Digest 68: Taking a Look at Optic Neuropathy and GLP-1s

August 22, 2025 | By Nora Taranto

Welcome Back to The Curbsiders Digest!

In this issue, we take a look at optic neuropathy and GLP-1s, plus anticoagulants in the elderly, new primary aldosterone guidelines, and so much more! Effortlessly absorb important medical news, with our twice monthly newsletter featuring easily digestible analysis of the latest practice-changing articles, and of course…bad puns. 

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Issue 68

08/22/2025

Appetizers (to whet your appetite) 

Palate Cleanser (aka the melon part of the meal) 

The Main Course

A Digestif or two

Appetizers

Brought to you hot off the stove, from a variety of specialties. Delivered in super tasty, bite-sized morsels. 
-Jennifer DeSalvo MD, Joshua Gilman MD, Laura Glick MD 

• New Primary Aldosteronism Guidelines. Primary aldosteronism (PA) is a frequent—but underrecognized—cause of secondary hypertension and is associated with an increased risk of cardiovascular complications compared to essential hypertension. The Endocrine Society recently released an updated guideline (prior guidelines were released in 2016) of practical clinical recommendations. The guidelines specifically focus on expanding screening for PA and determining best treatment options (medical or surgical) for patients with PA, and ultimately recommend screening for PA in all patients with hypertension. Screening should involve obtaining a morning serum/plasma aldosterone concentration and plasma renin level (concentration or activity) to determine the aldosterone-to-renin ratio, as well as a serum potassium. The authors also provide guidelines for lab interpretation (Recommendation 3).  If diagnosed with PA, patients should receive prompt PA-specific therapy—which may be either medical or surgical—depending on patient preferences and probability of lateralization (likelihood of unilateral disease). If medical therapy is indicated, authors recommend prescribing mineralocorticoid receptor antagonists (MRAs) as the first-line option. (LG) 
• Anticoagulants in The Elderly. A new substudy of COMBINE-AF, just published in JACC aimed to evaluate clinical outcomes in frail, elderly patients switched from vitamin-K antagonists (VKAs) to direct-acting oral anticoagulants (DOACs).  COMBINE-AF is a collection of the 71,683 participants from the four major randomized trials of DOACs vs VKAs in patients with atrial fibrillation.  5,913 patients were considered elderly (age > 75), frail (based on a frailty index above the median) and on VKAs (“VKA-experienced”). Patients were randomized to standard-dose DOAC or to VKA. The elderly, frail group was compared to the remaining patients (n=52,721) in the study.  There was no difference in the primary outcome (composite of stroke or systemic embolic events) in the frail, elderly population between those on DOACs versus VKAs, and there was no difference in effect between the frail, elderly population and the rest of the population (HR 0.83 vs 0.81, p interaction = 0.75). There was also no difference in major bleeding in the frail elderly population between those on DOACs vs VKAs, but there was a reduction in bleeding among those on DOACs (compared to those on VKAs) in the rest of the population without those three criteria. There was a significant reduction in fatal bleeding and intracranial hemorrhage with DOACs in both the frail, elderly subgroup and the rest of the population. DOACs significantly increased GI bleeding in both groups, with a greater increase in the frail, elderly group. (JG) 
• One (Invasive or Conservative) Strategy To Rule them All? A new meta-analysis out of JAHA compared invasive vs medical (“conservative”) management of non-ST-segment-elevation myocardial infarction (NSTEMI) in patients > 70 years old. 7 randomized controlled trials (RCTs) were ultimately included in the analysis, with a total of 2,997 patients (1,489 managed invasively and 1,508 conservatively). All of the RCTs were open-label trials, and the average follow up was 47.1 months. There was no significant difference in all-cause mortality (27.9% vs 26.6%: RR 1.05; 0.94-1.18) between the invasive and conservative approach.  There was an absolute but not statistically significant difference in major adverse cardiac event (MACE) favoring the invasive group (28.3% vs 33.5%; RR 0.82, 0.68-1.00), and the invasive group also had a lower risk of recurrent MI and ischemia- driven revascularization. But there were no significant differences in cardiovascular mortality, major bleeding, stroke/TIA, or length of hospitalization between the invasive and conservative groups. These findings may help with individualized decision-making in older patients.  (JG)
• HOPE for stroke patients? The HOPE trial recently published in JAMA challenges the current boundaries of acute ischemic stroke management by exploring the safety and efficacy of intravenous thrombolytics beyond the standard 4.5 hour therapeutic window after stroke symptom onset. This multi-center, open-label, blinded end-point trial enrolled 372 patients who presented 4.5-24 hours after onset of acute ischemic stroke, with evidence of salvageable brain tissue identified on perfusion imaging. Participants with no initial plan for endovascular thrombectomy were randomized 1:1 to receive IV alteplase or standard medical treatment. Among the study participants (median age 72 years, 43% female), the primary outcome of functional independence by modified Rankin Scale at 90 days was achieved in 40% of participants in the alteplase group compared to 26% in the control group (adjusted risk ratio 1.52, 95% CI 1.14-2.02, P=0.004). Symptomatic intracranial hemorrhage within 36 hours occurred more frequently in the alteplase group (3.8% vs 0.5% in the control group).  90-day all-cause mortality was 11% in both groups. (JD) 
• Thread carefully with vancomycin therapy – A research letter recently published in JAMA Internal Medicine sheds light on the prevalence and harms of vancomycin use via midline catheters for outpatient intravenous antimicrobial administration. Among 3317 hospitalized patients prescribed IV antimicrobials via midline catheters from 2017 to 2024, 597 (18%) patients received vancomycin–compared to 2720 (82%) who did not. The vancomycin and non-vancomycin recipient groups had similar treatment duration, catheter dwell time, and consultation with infectious disease specialities. Vancomycin recipients had significantly higher rates of major device complications (4.5% vs 0.8% in non-recipients), with higher rates of catheter-related bloodstream infections (2.5% vs 0.3%; P<0.001) and catheter-related venous thromboembolism (2% vs 0.6%; P<0.001).  Device failure, defined as premature midline catheter removal due to any complication, was more prevalent in vancomycin recipients (16.9% vs 9.6%; P<0.001). These findings persisted in adjusted hazard models accounting for both patients and device characteristics. (JD)

