FDA Imposes Class-Wide NAION Label on GLP-1s on 10 Versus 5 Events

FDA Orders Class-Wide GLP-1 Label Update for Eye Condition Risk

The FDA has mandated a class-wide labeling update for all approved GLP-1 receptor agonists, including major drugs from Eli Lilly and Novo Nordisk, to include a potential increased risk of non-arteritic anterior ischemic optic neuropathy (NAION). This serious eye condition can lead to vision loss due to optic nerve swelling. The decision follows an FDA assessment, including a meta-analysis of 126 clinical trials involving 78,217 patients, which identified 10 probable NAION events in GLP-1 treated patients versus 5 in placebo, showing an incidence rate of 6.4 events per 100,000 patient-years for GLP-1s compared to 3.8 for comparators.

• Mandatory Label Change for NAION Risk: The FDA has ordered a class-wide label update for all approved GLP-1 receptor agonists to include a warning about the potential increased risk of non-arteritic anterior ischemic optic neuropathy (NAION). This condition, characterized by optic nerve swelling, can lead to permanent vision loss, often in one eye, and has been reported across all currently marketed GLP-1s.
• FDA's Comprehensive Assessment: The regulatory decision is based on a thorough FDA assessment, which included a meta-analysis of 126 clinical trials involving 78,217 patients. This analysis identified a higher incidence of NAION in GLP-1 treated patients (6.4 events per 100,000 patient-years) compared to comparators (3.8 events per 100,000 patient-years), formalizing a previously recognized safety signal.
• Industry Impact and Market Context: Despite the formalization of the NAION safety signal, BMO analysts anticipate limited risk to obesity coverage for companies like Novo Nordisk and Eli Lilly, citing the rarity of the incidence and the nature of the update as a 'Warnings and Precautions' addition rather than an indication restriction. This update comes as GLP-1s, including Lilly's tirzepatide and Novo's semaglutide franchises, continue to be top-selling drugs, generating billions in annual sales.

FDA's Assessment of NAION Risk Across GLP-1s

Gastrointestinal adverse events dominate the tolerability profile of once-weekly semaglutide 2.4 mg in adults with overweight or obesity. In pooled Semaglutide Treatment Effect in People With Obesity (STEP) 1-3 data for participants randomized to 68 weeks of semaglutide 2.4 mg (n = 2117) or placebo (n = 1262), events were more common with semaglutide, most frequently nausea (43.9% vs. 16.1% of participants), diarrhoea (29.7% vs. 15.9%), vomiting (24.5% vs. 6.3%) and constipation (24.2% vs. 11.1%). Most GI AEs with semaglutide were non-serious (99.5% of AEs), mild-to-moderate (98.1%), transient and occurred most frequently during/shortly after dose escalation, with 4.3% permanently discontinuing treatment for GI AEs, while in STEP 4 semaglutide 2.4 mg maintenance was well tolerated among 803 participants tolerating 20 weeks of semaglutide run-in. Mean weight loss with semaglutide 2.4 mg in STEP 1-3 was similar in participants without (9.6%-17.1%) versus with GI AEs (11.4%-17.7%), and mediation analysis found that of the additional 7.6%-14.4% weight loss with semaglutide versus placebo, <1 percentage point was mediated by GI AEs. Consistent mediation findings were reported in SUSTAIN 3, 7 and 10, where nausea/vomiting by week 12 or throughout treatment contributed minimally (<0.1 kg) to superior weight loss with semaglutide versus exenatide extended release 2.0 mg, dulaglutide and liraglutide 1.2 mg, with nausea/vomiting-mediated differences of 0.05 or 0.09 kg of 3.78 kg at EOT (SUSTAIN 3), 0.06 or 0.03 kg of 2.26 kg at EOT (low-dose comparison) and 0.08 or 0.04 kg of 3.55 kg at EOT (high-dose comparison) (SUSTAIN 7) and 0.05 or 0.09 kg of 3.82 kg at EOT (SUSTAIN 10).

