GLP-1 is an incretin hormone that is released from the distal ileum in the small intestine and the colon within minutes of ingesting food. It has been shown to decrease glucagon secretion, increase glucose uptake and glycogen synthesis in the peripheral tissues, delay gastric emptying, and increase satiety.4
GLP-1 was first discovered in 1987 by Bernhard Kreymann and Stephen Robert Bloom, who were affiliated with the Royal Postgraduate Medical School Department of Medicine at Hammersmith Hospital in London, England.5 They established the insulinotropic actions of GLP-1 in humans and found that they were more effective than the glucose-dependent insulinotropic polypeptide (GIP) in stimulating insulin and reducing peak plasma glucose concentrations.4,6 In 2005, the FDA approved the first subcutaneous GLP-1 receptor agonist, exenatide (Byetta; Amylin Pharmaceuticals, Inc/Eli Lilly and Company), for the treatment of T2D. In the following years, more subcutaneous GLP-1 receptor agonists were approved for this indication, including liraglutide (Victoza; Novo Nordisk) in 2010, dulaglutide (Trulicity; Eli Lilly and Company) in 2014, lixisenatide (Adlyxin; Sanofi) in 2016, exenatide (Bydureon BCise; AstraZeneca) in 2017, and semaglutide (Ozempic; Novo Nordisk) in 2017. Semaglutide (Rybelsus; Novo Nordisk) was also FDA approved in 2019 as the first oral GLP-1 receptor agonist for T2D. Additionally, liraglutide (Saxenda; Novo Nordisk) and semaglutide (Wegovy; Novo Nordisk) were FDA approved in 2014 and 2021, respectively, to treat obesity. Tirzepatide (Mounjaro; Eli Lilly and Company), a combination GIP and GLP-1 receptor agonist, was FDA approved in 2022 to treat T2D and in 2023 to treat obesity.3
GLP-1 receptor agonists are known to possess positive cardiovascular effects. GLP-1 receptors are expressed on cells found in the cardiovascular system, including monocytes/macrophages, smooth muscle cells, and endothelial cells. Specifically, GLP-1 receptors are mainly expressed in the macrophage enrichment region of the atherosclerotic plaques. GLP-1 receptor agonists can prevent and stabilize atherosclerotic vascular disease by reducing the lipid deposition and plaque volume on the aortic surface by regulating markers of plaque instability and inflammation. These markers of plaque instability and inflammation include those linked to plaque hemorrhage, matrix turnover, cholesterol metabolism, and leukocyte recruitment. They can also alleviate the vascular remodeling after induced vascular injury by suppressing vascular smooth muscle cell proliferation and migration via the cAMP/PKA pathway. In addition, GLP-1 receptor agonists can reduce monocyte/macrophage accumulation in the arterial wall by inhibiting the adhesion of monocytes to activated endothelium in the arteries. This means that GLP-1 receptor agonists can limit and stabilize the development of atherosclerotic plaques through anti-inflammatory mechanisms and by preventing vascular remodeling, which ultimately can provide protective effects against major adverse cardiac events (MACEs). GLP-1 receptor signaling helps to control blood pressure through the tonic actions on the proximal tube sodium/hydrogen-mediated sodium reabsorption and the intrarenal renin-angiotensin II system. Further, GLP-1 receptor agonist treatment mediates renal vasodilation and attenuates renal autoregulatory responses, which can lower a patient’s blood pressure. Thus, GLP-1 receptor agonists can stabilize the atherosclerotic plaques, provide protection against MACEs, and lower blood pressure, which all produce beneficial cardiovascular effects for the patient.7
As the benefits of the GLP-1 receptor agonists with T2D, obesity, and cardiovascular health are becoming widely known, research into using these agents to treat other conditions has accelerated. Through these studies, potential new opportunities have risen to utilize GLP-1 receptor agonists to treat nonalcoholic fatty liver disease (NAFLD), Parkinson disease, Alzheimer disease, osteoarthritis, and chemical dependency.
