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Architect of VA Transformation Urges Innovation Amid Uncertainty
Architect of VA Transformation Urges Innovation Amid Uncertainty
PHOENIX – Three decades after he initiated the transformation of the Veterans Health Administration (VHA) into a model research and clinical health care system, former US Department of Veterans Affairs (VA) Under Secretary of Health Kenneth W. Kizer, MD, MPH, urged cancer specialists to embrace this challenging moment as an opportunity for bold innovation.
At the annual meeting of the Association of VA Hematology/Oncology (AVAHO), Kizer acknowledged that the VA faces an “uncertain and turbulent time” in areas such as funding, staffing, community care implementation, and the rollout of a new electronic health record system.
He also noted the grim rise of global instability, economic turmoil, climate change, infectious diseases, political violence, and mass shootings.
“This can be stressful. It can create negative energy. But this uncertainty can also be liberating, and it can prompt positive energy and innovation, depending on choices that we make,” said Kizer, who also has served as California’s top health official prior to leading the VHA from 1994 to 1999.
From “Bloated Bureaucracy’ to High-Quality Health Care System
Kizer has been credited with revitalizing VHA care through a greater commitment to quality, and harkened to his work with the VA as an example of how bold goals can lead to bold innovation.
“What were the perceptions of VA health care in 1994? Well, they weren’t very good, frankly,” Kizer recalled. He described the VA as having a reputation at that time as “highly dysfunctional” with “a very bloated and entrenched bureaucracy.” As for quality of care, it “wasn’t viewed as very good.”
The system’s problems were so severe that patients would park motorhomes in VA medical center parking lots as they waited for care. “While they might have an appointment for one day, they may not be seen for 3 or 4 or 5 days. So they would stay in their motorhome until they finally got into their clinic appointment,” Kizer said.
Overall, “the public viewed the VA as this bleak backwater of incompetence and difference and inefficiency, and there were very strong calls to privatize the VA,” Kizer said.
Kizer asked colleagues about what he should do after he was asked to take the under secretary job. “With one exception, they all said, don’t go near it. Don’t touch it. Walk away. That it’s impossible to change the organization.
“I looked at the VA and I saw an opportunity. When I told [members of the President Bill] Clinton [Administration] yes, my bold aim was that I would like to pursue this was to make VHA a model of excellent health care, an exemplary health care system. Most everyone else thought that I was totally delusional, but sometimes it’s good to be delusional.”
Revolutionary Changes Despite Opposition
Kizer sought reforms in 5 major strategic objectives, all without explicit congressional approval: creating an accountable management structure, decentralizing decision-making, integrating care, implementing universal primary care, and pursuing eligibility reform to create the current 8-tier VA system.
One major innovation was the implementation of community-based outpatient clinics (CBOCs): “Those were strongly opposed initially,” Kizer said. “Everyone, the veteran community in particular, had been led to believe that the only good care was in the hospital.”
The resistance was substantial. “There was a lot of opposition when we said we’re going to move out into the community where you live to make [care] easier to access,” Kizer said.
To make things more difficult, Congress wouldn’t fund the project: “For the first 3 years, every CBOC had to be funded by redirected savings from other things that we could do within the system,” he said. “All of this was through redirected savings and finding ways to save and reinvest.”
Innovation From the Ground Up
Kizer emphasized that many breakthrough innovations came from frontline staff rather than executive mandates. He cited the example of Barcode Medication Administration, which originated from a nurse in Topeka, Kan.
The nurse saw a barcode scanner put to work at a rental car company where it was used to check cars in and out. She wondered, “Why can’t we do this with medications when they’re given on the floor? We followed up on it, pursued those things, tested it out, it worked.”
The results were dramatic. “I was told at a meeting that they had achieved close to 80% reduction in medication errors,” Kizer said. After verifying the results personally, he “authorized $20 million, and we moved forward with it systemwide.”
This experience reinforced his belief in harvesting ideas from staff at all levels.
Innovation remains part of the VA’s culture “despite what some people would have you believe,” Kizer said. Recently, the VA has made major advances in areas such as patient transportation and the climate crisis, he said.
Inside the Recipe for Innovation
Boldness, persistence, adaptability, and tolerance for risk are necessary ingredients for high-risk goals, Kizer said. Ambition is also part of the picture.
He highlighted examples such as the Apollo moon landing, the first sub-4-minute mile, and the first swim across the English Channel by a woman.
In medicine, Kizer pointed to a national patient safety campaign that saved an estimated 122,000 lives. He also mentioned recent progress in organ transplantation such as recommendations from the National Academies of Sciences, Engineering, and Medicine to establish national performance goals and the Organ Procurement and Transplantation Network’s target of 60,000 deceased donor transplants by 2026.
Bold doesn’t mean being reckless or careless, Kizer said. “But it does require innovation. And it does require that you try some new things, some of which aren’t going to work out.”
The key mindset, he explained, is to “embrace the unknown” because “you often really don’t know how you will accomplish the aim when you start. But you’ll figure it out as you go.”
Kizer highlighted 2 opposing strategies to handling challenging times.
According to him, the “negative energy” approach focuses on frustrations, limitations, and asking “Why is this happening to me?”
In contrast, a “positive energy” approach expects problems, focuses on available resources and capabilities, and asks, “What are the opportunities that these changes are creating for me?”
Kizer made it crystal clear which option he prefers.
Dr. Kizer disclosed that his comments represent his opinions only, and he noted his ongoing connections to the VA.
PHOENIX – Three decades after he initiated the transformation of the Veterans Health Administration (VHA) into a model research and clinical health care system, former US Department of Veterans Affairs (VA) Under Secretary of Health Kenneth W. Kizer, MD, MPH, urged cancer specialists to embrace this challenging moment as an opportunity for bold innovation.
At the annual meeting of the Association of VA Hematology/Oncology (AVAHO), Kizer acknowledged that the VA faces an “uncertain and turbulent time” in areas such as funding, staffing, community care implementation, and the rollout of a new electronic health record system.
He also noted the grim rise of global instability, economic turmoil, climate change, infectious diseases, political violence, and mass shootings.
“This can be stressful. It can create negative energy. But this uncertainty can also be liberating, and it can prompt positive energy and innovation, depending on choices that we make,” said Kizer, who also has served as California’s top health official prior to leading the VHA from 1994 to 1999.
From “Bloated Bureaucracy’ to High-Quality Health Care System
Kizer has been credited with revitalizing VHA care through a greater commitment to quality, and harkened to his work with the VA as an example of how bold goals can lead to bold innovation.
“What were the perceptions of VA health care in 1994? Well, they weren’t very good, frankly,” Kizer recalled. He described the VA as having a reputation at that time as “highly dysfunctional” with “a very bloated and entrenched bureaucracy.” As for quality of care, it “wasn’t viewed as very good.”
The system’s problems were so severe that patients would park motorhomes in VA medical center parking lots as they waited for care. “While they might have an appointment for one day, they may not be seen for 3 or 4 or 5 days. So they would stay in their motorhome until they finally got into their clinic appointment,” Kizer said.
Overall, “the public viewed the VA as this bleak backwater of incompetence and difference and inefficiency, and there were very strong calls to privatize the VA,” Kizer said.
Kizer asked colleagues about what he should do after he was asked to take the under secretary job. “With one exception, they all said, don’t go near it. Don’t touch it. Walk away. That it’s impossible to change the organization.
“I looked at the VA and I saw an opportunity. When I told [members of the President Bill] Clinton [Administration] yes, my bold aim was that I would like to pursue this was to make VHA a model of excellent health care, an exemplary health care system. Most everyone else thought that I was totally delusional, but sometimes it’s good to be delusional.”
Revolutionary Changes Despite Opposition
Kizer sought reforms in 5 major strategic objectives, all without explicit congressional approval: creating an accountable management structure, decentralizing decision-making, integrating care, implementing universal primary care, and pursuing eligibility reform to create the current 8-tier VA system.
One major innovation was the implementation of community-based outpatient clinics (CBOCs): “Those were strongly opposed initially,” Kizer said. “Everyone, the veteran community in particular, had been led to believe that the only good care was in the hospital.”
The resistance was substantial. “There was a lot of opposition when we said we’re going to move out into the community where you live to make [care] easier to access,” Kizer said.
To make things more difficult, Congress wouldn’t fund the project: “For the first 3 years, every CBOC had to be funded by redirected savings from other things that we could do within the system,” he said. “All of this was through redirected savings and finding ways to save and reinvest.”
Innovation From the Ground Up
Kizer emphasized that many breakthrough innovations came from frontline staff rather than executive mandates. He cited the example of Barcode Medication Administration, which originated from a nurse in Topeka, Kan.
The nurse saw a barcode scanner put to work at a rental car company where it was used to check cars in and out. She wondered, “Why can’t we do this with medications when they’re given on the floor? We followed up on it, pursued those things, tested it out, it worked.”
The results were dramatic. “I was told at a meeting that they had achieved close to 80% reduction in medication errors,” Kizer said. After verifying the results personally, he “authorized $20 million, and we moved forward with it systemwide.”
This experience reinforced his belief in harvesting ideas from staff at all levels.
Innovation remains part of the VA’s culture “despite what some people would have you believe,” Kizer said. Recently, the VA has made major advances in areas such as patient transportation and the climate crisis, he said.
Inside the Recipe for Innovation
Boldness, persistence, adaptability, and tolerance for risk are necessary ingredients for high-risk goals, Kizer said. Ambition is also part of the picture.
He highlighted examples such as the Apollo moon landing, the first sub-4-minute mile, and the first swim across the English Channel by a woman.
In medicine, Kizer pointed to a national patient safety campaign that saved an estimated 122,000 lives. He also mentioned recent progress in organ transplantation such as recommendations from the National Academies of Sciences, Engineering, and Medicine to establish national performance goals and the Organ Procurement and Transplantation Network’s target of 60,000 deceased donor transplants by 2026.
Bold doesn’t mean being reckless or careless, Kizer said. “But it does require innovation. And it does require that you try some new things, some of which aren’t going to work out.”
The key mindset, he explained, is to “embrace the unknown” because “you often really don’t know how you will accomplish the aim when you start. But you’ll figure it out as you go.”
Kizer highlighted 2 opposing strategies to handling challenging times.
According to him, the “negative energy” approach focuses on frustrations, limitations, and asking “Why is this happening to me?”
In contrast, a “positive energy” approach expects problems, focuses on available resources and capabilities, and asks, “What are the opportunities that these changes are creating for me?”
Kizer made it crystal clear which option he prefers.
Dr. Kizer disclosed that his comments represent his opinions only, and he noted his ongoing connections to the VA.
PHOENIX – Three decades after he initiated the transformation of the Veterans Health Administration (VHA) into a model research and clinical health care system, former US Department of Veterans Affairs (VA) Under Secretary of Health Kenneth W. Kizer, MD, MPH, urged cancer specialists to embrace this challenging moment as an opportunity for bold innovation.
At the annual meeting of the Association of VA Hematology/Oncology (AVAHO), Kizer acknowledged that the VA faces an “uncertain and turbulent time” in areas such as funding, staffing, community care implementation, and the rollout of a new electronic health record system.
He also noted the grim rise of global instability, economic turmoil, climate change, infectious diseases, political violence, and mass shootings.
“This can be stressful. It can create negative energy. But this uncertainty can also be liberating, and it can prompt positive energy and innovation, depending on choices that we make,” said Kizer, who also has served as California’s top health official prior to leading the VHA from 1994 to 1999.
From “Bloated Bureaucracy’ to High-Quality Health Care System
Kizer has been credited with revitalizing VHA care through a greater commitment to quality, and harkened to his work with the VA as an example of how bold goals can lead to bold innovation.
“What were the perceptions of VA health care in 1994? Well, they weren’t very good, frankly,” Kizer recalled. He described the VA as having a reputation at that time as “highly dysfunctional” with “a very bloated and entrenched bureaucracy.” As for quality of care, it “wasn’t viewed as very good.”
The system’s problems were so severe that patients would park motorhomes in VA medical center parking lots as they waited for care. “While they might have an appointment for one day, they may not be seen for 3 or 4 or 5 days. So they would stay in their motorhome until they finally got into their clinic appointment,” Kizer said.
