Liraglutide

Pharmacotherapeutic group

Hypoglycemic agent - glucagon-like polypeptide receptor agonist.

ATX code A10BX07.

Pharmacological properties

Mechanism of action

The active ingredient of Saxenda® - liraglutide - is an analogue of human glucagon-like peptide-1 (GLP-1), produced by recombinant DNA biotechnology using the Saccharomycescerevisiae strain, which has 97% amino acid sequence homology to the endogenous human GLP-1. Lyraglutid binds and activates the GLP-1 receptor (GLP-1R).

Liraglutide is resistant to metabolic decay, its plasma half-life after subcutaneous administration is 13 hours. The pharmacokinetic profile of liraglutide, which allows it to be administered to patients 1 time per day, is the result of self-association, which results in slow absorption of the drug; binding to plasma proteins; as well as resistance to dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP).

GLP-1 is a physiological regulator of appetite and food consumption. GLP-1R is found in several areas of the brain involved in appetite regulation. In animal studies, the introduction of liraglutide resulted in its seizure in specific areas of the brain, including the hypothalamus, where liraglutide through specific activation of GLP-1R strengthened saturation signals and weakened hunger signals, thereby leading to weight loss.

Liraglutide reduces a person’s body weight primarily by reducing the weight of fatty tissue. A decrease in body weight occurs due to a decrease in food intake. Liraglutide does not increase 24-hour power consumption. Lyraglutid regulates appetite by increasing the feeling of filling the stomach and satiety, while at the same time reducing the feeling of hunger and reducing the estimated food intake.

Liraglutide stimulates insulin secretion and reduces the unreasonably high secretion of glucagon in a glucose-dependent manner, and also improves the function of the beta cells of the pancreas, which leads to a decrease in fasting glucose after meals. The mechanism for reducing the concentration of glucose also includes a slight delay in gastric emptying.

Pharmacodynamics

In long-term clinical studies involving patients with overweight or obesity, the use of Saxenda® in combination with a low-calorie diet and increased physical activity led to a significant decrease in body weight.

Effect on appetite, calorie intake, energy expenditure, gastric emptying and fasting glucose concentration after eating

The pharmacodynamic effects of liraglutide were studied in a five-week study involving 49 patients with obesity (body mass index (BMI) of 30-40 kg / m²) without diabetes.

Appetite, calorie intake and energy consumption

It is believed that weight loss when using the drug Saksenda® is associated with the regulation of appetite and calorie intake. Appetite was evaluated before and within 5 hours after a standard breakfast; unlimited food intake was assessed during follow-up lunch. Saxenda® increased the feeling of fullness and filling of the stomach after a meal and reduced the feeling of hunger and the estimated amount of the intended food intake, as well as reduced unlimited food intake compared with placebo. When evaluating with the respiratory chamber, no increase in 24-hour energy expenditure associated with therapy was noted.

Gastric emptying

The use of the drug Saksenda® led to a slight delay in gastric emptying during the first hour after a meal, resulting in a decrease in the rate of increase in concentration, as well as the total concentration of blood glucose after a meal.

The concentration of glucose, insulin and glucagon on an empty stomach and after eating

The concentration of glucose, insulin and glucagon on an empty stomach and after a meal was assessed before and within 5 hours after a standardized meal. Compared with placebo, Saxenda® reduced the concentration of fasting blood glucose after meals (AUC_{0-60 min}) during the first hour after a meal, and also reduced the 5-hour AUC of glucose and the increasing concentration of glucose (AUC_{0-300 min}). In addition, the drug Saksenda® reduced the postprandial concentration of glucagon (AUC_{0-300 min}) and insulin (AUC_{0-60 min}) and increasing insulin concentration (iAUC_{0-60 min}) after a meal compared with placebo.

The fasting concentration and increasing glucose and insulin concentrations were also evaluated during an oral glucose tolerance test (PTTG) with 75 g glucose before and after 1 year of therapy in 3,731 obese patients with impaired glucose tolerance and without glucose tolerance. Compared with placebo, Saxenda® reduced the fasting concentration and the increasing glucose concentration. The effect was more pronounced in patients with impaired glucose tolerance. In addition, the drug Saksenda® reduced the concentration on an empty stomach and increased the increasing concentration of insulin compared with placebo.

