Evaluating the Safety Profile of Glucagon-Like Peptide-1 Receptor Agonists: Adverse Events and Clinical Recommendations

Abstract

The rising global prevalence of obesity and its associated health problems necessitate effective intervention strategies. Historically, many anti-obesity medications have been developed and later withdrawn because of unfavorable adverse event profiles. By contrast, recently introduced glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) demonstrate remarkable efficacy for weight loss. Furthermore, they confer beneficial effects on cardiovascular and renal outcomes and metabolic dysfunction-associated liver disease. Despite these benefits, adverse events such as retained gastric content and pulmonary aspiration remain a concern. Consequently, this review summarizes current evidence and offers clinical guidance on GLP-1 RA-related adverse effects.

INTRODUCTION

The prevalence of obesity is increasing globally. The World Health Organization estimates that obesity more than doubled between 1990 and 2022, with approximately 890 million individuals affected by obesity in 2022.¹ Obesity is associated with several other health problems, such as hypertension, cardiovascular disease, type 2 diabetes mellitus (T2DM), dyslipidemia, and some types of cancer. To reduce these co-morbidities, guidelines recommend that individuals with obesity lose 5% to 10% of their initial body weight within 6 months of starting a weight-loss intervention. These interventions may include dietary changes, increased physical activity, behavior counseling, and the use of anti-obesity medications.²

Since 1890, various anti-obesity medications have been developed and subsequently withdrawn because of adverse events.³ Currently available long-term anti-obesity medications for adults include orlistat, naltrexone/bupropion extended release, liraglutide, phentermine/topiramate extended release, and semaglutide. Among these agents, the incretin-based therapies liraglutide and semaglutide demonstrate high weight-loss efficacy, in some instances comparable to that of bariatric and metabolic surgery. Furthermore, in addition to positive effects on glycemia and weight loss, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) also beneficially affect cardiovascular^4,5 and renal outcomes⁶ and have therapeutic potential in metabolic dysfunction-associated liver disease (MASLD).⁷ Trials investigating the effects of GLP-1 RAs on peripheral artery disease, Parkinson’s disease, and neurodegenerative disorders are ongoing.⁸ Although GLP-1 RAs have numerous beneficial effects, they also have adverse effects, which are a cause for concern. This article reviews the evidence on adverse effects associated with GLP-1 RAs and outlines the relevant clinical recommendations.

DELAYED GASTRIC EMPTYING

GLP-1 is associated with the ileal brake, a feedback mechanism that regulates gastric emptying so that the rate of nutrients entering the duodenum is balanced by the rate of nutrient absorption in the upper small intestine.⁹ GLP-1 decreases gastric emptying by inhibiting stomach peristalsis while increasing tonic contraction of the pyloric region.¹⁰ This mechanism improves glycemic control by slowing postprandial glucose absorption. However, users of GLP-1 RAs also report adverse gastrointestinal (GI) effects, including nausea and vomiting.^9,11 Traditionally, these GI symptoms were attributed to a delay in gastric emptying.¹² Although one study found that the presence of symptoms was not a direct indicator of delayed gastric emptying,¹¹ more recent evidence demonstrates a significant relationship between GI symptoms and residual gastric content, and suggests that ongoing gastric symptoms are predictive of increased residual gastric content measured by endoscopy.¹³

Although the prevalence of GI symptoms is different depending on the drug used, approximately 3.4% to 58.4% of GLP-1 RA users have experienced these effects.¹⁴ A cross-sectional study found that 56% of participants using GLP-1 RAs had increased residual gastric content, compared with only 19% of non-users, despite both groups following pre-procedural fasting guidelines before an elective procedure under anesthesia.¹⁵ Results from a retrospective study suggest that GLP-1-based therapy may increase the risk of retained gastric contents.¹¹ Although approximately 10% of patients had retained gastric contents, the risk was three times higher among GLP-1 RA users than for non-users. In addition to nausea and vomiting, retained gastric content resulting from delayed gastric emptying is a risk for aspiration pneumonia.¹⁶