Overall, “the public viewed the VA as this bleak backwater of incompetence and difference and inefficiency, and there were very strong calls to privatize the VA,” Kizer said.
Kizer asked colleagues about what he should do after he was asked to take the under secretary job. “With one exception, they all said, don’t go near it. Don’t touch it. Walk away. That it’s impossible to change the organization.
“I looked at the VA and I saw an opportunity. When I told [members of the President Bill] Clinton [Administration] yes, my bold aim was that I would like to pursue this was to make VHA a model of excellent health care, an exemplary health care system. Most everyone else thought that I was totally delusional, but sometimes it’s good to be delusional.”
Revolutionary Changes Despite Opposition
Kizer sought reforms in 5 major strategic objectives, all without explicit congressional approval: creating an accountable management structure, decentralizing decision-making, integrating care, implementing universal primary care, and pursuing eligibility reform to create the current 8-tier VA system.
One major innovation was the implementation of community-based outpatient clinics (CBOCs): “Those were strongly opposed initially,” Kizer said. “Everyone, the veteran community in particular, had been led to believe that the only good care was in the hospital.”
The resistance was substantial. “There was a lot of opposition when we said we’re going to move out into the community where you live to make [care] easier to access,” Kizer said.
To make things more difficult, Congress wouldn’t fund the project: “For the first 3 years, every CBOC had to be funded by redirected savings from other things that we could do within the system,” he said. “All of this was through redirected savings and finding ways to save and reinvest.”
Innovation From the Ground Up
Kizer emphasized that many breakthrough innovations came from frontline staff rather than executive mandates. He cited the example of Barcode Medication Administration, which originated from a nurse in Topeka, Kan.
The nurse saw a barcode scanner put to work at a rental car company where it was used to check cars in and out. She wondered, “Why can’t we do this with medications when they’re given on the floor? We followed up on it, pursued those things, tested it out, it worked.”
The results were dramatic. “I was told at a meeting that they had achieved close to 80% reduction in medication errors,” Kizer said. After verifying the results personally, he “authorized $20 million, and we moved forward with it systemwide.”
This experience reinforced his belief in harvesting ideas from staff at all levels.
Innovation remains part of the VA’s culture “despite what some people would have you believe,” Kizer said. Recently, the VA has made major advances in areas such as patient transportation and the climate crisis, he said.
Inside the Recipe for Innovation
Boldness, persistence, adaptability, and tolerance for risk are necessary ingredients for high-risk goals, Kizer said. Ambition is also part of the picture.
He highlighted examples such as the Apollo moon landing, the first sub-4-minute mile, and the first swim across the English Channel by a woman.
In medicine, Kizer pointed to a national patient safety campaign that saved an estimated 122,000 lives. He also mentioned recent progress in organ transplantation such as recommendations from the National Academies of Sciences, Engineering, and Medicine to establish national performance goals and the Organ Procurement and Transplantation Network’s target of 60,000 deceased donor transplants by 2026.
Bold doesn’t mean being reckless or careless, Kizer said. “But it does require innovation. And it does require that you try some new things, some of which aren’t going to work out.”
The key mindset, he explained, is to “embrace the unknown” because “you often really don’t know how you will accomplish the aim when you start. But you’ll figure it out as you go.”
Kizer highlighted 2 opposing strategies to handling challenging times.
According to him, the “negative energy” approach focuses on frustrations, limitations, and asking “Why is this happening to me?”
In contrast, a “positive energy” approach expects problems, focuses on available resources and capabilities, and asks, “What are the opportunities that these changes are creating for me?”
Kizer made it crystal clear which option he prefers.
Dr. Kizer disclosed that his comments represent his opinions only, and he noted his ongoing connections to the VA.
Architect of VA Transformation Urges Innovation Amid Uncertainty
Architect of VA Transformation Urges Innovation Amid Uncertainty
Large Language Models Cut Time, Cost of Guideline Development
, according to a pilot study from the American Gastroenterological Association (AGA).
Faster, cheaper study screening could allow societies to update clinical recommendations more frequently, improving alignment with the latest evidence, lead author Sunny Chung, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Each guideline typically requires 5 to 15 systematic reviews, making the process time-consuming (averaging more than 60 weeks) and costly (more than $140,000),” the investigators wrote in Gastroenterology . “One of the most critical yet time-consuming steps in systematic reviews is title and abstract screening. LLMs have the potential to make this step more efficient.”
To test this approach, the investigators developed, validated, and applied a dual-model LLM screening pipeline with human-in-the-loop oversight, focusing on randomized controlled trials in AGA guidelines.
The system was built using the 2021 guideline on moderate-to-severe Crohn’s disease, targeting biologic therapies for induction and maintenance of remission.
Using chain-of-thought prompting and structured inclusion criteria based on the PICO framework, the investigators deployed GPT-4o (OpenAI) and Gemini-1.5-Pro (Google DeepMind) as independent screeners, each assessing titles and abstracts according to standardized logic encoded in JavaScript Object Notation. This approach mimicked a traditional double-reviewer system.
After initial testing, the pipeline was validated in a 2025 update of the same guideline, this time spanning 6 focused clinical questions on advanced therapies and immunomodulators. Results were compared against manual screening by 2 experienced human reviewers, with total screening time documented.
The system was then tested across 4 additional guideline topics: fecal microbiota transplantation (FMT) for irritable bowel syndrome and Clostridioides difficile, gastroparesis, and hepatocellular carcinoma. A final test applied the system to a forthcoming guideline on complications of acute pancreatitis.
Across all topics, the dual-LLM system achieved 100% sensitivity in identifying randomized controlled trials (RCTs). For the 2025 update of the AGA guideline on Crohn’s disease, the models flagged 418 of 4,377 abstracts for inclusion, captur-ing all 25 relevant RCTs in just 48 minutes. Manual screening of the same dataset previously took almost 13 hours.
Comparable accuracy and time savings were observed for the other topics.
The pipeline correctly flagged all 13 RCTs in 4,820 studies on FMT for irritable bowel syndrome, and all 16 RCTs in 5,587 studies on FMT for Clostridioides difficile, requiring 27 and 66 minutes, respectively. Similarly, the system captured all 11 RCTs in 3,919 hepatocellular carcinoma abstracts and all 18 RCTs in 1,578 studies on gastroparesis, completing each task in under 65 minutes. Early testing on the upcoming guideline for pancreatitis yielded similar results.
Cost analysis underscored the efficiency of this approach. At an estimated $175–200 per hour for expert screeners, traditional abstract screening would cost around $2,500 per review, versus approximately $100 for the LLM approach—a 96% reduction.
The investigators cautioned that human oversight remains necessary to verify the relevance of studies flagged by the models. While the system’s sensitivity was consistent, it also selected articles that were ultimately excluded by expert reviewers. Broader validation will be required to assess performance across non-RCT study designs, such as observational or case-control studies, they added.
“As medical literature continues to expand, the integration of artificial intelligence into evidence synthesis processes will become increasingly vital,” Dr. Chung and colleagues wrote. “With further refinement and broader validation, this LLM-based pipeline has the potential to revolutionize evidence synthesis and set a new standard for guideline development.”
This study was funded by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. The investigators reported no conflicts of interest.
Ethan Goh, MD, executive director of the Stanford AI Research and Science Evaluation (ARISE) Network, described the AGA pilot as both timely and promising.
“I’m certainly bullish about the use case,” he said in an interview. “Their study design and application is also robust, so I would congratulate them.”
Goh, a general editor for BMJ Digital Health & AI, predicted “huge potential” in the strategy for both clinicians and the general population, who benefit from the most up-to-date guidelines possible.
“I believe that using AI can represent a much faster, more cost effective, efficient way of gathering all these information sources,” he said.
Still, humans will need to be involved in the process.
“[This AI-driven approach] will always need some degree of expert oversight and judgement,” Goh said.
Speaking more broadly about automating study aggregation, Goh said AI may still struggle to determine which studies are most clinically relevant.
“When we use [AI models] to pull out medical references, anecdotally, I don’t think they’re always getting the best ones all the time, or even necessarily the right ones,” he said.
And as AI models grow more impressive, these shortcomings become less apparent, potentially lulling humans into overconfidence.
“Humans are humans,” Goh said. “We get lazy over time. That will be one of the challenges. As the systems get increasingly good, humans start to defer more and more of their judgment to them and say, ‘All right, AI, you’re doing good. Just do 100% automation.’ And then [people] start fact checking or reviewing even less.”
AI could also undermine automated reviews in another way: AI-generated publications that appear genuine, but aren’t, may creep into the dataset.
Despite these concerns, Goh concluded on an optimistic note.
“I think that there are huge ways to use AI, tools, not to replace, but to augment and support human judgment,” he said.
Ethan Goh, MD, is senior research engineer and executive director of the Stanford AI Research and Science Evaluation (ARISE) Network, at Stanford (Calif.) University. He declared no conflicts of interest.
Ethan Goh, MD, executive director of the Stanford AI Research and Science Evaluation (ARISE) Network, described the AGA pilot as both timely and promising.
“I’m certainly bullish about the use case,” he said in an interview. “Their study design and application is also robust, so I would congratulate them.”
Goh, a general editor for BMJ Digital Health & AI, predicted “huge potential” in the strategy for both clinicians and the general population, who benefit from the most up-to-date guidelines possible.
“I believe that using AI can represent a much faster, more cost effective, efficient way of gathering all these information sources,” he said.
Still, humans will need to be involved in the process.
“[This AI-driven approach] will always need some degree of expert oversight and judgement,” Goh said.
Speaking more broadly about automating study aggregation, Goh said AI may still struggle to determine which studies are most clinically relevant.
“When we use [AI models] to pull out medical references, anecdotally, I don’t think they’re always getting the best ones all the time, or even necessarily the right ones,” he said.
And as AI models grow more impressive, these shortcomings become less apparent, potentially lulling humans into overconfidence.
“Humans are humans,” Goh said. “We get lazy over time. That will be one of the challenges. As the systems get increasingly good, humans start to defer more and more of their judgment to them and say, ‘All right, AI, you’re doing good. Just do 100% automation.’ And then [people] start fact checking or reviewing even less.”
AI could also undermine automated reviews in another way: AI-generated publications that appear genuine, but aren’t, may creep into the dataset.
Despite these concerns, Goh concluded on an optimistic note.
“I think that there are huge ways to use AI, tools, not to replace, but to augment and support human judgment,” he said.
Ethan Goh, MD, is senior research engineer and executive director of the Stanford AI Research and Science Evaluation (ARISE) Network, at Stanford (Calif.) University. He declared no conflicts of interest.
Ethan Goh, MD, executive director of the Stanford AI Research and Science Evaluation (ARISE) Network, described the AGA pilot as both timely and promising.
“I’m certainly bullish about the use case,” he said in an interview. “Their study design and application is also robust, so I would congratulate them.”
Goh, a general editor for BMJ Digital Health & AI, predicted “huge potential” in the strategy for both clinicians and the general population, who benefit from the most up-to-date guidelines possible.
“I believe that using AI can represent a much faster, more cost effective, efficient way of gathering all these information sources,” he said.
Still, humans will need to be involved in the process.
“[This AI-driven approach] will always need some degree of expert oversight and judgement,” Goh said.
Speaking more broadly about automating study aggregation, Goh said AI may still struggle to determine which studies are most clinically relevant.
“When we use [AI models] to pull out medical references, anecdotally, I don’t think they’re always getting the best ones all the time, or even necessarily the right ones,” he said.
And as AI models grow more impressive, these shortcomings become less apparent, potentially lulling humans into overconfidence.
“Humans are humans,” Goh said. “We get lazy over time. That will be one of the challenges. As the systems get increasingly good, humans start to defer more and more of their judgment to them and say, ‘All right, AI, you’re doing good. Just do 100% automation.’ And then [people] start fact checking or reviewing even less.”
AI could also undermine automated reviews in another way: AI-generated publications that appear genuine, but aren’t, may creep into the dataset.
Despite these concerns, Goh concluded on an optimistic note.
