Long-acting GLP-1 analogs for the treatment of type 2 diabetes mellitus

Type 2 diabetes mellitus is characterized by insulin resistance, impaired glucose-induced insulin secretion, and inappropriately elevated glucagon levels which eventually result in hyperglycemia. The currently available treatment modalities for type 2 diabetes are often unsatisfactory in getting patients to glycemic goals, even when used in combination, and therefore many patients develop microvascular and macrovascular diabetic complications. Additionally, these treatment modalities are often limited by inconvenient dosage regimens and safety and tolerability issues, the latter including hypoglycemia, bodyweight gain, edema, and gastrointestinal intolerance. There is, therefore, a need for new and more efficacious agents, targeting not only treatment, but also prevention of the disease, its progression, and its associated complications. Recently, an entirely new therapeutic option for the treatment of type 2 diabetes has become available in the US (since October 2005) and in Europe (since May 2007): the incretin-based therapies. The incretin-based therapies fall into two different classes: (i) incretin mimetics, i.e. injectable peptide preparations with actions similar to the natural incretin hormones; and (ii) the incretin enhancers, i.e. orally available agents that inhibit the degradation of the incretin hormones in the body and thereby increase their plasma levels and biologic actions. This article focuses on the incretin mimetics and outlines the scientific basis for the development of glucagon-like peptide-1 (GLP-1) analogs, reviews clinical experience gained so far, and discusses future expectations for long-acting forms of GLP-1 analogs.