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Interventions in people newly diagnosed with type 1 diabetes – Children’s Diabetes Foundation

Type 1 diabetes mellitus (T1DM) is characterized by a gradual loss of functional β-cells, leading to reliance on insulin and increased risk of complications resulting from hypoglycaemia and hyperglycaemia. Preserving β-cell function, particularly in patients newly diagnosed with T1DM, has been a focus of research for many years, but success has been limited. Furthermore, in the 1980s a theory was put forward that high glucose levels exacerbated the decline in β-cells (termed the glucotoxicity theory). In a single trial design, two papers have examined two potential approaches for preserving β-cell function: verapamil and tight glycaemic control.

The researchers used a factorial design to enable them to test two hypotheses in one trial. The trial included 113 patients aged 7–17 years who had been diagnosed with T1DM within the previous 31 days. The trial was conducted at six centres across the USA. To test the glucotoxity theory, 61 patients received automated insulin delivery (to facilitate tight glycaemic control), with the remaining 52 receiving standard care with a continuous glucose monitor. Patients were followed up regularly for 52 weeks, with a visit at 6 weeks after randomization and then at 13, 26, 39 and 52 weeks from the diagnosis of T1DM. At most visits (except the visit at 6 weeks), blood samples were taken to measure HbA1c levels and participants underwent a 2-hour mixed meal tolerance test to determine C-peptide levels.

Patients in the automated insulin delivery group achieved better glycaemic control than the patients in the standard care group, with a mean time in glucose range of 78% versus 64%. However, there were no statistical differences in the area under the curve for C-peptide after 52 weeks. These results indicate that tight glycaemic control did not prevent the decline in β-cell function. “This trial’s results put to rest further testing of the glucotoxicity theory,” say authors Gregory Forlenza and Roy Beck. Although tight glycaemic control does not preserve β-cell function, it can have other beneficial effects, particularly in terms of reducing the risk of microvascular complications of T1DM.

Verapamil is a calcium channel blocker that is already approved for other indications. In vitro work indicates that verapamil reduces β-cell apoptosis and a small trial in adults newly diagnosed with T1DM indicated that verapamil preserved β-cell function. “These promising results led us to design a much larger trial and conduct the trial in a paediatric population, which had not been previously studied with verapamil,” explain Forlenza and Beck.

Of the 113 patients included in the tight glycaemic control trial, 47 received verapamil (with 22 also receiving automated insulin delivery) and 41 received placebo (with 20 also receiving automated insulin delivery).

The mean C-peptide area under the curve was 0.66 pmol/ml at baseline and 0.65 pmol/ml at 52 weeks in the verapamil group, compared with 0.60 pmol/ml and 0.44 pmol/ml in the control group. These results represent a 30% relative treatment effect. A few patients experienced adverse effects, but verapamil was generally safe and well tolerated.

Over the course of T1DM, C-peptide levels usually increase shortly after diagnosis and then gradually decline. A similar pattern was seen in this study; however, C-peptide levels remained stable for longer in patients who received verapamil compared with those who received the placebo.

The authors suggest that these findings could have important clinical implications, given the lack of options for preserving β-cell function in people newly diagnosed with T1DM. “In view of its being readily available as a generic drug at low cost, oncea- day oral administration and a good safety profile, we expect that as the trial’s findings becomes widely known, verapamil will be prescribed frequently for newly diagnosed T1DM,” say Forlenza and Beck.

The researchers acknowledge several limitations of their studies, such as the small sample size and the need to only include children weighing >30 kg due to the available dosing options for extended-release verapamil. “As with many studies, the results answer one question but raise many other questions that will need to be addressed in future studies,” say Forlenza and Beck. For instance, this trial was not designed to determine how long verapamil treatment should be continued for, or whether initiating verapamil treatment several months or years after a T1DM diagnosis would be beneficial. Whether verapamil treatment would be beneficial in the earlier subclinical stages of T1DM or in children younger than those included in this study could also be explored.

Claire Greenhill

Original articles: Forlenza, G. P. et al. Effect of verapamil on pancreatic beta cell function in newly diagnosed pediatric type 1 diabetes: a randomized clinical trial. JAMA https:// doi.org/10.1001/jama.2023.2064 (2023); McVean, J. et al. Effect of tight glycemic control on pancreatic beta cell function in newly diagnosed pediatric type 1 diabetes: a randomized clinical trial. JAMA https://doi.org/10.1001/ jama.2023.2063 (2023)