Buy Trulicity solution 1.5 mg/0.5 ml syringe pen 0.5 ml 4 pcs
  • Buy Trulicity solution 1.5 mg/0.5 ml syringe pen 0.5 ml 4 pcs

Trulicity® [Dulaglutide]

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2019-09-19
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Clinical Pharmacology

Mechanism of action

Dulaglutide is a long-acting glucagon-like peptide l receptor agonist (GLP-1). Its molecule consists of two identical chains linked by disulfide bonds, each of which contains an analogue of a modified human GLP-1, covalently linked to a fragment of the heavy chain (Fc) of a modified human immunoglobulin G4 (IgG4) using a small polypeptide chain. The part of dulaglutide, which is an analogue of GLP-1, 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, dulaglutid is resistant to splitting of DPP-4 and has a large size, which slows down the 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 1 time per week. In addition, the dulaglutid molecule was created to reduce the Fc receptor mediated immune response and reduce the immunogenic potential.

The hypoglycemic effect of dulaglutide is due to several mechanisms of action of GLP-1. At elevated glucose concentrations, dulaglutide increases the content of intracellular cyclic adenosine monophosphate (cAMP) in the beta cells of the pancreas, which leads to an increase in insulin secretion. Dulaglutide inhibits the excessive secretion of glucagon in patients with type 2 diabetes, which leads to a decrease in the release of glucose by the liver. In addition, dulaglutid slows down the rate of gastric emptying.

Pharmacodynamics

In patients with type 2 diabetes, starting from the first injection, dulaglutid improves glycemic control by sustainably reducing the fasting blood glucose concentration, before eating and after meals, which is maintained for a week before the next dose.

A pharmacodynamic study of dulaglutide showed that in patients with type 2 diabetes, recovery of the first phase of insulin secretion was observed to the value observed in healthy individuals who received placebo and improvement of the second phase of insulin secretion in response to intravenous glucose bolus. In the same study, it was also shown that with a single dose of dulaglutid at a dose of 1.5 mg, the maximum insulin secretion by β-cells of the pancreas increased and β-cell function was improved in patients with type 2 diabetes compared with placebo.

The pharmacokinetic profile and the corresponding pharmacodynamic profile of dulaglutide allows you to administer the drug 1 time per week.

Clinical efficacy and safety

Glycemic control

The safety and efficacy of dulaglutide was evaluated during 6 randomized controlled phase III trials, in which 5171 patients with type 2 diabetes took part. Of these, 958 were over the age of 65, of which 93 were over the age of 75. These studies included 3136 patients who received dulaglutid, of which 1719 received dulaglutid at a dose of 1.5 mg once a week, and 1417 received dulaglutid at a dose of 0.75 mg once a week. In all studies, dulaglutide provided a clinically significant improvement in glycemic control, which was assessed by glycated hemoglobin (HbAlc).

Monotherapy

The use of dulaglutide in monotherapy was studied during a clinical study with active control lasting 52 weeks compared to metformin. The effectiveness of dulaglutide, when applied in doses of 1.5 mg or 0.75 mg 1 time per week, exceeded the effectiveness of metformin at a dose of 1500-2000 mg / day for reducing HbAlc, and a significantly larger number of patients reached the target HbAlc

The frequency of documented cases of symptomatic hypoglycemia with the use of dulaglutid in doses of 1.5 mg or 0.75 mg once a week and with the use of metformin was 0.62; 0.15 and 0.09 episodes / patient / year, respectively. Cases of severe hypoglycemia with the use of dulaglutide were not observed.

Therapy in combination with metformin

The safety and efficacy of dulaglutide was evaluated in a placebo-controlled and actively-controlled clinical trial (sitagliptin 100 mg / day) for 104 weeks, in which all drugs were used in combination with metformin. The use of dulaglutid in doses of 1.5 mg or 0.75 mg 1 time per week after 52 weeks resulted in a greater decrease in HbAlc compared with the use of sitagliptin, while a significantly larger number of patients using dulaglutid reached the target HbAlc

The frequency of documented symptomatic hypoglycemia with the use of dulaglutid in doses of 1.5 mg or 0.75 mg 1 time per week and with the use of sitagliptin was 0.19; 0.18 and 0.17 episodes / patient / year, respectively. Cases of severe hypoglycemia with the use of dulaglutide were not observed.

