#496 Hotcakes: Cannabidiol (CBD)-induced liver injury, IV iron for HFrEF, bedtime BP meds, Carpal Tunnel Syndrome & RA, & Finerenone for HFpEF

August 25, 2025 | By Rahul Ganatra

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Join us as we review recent practice-changing articles on cannabidiol (CBD)-induced liver injury, IV iron for HFrEF, bedtime administration of blood pressure meds, carpal tunnel syndrome & rheumatoid arthritis , & FDA approval of finerenone for HFpEF. Fill your brain hole with a delicious stack of hotcakes! Featuring Paul Williams (@PaulNWilliamz), Rahul Ganatra (@rbganatra), Nora Taranto (@norataranto) and Matt Watto (@doctorwatto).

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Show Segments

• Intro, disclaimer
• CBD-induced liver injury
• IV Iron in HFrEF
• Bedtime administration of BP medications
• Carpal tunnel syndrome and RA
• FDA approves Finerenone for HFpEF
• Outro

Hotcake #1 CBD-induced Liver Injury (Nora)

Florian J, Salcedo P, Burkhart K, et al. Cannabidiol and Liver Enzyme Level Elevations in Healthy Adults: A Randomized Clinical Trial. JAMA Intern Med. Published online July 07, 2025. doi:10.1001/jamainternmed.2025.2366

What was the research question? Does over-the-counter cannabidiol (CBD) cause liver injury? 

Why is this study important? Clinical trials for the only CBD preparation with FDA approval, Epidiolex (for treatment of some seizure disorders) revealed an elevated risk of drug-induced liver injury. Now, many over-the-counter preparations containing lower doses of CBD are available, but information on their safety is lacking. This study examined the effects of CBD on routine liver tests at doses typically present in over-the-counter preparations.  

How was the study done? In this single-center double-blinded placebo-controlled randomized trial, patients were randomized 3:1 to CBD 5 mg/kg/day, given as 2.5 mg/kg twice daily) or placebo. Labs were assessed weekly. The CBD agent used was the FDA-approved drug Epidiolex, which is approved for doses up to 25 mg/kg/day).  

Who were the patients? 201 healthy adults on no medications and with normal baseline liver tests (mean age 36) recruited from a pharmacology unit in Wisconsin were randomized. Patients were excluded if they smoked, had past or present alcohol use, alcohol use disorder, or other substance use disorders. 

Top-line results: This was a positive study: By day 28, more patients receiving CBD had AST or ALT >3x the upper limit of normal compared with placebo: 5.6% versus 0% (or, an absolute risk increase of ~6%).  

Learning points and limitations: This was a well-done study in young, healthy patients in a controlled setting. This highly selected study population and the use of a per-protocol analysis strengthen our confidence in the authors’ conclusion that the observed liver injury is actually due to CBD. The study had a short duration of follow-up and did not examine long-term use and the clinical significance of these findings is not clear.  

Bottom line: These data are compelling. I will definitely ask patients about CBD use, consider CBD as a potential cause of liver injury in patients presenting with liver enzyme elevations, and counsel individuals on other medications (which might affect CBD metabolism) about this specific risk of CBD. 

Hotcakes rating: 4.5 out of 5

Additional Reading: 

• A nice 2023 Review on CBD and safety: Found around a 7% prevalence of liver enzyme elevations across trials (this was typically with higher dosing of CBD).   
• 2024 Clinical Guidance from the Journal of Gastroenterology and Hepatology recommending screening for CBD use among individuals with elevated liver enzymes. 
• Editorial accompanying the JAMA Internal Medicine Study 

Hotcake #2 IV Iron in Heart Failure (Watto)

Anker SD, et al. Intravenous Ferric Carboxymaltose in Heart Failure With Iron Deficiency: The FAIR-HF2 DZHK05 Randomized Clinical Trial. JAMA. 2025 Jun 10;333(22):1965-1976. doi: 10.1001/jama.2025.3833. PMID: 40159390; PMCID: PMC11955906. 

What was the research question? Does IV iron therapy with high-dose ferric carboxymaltose (2,000 mg) improve outcomes in ambulatory patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency?

Why is this study important? Previous studies and meta-analyses have shown that intravenous iron in patients with HFrEF and iron deficiency improve symptoms and quality of life, but effects on mortality and hospitalizations have been inconsistent, with recent large trials (AFFIRM-AHF, IRONMAN, HEART-FID) failing to show a clear benefit. Many clinicians believe intravenous iron reduces hospitalizations, but the existence of a mortality benefit remains uncertain, a position reflected in guidelines from the European Society of Cardiology and the American College of Cardiology.

