Meeting News

RISE: Type 2 diabetes more aggressive in adolescents; early treatment unlikely to slow progression

Steven Kahn
Steven E. Kahn

ORLANDO, Fla. — Adolescents with prediabetes or newly diagnosed type 2 diabetes have much more aggressive disease than adults with similar glycemic profiles, and early treatment with insulin and metformin does not substantially slow its progression, according to data from three RISE studies presented here.

“Indirect evidence would suggest that the disease in youth is more aggressive than in adults. .... There has never before been a single study that has merged youth and adults using sophisticated methods together to examine this,” Steven E. Kahn, MB, ChB, professor of medicine and Leonard L. Wright and Marjorie C. Wright Chair at VA Puget Sound Health Care System/University of Washington, said during a press briefing. “This is exactly what the RISE study ... has done.”

Kahn and the RISE Consortium researchers enrolled 91 adolescents ages 10 to 19 years (mean age, 14.2 years; 71% girls; 28.8% white; 21.2% black; 37.9% Hispanic; 3% Asian; 9.1% mixed background; mean BMI, 36.6 kg/m2) and 355 adults (mean age, 52.7 years; 51.5% women; 46.8% white; 27.3% black; 19.2% Hispanic; 5.1% Asian; 1.1% mixed background; .6% other; mean BMI, 35.1 kg/m2). Participants had impaired glucose tolerance (80.3% of adolescents; 70.7% of adults) or type 2 diabetes duration less than 6 months. Adolescents and adults had similar glucose profiles; 66 adolescents and no adults were prescribed metformin.

In separate studies, the adult and pediatric participants who were not prescribed metformin underwent hyperglycemic clamp and oral glucose tolerance tests to assess insulin sensitivity, C-peptide and insulin responses and insulin concentrations. Researchers compared the baseline data between the two age groups.

In both studies, researchers found that insulin sensitivity was approximately 50% lower in the adolescents compared with the adults, Kahn said. The younger participants demonstrated hyper-responsive beta-cell function and reduced insulin clearance.

“Youth have beta-cell responses that are greater than adults’, and these differences, we believe, may provide for the first time a true explanation for the more aggressive disease course seen in youth who struggle not only with glucose problems early on in life, but also with complications seen in adults, at much younger age.”

In a study focusing on the entire adolescent cohort (n = 91), researchers randomly assigned the participants to receive either 12 months of metformin or 3 months of insulin glargine followed by 9 months of metformin; after 12 months, medications were discontinued for a 3-month washout period. Hyperglycemic clamp was used to assess beta-cell function at baseline and 12 months and at the 15 months (the end of the washout period).

Kristen Nadeau
Kristen J. Nadeau

At 6 months, HbA1c was reduced transiently from baseline in both groups, but this was not sustained at 12 months. At 12 and 15 months, beta-cell function was significantly worse than at baseline.

“Despite interventions done at an early phase in youth who had impaired glucose tolerance or were recently diagnosed with type 2 diabetes, the beta-cell dysfunction progressed and was worse than at baseline, showing no impact of early therapy,” Kristen J. Nadeau, MD, MS, associate professor in pediatrics-endocrinology at the University of Colorado Anschutz Medical Campus, said during the briefing. “These findings contrast with those published in adults that showed an improvement in beta-cell function both with metformin and with insulin for diabetes prevention and treatment. Since metformin and insulin are currently the only FDA-approved therapies for youth with type 2 diabetes, we clearly now need to understand more about these youth, why their diabetes is more aggressive and how we can better treat them.”

Nadeau and Kahn both emphasized that the results do not indicate that physicians should discontinue these medications in adolescents.

John Buse

“Clearly, we need to look into alternative therapies in this setting, but the biggest message is this epidemic of obesity in youth has real implications and these kids are in trouble,” said John Buse, MD, PhD, director of the Diabetes Center, director of the North Carolina Translational and Clinical Sciences Institute, and executive associate dean for clinical research at the University of North Carolina School of Medicine in Chapel Hill, who moderated the press briefing. “If we can’t treat them with insulin and metformin ... to get their HbA1c into a reasonable range for 80 years, they are going to have troubles with complications. It really increases the moral imperative to do something about the obesity epidemic, to restrict marketing of clearly unreasonable foods to children.”

The studies and commentary were published in Diabetes Care simultaneously with presentation at the American Diabetes Association Scientific Sessions. – by Jill Rollet

References:

The Restoring Insulin Secretion (RISE) Study in Youth and Adults Baseline Data and Results of the Pediatric Medication Study. Presented at: American Diabetes Association 78th Scientific Sessions; June 22-26, 2018; Orlando, Fla.

Buse JB, et al. Diabetes Care. 2018;doi:10.2337/dci18-0025.

RISE Consortium. Diabetes Care. 2018;doi:10.2337/dc18-0243.

RISE Consortium. Diabetes Care. 2018;doi:10.2337/dc18-0244.

RISE Consortium. Diabetes Care. 2018;doi:10.2337/dc18-0787.

Disclosures: Buse reports he receives research support from or serves as an advisor for Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia, Johnson & Johnson, Lexicon, Metavention, NovaTarg, Novo Nordisk, Sanofi, Senseonics, Theracos and vTv Therapeutics, and holds stock options in Mellitus Health and PhaseBio Pharmaceuticals. Kahn reports he is a paid consultant for Novo Nordisk. Nadeau reports no relevant financial disclosures. Please see the studies for all other authors’ relevant financial disclosures.