The effect on fasting concentration and increasing glucose concentration in patients with type 2 diabetes with overweight or obesity

Saxenda® reduced the fasting glucose concentration and the average increasing postprandial glucose concentration (90 minutes after a meal, the average value for 3 meals per day) compared with placebo.

Pancreatic Beta Cell Function

In clinical studies with a duration of up to one year using Saxenda® in patients with overweight or obesity and with or without diabetes mellitus, improvement and preservation of pancreatic beta-cell function was demonstrated using measurement methods such as the homeostatic beta function evaluation model cells (HOMA-B) and the ratio of concentrations of proinsulin and insulin.

Clinical efficacy and safety

The efficacy and safety of Saxenda® for long-term correction of body weight in combination with a low-calorie diet and increased physical activity was studied in 4 randomized, double-blind, placebo-controlled studies (3 studies lasting 56 weeks and 1 study lasting 32 weeks). The studies included a total of 5358 patients of 4 different populations: 1) patients with obesity or overweight, and also with one of the following conditions / diseases: impaired glucose tolerance, arterial hypertension, dyslipidemia; 2) patients with obesity or overweight with insufficiently controlled type 2 diabetes mellitus (HbA value_1c in the range of 7-10%), prior to the study for the correction of HbA_1c in these patients, they used: diet and exercise, metformin, sulfonylurea, and glitazone preparations individually or in any combination; 3) obese patients with moderate to severe obstructive apnea; 4) patients with obesity or overweight and concomitant arterial hypertension or dyslipidemia, who achieved a weight loss of at least 5% using a low-calorie diet.

Body mass

More pronounced weight loss was achieved in patients with obesity / overweight who received Saxenda® compared with patients who received placebo in all studied groups, including the presence or absence of glucose tolerance, type 2 diabetes and obstructive apnea of ​​moderate or severe.In study No. 1 (patients with obesity and overweight with the presence or absence of impaired glucose tolerance), the decrease in body weight was 8.0% in patients who received Saxenda®, compared with 2.6% in the placebo group. In Study No. 2 (obese and overweight patients with type 2 diabetes), a decrease in body weight was 5.9% in patients treated with Saxenda®, compared with 2.0% in the placebo group. In study No. 3 (patients with obesity and overweight with moderate or severe obstructive sleep apnea), the decrease in body weight was 5.7% in patients who received Saxenda®, compared with 1.6% in the placebo group. In study No. 4 (patients with obesity and overweight after a previous body weight loss of at least 5%), further weight loss was 6.3% in patients treated with Saxenda®, compared with 0.2% in the placebo group . In study 4, a larger number of patients retained a loss of body weight, which was achieved prior to the start of treatment with Saksenda® compared with placebo (81.4% and 48.9%, respectively). In addition, in all the studied populations, the majority of patients treated with Saxenda® achieved a decrease in body weight of at least 5% and more than 10% compared with patients receiving placebo.

In study No. 1 (patients with obesity and overweight with the presence or absence of impaired glucose tolerance) a decrease in body weight of not less than 5% at week 56 of therapy was observed in 63.5% of patients treated with Saxenda®, compared with , 6% in the placebo group. The ratio of patients whose weight loss on the 56th week of therapy reached more than 10% is 32.8% in the group of patients receiving Saxenda®, compared to 10.1% in the placebo group. Overall, weight loss occurred in approximately 92% of patients receiving Saxenda®, compared with approximately 65% ​​in the placebo group.

Weight loss after 12 weeks of therapy with Saxenda®

Patients with an early response to therapy were identified as patients who had achieved a weight loss of at least 5% after 12 weeks of therapy (4 weeks of increasing the dose and 12 weeks of therapy at a dose of 3 mg).

In two studies (patients with obesity or overweight without and with type 2 diabetes), 67.5% and 50.4% of patients achieved a decrease in body weight by at least 5% after 12 weeks of therapy. With continued therapy with Saxenda® (up to 1 year), 86.2% of these patients achieved a weight loss of at least 5% and 51% at least 10%. The mean weight loss in these patients who completed the study was 11.2% compared with baseline. In patients who achieved a reduction in body weight of less than 5% after 12 weeks of therapy at a dose of 3 mg and completed the study (1 year), the average reduction in body weight was 3.8%.

