GI and Hepatology News

Adult patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or advanced liver fibrosis showed improved liver histology with a once-weekly dose of semaglutide (Wegovy), an ongoing randomized placebo-controlled trial reported.

The glucagon-like peptide 1 receptor agonist (GLP-1 RA) is currently a candidate for treating MASH.

Preliminary results of the two-part phase 3, double-blind ESSENCE trial, conducted in at 253 clinical sites in 37 countries, were published in The New England Journal of Medicine.

 

A previous phase 2 study by Loomba et al suggested semaglutide was effective in reducing liver injury. “That study, however, did not show improvement in liver fibrosis, which this study has done,” study co-lead Philip Newsome, PhD, professor in the department of immunology and immunotherapy and Honorary Professor of Experimental Hepatology at the University of Birmingham in England, said in an interview.

“The results aligned with expectations in that the impact on liver fibrosis was anticipated — but with some uncertainty, so this study is important in that regard.” 

 

Study Details

From May 2020 to April 2023, researchers led by Newsome and Arun J. Sanyal, MBBS, MD, of Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University School of Medicine, Richmond, randomized 1197 patients with a mean age of 56 years. Of these, 57% were women and 67.5% were White individuals. Mean body mass index was 34.6, and 55.9% had type 2 diabetes.

All had biopsy-defined MASH and fibrosis stage 2 or 3 according to the Nonalcoholic Steatohepatitis Clinical Research Network classification and a Nonalcoholic Fatty Liver Disease Activity Score ≥ 4.

Rates of fibrosis were 31.3% for stage 2 fibrosis and 68.8% for stage 3. Diverse geographic site locations included Asia (25.1%), Europe (25.3%), North America (35.0%), and South America (7.9%), and others (6.8%).

In a 2:1 ratio, they were assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. A planned interim analysis of the first 800 patients was done at week 72, with primary endpoints being resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.

Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% CI, 21.1-36.2, P < .001).

A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of semaglutide recipients and 22.4% of placebo recipients (estimated difference, 14.4 percentage points; 95% CI, 7.5-21.3, P < .001). 

In secondary findings, the combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% in the semaglutide group vs 16.1% in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2-22.8; P < .001). 

The mean change in body weight was –10.5% with semaglutide and –2.0% with placebo (estimated difference, –8.5 percentage points; 95% CI, –9.6 to –7.4, P < .001). Mean changes in bodily pain scores did not differ significantly between arms. 

The histologic benefits of semaglutide also emerged in improvements on all prespecified noninvasive tests — including aspartate transaminase and alanine transaminase levels and liver stiffness. Emerging evidence has suggested an association between reductions in liver stiffness and clinical benefit. 

Gastrointestinal adverse events were more common in the semaglutide group.

 

Commenting on the study from a nonparticipant’s perspective, Naga P. Chalasani, MD, AGAF, professor of gastroenterology and hepatology at Indiana University School of Medicine, Indianapolis, said results from the ESSENCE trial were “long awaited and they certainly advance the field of MASH clinical trials substantially.”

Furthermore, he added, the results are well aligned with those of a phase 2b trial of semaglutide by Newsome and colleagues for what was then termed nonalcoholic steatohepatitis, and “they also align with what is known about the positive role of incretins, digestive hormones imitated by GLP-1s to improve liver health in patients with MASLD and MASH.” 

“The results from this study certainly make a case for semaglutide to be the backbone therapy for diabetic or obese patients with MASH and fibrosis,” Chalasani said. “More than 80% of patients with MASH and fibrosis have either diabetes and/or obesity.” 

He added that a better understanding is needed of how semaglutide works in patients with MASH cirrhosis since the previous small study was unsuccessful. “But this may need to be repeated as the published study was underpowered. Outcomes in the ESSENCE trial will help to clarify whether semaglutide will improve clinical outcomes beyond improving liver histology.”

According to Newsome, GLP-1s will become the backbone of therapy in MASH given their range of metabolic and liver benefit. But questions remain, he said. “Will there be further improvements with longer treatment with semaglutide? What noninvasive tests should we use to determine treatment success? Which patients will benefit from combination treatment?”

This study was supported by Novo Nordisk, the manufacturer of Wegovy. Sanyal reported having various financial relationships with multiple private-sector companies, including Novo Nordisk. Newsome reported consulting for Novo Nordisk and Boehringer Ingelheim. Several study coauthors reported having similar relationships with pharmaceutical companies or employment with Novo Nordisk. Chalasani declared being involved in several MASH clinical trials conducted by other pharmaceutical companies.

A version of this article appeared on Medscape.com.

Adult patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or advanced liver fibrosis showed improved liver histology with a once-weekly dose of semaglutide (Wegovy), an ongoing randomized placebo-controlled trial reported.

The glucagon-like peptide 1 receptor agonist (GLP-1 RA) is currently a candidate for treating MASH.

Preliminary results of the two-part phase 3, double-blind ESSENCE trial, conducted in at 253 clinical sites in 37 countries, were published in The New England Journal of Medicine.

 

A previous phase 2 study by Loomba et al suggested semaglutide was effective in reducing liver injury. “That study, however, did not show improvement in liver fibrosis, which this study has done,” study co-lead Philip Newsome, PhD, professor in the department of immunology and immunotherapy and Honorary Professor of Experimental Hepatology at the University of Birmingham in England, said in an interview.

“The results aligned with expectations in that the impact on liver fibrosis was anticipated — but with some uncertainty, so this study is important in that regard.” 

 

Study Details

From May 2020 to April 2023, researchers led by Newsome and Arun J. Sanyal, MBBS, MD, of Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University School of Medicine, Richmond, randomized 1197 patients with a mean age of 56 years. Of these, 57% were women and 67.5% were White individuals. Mean body mass index was 34.6, and 55.9% had type 2 diabetes.

All had biopsy-defined MASH and fibrosis stage 2 or 3 according to the Nonalcoholic Steatohepatitis Clinical Research Network classification and a Nonalcoholic Fatty Liver Disease Activity Score ≥ 4.

Rates of fibrosis were 31.3% for stage 2 fibrosis and 68.8% for stage 3. Diverse geographic site locations included Asia (25.1%), Europe (25.3%), North America (35.0%), and South America (7.9%), and others (6.8%).

In a 2:1 ratio, they were assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. A planned interim analysis of the first 800 patients was done at week 72, with primary endpoints being resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.

Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% CI, 21.1-36.2, P < .001).

A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of semaglutide recipients and 22.4% of placebo recipients (estimated difference, 14.4 percentage points; 95% CI, 7.5-21.3, P < .001). 

In secondary findings, the combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% in the semaglutide group vs 16.1% in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2-22.8; P < .001). 

The mean change in body weight was –10.5% with semaglutide and –2.0% with placebo (estimated difference, –8.5 percentage points; 95% CI, –9.6 to –7.4, P < .001). Mean changes in bodily pain scores did not differ significantly between arms. 

The histologic benefits of semaglutide also emerged in improvements on all prespecified noninvasive tests — including aspartate transaminase and alanine transaminase levels and liver stiffness. Emerging evidence has suggested an association between reductions in liver stiffness and clinical benefit. 

Gastrointestinal adverse events were more common in the semaglutide group.

 

Commenting on the study from a nonparticipant’s perspective, Naga P. Chalasani, MD, AGAF, professor of gastroenterology and hepatology at Indiana University School of Medicine, Indianapolis, said results from the ESSENCE trial were “long awaited and they certainly advance the field of MASH clinical trials substantially.”

Furthermore, he added, the results are well aligned with those of a phase 2b trial of semaglutide by Newsome and colleagues for what was then termed nonalcoholic steatohepatitis, and “they also align with what is known about the positive role of incretins, digestive hormones imitated by GLP-1s to improve liver health in patients with MASLD and MASH.” 

“The results from this study certainly make a case for semaglutide to be the backbone therapy for diabetic or obese patients with MASH and fibrosis,” Chalasani said. “More than 80% of patients with MASH and fibrosis have either diabetes and/or obesity.” 

He added that a better understanding is needed of how semaglutide works in patients with MASH cirrhosis since the previous small study was unsuccessful. “But this may need to be repeated as the published study was underpowered. Outcomes in the ESSENCE trial will help to clarify whether semaglutide will improve clinical outcomes beyond improving liver histology.”

According to Newsome, GLP-1s will become the backbone of therapy in MASH given their range of metabolic and liver benefit. But questions remain, he said. “Will there be further improvements with longer treatment with semaglutide? What noninvasive tests should we use to determine treatment success? Which patients will benefit from combination treatment?”

This study was supported by Novo Nordisk, the manufacturer of Wegovy. Sanyal reported having various financial relationships with multiple private-sector companies, including Novo Nordisk. Newsome reported consulting for Novo Nordisk and Boehringer Ingelheim. Several study coauthors reported having similar relationships with pharmaceutical companies or employment with Novo Nordisk. Chalasani declared being involved in several MASH clinical trials conducted by other pharmaceutical companies.

A version of this article appeared on Medscape.com.

Adult patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or advanced liver fibrosis showed improved liver histology with a once-weekly dose of semaglutide (Wegovy), an ongoing randomized placebo-controlled trial reported.

The glucagon-like peptide 1 receptor agonist (GLP-1 RA) is currently a candidate for treating MASH.

Preliminary results of the two-part phase 3, double-blind ESSENCE trial, conducted in at 253 clinical sites in 37 countries, were published in The New England Journal of Medicine.

 

A previous phase 2 study by Loomba et al suggested semaglutide was effective in reducing liver injury. “That study, however, did not show improvement in liver fibrosis, which this study has done,” study co-lead Philip Newsome, PhD, professor in the department of immunology and immunotherapy and Honorary Professor of Experimental Hepatology at the University of Birmingham in England, said in an interview.

“The results aligned with expectations in that the impact on liver fibrosis was anticipated — but with some uncertainty, so this study is important in that regard.” 

 

Study Details

From May 2020 to April 2023, researchers led by Newsome and Arun J. Sanyal, MBBS, MD, of Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University School of Medicine, Richmond, randomized 1197 patients with a mean age of 56 years. Of these, 57% were women and 67.5% were White individuals. Mean body mass index was 34.6, and 55.9% had type 2 diabetes.

All had biopsy-defined MASH and fibrosis stage 2 or 3 according to the Nonalcoholic Steatohepatitis Clinical Research Network classification and a Nonalcoholic Fatty Liver Disease Activity Score ≥ 4.

Rates of fibrosis were 31.3% for stage 2 fibrosis and 68.8% for stage 3. Diverse geographic site locations included Asia (25.1%), Europe (25.3%), North America (35.0%), and South America (7.9%), and others (6.8%).

In a 2:1 ratio, they were assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. A planned interim analysis of the first 800 patients was done at week 72, with primary endpoints being resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.

Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% CI, 21.1-36.2, P < .001).

A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of semaglutide recipients and 22.4% of placebo recipients (estimated difference, 14.4 percentage points; 95% CI, 7.5-21.3, P < .001). 

In secondary findings, the combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% in the semaglutide group vs 16.1% in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2-22.8; P < .001). 

The mean change in body weight was –10.5% with semaglutide and –2.0% with placebo (estimated difference, –8.5 percentage points; 95% CI, –9.6 to –7.4, P < .001). Mean changes in bodily pain scores did not differ significantly between arms. 

The histologic benefits of semaglutide also emerged in improvements on all prespecified noninvasive tests — including aspartate transaminase and alanine transaminase levels and liver stiffness. Emerging evidence has suggested an association between reductions in liver stiffness and clinical benefit. 

Gastrointestinal adverse events were more common in the semaglutide group.

 

Commenting on the study from a nonparticipant’s perspective, Naga P. Chalasani, MD, AGAF, professor of gastroenterology and hepatology at Indiana University School of Medicine, Indianapolis, said results from the ESSENCE trial were “long awaited and they certainly advance the field of MASH clinical trials substantially.”

Furthermore, he added, the results are well aligned with those of a phase 2b trial of semaglutide by Newsome and colleagues for what was then termed nonalcoholic steatohepatitis, and “they also align with what is known about the positive role of incretins, digestive hormones imitated by GLP-1s to improve liver health in patients with MASLD and MASH.” 

“The results from this study certainly make a case for semaglutide to be the backbone therapy for diabetic or obese patients with MASH and fibrosis,” Chalasani said. “More than 80% of patients with MASH and fibrosis have either diabetes and/or obesity.” 

He added that a better understanding is needed of how semaglutide works in patients with MASH cirrhosis since the previous small study was unsuccessful. “But this may need to be repeated as the published study was underpowered. Outcomes in the ESSENCE trial will help to clarify whether semaglutide will improve clinical outcomes beyond improving liver histology.”

According to Newsome, GLP-1s will become the backbone of therapy in MASH given their range of metabolic and liver benefit. But questions remain, he said. “Will there be further improvements with longer treatment with semaglutide? What noninvasive tests should we use to determine treatment success? Which patients will benefit from combination treatment?”

This study was supported by Novo Nordisk, the manufacturer of Wegovy. Sanyal reported having various financial relationships with multiple private-sector companies, including Novo Nordisk. Newsome reported consulting for Novo Nordisk and Boehringer Ingelheim. Several study coauthors reported having similar relationships with pharmaceutical companies or employment with Novo Nordisk. Chalasani declared being involved in several MASH clinical trials conducted by other pharmaceutical companies.

