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Prevention and Risk-Based Surveillance Key to Curbing HCC
BERLIN — according to a joint statement from United European Gastroenterology (UEG) and the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS).
The statement calls on EU and national policymakers to embed a twofold approach into healthcare systems that combines surveillance and prevention, rather than relying on voluntary participation. It also encourages stronger prevention measures, such as improved food labeling and restrictions on marketing unhealthy foods to children. The statement — which was also endorsed by the European Association for the Study of the Liver (EASL) — was presented at UEG Week 2025 .
“Curing HCC in early stages rather than treating the disease in a palliative setting should be the goal for all liver doctors and carers, and this is certainly the goal for patients,” said Thomas Seufferlein, MD, professor of gastroenterology at Ulm University, Germany, and one of the members of the DGVS who initiated the statement.
“We have to take HCC screening seriously which means setting up a structured, nationwide, well-documented, and evaluated program for HCC screening in Germany,” he said in an interview.
HCC is mainly curable in the early stages by local ablation, resection, or liver transplantation, “so early diagnosis is of the utmost importance for improving survival,” added Patrick Michl, MD, gastroenterologist, University of Heidelberg, Germany, DGVS member and co-initiator of the statement.
Risk-Stratified HCC Surveillance
In the face of rising rates worldwide, the UEG/DGVS call on policymakers to recognize liver cancer as a preventable and growing public health priority and to implement structured surveillance programs guided by risk thresholds. In particular, they support the recent policy statement from EASL recommending risk-based screening.
EASL’s key recommendations include:
- Targeted surveillance for individuals with an annual HCC risk exceeding 1.5%, where it is both clinically beneficial and cost-effective
- Risk scoring tools such as the age-male-albumin-bilirubin-platelets score that incorporates age, sex, platelet count, albumin, and bilirubin, to stratify patients by HCC risk, including those without established cirrhosis
- Enhanced surveillance for very high-risk groups, where MRI-based surveillance may be warranted despite higher costs, given its superior sensitivity for early-stage disease
- A de-escalation in low-risk individuals
- Patients with an annual HCC risk < 0.5% may be safely spared surveillance, avoiding unnecessary interventions
Evidence from France, Italy, and the UK showed that structured surveillance in high-risk groups is both clinically beneficial and cost-effective. National models in France have demonstrated higher curative treatment rates and fewer costly late-stage cases with structured surveillance. In the UK, health technology assessments indicate targeted surveillance is an efficient use of National Health Services resources, particularly when uptake is optimized. Italian models show that earlier diagnosis in well-defined high-risk groups can offset downstream treatment costs.
Seufferlein noted that Germany needs a “structured program to be implemented and there is currently little public awareness regarding this surveillance strategy.” However, he added there is a structured hepatitis B vaccination program in Germany, which has been successful. “Studies show that the inclusion of hep B vaccination in infancy and childhood has led to good uptake among young age groups.”
Germany, however, has yet to conduct national studies. “Prospective data on HCC surveillance benefits in Germany are lacking,” said Michl, “but multi-country models incorporating Germany’s cost structures suggest similar benefits would accrue if there were greater adherence to guideline-based recommendations and if publicly funded screening programs were implemented.”
Current recommendations in Germany for surveillance are based on evidence-based guidelines of the DGVS with stronger (‘should’) or weaker (‘may’) evidence-based recommendations. For example, patients with chronic hepatitis B virus infection should be offered regular surveillance once their platelet age gender–hepatitis B risk score is ≥ 10. In patients with advanced fibrosis because of chronic hepatitis C virus infection, regular surveillance should also be offered.
Barriers to Screening Uptake
HCC remains one of the most lethal cancers in Europe, largely because it is often diagnosed too late. Underdiagnosis of chronic liver disease, limited access to imaging, and reimbursement gaps prevent timely intervention.
Maria Buti, MD, consultant hepatologist, Hospital Vall d’Hebron, Barcelona, Spain, who was not involved in drafting the statement, remarked that “Patients with liver cirrhosis, or with advanced fibrosis, and also some high-risk noncirrhotic patients such as those with hepatitis B, clearly benefit from surveillance. Surveillance can change life expectancy and also reduce morbidity.”
However, structural barriers continue to impede uptake. “It is not always easy to identify patients with liver cirrhosis because the majority are completely asymptomatic in the early stages,” she said.
Even when risk factors are identified, adherence to 6-monthly surveillance remains patchy. “Sometimes physicians forget to request ultrasounds, or patients don’t understand the importance of it because they feel well,” Buti told GI & Hepatology News.
Expanded Training and Public Health Measures
The joint statement also advocates for expanded physician training in nutrition and hepatology, equitable access to diagnostic tools including MRI, and EU-wide nutrition labeling systems such as Nutri-Score.
The authors also called for strengthened public health measures to tackle obesity, alcohol misuse, and hepatitis transmission, and fiscal and regulatory measures such as taxation of obesogenic foods, and reducing the cost burden of healthier foods.
“If we decrease the percentage of people with liver cirrhosis through prevention, fewer people will need surveillance,” Buti stated.
Seufferlein, Michl, and Buti all declared no relevant disclosures. All three experts are members of the UEG Public Affairs Group.
A version of this article appeared on Medscape.com.
BERLIN — according to a joint statement from United European Gastroenterology (UEG) and the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS).
The statement calls on EU and national policymakers to embed a twofold approach into healthcare systems that combines surveillance and prevention, rather than relying on voluntary participation. It also encourages stronger prevention measures, such as improved food labeling and restrictions on marketing unhealthy foods to children. The statement — which was also endorsed by the European Association for the Study of the Liver (EASL) — was presented at UEG Week 2025 .
“Curing HCC in early stages rather than treating the disease in a palliative setting should be the goal for all liver doctors and carers, and this is certainly the goal for patients,” said Thomas Seufferlein, MD, professor of gastroenterology at Ulm University, Germany, and one of the members of the DGVS who initiated the statement.
“We have to take HCC screening seriously which means setting up a structured, nationwide, well-documented, and evaluated program for HCC screening in Germany,” he said in an interview.
HCC is mainly curable in the early stages by local ablation, resection, or liver transplantation, “so early diagnosis is of the utmost importance for improving survival,” added Patrick Michl, MD, gastroenterologist, University of Heidelberg, Germany, DGVS member and co-initiator of the statement.
Risk-Stratified HCC Surveillance
In the face of rising rates worldwide, the UEG/DGVS call on policymakers to recognize liver cancer as a preventable and growing public health priority and to implement structured surveillance programs guided by risk thresholds. In particular, they support the recent policy statement from EASL recommending risk-based screening.
EASL’s key recommendations include:
- Targeted surveillance for individuals with an annual HCC risk exceeding 1.5%, where it is both clinically beneficial and cost-effective
- Risk scoring tools such as the age-male-albumin-bilirubin-platelets score that incorporates age, sex, platelet count, albumin, and bilirubin, to stratify patients by HCC risk, including those without established cirrhosis
- Enhanced surveillance for very high-risk groups, where MRI-based surveillance may be warranted despite higher costs, given its superior sensitivity for early-stage disease
- A de-escalation in low-risk individuals
- Patients with an annual HCC risk < 0.5% may be safely spared surveillance, avoiding unnecessary interventions
Evidence from France, Italy, and the UK showed that structured surveillance in high-risk groups is both clinically beneficial and cost-effective. National models in France have demonstrated higher curative treatment rates and fewer costly late-stage cases with structured surveillance. In the UK, health technology assessments indicate targeted surveillance is an efficient use of National Health Services resources, particularly when uptake is optimized. Italian models show that earlier diagnosis in well-defined high-risk groups can offset downstream treatment costs.
Seufferlein noted that Germany needs a “structured program to be implemented and there is currently little public awareness regarding this surveillance strategy.” However, he added there is a structured hepatitis B vaccination program in Germany, which has been successful. “Studies show that the inclusion of hep B vaccination in infancy and childhood has led to good uptake among young age groups.”
Germany, however, has yet to conduct national studies. “Prospective data on HCC surveillance benefits in Germany are lacking,” said Michl, “but multi-country models incorporating Germany’s cost structures suggest similar benefits would accrue if there were greater adherence to guideline-based recommendations and if publicly funded screening programs were implemented.”
Current recommendations in Germany for surveillance are based on evidence-based guidelines of the DGVS with stronger (‘should’) or weaker (‘may’) evidence-based recommendations. For example, patients with chronic hepatitis B virus infection should be offered regular surveillance once their platelet age gender–hepatitis B risk score is ≥ 10. In patients with advanced fibrosis because of chronic hepatitis C virus infection, regular surveillance should also be offered.
Barriers to Screening Uptake
HCC remains one of the most lethal cancers in Europe, largely because it is often diagnosed too late. Underdiagnosis of chronic liver disease, limited access to imaging, and reimbursement gaps prevent timely intervention.
Maria Buti, MD, consultant hepatologist, Hospital Vall d’Hebron, Barcelona, Spain, who was not involved in drafting the statement, remarked that “Patients with liver cirrhosis, or with advanced fibrosis, and also some high-risk noncirrhotic patients such as those with hepatitis B, clearly benefit from surveillance. Surveillance can change life expectancy and also reduce morbidity.”
However, structural barriers continue to impede uptake. “It is not always easy to identify patients with liver cirrhosis because the majority are completely asymptomatic in the early stages,” she said.
Even when risk factors are identified, adherence to 6-monthly surveillance remains patchy. “Sometimes physicians forget to request ultrasounds, or patients don’t understand the importance of it because they feel well,” Buti told GI & Hepatology News.
Expanded Training and Public Health Measures
The joint statement also advocates for expanded physician training in nutrition and hepatology, equitable access to diagnostic tools including MRI, and EU-wide nutrition labeling systems such as Nutri-Score.
The authors also called for strengthened public health measures to tackle obesity, alcohol misuse, and hepatitis transmission, and fiscal and regulatory measures such as taxation of obesogenic foods, and reducing the cost burden of healthier foods.
“If we decrease the percentage of people with liver cirrhosis through prevention, fewer people will need surveillance,” Buti stated.
Seufferlein, Michl, and Buti all declared no relevant disclosures. All three experts are members of the UEG Public Affairs Group.
A version of this article appeared on Medscape.com.
BERLIN — according to a joint statement from United European Gastroenterology (UEG) and the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS).
The statement calls on EU and national policymakers to embed a twofold approach into healthcare systems that combines surveillance and prevention, rather than relying on voluntary participation. It also encourages stronger prevention measures, such as improved food labeling and restrictions on marketing unhealthy foods to children. The statement — which was also endorsed by the European Association for the Study of the Liver (EASL) — was presented at UEG Week 2025 .
“Curing HCC in early stages rather than treating the disease in a palliative setting should be the goal for all liver doctors and carers, and this is certainly the goal for patients,” said Thomas Seufferlein, MD, professor of gastroenterology at Ulm University, Germany, and one of the members of the DGVS who initiated the statement.
“We have to take HCC screening seriously which means setting up a structured, nationwide, well-documented, and evaluated program for HCC screening in Germany,” he said in an interview.
HCC is mainly curable in the early stages by local ablation, resection, or liver transplantation, “so early diagnosis is of the utmost importance for improving survival,” added Patrick Michl, MD, gastroenterologist, University of Heidelberg, Germany, DGVS member and co-initiator of the statement.
Risk-Stratified HCC Surveillance
In the face of rising rates worldwide, the UEG/DGVS call on policymakers to recognize liver cancer as a preventable and growing public health priority and to implement structured surveillance programs guided by risk thresholds. In particular, they support the recent policy statement from EASL recommending risk-based screening.
EASL’s key recommendations include:
- Targeted surveillance for individuals with an annual HCC risk exceeding 1.5%, where it is both clinically beneficial and cost-effective
- Risk scoring tools such as the age-male-albumin-bilirubin-platelets score that incorporates age, sex, platelet count, albumin, and bilirubin, to stratify patients by HCC risk, including those without established cirrhosis
- Enhanced surveillance for very high-risk groups, where MRI-based surveillance may be warranted despite higher costs, given its superior sensitivity for early-stage disease
- A de-escalation in low-risk individuals
- Patients with an annual HCC risk < 0.5% may be safely spared surveillance, avoiding unnecessary interventions
Evidence from France, Italy, and the UK showed that structured surveillance in high-risk groups is both clinically beneficial and cost-effective. National models in France have demonstrated higher curative treatment rates and fewer costly late-stage cases with structured surveillance. In the UK, health technology assessments indicate targeted surveillance is an efficient use of National Health Services resources, particularly when uptake is optimized. Italian models show that earlier diagnosis in well-defined high-risk groups can offset downstream treatment costs.
Seufferlein noted that Germany needs a “structured program to be implemented and there is currently little public awareness regarding this surveillance strategy.” However, he added there is a structured hepatitis B vaccination program in Germany, which has been successful. “Studies show that the inclusion of hep B vaccination in infancy and childhood has led to good uptake among young age groups.”
Germany, however, has yet to conduct national studies. “Prospective data on HCC surveillance benefits in Germany are lacking,” said Michl, “but multi-country models incorporating Germany’s cost structures suggest similar benefits would accrue if there were greater adherence to guideline-based recommendations and if publicly funded screening programs were implemented.”
Current recommendations in Germany for surveillance are based on evidence-based guidelines of the DGVS with stronger (‘should’) or weaker (‘may’) evidence-based recommendations. For example, patients with chronic hepatitis B virus infection should be offered regular surveillance once their platelet age gender–hepatitis B risk score is ≥ 10. In patients with advanced fibrosis because of chronic hepatitis C virus infection, regular surveillance should also be offered.
