Verapamil In Preclinical Type 1 Diabetes

Type 1 diabetes (T1D) is preceded by a presymptomatic phase featured by the presence of islet autoantibodies (aAbs) without (Stage 1) or with (Stage 2) dysglycemia. Clinical investigations targeting Stage 1 or Stage 2 disease have been using the time to clinical disease progression (Stage 3) as primary outcome, with a consequent need for relative high numerosity and prolonged follow-up. Additional hurdles limit the feasibility of disease modifying therapy (DMT) trials for preclinical T1D, including the need for an established screening program able to identify those who might be eligible and the enrolment of relatively large cohorts followed until clinical onset. To overcome these major limitations, our group recently explored the use of mathematical metabolic modelling of beta cell function in the early disease stages of T1D and its ability to quantify the response to treatment. We gathered, for the current proposal, sites with an established screening program for family members of people with T1D. The evidence obtained in our previous experience led to the design of this trial aimed to test the effect of a calcium channel blocker - verapamil - on beta cell function, as quantified through mathematical modelling, in Stage 1 disease. While this drug was previously tested in children and adolescents in the early clinical phases of the disease (Stage 3), it has never been used in Stage 1 disease. Verapamil inhibits beta cell apoptosis in animal models and has been shown to increase C-peptide secretion in adults with recent onset T1D and in youths. We hypothesize that an earlier treatment with verapamil targeting people with Stage 1 disease, whose residual beta cell function is greater than those with Stage 3 disease, may result in prolonged preservation of beta cell functional mass - and, consequently, in delayed clinical progression.