This year, GLP-1 receptor agonists have continued to make headlines for their transformative impact on metabolic health. From dramatically improving glyceamic control and promoting weight loss to reducing cardiovascular risk and offering potential benefits in conditions ranging from liver disease to neurodegeneration, these therapies are reshaping the landscape of type 2 diabetes and obesity management. Editorial board member Glenn D Braunstein (Cedars-Sinai Medical Center, CA, USA) highlights the latest advances, including dual- and tri-agonists, emerging oral formulations, and novel insights into both their benefits and unique challenges.

Glucagon-like peptide-1 (GLP-1) receptor agonists have revolutionized the treatment of type 2 diabetes mellitus and obesity. These agonists bind to G-protein-coupled receptors expressed in many tissues. They increase insulin synthesis and secretion from the beta cells of the pancreas, suppress glucagon, inhibit gastric, gallbladder and intestinal motility, enhance hepatic insulin sensitivity, and through an effect on the brain, decreases food intake. These physiological effects result in weight loss, improved blood sugar and glycohemoglobin levels, improvement in the lipid profile, and a decrease in blood pressure. As a class, they lower major adverse cardiovascular events like myocardial infarction, stroke, and death, improve cardiac parameters in patients with congestive heart failure, reduce atrial fibrillation-related events in obese patients, slows the progression of renal disease in both patients with diabetes and obesity, reduces obstructive sleep apnea, and decreases liver fat in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

In contrast to the individual GLP-1 receptor agonists, tirzepatide has a dual mode of action by binding to the GLP-1 receptor and also binding to the glucose-dependent insulinotropic peptide (GIP) receptor. GIP, another incretin, enhances insulin sensitivity and helps regulate lipid metabolism. The combination of these agonists leads to a greater weight loss than that seen with the monoagonists. Triagonists, which contain GLP-1 and GIP receptor agonists plus glucagon also are being tested. Glucagon reduces appetite, increases energy expenditure, increases insulin secretion, and increases lipid breakdown, while also enhancing hepatic glucose production. Triagonists show greater weight loss than mono- or dual-agonists.

Several preliminary studies have shown some efficacy of GLP-1 receptor agonists for neurodegenerative disorders such as Parkinson disease and Alzheimer disease, alcohol and other substance use disorders, and in polycystic ovarian syndrome. A reduction in obesity-related cancers like colorectal carcinoma also has been suggested.

Also on the horizon are oral GLP-1 receptor agonists (e.g. onforglipron) and combinations of GLP-1 receptor agonists and other glucose lowering agents such as amylin.

In addition to the common gastrointestinal side effects, two unique problems have emerged. The first has been termed “Ozempic face”,  which mimics accelerated skin aging with thinning of the skin and decreased elasticity and is due to the loss of facial fat resulting in wrinkles and sagging skin, and is primarily seen after rapid weight loss. Decreasing the rate of weight loss and use of cosmetic procedures such as fillers have been advocated to stabilize or reverse this adverse effect. The other problem is reduction of skeletal muscle mass, especially in older individuals with decrease in muscle mass at baseline. The loss of lean body mass is primarily seen in the first 3-6 months during the period of rapid weight loss. This problem can be mitigated by exercise and a high protein diet.

The recent drop in obesity rates in the United States has been attributed at least in part to the use of GLP-1 receptor agonists. As the price of these drugs decrease, and new more powerful agonists are approved, it is likely that the rates will drop further. It is also likely that we will see a reduction in bariatric surgery, as the weight loss seen with some of the newer formulations rival those seen with surgical procedures.

Disclosures: This short article was prepared by touchENDOCRINOLOGY in collaboration with Dr Braunstein. No fees or funding were associated with its publication. Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.