Metformin, sitagliptin

Pharmacological properties

Yanumet is a combination of two hypoglycemic drugs with a complementary (complementary) mechanism of action, which is designed to improve glycemia control in patients with type 2 diabetes: sitagliptin, a dipeptidyl peptidase inhibitor (DPP) -4, and metformin hydrochloride, a representative of the biguanide class.

Sitagliptin is an orally active, highly selective inhibitor of the enzyme DPP-4, which is used to treat type 2 diabetes mellitus. The pharmacological effects of DPP-4 inhibitors are mediated by the activation of incretins. By inhibiting DPP-4, sitagliptin increases the concentration of two known active hormones of the incretin family: the glucagon-like peptide (GLP) -1 and the glucose-dependent insulinotropic polypeptide (HIP). The incretins are part of the internal physiological system for regulating glucose homeostasis. With a normal or elevated blood glucose level, GLP-1 and GUI increase the synthesis and secretion of insulin by pancreatic β-cells. GLP-1 also inhibits the secretion of glucagon by pancreatic α-cells, thereby reducing the synthesis of glucose in the liver. If the blood glucose level is low, insulin release is not enhanced, and glucagon secretion is not suppressed. Being a highly selective and effective inhibitor of the DPP-4 enzyme, sitagliptin in therapeutic concentrations does not inhibit the activity of related enzymes - DPP-8 or DPP-9. Sitagliptin differs in chemical structure and pharmacological action from analogues of GLP-1, insulin, sulfonylureas or meglitinides, biguanides agonists of γ receptors activated by the peroxisome proliferator (PPAR) γ, α-glycosidase inhibitors and amylin analogues.

In a two-day study involving healthy volunteers, sitagliptin in mono mode increased the concentration of active GLP-1, while metformin in mono mode at a similar level increased the concentration of active and total GLP-1.

The simultaneous administration of sitagliptin and metformin had an additional enhancing effect on the concentration of active GLP-1. Sitagliptin, unlike metformin, increased the concentration of active HIP.

Metformin. This preparation of the biguanide group has a hypoglycemic effect, lowering the basal and postprandial plasma glucose levels, does not stimulate insulin secretion and therefore does not lead to hypoglycemia.

Metformin reduces the synthesis of glucose in the liver by inhibiting gluconeogenesis and glycogenolysis, reduces the absorption of glucose in the intestines and moderately increases insulin sensitivity in the muscles by enhancing peripheral uptake and utilization of glucose.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin enhances the transport capacity of certain types of membrane glucose transporters (GLUT-1 and -4).

The TECOS study was a randomized trial involving 14,671 patients with HbA_1c ≥6.5 to 8.0% with established cardiovascular disease who received sitagliptin (7332) 100 mg / day (or 50 mg / day if the baseline estimated glomerular filtration rate (rSCF) was ≥30 and 50 ml / min / 1.73 m²), or placebo (7339), both drugs were added to standard therapy taking into account the level of HbA_1c and risk factors for the cardiovascular system. Patients with eGFR 30 ml / min / 1.73 m² the study was not included. The study included 2004 patients aged ≥75 years and 3324 patients with renal failure (eGFR 60 ml / min / 1.73 m²).

During the study, the average difference between HbA_1c when using sitagliptin and placebo, it was 0.29% (0.01), 95% CI (–0.32; –0.27) p0.001.

The primary endpoint for the cardiovascular system was cardiovascular death, non-lethal myocardial infarction, non-lethal stroke, or hospitalization for unstable angina pectoris.Secondary endpoints for the cardiovascular system: cardiovascular death, non-lethal myocardial infarction or non-lethal stroke; the first appearance of the individual components of the primary endpoint; mortality from all causes; hospitalization for heart failure.

After observing an average of 3 years, sitagliptin when added to standard therapy did not increase the risk of serious adverse cardiovascular events or the risk of hospitalization for heart failure compared with conventional treatment without sitagliptin in patients with type 2 diabetes.

Frequency of composite and primary secondary cardiovascular endpoints

* The incidence per 100 patient-years is calculated as 100 x (the total number of patients with ≥1 occurrence during the corresponding period of drug use for the total number of patient-years of follow-up).

^†Based on the Cox model stratified by region. For composite endpoints, p-values ​​meet the search criteria of no less efficiency to demonstrate that the risk ratio is 1.3. For all other endpoints, the p-values ​​correspond to the criterion of differences in risk indicators.

^‡The analysis of hospitalization for heart failure was adjusted based on baseline history of heart failure at an initial level.

Pharmacokinetics Mechanism of action. 50 mg / 500 mg and 50 mg / 1000 mg combined tablets of Yanumet (sitagliptin / metformin hydrochloride) are bioequivalent when separate doses of sitagliptin phosphate (Januvia) and metformin hydrochloride are taken separately.

Given the proven bioequivalence of tablets with a minimum and maximum dose of metformin, tablets with an intermediate dose of metformin (850 mg) were also characterized by bioequivalence, provided that a fixed dose of drugs was combined in a tablet.

Suction. Sitagliptin. After taking a dose of 100 mg in healthy volunteers, sitagliptin was rapidly absorbed and reached peak plasma concentrations (median T_max) 1–4 hours after administration, while the average AUC of sitagliptin in plasma was 8.52 μmol · h, and C_max - 950 nmol. The bioavailability of sitagliptin is approximately 87%. Reception of sitagliptin simultaneously with fatty foods does not affect the pharmacokinetics of the drug.

The AUC of sitagliptin in plasma increases in proportion to the dose. Dose proportionality not established for indicators C_max and C_0–24 (WITH_max more proportional to the dose, whereas C_0–24 less proportional to the dose).

Metformin hydrochloride. After taking metformin, Tmax is reached after 2.5 hours. The bioavailability of metformin hydrochloride when applied on an empty stomach at a dose of 500 mg is 50-60%. After oral administration, the non-absorbed fraction, which is excreted in the feces, is 20–30%.

The absorption of metformin after oral administration is saturated and incomplete. It is assumed that the pharmacokinetics of its absorption are nonlinear.At standard doses and regimens of metformin, a stable plasma concentration is achieved within 24–48 hours and, as a rule, does not exceed 1 μg / ml. C_max in blood plasma did not exceed 4 μg / ml even when used in maximum doses.

Concomitant use of the drug with food reduces the rate and amount of absorbed metformin, as evidenced by a decrease in C_max in blood plasma by about 40%, a decrease in AUC by about 25%, and a 35-minute delay in reaching C_max in plasma (Tmax) after a single dose of 850 mg metformin with food. The clinical significance of lowering the pharmacokinetic parameters has not been established.

Distribution

Sitagliptin. The average volume of distribution in equilibrium after a single injection of 100 mg of sitagliptin in healthy volunteers is approximately 198 L. The sitagliptin fraction, which reversibly binds to plasma proteins, is relatively small (38%).

Metformin. The binding of metformin to plasma proteins is negligible. Metformin penetrates red blood cells. C_max blood lower than C_max in blood plasma, and is achieved in the same amount of time. Red blood cells most likely represent a second distribution chamber. The average volume of distribution (Vd) ranges from 63–276 liters.

Metabolism

Sitagliptin. Approximately 79% of sitagliptin is excreted unchanged in the urine, the metabolic transformation of the drug is minimal.

After introduction ¹⁴C-labeled sitagliptin inside approximately 16% of the introduced radioactivity was excreted as metabolites of sitagliptin. Identified in an insignificant concentration of 6 metabolites of sitagliptin that are not involved in the plasma DPP-4-inhibitory activity of sitagliptin. In vitro studies, the main enzyme responsible for ogre