#514 Hotcakes: Oral Semaglutide, Fish Oil in ESRD, IV Iron During Infection, New US Dietary Guidelines, & Anticoagulation after Ablation in AFib

February 16, 2026 | By Rahul Ganatra

Audio

Video

Transcript available via YouTube

Join us as we review and appraise recent practice-changing articles on oral semaglutide for obesity, fish oil in ESRD, IV iron during infection, the new US Dietary Guidelines, & anticoagulation after ablation in AFib. Fill your brain hole with a delicious stack of hotcakes! Featuring Paul Williams (@PaulNWilliamz), Rahul Ganatra (@rbganatra), Josh Gilman, & Matt Watto (@doctorwatto).

Claim CME for this episode at curbsiders.vcuhealth.org!

Patreon | Episodes | Subscribe | Spotify | YouTube | Newsletter | Contact | Swag! | CME

Show Segments

• Intro, disclaimer
• Oral Semaglutide for obesity
• Fish Oil for CV risk reduction in hemodialysis patients
• IV Iron for iron deficiency anemia during infection
• New USA Dietary Guidelines
• Anticoagulation after catheter ablation for AF
• Outro

Hotcake #1 Oral semaglutide for obesity (Watto)

Wharton S, Lingvay I, Bogdanski P, et al. Oral semaglutide at a dose of 25 mg in adults with overweight or obesity. N Engl J Med. 2025;393:1077–1087. doi:10.1056/NEJMoa2500969

What was the research question? In adults with overweight or obesity without diabetes, does once-daily oral semaglutide 25 mg, compared with placebo plus lifestyle intervention, lead to greater weight loss at 64 weeks?

Why is this study important? Injectable GLP-1 receptor agonists are effective but limited by access, need for refrigeration, and needle aversion. An effective oral option could meaningfully expand obesity treatment, particularly if efficacy approaches that of injectable semaglutide.

How was the study done? This was a phase 3, multicenter, double-blind, randomized, placebo-controlled trial at 22 sites in four countries. Participants were randomized 2:1 to oral semaglutide 25 mg daily or placebo, both with standardized lifestyle counseling (500-kcal/day deficit, 150 min/week activity). Dose was escalated over 12 weeks, then maintained to week 64, with follow-up to week 71. Coprimary endpoints were percent change in body weight and ≥5% weight loss at week 64. Analyses primarily used a treatment-policy (intention-to-treat) estimand with multiple imputation for missing data.

Who were the patients? Adults ≥18 years without diabetes, BMI ≥30 or BMI ≥27 with at least one obesity-related comorbidity. Mean age ~48 years; mean BMI ~37.6. The cohort was predominantly female (≈79%) and White (≈92%). About half had prediabetes at baseline. Key exclusions included diagnosed diabetes at screening.

Top-line results: This was a positive trial: at week 64, mean weight change was −13.6% with oral semaglutide vs −2.2% with placebo (between-group difference −11.4 percentage points; 95% CI −13.9 to −9.0; P<0.001). Clinically meaningful thresholds favored semaglutide: ≥10% loss in 63% vs 14%, ≥15% in 50% vs 6%, and ≥20% in 30% vs 3% (all P<0.001). Physical function (IWQOL-Lite-CT) improved more with semaglutide (mean difference +7.7 points). Gastrointestinal adverse events were common (74% vs 42% with placebo); serious adverse events were uncommon and similar between groups.

Learning points and limitations: Internal validity is strong: randomized, double-blind design with prespecified hierarchical testing. The primary analysis used ITT (treatment-policy) estimands, appropriately reflecting real-world discontinuation; hypothetical (per-protocol) estimands showed larger effects but are less clinically relevant. External validity is limited by a largely white female population and exclusion of patients with diabetes. There was no active comparator, so relative efficacy versus injectable semaglutide or higher-dose oral semaglutide cannot be determined. Cardiometabolic outcomes were secondary/exploratory and the trial was not powered for hard outcomes.

Bottom line: Oral semaglutide 25 mg daily produced substantial, clinically meaningful weight loss over 64 weeks compared with placebo, with expected GI side effects. For patients unwilling or unable to use injectables, this trial established a credible oral alternative, though long-term outcomes and comparative effectiveness remain unknown.