Palate Cleanser

The melon part. To get rid of the taste of those pesky apps.  And to fill your brain with some fun facts.

If you’re also feeling plagued by the “social clock” highlighted on social media to travel, explore hobbies, get married, buy a home, start a family etc. by a specific timeline, know you’re not alone–and it’s never too late. In her recent article woven with familiar stories of sacrifice for a career in medicine, Dr. Tasia Isbell empowers clinicians to follow their own unique timeline “because the social clock was never made for us, and measuring ourselves against it only steals joy from a journey that deserves to be honored.” She reminds readers to redefine success as practicing physicians by shifting our focus from test scores to rediscovering ourselves outside of the workplace – “[it is] time to build a version of adulthood that’s not a checklist, but a mosaic – one made at your own pace.” Check out her article, “Feeling behind in life as a young doctor? You’re not alone,” to learn more!

– Jennifer DeSalvo MD 

The Main Course

Alyssa Mancini MD

For those prescribed semaglutide, keep an eye out for NAION
Nonarteritic anterior ischemic optic neuropathy (NAION), a condition involving injury and death of the optic nerve that often causes severe and irreversible vision loss, is the second most common cause of blindness from optic nerve damage. In 2016, Ophthalmology published a large retrospective longitudinal cohort study (over 1 million enrollees, mean age 64 years, mean follow up 7.8 years) in which 0.1% of participants developed NAION, with associated risk factors of hypertension, hypercoagulable states, older age, and end-organ involvement from type 2 diabetes.  Studies have also looked into NAION risk associated with certain medication use, such as phosphodiesterase inhibitors, with mixed results.  

Now, in the era of GLP-1 receptor agonists (GLP-1 RA), questions have arisen about the risk of NAION with these drugs.  In 2024, Hathaway et al. (JAMA Ophthalmology) published results of a retrospective, matched cohort study of >16,000 participants seen in a neuro-ophthalmology clinic between 2017 and 2023. This study found a higher risk of NAION in patients prescribed semaglutide compared with patients prescribed non-GLP-1 RA medications for diabetes or obesity/overweight.  Also in 2024, Grauslund et al. (International Journal of Retina and Vitreous) published a 5-year longitudinal cohort study of all persons with type 2 diabetes in Denmark between 2018 and 2024 (424,152 participants, median age 65 years, 0.05% developed NAION) and found that semaglutide exposure was associated with a higher risk of NAION in this cohort. But neither study had a proposed mechanism for this association, and the number of NAION cases was relatively small in both, with concerns about both selection bias and residual confounding (in particular related to condition severity in the Hathaway study and lack of information about smoking, blood pressure, or BMI in the Grauslund study). Meanwhile, another international retrospective study (Ophthalmology) by Chou et al. did not find an association between semaglutide and NAION. 

