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Light During Nighttime Linked to Diabetes Risk
Concerned about your patient’s type 2 diabetes risk? Along with the usual preventive strategies — like diet and exercise and, when appropriate, glucagon-like peptide 1 (GLP-1) agonists — there’s another simple, no-risk strategy that just might help: Turning off the light at night.
A study in The Lancet found that people who were exposed to the most light between 12:30 a.m. and 6 a.m. were 1.5 times more likely to develop diabetes than those who remained in darkness during that time frame.
The study builds on growing evidence linking nighttime light exposure to type 2 diabetes risk. But unlike previous large studies that relied on satellite data of outdoor light levels (an indirect measure of light exposure), the recent study looked at personal light exposure — that is, light measured directly on individuals — as recorded by a wrist-worn sensor.
“Those previous studies likely underestimated the effect,” said study author Andrew Phillips, PhD, professor of sleep health at Flinders University in Adelaide, Australia, “since they did not capture indoor light environments.”
Using data from 85,000 participants from the UK Biobank, the recent study is the largest to date linking diabetes risk to personal light exposure at night.
“This is really a phenomenal study,” said Courtney Peterson, PhD, a scientist at the University of Alabama at Birmingham’s Diabetes Research Center, who was not involved in the study. “This is the first large-scale study we have looking at people’s light exposure patterns and linking it to their long-term health.”
What the Study Showed
The participants wore the light sensors for a week, recording day and night light from all sources — whether from sunlight, lamps, streetlights, or digital screens. The researchers then tracked participants for 8 years.
“About half of the people that we looked at had very dim levels of light at night, so less than 1 lux — that basically means less than candlelight,” said Dr. Phillips. “They were the people who were protected against type 2 diabetes.”
Participants in the top 10% of light exposure — who were exposed to about 48 lux , or the equivalent of relatively dim overhead lighting — were 1.5 times more likely to develop diabetes than those in the dark. That’s about the risk increase you’d get from having a family history of type 2 diabetes, the researchers said.
Even when they controlled for factors like socioeconomic status, smoking, diet, exercise, and shift work, “we still found there was this very strong relationship between light exposure and risk of type 2 diabetes,” said Dr. Phillips.
How Light at Night May Increase Diabetes Risk
The results are not entirely surprising, said endocrinologist Susanne Miedlich, MD, a professor at the University of Rochester Medical Center, Rochester, New York, who was not involved in the study.
Light at night can disrupt the circadian rhythm, or your body’s internal 24-hour cycle. And scientists have long known that circadian rhythm is important for all kinds of biologic processes, including how the body manages blood sugar.
One’s internal clock regulates food intake, sugar absorption, and the release of insulin. Dysregulation in the circadian rhythm is associated with insulin resistance, a precursor to type 2 diabetes.
Dr. Phillips speculated that the sleep hormone melatonin also plays a role.
“Melatonin does a lot of things, but one of the things that it does is it manages our glucose and our insulin responses,” Dr. Phillips said. “So if you’re chronically getting light exposure at night, that’s reducing a level of melatonin that, in the long term, could lead to poor metabolic outcomes.”
Previous studies have explored melatonin supplementation to help manage diabetes. “However, while melatonin clearly regulates circadian rhythms, its utility as a drug to prevent diabetes has not really panned out thus far,” Dr. Miedlich said.
Takeaways
Interventional studies are needed to confirm whether strategies like powering down screens, turning off lights, or using blackout curtains could reduce diabetes risk.
That said, “there’s no reason not to tell people to get healthy light exposure patterns and sleep, especially in the context of diabetes,” said Dr. Phillips.
Other known strategies for reducing diabetes risk include intensive lifestyle programs, which reduce risk by up to 58%, and GLP-1 agonists.
“Probably a GLP-1 agonist is going to be more effective,” Dr. Peterson said. “But this is still a fairly large effect without having to go through the expense of buying a GLP-1 or losing a lot of weight or making a big lifestyle change.”
A version of this article first appeared on Medscape.com.
Concerned about your patient’s type 2 diabetes risk? Along with the usual preventive strategies — like diet and exercise and, when appropriate, glucagon-like peptide 1 (GLP-1) agonists — there’s another simple, no-risk strategy that just might help: Turning off the light at night.
