Mitigating Meal-Related Glycemic Excursions in an Insulin-Sparing Manner During Closed-Loop Insulin Delivery: The Beneficial Effects of Adjunctive Pramlintide and Liraglutide

Abstract

OBJECTIVEClosed-loop (CL) insulin delivery effectively maintains glucose overnight but struggles when challenged with meals. Use of single-day, 30-μg/meal pramlintide lowers meal excursions during CL. We sought to further elucidate the potential benefits of adjunctive agents after 3–4 weeks of outpatient dose titration.RESEARCH DESIGN AND METHODSTwo CL studies were conducted: one evaluating adjunctive pramlintide and the other liraglutide. Ten subjects (age 16–23 years; A1C 7.2 ± 0.6% [55 ± 6.6 mmol/mol]) completed two 24-h sessions: one on CL alone and one on CL plus 60-μg pramlintide (CL + P), after a 3–4-week outpatient dose escalation. Eleven subjects (age 18–27 years; A1C 7.5 ± 0.9% [58 ± 9.8 mmol/mol]) were studied before and after treatment with 1.8 mg liraglutide (CL + L) after a similar 3–4-week dose escalation period. Timing and content of meals during CL were identical within experiments; meals were not announced.RESULTSPramlintide delayed the time to peak plasma glucose (PG) excursion (CL 1.6 ± 0.5 h vs. CL + P 2.6 ± 0.9 h, P < 0.001) with concomitant blunting of peak postprandial increments in PG (P < 0.0001) and reductions in postmeal incremental PG area under the curve (AUC) (P = 0.0002). CL + L also led to reductions in PG excursions (P = 0.05) and incremental PG AUC (P = 0.004), with a 28% reduction in prandial insulin delivery. Outpatient liraglutide therapy led to a weight loss of 3.2 ± 1.8 kg, with a 26% reduction in total daily insulin dose.CONCLUSIONSAdjunctive pramlintide and liraglutide treatment mitigated postprandial hyperglycemia during CL control; liraglutide demonstrated the additional benefit of weight loss in an insulin-sparing manner. Further investigations of these and other adjunctive agents in long-term outpatient CL studies are needed.

Impact of macronutrient content of meals on postprandial glucose control in the context of closed‐loop insulin delivery: A randomized cross‐over study

“…It is hoped that CLS will alleviate several day‐to‐day burdensome tasks for patients, including simplifying meal insulin bolus calculation . Fully‐automated CLSs have failed to provide adequate post‐meal glucose control, although promising and interesting avenues are being investigated, such as the intraperitoneal insulin delivery route or concomitant use of pramlintide . Faster acting insulins also improve the performance of CLS and should be further explored to simplify meal insulin bolus calculation.…”

ISPAD Clinical Practice Consensus Guidelines 2018: Diabetes technologies

“…Early studies focused on demonstrating feasibility of automated insulin delivery in carefully controlled in‐clinic studies, and were conducted in a range of patients including children, adolescents, adults, and in pregnant women . These included single hormone, dual hormone systems, and the incorporation of insulin absorption adjuncts . In‐clinic studies that simulated hypothetical real world challenges including exercise, alcohol, high fat meals, and inaccurate continuous glucose sensors followed, and demonstrated that the automated insulin delivery systems remained safe and effective.…”

Closing the Loop on Managing Youth With Type 1 Diabetes: Children Are Not Just Small Adults

“…Dual-hormone systems are also being explored, whether it be through the addition of glucagon in hopes of more closely approximating normal physiological function by infusing glucagon when sensor glucose levels trend low or through the addition of other adjunctive therapies, such as pramlintide or liraglutide (26,39,40).…”