Reditn M Mechanism of Action

Pharmacology: Pharmacodynamics: Combination products containing metformin and sitagliptin are used to improve glycemic control in type 2 diabetes mellitus (DM).
Metformin: Metformin decreases hepatic gluconeogenesis production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. Metformin improves glucose utilization in skeletal muscle and adipose tissue by increasing cell membrane glucose transport. This effect may be due to improved binding of insulin to insulin receptors since metformin is not effective in diabetics without some residual functioning pancreatic islet cells. Metformin causes a 10% to 20% decrease in fatty-acid oxidation and a slight increase in glucose oxidation. Unlike phenformin, metformin does not inhibit the mitochondrial oxidation of lactate unless its plasma concentrations become excessive (i.e., in patients with renal failure) and/or hypoxia is present. Clinically, metformin lowers fasting and postprandial hyperglycemia. The decrease in fasting plasma glucose is approximately 25% to 30%. Unlike oral sulfonylureas, it rarely causes hypoglycemia. Thus, metformin demonstrates more of an antihyperglycemic action than a hypoglycemic action. Metformin does not cause weight gain and in fact, may cause a modest weight loss due to drug-induced anorexia. Metformin also decreases plasma VLDL triglycerides resulting in modest decreases in plasma triglycerides and total cholesterol. Patients receiving metformin show a significant improvement in hemoglobin A1C, and a tendency toward improvement in the lipid profile, especially when baseline values are abnormally elevated.
Sitagliptin: Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which exerts its actions in patients with type 2 DM by slowing the inactivation of incretin hormones. Concentrations of the active, intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4.
The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells leading to reduced hepatic glucose production, and GLP-1 slows gastric emptying time. Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner; GLP-1 does not increase insulin secretion when the glucose concentration is less than 90 mg/dL. The contributions of GIP, which increases insulin secretion and regulates fat metabolism, to the overall effects of sitagliptin are unclear at this time. Sitagliptin is of benefit in patients with type 2 DM as their GLP-1 concentrations are decreased in response to a meal. The long-term safety of DPP-4 inhibitors are currently under investigation as DPP-4 is not an enzyme specific for the breakdown of incretin hormones. In fact, DPP-4 is responsible for the metabolism of many peptides including peptide YY, neuropeptide Y, and growth hormone-releasing hormone. DPP-4 is involved with T-cell activation and is expressed on lymphocytes as CD26. Whether there are long-term neurological or immunological consequences of inhibiting DPP-4 is unclear at this time.
Pharmacokinetics: Metformin; sitagliptin is administered orally.
Metformin: Metformin is distributed rapidly into peripheral body tissues and fluids and appears to distribute slowly into erythrocytes and to a deep tissue compartment (most likely GI tissues). The highest concentrations of metformin are found in the GI tract (10 times the concentrations in the plasma) and lower concentrations in the kidney, liver, and salivary gland tissue. Metformin is negligibly bound to plasma proteins. In healthy adult subjects receiving two metformin 1,000 mg; sitagliptin 50 mg XR tablets once daily with the evening meal for 7 days, steady-state for metformin is reached by Day 5 and the median T_max value for metformin is approximately 8 hours post-dose. The median T_max value for metformin after a single tablet of metformin-sitagliptin is 3.5 hours post-dose. It is not metabolized by the liver, which may explain why the risk of lactic acidosis is much lower for metformin than for phenformin (i.e., approximately 10% of patients have an inherited defect in the ability to metabolize phenformin).
About 90% of a dose is excreted by the kidneys, largely unchanged, through an active tubular process. Tubular secretion may be altered by many cationic drugs. Approximately 10% of an oral dose is excreted in the feces, presumably as unabsorbed metformin. Although the average elimination half-life in the plasma is 6.2 hours in patients with normal renal function, metformin is distributed to and accumulates in red blood cells, which leads to a much longer elimination half-life in the blood (17.6 hours).
Sitagliptin: Sitagliptin is not highly bound to plasma proteins (38%). In healthy adult subjects receiving two metformin 1,000 mg; sitagliptin 50 mg XR tablets once daily with the evening meal for 7 days, steady-state for sitagliptin is reached by Day 4 and the median T_max value for sitagliptin is approximately 3 hours post-dose. The median T_max value for sitagliptin after a single tablet of metformin-sitagliptin is 3 hours post-dose.
Metabolism is a minor pathway of elimination for sitagliptin with approximately 16% of a dose excreted as metabolites. The primary enzymes responsible for this limited metabolism are CYP3A4 and CYP2C8. Six metabolites have been detected at trace concentrations and are not expected to contribute significantly to sitagliptin activity. Elimination occurs primarily via renal excretion and involves active tubular secretion; approximately 79% of a dose is excreted unchanged in the urine. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin; the clinical relevance of this has not been established. Sitagliptin is also a substrate of P-glycoprotein, which may also be involved in mediating renal elimination. The apparent terminal half-life of sitagliptin 100 mg is 12.4 hours. One hundred percent of an administered dose is excreted in the urine (87%) or feces (13%) within 1 week of dosing.