GLP-1 Receptor Agonists

GLP-1 receptor agonists are a well-established class of glucose-lowering agents, with exenatide first approved to treat type 2 diabetes in 2005. ^[1] The class now includes agents injected twice daily, once daily, or once weekly, as well as a daily oral preparation of semaglutide, and later-developed agents such as semaglutide are characterized by greater efficacy on plasma glucose and body weight. ^[1] Owing to their effectiveness in reducing body weight, GLP-1 receptor agonists such as liraglutide and semaglutide have also been developed and approved for the treatment of obesity. ^[2]

All GLP-1 receptor agonists share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion, deceleration of gastric emptying, and a reduction in calorie intake and body weight. ^[1] They reduce body weight primarily through appetite suppression, modulating brain regions that control hunger and energy expenditure while peripherally enhancing insulin secretion, reducing glucagon release, and delaying gastric emptying. ^[3] Dual GIP/GLP-1 receptor agonism, as with tirzepatide, produces profound weight loss, glycemic control, and lipid lowering by pairing the anorexigenic mechanism of GLP-1 with the metabolic actions of GIP. ^[4]

In a meta-analysis of cardiovascular outcome trials, GLP-1 receptor agonist treatment reduced major adverse cardiovascular events by 12%, all-cause mortality by 12%, hospital admission for heart failure by 9%, and a composite kidney outcome by 17% in patients with type 2 diabetes. ^[5] A later meta-analysis found that GLP-1 receptor agonists reduced a composite kidney outcome by 18%, major adverse cardiovascular events by 13%, and all-cause death by 12% compared with placebo. ^[6] In a network meta-analysis of weight-lowering drugs, GLP-1 receptor agonists were among the most effective drugs for reducing weight, and semaglutide might be the most effective of the GLP-1 agonists. ^[7] Once-weekly semaglutide is efficacious for sustained weight loss in patients with overweight or obesity and without diabetes, though the risk of gastrointestinal adverse events was higher than with placebo. ^[8]

The most common side effects are gastrointestinal, including nausea, vomiting, and diarrhea, which are usually mild and occur in the first few weeks of treatment before reducing over time. ^[2] Use of GLP-1 receptor agonists was associated with an increased risk of gallbladder or biliary diseases, with a relative risk of 1.37, especially when used at higher doses, for longer durations, and for weight loss. ^[9] Randomized trial evidence indicates the occurrence of thyroid cancer is infrequent in individuals exposed to GLP-1 receptor agonists, with no conclusive evidence of an elevated risk. ^[10] Real-world studies show high discontinuation rates of 20% to 50% within the first year and frequent gastrointestinal disturbances, but no clear increase in the risk of severe events such as pancreatitis or pancreatic cancer. ^[11]