According to a series of study results being published in a special issue of Diabetes Care youth with type 2 diabetes experience a more rapid progression of co-morbidities far more aggressive than what is typically seen in adults, even when they receive the best currently available treatment and close monitoring of their condition.
The most recent findings from the ongoing Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study reveals that young people who develop type 2 diabetes are heading for a future of serious complications and that current treatment options are inadequate for this population, according to the study’s authors. Two commentaries and an editorial accompanying the study’s results “sound the alarm” for young people, who are increasingly developing type 2, noting that how to effectively treat this population “remains largely unknown” and most drugs known to successfully treat adults have not been studied in children or approved by the FDA to treat younger people with diabetes.
“The TODAY study has shown that youth with type 2 diabetes can face faster consequences than their adult counterparts,” said Griffin P. Rodgers, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, which funded the study. “Given the disease’s more rapid progression in youth, the need for better treatment and prevention cannot be overlooked.”
The study found that youth with type 2 diabetes were developing early and rapidly progressing signs of heart and kidney disease, poor glycemic control and diabetes-related eye disease, even in the group receiving more intensive two-drug therapy, shown in previously released results to be the most effective treatment for maintenance of glycemic control.
The TODAY study randomly assigned patients to one of three treatment arms: metformin alone; metformin plus rosiglitazone; and metformin plus an intensive lifestyle intervention that included diet, exercise and counseling on how to lose weight. Initial results of the study, reported last year in the New England Journal of Medicine, found that half of the youth in the study were unable to maintain glycemic control when treated with metformin alone and needed to be put on insulin. The study’s initial findings also showed that treating youth with both metformin and rosiglitazone reduced the need to transition them to insulin therapy by 25 percent.
The findings, published in the June issue of Diabetes Care, reflect ongoing monitoring of more than 500 participants (ages 10-17 when the study began in 2004) in all three treatment arms and a deeper analysis of the complications they are developing as the study continues.
“Substantial numbers of these kids, in addition to their diabetes, have developed hypertension, abnormal lipids and both early or more advanced kidney disease,” said Phil Zeitler, MD, PhD, Professor of Pediatrics at the University of Colorado and TODAY Study Chair. “We’re seeing a continuation of the way diabetes behaves differently in youth, and it’s a serious cause for concern for their future disease burden. At a time when they should be entering the most productive period of their lives, I think we can anticipate that instead of going to college and getting jobs, they will be visiting doctors and dealing with serious health care issues.”
Beta Cell Function and the Need for Early, Aggressive Treatment
Though it cannot currently be recommended for use as treatment in youth, adding rosiglitazone to metformin as a treatment not only reduced the need to transition participants to insulin therapy, it appears to have done so because it helped to preserve beta cell function, the most recent findings suggest.
The rate of deterioration of beta cell function in youth was almost four times higher than has been reported in adults, researchers found, noting a 20-35 percent decline in beta cell function per year on average, compared to 7-11 percent for adults (as reported in previous research).
In the first six months of treatment, those in the rosiglitazone plus metformin arm saw a 20 percent improvement in insulin sensitivity, while the other two treatment arms saw either a deterioration (metformin alone) or no change (metformin plus lifestyle). This initial boost in improving insulin sensitivity in the rosiglitazone plus metformin arm lessened the burden on the beta cell and preserved beta cell function while it deteriorated in the other two groups. This early preservation in beta cell function resulted in overall lower glycemic failure rates in the rosiglitazone plus metformin arm compared with the other two groups, said Silva Arslanian, MD, Richard L. Day Endowed Professor of Pediatric Endocrinology, director of the Weight Management and Wellness Center at Children’s Hospital of Pittsburg, University of Pittsburg Medical Center and director of the Pediatric Clinical and Translational Research Center.
“The message here is that if you are going to treat youth with type 2 diabetes effectively, it must be done early and aggressively targeting to improve beta cell function and insulin resistance,” she said.
The TODAY analysis also helped researchers predict which participants would ultimately fail treatment and require insulin therapy, Dr. Arslanian said. “It turns out that the participants who failed oral treatment had almost 50 percent lower beta cell function relative to insulin sensitivity to begin with, compared to those who were not failing,” she said. “In other words, it is the reserve in beta cell function that determines whether a person will respond well or poorly to any treatment.”
Their analysis also found that those youth whose A1C was higher at the beginning of the study experienced the poorest outcomes. For every 0.5 percent increase in A1C, the chances of failing treatment and requiring insulin therapy almost doubled, she said.
Hypertension and Kidney Disease
Both hypertension and kidney disease also progressed rapidly in the study participants, regardless of treatment arm. The incidence of hypertension rose from 11.6 percent of participants to 33.8 percent after 3.9 years, despite receiving the best possible treatment and monitoring, said Jane Lynch, MD, Professor of Pediatrics at the University of Texas Health Science Center in San Antonio.
Males were at 81 percent higher risk for developing high blood pressure than females, she noted, which is consistent with adult findings in terms of gender differences in hypertension.
As boys grew older, their risk for developing hypertension increased: for every additional year of age at baseline, there was a 14 percent greater risk of hypertension. Weight also played a role in increasing risk: for every one unit of increased BMI, there was a 6 percent increased risk for high blood pressure. There were no differences in hypertension risk based on differences in race, ethnicity or randomized treatment group.
In contrast, gender did not appear to impact the increased incidence of early kidney disease. The rates of microalbuminuria overall rose from 6.3 percent of participants at the beginning of the study to 16.6 percent of participants after 3.9 years.
Dr. Lynch said it was poor glycemic control that influenced whether kidney disease progressed in participants. For every 1 percent rise in A1C (e.g., from 7 percent to 8 percent), there was a 17 percent increased risk of developing early signs of kidney disease, defined as microalbumin, or protein in the urine. Some participants showed a substantially more advanced form of renal disease, Dr. Lynch noted, with 57 participants exhibiting macroalbuminaria and one-third of those advancing to proteinuria, an even more advanced stage of renal disease.
