The most common side effects of GLP-1 receptor agonists are nausea, vomiting, and diarrhea, though these tend to diminish over time. GLP-1 receptor agonists have minimal risk for hypoglycemia, but may increase the hypoglycemic potential of insulin and sulfonylureas when combined with those medications ( 118 ). Contrary to early signals, GLP-1 receptor agonists do not seem to substantially increase risk for pancreatitis, pancreatic cancer, or bone disease ( 119 ). They are associated with increased risk of gallbladder events ( 120 ). Semaglutide was associated with increased retinopathy complications in the SUSTAIN 6 trial (HR 1.76, 95% CI 1.11, 2.78), largely among those with baseline retinopathy who had rapid improvement of glycemic control ( 48 ). While this observation remains unexplained, this is also a recognized effect of intensification of glycemic control with insulin.

The contraindications and potential safety concerns of GLP-1RAs are included in Table 4.
The most frequently reported side effects of GLP-1RAs are nausea and vomiting (). These gastrointestinal symptoms are usually transient for longer-acting GLP-1RAs and can be mitigated by escalating the dose gradually () and educating patients to reduce meal size. GLP-1RAs may also increase the risk of gallbladder disease, including acute cholecystitis (,). Caution should be used in patients with prior gastric surgery (,). GLP-1RAs can lead to modest elevations in heart rate, although the clinical relevance of these effects is unclear (,,). GLP-1RAs are unlikely to cause hypoglycemia on their own, but they may increase the risk of hypoglycemia when used in combination with insulin or insulin secretagogues–most commonly sulfonylureas (). Although postmarketing case reports have suggested possible associations between GLP-1RAs and acute pancreatitis, none of the large trials has demonstrated any increase in the risk of pancreatitis (); that being said, patients at high pancreatitis risk were generally excluded from the trials. These agents should be discontinued if pancreatitis occurs. The FDA and the European Medicines Agency have not identified a link between this class of drugs and either pancreatitis or pancreatic cancer (). In the SUSTAIN-6 trial, diabetic retinopathy complications were reported with injectable semaglutide, although it is unclear if this is a direct effect of the drug or due to other factors such as rapid improvement in blood glucose control. Therefore, patients should be advised to undergo appropriate, guideline-recommended eye examinations before starting therapy if an examination has not been completed within the last 12 months ().

Glucagon-like peptide-1 receptor agonists (GLP-1RAs, incretin mimetics) and dipeptidyl peptidase-4 inhibitors (DPP-4is, incretin enhancers) are glucose-lowering therapies with proven cardiovascular safety, but their effect on microvascular disease is not fully understood. Both therapies increase GLP-1 receptor agonism, which is associated with attenuation of numerous pathological processes that may lead to microvascular benefits, including decreased reactive oxygen species (ROS) production, decreased inflammation and improved vascular function. DPP-4is also increase stromal cell-derived factor-1 (SDF-1), which is associated with neovascularisation and tissue repair. Rodent studies demonstrate several benefits of these agents in the prevention or reversal of nephropathy, retinopathy and neuropathy, but evidence from human populations is less clear. For nephropathy risk in human clinical trials, meta-analyses demonstrate that GLP-1RAs reduce the risk of a composite renal outcome (doubling of serum creatinine, eGFR reduction of 30%, end-stage renal disease or renal death), whereas the benefits of DPP-4is appear to be limited to reductions in the risk of albuminuria. The relationship between GLP-1RAs and retinopathy is less clear. Many large trials and meta-analyses show no effect, but an observed increase in the risk of retinopathy complications with semaglutide therapy (a GLP-1RA) in the SUSTAIN-6 trial warrants caution, particularly in individuals with baseline retinopathy. Similarly, DPP-4is are associated with increased retinopathy risk in both trials and meta-analysis. The association between GLP-1RAs and peripheral neuropathy is unclear due to little trial evidence. For DPP-4is, one trial and several observational studies show a reduced risk of peripheral neuropathy, with others reporting no effect. Evidence in other less-established microvascular outcomes, such as microvascular angina, cerebral small vessel disease, skeletal muscle microvascular disease and autonomic neuropathies (e.g. cardiac autonomic neuropathy, gastroparesis, erectile dysfunction), is sparse. In conclusion, GLP-1RAs are protective against nephropathy, whereas DPP-4is are protective against albuminuria and potentially peripheral neuropathy. Caution is advised with DPP-4is and semaglutide, particularly for patients with background retinopathy, due to increased risk of retinopathy. Well-designed trials powered for microvascular outcomes are needed to clarify associations of incretin therapies and microvascular diseases.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes mellitus. Recent research suggests that GLP-1 RAs may influence diabetic retinopathy (DR). We searched ClinicalTrials.gov for trials comparing FDA-approved GLP-1 RAs to placebo, insulin, or oral antidiabetic medicine. Rates of DR, ocular adverse events, demographics, and clinical characteristics were compared amongst cohorts on 93 trials. GLP-1 RA use was significantly associated with increased risk of early-stage DR (risk ratio (RR) = 1.31, 95% confidence interval (CI) [1.01, 1.68]) and early-stage retinal adverse events (RR = 1.29, 95% CI [1.01, 1.66]) compared to placebo. Compared to insulin, GLP-1 RA use protected against late-stage DR (RR = 0.38, 95% CI [0.15, 0.98]). Analysis of individual GLP-1 RAs showed that albiglutide is responsible for these trends, as it is significantly associated with a higher risk of early-stage DR (RR = 2.18, 95% CI [1.01, 4.67]) compared to placebo and a lower risk of late-stage DR (RR = 0.25, 95% CI [0.09, 0.70]) compared to insulin. Albiglutide similarly affected retinal and ocular adverse events. Demographic analysis revealed significant differences between GLP-1 RA and comparator groups for age, HbA1c, body weight, BMI, duration of diabetes, sex, race, and ethnicity. The influence of GLP-1 RAs on DR and the eye may depend on the specific GLP-1 RA and patient demographic and clinical characteristics.