How was the study done? Patients with HFrEF (LVEF ≤45%) and iron deficiency were randomized to ferric carboxymaltose (up to 2,000 mg IV initially, then 500 mg as maintenance every 4 months) or placebo and followed for a median of 16.6 months. Patients in the IV iron group continued to receive maintenance doses unless stop criteria of haemoglobin >16 mg/dl or serum ferritin >800 ng/ml were met on study visits (Anker, 2025).

Who were the patients? 1,105 patients (mean age ~70, hemoglobin 12.5 mg/dL, ferritin 72-74, transferrin saturation 18-19%) were randomized. Two-thirds had NYHA class II symptoms; one-third had class III symptoms. 

Top line results: The FAIR-HF2 trial was a negative trial. Ferric carboxymaltose did not reduce risk of cardiovascular death or heart failure hospitalization compared with placebo in the overall population or in the subgroup with Tsat <20%. The primary outcome (time to cardiovascular death or first heart failure hospitalization) occurred in 25.3% of the ferric carboxymaltose group vs 30.4% of the placebo group (hazard ratio 0.79, 95% CI 0.63–0.99, P=0.04); however, the trial’s prespecified statistical plan required more stringent significance thresholds for multiple endpoints, which were not met. 

Learning points & limitations: There are at least three ways this study could be underpowered. First, it was designed to find a >30% relative difference in the primary outcome between groups, but all point estimates are closer to 20%, with confidence intervals close to 1. Second, there was more heterogeneity in the data than expected, and third, about a third of patients dropped out, all of which reduce power. The use of the Hochberg procedure reduces the likelihood of a false positive finding, which is a strength. Limitations include difficulty blinding during IV iron administration and follow-up (as hematologic parameters change).  

Bottom line: IV iron may have some symptomatic benefits, but does not significantly reduce cardiovascular death or heart failure hospitalizations in a contemporary heart failure population.

Hotcakes rating: 3.5 out of 5 

Further reading:

• Rationale and Design of the FAIR-HF2-DZHK05 Trial: Ferric Carboxymaltose Assessment of Morbidity and Mortality in Patients With Iron Deficiency and Chronic Heart Failure. Anker SD, Friede T, Butler J, et al. European Journal of Heart Failure. 2025;27(4):681-689. doi:10.1002/ejhf.3574.
• Anker SD, et al. Systematic review and meta-analysis of intravenous iron therapy for patients with heart failure and iron deficiency. Nat Med. 2025 Mar 30. doi: 10.1038/s41591-025-03671-1. Epub ahead of print. PMID: 40159279. This review found a reduction in HF hospitalizations when combining patient level data from 5 trials of IV iron and a trend towards reduced CV mortality.
• Hypophosphatemia from IV FCM article by Zoller et al, 2023

Hotcake #3 Bedtime administration of BP meds (Rahul)

Garrison SR, Bakal JA, Kolber MR, et al. Antihypertensive medication timing and cardiovascular events and death: the bedmed randomized clinical trial. JAMA. 2025;333(23):2061.

What was the research question? Is taking blood pressure medicines at bedtime better than taking them in the morning with respect to CV risk reduction? 

Why is this study important? This has been an area of debate and controversy in the hypertension community. Two trials from a single group of investigators in Spain (MAPEC and Hygia) suggested huge reductions in MACE from bedtime BP meds: 40-60%! Unfortunately, these findings were not replicated in a third larger study (TIME), which showed no difference between morning and bedtime dosing. Also, it is possible that bedtime dosing could be dangerous (falls, glaucoma-related vision loss, etc). This study was designed to settle the debate.

How was the study done? For this open-label, pragmatic trial, patients were recruited from 400 primary care clinicians in 5 provinces in Canada through direct mailings, word of mouth, and a social media campaign. They were randomized 1:1 to take their BP meds while preparing for bed or upon waking. Follow-up was by telephone or email, and 24-hour ABPM was done in a subset of 10% of patients.

Who were the patients? 3,300 community-dwelling adults (mean age, 67) on one or more BP meds of any kind (of note, patients were not excluded if they were on BID or TID meds, they just had to be on something daily as well). ~20% had diabetes, ~10% had known CAD. 

Top-line results: BedMed was a negative trial: Over a median follow-up of 4.6 years, the rate of all-cause death or hospitalization for stroke, MI, or CHF per 100 patient-years was 2.3 in the bedtime vs 2.4 in the morning group (HR 0.96, 95% CI 0.77-1.19). Also, adherence was clearly better in the morning group: at 6 months: 95% vs 83%, at 6 years: 88% vs 70%. 

Learning points & limitations: This negative result is useful mainly because it helps us interpret the implausible findings from two earlier studies (Hygia and MAPEC) – that is, they are less likely to be true. The pragmatic design, early discontinuation due to lack of funding, and self-reporting of adherence are potential sources of bias towards a negative study. However, I am not very worried that these explain these results for three reasons: loss to follow-up was uncommon, sensitivity analyses were consistent with the primary analysis, and in the subgroup of patients who underwent ABPM, there was no difference in awake BP between groups.  