The safety and efficacy of dulaglutide was also assessed in the course of an actively controlled study in comparison with the use of liraglutide at a dose of 1.8 mg / day (the initial dose was 0.6 mg / day; after 1 week, the dose was increased to 1.2 mg / day, and then at 2 weeks to 1.8 mg / day) lasting 26 weeks; both drugs were used in combination with metformin. The use of dulaglutid at a dose of 1.5 mg 1 time per week resulted in a comparable decrease in HbAlc and the number of patients reaching the target HbAlc

The frequency of documented symptomatic hypoglycemia with the use of dulaglutid at a dose of 1.5 mg 1 time per week was 0.12 episodes / patient / year, and with the use of liraglutide - 0.29 episodes / patient / year. No cases of severe hypoglycemia were observed.

Therapy in combination with metformin and sulfonylurea derivatives

In a study with an active control of 78 weeks, dulaglutide was compared with insulin glargine, both drugs were used in combination with metformin and sulfonylurea derivatives. After 52 weeks, the use of dulaglutide at a dose of 1.5 mg 1 time per week resulted in a significantly greater decrease in HbAlc compared to insulin glargine, which persisted after 78 weeks; whereas a decrease in HbAlc when using dulaglutide at a dose of 0.75 mg once a week was comparable to a decrease in HbAlc when insulin glargine was used. In the use group of dulaglutid at a dose of 1.5 mg, a significantly larger number of patients reached the target HbAlc

The frequency of documented cases of symptomatic hypoglycemia with the use of dulaglutid in doses of 1.5 mg or 0.75 mg once a week and with the use of insulin glargine amounted to 1.67; 1.67 and 3.02 episodes / patient / year, respectively. With the use of dulaglutide in a dose of 1.5 mg once a week and with the use of 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 studies and studies with active control (the dose of exenatide was 5 mcg 2 times a day for the first 4 weeks and 10 mcg 2 times a day later), with the use of both drugs in combination with metformin and pioglitazone with the introduction of dulaglutide in doses 1.5 mg or 0.75 mg 1 time per week demonstrated a significantly more significant decrease in HbAlc compared with placebo and exenatide, which was accompanied by a significantly larger number of patients reaching the target HbAlc

The frequency of documented cases of symptomatic hypoglycemia with the use of dulaglutid in doses of 1.5 mg or 0.75 mg 1 time per week and with the use of exenatide 2 times a day, was 0.19; 0.14 and 0.75 episodes / patient / year, respectively. When using dulaglutide, no cases of severe hypoglycemia were observed; when exenatide was used, 2 cases of severe hypoglycemia were noted.

Therapy in combination with insulin, with or without metformin

In a clinical study, patients who received insulin 1 or 2 times a day before the study began, discontinued the previous therapy regimen and were randomly assigned to the groups of dulaglutide 1 time per week or insulin glargine 1 time per day; both regimens were administered in combination with prandial insulin lispro, administered 3 times per day in combination with metformin or without metformin. After 26 weeks, the efficacy of dulaglutide, when applied in doses of 1.5 mg or 0.75 mg 1 time per week, exceeded the effectiveness of insulin glargine with respect to the reduction of HbAlc, the same effect was maintained by the 52nd week of the study. The average change in HbAlc for the groups of use of dulaglutid at a dose of 1.5 mg or 0.75 mg 1 time per week and the use of insulin glargine 1 time per day was -1.64% [p

The frequency of documented cases of symptomatic hypoglycemia with the use of dulaglutid in doses of 1.5 mg or 0.75 mg once a week and with the use of insulin glargine amounted to 31.06: 35.66 and 40.95 episodes / patient / year, respectively. 10 patients reported severe hypoglycemia with the use of dulaglutid at a dose of 1.5 mg once a week, 7 patients with the use of dulaglutide at a dose of 0.75 mg once a week, and 15 patients with the use of insulin glargine.

Fasting blood glucose concentration

The use of dulaglutide resulted in a significantly greater decrease in fasting blood glucose concentration compared to the initial value. The main effect on fasting blood glucose concentration was observed after 2 weeks. An improvement in fasting blood glucose concentration persisted over the longest study period of –104 weeks.

