New research (the Ver-A-T1D trial) presented at this year's Annual Meeting of the European Association for the Study of Diabetes (EASD) (Vienna, 15-19 September) shows that slow-release (SR) verapamil (360mg daily) could have a potential effect on beta-cell function in adults with newly diagnosed type 1 diabetes. The study is led by Professor Thomas R. Pieber, Medical University of Graz, Austria, on behalf of the Ver-A-T1D Study Group.
Type 1 diabetes (T1D) is a chronic autoimmune disease where the body's immune system mistakenly attacks and destroys insulin-producing cells in the pancreas, called beta cells. This leads to little to no insulin production, a hormone crucial for regulating blood sugar levels. Without sufficient insulin, glucose (sugar) builds up in the bloodstream, causing hyperglycaemia (high blood sugar). T1D is typically diagnosed in childhood, adolescence, or young adulthood, but can occur at any age. Most people with the condition quickly progress to needing insulin replacement therapy for the rest of their lives.
Previous studies have shown that certain types of overexpression of proteins can lead to beta cell death, and verapamil, a calcium channel blocker, can prevent this overexpression and thus potentially preserve beta-cell function. The Ver-A-T1D trial investigated whether verapamil SR (360mg daily) could preserve beta-cell function in adults with newly diagnosed type 1 diabetes. This European multicentre, randomised, placebo-controlled study recruited 136 participants across 21 sites in 6 European countries (Austria, Belgium, France, Germany, Italy and United Kingdom), with recruitment completed in May 2024.
Verapamil is a well-known drug for high blood pressure and other heart diseases, has been approved by the US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) for this indication. Verapamil has been used in adults and children for more than 5 decades.
The primary endpoint measured stimulated C-peptide response (a marker of beta cell function) during a 2-hour mixed meal tolerance test at 12 months. Whilst the study narrowly missed statistical significance, it demonstrated encouraging trends towards beta-cell preservation with verapamil treatment.
The authors did a per-protocol analysis – one which gives results for those who fully followed the study protocol, assuming the best-case scenario for a treatment, but it may not represent what will happen when the treatment is used more widely. This analysis yielded statistically significant results, suggesting the biological plausibility of verapamil's protective effects.
Secondary outcomes showed improvements in glycated hemoglobin (HbA1c – a measure of blood sugar control) only during the first six months of treatment. Insulin requirements and continuous glucose monitoring revealed comparable glycaemic control between groups. Verapamil demonstrated the well-established safety profile with no unexpected adverse or events. The most common side effects were first-degree AV block (a mild heart rhythm problem, which rarely causes clinical symptoms) (22% of participants) and bradycardia (slow heartbeat) (16%), both mild and reversible with dose reduction.
Ver-A-T1D was powered based on a minimal clinically important difference (MCID) of 0.18 nmol/L/min, derived from the INNODIA natural course of disease study in adults and paediatric studies showing C-peptide declines of 0.24-0.40 nmol/L/min. However, the actual placebo decline in Ver-A-T1D was only 0.09 nmol/L/min, suggesting the adult population without treatment had slower disease progression than anticipated. This retrospectively underpowered the trial for detecting clinically meaningful differences.
Put another way, Ver-A-T1D study was designed based on the expectation that, without treatment, people with type 1 diabetes would lose a certain amount of insulin-producing capacity each year. Previous studies showed declines of about 0.24–0.40 nmol/L/min, so the trial planned to detect a smaller but still important difference of 0.18 nmol/L/min. In reality, the participants in Ver-A-T1D participants without treatment only lost capacity much more slowly-only 0.09 nmol/L/min - meaning their disease progressed less quickly than expected. Because of this, the study did not have enough statistical power to reliably show whether the treatment made a true, clinically meaningful difference.
Professor Pieber concludes: "The unique non-immunosuppressive mechanism, the established safety profile and cost-effective delivery make verapamil still an attractive option for combination with immune modulating interventions for beta-cell preservation in type 1 diabetes. The next important step will be to analyse the 24-month follow-up data of Ver-A-T1D to find out how well insulin-producing capacity will be preserved in our patients without treatment. More importantly, in the Ver-A-Long extension study, we will follow patients who did continue with verapamil treatment after the Ver-A-T1D trial. This will give us very important information about long-term preservation of beta cell function over three years when verapamil is continuously used in newly diagnosed people with type 1 diabetes.
"Based on the results of the Ver-A-T1D study, we are currently also working with our colleagues in the UK and Australia to redesign our T1D-Plus programme. Within this important platform trial, we will investigate the combination of verapamil with immune‑modulating agents, with the aim of fully halting the progression of type 1 diabetes."
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