Barriers to Screening Uptake
HCC remains one of the most lethal cancers in Europe, largely because it is often diagnosed too late. Underdiagnosis of chronic liver disease, limited access to imaging, and reimbursement gaps prevent timely intervention.
Maria Buti, MD, consultant hepatologist, Hospital Vall d’Hebron, Barcelona, Spain, who was not involved in drafting the statement, remarked that “Patients with liver cirrhosis, or with advanced fibrosis, and also some high-risk noncirrhotic patients such as those with hepatitis B, clearly benefit from surveillance. Surveillance can change life expectancy and also reduce morbidity.”
However, structural barriers continue to impede uptake. “It is not always easy to identify patients with liver cirrhosis because the majority are completely asymptomatic in the early stages,” she said.
Even when risk factors are identified, adherence to 6-monthly surveillance remains patchy. “Sometimes physicians forget to request ultrasounds, or patients don’t understand the importance of it because they feel well,” Buti told GI & Hepatology News.
Expanded Training and Public Health Measures
The joint statement also advocates for expanded physician training in nutrition and hepatology, equitable access to diagnostic tools including MRI, and EU-wide nutrition labeling systems such as Nutri-Score.
The authors also called for strengthened public health measures to tackle obesity, alcohol misuse, and hepatitis transmission, and fiscal and regulatory measures such as taxation of obesogenic foods, and reducing the cost burden of healthier foods.
“If we decrease the percentage of people with liver cirrhosis through prevention, fewer people will need surveillance,” Buti stated.
Seufferlein, Michl, and Buti all declared no relevant disclosures. All three experts are members of the UEG Public Affairs Group.
A version of this article appeared on Medscape.com.
FROM UEG WEEK 2025
Linerixibat Reduces Itching in PBC
BERLIN — , according to phase 3 results from the GLISTEN trial.
The therapy also improved sleep interference associated with itching and was generally well-tolerated, offering hope for patients who do not respond to existing treatments.
“Linerixibat has the potential to be the first global therapy indicated for pruritus,” asserted Andreas E. Kremer, MD, Department of Gastroenterology and Hepatology, University Hospital Zürich, Switzerland, who presented the findings at United European Gastroenterology (UEG) Week 2025.
Cholestatic pruritus is one of the most distressing and disabling symptoms of PBC, often unrelieved by existing first-line therapies such as ursodeoxycholic acid.
Up to 70% of patients with PBC experience cholestatic pruritus which can seriously impair quality of life, comparable to that seen in severe Parkinson’s disease or heart failure, said Kremer. With the limitations of existing treatments, symptom control remains a major unmet clinical need.
The GLISTEN Trial
Linerixibat is a minimally absorbed oral IBAT inhibitor that inhibits bile acid reuptake and reduces key mediators of pruritus.
Participants in the double-blind, placebo-controlled trial were randomized to oral linerixibat 40 mg twice daily (n = 119) or to placebo (n = 119) for 24 weeks. Patients had PBC and moderate-to-severe pruritus (Worst Itch Numerical Rating Scale [WI-NRS] ≥ 4).
The primary endpoint was change from baseline in monthly worst-itch score over 24 weeks. Key secondary endpoints included change in itch at week 2, change in sleep interference over 24 weeks, responder rates (≥ 2-, ≥ 3-, and ≥ 4-point reduction), and patient-reported global impression of severity and change.
The majority of participants (95%) were women and had a mean WI-NRS of 7.3 at baseline. After 24 weeks of twice daily dosing of linerixibat or placebo, participants entered a blinded crossover period for 8 weeks.
24-Week Data
Linerixibat produced a significant improvement in pruritus vs placebo, with a least-squares mean change in WI-NRS of -2.86 compared with -2.15, respectively, resulting in an adjusted mean difference of -0.72 (P = .001). The benefit appeared rapid, with superiority already evident at 2 weeks (P < .001), noted Kremer, adding this is important for patients.
Pruritus-related sleep interference NRS also improved significantly (-2.77 vs -2.24; difference, -0.53; P = .024). By week 24, 56% of patients with linerixibat achieved a ≥ 3-point reduction compared with 43% of those treated with placebo (nominal P = .043).
“A three-point reduction for a patient with pruritus is a clearly meaningful benefit,” said Kremer.
In addition, a greater proportion of patients with linerixibat rated their itch as “absent” (21% vs 9%) on the patient global impression of severity scales. The ideal goal for these patients is complete relief, “and here we saw that every fifth patient on linerixibat achieved such relief,” he pointed out.
Linerixibat was generally well-tolerated, and the most frequent on-treatment adverse event was diarrhea, which occurred in 61% of patients compared with 18% of those on placebo. There were five (4%) discontinuations on linerixibat vs one (< 1%) on placebo. Abdominal pain was experienced by 18% on linerixibat and 3% on placebo. There was also a slight elevation of alanine aminotransferase in 11 (9%) vs three patients (3%).
“In summary, it is a safe drug from our perspective,” said Kremer.
Focusing on Symptoms, Not Biochemical Response
Commenting for GI & Hepatology News, Frank Tacke, MD, head of the Department of Hepatology and Gastroenterology at Charité Medical University Berlin, Germany, explained that so far drugs for the treatment of PBC focused on the biochemical response. These treatments have shown a reduction in liver enzymes and in disease activity, but less of a reduction in symptoms, he explained. “This is the first drug at phase 3 that focuses on itching, which is one of the major symptoms in people with PBC. As such, this is a major breakthrough.”
Sabine Weber, MD, gastroenterologist at the University Hospital of Munich, Germany, said that the data suggested particular potential for patients whose pruritus doesn’t respond to first-line treatment, even if the treatment is otherwise effective.
“This is so important for patients who — due to their extreme itching — experience serious lifestyle effects such as isolation because they can’t go out socially,” she said. “We desperately need drugs to help these patients, and here we have one drug that seems to do this.”
Weber noted that linerixibat works differently from other PBC treatments. It is licensed in pediatric medicine for a number of diseases, but “this is the first time we’ve seen it for use in adults,” she added.
Kremer disclosed receiving research support from Gilead, Intercept Pharmaceuticals, and Roche; consulting for AbbVie, Advanz, Alentis, Alphasigma, AstraZeneca, Avior, Bayer, CymaBay Therapeutics, Eisai, Escient, Falk, Gilead, GSK, Intercept Pharmaceuticals, Ipsen, Mirum, MSD, Roche, Takeda, and Vifor; and receiving payment or honoraria from AbbVie, Advanz, Alphasigma, Falk, Gilead, GSK, Intercept Pharmaceuticals, Ipsen, Mirum, MSD, Roche, Takeda, and Vifor. Tache declared that he previously gave lectures for GSK. Weber declared no relevant conflicts of interest.
The GLISTEN study was funded by GSK.
A version of this article appeared on Medscape.com.
BERLIN — , according to phase 3 results from the GLISTEN trial.
The therapy also improved sleep interference associated with itching and was generally well-tolerated, offering hope for patients who do not respond to existing treatments.
“Linerixibat has the potential to be the first global therapy indicated for pruritus,” asserted Andreas E. Kremer, MD, Department of Gastroenterology and Hepatology, University Hospital Zürich, Switzerland, who presented the findings at United European Gastroenterology (UEG) Week 2025.
Cholestatic pruritus is one of the most distressing and disabling symptoms of PBC, often unrelieved by existing first-line therapies such as ursodeoxycholic acid.
Up to 70% of patients with PBC experience cholestatic pruritus which can seriously impair quality of life, comparable to that seen in severe Parkinson’s disease or heart failure, said Kremer. With the limitations of existing treatments, symptom control remains a major unmet clinical need.
The GLISTEN Trial
Linerixibat is a minimally absorbed oral IBAT inhibitor that inhibits bile acid reuptake and reduces key mediators of pruritus.
Participants in the double-blind, placebo-controlled trial were randomized to oral linerixibat 40 mg twice daily (n = 119) or to placebo (n = 119) for 24 weeks. Patients had PBC and moderate-to-severe pruritus (Worst Itch Numerical Rating Scale [WI-NRS] ≥ 4).
The primary endpoint was change from baseline in monthly worst-itch score over 24 weeks. Key secondary endpoints included change in itch at week 2, change in sleep interference over 24 weeks, responder rates (≥ 2-, ≥ 3-, and ≥ 4-point reduction), and patient-reported global impression of severity and change.
The majority of participants (95%) were women and had a mean WI-NRS of 7.3 at baseline. After 24 weeks of twice daily dosing of linerixibat or placebo, participants entered a blinded crossover period for 8 weeks.
24-Week Data
Linerixibat produced a significant improvement in pruritus vs placebo, with a least-squares mean change in WI-NRS of -2.86 compared with -2.15, respectively, resulting in an adjusted mean difference of -0.72 (P = .001). The benefit appeared rapid, with superiority already evident at 2 weeks (P < .001), noted Kremer, adding this is important for patients.
Pruritus-related sleep interference NRS also improved significantly (-2.77 vs -2.24; difference, -0.53; P = .024). By week 24, 56% of patients with linerixibat achieved a ≥ 3-point reduction compared with 43% of those treated with placebo (nominal P = .043).
“A three-point reduction for a patient with pruritus is a clearly meaningful benefit,” said Kremer.
In addition, a greater proportion of patients with linerixibat rated their itch as “absent” (21% vs 9%) on the patient global impression of severity scales. The ideal goal for these patients is complete relief, “and here we saw that every fifth patient on linerixibat achieved such relief,” he pointed out.
Linerixibat was generally well-tolerated, and the most frequent on-treatment adverse event was diarrhea, which occurred in 61% of patients compared with 18% of those on placebo. There were five (4%) discontinuations on linerixibat vs one (< 1%) on placebo. Abdominal pain was experienced by 18% on linerixibat and 3% on placebo. There was also a slight elevation of alanine aminotransferase in 11 (9%) vs three patients (3%).
“In summary, it is a safe drug from our perspective,” said Kremer.
Focusing on Symptoms, Not Biochemical Response
Commenting for GI & Hepatology News, Frank Tacke, MD, head of the Department of Hepatology and Gastroenterology at Charité Medical University Berlin, Germany, explained that so far drugs for the treatment of PBC focused on the biochemical response. These treatments have shown a reduction in liver enzymes and in disease activity, but less of a reduction in symptoms, he explained. “This is the first drug at phase 3 that focuses on itching, which is one of the major symptoms in people with PBC. As such, this is a major breakthrough.”
Sabine Weber, MD, gastroenterologist at the University Hospital of Munich, Germany, said that the data suggested particular potential for patients whose pruritus doesn’t respond to first-line treatment, even if the treatment is otherwise effective.
“This is so important for patients who — due to their extreme itching — experience serious lifestyle effects such as isolation because they can’t go out socially,” she said. “We desperately need drugs to help these patients, and here we have one drug that seems to do this.”
Weber noted that linerixibat works differently from other PBC treatments. It is licensed in pediatric medicine for a number of diseases, but “this is the first time we’ve seen it for use in adults,” she added.
Kremer disclosed receiving research support from Gilead, Intercept Pharmaceuticals, and Roche; consulting for AbbVie, Advanz, Alentis, Alphasigma, AstraZeneca, Avior, Bayer, CymaBay Therapeutics, Eisai, Escient, Falk, Gilead, GSK, Intercept Pharmaceuticals, Ipsen, Mirum, MSD, Roche, Takeda, and Vifor; and receiving payment or honoraria from AbbVie, Advanz, Alphasigma, Falk, Gilead, GSK, Intercept Pharmaceuticals, Ipsen, Mirum, MSD, Roche, Takeda, and Vifor. Tache declared that he previously gave lectures for GSK. Weber declared no relevant conflicts of interest.
The GLISTEN study was funded by GSK.
A version of this article appeared on Medscape.com.
BERLIN — , according to phase 3 results from the GLISTEN trial.
The therapy also improved sleep interference associated with itching and was generally well-tolerated, offering hope for patients who do not respond to existing treatments.
“Linerixibat has the potential to be the first global therapy indicated for pruritus,” asserted Andreas E. Kremer, MD, Department of Gastroenterology and Hepatology, University Hospital Zürich, Switzerland, who presented the findings at United European Gastroenterology (UEG) Week 2025.
Cholestatic pruritus is one of the most distressing and disabling symptoms of PBC, often unrelieved by existing first-line therapies such as ursodeoxycholic acid.
Up to 70% of patients with PBC experience cholestatic pruritus which can seriously impair quality of life, comparable to that seen in severe Parkinson’s disease or heart failure, said Kremer. With the limitations of existing treatments, symptom control remains a major unmet clinical need.
The GLISTEN Trial
Linerixibat is a minimally absorbed oral IBAT inhibitor that inhibits bile acid reuptake and reduces key mediators of pruritus.
Participants in the double-blind, placebo-controlled trial were randomized to oral linerixibat 40 mg twice daily (n = 119) or to placebo (n = 119) for 24 weeks. Patients had PBC and moderate-to-severe pruritus (Worst Itch Numerical Rating Scale [WI-NRS] ≥ 4).
The primary endpoint was change from baseline in monthly worst-itch score over 24 weeks. Key secondary endpoints included change in itch at week 2, change in sleep interference over 24 weeks, responder rates (≥ 2-, ≥ 3-, and ≥ 4-point reduction), and patient-reported global impression of severity and change.
The majority of participants (95%) were women and had a mean WI-NRS of 7.3 at baseline. After 24 weeks of twice daily dosing of linerixibat or placebo, participants entered a blinded crossover period for 8 weeks.
24-Week Data
Linerixibat produced a significant improvement in pruritus vs placebo, with a least-squares mean change in WI-NRS of -2.86 compared with -2.15, respectively, resulting in an adjusted mean difference of -0.72 (P = .001). The benefit appeared rapid, with superiority already evident at 2 weeks (P < .001), noted Kremer, adding this is important for patients.