ASPIRATION PNEUMONIA

Pulmonary aspiration during anesthesia is rare but potentially fatal. It occurs in approximately 1 in 3,000 to 4,000 elective procedures, is associated with significant morbidity, and represents the most common cause of anesthesia-related mortality.¹⁵ In terms of drug safety, semaglutide carries a warning to exercise caution regarding pulmonary aspiration during anesthesia or deep sedation because it delays gastric emptying. However, there are rare reports of aspiration occurring in these conditions despite adherence to preoperative fasting guidelines. Therefore, patients receiving semaglutide therapy are advised to discontinue the medication for an adequate period before any planned procedure or surgery.¹⁷ This advice applies not only to semaglutide,¹⁷ but also to liraglutide,^18,19 and insulin–liraglutide combination products.²⁰ Therefore, as part of the preoperative guidelines for GLP-1 RAs, a recommended withhold time is provided based on the half-life of each medication. Dulaglutide, which is administered at 0.75–1.5 mg once weekly, has a half-life of approximately 90 hours and a recommended withhold time of 27 hours. Liraglutide, which is typically given at 0.6–1.8 mg daily, has a half-life of about 13 hours and a withhold time of 39 hours. Semaglutide, which is administered at 0.25–1.0 mg once weekly, has a half-life of 160 hours and a suggested withhold time of 20 days.²¹

Preoperative assessment guidelines identify certain patients with a history of GLP-1 RA use as high risk. This includes patients on high doses or who have recently increased their dose, those who have recently initiated GLP-1 RA therapy, and those experiencing GI symptoms such as nausea, vomiting, or abdominal discomfort. These patients are considered high risk regardless of whether they have appropriately withheld the medication before the procedure or surgery. For these high-risk patients, a preoperative gastric ultrasound is recommended. If the gastric volume is less than 1.5 mL/kg, the procedure or surgery may proceed; if it exceeds this threshold, rapid sequence intubation should be considered, or the procedure should be delayed. For low-risk patients with a history of GLP-1 RA use who have withheld medication for an adequate period, the procedure or surgery can proceed without the need for a preoperative gastric ultrasound.²¹ The American Diabetes Association follows the recommendations of the American Society of Anesthesiologists (ASA). For GLP-1 RAs administered daily, the ASA advises withholding medication on the day of the procedure or surgery, whereas medication administered once weekly should be withheld for at least 7 days beforehand.²²

In the field of anesthesiology, several medical societies have jointly released modified summary recommendations for the perioperative use of GLP-1 RAs. The key points are as follows. (1) To standardize preoperative assessment for the risk of delayed gastric emptying, patients should be evaluated for any GI symptoms suggestive of this condition. Recent dose increases, high doses, and weekly administered agents may elevate this risk. It is also important to assess for other medical conditions, beyond GLP-1 RA use, that could contribute to delayed gastric emptying. (2) Based on the assessment, a selective preoperative care plan and shared decision-making are recommended. If there is no concern about delayed gastric emptying, GLP-1 RA therapy may be continued. If an elevated risk is identified, the following procedure should be implemented: (a) a liquid-only diet for at least 24 hours before the procedure, following the usual fasting guidelines and (b) if necessary, evaluate the feasibility of medication bridging if GLP-1 RAs need to be discontinued. (3) On the day of the procedure or surgery, reassess for delayed gastric emptying and mitigate any identified risks. If there is no concern, the procedure should proceed as planned. If the risk of delayed gastric emptying is elevated, the following procedure should be implemented: (a) consider point-of-care gastric ultrasound; (b) consider rapid sequence induction of general anesthesia if appropriate; and (c) minimize procedure cancellation whenever possible (Fig. 1).²³

Figure 1.

Modified summary recommendations to prevent aspiration pneumonia by the perioperative use of glucagon-like peptide 1 (GLP-1) receptor agonists (RAs).

GALLBLADDER DISEASE

Gallbladder motility is regulated by the vagus nerves and by gut hormones, including cholecystokinin (CCK), GLP-2, and fibroblast growth factor 19 (FGF19).²⁴ A study investigating the effect of liraglutide on the gallbladder showed that liraglutide treatment in people with obesity delayed gallbladder refilling compared with placebo. This effect was attributed to an increase in postprandial CCK concentration and a decrease in postprandial plasma concentrations of GLP-2 and FGF19.²⁵ Moreover, other GLP-1 RAs have been reported to decrease CCK-induced gallbladder emptying compared with placebo in healthy individuals.^26,27 Therefore, GLP-1 RA use may increase the risk of gallbladder or biliary diseases by inhibiting gallbladder motility and delaying gallbladder emptying, particularly in relation to the observed changes in CCK response.