A version of this article appeared on Medscape.com.

An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.

Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.

The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.

Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.

 

The Study

In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.

The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.

High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine. 

Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.

Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels. 

Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.

Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers. 

The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.

This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.

Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.

A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.
 

An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.

Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.

The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.

Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.

 

The Study

In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.

The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.

High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine. 

Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.

Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels. 

Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.

Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers. 

The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.

This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.

Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.

A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.
 

An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.

Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.

The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.

Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.

 

The Study

In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.

The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.

High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine. 

Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.

Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels. 

Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.

Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers. 

The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.

This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.

Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.

A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.
 

An irritable bowel syndrome (IBS) elimination diet based on a novel IBS–specific, immunoglobulin G (IgG) was superior to a sham diet for abdominal pain, an 8-center, randomized double-blind controlled trial found.

While elimination diets can provide a personalized approach to dietary therapy, existing studies have had serious methodological issues, noted lead author Prashant Singh, MBBS, of the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Mich., and colleagues in Gastroenterology.

For example, previous studies on IgG-based diets used assays developed without determining IBS trigger foods or establishing a 95% confidence interval–based cutoff using a healthy control comparison group.

 

Study Details

From June 2018 to December 2021, 238 IBS patients testing positive for at least one food on 18-food IgG ELISA (enzyme-linked immunosorbent assay) testing and an average daily abdominal pain intensity score of 3.0 to 7.5 on an 11.0-point scale during a 2-week run-in period were randomized for 8 weeks to an experimental antibody-guided diet or to a sham diet. The primary outcome was a 30% decrease in abdominal pain intensity (API) for 2 of the last 4 weeks of treatment.

The overall study population had a mean age of about 40 years, and more than three-quarters were female. The 3 IBS types – constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), and mixed bowel habits-predominant (IBS-M) – accounted for about a third each in both arms.

The experimental diet eliminated foods based on a positive ELISA result. Its sham counterpart had the same number of foods removed as the number of positive-testing food sensitivities, but the foods eliminated in the sham diet had tested negative on the IgG assay.

Participants reported daily abdominal pain intensity, bloating, and stool consistency, and frequency. They also reported dietary compliance and daily medication use.

Of the 238 randomized adults, 223 were included in the modified intention-to-treat analysis. A significantly greater proportion of subjects in the experimental group met the primary outcome than those in the sham group: 59.6% vs 42.1%, P = .02). “This highlights the potential effectiveness of a personalized elimination diet based on a novel IBS-specific IgG assay,” the authors wrote.

Symptom improvement between arms began to separate out at around 2 weeks, suggesting the effect of the experimental diet was relatively rapid in onset, and continued for at least 8 weeks. The durability of response, however, needs to be assessed in future studies “and it is unclear if there is a role for repeat IgG testing to monitor treatment response,” the authors wrote.

Subgroup analysis revealed that a higher proportion of those with IBS-C and IBS-M in the experimental diet group met the primary endpoint vs the sham group: 67.1% vs 35.8% and 66% vs 29.5%, respectively.

Interestingly, more patients in the experimental arm were noncompliant with their diet. “It is possible that subjects found the experimental diet more difficult to comply with compared with the sham diet or that because the experimental diet was more likely to improve symptoms, dietary indiscretion may have been more common in this group (a phenomenon seen with other elimination diets such as gluten-free diet in celiac disease),” the authors wrote.

Adverse events, deemed unrelated to either regimen, were 3 in the experimental arm vs 8 in the sham arm, which had 2 urinary tract infections.

The authors called for a larger, adequately powered study to assess the efficacy of an elimination diet based on this novel immunoglobulin G assay in patients with IBS-C and IBS-M. Future studies should perform detailed adherence assessments using food diaries.

“Mechanisms of how immunoglobulin G-antibody response to food antigen generates symptoms in irritable bowel syndrome are not well understood. Delineating this might provide new insights into food-related irritable bowel syndrome pathophysiology,” they concluded.

This study was funded by Biomerica Inc.

An irritable bowel syndrome (IBS) elimination diet based on a novel IBS–specific, immunoglobulin G (IgG) was superior to a sham diet for abdominal pain, an 8-center, randomized double-blind controlled trial found.

While elimination diets can provide a personalized approach to dietary therapy, existing studies have had serious methodological issues, noted lead author Prashant Singh, MBBS, of the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Mich., and colleagues in Gastroenterology.

For example, previous studies on IgG-based diets used assays developed without determining IBS trigger foods or establishing a 95% confidence interval–based cutoff using a healthy control comparison group.

 

Study Details

From June 2018 to December 2021, 238 IBS patients testing positive for at least one food on 18-food IgG ELISA (enzyme-linked immunosorbent assay) testing and an average daily abdominal pain intensity score of 3.0 to 7.5 on an 11.0-point scale during a 2-week run-in period were randomized for 8 weeks to an experimental antibody-guided diet or to a sham diet. The primary outcome was a 30% decrease in abdominal pain intensity (API) for 2 of the last 4 weeks of treatment.

The overall study population had a mean age of about 40 years, and more than three-quarters were female. The 3 IBS types – constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), and mixed bowel habits-predominant (IBS-M) – accounted for about a third each in both arms.

The experimental diet eliminated foods based on a positive ELISA result. Its sham counterpart had the same number of foods removed as the number of positive-testing food sensitivities, but the foods eliminated in the sham diet had tested negative on the IgG assay.

Participants reported daily abdominal pain intensity, bloating, and stool consistency, and frequency. They also reported dietary compliance and daily medication use.

Of the 238 randomized adults, 223 were included in the modified intention-to-treat analysis. A significantly greater proportion of subjects in the experimental group met the primary outcome than those in the sham group: 59.6% vs 42.1%, P = .02). “This highlights the potential effectiveness of a personalized elimination diet based on a novel IBS-specific IgG assay,” the authors wrote.

Symptom improvement between arms began to separate out at around 2 weeks, suggesting the effect of the experimental diet was relatively rapid in onset, and continued for at least 8 weeks. The durability of response, however, needs to be assessed in future studies “and it is unclear if there is a role for repeat IgG testing to monitor treatment response,” the authors wrote.

Subgroup analysis revealed that a higher proportion of those with IBS-C and IBS-M in the experimental diet group met the primary endpoint vs the sham group: 67.1% vs 35.8% and 66% vs 29.5%, respectively.

Interestingly, more patients in the experimental arm were noncompliant with their diet. “It is possible that subjects found the experimental diet more difficult to comply with compared with the sham diet or that because the experimental diet was more likely to improve symptoms, dietary indiscretion may have been more common in this group (a phenomenon seen with other elimination diets such as gluten-free diet in celiac disease),” the authors wrote.

Adverse events, deemed unrelated to either regimen, were 3 in the experimental arm vs 8 in the sham arm, which had 2 urinary tract infections.

The authors called for a larger, adequately powered study to assess the efficacy of an elimination diet based on this novel immunoglobulin G assay in patients with IBS-C and IBS-M. Future studies should perform detailed adherence assessments using food diaries.

“Mechanisms of how immunoglobulin G-antibody response to food antigen generates symptoms in irritable bowel syndrome are not well understood. Delineating this might provide new insights into food-related irritable bowel syndrome pathophysiology,” they concluded.

This study was funded by Biomerica Inc.

An irritable bowel syndrome (IBS) elimination diet based on a novel IBS–specific, immunoglobulin G (IgG) was superior to a sham diet for abdominal pain, an 8-center, randomized double-blind controlled trial found.

While elimination diets can provide a personalized approach to dietary therapy, existing studies have had serious methodological issues, noted lead author Prashant Singh, MBBS, of the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Mich., and colleagues in Gastroenterology.

For example, previous studies on IgG-based diets used assays developed without determining IBS trigger foods or establishing a 95% confidence interval–based cutoff using a healthy control comparison group.

 

Study Details

From June 2018 to December 2021, 238 IBS patients testing positive for at least one food on 18-food IgG ELISA (enzyme-linked immunosorbent assay) testing and an average daily abdominal pain intensity score of 3.0 to 7.5 on an 11.0-point scale during a 2-week run-in period were randomized for 8 weeks to an experimental antibody-guided diet or to a sham diet. The primary outcome was a 30% decrease in abdominal pain intensity (API) for 2 of the last 4 weeks of treatment.

The overall study population had a mean age of about 40 years, and more than three-quarters were female. The 3 IBS types – constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), and mixed bowel habits-predominant (IBS-M) – accounted for about a third each in both arms.

The experimental diet eliminated foods based on a positive ELISA result. Its sham counterpart had the same number of foods removed as the number of positive-testing food sensitivities, but the foods eliminated in the sham diet had tested negative on the IgG assay.

Participants reported daily abdominal pain intensity, bloating, and stool consistency, and frequency. They also reported dietary compliance and daily medication use.

Of the 238 randomized adults, 223 were included in the modified intention-to-treat analysis. A significantly greater proportion of subjects in the experimental group met the primary outcome than those in the sham group: 59.6% vs 42.1%, P = .02). “This highlights the potential effectiveness of a personalized elimination diet based on a novel IBS-specific IgG assay,” the authors wrote.

Symptom improvement between arms began to separate out at around 2 weeks, suggesting the effect of the experimental diet was relatively rapid in onset, and continued for at least 8 weeks. The durability of response, however, needs to be assessed in future studies “and it is unclear if there is a role for repeat IgG testing to monitor treatment response,” the authors wrote.

Subgroup analysis revealed that a higher proportion of those with IBS-C and IBS-M in the experimental diet group met the primary endpoint vs the sham group: 67.1% vs 35.8% and 66% vs 29.5%, respectively.

Interestingly, more patients in the experimental arm were noncompliant with their diet. “It is possible that subjects found the experimental diet more difficult to comply with compared with the sham diet or that because the experimental diet was more likely to improve symptoms, dietary indiscretion may have been more common in this group (a phenomenon seen with other elimination diets such as gluten-free diet in celiac disease),” the authors wrote.

Adverse events, deemed unrelated to either regimen, were 3 in the experimental arm vs 8 in the sham arm, which had 2 urinary tract infections.

The authors called for a larger, adequately powered study to assess the efficacy of an elimination diet based on this novel immunoglobulin G assay in patients with IBS-C and IBS-M. Future studies should perform detailed adherence assessments using food diaries.

“Mechanisms of how immunoglobulin G-antibody response to food antigen generates symptoms in irritable bowel syndrome are not well understood. Delineating this might provide new insights into food-related irritable bowel syndrome pathophysiology,” they concluded.

This study was funded by Biomerica Inc.

SAN DIEGO — In treating pancreas divisum, the common use of endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy showed no significant benefit over a sham procedure, suggesting that patients can be spared the intervention, which can carry risks of its own.

“This is a topic that has been debated for decades,” said first author Gregory A. Coté, MD, AGAF, Division Head, professor of medicine, Division of Gastroenterology & Hepatology, Oregon Health & Science University, in Portland, Oregon.

“Many doctors believe the procedure helps and offer it because we have limited options to help our patients, whereas others believe the procedure is harmful and doesn’t help,” he explained in a press briefing for the late-breaking study, presented at Digestive Disease Week (DDW) 2025.

The study’s findings supported the latter argument.

“Patients who underwent ERCP with sphincterotomy were just as likely as those who did not have this procedure to develop acute pancreatitis again,” Coté reported.

While clinical guidelines currently recommend ERCP as treatment for pancreas divisum, “these guidelines are likely to change based on this study,” he said.

Pancreas divisum, occurring in about 7%-10% of people, is an anatomic variation that can represent an obstructive risk factor for acute recurrent pancreatitis.

The common use of ERCP with minor papilla endoscopic sphincterotomy to treat the condition is based on prior retrospective studies showing that in patients who did develop acute pancreatitis, up to 70% with the treatment never developed acute pancreatitis again. However, there have been no studies comparing the use of the treatment with a control group.

Coté and colleagues conducted the multicenter SHARP trial, in which 148 patients with pancreas divisum were enrolled between September 2018 and August 2024 and randomized to receive either ERCP with minor papilla endoscopic sphincterotomy (n = 75) or a sham treatment (n = 73).

The patients, who had a median age of 51 years, had a median of 3 acute pancreatitis episodes prior to randomization.

With a median follow-up of 33.5 months (range, 6-48 months), 34.7% of patients in the ERCP arm experienced an acute pancreatitis incident compared with 43.8% in the sham arm, for a hazard ratio of 0.83 after adjusting for duct size and the number of episodes, which was not a statistically significant difference (P = .27).

A subgroup analysis further showed no indication of a treatment effect based on factors including age, diabetes status, sex, alcohol or tobacco use, or other factors.

“Compared with a sham ERCP group, we found that minor papillotomy did not reduce the risk of acute pancreatitis, incident chronic pancreatitis, endocrine pancreatic insufficiency or diabetes, or pancreas-related pain events,” Coté said.

The findings are particularly important because the treatment itself is associated with some risks, he added.

“Ironically, the problem with this procedure is that it can cause acute pancreatitis in 10%-20% of patients and may instigate other issues later,” such as the development of scarring of the pancreas related to incisions in the procedure.