“The future for young adults with advancing renal disease is very worrisome,” Dr. Lynch said. “These outcomes show evidence of a more rapid progression of hypertension and renal disease risk than we expected to see, and that’s under the best-case scenario of being treated with ACE inhibitor medications and counseling and very close monitoring.”
Lynch also noted that of the 205 participants who required ACE inhibitors for hypertension or kidney disease, 79 needed maximal ACE dosing and needed a second medication added during these 3.9 years of the study. “This is much more rapid progression than we see in adults,” she said.
Regardless of which treatment arm they were in, participants also experienced a worsening of cardiovascular risks, said Ruth Weinstock, MD, PhD, Distinguished Service Professor at SUNY Upstate Medical University in Syracuse, N.Y., and one of the investigators in the TODAY trial.
Researchers found that LDL (the so-called “bad” cholesterol), triglycerides and other inflammatory markers all rose over 12 months and then stabilized over the next 24 months. The percentage of youth with LDL levels over 130 mg/dl and those needing to be placed on cholesterol-lowering medications once their levels exceeded 130 mg/dl rose from 4.5 percent of participants to 10.7 percent over 36 months.
Also of concern, said Dr. Weinstock, was that only 55.9 percent of participants remained at their LDL goal of less than 100 mg/dl over the 36 months. “This is a frightening number. These are youth we hope will have many decades of life ahead of them and only half were at goal. I cannot tell you what the future looks like for these youth, but I can tell you I am concerned.”
Somewhat surprisingly, those whose treatment included lifestyle interventions did no better for their LDL goals than those whose treatment did not, Dr. Weinstock said, but, lifestyle intervention did make a difference in helping to keep triglyceride levels under control. Whereas LDL levels rose with increasing A1C levels regardless of treatment group, higher A1C levels were not associated with higher triglyceride levels in the lifestyle intervention group.
Overall, she said, “lipid disorders and chronic inflammation were common in youth with type 2 diabetes and they worsened over 36 months. Despite some treatment group differences, the diabetes treatment was generally inadequate to control this worsening risk. We are going to have to find better ways to decrease cardiovascular risk in youth with type 2.
Retinopathy and the Obesity Paradox
One area where the disease behaved similarly in youth to the way it does in adults, however, was in the case of retinopathy, a type of eye disease associated with type 2 diabetes. Previous research has shown that 15.5 percent of adults with a diabetes duration of three years develop retinopathy. In the TODAY population, 13.7 percent of participants developed nonproliferative retinopathy after an average duration of diabetes of 4.9 years. As with adults, greater incidence of retinopathy was associated with longer duration of diabetes, higher age and poorer glycemic control.
Another phenomenon previously seen only in adults – known as the “obesity paradox” – likewise appeared in the younger population, said Lynne Levitsky, MD, Chief of Pediatric Endocrinology at Massachusetts General Hospital and Associate Professor of Pediatrics at Harvard Medical School. “The most surprising thing we found,” she said, “was that for youth who were quite obese, there was a reduced chance of developing retinopathy.” This has been reported previously in adults, but never in young people.
Those in the most obese group of youth, with a BMI of 37.87-68.7, had considerably less retinopathy (9.3 percent) than those with a BMI of 31.5-37.86 (15.6 percent) and 21.6-31.5 (16.3 percent). “In young people, the obesity paradox is clear,” she said.
Though researchers expected the group treated with metformin plus intensive lifestyle interventions to experience greater weight loss and improvements in body composition, those gains were smaller than they hoped for and any positive effects were lost by 24 months, said Kenneth C. Copeland, MD, Milburn Chair and Chief of Pediatric Endocrinology, University of Oklahoma College of Medicine.
The group treated with metformin and rosiglitazone, conversely, experienced the largest accumulation of body fat but maintained the best glycemic control
“This does not say that lifestyle changes are not important,” Dr. Copeland said. “What it says is that reductions in body fat and BMI through lifestyle change are extremely hard to accomplish in this group of profoundly affected diabetic youth. The implications are that the time to intervene is before diabetes develops.”
“The development of type 2 diabetes among young individuals has significant public health consequences as these youth are likely to manifest the complications of diabetes, including retinopathy, nephropathy, neuropathy and cardiovascular disease, at a time that should be the most active and productive of their lives,” concluded an accompanying commentary by Dr. Rodgers and NIDDK colleagues Barbara Linder, MD, PhD, senior advisor for childhood diabetes research; and Judith Fradkin, MD, director of the Division of Diabetes, Endocrinology and Metabolic Diseases of NIDDK.
Study Chair Zeitler reiterated the importance of prevention and continued study of treatment options beyond those explored in this study.
“We need to prevent diabetes,” Dr. Zeitler said. “Before that, we need to prevent childhood obesity. Before that, we need to prevent pregnancies complicated by obesity and diabetes. There is a huge societal intervention that needs to happen. We also need a better understanding of how to treat the co-morbidities in these kids. Right now we are extrapolating from adults, but we have no information on whether this is the correct route, and that’s a critical issue to understand.”
The “faces” of those developing type 2 diabetes “are becoming younger by the year,” wrote Diabetes Care Editor in Chief William Cefalu, MD, in an editorial accompanying the study results. “We are not prepared as a medical community or as a global society at this time to effectively address the growing problem of type 2 diabetes in youth. To state that we have a huge challenge ahead and no real solutions is an understatement.”
“The need is imperative,” the NIH commentary concluded, “to promote research to understand how to establish healthy habits at a young age rather than trying to correct ‘bad’ habits later on.”