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摘要
Vildagliptin (Galvus (R)) is an anti hyperglycaemic agent that selectively inhibits the dipeptidyl peptidase-4 (DPP-4) enzyme. Such inhibition prevents the degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This results in improved glycaemic control as determined by glycated haemoglobin (HbA(lc)) and fasting plasma glucose (FPG) levels, and, in addition, an enhancement of pancreatic alpha- and beta-cell function. Vildagliptin is indicated in the EU and elsewhere in the world for the management of type 2 diabetes mellitus in combination with metformin, a sulfonylurea or a thiazolidinedione in patients with inadequate glycaemic control following monotherapy. Vildagliptin is also available as a fixed-dose formulation with metformin (Eucreas (R)).
Oral vildagliptin in combination with metformin, a sulfonylurea or a thiazolidinedione improved glycaemic control in adults with type 2 diabetes and appeared to slow the progression of beta-cell degeneration in trials of 24-52 weeks' duration. In trials in patients with diabetes inadequately controlled with metformin, vildagliptin provided an additional reduction of HbA(lc) levels of 1.1% and was shown to be as effective as pioglitazone as add-on therapy in a noninferiority trial. Vildagliptin had a low risk of hypoglycaemia, was weight-neutral overall and was generally well tolerated. Further investigation is required to accurately position vildagliptin relative to other, well established antidiabetic agents. However, the addition of vildagliptin expands the range of treatment options available, and as such, offers further potential for the management of patients with type 2 diabetes that is inadequately controlled with monotherapy.
Pharmacological Properties Vildagliptin is a rapid and selective inhibitor of DPP-4, the enzyme that is responsible for the inactivation of the incretin hormones GLP-1 and GIP, which play a key role in the maintenance of glucose homeostasis. The drug improves hyperglycaemia primarily by prolonging the half-lives of GLP-1 and GIP, and thus enhancing their action on islet cells, promoting glucose-dependent insulin secretion and suppression of inappropriate glucagon secretion. Additionally, vildagliptin appears to attenuate the decline in glucose-dependent beta-cell function and improve insulin sensitivity, and also to enhance the sensitivity of alpha-cells to glucose.
Vildagliptin is rapidly absorbed after oral administration, reaching peak plasma concentrations 1.5-1.7 hours after administration. Plasma concentrations of vildagliptin increase in an approximately dose-proportional manner; the absolute bioavailability of the drug is 85%. Systemic exposure to vildagliptin is unaffected by food intake, and the drug is distributed widely. Vildagliptin is predominantly metabolized in the kidney to inactive cyano and amide metabolites and approximately 85% of the drug is eliminated in the urine, with a terminal elimination half-life of approximately 3 hours following oral administration.
Therapeutic Efficacy In well designed monotherapy trials of 24-108 weeks' duration (n = 131-786), vildagliptin provided effective glycaemic control as assessed by the change from baseline in HbA(lc) and FPG levels relative to placebo. Vildagliptin was as effective as acarbose and rosiglitazone, but not metformin, in terms of lowering HbA(lc) when noninferiority criteria were met. A pooled analysis of data from five monotherapy trials (n = 1138) further confirmed that vildagliptin provided effective glycaemic control after 24 weeks of treatment.
In combination therapy trials of 24 weeks' duration in patients with type 2 diabetes for whom hyperglycaemia was inadequately controlled with prior metformin monotherapy, vildagliptin used as an adjunct to metformin provided better glycaemic control than placebo plus metformin (n = 416) and was as effective as pioglitazone plus metformin (n = 510) in improving glycaemic control in a noninferiority trial.
In other combination therapy studies also of 24 weeks' duration (n = 296-408), vildagliptin was more effective than placebo as add-on therapy to insulin, glimepiride or pioglitazone in patients with type 2 diabetes inadequately controlled by monotherapy despite receiving maximum effective doses.
Tolerability Vildagliptin was generally well tolerated as monotherapy and in combination with other antihyperglycaemic agents in adult patients with type 2 diabetes in clinical trials of up to 108 weeks' duration, with an adverse event incidence rate similar to placebo. The majority of adverse events were of mild to moderate severity and transient in nature. Hypoglycaemic events, weight gain and treatment-related discontinuations were rare. The most common adverse events reported for vildagliptin with a higher numerical frequency than placebo were nasopharyngitis, headache, dizziness and upper respiratory tract infection. It was also noted that vildagliptin reduced the occurrence of hypoglycaemic events associated with insulin therapy.
- 出版日期2008