Now, JAMA Ophthalmology has published a research letter with results from an even larger (read: nearly 4 million participants) observational cohort study of Medicare enrollees that assessed the association of GLP-1 RA use with NAION.

Breaking it down:
This study, by Fung et al., included Medicare enrollees aged 65 years or older with type 2 diabetes who were prescribed antidiabetic medications between 2007 and 2021. Patients with giant cell arteritis or optic neuritis (both of which can mimic NAION) were excluded. The reference group included patients using comparable second-line antidiabetic drugs and excluded patients using insulin or only metformin (to exclude both the less severe and more severe ends of the diabetes disease spectrum). The study population included 3,845,171 patients with type 2 diabetes–of whom 15.1% were prescribed GLP-1 RAs (dulaglutide 6.6%, semaglutide 4.9%, liraglutide 4.2%, exenatide 2.1%) and 28.4% were prescribed other second-line antidiabetic drugs (excluding those using insulin or only metformin). During a median follow-up of 3.7 years, 7660 patients (0.2%) developed NAION.

Compared with the reference group (those treated with other second-line antidiabetic agents), the use of any GLP-1 RA was associated with an increased risk of NAION (HR 1.15, 95% CI 1.04-1.27), and the effect persisted when all other non-GLP-1 RA antidiabetic medications were used as the reference. When comparing individual GLP-1 RAs, two of four were associated with an increased risk of NAION – semaglutide (HR 1.39, 95% CI 1.13-1.72) and liraglutide (HR 1.25, 95% CI 1.08-1.45). Other risk factors for NAION in this cohort included male sex; White race; having dual eligibility (Medicare and Medicaid); rural residence; history of diabetic retinopathy, OSA, or CKD; and amiodarone use. Interestingly, age was not found to be a risk factor in this cohort (though the authors attribute this to the narrow age distribution in the study). The median time between initiation of GLP-1 RA use and incidence of NAION was 3.3 years.

So how concerned should we be? 
The findings of an association between semaglutide use and an increased risk of NAION in this latest larger cohort study align with those from prior observational studies and a very recent meta-analysis. But the effect size is smaller than in initial studies, and there are still notable limitations – including the use of diagnosis codes to identify NAION (which may lead to misclassification and either under or over detection of the outcome), and lack of information about onset/duration of type 2 diabetes.  

Ultimately, it’s hard to know exactly what to do with this data. An editorial by Brian VanderBeek helps to put many of these studies into context, noting uncertainty about the absolute risk of NAION across studies. He also points out the challenges of optimal study design to answer these questions,  given difficulty identifying appropriate active comparators with multiple GLP-1 RA indications and given how challenging it can be to propensity score match in these studies since one cannot balance for confounders that are incompletely captured. It also remains unclear which patients could be at highest risk of developing this complication, and whether this could be a class effect or an effect specific to certain GLP-1 RAs.  That said, given the rapidly increasing use of GLP-1 RAs to treat both type 2 diabetes and obesity, and the gravity of NAION, more research (in larger, rigorously designed studies) is urgently needed – and clinicians should be aware of this possible ocular event in patients on these agents. 

Read The Study Here!

Digestifs

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we’ve got a few nibbles!

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This week on The Curbsiders: What a Fun(gal) episode! Episode #495 with Dr. Andrej Spec is chock full of pearls about endemic mycoses (histo, blasto, and coccidiodes)–how commonly they’re missed, how to identify patients at risk for fungal pneumonias, and how to diagnose these tricky pathogens (talking to the ID lab early is the name of the game!). 

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The Curbsiders Digest

Issue 68

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed

Jennifer DeSalvo,  Josh Gilman,  Alyssa Mancini, Laura Glick,  and Nora Taranto report no disclosures.

Kate Grant reports no disclosures.  

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