From the Discovery of GLP-1 to Today’s Diabetes/Obesity Therapy and Beyond

Glucagon-like peptide-1 (GLP-1) was discovered as an insulinotropic peptide from the gut during a search for candidates for the incretin effect. It was found to also inhibit glucagon secretion and is now considered an important regulator of glucose metabolism. In further investigations of its physiological effects, GLP-1 also inhibited gastrointestinal secretion and motility and inhibited appetite and food intake. Because of these effects, GLP-1 was eventually shown to be able to improve glucose control and beta cell function in patients with type 2 diabetes mellitus (T2DM) and was even associated with weight loss. Because of a very short half-life in the circulation due to renal clearance and enzymatic degradation, stable analogs were developed allowing long-term treatment. Analogs suitable for weekly administration proved highly effective in improving glycemic control in patients with T2DM, and the analogs showed efficacy with respect to weight loss. Moreover, in cardiovascular outcome trials, the agonists were protective against major cardiovascular events and showed renoprotection and neuroprotection. Several observational studies also indicated protection against psychiatric illnesses and dementia. Thus, GLP-1 receptor agonists seem to be an effective weapon against the obesity-associated cardiovascular-kidney-metabolic syndrome affecting millions of patients.