Meta-Analysis: PPIs Did Not Increase Risk of Cardiovascular Events

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Briefly noted -thanks to Ben Gold for this reference

AD Mosholder et al. The American Journal of Gastroenterology 2025; 120(2):p 362-369, Proton-Pump Inhibitors and Cardiovascular Adverse Events: A Meta-Analysis of Randomized Controlled Trials

Background: “Protopathic bias may result from the use of PPIs for cardiac symptoms mistaken for gastrointestinal symptoms (e.g. heartburn), producing a spurious association between cardiac events and PPI use. In addition, some cardiovascular risk factors may be more prevalent among users of PPIs eg. smoking, obesity) but may not be well captured in observational data sets, resulting in confounding.”

Methods: This meta-analysis included randomized trials with at least 100 subjects, treatment duration >30 days, and a non-PPI comparator (active or placebo). In total, this study examined 164 trials including 52 trials with PPI (n=14,998) vs placebo (n=8,323), 61 trials with PPI (n=12,505) vs any active comparator (n=8,566), and 51 trials with PPI (n=9,430) vs H2 receptor antagonist (n=6,050).

Key finding:

  • Cardiovascular outcomes were infrequent in randomized trials of PPIs, and our primary analysis found no overall association (summary incident rate ratio, MACE+ events, PPI:placebo, 0.72)

My take: This study found no clear association of cardiovascular events with PPI treatment.

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Andaman Sea, Thailand

Understanding Bleeding Risks in Percutaneous Liver Procedures —Who Needs FFP and Platelet Transfusions

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Background: “The most important factor contributing to bleeding risk in patients with liver disease is related to the presence of portal hypertension rather than coagulation abnormalities.1 The changes in the coagulation system in patients with cirrhosis create a re-balanced state, which is prothrombotic. Despite this well-known pathophysiology and recommendation against routine transfusion of blood products (especially fresh frozen plasma) by major guidelines, platelet and fresh frozen plasma transfusion remain a common practice before percutaneous liver procedures.2,3“

Methods: In this retrospective study from three centers in Spain, the researchers enrolled 1797 adults including 316 with cirrhosis (97% had compensated disease). They established a protocol that allowed, at the discretion of the radiologist, to transfuse patients with FFP or platelets if INR was 1.5 or greater or if platelets were 50,000 or below. The primary outcome of the study was major bleeding, which was defined as a drop in hemoglobin (2 or more units) or a need for transfusion of 2 or more units of blood within 1 week after the procedure. This study enrolled patients who underwent percutaneous liver biopsy (86% of cohort) and percutaneous ablation of liver tumors (14% of cohort). Only 6/25 (24%) with INR >1.5 received FFP. 16/22 (72%) with platelet counts below 50,000 received a platelet transfusion. Overall, 7 patients received FFP (1 with cirrhosis, 6 without) and 35 patients received platelets (16 with cirrhosis, 19 without).

Key findings:

  • Only 14 patients (0.8%) experienced major bleeding after the procedure, and there was no difference between those who had a diagnosis of cirrhosis versus those without cirrhosis. Bleeding occurred in 0.6% of patients with cirrhosis compared to 0.8% of those without.
  • Only 1 patient with an ablation procedure had major bleeding
  • Patients with a diagnosis of cirrhosis were more likely to receive a transfusion of any kind
  • Among those with major bleeding, none met the criteria for transfusion. That is, “no variable was identified to predict the risk of major bleeding.”

My take (borrowed from editorial): This study reinforces the recommendation that “correction of coagulation markers before procedures is unnecessary.”

The editorial notes that “the changes in the coagulation system in patients with cirrhosis
create a re-balanced state, which is prothrombotic.

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Dr. Maria Oliva-Hemker: Positioning Therapies for Pediatric Crohn’s Disease

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Recently, Dr. Maria Oliva-Hemker gave our group an excellent update on Crohn’s disease therapies.  My notes below may contain errors in transcription and in omission. Along with my notes, I have included many of her slides.

Key points:

