Xultophy: first insulin/incretin mimetic combination launched

15 December 2014

Xultophy is a prefilled pen containing a fixed-ratio combination of insulin degludec and liraglutide, licensed for the treatment of type II diabetes in combination with oral hypoglycaemics.

Xultophy is the first product to combine a basal insulin and an incretin mimetic to allow administration of both drugs in a single subcutaneous injection

PHARMACOLOGY

Insulin degludec is a long-acting basal insulin that is given once daily. It forms a depot of soluble multi-hexamers following subcutaneous injection which slowly releases insulin monomers throughout the day. Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue (incretin mimetic) that improves glycaemic control by lowering fasting and postprandial blood glucose.¹

Xultophy contains a fixed-ratio combination of insulin degludec 100 units and liraglutide 1.8mg per ml. Doses are administered by subcutaneous injection once daily and can be adjusted in dose steps of 1 unit of insulin degludec and 0.036mg of liraglutide. The maximum daily dose of Xultophy is 50 dose steps (50 units of insulin degludec and 1.8mg of liraglutide).¹

CLINICAL STUDIES

Investigators assessed the efficacy and safety of the combination product for the treatment of uncontrolled type II diabetes in two phase 3 clinical studies. The first study (DUAL-I) compared the combination with its components given alone in insulin-naive patients and the second study (DUAL-II) compared the combination with insulin degludec alone in patients transferring from basal insulin.^2,3

DUAL-I

The DUAL- I study was an open-label, treat-to-target trial which recruited 1,663 adults with type II diabetes inadequately controlled with metformin with or without pioglitazone (HbA_1c 7–10%). Patients continued their existing hypoglycaemic therapy and were randomised (2:1:1) to receive additional insulin degludec plus liraglutide, insulin degludec or liraglutide.²

Patients in the liraglutide arm followed a fixed-dose titration over 3 weeks to a dose of 1.8mg once daily. Patients randomised to receive combined insulin degludec/liraglutide or insulin degludec had their doses titrated to achieve a pre-breakfast plasma glucose concentration of 4–5mmol/L. The primary endpoint was HbA_1cafter 26 weeks of treatment.²

At 26 weeks, mean HbA_1c had decreased by 1.9% in patients treated with the combination product, 1.4% in those treated with insulin degludec and 1.3% in those given liraglutide. The main objective of the study was met, specifically the combination product was found to be non-inferior to insulin degludec and superior to liraglutide.²

DUAL-II

The 26-week, double-blind DUAL-II study (n=413) compared the combination with insulin degludec alone in patients already receiving 20–40 units basal insulin daily plus metformin with or without sulfonylurea/prandial glucose regulator ('glinide'). Patients had an HbA_1c of 7.5–10% and were randomised to receive the combination product or insulin degludec titrated to achieve a fasting plasma glucose of 4–5mmol/L. Basal insulin and sulfonylurea/glinide were discontinued at randomisation.³

Change from baseline in HbA_1C after 26 weeks (the primary endpoint) was -1.9% for the combination product versus -0.9% for insulin degludec (estimated treatment difference -1.1%, 95% CI -1.3 to -0.8, p<0.0001).³

Investigators noted a significant mean weight reduction of 2.7kg at 26 weeks in the combination product group compared with no weight change in the insulin degludec group (p<0.0001).³

Safety profile

In both studies, the safety profile of the combination product reflected that of the individual components. Gastrointestinal disturbances were commonly observed, probably due to the liraglutide component. Rates of hypoglycaemia were comparable to or lower than those seen with insulin degludec alone. Prescribers should consider reducing the dose of sulfonylurea if given concomitantly.^1–3