Preserved pharmacokinetic exposure and distinct glycemic effects of insulin degludec and liraglutide in IDegLira, a fixed‐ratio combination therapy

Abstract

Insulin degludec/liraglutide (IDegLira) is a novel fixed-ratio combination of the basal insulin insulin degludec (IDeg) and liraglutide, a glucagon-like peptide-1 analog. The pharmacokinetics (PK) and pharmacodynamics of IDegLira were assessed versus its components. A single-dose, randomized, 4-period crossover clinical pharmacology study in healthy subjects compared the bioavailability of IDegLira with its monocomponents. Dose proportionality, covariate effects on exposure, and exposure-response for change in glycated hemoglobin were analyzed based on data from a randomized treat-to-target phase 3 study in subjects with type 2 diabetes. Overall, the PK properties of IDeg and liraglutide were preserved for IDegLira. Liraglutide exposure was lower when dosed as IDegLira but met the criterion for equivalence. No relevant deviations from dose proportionality for the IDegLira components were observed. Covariate effects on exposure were consistent with previous results. Glycemic response to IDegLira was larger than with IDeg or liraglutide alone, reflecting their distinct glucose-lowering effects throughout the dose/exposure range. Keywords Clinical Pharmacology (CPH), Drug Interactions, Endocrinology (END), Pharmacodynamics (PDY), Population Pharmacokinetics Exposure-ResponseType 2 diabetes (T2D) is a progressive disease with an underlying complex pathophysiology involving multiple organs, necessitating a multitargeted approach to treatment.1 Accordingly, there is a need for therapies that have complementary mechanisms of action to help achieve improved glycemic control with fewer side effects than the currently available treatment options. 2IDegLira is a novel fixed-ratio combination of the basal insulin, insulin degludec (IDeg; 100 U/mL), and a once-daily glucagon-like peptide-1 (GLP-1) analog, liraglutide (3.6 mg/mL). IDegLira may be initiated and titrated, as performed with basal insulin, and administered in dose steps, in which 1 dose step is defined as 1 unit IDeg/0.036 mg liraglutide and can be titrated up to a maximum of 50 dose steps (50 units/1.8 mg). 3,4 IDeg is a new-generation basal insulin with an ultralong duration of action, providing a flat and stable glucose-lowering effect. [5][6][7][8] IDeg has been shown to be efficacious in lowering glycated hemoglobin (HbA 1c ) and fasting plasma glucose (FPG) levels in subjects with T2D, 9-11 with fewer hypoglycemic episodes, particularly nocturnal episodes, versus insulin glargine.12 The molecular structure of IDeg and its solubility at neutral pH (7) allow it to be coformulated with liraglutide.Liraglutide is an injectable, once-daily GLP-1 analog 13,14 that mimics the effects of native GLP-1 in restoring the insulin response to glucose, 15 providing both fasting and postprandial glycemic control 16,17 in a glucose-dependent manner. Liraglutide reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake.18-22 Although GLP-1 receptor agonist treatment has been associated with a moderately increased risk...

Insulin Degludec/Liraglutide: A Review in Type 2 Diabetes

“…4.1.1) [n = 1549], there were no clinically relevant changes in dose proportionality for the individual components of insulin degludec/ liraglutide, and the effects of covariates (e.g. bodyweight) on exposure were consistent with previous data for insulin degludec and liraglutide [14]. After subcutaneous injection, insulin degludec forms a depot of soluble multihexamers in the subcutaneous tissue, from which insulin degludec monomers are slowly and continuously absorbed into the circulation [9,10].…”

“…The bioequivalence of insulin degludec/liraglutide and its individually administered components was established in a single-dose study in healthy volunteers [14]. In a population pharmacokinetic analysis of data from the DUAL-I trial in type 2 diabetic patients (Sect.…”

Glycemic Control in a Real-Life Setting in Patients with Type 2 Diabetes Treated with IDegLira at a Single Swiss Center

“…It is also used as a treatment for obesity, and therefore is often associated with weight loss in patients with diabetes [8, 9]. The pharmacokinetic properties of the two individual components, insulin degludec and liraglutide, are preserved in the fixed-ratio combination product IDegLira [10]. IDegLira is administered in dose steps (1 U insulin degludec and 0.036 mg liraglutide) up to a maximum of 50 dose steps, corresponding to 50 U of insulin degludec and 1.8 mg of liraglutide.…”

Clinical Considerations When Initiating and Titrating Insulin Degludec/Liraglutide (IDegLira) in People with Type 2 Diabetes

“…The discrete pharmacokinetic properties of degludec and liraglutide are preserved when administered as the IDegLira co-formulation, with equivalence being demonstrated compared with both degludec and liraglutide monotherapy [39]. The maximum daily dose of IDegLira is 50 units/dose steps [7], as this delivers the maximum licenced liraglutide dose for diabetes of 1.8 mg [36].…”