Youth-Onset Diabetes Needs Different Approach to That in Adults

June 27, 2018

ORLANDO — In adolescents with impaired glucose tolerance (prediabetes) or recent-onset type 2 diabetes, early intervention with long-acting insulin followed by metformin, or metformin alone — both given for a year — failed to prevent deterioration in beta-cell function.

Dr Kristen J. Nadeau

Indeed, beta-cell function declined in both groups during treatment and worsened after treatment ended in the Restoring Insulin Secretion (RISE) pediatric medication study, reported here June 25 at the American Diabetes Association (ADA) 2018 Scientific Sessions.   

"The most striking part was the fact that in the prediabetes state, we were not seeing improvement, and yet there are a lot of pediatricians who use metformin in prediabetes because the Diabetes Prevention Program (DPP) showed that it was effective in adults, but we're not seeing that response," said Kristen J. Nadeau, MD, professor of pediatrics at the University of Colorado Anschutz Medical Campus, Aurora, during a press conference to discuss the findings, which were simultaneously published in Diabetes Care.  

"The big take-home message is that there's not evidence right now for indicating treatment in that prediabetic state [in adolescents], at least not with these therapies," Nadeau told Medscape Medical News

But "we are definitely not recommending stopping metformin in young people who have type 2 diabetes, because there are definitely benefits," in terms of lowering blood glucose.

"But metformin alone is not a long-term solution for many youth, so we do need to work on additional adjunctive therapies," she stressed.

Insulin and metformin are the only treatments approved for use in type 2 diabetes in youth, but "there are therapies available for type 2 diabetes [in adults] that we use off-label in pediatrics, such as GLP-1 agonists and SGLT2 inhibitors," Nadeau told Medscape Medical News.

Diabetes Much More Aggressive in Teens

Dr Steven E. Kahn

Co-investigator Steve E. Kahn, MBChB, of VA Puget Sound Health Care System, University of Washington, Seattle, said: "For all of us, when we saw the pediatric results, it was disappointing. It was not what we predicted based on everything we see in adults, where intensive insulin therapy preservers beta cells, and where metformin has been shown to be effective in adults as a first-line therapy and in prevention."

"What we've learned is that the disease is very different and potentially very aggressive [in adolescents]," Kahn told assembled journalists. "Understanding why they have this bad disease is going to be critical, because it may be that we have to tackle it at a more basic level than simply just medications that are available today."

"Early beta-cell failure creates permanent dependence on insulin, and thus youth may be at higher risk of future diabetes complications," he said.

John B. Buse, MD, PhD, of the University of North Carolina School of Medicine, Chapel Hill, who is a coauthor of an accompanying editorial to the RISE study, also published in Diabetes Care, concurred.

"The biggest message is that this epidemic of obesity in youth has real implications and these kids are in trouble. If we can't treat them with insulin or metformin...to get their HbA1c to a reasonable range for 80 years, they are going to have...complications."

"This really increases the moral imperative to do something about the obesity epidemic," he stressed.

Nadeau concurred: "I just want to echo that comment — since it's so difficult to treat, we need to prevent it — with exercise, diet, and healthy sleep. These kinds of things need to happen so kids are not getting to the point where we can't do anything."

RISE Results Support TODAY Study Findings

In the RISE pediatric medication study, 91 pubertal obese youth were randomized to either 12 months of metformin titrated to 1000 mg twice daily or 3 months of insulin glargine titrated twice a week to achieve a fasting glucose level of 4.4–5.0 mmol/L based on daily self-monitored blood glucose and followed immediately by 9 months of metformin.

The kids were on average 14 years old, had a mean body mass index (BMI) of 37.7 kg/m2, and an average HbA1c of 5.7%. Overall, 60% had impaired glucose tolerance and the remainder had type 2 diabetes of less than 6 months' duration.

Less than 30% were white. Most (77%) had received no glucose-lowering therapy, whereas 23% had taken metformin. Participants had hyperglycemic clamps and oral glucose tolerance tests performed on separate days at baseline, 12 months, and 15 months.

Both interventions were well tolerated and study retention was high, with 84 of 91 enrolled participants completing the 15-month evaluation. Investigators, and study participants and their families, were congratulated for adhering to the rigors of the study protocol, given the sophisticated assessments employed and amount of hospital visits involved.

No significant differences were observed between treatment groups at baseline, 12 months, or 15 months in beta-cell function, BMI percentile, HbA1c, fasting glucose, or 2-hour oral glucose tolerance test results.

And in both treatment groups, clamp-measured beta-cell function was significantly lower at 12 and 15 months versus baseline.

"These results support those observed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, which demonstrated that in 50% of youth with type 2 diabetes, initial assigned treatment failed, requiring the initiation of insulin therapy after an average follow-up of 3.9 years, which is in keeping with faster disease progression than reported in adults," say Nadeau and colleagues in their article.

Understanding of Type 2 Diabetes in Youth "Still Maturing"

These findings have clinical relevance because the vast majority of teenaged patients with type 2 diabetes are treated with metformin and insulin, and yet these data show standard treatments do little to alter the natural history of the disease, say Buse and David A. D'Alessio, MD, of Duke University Medical Center, Durham, North Carolina, and Matthew C. Riddle, MD, of Oregon Health & Science University, Portland, in their editorial.

Nadeau said more research is needed into what happens during puberty — when insulin resistance gets worse so there is more demand on the beta cells — "so that we can better understand why it is that youth look so different from a physiological point of view."

"Additionally, the results...call for further studies to identify new safe and effective treatment options for youth with impaired glucose tolerance or type 2 diabetes," she said.

Griffin P. Rogers, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which sponsors the RISE consortium of studies, agrees: "Our understanding of how type 2 diabetes affects youth is still maturing, and we must continue to explore treatments to ensure that these young people can live long, healthy lives. These results give us another piece of the puzzle to find which therapies will treat youth with type 2 diabetes."

RISE is supported by grants from the NIDDK, National Center for Advancing Translational Sciences, Department of Veterans Affairs, and Kaiser Permanente Southern California, with additional support from the American Diabetes Association, Allergan, Apollo Endosurgery, Abbott Laboratories, and Novo Nordisk. Kahn is a paid consultant on advisory boards for Novo Nordisk. Buse receives research support from, owns stock in, and/or is an advisor for Adocia, ADA, AstraZeneca, Dexcom, Elcelyx, Eli Lilly, Fractyl, Intarcia, Lexicon, Metavention, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, NovaTarg, Novo Nordisk, Sanofi, Shenzhen Hightide Biopharmaceutical, VTV Therapeutics, Boehringer Ingelheim, Johnson & Johnson, National Center for Advancing Translational Sciences, National Heart, Lung, and Blood Institute, Patient-Centered Outcomes Research Institute, and Theracos. Nadeau has reported no relevant financial relationships.

American Diabetes Association 2018 Scientific Sessions. June 25, 2018; Orlando, Florida. Symposium: The Restoring Insulin Secretion (RISE) Study in Youth and Adults.

Diabetes Care. Published online June 25, 2018. Full text, Editorial

Follow Lisa Nainggolan on Twitter:  @lisanainggolan1. For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

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