Drugs on the horizon for treatment of type 2 diabetes.

The only new pharmaceutical therapy for Type 2 (non-insulin-dependent) diabetes that has become available for clinical use in the last 40 years is the alpha-glucosidase inhibitor, acarbose, which reduces postprandial glucose levels by retarding digestion of complex carbohydrates in the gut. It has proved difficult to find other new metabolically active drugs that lack toxicity. Agents that reduce insulin resistance include the thiazolidinediones, which are very effective in animals. Of these, the only one that has been maintained in clinical evaluation appears from preliminary data to have an effect that although still useful, is not greater than that reported for current oral agents. Agents that reduce non-esterified fatty acid levels by inhibiting lipolysis, thereby allowing increased peripheral uptake of glucose, have so far given minimal reduction in glycaemia. The development of fatty acid oxidation inhibitors to reduce gluconeogenesis in the liver has been hampered by toxicity, but additional new agents are being studied. The most promising new approach for enhancing insulin secretion has been suggested by the demonstration that pharmacological doses of GLP-1 (7-36 amide), a natural enteric incretin hormone, improves pancreatic beta-cell and alpha-cell sensitivity to glucose and can induce normal basal glucose levels in diabetic man. The future development of GLP-1 agonists will be of great interest. This is timely as other insulin secretogogues, such as alpha 2 adrenergic blockers have proved relatively ineffective. Anti-obesity agents would in theory be beneficial, but have either had limited efficacy or have been avoided because of concern about long-term safety. Until new pharmaceutical agents become available, if near-normal glycaemia is to be achieved, many more Type 2 diabetic patients will need insulin therapy. When full insulin replacement therapy is not feasible, reducing the fasting blood glucose level towards normal with a single daily basal insulin supplement, either alone or in combination with oral agents, could become a more widely used therapy.