Pruritus-related sleep interference NRS also improved significantly (-2.77 vs -2.24; difference, -0.53; P = .024). By week 24, 56% of patients with linerixibat achieved a ≥ 3-point reduction compared with 43% of those treated with placebo (nominal P = .043).
“A three-point reduction for a patient with pruritus is a clearly meaningful benefit,” said Kremer.
In addition, a greater proportion of patients with linerixibat rated their itch as “absent” (21% vs 9%) on the patient global impression of severity scales. The ideal goal for these patients is complete relief, “and here we saw that every fifth patient on linerixibat achieved such relief,” he pointed out.
Linerixibat was generally well-tolerated, and the most frequent on-treatment adverse event was diarrhea, which occurred in 61% of patients compared with 18% of those on placebo. There were five (4%) discontinuations on linerixibat vs one (< 1%) on placebo. Abdominal pain was experienced by 18% on linerixibat and 3% on placebo. There was also a slight elevation of alanine aminotransferase in 11 (9%) vs three patients (3%).
“In summary, it is a safe drug from our perspective,” said Kremer.
Focusing on Symptoms, Not Biochemical Response
Commenting for GI & Hepatology News, Frank Tacke, MD, head of the Department of Hepatology and Gastroenterology at Charité Medical University Berlin, Germany, explained that so far drugs for the treatment of PBC focused on the biochemical response. These treatments have shown a reduction in liver enzymes and in disease activity, but less of a reduction in symptoms, he explained. “This is the first drug at phase 3 that focuses on itching, which is one of the major symptoms in people with PBC. As such, this is a major breakthrough.”
Sabine Weber, MD, gastroenterologist at the University Hospital of Munich, Germany, said that the data suggested particular potential for patients whose pruritus doesn’t respond to first-line treatment, even if the treatment is otherwise effective.
“This is so important for patients who — due to their extreme itching — experience serious lifestyle effects such as isolation because they can’t go out socially,” she said. “We desperately need drugs to help these patients, and here we have one drug that seems to do this.”
Weber noted that linerixibat works differently from other PBC treatments. It is licensed in pediatric medicine for a number of diseases, but “this is the first time we’ve seen it for use in adults,” she added.
Kremer disclosed receiving research support from Gilead, Intercept Pharmaceuticals, and Roche; consulting for AbbVie, Advanz, Alentis, Alphasigma, AstraZeneca, Avior, Bayer, CymaBay Therapeutics, Eisai, Escient, Falk, Gilead, GSK, Intercept Pharmaceuticals, Ipsen, Mirum, MSD, Roche, Takeda, and Vifor; and receiving payment or honoraria from AbbVie, Advanz, Alphasigma, Falk, Gilead, GSK, Intercept Pharmaceuticals, Ipsen, Mirum, MSD, Roche, Takeda, and Vifor. Tache declared that he previously gave lectures for GSK. Weber declared no relevant conflicts of interest.
The GLISTEN study was funded by GSK.
A version of this article appeared on Medscape.com.
MASLD/MASH Global Consensus Recommendations Address Guideline Discordance
These recommendations aim to boost guideline adherence and disease awareness, which have lagged despite a surge of national and international guidance in recent years, lead author Zobair M. Younossi, MD, of the Global NASH/MASH Council, Washington, DC, and colleagues, reported.
“Although these documents are similar in many ways, there are important differences in their recommendations, which have created some confusion within the field,” the panel wrote in Gastroenterology. “Areas of discordance among guidelines can be partly responsible for their low rate of implementation and the suboptimal awareness about this liver disease. Furthermore, these guidelines can be long and complex, making it challenging for busy clinicians to access the appropriate information quickly and efficiently.”
To address these gaps, more than 40 experts from around the world collaborated on the consensus project. The team reviewed 61 eligible documents published between 2018 and January 2025. Each guideline was evaluated across eight domains: epidemiology; screening; risk stratification using noninvasive tests (NITs); lifestyle management; treatment with existing medications; treatment with future medications; hepatocellular carcinoma (HCC) and preventive guidance; and pregnancy and pediatric populations.
Areas of discordance were advanced to a Delphi process using iterative online surveys, with a supermajority threshold of 67% required for acceptance. Four Delphi rounds were conducted, and by the end, all statements had achieved more than 90% agreement. The final recommendations were then summarized into practical algorithms for clinical use.
The results cover the full spectrum of MASLD care. For screening and diagnosis, experts agreed that individuals with type 2 diabetes, obesity plus cardiometabolic risk factors, or persistently elevated aminotransferases should be considered high risk. Alcohol thresholds were standardized, clarifying when to classify disease as MASLD, alcohol-related liver disease, or the hybrid “Met-ALD.”
For risk stratification, the panel endorsed a two-step algorithm beginning with the Fibrosis-4 (FIB-4) index, followed by vibration-controlled transient elastography (VCTE) or other NITs in patients above the threshold. This approach, the authors noted, was designed to be feasible in both primary care and specialty settings.
Lifestyle intervention remains the cornerstone of treatment, with weight-loss goals of 5% to reduce steatosis, 7%–10% to reduce inflammation, and at least 10% to improve fibrosis. To this end, the panel recommended a Mediterranean-style diet, increased physical activity, and reductions in sedentary time.
Drug therapy recommendations prioritized glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors for patients with diabetes or obesity, though these were not considered MASH-specific agents. Pioglitazone was noted as an option for diabetes management but not as direct MASH therapy. The panel did not recommend vitamin E, ursodeoxycholic acid, or omega-3 fatty acids, citing insufficient evidence.
The document also provides structured guidance on resmetirom, the first FDA-approved therapy for MASH. Its use was endorsed in patients with F2–F3 fibrosis confirmed by NITs, with safety checks at 3, 6, and 12 months, and efficacy evaluation after 1 year. Treatment futility was defined as concordant worsening across two NITs.
Preventive recommendations included hepatitis A and B vaccination and HCC surveillance every 6 months in patients with cirrhosis. Surveillance in noncirrhotic MASH was left to clinician judgment, based on individualized risk factors. Special considerations were outlined for pediatric and pregnant populations, although the evidence base in these groups remains sparse.
“Further research is required to determine the effectiveness of this algorithm in raising awareness of MASLD and its treatment,” Dr. Younossi and colleagues concluded.
The study was supported by the Global NASH/MASH Council, Inova Health System, and an unrestricted educational grant from Madrigal Pharmaceuticals. The investigators disclosed relationships with Sanofi, Gilead, AstraZeneca, and others.
The new consensus MASLD recommendations should help reconcile the “important differences” between guidelines from around the world, said Dr. Jaideep Behari, of the the University of Pittsburgh Medical Center.
Behari highlighted several points that may be underappreciated in clinical practice. “While many clinicians associate MASLD with obesity and type 2 diabetes, approximately a fifth of people living with MASLD are lean,” he said. “It may also come as a surprise to non-liver specialists that cardiovascular disease is the most common cause of mortality in patients with MASLD.”
He underscored the consensus recommendation to screen patients with type 2 diabetes, those with obesity and at least one cardiometabolic risk factor, and individuals with persistently elevated liver enzymes.
“Since many patients in the first two groups are mainly seen in primary care or endocrinology practices, physicians in these specialties need to be cognizant of these global consensus recommendations,” Behari said.
Turning to therapeutics, he described resmetirom as “a major milestone in the management of MASLD since it is the first drug approved in the US for treatment of MASH with F2 (moderate) or F3 (advanced) fibrosis.”
He noted that treatment requires careful patient selection and monitoring, including VCTE in the 8–20 kPa range, followed by serial liver injury testing. Efficacy should be assessed at 12 months, he noted, since “resmetirom was found to be effective in approximately a quarter of all treated patients in the pivotal clinical trial.”
“These limitations highlight the gaps in the treatment of MASLD/MASH and the need to continue development of other therapies,” Behari said.
Jaideep Behari, MD, PhD, AGAF, is director of the liver steatosis and metabolic wellness program at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. He reported research grant support from AstraZeneca, Madrigal, and recently completed research grant support from Gilead and Pfizer.
The new consensus MASLD recommendations should help reconcile the “important differences” between guidelines from around the world, said Dr. Jaideep Behari, of the the University of Pittsburgh Medical Center.
Behari highlighted several points that may be underappreciated in clinical practice. “While many clinicians associate MASLD with obesity and type 2 diabetes, approximately a fifth of people living with MASLD are lean,” he said. “It may also come as a surprise to non-liver specialists that cardiovascular disease is the most common cause of mortality in patients with MASLD.”
He underscored the consensus recommendation to screen patients with type 2 diabetes, those with obesity and at least one cardiometabolic risk factor, and individuals with persistently elevated liver enzymes.
“Since many patients in the first two groups are mainly seen in primary care or endocrinology practices, physicians in these specialties need to be cognizant of these global consensus recommendations,” Behari said.
Turning to therapeutics, he described resmetirom as “a major milestone in the management of MASLD since it is the first drug approved in the US for treatment of MASH with F2 (moderate) or F3 (advanced) fibrosis.”
He noted that treatment requires careful patient selection and monitoring, including VCTE in the 8–20 kPa range, followed by serial liver injury testing. Efficacy should be assessed at 12 months, he noted, since “resmetirom was found to be effective in approximately a quarter of all treated patients in the pivotal clinical trial.”
“These limitations highlight the gaps in the treatment of MASLD/MASH and the need to continue development of other therapies,” Behari said.
Jaideep Behari, MD, PhD, AGAF, is director of the liver steatosis and metabolic wellness program at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. He reported research grant support from AstraZeneca, Madrigal, and recently completed research grant support from Gilead and Pfizer.
The new consensus MASLD recommendations should help reconcile the “important differences” between guidelines from around the world, said Dr. Jaideep Behari, of the the University of Pittsburgh Medical Center.
Behari highlighted several points that may be underappreciated in clinical practice. “While many clinicians associate MASLD with obesity and type 2 diabetes, approximately a fifth of people living with MASLD are lean,” he said. “It may also come as a surprise to non-liver specialists that cardiovascular disease is the most common cause of mortality in patients with MASLD.”
He underscored the consensus recommendation to screen patients with type 2 diabetes, those with obesity and at least one cardiometabolic risk factor, and individuals with persistently elevated liver enzymes.
“Since many patients in the first two groups are mainly seen in primary care or endocrinology practices, physicians in these specialties need to be cognizant of these global consensus recommendations,” Behari said.
Turning to therapeutics, he described resmetirom as “a major milestone in the management of MASLD since it is the first drug approved in the US for treatment of MASH with F2 (moderate) or F3 (advanced) fibrosis.”
He noted that treatment requires careful patient selection and monitoring, including VCTE in the 8–20 kPa range, followed by serial liver injury testing. Efficacy should be assessed at 12 months, he noted, since “resmetirom was found to be effective in approximately a quarter of all treated patients in the pivotal clinical trial.”
“These limitations highlight the gaps in the treatment of MASLD/MASH and the need to continue development of other therapies,” Behari said.
Jaideep Behari, MD, PhD, AGAF, is director of the liver steatosis and metabolic wellness program at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. He reported research grant support from AstraZeneca, Madrigal, and recently completed research grant support from Gilead and Pfizer.
These recommendations aim to boost guideline adherence and disease awareness, which have lagged despite a surge of national and international guidance in recent years, lead author Zobair M. Younossi, MD, of the Global NASH/MASH Council, Washington, DC, and colleagues, reported.
“Although these documents are similar in many ways, there are important differences in their recommendations, which have created some confusion within the field,” the panel wrote in Gastroenterology. “Areas of discordance among guidelines can be partly responsible for their low rate of implementation and the suboptimal awareness about this liver disease. Furthermore, these guidelines can be long and complex, making it challenging for busy clinicians to access the appropriate information quickly and efficiently.”
To address these gaps, more than 40 experts from around the world collaborated on the consensus project. The team reviewed 61 eligible documents published between 2018 and January 2025. Each guideline was evaluated across eight domains: epidemiology; screening; risk stratification using noninvasive tests (NITs); lifestyle management; treatment with existing medications; treatment with future medications; hepatocellular carcinoma (HCC) and preventive guidance; and pregnancy and pediatric populations.
Areas of discordance were advanced to a Delphi process using iterative online surveys, with a supermajority threshold of 67% required for acceptance. Four Delphi rounds were conducted, and by the end, all statements had achieved more than 90% agreement. The final recommendations were then summarized into practical algorithms for clinical use.
The results cover the full spectrum of MASLD care. For screening and diagnosis, experts agreed that individuals with type 2 diabetes, obesity plus cardiometabolic risk factors, or persistently elevated aminotransferases should be considered high risk. Alcohol thresholds were standardized, clarifying when to classify disease as MASLD, alcohol-related liver disease, or the hybrid “Met-ALD.”
For risk stratification, the panel endorsed a two-step algorithm beginning with the Fibrosis-4 (FIB-4) index, followed by vibration-controlled transient elastography (VCTE) or other NITs in patients above the threshold. This approach, the authors noted, was designed to be feasible in both primary care and specialty settings.
Lifestyle intervention remains the cornerstone of treatment, with weight-loss goals of 5% to reduce steatosis, 7%–10% to reduce inflammation, and at least 10% to improve fibrosis. To this end, the panel recommended a Mediterranean-style diet, increased physical activity, and reductions in sedentary time.
Drug therapy recommendations prioritized glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors for patients with diabetes or obesity, though these were not considered MASH-specific agents. Pioglitazone was noted as an option for diabetes management but not as direct MASH therapy. The panel did not recommend vitamin E, ursodeoxycholic acid, or omega-3 fatty acids, citing insufficient evidence.
