Indications
Vildagliptin is primarily indicated for the management of type II diabetes mellitus in adults. As a monotherapy, it is suitable for those who cannot achieve adequate control with diet and exercise alone and are unable to use metformin due to contraindications or intolerance. The medication can also be used in dual therapy alongside metformin, a sulphonylurea, or a thiazolidinedione for patients whose glycemic levels are not satisfactorily managed with the maximum tolerated dose of a single medication. Furthermore, vildagliptin is available in a fixed-dose combination with metformin, intended for type II diabetes patients who show inadequate responses to monotherapy of either drug. This formulation may also be used as part of a triple therapy regimen, combined with a sulphonylurea or insulin, as an adjunct to diet and exercise.
Pharmacodynamics
Vildagliptin enhances glycemic control in individuals with type II diabetes mellitus by increasing glucose sensitivity in the pancreatic islets' beta-cells, thus facilitating glucose-dependent insulin secretion. Additionally, by elevating GLP-1 levels, vildagliptin improves alpha-cell sensitivity to glucose, thereby promoting glucagon secretion. The overall result is an increased insulin to glucagon ratio, which subsequently reduces fasting and postprandial hepatic glucose output. Importantly, vildagliptin does not alter gastric emptying or affect insulin secretion and blood glucose levels in individuals with normal glucose control. Clinical trials have demonstrated that vildagliptin, administered at doses between 50-100 mg daily, significantly improves various markers of beta-cell function, including the proinsulin to insulin ratio and measures of beta-cell responsiveness.
Absorption
Upon oral administration in a fasting state, vildagliptin is rapidly absorbed, reaching peak plasma concentrations approximately 1.7 hours post-ingestion. The plasma concentration of vildagliptin increases proportionally with the dose. While the presence of food delays the time to peak concentration (Tmax) to 2.5 hours and reduces the peak plasma concentration (Cmax) by 19%, it does not affect the total systemic exposure to the drug, as indicated by the area under the curve (AUC). The absolute bioavailability of vildagliptin stands at 85%.
Metabolism
Approximately 69% of orally administered vildagliptin is metabolized via processes independent of cytochrome P450 enzymes. Studies in rats suggest that DPP-4 partially contributes to the hydrolysis of vildagliptin. In humans, vildagliptin is metabolized into inactive cyano (57%) and amide (4%) hydrolysis products within the kidneys. The major inactive metabolite, LAY 151 (M20.7), is a carboxylic acid formed by the hydrolysis of the cyano group, comprising 57% of the administered dose. Other identified circulating metabolites include an N-glucuronide (M20.2), an N-amide hydrolysis product (M15.3), and two oxidation products (M21.6 and M20.9).
Mechanism of Action
Vildagliptin functions primarily by selectively inhibiting dipeptidyl peptidase-4 (DPP-4), an enzyme responsible for the rapid inactivation of the incretin hormones GLP-1 and GIP. These incretin hormones, which include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), play a critical role in regulating blood glucose levels and maintaining glucose homeostasis. By cleaving oligopeptides shortly after the second amino acid from the N-terminal, DPP-4 reduces the activity of these hormones. Vildagliptin effectively prolongs the half-life of GLP-1 and GIP by inhibiting DPP-4, thereby increasing their active concentrations in the bloodstream. This action leads to improved glucose control by enhancing glucose-dependant insulin secretion, and has a dose-dependent duration of effect. Consequently, vildagliptin reduces fasting and prandial glucose levels as well as HbA1c. Additionally, it augments the glucose sensitivity of both alpha- and beta-cells and facilitates better glucose-dependent insulin release. Furthermore, vildagliptin positively influences postprandial lipid profiles and overall lipid metabolism, providing a comprehensive approach to managing blood glucose levels in patients.