The concentration of blood glucose after a meal (postprandial glycemia)

The use of dulaglutide resulted in a significant decrease in mean postprandial glycemia compared to baseline (the change in glycemia from baseline to primary time point was from -1.95 mmol / l to -4.23 mmol / l).

Pancreatic beta cell function

The results of clinical studies have shown an improvement in the function of the beta cells of the pancreas when using dulaglutide, as determined using the homeostatic assessment model (HOMA2-% B). The effect on the run-cell function was maintained for the longest study period — 104 weeks.

Body mass

When using dulaglutid in a dose of 1.5 mg 1 time per week, a steady decrease in body weight was observed throughout the study (the change in the average value from the initial value to the final time point was from - 0.35 kg to -2.90 kg). The change in body weight with the use of dulaglutid at a dose of 0.75 mg once a week varied from 0.86 kg to -2.63 kg. A decrease in body weight was observed in patients who received dulaglutide, regardless of the occurrence of nausea, although numerically the decrease was greater in the group of patients who had nausea.

Results based on a patient survey

Dulaglutid significantly improved overall satisfaction with therapy compared to exenatide therapy 2 times a day. In addition, the detected frequency of hyperglycemia and hypoglycemia with the use of dulaglutide was significantly lower than with the use of exenatide 2 times a day.

Blood pressure (BP)

The effect of dulaglutide on blood pressure was assessed in a study involving 755 patients with type 2 diabetes with the help of ambulatory blood pressure control. Dulaglutide therapy was accompanied by a decrease in systolic blood pressure (a difference of -2.8 mm Hg compared to placebo) after 16 weeks. There was no difference in diastolic blood pressure. Similar results for systolic and diastolic blood pressure were shown at the end point of the study - 26 weeks.

Risk to the cardiovascular system

According to the results of a meta-analysis of phase II and III studies in 51 patients (dulaglutid: 26 (N = 3885); all comparison drugs: 25 (N = 2125)), at least one cardiovascular event was observed (death caused by on the part of the cardiovascular system, non-fatal myocardial infarction, non-fatal stroke or hospitalization due to unstable angina). The results showed that the use of dulaglutid did not increase the risk of cardiovascular disorders as compared with therapy with comparator drugs (risk ratio: 0.57; confidence interval: (0.30: 1.10)).

Preclinical safety

Preclinical studies of dulaglutid revealed no particular risk to humans according to standard studies of pharmacological safety and toxicity of multiple doses.

During the 6-month study of carcinogenicity in transgenic mice, no oncogenic response was observed. During a 2-year study of carcinogenicity in rats with a concentration of dulaglutid that is> 7 times higher than the therapeutic dose of dulaglutide in humans, 1.5 mg once a week, dulaglutide caused a significant dose-dependent increase in the frequency of C-cell tumors of the thyroid gland (adenomas and carcinomas). The significance of such results for a person is not currently known.

In the course of fertility studies at doses that were associated with reduced food intake and weight gain in the mother, there was a decrease in the number of yellow bodies and an increase in the duration of the estrous cycle; however, no effect on fertility and conception or on embryonic development was observed. In the course of reproductive toxicity studies in rats and rabbits, the effect on skeleton formation and reduction in fetal growth was observed with dulaglutide exposure, which was 11-44 times higher than the clinical one, but no congenital abnormalities were observed. The administration of dulaglutide to rats during the period of pregnancy and lactation caused a memory deficit in female offspring during exposure, which was 16 times higher than the proposed clinical exposure.

Indications

Trulicity ™ is indicated in adult patients with type 2 diabetes in order to improve glycemic control in the form of:

- monotherapy

If diet and exercise do not provide the necessary glycemic control in patients who do not show the use of metformin due to intolerance or the presence of contraindications.

- combination therapy

In combination with other hypoglycemic drugs, including insulin, if these drugs along with diet and exercise do not provide the necessary glycemic control.

Composition

Active substance: dulaglutid 1.5 mg;

Excipients: anhydrous citric acid 0.07 mg; mannitol 23.2 mg; polysorbate 80 (vegetable) 0.10 mg; sodium citrate dihydrate 1.37 mg; water for injection q.s. up to 0.5 ml.

