#484 Hotcakes: Vitamin D3, Omega-3 Fatty Acids, and Physical Performance, Gabapentin and Falls, Gepotidacin for UTI, and Intermittent Fasting for Weight Loss

May 26, 2025 | By Rahul Ganatra

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Join us as we review recent practice-changing articles on the effect of vitamin D₃ and omega-3 fatty acids on physical performance, gabapentin and falls, gepotidacin for uncomplicated UTI, and intermittent fasting for weight loss. Fill your brain hole with a delicious stack of hotcakes! Featuring Paul Williams (@PaulNWilliamz), Rahul Ganatra (@rbganatra), special guest Laura Glick (@LauraRGlick) and Matt Watto (@doctorwatto).

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Show Segments

• Intro, disclaimer
• Vitamin D3 vs omega-3 fatty acids and physical performance
• Gabapentin vs duloxetine and risk of falls
• Gepotidacin vs nitrofurantoin for uncomplicated UTI
• Intermittent fasting vs daily calorie restriction for weight loss
• Outro

Hotcake #1 Vitamin D₃, Omega 3’s, & physical performance (Watto)

Chou SH, et al. Effects of Supplemental Vitamin D3, Omega-3 Fatty Acids on Physical Performance Measures in the VITamin D and OmegA-3 TriaL. J Clin Endocrinol Metab. 2024 Dec 18;110(1):e44-e53. doi: 10.1210/clinem/dgae150. PMID: 38488491; PMCID: PMC11651677. 

What was the research question? Does daily supplementation with vitamin D₃ (2000 IU) or marine omega-3 fatty acids (1 g) over 2 years improve physical performance in older adults, compared with placebo?

Why is this study important? Observational studies suggest vitamin D or omega-3 supplementation might enhance muscle strength and function (e.g. walking speed) — which has some biologic plausibility. Vitamin D receptors are present in muscle and omega-3 fatty acids favorably affect inflammation, protein synthesis, and protein degradation. However, well-designed randomized trials supporting these benefits are lacking.

How was the study done? This was a substudy of patients from the VITAL trial (25,000 people followed for a median of five years), which tested whether vitamin D and omega 3’s reduced the incidence of cancer and heart disease; that was a negative trial, published in NEJM in 2019.

Who were the patients? 1,054 generally healthy older adults (mean age in the mid 60s) in the Boston area who were NOT vitamin D deficient and who were able to attend 2-year and 4-year follow-up visits.  

Top-line results: This was a negative trial: neither vitamin D₃ nor omega-3 fatty acids improved grip strength, walking speed, balance, chair stands, or Timed-Up and Go (TUG) scores over two years. Notably, even in subgroup analyses stratified by age, sex, BMI, or baseline vitamin D/omega-3 levels, the null results held firm.

Learning points & limitations: Deciding whether this could be a false negative is challenging because the authors don’t justify the sample size or estimate the proposed effect size. Without this information, it is impossible to assess whether this negative result could be due to the study being underpowered for this comparison. There was also some crossover with vitamin D: almost half of people in the placebo group reported taking their own vitamin D supplement, both of which are sources of chance favoring a negative outcome. That said, serum vitamin D and omega 3 levels clearly went up, so it seems reasonable that if there was a big effect on any of the physical parameters studied, this study would have found them. 

Bottom line/Hotcakes rating: Vitamin D is over-hyped and overprescribed. Based on the well-done VITAL trial and this ancillary study, Vitamin D does not improve muscle function or prevent frailty. 3 out of 5 

Further reading:

• Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease | New England Journal of Medicine

Hotcake #2 Gabapentin and Falls (Paul)

Assessing the Risk for Falls in Older Adults After Initiating Gabapentin Versus Duloxetine | Annals of Internal Medicine

What was the research question? Does initiating gabapentin in patients with neuropathic pain or fibromyalgia increase the risk of falls compared with duloxetine?

Why is this study important? Gabapentin is widely used and associated with many potential harms. The potential for falls is an especially worrisome outcome in older adults, and carries significant morbidity and mortality.

How was the study done? This retrospective cohort study used a target trial emulation framework and a new user, active comparator design. Patients in the IBM MarketScan database who filled prescriptions for gabapentin or duloxetine for diabetic neuropathy, postherpetic neuralgia, or fibromyalgia were identified using claims data. The primary outcome of any fall-related visit was assessed using ICD-9/ICD-10 codes through a maximum of 6 months. Stabilized inverse probability of treatment weighting (a technique similar to propensity score matching) was used to account for baseline differences between groups.

