Once-Weekly Mazdutide: Effective for Overweight and Obesity (GLORY-1 Study)

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L Ji et al. NEJM 2025; 392: 2215-2225. Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight

This study from China enrolled young participants (mean age 34 yrs) and lower BMI (mean 31.1) than in similar studies of other GLP1 RAs and GLP 1 RA/GIP dual agonists. However, there was a high prevalence of dyslipidemia (62.3%), MAFLD (48.9%), hyperuricemia (40.2%), and hypertension (22.8%).

Key findings:

  • At week 48, the mean percentage change in body weight from baseline was –11.00% in the 4-mg mazdutide group, –14.01% in the 6-mg mazdutide group, and 0.30% in the placebo group

My take: Mazdutide resulted in significant weight loss along with improvements in cardiometabolic measures. This study shows beneficial effects in a younger cohort with significant cardiometabolic disease. Improvements in younger populations is likely to result in more substantial effects on outcomes than improvement in older cohorts.

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Etrasimod for Eosinophilic Esophagitis?

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ES Dellon et al. Lancet Gastroenterol Hepatol 2025; 10: 622–33. Etrasimod as a treatment for eosinophilic oesophagitis (VOYAGE): a double-blind, placebo-controlled, randomised, phase 2 trial

Background: “Etrasimod is an oral, once-daily, selective S1P1,4,5 receptor
modulator for the treatment of moderately to severely active ulcerative colitis and in development for the treatment of other immune-mediated inflammatory diseases. Etrasimod prevents trafficking of lymphocytes to inflamed mucosal tissue and sites of primary disease
manifestation, offering a unique, promising mechanism for the treatment of eosinophilic oesophagitis.”

There were 108 participants in this study: 41 patients received etrasimod 2 mg, 39 received etrasimod 1 mg, and 28 received placebo.

Key findings:

  • Median percentage changes from baseline in peak eosinophil count (PEC) at week 16:6 were −58·4% for etrasimod 2 mg (p=0·010 vs placebo), −39·4% for etrasimod 1 mg (p=0·29 vs placebo) and −21·5% for placebo.
  • Significant reductions from baseline in oesophageal PEC were achieved with both etrasimod
    doses (n=27 for 2 mg n=28 for 1 mg) at week 24 versus placebo (n=19), with a numerically larger reduction seen with the 2 mg dose, which had a median placebo-adjusted difference of –103·9% from baseline in oesophageal PEC. Oesophageal PEC did not decrease further with longer etrasimod treatment during the extension period (to 52 weeks in a smaller subset)
  • Etrasimod 2 mg was associated with a significant improvement in DSQ score at week 24 versus placebo in patients with no history of dilation (LS mean −21·6 vs –9·6, p=0·031)
  • No serious treatment-emergent adverse events occurred.

My take (borrowed from the authors): “This [phase 2] study provides the first evidence
that targeting the S1P pathway can improve disease activity in eosinophilic oesophagitis. Given that current treatment options for eosinophilic oesophagitis have variable and incomplete response rates, etrasimod presents a promising option.” Larger studies are warranted.

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Wat Arun (Temple of Dawn), Bangkok

Sulfasalazine vs 5-ASA: Treatment Outcomes in Pediatric UC

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I Mansuri et al. J Pediatr Gastroenterol Nutr. 2025;80:988–997. Clinical outcomes of maintenance therapy with sulfasalazine compared to 5-aminosalicylates in children with ulcerative colitis

Methods: This was a retrospective review of children diagnosed with UC between June 1999 and December 2019 at Boston Children’s Hospital. 124 started on sulfasalazine (SZ) and 309 on 5-aminosalicylates (5-ASA). Most patients had mild to moderate disease based on PUCAI score; ~12% had severe disease.

