Long-lived human analogue of GLP-1

Given the pronounced hypoglycemic effect of GLP-1, pharmaceutical companies have focused their efforts on creating drugs that support or imitate the effect of this hormone. As a result, 2 groups of drugs were created:

substances that mimic the action of GLP-1 (GLP-1 agonists);
substances that prolong the action of endogenous GLP-1 ( DPP-4 ).

Native GLP-1 is rapidly destroyed by the enzyme dipeptidyl peptidase-4 (DPP-4): when administered intravenously, the half-life of GLP-1 is only 1.5-2.0 minutes (Fig. 7).

Therefore, drugs have been synthesized (GLP-1 mimetic and analogues) that are resistant to the destructive effect of DPP-4, which increases the duration of their action to 12 hours (GLP-1 mimetic - Exenatide) or 24 hours (human GLP-1 analogue - liraglutide) . GLP-1 agonists slow gastric emptying and promote faster satiety, which leads to weight loss. GLP-1 receptor agonists have been reported to improve myocardial function in people who have had myocardial infarction, as well as improve endothelial function and reduce systolic blood pressure.

The second method of overcoming the destructive effect of DPP-4 was the creation of inhibitors of this enzyme. These drugs are taken orally and interfere with the process of destruction of the body's own GLP-1.

Below is a comparison of DPP-4 inhibitors and GLP-1 agonists on a number of parameters:

DPP-4 i: Route of administration: orally
GLP-1 concentration: physiological (can be increased by 2 times)
GIP concentration: increase
Side effects from the gastrointestinal tract: rare
Effect on body weight: negligible
Frequency of hypoglycemia: low
Decrease in HbA1c: — 0.5% — 1.1%
Effect on β-cell mass*: increases

aGLP-1

Method of administration:

GLP-1 concentration: pharmacological (can be increased 5 times)

GIP concentration: No effect

Side effects from the gastrointestinal tract: up to 10% (nausea, vomiting). They are transitory in nature.

Effect on body weight: Reduce body weight by an average of 4 kg per month

Frequency of hypoglycemia: low

Decrease in HbA1c: — 0.8% — 1.8%

Effect on β-cell mass*: increases

* — in an animal experiment

The first of the group of human GLP-1 analogues is liraglutide (Victoza). In July 2009, this drug was approved for use in Europe, in January 2010 - in the USA, in Russia Victoza was registered in May 2010.

The molecule of the drug liraglutide is 97% homologous in amino acid composition to native human GLP-1, while the similarity of the incretin mimetic Exenatide (Byeta) with human GLP-1 is only 53%. Next, we will describe the effects of a group of GLP-1 agonists using the example of a human analogue.

Mechanism of action

The liraglutide molecule was obtained by modifying human GLP-1 by replacing one amino acid (arginine with lysine) at position 34 and adding palmitic acid to the C16 lysine at position 26 (Fig. 8).

These changes provided protection of liraglutide from degradation by DPP-4, as well as the ability to bind to plasma albumin and form micelle-like aggregates in subcutaneous fat. These aggregates are slowly absorbed from the subcutaneous depot and circulate in the blood for a long time. The half-life of liraglutide is 10-14 hours, which ensures its stable concentration when administered once a day after 3 consecutive injections.

As an analogue of human GLP-1, liraglutide has effects similar to human GLP-1:

Glucose-dependent stimulation of insulin secretion and suppression of glucagon secretion. Against the background of hyperglycemia, liraglutide stimulates insulin secretion and suppresses glucagon secretion, and with normal or low glycemic values these effects are not observed.
This mechanism helps prevent the development of hypoglycemic conditions.

Improved β-cell function (assessed by HOMA-B index and proinsulin/insulin ratio);

Slowing down the evacuation of food from the stomach and, as a result, reducing postprandial hyperglycemia.

Acceleration of the saturation process, which leads to a decrease in food consumption and a significant decrease in body weight mainly due to visceral fat.

Beneficial cardiovascular effects (decrease in systolic blood pressure, reduction in the area of myocardial infarction in the experiment) due to the binding of liraglutide to GLP-1 receptors in the heart muscle.

Release form and dosage regimen

The drug liraglutide is available as a solution for subcutaneous administration, in a pre-filled syringe pen. Each pen can be designed to deliver 15 doses of 1.2 mg or 10 doses of 1.8 mg. The pen should be stored in the refrigerator at a temperature of +2 to +8°C. After the first use, it can be kept at room temperature (below 30°C) or in the refrigerator (2-8°C) for a month. The handle must not be frozen.

Liraglutide is injected once daily subcutaneously into the abdomen, thigh, or upper arm at any time of the day. Within 1 week from the start of treatment, the dose of liraglutide should be 0.6 mg per day to ensure optimal tolerability of the drug. From the second week, the daily dose must be increased to 1.2 mg. If it is impossible to achieve target values at this dose of the drug, the amount of liraglutide administered can be increased to a maximum of 1.8 mg per day.

Efficacy of liraglutide in clinical studies

The phase III liraglutide research program “Study of the Effect and Action of Liraglutide in Diabetes (LEAD™)” included about 6,500 patients from 41 countries, including Russia. Among them, approximately 4,445 patients received liraglutide. The goal of the program was to determine the indications for the use of liraglutide for the treatment of T2DM in monotherapy and in combination with traditional glucose-lowering drugs. The LEAD program compared the efficacy and safety of liraglutide with sulfonylureas, glitazones, insulin glargine, and exenatide. (Fig. 9).

The effects of liraglutide compared with sitagliptin in combination with metformin in patients with T2DM were assessed in an international, multicenter, 26-week, randomized, open-label, parallel-group study.

The dynamics of HbAlc reduction in these studies averaged -1.6%. Two years of liraglutide monotherapy (1.8 and 1.2 mg) demonstrated significant and sustained improvements in glycemic control (-1.1 and -0.9%, respectively, compared with -0.6% on glimepiride) and body weight ( -2.7 kg and -2.1 kg compared with + 1.1 kg on glimepiride) against the background of a low risk of hypoglycemia (6 times less often) compared with motor therapy with glimepiride.
The maximum reduction in HbA1c when adding liraglutide to metformin monotherapy was 2.74% in the subgroup of patients with an initial HbA1c level >9.5%.