Glycemic control

Therapy with Saxenda® significantly improved glycemic indicators in sub-populations with normoglycemia, impaired glucose tolerance (mean decrease in HbA_1c- 0.3%) and diabetes mellitus type 2 (average reduction in HbA_1c- 1.3%) compared with placebo (average decrease in HbA_1c- 0.1% and - 0.4%, respectively). In a study involving patients with impaired glucose tolerance, type 2 diabetes developed in a smaller number of patients who received Saxenda® compared with the placebo group (0.2% and 1.1%, respectively). A greater number of patients with impaired glucose tolerance observed a reverse development of this condition compared with the placebo group (69.2% and 32.7%, respectively).

In a study involving patients with type 2 diabetes mellitus, 69.2% and 56.5% of patients treated with Saxenda® reached the target HbA value._1c? 7% and ≤ 6.5%, respectively, compared with 27.2% and 15.0% in patients receiving placebo.

Cardiometabolic parameters

In a study involving patients with obesity or overweight with or without impaired glucose tolerance with the use of the drug Saksenda®, there was a significant decrease in systolic blood pressure (by 4.3 points versus 1.5 points), diastolic blood pressure (by 2.7 point versus 1.8 points), waist circumference (by 8.2 cm versus 4.0 cm) and a significant change in fasting lipid concentration (decrease in total cholesterol by 3.2% versus 0.9%; decrease in low-density lipoprotein by 3, 1% vs. 0.7%; increase in lipop high density of rotheins by 2.3% versus 0.5%; a decrease in triglycerides by 13.6% versus 4.8% compared with placebo.

Apnea-hypnea index

With the use of Saxenda®, there was a significant decrease compared with placebo in the severity of obstructive sleep apnea, which was assessed by a decrease in the apnea-hypnea index (IH) by 12.2 cases per hour and 6.1 cases per hour, respectively.

Immunogenicity

Given the potential immunogenic properties of protein and peptide drugs, patients may receive antibodies to liraglutide after therapy with Saxenda®. In clinical studies, 2.5% of patients treated with Saxenda® developed antibodies to liraglutide. The formation of antibodies did not lead to a decrease in the effectiveness of Saxenda®.

Evaluation of cardiovascular events

Significant adverse cardiovascular events (MACE) were assessed by a group of external independent experts and identified as non-fatal myocardial infarction, non-fatal stroke and death due to cardiovascular disease. In all long-term clinical studies using Saxenda®, 6 MACEs were observed in patients who received Saxenda® and 10 MACEs in patients who received placebo. The risk ratio and 95% CI when comparing the drug Saksenda® and placebo was 0.31 [0.10; 0.92]. In clinical studies of phase 3, an increase in heart rate (HR) of an average of 2.5 beats per minute (from 1.6 to 3.6 beats per minute in individual studies) was observed in patients who received Saxenda®. The greatest increase in heart rate was observed after 6 weeks of therapy. This increase was reversible and disappeared after cessation of therapy with liraglutide.

Patient Evaluation Results

Saksenda® compared with placebo improved patient-defined scores for individual indicators. There was a significant improvement in the overall assessment of the Simplified questionnaire on the effect of body weight on quality of life (IWQoL-Lite) and on all scales of the SF-36 quality of life questionnaire, which indicates a positive effect on the physical and psychological components of the quality of life.

Preclinical safety data

Preclinical data based on studies of pharmacological safety, repeated dose toxicity, and genotoxicity did not reveal any danger to humans.

In two-year studies of carcinogenicity in rats and mice, C-cell tumors of the thyroid gland were identified, which were not fatal. Non-toxic dose (NOAEL) in rats has not been established. In monkeys treated for 20 months, the development of these tumors was not observed. The results obtained in rodent studies are due to the fact that rodents are particularly sensitive to GLP? 1 receptor mediated non-genotoxic specific mechanism. The significance of the data obtained for humans is low, but cannot be completely excluded. The appearance of other neoplasms associated with the therapy was not noted.