Key findings:

  • At 1 year, 54%, 44.3%, and 36.6% of patients on SZ, 5-ASA, and those who switched, respectively, were in steroid-free remission (p = 0.13)
  • All medication switches due to adverse reactions (24) were from SZ to 5-ASA. No patient was switched from 5-ASA to SZ because of adverse reactions. The non-severe adverse reactions noted were nausea, vomiting, abdominal pain, non-severe skin rash, headache, mild leucopenia, and lymphadenitis. Three patients had serious skin reactions, and one had pancreatitis.
  • SZ tended to have more minor adverse reactions. Except for countering adverse reactions, switching between SZ and 5-ASA did not offer therapeutic benefits. Disease severity at diagnosis predicted early treatment escalation

Discussion Points:

  • SZ offers advantages such as lower cost and availability in suspension form; the suspension form is particularly beneficial for young children and those unable to swallow the solid form of medication.
  • 5-ASA formulations can be almost 10–50 times more expensive than SZ. For example, the wholesale acquisition cost of monthly generic SZ is $30 compared to $274 for generic Lialda, $1131 for generic Pentasa, and $1890 for generic Asacol HD

My take: About 20% of patients had to switch from Sz to 5-ASA due to adverse reactions; though, Sz had a mildly higher response rate (not statistically-significant). Switching between SZ and 5-ASA or vice versa is unlikely to provide much therapeutic benefit; patients who switched agents for medical reasons (rather than reactions) were more likely to require escalation to either a biologic or immune modulator.

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Chatttahoochee River (Sandy Springs)

Retrospective Study on Botulinum Toxin for Refractory Constipation in Children

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D Patel et al. J Pediatr Gastroenterol Nutr. 2025;80:956–962. Efficacy of anal botulinum toxin injection in children with functional constipation

Methods: This was a retrospective, multicenter study including pediatric patients (n=63) who received anal botulinum toxin (BTX) for functional constipation (FC) refractory to medical therapy.  Response to therapy was assessed based on improvement in weekly frequency of BM (bowel movements) to 3 or more per week and/or resolution of functional incontinence (FI)

Key findings:

  • There was a a response rate of 10% in group 1 (FC +FI), 50% in group 2 (only FC) and 14% in group 3 (only FI); the an overall symptom resolution in 21% of patients
  • Fecal incontinence was the most common side effect, reported in 11% of all patients 

My take: In this highly-selected refractory population, there was a poor response to BTX in those with fecal incontinence (groups 1 and 3). The results should be interpreted with caution due to the retrospective nature of the study and the a lack of a control group.

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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.

Liver Transplantation for PSC: Long-term Outcomes and Complications

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M Mouchli et al. Liver Transplantation 2025; 31: 781-792. Long-term (15 y) complications and outcomes after liver transplantation for primary sclerosing cholangitis: Impact of donor and recipient factors

Methods: Using Mayo clinic prospectively maintained transplant database, 293 adult patients (>18 y, mean age 47 yrs) with PSC who underwent LT from 1984-2012 were identified. Patients with cholangiocarcinoma were excluded. One hundred and thirty-four patients received LT before 1995, and 159 were transplanted after 1995.

Key findings:

  • The 1-, 5-, 10-, and 15-year cumulative incidence of recurrent PSC was 1.0%, 8.0%, 23.5%, and 34.3%, respectively.
  • Vascular and biliary complications are frequent: hepatic artery thrombosis (N = 30), portal vein stenosis/thrombosis (N = 48), biliary leak (N = 47), biliary strictures (N = 87)
  • Graft failure occurred in 70 patients
  • Donor age >60 years was associated with an increased risk of recurrent PSC. 

My take: Overall, there was a good survival rate despite the increased frequency of vascular and biliary complications. Also, 2/3rds of patients did NOT have recurrent PSC. Older donor age was associated with higher graft failure in this cohort.