Rapid weight loss, a common outcome of GLP-1 RA therapy, can further complicate this association and is itself a well-known risk factor for gallbladder disease.²⁸ Compared to the general population, bariatric surgery can lead to a five-fold increased risk of symptomatic gallstone disease.²⁸ A meta-analysis evaluating the risk of gallbladder and biliary disease showed that intensive weight management strategies increased the risk of a composite outcome (gallbladder or biliary disease, cholelithiasis, cholecystitis, and cholecystectomy) when compared with placebo or control groups.^29-31 This concern was first amplified by specific findings from cardiovascular outcome trials. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial reported adverse gallbladder event rates of 3.1% in the liraglutide group compared with 1.9% in the placebo group.³⁰ Furthermore, a comprehensive meta-analysis that investigated the association of GLP-1 RA use with the risk of gallbladder and biliary disease showed that these agents were associated with an increased risk of gallstones, cholecystitis, cholecystectomy, etc. This risk was higher when the drug was used at higher doses, for longer durations, and for weight loss.³¹ According to Son et al.,³² 500 to 600 mg/day of ursodeoxycholic acid is recommended for 6 months in patients undergoing bariatric surgery, as this period of rapid weight loss carries the highest risk for gallstone formation.^32,33 Therefore, physicians should be concerned about the increased risk of gallbladder or biliary disease associated with GLP-1 RA use and should consider ursodeoxycholic acid prophylaxis to prevent gallstone formation, especially in the context of rapid weight loss.

NON-ARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY

Non-arteritic anterior ischemic optic neuropathy (NA-AION) is one of the most important causes of blindness or severe visual impairment in middle-aged and elderly individuals. It is characterized by unilateral optic disc swelling and sudden, painless vision loss. NA-AION is generally believed to result from an ischemic infarction of the optic nerve head, although its exact pathogenesis remains unknown. It typically occurs in patients over the age of 50 who have small optic discs and vascular risk factors.³⁴ The estimated annual incidence in populations over 50 years old ranges from 2.3 to 10.2 cases per 100,000 people.³⁵ Although numerous treatment options have been proposed, there is currently no proven effective medical or surgical treatment or preventive measure for NA-AION.³⁴ Therefore, NA-AION remains a devastating condition that often leads to permanent visual disability.³⁵

In a study by Hathaway et al.,³⁵ NA-AION occurred in 20 patients in a semaglutide cohort and in three patients in a non-semaglutide cohort over 6 years. The 36-month cumulative incidence in the semaglutide group was 6.7%, compared with 0.8% in the non-semaglutide group, and the risk was particularly high during the first 12 months of therapy, with a 1-year cumulative incidence of 5.5%. Cox regression analysis suggested that semaglutide use was associated with an increased risk of NA-AION.³⁵ However, a large multinational cohort study including more than 37,000 patients with T2DM and 130,000 individuals with obesity found no significant association between semaglutide and NA-AION.³⁶ These discrepant findings may reflect important methodological differences between the two studies. Hathaway et al.³⁵ analyzed a relatively small single-center cohort derived from a tertiary ophthalmology practice, which may be more susceptible to selection bias and statistical instability due to the limited number of events. In contrast, the multinational analysis³⁶ used several large real-world databases encompassing a more diverse and generalizable population, with substantially greater statistical power. Variations in case ascertainment, population characteristics, and covariate adjustment may also have contributed to differences in the results. Overall, avoiding semaglutide solely because of concerns regarding NA-AION does not appear warranted, as its benefits in glycemic control and cardiometabolic health are likely to outweigh any potential risk.

In June 2025, the European Medicines Agency (EMA) concluded that NA-AION occurs in approximately 1 in 10,000 people taking semaglutide based on various study results. Therefore, the EMA recommended updating the product information for semaglutide medicines to include NA-AION as an adverse effect with a frequency categorized as ‘very rare.’ However, patients receiving semaglutide treatment are advised to contact their physician immediately if they experience sudden vision loss or a rapid deterioration in vision, and to discontinue semaglutide if NA-AION is confirmed.³⁷

