Early macrovascular, microvascular complications common with youth-onset type 2 diabetes
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BALTIMORE — Most children with youth-onset type 2 diabetes develop macrovascular or microvascular complications within a decade of diagnosis, and the risk for beta cell function failure increases over time, according to a speaker.
In findings from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and TODAY2 clinical trials presented at the Association of Diabetes Care and Educational Specialists Annual Conference, the percentage of participants with microvascular and macrovascular complications climbed over more than a decade of follow-up, with at least half of study participants developing dyslipidemia, hypertension, nephropathy and diabetic retinopathy by the end of follow-up.
“Type 2 diabetes is much more aggressive in youth than adult-onset type 2 diabetes,” Jeanie B. Tryggestad, MD, associate professor of pediatric diabetes and endocrinology at University of Oklahoma Health Sciences Center, said during a presentation. “These complications are happening very early in the disease process, and we did have six deaths within the TODAY trial.”
Tryggestad discussed data from the TODAY clinical trial, which took place from March 1, 2004, to Feb. 28, 2011; the TODAY2 phase 1 trial, which took place from March 1, 2011, to Feb.y 28, 2014; and from the TODAY2 phase 2 trial, which took place from March 1, 2014, to Feb. 29, 2020. Height, weight, blood pressure and HbA1c were assessed at all visits in all three trials, and diabetes care and management and medical history were recorded. Participants had neuropathy measures, lipids and kidney function labs measured annually.
Prevalence of macrovascular disease increases with time
Researchers assessed beta cell function by calculating oral disposition index during oral glucose tolerance tests. Participants with beta cell function failure had a gradual decline in oral disposition index, whereas those without beta cell failure had a relatively stable oral disposition index at 24 and 36 months compared with baseline.
“We see an increase in beta cell failure with a decrease in function over time, and we need new approaches to preserve that beta cell function,” Tryggestad said. “The medications we currently are using are not accomplishing that goal. We need to identify new interventions.”
In an analysis of macrovascular complications, a cohort of 397 TODAY participants had significantly higher low frequency power of heart rate variability [47.3 normalized units (n.u.) vs. 39.5 n.u.], lower high frequency power of heart rate variability (52.7 n.u. vs. 60.5 n.u.) and a higher low frequency-to-high frequency ratio (1.4 vs. 1; P < .0001 for all) than a control cohort of 133 children with obesity and no diabetes. A group of 411 TODAY participants with type 2 diabetes also had a lower percentage of children with a normal left ventricular mass and wall thickness compared with a group of 194 children with obesity and no diabetes, as well as a group 51 normal weight youths (84.3% vs. 94.3% vs. 100%).
At baseline, 20.8% of TODAY participants had dyslipidemia and 19.2% had hypertension. At the end of follow-up, the proportion of those with dyslipidemia increased to 51.6%, and the percentage with hypertension increased to 67.5%.
Risk factors for microvascular complications
Microvascular disease also increased over time. At baseline, 9% of TODAY participants had any microvascular disease. That rate increased to 80.1% during follow-up. Hispanic children (adjusted HR = 1.5; 95% CI, 1.13-2) and Black children (aHR = 1.46; 95% CI, 1.09-1.16) had a higher risk for developing microvascular complications than white children. The risk for any microvascular complication increased with each 1% increase in HbA1c (aHR = 1.18; 95% CI, 1.14-1.23), each 5 kg/m2 increase in BMI (aHR = 1.08; 95% CI, 1.01-1.15), and among those with hypertension (aHR = 1.39; 95% CI, 1.12-1.72) or dyslipidemia (aHR = 1.28; 95% CI, 1.03-1.59).
The percentage of TODAY participants with nephropathy increased over time from 8% at baseline to 54.8% at the end of follow-up. The presence of neuropathy increased from 1% at baseline to a cumulative incidence of 32.4% at the end of follow-up. During the initial TODAY study, 86.3% of participants had no definitive diabetic retinopathy. During TODAY2, 50% of participants had some form of diabetic retinopathy detected, with 22.8% having very mild nonproliferative diabetic retinopathy and 16.3% having mild nonproliferative diabetic retinopathy.
When microvascular complications were broken down into kidney, nerve and retinal, Tryggestad noted more than 100 participants had at least two forms of complications, and 48 participants had all three forms.
“If they had one microvascular complication, that usually happened about 6 years into the study,” Tryggestad said. “If they had two complications, the first complication came between year 4 and 5 and the second complication at about year 10. In the 48 that had all three complications, the first came at about year 4, the second at about year 7 and the third at year 10. There are a few outliers that developed the third complication by year 4, so it can be very aggressive.”
The risk for multiple microvascular complications was higher for Hispanic children (aHR = 1.57; 95% CI, 1.06-2.33) and Black children (aHR = 1.8; 95% CI, 1.2-2.68) compared with white children. The risk was also increased with each 1% increase in HbA1c (aHR = 1.78; 95% CI, 1.64-1.93) and for those with hypertension (aHR = 3.09; 95% CI, 2.31-4.15) or dyslipidemia (aHR = 2.43; 95% CI, 1.83-3.22).
The causes of the six deaths that occurred among TODAY participants included myocardial infarction, kidney failure, sepsis complication with end-stage kidney disease, postoperative sepsis with multiorgan failure and drug overdose.
Novel interventions to prevent youth-onset diabetes
The findings revealed the importance of prompt disease screening and treatment for children with type 2 diabetes, according to Tryggestad. After diagnosis, providers should begin treatment with metformin and insulin therapy if HbA1c is above 8.5%. A GLP-1 receptor agonist should also be considered to optimize glycemic control.
Youths should be screened for dyslipidemia, hypertension, nephropathy and retinopathy at diabetes diagnosis and then annually thereafter. Providers should prescribe an antihypertensive medication if blood pressure is above the 95% for height or systolic BP is greater than 135 mm Hg. If urine albumin-to-creatine ratio is greater than 30 mg/g, providers should prescribe an angiotensin-converting enzyme inhibitor.
Even with screening and treatment, Tryggestad said, novel interventions are needed not only to improve adherence to type 2 diabetes management, but also to prevent the disease.
“Some of these novel interventions may happen very early on, even as pre-pregnancy interventions since we know that exposure to diabetes increases the risk for diabetes in future generations,” Tryggestad said.
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Tryggestad JB, et al. S11. Presented at: ADCES22; Aug. 12-15, 2022; Baltimore.
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