Clinical Context

Rates of type 2 diabetes have increased in the United States, and this increase includes rates of youth-onset type 2 diabetes. There has been a paucity of research addressing the best practice in the management of youth-onset type 2 diabetes, and the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial addressed this issue. Results of this trial were published in the June 14, 2012, issue of the New England Journal of Medicine.^[1]

The TODAY trial enrolled adolescents between 10 and 17 years of age who had a duration of type 2 diabetes of less than 2 years. All participants had a body mass index at the 85th percentile for age and sex, or more.

Participants were randomly assigned to receive metformin alone, metformin plus an intensive lifestyle intervention, or metformin plus rosiglitazone. Rates of having a sustained HbA1c level of 8% or higher were 51.7%, 46.6%, and 38.6% in the 3 groups, respectively. Only the difference between the metformin alone and the metformin plus rosiglitazone groups was statistically significant. Nearly 20% of the study cohort experienced adverse events during the trial, with higher rates of adverse events seen in the metformin alone vs the metformin plus rosiglitazone groups.

There is also a lack of information regarding the rate of complications over time associated with youth-onset type 2 diabetes. The current study revisits the TODAY cohort to analyze this issue.

Study Synopsis and Perspective

Newly published data show alarmingly high rates and severity of early diabetes-specific complications in individuals who develop type 2 diabetes at a young age. This suggests that intervention should be early and aggressive among these young people, said one of the researchers.

The results for the 500 young adult participants in the TODAY 2 study were published online July 28 in the New England Journal of Medicine by the TODAY study group.^[2]

At follow-up, after originally participating in the TODAY trial when they were young teenagers, the participants had a mean age of 26.4 years.

At this time, more than two thirds had hypertension and half had dyslipidemia, or high levels of cholesterol or fats in the blood.

Overall, 60% had at least 1 diabetic microvascular complication (retinal disease, neuropathy, or diabetic kidney disease) and more than a quarter had 2 or more such complications.

"These data illustrate the serious personal and public health consequences of youth-onset type 2 diabetes in the transition to adulthood," the researchers write.

"The fact that these youth are accumulating complications at a rapid rate and are broadly affected early in adulthood certainly suggests that aggressive therapy is needed, both for glycemic control and treatment of risk factors like hypertension and dyslipidemia," study coauthor Philip S. Zeitler, MD, says.

"In the absence of studies specifically addressing this, we need to take a more aggressive approach than people might be inclined to, given that the age at diagnosis is young, around 14 years," he says.

"Contrary to the inclination to be 'gentle' in treating them because they are kids, these data suggest that we can't let these initial years go by without strong intervention, and we need to be prepared for polypharmacy."

Unfortunately, as Dr Zeitler and his coauthors explained, youth-onset type 2 diabetes is characterized by a suboptimal response to currently approved medical therapies for diabetes.

New pediatric indications in the United States for drugs used to treat type 2 diabetes in adults, including the recent US Food and Drug Administration approval of extended-release exenatide for children as young as 10 years of age, "helps, but only marginally," Dr Zeitler, from Children's Hospital Colorado Clinical & Translational Research Center, Aurora, says.^[3]

"In some cases, it will help get them covered by carriers, which is always good. But this is still a very limited set of medications. It doesn't include more recently approved more potent glucagon-like peptide-1 (GLP-1) agonists, like semaglutide, and doesn't include the sodium-glucose cotransporter 2 (SGLT2) inhibitors. Pediatricians are used to using medications off-label, and that is necessary here while we await further approvals," he says.

In the United States, most with youth-onset type 2 diabetes are covered by public insurance or are uninsured, depending on which state they live in, Dr Zeitler says. Although the 2 major Medicaid programs in Colorado allow full access to adult formularies, that is not the case everywhere. What is more, patients often face further access barriers in states without expanded Medicaid.

In TODAY 2, patients participated in an observational follow-up in their usual care settings in 2011-2020. At the start, they were receiving metformin with or without insulin for diabetes, but whether this continued and whether they were treated for other risk factors was down to individual circumstances.

Participants' median A1c increased over time, and the percentage with A1c less than 6% (48 mmol/mol) declined from 75% at the time of TODAY entry to just 19% at the 15-year end of follow-up.

The proportion with an A1c of 10% (86 mmol/mol) or greater rose from 0% at baseline to 34% at 15 years.

At that time, nearly 50% were receiving both metformin and insulin, whereas more than a quarter were receiving no medications.

The prevalence of hypertension increased from 19.2% at baseline to 67.5% at 15 years, whereas dyslipidemia rose from 20.8% to 51.6%.

Kidney disease prevalence increased from 8.0% at baseline to 54.8% at 15 years. Nerve disease rose from just 1.0% to 32.4%. Retinal disease jumped from 13.7% with milder nonproliferative retinopathy in 2010 to 2011 to 51.0% with any eye disease in 2017 to 2018, including 8.8% with moderate to severe retinal changes and 3.5% with macular edema.

Overall, at the time of the last visit, 39.9% had no diabetes complications and 31.8% had 1, 21.3% had 2, and 7.1% had 3 complications.

There were 17 adjudicated serious cardiovascular events, including 4 myocardial infarctions, 6 congestive heart failure events, 3 diagnoses of coronary artery disease, and 4 strokes.

Six participants died, 1 each from myocardial infarction, kidney failure, and drug overdose and 3 from sepsis.

Dr Zeitler says the macrovascular events are "shocking," noting that although the numbers are small, for people in their mid-20s "they should be zero.... While we don't yet know if the rates are the same or faster than in adults, even if they are the same, these kids are only in their late 20s, as opposed to adults experiencing these problems in their 50s, 60s, and 70s."

"The fact that these complications are occurring when these individuals should be in the prime of their life for both family and work has huge implications," he says.

The reasons for the findings are both biologic and socioeconomic, he says.

"We know already that many kids with type 2 have rapid [deterioration of] beta-cell [function], which is probably very biologic. It stands to reason that an individual who can get diabetes as an adolescent probably has more fragile beta cells in some way.

"But we also know that many other things contribute, [such as] stress, social determinants, access to quality care and medications, access to healthy foods and physical activity, availability of family supervision given the realities of families' economic status and jobs, etc."

It is also known that youth with type 2 diabetes have much more severe insulin resistance than adults with the condition, and that "once the kids left...the [TODAY] study, risk factor treatment in the community was less than ideal, and a lot of kids who met criteria for treatment of their blood pressure or lipids were not being treated. This is likely at least partly sociologic and partly the general pediatric hesitancy to use medications."

He says the TODAY team will soon have some new data to show that "glycemia during the early years makes a difference, again supporting intensive intervention early on."

N Engl J Med. 2021;385(5):416-426

Clinical Implications

• A previous randomized trial comparing metformin alone, metformin plus an intensive lifestyle intervention, or metformin plus rosiglitazone in the treatment of youth-onset type 2 diabetes found that metformin plus rosiglitazone was significantly more effective than metformin alone in maintaining good glycemic control, with metformin plus lifestyle intervention having intermediate results.
• The current study finds high rates of approximately 80% of microvascular complications of youth-onset type 2 diabetes during 15 years of follow-up. Rates of kidney, nerve, and retinal damage were all high.
• Implications for the healthcare team: The healthcare team should focus on prevention and aggressive treatment of youth-onset type 2 diabetes to prevent the risk for complications.

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