Pharmacokinetics, Pharmacodynamics, and Modulation of Hepatic Glucose Production With Insulin Glargine U300 and Glargine U100 at Steady State With Individualized Clinical Doses in Type 1 Diabetes

Abstract

OBJECTIVE This study characterized the pharmacokinetics (PK), pharmacodynamics (PD), and endogenous (hepatic) glucose production (EGP) of clinical doses of glargine U300 (Gla-300) and glargine U100 (Gla-100) under steady-state (SS) conditions in type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS T1DM subjects (N = 18, age 40 ± 12 years, T1DM duration 26 ± 12 years, BMI 23.4 ± 2 kg/m2, A1C 7.19 ± 0.52% [55 ± 5.7 mmol · mol−1−1]) were studied after 3 months of Gla-300 or Gla-100 (evening dosing) titrated to fasting euglycemia (random, crossover) with the euglycemic clamp using individualized doses (Gla-300 0.35 ± 0.08, Gla-100 0.28 ± 0.07 units · kg−1). RESULTS Plasma free insulin concentrations (free immunoreactive insulin area under the curve) were equivalent over 24 h with Gla-300 versus Gla-100 (point estimate 1.11 [90% CI 1.03; 1.20]) but were reduced in the first 6 h (0.91 [90% CI 0.86; 0.97]) and higher in the last 12 h postdosing (1.38 [90% CI 1.21; 1.56]). Gla-300 and Gla-100 both maintained 24 h euglycemia (0.99 [90% CI 0.98; 1.0]). The glucose infusion rate was equivalent over 24 h (1.03 [90% CI 0.88; 1.21]) but was lower in first (0.77 [90% CI 0.62; 0.95]) and higher (1.53 [90% CI 1.23; 1.92]) in the second 12 h with Gla-300 versus Gla-100. EGP was less suppressed during 0–6 h but more during 18–24 h with Gla-300. PK and PD within-day variability (fluctuation) was 50% and 17% lower with Gla-300. CONCLUSIONS Individualized, clinical doses of Gla-300 and Gla-100 resulted in a similar euglycemic potential under SS conditions. However, Gla-300 exhibited a more stable profile, with lower variability and more physiological modulation of EGP compared with Gla-100.

Greater Suppression of Glucagon, Lipolysis, and Ketogenesis with Insulin Glargine U300 as Compared with Glargine U100 in Type 1 Diabetes Mellitus

“…Subjects, study design, and methods have been previously described in detail. 3 In brief, 18 persons with T1DM (age 40 -12 years, diabetes duration 26 -12 years, body mass index 23.4 -2 kg/m 2 , A1C 7.19% -0.52% [55 -6 mmol/ mol], plasma C-peptide 0.01 -0.01 ng/mL) were studied after 3 months of optimization of glycemic control with Gla-300 or Gla-100 (evening dosing), titrated to fasting Section of Endocrinology & Metabolism, Department of Medicine, Perugia University School of Medicine, Perugia, Italy. Preliminary data from this study were submitted to the 77th Scientific Sessions (2017), June 9-13, 2017, San Diego, California, and has been accepted for poster presentation with abstract publication in Diabetes.…”

“…R ecent studies have compared the pharmacokinetics (PK) and pharmacodynamics (PD) of the long-acting (basal) insulin analogues glargine U300 (Gla-300) and glargine U100 (Gla-100) in type 1 diabetes mellitus (T1DM) at fixed insulin doses after single injection, 1 at steady state, 2 and at individual doses that persons with T1DM require daily. 3 In addition to glucose metabolism, insulin regulates several physiological pathways, such as modulation of glucagon secretion, 4 effects on lipid 5 and protein 6 metabolism, and endothelial function. 7 Only one study, investigating PK/PD of glargine and detemir at steady state in T1DM, however, has reported on the effects of long-acting insulin analogues, on regulation of alanine, lactate, and lipid metabolism.…”

“…8 The aim of this study was to establish the potential differences between clinical doses of Gla-300 and Gla-100 on suppression of glucagon, lipolysis, and ketogenesis, in a group of persons with T1DM in whom the results of glucose metabolism have already been described. 3…”

Efficacy and safety of a morning injection of insulin glargine 300 units/mL versus insulin glargine 100 units/mL in adult patients with type 1 diabetes: A multicentre, randomized controlled trial using continuous glucose monitoring

“…Insulin glargine 300 units/mL (Gla‐300) has shown low within‐ and between‐day glycaemic variability, with a flatter, more stable pharmacokinetic profile and less fluctuation in glycaemic control compared with insulin glargine 100 units/mL (Gla‐100) or insulin degludec 100 units/mL . Importantly, Gla‐300 has been associated with less within‐day variability in patients with T1D, with duration of insulin action exceeding 24 hours at steady state with clinical, individual doses . Furthermore, in a pharmacokinetic/pharmacodynamic study of patients with T1D, Gla‐300 was shown to have a longer duration of action than the same dose of Gla‐100.…”

“…9,10 Importantly, Gla-300 has been associated with less within-day variability in patients with T1D, with duration of insulin action exceeding 24 hours at steady state with clinical, individual doses. 11 Furthermore, in a pharmacokinetic/pharmacodynamic study of patients with T1D, Gla-300 was shown to have a longer duration of action than the same dose of Gla-100. Doses may not be representative of randomized clinical trials as higher doses of Gla-300 were required for participants in the EDITION phase 3 clinical trial in patients with T1D.…”