RISE: Adults, adolescents differ in ability to recover beta-cell function

SAN FRANCISCO — Adults with impaired glucose tolerance or type 2 diabetes who undergo a regimen of metformin or liraglutide plus metformin may experience increases in beta-cell response, but sustained improvements require ongoing treatment, according to a presenter at the American Diabetes Association Scientific Sessions.

In addition, the beneficial effects of some treatments are not found in children with type 2 diabetes, indicating a more aggressive form of the disease in this population.

Adult outcomes

During a press conference, Kieren J. Mather, MD, professor of medicine at Indiana University School of Medicine in Bloomington, detailed the findings from the Restoring Insulin Secretion (RISE) Adult Medication Study that were simultaneously published in Diabetes Care. Researchers recruited 267 adults with type 2 diabetes (mean age, 53.9 years; mean BMI, 35 kg/m²; 43% women) for a randomized trial comparing the effects of three treatment strategies — metformin, insulin glargine (Lantus, Sanofi) for 3 months and then metformin for 9 months, and liraglutide (Victoza, Novo Nordisk) plus metformin for 12 months — as well as a placebo regimen.

Participants were randomly assigned to one of the four groups and followed for 15 months. Steady-state C-peptide, acute C-peptide response to arginine at maximal glycemic potentiation, and acute C-peptide response to glucose were used to assess beta-cell response, according to the researchers. These measures were evaluated along with insulin sensitivity via hyperglycemic clamp. These assessments took place at baseline, 12 months and 15 months, with participants discontinuing whichever medication plan they were assigned to during the final 3 months.

Adults with type 2 diabetes who undergo a regimen of metformin or liraglutide plus metformin may experience increases beta-cell response, but sustained improvements require ongoing treatment.

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Compared with baseline measures, beta-cell responses measured using C-peptide improved in all three active treatment groups at 12 months when on treatment (P < .05 to P < .001 compared with baseline), with the greatest improvement observed in those who received liraglutide plus metformin.

However, all treatment effects compared with baseline were no longer statistically significant in any of the groups at 15 months, which included a 3-month “washout” period when medications were no longer taken, the researchers reported.

“After 12 months of treatment, improvements in beta-cell responses were seen in all three active treatment groups with some difference between them, but nevertheless, improvements in all three treatment groups. However, despite those improvements … we did not see sustained improvements in beta-cell function in any treatment group,” Mather said. “The RISE investigators see a need for sustained treatment in order to see persisting benefits for this type of population.”

Pediatric outcomes

Using the same assessment parameters as the RISE trial in adults, a similar trial was conducted with 91 children with type 2 diabetes. Only treatments for metformin (n = 47; mean age, 13.9 years; 80.9% girls) and insulin glargine plus metformin (n = 44; mean age, 14.9 years; 61.4% girls) were tested via random assignment due to the unclear evidence surrounding liraglutide’s effects on children, according to Steven E. Kahn, MB, ChB, Leonard L. Wright and Marjorie C. Wright Term Chair and professor of medicine and metabolism, endocrinology and nutrition at the VA Puget Sound Health Care System and University of Washington in Seattle, who presented the findings of this comparison trial, which were simultaneously published in Diabetes.

Unlike in the adult comparison cohort for this study (n = 132), the children assigned to insulin glargine plus metformin or metformin alone did not have significant changes in beta-cell response at 12 months while beta-cell response got worse from 12 months to 15 months. Specifically, steady-state C-peptide lowered by a significant amount from baseline to 12 months (P = .004) and 12 months to 15 months (P = .024) in children taking insulin glargine plus metformin compared with adults taking the same treatment.

“The difference in beta-cell outcomes in response to medications in youth vs. adults supports, in our mind, a more adverse trajectory of beta-cell deterioration in youth,” Kahn said. “Therefore, we feel there is an urgent need for the community to better understand what differs between youth and adults in terms of the pathophysiology of type 2 diabetes in a way that would allow us to more precisely target or develop new interventions that would not only benefit adults but, more importantly, will be helpful in youth who have diabetes.” – by Phil Neuffer

Reference:

Ehrmann D, Mather K, Edelstein S, Kahn S for The RISE Consortium. Results and comparisons from the RISE Clinical Trial – Adult Medication Study. Presented at: American Diabetes Association 79th Scientific Sessions; June 7-11, 2019; San Francisco.

RISE Consortium. Diabetes Care. 2019;doi:10.2337/dc19-0556.

RISE Consortium. Diabetes. 2019;doi:10.2337/db19-0299.

Disclosures: Mather reports that he received an investigator-initiated grant from Novo Nordisk during the conduct of this study. Kahn reports that he has served as a paid consultant on advisory boards and has been a steering committee member for Novo Nordisk-sponsored clinical trials.