Levemir Mechanism of Action

Pharmacotherapeutic Group: Drugs used in diabetes. Insulins and analogues for injection, long-acting. ATC Code: A10AE05.
Pharmacology: Pharmacodynamics: Mechanism of Action: Levemir is a soluble, long-acting basal insulin analogue with a prolonged duration of effect used as a basal insulin.
The time action profile of Levemir is significantly less variable than NPH insulin and insulin glargine.
The prolonged action of Levemir is mediated by the strong self-association of insulin detemir molecules at the injection site and albumin binding via the fatty acid side chain. Insulin detemir is distributed more slowly to peripheral target tissues compared to NPH insulin. These combined mechanisms of protraction provide a more reproducible absorption and action profile of Levemir compared to NPH insulin.
The duration of action is up to 24 hours depending on dose providing an opportunity for once- or twice daily administration. If administered twice daily, steady state will occur after 2-3 dose administrations. For doses in the interval of 0.2–0.4 U/kg, Levemir exerts more than 50% of its maximum effect from 3-4 hours and up to approximately 14 hours after dose administration.
Dose proportionality in pharmacodynamic response (maximum effect, duration of action, total effect) is observed after subcutaneous administration.
Lower day-to-day variability in FPG was demonstrated during treatment with Levemir compared to NPH in long-term clinical trials.
Studies in patients with type 2 diabetes treated with basal insulin in combination with oral antidiabetic medicines demonstrated that glycaemic control (HbA_1c) with Levemir is comparable to NPH insulin and insulin glargine and associated with less weight gain, see Table 1.