Steven Kahn
Steven E. Kahn

ORLANDO, Fla. — Adolescents with prediabetes or newly diagnosed type 2 diabetes have much more aggressive disease than adults with similar glycemic profiles, and early treatment with insulin and metformin does not substantially slow its progression, according to data from three RISE studies presented here.

“Indirect evidence would suggest that the disease in youth is more aggressive than in adults. .... There has never before been a single study that has merged youth and adults using sophisticated methods together to examine this,” Steven E. Kahn, MB, ChB, professor of medicine and Leonard L. Wright and Marjorie C. Wright Chair at VA Puget Sound Health Care System/University of Washington, said during a press briefing. “This is exactly what the RISE study ... has done.”

Kahn and the RISE Consortium researchers enrolled 91 adolescents ages 10 to 19 years (mean age, 14.2 years; 71% girls; 28.8% white; 21.2% black; 37.9% Hispanic; 3% Asian; 9.1% mixed background; mean BMI, 36.6 kg/m2) and 355 adults (mean age, 52.7 years; 51.5% women; 46.8% white; 27.3% black; 19.2% Hispanic; 5.1% Asian; 1.1% mixed background; .6% other; mean BMI, 35.1 kg/m2). Participants had impaired glucose tolerance (80.3% of adolescents; 70.7% of adults) or type 2 diabetes duration less than 6 months. Adolescents and adults had similar glucose profiles; 66 adolescents and no adults were prescribed metformin.

In separate studies, the adult and pediatric participants who were not prescribed metformin underwent hyperglycemic clamp and oral glucose tolerance tests to assess insulin sensitivity, C-peptide and insulin responses and insulin concentrations. Researchers compared the baseline data between the two age groups.

In both studies, researchers found that insulin sensitivity was approximately 50% lower in the adolescents compared with the adults, Kahn said. The younger participants demonstrated hyper-responsive beta-cell function and reduced insulin clearance.

“Youth have beta-cell responses that are greater than adults’, and these differences, we believe, may provide for the first time a true explanation for the more aggressive disease course seen in youth who struggle not only with glucose problems early on in life, but also with complications seen in adults, at much younger age.”

In a study focusing on the entire adolescent cohort (n = 91), researchers randomly assigned the participants to receive either 12 months of metformin or 3 months of insulin glargine followed by 9 months of metformin; after 12 months, medications were discontinued for a 3-month washout period. Hyperglycemic clamp was used to assess beta-cell function at baseline and 12 months and at the 15 months (the end of the washout period).

Kristen Nadeau
Kristen J. Nadeau

At 6 months, HbA1c was reduced transiently from baseline in both groups, but this was not sustained at 12 months. At 12 and 15 months, beta-cell function was significantly worse than at baseline.

“Despite interventions done at an early phase in youth who had impaired glucose tolerance or were recently diagnosed with type 2 diabetes, the beta-cell dysfunction progressed and was worse than at baseline, showing no impact of early therapy,” Kristen J. Nadeau, MD, MS, associate professor in pediatrics-endocrinology at the University of Colorado Anschutz Medical Campus, said during the briefing. “These findings contrast with those published in adults that showed an improvement in beta-cell function both with metformin and with insulin for diabetes prevention and treatment. Since metformin and insulin are currently the only FDA-approved therapies for youth with type 2 diabetes, we clearly now need to understand more about these youth, why their diabetes is more aggressive and how we can better treat them.”

Nadeau and Kahn both emphasized that the results do not indicate that physicians should discontinue these medications in adolescents.

John Buse

“Clearly, we need to look into alternative therapies in this setting, but the biggest message is this epidemic of obesity in youth has real implications and these kids are in trouble,” said John Buse, MD, PhD, director of the Diabetes Center, director of the North Carolina Translational and Clinical Sciences Institute, and executive associate dean for clinical research at the University of North Carolina School of Medicine in Chapel Hill, who moderated the press briefing. “If we can’t treat them with insulin and metformin ... to get their HbA1c into a reasonable range for 80 years, they are going to have troubles with complications. It really increases the moral imperative to do something about the obesity epidemic, to restrict marketing of clearly unreasonable foods to children.”

The studies and commentary were published in Diabetes Care simultaneously with presentation at the American Diabetes Association Scientific Sessions. – by Jill Rollet

References:

The Restoring Insulin Secretion (RISE) Study in Youth and Adults Baseline Data and Results of the Pediatric Medication Study. Presented at: American Diabetes Association 78th Scientific Sessions; June 22-26, 2018; Orlando, Fla.

Buse JB, et al. Diabetes Care. 2018;doi:10.2337/dci18-0025.

RISE Consortium. Diabetes Care. 2018;doi:10.2337/dc18-0243.

RISE Consortium. Diabetes Care. 2018;doi:10.2337/dc18-0244.

RISE Consortium. Diabetes Care. 2018;doi:10.2337/dc18-0787.

Disclosures: Buse reports he receives research support from or serves as an advisor for Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia, Johnson & Johnson, Lexicon, Metavention, NovaTarg, Novo Nordisk, Sanofi, Senseonics, Theracos and vTv Therapeutics, and holds stock options in Mellitus Health and PhaseBio Pharmaceuticals. Kahn reports he is a paid consultant for Novo Nordisk. Nadeau reports no relevant financial disclosures. Please see the studies for all other authors’ relevant financial disclosures.

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