“No one wants to offer an expensive procedure that has its own risks if it doesn’t help,” Coté said.

Based on the findings, “pancreas divisum anatomy should no longer be considered an indication for ERCP, even for idiopathic acute pancreatitis,” he concluded.

A version of this article appeared on Medscape.com.

SAN DIEGO — In treating pancreas divisum, the common use of endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy showed no significant benefit over a sham procedure, suggesting that patients can be spared the intervention, which can carry risks of its own.

“This is a topic that has been debated for decades,” said first author Gregory A. Coté, MD, AGAF, Division Head, professor of medicine, Division of Gastroenterology & Hepatology, Oregon Health & Science University, in Portland, Oregon.

“Many doctors believe the procedure helps and offer it because we have limited options to help our patients, whereas others believe the procedure is harmful and doesn’t help,” he explained in a press briefing for the late-breaking study, presented at Digestive Disease Week (DDW) 2025.

The study’s findings supported the latter argument.

“Patients who underwent ERCP with sphincterotomy were just as likely as those who did not have this procedure to develop acute pancreatitis again,” Coté reported.

While clinical guidelines currently recommend ERCP as treatment for pancreas divisum, “these guidelines are likely to change based on this study,” he said.

Pancreas divisum, occurring in about 7%-10% of people, is an anatomic variation that can represent an obstructive risk factor for acute recurrent pancreatitis.

The common use of ERCP with minor papilla endoscopic sphincterotomy to treat the condition is based on prior retrospective studies showing that in patients who did develop acute pancreatitis, up to 70% with the treatment never developed acute pancreatitis again. However, there have been no studies comparing the use of the treatment with a control group.

Coté and colleagues conducted the multicenter SHARP trial, in which 148 patients with pancreas divisum were enrolled between September 2018 and August 2024 and randomized to receive either ERCP with minor papilla endoscopic sphincterotomy (n = 75) or a sham treatment (n = 73).

The patients, who had a median age of 51 years, had a median of 3 acute pancreatitis episodes prior to randomization.

With a median follow-up of 33.5 months (range, 6-48 months), 34.7% of patients in the ERCP arm experienced an acute pancreatitis incident compared with 43.8% in the sham arm, for a hazard ratio of 0.83 after adjusting for duct size and the number of episodes, which was not a statistically significant difference (P = .27).

A subgroup analysis further showed no indication of a treatment effect based on factors including age, diabetes status, sex, alcohol or tobacco use, or other factors.

“Compared with a sham ERCP group, we found that minor papillotomy did not reduce the risk of acute pancreatitis, incident chronic pancreatitis, endocrine pancreatic insufficiency or diabetes, or pancreas-related pain events,” Coté said.

The findings are particularly important because the treatment itself is associated with some risks, he added.

“Ironically, the problem with this procedure is that it can cause acute pancreatitis in 10%-20% of patients and may instigate other issues later,” such as the development of scarring of the pancreas related to incisions in the procedure.

“No one wants to offer an expensive procedure that has its own risks if it doesn’t help,” Coté said.

Based on the findings, “pancreas divisum anatomy should no longer be considered an indication for ERCP, even for idiopathic acute pancreatitis,” he concluded.

A version of this article appeared on Medscape.com.

SAN DIEGO — In treating pancreas divisum, the common use of endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy showed no significant benefit over a sham procedure, suggesting that patients can be spared the intervention, which can carry risks of its own.

“This is a topic that has been debated for decades,” said first author Gregory A. Coté, MD, AGAF, Division Head, professor of medicine, Division of Gastroenterology & Hepatology, Oregon Health & Science University, in Portland, Oregon.

“Many doctors believe the procedure helps and offer it because we have limited options to help our patients, whereas others believe the procedure is harmful and doesn’t help,” he explained in a press briefing for the late-breaking study, presented at Digestive Disease Week (DDW) 2025.

The study’s findings supported the latter argument.

“Patients who underwent ERCP with sphincterotomy were just as likely as those who did not have this procedure to develop acute pancreatitis again,” Coté reported.

While clinical guidelines currently recommend ERCP as treatment for pancreas divisum, “these guidelines are likely to change based on this study,” he said.

Pancreas divisum, occurring in about 7%-10% of people, is an anatomic variation that can represent an obstructive risk factor for acute recurrent pancreatitis.

The common use of ERCP with minor papilla endoscopic sphincterotomy to treat the condition is based on prior retrospective studies showing that in patients who did develop acute pancreatitis, up to 70% with the treatment never developed acute pancreatitis again. However, there have been no studies comparing the use of the treatment with a control group.

Coté and colleagues conducted the multicenter SHARP trial, in which 148 patients with pancreas divisum were enrolled between September 2018 and August 2024 and randomized to receive either ERCP with minor papilla endoscopic sphincterotomy (n = 75) or a sham treatment (n = 73).

The patients, who had a median age of 51 years, had a median of 3 acute pancreatitis episodes prior to randomization.

With a median follow-up of 33.5 months (range, 6-48 months), 34.7% of patients in the ERCP arm experienced an acute pancreatitis incident compared with 43.8% in the sham arm, for a hazard ratio of 0.83 after adjusting for duct size and the number of episodes, which was not a statistically significant difference (P = .27).

A subgroup analysis further showed no indication of a treatment effect based on factors including age, diabetes status, sex, alcohol or tobacco use, or other factors.

“Compared with a sham ERCP group, we found that minor papillotomy did not reduce the risk of acute pancreatitis, incident chronic pancreatitis, endocrine pancreatic insufficiency or diabetes, or pancreas-related pain events,” Coté said.

The findings are particularly important because the treatment itself is associated with some risks, he added.

“Ironically, the problem with this procedure is that it can cause acute pancreatitis in 10%-20% of patients and may instigate other issues later,” such as the development of scarring of the pancreas related to incisions in the procedure.

“No one wants to offer an expensive procedure that has its own risks if it doesn’t help,” Coté said.

Based on the findings, “pancreas divisum anatomy should no longer be considered an indication for ERCP, even for idiopathic acute pancreatitis,” he concluded.

A version of this article appeared on Medscape.com.

SAN DIEGO — The session started with a question that many in the audience at Digestive Disease Week (DDW) 2025 seemed to relate to: “How many of you find yourself squeezing workouts into a weekend after a hectic work week?”

Although regular exercise three or more times a week is often viewed as preferable, Shiyi Yu, MD, a resident physician in the Department of Gastroenterology at Guangdong Provincial People’s Hospital in Guangzhou, China, had good news for weekend warriors.

Both patterns reduce digestive disease almost equally.

Her study compared weekend warriors with those she called “active regulars” and sedentary folks to see how activity patterns affect digestive disease risks.

Her bottom line: “Your gut does not care about your schedule.”

The researchers analyzed wrist-based accelerometer data from 89,595 participants in the UK Biobank. To categorize participants as active or inactive, they used the World Health Organization 2020 guidelines for physical activity, which recommend at least 150-300 minutes of moderate-intensity aerobic physical activity or at least 75-150 minutes of vigorous-intensity aerobic physical activity, or an equivalent combination throughout the week. Median age of participants was 63.3 years and 48.8% were men.

They divided participants into three groups:

• About 43% were weekend warriors who met or exceeded 150 minutes of moderate to vigorous physical activity (MVPA), with 50% or more of total MVPA achieved in 1-2 days.
• About 23% were active regulars who met or exceeded 150 minutes a week but spread over more days.
• About 34% were inactive participants who were active less than 150 minutes a week.

The researchers followed the participants for a median of 7.9 years, looking for the incidence of multiple digestive diseases, identified using the International Classification of Diseases, 10th Revision, codes. These included diverticulosis, constipation, metabolic dysfunction–associated steatotic liver disease, cholelithiasis, and gastroesophageal reflux disease. 

Both activity patterns “showed similar risk reduction with no significant difference,” Yu said. At the threshold ≥ 150 minutes, for instance, hazard ratios for any digestive disease were 0.83 for weekend warriors and 0.79 for active regulars, compared with sedentary participants.

The analysis was repeated using a median threshold ≥ 230.4 minutes of MVPA a week, and the researchers found the same results.

As a validation cohort, the researchers used more than 6,000 participants from the National Institutes of Health’s All of Us Research Program with over 6 months of wrist-based accelerometer data.

A recent meta-epidemiology study found that the weekend warrior pattern offers other health benefits, including reducing the risk for cardiovascular disease mortality, mental disorders, and metabolic syndrome.

 

A Pleasant Surprise

The digestive disease study’s findings were “a surprise and a pleasant one,” said Aasma Shaukat, MD, MPH, AGAF, professor of medicine and a gastroenterologist at NYU Grossman School of Medicine, New York City.

“We often think if we’re not able to exercise regularly, then there’s no hope for us,” said Shaukat, who moderated the session. “But this implies that even if we have time only during the weekend to engage in physical activity, it still confers benefits in reducing our risk of any GI health disorder, as well as cardiovascular or other health disorders, compared to people inactive at baseline.”

“It gives us flexibility in terms of how we structure our exercise. Obviously, people should try to get into the habit of doing regular activity; it’s more sustainable. But a good alternative, according to this research, is that packing all of that in over the weekend seems to confer benefit. So all is not lost.”

Will this change her conversation with patients moving forward? Absolutely, Shaukat said. She generally recommends physical activity for at least 30 minutes three times a week. Now Shaukat said she can tell patients: “If that’s not possible, take that time out during the weekend for your health”.

This study was funded by grants from the National Natural Science Foundation of China and its Regional Innovation and Development Joint Foundation. Yu and Shaukat reported no disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — The session started with a question that many in the audience at Digestive Disease Week (DDW) 2025 seemed to relate to: “How many of you find yourself squeezing workouts into a weekend after a hectic work week?”

Although regular exercise three or more times a week is often viewed as preferable, Shiyi Yu, MD, a resident physician in the Department of Gastroenterology at Guangdong Provincial People’s Hospital in Guangzhou, China, had good news for weekend warriors.

Both patterns reduce digestive disease almost equally.

Her study compared weekend warriors with those she called “active regulars” and sedentary folks to see how activity patterns affect digestive disease risks.

Her bottom line: “Your gut does not care about your schedule.”

The researchers analyzed wrist-based accelerometer data from 89,595 participants in the UK Biobank. To categorize participants as active or inactive, they used the World Health Organization 2020 guidelines for physical activity, which recommend at least 150-300 minutes of moderate-intensity aerobic physical activity or at least 75-150 minutes of vigorous-intensity aerobic physical activity, or an equivalent combination throughout the week. Median age of participants was 63.3 years and 48.8% were men.

They divided participants into three groups:

• About 43% were weekend warriors who met or exceeded 150 minutes of moderate to vigorous physical activity (MVPA), with 50% or more of total MVPA achieved in 1-2 days.
• About 23% were active regulars who met or exceeded 150 minutes a week but spread over more days.
• About 34% were inactive participants who were active less than 150 minutes a week.

The researchers followed the participants for a median of 7.9 years, looking for the incidence of multiple digestive diseases, identified using the International Classification of Diseases, 10th Revision, codes. These included diverticulosis, constipation, metabolic dysfunction–associated steatotic liver disease, cholelithiasis, and gastroesophageal reflux disease. 

Both activity patterns “showed similar risk reduction with no significant difference,” Yu said. At the threshold ≥ 150 minutes, for instance, hazard ratios for any digestive disease were 0.83 for weekend warriors and 0.79 for active regulars, compared with sedentary participants.

The analysis was repeated using a median threshold ≥ 230.4 minutes of MVPA a week, and the researchers found the same results.

As a validation cohort, the researchers used more than 6,000 participants from the National Institutes of Health’s All of Us Research Program with over 6 months of wrist-based accelerometer data.

A recent meta-epidemiology study found that the weekend warrior pattern offers other health benefits, including reducing the risk for cardiovascular disease mortality, mental disorders, and metabolic syndrome.

 

A Pleasant Surprise

The digestive disease study’s findings were “a surprise and a pleasant one,” said Aasma Shaukat, MD, MPH, AGAF, professor of medicine and a gastroenterologist at NYU Grossman School of Medicine, New York City.

“We often think if we’re not able to exercise regularly, then there’s no hope for us,” said Shaukat, who moderated the session. “But this implies that even if we have time only during the weekend to engage in physical activity, it still confers benefits in reducing our risk of any GI health disorder, as well as cardiovascular or other health disorders, compared to people inactive at baseline.”

“It gives us flexibility in terms of how we structure our exercise. Obviously, people should try to get into the habit of doing regular activity; it’s more sustainable. But a good alternative, according to this research, is that packing all of that in over the weekend seems to confer benefit. So all is not lost.”

Will this change her conversation with patients moving forward? Absolutely, Shaukat said. She generally recommends physical activity for at least 30 minutes three times a week. Now Shaukat said she can tell patients: “If that’s not possible, take that time out during the weekend for your health”.

This study was funded by grants from the National Natural Science Foundation of China and its Regional Innovation and Development Joint Foundation. Yu and Shaukat reported no disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — The session started with a question that many in the audience at Digestive Disease Week (DDW) 2025 seemed to relate to: “How many of you find yourself squeezing workouts into a weekend after a hectic work week?”