The document also provides structured guidance on resmetirom, the first FDA-approved therapy for MASH. Its use was endorsed in patients with F2–F3 fibrosis confirmed by NITs, with safety checks at 3, 6, and 12 months, and efficacy evaluation after 1 year. Treatment futility was defined as concordant worsening across two NITs.
Preventive recommendations included hepatitis A and B vaccination and HCC surveillance every 6 months in patients with cirrhosis. Surveillance in noncirrhotic MASH was left to clinician judgment, based on individualized risk factors. Special considerations were outlined for pediatric and pregnant populations, although the evidence base in these groups remains sparse.
“Further research is required to determine the effectiveness of this algorithm in raising awareness of MASLD and its treatment,” Dr. Younossi and colleagues concluded.
The study was supported by the Global NASH/MASH Council, Inova Health System, and an unrestricted educational grant from Madrigal Pharmaceuticals. The investigators disclosed relationships with Sanofi, Gilead, AstraZeneca, and others.
These recommendations aim to boost guideline adherence and disease awareness, which have lagged despite a surge of national and international guidance in recent years, lead author Zobair M. Younossi, MD, of the Global NASH/MASH Council, Washington, DC, and colleagues, reported.
“Although these documents are similar in many ways, there are important differences in their recommendations, which have created some confusion within the field,” the panel wrote in Gastroenterology. “Areas of discordance among guidelines can be partly responsible for their low rate of implementation and the suboptimal awareness about this liver disease. Furthermore, these guidelines can be long and complex, making it challenging for busy clinicians to access the appropriate information quickly and efficiently.”
To address these gaps, more than 40 experts from around the world collaborated on the consensus project. The team reviewed 61 eligible documents published between 2018 and January 2025. Each guideline was evaluated across eight domains: epidemiology; screening; risk stratification using noninvasive tests (NITs); lifestyle management; treatment with existing medications; treatment with future medications; hepatocellular carcinoma (HCC) and preventive guidance; and pregnancy and pediatric populations.
Areas of discordance were advanced to a Delphi process using iterative online surveys, with a supermajority threshold of 67% required for acceptance. Four Delphi rounds were conducted, and by the end, all statements had achieved more than 90% agreement. The final recommendations were then summarized into practical algorithms for clinical use.
The results cover the full spectrum of MASLD care. For screening and diagnosis, experts agreed that individuals with type 2 diabetes, obesity plus cardiometabolic risk factors, or persistently elevated aminotransferases should be considered high risk. Alcohol thresholds were standardized, clarifying when to classify disease as MASLD, alcohol-related liver disease, or the hybrid “Met-ALD.”
For risk stratification, the panel endorsed a two-step algorithm beginning with the Fibrosis-4 (FIB-4) index, followed by vibration-controlled transient elastography (VCTE) or other NITs in patients above the threshold. This approach, the authors noted, was designed to be feasible in both primary care and specialty settings.
Lifestyle intervention remains the cornerstone of treatment, with weight-loss goals of 5% to reduce steatosis, 7%–10% to reduce inflammation, and at least 10% to improve fibrosis. To this end, the panel recommended a Mediterranean-style diet, increased physical activity, and reductions in sedentary time.
Drug therapy recommendations prioritized glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors for patients with diabetes or obesity, though these were not considered MASH-specific agents. Pioglitazone was noted as an option for diabetes management but not as direct MASH therapy. The panel did not recommend vitamin E, ursodeoxycholic acid, or omega-3 fatty acids, citing insufficient evidence.
The document also provides structured guidance on resmetirom, the first FDA-approved therapy for MASH. Its use was endorsed in patients with F2–F3 fibrosis confirmed by NITs, with safety checks at 3, 6, and 12 months, and efficacy evaluation after 1 year. Treatment futility was defined as concordant worsening across two NITs.
Preventive recommendations included hepatitis A and B vaccination and HCC surveillance every 6 months in patients with cirrhosis. Surveillance in noncirrhotic MASH was left to clinician judgment, based on individualized risk factors. Special considerations were outlined for pediatric and pregnant populations, although the evidence base in these groups remains sparse.
“Further research is required to determine the effectiveness of this algorithm in raising awareness of MASLD and its treatment,” Dr. Younossi and colleagues concluded.
The study was supported by the Global NASH/MASH Council, Inova Health System, and an unrestricted educational grant from Madrigal Pharmaceuticals. The investigators disclosed relationships with Sanofi, Gilead, AstraZeneca, and others.
FROM GASTROENTEROLOGY
Healthy Diet, Exercise Cut Liver Death Risk in Drinkers
Following a healthy diet and engaging in a high level of physical activity can significantly lower the risk for alcohol-related liver mortality, even among all drinking patterns, including heavy and binge drinking, according to a new study from Indiana University researchers.
Notably, any amount of daily alcohol intake or binge drinking increases the liver mortality risk, the researchers found. However, that risk can be reduced somewhat with healthy dietary patterns and increased physical activity.
Although previous studies suggested that one or two drinks per day could be associated with lower risks for cardiovascular disease, cancer, or liver-related outcomes, other confounders and unmeasured lifestyle behaviors could vary significantly between consumers and influence their health risks, the researchers said.
“A significant knowledge gap exists regarding the interplay of dietary patterns and physical activity with alcohol-attributable liver-specific mortality,” said senior author Naga Chalasani, MD, AGAF, professor of gastroenterology and hepatology at the Indiana University School of Medicine in Indianapolis.
“It is not well understood whether healthy diets or increased physical activity levels explain differences in liver-specific mortality risks between lifetime abstainers and light-to-moderate alcohol consumers,” he said. “More importantly, it remains unclear whether a healthy diet and physical activity can lower liver-specific mortality in individuals engaging in high-risk alcohol consumption, such as heavy or binge drinking.”
The study was published online in the Journal of Hepatology.
Analyzing Alcohol-Related Effects
Chalasani and colleagues analyzed data from more than 60,000 adults in the National Health and Nutrition Examination Surveys for 1984-2018 and linked data in the National Death Index through December 2019.
The research team looked at self-reported alcohol use, diet quality based on the Healthy Eating Index, and physical activity levels. Heavy drinking was defined as more than three drinks per day for women and more than four drinks per day for men, while binge drinking was defined as four or more drinks per day for women and five or more drinks per day for men.
Physically active participants had at least 150 minutes of moderate-intensity physical activity or 75 minutes of vigorous-intensity physical activity per week. Participants with healthier diets were in the top quartile of the Healthy Eating Index, which included diets high in vegetables, fruits, whole grains, seafood, plant-based proteins, and unsaturated fats, as well as diets low in solid fats, alcohol, and added sugars.
During a 12-year follow-up period, 12,881 deaths were reported, including 252 related to liver disease. An increased risk for liver-related death was associated with older age, smoking, diabetes, higher BMI, waist circumference, average daily alcohol intake, and binge drinking.
Compared to nondrinkers, those with daily alcohol intake had an increased liver-specific mortality risk, with an adjusted subdistribution hazard ratio (aSHR) of 1.04 for men and 1.08 for women.
Binge drinking had an even greater liver mortality risk, with an aSHR of 1.52 for men and 2.52 for women, than nonbinge drinking.
In contrast, a healthier diet — among those at the top quartile of the Healthy Eating Index — had a lower liver mortality risk in nonheavy drinkers (aSHR, 0.35), heavy drinkers (aSHR, 0.14), and binge drinkers (aSHR, 0.16).
In addition, physically active participants had a lower liver mortality risk for nonheavy drinkers (aSHR, 0.52), heavy drinkers (aSHR, 0.64), and binge drinkers (aSHR, 0.31).
Overall, the benefits of higher diet quality and physical activity were substantially greater in women than in men, the researchers found.
“The uniqueness of our study lies in its ability to simultaneously assess the moderating effects of two important lifestyle behaviors on liver mortality risk across different levels and patterns of alcohol consumption in a representative US population, offering a more nuanced and complete view of the risks of drinking,” Chalasani said.
Messaging From Clinicians to Patients
Despite some attenuation from a healthy diet and physical activity, alcohol consumption still carries an increased liver mortality risk, the researchers noted. Economically disadvantaged groups face higher exposure to high-risk alcohol use, unhealthy diets, and physical activity — and as a result, increased liver mortality.
“This study challenges the long-held belief that light-to-moderate drinking might be safe for the liver. It shows that any level of alcohol raises risk, but healthy diet and exercise can meaningfully reduce that harm,” said Joseph Ahn, MD, AGAF, assistant professor of medicine in the Division of Gastroenterology and Hepatology at the Mayo Clinic in Rochester, Minnesota.
“The results should change how we think about alcohol — not as something potentially protective, but as a risk factor that can be partly mitigated by lifestyle,” he said.
“The key takeaway is that there is no safe level of alcohol for liver health. Clinicians should move away from reassuring patients about ‘moderate’ drinking and instead stress both alcohol reduction and the protective role of diet and physical activity,” Ahn added. “The next step is bringing these insights into guidelines and patient counseling, especially for populations at higher risk.”
The study was funded by departmental internal funding. Chalasani declared having no conflicts of interest for this paper, but he disclosed paid consulting agreements with numerous pharmaceutical companies. Ahn reported having no disclosures.
A version of this article appeared on Medscape.com.
Following a healthy diet and engaging in a high level of physical activity can significantly lower the risk for alcohol-related liver mortality, even among all drinking patterns, including heavy and binge drinking, according to a new study from Indiana University researchers.
Notably, any amount of daily alcohol intake or binge drinking increases the liver mortality risk, the researchers found. However, that risk can be reduced somewhat with healthy dietary patterns and increased physical activity.
Although previous studies suggested that one or two drinks per day could be associated with lower risks for cardiovascular disease, cancer, or liver-related outcomes, other confounders and unmeasured lifestyle behaviors could vary significantly between consumers and influence their health risks, the researchers said.
“A significant knowledge gap exists regarding the interplay of dietary patterns and physical activity with alcohol-attributable liver-specific mortality,” said senior author Naga Chalasani, MD, AGAF, professor of gastroenterology and hepatology at the Indiana University School of Medicine in Indianapolis.
“It is not well understood whether healthy diets or increased physical activity levels explain differences in liver-specific mortality risks between lifetime abstainers and light-to-moderate alcohol consumers,” he said. “More importantly, it remains unclear whether a healthy diet and physical activity can lower liver-specific mortality in individuals engaging in high-risk alcohol consumption, such as heavy or binge drinking.”
The study was published online in the Journal of Hepatology.
Analyzing Alcohol-Related Effects
Chalasani and colleagues analyzed data from more than 60,000 adults in the National Health and Nutrition Examination Surveys for 1984-2018 and linked data in the National Death Index through December 2019.
The research team looked at self-reported alcohol use, diet quality based on the Healthy Eating Index, and physical activity levels. Heavy drinking was defined as more than three drinks per day for women and more than four drinks per day for men, while binge drinking was defined as four or more drinks per day for women and five or more drinks per day for men.
Physically active participants had at least 150 minutes of moderate-intensity physical activity or 75 minutes of vigorous-intensity physical activity per week. Participants with healthier diets were in the top quartile of the Healthy Eating Index, which included diets high in vegetables, fruits, whole grains, seafood, plant-based proteins, and unsaturated fats, as well as diets low in solid fats, alcohol, and added sugars.
During a 12-year follow-up period, 12,881 deaths were reported, including 252 related to liver disease. An increased risk for liver-related death was associated with older age, smoking, diabetes, higher BMI, waist circumference, average daily alcohol intake, and binge drinking.
Compared to nondrinkers, those with daily alcohol intake had an increased liver-specific mortality risk, with an adjusted subdistribution hazard ratio (aSHR) of 1.04 for men and 1.08 for women.
Binge drinking had an even greater liver mortality risk, with an aSHR of 1.52 for men and 2.52 for women, than nonbinge drinking.
In contrast, a healthier diet — among those at the top quartile of the Healthy Eating Index — had a lower liver mortality risk in nonheavy drinkers (aSHR, 0.35), heavy drinkers (aSHR, 0.14), and binge drinkers (aSHR, 0.16).
In addition, physically active participants had a lower liver mortality risk for nonheavy drinkers (aSHR, 0.52), heavy drinkers (aSHR, 0.64), and binge drinkers (aSHR, 0.31).
Overall, the benefits of higher diet quality and physical activity were substantially greater in women than in men, the researchers found.
“The uniqueness of our study lies in its ability to simultaneously assess the moderating effects of two important lifestyle behaviors on liver mortality risk across different levels and patterns of alcohol consumption in a representative US population, offering a more nuanced and complete view of the risks of drinking,” Chalasani said.
Messaging From Clinicians to Patients
Despite some attenuation from a healthy diet and physical activity, alcohol consumption still carries an increased liver mortality risk, the researchers noted. Economically disadvantaged groups face higher exposure to high-risk alcohol use, unhealthy diets, and physical activity — and as a result, increased liver mortality.
“This study challenges the long-held belief that light-to-moderate drinking might be safe for the liver. It shows that any level of alcohol raises risk, but healthy diet and exercise can meaningfully reduce that harm,” said Joseph Ahn, MD, AGAF, assistant professor of medicine in the Division of Gastroenterology and Hepatology at the Mayo Clinic in Rochester, Minnesota.
“The results should change how we think about alcohol — not as something potentially protective, but as a risk factor that can be partly mitigated by lifestyle,” he said.
“The key takeaway is that there is no safe level of alcohol for liver health. Clinicians should move away from reassuring patients about ‘moderate’ drinking and instead stress both alcohol reduction and the protective role of diet and physical activity,” Ahn added. “The next step is bringing these insights into guidelines and patient counseling, especially for populations at higher risk.”
The study was funded by departmental internal funding. Chalasani declared having no conflicts of interest for this paper, but he disclosed paid consulting agreements with numerous pharmaceutical companies. Ahn reported having no disclosures.