DIABETIC RETINOPATHY

Diabetic retinopathy is a microvascular complication of patients with diabetes and a leading cause of blindness.³⁸ The issue of diabetic retinopathy associated with GLP-1 RA use was raised in the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN)-6 study, which investigated the effects of semaglutide on cardiovascular outcomes.³⁹ The primary outcomes (the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) were lower in the semaglutide group than in the placebo group. Although new or worsening diabetic nephropathy was lower, there was a higher incidence of diabetic retinopathy in the semaglutide group than in the placebo group.³⁹ This unexpected effect may be associated with the rapid glucose-lowering effect of semaglutide, because previous studies report that rapid glucose-lowering worsens retinopathy.^40,41 A meta-analysis to investigate the relationship between retinopathy outcomes and changes in glycemic control with GLP-1 RA treatment showed no significant association between GLP-1 RA use and retinopathy risk. However, there was a significant association with the Ln (odds ratio) for retinopathy, which increased by 0.77 for every 1% greater average reduction in glycosylated hemoglobin.⁴² This suggests that retinopathy status should be assessed when intensifying glucose-lowering therapy.

In these studies, retinopathy was not the primary outcome. Recently, Barkmeier et al.⁴³ investigated the relative risk associated with GLP-1 RAs on developing sight-threatening diabetic retinopathy in a retrospective observational study of T2DM patients with a moderate cardiovascular risk. The primary outcome was time to treatment for sight-threatening diabetic retinopathy. No difference in diabetic retinopathy following treatment with commonly prescribed GLP-1 RAs was found.⁴³ Currently, a study examining the effect of semaglutide on diabetic eye disease in patients with T2DM (Research Study to Look at How Semaglutide Compared to Placebo Affects Diabetic Eye Disease in People With Type 2 Diabetes [FOCUS] trial, NCT03811561) is underway and will provide more information about the link between GLP-1 RAs and retinopathy.⁴⁴ Overall, although there is a lack of evidence that GLP-1 RAs cause diabetic retinopathy, because these agents have a rapid glucose-lowering effect, they could transiently worsen diabetic retinopathy. Therefore, physicians should recommend that GLP-1 RAs users have regular checks for diabetic retinopathy. For patients at high risk, it may be better to check for the presence of diabetic retinopathy before starting GLP-1 RAs.

PANCREATITIS

In 2009, a small study showed that sitagliptin treatment in a transgenic rat model increased pancreatic ductal turnover, ductal metaplasia, septal fibrosis, and even necrotizing pancreatitis.⁴⁵ This suggests that incretin agents may promote acute pancreatitis through ductal hyperplasia and potentially increase the risk of pancreatic adenocarcinoma in chronic pancreatitis. However, human pancreatic GLP-1 receptors are expressed in insulin, somatostatin, and acinar cells, but not in ductal cells, indicating that incretin-based therapies are unlikely to promote ductal hyperplasia or duct-derived pancreatitis.⁴⁶ GLP-1 stimulates amylase secretion in pancreatic acini from wild-type mice, but this response is absent in GLP-1 receptor knockout mice.⁴⁷ Exenatide, a GLP-1 RA, acutely increases plasma amylase levels in humans with T2DM, particularly after a meal.⁴⁸ GLP-1 RAs are associated with higher rates of elevated serum amylase and lipase in patients with T2DM compared with controls, suggesting possible acinar hypersecretion or subclinical pancreatic inflammation.⁴⁹ GLP-1 receptor signaling in acinar cells induces mild growth-dependent acinar proliferation and constitutive pancreatic enzyme release, explaining enzyme elevations during GLP-1 treatment without indicating subclinical pancreatitis.⁵⁰ Mild elevations of lipase and amylase are common in patients with T2DM, occurring in up to 20%, which can complicate the evaluation for acute pancreatitis.⁵¹ Large observational data show that exenatide has an acute pancreatitis risk comparable to metformin or glyburide, demonstrating noninferiority with no increased risk.⁵² A large multinational cohort study across Canada, the United States, and the United Kingdom found that incretin-based drugs do not increase the risk of acute pancreatitis compared with other oral antidiabetic agents.⁵³ Meta-analysis of cardiovascular outcome trials shows no increased pancreatitis risk with GLP-1 RAs.⁵⁴ An updated meta-analysis of randomized controlled trials shows no association between GLP-1 RA (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) use and pancreatitis in patients with T2DM.⁵⁵ In a comorbidity-free United States-based population with T2DM, the use of GLP-1 RAs did not increase the risk of pancreatitis. The use of GLP-1 RAs was associated with a lower lifetime risk of pancreatitis.⁵⁶ Acute (within 6 months), chronic, or recurrent pancreatitis is an absolute contraindication to using liraglutide and semaglutide in major clinical trials.^57,58 However, a recent real-world study did not observe a higher frequency of acute pancreatitis with GLP-1 RA exposure in adults with T2DM and a history of acute pancreatitis, regardless of etiology.⁵⁹

