Pediatric Diabetes & Endocrinology

Revealing Long-Term Health Outcomes in Pediatric Type 2 Diabetes

    As the incidence of pediatric type 2 diabetes has increased steadily over time, mounting evidence illustrates the lasting impact of the disease on adult health outcomes. To better assess the long-term health consequences of type 2 diabetes, Rachelle Gandica, MD, a pediatric endocrinologist at NewYork-Presbyterian/Columbia, served as an investigator collaborating on the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) and TODAY2 studies. The Naomi Berrie Diabetes Center of NewYork-Presbyterian/Columbia was the only participating study site in New York City and one of only two in the state.

    TODAY and TODAY 2 Trial Results Reveal Long-Term Health Outcomes

    The TODAY trial was a longitudinal study of adolescents/young adults with youth-onset type 2 diabetes. Conducted at 15 sites across the United States starting in 2004, the investigators sought to assess the impact of three randomly assigned interventions (metformin; metformin + rosiglitazone; or metformin + an intensive lifestyle intervention) on loss of glycemic control. The trial enrolled 699 participants between the ages of 10 and 17 diagnosed with type 2 diabetes.

    The results of the initial TODAY study, according to Dr. Gandica, were quite sobering. The study’s primary endpoint was time to loss of glycemic control, defined as a hemoglobin A1c (HbA1c) greater than or equal to 8% for at least six months, or the inability to wean off of insulin injections for three or more months after an acute metabolic decompensation.

    “We found that, by 60 months post-randomization, about half of the participants overall had reached glycemic failure,” she says. “There was a statistically significant improvement in the metformin + rosiglitazone arm relative to metformin alone (51.7% vs. 38.6% failure at 60 months), which showed us that two agents could be more helpful than one, though this difference wasn’t that clinically meaningful.” Another disappointing finding, says Dr. Gandica, was that the intensive lifestyle intervention didn’t make much of an impact on patients’ time to glycemic failure.

    We found that, by 60 months post-randomization, about half of the participants overall had reached glycemic failure.

    — Dr. Rachelle Gandica

    The TODAY2 follow-up study consisted of two phases. In Phase 1, TODAY2 participants were immediately transitioned to non-blinded, standard diabetes care with monitoring and follow-up for up to two years. “At that point, we were still supporting them through the study and helping them figure out their ongoing care,” says Dr. Gandica. “Phase 2 was completely observational. The patients were getting their medicine from the community, however their family deemed appropriate, and we followed their outcomes. Many of them chose to continue to get their care here at the Naomi Berrie Diabetes Center”

    A primary question of interest throughout both phases was whether having more treatment success during the TODAY study, as was observed in the metformin + rosiglitazone arm, could have a protective effect on patient outcomes into the future. Unfortunately, that was far from the case, says Dr. Gandica. During the first 36 months of TODAY2, rates of glycemic failure did not differ among participants by original treatment group assignment, suggesting that any added treatment benefit of using rosiglitazone as a second agent in youth-onset type 2 diabetes did not persist after its discontinuation.

    Long-term follow-up for TODAY2 ended in 2020, and overall outcome data were published in The New England Journal of Medicine the following year. The 550 participants of TODAY2 Phase 2 had an average age of 26.4 years and 12.6 years of study participation at the time of discontinuation. Following the group’s average HbA1c tells a striking story, notes Dr. Gandica. While 75% of participants had HbA1c levels under 6.5% at study baseline, that number fell to 19% at the end of TODAY2 follow-up, with an overall mean HbA1c of 9.4%. Long-term follow-up also revealed high rates of vascular complications of type 2 diabetes: By year 15 of follow-up, there were 17 observed serious cardiovascular events, representing a rate of 3.7/1000 patient-years. Additionally, 80.1% percent of participants had experienced at least one microvascular complication, including kidney, nerve, and retinal complications. Six deaths were also reported at the time of study discontinuation.

    Dr. Gandica notes that she and other investigators were shocked by the rapid progression of cardiovascular risk factors in the study group. At baseline, 33% of participants had one or more additional cardiovascular risk factor, including smoking, high LDL cholesterol, hypertension, and hypertriglyceridemia. This number had grown to 83% by the time of study discontinuation, with 29% of participants having one risk factor, 34% having two, 16% having three, and 4% having all four. “It was truly striking,” says Dr. Gandica. “These results showed that youth-onset type 2 diabetes is a much more aggressive disease than adult type 2. No one in the adult diabetes research community expected to see these kinds of outcomes.”

    These results showed that youth-onset type 2 diabetes is a much more aggressive disease than adult type 2. No one in the adult diabetes research community expected to see these kinds of outcomes.

    — Dr. Rachelle Gandica

    Valuable Insights to Guide Future Care

    TODAY2 also revealed valuable insights on the impact of healthcare coverage on ongoing diabetes care, as the follow-up period encompassed the 2014 passage of the Affordable Care Act and implementation of Medicaid expansion in select states. “Medicaid expansion made a massive difference for the transition to community care,” says Dr. Gandica. “In states with expansion, more than 90% of participants had some form of healthcare coverage, versus about 65% in states without.” Sixty-six percent of participants without healthcare coverage reported having no outpatient visits for diabetes care in the prior six months, compared to 42% of those with commercial insurance and 32% of those with government insurance.

    Dr. Gandica says the wealth of data from the TODAY and TODAY2 study yielded many lessons in the care of patients with youth-onset type 2 diabetes. “We were able to identify factors that predict future loss of glycemic control” she says. A baseline HbA1c at or greater than 6.2% was optimally predictive of glycemic failure at any time, and an absolute rise in HbA1c over 0.5% was associated with a loss of control within 3 to 6 months. Dr. Gandica hopes that these indicators will help providers and parents monitor young patients more closely and pursue aggressive treatment to prevent the dire health outcomes observed in long-term follow-up. She also says that the advent of new therapeutic options, including GLP-1 agonists approved for pediatric use like liraglutide, exenatide, and dulaglutide, has major potential for improving glycemic outcomes in youth-onset type 2 diabetes.

    Dr. Gandica adds that these conclusions from TODAY and TODAY2 illustrate the caliber of research happening at NewYork-Presbyterian/Columbia. “We have such a uniquely diverse patient population. The participants in this trial came from both near and far communities, people travel to the Berrie Center for this cutting-edge research,” she says. “We’re proud of our reputation as a place to come to be involved in landmark research in both type 2 and type 1 diabetes.”

      Learn More

      Gandica, R. Latest Outcomes from the TODAY Study. Oral presentation at: American Diabetes Association 83rd Scientific Sessions; June 2023; San Diego, CA.

      TODAY Study Group. Long-Term Complications in Youth-Onset Type 2 Diabetes. New England Journal of Medicine. 2021;385(5):416-426. doi:10.1056/nejmoa2100165.

      For more information

      image of Dr. Rachelle Gandica
      Dr. Rachelle Gandica
      [email protected]