A version of this article appeared on Medscape.com.
Following a healthy diet and engaging in a high level of physical activity can significantly lower the risk for alcohol-related liver mortality, even among all drinking patterns, including heavy and binge drinking, according to a new study from Indiana University researchers.
Notably, any amount of daily alcohol intake or binge drinking increases the liver mortality risk, the researchers found. However, that risk can be reduced somewhat with healthy dietary patterns and increased physical activity.
Although previous studies suggested that one or two drinks per day could be associated with lower risks for cardiovascular disease, cancer, or liver-related outcomes, other confounders and unmeasured lifestyle behaviors could vary significantly between consumers and influence their health risks, the researchers said.
“A significant knowledge gap exists regarding the interplay of dietary patterns and physical activity with alcohol-attributable liver-specific mortality,” said senior author Naga Chalasani, MD, AGAF, professor of gastroenterology and hepatology at the Indiana University School of Medicine in Indianapolis.
“It is not well understood whether healthy diets or increased physical activity levels explain differences in liver-specific mortality risks between lifetime abstainers and light-to-moderate alcohol consumers,” he said. “More importantly, it remains unclear whether a healthy diet and physical activity can lower liver-specific mortality in individuals engaging in high-risk alcohol consumption, such as heavy or binge drinking.”
The study was published online in the Journal of Hepatology.
Analyzing Alcohol-Related Effects
Chalasani and colleagues analyzed data from more than 60,000 adults in the National Health and Nutrition Examination Surveys for 1984-2018 and linked data in the National Death Index through December 2019.
The research team looked at self-reported alcohol use, diet quality based on the Healthy Eating Index, and physical activity levels. Heavy drinking was defined as more than three drinks per day for women and more than four drinks per day for men, while binge drinking was defined as four or more drinks per day for women and five or more drinks per day for men.
Physically active participants had at least 150 minutes of moderate-intensity physical activity or 75 minutes of vigorous-intensity physical activity per week. Participants with healthier diets were in the top quartile of the Healthy Eating Index, which included diets high in vegetables, fruits, whole grains, seafood, plant-based proteins, and unsaturated fats, as well as diets low in solid fats, alcohol, and added sugars.
During a 12-year follow-up period, 12,881 deaths were reported, including 252 related to liver disease. An increased risk for liver-related death was associated with older age, smoking, diabetes, higher BMI, waist circumference, average daily alcohol intake, and binge drinking.
Compared to nondrinkers, those with daily alcohol intake had an increased liver-specific mortality risk, with an adjusted subdistribution hazard ratio (aSHR) of 1.04 for men and 1.08 for women.
Binge drinking had an even greater liver mortality risk, with an aSHR of 1.52 for men and 2.52 for women, than nonbinge drinking.
In contrast, a healthier diet — among those at the top quartile of the Healthy Eating Index — had a lower liver mortality risk in nonheavy drinkers (aSHR, 0.35), heavy drinkers (aSHR, 0.14), and binge drinkers (aSHR, 0.16).
In addition, physically active participants had a lower liver mortality risk for nonheavy drinkers (aSHR, 0.52), heavy drinkers (aSHR, 0.64), and binge drinkers (aSHR, 0.31).
Overall, the benefits of higher diet quality and physical activity were substantially greater in women than in men, the researchers found.
“The uniqueness of our study lies in its ability to simultaneously assess the moderating effects of two important lifestyle behaviors on liver mortality risk across different levels and patterns of alcohol consumption in a representative US population, offering a more nuanced and complete view of the risks of drinking,” Chalasani said.
Messaging From Clinicians to Patients
Despite some attenuation from a healthy diet and physical activity, alcohol consumption still carries an increased liver mortality risk, the researchers noted. Economically disadvantaged groups face higher exposure to high-risk alcohol use, unhealthy diets, and physical activity — and as a result, increased liver mortality.
“This study challenges the long-held belief that light-to-moderate drinking might be safe for the liver. It shows that any level of alcohol raises risk, but healthy diet and exercise can meaningfully reduce that harm,” said Joseph Ahn, MD, AGAF, assistant professor of medicine in the Division of Gastroenterology and Hepatology at the Mayo Clinic in Rochester, Minnesota.
“The results should change how we think about alcohol — not as something potentially protective, but as a risk factor that can be partly mitigated by lifestyle,” he said.
“The key takeaway is that there is no safe level of alcohol for liver health. Clinicians should move away from reassuring patients about ‘moderate’ drinking and instead stress both alcohol reduction and the protective role of diet and physical activity,” Ahn added. “The next step is bringing these insights into guidelines and patient counseling, especially for populations at higher risk.”
The study was funded by departmental internal funding. Chalasani declared having no conflicts of interest for this paper, but he disclosed paid consulting agreements with numerous pharmaceutical companies. Ahn reported having no disclosures.
A version of this article appeared on Medscape.com.
Ocaliva for Primary Biliary Cholangitis Withdrawn From US Market
The decision follows a request from the FDA. The FDA has also placed a clinical hold on all of Intercept’s clinical trials involving obeticholic acid.
PBC is a rare, progressive, and chronic autoimmune disease that affects the bile ducts in the liver and is most prevalent in women older than 40 years of age. PBC causes a buildup of bile acid in the liver, resulting in inflammation and fibrosis, which — if not treated — can lead to cirrhosis, a liver transplant, or death.
Ocaliva, a farnesoid X receptor agonist, received accelerated FDA approval in 2016 for the treatment of PBC in adults with an inadequate response to or intolerance of ursodeoxycholic acid.
Yet, in September 2024, staff reviewers at the FDA said a confirmatory trial did not show that the drug was effective for PBC.
Ocaliva has also been linked to an increased risk of serious liver injury in patients with PBC with and without cirrhosis.
The company has advised patients currently taking Ocaliva for PBC to consult their healthcare provider before making any changes.
Intercept will provide additional information to support healthcare professionals and patients as it works with the FDA on the transition process.
Healthcare professionals who have questions about this development can contact Intercept Medical Information at [email protected] or call 1-844-782-4278.
A version of this article appeared on Medscape.com.
The decision follows a request from the FDA. The FDA has also placed a clinical hold on all of Intercept’s clinical trials involving obeticholic acid.
PBC is a rare, progressive, and chronic autoimmune disease that affects the bile ducts in the liver and is most prevalent in women older than 40 years of age. PBC causes a buildup of bile acid in the liver, resulting in inflammation and fibrosis, which — if not treated — can lead to cirrhosis, a liver transplant, or death.
Ocaliva, a farnesoid X receptor agonist, received accelerated FDA approval in 2016 for the treatment of PBC in adults with an inadequate response to or intolerance of ursodeoxycholic acid.
Yet, in September 2024, staff reviewers at the FDA said a confirmatory trial did not show that the drug was effective for PBC.
Ocaliva has also been linked to an increased risk of serious liver injury in patients with PBC with and without cirrhosis.
The company has advised patients currently taking Ocaliva for PBC to consult their healthcare provider before making any changes.
Intercept will provide additional information to support healthcare professionals and patients as it works with the FDA on the transition process.
Healthcare professionals who have questions about this development can contact Intercept Medical Information at [email protected] or call 1-844-782-4278.
A version of this article appeared on Medscape.com.
The decision follows a request from the FDA. The FDA has also placed a clinical hold on all of Intercept’s clinical trials involving obeticholic acid.
PBC is a rare, progressive, and chronic autoimmune disease that affects the bile ducts in the liver and is most prevalent in women older than 40 years of age. PBC causes a buildup of bile acid in the liver, resulting in inflammation and fibrosis, which — if not treated — can lead to cirrhosis, a liver transplant, or death.
Ocaliva, a farnesoid X receptor agonist, received accelerated FDA approval in 2016 for the treatment of PBC in adults with an inadequate response to or intolerance of ursodeoxycholic acid.
Yet, in September 2024, staff reviewers at the FDA said a confirmatory trial did not show that the drug was effective for PBC.
Ocaliva has also been linked to an increased risk of serious liver injury in patients with PBC with and without cirrhosis.
The company has advised patients currently taking Ocaliva for PBC to consult their healthcare provider before making any changes.
Intercept will provide additional information to support healthcare professionals and patients as it works with the FDA on the transition process.
Healthcare professionals who have questions about this development can contact Intercept Medical Information at [email protected] or call 1-844-782-4278.
A version of this article appeared on Medscape.com.
SGLT2 Inhibition Promising for Patients With Cirrhosis and on Diuretics
, a large cohort study of more than 10,000 patients found.
Reporting in JAMA Network Open, Dian J. Chiang, MD, MPH, a section head of Hepatology at the Cleveland Clinic in Cleveland looked at the impact of these antihyperglycemic agents, also known as gliflozins, used in diabetes and kidney disease to block the reabsorption of glucose in the kidneys and causing more glucose to be excreted in the urine.
“Patients with cirrhosis were previously not included in SGLT2 inhibition clinical trials, and there is no large real-world evidence on the safety and effectiveness of this class of medication in patients with cirrhosis. Therefore, we decided to conduct the study to assess its safety and effectiveness,” Chiang told GI & Hepatology News.
The study’s primary endpoint was a composite of serious hepatic events, defined as ascites, varices, hyponatremia, and all-cause mortality. Secondary outcomes included variceal bleeding, paracentesis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, liver carcinoma, hypoglycemia, and all-cause hospitalizations.
The cohort consisted of 10,660 propensity-matched adult patients with cirrhosis from more than 120 healthcare organizations in the TriNetX database who were receiving furosemide and spironolactone from January 2013 to July 2021. Those also receiving SGLT2 inhibitors (n = 5330) were compared with a matched control group receiving diuretics only (n = 5330). The mean age of participants was 63.8 years, 57.8% were men, 66.3% were White individuals, and all were followed for 3 years.
The SGLT2 inhibitor group had a 32% lower incidence of serious liver events than the control group, for a hazard ratio (HR) of 0.68 (95% CI, 0.66-0.71; P < .001).
Secondary risk reductions in the intervention group were as follows:
- Hepatorenal syndrome: HR, 0.47 (95% CI, 0.40-0.56)
- Spontaneous bacterial peritonitis: HR, 0.55 (95% CI, 0.46-0.65)
- Paracentesis: HR, 0.54 (95% CI, 0.50-0.60)
- Variceal bleeding: HR, 0.79 (95% CI, 0.73-0.84)
- Hypoglycemia: HR, 0.75 (95% CI, 0.62-0.91)
- All-cause hospitalizations: HR, 0.67 (95% CI, 0.63-0.71)
The authors conjectured that SGLT2 inhibition might also benefit patients with other stages of liver disease. They pointed to a 2020 study in patients with diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and high baseline fibrosis that revealed a significant reduction in fibrosis after 12 months’ SGLT2 inhibition.
The study findings also align with those of another large propensity-matched cohort in which patients with type 2 diabetes and cirrhosis receiving metformin plus SGLT2 inhibition showed significantly lower 5-year mortality, decreased incidence of decompensated cirrhosis, and reduced hepatocellular carcinoma incidence compared with those taking metformin alone.
Prospective trials are needed to further evaluate safety and efficacy, however, the authors stressed. Future studies should specifically examine changes in sodium levels following SGLT2 inhibitor initiation, as well as the incidence of recurrent urinary tract infections and euglycemic diabetic ketoacidosis, given that these are known adverse effects of this drug class. Additionally, research comparing different types and dosing regimens would provide valuable insights into optimizing treatment.
Commenting on the analysis but not participating in it, Karn Wijarnpreecha, MD, MPH, a hepatologist at College of Medicine, The University of Arizona, Phoenix, said the study was interesting but did not show the adjusted HR for all-cause mortality separately from other serious liver events, “so we do not know if SGLT2 inhibitor group was associated with lower mortality.”
It would be premature to conclude that using SGLT2 inhibitors in patients with cirrhosis and ascites and on diuretics will decrease the need for liver transplant or significantly improve liver-related outcomes based on this study, Wijarnpreecha told GI & Hepatology News. “Moreover, we do not know the dose of diuretics or specific drugs and doses for SGLT2 inhibitors that were used in the study. Indications for using SGLT2 inhibitors are mainly from diabetes and heart failure, so this may not apply to those with cirrhosis without these two conditions as well.”
In addition, the etiology of cirrhosis in this database study is unknown. “Is it mainly from MASLD or alcohol or other conditions such as viral hepatitis or autoimmmunity? We need more thorough study to answer this question.” He also pointed out that the authors urged caution in using SGLT2 inhibitors in the context of hepatic encephalopathy (HE), which could be worsened with these agents. “This should be taken into consideration before starting medication in decompensated cirrhosis with HE,” Wijarnpreecha said.
In an accompanying commentary, Mohamed I. Elsaid, PhD, MPH, a biomedical informatics researcher and assistant professor at The Ohio State University in Columbus, Ohio, said that if confirmed, the findings could substantially improve cirrhosis care. “The signal is exciting but needs strong confirmation from large observational studies and prospective trials,” he wrote. “To turn promise into practice, the next wave of observational studies must embrace the target-trial emulation framework for bolstering firm causal conclusions and doubly robust learners that tease apart who benefits, who does not, and why.”
He added that head-to-head comparisons with the type 2 diabetes drugs known as incretin mimetics will clarify the best antihyperglycemic agents for different patient phenotypes. “With these advanced causal-inference approaches, repurposed type 2 diabetes therapies could shift cirrhosis management from reactive to proactive, improving quality of life and bending the mortality curve,” Elsaid wrote.
For Wijarnpreecha, important pending questions include the benefits of SGLT2 inhibition in cirrhosis without diabetes or heart failure “Can it be used to prevent cirrhosis in MASLD if we start at the early fibrosis stage in F0-F3?”