Although regular exercise three or more times a week is often viewed as preferable, Shiyi Yu, MD, a resident physician in the Department of Gastroenterology at Guangdong Provincial People’s Hospital in Guangzhou, China, had good news for weekend warriors.

Both patterns reduce digestive disease almost equally.

Her study compared weekend warriors with those she called “active regulars” and sedentary folks to see how activity patterns affect digestive disease risks.

Her bottom line: “Your gut does not care about your schedule.”

The researchers analyzed wrist-based accelerometer data from 89,595 participants in the UK Biobank. To categorize participants as active or inactive, they used the World Health Organization 2020 guidelines for physical activity, which recommend at least 150-300 minutes of moderate-intensity aerobic physical activity or at least 75-150 minutes of vigorous-intensity aerobic physical activity, or an equivalent combination throughout the week. Median age of participants was 63.3 years and 48.8% were men.

They divided participants into three groups:

• About 43% were weekend warriors who met or exceeded 150 minutes of moderate to vigorous physical activity (MVPA), with 50% or more of total MVPA achieved in 1-2 days.
• About 23% were active regulars who met or exceeded 150 minutes a week but spread over more days.
• About 34% were inactive participants who were active less than 150 minutes a week.

The researchers followed the participants for a median of 7.9 years, looking for the incidence of multiple digestive diseases, identified using the International Classification of Diseases, 10th Revision, codes. These included diverticulosis, constipation, metabolic dysfunction–associated steatotic liver disease, cholelithiasis, and gastroesophageal reflux disease. 

Both activity patterns “showed similar risk reduction with no significant difference,” Yu said. At the threshold ≥ 150 minutes, for instance, hazard ratios for any digestive disease were 0.83 for weekend warriors and 0.79 for active regulars, compared with sedentary participants.

The analysis was repeated using a median threshold ≥ 230.4 minutes of MVPA a week, and the researchers found the same results.

As a validation cohort, the researchers used more than 6,000 participants from the National Institutes of Health’s All of Us Research Program with over 6 months of wrist-based accelerometer data.

A recent meta-epidemiology study found that the weekend warrior pattern offers other health benefits, including reducing the risk for cardiovascular disease mortality, mental disorders, and metabolic syndrome.

 

A Pleasant Surprise

The digestive disease study’s findings were “a surprise and a pleasant one,” said Aasma Shaukat, MD, MPH, AGAF, professor of medicine and a gastroenterologist at NYU Grossman School of Medicine, New York City.

“We often think if we’re not able to exercise regularly, then there’s no hope for us,” said Shaukat, who moderated the session. “But this implies that even if we have time only during the weekend to engage in physical activity, it still confers benefits in reducing our risk of any GI health disorder, as well as cardiovascular or other health disorders, compared to people inactive at baseline.”

“It gives us flexibility in terms of how we structure our exercise. Obviously, people should try to get into the habit of doing regular activity; it’s more sustainable. But a good alternative, according to this research, is that packing all of that in over the weekend seems to confer benefit. So all is not lost.”

Will this change her conversation with patients moving forward? Absolutely, Shaukat said. She generally recommends physical activity for at least 30 minutes three times a week. Now Shaukat said she can tell patients: “If that’s not possible, take that time out during the weekend for your health”.

This study was funded by grants from the National Natural Science Foundation of China and its Regional Innovation and Development Joint Foundation. Yu and Shaukat reported no disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — Patients with obesity and type 2 diabetes treated with glucagon-like peptide 1 (GLP-1) receptor agonists had significantly reduced rates of colorectal cancer (CRC) risk and associated mortality compared with those undergoing bariatric surgery, new research showed.

CRC risk was also lower for patients taking GLP-1s than the general population.

“Our findings show we might need to evaluate these therapies beyond their glycemic or weight loss [effects],” said first author Omar Al Ta’ani, MD, of the Allegheny Health Network, Pittsburgh.

This supports future prospective studies examining GLP-1s for CRC reduction, added Ta’ani, who presented the results at Digestive Disease Week (DDW) 2025.

Patients with type 2 diabetes and obesity are known to have a higher risk for CRC, stemming from metabolic risk factors. Whereas prior studies suggested that GLP-1s decrease the risk for CRC compared with other antidiabetic medications, studies looking at the risk for CRC associated with bariatric surgery have had more mixed results, Ta’ani said.

For the comparison, Ta’ani and colleagues conducted a retrospective analysis of the TriNetX database, identifying patients with type 2 diabetes and obesity (body mass index [BMI] > 30) enrolled in the database between 2005 and 2019.

Overall, the study included 94,098 GLP-1 users and 24,969 patients who underwent bariatric surgery. Those with a prior history of CRC were excluded.

Using propensity score matching, patients treated with GLP-1s were matched 1:1 with patients who had bariatric surgery based on wide-ranging factors including age, race, gender, demographics, diseases, medications, personal and family history, and hemoglobin A1c.

After the propensity matching, each group included 21,022 patients. About 64% in each group were women; their median age was 53 years and about 65% were White.

Overall, the results showed that patients on GLP-1s had a significantly lower CRC risk compared with those who had bariatric surgery (adjusted hazard ratio [aHR], 0.29; P < .0001). The lower risk was also observed among those with high obesity (defined as BMI > 35) compared with those who had surgery (aHR, 0.39; P < .0001).

The results were consistent across genders; however, the differences between GLP-1s and bariatric surgery were not observed in the 18- to 45-year-old age group (BMI > 30, P = .0809; BMI > 35, P = .2318).

Compared with the general population, patients on GLP-1s also had a reduced risk for CRC (aHR, 0.28; P < .0001); however, the difference was not observed between the bariatric surgery group and the general population (aHR, 1.11; P = .3).

Among patients with type 2 diabetes with CRC and a BMI > 30, the 5-year mortality rate was lower in the GLP-1 group vs the bariatric surgery group (aHR, 0.42; P < .001).

Speculating on the mechanisms of GLP-1s that could result in a greater reduction in CRC risk, Ta’ani explained that the key pathways linking type 2 diabetes, obesity, and CRC include hyperinsulinemia, chronic inflammation, and impaired immune surveillance.

Studies have shown that GLP-1s may be more effective in addressing the collective pathways, he said. They “may improve insulin resistance and lower systemic inflammation.” 

Furthermore, GLP1s “inhibit tumor pathways like Wnt/beta-catenin and PI3K/Akt/mTOR signaling, which promote apoptosis and reduce tumor cell proliferation,” he added.

 

Bariatric Surgery Findings Questioned

Meanwhile, “bariatric surgery’s impact on CRC remains mixed,” said Ta’ani.

Commenting on the study, Vance L. Albaugh, MD, an assistant professor of metabolic surgery at the Metamor Institute, Pennington Biomedical Research Center, Baton Rouge, Louisiana, noted that prior studies, including a recent meta-analysis, suggest a potential benefit of bariatric surgery in cancer prevention.

“I think the [current study] is interesting, but it’s been pretty [well-reported] that bariatric surgery does decrease cancer incidence, so I find it questionable that this study shows the opposite of what’s in the literature,” Albaugh, an obesity medicine specialist and bariatric surgeon, said in an interview.

Ta’ani acknowledged the study’s important limitations, including that with a retrospective design, causality cannot be firmly established.

And, as noted by an audience member in the session’s Q&A, the study ended in 2019, which was before GLP-1s had taken off as anti-obesity drugs and before US Food and Drug Administration approvals for weight loss.

Participants were matched based on BMI, however, Ta’ani pointed out.

Albaugh agreed that the study ending in 2019 was a notable limitation. However, the relatively long study period — extending from 2005 to 2019 — was a strength.

“It’s nice to have a very long period to capture people who are diagnosed, because it takes a long time to develop CRC,” he said. “To evaluate effects [of more recent drug regimens], you would not be able to have the follow-up they had.”

Other study limitations included the need to adjust for ranges of obesity severity, said Albaugh. “The risk of colorectal cancer is probably much different for someone with a BMI of 60 vs a BMI of 30.” 

Ultimately, a key question the study results raise is whether GLP-1 drugs have protective effects above and beyond that of weight loss, he said.

“I think that’s a very exciting question and that’s what I think the researchers’ next work should really focus on.”

Ta’ani had no disclosures to report. Albaugh reported that he had consulted for Novo Nordisk.

A version of this article appeared on Medscape.com.

SAN DIEGO — Patients with obesity and type 2 diabetes treated with glucagon-like peptide 1 (GLP-1) receptor agonists had significantly reduced rates of colorectal cancer (CRC) risk and associated mortality compared with those undergoing bariatric surgery, new research showed.

CRC risk was also lower for patients taking GLP-1s than the general population.

“Our findings show we might need to evaluate these therapies beyond their glycemic or weight loss [effects],” said first author Omar Al Ta’ani, MD, of the Allegheny Health Network, Pittsburgh.

This supports future prospective studies examining GLP-1s for CRC reduction, added Ta’ani, who presented the results at Digestive Disease Week (DDW) 2025.

Patients with type 2 diabetes and obesity are known to have a higher risk for CRC, stemming from metabolic risk factors. Whereas prior studies suggested that GLP-1s decrease the risk for CRC compared with other antidiabetic medications, studies looking at the risk for CRC associated with bariatric surgery have had more mixed results, Ta’ani said.

For the comparison, Ta’ani and colleagues conducted a retrospective analysis of the TriNetX database, identifying patients with type 2 diabetes and obesity (body mass index [BMI] > 30) enrolled in the database between 2005 and 2019.

Overall, the study included 94,098 GLP-1 users and 24,969 patients who underwent bariatric surgery. Those with a prior history of CRC were excluded.

Using propensity score matching, patients treated with GLP-1s were matched 1:1 with patients who had bariatric surgery based on wide-ranging factors including age, race, gender, demographics, diseases, medications, personal and family history, and hemoglobin A1c.

After the propensity matching, each group included 21,022 patients. About 64% in each group were women; their median age was 53 years and about 65% were White.

Overall, the results showed that patients on GLP-1s had a significantly lower CRC risk compared with those who had bariatric surgery (adjusted hazard ratio [aHR], 0.29; P < .0001). The lower risk was also observed among those with high obesity (defined as BMI > 35) compared with those who had surgery (aHR, 0.39; P < .0001).

The results were consistent across genders; however, the differences between GLP-1s and bariatric surgery were not observed in the 18- to 45-year-old age group (BMI > 30, P = .0809; BMI > 35, P = .2318).

Compared with the general population, patients on GLP-1s also had a reduced risk for CRC (aHR, 0.28; P < .0001); however, the difference was not observed between the bariatric surgery group and the general population (aHR, 1.11; P = .3).

Among patients with type 2 diabetes with CRC and a BMI > 30, the 5-year mortality rate was lower in the GLP-1 group vs the bariatric surgery group (aHR, 0.42; P < .001).

Speculating on the mechanisms of GLP-1s that could result in a greater reduction in CRC risk, Ta’ani explained that the key pathways linking type 2 diabetes, obesity, and CRC include hyperinsulinemia, chronic inflammation, and impaired immune surveillance.

Studies have shown that GLP-1s may be more effective in addressing the collective pathways, he said. They “may improve insulin resistance and lower systemic inflammation.” 

Furthermore, GLP1s “inhibit tumor pathways like Wnt/beta-catenin and PI3K/Akt/mTOR signaling, which promote apoptosis and reduce tumor cell proliferation,” he added.

 

Bariatric Surgery Findings Questioned

Meanwhile, “bariatric surgery’s impact on CRC remains mixed,” said Ta’ani.

Commenting on the study, Vance L. Albaugh, MD, an assistant professor of metabolic surgery at the Metamor Institute, Pennington Biomedical Research Center, Baton Rouge, Louisiana, noted that prior studies, including a recent meta-analysis, suggest a potential benefit of bariatric surgery in cancer prevention.

“I think the [current study] is interesting, but it’s been pretty [well-reported] that bariatric surgery does decrease cancer incidence, so I find it questionable that this study shows the opposite of what’s in the literature,” Albaugh, an obesity medicine specialist and bariatric surgeon, said in an interview.

Ta’ani acknowledged the study’s important limitations, including that with a retrospective design, causality cannot be firmly established.

And, as noted by an audience member in the session’s Q&A, the study ended in 2019, which was before GLP-1s had taken off as anti-obesity drugs and before US Food and Drug Administration approvals for weight loss.

Participants were matched based on BMI, however, Ta’ani pointed out.

Albaugh agreed that the study ending in 2019 was a notable limitation. However, the relatively long study period — extending from 2005 to 2019 — was a strength.

“It’s nice to have a very long period to capture people who are diagnosed, because it takes a long time to develop CRC,” he said. “To evaluate effects [of more recent drug regimens], you would not be able to have the follow-up they had.”

Other study limitations included the need to adjust for ranges of obesity severity, said Albaugh. “The risk of colorectal cancer is probably much different for someone with a BMI of 60 vs a BMI of 30.” 

Ultimately, a key question the study results raise is whether GLP-1 drugs have protective effects above and beyond that of weight loss, he said.

“I think that’s a very exciting question and that’s what I think the researchers’ next work should really focus on.”