“I think that there are huge ways to use AI, tools, not to replace, but to augment and support human judgment,” he said.
Ethan Goh, MD, is senior research engineer and executive director of the Stanford AI Research and Science Evaluation (ARISE) Network, at Stanford (Calif.) University. He declared no conflicts of interest.
, according to a pilot study from the American Gastroenterological Association (AGA).
Faster, cheaper study screening could allow societies to update clinical recommendations more frequently, improving alignment with the latest evidence, lead author Sunny Chung, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Each guideline typically requires 5 to 15 systematic reviews, making the process time-consuming (averaging more than 60 weeks) and costly (more than $140,000),” the investigators wrote in Gastroenterology . “One of the most critical yet time-consuming steps in systematic reviews is title and abstract screening. LLMs have the potential to make this step more efficient.”
To test this approach, the investigators developed, validated, and applied a dual-model LLM screening pipeline with human-in-the-loop oversight, focusing on randomized controlled trials in AGA guidelines.
The system was built using the 2021 guideline on moderate-to-severe Crohn’s disease, targeting biologic therapies for induction and maintenance of remission.
Using chain-of-thought prompting and structured inclusion criteria based on the PICO framework, the investigators deployed GPT-4o (OpenAI) and Gemini-1.5-Pro (Google DeepMind) as independent screeners, each assessing titles and abstracts according to standardized logic encoded in JavaScript Object Notation. This approach mimicked a traditional double-reviewer system.
After initial testing, the pipeline was validated in a 2025 update of the same guideline, this time spanning 6 focused clinical questions on advanced therapies and immunomodulators. Results were compared against manual screening by 2 experienced human reviewers, with total screening time documented.
The system was then tested across 4 additional guideline topics: fecal microbiota transplantation (FMT) for irritable bowel syndrome and Clostridioides difficile, gastroparesis, and hepatocellular carcinoma. A final test applied the system to a forthcoming guideline on complications of acute pancreatitis.
Across all topics, the dual-LLM system achieved 100% sensitivity in identifying randomized controlled trials (RCTs). For the 2025 update of the AGA guideline on Crohn’s disease, the models flagged 418 of 4,377 abstracts for inclusion, captur-ing all 25 relevant RCTs in just 48 minutes. Manual screening of the same dataset previously took almost 13 hours.
Comparable accuracy and time savings were observed for the other topics.
The pipeline correctly flagged all 13 RCTs in 4,820 studies on FMT for irritable bowel syndrome, and all 16 RCTs in 5,587 studies on FMT for Clostridioides difficile, requiring 27 and 66 minutes, respectively. Similarly, the system captured all 11 RCTs in 3,919 hepatocellular carcinoma abstracts and all 18 RCTs in 1,578 studies on gastroparesis, completing each task in under 65 minutes. Early testing on the upcoming guideline for pancreatitis yielded similar results.
Cost analysis underscored the efficiency of this approach. At an estimated $175–200 per hour for expert screeners, traditional abstract screening would cost around $2,500 per review, versus approximately $100 for the LLM approach—a 96% reduction.
The investigators cautioned that human oversight remains necessary to verify the relevance of studies flagged by the models. While the system’s sensitivity was consistent, it also selected articles that were ultimately excluded by expert reviewers. Broader validation will be required to assess performance across non-RCT study designs, such as observational or case-control studies, they added.
“As medical literature continues to expand, the integration of artificial intelligence into evidence synthesis processes will become increasingly vital,” Dr. Chung and colleagues wrote. “With further refinement and broader validation, this LLM-based pipeline has the potential to revolutionize evidence synthesis and set a new standard for guideline development.”
This study was funded by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. The investigators reported no conflicts of interest.
, according to a pilot study from the American Gastroenterological Association (AGA).
Faster, cheaper study screening could allow societies to update clinical recommendations more frequently, improving alignment with the latest evidence, lead author Sunny Chung, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Each guideline typically requires 5 to 15 systematic reviews, making the process time-consuming (averaging more than 60 weeks) and costly (more than $140,000),” the investigators wrote in Gastroenterology . “One of the most critical yet time-consuming steps in systematic reviews is title and abstract screening. LLMs have the potential to make this step more efficient.”
To test this approach, the investigators developed, validated, and applied a dual-model LLM screening pipeline with human-in-the-loop oversight, focusing on randomized controlled trials in AGA guidelines.
The system was built using the 2021 guideline on moderate-to-severe Crohn’s disease, targeting biologic therapies for induction and maintenance of remission.
Using chain-of-thought prompting and structured inclusion criteria based on the PICO framework, the investigators deployed GPT-4o (OpenAI) and Gemini-1.5-Pro (Google DeepMind) as independent screeners, each assessing titles and abstracts according to standardized logic encoded in JavaScript Object Notation. This approach mimicked a traditional double-reviewer system.
After initial testing, the pipeline was validated in a 2025 update of the same guideline, this time spanning 6 focused clinical questions on advanced therapies and immunomodulators. Results were compared against manual screening by 2 experienced human reviewers, with total screening time documented.
The system was then tested across 4 additional guideline topics: fecal microbiota transplantation (FMT) for irritable bowel syndrome and Clostridioides difficile, gastroparesis, and hepatocellular carcinoma. A final test applied the system to a forthcoming guideline on complications of acute pancreatitis.
Across all topics, the dual-LLM system achieved 100% sensitivity in identifying randomized controlled trials (RCTs). For the 2025 update of the AGA guideline on Crohn’s disease, the models flagged 418 of 4,377 abstracts for inclusion, captur-ing all 25 relevant RCTs in just 48 minutes. Manual screening of the same dataset previously took almost 13 hours.
Comparable accuracy and time savings were observed for the other topics.
The pipeline correctly flagged all 13 RCTs in 4,820 studies on FMT for irritable bowel syndrome, and all 16 RCTs in 5,587 studies on FMT for Clostridioides difficile, requiring 27 and 66 minutes, respectively. Similarly, the system captured all 11 RCTs in 3,919 hepatocellular carcinoma abstracts and all 18 RCTs in 1,578 studies on gastroparesis, completing each task in under 65 minutes. Early testing on the upcoming guideline for pancreatitis yielded similar results.
Cost analysis underscored the efficiency of this approach. At an estimated $175–200 per hour for expert screeners, traditional abstract screening would cost around $2,500 per review, versus approximately $100 for the LLM approach—a 96% reduction.
The investigators cautioned that human oversight remains necessary to verify the relevance of studies flagged by the models. While the system’s sensitivity was consistent, it also selected articles that were ultimately excluded by expert reviewers. Broader validation will be required to assess performance across non-RCT study designs, such as observational or case-control studies, they added.
“As medical literature continues to expand, the integration of artificial intelligence into evidence synthesis processes will become increasingly vital,” Dr. Chung and colleagues wrote. “With further refinement and broader validation, this LLM-based pipeline has the potential to revolutionize evidence synthesis and set a new standard for guideline development.”
This study was funded by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. The investigators reported no conflicts of interest.
FROM GASTROENTEROLOGY
New Guidelines for Pregnancy and IBD Aim to Quell Fears
, suggesting this approach will not harm the fetus.
The guidelines also recommend that all women with IBD receive preconception counseling and be followed as high-risk pregnancies.
“Management of chronic illness in pregnant women has always been defined by fear of harming the fetus,” said Uma Mahadevan, MD, AGAF, director of the Colitis and Crohn’s Disease Center at the University of California San Francisco and chair of the Global Consensus Consortium that developed the guidelines.
As a result, pregnant women are excluded from clinical trials of experimental therapies for IBD. And when a new therapy achieves regulatory approval, there are no human pregnancy safety data, only animal data. To fill this gap, the PIANO study, of which Mahadevan is principal investigator, looked at the safety of IBD medications in pregnancy and short- and long-term outcomes of the children.
“With our ongoing work in pregnancy in the patient with IBD, we realized that inflammation in the mother is the leading cause of poor outcome for the infant,” she told GI & Hepatology News.
“We also have a better understanding of placental transfer of biologic agents” and the lack of exposure to the fetus during the first trimester, “a key period of organogenesis,” she added.
Final recommendations were published simultaneously in six international journals, namely, Clinical Gastroenterology and Hepatology, American Journal of Gastroenterology, GUT, Inflammatory Bowel Diseases, Journal of Crohn’s and Colitis, and Alimentary Pharmacology and Therapeutics.
Surprising, Novel Findings
Limited provider knowledge led to varied practices in caring for women with IBD who become pregnant, according to the consensus authors. Practices are affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus.
“The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike,” the authors of the guidelines wrote.
Therefore, the Global Consensus Consortium — a group of 39 IBD experts, including teratologists and maternal fetal medicine specialists and seven patient advocates from six continents — convened to review and assess current data and come to an agreement on best practices. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used when sufficient published data were available, and the Research and Development process when expert opinion was needed to guide consistent practice.
“Some of the findings were expected, but others were novel,” said Mahadevan.
Recommendations that might surprise clinicians include GRADE statement 9, which suggests that pregnant women with IBD take low-dose aspirin by 12 to 16 weeks’ gestation to prevent preterm preeclampsia. “This is based on the ASPRE study, showing that women at risk of preeclampsia can lower their risk by taking low-dose aspirin,” with no risk for flare, Mahadevan said.
In addition, GRADE statements 17-20 recommend/suggest that women continue their biologic throughout pregnancy without stopping. “North America has always recommended continuing during the third trimester, while Europe only recently has come to this,” Mahadevan said. “However, there was always some looseness about stopping at week X, Y, or Z. Now, we do recommend continuing the dose on schedule with no holding.”
Continuing medications considered low risk for use during pregnancy, such as 5-amino salicylic acids, sulfasalazine, thiopurines, and all monoclonal antibodies during preconception, pregnancy, and lactation, was also recommended.
However, small-molecule drugs such as S1P receptor molecules and JAK inhibitors should be avoided for at least 1 month, and in some cases for 3 months prior to attempting conception, unless there is no alternative for the health of the mother. They should also be avoided during lactation.
Grade statement 33, which suggests that live rotavirus vaccine may be provided in children with in utero exposure to biologics, is also new, Mahadevan noted. “All prior recommendations were that no live vaccine should be given in the first 6 months or longer if infants were exposed to biologics in utero, but based on a prospective Canadian study, there is no harm when given to these infants.”
Another novel recommendation is that women with IBD on any monoclonal antibodies, including newer interleukin-23s, may breastfeed even though there are not clinical trial data at this point. The recommendation to continue them through pregnancy and lactation is based on placental physiology, as well as on the physiology of monoclonal antibody transfer in breast milk, according to the consortium.
Furthermore, the authors noted, there was no increase in infant infections at 4 months or 12 months if they were exposed to a biologic or thiopurine (or both) during pregnancy.
Overall, the consortium recommended that all pregnancies for women with IBD be considered as “high risk” for complications. This is due to the fact that many parts of the world, including the US, are “resource-limited,” Mahadevan explained. Since maternal fetal medicine specialists are not widely available, the consortium suggested all these patients be followed with increased monitoring and surveillance based on available resources.
In addition to the guidelines, patient videos in seven languages, a professional slide deck in English and Spanish, and a video on the global consensus are all available at https://pianostudy.org/.
This study was funded by The Leona B. and Harry H. Helmsley Charitable Trust.
Mahadevan reported being a consultant for AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Enveda, Gilead, Janssen, Lilly, Merck, Pfizer, Protagonist, Roivant, and Takeda.
A version of this article appeared on Medscape.com.
, suggesting this approach will not harm the fetus.
The guidelines also recommend that all women with IBD receive preconception counseling and be followed as high-risk pregnancies.
“Management of chronic illness in pregnant women has always been defined by fear of harming the fetus,” said Uma Mahadevan, MD, AGAF, director of the Colitis and Crohn’s Disease Center at the University of California San Francisco and chair of the Global Consensus Consortium that developed the guidelines.
As a result, pregnant women are excluded from clinical trials of experimental therapies for IBD. And when a new therapy achieves regulatory approval, there are no human pregnancy safety data, only animal data. To fill this gap, the PIANO study, of which Mahadevan is principal investigator, looked at the safety of IBD medications in pregnancy and short- and long-term outcomes of the children.