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RSV Vaccine and Treatment Lowered Hospitalizations in Infants

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Beth Mole, Ars Technica 5/08/25: New RSV vaccine, treatment linked to dramatic fall in baby hospitalizations

An excerpt:

RSV, or respiratory syncytial (sin-SISH-uhl) virus, is the leading cause of hospitalization for infants in the US. An estimated 58,000–80,000 children younger than 5 years old are hospitalized each year. Newborns—babies between 0 and 2 months—are the most at risk of being hospitalized with RSV…

But the 2024–2025 season was different—there were two new ways to protect against the infection. One is a maternal vaccine, Pfizer’s Abrysvo, which is given to pregnant people when their third trimester aligns with RSV season (generally September through January)…the other new protection against RSV is a long-acting monoclonal antibody treatment, nirsevimab, which is given to babies under 8 months old as they enter or are born into their first RSV season and may not be protected by maternal antibodies.

For the new study, CDC researchers looked at RSV hospitalization rates across two different RSV surveillance networks of hospitals and medical centers (called RSV-NET and NVSN)…

The analysis found that among newborns (0–2 months), RSV hospitalizations fell 52 percent in RSV-NET and 45 percent in NVSN compared with the rates from the 2018–2020 period.However, when the researcher excluded data from NVSN’s surveillance site in Houston—where the 2024–2035 RSV season started before the vaccine and treatment were rolled out—there was a 71 percent decline in hospitalizations in NVSN.

For a broader group of infants—0 to 7 months old—RSV-NET showed a 43 percent drop in hospitalizations in the 2024–2025 RSV season, and NVSN saw a 28 percent drop.Again, when Houston was excluded from the NVSN data, there was a 56 percent drop.

Lastly, the researchers looked at hospitalization rates for toddlers and children up to 5 years old, who wouldn’t have been protected by the new products. There, they saw RSV hospitalization rates were actually higher in the 2024–2025 season than in the pre-pandemic years.

Related CDC link: Healthcare Providers: RSV Immunization for Infants and Young Children

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Real-World Results of Obesity Pharmacotherapy With Tirzepatide and Semaglutide

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Happy July 4th!

L Gasoyan et al. Obesity 2025; DOI: 10.1002/oby.24331. Open Access! Changes in weight and glycemic control following obesity treatment with semaglutide or tirzepatide by discontinuation status

Methods: This retrospective cohort study used electronic health record data from a large health system in Ohio and Florida to identify adults with overweight or obesity without type 2 diabetes who initiated injectable semaglutide or tirzepatide between 2021 and 2023; 6109 received semaglutide, and 1772 received tirzepatide. Classification as high maintenance doses for semaglutide were 1.7, 2.0, or 2.4 mg and for tirzepatide 10.0, 12.5, or 15.0 mg, and all other dosages classified as low. The study grouped patients who discontinued pharmacotherapy into those who discontinued early (within 3 months of the index date) and late (within 3–12 months)

Key findings:

  • 80.8% had low maintenance dosages
  • Mean (SD) percentage weight reduction at 1 year was 8.7% (9.6%)
  • ~50% discontinued medication within 1 year
  • Patients receiving tirzepatide had more weight loss than those receiving semaglutide (see below). Among patients who did not discontinue obesity pharmacotherapy at year 1, the mean (SD) percentage reduction in weight was 10.9% with semaglutide and 15.3% with tirzepatide
  • In those receiving high dose medication, mean (SD) percentage reduction in weight was 14.7% with semaglutide and 18.0% with tirzepatide
  • Patients who continuing therapy had more weight loss than those who discontinued therapy (see below); Mean (SD) percentage weight reduction at 1 year was 3.6% (8.1%) with early discontinuation, 6.8% (9.1%) with late discontinuation, and 11.9% (9.2%) with non-discontinuation (p < 0.001).

DISCONTINUATION OF THERAPY:

Cumulative incidence of obesity pharmacotherapy discontinuation by index medication. s. Discontinuation of obesity pharmacotherapy was defined as a greater than 90-day gap between exhaustion of previous supply and next dispense or between exhaustion of last supply and end of study follow-up

SEMAGLUTIDE VS TIRZEPATIDE:

RESULTS WITH ONGOING TREATMENT VS TREATMENT DISCONTINUATION:

My take: This study showed higher rates of medication discontinuation in a real world setting compared to prior publications. In addition, the majority were receiving lower doses yet still achieving good results. However, increased discontinuation and lower doses likely explain the discrepancy in weight loss in this cohort which was less than in prior studies. It is important that patients taking these medications receive adequate counseling at the start to improve rates of adherence and long-term outcomes, including mitigation of muscle loss and bone loss.

