title: Novel hepato-preferential basal insulin peglispro (BIL) does not differentially affect insulin sensitivity compared with insulin glargine in patients with type 1 and type 2 diabetes.
abstract: Basal insulin peglispro (BIL) is a novel PEGylated basal insulin with a flat pharmacokinetic and glucodynamic profile and reduced peripheral effects, which results in a hepato-preferential action. In Phase 3 trials, patients with T1DM treated with BIL had lower prandial insulin requirements, yet improved prandial glucose control, relative to insulin glargine (GL). We hypothesized that this may be because of an enhanced sensitivity to prandial insulin with BIL resulting from lower chronic peripheral insulin action.
  
  
  
  Two open-label, randomized, 2-period crossover clinical studies were conducted in 28 patients with T1DM and 24 patients with T2DM. In each study period, patients received once-daily, individualized, stable, subcutaneous doses of BIL or GL for 5 weeks before a euglycaemic 2-step hyperinsulinemic clamp procedure (with [6,6-2H2]-glucose in 12 of the patients with T1DM). M-values were derived from the clamp procedure for all patients, with rate of glucose appearance (Ra) and disappearance (Rd) and insulin sensitivity index (SI) determined from the clamps with [6,6-2H2]-glucose.
  
  
  
  There were no statistically significant differences between BIL and GL in key measures of hepatic (% Ra suppression during the low-dose insulin infusion; 78.7% with BIL, 81.8% with GL) or peripheral (M-value and M/I during the high-dose insulin infusion, Rd and SI) insulin sensitivity in patients with T1DM or T2DM.
  
  
  
  The need to reduce prandial insulin observed with BIL during phase 3 trials cannot be explained by the differential effects of BIL and GL on sensitivity to prandial insulin in either T1DM or T2DM.
authors.affiliation: Eli Lilly and Company, Departments of endocrinology, clinical pharmacology, PK/PD and drug disposition Indianapolis, Indiana.
authors.forename: Niels
authors.initials: N
authors.lastname: Porksen
authors.affiliation: Eli Lilly and Company, Departments of endocrinology, clinical pharmacology, PK/PD and drug disposition Indianapolis, Indiana.
authors.forename: Helle
authors.initials: H
authors.lastname: Linnebjerg
authors.affiliation: Eli Lilly and Company, Departments of endocrinology, clinical pharmacology, PK/PD and drug disposition Indianapolis, Indiana.
authors.forename: Parag
authors.initials: P
authors.lastname: Garhyan
authors.affiliation: Lilly-NUS Centre for Clinical Pharmacology, Department of Statistics, Singapore, Singapore.
authors.forename: Eric C Q
authors.initials: EC
authors.lastname: Lam
authors.affiliation: Eli Lilly and Company, Departments of endocrinology, clinical pharmacology, PK/PD and drug disposition Indianapolis, Indiana.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Knadler
authors.affiliation: Eli Lilly and Company, Departments of endocrinology, clinical pharmacology, PK/PD and drug disposition Indianapolis, Indiana.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Jacober
authors.affiliation: Profil, Neuss, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hoevelmann
authors.affiliation: Profil, Neuss, Germany.
authors.forename: Leona
authors.initials: L
authors.lastname: Plum-Moerschel
authors.affiliation: Profil Institute for Clinical Research, Chula Vista, California.
authors.forename: Elaine
authors.initials: E
authors.lastname: Watkins
authors.affiliation: Cardiometabolic Risk Unit, Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy.
authors.forename: Amalia
authors.identifier: 0000-0003-2594-1651
authors.initials: A
authors.lastname: Gastaldelli
authors.affiliation: Profil, Neuss, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Heise
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000187:drug effects; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D000069036:Insulin Glargine / Q000008:administration & dosage*; D061268:Insulin Lispro / Q000008:administration & dosage / Q000031:analogs & derivatives*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D062407:Meals; D008687:Metformin / Q000008:administration & dosage; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000069036:Insulin Glargine; D061268:Insulin Lispro; D008687:Metformin; D011092:Polyethylene Glycols; C000621851:basal insulin peglispro; C517652:hemoglobin A1c protein, human
keywords: 
  Phase 1 to 2 study; basal insulin; drug mechanism; insulin resistance; type 1 diabetes; type 2 diabetes