“With our ongoing work in pregnancy in the patient with IBD, we realized that inflammation in the mother is the leading cause of poor outcome for the infant,” she told GI & Hepatology News.
“We also have a better understanding of placental transfer of biologic agents” and the lack of exposure to the fetus during the first trimester, “a key period of organogenesis,” she added.
Final recommendations were published simultaneously in six international journals, namely, Clinical Gastroenterology and Hepatology, American Journal of Gastroenterology, GUT, Inflammatory Bowel Diseases, Journal of Crohn’s and Colitis, and Alimentary Pharmacology and Therapeutics.
Surprising, Novel Findings
Limited provider knowledge led to varied practices in caring for women with IBD who become pregnant, according to the consensus authors. Practices are affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus.
“The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike,” the authors of the guidelines wrote.
Therefore, the Global Consensus Consortium — a group of 39 IBD experts, including teratologists and maternal fetal medicine specialists and seven patient advocates from six continents — convened to review and assess current data and come to an agreement on best practices. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used when sufficient published data were available, and the Research and Development process when expert opinion was needed to guide consistent practice.
“Some of the findings were expected, but others were novel,” said Mahadevan.
Recommendations that might surprise clinicians include GRADE statement 9, which suggests that pregnant women with IBD take low-dose aspirin by 12 to 16 weeks’ gestation to prevent preterm preeclampsia. “This is based on the ASPRE study, showing that women at risk of preeclampsia can lower their risk by taking low-dose aspirin,” with no risk for flare, Mahadevan said.
In addition, GRADE statements 17-20 recommend/suggest that women continue their biologic throughout pregnancy without stopping. “North America has always recommended continuing during the third trimester, while Europe only recently has come to this,” Mahadevan said. “However, there was always some looseness about stopping at week X, Y, or Z. Now, we do recommend continuing the dose on schedule with no holding.”
Continuing medications considered low risk for use during pregnancy, such as 5-amino salicylic acids, sulfasalazine, thiopurines, and all monoclonal antibodies during preconception, pregnancy, and lactation, was also recommended.
However, small-molecule drugs such as S1P receptor molecules and JAK inhibitors should be avoided for at least 1 month, and in some cases for 3 months prior to attempting conception, unless there is no alternative for the health of the mother. They should also be avoided during lactation.
Grade statement 33, which suggests that live rotavirus vaccine may be provided in children with in utero exposure to biologics, is also new, Mahadevan noted. “All prior recommendations were that no live vaccine should be given in the first 6 months or longer if infants were exposed to biologics in utero, but based on a prospective Canadian study, there is no harm when given to these infants.”
Another novel recommendation is that women with IBD on any monoclonal antibodies, including newer interleukin-23s, may breastfeed even though there are not clinical trial data at this point. The recommendation to continue them through pregnancy and lactation is based on placental physiology, as well as on the physiology of monoclonal antibody transfer in breast milk, according to the consortium.
Furthermore, the authors noted, there was no increase in infant infections at 4 months or 12 months if they were exposed to a biologic or thiopurine (or both) during pregnancy.
Overall, the consortium recommended that all pregnancies for women with IBD be considered as “high risk” for complications. This is due to the fact that many parts of the world, including the US, are “resource-limited,” Mahadevan explained. Since maternal fetal medicine specialists are not widely available, the consortium suggested all these patients be followed with increased monitoring and surveillance based on available resources.
In addition to the guidelines, patient videos in seven languages, a professional slide deck in English and Spanish, and a video on the global consensus are all available at https://pianostudy.org/.
This study was funded by The Leona B. and Harry H. Helmsley Charitable Trust.
Mahadevan reported being a consultant for AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Enveda, Gilead, Janssen, Lilly, Merck, Pfizer, Protagonist, Roivant, and Takeda.
A version of this article appeared on Medscape.com.
, suggesting this approach will not harm the fetus.
The guidelines also recommend that all women with IBD receive preconception counseling and be followed as high-risk pregnancies.
“Management of chronic illness in pregnant women has always been defined by fear of harming the fetus,” said Uma Mahadevan, MD, AGAF, director of the Colitis and Crohn’s Disease Center at the University of California San Francisco and chair of the Global Consensus Consortium that developed the guidelines.
As a result, pregnant women are excluded from clinical trials of experimental therapies for IBD. And when a new therapy achieves regulatory approval, there are no human pregnancy safety data, only animal data. To fill this gap, the PIANO study, of which Mahadevan is principal investigator, looked at the safety of IBD medications in pregnancy and short- and long-term outcomes of the children.
“With our ongoing work in pregnancy in the patient with IBD, we realized that inflammation in the mother is the leading cause of poor outcome for the infant,” she told GI & Hepatology News.
“We also have a better understanding of placental transfer of biologic agents” and the lack of exposure to the fetus during the first trimester, “a key period of organogenesis,” she added.
Final recommendations were published simultaneously in six international journals, namely, Clinical Gastroenterology and Hepatology, American Journal of Gastroenterology, GUT, Inflammatory Bowel Diseases, Journal of Crohn’s and Colitis, and Alimentary Pharmacology and Therapeutics.
Surprising, Novel Findings
Limited provider knowledge led to varied practices in caring for women with IBD who become pregnant, according to the consensus authors. Practices are affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus.
“The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike,” the authors of the guidelines wrote.
Therefore, the Global Consensus Consortium — a group of 39 IBD experts, including teratologists and maternal fetal medicine specialists and seven patient advocates from six continents — convened to review and assess current data and come to an agreement on best practices. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used when sufficient published data were available, and the Research and Development process when expert opinion was needed to guide consistent practice.
“Some of the findings were expected, but others were novel,” said Mahadevan.
Recommendations that might surprise clinicians include GRADE statement 9, which suggests that pregnant women with IBD take low-dose aspirin by 12 to 16 weeks’ gestation to prevent preterm preeclampsia. “This is based on the ASPRE study, showing that women at risk of preeclampsia can lower their risk by taking low-dose aspirin,” with no risk for flare, Mahadevan said.
In addition, GRADE statements 17-20 recommend/suggest that women continue their biologic throughout pregnancy without stopping. “North America has always recommended continuing during the third trimester, while Europe only recently has come to this,” Mahadevan said. “However, there was always some looseness about stopping at week X, Y, or Z. Now, we do recommend continuing the dose on schedule with no holding.”
Continuing medications considered low risk for use during pregnancy, such as 5-amino salicylic acids, sulfasalazine, thiopurines, and all monoclonal antibodies during preconception, pregnancy, and lactation, was also recommended.
However, small-molecule drugs such as S1P receptor molecules and JAK inhibitors should be avoided for at least 1 month, and in some cases for 3 months prior to attempting conception, unless there is no alternative for the health of the mother. They should also be avoided during lactation.
Grade statement 33, which suggests that live rotavirus vaccine may be provided in children with in utero exposure to biologics, is also new, Mahadevan noted. “All prior recommendations were that no live vaccine should be given in the first 6 months or longer if infants were exposed to biologics in utero, but based on a prospective Canadian study, there is no harm when given to these infants.”
Another novel recommendation is that women with IBD on any monoclonal antibodies, including newer interleukin-23s, may breastfeed even though there are not clinical trial data at this point. The recommendation to continue them through pregnancy and lactation is based on placental physiology, as well as on the physiology of monoclonal antibody transfer in breast milk, according to the consortium.
Furthermore, the authors noted, there was no increase in infant infections at 4 months or 12 months if they were exposed to a biologic or thiopurine (or both) during pregnancy.
Overall, the consortium recommended that all pregnancies for women with IBD be considered as “high risk” for complications. This is due to the fact that many parts of the world, including the US, are “resource-limited,” Mahadevan explained. Since maternal fetal medicine specialists are not widely available, the consortium suggested all these patients be followed with increased monitoring and surveillance based on available resources.
In addition to the guidelines, patient videos in seven languages, a professional slide deck in English and Spanish, and a video on the global consensus are all available at https://pianostudy.org/.
This study was funded by The Leona B. and Harry H. Helmsley Charitable Trust.
Mahadevan reported being a consultant for AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Enveda, Gilead, Janssen, Lilly, Merck, Pfizer, Protagonist, Roivant, and Takeda.
A version of this article appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
VHA Workforce Continues to Contract as Fiscal Year Ends
The size of the Veterans Health Administration (VHA) workforce continues to contract according to the latest data released by the US Department of Veterans Affairs (VA). Applications for employment are down 44% in fiscal year (FY) 2025 with just 14,485 cumulative new hires and 28,969 losses. In 2024, the VHA had 416,667 workers—it now has 401,224.
The reductions align with VA Secretary Doug Collins’ goal of downsizing the VA’s workforce by 30,000 employees by the end of 2025. In August, Collins outlined how a federal hiring freeze, deferred resignations, retirements, and normal attrition have eliminated the need for the "large-scale" reduction-in-force he proposed earlier this year.
Compared with July’s numbers, the VHA now employs 139 fewer medical officers/physicians, 418 fewer registered nurses, 107 fewer social workers, and 65 fewer psychologists. Staffing of licensed practical nurses, medical support assistants, and nursing assistants is also down (reduced by 77, 129, and 29, respectively).
Retention rates for the first 2 years of onboarding hover around 80% for physicians and nurses. However, retention incentives have dropped from 19,484 to 8982 and recruitment incentives from 6069 to 1299.
In voluntary exit surveys, 78% of 6762 medical and dental staff who left said they would work again for the VA, while 79% said they would recommend the VA as an employer. These rates are down from a similar survey in May 2023 when 81% noted that they would work again for the VA and 82% would recommend the VA to others. Personal matters, geographic relocation, and poor working relationships with supervisors or colleagues were among the reasons cited for leaving in August 2025.
Of 435 psychologists, 69% said they would work again for the VA, and 62% said they would recommend the VA as an employer (71% and 67%, respectively in May 2023). Their reasons for leaving in August 2025 included a lack of trust in senior leaders and policy or technology barriers to getting the work done.
An August survey from the Office of the Inspector General found that VHA facilities reported 4434 staffing shortages this fiscal year—a 50% increase from fiscal year 2024. Most (94%) of the 139 facilities reported severe shortages for medical officers, and 79% of facilities reported severe shortages for nurses. Due to the timing of the questionnaire, the responses did not yet reflect the full impact from workforce reshaping efforts.
The size of the Veterans Health Administration (VHA) workforce continues to contract according to the latest data released by the US Department of Veterans Affairs (VA). Applications for employment are down 44% in fiscal year (FY) 2025 with just 14,485 cumulative new hires and 28,969 losses. In 2024, the VHA had 416,667 workers—it now has 401,224.
The reductions align with VA Secretary Doug Collins’ goal of downsizing the VA’s workforce by 30,000 employees by the end of 2025. In August, Collins outlined how a federal hiring freeze, deferred resignations, retirements, and normal attrition have eliminated the need for the "large-scale" reduction-in-force he proposed earlier this year.
Compared with July’s numbers, the VHA now employs 139 fewer medical officers/physicians, 418 fewer registered nurses, 107 fewer social workers, and 65 fewer psychologists. Staffing of licensed practical nurses, medical support assistants, and nursing assistants is also down (reduced by 77, 129, and 29, respectively).
Retention rates for the first 2 years of onboarding hover around 80% for physicians and nurses. However, retention incentives have dropped from 19,484 to 8982 and recruitment incentives from 6069 to 1299.
In voluntary exit surveys, 78% of 6762 medical and dental staff who left said they would work again for the VA, while 79% said they would recommend the VA as an employer. These rates are down from a similar survey in May 2023 when 81% noted that they would work again for the VA and 82% would recommend the VA to others. Personal matters, geographic relocation, and poor working relationships with supervisors or colleagues were among the reasons cited for leaving in August 2025.
Of 435 psychologists, 69% said they would work again for the VA, and 62% said they would recommend the VA as an employer (71% and 67%, respectively in May 2023). Their reasons for leaving in August 2025 included a lack of trust in senior leaders and policy or technology barriers to getting the work done.
