insufficiency, and AGT or early CFRD will be enrolled.

Following screening and confirmation of glycemic status by oral glucose tolerance testing (OGTT), participants will complete a two-week blinded continuous glucose monitoring (CGM) run-in period to establish baseline glycemia. Participants will then undergo a baseline mixed meal tolerance test (MMTT) to assess beta cell function. Verapamil extended release (ER) therapy will be initiated at 120 mg daily and titrated over approximately six weeks to a target dose of 360 mg daily as tolerated. Participants will continue treatment for six months, after which CGM and MMTT assessments will be repeated.

The primary efficacy endpoint is the change from baseline in MMTT-stimulated incremental C-peptide area under the curve (AUC) during the first 30 minutes following mixed meal ingestion, a validated measure of first-phase insulin secretion and beta cell function in CF. Secondary efficacy endpoints include changes in additional MMTT-derived measures of insulin secretion and glucose metabolism, hemoglobin A1c, and CGM-derived measures of dysglycemia including time spent in hyperglycemic and hypoglycemic ranges, average glucose, glucose variability, and coefficient of variation. Safety and tolerability assessments will include monitoring of liver function tests, blood pressure, heart rate, electrocardiograms, pulmonary function tests, weight, hypoglycemia, gastrointestinal symptoms, CFTR modulator levels, adverse events, and medication adherence.

The results of this pilot study will provide important preliminary data regarding the feasibility, safety, and potential efficacy of verapamil as a novel therapeutic strategy targeting beta cell dysfunction in CF-related dysglycemia and will help inform the design of future larger randomized clinical trials.

• Change in 180 minute C-peptide area under the curve after mixed-meal tolerance test [Time frame: Baseline, 6 months]
• Change in insulin level area under the curve after mixed-meal tolerance test [Time frame: Baseline, 6 months]
• Change in proinsulin area under the curve after mixed-meal tolerance test [Time frame: Baseline, 6 months]
• Change in glucose area under the curve after mixed-meal tolerance test [Time frame: Baseline, 6 months]
• Change in hemoglobin A1c [Time frame: Baseline, 6 months]
• Change in elexacaftor/tezacaftor/ivacaftor trough levels [Time frame: Baseline, 8 weeks, 6 months]
• Change in aspartate aminotransferase (AST) [Time frame: Baseline, 8 weeks, 6 months]
• Change in alanine aminotransferase (ALT) [Time frame: Baseline, 8 weeks, 6 months]
• Change in glucose management indicator (GMI) % [Time frame: Baseline, 8 weeks, 6 months]
• Change in average glucose (AG) mg/dL [Time frame: Baseline, 8 weeks, 6 months]
• Change in standard deviation (SD) [Time frame: Baseline, 8 weeks, 6 months]
• Change in coefficient of variation (CV) [Time frame: Baseline, 8 weeks, 6 months]