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Trulicity® [Dulaglutide]

Dosage and Administration

Externally: the gel is applied evenly in a thin layer in the morning and evening on the skin over the painful area and lightly massaged until completely absorbed. The dose of the drug depends on the area of ​​the damaged surface, but should not exceed 3-4 cm of gel (1.5-2 g). The gel can be applied under the occlusive dressing.

Adverse reactions

In some cases, possible allergic reactions (skin rash).

With care: a renal failure (long use).

  • Brand name: Troxerutin
  • Active ingredient: Troxerutin
  • Dosage form: Gel for external use
  • Manufacturer: Sopharma

Studies and clinical trials of Dulaglutide (Click to expand)

  1. Monotherapy with the once-weekly GLP-1 analogue dulaglutide for 12 weeks in patients with Type 2 diabetes: dose-dependent effects on glycaemic control in a randomized, double-blind, placebo-controlled study
  2. P303 Efficacité de dulaglutide hebdomadaire à durée d’action prolongée, comparé à l’exénatide à action rapide, administré deux fois par jour chez des patients présentant un diabète de type 2 (DT2) : analyse post-hoc, déterminant l’impact du taux initial d’HbA1
  3. Efficacy and Safety of Dulaglutide Versus Sitagliptin after 52 Weeks in Type 2 Diabetes (AWARD-5)
  4. Efficacy and Safety of Dulaglutide Versus Placebo and Exenatide in Type 2 Diabetes (AWARD-1)
  5. Safety and Efficacy of Dulaglutide Versus Sitagliptin after 104 Weeks in Type 2 Diabetes (AWARD-5)
  6. Effects of the Once-Weekly Glucagon-Like Peptide-1 Receptor Agonist Dulaglutide on Ambulatory Blood Pressure and Heart Rate in Patients With Type 2 Diabetes Mellitus
  7. Safe and Effective Use of the Single-Use Pen for Injection of Once Weekly Dulaglutide in Injection-Naïve Patients with Type 2 Diabetes
  8. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial
  9. Efficacy and Safety of Once Weekly Dulaglutide vs. Insulin Glargine in Combination with Metformin and Glimepiride in Type 2 Diabetes Patients (AWARD-2)
  10. Efficacy and Safety of Once Weekly Dulaglutide vs. Once Daily Liraglutide in Type 2 Diabetes (AWARD 6)
  11. The Two-Week Fasting Glucose as a Predictor of Response to Once Weekly Dulaglutide 1.5 mg
  12. Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1)
  13. Efficacy of Once Weekly Dulaglutide Compared with Twice-Daily Exenatide in Patients with Type 2 Diabetes: A Post-Hoc Analysis to Determine the Influence of Baseline HbA1c
  14. Better Glycemic Control and Less Weight Gain with Once Weekly Dulaglutide vs. Once Daily Insulin Glargine, Both Combined with Pre-Meal Insulin Lispro, in Type 2 Diabetes Patients (AWARD-4)
  15. Patient Experience With The Single-Use Pen For Injection of Once Weekly Dulaglutide in Injection-Naive Patients With Type 2 Diabetes
  16. Assessing Consistency in a Network Meta-Analysis to Compare Once Weekly Dulaglutide Versus Other Glp-1 Receptor Agonists in Patients with Type 2 Diabetes
  17. Efficacy and Safety of Dulaglutide Monotherapy Versus Metformin in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-3)
  18. Dulaglutide: First Global Approval
  19. Efficacy and Safety of Dulaglutide Versus Sitagliptin After 52 Weeks in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-5)
  20. Application of Adaptive Design Methodology in Development of a Long-Acting Glucagon-like Peptide-1 Analog (Dulaglutide): Statistical Design and Simulations
  21. OP8 THE 2-WEEK FASTING GLUCOSE AS A PREDICTOR OF GLYCEMIC RESPONSE TO ONCE-WEEKLY DULAGLUTIDE 1.5 MG
  22. Dulaglutide: The Newest GLP-1 Receptor Agonist for the Management of Type 2 Diabetes
  23. Therapy: Once-weekly dulaglutide noninferior to once-daily liraglutide
  24. Dulaglutide: a novel once-weekly glucagon-like peptide-1 receptor agonist

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