TODAY Study Finds Faster Progression of Diabetes Comorbidities in Youth

Children and teenagers with type 2 diabetes are at high risk of developing heart and kidney disease

Children and teenagers with type 2 diabetes are at high risk for developing early and rapidly progressing signs of risk for heart disease and kidney disease, as well as faster deterioration of β-cell function, according to recent findings from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. This rapid progression in comorbidities is far more aggressive than what is seen in adults, and occurred even among youths receiving intensive combination therapy, researchers reported in a special issue of Diabetes Care.

“This population of children and adolescents with type 2 diabetes has a heavy burden of problems related to their diabetes that are risk factors for future cardiovascular and renal problems,” said Philip Zeitler, MD, PhD, study chair and a pediatric endocrinologist at Children's Hospital Colorado, Aurora. “Furthermore, the burden increased rapidly during their time in the study, despite very attentive and careful medical care and medical team support. This is very concerning for the future health of these young adults. Just when they should be entering college and getting jobs, we can anticipate that they will be visiting doctors and dealing with serious health care issues.”

Study Findings

The current report is based on ongoing monitoring of almost 700 patients with type 2 diabetes aged 10 to 17 years at study entry. The subjects were randomized to metformin alone, metformin plus rosiglitazone (Avandia, which is not FDA approved for children or adolescents), or metformin plus intensive lifestyle interventions (diet, exercise, and counseling on how to lose weight). The following key findings were reported:

  • All subjects had an almost fourfold higher rate of functional deterioration of insulin producing β-cells than that seen historically in adults (20%-35% vs 7%-11% decline per year, respectively).
  • The group that received rosiglitazone plus metformin had a 20% improvement in insulin sensitivity while the other two treatment groups had deteriorations or no change in this measure; this benefit with combination therapy translated into early preservation in β-cell function and lower overall glycemic failure rates.
  • The incidence of hypertension, regardless of treatment received, increased from 11.6% to 33.8% after 3.9 years; as expected, the incidence was 81% higher in boys than girls (similar gender differences are seen in adults).
  • Low-density lipoproteins (LDL), triglycerides, and other inflammatory markers increased over the first year and then stabilized; only 56% of participants remained at the LDL goal of <100 mg/dL and the percentage of subjects who required cholesterol lowering medications increased from 4.5% to 10.7% over a 3-year period.
  • The incidence of microalbuminuria (signs of early kidney disease) increased overall from 6.3% to 16.6% of participants over 3.9 years, regardless of gender or treatment received.

Implications for Treatment

The findings suggest that “intensification of therapy with addition of a second oral agent or insulin likely needs to occur more quickly with only minimally elevated A1c, rather than waiting for [treatment] failure,” Dr. Zeitler said. “The best options for intensification are unclear at the moment, and early initiation of insulin if metformin is not maintaining control may be the best choice.” While it is unclear how best to treat the comorbidities of diabetes in these young patients, “the heavy burden and rapid progression suggest that further study is going to be needed,” he added.

The TODAY study findings complement the recently released American Academy of Pediatrics guidelines on type 2 diabetes, especially regarding the need to intensify early treatment if goals are not met, explained co-author of the guidelines Janet H. Silverstein, MD, Professor and Chief of Pediatric Endocrinology, University of Florida, Gainesville. “The guidelines recommend lifestyle changes (60 minutes of activity and no more than 2 hours of non-academic TV, computer, or video screen time daily). Potential tools for intensification listed in the guidelines include: more frequent blood glucose monitoring; more frequent patient contact; education sessions or counseling sessions with a psychologist/social worker, diabetes educator, or dietitian; and increasing the dose of medication or adding a medication to the diabetes regimen,” she said.

“The prognosis for these youths is not good,” Dr. Silverstein noted. “Perhaps the TODAY study will raise awareness of the risks these children face and prompt practitioners to test for and treat the complications early, as recommended in the guidelines. The medical community must recognize that achieving lifestyle change is difficult in the very high risk population enrolled in the TODAY trial and we all must be advocates for improving the environment of our communities to provide neighborhoods that encourage active play and socialization,” she said.

Dr. Zeitler agreed: “We need to prevent diabetes. Before that, we need to prevent childhood obesity. Before that, we need to prevent pregnancies complicated by obesity and diabetes. There is a huge societal intervention that needs to happen. We also need a better understanding of how to treat the comorbidities in these kids. Right now, we are extrapolating from adults, but we have no information on whether this is the correct route, and that is a critical issue to understand.”

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