Purpose: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are important therapeutic options for type 2 diabetes and obesity; however, concerns about ophthalmic safety persist. This study examined associations between GLP-1 RAs and ocular adverse events (AEs).

Design: Global observational pharmacovigilance study.

Methods: We searched the US FAERS database (via OpenVigil 2.1) and WHO's VigiBase (via VigiAccess) for optic nerve and retinal AEs associated with semaglutide and tirzepatide, covering the period from their respective approval dates-December 2017 for semaglutide and May 2022 for tirzepatide-through September 2024. In FAERS, all other drugs were compared, while in VigiBase, metformin, empagliflozin, dulaglutide, and insulin served as controls. Disproportionality metrics included reporting odds ratios (RORs) with 95% confidence intervals.

Results: Semaglutide and tirzepatide accounted for 76 444 cases (0.59%) in FAERS (n = 12 936 341) and 118 639 cases (0.34%) in VigiBase (n > 35 000 000). Semaglutide showed significantly higher odds of ischemic optic neuropathy (ION) (

Faers: ROR = 11.12, 95% CI = 8.15-15.16; VigiBase: ROR = 68.58, 95% CI = 16.75-280.67), diabetic retinopathy (DR) (

Faers: ROR = 17.28, 95% CI = 13.62-21.91; VigiBase: ROR = 7.81, 95% CI = 5.60-10.90), as well as retinal/vitreous detachment, retinal/vitreous hemorrhage, and retinal tear (

Faers: ROR = 2.44-5.89, 95% CI = 1.70-8.97, all P < .001, IC025 = 0.49, compared to all other drugs. VigiBase: ROR = 5.49-20.91, 95% CI = 2.71-90.11, all P ≤ .0001, IC025 ≥ 0.53, compared to metformin). Unique to VigiBase were macular edema (ROR = 3.87, 95% CI = 1.89-7.92), macular hole (ROR = 20.90, 95% CI = 2.65-165.01), and papilledema (ROR = 6.97, 95% CI = 2.53-19.17) (all P ≤ .004, IC025 ≥ 0.27, compared to metformin). Sensitivity analyses using empagliflozin and dulaglutide revealed significant associations with ION and DR, while vitreous detachment and hemorrhage were significant when compared to dulaglutide. Additionally, when insulin was used as a comparator, semaglutide showed a higher ROR for ION (ROR = 9.84, 95% CI = 4.25-22.81, P < .0001, IC025 = 0.42). However, tirzepatide was only significantly associated with DR in FAERS.

Conclusions: Given the widespread use of semaglutide, its association with ocular AEs highlight the need for global pharmacovigilance and post-marketing surveillance.

Aim: Recent findings have raised concern about a potential association between semaglutide use and non-arteritic anterior ischaemic optic neuropathy (NAION), a rare form of permanent vision loss. This report provides a critical analysis of the current knowledge of GLP-1 receptor agonist (RA) use and risk of NAION in patients with type 2 diabetes (T2D).

Methods: A literature search strategy was conducted for all English-language literature with a systematic review of key references up to April 2025.

