medwireNews: Two linked randomized trials published in JAMA support a role for verapamil, but not for intensive glycemic control, to slow C-peptide decline in children with newly diagnosed type 1 diabetes.
The trials recruited 113 children aged between 7 and 17 years who had been diagnosed with type 1 diabetes within the preceding 31 days. Sixty-one of these children were randomly assigned to receive intensive glucose control; they were given a hybrid closed-loop insulin delivery system and followed up every 1–3 days for the first 2 weeks, at least twice weekly for the second 2 weeks and every 1–2 weeks for the remainder of the trial, which lasted 52 weeks.
This achieved an average time in target glucose range of 82%, compared with 73% in the 52 participants who received standard care, consisting of a continuous glucose monitor and usual support from their diabetes healthcare team.
However, intensive glucose control did not preserve beta-cell function, report Roy Beck (Jaeb Center for Health Research, Tampa, Florida, USA) and co-researchers.
Both groups experienced an increase in average C-peptide area under the curve (AUC) during a mixed-meal tolerance test during the first 13 weeks, followed by a decline. Overall, the AUC decreased from 0.57 pmol/mL at baseline to 0.45 pmol/mL at week 52 in the intensive control group and from 0.60 pmol/mL to 0.50 pmol/mL in the standard-care group. The difference between the two groups at week 52 was not statistically significant.
In a linked editorial, Jennifer Couper (Women’s and Children’s Hospital, Adelaide, South Australia) says: “It seems 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.”
But she adds: “Undoubtedly though this level of glycemic control, if maintained, will significantly reduce the risk of vascular complications.”
The verapamil trial involved a subset of 88 study participants who weighed 30 kg or more and, having already been randomized to undertake tight or standard glucose control, were additionally randomly assigned to take the calcium-channel blocker verapamil or placebo.
Those taking verapamil started at a dose of 60 or 120 mg/day according to weight, escalated to a maximum of 360 mg/day for children weighing more than 50 kg. At baseline, their average C-peptide AUC was 0.66 pmol/mL, and by week 52 this was an almost identical 0.65 pmol/mL.
In the placebo group, by contrast, there was a decrease from 0.60 to 0.44 pmol/mL, with the week 52 value being a significant 30% higher in the verapamil than placebo group. At week 52, 95% of the verapamil group had a peak C-peptide level of at least 0.20 pmol/mL, compared with 71% of the placebo group.
“We observed few treatment-related adverse events, none of which were serious, which is consistent with the known safety profile of verapamil,” say Beck and colleagues.
There was one episode of severe hypoglycemia in each group and one episode of diabetic ketoacidosis in the placebo group.
Couper says that the “modest” 30% improvement in beta-cell function with verapamil, “accepting the difficulties in comparisons across trials, lies approximately midway in the range of increments in C-peptide secretion at 1 year that are reported for immunomodulatory agents.”
She believes that “[a] well-tolerated, inexpensive, oral treatment such as verapamil with modest benefits on C-peptide production is 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.”
The findings therefore support “investigation of verapamil in combination with other effective agents during the earlier stages of type 1 diabetes before insulin dependence develops,” concludes Couper.
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