Evaluating DCCR in Prader–Willi syndrome with pre-diabetes or diabetes

touchENDOCRINOLOGY coverage of ECE 2026

Prader–Willi syndrome is associated with complex metabolic and endocrine challenges, including an increased risk of impaired glucose regulation. Could you begin by outlining the clinical background for this study and explaining why evaluating DCCR specifically in patients with pre-diabetes or diabetes was an important question to address?

Prader–Willi syndrome is a neurometabolic disorder caused by abnormalities involving chromosome 15. It is essentially a disorder of the hypothalamus, which regulates metabolism, satiety, hunger, temperature and hormone production. One of the major challenges in Prader–Willi syndrome is hyperphagia, for which there has historically been no effective treatment, representing a significant unmet clinical need. Without a strictly controlled food environment and reduced calorie intake, patients with Prader–Willi syndrome will typically develop severe obesity.

The only treatment that is available at the moment is growth hormone therapy. While this can help reduce fat mass and increase muscle mass, it does not address the underlying hyperphagia.
DCCR, or diazoxide choline-controlled release, is a modified form of diazoxide that has been investigated as a treatment for hyperphagia in children with Prader–Willi syndrome. Those trials have now been completed and demonstrated reductions in hyperphagia, leading to FDA approval, and the drug is currently being used in the United States.

A side effect of DCCR is that blood glucose levels can increase because the drug reduces insulin secretion from the pancreas. In the studies, we observed small increases in glucose levels and HbA1c, indicating slightly higher average blood glucose levels. This naturally raised the question of whether the drug is safe to use in children who already have pre-diabetes or diabetes.

That was the rationale for this study. The analysis used the same dataset from the earlier trials evaluating the effects of DCCR on hyperphagia, but the data were re-analyzed to determine whether the drug had different effects in patients with pre-diabetes or diabetes compared with those without impaired glucose regulation.

Can you briefly outline the study design, patient population and key endpoints?

The study was conducted over several years. The initial phase consisted of a 13-week placebo-controlled trial, in which half of the patients received DCCR and the other half received placebo. This was followed by an open-label extension study, which continued for quite a long period, partly because it spanned the COVID-19 pandemic. At the end of the open-label extension, there was also a placebo-controlled withdrawal phase.

For the current analysis examining the effects of DCCR in patients with pre-diabetes or diabetes, the investigators used data from the initial 13-week placebo-controlled study together with the open-label extension phase, but not the randomized withdrawal phase, as including that would have made the analysis considerably more complex.

In total, 125 patients with Prader–Willi syndrome were enrolled in the initial study, and approximately 115 went on to participate in the open-label extension study. Using the updated American Diabetes Association criteria, around 60% of patients were classified as having pre-diabetes or diabetes, while 40% did not have impaired glucose regulation.

The ADA criteria used were relatively strict, defining pre-diabetes as either a fasting blood glucose level of 5.6 mmol/L or higher, or an HbA1c of 39 mmol/mol or higher.

What were the main aims of the analysis, and what did you expect DCCR to improve?

There were two main questions addressed in this analysis. The first was whether patients with and without pre-diabetes or diabetes responded to DCCR in the same way in terms of improvements in hyperphagia. The second was whether DCCR was safe to use in patients with impaired glucose regulation. Specifically, the investigators wanted to know whether blood glucose levels increased substantially, whether there were significant side effects and whether patients had to discontinue treatment because of worsening glucose control.

To evaluate efficacy, the study used the Hyperphagia Questionnaire for Clinical Trials, or HQ-CT. The hypothesis was that there would not be a major difference in response between patients with pre-diabetes or diabetes and those without, because the mechanism of action of DCCR is primarily in the hypothalamus and related tissues, and there was no reason to expect that this would differ according to diabetes status.

In terms of safety, previous data from the overall study population had already shown that blood glucose levels tend to rise initially, particularly at the start of treatment, but then stabilize relatively quickly and generally do not increase dramatically. Based on this, the expectation was that DCCR would also be safe in patients with pre-diabetes or diabetes, and that glucose levels would not rise to the extent that patients would frequently need to stop treatment or develop type 2 diabetes.

What were the key efficacy and safety findings presented at ECE 2026? Were there any outcomes that were especially notable in relation to glycemic control, body composition, hyperphagia, or tolerability in this higher-risk subgroup?

The key efficacy finding was that DCCR reduced hyperphagia to a similar extent in patients with and without pre-diabetes or diabetes. At baseline, hyperphagia scores were comparable between the two groups, at around 21–22 points. With treatment, scores fell substantially, to approximately 8.7 in patients without pre-diabetes or diabetes and 9.7 in those with pre-diabetes or diabetes, with no significant difference between the groups. This demonstrated that DCCR was effective in reducing hyperphagia regardless of glycemic status.

In terms of safety and glycemic control, fasting blood glucose and HbA1c levels were, as expected, slightly higher in patients with pre-diabetes or diabetes at baseline. Fasting glucose was around 5.7 mmol/L in the pre-diabetes/diabetes group compared with approximately 5.3 mmol/L in patients without impaired glucose regulation. During DCCR treatment, fasting glucose increased modestly, to around 5.9 mmol/L in the pre-diabetes/diabetes group and 5.4 mmol/L in the group without diabetes. Overall, this represented only a small increase: approximately 0.2 mmol/L in those with pre-diabetes or diabetes and 0.1 mmol/L in those without.

Importantly, these increases were limited and did not lead to large numbers of patients progressing to type 2 diabetes. There was also no increase in treatment discontinuation related to glucose control. The proportion of patients who stopped treatment was similar in both groups: approximately 4% in the pre-diabetes/diabetes group and 6% in the group without impaired glucose regulation. In most cases, discontinuations were not related to glucose or diabetes-related issues.

Overall, the conclusion presented at ECE 2026 was that DCCR is both effective and generally safe in patients with Prader–Willi syndrome who have pre-diabetes or diabetes. However, careful glucose monitoring remains important, particularly at the start of treatment. The recommendation is to monitor fasting glucose weekly initially, with more frequent monitoring if glucose levels rise, alongside consideration of dose adjustment or the introduction or intensification of anti-hyperglycemic therapy such as metformin when needed.

How do you see these findings influencing future clinical practice and research?

I hope these findings will help clinicians who are not yet very experienced with DCCR feel more confident about using the treatment in patients with Prader–Willi syndrome, including those with pre-diabetes or diabetes. In the meantime, a guideline has also been published in the Journal of the Endocrine Society that provides practical recommendations for monitoring blood glucose levels during treatment. Together, I hope these data reinforce that DCCR is a viable option for patients with impaired glucose regulation, provided that appropriate glucose monitoring is in place.

In terms of future research and clinical development, DCCR is currently licensed in the United States, but not yet in Europe or the UK. I hope these findings will support further progress towards licensing in Europe and the UK or help facilitate additional clinical trials of DCCR in these regions.