According to the study results, while taking liraglutide, 52-65% of patients achieve HbA1c levels <7% with a minimal risk of hypoglycemia. Liraglutide also causes rapid and sustained weight loss, a clinically significant reduction in systolic blood pressure, and an improvement in β-cell function.

Trulicity, 4 pcs., 0.5 ml, 1.5 mg/0.5 ml, solution for subcutaneous administration

Mechanism of action.

Dulaglutide is a long-acting GLP-1 receptor agonist. Its molecule consists of two identical chains linked by disulfide bonds, each containing a modified human GLP-1 analog covalently linked to the heavy chain fragment (Fc) of modified human IgG4 via a small polypeptide chain. The GLP-1 analog portion of dulaglutide is approximately 90% homologous to native human GLP-1. T1/2 of native human GLP-1 due to DPP-4 cleavage and renal clearance is 1.5–2 minutes. Unlike native GLP-1, dulaglutide is resistant to degradation by DPP-4 and is large in size, which slows absorption and reduces renal clearance. Such structural features provide a soluble form and a T1/2 duration of 4.7 days, making the drug suitable for subcutaneous administration once a week. In addition, the dulaglutide molecule was designed to reduce the Fcγ receptor-mediated immune response and reduce its immunogenic potential.

The hypoglycemic effect of dulaglutide is due to several mechanisms of action of GLP-1. With increased glucose concentrations, dulaglutide increases the content of intracellular cAMP in pancreatic β-cells, which leads to increased insulin secretion. Dulaglutide suppresses excess glucagon secretion in patients with type 2 diabetes mellitus, resulting in decreased hepatic glucose output. In addition, dulaglutide slows the rate of gastric emptying.

Pharmacodynamics

In patients with type 2 diabetes mellitus, from the first dose, dulaglutide improves glycemic control through sustained reductions in fasting, preprandial and postprandial blood glucose concentrations that are maintained for a week before the next dose.

A pharmacodynamic study of dulaglutide showed that in patients with type 2 diabetes mellitus, there was a restoration of the first phase of insulin secretion to the value observed in healthy subjects receiving placebo, and an improvement in phase II insulin secretion in response to an intravenous bolus of glucose. The same study also showed that a single 1.5 mg dose of dulaglutide increased maximal pancreatic β-cell insulin secretion and improved β-cell function in patients with type 2 diabetes mellitus compared with placebo.

The pharmacokinetic profile and corresponding pharmacodynamic profile of dulaglutide allow the drug to be administered once a week.

Clinical efficacy and safety

Glycemic control.

The safety and efficacy of dulaglutide were assessed in 6 phase III randomized controlled trials, which included 5171 patients with type 2 diabetes mellitus. Of these, 958 were over the age of 65 years, of whom 93 were over the age of 75 years. The study data included 3136 patients who received dulaglutide, of whom 1719 received dulaglutide 1.5 mg once weekly and 1417 received dulaglutide 0.75 mg once weekly. In all studies, dulaglutide provided a clinically significant improvement in glycemic control, as measured by glycated hemoglobin (HbAlc).

Monotherapy

The use of dulaglutide as monotherapy was studied in a 52-week active-controlled clinical trial compared with metformin. The effectiveness of dulaglutide when used in doses of 1.5 or 0.75 mg once a week was superior to the effectiveness of metformin at a dose of 1500-2000 mg/day in reducing HbAlc and significantly more patients achieved the target HbAlc <7 and ≤6.5% when using dulaglutide in doses of 1.5 or 0.75 mg once a week than when using metformin after 26 weeks.

The incidence of documented cases of symptomatic hypoglycemia when using dulaglutide in doses of 1.5 or 0.75 mg once a week and when using metformin was 0.62; 0.15 and 0.09 episodes/patients/year, respectively. There were no cases of severe hypoglycemia with dulaglutide.

Therapy in combination with metformin

The safety and efficacy of dulaglutide were assessed in a placebo-controlled and active-controlled clinical study (sitagliptin 100 mg/day) lasting 104 weeks, in which all drugs were used in combination with metformin. The use of dulaglutide in doses of 1.5 or 0.75 mg once a week after 52 weeks led to a greater reduction in HbAlc compared with the use of sitagliptin, while significantly more patients using dulaglutide achieved the target HbAlc <7 and ≤6.5 %. These effects persisted until the end of the study (104 weeks).

The frequency of documented symptomatic hypoglycemia when using dulaglutide in doses of 1.5 or 0.75 mg once a week and when using sitagliptin was 0.19; 0.18 and 0.17 episodes/patients/years, respectively. There were no cases of severe hypoglycemia with dulaglutide.

The safety and efficacy of dulaglutide were also assessed in an active-controlled study compared with liraglutide 1.8 mg/day (initial dose 0.6 mg/day; after 1 week the dose was increased to 1.2 mg/day and then on the 2nd week - up to 1.8 mg/day) for a duration of 26 weeks; both drugs were used in combination with metformin. Dulaglutide 1.5 mg once weekly resulted in comparable reductions in HbAlc and the number of patients achieving target HbAlc <7 and ≤6.5% compared with liraglutide therapy.

The incidence of documented symptomatic hypoglycemia with dulaglutide 1.5 mg once weekly was 0.12 episodes/patient/year and with liraglutide 0.29 episodes/patient/year. There were no cases of severe hypoglycemia.

Therapy in combination with metformin and sulfonylureas

In a 78-week active control study, dulaglutide was compared with insulin glargine, both drugs used in combination with metformin and sulfonylureas. After 52 weeks, the use of dulaglutide at a dose of 1.5 mg once a week led to a significantly greater decrease in HbAlc compared to the use of insulin glargine, which persisted after 78 weeks; whereas the reduction in HbAlc with dulaglutide 0.75 mg once weekly was comparable to the reduction in HbAlc with insulin glargine. In the dulaglutide 1.5 mg group, a significantly higher number of patients achieved target HbAlc <7 or ≤6.5% at 52 and 78 weeks compared to the insulin glargine group.

The incidence of documented cases of symptomatic hypoglycemia when using dulaglutide in doses of 1.5 or 0.75 mg once a week and when using insulin glargine was 1.67; 1.67 and 3.02 episodes/patients/years, respectively. When using dulaglutide at a dose of 1.5 mg once a week and insulin glargine, the same number of cases of severe hypoglycemia was observed (2 cases each).

