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ORLANDO -- Early pharmacologic intervention did not stop disease progression in youth with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes, researchers reported here.

Neither treatment with 12 months of metformin alone nor 3 months of insulin glargine, followed by 9 months of metformin, prevented the progression of β-cell deterioration in young patients with IGT or recently diagnosed type 2 diabetes, according to Sharon Edelstein, of the Biostatistics Center at George Washington University in Washington, and colleagues in The RISE Consortium.

In the pediatric outcomes analysis of the , both treatment groups actually saw a significant decline in β-cell function over a 12-month period, they reported at the American Diabetes Association (ADA) annual meeting. The results were simultaneously published in Diabetes Care.

Although the treatments were well-tolerated, there were no improvements in fasting glucose or a 2-hour oral glucose tolerance test (OGTT) in the metformin-only treatment group after 12 months of treatment, or within the 3 months after discontinuation.

And while the insulin glargine plus metformin group saw a significantly lower 2-hour OGTT after 12 months of treatment, this rebounded back to baseline levels 3 months after treatment discontinuation. This group also saw an increase in fasting glucose compared to baseline during the 3 months after treatment discontinuation.

Despite an initial decline in HbA1c seen in both treatment after 6months of treatment, they eventually rebounded back to baseline by the end of treatment, then increased during the 3 months after treatment discontinuation, ending up around 6% in both groups.

These findings are in direct contrast to what previous studies have been found in the adult population, which the researchers suggested this may indicate a more aggressive disease course for type 2 diabetes in younger patients.

"This was not what anybody predicted based on everything we see in adults, where intensive insulin therapy preserves beta cells, and where metformin is shown to be effective in adults as a first-line therapy and in prevention," explained co-author Steven Kahn, MB, ChB, of the University of Washington in Seattle at an ADA press conference.

The authors were disappointed by the results, he noted.

"We are not spinning around and saying not to use insulin or not to use metformin if you're a treating physician -- you have to carry on using these," Kahn stressed. "We had hoped that earlier, aggressive intervention would have had a much more beneficial effect than what we'd seen. We're not turning around and saying don't treat these kids with the drugs that are approved."

Although this study looked at the only two agents currently approved for the treatment of type 2 diabetes in a pediatric population, Kahn also noted the importance of looking into other potential interventions that may work more effectively as preventative therapies.

There were 91 participants in the study, ages 10-19 years, who had existing impaired glucose tolerance, marked by a fasting glucose of 100-125 mg/dL or a 2-hour glucose of 140-199 mg/dL, or type 2 diabetes diagnosed within the previous 6 months. All participants were also either overweight or had obesity.

Metformin doses were titrated up to 1,000 mg twice per day, while insulin glargine was titrated twice per week with a target fasting glucose of 79.2-90.0 mg/dL (4.4-5.0 mmol/L) monitored daily with self-measured blood glucose.

β-cell responses of stead-state C-peptide and ACPRmax paired with insulin sensitivity (M/I) were measured by a hyperglycemia clamp, which was performed at baseline, after 12 months of treatment, and 3 months after treatment discontinuation.

"I think the biggest message is [that] this epidemic of obesity in youth has real implications and these kids are in trouble," commented John Buse, MD, PhD, of the University of North Carolina School of Medicine in Chapel Hill. "If we can't treat them with insulin, metformin...to get their A1c to a reasonable range for 80 years, they are going to have troubles with complications. I think it increases the moral imperative to do something about the obesity epidemic -- to restrict marketing of clearly unreasonable foods to children."

"Clearly we need to look into alternative therapies," Buse added, suggesting in an that "potential use of existing agents such as thiazolidinediones, glucagon-like peptide 1 receptor agonists, or sodium-glucose cotransporter inhibitors deserves consideration."

Two additional studies conducted by the RISE Consortium are currently ongoing, which are assessing similar pharmacologic intervention and bariatric surgical intervention in adult populations, the researchers noted.