Results: Across studies including patients with T2D, the relative increase in NAION risk associated with the use of a GLP-1 RA, mainly semaglutide, ranged from nonsignificant to fourfold, while the absolute number of affected patients remained low. Given the retrospective design of the main studies, no causal link could be established between the use of GLP-1RAs and NAION. Some mechanistic hypotheses have been put forward without any being formally demonstrated to date. The profound metabolic and haemodynamic changes induced by GLP-1RAs might be the trigger of NAION in predisposed patients with an optic "disc-at-risk", a potent anatomical risk factor easily detected by ocular examination.

Conclusion: Pending studies clarifying this risk, these findings call for cautious use of GLP-1 RAs, particularly in patients with ocular risk factors. Given the widespread use of GLP-1RAs, clinicians should be aware of this potential risk, without overshadowing the remarkable benefit of GLP-1RAs in patients with type 2 diabetes.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) medications have transformed the treatment of type 2 diabetes and obesity, with associated reductions in cardiovascular and nephrological complications. Semaglutide and tirzepatide are second-generation GLP-1RA medications approved by the Food and Drug Administration for the treatment of diabetes and obesity. The main associated adverse outcomes are gastrointestinal outcomes, including nausea, vomiting, diarrhea, gastroparesis, and constipation. Studies also reported potential associations of GLP-1RAs with thyroid C-cell tumors and pancreatitis.
Nonarteritic anterior ischemic optic neuropathy (NAION) is characterized by loss of vision caused by loss of blood flow to the optic nerve. Its prevalence is higher in patients with diabetes, obesity, hypertension, hyperlipidemia, cerebrovascular disease, and obstructive sleep apnea. Although the etiopathogenesis of NAION is not fully understood, decreased arterial perfusion of the optic nerve and the associated swelling and compression of the optic nerve are implicated. Several retrospective studies from 2024 and 2025 reported a potential association of semaglutide with NAION in patients with diabetes and patients with obesity. However, a meta-analysis of randomized clinical trials did not detect an association of GLP1-RA therapy, including semaglutide, with NAION. A rare condition, NAION has an incidence rate of 2.5 to 11.8 incidents per 100 000 individuals. These inconsistent findings may be due to limited sample sizes and different study designs. Importantly, it remains unknown if semaglutide or tirzepatide is associated with other optic nerve and visual pathway disorders. This study leveraged a nationwide, multicenter database of electronic health records (EHRs) of more than 118 million US patients to conduct rigorous target trial emulation in patients with type 2 diabetes to examine associations of semaglutide or tirzepatide with optic nerve and visual pathway disorders, including NAION.

Hayreh and Zimmerman have proposed that optic nerve swelling is a precursor to NAION. This hypothesis is supported by cases 2 and 3, with bilateral optic nerve swelling on presentation and case 8, with sequential optic nerve swelling. cases 3 and 8 occurred in the setting of significant reductions in HbA 1c level.

PAMM is a result of compromise of the deep capillary plexus of the retina with infarction of the inner nuclear layer. Despite recent concern that PAMM could be a result of giant cell arteritis (GCA), the patient in case 9 had no signs or symptoms of GCA. There are GLP1 receptors in a small number of neurons in the ganglion cell layer of the retina, but their function and the effect of GLP1-RA on these cells is unknown.

Papillitis can occur in patients with diabetes without infarction, but it is typically unilateral, and sequential papillitis, as in case 8, is unusual. Because of the association of diabetic papillitis and rapid correction of hyperglycemia, it is plausible that this patient’s clinical course was influenced by her use of semaglutide.

In a retrospective cohort study of NAION and semaglutide use at a single institution, an increased risk of NAION was demonstrated with a hazard ratio of 7.64 (95% CI, 2.21-26.36). In an accompanying editorial, Mollan suggested that rapid correction of hyperglycemia is one possible mechanism that could explain the increased incidence of NAION. In support of this hypothesis, dipeptidyl peptidase 4 inhibitors, also considered incretins, do not decrease blood glucose as rapidly as GLP1-RA and have not been associated with NAION to date.

In response to the retrospective study and its accompanying editorial, the American Academy of Ophthalmology has issued a press release for clinicians prescribing and patients using semaglutide. The Academy has not recommended that patients stop using semaglutide, but rather, that patients experiencing vision loss while taking semaglutide should stop the drug and contact the physician prescribing the medication.

Importance Semaglutide, a glucagonlike peptide-1 receptor agonist (GLP-1RA), has recently been implicated in cases of nonarteritic anterior ischemic optic neuropathy (NAION), raising safety concerns in the treatment of type 2 diabetes (T2D).