Therapy in combination with metformin and pioglitazone

In placebo-controlled and active-controlled studies (exenatide dose was 5 mcg twice daily for the first 4 weeks and 10 mcg twice daily thereafter), when both drugs were used in combination with metformin and pioglitazone, when dulaglutide was administered in Doses of 1.5 or 0.75 mg once weekly demonstrated a significantly greater reduction in HbAlc compared with placebo and exenatide, which was accompanied by a significantly greater number of patients achieving the target HbAlc <7 or ≤6.5%.

The incidence of documented cases of symptomatic hypoglycemia when using dulaglutide in doses of 1.5 or 0.75 mg once a week and exenatide twice a day was 0.19; 0.14 and 0.75 episodes/patients/year, respectively. No cases of severe hypoglycemia were observed when using dulaglutide; 2 cases of severe hypoglycemia were observed when using exenatide.

Therapy in combination with insulin, with or without metformin

In the clinical trial, patients who were receiving insulin once or twice daily before the start of the study discontinued their previous regimen and were randomized to once-weekly dulaglutide or once-daily insulin glargine; Both treatment regimens were administered in combination with prandial insulin lispro administered 3 times daily with or without metformin. After 26 weeks, the effectiveness of dulaglutide when used in doses of 1.5 or 0.75 mg once a week was superior to the effectiveness of insulin glargine in reducing HbAlc, and the same effect remained at week 52 of the study. The average change in HbAlc for the groups using dulaglutide at a dose of 1.5 or 0.75 mg once a week and the group using insulin glargine once a day was −1.64% (p<0.025), −1.59% [p< 0.025] and −1.41%, respectively, after 26 weeks; −1.48% [p<0.025], −1.42% [p<0.025] and −1.23%, respectively, after 52 weeks. More patients on dulaglutide achieved an HbAlc target of <7 or ≤6.5% at 26 weeks and <7% at 52 weeks than with insulin glargine.

The frequency of documented cases of symptomatic hypoglycemia when using dulaglutide in doses of 1.5 or 0.75 mg once a week and when using insulin glargine was 31.06; 35.66 and 40.95 episodes/patients/years, respectively. 10 patients reported severe hypoglycemia with dulaglutide 1.5 mg once weekly, 7 patients with dulaglutide 0.75 mg once weekly, and 15 patients with insulin glargine.

Fasting blood glucose concentration

The use of dulaglutide led to a significantly greater decrease in fasting blood glucose concentration compared to the baseline value. The main effect on fasting blood glucose concentrations was observed after 2 weeks. Improvements in fasting blood glucose levels persisted throughout the longest study period, 104 weeks.

Blood glucose concentration after meals (postprandial glycemia)

The use of dulaglutide led to a significant decrease in mean postprandial glycemia compared with baseline (change in glycemia from baseline to primary time point ranged from −1.9 to −4.23 mmol/L).

Pancreatic β-cell function

The results of clinical studies showed an improvement in pancreatic β-cell function with dulaglutide, as determined by the homeostatic assessment model (HOMA2-%B). The effect on β-cell function was maintained during the longest study period of 104 weeks.

Body mass

When using dulaglutide at a dose of 1.5 mg once a week, there was a steady decrease in body weight throughout the study (the change in the mean value from the initial value to the final time point ranged from −0.35 to −2.9 kg), Change in body weight during The use of dulaglutide at a dose of 0.75 mg once a week varied from 0.86 to −2.63 kg. Weight loss was observed in patients who received dulaglutide regardless of the occurrence of nausea, although the decrease was greater in the group of patients who experienced nausea.

Results based on patient survey

Dulaglutide significantly improved overall treatment satisfaction compared with exenatide twice daily. In addition, the observed incidence of hyperglycemia and hypoglycemia with dulaglutide was significantly lower than with exenatide twice daily.

HELL

The effect of dulaglutide on blood pressure was assessed in a study involving 755 patients with type 2 diabetes mellitus using ambulatory blood pressure monitoring. Dulaglutide therapy was associated with a decrease in sBP (−2.8 mmHg difference compared with placebo) after 16 weeks. No difference in DBP was observed. Similar results for SBP and DBP were shown at the study endpoint of 26 weeks.

Risk for cardiovascular system

In the meta-analysis, phase II and III studies, 51 patients (dulaglutide: 26 (N=3885); all comparators: 25 (N=2125) experienced at least one CCC event (death due to CCC disorders ; non-fatal myocardial infarction, non-fatal stroke, or hospitalization due to unstable angina).

The results showed that the risk of CCC disorders was not increased with dulaglutide compared with comparator therapy (hazard ratio: 0.57; CI: (0.3, 1.1).

Preclinical safety

Preclinical studies of dulaglutide did not indicate a particular risk in humans based on standard pharmacological safety and repeated dose toxicity studies.

No oncogenic response was observed in a 6-month carcinogenicity study in transgenic mice. In a 2-year carcinogenicity study in rats, at dulaglutide concentrations ≥7 times the human therapeutic dose of dulaglutide 1.5 mg once weekly, dulaglutide caused a significant dose-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas). ). The significance of these results for humans is currently unknown.

In fertility studies, at doses that were associated with reductions in maternal food intake and weight gain, a reduction in the number of corpora lutea and an increase in estrous cycle length were observed; however, no effects were observed on fertility and conception rates or on embryonic development. In reproductive toxicity studies in rats and rabbits, effects on skeletal formation and decreased fetal growth were observed with dulaglutide exposures ranging from 11 to 44 times clinical exposure, but no congenital anomalies were observed. Administration of dulaglutide to rats during pregnancy and lactation caused memory deficits in female offspring at exposures that were 16 times the suggested clinical exposure.

Antihyperglycemic effect of liraglutide

Studies have shown that liraglutide was more effective than other drugs in reducing HbA1c levels in all series of trials. At the same time, the maximum decrease in HbA1c during monotherapy was 1.6% compared to the initial value.

In monotherapy, liraglutide at a dose of 1.8 mg per day demonstrated significantly greater efficacy than at a dose of 1.2 mg per day (HbA1c levels decreased by 1.6 and 1.2%, respectively), and significantly greater efficacy than glimepiride monotherapy in dose of 8 mg per day (HbA1c decreased by 0.9%) over 52 weeks of treatment (Fig. 10).