An August survey from the Office of the Inspector General found that VHA facilities reported 4434 staffing shortages this fiscal year—a 50% increase from fiscal year 2024. Most (94%) of the 139 facilities reported severe shortages for medical officers, and 79% of facilities reported severe shortages for nurses. Due to the timing of the questionnaire, the responses did not yet reflect the full impact from workforce reshaping efforts.
The size of the Veterans Health Administration (VHA) workforce continues to contract according to the latest data released by the US Department of Veterans Affairs (VA). Applications for employment are down 44% in fiscal year (FY) 2025 with just 14,485 cumulative new hires and 28,969 losses. In 2024, the VHA had 416,667 workers—it now has 401,224.
The reductions align with VA Secretary Doug Collins’ goal of downsizing the VA’s workforce by 30,000 employees by the end of 2025. In August, Collins outlined how a federal hiring freeze, deferred resignations, retirements, and normal attrition have eliminated the need for the "large-scale" reduction-in-force he proposed earlier this year.
Compared with July’s numbers, the VHA now employs 139 fewer medical officers/physicians, 418 fewer registered nurses, 107 fewer social workers, and 65 fewer psychologists. Staffing of licensed practical nurses, medical support assistants, and nursing assistants is also down (reduced by 77, 129, and 29, respectively).
Retention rates for the first 2 years of onboarding hover around 80% for physicians and nurses. However, retention incentives have dropped from 19,484 to 8982 and recruitment incentives from 6069 to 1299.
In voluntary exit surveys, 78% of 6762 medical and dental staff who left said they would work again for the VA, while 79% said they would recommend the VA as an employer. These rates are down from a similar survey in May 2023 when 81% noted that they would work again for the VA and 82% would recommend the VA to others. Personal matters, geographic relocation, and poor working relationships with supervisors or colleagues were among the reasons cited for leaving in August 2025.
Of 435 psychologists, 69% said they would work again for the VA, and 62% said they would recommend the VA as an employer (71% and 67%, respectively in May 2023). Their reasons for leaving in August 2025 included a lack of trust in senior leaders and policy or technology barriers to getting the work done.
An August survey from the Office of the Inspector General found that VHA facilities reported 4434 staffing shortages this fiscal year—a 50% increase from fiscal year 2024. Most (94%) of the 139 facilities reported severe shortages for medical officers, and 79% of facilities reported severe shortages for nurses. Due to the timing of the questionnaire, the responses did not yet reflect the full impact from workforce reshaping efforts.
GLP-1 Use After Bariatric Surgery on the Rise
, a large retrospective cohort study showed.
GLP-1 initiation was also more common among women, those who underwent sleeve gastrectomy, and those with lower postoperative weight loss as measured by BMI.
“Some patients do not lose as much weight as expected, or they regain weight after a few years. In such cases, GLP-1 therapies are emerging as an important option for weight management,” said principal investigator Hemalkumar Mehta, PhD, associate professor at Johns Hopkins Bloomberg School of Public Health in Baltimore.
“We also noted many personal stories circulating on social media in which patients shared their experiences using GLP-1 after bariatric surgery,” he told GI & Hepatology News.
But when the researchers reviewed the scientific literature, they found no published evidence on GLP-1 use in this setting and little or no data on outcomes with the newer drugs such as semaglutide and tirzepatide. “This gap motivated us to conduct the current study,” said Mehta. The study was published in JAMA Surgery.
The researchers analyzed data from a national multicenter database of electronic health records of approximately 113 million US adults to characterize the use of and factors associated with GLP-1 initiation after bariatric surgery.
Among 112,858 individuals undergoing bariatric surgery during the study period, the mean age was 45.2 years, and 78.9% were women.
By self-report race, 1.1% were Asian, 22.1% were Black or African American, 64.2% were White individuals, and 12.6% reported belonging to other races (American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or unknown).
A total of 15,749 individuals (14%) initiated GLP-1s post-surgery, with 3391 (21.5%) beginning within 2 years of surgery and the remainder initiating during postsurgical years 3-4 (32.3%), 5-6 (25.2%), or later (21%).
Notably, the proportion of GLP-1 use increased more in the more recent cohort, from 1.7% in the January 2015-December 2019 cohort to 12.6% from June 2020 to May 2025.
Differences Between Users and Nonusers
Those who initiated GLP-1s differed significantly from those who did not: GLP-1 users vs nonusers were younger (mean age, 44.9 years vs 45.2 years), and use was more common among women vs men (15.1% vs 9.7%), among Black or African American vs White patients (15.8% vs 13.5%), and among those who underwent sleeve gastrectomy vs Roux-en-Y gastric bypass (14.9% vs 12.1%).
Looked at another way, women (adjusted hazard ratio [aHR], 1.61), those undergoing sleeve gastrectomy (aHR, 1.42), and those with type 2 diabetes (aHR, 1.34) were more likely to initiate GLP-1s than their counterparts.
The overall median presurgical BMI was 42. On analyzing obesity classification based on BMI, the researchers found that the chances of GLP-1 use were 1.73 times higher among class 1 obesity patients (BMI, 30.0-34.9), 2.19 times higher among class 2 obesity patients (BMI, 35.0-39.9), and 2.69 times higher among patients with class 3 obesity (BMI ≥ 40) than among overweight patients (BMI, 25.0-29.9).
The median post-surgery BMI for GLP-1 users at drug initiation was 36.7. Each one-unit increase in postsurgical BMI was associated with an 8% increase in the likelihood of GLP-1 initiation (aHR, 1.08).
“Importantly, our study did not specifically evaluate the effectiveness of GLP-1 therapy on weight loss after surgery,” Mehta noted. That issue and others, such as optimal timing for initiating GLP-1s, are currently under investigation.
In a related editorial, Kate Lauer, MD, of the University of Wisconsin-Madison and colleagues noted that the study had several limitations. It relied on data prior to the USFDA approvals of semaglutide and tirzepatide, the two most prescribed GLP-1s currently, potentially limiting its applicability to current practice.
Furthermore, the prescribing data did not capture dose, titration schedules, or adherence, which are “critical for understanding treatment efficacy,” they wrote. “Nonetheless, the findings highlight two important trends: (1) GLP-1s are being increasingly used as an adjunct after bariatric surgery, and (2) there is substantial variability in the timing of their initiation.”
‘Logical’ to Use GLP-1s Post Surgery
Commenting on the study findings for GI & Hepatology News, Louis Aronne, MD, director of the Comprehensive Weight Control Center at Weill Cornell Medicine in New York City, who was not involved in the study, said, “I think it is perfectly logical to use GLP-1s in patients who have had bariatric surgery.”
In this study, weight loss in those who took GLP-1s was about 12% (from a median BMI of 42 pre-surgery to 36.7 when a GLP-1 was initiated), which is significantly less than average, Aronne noted. “The patients still had Class 2 obesity.”
“Obesity is the same as other metabolic diseases,” he added. “We have to use common sense and good medical judgment when treating patients. If surgery isn’t completely effective and weight loss is inadequate, I would recommend medications.”
Of note, his team has found that lower doses of GLP-1s are required in those who have had surgery than in those who have not. “My opinion is that patients who have undergone bariatric surgery seem to be more sensitive to the medications than the average patient, but this hasn’t been carefully studied.”
To prepare patients for the possible use of GLP1s post-surgery, he suggested telling those with very high BMI that “they may need medication in addition to the procedure in order to get the best result.”
Mehta added, “Ultimately, the decision to start GLP-1s after surgery is shared between patients and clinicians. Given the amount of media coverage on GLP-1 therapies, it is not surprising that more patients are initiating these discussions with their doctors.”
Mehta is supported by the US National Institute on Aging and reported receiving grants from the institute for this study; no other funding was reported. Lauer reported receiving grants from the US National Institutes of Health.
A version of this article first appeared on Medscape.com.
, a large retrospective cohort study showed.
GLP-1 initiation was also more common among women, those who underwent sleeve gastrectomy, and those with lower postoperative weight loss as measured by BMI.
“Some patients do not lose as much weight as expected, or they regain weight after a few years. In such cases, GLP-1 therapies are emerging as an important option for weight management,” said principal investigator Hemalkumar Mehta, PhD, associate professor at Johns Hopkins Bloomberg School of Public Health in Baltimore.
“We also noted many personal stories circulating on social media in which patients shared their experiences using GLP-1 after bariatric surgery,” he told GI & Hepatology News.
But when the researchers reviewed the scientific literature, they found no published evidence on GLP-1 use in this setting and little or no data on outcomes with the newer drugs such as semaglutide and tirzepatide. “This gap motivated us to conduct the current study,” said Mehta. The study was published in JAMA Surgery.
The researchers analyzed data from a national multicenter database of electronic health records of approximately 113 million US adults to characterize the use of and factors associated with GLP-1 initiation after bariatric surgery.
Among 112,858 individuals undergoing bariatric surgery during the study period, the mean age was 45.2 years, and 78.9% were women.
By self-report race, 1.1% were Asian, 22.1% were Black or African American, 64.2% were White individuals, and 12.6% reported belonging to other races (American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or unknown).
A total of 15,749 individuals (14%) initiated GLP-1s post-surgery, with 3391 (21.5%) beginning within 2 years of surgery and the remainder initiating during postsurgical years 3-4 (32.3%), 5-6 (25.2%), or later (21%).
Notably, the proportion of GLP-1 use increased more in the more recent cohort, from 1.7% in the January 2015-December 2019 cohort to 12.6% from June 2020 to May 2025.
Differences Between Users and Nonusers
Those who initiated GLP-1s differed significantly from those who did not: GLP-1 users vs nonusers were younger (mean age, 44.9 years vs 45.2 years), and use was more common among women vs men (15.1% vs 9.7%), among Black or African American vs White patients (15.8% vs 13.5%), and among those who underwent sleeve gastrectomy vs Roux-en-Y gastric bypass (14.9% vs 12.1%).
Looked at another way, women (adjusted hazard ratio [aHR], 1.61), those undergoing sleeve gastrectomy (aHR, 1.42), and those with type 2 diabetes (aHR, 1.34) were more likely to initiate GLP-1s than their counterparts.
The overall median presurgical BMI was 42. On analyzing obesity classification based on BMI, the researchers found that the chances of GLP-1 use were 1.73 times higher among class 1 obesity patients (BMI, 30.0-34.9), 2.19 times higher among class 2 obesity patients (BMI, 35.0-39.9), and 2.69 times higher among patients with class 3 obesity (BMI ≥ 40) than among overweight patients (BMI, 25.0-29.9).
The median post-surgery BMI for GLP-1 users at drug initiation was 36.7. Each one-unit increase in postsurgical BMI was associated with an 8% increase in the likelihood of GLP-1 initiation (aHR, 1.08).
“Importantly, our study did not specifically evaluate the effectiveness of GLP-1 therapy on weight loss after surgery,” Mehta noted. That issue and others, such as optimal timing for initiating GLP-1s, are currently under investigation.
In a related editorial, Kate Lauer, MD, of the University of Wisconsin-Madison and colleagues noted that the study had several limitations. It relied on data prior to the USFDA approvals of semaglutide and tirzepatide, the two most prescribed GLP-1s currently, potentially limiting its applicability to current practice.
Furthermore, the prescribing data did not capture dose, titration schedules, or adherence, which are “critical for understanding treatment efficacy,” they wrote. “Nonetheless, the findings highlight two important trends: (1) GLP-1s are being increasingly used as an adjunct after bariatric surgery, and (2) there is substantial variability in the timing of their initiation.”
‘Logical’ to Use GLP-1s Post Surgery
Commenting on the study findings for GI & Hepatology News, Louis Aronne, MD, director of the Comprehensive Weight Control Center at Weill Cornell Medicine in New York City, who was not involved in the study, said, “I think it is perfectly logical to use GLP-1s in patients who have had bariatric surgery.”
In this study, weight loss in those who took GLP-1s was about 12% (from a median BMI of 42 pre-surgery to 36.7 when a GLP-1 was initiated), which is significantly less than average, Aronne noted. “The patients still had Class 2 obesity.”
