Monograph of Vildagliptin

Introduction/Overview

Vildagliptin is a dipeptidyl peptidase‑4 (DPP‑4) inhibitor employed in the management of type 2 diabetes mellitus (T2DM). The drug represents a pivotal class of antihyperglycemic agents that modulate incretin hormones, thereby improving glycaemic control while preserving a low risk of hypoglycaemia when used as monotherapy or in combination with other agents. The significance of vildagliptin lies in its efficacy, tolerability, and suitability for patients with varying degrees of renal function, which often limits the use of other antidiabetic medications.

Learning objectives for this chapter include the following:

• Describe the chemical classification and pharmacological class of vildagliptin.
• Explain the mechanism of action at the molecular and cellular levels.
• Summarize absorption, distribution, metabolism, and excretion characteristics.
• Identify therapeutic indications and common off‑label uses.
• Recognise common and serious adverse events, as well as drug interactions.
• Apply special considerations relevant to pregnancy, lactation, pediatrics, geriatrics, renal, and hepatic impairment.

Classification

Drug Class

Vildagliptin belongs to the class of dipeptidyl peptidase‑4 inhibitors, commonly referred to as DPP‑4 inhibitors. These agents are characterized by selective inhibition of the DPP‑4 enzyme, which is responsible for the rapid catabolism of incretin hormones. By preserving circulating levels of glucagon‑like peptide‑1 (GLP‑1) and glucose‑dependent insulinotropic polypeptide (GIP), DPP‑4 inhibitors enhance insulin secretion and suppress glucagon release in a glucose‑dependent manner.

Chemical Classification

From a structural perspective, vildagliptin is a chiral heterocyclic compound incorporating a benzimidazole core. The molecule features a substituted 3‑(4‑methyl‑2‑oxo‑1,3‑dihydro‑2‑H‑pyrrolo[2,1‑c]pyrazol‑2‑yl)-3‑methyl‑1‑piperidyl‑2‑carboxylate scaffold, rendering it distinct from other DPP‑4 inhibitors that typically contain a pyridazinone or thienopyrimidine nucleus. The presence of a piperidine ring and an ester functionality contributes to its pharmacokinetic properties, particularly in terms of lipophilicity and metabolic stability.

Mechanism of Action

Pharmacodynamics

Vildagliptin exerts its antihyperglycaemic effect by competitively inhibiting DPP‑4 enzymatic activity. Inhibition of DPP‑4 prolongs the half‑life of incretin hormones, notably GLP‑1 and GIP, thereby amplifying insulinotropic and glucagonostatic actions. Consequently, glucose‑dependent insulin secretion is increased while glucagon release is suppressed during post‑prandial states. These dual effects contribute to a reduction in hepatic glucose output and an improvement in peripheral glucose uptake.

Receptor Interactions

GLP‑1 exerts its actions by binding to the GLP‑1 receptor (GLP‑1R), a G‑protein coupled receptor expressed on pancreatic β‑cells, as well as in the central nervous system and gastrointestinal tract.

GIP, acting through its receptor (GIPR), similarly enhances insulin secretion in a glucose‑dependent manner. Vildagliptin’s indirect modulation of these receptors is mediated by maintaining elevated concentrations of their endogenous ligands.

Molecular/Cellular Mechanisms

At the cellular level, DPP‑4 inhibition leads to increased intracellular cyclic AMP (cAMP) in β‑cells, which promotes insulin granule exocytosis. Simultaneously, suppression of glucagon secretion via GLP‑1R activation reduces hepatic gluconeogenesis. In addition, vildagliptin has been shown to improve pancreatic β‑cell function over time, potentially through the attenuation of glucotoxicity and lipotoxicity. These mechanisms are corroborated by reductions in glycated haemoglobin (HbA1c) observed in clinical trials.

Pharmacokinetics

Absorption

Following oral administration, vildagliptin is rapidly absorbed, with peak plasma concentrations (C_max) attained approximately 2–3 hours post‑dose. The absolute bioavailability is estimated at 65–70%, although inter‑individual variability may occur due to differences in gastrointestinal transit times and first‑pass metabolism.

Distribution

The drug exhibits moderate plasma protein binding, approximately 40–50%, largely to albumin. Volume of distribution is reported to be around 2–3 L/kg, indicating limited extensive tissue penetration. The distribution is not significantly altered in patients with mild to moderate hepatic impairment.

Metabolism

Vildagliptin undergoes limited hepatic metabolism. The primary metabolic pathway involves hydrolysis of the ester moiety, yielding an inactive carboxylic acid metabolite. Cytochrome P450 enzymes play a minor role, and the drug is not a significant inhibitor or inducer of major CYP isoforms. As a result, drug–drug interactions mediated through CYP pathways are infrequent.

Excretion

Renal excretion predominates, with approximately 80–90% of the administered dose eliminated unchanged via glomerular filtration and active tubular secretion. The terminal half‑life (t_1/2) is approximately 5–7 hours in individuals with normal renal function. Dose adjustments are recommended for patients with reduced creatinine clearance (CrCl) to maintain therapeutic exposure.