After 1 year of treatment, the number of patients achieving treatment goals (HbA1 < 7%) was significantly higher among those taking liraglutide at both doses (58% and 62% at doses of 1.2 mg and 1.8 mg, respectively) compared with glimepiride at a dose of 8 mg (31%).
In all of these LEAD studies, liraglutide provided rapid and sustained reductions in fasting hyperglycemia, greater than glimepiride and rosiglatizone and comparable to insulin glargine.
When compared with the GLP-1 mimetic exenatide, liraglutide was significantly more effective in reducing HbA1c levels (by 1.1% versus 0.8%) and fasting hyperglycemia. However, hyperglycemia after breakfast and dinner was better reduced when taking exenatide due to its twice-daily administration.

Improvement in glycemic control during treatment with liraglutide was accompanied by a decrease in the risk of developing hypoglycemic symptoms: patients on monotherapy did not experience a single episode of severe hypoglycemia, the incidence of mild hypoglycemia was less than 0.5 cases per patient per year, which was significantly lower than in the glimepiride group ( 2 cases per patient per year).

Mild hypoglycemia also occurred less frequently in patients receiving liraglutide compared with patients receiving exenatide (1.93 with liraglutide versus 2.60 events per patient per year with exenatide).

An increased incidence of mild hypoglycemia was noted when liraglutide was combined with glimepiride.

The Lancet in 2010 published the results of the first international multicenter 26-week randomized, open-label study of liraglutide compared with sitagliptin in combination with metformin in patients with type 2 diabetes.

Liraglutide provided significantly greater reductions in HbA1c, fasting plasma glucose (FPG) and body weight compared with sitagliptin (Januvia) with similar or higher overall treatment satisfaction.
Using liraglutide at a dose of 1.8 mg and 1.2 mg, 54.6 and 43.4% of patients, respectively, achieved treatment goals, and in the sitagliptin 100 mg group - 22.4% of patients (Fig. 11).

Key results comparing liraglutide and sitagliptin therapy in terms of hypoglycemic effect are as follows:

The drug liraglutide provided a greater reduction in HbA1c levels (-1.50% and -1.24% at dosages of 1.8 mg and 1.2 mg, respectively) compared to sitagliptin (-0.90%).
The mean reduction in fasting plasma glucose was significantly greater in the liraglutide-treated group.
The study also assessed patient satisfaction with treatment using the Diabetes Treatment Satisfaction Questionnaire (DTSQ), which is used in many diabetes drug trials: The increase in overall treatment satisfaction was greater with liraglutide 1.8 mg than with liraglutide 1.8 mg. during therapy with sitagliptin.
There were no differences in perceived comfort of treatment (oral versus injectable route).

Trulicity™

Mechanism of action

Dulaglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist. Its molecule consists of two identical chains linked by disulfide bonds, each of which contains an analogue of modified human GLP-1. covalently linked to the heavy chain (Fc) fragment of modified human immunoglobulin G4 (IgG4) by a small polypeptide chain. The GLP-1 analog portion of dulaglutide is approximately 90% homologous to native human GLP-1. The half-life (t1/2) of native human GLP-1 due to cleavage by dipeptidyl peptidase-4 (DPP-4) and renal clearance is 1.5-2 minutes. Unlike native GLP-1, dulaglutide is resistant to degradation by DPP-4 and is large in size, which slows absorption and reduces renal clearance. Such structural features provide a soluble form and a half-life of 4.7 days, making the drug suitable for subcutaneous administration once a week. In addition, the dulaglutide molecule was designed to reduce the Fcγ receptor-mediated immune response and reduce its immunogenic potential.

The hypoglycemic effect of dulaglutide is due to several mechanisms of action of GLP-1. With increased glucose concentrations, dulaglutide increases the content of intracellular cyclic adenosine monophosphate (cAMP) in the beta cells of the pancreas, which leads to increased insulin secretion. Dulaglutide suppresses excess glucagon secretion in patients with type 2 diabetes mellitus, which leads to decreased glucose output by the liver. In addition, dulaglutide slows the rate of gastric emptying.

Pharmacodynamics

In patients with type 2 diabetes mellitus, from the first dose, dulaglutide improves glycemic control through a sustained reduction in fasting, preprandial and postprandial blood glucose concentrations, which is maintained for a week before the next dose.

A pharmacodynamic study of dulaglutide showed that in patients with type 2 diabetes mellitus there was a restoration of the first phase of insulin secretion to the value observed in healthy subjects receiving placebo, and an improvement in the second phase of insulin secretion in response to intravenous bolus administration of glucose. The same study also showed that a single 1.5 mg dose of dulaglutide increased maximal pancreatic β-cell insulin secretion and improved β-cell function in patients with type 2 diabetes compared to placebo.

The pharmacokinetic profile and corresponding pharmacodynamic profile of dulaglutide allow the drug to be administered once a week.

Clinical efficacy and safety

Glycemic control

The safety and efficacy of dulaglutide were assessed in 6 phase III randomized controlled trials, which included 5171 patients with type 2 diabetes mellitus. Of these, 958 were over 65 years of age, of whom 93 were over 75 years of age. The study data included 3136 patients who received dulaglutide, of whom 1719 received dulaglutide 1.5 mg once weekly and 1417 received dulaglutide 0.75 mg once weekly. In all studies, dulaglutide provided a clinically significant improvement in glycemic control, as measured by glycated hemoglobin (HbAlc).

Monotherapy

Dulaglutide monotherapy was studied in a 52-week active-controlled clinical trial compared with metformin. The effectiveness of dulaglutide when used in doses of 1.5 mg or 0.75 mg once a week was superior to the effectiveness of metformin at a dose of 1500-2000 mg/day in reducing HbAlc and significantly more patients achieved the target HbAlc <7.0% and ≤ 6.5% when using dulaglutide in doses of 1.5 mg or 0.75 mg once a week than when using metformin after 26 weeks.

The incidence of documented cases of symptomatic hypoglycemia when using dulaglutide in doses of 1.5 mg or 0.75 mg once a week and when using metformin was 0.62; 0.15 and 0.09 episodes/patient/year, respectively. There were no cases of severe hypoglycemia with dulaglutide.

