Two RISE Clinical Trials in Youth and Adults with Impaired Glucose Tolerance or Newly Diagnosed Type 2 Diabetes Reveal Surprising Differences in Beta-Cell (β-cell) Function During and After Treatment

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Two RISE Clinical Trials in Youth and Adults with Impaired Glucose Tolerance or Newly Diagnosed Type 2 Diabetes Reveal Surprising Differences in Beta-Cell (β-cell) Function During and After Treatment
San Francisco, California

In a study measuring Beta-cell (β-cell) function in adults with impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetes (T2D), researchers from the Restoring Insulin Secretion (RISE) Adult Medication Study found β-cell function was improved during active treatment but did not produce any lasting benefits after treatment cessation. Results presented today at a symposium at the American Diabetes Association’s® (ADA’s) 79th Scientific Sessions® suggest continued intervention may be required to alter progressive β-cell dysfunction.

Given the increased recognition of the critical role of β-cells (cells that store and release insulin in the body), in the pathogenesis of T2D, research efforts have begun to focus on prevention of the loss of insulin secretion among individuals at high risk for T2D or in early stages of the disease in order to reduce long term complications of T2D.

The RISE Adult Medication Study was a controlled, randomized trial that enrolled 267 adults with IGT (n=197, 74%) or recently diagnosed T2D (n=70, 26%). Participants were randomly assigned to receive one of four treatment regimens: 1) 12 months of metformin alone; 2) 3 months of insulin glargine with a target fasting glucose 4.4-5 mmol/L, followed by 9 months of metformin; 3) 12 months of liraglutide combined with metformin; or 4) 12 months of placebo.

Using a hyperglycemic clamp, researchers sought to answer whether β-cell function improvement is maintained after 12 months of treatment and three months of withdrawal. During the hyperglycemic clamp, researchers raise the patient’s glucose concentration above their optimal glucose level by administering an intravenous infusion of glucose. The desired high blood glucose level is maintained by adjusting the glucose infusion amount. This enabled researchers to then assess how fast the person’s body is metabolizing glucose.

All three active treatment regimens produced on-treatment reductions in weight and improvements in HbA1c compared to placebo, with the greatest improvements appearing in the liraglutide plus metformin group.  Additionally, at 12 months, glucose-stimulated C-peptide responses improved in the three active treatment groups, with the greatest improvements in the liraglutide plus metformin group, however, the arginine-stimulated incremental C-peptide response was reduced in the liraglutide plus metformin group.

Despite the benefits shown during the 12 months of treatment, at three months after treatment, there were no sustained improvements in β-cell function in any treatment group. Researchers concluded that the interventions that improved β-cell function during active treatment failed to produce lasting benefits. These observations suggest that continued intervention may be required in order to alter the progressive β-cell dysfunction in IGT or early type 2 diabetes.

“We are somewhat surprised by these findings. We expected some of the participants would have seen beneficial effects after treatment ended; however, that was not the case and suggests long-term management may be required to prevent loss of β-cell function,” said RISE study investigator Kieren J. Mather, MD, professor of medicine at Indiana University School of Medicine.

The study, “Lack of Durable Improvements in β-Cell Function following Withdrawal of Pharmacological Interventions in Adults with Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes is published online simultaneously today in the ADA’s flagship journal Diabetes Care, the highest-ranked, peer-reviewed journal in the field of diabetes treatment and prevention.

The RISE Consortium also presented a direct comparison of two of its studies comparing outcomes in youth and adults during the symposium today at the 79th Scientific Sessions. Because the pathogenesis of T2D in youth is poorly understood, as well as how it differs from T2D in adults, the RISE Consortium offered the first direct comparison of the RISE Adult Medication Study and the RISE Pediatric Medication Study, both of which used the same approaches.

The RISE Pediatric Medication Study was conducted from 2013 to 2016 and enrolled 91 youth between the ages of 10 and 19 years with IGT (60%) or type 2 diabetes of

Results were assessed using the same methodology as the same two treatment groups in the adult study. Research indicated temporal changes in β-cell function were dissimilar between the two age groups in both studies. Among the youth in the pediatric study, β-cell function deteriorated both during treatment and after treatment withdrawal, with no differences between treatment groups. This contrasted to the results in the adult study participants, where β-cell function improved during treatment but was not sustained after treatment ended.

“The difference in the outcomes between the youth and adults is quite stark and highlights that type 2 diabetes in youth may have a different underlying pathology and, therefore, a different natural history,” stated RISE Consortium chair Steven E. Kahn, MB, ChB, professor and Leonard L. Wright and Marjorie C. Wright Chair in the Division of Metabolism, Endocrinology and Nutrition, and Director of the Diabetes Research Center at VA Puget Sound Health Care System and the University of Washington School of Medicine in Seattle. “These variances underscore an urgent need to better understand why these differences are occurring and to then develop new approaches to slow and even prevent progression of β-cell dysfunction. It is imperative for us to better understand the disease process in youth in order to identify what makes their type 2 diabetes more aggressive, so we can improve long-term outcomes.”

The study, “Effects of treatment of impaired glucose tolerance or recently diagnosed type 2 diabetes with metformin alone or in combination with insulin glargine on β-cell function: Comparison of responses in youth and adults,” will be published simultaneously today in the ADA journal Diabetes, which is focused on original research about the physiology and pathophysiology of diabetes.

To speak with Dr. Mather or Dr. Kahn, please contact the ADA Press Office on-site at San Francisco’s Moscone Convention Center June 7-11 by phone at 415-978-3606 or by email at SciSessionsPress@diabetes.org.

The American Diabetes Association’s 79th Scientific Sessions, the world’s largest scientific meeting focused on diabetes research, prevention and care, is being held June 7-11, 2019, at the Moscone Center in San Francisco, California. Nearly 15,000 leading physicians, scientists, health care professionals and industry representatives from around the world are convened at the Scientific Sessions to unveil cutting-edge research, treatment recommendations and advances toward a cure for diabetes. During the five-day meeting, attendees receive exclusive access to more than 850 presentations and 2,000 original research presentations, participate in provocative and engaging exchanges with leading diabetes experts, and can earn Continuing Medical Education (CME) or Continuing Education (CE) credits for educational sessions. The program is grouped into eight thematic areas: Acute and Chronic Complications; Behavioral Medicine, Clinical Nutrition, Education and Exercise; Clinical Diabetes/Therapeutics; Epidemiology/Genetics; Immunology/Transplantation; Insulin Action/Molecular Metabolism; Integrated Physiology/Obesity; and Islet Biology/Insulin Secretion. Gretchen Youssef, MS, RDN, CDE, President of Health Care and Education, will deliver her address, “It’s All About Access!,” on Saturday, June 8, and Louis H. Philipson, MD, PhD, FACP, President of Medicine and Science, will deliver his lecture, “Precision Medicine—Addressing the Many Faces of Diabetes,” on Sunday, June 9. Join the Scientific Sessions conversation on social media using #ADA2019.

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