Glycemic Control in Youth-onset Type 2 Diabetes: Predicting the Tomorrow Based on Lessons Learnt from TODAY

The prevalence of youth-onset type 2 diabetes is increasing globally, particularly in the socioeconomically weaker and First Nations communities. Predominantly, it is a disease of adolescent onset, occurring almost universally in youth who are overweight or obese, the majority of whom have a strong family history of type 2 diabetes and/or exposure to maternal gestational diabetes. Youth-onset type 2 diabetes represents a distinct clinical entity marked by high rates of complications/comorbidities (60%-72% experience 1 or more complications/comorbidity by early adulthood) and mortality. Notably, mortality rates are 2.4 times higher in youth with type 2 diabetes compared with the general population. In fact, youth with type 2 diabetes are at a greater risk of mortality than those with type 1 diabetes, despite a shorter disease duration (1).

The high risk of complications and mortality in youth-onset type 2 diabetes underscores the importance of stringent glycemic control in such a patient population. Unfortunately, treatment failure rates are higher in subjects with youth-onset type 2 diabetes than in those with late-onset diabetes. In the landmark Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, treatment failure was observed in 45.6% of the participants over an average follow-up of 3.86 years; the failure rate in participants taking metformin alone was 51.7% (2), whereas it was only 21% among adults on metformin in the A Diabetes Outcome Progression Trial (3). In the TODAY study, a baseline glycated hemoglobin (HbA_1c) ≥ 6.3% predicted glycemic failure over the first 48 months (4).

As a continuation of the TODAY study, in 2011, the original trial participants were enrolled in a predominately observational follow-up study (TODAY2). Between 2011 and 2014, the participants continued to receive standard diabetes-related care every 3 months from the TODAY study team and were treated with metformin and/or insulin to maintain glycemic control. Eventually, they were followed up for a period of 6.8 years (range, 4-9 years) and rates of glycemic failure (defined as HbA_1c ≥ 8% at 2 or more consecutive visits) within and beyond the first 48 months were reported by Zeitler et al (5). Of note, among the 584 TODAY participants, 320 (54.8%) attained glycemic failure within the first 48 months of the study (early failure); of the 264 participants who did not reach glycemic failure by 48 months, 90 subsequently lost glycemic control by the end of follow-up (late failure). Overall, in the long term, with as long as 9 years of follow-up, 410 (70.2%) participants reached glycemic failure, an alarming figure. Likewise, data from the SEARCH for Diabetes in Youth (SEARCH) study showed that after 7 years of follow-up, only 35% of the participants could meet glycemic targets (HbA_1c < 7%) (6).

The authors reported that the strongest baseline predictors of overall glycemic failure (early and late failure) included C-peptide index, HbA_1c, proinsulin/insulin ratio, and maternal history of diabetes (5). Notably, initial treatment with metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle intervention could not predict long-term glycemic failure. Thus, initial therapy with metformin and rosiglitazone, although beneficial in the short time, might not be able to avert glycemic failure in the longer term.

As far as late deterioration of glycemic control was concerned, the significant predictors were baseline β-cell function (C-peptide index), proinsulin/insulin ratio and HbA_1c at 48 months. Receiver operating characteristic curve analysis revealed that a baseline HbA_1c ≥ 6.2% was optimally predictive of loss of glycemic control at any time, very similar to what was shown in the original TODAY study that had examined glycemic control up to 48 months (4). Besides, the HbA_1c trajectory of the study participants revealed that those who never lost glycemic control throughout follow-up had no appreciable change in HbA_1c over time, whereas those who lost control had a slow yet steady rise in HbA_1c for many months that was followed by an accelerated worsening of HbA_1c approximately 3 months before glycemic failure. Surprisingly, the gradual rise in HbA_1c was generally within the recommended treatment targets (ie, < 7%). An absolute HbA_1c rise of more than 0.5% was related to loss of glycemic control in 94% of the participants who had reached glycemic failure and had experienced such a rise within 6 months, irrespective of the baseline HbA_1c value.

The results reinforce that youth-onset type 2 diabetes is a distinct clinical entity with high rates of treatment failure, likely because of significant β-cell dysfunction seen in such subjects early in the course of the disease (7). Furthermore, strict glycemic control and stringent monitoring are essential in subjects with youth-onset type 2 diabetes. In addition, overcoming treatment inertia and early intensification of therapy is of paramount importance to avoid glycemic failure in the youth. Last, although it could not be achieved in the present study, weight loss should be encouraged because weight loss over the first year after diagnosis has been shown to correlate with improvement in HbA_1c (8).

Funding

None.

Author Contributions

Both R.P. and S.K.P. contributed equally to the manuscript.

Disclosures

None of the authors reported a conflict of interest.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.