In animal studies, no direct adverse effect of the drug on fertility was found, but a slight increase in the frequency of early fetal death was observed with the use of the highest doses of the drug.The introduction of liraglutide in the middle of the gestational period caused a decrease in the mother’s body weight and fetal growth, with unexplored effects on the ribs in rats, and in rabbits, deviations in the skeleton structure. The growth of newborns was reduced in rats during treatment with liraglutide, and this decrease was maintained after the end of breastfeeding in the group receiving high doses of the drug. It is not known what caused such a decrease in the growth of newborn rats - a decrease in calorie intake by maternal individuals or the direct effect of GLP-1 on the fetus / neonates.

Pharmacokinetics

Suction

Absorption of liraglutide after subcutaneous injection occurs slowly, the time to reach maximum concentration (t_max) - about 11 hours after administration. In patients with obesity (BMI 30-40 kg / m²) after administration of liraglutide in a dose of 3 mg, the average equilibrium concentration of liraglutide (AUC_τ/24) reaches approximately 31 nmol / l. In the dose range from 0.6 mg to 3 mg, the exposure of liraglutide increases in proportion to the dose. The absolute bioavailability of liraglutide after subcutaneous administration is approximately 55%.

Distribution

The average apparent volume of distribution after subcutaneous administration of liraglutide in a dose of 3 mg is 20-25 liters (for individuals with a body weight of about 100 kg). Liraglutide is largely bound to plasma proteins (> 98%).

Metabolism

For 24 hours after administration to a single dose of healthy volunteers [³H]? Liraglutide the main component in plasma remained unchanged liraglutide. Two metabolites were detected (≤ 9% and ≤ 5% of the total radioactivity level in the blood plasma).

Removal

Liraglutide is metabolized endogenously like large proteins without the participation of any specific organ as the main route of elimination. After a dose [³H] lraglutide unchanged liraglutide was not detected in urine or feces. Only a small part of the administered radioactivity in the form of liraglutide metabolites was excreted by the kidneys or through the intestines (6% and 5%, respectively). Radioactive substances are excreted by the kidneys or through the intestines, mainly during the first 6–8 days and are 3 metabolites.

The mean clearance after subcutaneous injection of liraglutide is approximately 0.9? 1.4 l / h, the half-life is approximately 13 h.

Special patient groups

Elderly patients

Dose adjustment based on age is not required. According to the results of a population pharmacokinetic analysis in patients with obesity or overweight at the age of 18–82 years, age did not have a clinically significant effect on the pharmacokinetics of liraglutide when given subcutaneously at a dose of 3 mg.

Floor

Based on data from a population-based pharmacokinetic analysis, the weight-adjusted clearance of liraglutide in women after subcutaneous administration at a dose of 3 mg is 24% less than in men than in men. Based on the data on the response to the drug, dose adjustment based on gender is not required.

Ethnicity

According to the results of population pharmacokinetic analysis, which included research data from patients with obesity or overweight Caucasoid, Negroid, Asian and Latin American racial groups, ethnicity did not have a clinically significant effect on the pharmacokinetics of liraglutide when given subcutaneously with a dose of 3 mg.

Body mass

Liraglutide exposure decreases with increasing initial body weight. The use of liraglutide in a dose of 3 mg daily provides adequate exposure in the range of body weight 60-234 kg, according to the evaluation of the response to the systemic exposure of the drug in clinical studies. The exposure of liraglutide in patients with a body weight of more than 234 kg has not been studied.

Patients with impaired liver function

The pharmacokinetics of liraglutide was evaluated in patients with varying degrees of abnormal liver function in a single dose study (0.75 mg).Liraglutide exposure was 23% and 13% less in patients with mild or moderately impaired liver function, respectively, compared with healthy volunteers. Exposure was significantly lower (by 44%) in patients with severe hepatic impairment (> 9 points according to the ChildPugh classification).

Patients with renal failure

In the single-dose study (0.75 mg), liraglutide exposure was lower in patients with renal insufficiency compared with those with normal renal function. The exposure of liraglutide was less by 33%, 14%, 27% and 26%, respectively, in patients with mild renal failure (creatinine clearance 50–80 ml / min), moderate (30–50 ml / min), severe (< 30 ml / min) and in patients with end-stage renal disease who need hemodialysis.

Children

Clinical studies of the efficacy and safety of Saxenda® in children have not been conducted.