RISE Trials: Restoring Insulin Secretion In Adults and Children — ADA 2019

Data from RISE trials on improvements of beta-cell function in type 2 diabetes found response to treatment differs in adults vs youth.

The Restoring Insulin Secretion (RISE) Adult Medication Study measured the function of beta cells (b- cell) in adults with impaired glucose tolerance or newly diagnosed type 2 diabetes. Researchers found that b- cell function had improved through active treatment, but a lasting effect was not seen after treatment was stopped. Suggestions, from the RISE trials results, of continued treatment being offered for patients with progressive b- cell dysfunction were presented at the American Diabetes Association’s (ADA’s) 79th Scientific Sessions in San Francisco. The presenters at the Scientific Session also showed the direct comparison in the youth population which showed an opposite benefit, hinting at a more aggressive form of the disease in youth.

As we know, b- cells’ main function is to secrete and produce insulin to regulate blood glucose levels. The progression of prediabetes to type 2 diabetes is caused by the worsening dysfunction of the b- cells. This has led researchers into further investigating a prevention for inadequate amounts of insulin secretion among patients who are at high risk for type 2 diabetes (prediabetes) to reduce the progression to type 2 diabetes.

The RISE Adult Medication Study compared the approaches to improving the function of b- cells in adults with impaired glucose tolerance and newly diagnosed type 2 diabetes. The controlled, randomized study enrolled 267 adults into a four-arm randomized approach comparing insulin glargine for 3 months followed by metformin for 9 months, or liraglutide combined with metformin for 12 months, against 12 months of blinded metformin alone or matched placebo. Out of the 267 adults in the study, 197 (74%) had impaired glucose tolerance and 70 (26%) were recently diagnosed with type 2 diabetes. Participants received active treatment for 12 months. Study measurements were repeated 3 months after treatment withdrawal for lasting benefit. HbA1c was measured quarterly to detect glycemic responses.

The hyperglycemic clamp was used to measure insulin sensitivity and three b- cell response measures: steady-state C-peptide, acute C-peptide response to arginine at maximal glycemic potentiation, and acute C-peptide response to glucose. These assessments were received at baseline, 12 months, 15 months, and 3 months after the discontinuation of the active treatment.

At the end of 12 months of treatment, the greatest increases in glucose-stimulated b- cell responses were seen with liraglutide combined with metformin. Also, the arginine-stimulated response was lower at month 12 with liraglutide combined with metformin. The acute C-peptide response to glucose was higher at 12 months compared with baseline among those who took liraglutide plus metformin (P < .01). In addition, there were “significant differences” at 12 months between the steady-state C-peptide measures among those taking liraglutide plus metformin compared to those taking other treatments.  This evidence led researchers to conclude that liraglutide combined with metformin improved b- cell function in 12 months compared to the other treatment groups. After the 3-month discontinuation of treatment, there was no on-going improvement in b- cell function with any treatment group. Observations have led to the suggestion of continued interventions being required for progressive improvement in b- cell function in adults with impaired glucose tolerance and type 2 diabetes.

Presenters at the 79th Scientific Sessions also compared the RISE Adult Medication Study to the RISE Pediatric Medication Study, as both studies used the same assessment measures.

The RISE Pediatric Medication Study was conducted in 91 youth with type 2 diabetes. Youth were assigned to one of the two randomized approaches: metformin alone for 12 months (n = 47), or insulin glargine followed by metformin for 9 months (n = 44). Unlike the adult study, results in the youth showed no significant changes or improvements in b- cell function. Changes in beta-cell response at 12 months worsen from 12 months to 15 months.

RISE Consortium chairs Steven E. Kahn, Leonard L. Wright, and Marjorie C. Wright highlighted the differences and pondered the thought that youth with type 2 diabetes may have a different underlying pathology. Presenters stressed the importance of further understanding why these differences are occurring and developing new approaches to prevent progression of b- cell dysfunction.

Practice Pearls:

• On-going active treatment with metformin and liraglutide has shown to improve b- cell function in patients with impaired glucose tolerance and newly diagnosed type 2 diabetes.
• Data from the models in adults has shown that GLP-1 receptor agonists can protect b- cell function.
• It’s important to understand the differences between adults and youth with type 2 diabetes, in terms of pathophysiology, so that health-care providers can be more specific in developing interventions to benefit these patients.

References:

1.     Consortium, The RISE. “Impact of Insulin and Metformin Versus Metformin Alone on β-Cell Function in Youth With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes.” Diabetes Care, American Diabetes Association, 1 Aug. 2018, care.diabetesjournals.org/content/41/8/1717?ijkey=91ca85bff0d89ac1ba94931bb49bc54041e529a7&keytype2=tf_ipsecsha.
2.     Consortium*, The RISE. “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.” Diabetes Care, American Diabetes Association, 7 June 2019, care.diabetesjournals.org/content/early/2019/05/31/dc19-0556.
3.     Mather K, et al. 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.

Maya Rudolph, Florida A&M University, College of Pharmacy, PharmD Candidate

RISE trials data Reported at the American Diabetes Association 79th Scientific Sessions June, 2019