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PRO and CON: All Pediatric Transplant Centers Should Have Living Donor Liver Transplant Option

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S Zielsdorf et al. Liver Transplantation 2025; 31: 832-835. PRO: All pediatric transplant centers should have LDLT as an option

Zielsdorf et make a compelling argument that all liver transplant patients should have access to LDLT. By improving access to transplantation, transplant recipients are in better health at the time of LDLT and have better outcomes. This also results in fewer deaths on the waiting list, even for patients who do not receive a LDLT.

The authors note that “whether LDLT is a superior option in and of itself or is instead a proxy for higher volume and more experienced centers, with associated better outcomes, may not be entirely feasible to tease out from the data.”

N Galvan et al. Liver Transplantation 2025; 31: 836-839. CON: LDLT should not be a requirement for pediatric transplant programs

Galvan et al counter with their good statistics from their large-volume center in Houston. In their center, 91% of the liver transplants performed over a decade were size-matched, whole organ allografts. They attribute some of their success to their central U.S. location allowing them to access more donors without compromising warm ischemia time. Other factors that make LDLT less viable at their center include lack of Medicaid reimbursement for living donor operations (51% of their patients rely on public insurance) and concern that the donor is oftentimes a primary caregiver.

They note that most programs in U.S. “are low-volume centers, that is, <5 pediatric liver transplants/year, making up 75% of the pediatric centers in the country that account for 38.5% of the pediatric cases…Experience is garnered by volume, and so the question,…is whether it is worth consolidating small-volume programs.”

My take: LDLT is an important tool to improve outcomes. The ability to access LDLT and technical variant grafts could be life-saving for a patient. Thus, from a public policy standpoint, it would make more sense to have fewer high-volume liver transplant centers that offer these options. Centers, like Houston, which have improved organ availability/acceptance and main high-volume, are the exception and not the rule with regard to outcomes.

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Pilot Study: Mediterranean Diet vs Low FODMAP for Irritable Bowel Syndrome

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S Singh et al. Neurogastroenterology and Motility 2025; https://doi.org/10.1111/nmo.70060. Open Access! Efficacy of Mediterranean Diet vs. Low-FODMAP Diet in Patients With Nonconstipated Irritable Bowel Syndrome: A Pilot Randomized Controlled Trial

Methods: Patients were randomized controlled trial (RCT), adult patients with diarrhea-predominant IBS (IBS-D) or mixed bowel pattern (IBS-M) were randomized to Mediterranean diet (MD) versus a diet low in fermentable oligo-, di-, monosaccharides, and polyols (LFD) for 4 weeks. 10 patients completed the study in each group. The primary endpoint was the proportion of patients with ≥ 30% decrease in abdominal pain intensity (API) for ≥ 2/4 weeks. Daily variables included abdominal pain intensity (API) and bloating, while IBS symptom severity score (IBS-SSS) and IBS adequate relief (IBS-AR) were scored weekly

Key findings:

  • 73% percent of the MD group met the primary endpoint compared to 81.8% of the LFD group (p = 1.0)
  • Although not statistically significant, a numerically higher proportion of the LFD group reported adequate relief and met the responder endpoint for IBS-SSS (50-point reduction) compared to the MD group (54.6% vs. 27.3% for IBS-AR and 81.8% vs. 45.5% for IBS-SSS, p = 0.39 and 0.18, respectively)
  • The LFD group also had a significantly greater reduction in IBS-SSS score over the 4-week treatment period compared to the MD group (−105.5 vs. −60, p = 0.02)

My take (borrowed from authors): A Mediterannean diet “improves abdominal symptoms in the majority of patients with IBS-D and IBS-M. Larger, adequately powered, real-world studies comparing the efficacy of a MD with LFD and NICE diet are needed to validate these preliminary findings and to help patients and providers to know if a MD should be added to the list of effective, evidence-based diet interventions for patients with IBS.”