Who were the patients? Among 57,000 patients (mean age, mid-70s), 52,000 were new gabapentin users and 5,000 were new duloxetine users. There were many differences between groups at baseline, but these were generally well-balanced in the authors’ analysis.

Top-line results: Over a maximum of 6 months of follow-up, incident gabapentin users had a lower hazard of falls (HR 0.52 [95% CI, 0.43 to 0.64]) compared with duloxetine users. There was no difference in secondary outcomes reflecting severe falls.

Learning points & limitations: This was a well-done study with multiple design features (active comparator, new user design, use of negative controls, alternate definitions of the primary outcome, and varying exposure windows) that increase our confidence in these findings. Despite this, residual confounding by indication (i.e., physicians avoid gabapentin in patients at greatest risk of falls) is almost certainly contributing, and the short duration of therapy (on average 4 – 6 weeks in both groups) could obscure a real relationship between gabapentin and fall risk. 

Bottom line/Hotcakes rating: I’ll give this study 4 out of 5 hotcakes, because it’s so important and the design is interesting.  But there are some limitations in the design, so I am not yet fully convinced gabapentin is safe or even safer than duloxetine in the long term, although it seems like short-term use of a low dose may be safe.

Hotcake #3 Gepotidacin (Rahul)

Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials – The Lancet

What was the research question? Is gepotidacin (JEP-oh-TIE-dah-SIN) noninferior to nitrofurantoin for treating uncomplicated UTI (that is, simple cystitis) in adolescent and adult women?

Why is this study important? Gepotidacin received FDA approval in March 2025 for treatment of women aged 12 and older with uncomplicated UTI caused by susceptible organisms. This is the first new antibiotic for this indication approved in almost 30 years. Gepotidacin is a novel antibiotic that works by inhibiting DNA gyrase and topoisomerase IV (at different sites from fluoroquinolones) and blocks bacterial DNA replication. 

How was the study done? This paper reports the results of two non-inferiority trials that were identical except for collection of pharmacokinetic data and post-treatment ECGs in different subgroups. Patients had to be enrolled within 4 days of symptom onset, and they were then randomized 1:1 to take either gepotidacin 1,500 mg twice daily for 5 days, or nitrofurantoin 100 mg twice daily for 5 days. Symptoms were assessed by interview over 4 visits, and urine was collected for culture at baseline and test-of-cure at the end. The primary analysis population was limited to people with nitrofurantoin-susceptible organisms to level the playing field. 

Who were the patients? A total of 3,100 patients receiving care (from GPs, OB/gyns, or urologists) at 219 outpatient sites in 18 countries were randomized. The mean age was in the low 50s, mostly in Europe and the Americas, 85% were white. About 40% of women had a history of recurrent UTIs. Only about half of patients ended up having a nitrofurantoin-susceptible pathogen, 90% of which were E. coli, followed by small amounts of klebsiella pneumoniae, citrobacter freundii, staph saprophyticus, and enterococcus faecalis.

Top-line results: EAGLE-2 and EAGLE-3 were both positive noninferiority trials (and in addition, EAGLE-3 was positive for superiority). In both trials the non-inferiority margin was 10%, and both trials were stopped early for efficacy. In EAGLE-2, gepotidacin led to “therapeutic success” at 10-13 days, defined as complete symptom resolution plus a 2-log or greater reduction in uropathogen colony counts on test of cure, in 51% (vs 47% with nitrofurantoin). In EAGLE-3, the numbers were 59% with gepotidacin vs 44% with nitrofurantoin, a 15% difference that met criteria for superiority as well as noninferiority. Adverse effects were mild, with diarrhea occurring in 15-20% and nausea in about 10% of patients on gepotidacin, compared with ~5% each for nitrofurantoin. Rates of C diff were low (<1%), but all 8 cases of C. diff were among patients receiving gepotidacin.

Learning points & limitations: There are a few design features and sources of chance and bias that bias towards equivalence. For example, limiting the primary analysis to people with nitrofurantoin-susceptible isolates reduces power, and using a very stringent primary outcome of complete symptom resolution plus microbiologic test of cure reduces event rates, both of which probably bias towards equivalence. On the other hand, this was not a highly selected population, and the restriction of the primary analysis to nitrofurantoin-susceptible isolates is necessary to avoid bias towards superiority of gepotidacin, so the net direction of bias is hard to estimate.

