title: Mitigating Meal-Related Glycemic Excursions in an Insulin-Sparing Manner During Closed-Loop Insulin Delivery: The Beneficial Effects of Adjunctive Pramlintide and Liraglutide.
abstract: Closed-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.
  
  
  
  Two 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.
  
  
  
  Pramlintide 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.
  
  
  
  Adjunctive 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.
authors.affiliation: Yale School of Medicine, New Haven, CT jennifer.sherr@yale.edu.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sherr
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Neha S
authors.initials: NS
authors.lastname: Patel
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Camille I
authors.initials: CI
authors.lastname: Michaud
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Miladys M
authors.initials: MM
authors.lastname: Palau-Collazo
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Van Name
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: William V
authors.initials: WV
authors.lastname: Tamborlane
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Eda
authors.initials: E
authors.lastname: Cengiz
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Lori R
authors.initials: LR
authors.lastname: Carria
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Tichy
authors.affiliation: Yale School of Medicine, New Haven, CT.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Weinzimer
mesh_terms: D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007328:Insulin / Q000008:administration & dosage* / Q000009:adverse effects; D007332:Insulin Infusion Systems; D058228:Islet Amyloid Polypeptide / Q000008:administration & dosage* / Q000009:adverse effects; D000069450:Liraglutide / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D062407:Meals / Q000502:physiology; D019518:Postprandial Period / Q000187:drug effects; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D000069450:Liraglutide; C105254:pramlintide