PANCREATIC CANCER

Diabetes can induce chronic inflammation due to sustained hyperglycemia. Additionally, in animal models, incretin-based therapies cause low-grade chronic pancreatitis.⁶⁰ Such chronic inflammation and proliferative changes in pancreatic cells have raised concerns about the role of incretin-based therapies in pancreatic cancer development.⁶¹ However, a preclinical study reported that exendin-4 treatment in human pancreatic cancer cells did not cause cancer cell proliferation or inhibit apoptosis following exposure to cytotoxic agents, suggesting that GLP-1 RAs do not promote the growth or survival of human pancreatic cancer cells.⁶² According to a prospective cardiovascular outcome-focused meta-analysis published in 2020, there was no significant increase in the risk of pancreatic cancer associated with incretin-based therapies.⁵⁴ In an Israeli cohort study of diagnosed patients with T2DM, follow-up of those treated with GLP-1 RAs and basal insulin showed that the annual incidence of pancreatic cancer was higher in the basal insulin group than in the GLP-1 RA group.⁶³ A cohort study from the United States also demonstrated that the prevalence of pancreatic cancer was not higher in patients with T2DM treated with GLP-1 RAs than in those who were not.⁶⁴ A retrospective cohort study conducted in China and published in 2025 followed patients who had been prescribed either GLP-1 RAs or other antidiabetic medications between January 2013 and March 2019 for 5 years. The study reported that the risk of pancreatic cancer was significantly lower in patients receiving GLP-1 RAs than in those receiving other antidiabetic medications, and that combination therapy with GLP-1 RAs was associated with a lower risk of pancreatic cancer than monotherapy.⁶⁵

Overall, the existing evidence does not suggest that patients treated with GLP-1 RAs have a higher risk of pancreatic cancer than those receiving other therapies. Nevertheless, further studies and clinical trials are warranted to elucidate any underlying mechanisms and to confirm a causal relationship. Additionally, in patients with diabetes who present with poorly controlled hyperglycemia, unexplained weight loss, or other symptoms suggestive of pancreatic cancer, a diagnostic evaluation should be undertaken without delay. Regular screening or surveillance for pancreatic cancer may also be considered in such patients.

SARCOPENIA

Sarcopenia can have serious physiological and clinical consequences and is characterized by age-related loss of skeletal muscle mass, strength, and function.^66-68 Specifically, the criteria for sarcopenia are as follows: (1) low muscle strength; (2) low muscle quantity or quality; and (3) low physical performance. The presence of criterion 1 alone is defined as probable sarcopenia; if criteria 1 and 2 are present, sarcopenia diagnosis is confirmed; and if criteria 1, 2, and 3 are present, sarcopenia is considered severe.⁶⁹ GLP-1 RAs induce significant weight loss, and concerns have been raised regarding their impact on muscle mass. A meta-analysis evaluating the effects of GLP-1 RAs on various measures of muscle mass in individuals with obesity or overweight found that muscle mass accounted for less than 20% of total weight loss.⁷⁰ Although no studies have reported an evaluation of muscle strength in relation to the use of GLP-1 RAs, according to a recent systematic review and meta-analysis, bariatric surgery results in an average reduction in body mass index of 10.8 kg/m² and a mean decrease in lean mass of 7.4 kg without affecting hand grip strength.⁷¹ No studies have evaluated muscle function in relation to the use of GLP-1 RAs. When recent studies are considered collectively, skeletal muscle changes associated with GLP-1 RA treatment appear to be adaptive. Z-scores indicate that muscle volume changes are within the expected range when considering age, disease status, and the amount of weight loss achieved.⁷² In GLP-1 RA users, improvements in insulin sensitivity and reductions in intramuscular fat infiltration may be part of an adaptive process that enhances muscle quality while reducing muscle volume, and lowers the likelihood of loss of strength and function.⁶⁸

