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37-Year-Old Hypertensive Drug Improves Beta Cell Function and Insulin Production

Jul 21, 2018
 

Researchers discover safe and effective therapy to reduce insulin requirements and hypoglycemic episodes in adult subjects with recent onset type 1.

The findings from a study show that regular oral administration of verapamil, a common blood pressure medication first approved for medical use in 1981, enabled patients to produce higher levels of their own insulin, limiting their need for insulin injections to balance out their blood sugar levels.

The randomized, double-blind, placebo-controlled human trial identified verapamil as a safe, effective, and promising therapy — a groundbreaking finding in the field of diabetes research.

The data collected from the clinical trial gives every indication to believe that individuals with type 1 diabetes have the promise of a treatment approach that would reduce their external insulin requirements and improve their glucose levels and quality of life, thanks to the effects that verapamil has in promoting the body’s own beta cell function.

While this research is not an end-all cure for type 1 diabetes, these findings are getting us closer to disease-altering therapies that can enable individuals with type 1 diabetes to better manage their disease and maintain some of their body’s own insulin production.

In the current double-blind placebo-controlled Phase 2 clinical trial (NCT02372253), 26 adults with recent-onset (within 3 months) type 1 diabetes were randomized to oral verapamil or placebo added to insulin for 12 months.

The plan for the study was announced in 2014 and was based on more than a decade of work by the UAB team in animal models, which suggested that verapamil, a calcium channel blocker, downregulates thioredoxin-interacting protein (TXNIP), which induces beta-cell apoptosis (cell death).

Verapamil therefore appears to bolster remaining endogenous beta-cell function, which has been shown to persist in people with type 1 diabetes longer than previously thought.  And in 2016, the same investigators reported the first human data from a large observational study in patients with type 1 or type 2 diabetes showing that those who took verapamil had lower average fasting serum glucose levels.

A total of 11 participants in the verapamil group and 13 participants in the placebo group completed the 1-year trial. Verapamil was started at a dose of 120 mg/day and titrated up, if tolerated, to a maximum of 360 mg/day. The primary endpoint, endogenous beta-cell function, was assessed by measuring the mixed-meal tolerance test stimulated C-peptide area under the curve at baseline, 3 months, and 12 months. After adjustment for any pre-existing differences at baseline, stimulated C-peptide was significantly greater in the verapamil group compared with the placebo group at both 3 and 12 months (P = .0334 and P = .0377, respectively).

And within each individual from baseline to 3 and 12 months, the verapamil-treated participants maintained a significantly higher percentage of stimulated C-peptide area under the curve compared with the placebo group (P = .0491 and P = .0451, respectively).

The verapamil clinical trial monitored 24 patients age 18 to 45, each over the course of one year. Eleven patients received verapamil and 13 received placebo. All clinical trial participants were diagnosed with type 1 diabetes within three months of their start in the trial and continued with their prescribed insulin pump therapy throughout the duration of the study. Researchers monitored the placebo and verapamil groups’ total daily dose of insulin, the amount of insulin produced, the percent change in insulin production, and their HbA1C levels. In addition, the number of hypoglycemic events that the patients experienced were recorded, and the percent of time each patient registered in healthy blood glucose ranges was analyzed using a continuous glucose monitoring system.

Verapamil also reduced the increase in insulin requirements typical of patients with recent-onset type 1 diabetes. At baseline, both groups were taking an average total of 0.26 units/kg/day. By 12 months, that requirement had risen by just 27% in the verapamil group compared with 70% in the placebo group (P = .0312), consistent with a slower decline in beta-cell function.

Throughout the study, both groups maintained average HbA1c levels between 6% and 7%. At 6 months, HbA1c was slightly but nonsignificantly lower in the verapamil group (P = .083).

Rates of hypoglycemia (≤ 2.2 mmol/L or ≤ 40 mg/dL) were 0.5 events/month in the verapamil group and 2.7 events/month in the placebo group (P = .0387). There were no severe hypoglycemic events requiring assistance from another person.

Overall, adverse events were mild and none required treatment discontinuation or dose reduction. Verapamil did not cause any hypotension or lowering of blood pressure in these normotensive patients, and there was no trend toward lower blood pressure in the verapamil group versus placebo. Heart rate and echocardiogram results remained normal.

Practice Pearls:

  • Verapamil reduced the increase in insulin requirements typical of patients with recent-onset type 1 diabetes.
  • Stimulated C-peptide was significantly greater in the verapamil group compared with the placebo group at both 3 and 12 months.
  • Future larger long-term studies are needed to help determine the effect of verapamil on both the pediatric and adult population who have type 1 diabetes diagnosed 3 months of less,and individuals with type 1 diabetes who have been living with and/or diagnosed longer than three months.
  • Verapamil is the first therapy to have demonstrated a clinically significant effect preserving beta-cell function and the patient’s own insulin production in adults with type 1 diabetes.

Reference:

Fernando Ovalle, Tiffany Grimes, Guanlan Xu, Anish J. Patel, Truman B. Grayson, Lance A. Thielen, Peng Li, Anath Shalev. Verapamil and beta cell function in adults with recent-onset type 1 diabetes. Nature Medicine, 2018; DOI: 10.1038/s41591-018-0089-4  Nature Medicine Nature Medicine Published online July 9, 2018