Predictors of response to insulin therapy in youth with poorly‐controlled type 2 diabetes in the TODAY trial

Abstract

Objective To understand the factors associated with glycemic control after starting insulin in youth with type 2 diabetes following glycemic failure (persistent HbA1c ≥8%) with metformin alone, metformin + rosiglitazone or metformin + lifestyle in the TODAY study. Methods Change in HbA1c after add‐on insulin therapy and the factors predictive of glycemic response were evaluated. At 1‐year postinsulin initiation, 253 youth had a mean of 3.9 ± 1.0 visits since the time of insulin initiation. Participants were divided into three groups according to glycemic control: consistent decrease in HbA1c by ≥0.5%, change <0.5%, or consistent increase in HbA1c ≥0.5%, at 75% or more of the visits. Results Within 1‐year postinsulin initiation, 33.2% of participants had a consistent HbA1c decrease of ≥0.5%, 46.2% changed HbA1c <0.5%, and 20.6% had an increase ≥0.5%. At randomization into TODAY and at time of insulin initiation, the three glycemia groups were similar in age, sex, race‐ethnicity, pubertal stage, BMI z‐score, diabetes duration, and insulin secretion indices. Consistent HbA1c improvement was associated with higher insulin sensitivity (1/fasting insulin) at randomization and at time of failure, higher adiponectin at randomization, and was not associated with indices of β‐cell function. Conclusions Response to add‐on insulin was highly variable among youth in TODAY. Greater insulin sensitivity and higher adiponectin concentrations at randomization were associated with improved glycemic control after initiation of insulin. Due to limited information on adherence to insulin injections, the roles of adherence to the prescribed insulin regimen or psychosocial factors are unknown.

Glycemic control in youth‐onset type 2 diabetes correlates with weight loss

“…37,38 However, after TODAY subjects met criteria for insulin rescue, only 33% of the subjects achieved a HbA1c improvement of at least 0.5%. 39 It is unknown, whether medication non-adherence may contribute to the poor efficacy of insulin treatment. We posit that medication non-adherence may also explain the The TODAY study demonstrated that intensive lifestyle modifications mitigated weight gain in subjects on metformin monotherapy.…”

“…The TODAY study showed that baseline beta‐cell function, and not medication adherence, is the dominant predictor for long‐term glycemic outcome 37,38 . However, after TODAY subjects met criteria for insulin rescue, only 33% of the subjects achieved a HbA1c improvement of at least 0.5% 39 . It is unknown, whether medication non‐adherence may contribute to the poor efficacy of insulin treatment.…”

Youth-onset type 2 diabetes: translating epidemiology into clinical trials

“…Once participants reached the primary outcome in the TODAY study, metformin was continued, rosiglitazone (if present) discontinued and insulin initiated. Importantly, there was only a modest improvement in HbA 1c (<5.5 mmol/mol [<0.5%]) 6 months after insulin initiation, and no significant improvement in 1 year, such that mean HbA 1c was still 85.8 mmol/mol (10.0%) [25], highlighting the difficulty in achieving glycaemic control with only metformin and insulin once beta cell function has declined.…”

Youth with type 2 diabetes have a high rate of treatment failure after discontinuation of insulin: A Pediatric Diabetes Consortium study

“…In 2012, the TODAY study published the first trial comparing metformin alone, metformin plus an intensive lifestyle intervention, and metformin plus rosiglitazone, and only half of participants experienced durable glycemic control on metformin alone 15 . Of the adolescents with type 2 diabetes in the TODAY trial that failed oral antidiabetic treatment and were then started on insulin therapy, only 33% maintained a consistent reduction in HbA1c after 6 months of add‐on insulin therapy 18 . In the SEARCH study of youth with type 2 diabetes who were on metformin monotherapy at baseline, at mean follow‐up of 7 years, 27% had insulin added or switched to insulin alone 14 .…”

“…15 Of the adolescents with type 2 diabetes in the TODAY trial that failed oral antidiabetic treatment and were then started on insulin therapy, only 33% maintained a consistent reduction in HbA1c after 6 months of add-on insulin therapy. 18 In the SEARCH study of youth with type 2 diabetes who were on metformin monotherapy at baseline, at mean follow-up of 7 years, 27% had insulin added or switched to insulin alone. 14 We similarly show high treatment failure rates in youth with type 2 diabetes who were initially successful in coming off insulin therapy yet could not sustain durable glycemic control on metformin or lifestyle alone, and ultimately, more than 50% of individuals required re-intensification of diabetes therapy.…”