Comparative and pooled data position tirzepatide with greater glycemic and weight efficacy and a comparable gastrointestinal adverse event profile to semaglutide at diabetes doses, alongside signals for biliary disease. In the open-label, 40-week phase 3 SURPASS-2 trial in 1879 patients with mean glycated hemoglobin 8.28%, mean age 56.6 years and mean weight 93.7 kg, estimated mean change in glycated hemoglobin was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide 1 mg, with estimated differences of -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), and greater reductions in body weight with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively), with hypoglycemia (blood glucose level, <54 mg per deciliter) in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group) versus 0.4% with semaglutide, and serious adverse events in 5 to 7% versus 3%. Adjusted indirect comparisons showed no statistically significant differences in odds of gastrointestinal AEs for tirzepatide 5, 10 and 15 mg versus semaglutide 0.5 mg, while meta-analyses linked tirzepatide to gallbladder/biliary diseases (RR = 1.52; 95%CI: 1.17-1.98) and cholelithiasis (RR = 1.67; 95%CI: 1.14-2.44), and to the composite of gallbladder or biliary disease versus placebo or basal insulin (RR 1.97, [95% CI] 1.14 to 3.42) without a significantly increased risk of pancreatitis (RR 1.46, [95% CI] 0.59 to 3.61). A network meta-analysis in 33,354 non-diabetic individuals with overweight or obesity found nausea, vomiting, diarrhea, and constipation were the most common gastrointestinal adverse effects, with all evaluated GLP-1 RAs increasing nausea risk, liraglutide, orforglipron, semaglutide, and tirzepatide increasing vomiting risk, and semaglutide and liraglutide increasing constipation risk.

Real-world use shows frequent deviation from titration schedules and high early discontinuation driven by tolerability interruptions and financial barriers. Among 15,811 commercially insured US adults starting semaglutide for weight management between June 2021 and December 2023, most deviated from the recommended monthly dose-escalation schedule within the first 5 months, and by the fifth month nearly one-half (46%) had discontinued treatment, with similar rates (48%) among those initiating after supply stabilization, with discontinuation rates increased from 41% in the lowest quintile ($1-$54 per month) to 51% in the highest quintile ($161-$1460 per month) and higher rates also associated with lower household income and education level. In a Danish primary care cohort of 206 individuals (76% women; mean age 48 years, standard deviation (SD) 13; mean baseline body weight 105 kg (SD 23.8)), 38% (n = 78) had permanently discontinued semaglutide at 12 months whilst 15% (n = 30) had temporarily discontinued (paused) semaglutide and approximately 48% (n = 98) remained on treatment, amongst whom 40% were treated with ≤ 1.0 mg/week, 30% with 1.7 mg/week and 30% with 2.4 mg/week, with relative mean body weight change after 12 months of -13.6 (95% CI -15.0 to -12.2)% in those who had not discontinued and had baseline and follow-up weight.

Unpacking the NAION Safety Signal for GLP-1s

Gastrointestinal adverse events are the most frequently reported safety signals across anti-obesity trials, particularly with GLP-1 receptor agonists such as semaglutide and tirzepatide, especially during dose escalation. These events are generally mild to moderate and resolve over time, while serious adverse events remain comparable to placebo or controls in large randomized datasets.

• Gastrointestinal events dominate tolerability: nausea, vomiting, diarrhea, and constipation are the most common side effects, generally emerging during dose escalation and resolving over time, with nausea 14.7-62%, vomiting 3-30.3%, and diarrhoea 5-34.9% reported across GLP-1-based therapies.

• Tirzepatide-specific GI risk estimates: versus placebo, nausea (relative risk [RR] 3.11; 2.74-3.54), vomiting (RR 5.94; 4.50-7.85), diarrhea (RR 2.92; 2.53-3.37), and constipation (RR 2.85; 2.38-3.42), with serious GI events (RRs 3.07; 2.03-4.66) and discontinuation due to adverse events (RRs 2.29; 1.74-3.01) significant, while serious adverse events were not statistically significant (RR 0.93; 0.76-1.13).

• Class-level GI and gallbladder increase: GLP-1 RAs increased gastrointestinal (GI; +63%) and gallbladder (+26%) disorders, with additional complications including cholelithiasis, cholecystitis, gastroparesis, and bowel obstruction, while in network analysis gastrointestinal adverse events increased with all treatments (RR 1.33-1.91).