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Guselkumab for Crohn’s Disease: Pivotal GRAVITI Study

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A Hart et al. Gastroenterol 2025 (ePUB Ahead of Print) Open Access! Efficacy and Safety of Guselkumab Subcutaneous Induction and Maintenance in Participants With Moderately to Severely Active Crohn’s Disease: Results From the Phase 3 GRAVITI Study

Background: “Guselkumab is a selective dual-acting IL-23p19 subunit inhibitor that potently neutralizes IL-23 by binding to the p19 subunit and to CD64, a receptor on cells that produce IL-23…In the double-blind Phase 2 GALAXI 1 study and the 2 identically designed double-blind Phase 3 GALAXI 2 and GALAXI 3 studies, guselkumab intravenous (IV) induction (200 mg at weeks 0, 4, and 8) followed by subcutaneous (SC) maintenance (200 mg every 4 weeks or 100 mg every 8 weeks) demonstrated efficacy compared with placebo… In addition, guselkumab demonstrated superiority to ustekinumab for multiple endoscopic-based endpoints at week 48 in pooled data from GALAXI 2 and GALAXI 3… The GRAVITI study…evaluated the efficacy and safety of guselkumab SC induction followed by SC maintenance in participants with moderately to severely active Crohn’s disease.

Methods: This was a Phase 3 double-blind, placebo-controlled, treat-through GRAVITI study randomized 347 participants 1:1:1 to guselkumab 400 mg SC every 4 weeks→100 mg SC every 8 weeks (n = 115), guselkumab 400 mg SC every 4 weeks→200 mg SC every 4 weeks (n = 115), or placebo (n = 117).  Placebo participants meeting rescue criteria received guselkumab from week 16 onward. 

Key Findings:

  •  At week 12, significantly greater proportions of participants receiving guselkumab 400 mg achieved clinical remission vs placebo (56.1% vs 21.4%; P < .001), and endoscopic response vs placebo (41.3% vs 21.4%; P < .001)
  • At week 48, significantly greater proportions of participants in both guselkumab groups (100 mg SC every 8 weeks: 60.0%; 200 mg SC every 4 weeks: 66.1%) achieved clinical remission vs placebo (17.1%; P < .001 each) and endoscopic response (44.3%; 51.3%; vs placebo 6.8%; P < .001 each)
  • Immunogenicity: “Antibodies to guselkumab were detected in 24 (8.8%) of the 274 guselkumab-treated participants through week 48. Only 3 of 274 participants (1.1% of the total population) were positive for neutralizing antibodies. Through week 48, no impact of antibodies to guselkumab on serum guselkumab concentrations, efficacy, or injection-site reactions was observed”
At week 12: Compared to placebo, patients receiving Guselkumab had improved clinical remission and endoscopic response. Being naive to previous biologics was associated with a higher endoscopic response but with a lower clinical remission rate.
At week 48: Being naive to previous biologics was associated with a higher clinical remission
At week 48: Being naive to previous biologics was associated with a higher endoscopic remission

Discussion: “The results presented here from GRAVITI were consistent with those reported in the double-blind, treat-through GALAXI trials in which guselkumab induction was administered IV in participants with moderately to severely active Crohn’s disease. For example, 41.3% of participants in the GRAVITI study achieved endoscopic response 12 weeks … whereas 36.9% of participants in the pooled GALAXI studies achieved endoscopic response 12 weeks after guselkumab… IV induction (placebo: 12.2%).”

My take: This study shows that Guselkumab with a SC induction is safe and effective in participants with moderately to severely active Crohn’s disease. IV induction does not appear to be needed. Though IL-23 agents have been important advances, there are still a large number of patients without a good response.

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