Ta’ani had no disclosures to report. Albaugh reported that he had consulted for Novo Nordisk.

A version of this article appeared on Medscape.com.

SAN DIEGO — Patients with obesity and type 2 diabetes treated with glucagon-like peptide 1 (GLP-1) receptor agonists had significantly reduced rates of colorectal cancer (CRC) risk and associated mortality compared with those undergoing bariatric surgery, new research showed.

CRC risk was also lower for patients taking GLP-1s than the general population.

“Our findings show we might need to evaluate these therapies beyond their glycemic or weight loss [effects],” said first author Omar Al Ta’ani, MD, of the Allegheny Health Network, Pittsburgh.

This supports future prospective studies examining GLP-1s for CRC reduction, added Ta’ani, who presented the results at Digestive Disease Week (DDW) 2025.

Patients with type 2 diabetes and obesity are known to have a higher risk for CRC, stemming from metabolic risk factors. Whereas prior studies suggested that GLP-1s decrease the risk for CRC compared with other antidiabetic medications, studies looking at the risk for CRC associated with bariatric surgery have had more mixed results, Ta’ani said.

For the comparison, Ta’ani and colleagues conducted a retrospective analysis of the TriNetX database, identifying patients with type 2 diabetes and obesity (body mass index [BMI] > 30) enrolled in the database between 2005 and 2019.

Overall, the study included 94,098 GLP-1 users and 24,969 patients who underwent bariatric surgery. Those with a prior history of CRC were excluded.

Using propensity score matching, patients treated with GLP-1s were matched 1:1 with patients who had bariatric surgery based on wide-ranging factors including age, race, gender, demographics, diseases, medications, personal and family history, and hemoglobin A1c.

After the propensity matching, each group included 21,022 patients. About 64% in each group were women; their median age was 53 years and about 65% were White.

Overall, the results showed that patients on GLP-1s had a significantly lower CRC risk compared with those who had bariatric surgery (adjusted hazard ratio [aHR], 0.29; P < .0001). The lower risk was also observed among those with high obesity (defined as BMI > 35) compared with those who had surgery (aHR, 0.39; P < .0001).

The results were consistent across genders; however, the differences between GLP-1s and bariatric surgery were not observed in the 18- to 45-year-old age group (BMI > 30, P = .0809; BMI > 35, P = .2318).

Compared with the general population, patients on GLP-1s also had a reduced risk for CRC (aHR, 0.28; P < .0001); however, the difference was not observed between the bariatric surgery group and the general population (aHR, 1.11; P = .3).

Among patients with type 2 diabetes with CRC and a BMI > 30, the 5-year mortality rate was lower in the GLP-1 group vs the bariatric surgery group (aHR, 0.42; P < .001).

Speculating on the mechanisms of GLP-1s that could result in a greater reduction in CRC risk, Ta’ani explained that the key pathways linking type 2 diabetes, obesity, and CRC include hyperinsulinemia, chronic inflammation, and impaired immune surveillance.

Studies have shown that GLP-1s may be more effective in addressing the collective pathways, he said. They “may improve insulin resistance and lower systemic inflammation.” 

Furthermore, GLP1s “inhibit tumor pathways like Wnt/beta-catenin and PI3K/Akt/mTOR signaling, which promote apoptosis and reduce tumor cell proliferation,” he added.

 

Bariatric Surgery Findings Questioned

Meanwhile, “bariatric surgery’s impact on CRC remains mixed,” said Ta’ani.

Commenting on the study, Vance L. Albaugh, MD, an assistant professor of metabolic surgery at the Metamor Institute, Pennington Biomedical Research Center, Baton Rouge, Louisiana, noted that prior studies, including a recent meta-analysis, suggest a potential benefit of bariatric surgery in cancer prevention.

“I think the [current study] is interesting, but it’s been pretty [well-reported] that bariatric surgery does decrease cancer incidence, so I find it questionable that this study shows the opposite of what’s in the literature,” Albaugh, an obesity medicine specialist and bariatric surgeon, said in an interview.

Ta’ani acknowledged the study’s important limitations, including that with a retrospective design, causality cannot be firmly established.

And, as noted by an audience member in the session’s Q&A, the study ended in 2019, which was before GLP-1s had taken off as anti-obesity drugs and before US Food and Drug Administration approvals for weight loss.

Participants were matched based on BMI, however, Ta’ani pointed out.

Albaugh agreed that the study ending in 2019 was a notable limitation. However, the relatively long study period — extending from 2005 to 2019 — was a strength.

“It’s nice to have a very long period to capture people who are diagnosed, because it takes a long time to develop CRC,” he said. “To evaluate effects [of more recent drug regimens], you would not be able to have the follow-up they had.”

Other study limitations included the need to adjust for ranges of obesity severity, said Albaugh. “The risk of colorectal cancer is probably much different for someone with a BMI of 60 vs a BMI of 30.” 

Ultimately, a key question the study results raise is whether GLP-1 drugs have protective effects above and beyond that of weight loss, he said.

“I think that’s a very exciting question and that’s what I think the researchers’ next work should really focus on.”

Ta’ani had no disclosures to report. Albaugh reported that he had consulted for Novo Nordisk.

A version of this article appeared on Medscape.com.

SAN DIEGO — Molecular residual disease (MRD) positivity, as detected via circulating tumor (ct) DNA following curative resection, was significantly associated with improved disease-free survival after chemotherapy in patients with stage II or III colorectal cancer (CRC), the results of the BESPOKE study showed.

“These findings highlight the value of utilizing ctDNA to select which patients should receive management chemotherapy and which patients can be potentially spared chemotherapy’s physical, emotional, and financial toxicities without compromising their long-term outcomes,” said first author Kim Magee of Natera, a clinical genetic testing company in Austin, Texas.

“ctDNA is emerging as the most powerful and prognostic biomarker in colorectal cancer,” said Magee, who presented the findings at Digestive Disease Week (DDW) 2025.

In stage II CRC, as many as 80% of patients are cured by surgery alone, while only about 5% benefit from chemotherapy. In stage III CRC, about half of patients are cured by surgery alone, while only 20% benefit from chemotherapy, and 30% recur despite chemotherapy, Magee explained.

The inability to pinpoint which patients will most benefit from chemotherapy means “we know we are needlessly treating [many] of these patients,” she said.

 

ctDNA Offers Insights Into Tumor’s Real-Time Status

Just as cells release fragments (cell-free DNA) into the blood as they regenerate, tumor cells also release fragments — ctDNA — which can represent a biomarker of a cancer’s current state, Magee explained.

Because the DNA fragments have a half-life of only about 2 hours, they represent a key snapshot in real time, “as opposed to imaging, which can take several weeks or months to show changes,” she said.

To determine the effects of ctDNA testing on treatment decisions and asymptomatic recurrence rates, Magee and colleagues analyzed data from the multicenter, prospective study, which used the Signatera (Natera) residual disease test.

The study included 1794 patients with resected stage II-III CRC who were treated with the standard of care between May 2020 and March 2023 who had complete clinical and laboratory data available.

ctDNA was collected 2-6 weeks post surgery and at surveillance months 2, 4, 6, and every 3 months through month 24.

Among the 1166 patients included in a final analysis, 694 (59.5%) patients received adjunctive chemotherapy, and 472 (40.5%) received no chemotherapy.

Among those with stage II CRC, a postoperative MRD positivity rate was 7.54%, while the rate in those with stage III disease was 28.35%.

Overall, 16.1% of patients had a recurrence by the trial end at 24 months.

The results showed that among patients who tested negative for ctDNA, the disease-free survival estimates were highly favorable, at 91.8% for stage II and 87.4% for stage III CRC.

Comparatively, for those who were ctDNA-positive, disease-free survival rates were just 45.9% and 35.5%, respectively, regardless of whether those patients received adjunctive chemotherapy.

At the study’s first ctDNA surveillance timepoint, patients who were ctDNA-positive with stage II and III CRC combined had substantially worse disease-free survival than patients who were ctDNA-negative (HR, 26.4; P < .0001).

 

Impact of Chemotherapy

Patients who were found to be MRD-positive on ctDNA testing and treated with chemotherapy had a 40.3% 2-year disease-free survival rate compared with just 24.7% among MRD-positive patients who did not receive chemotherapy.

Meanwhile, those who were MRD-negative and treated with chemotherapy had a substantially higher 2-year disease-free survival rate of 89.7% — nearly identical to the 89.5% observed in the no-chemotherapy group.

The findings underscored that “the adjuvant chemotherapy benefits were only observed among those who were ctDNA-positive,” Magee said.

“ctDNA can guide postsurgical treatment decisions by identifying which patients are most likely to benefit from chemotherapy, and in the surveillance setting, ctDNA can predict recurrence — usually ahead of scans,” she added. “This opens the opportunity to intervene and give those patients a second chance at cure.”

On the heels of major recent advances including CT, MRI, and PET-CT, “we believe that ctDNA represents the next major pivotal advancement in monitoring and eventually better understanding cancer diagnostics,” Magee said.

 

Commenting on the study, William M. Grady, MD, AGAF, medical director of the Fred Hutchinson Cancer Center Gastrointestinal Cancer Prevention Clinic, Seattle, said the BESPOKE trial represents a “well-done” study, adding to research underscoring that “MRD testing is a more accurate prognostic assay than the current standards of CT scan and CEA [carcinoembryonic antigen, a tumor marker] testing.”

However, “a limitation is that this is 2 years of follow-up, [while] 5-year follow-up data would be ideal,” he said in an interview, noting, importantly, that “a small number of patients who have no evidence of disease (NED) at 2 years develop recurrence by 5 years.”

Furthermore, more research demonstrating the outcomes of MRD detection is needed, Grady added.

“A caveat is that studies are still needed showing that if you change your care of patients based on the MRD result, that you improve outcomes,” he said. “These studies are being planned and initiated at this time, from my understanding.”

Oncologists treating patients with CRC are commonly performing MRD assessment with ctDNA assays; however, Grady noted that the practice is still not the standard of care.

Regarding the suggestion of ctDNA representing the next major, pivotal step in cancer monitoring, Grady responded that “I think this is aspirational, and further studies are needed to make this claim.”

However, “it does look like it has the promise to turn out to be true.”

Magee is an employee of Nater. Grady has been on the scientific advisory boards for Guardant Health and Freenome and has consulted for Karius.

A version of this article appeared on Medscape.com.

SAN DIEGO — Molecular residual disease (MRD) positivity, as detected via circulating tumor (ct) DNA following curative resection, was significantly associated with improved disease-free survival after chemotherapy in patients with stage II or III colorectal cancer (CRC), the results of the BESPOKE study showed.

“These findings highlight the value of utilizing ctDNA to select which patients should receive management chemotherapy and which patients can be potentially spared chemotherapy’s physical, emotional, and financial toxicities without compromising their long-term outcomes,” said first author Kim Magee of Natera, a clinical genetic testing company in Austin, Texas.

“ctDNA is emerging as the most powerful and prognostic biomarker in colorectal cancer,” said Magee, who presented the findings at Digestive Disease Week (DDW) 2025.

In stage II CRC, as many as 80% of patients are cured by surgery alone, while only about 5% benefit from chemotherapy. In stage III CRC, about half of patients are cured by surgery alone, while only 20% benefit from chemotherapy, and 30% recur despite chemotherapy, Magee explained.

The inability to pinpoint which patients will most benefit from chemotherapy means “we know we are needlessly treating [many] of these patients,” she said.

 

ctDNA Offers Insights Into Tumor’s Real-Time Status

Just as cells release fragments (cell-free DNA) into the blood as they regenerate, tumor cells also release fragments — ctDNA — which can represent a biomarker of a cancer’s current state, Magee explained.

Because the DNA fragments have a half-life of only about 2 hours, they represent a key snapshot in real time, “as opposed to imaging, which can take several weeks or months to show changes,” she said.

To determine the effects of ctDNA testing on treatment decisions and asymptomatic recurrence rates, Magee and colleagues analyzed data from the multicenter, prospective study, which used the Signatera (Natera) residual disease test.

The study included 1794 patients with resected stage II-III CRC who were treated with the standard of care between May 2020 and March 2023 who had complete clinical and laboratory data available.

ctDNA was collected 2-6 weeks post surgery and at surveillance months 2, 4, 6, and every 3 months through month 24.

Among the 1166 patients included in a final analysis, 694 (59.5%) patients received adjunctive chemotherapy, and 472 (40.5%) received no chemotherapy.

Among those with stage II CRC, a postoperative MRD positivity rate was 7.54%, while the rate in those with stage III disease was 28.35%.

Overall, 16.1% of patients had a recurrence by the trial end at 24 months.

The results showed that among patients who tested negative for ctDNA, the disease-free survival estimates were highly favorable, at 91.8% for stage II and 87.4% for stage III CRC.

Comparatively, for those who were ctDNA-positive, disease-free survival rates were just 45.9% and 35.5%, respectively, regardless of whether those patients received adjunctive chemotherapy.

At the study’s first ctDNA surveillance timepoint, patients who were ctDNA-positive with stage II and III CRC combined had substantially worse disease-free survival than patients who were ctDNA-negative (HR, 26.4; P < .0001).

