The Differential and Combined Action of Insulin Glargine and Lixisenatide on the Fasting and Postprandial Components of Glucose Control

Abstract

Background: iGlarLixi is an injectable combination of long acting insulin glargine (iGlar) and glucagon-like peptide 1 receptor agonist lixisenatide in a fixed ratio, which was proven safe and effective for the treatment of type 2 diabetes. Lixisenatide and iGlar act differently on fasting and postprandial plasma glucose (fasting plasma glucose [FPG] and postprandial glucose [PPG]). Here, we deconstruct quantitatively their respective FPG and PPG effects. Method: This post hoc study analyzes data from the Lixilan-O trial, where 1170 subjects with type 2 diabetes were randomly assigned to 30 weeks of once daily injections of lixisenatide, iGlar, and iGlarLixi (1:2:2). The FPG and PPG components of glucose control were assessed in terms of mean glucose (fasting mean plasma glucose [FMPG] and prandial mean plasma glucose [PMPG], respectively). The MPGP was computed across all meals as a delta between post- and premeal glucose; glucose variability was measured by the high blood glucose index (HBGI) (fasting HBGI and prandial HBGI [PHBGI], respectively), and glycemic exposure measured by area under the curve (AUC) computed overall. All metrics were derived from seven-point self-monitoring glucose profiles. Results: Insulin glargine lowered significantly FMPG by 15.3 mg/dL ( P < .01) without any significant change in PMPG. Lixisenatide, when added to iGlar, reduced PMPG by 9.7 mg/dL ( P < .01), AUC by 96.3 mg∙h/dL ( P < .01), and PHBGI by 2.4 ( P < .01), primarily due to attenuation of PPG and without significant change in mean FPG. Conclusion: Insulin glargine and lixisenatide act selectively on FPG and PPG. Their combination iGlarLixi offers more effective glucose control than its components due to the cumulative effect on FPG and PPG, which is evidenced by reduced average glycemia, glycemic exposure, and glucose variability.