Objective To investigate the potential association between semaglutide and NAION in the Observational Health Data Sciences and Informatics (OHDSI) network.

Design, Setting, and Participants This was a retrospective study across 14 databases (6 administrative claims and 8 electronic health records). Included were adults with T2D taking semaglutide, other GLP-1RA (dulaglutide, exenatide), or non–GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from December 1, 2017, to December 31, 2023. The incidence proportion and rate of NAION were calculated. Association between semaglutide and NAION was assessed using 2 approaches: an active-comparator cohort design comparing new users of semaglutide with those taking other GLP-1RAs and non–GLP-1RA drugs, and a self-controlled case-series (SCCS) analysis to compare individuals’ risks during exposure and nonexposure periods for each drug. The cohort design used propensity score–adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The SCCS used conditional Poisson regression models to estimate incidence rate ratios (IRRs). Network-wide HR and IRR estimates were generated using a random-effects meta-analysis model.

Exposures GLP-1RA and non–GLP-1RAs.

Main Outcomes and Measures NAION under 2 alternative definitions based on diagnosis codes: one more inclusive and sensitive, the other more restrictive and specific.

Results The study included 37.1 million individuals with T2D, including 810 390 new semaglutide users.

Given that GLP-1 RAs can effectively and consistently reduce insulin resistance in patients with diabetes, these agents were anticipated to reduce the risk of nAMD in patients with diabetes through this mechanism. However, our analysis revealed the opposite: patients with diabetes who were exposed to GLP-1 RAs had a substantially higher risk of being diagnosed with nAMD, with a shorter time to diagnosis, compared with propensity-matched patients who were unexposed. These findings should be put into context of the known literature, as there have been numerous reports of unexpected worsening of diabetic retinopathy following a rapid reduction in blood glucose levels, occasionally resulting in permanent visual impairment in patients with insulin-dependent diabetes. Similar findings were observed in patients with diabetes in the SUSTAIN 6 trial, where Marso and colleagues found a higher risk of diabetic retinopathy complications with semaglutide compared with placebo. Notably, the authors reported an unexpectedly higher rate of retinopathy complications, such as vitreous hemorrhage, blindness, or the need for treatment (ie, with laser photocoagulation or an intravitreal agent), in patients randomized to the semaglutide group. At the same time, findings from clinical trials contradict those from experimental studies, the latter of which demonstrate that GLP-1 RAs may prevent the onset of diabetic retinopathy or dampen its progression via anti-inflammatory and anti-apoptotic pathways.
Our findings expand on the growing body of literature raising concerns regarding the potential ocular safety of systemic GLP-1 RA therapy in patients with diabetes. More recently, a retrospective matched cohort study of 16 827 patients with diabetes identified a substantially higher risk of nonarteritic anterior ischemic optic neuropathy in participants who were exposed to semaglutide. One possible explanation for this phenomenon is the exacerbation of underlying hypoxic mechanisms, which may contribute to the development of nonarteritic anterior ischemic optic neuropathy, as well as nAMD. GLP-1 RAs can cause a rapid systemic reduction in glucose levels, including in the retina, which may induce a temporary hypoxic state.

GLP-1 receptor agonists (GLP-1 RAs) are used extensively to treat diabetes or obesity. Semaglutide was first approved by Health Canada for the treatment of diabetes in 2018, but its use expanded substantially following its approval for obesity management in 2021. Beyond glucose homeostasis, GLP-1 RAs exhibit anti-inflammatory effects across various organs, suggesting potential benefits in treating inflammatory diseases.
At the same time, adverse events of GLP-1 RA therapy must be cautiously examined. Two major phase 3a trials, the PIONEER 6 and SUSTAIN 6 trials, which had follow-up durations of 24 and 20 months, respectively, explored the cardiovascular effects of GLP-1 RAs in patients with diabetes at high cardiovascular risk. The SUSTAIN 6 trial reported an increased risk of diabetic retinopathy complications compared with the placebo group, and the PIONEER 6 trial observed a 0.8% higher proportion of diabetic retinopathy cases. More recently, a retrospective matched cohort study of patients with diabetes identified a substantially higher risk of nonarteritic anterior ischemic optic neuropathy in participants who were exposed to semaglutide. It has been postulated that the rapid reduction in blood glucose levels triggered by GLP-1 RAs leads to a hypoxic state of the retina that promotes further abnormal angiogenesis. Given that the underlying pathogenesis of nAMD involves abnormal and excessive angiogenesis, we aimed to evaluate this hypothesis by investigating an association between systemic exposure to GLP-1 RAs and the incidence of nAMD using data from a population-based study.