Introduction

Vildagliptin is an orally active antihyperglycemic agent that selectively inhibits the dipeptidyl peptidase-4 (DPP-4) enzyme. It is used to manage type II diabetes mellitus, where GLP-1 secretion and insulinotropic effects are impaired.[1] By inhibiting DPP-4, vildagliptin prevents the degradation of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are incretin hormones that promote insulin secretion and regulate blood glucose levels. Elevated levels of GLP-1 and GIP consequently results in improved glycemic control.6 In clinical trials, vildagliptin has a relatively low risk of hypoglycemia.[1] Oral vildagliptin was approved by the European Medicines Agency in 2008 for the treatment of type II diabetes mellitus in adults as monotherapy or in combination with metformin, a sulfonylurea, or a thiazolidinedione in patients with inadequate glycemic control following monotherapy. It is marketed as Galvus.[2] Vildagliptin is also available as Eucreas, a fixed-dose formulation with metformin for adults in who do not adequately glycemic control from monotherapy. In the European Union it was granted marketing authorization by the European Medicine Agency (EMA) in 2007, whereas 2 years later, the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom issued a clinical guidance supporting its use as second-line therapy adjunct to ?rst-line metformin or sulfonylurea. Finally, in a recently updated position statement, the American Diabetes Association and the European Association for the Study of Diabetes have advocated the use of DPP-4 inhibitors as first-line agent in circumstances where metformin is contraindicated or not tolerated, or within a dual or triple agent regimen [3-4].

Indication

Vildagliptin is indicated in the treatment of type II diabetes mellitus in adults. As monotherapy, vildagliptin is indicated in adults inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.[2] It is also indicated as dual therapy in combination with metformin, a sulphonylurea, or a thiazolidinedione in adults patients with insufficient glycemic control despite maximal tolerated dose of monotherapy. Vildagliptin is also marketed in a combination product with metformin for the treatment of adults with type II diabetes mellitus who inadequately respond to either monotherapy of vildagliptin or metformin. This fixed-dose formulation can be used in combination with a sulphonylurea or insulin (i.e., triple therapy) as an adjunct to diet and exercise in adults who do not achieve adequate glycemic control with monotherapy or dual therapy.[2]

Pharmacology

Figure 1 illustrates the mechanism of action of this drug.[5] Vildagliptin is a selective, reversible, competitive inhibitor of DPP4, an enzyme and binding protein present in many tissues such as the kidneys, liver, brushborder membranes of the intestine, pancreatic duct, lymphocytes, and endothelial cells. Vildagliptin binds to and forms a complex with DPP4, resulting in its inhibition. DPP4 is involved in the inactivation of many neuropeptides, cytokines, chemokines, and gastrointestinal hormones. Two important hormones involved in glucose homeostasis and inactivated by DPP4 are glucosedependent insulinotropic polypeptide (GIP) and GLP-1. [6-9] GIP and GLP-1 are incretins, which are hormones released from the gut that stimulate insulin secretion in response to food intake. However, GIP does not stimulate insulin release in patients with type 2 diabetes mellitus as it does in patients without diabetes. GLP-1, the most potent insulinotropic hormone, enhances glucose-dependent secretion of insulin from pancreatic β-cells and inhibits glucagon secretion. Inhibition of DPP4, which results in increased levels of active GLP-1, has been shown to be an effective treatment for type 2 diabetes mellitus.[5]

Pharmacokinetics

The disposition of vildagliptin has been described in both a preclinical study with healthy volunteers and another study in patients with type 2 diabetes mellitus. Participants in both studies received vildagliptin 100 mg orally; vildagliptin was rapidly absorbed, with a peak plasma vildagliptin concentration observed at one to two hours after the dose was given. Vildagliptin displayed an oral bioavailability of 85% in healthy volunteers, and its pharmacokinetics were not affected by food. An absolute oral bioavailability exceeding 90% and an average clearance rate from plasma of 1.5 L/hr/kg with a volume of distribution of 0.7 L/kg were observed following a 1-μmol/kg oral dose administered to cynomolgus monkeys.  The terminal elimination half-life of vildagliptin is 90 minutes, and the vildagliptin–DPP4 complex exhibits a slow dissociation half-life of 55 minutes. Maximum inhibition of DPP4 activity is seen minutes after a vildagliptin dose, and ≥50% inhibition of DPP4 continues for 10 hours or longer. One clinical trial showed mean ± S.D. DPP4 levels to be 60% ± 5% of baseline 24 hours after a 100-mg dose of vildagliptin (p < 0.001). [5]

Dosage and administration

Vildagliptin was evaluated in a dose–response study by Ristic et al. [10] assessing regimens of vildagliptin 25 mg twice daily, 25 mg daily, 50 mg daily, and 100 mg daily. Both vildagliptin 50- and 100-mg dosages led to signi?cant reductions in HbA1c . Significant decreases in HbA1c , fasting plasma glucose levels, and prandial glucose levels were observed with doses of 25 mg twice daily.The highest vildagliptin dosage evaluated in the clinical trials was vildagliptin 100 mg twice daily in patients with type 2 diabetes mellitus; however, HbA1c values were not assessed for this dosage regimen. Because the labeling for vildagliptin is not yet FDA approved, dosage recommendations from the manufacturer are not available at this time. However, the drug’s pharmacokinetic properties allow for the possibility of once- or twice-daily dosing.[5,11]  

Conclusion

In conclusion, vildagliptin could pose a reasonable therapeutic option for patients with type 2 diabetes when choosing an optimal treatment through a shared decision making process, taking into consideration the personal preferences of each individual patient.

References

[1] Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem. 1993;214(3):829-835. 

[2] Zhou Y, Zhang Y, Zhao D, et al. TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024;52(D1):D1465-D1477. 

[3] Bekiari E, Rizava C, Athanasiadou E, et al. Systematic review and meta-analysis of vildagliptin for treatment of type 2 diabetes. Endocrine. 2016;52(3):458-480. 

[4] Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58(3):429-442. 

[5] Lauster CD, McKaveney TP, Muench SV. Vildagliptin: a novel oral therapy for type 2 diabetes mellitus. Am J Health Syst Pharm. 2007;64(12):1265-1273. 

[6] Brandt I, Joossens J, Chen X et al. Inhibition of dipeptidyl-peptidase IV catalyzed peptide truncation by vildagliptin ((2S)-{[(3-hydroxyadamanta1-yl) amino]acetyl}-pyrrolidine-2- carbonitrile). Biochem Pharmacol. 2005; 70:134-43.

[7] Mentlein R. Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides. Regul Pept. 1999; 85:9-24.

[8] Efendic S, Portwood N. Overview of incretin hormones. Horm Metab Res. 2004; 36:742-6. 

[9] Villhauer EB, Brinkman JA, Naderi GB et al. 1-[[(3-hydroxy-1- adamantyl)amino]acetyl]-2-cyano-(S)- pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem. 2003; 46:2774-89.

[10] Mari A, Sallas M, He YL et al. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed β-cell function in patients with type 2 diabetes. J Clin Endocrinol Metab. 2005; 90:4888-94.

[11] Ristic S, Byiers S, Foley J et al. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response. Diabetes Obes Metab. 2005; 7:692-8.