NEUROPSYCHIATRIC EVENTS

On July 11, 2023, the EMA issued a statement about links between GLP-1 RAs and suicide.⁷³ Since then, many studies have investigated GLP-1 RAs and suicide using various adverse event data sources, but data are not consistent.^74-77 Some studies found that GLP-1 RA use increased suicide risk,^75,77 while others did not.^78-81 Strumila et al.⁸² investigated the complex interplay between GLP-1 RAs and suicidal thoughts and behavior and tried to evaluate causality based on the Bradford Hill Criteria. They suggest that inconsistent findings may result from the definition of suicidality. The term suicidality can have various meanings, including suicide ideation, attempt, and completion, and studies have investigated different definitions of suicidality.⁸³

However, there are several reasons that suicide risk may be higher in patients using GLP-1 RAs. First, regardless of GLP-1 RA use, obesity is a risk factor for suicide. Individuals with a higher body mass index have increased suicidal ideation and greater feelings of perceived burdensomeness.⁸⁴ Second, rapid weight loss may mediate the connection between GLP-1 RAs and suicide, which is supported by the observation that bariatric surgery, the most effective treatment for weight loss, increases the risk of suicide.⁸⁵ Cohort studies, including the Swedish Obese Subjects study and the Scandinavian Obesity Surgery Registry, showed nonfatal self-harm events and death by suicide were higher in the surgery group than in the control group.⁸⁶ These studies also suggest several possible mechanisms, including high prevalence of mental health diseases, psychiatric and psychotropic medication use, undiagnosed mental health issues, alcohol and substance use, and frustration caused by unmet weight loss. Third, biological stress may increase suicide risk,⁸⁷ including the stress of a low-calorie diet and a dysregulated cortisol system. Finally, the failure of medication-induced changes to meet high expectations might result in disappointment and, in extreme cases, possibly suicidal ideation.

Although there are many possible mechanistic links, when applying the Bradford Hill Criteria to assess a direct causal link between GLP-1 RAs and suicidality, there is insufficient evidence to meet the criteria.⁸² Indeed, in 2024, the EMA reported that there was no evidence suggesting a link between GLP-1 RAs and suicidal thought and behavior.⁸⁸ In addition, a recent systematic review of the effects of GLP-1 RAs on suicidality concluded that there is inadequate information to ascertain whether causality exists.⁸⁹ Nevertheless, practitioners prescribing GLP-1 RAs should be vigilant of the emergence of suicidal ideation and be aware of the higher risk of mental illness in people who are candidates for GLP-1 RAs.⁸⁹

ABUSE/MISUSE

As interest in GLP-1-based drugs has increased, they have been promoted on social media by influencers and celebrities,^90,91 which has sparked the misuse and abuse of these drugs, especially in those who want to use them in the absence of obesity and T2DM. Chiappini et al.⁹¹ analyzed the Food and Drug Administration Adverse Event Reporting System in 2018 and 2022. They reported a 6% off-label use of GLP-1 RAs, whereas ‘drug abuse,’ ‘drug withdrawal syndrome,’ and ‘prescription drug used without a prescription’ were reported >3.5 times as frequently, and ‘intentional product use issue’ was reported almost twice as frequently in 2022 than in 2018. These results suggest semaglutide may be associated with increasing levels of abuse and misuse. Another report showed a higher frequency of semaglutide off-label use than for other comparators in adverse drug reactions documented in the EudraVigilance database.⁹² Therefore, several medical agencies have issued warnings over off-label use.^93,94

The phenomenon of drug misuse and abuse for weight loss is related to image and performance-enhancing drugs used to alter physical appearance and/or performance, such as anabolic androgenic steroids, human growth hormone, and weight-loss drugs.⁹¹ The celebrity-driven narrative surrounding GLP-1 RAs has likely transformed their public image from a critical medical intervention for T2DM and obesity into a cosmetic product for physical enhancement. This interest could result in a shortage of these drugs, making them unavailable to those who need them for obesity and T2DM. Therefore, policies to optimize the use and distribution of GLP-1 RAs are needed.⁹⁵

CONCLUSION

GLP-1 RAs demonstrate high efficacy in lowering glucose levels and promoting weight loss. Their benefits extend beyond glycemic control to cardiovascular outcomes, diabetic kidney disease, and MASLD. However, clinicians must be mindful of rare but serious adverse events, such as pulmonary aspiration and NA-AION. Furthermore, the increased susceptibility of people with obesity to mental illness warrants careful consideration (Table 1, Fig. 2). Clinicians should ensure appropriate patient education and multidisciplinary monitoring strategies to mitigate these rare but serious adverse events. Finally, there is a need to ensure that these medications are not used for unapproved indications and to establish policies that prioritize access for those who will benefit most.