A study in The Lancet found that people who were exposed to the most light between 12:30 a.m. and 6 a.m. were 1.5 times more likely to develop diabetes than those who remained in darkness during that time frame.
The study builds on growing evidence linking nighttime light exposure to type 2 diabetes risk. But unlike previous large studies that relied on satellite data of outdoor light levels (an indirect measure of light exposure), the recent study looked at personal light exposure — that is, light measured directly on individuals — as recorded by a wrist-worn sensor.
“Those previous studies likely underestimated the effect,” said study author Andrew Phillips, PhD, professor of sleep health at Flinders University in Adelaide, Australia, “since they did not capture indoor light environments.”
Using data from 85,000 participants from the UK Biobank, the recent study is the largest to date linking diabetes risk to personal light exposure at night.
“This is really a phenomenal study,” said Courtney Peterson, PhD, a scientist at the University of Alabama at Birmingham’s Diabetes Research Center, who was not involved in the study. “This is the first large-scale study we have looking at people’s light exposure patterns and linking it to their long-term health.”
What the Study Showed
The participants wore the light sensors for a week, recording day and night light from all sources — whether from sunlight, lamps, streetlights, or digital screens. The researchers then tracked participants for 8 years.
“About half of the people that we looked at had very dim levels of light at night, so less than 1 lux — that basically means less than candlelight,” said Dr. Phillips. “They were the people who were protected against type 2 diabetes.”
Participants in the top 10% of light exposure — who were exposed to about 48 lux , or the equivalent of relatively dim overhead lighting — were 1.5 times more likely to develop diabetes than those in the dark. That’s about the risk increase you’d get from having a family history of type 2 diabetes, the researchers said.
Even when they controlled for factors like socioeconomic status, smoking, diet, exercise, and shift work, “we still found there was this very strong relationship between light exposure and risk of type 2 diabetes,” said Dr. Phillips.
How Light at Night May Increase Diabetes Risk
The results are not entirely surprising, said endocrinologist Susanne Miedlich, MD, a professor at the University of Rochester Medical Center, Rochester, New York, who was not involved in the study.
Light at night can disrupt the circadian rhythm, or your body’s internal 24-hour cycle. And scientists have long known that circadian rhythm is important for all kinds of biologic processes, including how the body manages blood sugar.
One’s internal clock regulates food intake, sugar absorption, and the release of insulin. Dysregulation in the circadian rhythm is associated with insulin resistance, a precursor to type 2 diabetes.
Dr. Phillips speculated that the sleep hormone melatonin also plays a role.
“Melatonin does a lot of things, but one of the things that it does is it manages our glucose and our insulin responses,” Dr. Phillips said. “So if you’re chronically getting light exposure at night, that’s reducing a level of melatonin that, in the long term, could lead to poor metabolic outcomes.”
Previous studies have explored melatonin supplementation to help manage diabetes. “However, while melatonin clearly regulates circadian rhythms, its utility as a drug to prevent diabetes has not really panned out thus far,” Dr. Miedlich said.
Takeaways
Interventional studies are needed to confirm whether strategies like powering down screens, turning off lights, or using blackout curtains could reduce diabetes risk.
That said, “there’s no reason not to tell people to get healthy light exposure patterns and sleep, especially in the context of diabetes,” said Dr. Phillips.
Other known strategies for reducing diabetes risk include intensive lifestyle programs, which reduce risk by up to 58%, and GLP-1 agonists.
“Probably a GLP-1 agonist is going to be more effective,” Dr. Peterson said. “But this is still a fairly large effect without having to go through the expense of buying a GLP-1 or losing a lot of weight or making a big lifestyle change.”
A version of this article first appeared on Medscape.com.
Concerned about your patient’s type 2 diabetes risk? Along with the usual preventive strategies — like diet and exercise and, when appropriate, glucagon-like peptide 1 (GLP-1) agonists — there’s another simple, no-risk strategy that just might help: Turning off the light at night.
A study in The Lancet found that people who were exposed to the most light between 12:30 a.m. and 6 a.m. were 1.5 times more likely to develop diabetes than those who remained in darkness during that time frame.
