Safety and Tolerability of the Treatment of Youth-Onset Type 2 Diabetes

Abstract

OBJECTIVEData related to the safety and tolerability of treatments for pediatric type 2 diabetes are limited. The TODAY clinical trial assessed severe adverse events (SAEs) and targeted nonsevere adverse events (AEs) before and after treatment failure, which was the primary outcome (PO).RESEARCH DESIGN AND METHODSObese 10- to 17-year-olds (N = 699) with type 2 diabetes for <2 years and hemoglobin A1c (A1C) ≤8% on metformin monotherapy were randomized to one of three treatments: metformin, metformin plus rosiglitazone (M + R), or metformin plus lifestyle program (M + L). Participants were followed for 2–6.5 years.RESULTSGastrointestinal (GI) disturbance was the most common AE (41%) and was lower in the M + R group (P = 0.018). Other common AEs included anemia (20% before PO, 14% after PO), abnormal liver transaminases (16, 15%), excessive weight gain (7, 9%), and psychological events (10, 18%); the AEs were similar across treatments. Permanent medication reductions/discontinuations occurred most often because of abnormal liver transaminases and were lowest in the M + R group (P = 0.005). Treatment-emergent SAEs were uncommon and similar across treatments. Most (98%) were unrelated or unlikely related to the study intervention. There were no deaths and only 18 targeted SAEs (diabetic ketoacidosis, n = 12; severe hypoglycemia, n = 5; lactic acidosis, n = 1). There were 62 pregnancies occurring in 45 participants, and 6 infants had congenital anomalies.CONCLUSIONSThe TODAY study represents extensive experience managing type 2 diabetes in youth and found that the three treatment approaches were generally safe and well tolerated. Adding rosiglitazone to metformin may reduce GI side effects and hepatotoxicity.

Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association

“…However, accumulating evidence provides support for more appropriate goals. The TODAY study showed that hypoglycemia is rare in adolescents with type 2 diabetes, even with insulin therapy ( 73 ), suggesting that more stringent A1C targets are acceptable. Also in TODAY, individuals with an A1C of >6.3% after 3 months of metformin or an increasing A1C, even in the nondiabetes range ( 74 ), had a substantially increased risk for loss of glycemic control, likely reflecting a greater degree of β-cell dysfunction ( 75 , 76 ).…”

“…This can be done alone or in combination with metformin, unless metformin is contraindicated. Because studies indicate that adherence with insulin therapy is a challenge in youth with type 2 diabetes ( 73 , 119 ), starting with a single daily dose of a long-acting insulin analog (glargine [Lantus, Basalglar, Toujeo], detemir [Levemir], or degludec [Tresiba]) may be preferred. Premixed insulins may be appropriate in some circumstances.…”

“…The most significant adverse effect of insulin therapy in type 2 diabetes, as in type 1 diabetes, is hypoglycemia. Although the incidence of hypoglycemia in youth with type 2 diabetes is low, even with insulin therapy ( 73 ), patients treated with insulin should be educated about avoidance, recognition, and treatment of hypoglycemia and should be instructed on the use of glucagon for treatment of severe hypoglycemia. Also, since insulin may result in weight gain, involvement of a nutritionist in patient care and education is essential when insulin is initiated.…”

Current Perspectives on Management of Type 2 Diabetes in Youth

“…Adverse effects related to insulin use include weight gain and hypoglycemia. Hypoglycemia is rare in youth with T2DM due to insulin resistance [ 18 ]. Insulin regimens should be carefully tailored to lifestyle and individual needs.…”

“…However, more stringent goals such as less than 6.5% may be appropriate for selected individuals if the goal can be met without significant hypoglycemia or other adverse effects and in those with short duration of diabetes or patients who receive therapy with lifestyle or metformin only with significant weight improvement [ 15 ]. The lower target of <6.5% in selected instances is supported by the evidence that hypoglycemia in patients with T2DM receiving insulin is rare [ 18 ] and A1C > 6.3% after 3 months of metformin or any increasing A1C even in the non-diabetes range was associated with increased risk for loss of glycemic control in the TODAY study [ 10 ]. The A1C targets should also be individualized based on baseline A1C at the time of diagnosis.…”