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.

Inclusion criteria

• Age 14 years and older
• Genetically-confirmed diagnosis of cystic fibrosis
• Clinical diagnosis of pancreatic insufficiency, defined as requiring pancreatic enzyme replacement therapy (PERT)
• Diagnosis of AGT or CFRD within 3-months of study enrollment

• AGT is defined as having either a OGTT 2-hour glucose >140 mg/dL and <200 mg/dL or OGTT 1-hour glucose >200 mg/dL
• CFRD is defined as having a fasting glucose >126 mg/dL and/or OGTT 2-hour glucose >200 mg/dL
• Willing to attempt to maximize verapamil to the goal study dosage of 360 mg PO daily
• If taking elexacaftor/tezacaftor/ivacaftor (ETI), willing to adjust dosing

Exclusion criteria

• Severe lung disease indicated by forced expiratory volume in 1 second (FEV1) <50% predicted on most recent spirometry testing
• Body mass index (BMI) <18 kg/m2
• Weight <50 kg
• Current or planned pregnancy within the next 6 months
• Treatment with IV antibiotics for a CF exacerbation within 1 month
• Systemic supraphysiologic glucocorticoid use within 1 month
• Initiation or discontinuation of a CFTR modulator within 3 months (i.e. recent change in CFTR modulator formulation/usage)
• Current use of insulin, a GLP-1 receptor agonist, or oral anti-diabetic agent
• Most recent HbA1c >7%
• Not taking a CFTR modulator due to genotype-ineligibility
• Current use of vanzacaftor/tezacaftor/deutivcaftor
• Known hypersensitivity to verapamil
• Blood pressure (BP) <90/60 (adults) or <5th centile for age and gender (youth) in 2 out of 3 measurements
• Heart rate (HR) <60 bpm (adults) or <2nd centile for age and gender (youth) in 2 out of 3 measurements
• History of previously diagnosed vasovagal syncopal episodes related to hypotension
• History of significant cardiac disease (e.g. severe ventricular dysfunction, hypertrophic cardiomyopathy)
• History of certain arrhythmias (e.g. AV block, accessory pathway such as Wolff-Parkinson-White or Lown-Ganong-Levine syndromes)
• Abnormal liver function tests defined as AST or ALT >1.5 upper limit of normal [ULN] at the time of screening, or end stage cirrhosis
• End stage renal disease on dialysis
• History of Duchenne's muscular dystrophy
• Need for the use of any pertinent medications (beta blockers, carbamazepine, phenobarbital, phenytoin, HMG-CoA reductase inhibitors, lithium, theophylline, clonidine).
• Allergy to any of the components of the MMTT standardized meal