“Obesity is the same as other metabolic diseases,” he added. “We have to use common sense and good medical judgment when treating patients. If surgery isn’t completely effective and weight loss is inadequate, I would recommend medications.”
Of note, his team has found that lower doses of GLP-1s are required in those who have had surgery than in those who have not. “My opinion is that patients who have undergone bariatric surgery seem to be more sensitive to the medications than the average patient, but this hasn’t been carefully studied.”
To prepare patients for the possible use of GLP1s post-surgery, he suggested telling those with very high BMI that “they may need medication in addition to the procedure in order to get the best result.”
Mehta added, “Ultimately, the decision to start GLP-1s after surgery is shared between patients and clinicians. Given the amount of media coverage on GLP-1 therapies, it is not surprising that more patients are initiating these discussions with their doctors.”
Mehta is supported by the US National Institute on Aging and reported receiving grants from the institute for this study; no other funding was reported. Lauer reported receiving grants from the US National Institutes of Health.
A version of this article first appeared on Medscape.com.
, a large retrospective cohort study showed.
GLP-1 initiation was also more common among women, those who underwent sleeve gastrectomy, and those with lower postoperative weight loss as measured by BMI.
“Some patients do not lose as much weight as expected, or they regain weight after a few years. In such cases, GLP-1 therapies are emerging as an important option for weight management,” said principal investigator Hemalkumar Mehta, PhD, associate professor at Johns Hopkins Bloomberg School of Public Health in Baltimore.
“We also noted many personal stories circulating on social media in which patients shared their experiences using GLP-1 after bariatric surgery,” he told GI & Hepatology News.
But when the researchers reviewed the scientific literature, they found no published evidence on GLP-1 use in this setting and little or no data on outcomes with the newer drugs such as semaglutide and tirzepatide. “This gap motivated us to conduct the current study,” said Mehta. The study was published in JAMA Surgery.
The researchers analyzed data from a national multicenter database of electronic health records of approximately 113 million US adults to characterize the use of and factors associated with GLP-1 initiation after bariatric surgery.
Among 112,858 individuals undergoing bariatric surgery during the study period, the mean age was 45.2 years, and 78.9% were women.
By self-report race, 1.1% were Asian, 22.1% were Black or African American, 64.2% were White individuals, and 12.6% reported belonging to other races (American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or unknown).
A total of 15,749 individuals (14%) initiated GLP-1s post-surgery, with 3391 (21.5%) beginning within 2 years of surgery and the remainder initiating during postsurgical years 3-4 (32.3%), 5-6 (25.2%), or later (21%).
Notably, the proportion of GLP-1 use increased more in the more recent cohort, from 1.7% in the January 2015-December 2019 cohort to 12.6% from June 2020 to May 2025.
Differences Between Users and Nonusers
Those who initiated GLP-1s differed significantly from those who did not: GLP-1 users vs nonusers were younger (mean age, 44.9 years vs 45.2 years), and use was more common among women vs men (15.1% vs 9.7%), among Black or African American vs White patients (15.8% vs 13.5%), and among those who underwent sleeve gastrectomy vs Roux-en-Y gastric bypass (14.9% vs 12.1%).
Looked at another way, women (adjusted hazard ratio [aHR], 1.61), those undergoing sleeve gastrectomy (aHR, 1.42), and those with type 2 diabetes (aHR, 1.34) were more likely to initiate GLP-1s than their counterparts.
The overall median presurgical BMI was 42. On analyzing obesity classification based on BMI, the researchers found that the chances of GLP-1 use were 1.73 times higher among class 1 obesity patients (BMI, 30.0-34.9), 2.19 times higher among class 2 obesity patients (BMI, 35.0-39.9), and 2.69 times higher among patients with class 3 obesity (BMI ≥ 40) than among overweight patients (BMI, 25.0-29.9).
The median post-surgery BMI for GLP-1 users at drug initiation was 36.7. Each one-unit increase in postsurgical BMI was associated with an 8% increase in the likelihood of GLP-1 initiation (aHR, 1.08).
“Importantly, our study did not specifically evaluate the effectiveness of GLP-1 therapy on weight loss after surgery,” Mehta noted. That issue and others, such as optimal timing for initiating GLP-1s, are currently under investigation.
In a related editorial, Kate Lauer, MD, of the University of Wisconsin-Madison and colleagues noted that the study had several limitations. It relied on data prior to the USFDA approvals of semaglutide and tirzepatide, the two most prescribed GLP-1s currently, potentially limiting its applicability to current practice.
Furthermore, the prescribing data did not capture dose, titration schedules, or adherence, which are “critical for understanding treatment efficacy,” they wrote. “Nonetheless, the findings highlight two important trends: (1) GLP-1s are being increasingly used as an adjunct after bariatric surgery, and (2) there is substantial variability in the timing of their initiation.”
‘Logical’ to Use GLP-1s Post Surgery
Commenting on the study findings for GI & Hepatology News, Louis Aronne, MD, director of the Comprehensive Weight Control Center at Weill Cornell Medicine in New York City, who was not involved in the study, said, “I think it is perfectly logical to use GLP-1s in patients who have had bariatric surgery.”
In this study, weight loss in those who took GLP-1s was about 12% (from a median BMI of 42 pre-surgery to 36.7 when a GLP-1 was initiated), which is significantly less than average, Aronne noted. “The patients still had Class 2 obesity.”
“Obesity is the same as other metabolic diseases,” he added. “We have to use common sense and good medical judgment when treating patients. If surgery isn’t completely effective and weight loss is inadequate, I would recommend medications.”
Of note, his team has found that lower doses of GLP-1s are required in those who have had surgery than in those who have not. “My opinion is that patients who have undergone bariatric surgery seem to be more sensitive to the medications than the average patient, but this hasn’t been carefully studied.”
To prepare patients for the possible use of GLP1s post-surgery, he suggested telling those with very high BMI that “they may need medication in addition to the procedure in order to get the best result.”
Mehta added, “Ultimately, the decision to start GLP-1s after surgery is shared between patients and clinicians. Given the amount of media coverage on GLP-1 therapies, it is not surprising that more patients are initiating these discussions with their doctors.”
Mehta is supported by the US National Institute on Aging and reported receiving grants from the institute for this study; no other funding was reported. Lauer reported receiving grants from the US National Institutes of Health.
A version of this article first 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.
Forceps Assistance Improves Outcomes in Difficult ERCP Cannulations
The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.
Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.
First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).
The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.
SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.
The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).
Patients who crossed over to forceps assistance all had successful cannulations.
The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”
While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”
Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”
The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”
Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”
He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”
DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.
Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”
This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.
A version of this article first appeared on Medscape.com.
The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.
Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.
First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).
The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.
SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.
The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).
Patients who crossed over to forceps assistance all had successful cannulations.
The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”
While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”
Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”
The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”
Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”
He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”
DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.
Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”
This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.
A version of this article first appeared on Medscape.com.
The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.
Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.
First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).
The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.
SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.
The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).
Patients who crossed over to forceps assistance all had successful cannulations.
The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”
While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”
Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”
The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”
Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”
He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”
DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.
Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”
This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.
A version of this article first appeared on Medscape.com.
GI Disorders Linked With Sleep Problems
“Emerging evidence suggests a bidirectional relationship between GI diseases and sleep disorders, whereby dysfunction in one domain may exacerbate the other,” wrote Shicheng Ye, PhD, of The Third Clinical Medical College of Guangzhou University of Chinese Medicine, and colleagues. However, previous studies on the association between GI and sleep problems have been small, and the role of depression as a mediator has not been well explored.
In the study, which was published online in BMC Gastroenterology, the researchers reviewed data from the US National Health and Nutrition Examination Survey between 2005 and 2014. The study population included 10,626 adults aged 20 years or older, with a mean age of 45.6 years, 50.8% of whom were women. Of these, 6444 were identified as having GI disease on the basis of a “yes” response to the question of whether they had a stomach or intestinal illness with vomiting or diarrhea within the past 30 days.
Researchers also examined responses to survey questions related to sleep duration, trouble sleeping, and diagnosis of a sleep disorder. Individuals with vs without GI diseases had a significantly higher prevalence of sleep trouble (37.99% vs 24.21%; P < .001) and a greater frequency of diagnosed sleep disorders (14.99% vs 8.08%; P < .001).
An analysis adjusted for demographic, lifestyle, and clinical factors found that individuals with vs without GI diseases were 70% more likely to have sleep trouble. Individuals with vs without GI diseases were also significantly more likely to have a diagnosed sleep disorder and a reduction in sleep duration (adjusted odds ratio, 1.8; adjusted beta, -0.15).
The association between GI diseases and sleep problems remained consistent across individuals of multiple subgroups, including those without hypertension, diabetes, or a history of smoking. It also remained significant among individuals with coronary heart disease and higher scores on the dietary index for gut microbiota. No significant interaction effects related to age, sex, or chronic disease appeared in any subgroup (P > .05).
An additional mediation analysis found that depression partly mediated the associations between GI diseases and sleep issues. Depression accounted for 21.29% of the total effect on sleep problems, 19.23% of the effect on sleep disorders, and 26.68% of the effect on sleep duration.
The mediating role of depression on the association between GI disease and sleep problems may not be exclusive, the researchers wrote. Other potential mechanisms may include systemic inflammation, visceral hypersensitivity, and metabolic dysfunction.
The findings were limited by several factors, including the possibly underpowered sample size for machine-learning models and the reliance on self-reports of GI diseases, sleep outcomes, and coronary heart disease, the researchers noted. Other limitations included the inability to adjust for confounding factors, including obstructive sleep apnea, chronic pain, and hypertension.
However, the results illustrate the need to address both psychological and GI factors in clinical practice to improve sleep health, the researchers wrote. More research is needed to identify causal pathways and develop targeted, multidimensional interventions for this interconnected trio of health problems.
Increasing Evidence for Gut-Brain Interaction
Both sleep disorders and disorders of GBI (DGBI) are highly prevalent worldwide, Jatin Roper, MD, gastroenterologist and associate professor of medicine at Duke University, Durham, North Carolina, told GI & Hepatology News.
“A growing body of evidence suggests that DGBI, including irritable bowel syndrome, are caused by imbalances in signaling between the brain and the intestine, which include the vagus nerve, hormonal signals, the gut microbiota, and immune system,” said Roper, who was not involved in the current study.
“Since many sleep disturbances are centrally mediated, it is plausible that sleep and gastrointestinal disorders could be mechanistically linked,” he said. Rigorous analysis of patient databases for a possible association between sleep and GI disorders, as was done in the current study, is an important step.
The current study findings were not unexpected, “particularly the finding that depression may mediate a link between sleep and GI disorders, because depression is well known to be associated to sleep disturbances and DGBI,” Roper said.
However, GI doctors often do not ask patients about problems with sleep, and pulmonary doctors or sleep specialists may not ask patients about GI symptoms, Roper noted. Similarly, patients may not bring up all their symptoms when seeing these specialists.
“The current study underscores the need for comprehensive, multisystem evaluations in specialty clinics for sleep and GI conditions and appropriate referrals to specialists, when necessary,” he said.
The research raised an important question of whether sleep and GI disorders are associated with each other because of other underlying medical conditions, which may be difficult to control for in cross-sectional studies, or whether sleep problems cause GI problems or vice versa, Roper said. Other uncertainties include whether the conditions are biologically linked, possibly through shared changes in the brain-gut axis.
Long-term observational studies would be useful to identify whether sleep disturbances precede DGBI or vice versa, Roper added.
The study received no outside funding. The researchers and Roper had no financial conflicts to disclose.
A version of this article first appeared on Medscape.com.
“Emerging evidence suggests a bidirectional relationship between GI diseases and sleep disorders, whereby dysfunction in one domain may exacerbate the other,” wrote Shicheng Ye, PhD, of The Third Clinical Medical College of Guangzhou University of Chinese Medicine, and colleagues. However, previous studies on the association between GI and sleep problems have been small, and the role of depression as a mediator has not been well explored.
