Rapid-acting insulin secretagogues: a clinical need?

The history of achieving adequate insulin secretion in Type 2 diabetes has interesting parallels with Type 1 diabetes. Initial insulin secretagogue therapy involved short-acting sulphonylureas--tolbutamide being introduced 40 years ago--and early insulin therapy used unmodified (soluble) insulin. Subsequently, long-acting sulphonylureas and insulin were introduced, but more recently short-acting agents have become popular again. This approach was endorsed by the European non-insulin-dependent diabetes mellitus guidelines of 1989/1993. The trend at present is to match modern rapid-acting agents (such as repaglinide or the rapid-acting insulin analogues) to physiological meal-time insulin requirements in both types of diabetes. The fundamental reasons for tailoring therapy to meal-times fall into two categories: a pathophysiological rationale and a behavioural rationale. The pathophysiological rationale for tailoring treatment to mealtimes is based on the importance of restoring the mealtime insulin secretion profiles of patients with Type 2 diabetes to physiological levels to re-establish the tight control of blood glucose levels seen in healthy individuals. The behavioural rationale is derived from the observation that most people with Type 2 diabetes are overweight and would like to reduce calorie consumption, but that the risk of hypoglycaemia does not allow them to be flexible over their day-to-day calorie intake. These observations suggest that the matching of a meal-time pharmacodynamic profile to a patient's eating habits would provide a knowledge-based rationale for achieving good blood glucose control once dietary means alone are inadequate. Evidently, this can be usefully combined with other pharmacological approaches (insulin sensitizers or basal insulin). The need for combination therapy is increasingly likely as the defect in insulin secretion progresses.