TODAY follow-up trial shows accelerating rate of serious CV, health issues in youth-onset disease
SAN FRANCISCO -- Cardiovascular (CV) events, as well as cases of kidney, eye, and nerve diseases, occurred at unexpectedly high rates in adolescents with type 2 diabetes, according to follow-up data from the TODAY trial.
In a group of 517 adolescents with type 2 diabetes, 30% had abnormal echocardiographies, about 14% had a rapid glomerular filtration rate decline, and 9% required treatment for advanced diabetic retinopathy by the end of a 12-year period, reported Philip Zeitler, MD, PhD, of the Children's Hospital Colorado in Aurora, at the American Diabetes Association (ADA) annual meeting.
"The burden of complications is accelerated in these individuals with youth onset diabetes as they transition to young adulthood," Zeitler said at an ADA press conference. "Cardiovascular risk factors are highly prevalent in the population; target organ damage is already evident; and serious cardiovascular events are already occurring at rates unexpected for this age -- these kids are in their mid-20s and having problems you would expect from your grandparents."
The study (TODAY2) was an extension of TODAY, a trial randomizing 699 kids (ages 10-17 years) to metformin alone or with added rosiglitazone (Avandia)/lifestyle interventions, who were then followed from 2004 to 2011 at diabetes care centers. At the trial's conclusion, all participants were taken off therapy. The first phase of TODAY2 ran for 5 years with patients seen every 3 months. The second phase continues as an observational study through 2020. The cohort in this phase has had the disease for a mean 7.5 years.
Within this cohort (mean age 21), 236 pregnancies occurred, which resulted in "disturbing" rates of maternal and offspring complications, Zeitler said
Of note, five deaths due to heart attack, sepsis, post-operative arrest, and overdose occurred in the group, Zeitler reported.
"Taken together, TODAY has provided a picture of youth onset type 2 diabetes as a serious disorder with life-threatening and life-altering personal implications for patients and public health impacts for society," Zeitler said.
Rise in Youth T2D
Type 2 diabetes is increasing in prevalence in the U.S. at a "particularly alarming" rate, said press conference moderator Alvin Powers, MD, of Vanderbilt University in Nashville.
"In [U.S.] pediatric diabetes clinics...in some parts of the country, there are almost as many children or adolescents with type 2 diabetes as there are with type 1 diabetes," Powers said. "While these studies were performed in the U.S., I think it's an alarm throughout the world as rates of diabetes increase in other populations."
The ADA issued a statement in 2018 on the evaluation and management of youth type 2 diabetes that detailed more aggressive intervention and prevention methods, Zeitler said.
However, the evidence supporting these guidelines was mainly extrapolated from adult data, and had to rely on the assumption that risk factors and outcomes would not significantly differ between groups, he added.
"The problem is, we don't have an evidence base for aggressively treating these kids," Zeitler said. "But the real problem is, we probably never will because it's very difficult to do these kinds of studies in kids."
Prior studies have demonstrated individuals who develop type 2 diabetes early are more likely to suffer CV complications than those diagnosed later in life.
One reason kids with type 2 diabetes experience so many complications could be that individuals who develop diabetes during puberty are more vulnerable to an environment that cultivates the development of the disease. Or puberty could simply be a more detrimental time for β-cell function, said Kieren Mather, MD, of Indiana University School of Medicine, during a post-presentation discussion.
"Puberty is itself a stress of the β cell because it's a markedly insulin-resistant state, so you're adding diabetes on top of that physiological phenomenon that's a challenge," said Mather, who was not involved in TODAY.
In terms of echocardiography results, the most prevalent change was seen in the left atrial internal diameter, Zeitler said. But several CV outcomes showed a 12-year cumulative increase from baseline, including elevated LDL cholesterol (3% to 26%) and hypertension (19% to 55%). Also, 10 arrhythmias, six cases of coronary artery disease/MI, and 12 cases of heart failure/left ventricular dysfunction occurred. Overall, 38 CV events were validated, he said.
Adolescents in the cohort also had a much higher prevalence of kidney dysfunction by the end of the trial period, including increased urine albumin excretion (8% to 40%) and hyperfiltration (12% to 48%). Two patients developed both chronic kidney disease and end-stage kidney disease in the study period, Zeitler added.
Prior to the end of TODAY, most kids had no eye disease and just 14% had mild disease, Zeitler said. However, by the end of TODAY2, optic outcomes worsened and 92 patients experienced at least one form of eye disease.
Finally, by the end of the 12-year period, nerve function deteriorated among the cohort, with a cumulative incidence of 26% for neuropathy, as measured through the Michigan neuropathy screening instrument (MNSI), Zeitler said.
Patients with loss of glycemic control (HbA1c ≥8%) were at a higher risk for retinopathy compared to patients who maintained glucose control, and this also held true for neuropathy.
Also, compared with several reference studies, a much higher rate of preterm delivery was observed in the women in this cohort (6.5%-9.9% vs 23.7%), as was stillbirth (0.4% vs 3.8), Zeitler said. Infants born to mothers with type 2 diabetes were much more likely to have neonatal hypoglycemia than a comparison group of women (28.7% vs 2.1%). They were also more likely to undergo respiratory distress (14% vs 7%).
Zeitler and colleagues also examined the prevalence and type of health insurance utilized by individuals once they entered TODAY2.
"We thought it was important to study health insurance status since health insurance coverage is strongly correlated with access to healthcare," said co-author Ruth Weinstock, MD, PhD, of Upstate University Hospital in Syracuse, New York, who presented these findings at the ADA meeting.
The authors found 88% had insurance in Medicaid expansion states versus 74% in non-expansion states, Weinstock said. Uninsured patients tended to have poorer glycemic control and those with more education and higher insured rates tended to have lower HbA1c levels, though neither of these outcomes were significant, she added.
Zeitler emphasized youth onset type 2 diabetes often occurs in a context complicated by a lack of access to care or other factors.
"It's a context of very low socioeconomic status, family dysfunction, a great deal of family stress, illness burden, mothers with dialysis, etc," Zietler said at the press conference.
The last visit of participants in this trial will occur in 2020, resulting in almost 20 years of data, Zeitler said. Paired with other trials such as RISE and SEARCH, TODAY demonstrated that about half of kids with type 2 diabetes have rapidly progressing disease, and are already experiencing early mortality, Zeitler said.
"More aggressive management is needed to treat youth onset type 2 diabetes and its complications," he emphasized. "It is unclear if the U.S. healthcare system is fully prepared for the needs of these individuals."
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.
Zeitler disclosed relevant relationships with Boehringer Ingelheim Pharmaceuticals, Eli Lilly, Janssen Research & Development, Merck, and Novo Nordisk.
Mather disclosed relevant relationships and support from Roche Diabetes Care, Novo Nordisk, Abbott, and Merck.
Weinstock disclosed relevant relationships with insilogic LLC, Unitio, Boehringer Ingelheim Pharmaceuticals, Jaeb Center for Health Research, Kowa Pharmaceutical Europe, Medtronic MiniMed, and Oramed Pharmaceuticals.
Powers reported no disclosures.
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American Diabetes Association
Source Reference: Zeitler P, et al "Longitudinal outcomes in youth with type 2 diabetes -- the TODAY2 study" American Diabetes Association 2019.
Read the original article on Medpage Today: Complication Rates Ramp up in Kids with T2D