Insulin degludec/liraglutide is a combination having complementary mechanisms of action to improve glycaemic control.
Insulin degludec is a basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting in a depot from which insulin degludec is continuously and slowly absorbed into the circulation leading to a flat and stable glucose-lowering effect of insulin degludec with a low day-today variability in insulin action.
Insulin degludec binds specifically to the human insulin receptor and results in the same pharmacological effects as human insulin.
The blood glucose-lowering effect of insulin degludec is due to the facilitated uptake of glucose following the binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.
Liraglutide is a Glucagon-Like Peptide-1 (GLP-1) analogue with 97% sequence homology to human GLP-1 that binds to and activates the GLP-1 receptor (GLP-1R). Following subcutaneous administration, the protracted action profile is based on three mechanisms: self-association, which results in slow absorption; binding to albumin; and higher enzymatic stability towards the dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase (NEP) enzymes, resulting in a long plasma half-life.
Liraglutide action is mediated via a specific interaction with GLP-1 receptors and improves glycaemic control by lowering fasting and postprandial blood glucose. Liraglutide stimulates insulin secretion and lowers inappropriately high glucagon secretion in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, during hypoglycaemia liraglutide diminishes insulin secretion and does not impair glucagon secretion. The mechanism of blood glucose-lowering also involves a minor delay in gastric emptying.
Liraglutide reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake.
GLP-1 is a physiological regulator of appetite and food intake, but the exact mechanism of action is not entirely clear. In animal studies, peripheral administration of liraglutide led to uptake in specific brain regions involved in regulation of appetite, where liraglutide, via specific activation of the GLP1R, increased key satiety and decreased key hunger signals, thereby leading to lower body weight.
GLP-1 receptors are also expressed in specific locations in the heart, vasculature, immune system, and kidneys. In mouse models of atherosclerosis, liraglutide prevented aortic plaque progression and reduced inflammation in the plaque. In addition, liraglutide had a beneficial effect on plasma lipids. Liraglutide did not reduce the plaque size of already established plaques.
Insulin degludec/liraglutide combination has a stable pharmacodynamic profile with a duration of action reflecting the combination of the individual action profiles of insulin degludec and liraglutide that allows for administration of insulin degludec/liraglutide once daily at any time of the day with or without meals. Insulin degludec/liraglutide improves glycaemic control through the sustained lowering of fasting plasma glucose levels and postprandial glucose levels after all meals.
Postprandial glucose reduction was confirmed in a 4 hour standardised meal test substudy in patients uncontrolled on metformin alone or in combination with pioglitazone. Insulin degludec/liraglutide decreased the postprandial plasma glucose excursion (mean over 4 hours) significantly more than insulin degludec. The results were similar for insulin degludec/liraglutide and liraglutide.
Overall, the pharmacokinetics of insulin degludec and liraglutide were not affected in a clinically relevant manner when administered as insulin degludec/liraglutide fixed-dose combination compared with independent injections of insulin degludec and liraglutide.
The following reflects the pharmacokinetic properties of insulin degludec/liraglutide fixed-dose combination unless stated that the presented data is from administration of insulin degludec or liraglutide alone.
The overall exposure of insulin degludec was equivalent following administration of insulin degludec/liraglutide versus insulin degludec alone while the Cmax was higher by 12%. The overall exposure of liraglutide was equivalent following administration of insulin degludec/liraglutide versus liraglutide alone while Cmax was lower by 23%. The differences are considered of no clinical relevance since insulin degludec/liraglutide is initiated and titrated according to the individual patient’s blood glucose targets.
Insulin degludec and liraglutide exposure increased proportionally with the insulin degludec/liraglutide dose within the full dose range based on a population pharmacokinetic analysis.
The pharmacokinetic profile of insulin degludec/liraglutide is consistent with once-daily dosing and steady-state concentration of insulin degludec and liraglutide is reached after 2–3 days of daily administration.
Insulin degludec and liraglutide are extensively bound to plasma proteins (>99% and >98%, respectively).
Degradation of insulin degludec is similar to that of human insulin; all metabolites formed are inactive.