 

Impact of Chemotherapy

Patients who were found to be MRD-positive on ctDNA testing and treated with chemotherapy had a 40.3% 2-year disease-free survival rate compared with just 24.7% among MRD-positive patients who did not receive chemotherapy.

Meanwhile, those who were MRD-negative and treated with chemotherapy had a substantially higher 2-year disease-free survival rate of 89.7% — nearly identical to the 89.5% observed in the no-chemotherapy group.

The findings underscored that “the adjuvant chemotherapy benefits were only observed among those who were ctDNA-positive,” Magee said.

“ctDNA can guide postsurgical treatment decisions by identifying which patients are most likely to benefit from chemotherapy, and in the surveillance setting, ctDNA can predict recurrence — usually ahead of scans,” she added. “This opens the opportunity to intervene and give those patients a second chance at cure.”

On the heels of major recent advances including CT, MRI, and PET-CT, “we believe that ctDNA represents the next major pivotal advancement in monitoring and eventually better understanding cancer diagnostics,” Magee said.

 

Commenting on the study, William M. Grady, MD, AGAF, medical director of the Fred Hutchinson Cancer Center Gastrointestinal Cancer Prevention Clinic, Seattle, said the BESPOKE trial represents a “well-done” study, adding to research underscoring that “MRD testing is a more accurate prognostic assay than the current standards of CT scan and CEA [carcinoembryonic antigen, a tumor marker] testing.”

However, “a limitation is that this is 2 years of follow-up, [while] 5-year follow-up data would be ideal,” he said in an interview, noting, importantly, that “a small number of patients who have no evidence of disease (NED) at 2 years develop recurrence by 5 years.”

Furthermore, more research demonstrating the outcomes of MRD detection is needed, Grady added.

“A caveat is that studies are still needed showing that if you change your care of patients based on the MRD result, that you improve outcomes,” he said. “These studies are being planned and initiated at this time, from my understanding.”

Oncologists treating patients with CRC are commonly performing MRD assessment with ctDNA assays; however, Grady noted that the practice is still not the standard of care.

Regarding the suggestion of ctDNA representing the next major, pivotal step in cancer monitoring, Grady responded that “I think this is aspirational, and further studies are needed to make this claim.”

However, “it does look like it has the promise to turn out to be true.”

Magee is an employee of Nater. Grady has been on the scientific advisory boards for Guardant Health and Freenome and has consulted for Karius.

A version of this article appeared on Medscape.com.

SAN DIEGO — Molecular residual disease (MRD) positivity, as detected via circulating tumor (ct) DNA following curative resection, was significantly associated with improved disease-free survival after chemotherapy in patients with stage II or III colorectal cancer (CRC), the results of the BESPOKE study showed.

“These findings highlight the value of utilizing ctDNA to select which patients should receive management chemotherapy and which patients can be potentially spared chemotherapy’s physical, emotional, and financial toxicities without compromising their long-term outcomes,” said first author Kim Magee of Natera, a clinical genetic testing company in Austin, Texas.

“ctDNA is emerging as the most powerful and prognostic biomarker in colorectal cancer,” said Magee, who presented the findings at Digestive Disease Week (DDW) 2025.

In stage II CRC, as many as 80% of patients are cured by surgery alone, while only about 5% benefit from chemotherapy. In stage III CRC, about half of patients are cured by surgery alone, while only 20% benefit from chemotherapy, and 30% recur despite chemotherapy, Magee explained.

The inability to pinpoint which patients will most benefit from chemotherapy means “we know we are needlessly treating [many] of these patients,” she said.

 

ctDNA Offers Insights Into Tumor’s Real-Time Status

Just as cells release fragments (cell-free DNA) into the blood as they regenerate, tumor cells also release fragments — ctDNA — which can represent a biomarker of a cancer’s current state, Magee explained.

Because the DNA fragments have a half-life of only about 2 hours, they represent a key snapshot in real time, “as opposed to imaging, which can take several weeks or months to show changes,” she said.

To determine the effects of ctDNA testing on treatment decisions and asymptomatic recurrence rates, Magee and colleagues analyzed data from the multicenter, prospective study, which used the Signatera (Natera) residual disease test.

The study included 1794 patients with resected stage II-III CRC who were treated with the standard of care between May 2020 and March 2023 who had complete clinical and laboratory data available.

ctDNA was collected 2-6 weeks post surgery and at surveillance months 2, 4, 6, and every 3 months through month 24.

Among the 1166 patients included in a final analysis, 694 (59.5%) patients received adjunctive chemotherapy, and 472 (40.5%) received no chemotherapy.

Among those with stage II CRC, a postoperative MRD positivity rate was 7.54%, while the rate in those with stage III disease was 28.35%.

Overall, 16.1% of patients had a recurrence by the trial end at 24 months.

The results showed that among patients who tested negative for ctDNA, the disease-free survival estimates were highly favorable, at 91.8% for stage II and 87.4% for stage III CRC.

Comparatively, for those who were ctDNA-positive, disease-free survival rates were just 45.9% and 35.5%, respectively, regardless of whether those patients received adjunctive chemotherapy.

At the study’s first ctDNA surveillance timepoint, patients who were ctDNA-positive with stage II and III CRC combined had substantially worse disease-free survival than patients who were ctDNA-negative (HR, 26.4; P < .0001).

 

Impact of Chemotherapy

Patients who were found to be MRD-positive on ctDNA testing and treated with chemotherapy had a 40.3% 2-year disease-free survival rate compared with just 24.7% among MRD-positive patients who did not receive chemotherapy.

Meanwhile, those who were MRD-negative and treated with chemotherapy had a substantially higher 2-year disease-free survival rate of 89.7% — nearly identical to the 89.5% observed in the no-chemotherapy group.

The findings underscored that “the adjuvant chemotherapy benefits were only observed among those who were ctDNA-positive,” Magee said.

“ctDNA can guide postsurgical treatment decisions by identifying which patients are most likely to benefit from chemotherapy, and in the surveillance setting, ctDNA can predict recurrence — usually ahead of scans,” she added. “This opens the opportunity to intervene and give those patients a second chance at cure.”

On the heels of major recent advances including CT, MRI, and PET-CT, “we believe that ctDNA represents the next major pivotal advancement in monitoring and eventually better understanding cancer diagnostics,” Magee said.

 

Commenting on the study, William M. Grady, MD, AGAF, medical director of the Fred Hutchinson Cancer Center Gastrointestinal Cancer Prevention Clinic, Seattle, said the BESPOKE trial represents a “well-done” study, adding to research underscoring that “MRD testing is a more accurate prognostic assay than the current standards of CT scan and CEA [carcinoembryonic antigen, a tumor marker] testing.”

However, “a limitation is that this is 2 years of follow-up, [while] 5-year follow-up data would be ideal,” he said in an interview, noting, importantly, that “a small number of patients who have no evidence of disease (NED) at 2 years develop recurrence by 5 years.”

Furthermore, more research demonstrating the outcomes of MRD detection is needed, Grady added.

“A caveat is that studies are still needed showing that if you change your care of patients based on the MRD result, that you improve outcomes,” he said. “These studies are being planned and initiated at this time, from my understanding.”

Oncologists treating patients with CRC are commonly performing MRD assessment with ctDNA assays; however, Grady noted that the practice is still not the standard of care.

Regarding the suggestion of ctDNA representing the next major, pivotal step in cancer monitoring, Grady responded that “I think this is aspirational, and further studies are needed to make this claim.”

However, “it does look like it has the promise to turn out to be true.”

Magee is an employee of Nater. Grady has been on the scientific advisory boards for Guardant Health and Freenome and has consulted for Karius.

A version of this article appeared on Medscape.com.

SAN DIEGO — Patients with cirrhosis treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors show significant reductions in a range of portal hypertension complications and all-cause mortality compared with those not receiving the drugs, new research shows.

“Our study found that SGLT2 inhibitors were associated with fewer portal hypertension complications and lower mortality, suggesting they may be a valuable addition to cirrhosis management,” first author Abhinav K. Rao, MD, of the Medical University of South Carolina, Charleston, South Carolina, told GI & Hepatology News.

The findings were presented at Digestive Disease Week (DDW) 2025.

Portal hypertension, a potentially life-threatening complication of cirrhosis, can be a key driver of additional complications including ascites and gastro-esophageal varices in cirrhosis.

Current treatments such as beta-blockers can prevent some complications, however, more effective therapies are needed.

SGLT2 inhibitors are often used in the treatment of cardiovascular disease as well as metabolic dysfunction–associated steatohepatitis (MASH)–mediated liver disease; research is lacking regarding their effects in portal hypertension in the broader population of people with cirrhosis.

“The therapeutic efficacy of SGLT2 inhibitors might be related to their ability to improve vascular function, making them attractive in portal hypertension,” Rao explained.

To investigate, Rao and colleagues evaluated data on 637,079 patients with cirrhosis in the TriNetX database, which includes patients in the United States from 66 healthcare organizations.

Patients were divided into three subgroups, including those with MASH, alcohol-associated, and other etiologies of cirrhosis.

Using robust 1:1 propensity score matching, patients in each subgroup were stratified as either having or not having been treated with SGLT2 inhibitors, limited to those who initiated the drugs within 1 year of their cirrhosis diagnosis to prevent immortal time bias. Patients were matched on other characteristics.

For the primary outcome of all-cause mortality, with an overall median follow-up of 2 years, patients prescribed SGLT2 inhibitors in the MASH cirrhosis (n = 47,385), alcohol-associated cirrhosis (n = 107,844), and other etiologies of cirrhosis (n = 59,499) groups all had a significantly lower risk for all-cause mortality than those not prescribed SGLT2 inhibitors (P < .05 for all).

 

SGLT2 Inhibitors in MASH Cirrhosis

Specifically looking at the MASH cirrhosis group, Rao described outcomes of the two groups of 3026 patients each who were and were not treated with SGLT2 inhibitors.

The patients had similar rates of esophageal varices (25% in the SGLT2 group and 22% in the no SGLT2 group), ascites (19% in each group), and a similar rate of 19% had hepatic encephalopathy (HE).

About 57% of patients in each treatment group used beta-blockers and 33% used glucagon-like peptide 1 (GLP-1) receptor agonists. Those with a history of liver transplantation, hemodialysis, or transjugular intrahepatic portosystemic shunt placement were excluded.

The secondary outcome results in those patients showed that treatment with SGLT2 inhibitors was associated with significantly reduced risks of developing portal hypertension complications including ascites, HE, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (P < .05 for all).

Esophageal variceal bleeding was also reduced with SGLT-2 inhibitors; however the difference was not statistically significant.

 

Effects Diminished With Beta-Blocker Treatment

In a secondary analysis of patients in the MASH cirrhosis group treated with one type of a nonselective beta-blockers (n = 509) and another nonselective beta-blockers (n = 2561), the beneficial effects of SGLT2 inhibitors on portal hypertension, with the exception of HE and SBP, were found to be somewhat diminished, likely because patients were already benefitting from the beta-blockers, Rao noted.

Other Groups

In outcomes of the non–MASH-related cirrhosis groups, patients prescribed SGLT2 inhibitors also had a reduced risk for specific, as well as any portal hypertension complications (P < .05), Rao noted.

Overall, the findings add to previous studies on SGLT2 inhibitors in MASH and expand on the possible benefits, he said.

“Our findings validate these [previous] results and suggest potential benefits across for patients with other types of liver disease and raise the possibility of a beneficial effect in portal hypertension,” he said.

“Given the marked reduction in portal hypertension complications after SGLT2 inhibitor initiation, the associated survival benefit may not be surprising,” he noted.

“However, we were intrigued by the consistent reduction in portal hypertension complications across all cirrhosis types, especially since SGLT-2 inhibitors are most commonly used in patients with diabetes who have MASH-mediated liver disease.”

 

‘Real World Glimpse’ at SGLT2 Inhibitors; Limitations Need Noting 

Commenting on the study, Rotonya M. Carr, MD, Division Head of Gastroenterology at the University of Washington, Seattle, said the study sheds important light on an issue previously addressed only in smaller cohorts.

“To date, there have only been a few small prospective, retrospective, and case series studies investigating SGTL2 inhibitors in patients with cirrhosis,” she told GI & Hepatology Newsv.

“This retrospective study is a real-world glimpse at how patients with cirrhosis may fare on these drugs — very exciting data.”

Carr cautioned, however, that, in addition to the retrospective study design, limitations included that the study doesn’t provide details on the duration of therapy, preventing an understanding of whether the results represent chronic, sustained use of SGLT2 inhibitors.

“[Therefore], we cannot interpret these results to mean that chronic, sustained use of SGTL2 inh is beneficial, or does not cause harm, in patients with cirrhosis.”

“While these data are provocative, more work needs to be done before we understand the full safety and efficacy of SGTL2 inhibitors for patients with cirrhosis,” Carr added.

“However, these data are very encouraging, and I am optimistic that we will indeed see both SGTL2 inhibitors and GLP-1s among the group of medications we use in the future for the primary management of patients with liver disease.”

The authors had no disclosures to report. Carr’s disclosures included relationships with Intercept and Novo Nordisk and research funding from Merck.

A version of this article appeared on Medscape.com.