Table 1.

Summary of adverse events associated with GLP-1 RAs and associated recommendations

Adverse event	Current evidence	Recommendation(s)
Delayed gastric emptying	About 10% of patients have retained gastric contents.	Before a procedure or operation, assess gastrointestinal symptoms and follow the recommendations based on retained gastric contents (delayed gastric emptying)
Aspiration pneumonia	GLP-1 RA use increases the risk of peri-anesthetic pulmonary aspiration, rare but potentially severe, leading to major anesthesia issues.	1. For GLP-1 RAs administered daily, withhold medication on the day of the procedure or surgery; for GLP-1 RAs administered once weekly, withhold medication for at least 7 days before the procedure (American Diabetes Association) 2. Modified summary of recommendations from a multisociety consensus regarding the perioperative use of GLP-1 RAs: (1) To standardize preoperative assessment for the risk of delayed gastric emptying, patients should be evaluated for any gastrointestinal symptoms suggestive of delayed gastric emptying. (2) Based on the assessment, a selective preoperative care plan and shared decision-making are recommended. If there is no concern about delayed gastric emptying, GLP-1 RAs therapy may be continued. If an elevated risk is identified, the following procedure should be implemented: (a) a liquid-only diet for at least 24 hours before the procedure is recommended, following the usual fasting guidelines, and (b) if necessary, evaluate the feasibility of medication bridging if GLP-1 RAs need to be discontinued. (3) On the day of the procedure or surgery, reassess for delayed gastric emptying and mitigate any identified risks. If there is no concern, the procedure should proceed as planned. If the risk of delayed gastric emptying is elevated, the following procedure should be implemented: (a) consider point-of-care gastric ultrasound; and/or (b) consider rapid sequence induction of general anesthesia if appropriate; and (c) minimize procedure cancellation whenever possible.
Gallbladder disease	Up to 3% of patients have gallbladder disease.	Physicians should be concerned about the increased risk of gallbladder or biliary disease associated with GLP-1 RA use and should consider ursodeoxycholic acid prophylaxis to prevent gallstone formation, especially in the context of rapid weight loss.
Non-arteritic anterior ischemic optic neuropathy	Categorized by the European Medicines Agency as very rare	If patients experience sudden vision loss or a rapid deterioration in vision, they should contact their physician immediately; if NA-AION is confirmed, semaglutide should be discontinued.
Diabetic retinopathy	Lack of evidence	Physicians should recommend regular checks for diabetic retinopathy. For patients at high risk, it may be better to check for the presence of diabetic retinopathy before starting GLP-1 RAs.
Pancreatic cancer	Lack of evidence; further studies and clinical trials are warranted.	In patients with poorly controlled hyperglycemia, unexplained weight loss, or suggestive symptoms, a prompt diagnostic evaluation is suggested. Regular screening or surveillance is recommended in high-risk patients.
Pancreatitis	GLP-1 RAs do not increase the risk of acute pancreatitis.	GLP-1 RAs can be safely used in most patients, including many with a history of pancreatitis, while avoiding initiation only in those with very recent acute pancreatitis and using clinical monitoring rather than enzyme-based decision-making.
Sarcopenia	No studies have investigated the link between muscle function and GLP-1 RAs.	Sarcopenia risk should be monitored in patients receiving GLP-1 RAs, especially older patients or those with rapid weight loss. Although current evidence suggests that muscle loss is proportionally small and largely adaptive, periodic assessment of muscle strength and function is advised, and resistance exercise and adequate protein intake should be encouraged.
Neuropsychiatric events (suicidality)	Lack of causal evidence	Be aware of the higher risk of mental illness in people who are candidates for GLP-1 RAs.
Abuse/misuse		Follow drug indications and optimize use and distribution policies.

GLP-1 RA, glucagon-like peptide 1 receptor agonist; NA-AION, non-arteritic anterior ischemic optic neuropathy.

Figure 2.

Benefits and safety concerns of glucagon-like peptide 1 (GLP-1) receptor agonists (RAs). HbA1c, glycosylated hemoglobin.