Youth-onset T2D linked to long-term complications

Patients with youth-onset type 2 diabetes (T2D) are at an increased risk of developing long-term complications, according to follow-up results of the US-based TODAY* study.

“These prospective, longitudinal data indicate that diabetes-related complications appear early in youth-onset T2D and accumulate rapidly,” the authors noted.

The results were based on long-term follow-up of the TODAY trial (TODAY2) conducted in 2004–2011. Patients aged 10–17 years with youth-onset T2D for <2 years were initially assigned to receive metformin alone, metformin plus rosiglitazone, or metformin plus intensive lifestyle intervention with the outcome assessed being time to loss of glycaemic control.

Trial completers were enrolled in the observational follow-up study (2011–2020). They received diabetes care from the TODAY study plus metformin with or without insulin in the first phase (March 2011–February 2014), while from March 2014–January 2020, care was provided by the patients’ healthcare providers. Average follow-up was 10.2 years. Patients were assessed annually for diabetic kidney disease, hypertension, dyslipidaemia, and nerve disease, while presence of retinal disease was examined twice during the follow-up. The present analysis includes 500 patients (mean age 26.4 years, mean 13.3 years since diabetes diagnosis).

The proportion of patients with mean HbA_1c levels in the non-diabetes range (<6 percent) decreased from 75 percent at baseline to 19 percent at end of follow-up. The overall median BMI was 35.0–37.5 kg/m². Almost half the patients were on both metformin and insulin at the final visit.

In terms of cumulative incidence at 15 years, more than two-thirds of patients (67.5 percent) developed hypertension (from 19.2 percent at baseline), while about one-third (32.4 percent) developed nerve disease (from 1.0 percent at baseline). More than half of the patients had dyslipidaemia or diabetic kidney disease (51.6 and 54.8 percent, respectively [from 20.8 and 8.0 percent, respectively, at baseline]). [N Engl J Med 2021;385:416-426]

Retinal disease prevalence increased from 13.7 percent with very mild non-proliferative diabetic retinopathy in 2010–2011 to 51.0 percent with eye disease in 2017–2018. Of these, 8.8 and 3.5 percent had moderate-to-severe retinal changes and macular oedema, respectively.

The cumulative incidence of any microvascular complication increased from 50.0 percent at 9 years to 80.1 percent at 15 years, with no difference between original treatment groups.

Factors associated with an increased risk of any microvascular complication were minority race or ethnicity (hazard ratios [HRs], 1.50 and 1.46 for Hispanic and non-Hispanic Black, respectively, vs non-Hispanic White), elevated HbA_1c (HR, 1.18 per 1 percent increase), low insulin sensitivity (HR, 0.80 per 1 standard deviation [SD] increase), dyslipidaemia (HR, 1.45), and hypertension (HR, 1.44). Similar factors were associated with accumulation of microvascular complications (odds ratios [ORs], 1.57 and 1.80 for Hispanic and non-Hispanic Black, respectively, vs non-Hispanic White; OR, 1.80 per 1 percent increase in HbA_1c; OR, 0.64 per 1 SD increase in insulin sensitivity; OR, 2.77 for dyslipidaemia; OR, 3.18 for hypertension).

About 60 percent of patients had ≥1 complication, with 28.4 percent having ≥2 complications. Seventeen serious cardiovascular events were reported. The rate of all adjudicated heart, vascular, and cerebrovascular events was 3.73 per 1,000 person-years (PYs). The rate of all eye disease events was 12.17 per 1,000 PYs, liver, pancreas, or gallbladder events 6.70 per 1,000 PYs, nerve events 2.35 per 1,000 PYs, and kidney events 0.44 per 1,000 PYs.

Six deaths were reported over the follow-up period, one each due to myocardial infarction, kidney failure, drug overdose, and sepsis, and two due to sepsis with multiorgan failure.

Tackling complications in youth-onset T2D patients

“[T]hese data illustrate the serious personal and public health consequences of youth-onset T2D in the transition to adulthood,” the authors pointed out.

The results particularly contrast with the rate of microvascular complications known to develop in youth-onset type 1 diabetes (T1D; approximately 25 percent after >10 years of T1D). [BMJ 2008;336:697-701]

While the causes of the increased complication risk in youth-onset T2D are currently uncertain, rapid deterioration of beta-cell function and severe insulin resistance are among factors likely to blame, the authors suggested.

The known poor response to currently approved medications and potential lack of adherence in this population add to the challenge, they said, calling for further research into identifying strategies to manage glycaemia and risk factors for complications in patients with youth-onset T2D.