Type 2 diabetes in youth: Rationale for use of off-label antidiabetic agents.

Abstract

Dr. Kelsey has been a site PI for clinical trials related to youth-onset type 2 diabetes sponsored by Janssen, Boehringer-Ingelheim, Merck, and Daiichi-Sankyo; Dr. Zeitler has been site PI for clinical trials related to youth-onset type 2 diabetes sponsored by Janssen and is a consultant on research design and oversight for clinical trials related to youth-onset type 2 diabetes sponsored by Janssen, Merck, Daiichi-Sankyo, Boehringer-Ingelheim, Novo-Nordisk, and Eli Lilly. Dr. Shah has been a site PI for clinical trials related to youth-onset type 2 diabetes sponsored by Takeda, Daiichi-Sankyo, and Eli Lilly; Dr. Nadeau does not have any conflicts of interest to disclose. The peer review history for this article is available at https://publons.com/publon/10.1111/pedi.13350. Data sharing is not applicable to this article as no new data were created or analyzed in this study. FIGURE S1: The supplementary figure provides a more detailed suggested algorithm for medication adjustment, based on the ST2OMP treatment algorithms, with each panel representing a different in-clinic scenario at the time of HbA1c measurement: (a) Patient has been on metformin monotherapy for at least 2 months. Of note, the threshold for starting insulin is higher in these patients due to a greater opportunity to achieve glycemic control by adding multiple non-insulin agents; (b) Patient is prescribed metformin and one additional non-insulin agent; (c) Patient is prescribed metformin and 2 other non-insulin agents; (d) Patient is prescribed metformin, 2 or more non-insulin agents, and insulin; (e) Patient is being treated for presumed type 1 diabetes based on presentation and has a revised diagnosis of type 2 diabetes. Of note, it is critical to assess adherence and reinvigorate current treatment if suspicion that doses are being missed prior to adding new agents, with the exception that insulin needs to be added regardless of adherence if evidence of metabolic decompensation. Also, we recommend to schedule for a nurse certified diabetes educator visit for patients with HbA1c ≥ 11% 1 month after insulin is added. Second tier agent considerations: GLP-1 agonist (liraglutide, exenatide, exenatide XR, dulaglutide, semaglutide): Consider if patient is overweight and/or needs appetite suppression. Caution if history of pancreatitis or family history of medullary thyroid carcinoma. Thiazolidinedione (pioglitazone): TODAY study outcomes suggest better glycemic outcomes in girls than boys when thiazolidinediones are used as add-on to metformin. There is evidence for improvement of NAFLD with pioglitazone. Discuss risks for edema, especially if on insulin. SGLT2 inhibitor (canagliflozin, empagliflozin, dapagliflozin, ertugliflozin): Consider if daytime/post-prandial hyperglycemia. Caution in patients with low reliability or metabolic decompensation due to risk for euglycemic diabetic ketoacidosis.2 If well-tolerate and insurance allows, consider switching to SGLT2i-metformin combination medication. Caution in patients with history of chronic/recurrent UTI. DPP-4 inhibitor (sitagliptin, saxagliptin, linagliptin): Little utility unless required as 2nd line by insurance. Long-acting insulins: Detemir, glargine, degludac, NPH, if insurance does not cover others. Rapid-acting insulins: Aspart, lispro, regular if insurance does not cover others. aPioglitazone can be used as alternative agent for patients not tolerating metformin; bIn absence of significant adverse effects, new agent should be titrated up each visit to maximal dose; cThese agents would typically be added sequentially, 3 months apart; d Patients with HbA1c ≥11% will also be scheduled for a CDE visit 1 month after insulin is added. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.