Therapy in combination with metformin

The safety and efficacy of dulaglutide were assessed in a placebo-controlled and active-controlled clinical study (sitagliptin 100 mg/day) lasting 104 weeks, in which all drugs were used in combination with metformin. Dulaglutide 1.5 mg or 0.75 mg once weekly at 52 weeks resulted in greater reductions in HbAlc compared with sitagliptin, with significantly more patients achieving the HbAlc target <7.0% with dulaglutide and ≤6.5%. These effects persisted until the end of the study (104 weeks).

The frequency of documented symptomatic hypoglycemia when using dulaglutide in doses of 1.5 mg or 0.75 mg once a week and when using sitagliptin was 0.19; 0.18 and 0.17 episodes/patient/year, respectively. There were no cases of severe hypoglycemia with dulaglutide.

The safety and efficacy of dulaglutide were also assessed in an active-controlled study compared with liraglutide 1.8 mg/day (initial dose 0.6 mg/day; after 1 week the dose was increased to 1.2 mg/day and then by 2 weeks). week - up to 1.8 mg/day) for 26 weeks; both drugs were used in combination with metformin. Dulaglutide 1.5 mg once weekly resulted in comparable reductions in HbAlc and the number of patients achieving target HbAlc <7.0% and ≤6.5% compared with liraglutide therapy.

Therapy in combination with metformin and sulfonylureas

In a 78-week active control study, dulaglutide was compared with insulin glargine, both drugs used in combination with metformin and sulfonylureas. After 52 weeks, the use of dulaglutide at a dose of 1.5 mg once a week led to a significantly greater reduction in HbAlc compared to the use of insulin glargine, which persisted after 78 weeks; whereas the reduction in HbAlc with dulaglutide 0.75 mg once weekly was comparable to the reduction in HbAlc with insulin glargine. In the dulaglutide 1.5 mg group, significantly more patients achieved target HbAlc <7.0% or ≤6.5% at 52 and 78 weeks compared with the insulin glargine group.

The incidence of documented cases of symptomatic hypoglycemia when using dulaglutide in doses of 1.5 mg or 0.75 mg once a week and when using insulin glargine was 1.67; 1.67 and 3.02 episodes/patient/year, respectively. When using dulaglutide at a dose of 1.5 mg once a week and when using insulin glargine, the same number of cases of severe hypoglycemia was observed (2 cases each).

Therapy in combination with metformin and pioglitazone

In placebo-controlled and active-controlled studies (exenatide dose was 5 mcg twice daily for the first 4 weeks and 10 mcg twice daily thereafter), when both drugs were used in combination with metformin and pioglitazone, when dulaglutide was administered in Doses of 1.5 mg or 0.75 mg once weekly demonstrated significantly greater reductions in HbAlc compared with placebo and exenatide, which was accompanied by significantly more patients achieving the target HbAlc <7.0% or ≤6.5%.

The incidence of documented cases of symptomatic hypoglycemia when using dulaglutide in doses of 1.5 mg or 0.75 mg once a week and when using exenatide 2 times a day was 0.19; 0.14 and 0.75 episodes/patient/year, respectively. No cases of severe hypoglycemia were observed when using dulaglutide; 2 cases of severe hypoglycemia were observed when using exenatide.

Therapy in combination with insulin, with or without metformin

In the clinical trial, patients who were receiving insulin once or twice daily before the start of the study discontinued their previous regimen and were randomized to once-weekly dulaglutide or once-daily insulin glargine; both treatment regimens were administered in combination with prandial insulin lispro. administered 3 times a day in combination with metformin or without metformin. After 26 weeks, the effectiveness of dulaglutide when used in doses of 1.5 mg or 0.75 mg once a week was superior to the effectiveness of insulin glargine in reducing HbAlc, and the same effect remained at 52 weeks of the study. The average change in HbAlc for the groups using dulaglutide at a dose of 1.5 mg or 0.75 mg once a week and the group using insulin glargine once a day was: -1.64% [p<0.025], -1.59% [ p<0.025] and -1.41%, respectively, after 26 weeks; -1.48% [p<0.025], -1.42% [p<0.025] and -1.23%, respectively, at 52 weeks. More patients with dulaglutide achieved target HbAlc <7.0% or ≤6.5% at 26 weeks and <7.0% at 52 weeks than with insulin glargine.

The frequency of documented cases of symptomatic hypoglycemia when using dulaglutide in doses of 1.5 mg or 0.75 mg once a week and when using insulin glargine was 31.06; 35.66 and 40.95 episodes/patient/year, respectively. 10 patients reported severe hypoglycemia with dulaglutide 1.5 mg once weekly, 7 patients with dulaglutide 0.75 mg once weekly, and 15 patients with insulin glargine.

Fasting blood glucose concentration

The use of dulaglutide led to a significantly greater decrease in fasting blood glucose concentration compared to the initial value. The main effect on fasting blood glucose concentrations was observed after 2 weeks. Improvements in fasting blood glucose concentrations were maintained throughout the longest study period, 104 weeks.

Blood glucose concentration after meals (postprandial glycemia)

The use of dulaglutide led to a significant decrease in mean postprandial glycemia compared with baseline (change in glycemia from baseline to primary time point ranged from -1.95 mmol/L to -4.23 mmol/L).

Pancreatic beta cell function

Results from clinical studies showed an improvement in pancreatic beta cell function with dulaglutide, as measured by the homeostatic assessment model (HOMA2-%B). The effect on beta cell function was maintained over the longest period of the study, 104 weeks.

Body mass

When using dulaglutide at a dose of 1.5 mg once a week, there was a sustained decrease in body weight throughout the study (mean change from baseline to final time point ranged from -0.35 kg to -2.90 kg). Changes in body weight when using dulaglutide at a dose of 0.75 mg once a week ranged from 0.86 kg to -2.63 kg. Weight loss was observed in patients who received dulaglutide regardless of the occurrence of nausea, although the decrease was greater in the group of patients who experienced nausea.

Results based on patient survey

Blood pressure (BP)

The effect of dulaglutide on blood pressure was assessed in a study involving 755 patients with type 2 diabetes mellitus using ambulatory blood pressure monitoring. Dulaglutide therapy was associated with a reduction in systolic blood pressure (difference -2.8 mmHg compared to placebo) after 16 weeks. No difference in diastolic blood pressure was observed. Similar results for systolic and diastolic blood pressure were shown at the study end point of 26 weeks.