Click on icon to see table/diagram/image

In trials with the use of OAD-insulin combination therapy, Levemir treatment resulted in a 61-65% lower risk of minor nocturnal hypoglycaemia compared to NPH insulin.
An open-label randomised clinical trial in patients with type 2 diabetes not reaching target with oral antidiabetic medicinal products was conducted. The trial started with a 12-week run-in period with liraglutide+metformin, where 61% reached an HbA_1c <7%. The 39% of patients not achieving target were randomised to have Levemir once-daily added (n=160) or continue on liraglutide+metformin (n=149) for 52 weeks. Addition of Levemir provided a further reduction of HbA_1c of 0.51% and 0.50% (from 7.6% to 7.1%) after 26 and 52 weeks, whereas no changes were seen for liraglutide+metformin (0.02% and 0.01% after 26 and 52 weeks); the changes were significant with addition of Levemir after 26 and 52 weeks (p<0.0001). The proportions of patients achieving the HbA_1c <7% target were higher with addition of Levemir compared to liraglutide+metformin after 26 weeks (43.1% vs 16.8%; p<0.0001) and 52 weeks (51.9% vs. 21.5%; p<0.0001). There were no major hypoglycaemic episodes. Minor hypoglycaemic episodes (per patient year) were higher with addition of Levemir compared to liraglutide+metformin after 26 weeks (0.286 vs 0.029; p=0.0037) and after 52 weeks (0.228 vs 0.034; p=0.0011). When adding Levemir to liraglutide, the weight benefit of liraglutide was sustained; after 26 weeks weight changes with addition of Levemir and liraglutide+metformin were -0.16 kg vs -0.95 kg (p=0.0283) and after 52 weeks -0.05 kg vs - 1.02 kg (p=0.0416).
A 26-week, double blind, randomised clinical trial was conducted to investigate the efficacy and safety of adding liraglutide (1.8 mg) vs placebo in patients with type 2 diabetes inadequately controlled on basal insulin with or without metformin. The insulin dose was reduced by 20% for patients with baseline HbA_1c ≤ 8.0% in order to minimise the risk of hypoglycaemia. Subsequently, patients were allowed to up-titrate their insulin dose to no higher than the pre-randomisation dose. Levemir was the basal insulin product for 33% (n = 147) of the patients (97.3% using metformin). In these patients, addition of liraglutide resulted in a greater decline in HbA_1c compared to addition of placebo (to 6.93% vs to 8.24%), a greater decline in fasting plasma glucose (to 7.20 mmol/l vs to 8.13 mmol/l), and a greater decline in body weight (-3.47 kg vs -0.43 kg). Baseline values for these parameters were similar in the two groups. Observed rates of minor hypoglycaemic episodes were similar and no severe hypoglycaemic episodes were observed in either group.
In long-term trials (≥6 months) in patients with type 1 diabetes receiving a basal-bolus insulin therapy, fasting plasma glucose was improved with Levemir compared with NPH insulin. Glycaemic control (HbA_1c) with Levemir was comparable to NPH insulin, with a lower risk of nocturnal hypoglycaemia and no associated weight gain.
In clinical trials using basal bolus insulin therapy, the overall rates of hypoglycaemia with Levemir and NPH insulin were similar. Analyses of nocturnal hypoglycaemia in patients with type 1 diabetes showed a significantly lower risk of minor nocturnal hypoglycaemia (able to self-treat and confirmed by capillary blood glucose less than 2.8 mmol/l or 3.1 mmol/l if expressed as plasma glucose) than with NPH insulin, whereas no difference was seen in type 2 diabetes. The nocturnal glucose profile is flatter and smoother with Levemir than with NPH insulin, resulting in a lower risk of nocturnal hypoglycaemia.
Antibody development has been observed with the use of Levemir. However, this does not appear to have any impact on glycaemic control.
Pregnancy: In a randomised controlled clinical trial, pregnant women with type 1 diabetes (n=310) were treated in a basal-bolus regimen where Levemir (n=152) was compared to NPH insulin (n=158) with insulin aspart as mealtime insulin. Levemir was shown to be non-inferior to NPH insulin measured by HbA_1c at gestational week 36. The development in mean HbA_1c through pregnancy was similar for subjects in the Levemir and NPH insulin groups. The target of HbA_1c ≤6.0% at both gestational week 24 and 36 was reached by 41% of the subjects in the Levemir group and by 32% in the NPH insulin group. At gestational week 24 and 36, mean FPG was statistically significantly lower in the Levemir group than in the NPH insulin group. There was no statistically significant difference between Levemir and NPH insulin treatment groups in the rate of hypoglycaemic episodes during pregnancy. The overall frequencies of maternal adverse events during pregnancy were similar for Levemir and NPH insulin treatment groups; however, a numerically higher frequency of serious adverse events during pregnancy in the mothers (61 (40%) vs. 49 (31%)) and in the offspring during pregnancy and after birth (36 (24%) vs. 32 (20%)) was seen for Levemir compared to NPH insulin. The number of live born children of women becoming pregnant after randomisation were 50 (83%) for Levemir and 55 (89%) for NPH insulin. The frequency of children with congenital malformations was 4 (5%) in the Levemir group and 11 (7%) in the NPH insulin group. Thereof, 3 (4%) children in the Levemir group and 3 (2%) children in the NPH insulin group had major malformations.
Paediatric Population: The efficacy and safety of Levemir has been studied for up to 12 months in three randomised controlled clinical trials in adolescents and children with type 1 diabetes aged 1 year and above (n=1,045 in total); the trials included in total 167 children aged 1-5 years. The trials demonstrated that glycaemic control (HbA_1c) with Levemir is comparable to NPH insulin and insulin degludec when given as basal-bolus therapy. In the trial comparing Levemir vs insulin degludec, the rate of hyperglycaemic episodes with ketosis was significantly higher for Levemir, 1.09 and 0.68 episodes per patient-year of exposure, respectively. A lower rate of nocturnal hypoglycaemia (based on SMPG (Self Monitoring Plasma Glucose) measurements) and less weight gain (SD score, weight corrected for gender and age) were observed with insulin detemir than with NPH insulin. One trial was extended for an additional 12 months (total of 24 months treatment data) to assess antibody formation after long-term treatment with Levemir. After an increase in insulin antibodies during the first year, the insulin antibodies decreased during the second year to a level slightly higher than pre-trial level. Results indicate that antibody development had no negative effect on glycaemic control and insulin detemir dose.
Efficacy and safety data for adolescent patients with type 2 diabetes mellitus have been extrapolated from data for children, adolescent and adult patients with type 1 diabetes mellitus and adult patients with type 2 diabetes mellitus. Results support the use of Levemir in adolescent patients with type 2 diabetes mellitus.
Pharmacokinetics: Absorption: Maximum serum concentration is reached between 6 and 8 hours after administration. When administered twice daily, steady state serum concentrations are reached after 2-3 dose administrations. Within-patient variation in absorption is lower for Levemir than for other basal insulin preparations.
Distribution: An apparent volume of distribution for Levemir (approximately 0.1 l/kg) indicates that a high fraction of insulin detemir is circulating in the blood. The results of the in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein bound drugs.
Metabolism: Degradation of Levemir is similar to that of human insulin; all metabolites formed are inactive.
Elimination: The terminal half-life after subcutaneous administration is determined by the rate of absorption from the subcutaneous tissue. The terminal half-life is between 5 and 7 hours depending on dose.
Linearity: Dose proportionality in serum concentrations (maximum concentration, extent of absorption) is observed after subcutaneous administration in the therapeutic dose range. There are no clinically relevant differences between genders in pharmacokinetic properties of Levemir. No pharmacokinetic or pharmacodynamic interactions were observed between liraglutide and Levemir when administering a single dose of Levemir 0.5 U/kg with liraglutide 1.8 mg at steady state in patients with type 2 diabetes.
Special Populations: The pharmacokinetic properties of Levemir were investigated in young children (1 to 5 years), children (6 to 12 years) and adolescents (13 to 17 years) and compared to adults with type 1 diabetes. There were no clinical differences in pharmacokinetic properties between young children, children, adolescents and adults. There were no clinically relevant differences in the pharmacokinetics of Levemir between elderly and young patients or between patients with renal or hepatic impairment and healthy subjects.
Toxicology: Preclinical Safety Data: In vitro tests in human cell lines investigating binding to the insulin and IGF-1 receptor sites have shown that insulin detemir has a reduced affinity to both receptors as well as a reduced effect on cell growth compared to human insulin. Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or toxicity to reproduction.