SAN DIEGO — Patients with cirrhosis treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors show significant reductions in a range of portal hypertension complications and all-cause mortality compared with those not receiving the drugs, new research shows.

“Our study found that SGLT2 inhibitors were associated with fewer portal hypertension complications and lower mortality, suggesting they may be a valuable addition to cirrhosis management,” first author Abhinav K. Rao, MD, of the Medical University of South Carolina, Charleston, South Carolina, told GI & Hepatology News.

The findings were presented at Digestive Disease Week (DDW) 2025.

Portal hypertension, a potentially life-threatening complication of cirrhosis, can be a key driver of additional complications including ascites and gastro-esophageal varices in cirrhosis.

Current treatments such as beta-blockers can prevent some complications, however, more effective therapies are needed.

SGLT2 inhibitors are often used in the treatment of cardiovascular disease as well as metabolic dysfunction–associated steatohepatitis (MASH)–mediated liver disease; research is lacking regarding their effects in portal hypertension in the broader population of people with cirrhosis.

“The therapeutic efficacy of SGLT2 inhibitors might be related to their ability to improve vascular function, making them attractive in portal hypertension,” Rao explained.

To investigate, Rao and colleagues evaluated data on 637,079 patients with cirrhosis in the TriNetX database, which includes patients in the United States from 66 healthcare organizations.

Patients were divided into three subgroups, including those with MASH, alcohol-associated, and other etiologies of cirrhosis.

Using robust 1:1 propensity score matching, patients in each subgroup were stratified as either having or not having been treated with SGLT2 inhibitors, limited to those who initiated the drugs within 1 year of their cirrhosis diagnosis to prevent immortal time bias. Patients were matched on other characteristics.

For the primary outcome of all-cause mortality, with an overall median follow-up of 2 years, patients prescribed SGLT2 inhibitors in the MASH cirrhosis (n = 47,385), alcohol-associated cirrhosis (n = 107,844), and other etiologies of cirrhosis (n = 59,499) groups all had a significantly lower risk for all-cause mortality than those not prescribed SGLT2 inhibitors (P < .05 for all).

 

SGLT2 Inhibitors in MASH Cirrhosis

Specifically looking at the MASH cirrhosis group, Rao described outcomes of the two groups of 3026 patients each who were and were not treated with SGLT2 inhibitors.

The patients had similar rates of esophageal varices (25% in the SGLT2 group and 22% in the no SGLT2 group), ascites (19% in each group), and a similar rate of 19% had hepatic encephalopathy (HE).

About 57% of patients in each treatment group used beta-blockers and 33% used glucagon-like peptide 1 (GLP-1) receptor agonists. Those with a history of liver transplantation, hemodialysis, or transjugular intrahepatic portosystemic shunt placement were excluded.

The secondary outcome results in those patients showed that treatment with SGLT2 inhibitors was associated with significantly reduced risks of developing portal hypertension complications including ascites, HE, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (P < .05 for all).

Esophageal variceal bleeding was also reduced with SGLT-2 inhibitors; however the difference was not statistically significant.

 

Effects Diminished With Beta-Blocker Treatment

In a secondary analysis of patients in the MASH cirrhosis group treated with one type of a nonselective beta-blockers (n = 509) and another nonselective beta-blockers (n = 2561), the beneficial effects of SGLT2 inhibitors on portal hypertension, with the exception of HE and SBP, were found to be somewhat diminished, likely because patients were already benefitting from the beta-blockers, Rao noted.

Other Groups

In outcomes of the non–MASH-related cirrhosis groups, patients prescribed SGLT2 inhibitors also had a reduced risk for specific, as well as any portal hypertension complications (P < .05), Rao noted.

Overall, the findings add to previous studies on SGLT2 inhibitors in MASH and expand on the possible benefits, he said.

“Our findings validate these [previous] results and suggest potential benefits across for patients with other types of liver disease and raise the possibility of a beneficial effect in portal hypertension,” he said.

“Given the marked reduction in portal hypertension complications after SGLT2 inhibitor initiation, the associated survival benefit may not be surprising,” he noted.

“However, we were intrigued by the consistent reduction in portal hypertension complications across all cirrhosis types, especially since SGLT-2 inhibitors are most commonly used in patients with diabetes who have MASH-mediated liver disease.”

 

‘Real World Glimpse’ at SGLT2 Inhibitors; Limitations Need Noting 

Commenting on the study, Rotonya M. Carr, MD, Division Head of Gastroenterology at the University of Washington, Seattle, said the study sheds important light on an issue previously addressed only in smaller cohorts.

“To date, there have only been a few small prospective, retrospective, and case series studies investigating SGTL2 inhibitors in patients with cirrhosis,” she told GI & Hepatology Newsv.

“This retrospective study is a real-world glimpse at how patients with cirrhosis may fare on these drugs — very exciting data.”

Carr cautioned, however, that, in addition to the retrospective study design, limitations included that the study doesn’t provide details on the duration of therapy, preventing an understanding of whether the results represent chronic, sustained use of SGLT2 inhibitors.

“[Therefore], we cannot interpret these results to mean that chronic, sustained use of SGTL2 inh is beneficial, or does not cause harm, in patients with cirrhosis.”

“While these data are provocative, more work needs to be done before we understand the full safety and efficacy of SGTL2 inhibitors for patients with cirrhosis,” Carr added.

“However, these data are very encouraging, and I am optimistic that we will indeed see both SGTL2 inhibitors and GLP-1s among the group of medications we use in the future for the primary management of patients with liver disease.”

The authors had no disclosures to report. Carr’s disclosures included relationships with Intercept and Novo Nordisk and research funding from Merck.

A version of this article appeared on Medscape.com.

SAN DIEGO — Patients with cirrhosis treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors show significant reductions in a range of portal hypertension complications and all-cause mortality compared with those not receiving the drugs, new research shows.

“Our study found that SGLT2 inhibitors were associated with fewer portal hypertension complications and lower mortality, suggesting they may be a valuable addition to cirrhosis management,” first author Abhinav K. Rao, MD, of the Medical University of South Carolina, Charleston, South Carolina, told GI & Hepatology News.

The findings were presented at Digestive Disease Week (DDW) 2025.

Portal hypertension, a potentially life-threatening complication of cirrhosis, can be a key driver of additional complications including ascites and gastro-esophageal varices in cirrhosis.

Current treatments such as beta-blockers can prevent some complications, however, more effective therapies are needed.

SGLT2 inhibitors are often used in the treatment of cardiovascular disease as well as metabolic dysfunction–associated steatohepatitis (MASH)–mediated liver disease; research is lacking regarding their effects in portal hypertension in the broader population of people with cirrhosis.

“The therapeutic efficacy of SGLT2 inhibitors might be related to their ability to improve vascular function, making them attractive in portal hypertension,” Rao explained.

To investigate, Rao and colleagues evaluated data on 637,079 patients with cirrhosis in the TriNetX database, which includes patients in the United States from 66 healthcare organizations.

Patients were divided into three subgroups, including those with MASH, alcohol-associated, and other etiologies of cirrhosis.

Using robust 1:1 propensity score matching, patients in each subgroup were stratified as either having or not having been treated with SGLT2 inhibitors, limited to those who initiated the drugs within 1 year of their cirrhosis diagnosis to prevent immortal time bias. Patients were matched on other characteristics.

For the primary outcome of all-cause mortality, with an overall median follow-up of 2 years, patients prescribed SGLT2 inhibitors in the MASH cirrhosis (n = 47,385), alcohol-associated cirrhosis (n = 107,844), and other etiologies of cirrhosis (n = 59,499) groups all had a significantly lower risk for all-cause mortality than those not prescribed SGLT2 inhibitors (P < .05 for all).

 

SGLT2 Inhibitors in MASH Cirrhosis

Specifically looking at the MASH cirrhosis group, Rao described outcomes of the two groups of 3026 patients each who were and were not treated with SGLT2 inhibitors.

The patients had similar rates of esophageal varices (25% in the SGLT2 group and 22% in the no SGLT2 group), ascites (19% in each group), and a similar rate of 19% had hepatic encephalopathy (HE).

About 57% of patients in each treatment group used beta-blockers and 33% used glucagon-like peptide 1 (GLP-1) receptor agonists. Those with a history of liver transplantation, hemodialysis, or transjugular intrahepatic portosystemic shunt placement were excluded.

The secondary outcome results in those patients showed that treatment with SGLT2 inhibitors was associated with significantly reduced risks of developing portal hypertension complications including ascites, HE, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (P < .05 for all).

Esophageal variceal bleeding was also reduced with SGLT-2 inhibitors; however the difference was not statistically significant.

 

Effects Diminished With Beta-Blocker Treatment

In a secondary analysis of patients in the MASH cirrhosis group treated with one type of a nonselective beta-blockers (n = 509) and another nonselective beta-blockers (n = 2561), the beneficial effects of SGLT2 inhibitors on portal hypertension, with the exception of HE and SBP, were found to be somewhat diminished, likely because patients were already benefitting from the beta-blockers, Rao noted.

Other Groups

In outcomes of the non–MASH-related cirrhosis groups, patients prescribed SGLT2 inhibitors also had a reduced risk for specific, as well as any portal hypertension complications (P < .05), Rao noted.

Overall, the findings add to previous studies on SGLT2 inhibitors in MASH and expand on the possible benefits, he said.

“Our findings validate these [previous] results and suggest potential benefits across for patients with other types of liver disease and raise the possibility of a beneficial effect in portal hypertension,” he said.

“Given the marked reduction in portal hypertension complications after SGLT2 inhibitor initiation, the associated survival benefit may not be surprising,” he noted.

“However, we were intrigued by the consistent reduction in portal hypertension complications across all cirrhosis types, especially since SGLT-2 inhibitors are most commonly used in patients with diabetes who have MASH-mediated liver disease.”

 

‘Real World Glimpse’ at SGLT2 Inhibitors; Limitations Need Noting 

Commenting on the study, Rotonya M. Carr, MD, Division Head of Gastroenterology at the University of Washington, Seattle, said the study sheds important light on an issue previously addressed only in smaller cohorts.

“To date, there have only been a few small prospective, retrospective, and case series studies investigating SGTL2 inhibitors in patients with cirrhosis,” she told GI & Hepatology Newsv.

“This retrospective study is a real-world glimpse at how patients with cirrhosis may fare on these drugs — very exciting data.”

Carr cautioned, however, that, in addition to the retrospective study design, limitations included that the study doesn’t provide details on the duration of therapy, preventing an understanding of whether the results represent chronic, sustained use of SGLT2 inhibitors.

“[Therefore], we cannot interpret these results to mean that chronic, sustained use of SGTL2 inh is beneficial, or does not cause harm, in patients with cirrhosis.”

“While these data are provocative, more work needs to be done before we understand the full safety and efficacy of SGTL2 inhibitors for patients with cirrhosis,” Carr added.

“However, these data are very encouraging, and I am optimistic that we will indeed see both SGTL2 inhibitors and GLP-1s among the group of medications we use in the future for the primary management of patients with liver disease.”

The authors had no disclosures to report. Carr’s disclosures included relationships with Intercept and Novo Nordisk and research funding from Merck.

A version of this article appeared on Medscape.com.

SAN DIEGO — An artificial intelligence (AI)–enhanced digital collaborative care model led to rapid, clinically significant, and sustained symptom relief for patients with irritable bowel syndrome (IBS) seen at Cleveland Clinic, Cleveland, Ohio, an observational study found.

Symptom tracking at 4-week intervals showed that “almost everybody got better” regardless of IBS subtype, with relief starting in the first 4 weeks, Stephen Lupe, PsyD, gastrointestinal psychologist and director of Behavioral Medicine, Department of Gastroenterology, Hepatology, and Nutrition at Cleveland Clinic, Cleveland, said in an interview with GI & Hepatology News.

The findings were presented at Digestive Disease Week (DDW) 2025.

 

Digital Boost to Collaborative Care Model

The combination of dietary interventions and brain-gut behavioral therapy has demonstrated excellent outcomes for patients with IBS, but patients struggle to access these needed services, Lupe noted. A medical home collaborative care model in which patients get care from a multidisciplinary team has been shown to be a good way to successfully deliver this combination of care.

“When you do collaborative in-person care, people get better quicker,” Lupe said.

However, scaling access to this model remains a challenge. For their study, Cleveland Clinic researchers added an AI-enhanced digital platform, Ayble Health, to the in-person collaborative care model to expand access to disease-management services and evaluated whether it improved clinical outcomes for study’s 171 participants, who were recruited via social media advertisements.

Here’s how the platform works. Once a patient enrolls in Ayble Health, a personalized care plan is recommended based on a virtual visit, screening questionnaire, and baseline survey.

The platform includes brain-gut programs, including guided audio content on mindfulness, hypnosis, meditation, cognitive behavioral therapy, and breathing techniques; personalized nutrition support to find and remove trigger foods, a food barcode scanner, and a comprehensive groceries database; and AI-powered wellness tools to help manage and track symptoms. Lupe worked with Ayble Health to develop the platform’s behavioral health content and care pathways.

