Kids With T2D Face Dire Complications as Young Adults

SAN DIEGO — Children with type 2 diabetes face a strikingly high complication rate as they age into young adulthood, with an 80% incidence of at least one vascular complication during up to 15 years of follow-up, show findings from the TODAY prospective, longitudinal study of 699 US children newly diagnosed with type 2 diabetes.

Arterial stiffness and worsened cardiac function often appear in these children within 2-5 years of diagnosis and seem driven in part by the development of hypertension and worsening A1c levels, said Rachelle G. Gandica, MD, at the American Diabetes Association (ADA) 83rd Scientific Sessions.

Indeed, an A1c > 6.2% at study entry generally predicts these children will fail treatment and is a red flag, said Gandica. "I teach fellows this all the time, that if a child's A1c is above 6.2% they will fail, and you have to watch for that," she noted.

The results from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed, for example, an overall cardiovascular event rate of 3.7/1000 patient-years in a population that had just reached an average age of 26 years old, with type 2 diabetes diagnosed for an average of more than 13 years.

During follow-up, there were six cases of congestive heart failure, four myocardial infarctions, four strokes, and three cases of coronary artery disease in the cohort. Hypertension ballooned from a prevalence of 19% at study entry to 68% by the end of follow-up.

Gandica called these and other findings "sobering details" that document the toll type 2 diabetes takes on children, who averaged 14 years old at the time they entered the study — when their diabetes had been diagnosed for an average of about 8 months — and then underwent an average 12.6 years of follow-up.

Investigators also found:

After more than 12 years of type 2 diabetes, 49% of the cohort had developed diabetic retinopathy, with 3.5% having macular edema.
Kidney damage (diabetic nephropathy) affected 8% of the cohort at entry, and then increased to a prevalence of 55% after up to 14 years of follow-up.
Among the 452 girls who entered the study, 141 (31%) later became pregnant, with a total of 260 pregnancies. A quarter of the pregnancies resulted in preterm deliveries (43% went to term), 25% resulted in miscarriage or fetal demise, with the remaining 8% having elective terminations or unknown outcomes.
Complications in neonates were common, including hypoglycemia (29%), respiratory disorder (19%), and cardiac issues (10%).

Dire Prognosis a Reason to Aggressively Treat These Patients

It has become apparent from this and other studies in youth with type 2 diabetes that the difference in outcomes between youth and adults is stark and could indicate that type 2 diabetes in childhood or adolescence likely has a different underlying pathology and natural history, with a more aggressive disease course.

Dr Rachelle Gandica

The dire prognosis is therefore a reason to aggressively treat these patients with antidiabetic medications from drug classes with proven cardiovascular disease protection, specifically sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists, said Gandica, a pediatric endocrinologist at Columbia University Medical Center in New York City.

"It's fair to say we now more aggressively use [these agents] in children," she said in an interview, and noted the very recent approval, just last week, by the US Food and Drug Administration of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) for children as young as 10 years, as reported by Medscape Medical News.

"I look forward to prescribing empagliflozin to children with type 2 diabetes to lower their blood pressure and get additional cardiovascular disease benefits," Gandica said.

Other newer type 2 diabetes medications approved for US children in the past few years include the once-weekly injectable GLP-1 agonist exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for children with type 2 diabetes aged 10 and older, in 2021, and the daily injectable GLP-1 agonist liraglutide (Victoza, Novo Nordisk) in 2019.

A1c Spike Heralds Treatment Failure: "Watch for That"

TODAY enrolled 699 children with type 2 diabetes for an average of 8 months since diagnosis at 16 US sites starting in 2004. The protocol began with a run-in phase of up to 6 months, when participating children came off any pre-existing antidiabetes medications and then began a metformin-only regimen to bring A1c below 8.0%. If achieved, patients were eligible to continue to randomization.

Participants were randomized to one of three treatment groups: metformin alone, metformin plus lifestyle interventions, or metformin plus rosiglitazone (Avandia, GSK). The primary endpoint was the incidence of treatment failure, defined as A1c that rose back above 8.0% for at least 6 months or persistent metabolic decompensation during initial follow-up, for an average of just under 4 years.

The results showed that only metformin plus rosiglitazone significantly surpassed metformin alone for preventing treatment failure, reported in 2012 in the New England Journal of Medicine.

More recent reports on findings from longer-term follow-up have appeared in several journals, including the cardiovascular disease results, reported in 2021 also in the New England Journal of Medicine.

Another key finding from TODAY is the importance of A1c as a risk marker for impending treatment failure. Study findings show that an A1c of 6.2% or higher when children entered the study best predicted loss of glycemic control during follow-up. Also, a rise in A1c of at least 0.5 percentage points was significantly associated with loss of glycemic control within the following 3-6 months.

That's an important message for clinicians, Gandica concluded.

TODAY and TODAY2 received no commercial funding. Gandica has reported no relevant financial relationships.

ADA Scientific Sessions. Session CT-1.5-SY25. Presented June 24, 2023.

Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler

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