U.S. Department of Health and Human Services

The Course of Type 2 Diabetes and Complication Onset in Youth Today

Four new analyses of data from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial have revealed important information about the challenges of controlling type 2 diabetes progression and preventing its complications in young people. Although type 2 diabetes is most commonly diagnosed in people over the age of 40, an increase in childhood obesity and other factors has led to a signiicant rise in cases in people under 20 years of age. Prior to this study, it was unknown whether treatments developed for adults would work well for younger patients. TODAY tested how well three treatment approaches controlled blood glucose levels in ethnically and racially diverse youth ages 10 to 17 who were overweight or obese and had been diagnosed with type 2 diabetes no more than two years before enrollment in the study. All participants received metformin, the irst-line drug of choice among adults with type 2 diabetes, and currently the only oral medication approved for use in children. Participants were randomly assigned 
to receive metformin alone; metformin plus another diabetes drug, rosiglitazone; or metformin plus a program of intensive lifestyle changes aimed at helping participants lose weight and increase physical activity. Unfortunately, metformin alone failed to maintain acceptable, long-term, blood glucose control in most participants over an average follow-up of 46 
months—a much higher failure rate than expected— and the addition of the lifestyle intervention provided only a modest improvement that was not statistically signiicant. Although blood glucose levels remained healthier, on average, in participants who received both metformin and rosiglitazone than in the other groups, the two-drug combination still failed 38.6 percent of the time over the course of the study. Importantly, after the trial began, the U.S. Food and Drug Administration (FDA) restricted use of rosiglitazone because of studies linking the medicine to a higher risk of heart attacks and stroke in adults. Although the FDA recently lifted restrictions on use of rosiglitazone in adults, the drug 
remains unapproved for use in children. Since publishing their initial results in 2012, TODAY researchers have examined the data to glean as much as possible about the way the different study treatments affected the participants’ metabolic function, as well as their progression toward some of the serious complications of the disease. The cells of people 
developing type 2 diabetes do not absorb as much glucose as they should in response to insulin. At first, the pancreas compensates by producing more insulin, but when the organ can no longer keep up with demand, diabetes results. In most adults with type 2 diabetes, the pancreas gradually loses the capacity to produce insulin as the disease progresses, so supplementary insulin often becomes required. To better understand the way the disease progressed in youth in the three TODAY treatment groups, study scientists analyzed changes in participants’ insulin resistance and capacity for pancreatic insulin production over the course of the trial. They found that average insulin sensitivity gradually 
fell for the metformin and metformin plus lifestyle groups, while for the metformin plus rosiglitazone group it improved signiicantly in the irst six months of the trial, but later gradually fell back to initial levels.

Thus, at the end of the trial, average insulin sensitivity among those youth getting both medicines was about where it began, but it had worsened among those getting just metformin or metformin plus lifestyle. In contrast, insulin-production capacity fell similarly in all three groups. Importantly, TODAY scientists found that in all of the treatment groups, the participants with the poorest blood glucose control and insulin production at the beginning of the trial were the ones most likely to have higher than recommended blood glucose levels before the study ended. This points to the importance 
of beginning treatment for pediatric type 2 diabetes before signiicant loss of insulin production capacity or deterioration of blood glucose control occurs.

One of the major concerns about the increasing frequency with which type 2 diabetes is appearing in young people is that data from studies in adults show that the onset and severity of diabetes complications correlate with the duration of the disease. Thus, there is great concern that having diabetes for the vast majority of their lives may leave these young people vulnerable to particularly early and severe disease complications.

TODAY researchers, therefore, examined participants for early signs of retinopathy, a diabetes complication of the eye that is the most common cause of adult-onset blindness. Study scientists photographed a majority of participants’ retinas during the last year of the study and found that retinopathy was beginning to develop in almost 14 percent of those participants. Among the TODAY participants, increasing time since initial diagnosis of diabetes, greater age, and 
poorer blood glucose control were all associated with a greater likelihood of retinopathy, reinforcing the importance of early treatment of type 2 diabetes. At multiple stages during the trial, TODAY participants were also tested for key complication risk factors and early signs of kidney and heart complications. Thus, for example, TODAY researchers identiied hypertension (high blood pressure)—a major risk factor for both heart attack and kidney disease, both 
common complications of diabetes—in more than 11 percent of participants when the study began, and almost 34 percent by the end of the study, an average of less than ive years after developing diabetes. Boys were more likely than girls to have hypertension or develop it over the course of the trial. The more obese participants were, the more likely they were to have or develop high blood pressure, as well. These indings parallel results in adolescents who do not have diabetes, among whom obesity and male sex are risk factors for developing hypertension. The researchers also looked for an early sign of kidney urine. More than six percent of TODAY participants had elevated urine albumin when the study began, and more than 16 percent did when it ended; elevated urine albumin was most likely to occur in participants whose blood glucose was more poorly controlled. Two major risk factors for heart disease, dyslipidemia (the elevation 
of unhealthy blood fats and/or lowering of healthy blood fat levels) and signs of chronic inlammation, were also found to be present at concerning levels when the study began, and at increasing rates as it progressed. In general, none of the treatment approaches were clearly superior to the others at preventing the development of diabetes complications or their risk factors in the TODAY participants, underscoring the importance of further research to identify better ways to prevent, treat, or cure type 2 diabetes in the young.

The TODAY Study Group. Effects of metformin, metformin 
plus rosiglitazone, and metformin plus lifestyle on insulin 
sensitivity and β‑cell function in TODAY. Diabetes Care 36: 
1749‑1757, 2013.

The TODAY Study Group. Retinopathy in youth with 
type 2 diabetes participating in the TODAY clinical trial. 
Diabetes Care 36: 1772‑1774, 2013.

The TODAY Study Group. Rapid rise in hypertension and 
nephropathy in youth with type 2 diabetes: the TODAY 
clinical trial. Diabetes Care 36: 1735‑1741, 2013.

The TODAY Study Group. Lipid and inlammatory 
cardiovascular risk worsens over 3 years in youth with 
type 2 diabetes: the TODAY clinical trial. Diabetes Care 36: 
1758‑1764, 2013.