Bottom line/Hotcakes rating: I’m excited to have more options for uncomplicated UTI, but with comparable efficacy to nitrofurantoin and more side effects at likely higher cost, I wouldn’t say “the eagle has landed” just yet. 3 out of 5

Further reading:

• https://pubmed.ncbi.nlm.nih.gov/28373199/ – 2017 phase 2 trial of IV dosing for SSTI, it didn’t really work.
• https://pubmed.ncbi.nlm.nih.gov/29617982/ – 2018 phase 2 trial of PO dosing for urogenital gonorrhea, a single dose did work for this, it is in a phase 3 trial now.
• https://clinicaltrials.gov/study/NCT04484740 – phase 1 trial of PO dosing penetration into tonsils and prostate (e.g. for pharyngeal gonorrhea and prophylaxis for prostatectomy) – stay tuned.
• https://clinicaltrials.gov/study/NCT01934205 – phase 1 study of IV dosing PK on plasma and pulmonary levels (e.g. for pneumonia and BSI) – stay tuned. 

Hotcake #4: Intermittent Fasting (Laura)

Victoria A. Catenacci, Danielle M. Ostendorf, Zhaoxing Pan, et al. The Effect of 4:3 Intermittent Fasting on Weight Loss at 12 Months: A Randomized Clinical Trial. Ann Intern Med. [Epub 1 April 2025]. doi:10.7326/ANNALS-24-01631. 

What was the research question? Does 4:3 intermittent fasting with comprehensive behavioral support result in more weight loss at 12 months than daily calorie restriction?

Why is this study important? Prior studies have not shown a consistent weight loss advantage for intermittent fasting over daily calorie restriction. However, intermittent fasting may lead to better adherence because it provides more flexibility compared with daily caloric restriction.

How was the study done? In this single-center open-label RCT, overweight or obese adults were randomized to a 4:3 intermittent-fasting (IMF) diet (reduced calorie intake by 80% on 3 non-consecutive days + no restrictions on the other 4 days) or a traditional daily calorie-restricted (DCR) diet (a 34% daily calorie reduction). Both groups also enrolled in a high-intensity comprehensive weight loss program (behavioral support, counseling, and a gym membership). The primary outcome was change in body weight at 12 months. 

Who were the patients? 165 adults (75% women, mean age 42, mean BMI 34 kg/m2) at a single-center in Denver, Colorado were enrolled. Patients were highly educated and relatively affluent. There was differential loss to follow-up: 20% of the IMF group dropped out compared with 30% of the DCR group. 

Author’s claim/Top-line results: This was a positive trial: at 12 months, participants in the IMF group lost more weight on average than those in the DCR group: 7.7 kg vs. 4.8 kg. Both groups also had improvements in secondary outcomes (systolic blood pressure, cholesterol levels and fasting glucose levels) with point estimates favoring the intermittent fasting group. 

Learning Points & Limitations: This being a single-center study among fairly healthy, educated, and affluent patients (who all also enrolled in a comprehensive weight loss program) raises concern that the results may not generalize broadly. For a highly motivated / not very ill population, it seems like 4:3 IMF allows people to achieve greater weight loss through greater percentage caloric restriction than DCR (maybe through higher adherence / less dropout), but questions remain about the impact on lean mass and physical activity. 

Bottom line/hotcakes rating: Consider 4:3 intermittent fasting as an alternative to daily calorie restriction for weight loss, as it may result in greater weight loss and better adherence. 3.5 out of 5

Additional reading:

• Ezzati A, Rosenkranz SK, Phelan J, Logan C. The Effects of Isocaloric Intermittent Fasting vs Daily Caloric Restriction on Weight Loss and Metabolic Risk Factors for Noncommunicable Chronic Diseases: A Systematic Review of Randomized Controlled or Comparative Trials. J Acad Nutr Diet. 2023;123(2):318-329.e1. doi:10.1016/j.jand.2022.09.013.

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. State the impact of Vitamin D supplementation on physical performance
2. Identify limitations in the evidence on whether gabapentin increases fall risk 
3. Discuss the evidence supporting gepotidacin for uncomplicated UTI

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Ganatra RB, Glick LR, Williams PN, Watto MF. “#484 Hotcakes: Vitamin D3, Omega-3 Fatty Acids, and Physical Performance, Gabapentin and Falls, Gepotidacin for UTI, and Intermittent Fasting for Weight Loss”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, May 26, 2025.