Patients may choose to follow any combination of three care pathways: A care team overseen by gastro-psychologists, dietitians, and gastroenterologists; a holistic nutrition program including a personalized elimination diet; and a brain-gut behavioral therapy program with gut-directed hypnosis, cognitive behavioral therapy, and acceptance and commitment therapy. They go at their own pace, can connect with Ayble Health’s virtual care team to help with education and goal setting, and continue to consult their Cleveland Clinic providers as needed for evaluation and treatment.

“The care team is still there. We’ve just augmented it to make sure that as many people as possible get behavioral skills training and dietary support, with monitoring between visits — instead of the traditional, ‘I’ll see you in 6 months approach,” Lupe explained.

 

IBS Symptom Scores Improve

Of the study’s 171 patients, 20 had IBS-diarrhea, 23 had IBS-constipation, 32 had IBS-mixed, and 8 had IBS-unspecified. The remaining 88 patients reported IBS without indication of subtype.

At intake, all patients had active IBS symptoms, with scores ≥ 75 on the IBS symptom severity scale (IBS-SSS). Most patients enrolled in more than one care pathway, and 95% of participants completed at least 4 weeks on their chosen pathways.

Overall, patients saw an average 140-point decrease in IBS-SSS from intake through follow-up lasting up to 42 weeks. A drop in IBS-SSS score ≥ 50 points was considered a clinically meaningful change.

Symptom improvements occurred as early as week 4, were sustained and were uniform across IBS subtypes, suggesting that the AI-enhanced digital collaborative care model has wide utility in patients with IBS, Lupe said.

Patients with the most severe IBS symptoms showed the greatest improvement, but even 50% of those with mild symptoms had clinically meaningful changes in IBS-SSS.

Improvement in IBS symptoms was seen across all care pathways, but the combination of multiple pathways improved outcomes better than a single care pathway alone. The combination of nutrition and brain-gut behavioral therapy demonstrated the greatest reduction in IBS-SSS scores and proportion of patients achieving clinically meaningful results (95%).

The digital comprehensive car model for IBS is now “up and running” at Cleveland Clinic, and the team plans to proactively reach out to patients with gastrointestinal disorders recently seen at their center to alert them to the availability of this tool, Lupe said.

A randomized controlled trial is planned to further validate these observational findings, he added.

 

‘Wave of the Future’

The digital collaborative care model is “innovative, and I think is the wave of the future,” Kyle Staller, MD, MPH, gastroenterologist and director of the Gastrointestinal Motility Laboratory at Massachusetts General Hospital, Boston, who wasn’t involved in the study, told GI & Hepatology News.

“These digital platforms bundle nondrug options, such as cognitive-behavioral therapy, dietary therapy, hypnotherapy, so patients can choose what suits them, rather than the gastroenterologist hunting down each individual resource, which requires a lot of work,” Staller said.

The study “provides real-world evidence that a deliberative, digital, collaborative care model that houses various types of nondrug IBS treatment under one roof can provide meaningful benefit to patients,” Staller told GI & Hepatology News.

Importantly, he said, “patients chose which option they wanted. At the end of the day, the way that we should be thinking about IBS care is really making sure that we engage the patient with treatment choices,” Staller said.

This study had no specific funding. Three authors had relationships with Ayble Health. Lupe is a scientific advisor for Boomerang Health and paid lecturer for Takeda Pharmaceuticals. Staller disclosed having relationships with Mahana Therapeutics, Ardelyx Inc, Gemelli Biotech, Salix Pharmaceuticals, and Takeda Pharmaceuticals.

A version of this article appeared on Medscape.com.

SAN DIEGO — An artificial intelligence (AI)–enhanced digital collaborative care model led to rapid, clinically significant, and sustained symptom relief for patients with irritable bowel syndrome (IBS) seen at Cleveland Clinic, Cleveland, Ohio, an observational study found.

Symptom tracking at 4-week intervals showed that “almost everybody got better” regardless of IBS subtype, with relief starting in the first 4 weeks, Stephen Lupe, PsyD, gastrointestinal psychologist and director of Behavioral Medicine, Department of Gastroenterology, Hepatology, and Nutrition at Cleveland Clinic, Cleveland, said in an interview with GI & Hepatology News.

The findings were presented at Digestive Disease Week (DDW) 2025.

 

Digital Boost to Collaborative Care Model

The combination of dietary interventions and brain-gut behavioral therapy has demonstrated excellent outcomes for patients with IBS, but patients struggle to access these needed services, Lupe noted. A medical home collaborative care model in which patients get care from a multidisciplinary team has been shown to be a good way to successfully deliver this combination of care.

“When you do collaborative in-person care, people get better quicker,” Lupe said.

However, scaling access to this model remains a challenge. For their study, Cleveland Clinic researchers added an AI-enhanced digital platform, Ayble Health, to the in-person collaborative care model to expand access to disease-management services and evaluated whether it improved clinical outcomes for study’s 171 participants, who were recruited via social media advertisements.

Here’s how the platform works. Once a patient enrolls in Ayble Health, a personalized care plan is recommended based on a virtual visit, screening questionnaire, and baseline survey.

The platform includes brain-gut programs, including guided audio content on mindfulness, hypnosis, meditation, cognitive behavioral therapy, and breathing techniques; personalized nutrition support to find and remove trigger foods, a food barcode scanner, and a comprehensive groceries database; and AI-powered wellness tools to help manage and track symptoms. Lupe worked with Ayble Health to develop the platform’s behavioral health content and care pathways.

Patients may choose to follow any combination of three care pathways: A care team overseen by gastro-psychologists, dietitians, and gastroenterologists; a holistic nutrition program including a personalized elimination diet; and a brain-gut behavioral therapy program with gut-directed hypnosis, cognitive behavioral therapy, and acceptance and commitment therapy. They go at their own pace, can connect with Ayble Health’s virtual care team to help with education and goal setting, and continue to consult their Cleveland Clinic providers as needed for evaluation and treatment.

“The care team is still there. We’ve just augmented it to make sure that as many people as possible get behavioral skills training and dietary support, with monitoring between visits — instead of the traditional, ‘I’ll see you in 6 months approach,” Lupe explained.

 

IBS Symptom Scores Improve

Of the study’s 171 patients, 20 had IBS-diarrhea, 23 had IBS-constipation, 32 had IBS-mixed, and 8 had IBS-unspecified. The remaining 88 patients reported IBS without indication of subtype.

At intake, all patients had active IBS symptoms, with scores ≥ 75 on the IBS symptom severity scale (IBS-SSS). Most patients enrolled in more than one care pathway, and 95% of participants completed at least 4 weeks on their chosen pathways.

Overall, patients saw an average 140-point decrease in IBS-SSS from intake through follow-up lasting up to 42 weeks. A drop in IBS-SSS score ≥ 50 points was considered a clinically meaningful change.

Symptom improvements occurred as early as week 4, were sustained and were uniform across IBS subtypes, suggesting that the AI-enhanced digital collaborative care model has wide utility in patients with IBS, Lupe said.

Patients with the most severe IBS symptoms showed the greatest improvement, but even 50% of those with mild symptoms had clinically meaningful changes in IBS-SSS.

Improvement in IBS symptoms was seen across all care pathways, but the combination of multiple pathways improved outcomes better than a single care pathway alone. The combination of nutrition and brain-gut behavioral therapy demonstrated the greatest reduction in IBS-SSS scores and proportion of patients achieving clinically meaningful results (95%).

The digital comprehensive car model for IBS is now “up and running” at Cleveland Clinic, and the team plans to proactively reach out to patients with gastrointestinal disorders recently seen at their center to alert them to the availability of this tool, Lupe said.

A randomized controlled trial is planned to further validate these observational findings, he added.

 

‘Wave of the Future’

The digital collaborative care model is “innovative, and I think is the wave of the future,” Kyle Staller, MD, MPH, gastroenterologist and director of the Gastrointestinal Motility Laboratory at Massachusetts General Hospital, Boston, who wasn’t involved in the study, told GI & Hepatology News.

“These digital platforms bundle nondrug options, such as cognitive-behavioral therapy, dietary therapy, hypnotherapy, so patients can choose what suits them, rather than the gastroenterologist hunting down each individual resource, which requires a lot of work,” Staller said.

The study “provides real-world evidence that a deliberative, digital, collaborative care model that houses various types of nondrug IBS treatment under one roof can provide meaningful benefit to patients,” Staller told GI & Hepatology News.

Importantly, he said, “patients chose which option they wanted. At the end of the day, the way that we should be thinking about IBS care is really making sure that we engage the patient with treatment choices,” Staller said.

This study had no specific funding. Three authors had relationships with Ayble Health. Lupe is a scientific advisor for Boomerang Health and paid lecturer for Takeda Pharmaceuticals. Staller disclosed having relationships with Mahana Therapeutics, Ardelyx Inc, Gemelli Biotech, Salix Pharmaceuticals, and Takeda Pharmaceuticals.

A version of this article appeared on Medscape.com.

SAN DIEGO — An artificial intelligence (AI)–enhanced digital collaborative care model led to rapid, clinically significant, and sustained symptom relief for patients with irritable bowel syndrome (IBS) seen at Cleveland Clinic, Cleveland, Ohio, an observational study found.

Symptom tracking at 4-week intervals showed that “almost everybody got better” regardless of IBS subtype, with relief starting in the first 4 weeks, Stephen Lupe, PsyD, gastrointestinal psychologist and director of Behavioral Medicine, Department of Gastroenterology, Hepatology, and Nutrition at Cleveland Clinic, Cleveland, said in an interview with GI & Hepatology News.

The findings were presented at Digestive Disease Week (DDW) 2025.

 

Digital Boost to Collaborative Care Model

The combination of dietary interventions and brain-gut behavioral therapy has demonstrated excellent outcomes for patients with IBS, but patients struggle to access these needed services, Lupe noted. A medical home collaborative care model in which patients get care from a multidisciplinary team has been shown to be a good way to successfully deliver this combination of care.

“When you do collaborative in-person care, people get better quicker,” Lupe said.

However, scaling access to this model remains a challenge. For their study, Cleveland Clinic researchers added an AI-enhanced digital platform, Ayble Health, to the in-person collaborative care model to expand access to disease-management services and evaluated whether it improved clinical outcomes for study’s 171 participants, who were recruited via social media advertisements.

Here’s how the platform works. Once a patient enrolls in Ayble Health, a personalized care plan is recommended based on a virtual visit, screening questionnaire, and baseline survey.

The platform includes brain-gut programs, including guided audio content on mindfulness, hypnosis, meditation, cognitive behavioral therapy, and breathing techniques; personalized nutrition support to find and remove trigger foods, a food barcode scanner, and a comprehensive groceries database; and AI-powered wellness tools to help manage and track symptoms. Lupe worked with Ayble Health to develop the platform’s behavioral health content and care pathways.

Patients may choose to follow any combination of three care pathways: A care team overseen by gastro-psychologists, dietitians, and gastroenterologists; a holistic nutrition program including a personalized elimination diet; and a brain-gut behavioral therapy program with gut-directed hypnosis, cognitive behavioral therapy, and acceptance and commitment therapy. They go at their own pace, can connect with Ayble Health’s virtual care team to help with education and goal setting, and continue to consult their Cleveland Clinic providers as needed for evaluation and treatment.

“The care team is still there. We’ve just augmented it to make sure that as many people as possible get behavioral skills training and dietary support, with monitoring between visits — instead of the traditional, ‘I’ll see you in 6 months approach,” Lupe explained.

 

IBS Symptom Scores Improve

Of the study’s 171 patients, 20 had IBS-diarrhea, 23 had IBS-constipation, 32 had IBS-mixed, and 8 had IBS-unspecified. The remaining 88 patients reported IBS without indication of subtype.

At intake, all patients had active IBS symptoms, with scores ≥ 75 on the IBS symptom severity scale (IBS-SSS). Most patients enrolled in more than one care pathway, and 95% of participants completed at least 4 weeks on their chosen pathways.

Overall, patients saw an average 140-point decrease in IBS-SSS from intake through follow-up lasting up to 42 weeks. A drop in IBS-SSS score ≥ 50 points was considered a clinically meaningful change.

Symptom improvements occurred as early as week 4, were sustained and were uniform across IBS subtypes, suggesting that the AI-enhanced digital collaborative care model has wide utility in patients with IBS, Lupe said.

Patients with the most severe IBS symptoms showed the greatest improvement, but even 50% of those with mild symptoms had clinically meaningful changes in IBS-SSS.

Improvement in IBS symptoms was seen across all care pathways, but the combination of multiple pathways improved outcomes better than a single care pathway alone. The combination of nutrition and brain-gut behavioral therapy demonstrated the greatest reduction in IBS-SSS scores and proportion of patients achieving clinically meaningful results (95%).

The digital comprehensive car model for IBS is now “up and running” at Cleveland Clinic, and the team plans to proactively reach out to patients with gastrointestinal disorders recently seen at their center to alert them to the availability of this tool, Lupe said.

A randomized controlled trial is planned to further validate these observational findings, he added.

 

‘Wave of the Future’

The digital collaborative care model is “innovative, and I think is the wave of the future,” Kyle Staller, MD, MPH, gastroenterologist and director of the Gastrointestinal Motility Laboratory at Massachusetts General Hospital, Boston, who wasn’t involved in the study, told GI & Hepatology News.