Early glycemic control may not prevent beta-cell deterioration in youth-onset diabetes
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Key takeaways:
- Young people with type 2 diabetes had long-term beta-cell deterioration, regardless of early glycemic control.
- Those with an early HbA1c of less than 5.7% had the steepest increase in HbA1c over time.
Youths with type 2 diabetes who had a lower mean HbA1c shortly after diagnosis have similar long-term beta-cell deterioration as those with a higher HbA1c, according to findings published in Diabetes Care.
In an analysis of long-term data from youths who participated in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, HbA1c increased 2 to 9 years after diagnosis for all participants, regardless of mean HbA1c in the first 6 months of the study. Additionally, adolescents who achieved an HbA1c of less than 5.7% with metformin in TODAY had the steepest increase in HbA1c over time.
“HbA1c significantly increased in all early glycemic groups over time, showing poor response amongst youth with type 2 diabetes to metformin, rosiglitazone and intensive lifestyle interventions,” Kristen Nadeau, MD, MS, professor of pediatric endocrinology at University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado, told Healio. “Beta-cell function significantly decreased over time, even in those with lower early glycemia, or those who still had remaining beta-cell function to lose. In contrast, those with early HbA1c of more than 7% had no further decline in beta-cell function, likely because youth with early glycemia of 7% or more already had advanced loss of beta-cell function. In addition, once HbA1c was between 6.4 and 7%, C-peptide index was no longer higher with higher BMI or insulin resistance, suggesting that C-peptide secretion is already constrained once HbA1c is between 6.4 and 7%.”
In the TODAY study, youths diagnosed with type 2 diabetes before age 18 years and within 2 years of enrollment were randomly assigned to metformin alone, metformin plus rosiglitazone or metformin with intensive lifestyle intervention from 2004 to 2011. The primary outcome was time to treatment failure, defined as an HbA1c of 8% or higher for 6 consecutive months. Participants received insulin once they met the primary outcome.
In a new study, researchers analyzed long-term data from 656 TODAY participants who completed a mean 6.4 years of follow-up. Demographics, medical history and medication use were collected. BMI was measured quarterly up until 2014 and then annually until 2020. Fasting HbA1c, insulin, C-peptide and glucose were measured through blood samples. A 2-hour oral glucose tolerance test was performed at TODAY randomization, 6 months, and years 2, 3, 4, 5, 6 and 9. Participants were categorized into five groups based on their mean HbA1c during the first 6 months of TODAY: HbA1c less than 5.7%, 5.7% to 6.3%, 6.4% to 6.9%, 7% to 7.9% and at least 8%.
HbA1c gradually increases over time
At 2 years, youths with an early HbA1c of less than 5.7% had the lowest mean HbA1c and the group with an early HbA1c of 8% or higher had the highest HbA1c. All five groups had a mean HbA1c increase from year 2 to year 9. The group with an early HbA1c of less than 5.7% had the largest rate of increase of the five groups, with a mean HbA1c increase of 0.4% per year.
At baseline, insulin sensitivity was higher in the group with an early HbA1c of less than 5.7% than the other glycemic groups. However, there was no difference between any of the groups in insulin sensitivity by year 9. From year 2 to year 9, females had a lower insulin sensitivity than males, regardless of their HbA1c group (P = .003). Mean BMI within the first 6 months of TODAY randomization was negatively associated with insulin sensitivity among youths with an early HbA1c of less than 6.4%.
C-peptide index similar between most HbA1c groups at 9 years
C-peptide index and insulin secretion relative to demand was highest in youths with the lowest HbA1c at baseline and progressively decreased with higher HbA1c. By year 6, C-peptide index was higher in youths with an HbA1c less than 5.7% than all other groups and higher in the 5.7% to 6.3% group than the two highest HbA1c groups. By year 9, the youths with an HbA1c of less than 6.4% had a higher C-peptide index than those with an HbA1c of 8% or more, but all other between-group differences disappeared. C-peptide index and insulin secretion relative to demand both declined among youths with an early HbA1c of less than 7% from year 2 to year 9, with the steepest decrease observed in those with an HbA1c of less than 5.7%.
“Based on more encouraging responses in adults, it was surprising that metformin, rosiglitazone and intensive lifestyle interventions did not improve insulin sensitivity or beta-cell function in youth with type 2 diabetes in TODAY,” Nadeau said. “It was also surprising that even youth with type 2 diabetes who were still in what has traditionally been considered good glycemic control after 2 months of treatment with metformin will have deterioration of glycemic control over time.”
Nadeau said future studies should focus on bariatric surgery and newer classes of agents such as SGLT2 inhibitors and GLP-1 receptor agonists to see if they can slow beta-cell decline in youth-onset type 2 diabetes.
“In addition, due to the severity of the disease in youth, we need studies of early contributors to type 2 diabetes in youth and the natural history of insulin sensitivity and secretion during puberty to better understand who develops youth-onset type 2 diabetes, the factors that drive poor beta-cell function in some youth and how it can be prevented,” Nadeau said.
For more information:
Kristen Nadeau, MD, MS, can be reached at kristen.nadeau@childrenscolorado.org.
Perspective
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Carmella Evans-Molina, MD, PhD
Youth-onset type 2 diabetes is increasing in incidence; however, very little is known about the long-term metabolic trajectory of individuals diagnosed with type 2 diabetes during childhood. This report from the TODAY study group addresses the important question of whether tight glycemic control within the first 6 months of diagnosis influences long-term metabolic outcomes. The concerning and surprising result was — no. In all participants, regardless of starting HbA1c, glycemic control worsened over 6.4 years of follow-up and beta-cell failure was progressive and striking in study participants.
These findings highlight important distinctions between youth and adult-onset type 2 diabetes, both in the aggressiveness of beta-cell failure and the pliability or reversibility of disease outcomes in response to intervention. In this study, neither tight glycemic control nor the specific study interventions (metformin, metformin plus rosiglitazone, or metformin plus intensive lifestyle intervention) altered the course of youth-onset type 2 diabetes.
Whether newer agents like GLP-1 agonists or SGLT2 inhibitors would produce different long-term outcomes is unknown and should be tested. In general, therapies that target beta-cell health in diabetes are lacking, and results from this study highlight this unmet need. Additionally, an important overarching question arising from this study is whether we are simply waiting too long to intervene in at-risk children, and perhaps it may be time to reconsider our thresholds for the diagnosis of type 2 diabetes in youth.
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