Chiang conceded that the study had limitations as it relied on 10th revision of the International Classification of Diseases codes to define outcomes, which may not have captured the complexity of cirrhotic complications. “And the retrospective design may have introduced confounding, selection, and information bias, which could have impacted the results,” he said. “Future prospective studies may help confirm our findings.”
No specific funding was reported for this study. The study authors and Wijarnpreecha had no relevant conflicts of interest to declare. Elsaid reported receiving research funding from Genentech and AstraZeneca outside of the submitted work.
A version of this article first appeared on Medscape.com.
, a large cohort study of more than 10,000 patients found.
Reporting in JAMA Network Open, Dian J. Chiang, MD, MPH, a section head of Hepatology at the Cleveland Clinic in Cleveland looked at the impact of these antihyperglycemic agents, also known as gliflozins, used in diabetes and kidney disease to block the reabsorption of glucose in the kidneys and causing more glucose to be excreted in the urine.
“Patients with cirrhosis were previously not included in SGLT2 inhibition clinical trials, and there is no large real-world evidence on the safety and effectiveness of this class of medication in patients with cirrhosis. Therefore, we decided to conduct the study to assess its safety and effectiveness,” Chiang told GI & Hepatology News.
The study’s primary endpoint was a composite of serious hepatic events, defined as ascites, varices, hyponatremia, and all-cause mortality. Secondary outcomes included variceal bleeding, paracentesis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, liver carcinoma, hypoglycemia, and all-cause hospitalizations.
The cohort consisted of 10,660 propensity-matched adult patients with cirrhosis from more than 120 healthcare organizations in the TriNetX database who were receiving furosemide and spironolactone from January 2013 to July 2021. Those also receiving SGLT2 inhibitors (n = 5330) were compared with a matched control group receiving diuretics only (n = 5330). The mean age of participants was 63.8 years, 57.8% were men, 66.3% were White individuals, and all were followed for 3 years.
The SGLT2 inhibitor group had a 32% lower incidence of serious liver events than the control group, for a hazard ratio (HR) of 0.68 (95% CI, 0.66-0.71; P < .001).
Secondary risk reductions in the intervention group were as follows:
- Hepatorenal syndrome: HR, 0.47 (95% CI, 0.40-0.56)
- Spontaneous bacterial peritonitis: HR, 0.55 (95% CI, 0.46-0.65)
- Paracentesis: HR, 0.54 (95% CI, 0.50-0.60)
- Variceal bleeding: HR, 0.79 (95% CI, 0.73-0.84)
- Hypoglycemia: HR, 0.75 (95% CI, 0.62-0.91)
- All-cause hospitalizations: HR, 0.67 (95% CI, 0.63-0.71)
The authors conjectured that SGLT2 inhibition might also benefit patients with other stages of liver disease. They pointed to a 2020 study in patients with diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and high baseline fibrosis that revealed a significant reduction in fibrosis after 12 months’ SGLT2 inhibition.
The study findings also align with those of another large propensity-matched cohort in which patients with type 2 diabetes and cirrhosis receiving metformin plus SGLT2 inhibition showed significantly lower 5-year mortality, decreased incidence of decompensated cirrhosis, and reduced hepatocellular carcinoma incidence compared with those taking metformin alone.
Prospective trials are needed to further evaluate safety and efficacy, however, the authors stressed. Future studies should specifically examine changes in sodium levels following SGLT2 inhibitor initiation, as well as the incidence of recurrent urinary tract infections and euglycemic diabetic ketoacidosis, given that these are known adverse effects of this drug class. Additionally, research comparing different types and dosing regimens would provide valuable insights into optimizing treatment.
Commenting on the analysis but not participating in it, Karn Wijarnpreecha, MD, MPH, a hepatologist at College of Medicine, The University of Arizona, Phoenix, said the study was interesting but did not show the adjusted HR for all-cause mortality separately from other serious liver events, “so we do not know if SGLT2 inhibitor group was associated with lower mortality.”
It would be premature to conclude that using SGLT2 inhibitors in patients with cirrhosis and ascites and on diuretics will decrease the need for liver transplant or significantly improve liver-related outcomes based on this study, Wijarnpreecha told GI & Hepatology News. “Moreover, we do not know the dose of diuretics or specific drugs and doses for SGLT2 inhibitors that were used in the study. Indications for using SGLT2 inhibitors are mainly from diabetes and heart failure, so this may not apply to those with cirrhosis without these two conditions as well.”
In addition, the etiology of cirrhosis in this database study is unknown. “Is it mainly from MASLD or alcohol or other conditions such as viral hepatitis or autoimmmunity? We need more thorough study to answer this question.” He also pointed out that the authors urged caution in using SGLT2 inhibitors in the context of hepatic encephalopathy (HE), which could be worsened with these agents. “This should be taken into consideration before starting medication in decompensated cirrhosis with HE,” Wijarnpreecha said.
In an accompanying commentary, Mohamed I. Elsaid, PhD, MPH, a biomedical informatics researcher and assistant professor at The Ohio State University in Columbus, Ohio, said that if confirmed, the findings could substantially improve cirrhosis care. “The signal is exciting but needs strong confirmation from large observational studies and prospective trials,” he wrote. “To turn promise into practice, the next wave of observational studies must embrace the target-trial emulation framework for bolstering firm causal conclusions and doubly robust learners that tease apart who benefits, who does not, and why.”
He added that head-to-head comparisons with the type 2 diabetes drugs known as incretin mimetics will clarify the best antihyperglycemic agents for different patient phenotypes. “With these advanced causal-inference approaches, repurposed type 2 diabetes therapies could shift cirrhosis management from reactive to proactive, improving quality of life and bending the mortality curve,” Elsaid wrote.
For Wijarnpreecha, important pending questions include the benefits of SGLT2 inhibition in cirrhosis without diabetes or heart failure “Can it be used to prevent cirrhosis in MASLD if we start at the early fibrosis stage in F0-F3?”
Chiang conceded that the study had limitations as it relied on 10th revision of the International Classification of Diseases codes to define outcomes, which may not have captured the complexity of cirrhotic complications. “And the retrospective design may have introduced confounding, selection, and information bias, which could have impacted the results,” he said. “Future prospective studies may help confirm our findings.”
No specific funding was reported for this study. The study authors and Wijarnpreecha had no relevant conflicts of interest to declare. Elsaid reported receiving research funding from Genentech and AstraZeneca outside of the submitted work.
A version of this article first appeared on Medscape.com.
, a large cohort study of more than 10,000 patients found.
Reporting in JAMA Network Open, Dian J. Chiang, MD, MPH, a section head of Hepatology at the Cleveland Clinic in Cleveland looked at the impact of these antihyperglycemic agents, also known as gliflozins, used in diabetes and kidney disease to block the reabsorption of glucose in the kidneys and causing more glucose to be excreted in the urine.
“Patients with cirrhosis were previously not included in SGLT2 inhibition clinical trials, and there is no large real-world evidence on the safety and effectiveness of this class of medication in patients with cirrhosis. Therefore, we decided to conduct the study to assess its safety and effectiveness,” Chiang told GI & Hepatology News.
The study’s primary endpoint was a composite of serious hepatic events, defined as ascites, varices, hyponatremia, and all-cause mortality. Secondary outcomes included variceal bleeding, paracentesis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, liver carcinoma, hypoglycemia, and all-cause hospitalizations.
The cohort consisted of 10,660 propensity-matched adult patients with cirrhosis from more than 120 healthcare organizations in the TriNetX database who were receiving furosemide and spironolactone from January 2013 to July 2021. Those also receiving SGLT2 inhibitors (n = 5330) were compared with a matched control group receiving diuretics only (n = 5330). The mean age of participants was 63.8 years, 57.8% were men, 66.3% were White individuals, and all were followed for 3 years.
The SGLT2 inhibitor group had a 32% lower incidence of serious liver events than the control group, for a hazard ratio (HR) of 0.68 (95% CI, 0.66-0.71; P < .001).
Secondary risk reductions in the intervention group were as follows:
- Hepatorenal syndrome: HR, 0.47 (95% CI, 0.40-0.56)
- Spontaneous bacterial peritonitis: HR, 0.55 (95% CI, 0.46-0.65)
- Paracentesis: HR, 0.54 (95% CI, 0.50-0.60)
- Variceal bleeding: HR, 0.79 (95% CI, 0.73-0.84)
- Hypoglycemia: HR, 0.75 (95% CI, 0.62-0.91)
- All-cause hospitalizations: HR, 0.67 (95% CI, 0.63-0.71)
The authors conjectured that SGLT2 inhibition might also benefit patients with other stages of liver disease. They pointed to a 2020 study in patients with diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and high baseline fibrosis that revealed a significant reduction in fibrosis after 12 months’ SGLT2 inhibition.
The study findings also align with those of another large propensity-matched cohort in which patients with type 2 diabetes and cirrhosis receiving metformin plus SGLT2 inhibition showed significantly lower 5-year mortality, decreased incidence of decompensated cirrhosis, and reduced hepatocellular carcinoma incidence compared with those taking metformin alone.
Prospective trials are needed to further evaluate safety and efficacy, however, the authors stressed. Future studies should specifically examine changes in sodium levels following SGLT2 inhibitor initiation, as well as the incidence of recurrent urinary tract infections and euglycemic diabetic ketoacidosis, given that these are known adverse effects of this drug class. Additionally, research comparing different types and dosing regimens would provide valuable insights into optimizing treatment.
Commenting on the analysis but not participating in it, Karn Wijarnpreecha, MD, MPH, a hepatologist at College of Medicine, The University of Arizona, Phoenix, said the study was interesting but did not show the adjusted HR for all-cause mortality separately from other serious liver events, “so we do not know if SGLT2 inhibitor group was associated with lower mortality.”
It would be premature to conclude that using SGLT2 inhibitors in patients with cirrhosis and ascites and on diuretics will decrease the need for liver transplant or significantly improve liver-related outcomes based on this study, Wijarnpreecha told GI & Hepatology News. “Moreover, we do not know the dose of diuretics or specific drugs and doses for SGLT2 inhibitors that were used in the study. Indications for using SGLT2 inhibitors are mainly from diabetes and heart failure, so this may not apply to those with cirrhosis without these two conditions as well.”
In addition, the etiology of cirrhosis in this database study is unknown. “Is it mainly from MASLD or alcohol or other conditions such as viral hepatitis or autoimmmunity? We need more thorough study to answer this question.” He also pointed out that the authors urged caution in using SGLT2 inhibitors in the context of hepatic encephalopathy (HE), which could be worsened with these agents. “This should be taken into consideration before starting medication in decompensated cirrhosis with HE,” Wijarnpreecha said.
In an accompanying commentary, Mohamed I. Elsaid, PhD, MPH, a biomedical informatics researcher and assistant professor at The Ohio State University in Columbus, Ohio, said that if confirmed, the findings could substantially improve cirrhosis care. “The signal is exciting but needs strong confirmation from large observational studies and prospective trials,” he wrote. “To turn promise into practice, the next wave of observational studies must embrace the target-trial emulation framework for bolstering firm causal conclusions and doubly robust learners that tease apart who benefits, who does not, and why.”
He added that head-to-head comparisons with the type 2 diabetes drugs known as incretin mimetics will clarify the best antihyperglycemic agents for different patient phenotypes. “With these advanced causal-inference approaches, repurposed type 2 diabetes therapies could shift cirrhosis management from reactive to proactive, improving quality of life and bending the mortality curve,” Elsaid wrote.
For Wijarnpreecha, important pending questions include the benefits of SGLT2 inhibition in cirrhosis without diabetes or heart failure “Can it be used to prevent cirrhosis in MASLD if we start at the early fibrosis stage in F0-F3?”
Chiang conceded that the study had limitations as it relied on 10th revision of the International Classification of Diseases codes to define outcomes, which may not have captured the complexity of cirrhotic complications. “And the retrospective design may have introduced confounding, selection, and information bias, which could have impacted the results,” he said. “Future prospective studies may help confirm our findings.”
No specific funding was reported for this study. The study authors and Wijarnpreecha had no relevant conflicts of interest to declare. Elsaid reported receiving research funding from Genentech and AstraZeneca outside of the submitted work.
A version of this article first appeared on Medscape.com.
Augmenting DNA Damage by Chemotherapy With CDK7 Inhibition to Disrupt PARP Expression in Cholangiocarcinoma
Wegovy Approved for MASH With Fibrosis, No Cirrhosis
The once-weekly 2.4 mg semaglutide subcutaneous injection is given in conjunction with a reduced calorie diet and increased physical activity.
Among people living with overweight or obesity globally, 1 in 3 also have MASH.
The accelerated approval was based on part-one results from the ongoing two-part, phase-3 ESSENCE trial, in which Wegovy demonstrated a significant improvement in liver fibrosis with no worsening of steatohepatitis, as well as resolution of steatohepatitis with no worsening of liver fibrosis, compared with placebo at week 72. Those results were published online in April in The New England Journal of Medicine.
For the trial, 800 participants were randomly assigned to either Wegovy (534 participants) or placebo (266 participants) in addition to lifestyle changes. The mean age was 56 years and the mean BMI was 34. Most patients were white individuals (67.5%) and women (57.1%), and 55.9% of the patients had type 2 diabetes; 250 patients (31.3%) had stage II fibrosis and 550 (68.8%) had stage III fibrosis. Participants were on stable doses of lipid-lowering, glucose-management, and weight-loss medications.
At week 72, the first primary endpoint showed 63% of the 534 people treated with Wegovy achieved resolution of steatohepatitis and no worsening of liver fibrosis compared with 34% of 266 individuals treated with placebo — a statistically significant difference.