• Rare serious and pharmacovigilance signals: rare gallbladder disorders and acute pancreatitis, injection-site reactions and worsening of pre-existing diabetic retinopathy, and although rare, associations with nonarteritic anterior ischemic optic neuropathy, pancreatitis, medullary thyroid carcinoma, and acute kidney injury (AKI) have been reported, primarily through pharmacovigilance and case-based evidence, with no differences in stroke, pancreatitis or neoplasm between groups in 21 trials encompassing 99,592 patients.

• Discontinuation and non-GLP-1 agents: treatment discontinuation was highest with semaglutide 7.2 mg (RR 3.09), with discontinuation generally <15% across GLP-1-based therapies, while orlistat commonly linked to steatorrhea and flatulence, and phentermine was associated with reduced GI motility.

Navigating the Evolving GLP-1 Treatment Landscape

The pharmacologic landscape has shifted from glucagon-like peptide-1 receptor agonists (GLP-1RAs), namely liraglutide, dulaglutide, albiglutide, exenatide, and semaglutide, found to have beneficial effects on glycated hemoglobin, weight, lipid profile, and liver fat, toward multi-receptor incretin co-agonists. Tirzepatide is a dual GIP/GLP-1RA, the first drug of the group to be approved for diabetes and obesity with remarkably lower gastrointestinal side effects compared to GLP-1 monoagonists, with mean weight loss of 21% at 72 weeks. Six medications are currently approved by the US Food and Drug Administration for long-term use: glucagon-like peptide receptor 1 (GLP-1) agonists (semaglutide and liraglutide only), tirzepatide (a glucose-dependent insulinotropic polypeptide/GLP-1 agonist), phentermine-topiramate, naltrexone-bupropion, and orlistat. The revolutionary triple agonists at the GLP-1, GIP, and Glucagon receptors have demonstrated the highest achievable weight loss with pharmacotherapy, with Retatrutide and Efocipegtrutide belonging to this novel group, while Orforglipron has a high weight loss efficacy (-15% weight reduction) and combinations of GLP-1 RA, GIP and glucagon RA (retatrutide) have shown WL efficacy closing on to that observed in bariatric surgery.

Metabolic bariatric surgery (MBS) was associated with a significantly higher reduction of HbA1c, diabetes remission and BMI compared with medical therapy, with complete diabetes remission significantly increased with all surgical procedures in comparison with non-surgical therapy, except for GCP, and only BPD, RYGB and OAGB associated with a significant reduction of BMI. Weight loss from metabolic and bariatric surgeries (ie, laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass) ranges from 25% to 30% at 12 months, and in the SADISLEEVE randomised, open-label, superiority trial at 2 years of follow-up, mean %EWL was statistically significantly higher in the SADI-S group compared with the RYGB group (-76·0% [SD 26·7] vs -68·1% [28·7], mean difference -6·72% [95% CI -12·64 to -0·80], p=0·026). Endoscopic approaches provide intermediate durability, with endoscopic procedures (ie, intragastric balloon and endoscopic sleeve gastroplasty) attaining 10% to 13% weight loss at 6 months, and in a prospective cohort, mean TBWL was 15.9% (95% CI, 11.7-20.5, p < .001) at 5 years after endoscopic sleeve gastroplasty and 90 and 61% of patients maintained 5 and 10% TBWL, respectively.

Lifestyle and maintenance data contextualize these efficacy gains, with multicomponent behavioral interventions often producing 5% to 10% weight loss, although weight regain occurs in 25% or more of participants at 2-year follow-up, and intensive lifestyle interventions generally achieving approximately 5% weight loss, but attrition and weight regain after programme completion are common. In the Tehran Lipid and Glucose Study framework, four trajectory groups of BMI from childhood to young adulthood were identified, including Normal weight (41%), Young adulthood overweight (36%), Early childhood increasing overweight and adulthood obesity (19%), and Early childhood increasing obesity (4%), with only Young adulthood overweight and Early childhood increasing obesity affected by the intervention (β=-0.52 and p = 0.018; β=-1.48 and p < 0.001, respectively). Randomized withdrawal trials, including Semaglutide Treatment Effect in People with Obesity (STEP) 4 and SURMOUNT 4, show that discontinuation of GLP-1-based therapy is consistently followed by rapid weight regain (typically observed within one year of withdrawal) and a decline in cardiometabolic benefits.