Pharmacodynamics
Januvia® (sitagliptin) is an orally active, highly selective inhibitor of the DPP-4 enzyme intended for the treatment of type 2 diabetes mellitus. Sitagliptin differs in chemical structure and pharmacological action from GLP-1 analogues, insulin, sulfonylurea derivatives, biguanides, gamma agonists peroxisome proliferator-activated receptors (PPAR-γ), alpha-glucosidase inhibitors, amylin analogues. By inhibiting DPP-4, sitagliptin increases the concentration of two hormones of the incretin family: GLP-1 and GIP. Hormones of the incretin family are secreted in the intestine during the day, their concentration increases in response to food intake. Incretins are part of the internal physiological system for the regulation of glucose homeostasis. At normal or elevated blood glucose concentrations, hormones of the incretin family contribute to an increase in insulin synthesis, as well as its secretion by pancreatic beta cells due to intracellular signaling mechanisms associated with cAMP.

GLP-1 also contributes to the suppression of increased secretion of glucagon by pancreatic alpha cells. A decrease in the concentration of glucagon against the background of an increase in the concentration of insulin contributes to a decrease in the production of glucose by the liver, which ultimately leads to a decrease in glycemia. This mechanism of action differs from the mechanism of action of sulfonylurea derivatives, which stimulate the release of insulin even at low blood glucose concentrations, which is fraught with the development of sulfonylated hypoglycemia not only in patients with type 2 diabetes mellitus, but also in healthy individuals.

At low blood glucose concentrations, the listed effects of incretins on insulin release and a decrease in glucagon secretion are not observed. GLP-1 and GIP do not affect the release of glucagon in response to hypoglycemia. Under physiological conditions, the activity of incretins is limited by the DPP-4 enzyme, which rapidly hydrolyzes incretins to form inactive products.

Sitagliptin prevents the hydrolysis of incretins by the DPP-4 enzyme, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By increasing the concentration of incretins, sitagliptin increases glucose-dependent insulin release and helps to reduce glucagon secretion. In patients with type 2 diabetes mellitus with hyperglycemia, these changes in insulin and glucagon secretion lead to a decrease in HbA1c concentration and a decrease in fasting and post-exercise plasma glucose concentrations.

In patients with type 2 diabetes mellitus, taking a single dose of Januvia® leads to inhibition of the activity of the DPP-4 enzyme for 24 hours, which leads to an increase in the concentration of circulating incretins GLP-1 and GIP by 2-3 times, an increase in plasma concentration of insulin and C -peptide, a decrease in the concentration of glucagon in the blood plasma, a decrease in fasting glycemia, as well as after a glucose load or a food load.

Effect on blood pressure. In a randomized placebo-controlled cross-over study involving patients with arterial hypertension, the combined use of antihypertensive drugs (one or more of the list: ACE inhibitors, ARA II, CCBs, beta-blockers, diuretics) with Januvia® was generally well tolerated by patients. In this category of patients, Januvia® showed a slight hypotensive effect: at a daily dose of 100 mg, sitagliptin reduced the average daily ambulatory SBP value by 2 mm Hg. compared to the placebo group. In patients with normal blood pressure, no hypotensive effect was observed.

Influence on the electrophysiology of the heart. In a randomized, placebo-controlled cross-over study in healthy volunteers, Januvia® was taken as a single dose of 100 or 800 mg (8 times the recommended dose), or placebo. After taking the recommended therapeutic dose of 100 mg, no effect of the drug on the duration of the QT interval was observed both at the time of its plasma Cmax and at other checkpoints throughout the study. After taking 800 mg, the maximum increase in the placebo-adjusted mean change in the duration of the QT interval compared with the baseline value 3 hours after taking the drug was 8 ms. This slight increase was judged to be clinically insignificant. After taking a dose of 800 mg, the plasma Cmax of sitagliptin was approximately 11 times higher than the corresponding value after taking a therapeutic dose of 100 mg.Indications
Monotherapy

Januvia® is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Combination Therapy

combination with metformin. Januvia® in combination with metformin in patients with type 2 diabetes mellitus to improve glycemic control as initial therapy or when diet and exercise in combination with monotherapy with one of the listed drugs does not lead to adequate glycemic control.

Combination with sulfonylurea derivatives. Januvia® in combination with sulfonylurea derivatives in patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise in combination with monotherapy with one of the listed drugs does not lead to adequate glycemic control.

Combination with PPAR-γ agonists. Januvia® in combination with PPAR-γ agonists (thiazolidinediones) in patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise in combination with monotherapy with one of the listed drugs does not lead to adequate glycemic control;

Combination with metformin and sulfonylurea derivatives. Januvia® in combination with metformin and sulfonylurea derivatives in patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise in combination with therapy with two of the listed drugs do not lead to adequate glycemic control;

Combination with metformin and PPAR-γ agonists. Januvia® in combination with metformin and PPAR-γ agonists (thiazolidinediones) in patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise in combination with therapy with two of the listed drugs do not lead to adequate glycemic control;

combination with insulin. Januvia® as an adjunct to insulin (with or without metformin) in patients with type 2 diabetes mellitus in cases where diet, exercise and a stable dose of insulin do not result in adequate glycemic control.
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