A Review of Type 2 Diabetes Drug Classes

US Endocrinology, 2008;4(1):58-61

Both insulin and glucagon levels are influenced by incretin hormones: glucagon-like peptide-1 (GLP-1), which is secreted by the intestinal glucose-responsive neuroendocrine (L) cells of the intestinal mucosa after a meal, and glucose-dependent insulinotropic polypeptide (GIP), secreted by intestinal K cells that are mainly located in the jejunum and throughout the gut. Both incretins have a significant number of glucose-regulating actions, including exerting an insulinotropic effect—that is, a glucose-dependent secretion of insulin. GLP-1 not only stimulates insulin secretion and inhibits glucagon secretion under hyperglycemic conditions, but also slows gastric emptying and acts as a mediator of satiety in the central nervous system.2 The incretin effect is the phenomenon by which greater insulin secretion occurs after oral glucose intake than after the infusion of comparable amounts of intravenous glucose.3 In type 2 diabetes, exogenous GLP-1 can normalize blood glucose.4 Different classes of diabetes drugs act at different parts of this glucose–insulin pathway. They include agents that increase the amount of insulin secreted by the pancreas, increase the sensitivity of target organs to insulin, and decrease the rate at which glucose is absorbed in the gastrointestinal tract. The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have both stated that treatment for type 2 diabetes requires a progressive pharmacological approach to cover all of these aspects.5 Most existing antidiabetic drugs were developed without a prior definition of molecular targets. The advances being made in understanding the pathogenesis of type 2 diabetes and the molecules involved provide the opportunity to develop new treatment interventions.6 This article will review each class, examine the various compounds within them, and comment on their mechanisms of action.

Insulin Secretagogs

Sulfonylureas

Sulfonylureas were the first widely used oral antidiabetic treatments, having been available in the US since 1954. They trigger insulin release by acting directly on the KATP channel of the pancreatic b-cells.7 As insulin secretion is relatively deficient in type 2 diabetes, use of insulin secretagogues is logical for patients in whom the b-cell defect is not too advanced. Treatment with sulfonylureas has been shown to reduce glyclated hemoglobin (HbA1c) by approximately 1–2%.8 Furthermore, in the UK Prospective Diabetes Study (UKPDS) it was also associated with a significant reduction in microvascular complications, with a trend toward reduction in myocardial infarction but no significant effect on diabetesrelated or all-cause mortality.9

Sulfonylureas have the advantage of being available in multiple formulations at low cost with minimal side effects, and with demonstrated efficacy in controlling hyperglycemia. Sulfonylureas are approved for use as monotherapy and in combination with insulin and all other oral agent classes except the rapid-acting secretagogs.
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