Calcium Channel Blocker Preserves Some Beta Cell Function in Early T1D

— But intensive glucose control didn't preserve pancreatic C-peptide secretion

A calcium channel blocker helped to partially preserve stimulated C-peptide secretion in kids with newly diagnosed type 1 diabetes, although more intensive management did not, according to a randomized clinical trial.

Children and adolescents who were randomized to receive once-daily oral verapamil within 31 days of diagnosis had a larger average C-peptide area under the curve after 52 weeks compared with placebo (adjusted between-group difference 0.14 pmol/mL, P=0.04), found Roy Beck, MD, PhD, of the Jaeb Center for Health Research in Tampa, Florida, and colleagues.

After 52 weeks of treatment, the verapamil group maintained a 30% higher C-peptide level: the mean area under the curve dropped from a baseline of 0.66 to 0.65 pmol/mL in the verapamil group, as compared with a drop from 0.60 to 0.44 pmol/mL in the placebo group.

That magnitude of benefit "is in the midrange of improvement reported for immunosuppressive agents that have been evaluated for newly diagnosed type 1 diabetes in randomized clinical trials," the researchers reported in JAMA. The trial was also presented at the International Conference on Advanced Technologies & Treatments for Diabetes in Berlin.

On top of preserving C-peptide secretion, there was a significantly higher percentage of patients on verapamil with a 52-week peak C-peptide level of 0.2 pmol/mL or greater (95%; 41 of 43 patients) compared with the placebo group (71%; 27 of 38).

Verapamil treatment didn't impact HbA1c at 52 weeks, though (6.6% vs 6.9% for placebo; P=0.65). Continuous glucose monitoring parameters and insulin doses were also similar between groups. 

Although verapamil showed only "modest benefits on C-peptide production," these findings are still clinically relevant to practice "because even stimulated C-peptide levels of 0.2 pmol/mL or greater are associated with a substantial reduction in the risk of retinopathy and nephropathy," wrote Jennifer Couper, MD, of Women's and Children's Hospital North Adelaide in Australia, in an accompanying editorial.

The fact that verapamil is also a well-tolerated and inexpensive oral treatment also favors its use, she added.

Treatment was deemed safe, as 17% and 20% of the verapamil and placebo groups, respectively, experienced a non-serious adverse event considered to be related to treatment. Only one event of severe hypoglycemia occurred in each group. The sole diabetic ketoacidosis event occurred in the placebo group. Three patients in the verapamil group experienced electrocardiogram abnormalities: one case of prolonged PR interval, one case of second-degree heart block plus prolonged PR interval, and one case of first-degree heart block.

"In view of the favorable safety profile compared with immunosuppressive agents, once-daily oral administration, and low cost, initiation of verapamil therapy could be considered for patients with newly diagnosed type 1 diabetes," the researchers suggested.

The trial included 88 patients ages 7 to 17 years (average 12.7) treated at six U.S. centers who weighed 30 kg (66 lb) or more and had at least one positive islet autoantibody.

The trial had a two-by-two factorial design, with patients randomly assigned to verapamil or placebo as well as to receive intensive diabetes management with an automated insulin delivery system (either Tandem Diabetes Care or Medtronic) or standard diabetes management.

A total of 22 received verapamil plus intensive management, 20 received intensive management plus placebo, 25 received standard care plus verapamil, and 21 received standard care plus placebo.

In the comparison of intensity of diabetes management, the automated insulin delivery group achieved "excellent" glucose control but didn't contribute to preserving pancreatic C-peptide secretion. 

That portion of the trial, also published in JAMA and presented at the meeting, showed a similar magnitude of decline in average C-peptide area under the curve during the 52-week trial between the groups (treatment group difference -0.01, 95% CI -0.11 to 0.10, P=0.89). This was marked by a drop from 0.57 pmol/mL at baseline to 0.45 pmol/mL at 52 weeks in the intensive management group and a drop from 0.60 to 0.50 pmol/mL in the standard care group.

However, those on intensive treatment spent an average of 16% (95% CI 10-22) more time in the target C-peptide range (70-180 mg/dL) -- translating to about 3.8 hours more per day. The intensive group had 78% of their time in target range, compared with only 64% for the standard care group.

Safety was generally similar between the groups though, with one event of severe hypoglycemia and one diabetic ketoacidosis event occurring in each group. 

There was no interaction between intensive management and verapamil on C-peptide preservation, Beck's group pointed out.

While the verapamil-placebo randomization was exclusive to youth weighing 30 kg or more, the management intensity randomization didn't include the weight stipulation.

Couper wrote that it was "unlikely that an even higher percentage of time with normoglycemia would afford better results, thus laying to rest the question of whether the best control that can be achieved currently improves beta cell function."

Though this strategy may not improve beta cell function, she said that maintaining this tight level of glycemic control would "undoubtedly" reduce the risk for vascular complications.

"Which combination of beta cell-preserving therapy and automated insulin delivery systems will ultimately promote the best long-term outcomes for an individual is another central question," Couper concluded, calling for more research. She also suggested research focus on possible treatment combinations involving verapamil during the early stages of type 1 diabetes before insulin dependence sets in.

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