Treatment of Patients with Type 2 Diabetes Mellitus
Therapy for type 2 diabetes mellitus should aim to control not only fasting, but also postprandial glucose levels. Nateglinide, a d-phenylalanine derivative, restores postprandial early phase insulin secretion in a transient and glucose-sensitive manner without affecting basal insulin levels. As nateglinide is administered immediately before meals it provides greater lifestyle flexibility than agents that require patients to eat to avoid hypoglycemic events (e.g. long-acting sulfonylureas). In randomised, double-blind trials in patients with type 2 diabetes, nateglinide monotherapy (mealtime treatment of 120 mg three times daily) significantly improved long-term glycaemic control by significantly reducing glyated haemoglobin (HbA_1c) and preventing mealtime glucose spikes. The combination of nateglinide with insulin-sensitising agents, for example, metformin and thiazolidinediones, addresses the dual defects of loss of insulin secretion and insulin resistance to provide optimal management of type 2 diabetes, and more patients achieve HbA_1c goal with nateglinide combination therapy rather than with monotherapy with other oral agents. Nateglinide also restores early insulin secretion and reduces postprandial hyperglycaemia in prediabetic subjects with impaired glucose tolerance (IGT) and appears similarly effective in elderly and non-elderly populations with type 2 diabetes. It has an excellent safety and tolerability profile, with a low propensity to cause hypoglycaemia due to its transient, selective effect on early phase insulin secretion. Nateglinide as monotherapy or combination therapy is an effective option to reduce mealtime glucose in patients with type 2 diabetes. The results of ongoing research into its potential role in delaying progression to overt diabetes, and protecting against cardiovascular events, in prediabetic patients with IGT are awaited.

Estimates suggest that by the year 2025, diabetes mellitus will affect over 5% of individuals or 300 million people globally; this represents a significant drain on healthcare resources. Type 2 diabetes is characterised by defects in insulin secretion and insulin resistance. The resulting chronic hyperglycaemia is an independent risk factor for microvascular complications and for cardiovascular disease - the major cause of mortality and morbidity in patients with diabetes.

Epidemiological studies in Europe, the US and Asia have documented the independent prognostic importance of postprandial hyperglycaemia, a central feature of early diabetes and impaired glucose tolerance (IGT). Indeed, the Diabetes Epidemiology Collaborative analyses of Diagnostic Criteria in Europe and Asia concluded that 2-h postprandial glucose is a better predictor of premature death than fasting blood glucose. Other baseline data from the Nateglinide and Valsartan in IGT Outcomes Research (NAVIGATOR) study indicate that IGT may go undiagnosed in up to 31% of middle-aged patients at risk of cardiovascular disease. Accordingly, the monitoring and control of postprandial hyperglycaemia is an important aim of diabetes management. Postprandial hyperglycaemia and IGT can be detected following an oral glucose tolerance test; the latter is defined by the American Diabetes Association as a plasma glucose level of 7.8-11.1 mmol/l (145-200 mg/dl) 2 h after a 75-g glucose load. Current European guidelines for diabetes management include recommendations of the monitoring of postprandial hyperglycaemia and provide targets.

Insulin is normally excreted in a biphasic pattern, with basal secretion augmented by 'early phase' pulses triggered at mealtimes by postprandial glucose spikes. Postprandial hyperglycaemia is caused primarily by impairment of early phase insulin secretion, and the correction of this defect is an important determinant of long-term glycaemic control. While oral glucose-lowering treatment with metformin and thiazolidinediones corrects fasting glucose, these agents do not address the problem of mealtime glucose spikes that have been shown to trigger atherogenic processes.

Nateglinide, a d-phenylalanine derivative, is a rapid-acting secretagogue designed to restore early phase insulin secretion. Nateglinide improves glycaemic control in patients with type 2 diabetes, both as monotherapy and in combination with other oral glucose-lowering agents. This article reviews the latest published data concerning the cellular pharmacology, pharmacokinetics/pharmacodynamics and clinical efficacy and tolerability of nateglinide and discusses its current and future role in the management of type 2 diabetes mellitus and prediabetic IGT.