Hotcakes rating: 3.5 out of 5

Additional reading:

• Once-Weekly Semaglutide in Adults with Overweight or Obesity | New England Journal of Medicine
• Knop FK et al. Oral semaglutide 50 mg in obesity (OASIS 1). Lancet. 2023.

Hotcake #2 Fish oil supplementation and cardiovascular events in hemodialysis patients (Paul)

Lok CE et al. 2026.  Fish-oil supplementation and cardiovascular events in patients receiving hemodialysis.  N Eng J Med 394:128-137.

What was the research question? Do patients on hemodialysis benefit from supplementation with n-3 polyunsaturated fatty acids?

Why is this study important? Cardiovascular disease affects more than two-thirds of persons receiving hemodialysis and accounts for >75% of deaths in this population. Cardiovascular mortality is 20 times higher compared to the general population. However, there are few medical interventions with benefit in this patient population (e.g. RCTs have shown no benefit from statin initiation). The cardiovascular benefits of n-3 polyunsaturated fats in the general population is uncertain, with studies showing mixed results. 

How was the study done? Participants were randomized 1:1 to oral supplementation with fish oil (4g total of steam deodorized, citrus-flavored EPA and DHA) or a citrus-flavored corn oil placebo. The primary endpoint was a composite of all serious (fatal and nonfatal) cardiovascular events: death, MI, stroke, and PVD leading to amputation. Analysis of outcomes was done using the intention to treat principle, including all patients who took at least one dose of fish oil or placebo. Safety was assessed by monitoring bleeding events, and adherence was monitored in a subset of patients.

Who were the patients? 1,200 stable outpatients at 26 sites in Canada and Australia were enrolled. They had a mean age in the mid-60s, had ESRD on hemodialysis 3-4x/week, and could not have CHF or arrhythmias requiring ICDs. 

Top-line results: This was a positive trial: the rate of all serious cardiovascular events was about 40% lower in the fish oil group than in the placebo group (0.31 per thousand patient days vs 0.61 per thousand patient days; HR 0.57, 95% CI, 0.47 to 0.70; P<0.001) over 3.5 years.  Effects on secondary end-points including nonfatal CV events, PVD leading to amputation, nonfatal stroke, and death from any cause were in the same direction of the primary endpoint.

Learning points and limitations: This study was well done, and there are no clear sources of chance or bias threatening the authors’ conclusions–it seems like it should be practice-changing. Demonstrating a benefit despite low event rates in this study strengthens these findings (this patient population was somewhat less sick than typical ESRD patients in the US). Making sense of these results in the context of other studies of fish oil showing conflicting results is challenging. Possible reasons for the lack of consistent benefits in prior studies include heterogeneity in the types of omega 3 FAs (EPA vs EPA + DHA combos), the dose (earlier trials used <2g/day, while more recent trials used ~4g/day), and patient populations (primary vs secondary vs those with dyslipidemia or hypertriglyceridemia). 

Bottom line: This study gets a full stack not only for its excellent trial name, but I cannot find too much to complain about in a study that looks at a benign intervention in a high-risk population that was carefully done and showed good results. 

Hotcakes rating: 5 out of 5

Further reading:

• Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial – PubMed 
• Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia | New England Journal of Medicine 
• Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial | Cardiology | JAMA 

Hotcake #3 IV Iron during infection (Rahul)

Sohail H, Collins JE, Chan KH, Alamgir MA, Kamran AS. A retrospective, real-world study of iv iron use to treat iron deficiency anemia during acute infection. Blood. Published online January 27, 2026:blood.2025031965. 

What was the research question? Does IV iron in patients hospitalized with acute infections impact survival?

Why is this study important? Iron deficiency anemia (IDA) is common among inpatients, and prior data on the risk of IV iron and infection have been limited. Systematic reviews (e.g. Litton et al, 2013 and Shah et al, 2021) suggest a modest increase in infections after IV iron administration, raising concern about the safety of administration during active infections. As a result, the potential for harm of IV iron in the setting of acute infection is unknown.

