Pharmacokinetics, Pharmacodynamics, and Modulation of Hepatic Glucose Production With Insulin Glargine U-300 and Glargine U-100 at Steady State With Individualized Clinical Doses in Type 1 Diabetes.

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 conditions (SS) 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]), 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.