Emerging Therapies Mimicking the Effects of Amylin and Glucagon-Like Peptide 1

Abstract

Current therapies for type 2 diabetes are frequently associated with inadequate control of postprandial hyperglycemia, weight gain, and, in the case of oral agents, loss of efficacy over time. A better understanding of physiological responses to meals is leading to the development of new agents whose therapeutic action is based on the enhancement of gastrointestinal hormone action. These therapies are associated with slowing of gastric emptying, stimulation of insulin and inhibition of glucagon secretion, improved control of postprandial hyperglycemia, and control of body weight. This review summarizes several limitations in the treatment of type 2 diabetes and describes the mechanisms of action and clinical data obtained with amylin and glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment of diabetes. Despite considerable effort by patients and physicians, the results of treating type 2 diabetes are often disappointing. This review examines the limitations of current antihyperglycemic therapies and assesses the potential of the emerging class of agents that mimic or enhance the actions of amylin and GLP-1, which are both gastrointestinal peptide hormones that in concert with insulin and glucagon regulate fuel homeostasis and eating behavior (1–4). Several agents from this class have been recently approved for clinical use or are in the advanced stages of development. Their mechanisms of action and therapeutic effects, as described in peer-reviewed publications, will be discussed. The evidence-based target for glycemic control is an HbA1c (A1C) ≤7% (5), although several groups have proposed an A1C target of 6.5% based on epidemiological analyses (6,7). In clinical trials, patients have achieved A1C values near 7% using basal-bolus insulin treatment in type 1 (8) or type 2 (9) diabetes or combinations of oral treatments and insulin for type 2 diabetes (10). However, routinely maintaining glycemic control at …