In the study, which was published online in BMC Gastroenterology, the researchers reviewed data from the US National Health and Nutrition Examination Survey between 2005 and 2014. The study population included 10,626 adults aged 20 years or older, with a mean age of 45.6 years, 50.8% of whom were women. Of these, 6444 were identified as having GI disease on the basis of a “yes” response to the question of whether they had a stomach or intestinal illness with vomiting or diarrhea within the past 30 days.
Researchers also examined responses to survey questions related to sleep duration, trouble sleeping, and diagnosis of a sleep disorder. Individuals with vs without GI diseases had a significantly higher prevalence of sleep trouble (37.99% vs 24.21%; P < .001) and a greater frequency of diagnosed sleep disorders (14.99% vs 8.08%; P < .001).
An analysis adjusted for demographic, lifestyle, and clinical factors found that individuals with vs without GI diseases were 70% more likely to have sleep trouble. Individuals with vs without GI diseases were also significantly more likely to have a diagnosed sleep disorder and a reduction in sleep duration (adjusted odds ratio, 1.8; adjusted beta, -0.15).
The association between GI diseases and sleep problems remained consistent across individuals of multiple subgroups, including those without hypertension, diabetes, or a history of smoking. It also remained significant among individuals with coronary heart disease and higher scores on the dietary index for gut microbiota. No significant interaction effects related to age, sex, or chronic disease appeared in any subgroup (P > .05).
An additional mediation analysis found that depression partly mediated the associations between GI diseases and sleep issues. Depression accounted for 21.29% of the total effect on sleep problems, 19.23% of the effect on sleep disorders, and 26.68% of the effect on sleep duration.
The mediating role of depression on the association between GI disease and sleep problems may not be exclusive, the researchers wrote. Other potential mechanisms may include systemic inflammation, visceral hypersensitivity, and metabolic dysfunction.
The findings were limited by several factors, including the possibly underpowered sample size for machine-learning models and the reliance on self-reports of GI diseases, sleep outcomes, and coronary heart disease, the researchers noted. Other limitations included the inability to adjust for confounding factors, including obstructive sleep apnea, chronic pain, and hypertension.
However, the results illustrate the need to address both psychological and GI factors in clinical practice to improve sleep health, the researchers wrote. More research is needed to identify causal pathways and develop targeted, multidimensional interventions for this interconnected trio of health problems.
Increasing Evidence for Gut-Brain Interaction
Both sleep disorders and disorders of GBI (DGBI) are highly prevalent worldwide, Jatin Roper, MD, gastroenterologist and associate professor of medicine at Duke University, Durham, North Carolina, told GI & Hepatology News.
“A growing body of evidence suggests that DGBI, including irritable bowel syndrome, are caused by imbalances in signaling between the brain and the intestine, which include the vagus nerve, hormonal signals, the gut microbiota, and immune system,” said Roper, who was not involved in the current study.
“Since many sleep disturbances are centrally mediated, it is plausible that sleep and gastrointestinal disorders could be mechanistically linked,” he said. Rigorous analysis of patient databases for a possible association between sleep and GI disorders, as was done in the current study, is an important step.
The current study findings were not unexpected, “particularly the finding that depression may mediate a link between sleep and GI disorders, because depression is well known to be associated to sleep disturbances and DGBI,” Roper said.
However, GI doctors often do not ask patients about problems with sleep, and pulmonary doctors or sleep specialists may not ask patients about GI symptoms, Roper noted. Similarly, patients may not bring up all their symptoms when seeing these specialists.
“The current study underscores the need for comprehensive, multisystem evaluations in specialty clinics for sleep and GI conditions and appropriate referrals to specialists, when necessary,” he said.
The research raised an important question of whether sleep and GI disorders are associated with each other because of other underlying medical conditions, which may be difficult to control for in cross-sectional studies, or whether sleep problems cause GI problems or vice versa, Roper said. Other uncertainties include whether the conditions are biologically linked, possibly through shared changes in the brain-gut axis.
Long-term observational studies would be useful to identify whether sleep disturbances precede DGBI or vice versa, Roper added.
The study received no outside funding. The researchers and Roper had no financial conflicts to disclose.
A version of this article first appeared on Medscape.com.
“Emerging evidence suggests a bidirectional relationship between GI diseases and sleep disorders, whereby dysfunction in one domain may exacerbate the other,” wrote Shicheng Ye, PhD, of The Third Clinical Medical College of Guangzhou University of Chinese Medicine, and colleagues. However, previous studies on the association between GI and sleep problems have been small, and the role of depression as a mediator has not been well explored.
In the study, which was published online in BMC Gastroenterology, the researchers reviewed data from the US National Health and Nutrition Examination Survey between 2005 and 2014. The study population included 10,626 adults aged 20 years or older, with a mean age of 45.6 years, 50.8% of whom were women. Of these, 6444 were identified as having GI disease on the basis of a “yes” response to the question of whether they had a stomach or intestinal illness with vomiting or diarrhea within the past 30 days.
Researchers also examined responses to survey questions related to sleep duration, trouble sleeping, and diagnosis of a sleep disorder. Individuals with vs without GI diseases had a significantly higher prevalence of sleep trouble (37.99% vs 24.21%; P < .001) and a greater frequency of diagnosed sleep disorders (14.99% vs 8.08%; P < .001).
An analysis adjusted for demographic, lifestyle, and clinical factors found that individuals with vs without GI diseases were 70% more likely to have sleep trouble. Individuals with vs without GI diseases were also significantly more likely to have a diagnosed sleep disorder and a reduction in sleep duration (adjusted odds ratio, 1.8; adjusted beta, -0.15).
The association between GI diseases and sleep problems remained consistent across individuals of multiple subgroups, including those without hypertension, diabetes, or a history of smoking. It also remained significant among individuals with coronary heart disease and higher scores on the dietary index for gut microbiota. No significant interaction effects related to age, sex, or chronic disease appeared in any subgroup (P > .05).
An additional mediation analysis found that depression partly mediated the associations between GI diseases and sleep issues. Depression accounted for 21.29% of the total effect on sleep problems, 19.23% of the effect on sleep disorders, and 26.68% of the effect on sleep duration.
The mediating role of depression on the association between GI disease and sleep problems may not be exclusive, the researchers wrote. Other potential mechanisms may include systemic inflammation, visceral hypersensitivity, and metabolic dysfunction.
The findings were limited by several factors, including the possibly underpowered sample size for machine-learning models and the reliance on self-reports of GI diseases, sleep outcomes, and coronary heart disease, the researchers noted. Other limitations included the inability to adjust for confounding factors, including obstructive sleep apnea, chronic pain, and hypertension.
However, the results illustrate the need to address both psychological and GI factors in clinical practice to improve sleep health, the researchers wrote. More research is needed to identify causal pathways and develop targeted, multidimensional interventions for this interconnected trio of health problems.
Increasing Evidence for Gut-Brain Interaction
Both sleep disorders and disorders of GBI (DGBI) are highly prevalent worldwide, Jatin Roper, MD, gastroenterologist and associate professor of medicine at Duke University, Durham, North Carolina, told GI & Hepatology News.
“A growing body of evidence suggests that DGBI, including irritable bowel syndrome, are caused by imbalances in signaling between the brain and the intestine, which include the vagus nerve, hormonal signals, the gut microbiota, and immune system,” said Roper, who was not involved in the current study.
“Since many sleep disturbances are centrally mediated, it is plausible that sleep and gastrointestinal disorders could be mechanistically linked,” he said. Rigorous analysis of patient databases for a possible association between sleep and GI disorders, as was done in the current study, is an important step.
The current study findings were not unexpected, “particularly the finding that depression may mediate a link between sleep and GI disorders, because depression is well known to be associated to sleep disturbances and DGBI,” Roper said.
However, GI doctors often do not ask patients about problems with sleep, and pulmonary doctors or sleep specialists may not ask patients about GI symptoms, Roper noted. Similarly, patients may not bring up all their symptoms when seeing these specialists.
“The current study underscores the need for comprehensive, multisystem evaluations in specialty clinics for sleep and GI conditions and appropriate referrals to specialists, when necessary,” he said.
The research raised an important question of whether sleep and GI disorders are associated with each other because of other underlying medical conditions, which may be difficult to control for in cross-sectional studies, or whether sleep problems cause GI problems or vice versa, Roper said. Other uncertainties include whether the conditions are biologically linked, possibly through shared changes in the brain-gut axis.
Long-term observational studies would be useful to identify whether sleep disturbances precede DGBI or vice versa, Roper added.
The study received no outside funding. The researchers and Roper had no financial conflicts to disclose.
A version of this article first appeared on Medscape.com.
Support GI Research Through a Named Research Award
Did you know you can honor a family member, friend, or colleague whose life has been touched by GI research through a gift to the AGA Research Foundation? Your gift will honor a loved one or yourself and support the AGA Research Awards Program, while giving you a tax benefit.
Named award. An AGA pilot award can be renamed after you or a loved one, and targeted for a specific gastrointestinal research area. A new pilot research award can be established with a pledge of $40,000+ or through an estate gift. Gifts of cash or appreciated securities may be used to establish a named award.
Your next step. A named award gift is a wonderful way to acknowledge a loved one’s vision for the future. To learn more about ways to recognize your honoree, contact us at [email protected].
A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs.
Did you know you can honor a family member, friend, or colleague whose life has been touched by GI research through a gift to the AGA Research Foundation? Your gift will honor a loved one or yourself and support the AGA Research Awards Program, while giving you a tax benefit.
Named award. An AGA pilot award can be renamed after you or a loved one, and targeted for a specific gastrointestinal research area. A new pilot research award can be established with a pledge of $40,000+ or through an estate gift. Gifts of cash or appreciated securities may be used to establish a named award.
Your next step. A named award gift is a wonderful way to acknowledge a loved one’s vision for the future. To learn more about ways to recognize your honoree, contact us at [email protected].
A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs.
Did you know you can honor a family member, friend, or colleague whose life has been touched by GI research through a gift to the AGA Research Foundation? Your gift will honor a loved one or yourself and support the AGA Research Awards Program, while giving you a tax benefit.
Named award. An AGA pilot award can be renamed after you or a loved one, and targeted for a specific gastrointestinal research area. A new pilot research award can be established with a pledge of $40,000+ or through an estate gift. Gifts of cash or appreciated securities may be used to establish a named award.
Your next step. A named award gift is a wonderful way to acknowledge a loved one’s vision for the future. To learn more about ways to recognize your honoree, contact us at [email protected].
A lack of funding can prevent talented individuals from pursuing a research career, thereby denying them the opportunity to conduct work that will ultimately benefit patients with critical needs.
From Neglect to Novelty: Emerging Treatment Strategies in Papillary Renal Cell Carcinoma
This transcript has been edited for clarity.
Hi, I’m Doctor Monty Pal, and I’m a medical oncologist at City of Hope Comprehensive Cancer Center.
I run the kidney cancer program there, and it’s really been amazing to see the tidal wave of new therapies that we’ve developed for kidney cancer over the years.
What I will say is that most of the treatments that we have, the doublet therapies and adjuvant treatments, really pertain to the most dominant subset of kidney cancer, and that’s clear cell; that really represents about 75%-80% of all cases of kidney cancer.
Having said that, I’d like to focus on perhaps a less dominant subset of kidney cancer known as papillary. This represents about 15%-20% of cases.
To be fair, there are other rare subtypes and those certainly warrant focus as well: Chromophobe represents about 5% of all diseases; translocation, unclassified, a percentage point or 2.
But papillary really is a setting in which we can do — and as I’ll demonstrate, have done — clinical trials.
Now papillary kidney cancer is similar in terms of its demographics to clear cell renal cell carcinoma (RCC). There still tends to be a male predominance. It may have a slightly lower age of initial presentation, but otherwise there’s many commonalities.
I do think one of the areas where it differs, and this is critical, is in the context of biology: We think that papillary RCC is really driven by the MET proto-oncogene amongst other things. With that in mind, there have been a whole host of therapies directed at the MET proto-oncogene, and we’ll discuss that in just a moment.
I wanted to first talk about management of localized papillary kidney cancer. This management doesn’t differ significantly from what we would perhaps consider in the context of localized clear cell kidney cancer. For stage 1 through 3 disease, patients still receive surgery as the mainstay, and I would argue that, in the context of stage 4 disease, we should still really consider aggressive local definitive therapies if at all possible.
