GLP-1 based therapy of obesity and type 2 diabetes

Abstract GLP-1 is 30-amino acid peptide that is secreted from the intestine in response to food intake. The release mechanism involves luminal exposure to as well as absorption and metabolism of the major nutrients. It functions mainly as a part of the ileal brake mechanism whereby nutrient entry in distal segments of the small intestine inhibit gastrointestinal secretion and motility as well as appetite and food intake, signalling nutritional abundance. It also functions as a second line incretin hormone. It acts on the brain via sensory vagal afferents, but also interacts with exposed neurons expressing the GLP-1 receptor in the circumventricular organs, in turn activating brain nuclei involved in appetite regulation and reward. High doses of GLP-1 cause nausea and vomiting, but slow dosing titration mitigates this. GLP-1 Receptor Agonists owe their actions to these physiological mechanisms and therefore represent powerful antidiabetic agents (A1c levels below 5.7%) and cause major weight loss (up to 20%), but also appear to reduce the systemic low-grade inflammation of obesity and type 2 diabetes and to exert beneficial action on the blood vessels, providing the GLP-1RAs with preventive effects on cardiovascular, hepatic, renal and central nervous system complications. Orally active GLP-1rAs have also been developed. It is emphasized that GLP-1RA therapy should be accompanied by lifestyle changes for efficacy and to prevent side effects of the weight loss. In addition, any prescription of a GLP-1RA should include a plan to mitigate adverse effects of treatment termination. Nevertheless, GLP-1RAs represent a major breakthrough in the therapy of metabolic disease and are now included among the essential medicines of the WHO.