The second primary endpoint showed 37% of people treated with Wegovy achieved improvement in liver fibrosis and no worsening of steatohepatitis compared with 22% of those treated with placebo, also a significant difference.
A confirmatory secondary endpoint at week 72 showed 33% of patients treated with Wegovy achieved both resolution of steatohepatitis and improvement in liver fibrosis compared with 16% of those treated with placebo — a statistically significant difference in response rate of 17%.
In addition, 83.5% of the patients in the semaglutide group maintained the target dose of 2.4 mg until week 72.
Wegovy is also indicated, along with diet and physical activity, to reduce the risk for major cardiovascular events in adults with known heart disease and with either obesity or overweight. It is also indicated for adults and children aged 12 years or older with obesity, and some adults with overweight who also have weight-related medical problems, to help them lose excess body weight and keep the weight off.
What’s Next for Wegovy?
In February 2025, Novo Nordisk filed for regulatory approval in the EU, followed by regulatory submission in Japan in May 2025. Also in May, the FDA accepted a filing application for oral semaglutide 25 mg.
Furthermore, “There’s an expected readout of part 2 of ESSENCE in 2029, which aims to demonstrate treatment with Wegovy lowers the risk of liver-related clinical events, compared to placebo, in patients with MASH and F2 or F3 fibrosis at week 240,” a Novo Nordisk spokesperson told GI & Hepatology News.
Although the company has the technology to produce semaglutide as a pill or tablet, she said, “the US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity.” The company has not yet submitted the 50 mg oral semaglutide to regulatory authorities.
“The oral form requires more active pharmaceutical ingredient (API),” she noted. “Given that we have a fixed amount of API, the injectable form enables us to treat more patients. We are currently expanding our oral and injectable production capacities globally with the aim of serving as many patients as possible. It requires time to build, install, validate, and ramp-up these production processes.”
A version of this article appeared on Medscape.com.
The once-weekly 2.4 mg semaglutide subcutaneous injection is given in conjunction with a reduced calorie diet and increased physical activity.
Among people living with overweight or obesity globally, 1 in 3 also have MASH.
The accelerated approval was based on part-one results from the ongoing two-part, phase-3 ESSENCE trial, in which Wegovy demonstrated a significant improvement in liver fibrosis with no worsening of steatohepatitis, as well as resolution of steatohepatitis with no worsening of liver fibrosis, compared with placebo at week 72. Those results were published online in April in The New England Journal of Medicine.
For the trial, 800 participants were randomly assigned to either Wegovy (534 participants) or placebo (266 participants) in addition to lifestyle changes. The mean age was 56 years and the mean BMI was 34. Most patients were white individuals (67.5%) and women (57.1%), and 55.9% of the patients had type 2 diabetes; 250 patients (31.3%) had stage II fibrosis and 550 (68.8%) had stage III fibrosis. Participants were on stable doses of lipid-lowering, glucose-management, and weight-loss medications.
At week 72, the first primary endpoint showed 63% of the 534 people treated with Wegovy achieved resolution of steatohepatitis and no worsening of liver fibrosis compared with 34% of 266 individuals treated with placebo — a statistically significant difference.
The second primary endpoint showed 37% of people treated with Wegovy achieved improvement in liver fibrosis and no worsening of steatohepatitis compared with 22% of those treated with placebo, also a significant difference.
A confirmatory secondary endpoint at week 72 showed 33% of patients treated with Wegovy achieved both resolution of steatohepatitis and improvement in liver fibrosis compared with 16% of those treated with placebo — a statistically significant difference in response rate of 17%.
In addition, 83.5% of the patients in the semaglutide group maintained the target dose of 2.4 mg until week 72.
Wegovy is also indicated, along with diet and physical activity, to reduce the risk for major cardiovascular events in adults with known heart disease and with either obesity or overweight. It is also indicated for adults and children aged 12 years or older with obesity, and some adults with overweight who also have weight-related medical problems, to help them lose excess body weight and keep the weight off.
What’s Next for Wegovy?
In February 2025, Novo Nordisk filed for regulatory approval in the EU, followed by regulatory submission in Japan in May 2025. Also in May, the FDA accepted a filing application for oral semaglutide 25 mg.
Furthermore, “There’s an expected readout of part 2 of ESSENCE in 2029, which aims to demonstrate treatment with Wegovy lowers the risk of liver-related clinical events, compared to placebo, in patients with MASH and F2 or F3 fibrosis at week 240,” a Novo Nordisk spokesperson told GI & Hepatology News.
Although the company has the technology to produce semaglutide as a pill or tablet, she said, “the US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity.” The company has not yet submitted the 50 mg oral semaglutide to regulatory authorities.
“The oral form requires more active pharmaceutical ingredient (API),” she noted. “Given that we have a fixed amount of API, the injectable form enables us to treat more patients. We are currently expanding our oral and injectable production capacities globally with the aim of serving as many patients as possible. It requires time to build, install, validate, and ramp-up these production processes.”
A version of this article appeared on Medscape.com.
The once-weekly 2.4 mg semaglutide subcutaneous injection is given in conjunction with a reduced calorie diet and increased physical activity.
Among people living with overweight or obesity globally, 1 in 3 also have MASH.
The accelerated approval was based on part-one results from the ongoing two-part, phase-3 ESSENCE trial, in which Wegovy demonstrated a significant improvement in liver fibrosis with no worsening of steatohepatitis, as well as resolution of steatohepatitis with no worsening of liver fibrosis, compared with placebo at week 72. Those results were published online in April in The New England Journal of Medicine.
For the trial, 800 participants were randomly assigned to either Wegovy (534 participants) or placebo (266 participants) in addition to lifestyle changes. The mean age was 56 years and the mean BMI was 34. Most patients were white individuals (67.5%) and women (57.1%), and 55.9% of the patients had type 2 diabetes; 250 patients (31.3%) had stage II fibrosis and 550 (68.8%) had stage III fibrosis. Participants were on stable doses of lipid-lowering, glucose-management, and weight-loss medications.
At week 72, the first primary endpoint showed 63% of the 534 people treated with Wegovy achieved resolution of steatohepatitis and no worsening of liver fibrosis compared with 34% of 266 individuals treated with placebo — a statistically significant difference.
The second primary endpoint showed 37% of people treated with Wegovy achieved improvement in liver fibrosis and no worsening of steatohepatitis compared with 22% of those treated with placebo, also a significant difference.
A confirmatory secondary endpoint at week 72 showed 33% of patients treated with Wegovy achieved both resolution of steatohepatitis and improvement in liver fibrosis compared with 16% of those treated with placebo — a statistically significant difference in response rate of 17%.
In addition, 83.5% of the patients in the semaglutide group maintained the target dose of 2.4 mg until week 72.
Wegovy is also indicated, along with diet and physical activity, to reduce the risk for major cardiovascular events in adults with known heart disease and with either obesity or overweight. It is also indicated for adults and children aged 12 years or older with obesity, and some adults with overweight who also have weight-related medical problems, to help them lose excess body weight and keep the weight off.
What’s Next for Wegovy?
In February 2025, Novo Nordisk filed for regulatory approval in the EU, followed by regulatory submission in Japan in May 2025. Also in May, the FDA accepted a filing application for oral semaglutide 25 mg.
Furthermore, “There’s an expected readout of part 2 of ESSENCE in 2029, which aims to demonstrate treatment with Wegovy lowers the risk of liver-related clinical events, compared to placebo, in patients with MASH and F2 or F3 fibrosis at week 240,” a Novo Nordisk spokesperson told GI & Hepatology News.
Although the company has the technology to produce semaglutide as a pill or tablet, she said, “the US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity.” The company has not yet submitted the 50 mg oral semaglutide to regulatory authorities.
“The oral form requires more active pharmaceutical ingredient (API),” she noted. “Given that we have a fixed amount of API, the injectable form enables us to treat more patients. We are currently expanding our oral and injectable production capacities globally with the aim of serving as many patients as possible. It requires time to build, install, validate, and ramp-up these production processes.”
A version of this article appeared on Medscape.com.
Skip Antibiotic Prophylaxis for Upper GI Bleeding in Cirrhosis?
Pooled data from 14 randomized controlled trials (RCTs) found a high probability that no or shorter durations of antibiotic prophylaxis are not worse than longer durations in preventing death from any cause in these patients.
The findings suggest that recommendations for routine antibiotic prophylaxis in patients with cirrhosis and upper GI bleeding “should be reassessed,” the authors said.
They acknowledged, however, that the studies were of low-to-moderate quality and higher quality randomized clinical trial data are needed.
The study, with first author Connor Prosty, MD, of McGill University, in Montreal, Quebec, Canada, was published online in JAMA Internal Medicine.
Questionable Benefit?
Antibiotic prophylaxis became standard decades ago, when up to 60% of variceal bleeds were complicated by infections, which were thought to increase the risk for rebleeding and death.
Yet, the evidence to support the recommendation remains limited, and a recent RCT called into question the necessity of prophylaxis. The study showed no statistically significant difference in mortality or infection among patients with Child-Pugh class A cirrhosis randomized to receive no prophylaxis compared to third-generation cephalosporin.
While generally perceived as safe, antibiotics have potential adverse effects and can select for resistant superinfections, Prosty and colleagues pointed out.
They also noted that shorter courses of antibiotics have been proven to be as good, if not better, than longer courses across numerous other infectious indications. Recommendations for primary and secondary antibiotic prophylaxis for spontaneous bacterial peritonitis are being reassessed due to a weak evidence base, lack of mortality benefit, and potential for harm.
To revisit antibiotic prophylaxis for upper GI bleeding in patients with cirrhosis, Prosty and colleagues did a systematic review and meta-analysis of 14 RCTs involving 1322 patients.
Two of the trials compared longer (5-7 days) with shorter (2-3 days) antibiotics, and 12 compared any antibiotic prophylaxis (1-10 days) to none.
The primary outcome was all-cause mortality, with a prespecified noninferiority margin of 5% on the risk difference (RD) scale. Secondary outcomes included early rebleeding and bacterial infections.
Overall, shorter antibiotic durations (including none) had a 97.3% probability of noninferiority to longer durations for all-cause mortality (RD, 0.9%; 95% credible interval [CrI], -2.6% to 4.9%).
Shorter durations had a 73.8% probability of noninferiority for early rebleeding (RD, 2.9%; 95% CrI, -4.2% to 10.0%) but were associated with more study-defined bacterial infections (RD, 15.2%; 95% CrI, 5.0%-25.9%). However, the authors cited methodological concerns about the definitions of these infections in the included studies.
The probabilities of noninferiority of shorter durations for mortality, early rebleeding, and bacterial infections were higher in studies published after 2004.
Change Practice Now?
“Our findings re-open the discussion surrounding the long-standing and firmly held belief that antibiotic prophylaxis has a mortality benefit in patients with cirrhosis presenting with upper gastrointestinal bleeds,” Prosty and colleagues wrote.
They cautioned, however, that the study quality was “low to moderate, bacterial infections were heterogeneously defined, and no studies reported adverse events. Higher-quality RCTs are needed to determine the benefit and optimal duration of antibiotic prophylaxis in the modern era of advanced interventions.”
The authors of a commentary published with the study noted that management of upper GI bleeding in cirrhosis patients has “greatly improved” since the 1990s, when some of the trials included in the analysis were conducted.
Hepatologists Catherine Mezzacappa, MD, MPH, and Guadalupe Garcia-Tsao, MD, both at the Yale School of Medicine, New Haven, Connecticut, agree that it “may be time to revisit whether prophylactic antibiotics continue to provide benefit in patients with cirrhosis and upper GI bleeding, and if so, in which patients.”
They caution, however, that the current level of evidence is “inadequate to answer whether it is time to stop this practice, which has become the standard of care.
New trials for shorter duration and no antibiotic prophylaxis “should be designed in specific patient populations to compare sequelae of antibiotic prophylaxis, including subsequent infections and all-cause mortality,” Mezzacappa and Garcia-Tsao concluded.
The study received no specific funding. The authors and commentary writers had no relevant disclosures.
A version of this article appeared on Medscape.com.
Pooled data from 14 randomized controlled trials (RCTs) found a high probability that no or shorter durations of antibiotic prophylaxis are not worse than longer durations in preventing death from any cause in these patients.
The findings suggest that recommendations for routine antibiotic prophylaxis in patients with cirrhosis and upper GI bleeding “should be reassessed,” the authors said.
They acknowledged, however, that the studies were of low-to-moderate quality and higher quality randomized clinical trial data are needed.
The study, with first author Connor Prosty, MD, of McGill University, in Montreal, Quebec, Canada, was published online in JAMA Internal Medicine.
Questionable Benefit?
Antibiotic prophylaxis became standard decades ago, when up to 60% of variceal bleeds were complicated by infections, which were thought to increase the risk for rebleeding and death.
Yet, the evidence to support the recommendation remains limited, and a recent RCT called into question the necessity of prophylaxis. The study showed no statistically significant difference in mortality or infection among patients with Child-Pugh class A cirrhosis randomized to receive no prophylaxis compared to third-generation cephalosporin.
While generally perceived as safe, antibiotics have potential adverse effects and can select for resistant superinfections, Prosty and colleagues pointed out.
They also noted that shorter courses of antibiotics have been proven to be as good, if not better, than longer courses across numerous other infectious indications. Recommendations for primary and secondary antibiotic prophylaxis for spontaneous bacterial peritonitis are being reassessed due to a weak evidence base, lack of mortality benefit, and potential for harm.
To revisit antibiotic prophylaxis for upper GI bleeding in patients with cirrhosis, Prosty and colleagues did a systematic review and meta-analysis of 14 RCTs involving 1322 patients.