How was the study done? This was a retrospective cohort study using data from TriNetX, a commercially available database of deidentified data from several healthcare organizations around the world. Patients hospitalized with IDA and acute infections (receiving antibiotics) were identified by ICD10 codes. Patients in the IV iron group received IV iron within 7 days of their index date; patients in the control group could not have received IV iron within 1 month before or 3 months after their index date. Propensity score matching was used to control for baseline differences, and survival (and other outcomes) was reported at 14 and 90 days.

Who were the patients? More than 300,000 patients from the database who were hospitalized with infections and IDA were included; these included patients with MRSA bacteremia, pneumonia, UTI, colitis, and cellulitis. Mean age was in the 50-60s. Comorbidities were common: diabetes and other anemias were present in half of patients, and CHF and CKD in more than a third. 

Top-line results: This was a positive study. From the paper: “Administration of IV iron therapy during acute infections was associated with improved 14- and 90-day survival.” The reported absolute risk reductions ranged from 1-4% at 14 days, and 3-6% at 90 days, with relative reductions of about 50%.

Learning points and limitations: There are at least three serious threats to the authors’ conclusions that decrease my confidence in these results: immortal time bias, residual confounding, and selection bias. Immortal time bias is the most serious. This occurs when an outcome (in this case death) cannot occur in one group during part of the follow-up period, which creates the appearance of benefit. In this study, for patients to be included in the IV iron group, by definition they had to survive for the duration of the period labeled “immortal time” in the figure below. If they died before they could receive iron, those deaths were counted for the no-IV-iron group. Also, residual confounding is virtually guaranteed because several clinically important covariates (e.g. white count, platelet count, coagulation parameters, measures of hepatic and renal function, etc) were not available for propensity matching, and finally, we do not know what population (if any) the TriNetX database is representative of, making selection bias a real concern. 

Bottom line: The lack of accounting for immortal time bias in the analysis prevents a causal interpretation of these results – confounding and bias could completely explain the author’s findings. As such, the use of causal language in the manuscript is unjustified. Even if IV iron is safe in acute infection, this study would not be able to show that. It is valuable only as a learning opportunity to identify this important source of bias in observational studies. 

Hotcakes rating: 1 of 5

Further reading:

• Immortal time bias – from the Center for Evidence Based Medicine catalogue of bias
• British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults – PubMed
• Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials – PubMed
• Risk of Infection Associated With Administration of Intravenous Iron: A Systematic Review and Meta-analysis – PubMed 

Hot take: Updated Dietary Guidance for Americans (Rahul)

U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2025-2030. January 2026. Available at: DietaryGuidelines.gov 

Summary: These guidelines, updated every 5 years, shape federally-funded nutrition programs that could potentially affect >40M people on SNAP and >30M kids participating in the National School Lunch Program. Many recommendations in the updated guidance are good: eating more “real foods” (fruits, vegetables, and whole grains) while limiting added sugars, refined carbs, and highly processed foods. However, recommendations concerning protein and fat are a departure from prior guidelines and are not supported by the accompanying scientific report. For example, these guidelines recommend healthy adults target 1.2-1.6 g/kg of protein per day, which is higher than the 0.8 g/kg recommended by the National Academy of Sciences, and doesn’t appear in the scientific report. This could be problematic because without resistance exercise, excess dietary protein gets converted to visceral adiposity. Finally, the healthy fat recommendations also lack sufficient detail: the guidelines list butter and beef tallow as “healthy fats,” but these are very high in saturated fats, which the guidelines recommend limiting to no more than 10% of total daily calories.

Bottom Line: As one editorialist pointed out in JAMA, the new guidelines effectively recommends against 70% the current food supply in the United States. Some recommendations make sense, while others are at odds with available evidence. Look for expert analysis to know how to counsel patients – the American College of Cardiology produced a good expert evidence synthesis, and the interactive “healthy eating plate” from the Harvard School of Public Health are both good resources to make sense of this confusing document.   