Half‑life and Dosing Considerations

Standard dosing involves 50 mg orally twice daily, which achieves steady‑state concentrations within 5–7 days. In patients with CrCl < 30 mL/min, a reduced dose of 25 mg twice daily is advised. The drug’s predictable pharmacokinetics and lack of significant accumulation make it suitable for long‑term therapy. No routine therapeutic drug monitoring is necessary.

Therapeutic Uses/Clinical Applications

Approved Indications

Vildagliptin is approved for the adjunctive treatment of adults with T2DM, either as monotherapy or in combination with other antidiabetic agents such as metformin, sulfonylureas, or insulin. The drug is indicated to improve glycaemic control, as evidenced by reductions in fasting plasma glucose and HbA1c levels. Its glucose‑dependent mechanism confers a low intrinsic risk of hypoglycaemia, which is particularly advantageous when combined with agents that carry a higher hypoglycaemic potential.

Off-Label Uses

While not routinely employed for other metabolic conditions, vildagliptin has been examined in small exploratory studies for the management of impaired glucose tolerance and prediabetes. However, evidence supporting efficacy in these populations remains limited, and such use is generally discouraged outside of clinical trials. Off‑label application in type 1 diabetes is also not supported by data, given the absence of endogenous incretin responses in this patient group.

Adverse Effects

Common Side Effects

The most frequently reported adverse events include mild gastrointestinal disturbances such as nausea, diarrhoea, and abdominal pain. Headache and upper respiratory tract infections (nasopharyngitis) have also been documented. These events are typically transient, resolving within a few days of therapy initiation.

Serious or Rare Adverse Reactions

Serious complications are uncommon but may involve hypersensitivity reactions, including rash, pruritus, and in severe cases, angioedema. Cases of acute pancreatitis, though rare, have been reported and should prompt immediate discontinuation if suspected. Additionally, gallbladder disease and cholelithiasis may develop, particularly in patients with pre‑existing biliary risk factors.

Black Box Warnings

Vildagliptin does not carry a formal black box warning; nevertheless, the safety profile necessitates vigilance for signs of pancreatitis or hypersensitivity. Clinicians should counsel patients regarding potential symptoms such as severe abdominal pain, persistent nausea, or fever. Monitoring pancreatic enzyme levels is not routinely recommended but may be considered in high‑risk individuals.

Drug Interactions

Major Drug‑Drug Interactions

Vildagliptin is not a significant inhibitor or inducer of the cytochrome P450 system, thereby reducing the likelihood of interactions via metabolic pathways. However, co‑administration with gliptins that share the same mechanism (e.g., sitagliptin, saxagliptin) may lead to additive effects on incretin levels, potentially increasing hypoglycaemic risk when combined with sulfonylureas or insulin. Concomitant use with medications that markedly alter renal clearance, such as nephrotoxic agents, could affect vildagliptin exposure.

Contraindications

Absolute contraindications include severe renal impairment (CrCl < 15 mL/min), hypersensitivity to vildagliptin or any of its excipients, and active pancreatitis. The drug should also be avoided in patients with severe hepatic dysfunction, given the potential for altered metabolism, although limited data exist in this subgroup.

Special Considerations

Use in Pregnancy/Lactation

Vildagliptin is classified as pregnancy category B, indicating that animal studies have not demonstrated fetal risk, but adequate human data are lacking. Limited case reports suggest no significant teratogenicity; however, the benefit‑risk ratio is uncertain in pregnancy. Lacking sufficient lactation data, the drug is generally not recommended during breastfeeding due to potential excretion into breast milk.

Pediatric/Geriatric Considerations

In pediatric patients, vildagliptin is not approved, and dosing regimens are not established. In geriatric populations, renal function often declines; therefore, dose adjustment based on CrCl is essential. No pharmacodynamic differences have been observed in older adults, but the risk of hypoglycaemia may increase when combined with insulin or sulfonylureas.

Renal/Hepatic Impairment

Renal impairment necessitates dose reduction. For patients with CrCl 30–60 mL/min, the recommended dose is 50 mg once daily. In CrCl < 30 mL/min, a 25 mg twice‑daily dose is advised. No adjustment is typically required for mild to moderate hepatic impairment; however, caution is advised in severe hepatic disease due to potential accumulation of inactive metabolites.

Summary/Key Points

• Vildagliptin is a DPP‑4 inhibitor that prolongs incretin activity, enhancing glucose‑dependent insulin secretion and suppressing glucagon release.
• It is absorbed rapidly with a bioavailability of ~65–70%, distributed moderately, and predominantly excreted unchanged via the kidneys.
• Standard dosing is 50 mg twice daily, with reductions based on renal function to maintain therapeutic exposure.
• Common adverse events include gastrointestinal symptoms and headache; serious events are rare but include pancreatitis and hypersensitivity reactions.
• Drug interactions are minimal, but additive hypoglycaemic risk may arise when combined with agents that lower glucose independently.
• Special populations such as pregnant women, lactating mothers, and patients with renal or hepatic impairment require careful consideration and, where appropriate, dose modification.

Clinicians should weigh the benefits of improved glycaemic control against the potential risks in individual patients, particularly those with compromised renal function or a history of pancreatitis. Ongoing surveillance and patient education remain integral components of effective vildagliptin therapy.

References

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8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.