Having said that, the role of adjuvant therapy is a bit unclear in this context. I would suggest that in the context of adjuvant therapy for papillary kidney cancer, it’s a bit of a no go until we have greater data in this setting. Therapies like pembrolizumab and sunitinib really were only tested in the context of clear cell disease.
And with that background, I wanted to move into metastatic disease. For patients with stage 4 papillary kidney cancer, therapy may or may not resemble the treatments that we use for clear cell kidney cancer.
There have been trials in yesteryear with really creative names, ASPEN and ESPN for instance, that actually juxtaposed older therapies against one another. Sunitinib against everolimus, for instance, was common to both of those studies. And it really suggested perhaps that sunitinib was the preferred choice between those two targeted therapies. Sunitinib then became a bit of a standard when it came to randomized trials, and in fact, it still remains something that’s incorporated as a base regimen at phase 3 clinical trials.
I’ll show you that in the PAPMET clinical trial, which was a randomized phase 2 experience, we were able to compare sunitinib to cabozantinib, crizotinib, and savolitinib. The latter three drugs are all so-called MET inhibitors. And what’s quite interesting about this study is that cabozantinib, the dual VEGF/MET inhibitor, really is the one that seemed to win out.
When you look at median progression-free survival (PFS), in sunitinib in that study was around 6 months. When you look at cabozantinib, it was around 9 months.
Having said that, with cabozantinib, there was no overall survival advantage, and I will say that the PFS benefit is modest. So, we still need more in the way of clinical trials.
To that end, there’s a number of single arm studies supporting cabozantinib-based regimens, cabozantinib/atezolizumab and cabozantinib/nivolumab, with healthy response rates. For papillary kidney cancer, the response rate with those regimens is around 43%-47%.
In the context of lenvatinib and pembrolizumab, we actually see the response rate augmented to approximately 53%.
So, with those numbers in mind, I definitely think that doublet therapy is promising, but as we always tell our fellows in the clinic, randomization is really king.
So, we do have two phase 3 clinical trials, STELLAR-304, which is a study that I’m running, and the second study is known as SAMETA. Both evaluate papillary patients, but in very different ways.
STELLAR-304 includes patients with papillary, translocation, and unclassified kidney cancer and randomizes to sunitinib vs zanzalintinib, a novel TKI, with nivolumab.
In contrast, SAMETA takes the very interesting approach of actually selecting out patients with MET abnormalities and randomizing them to sunitinib vs savolitinib.
There are other approaches. For instance, the SUNNIFORECAST study recently assessed nivolumab and ipilimumab. There are randomized phase 2 studies looking at axitinib and pembrolizumab or perhaps axitinib and, sorry, cabozantinib with atezolizumab.
But I do think these phase 3 studies, SAMETA and STELLAR-304, are the ones that are really poised to change the landscape of therapy for papillary kidney cancer.
Sumanta K. Pal, MD, Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, has disclosed the following relevant financial relationships: Received travel from: CRISPR; Ipsen. A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Hi, I’m Doctor Monty Pal, and I’m a medical oncologist at City of Hope Comprehensive Cancer Center.
I run the kidney cancer program there, and it’s really been amazing to see the tidal wave of new therapies that we’ve developed for kidney cancer over the years.
What I will say is that most of the treatments that we have, the doublet therapies and adjuvant treatments, really pertain to the most dominant subset of kidney cancer, and that’s clear cell; that really represents about 75%-80% of all cases of kidney cancer.
Having said that, I’d like to focus on perhaps a less dominant subset of kidney cancer known as papillary. This represents about 15%-20% of cases.
To be fair, there are other rare subtypes and those certainly warrant focus as well: Chromophobe represents about 5% of all diseases; translocation, unclassified, a percentage point or 2.
But papillary really is a setting in which we can do — and as I’ll demonstrate, have done — clinical trials.
Now papillary kidney cancer is similar in terms of its demographics to clear cell renal cell carcinoma (RCC). There still tends to be a male predominance. It may have a slightly lower age of initial presentation, but otherwise there’s many commonalities.
I do think one of the areas where it differs, and this is critical, is in the context of biology: We think that papillary RCC is really driven by the MET proto-oncogene amongst other things. With that in mind, there have been a whole host of therapies directed at the MET proto-oncogene, and we’ll discuss that in just a moment.
I wanted to first talk about management of localized papillary kidney cancer. This management doesn’t differ significantly from what we would perhaps consider in the context of localized clear cell kidney cancer. For stage 1 through 3 disease, patients still receive surgery as the mainstay, and I would argue that, in the context of stage 4 disease, we should still really consider aggressive local definitive therapies if at all possible.
Having said that, the role of adjuvant therapy is a bit unclear in this context. I would suggest that in the context of adjuvant therapy for papillary kidney cancer, it’s a bit of a no go until we have greater data in this setting. Therapies like pembrolizumab and sunitinib really were only tested in the context of clear cell disease.
And with that background, I wanted to move into metastatic disease. For patients with stage 4 papillary kidney cancer, therapy may or may not resemble the treatments that we use for clear cell kidney cancer.
There have been trials in yesteryear with really creative names, ASPEN and ESPN for instance, that actually juxtaposed older therapies against one another. Sunitinib against everolimus, for instance, was common to both of those studies. And it really suggested perhaps that sunitinib was the preferred choice between those two targeted therapies. Sunitinib then became a bit of a standard when it came to randomized trials, and in fact, it still remains something that’s incorporated as a base regimen at phase 3 clinical trials.
I’ll show you that in the PAPMET clinical trial, which was a randomized phase 2 experience, we were able to compare sunitinib to cabozantinib, crizotinib, and savolitinib. The latter three drugs are all so-called MET inhibitors. And what’s quite interesting about this study is that cabozantinib, the dual VEGF/MET inhibitor, really is the one that seemed to win out.
When you look at median progression-free survival (PFS), in sunitinib in that study was around 6 months. When you look at cabozantinib, it was around 9 months.
Having said that, with cabozantinib, there was no overall survival advantage, and I will say that the PFS benefit is modest. So, we still need more in the way of clinical trials.
To that end, there’s a number of single arm studies supporting cabozantinib-based regimens, cabozantinib/atezolizumab and cabozantinib/nivolumab, with healthy response rates. For papillary kidney cancer, the response rate with those regimens is around 43%-47%.
In the context of lenvatinib and pembrolizumab, we actually see the response rate augmented to approximately 53%.
So, with those numbers in mind, I definitely think that doublet therapy is promising, but as we always tell our fellows in the clinic, randomization is really king.
So, we do have two phase 3 clinical trials, STELLAR-304, which is a study that I’m running, and the second study is known as SAMETA. Both evaluate papillary patients, but in very different ways.
STELLAR-304 includes patients with papillary, translocation, and unclassified kidney cancer and randomizes to sunitinib vs zanzalintinib, a novel TKI, with nivolumab.
In contrast, SAMETA takes the very interesting approach of actually selecting out patients with MET abnormalities and randomizing them to sunitinib vs savolitinib.
There are other approaches. For instance, the SUNNIFORECAST study recently assessed nivolumab and ipilimumab. There are randomized phase 2 studies looking at axitinib and pembrolizumab or perhaps axitinib and, sorry, cabozantinib with atezolizumab.
But I do think these phase 3 studies, SAMETA and STELLAR-304, are the ones that are really poised to change the landscape of therapy for papillary kidney cancer.
Sumanta K. Pal, MD, Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, has disclosed the following relevant financial relationships: Received travel from: CRISPR; Ipsen. A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Hi, I’m Doctor Monty Pal, and I’m a medical oncologist at City of Hope Comprehensive Cancer Center.
I run the kidney cancer program there, and it’s really been amazing to see the tidal wave of new therapies that we’ve developed for kidney cancer over the years.
What I will say is that most of the treatments that we have, the doublet therapies and adjuvant treatments, really pertain to the most dominant subset of kidney cancer, and that’s clear cell; that really represents about 75%-80% of all cases of kidney cancer.
Having said that, I’d like to focus on perhaps a less dominant subset of kidney cancer known as papillary. This represents about 15%-20% of cases.
To be fair, there are other rare subtypes and those certainly warrant focus as well: Chromophobe represents about 5% of all diseases; translocation, unclassified, a percentage point or 2.
But papillary really is a setting in which we can do — and as I’ll demonstrate, have done — clinical trials.
Now papillary kidney cancer is similar in terms of its demographics to clear cell renal cell carcinoma (RCC). There still tends to be a male predominance. It may have a slightly lower age of initial presentation, but otherwise there’s many commonalities.
I do think one of the areas where it differs, and this is critical, is in the context of biology: We think that papillary RCC is really driven by the MET proto-oncogene amongst other things. With that in mind, there have been a whole host of therapies directed at the MET proto-oncogene, and we’ll discuss that in just a moment.
I wanted to first talk about management of localized papillary kidney cancer. This management doesn’t differ significantly from what we would perhaps consider in the context of localized clear cell kidney cancer. For stage 1 through 3 disease, patients still receive surgery as the mainstay, and I would argue that, in the context of stage 4 disease, we should still really consider aggressive local definitive therapies if at all possible.
Having said that, the role of adjuvant therapy is a bit unclear in this context. I would suggest that in the context of adjuvant therapy for papillary kidney cancer, it’s a bit of a no go until we have greater data in this setting. Therapies like pembrolizumab and sunitinib really were only tested in the context of clear cell disease.
And with that background, I wanted to move into metastatic disease. For patients with stage 4 papillary kidney cancer, therapy may or may not resemble the treatments that we use for clear cell kidney cancer.
There have been trials in yesteryear with really creative names, ASPEN and ESPN for instance, that actually juxtaposed older therapies against one another. Sunitinib against everolimus, for instance, was common to both of those studies. And it really suggested perhaps that sunitinib was the preferred choice between those two targeted therapies. Sunitinib then became a bit of a standard when it came to randomized trials, and in fact, it still remains something that’s incorporated as a base regimen at phase 3 clinical trials.
I’ll show you that in the PAPMET clinical trial, which was a randomized phase 2 experience, we were able to compare sunitinib to cabozantinib, crizotinib, and savolitinib. The latter three drugs are all so-called MET inhibitors. And what’s quite interesting about this study is that cabozantinib, the dual VEGF/MET inhibitor, really is the one that seemed to win out.
When you look at median progression-free survival (PFS), in sunitinib in that study was around 6 months. When you look at cabozantinib, it was around 9 months.
Having said that, with cabozantinib, there was no overall survival advantage, and I will say that the PFS benefit is modest. So, we still need more in the way of clinical trials.
To that end, there’s a number of single arm studies supporting cabozantinib-based regimens, cabozantinib/atezolizumab and cabozantinib/nivolumab, with healthy response rates. For papillary kidney cancer, the response rate with those regimens is around 43%-47%.
In the context of lenvatinib and pembrolizumab, we actually see the response rate augmented to approximately 53%.
So, with those numbers in mind, I definitely think that doublet therapy is promising, but as we always tell our fellows in the clinic, randomization is really king.
So, we do have two phase 3 clinical trials, STELLAR-304, which is a study that I’m running, and the second study is known as SAMETA. Both evaluate papillary patients, but in very different ways.
STELLAR-304 includes patients with papillary, translocation, and unclassified kidney cancer and randomizes to sunitinib vs zanzalintinib, a novel TKI, with nivolumab.
In contrast, SAMETA takes the very interesting approach of actually selecting out patients with MET abnormalities and randomizing them to sunitinib vs savolitinib.
There are other approaches. For instance, the SUNNIFORECAST study recently assessed nivolumab and ipilimumab. There are randomized phase 2 studies looking at axitinib and pembrolizumab or perhaps axitinib and, sorry, cabozantinib with atezolizumab.
But I do think these phase 3 studies, SAMETA and STELLAR-304, are the ones that are really poised to change the landscape of therapy for papillary kidney cancer.
Sumanta K. Pal, MD, Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, has disclosed the following relevant financial relationships: Received travel from: CRISPR; Ipsen. A version of this article appeared on Medscape.com.