Further reading:

• The full DGA scientific report
• How Do the 2025-2030 Dietary Guidelines For Americans Measure Up For Cardiovascular Health? – expert analysis from the ACC
• Healthy Eating Plate • The Nutrition Source – separate dietary guidance from the Department of Nutrition of the Harvard T.H. Chan School of Public Health
• The 2025-2030 Dietary Guidelines for Americans – PubMed – editorial in JAMA

Hotcake #4: Anticoagulation After Catheter Ablation for AFib (Josh)

Kim D, Shim J, Choi EK, et al. Long-term anticoagulation discontinuation after catheter ablation for atrial fibrillation: the alone-af randomized clinical trial. JAMA. 2025;334(14):1246-1254.

What was the research question? After successful AFib ablation (without recurrence), is anticoagulation still beneficial? 

Why is this study important?  Evidence is limited to inform anticoagulation management after successful catheter ablation for Afib. The 2023 ACC/AHA AFib guidelines recommend using the CHADS2VASc score to guide long-term anticoagulation decisions after ablation (anticoagulating for CHADS2VASc ≥2 in men, ≥3 in women). Yet the guidelines note that there is a lack of any randomized data on this specific group of patients, and this recommendation is based on extrapolating data from patients who have not undergone ablation.

How was the study done? This was an open-label, multicenter, superiority randomized control trial at 18 centers in South Korea. Eligible patients had non-valvular AFib and a CHAD2VASc score ≥1 in men and ≥2 in women, and underwent ablation and were without recurrence for >1 year. Patients were randomized 1:1 to stop anticoagulation or continue it. The primary outcome was the first occurrence of a composite of stroke, systemic embolism, or major bleeding at 2 years. 

Who were the patients? 840 patients with a mean age of 64 were randomized. Among them, 75% were men and 65% had paroxysmal AFib; mean CHADS2VASc score was 2.1 (30% had score <2, 40% had a score of 2, 20% had a score of 3, and 10% had a score >3). The mean HAS-BLED score was 1.8. The majority of patients were on apixaban (78%).

Top-line results: This was a positive trial. The authors found that discontinuing anticoagulation >1 year after successful ablation led to lower rates of adverse events compared to continuing anticoagulation: at 2 years, the primary endpoint occurred in 1 of 417 patients in the discontinuation group compared to 8 of 423 patients in the anticoagulation group (0.3% vs 2.2%, ARR -1.9%).

Learning points and limitations: This was a well-done study without many sources of chance and bias that could threaten the authors’ conclusions. Especially in the era of wearables and smartwatches that can detect Afib, monitoring for recurrence after ablation is easier now than ever before. The low rate of events illustrates that these patients have a very low risk of stroke – much lower than predicted by CHADS2VASc scores, suggesting a new risk stratification tool is needed in this population. 

Bottom line: I think it’s a well designed trial, reproducible and highly applicable, and it sheds light onto the very low risk of stroke in post-ablation patients whose Afib does not recur. 

Hotcakes rating: 4.5 out of 5

Hot take: OCEAN trial (Josh)

The OCEAN trial complements the results of the ALONE-AF trial and also evaluated anticoagulation strategies after ablation for Afib. In OCEAN, patients were randomized >1 year after successful ablation to receive either rivaroxaban or aspirin and were followed for 3 years. The primary outcome was a composite of stroke, systemic embolism, or new covert embolic stroke found on MRI, which all patients underwent. The primary safety outcome was a composite of fatal and non-fatal major bleeding. This trial was negative: among 1,284 patients with a mean CHADS2VaSc of 2.2, there was no difference in the primary outcome or the safety outcome between the two groups. Coupled with the results of ALONE-AF, these results add additional evidence to the lower risk of stroke in post-ablation patients that remain free from atrial fibrillation. The risk of stroke seems to be well below the predicted risk based on the CHADSVASc score. So, my hot take is that the CHADS2VASc score may not be applicable to estimate the risk of stroke in very low-risk patients after successful catheter ablation.

Links

Links are included in the show notes above.

Goals

Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

1. Describe the efficacy and side effects of oral semaglutide for weight loss
2. Decide whether to prescribe fish oil for CV risk reduction in hemodialysis
3. Discuss immortal time bias in an observational study of IV iron administration

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Ganatra RB, Williams PN, Gilman J, Watto MF. “#515 Hotcakes: Oral Semaglutide, Fish Oil in ESRD, IV Iron During Infection, New US Dietary Guidelines, & Anticoagulation after Ablation in AFib”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list February 16, 2026.