  • Early advanced therapy results in better outcomes (see The PROFILE study results below as one example)
  • Anti-TNFs are the only therapy with a specific FDA pediatric indication. Medications can take 8-10 years after use in adults for pediatric labeling
  • IL-23 specific agents (like risankizumab) are more effective than ustekinumab that target both IL-23/IL-12
  • Recent studies show that ustekinumab is effective in children. Also, in patients who respond to ustekinumab, there is good durability
  • Infliximab is a top-line therapy in Crohn’s disease
  • Risankizumab is a top-line therapy in both biologic-naive and biologic-exposed patients with Crohn’s disease. Higher maintenance doses may capture more patients.
  • Upadacitinib is a very good therapy in patients with prior advanced therapies with either Crohn’s or ulcerative colitis. It also has a rapid onset of action (within 2 weeks)
  • Vedolizumab is less effective in those who are biologic-exposed. However, patients with predominantly colonic (UC-like) involvement may be better-suited for this therapy
  • Close monitoring and treat-to-target approaches are recommended. Usually followup scope is undertaken after one year (&/or one year after switching therapy)
  • Combination advanced therapies have shown effectiveness but it is unclear which combinations are optimal
This slide shows the Montreal Classification, an organ-based phenotype, to describe the anatomic extent and behaviors of Crohn’s disease;. The figure on the right illustrates extraintestinal manifestations of IBD. It is expected that disease classification will rely more on a molecular based approach.
The STRIDE project which defined goals of treatment was the result of consensus achieved by the International Organization of IBD. The first recommendations came out in 2015 and then these were updated in 2021 to incorporate a pediatric component.
The PROFILE study with 386 adults showed how important early effective advanced therapies. Patients receiving infliximab/azathioprine within a median of 15 days from diagnosis had remarkably better outcomes compared to step up treatment with prednisone + azathioprine.
The cytokine IL12 and IL23 shown as circles with 2 subunits attaching to their receptors share a p40 subunit (shown in red). Ustekinumab binds to that p40 subunit thereby inhibiting both the IL12 and IL23 pathways. IL23 inhibitor. Risankizumab, Mirkizumab, Guselkumab inhibit only the p19 subunit (shown in blue) and so  they only downregulate the IL-23 pathway.
Jak inhibitors targets are intracellular in location.
Pediatric data: Multicenter 2015-2020; primary outcome was CS-free remission after 1 yr. Prior to use, 50% failed 1 anti TNF and 30% 2 anti TNF. At one year, 59/101 were in steroid free remission
Upadactinib studies: Oral induction dose for UC and CD is 45 mg daily for induction
and with reduction in maintenance to 30 mg or 15 mg
Due to limited head-to-head studies, network meta analyses provides indirect evidence of comparative effectiveness. It relies on how effective a medication was compared to placebo. One of the problems with these comparisons is that there are different populations in each of these studies.
In patients who need speed to reduce symptoms, upadacitinib is favored over IL-23 agents

Though Dr. Oliva-Hemker’s lecture did not focus on ulcerative colitis, she did note that their center has recommended frequent colonoscopies (often yearly) in many of their patients with the combination of ulcerative colitis and PSC. This is due cases of colon cancer in their pediatric cohort.

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Impact of CFTR Modulators on the Need for Liver and Lung Transplantation in Patients with Cystic Fibrosis

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M Mendizabal et al. Liver Transplantation 2025; 31: 412-416. Have CFTR modulators changed the need for liver and lung transplantation among patients with cystic fibrosis? An analysis of the UNOS database

This article notes that there have been 146,851 waitlistings and 95,254 liver transplants in the U.S. between 2012 and 2023. This includes 194 waitlistings and 138 transplants in patients with cystic fibrosis.

Key finding:

My take: This is great news for patients with cystic fibrosis. The drop in lung transplants is surely the tip of the iceberg. Think about your next breath! For patients with cystic fibrosis, these new medications make every single breath better. Longer followup is needed to determine if the long-term use of these agents may lower the rate of end-stage liver disease as well.

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Gene Therapy for Alpha-One Antitrypsin Deficiency

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An excerpt from NY Times:

Researchers have corrected a disease-causing gene mutation with a single infusion carrying a treatment that precisely targeted the errant gene.This was the first time a mutated gene has been restored to normal….

The study involved patients who have alpha-1 antitrypsin deficiency, or AATD, a genetic disease that affects an estimated 100,000 Americans…

When the nanoparticles reached the liver, the lipid layer peeled off, releasing the editor — a disabled CRISPR molecule that acted like a GPS for the genome and an enzyme to fix the mutation. The CRISPR molecule crawled along the patient’s DNA until it found the one incorrect letter that needed to be repaired among the three billion DNA letters in the genome. Then the editing enzyme replaced that letter with the correct one… Those who got the highest dose made enough normal alpha-1 antitrypsin to be in a range where no more damage should occur. 

My take: This is exciting news, though, long-term data is needed to determine if this will be a durable cure. Cost/availability will be an important consideration if effective.

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The Importance of the EARNEST Trial –Vedolizumab for Chronic Pouchitis

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V Jairath et al. Clin Gastroenterol Hepatol 2025; 23: 321-330. Open Access! Mucosal Healing With Vedolizumab in Patients With Chronic Pouchitis: EARNEST, a Randomized, Double-Blind, Placebo-Controlled Trial

Methods: EARNEST, a randomized, double-blind, placebo-controlled study, evaluated vedolizumab efficacy and safety in adults with chronic pouchitis. 

