title: The development of an oral antidiabetic combination tablet: design, evaluation and clinical benefits for patients with type 2 diabetes.
abstract: Type 2 diabetes is a chronic and progressive disease. Oral antidiabetic monotherapies directly address only one defect as their primary mechanism of action, and do not control blood glucose sufficiently well to meet current glycaemic targets. In consequence, most patients need combination therapy within a few years. However, the co-administration of two or more oral antidiabetic drugs may render treatment regimens difficult to follow. Combining oral antidiabetic agents into a single tablet provides a means of intensifying antidiabetic therapy while supporting good patient compliance. An insulin sensitiser and an insulin secretagogue represent a rational oral antidiabetic combination, as they address the dual endocrine defects of insulin resistance and impaired beta-cell function in type 2 diabetes. Nevertheless, the components of a combination tablet must be carefully chosen. Metformin (an insulin sensitiser) and glibenclamide (an insulin secretagogue) are well supported by decades of clinical evidence, and the pharmacokinetics of these agents support twice-daily co-administration. The final technical challenge is to optimise their delivery within a single-tablet combination. A recently-introduced metformin-glibenclamide combination tablet (Glucovance) has been extensively studied in well-designed clinical trials, where it has been shown to be more effective than its component monotherapies in controlling fasting and postprandial glycaemia. This treatment provides a case study in the development of a single-tablet oral antidiabetic combination, in terms of the pharmacokinetic issues facing the development of this preparation, and the implications of the pharmacokinetic properties of the components of the combination tablet on their pharmacodynamic actions and risk-benefit profile.
authors.affiliation: Merck Santé, Lyon, France. hhowlett@merckpharma.co.uk
authors.forename: H
authors.initials: H
authors.lastname: Howlett
authors.forename: F
authors.initials: F
authors.lastname: Porte
authors.forename: T
authors.initials: T
authors.lastname: Allavoine
authors.forename: T
authors.initials: T
authors.lastname: Kuhn
authors.forename: G
authors.initials: G
authors.lastname: Nicholson
mesh_terms: D000284:Administration, Oral; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005905:Glyburide / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D008687:Metformin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013607:Tablets
chemical_list: D004338:Drug Combinations; C417231:Glucovance; D007004:Hypoglycemic Agents; D013607:Tablets; D008687:Metformin; D005905:Glyburide