Cardiovascular risk

In a meta-analysis of phase II and III studies, 51 patients (dulaglutide: 26 (N=3885); all comparators: 25 (N=2125)) experienced at least one cardiovascular event (caused death). cardiovascular system; non-fatal myocardial infarction, non-fatal stroke or hospitalization due to unstable angina). The results showed that dulaglutide did not increase the risk of cardiovascular events compared with comparator drugs (hazard ratio: 0.57; confidence interval: (0.30, 1.10)).

Preclinical safety

Preclinical studies of dulaglutide did not indicate any particular risk to humans based on standard pharmacological safety and repeated dose toxicity studies.

Effect of liraglutide on body weight of patients with T2DM

Various studies have shown that liraglutide leads to a significant reduction in body weight, both as monotherapy and as part of combination therapy, compared with glitazones and insulin glargine, which traditionally cause weight gain (Fig. 12).

Weight loss occurred in the first 16 weeks of treatment and was maintained at the achieved level throughout the year of treatment. The decrease in weight was more pronounced the higher the initial body mass index (from 2 to 7 kg per year). Body weight loss occurred mainly due to visceral fat, which was confirmed by both a decrease in waist circumference (-3-3.6 cm) and a study of body composition using computed tomography.

Treatment with liraglutide in a comparative study with sitagliptin was also accompanied by a more significant decrease in body weight: -3.38 kg and -2.86 kg for dosages, respectively, of 1.8 mg and 1.2 mg, compared with -0.96 kg for sitagliptin.

The high effectiveness of liraglutide in reducing body weight suggests the possibility of its use in the future for the treatment of obesity (the drug is currently registered only for the treatment of T2DM).

Effect of liraglutide on the cardiovascular system

A number of studies have shown that liraglutide “inherited” from GLP-1 not only the glucose-lowering effect, but also cardioprotective properties. The studies noted a significant decrease in systolic blood pressure, which was observed approximately 2 weeks from the start of treatment and reached a maximum of -6.6 mm Hg. Art. at a dose of 1.2 mg and -5.5 mmHg. Art. at a dose of 1.8 mg (Fig. 13).

The antihypertensive effect of the drug is probably associated with a vasodilatory effect due to stimulation of the production of endothelial nitric oxide synthase (NOS). A hypothesis has also been put forward about the natriuretic or diuretic effect of the drug.

In phase II clinical studies, the highest dose reduced levels of three cardiovascular risk biomarkers (triglycerides, plasminogen activator inhibitor-1, and B-type natriuretic peptide), supporting a direct cardioprotective effect of liraglutide.

Effect of liraglutide on β-cell mass and function

To date, the only way to assess the functional activity of beta cells in vivo is the HOMA-B homeostasis model assessment model: using a special formula, the ratio of fasting glucose and plasma insulin levels is calculated.

According to a series of studies, the use of liraglutide was accompanied by a significant increase in HOMA-B by 40-71%, as well as a change in the proinsulin/insulin ratio, which may indirectly reflect the drug’s ability to restore the functional activity of pancreatic beta cells.

Improvement in β-cell function, as assessed by the HOMA-B index, was significantly greater with liraglutide at both doses compared with placebo and rosiglitazone and comparable to that with glimepiride.
Liraglutide at a dose of 1.8 mg once caused a significantly greater increase in the HOMA-B index (by 32%) compared with exenatide at a dose of 10 mcg twice a day (by 3%).
In a 26-week, randomized, open-label study of liraglutide versus sitagliptin in combination with metformin in patients with type 2 diabetes, improvement in β-cell function as measured by HOMA-B was significantly greater with liraglutide at both doses compared with sitagliptin.

Trulicity solution 1.5 mg/0.5 ml syringe pen 4 pcs ➤ instructions for use

Security Profile Overview

The safety of dulaglutide was studied during initial phase II and III clinical studies, where patients received dulaglutide alone or in combination with other hypoglycemic drugs. The most common adverse reactions (ADRs) in clinical studies were gastrointestinal reactions, including nausea, vomiting and diarrhea. In general, these reactions were mild to moderate and temporary in nature. The results of the long-term cardiovascular outcome study were similar.

ADRs identified during the assessment of the results of clinical trials of phases II and III, a long-term study of cardiovascular outcomes and post-registration experience of use are distributed according to systemic classes indicating the frequency of their occurrence according to WHO recommendations: very often: ≥1/10; often: ≥1/100 - <1/10; uncommon: ≥1/1000 - <1/100; rare: ≥1/10000 - <1/1000; very rare: <1/10000; frequency unknown (cannot be determined from available data).

Immune system disorders: uncommon – hypersensitivity, rare – anaphylactic reaction#;

Metabolic and nutritional disorders: very often - hypoglycemia* when used in combination with insulin, glimepiride, metformin† or metformin and glimepiride; often – hypoglycemia* when used as monotherapy or in combination with metformin and pioglitazone; uncommon – dehydration;

Gastrointestinal disorders: very common - nausea, diarrhea, vomiting†, abdominal pain†; often - loss of appetite, dyspepsia, constipation, flatulence, bloating, gastroesophageal reflux disease, belching; rarely – acute pancreatitis; with unknown frequency - non-mechanical intestinal obstruction;

Disorders of the liver and biliary tract: infrequently - cholelithiasis, cholecystitis;

Disorders of the skin and subcutaneous tissue: rarely - angioedema;

General disorders and disorders at the injection site: often - weakness; uncommon – reactions at the injection site;

Laboratory and instrumental data: often - sinus tachycardia, first degree atrioventricular block.

# Post-registration experience of use

* Documented symptomatic hypoglycemia with blood glucose concentration ≤3.9 mmol/L.

†For dulaglutide 1.5 mg only. The incidence of adverse reactions for dulaglutide 0.75 mg is in the lower category.

Description of individual HP

Hypoglycemia

When using dulaglutide in doses of 0.75 mg and 1.5 mg once a week as monotherapy or in combination with metformin or metformin and pioglitazone, the frequency of documented symptomatic hypoglycemia ranged from 5.9% to 10.9%, or from 0. 14 to 0.62 events/patient/year, no cases of severe hypoglycemia were observed.

