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RISE Clinical Trial: No durable improvement to beta-cell function from various diabetes treatments


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Results from the Adult Medication Study of the Restoring Insulin Secretion (RISE) Clinical Trial showed no long-term improvement in beta-cell function from various diabetes treatments. Improvements seen during the 12-month treatment period had disappeared three months later, and A1C worsened in two of the treatment arms.

Steven E. Kahn, MB, ChB
Steven E. Kahn, MB, ChB

“You have to treat adults and you have to keep them on treatment to see an improvement. When you take treatment away, they regress back to baseline,” said Steven E. Kahn, MB, ChB, the Leonard L. Wright & Marjorie C. Wright Term Chair of Medicine and Professor of Medicine and Metabolism, Endocrinology and Nutrition at the University of Washington and VA Puget Sound Health Care System.

The RISE trials are designed to test pharmacologic interventions designed to preserve or improve beta-cell function in prediabetes or early type 2 diabetes in children and adults. A third arm evaluated gastric banding versus metformin in adults.

The pediatric trial was reported in 2018 and the surgical trial is still in progress. The adult medication trial was discussed at the Scientific Sessions on Sunday, June 9, and published simultaneously in Diabetes.

In the adult medication trial, 267 adults with impaired glucose tolerance or diagnosed type 2 diabetes for less than one year were randomized to placebo or one of three treatment arms: 1,000 mg daily of metformin, metformin plus 1.8 mg liraglutide, or glargine followed by metformin. Patients were treated for 12 months, then washed out for three months for a final evaluation. Primary endpoints included steady-state C-peptide and ACPRmax (the maximum C-peptide response to arginine) during hyperglycemic clamp. Levels were measured at baseline, at the end of treatment, and after washout.

Secondary outcomes included body mass index (BMI), A1C, blood pressure, and lipid measures.

Kieren J. Mather, MD
Kieren J. Mather, MD

Adherence was better than 90 percent in all four arms, reported Kieren J. Mather, MD, Professor of Medicine in the Department of Internal Medicine at Indiana University School of Medicine.

Liraglutide plus metformin showed the greatest effect on C-peptide concentrations and ACPRmax, but there were no significant differences between treatment groups at the final visit after three months of washout. Liraglutide plus metformin improved beta-cell function during the treatment period, but the effects disappeared after treatment was stopped.

Researchers also performed a preplanned subanalysis of participants with impaired glucose tolerance.

“The findings in participants with impaired glucose tolerance did not differ from the whole cohort,” Dr. Mather said.

All of the treatment arms showed improvement in BMI, A1C, systolic blood pressure, low-density lipoprotein (LDL) cholesterol, and triglycerides. Residual effects of treatment differed by arm.

The metformin and liraglutide plus metformin groups retained significant weight loss three months after treatment ended. The metformin and glargine/metformin groups had a higher A1C after washout than at baseline. The glargine/metformin group showed no change in high-density lipoprotein cholesterol after washout. There were no significant differences in systolic blood pressure, LDL cholesterol, or triglycerides after washout.

“Continued intervention may be required to alter the progressive loss of beta-cell function in impaired glucose tolerance or early type 2 diabetes,” Dr. Edelstein said.