During 24 hours following administration of a single radiolabelled [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Two minor plasma metabolites were detected (≤9% and ≤5% of total plasma radioactivity exposure). Liraglutide is metabolised in a similar manner to large proteins without a specific organ having been identified as major route of elimination.
The half-life of insulin degludec is approximately 25 hours and the half-life of liraglutide is approximately 13 hours.
Age had no clinically relevant effect on the pharmacokinetics of insulin degludec/liraglutide based on results from a population pharmacokinetic analysis including adult patients up to 83 years treated with insulin degludec/liraglutide.
Gender had no clinically relevant effect on the pharmacokinetics of insulin degludec/liraglutide based on results from a population pharmacokinetic analysis.
Ethnic origin had no clinically relevant effect on the pharmacokinetics of insulin degludec/liraglutide based on results from a population pharmacokinetic analysis including White, Black, Indian, Asian and Hispanic groups.
Insulin degludec:
There is no difference in the pharmacokinetics of insulin degludec between healthy subjects and patients with renal impairment.
Liraglutide:
Liraglutide exposure was reduced in patients with renal impairment compared to individuals with normal renal function. Liraglutide exposure was lowered by 33%, 14%, 27% and 26%, in patients with mild (creatinine clearance, CrCl 50-80 mL/min), moderate (CrCl 30-50 mL/min), and severe (CrCl <30 mL/min) renal impairment and in end-stage renal disease requiring dialysis, respectively. Similarly, in a 26-week clinical trial, patients with type 2 diabetes and moderate renal impairment (CrCl 30-59 mL/min) had 26% lower liraglutide exposure when compared with a separate trial including patients with type 2 diabetes with normal renal function or mild renal impairment.
Insulin degludec:
There is no difference in the pharmacokinetics of insulin degludec between healthy subjects and patients with hepatic impairment.
Liraglutide:
The pharmacokinetics of liraglutide was evaluated in patients with varying degrees of hepatic impairment in a single-dose trial. Liraglutide exposure was decreased by 13–23% in patients with mild to moderate hepatic impairment compared to healthy subjects. Exposure was significantly lower (44%) in patients with severe hepatic impairment (Child Pugh score >9).
No studies have been performed with insulin degludec/liraglutide in children and adolescents below 18 years of age.
The non-clinical development programme for insulin degludec/liraglutide included pivotal combination toxicity studies of up to 90 days duration in a single relevant species (Wistar rats) to support the clinical development programme. Local tolerance was assessed in rabbits and pigs.
Non-clinical safety data revealed no safety concern for humans based on repeated dose toxicity studies.
The local tissue reactions in the two studies in rabbits and pigs, respectively, were limited to mild inflammatory reactions.
No studies have been conducted with the insulin degludec/liraglutide combination to evaluate carcinogenesis, mutagenesis or impairment of fertility. The following data are based upon studies with insulin degludec and liraglutide individually.
Non-clinical data reveal no safety concern for humans based on studies of safety pharmacology, repeated dose toxicity, carcinogenic potential, and toxicity to reproduction. The ratio of mitogenic relative to metabolic potency for insulin degludec is unchanged compared to human insulin.
Non-clinical data reveal no special hazards for human based on conventional studies of safety pharmacology, repeat-dose toxicity, or genotoxicity. Non-lethal thyroid C-cell tumours were seen in 2-year carcinogenicity studies in rats and mice. In rats, a no observed adverse effect level (NOAEL) was not observed. These tumours were not seen in monkeys treated for 20 months. These findings in rodents are caused by a non-genotoxic, specific GLP-1 receptor-mediated mechanism to which rodents are particularly sensitive. The relevance for humans is likely to be low but cannot be completely excluded. No other treatment-related tumours have been found.
Animal studies did not indicate direct harmful effects with respect to fertility but slightly increased early embryonic deaths at the highest dose. Dosing with liraglutide during mid-gestation caused a reduction in maternal weight and foetal growth with equivocal effects on ribs in rats and skeletal variation in the rabbit. Neonatal growth was reduced in rats while exposed to liraglutide, and persisted in the post-weaning period in the high dose group. It is unknown whether the reduced pup growth is caused by reduced pup milk intake due to a direct GLP-1 effect or reduced maternal milk production due to decreased caloric intake.
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