Bottom line: I loved this paper since it answered three questions for the price of one: There’s no reason for patients to take blood pressure medication at night if they don’t want to, but if they do want to, they can safely do so. If I have to make a recommendation, morning administration was clearly more sustainable – so that will be my default.

Hotcakes rating: 5 out of 5 (because why not?)

Further reading:

• The original Hygia chronotherapy trial: Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial – PubMed
• Commentary on the problems with Hygia: Missing Verification of Source Data in Hypertension Research: The HYGIA PROJECT in Perspective
• Another great commentary on problems with Hygia and review of other relevant literature: Lowering Nighttime Blood Pressure with Bedtime Dosing of Antihypertensive Medications Controversies in Hypertension – Con Side of the Argument – PMC   

Hotcake #4 Carpal Tunnel Syndrome and RA (Paul)

George RJ, Frechette N, Oviedo M, et al. Carpal tunnel syndrome as an early underrecognized feature of rheumatoid arthritis: a population-based study of carpal tunnel syndrome occurrence before and after rheumatoid arthritis incidence. Arthritis Care Res (Hoboken). Published online May 5, 2025.

What was the research question? Is carpal tunnel syndrome (CTS) more likely to occur either before or after a diagnosis of rheumatoid arthritis (RA) than in individuals without RA?

Why is this study important? Carpal tunnel syndrome is really common, and is the most common peripheral nerve entrapment syndrome.  It is associated with other common conditions, including hypothyroidism and diabetes. Rheumatoid arthritis, being an inflammatory disease, could be causally linked to the pathogenesis of CTS.

How was the study done? This was a population-based study using data from the Rochester Epidemiology Project. Patients with RA (by 1987 ACR criteria) were matched 1:1 with patients without RA by age, sex, and RA incidence year (referred to as the “index year”). RA and CTS were identified using billing codes. A case-control study was performed to examine the association with CTS before RA diagnosis, and a retrospective cohort study was done to examine occurrence of CTS after RA diagnosis.

Who were the patients? 2,600 patients (mean age, 56) who met diagnostic criteria for RA and matched patients without RA were included.

Top-line results: This was a positive study: patients had a more than 2-fold increase in the likelihood of CTS in the years preceding RA diagnosis, and a 1.8-fold increased likelihood of incident CTS following RA onset. 

Leaning point & Limitations: Within the limitations of residual confounding and ascertainment bias inherent in retrospective observational studies, this is likely the best data to inform the question of whether CTS and RA are associated. This study does not tell us whether RA causes CTS, or whether both are caused by some other third variable – but the fact that CTS is more common both before and after RA diagnosis strongly supports the association between the two.

Bottom Line: These results don’t imply we should screen all patients with CTS for RA, but it should make us think more carefully about evaluating for underlying RA in patients coming in with wrist pain consistent with CTS.

Hotcakes rating: 3 out of 5

Hot take #1 Finerenone for HFpEF (Watto)

U.S. FDA Approves KERENDIA® (finerenone) to Treat Patients With Heart Failure With Left Ventricular Ejection Fraction ≥40% Following Priority Review 

Summary: The efficacy of aldosterone antagonists (MRAs) in reducing mortality for patients with HFrEF was established in RALES (1999; spironolactone) and EMPHASIS-HF (2011; eplerenone), but the 2014 TOPCAT trial (spironolactone) in patients with HFpEF was negative. However, a 2017 analysis highlighted lack of spironolactone metabolites or expected potassium variations at Eastern European sites in TOPCAT, suggesting nonadherence to the protocol. Now, following the results of the FINEARTS-HF (Solomon, 2024), as of July 2025, the non-steroidal MRA finerenone became the first drug in this class to earn FDA approval for heart failure with LVEF >40%. In this study, finerenone reduced unplanned hospitalizations and urgent visits for heart failure, but not cardiovascular death. Finerenone was previously approved for managing CKD in patients with diabetes. 

Bottom line: Non-steroidal mineralocorticoid receptor antagonists (MRAs) can be prescribed for patients with HFpEF to reduce heart failure events. It is reasonable to extrapolate this indication to the more affordable steroidal MRAs like spironolactone or eplerenone. 

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. Recall the absolute risk of cannabidiol-induced liver injury
2. Counsel patients on the pros and cons of bedtime versus morning antihypertensive administration
3. Discuss the likelihood of IV Iron benefitting patients with HFrEF

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Ganatra RB, Taranto NP, Williams PN, Watto MF. “#496 Hotcakes: Cannabidiol (CBD)-induced liver injury, IV iron for HFrEF, bedtime BP meds, Carpal Tunnel Syndrome & RA, & Finerenone for HFpEF”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list August 25, 2025.