Key findings:

  • More patients treated with vedolizumab vs placebo achieved mucosal healing, reduction in ulcers and ulcerated pouch area and SES-CD remission.
Reduction in the Number of Ulcers was much better for Vedolizumab than Placebo
Proportion of patients with (A) change in ulcerated surface area
and (B) with no ulcers (ulcers >5 mm, erosions ≤5 mm)

My take: Fortunately, chronic pouchitis is uncommon in the pediatric population. This study shows that many patients with chronic pouchitis improve with vedolizumab.

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Are Muscle-Building Supplements Risky for Teens?

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K Camero, NBC News, Feb 21, 2025. Overuse of muscle-building products associated with body image condition

An excerpt:

A Canadian study, published Wednesday in the journal PLOS Mental Health, finds that young people who consume multiple muscle-building products are more likely to show symptoms of a condition called muscle dysphoria…

About 2,730 Canadian teens and adults ages 16–30, mostly white males and females, were recruited via Instagram and Snapchat advertisements…

26% of the boys and men scored above the level for muscle dysmorphia — that is, being extremely preoccupied with a perceived lack of muscle mass or tone. Use of the workout supplements and products was associated with more symptoms of muscle dysmorphia…

About 55% adolescents and young men in the U.S. use bodybuilding supplements, according to some estimates…

Experts said the findings spotlight how unrealistic body ideals — often fueled by fitness influencers who promote or sell workout supplements online — may be driving more children and young adults to overuse powders or pills.

My take: The patients in this study may not be representative of the entire population; thus, the percentages of those affected should be interpreted carefully. Nevertheless, it is likely that a very significant proportion of young men have “muscle dysphoria” (also termed “‘bigorexia”). Supplements are poorly regulated and can result in adverse effects at any dosage (see posts below).

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Appendectomy vs Antibiotics: The Better Choice for Pediatric Appendicitis

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Briefly noted: SD St Peter et al. The Lancet, Volume 405, Issue 10474, 233 – 240. Appendicectomy versus antibiotics for acute uncomplicated appendicitis in children: an open-label, international, multicentre, randomised, non-inferiority trial

Methods: Children (n=936) aged 5–16 years with suspected non-perforated appendicitis (based on clinical diagnosis with or without radiological diagnosis) were randomly assigned (1:1) to the antibiotic or the appendectomy group. Treatment failure: Within 1 year of random assignment, n the antibiotic group, failure was defined as removal of the appendix, and in the appendectomy group, failure was defined as a normal appendix based on pathology.

Key findings:

  • Treatment failure occurred in 153 (34%) of 452 patients in the antibiotic group, compared with 28 (7%) of 394 in the appendectomy group 
  • There were no deaths or serious adverse events in either group
  • The relative risk of having a mild-to-moderate adverse event in the antibiotic group compared with the appendectomy group was 4·3 

My take: Appendectomy was superior to antibiotic management of acute non-perforated appendicitis.

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Bamboo forest at East Palisades Trail, Chattahoochee River, Atlanta

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Does a Less Restrictive Low FODMAP Diet Work?

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In the movie There’s Something About Mary, there is a scene (YouTube: 7-minute abs) where the main character picks up a hitchhiker. The hitchhiker reveals his brilliant idea for the 7-minute ab workout to replace the 8-minute ab workout. Of course, he becomes upset when the lead character suggests that someone else could invent the 6-minute ab workout.

This is what I was thinking of when I read a recent article describing a simplified, less restrictive low FODMAP diet.

P Singh et al. Clin Gastroenterol Hepatol 2025; 23: 362-364. Is a Simplified, Less Restrictive Low FODMAP Diet Possible? Results From a Double-Blind, Pilot Randomized Controlled Trial

This pilot study with 35 subjects with IBS-D were randomized to a standard low FODMAP diet (LFD) or to a simplified FODMAP diet which eliminated solely fructans and galactooligosaccharides. The primary endpoint was the proportion of subjects meeting the FDA responder definition for abdominal pain intensity (ie. a >/= 30% reduction in weekly average of daily abdominal pain scores for 2 of the 4-week treatment period).

Key findings:

  • There was a similar reduction in key symptoms (see below)
  • Fewer individuals in the simplified diet dropped out due to side effects or difficulty with adherence (12.5% vs 26.3%)
Blue columns indicate response to traditional low FODMAP diet (n=19)
and orange represents response to simplified low FODMAP diet (n=16)

My take: Larger trials are needed. This study suggests that a simplified version of a low FODMAP diet would improve symptoms in most patients with IBS-D.

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