When using dulaglutide in doses of 0.75 mg and 1.5 mg once a week in combination with a sulfonylurea derivative and metformin, the frequency of documented symptomatic hypoglycemia was 39.0% and 40.3%, respectively, or 1.67 and 1.67 events/patient/year, respectively. The incidence of severe hypoglycemia events was 0% and 0.7%, or 0.00 and 0.01 events/patient/year, for each dose, respectively. The incidence of documented cases of symptomatic hypoglycemia when using dulaglutide 1.5 mg with a sulfonylurea was 11.3% and 0.90 episodes/patient/year. There were no cases of severe hypoglycemia.

The incidence of documented cases of symptomatic hypoglycemia when using dulaglutide 1.5 mg with insulin glargine was 35.3% and 3.38 episodes/patient/year. The incidence of severe hypoglycemia was 0.7% and 0.01 episodes/patient/year.

When using dulaglutide in doses of 0.75 mg and 1.5 mg once a week in combination with prandial insulin, the incidence of hypoglycemia was 85.3% and 80.0%, or 35.66 and 31.06 events/patient/year. respectively. The incidence of severe hypoglycemia events was 2.4% and 3.4%, or 0.05 and 0.06 events/patient/year, respectively.

Adverse reactions from the gastrointestinal tract

Cumulative reporting of GI events up to 104 weeks with dulaglutide 0.75 mg and 1.5 mg once weekly, respectively, included nausea (12.9% and 21.2%), diarrhea ( 10.7% and 13.7%) and vomiting (6.9% and 11.5%). They were usually mild or moderate in severity, peaking in frequency during the first 2 weeks of therapy and decreasing rapidly over the next 4 weeks, after which the frequency remained relatively constant.

In clinical pharmacological studies that were conducted in patients with T2DM and lasted up to 6 weeks, most gastrointestinal events were observed within the first 2-3 days after taking the first dose, their frequency decreased with subsequent doses.

Acute pancreatitis

The incidence of acute pancreatitis in phase II and III clinical trials was 0.07% with dulaglutide compared with 0.14% with placebo and 0.19% with comparators, with or without additional baseline hypoglycemic therapy.

Pancreatic enzymes

When using dulaglutide, the average increase in the activity of pancreatic enzymes (lipase and/or pancreatic amylase) is 11-21% compared to baseline values. In the absence of other signs and symptoms of acute pancreatitis, elevated pancreatic enzymes are not predictive of the development of acute pancreatitis.

Increased heart rate

When using dulaglutide in doses of 0.75 mg and 1.5 mg once a week, a small average increase in heart rate of 2-4 beats per minute (bpm) was observed, with the incidence of sinus tachycardia with an increase in heart rate compared with a baseline rate of ≥15 beats/min was 1.3% and 1.4%, respectively.

First degree atrioventricular block/increased PR interval

When using dulaglutide in doses of 0.75 mg and 1.5 mg once a week, a small average increase in the PR interval of 2-3 ms was observed compared to baseline, while the frequency of first degree atrioventricular block was 1.5% and 2. 4%, respectively.

Immunogenicity

In clinical studies, the use of dulaglutide was accompanied by the detection of antibodies to dulaglutide with a frequency of 1.6%, indicating that structural changes in GLP-1 and modified IgG4 regions in the dulaglutide molecule, along with high homology to native GLP-1 and native IgG4, minimize the risk development of an immune response during dulaglutide therapy. Patients who developed antibodies to dulaglutide generally had low antibody titers; however, despite the small number of patients who developed antibodies to dulaglutide, evaluation of the results of phase III clinical trials did not reveal a clear effect of antibodies to dulaglutide on changes in HbA1c. None of the patients with systemic hypersensitivity developed antibodies to dulaglutide.

Hypersensitivity

In phase II and III clinical studies, systemic hypersensitivity events (eg, urticaria, edema) were observed in 0.5% of patients receiving dulaglutide. In post-registration experience with dulaglutide, cases of anaphylactic reactions have been reported rarely.

Reactions at the injection site

Administration site reactions were observed in 1.9% of patients treated with dulaglutide. Potentially immune-mediated injection site adverse events (eg, rash, erythema) were reported in 0.7% of patients and were usually mild.

Early termination of participation in clinical trials due to an adverse event

In 26-week studies, the rate of early withdrawal due to adverse events was 2.6% (0.75 mg once weekly) and 6.1% (1.5 mg once weekly) with dulaglutide compared with 3.7% with placebo. Throughout the study (up to 104 weeks), the rate of early discontinuation due to adverse events with dulaglutide was 5.1% (0.75 mg once a week) and 8.4% (1.5 mg once a week). . The most common adverse events that led to early discontinuation of participation in the dulaglutide 0.75 mg and 1.5 mg once weekly groups were nausea (1.0% and 1.9%), diarrhea (0.5% and 0.6%) and vomiting (0.4% and 0.6%), mainly such reactions were observed during the first 4-6 weeks of therapy.

Safety of use and side effects of GLP-1 analogues

The most commonly reported side effects when taking liraglutide are gastrointestinal. In the LEAD studies, the incidence of nausea ranged from 11 to 29% (with liraglutide monotherapy it was 27%). Nausea was transient and almost completely disappeared after 12 weeks of treatment. The dose of liraglutide did not affect the frequency and severity of nausea. Nausea was significantly less severe with liraglutide compared with exenatide.

The incidence of hypoglycemic events on liraglutide is 0.03 events per year at the 1.2 mg dose, 0.09 events per year at the 1.8 mg dose, which is lower than that observed in patients on placebo (0.13 events per year), and significantly lower than with glimepiride (1.23 events per year). Only in combination of liraglutide with SM drugs may the frequency of hypoglycemic conditions increase, which must be taken into account when prescribing these drugs in combination. To avoid hypoglycemia in this case, the dose of SM must be reduced.

In studies examining the use of liraglutide in patients with hepatic and moderate renal impairment (creatinine clearance <60-90 ml/min), no dose adjustment was required. There was also no effect of ethnicity, gender, age, baseline blood pressure, or body weight on the safety profile.

The formation of antibodies to liraglutide is very low (8.6% of patients) in contrast to exenatide (58.3% of patients), which is explained by high homology to human GLP-1.

These data suggest that treatment with liraglutide will maintain satisfactory long-term glycemic control because there will be no escape effect from the drug due to antibody formation.