Two of the trials compared longer (5-7 days) with shorter (2-3 days) antibiotics, and 12 compared any antibiotic prophylaxis (1-10 days) to none.
The primary outcome was all-cause mortality, with a prespecified noninferiority margin of 5% on the risk difference (RD) scale. Secondary outcomes included early rebleeding and bacterial infections.
Overall, shorter antibiotic durations (including none) had a 97.3% probability of noninferiority to longer durations for all-cause mortality (RD, 0.9%; 95% credible interval [CrI], -2.6% to 4.9%).
Shorter durations had a 73.8% probability of noninferiority for early rebleeding (RD, 2.9%; 95% CrI, -4.2% to 10.0%) but were associated with more study-defined bacterial infections (RD, 15.2%; 95% CrI, 5.0%-25.9%). However, the authors cited methodological concerns about the definitions of these infections in the included studies.
The probabilities of noninferiority of shorter durations for mortality, early rebleeding, and bacterial infections were higher in studies published after 2004.
Change Practice Now?
“Our findings re-open the discussion surrounding the long-standing and firmly held belief that antibiotic prophylaxis has a mortality benefit in patients with cirrhosis presenting with upper gastrointestinal bleeds,” Prosty and colleagues wrote.
They cautioned, however, that the study quality was “low to moderate, bacterial infections were heterogeneously defined, and no studies reported adverse events. Higher-quality RCTs are needed to determine the benefit and optimal duration of antibiotic prophylaxis in the modern era of advanced interventions.”
The authors of a commentary published with the study noted that management of upper GI bleeding in cirrhosis patients has “greatly improved” since the 1990s, when some of the trials included in the analysis were conducted.
Hepatologists Catherine Mezzacappa, MD, MPH, and Guadalupe Garcia-Tsao, MD, both at the Yale School of Medicine, New Haven, Connecticut, agree that it “may be time to revisit whether prophylactic antibiotics continue to provide benefit in patients with cirrhosis and upper GI bleeding, and if so, in which patients.”
They caution, however, that the current level of evidence is “inadequate to answer whether it is time to stop this practice, which has become the standard of care.
New trials for shorter duration and no antibiotic prophylaxis “should be designed in specific patient populations to compare sequelae of antibiotic prophylaxis, including subsequent infections and all-cause mortality,” Mezzacappa and Garcia-Tsao concluded.
The study received no specific funding. The authors and commentary writers had no relevant disclosures.
A version of this article appeared on Medscape.com.
Pooled data from 14 randomized controlled trials (RCTs) found a high probability that no or shorter durations of antibiotic prophylaxis are not worse than longer durations in preventing death from any cause in these patients.
The findings suggest that recommendations for routine antibiotic prophylaxis in patients with cirrhosis and upper GI bleeding “should be reassessed,” the authors said.
They acknowledged, however, that the studies were of low-to-moderate quality and higher quality randomized clinical trial data are needed.
The study, with first author Connor Prosty, MD, of McGill University, in Montreal, Quebec, Canada, was published online in JAMA Internal Medicine.
Questionable Benefit?
Antibiotic prophylaxis became standard decades ago, when up to 60% of variceal bleeds were complicated by infections, which were thought to increase the risk for rebleeding and death.
Yet, the evidence to support the recommendation remains limited, and a recent RCT called into question the necessity of prophylaxis. The study showed no statistically significant difference in mortality or infection among patients with Child-Pugh class A cirrhosis randomized to receive no prophylaxis compared to third-generation cephalosporin.
While generally perceived as safe, antibiotics have potential adverse effects and can select for resistant superinfections, Prosty and colleagues pointed out.
They also noted that shorter courses of antibiotics have been proven to be as good, if not better, than longer courses across numerous other infectious indications. Recommendations for primary and secondary antibiotic prophylaxis for spontaneous bacterial peritonitis are being reassessed due to a weak evidence base, lack of mortality benefit, and potential for harm.
To revisit antibiotic prophylaxis for upper GI bleeding in patients with cirrhosis, Prosty and colleagues did a systematic review and meta-analysis of 14 RCTs involving 1322 patients.
Two of the trials compared longer (5-7 days) with shorter (2-3 days) antibiotics, and 12 compared any antibiotic prophylaxis (1-10 days) to none.
The primary outcome was all-cause mortality, with a prespecified noninferiority margin of 5% on the risk difference (RD) scale. Secondary outcomes included early rebleeding and bacterial infections.
Overall, shorter antibiotic durations (including none) had a 97.3% probability of noninferiority to longer durations for all-cause mortality (RD, 0.9%; 95% credible interval [CrI], -2.6% to 4.9%).
Shorter durations had a 73.8% probability of noninferiority for early rebleeding (RD, 2.9%; 95% CrI, -4.2% to 10.0%) but were associated with more study-defined bacterial infections (RD, 15.2%; 95% CrI, 5.0%-25.9%). However, the authors cited methodological concerns about the definitions of these infections in the included studies.
The probabilities of noninferiority of shorter durations for mortality, early rebleeding, and bacterial infections were higher in studies published after 2004.
Change Practice Now?
“Our findings re-open the discussion surrounding the long-standing and firmly held belief that antibiotic prophylaxis has a mortality benefit in patients with cirrhosis presenting with upper gastrointestinal bleeds,” Prosty and colleagues wrote.
They cautioned, however, that the study quality was “low to moderate, bacterial infections were heterogeneously defined, and no studies reported adverse events. Higher-quality RCTs are needed to determine the benefit and optimal duration of antibiotic prophylaxis in the modern era of advanced interventions.”
The authors of a commentary published with the study noted that management of upper GI bleeding in cirrhosis patients has “greatly improved” since the 1990s, when some of the trials included in the analysis were conducted.
Hepatologists Catherine Mezzacappa, MD, MPH, and Guadalupe Garcia-Tsao, MD, both at the Yale School of Medicine, New Haven, Connecticut, agree that it “may be time to revisit whether prophylactic antibiotics continue to provide benefit in patients with cirrhosis and upper GI bleeding, and if so, in which patients.”
They caution, however, that the current level of evidence is “inadequate to answer whether it is time to stop this practice, which has become the standard of care.
New trials for shorter duration and no antibiotic prophylaxis “should be designed in specific patient populations to compare sequelae of antibiotic prophylaxis, including subsequent infections and all-cause mortality,” Mezzacappa and Garcia-Tsao concluded.
The study received no specific funding. The authors and commentary writers had no relevant disclosures.
A version of this article appeared on Medscape.com.
Journal Highlights: May-July 2025
Esophagus/Motility
Nguyen AD, et al. AGA Clinical Practice Update on Incorporating Functional Lumen Imaging Probe Into Esophageal Clinical Practice: Expert Review. Gastroenterology. 2025 Jul. doi: 10.1053/j.gastro.2025.05.011.
Hartnett DA, et al. Distribution of Esophageal Eosinophilia as a Predictor of Proton Pump Inhibitor Response in Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.06.032.
Gyawali CP, et al. pH Impedance Monitoring on Proton Pump Inhibitor Therapy Impacts Management Decisions in Proven GERD but not in Unproven GERD. Clin Gastroenterol Hepatol. 2025 May. doi: 10.1016/j.cgh.2025.02.032.
Stomach
Wiklund AK, et al. Risk of Gastric Adenocarcinoma After Eradication of Helicobacter pylori. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.239.
Sonaiya S, et al. Over-the-Scope Clip versus Standard Endoscopic Therapy as First-Line Intervention for Nonvariceal Upper Gastrointestinal Bleeding: A Cost-Effectiveness Analysis. Tech Innov Gastrointest. 2025 Jun. doi: 10.1016/j.tige.2025.250935.
Colon
Hassan C, et al. Colon Cancer Screening, Surveillance, and Treatment: Novel Artificial Intelligence Driving Strategies in the Management of Colon Lesions. Gastroenterology. 2025 Mar. doi: 10.1053/j.gastro.2025.02.021.
Pancreas
Wilcox CM, et al; US Pancreatic Disease Study Group. Management of the Disconnected Pancreatic Duct in Pancreatic Necrosis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.05.024.
Ghimire C, et al. The effect of advances in pancreatic cancer treatment in population mortality: A SEER-based study. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100739.
Hepatology
Canivet CM, et al. Validation of the AASLD/EASL Multi-Step Screening Strategies for MASLD. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100747.
Miscellaneous
Chang L, et al. Gut Feelings: The Critical Role of Interoception in Obesity and Disorders of Gut-Brain Interaction. Gastroenterology. 2025 Aug. doi: 10.1053/j.gastro.2025.04.002.
Bashiri K, et al. Advancing Hemostatic Powder Technologies for Management of Gastrointestinal Bleeding: Challenges and Solutions. Tech Innov Gastrointest. 2025 Jul. doi: 10.1016/j.tige.2025.250940.
Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.
Esophagus/Motility
Nguyen AD, et al. AGA Clinical Practice Update on Incorporating Functional Lumen Imaging Probe Into Esophageal Clinical Practice: Expert Review. Gastroenterology. 2025 Jul. doi: 10.1053/j.gastro.2025.05.011.
Hartnett DA, et al. Distribution of Esophageal Eosinophilia as a Predictor of Proton Pump Inhibitor Response in Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.06.032.
Gyawali CP, et al. pH Impedance Monitoring on Proton Pump Inhibitor Therapy Impacts Management Decisions in Proven GERD but not in Unproven GERD. Clin Gastroenterol Hepatol. 2025 May. doi: 10.1016/j.cgh.2025.02.032.
Stomach
Wiklund AK, et al. Risk of Gastric Adenocarcinoma After Eradication of Helicobacter pylori. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.239.
Sonaiya S, et al. Over-the-Scope Clip versus Standard Endoscopic Therapy as First-Line Intervention for Nonvariceal Upper Gastrointestinal Bleeding: A Cost-Effectiveness Analysis. Tech Innov Gastrointest. 2025 Jun. doi: 10.1016/j.tige.2025.250935.
Colon
Hassan C, et al. Colon Cancer Screening, Surveillance, and Treatment: Novel Artificial Intelligence Driving Strategies in the Management of Colon Lesions. Gastroenterology. 2025 Mar. doi: 10.1053/j.gastro.2025.02.021.
Pancreas
Wilcox CM, et al; US Pancreatic Disease Study Group. Management of the Disconnected Pancreatic Duct in Pancreatic Necrosis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.05.024.
Ghimire C, et al. The effect of advances in pancreatic cancer treatment in population mortality: A SEER-based study. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100739.
Hepatology
Canivet CM, et al. Validation of the AASLD/EASL Multi-Step Screening Strategies for MASLD. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100747.
Miscellaneous
Chang L, et al. Gut Feelings: The Critical Role of Interoception in Obesity and Disorders of Gut-Brain Interaction. Gastroenterology. 2025 Aug. doi: 10.1053/j.gastro.2025.04.002.
Bashiri K, et al. Advancing Hemostatic Powder Technologies for Management of Gastrointestinal Bleeding: Challenges and Solutions. Tech Innov Gastrointest. 2025 Jul. doi: 10.1016/j.tige.2025.250940.
Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.
Esophagus/Motility
Nguyen AD, et al. AGA Clinical Practice Update on Incorporating Functional Lumen Imaging Probe Into Esophageal Clinical Practice: Expert Review. Gastroenterology. 2025 Jul. doi: 10.1053/j.gastro.2025.05.011.
Hartnett DA, et al. Distribution of Esophageal Eosinophilia as a Predictor of Proton Pump Inhibitor Response in Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.06.032.
Gyawali CP, et al. pH Impedance Monitoring on Proton Pump Inhibitor Therapy Impacts Management Decisions in Proven GERD but not in Unproven GERD. Clin Gastroenterol Hepatol. 2025 May. doi: 10.1016/j.cgh.2025.02.032.
Stomach
Wiklund AK, et al. Risk of Gastric Adenocarcinoma After Eradication of Helicobacter pylori. Gastroenterology. 2025 Feb. doi: 10.1053/j.gastro.2025.01.239.
Sonaiya S, et al. Over-the-Scope Clip versus Standard Endoscopic Therapy as First-Line Intervention for Nonvariceal Upper Gastrointestinal Bleeding: A Cost-Effectiveness Analysis. Tech Innov Gastrointest. 2025 Jun. doi: 10.1016/j.tige.2025.250935.
Colon
Hassan C, et al. Colon Cancer Screening, Surveillance, and Treatment: Novel Artificial Intelligence Driving Strategies in the Management of Colon Lesions. Gastroenterology. 2025 Mar. doi: 10.1053/j.gastro.2025.02.021.
Pancreas
Wilcox CM, et al; US Pancreatic Disease Study Group. Management of the Disconnected Pancreatic Duct in Pancreatic Necrosis. Clin Gastroenterol Hepatol. 2025 Jul. doi: 10.1016/j.cgh.2025.05.024.
Ghimire C, et al. The effect of advances in pancreatic cancer treatment in population mortality: A SEER-based study. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100739.
Hepatology
Canivet CM, et al. Validation of the AASLD/EASL Multi-Step Screening Strategies for MASLD. Gastro Hep Adv. 2025 Jul. doi: 10.1016/j.gastha.2025.100747.
Miscellaneous
Chang L, et al. Gut Feelings: The Critical Role of Interoception in Obesity and Disorders of Gut-Brain Interaction. Gastroenterology. 2025 Aug. doi: 10.1053/j.gastro.2025.04.002.
Bashiri K, et al. Advancing Hemostatic Powder Technologies for Management of Gastrointestinal Bleeding: Challenges and Solutions. Tech Innov Gastrointest. 2025 Jul. doi: 10.1016/j.tige.2025.250940.
Dr. Trieu is assistant professor of medicine, interventional endoscopy, in the Division of Gastroenterology at Washington University in St. Louis School of Medicine, Missouri.