Verapamil May Improve Beta-Cell Function in Type 1 Diabetes

The old antihypertensive drug verapamil may help reduce insulin requirements and hypoglycemic episodes in adults with type 1 diabetes, new research suggests.

Results from the study were published online July 9 as a research letter in Nature Medicine by Anath Shalev, MD, professor of medicine and director of the University of Alabama at Birmingham (UAB) Comprehensive Diabetes Center, and colleagues.

In the 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.

Now, with the current study, "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," Shalev told Medscape Medical News, stressing that the drug is "safe, well-tolerated, inexpensive, and readily available."

At the same time, she cautioned, "Verapamil has been FDA-approved for over 30 years, but improved beta-cell function is still not an FDA-approved indication, and we therefore cannot recommend its generalized use for this indication. Nevertheless, patients with diabetes and their physicians will now be able to consider the pros and cons for its use in an individualized manner case by case."

Verapamil Appears to Improve Beta-Cell Function

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).

Lower Insulin Requirements, Less Hypoglycemia With Verapamil

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 HbA_1c levels between 6% and 7%. At 6 months, HbA_1c 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.

The lower rate of hypoglycemia is likely because of the reduced overall insulin doses, Shalev told Medscape Medical News.

Overall, adverse events were mild and none required treatment discontinuation or dose reduction. The only adverse event that occurred more commonly with verapamil was constipation, a known side effect of the drug, but cases were mild, the investigators said.

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.

Current and Future Implications

Although this study was conducted in patients within 3 months of type 1 diabetes diagnosis, Shalev believes it could benefit those who have had the condition longer.

"Based on what we know about the mode of action, we feel that it is reasonable to believe that it will have some beneficial effects as long as there is some remaining beta-cell function left, which based on the natural history of diabetes could, for many patients, mean years."

Of course studies are needed to confirm this, she noted, along with investigations of verapamil use in children and adolescents, and people with type 2 diabetes, with longer follow-up among all groups.

"We are working with JDRF to push ahead in this regard," Shalev said.

The study was supported by JDRF and UAB. Shalev has reported no relevant financial relationships.

Nat Med. Published online July 9, 2018. Abstract

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