The risk of developing acute pancreatitis during treatment with liraglutide is no more than 1.6 cases per 1000 patient-years, and exacerbation of chronic pancreatitis is no more than 0.6 cases per 1000 patient-years.

These values do not exceed the incidence of pancreatitis in the general healthy population and are significantly lower than in the general population of patients with type 2 diabetes.

Trulicity: Questionable Cardiovascular Benefit for Diabetics

#1. In late February 2022, the US Food and Drug Administration (FDA) expanded the indications for Trulicity (dulaglutide), an agonist marketed by Eli Lilly and Boehringer Ingelheim. glucagon-like peptide-1 receptor (GLP-1R). From now on, Trulicity can be used in adult patients with type 2 diabetes mellitus who have a history of cardiovascular disease or multiple cardiovascular risk factors. Trulicity has been shown to reduce the risk of major cardiovascular events (MACE).

Short

non-fatal myocardial infarction: HR 0.96 [95% CI: 0.79–1.16] (p=0.65);
non-fatal stroke: HR 0.76 [95% CI: 0.61–0.95] (p=0.017);
death due to cardiovascular complications: HR 0.91 [95% CI: 0.78–1.06] (p=0.21).

Trulicity confirmed that long-term use was associated with reduced progression of kidney disease in type 2 diabetes: HR 0.85 [95% CI: 0.77–0.93]; p=0.0004).

Trulicity lowered HbA1c by 0.46% (versus an increase of 0.16% in the placebo group) and reduced body weight by 2.95 kg (versus a decrease of 1.49 kg in the placebo group).

And yet investors do not share Eli Lilly’s enthusiasm. And it’s true: if you look closely at the numbers, it turns out that 12.0% of those receiving Trulicity and 13.4% of those in the control group experienced adverse cardiovascular outcomes. The event rate difference of 0.3 per 100 person-years is very tiny, but the notorious p-value allowed it to be declared statistically significant. In other words, the clinical significance of dulaglutide reported in these clinical trials is greatly exaggerated.

Again, the benefit of Trulicity was manifested mainly in reducing the risk of non-fatal stroke - there is virtually no benefit for the other two components of MACE.

But there are still advantages from such a test, because dulaglutide has proven that it works without reference to the presence or absence of any chronic cardiovascular disease in diabetics.

The aforementioned cardiovascular efficacy of semaglutide should not be taken seriously as Novo Nordisk has not performed an analysis that would support a clear benefit over placebo. So Trulicity, which will have cardiovascular benefits added to its prescribing information in the first half of next year, will continue to make big money.

Indications for use of the drug liraglutide in patients with type 2 diabetes

Patients with T2DM with overweight or obesity who do not achieve therapeutic goals on traditional PSSP (HbA1c > 7%);
Patients with type 2 diabetes who are unable to strictly adhere to the diet (the drug can be administered during the day at any time, regardless of food intake);
Patients with T2DM who prefer a single dose of the drug;
Patients with T2DM at high risk of hypoglycemia;
As a step prior to the prescription of insulin therapy, in the absence of severe decompensation of diabetes (HbA1c level <8.0-8.5%), if weight loss is the desired goal.

Liraglutide: achieving comprehensive diabetes treatment goals

Liraglutide has an effect similar to human GLP-1: against the background of hyperglycemia, it stimulates insulin secretion and suppresses glucagon secretion, and at normal or low glycemia these effects are not observed. This mechanism helps prevent the development of hypoglycemic conditions.
Liraglutide also improves β-cell function, slows gastric emptying and reduces postprandial hyperglycemia, accelerates satiety, and has beneficial cardiovascular effects.
The use of the drug liraglutide leads to a significant reduction in body weight both in monotherapy and as part of combination therapy. Weight loss occurs in the first weeks of treatment and is maintained at the achieved level throughout the year of treatment. The higher the initial body mass index, the more pronounced the weight loss. Body weight loss occurs mainly due to visceral fat.
A meta-analysis of these studies showed that the addition of liraglutide injections to previous antihyperglycemic therapy resulted in a reduction in HbA1c levels by 1.26-1.36%, thus setting the average HbA1c endpoint at 6.96-7.05%. At the same time, the proportion of patients who achieved the target HbA1c level <7% during combination therapy with liraglutide was 71% (Fig. 14).

A meta-analysis of LEAD studies showed the following advantages of liraglutide in comparison with representatives of all classes of hypoglycemic drugs: the odds ratio of achieving control of HbAlc and body weight without hypoglycemia for liraglutide is 2.0 - 10.3 times higher than in patients receiving comparator drugs. All results are statistically significant.

Thus, with the use of the drug liraglutide, the percentage of patients who manage to achieve control of HbA1c, body weight and SBP is higher than with therapy with any comparison drugs (Fig. 15).

Sources:

Ametov AS First GLP-1 analog liraglutide: the result of clinical trails on efficacy / AS Ametov, LL Kamynina // Diabetes Mellit. – 2011. – T. – No. 4 – 39 p.
Shestakova M.V. LIRAGLUTIDE POSSIBILITIES OF AN INTEGRATIVE THERAPEUTIC APPROACH IN THE THERAPY OF TYPE 2 DM / Shestakova M.V. // Diabetes mellitus – 2009. – No. 5.

Trulicity, 0.75 mg/0.5 ml, solution for subcutaneous administration, 0.5 ml, 4 pcs.

Mechanism of action.

Pharmacodynamics

The pharmacokinetic profile and corresponding pharmacodynamic profile of dulaglutide allow the drug to be administered once a week.

Clinical efficacy and safety

Glycemic control.

Monotherapy

Therapy in combination with metformin

Therapy in combination with metformin and sulfonylureas

Therapy in combination with metformin and pioglitazone

Therapy in combination with insulin, with or without metformin

Fasting blood glucose concentration

Blood glucose concentration after meals (postprandial glycemia)

Pancreatic β-cell function

Body mass

Results based on patient survey

HELL

Risk for cardiovascular system

The results showed that the risk of CCC disorders was not increased with dulaglutide compared with comparator therapy (hazard ratio: 0.57; CI: (0.3, 1.1).

Preclinical safety

Preclinical studies of dulaglutide did not indicate a particular risk in humans based on standard pharmacological safety and repeated dose toxicity studies.