The study builds on growing evidence linking nighttime light exposure to type 2 diabetes risk. But unlike previous large studies that relied on satellite data of outdoor light levels (an indirect measure of light exposure), the recent study looked at personal light exposure — that is, light measured directly on individuals — as recorded by a wrist-worn sensor.
“Those previous studies likely underestimated the effect,” said study author Andrew Phillips, PhD, professor of sleep health at Flinders University in Adelaide, Australia, “since they did not capture indoor light environments.”
Using data from 85,000 participants from the UK Biobank, the recent study is the largest to date linking diabetes risk to personal light exposure at night.
“This is really a phenomenal study,” said Courtney Peterson, PhD, a scientist at the University of Alabama at Birmingham’s Diabetes Research Center, who was not involved in the study. “This is the first large-scale study we have looking at people’s light exposure patterns and linking it to their long-term health.”
What the Study Showed
The participants wore the light sensors for a week, recording day and night light from all sources — whether from sunlight, lamps, streetlights, or digital screens. The researchers then tracked participants for 8 years.
“About half of the people that we looked at had very dim levels of light at night, so less than 1 lux — that basically means less than candlelight,” said Dr. Phillips. “They were the people who were protected against type 2 diabetes.”
Participants in the top 10% of light exposure — who were exposed to about 48 lux , or the equivalent of relatively dim overhead lighting — were 1.5 times more likely to develop diabetes than those in the dark. That’s about the risk increase you’d get from having a family history of type 2 diabetes, the researchers said.
Even when they controlled for factors like socioeconomic status, smoking, diet, exercise, and shift work, “we still found there was this very strong relationship between light exposure and risk of type 2 diabetes,” said Dr. Phillips.
How Light at Night May Increase Diabetes Risk
The results are not entirely surprising, said endocrinologist Susanne Miedlich, MD, a professor at the University of Rochester Medical Center, Rochester, New York, who was not involved in the study.
Light at night can disrupt the circadian rhythm, or your body’s internal 24-hour cycle. And scientists have long known that circadian rhythm is important for all kinds of biologic processes, including how the body manages blood sugar.
One’s internal clock regulates food intake, sugar absorption, and the release of insulin. Dysregulation in the circadian rhythm is associated with insulin resistance, a precursor to type 2 diabetes.
Dr. Phillips speculated that the sleep hormone melatonin also plays a role.
“Melatonin does a lot of things, but one of the things that it does is it manages our glucose and our insulin responses,” Dr. Phillips said. “So if you’re chronically getting light exposure at night, that’s reducing a level of melatonin that, in the long term, could lead to poor metabolic outcomes.”
Previous studies have explored melatonin supplementation to help manage diabetes. “However, while melatonin clearly regulates circadian rhythms, its utility as a drug to prevent diabetes has not really panned out thus far,” Dr. Miedlich said.
Takeaways
Interventional studies are needed to confirm whether strategies like powering down screens, turning off lights, or using blackout curtains could reduce diabetes risk.
That said, “there’s no reason not to tell people to get healthy light exposure patterns and sleep, especially in the context of diabetes,” said Dr. Phillips.
Other known strategies for reducing diabetes risk include intensive lifestyle programs, which reduce risk by up to 58%, and GLP-1 agonists.
“Probably a GLP-1 agonist is going to be more effective,” Dr. Peterson said. “But this is still a fairly large effect without having to go through the expense of buying a GLP-1 or losing a lot of weight or making a big lifestyle change.”
A version of this article first appeared on Medscape.com.
FROM THE LANCET
Medicare Rates in 2025 Would Cut Pay For Docs by 3%
Federal officials on July 11 proposed Medicare rates that effectively would cut physician pay by about 3% in 2025, touching off a fresh round of protests from medical associations.
, the Centers for Medicare & Medicaid Services said.
The American Medical Association (AMA), the American Academy of Family Physicians (AAFP) and other groups on July 10 reiterated calls on Congress to revise the law on Medicare payment for physicians and move away from short-term tweaks.
This proposed cut is mostly due to the 5-year freeze in the physician schedule base rate mandated by the 2015 Medicare Access and CHIP Reauthorization Act (MACRA). Congress designed MACRA with an aim of shifting clinicians toward programs that would peg pay increases to quality measures.
Lawmakers have since had to soften the blow of that freeze, acknowledging flaws in MACRA and inflation’s significant toll on medical practices. Yet lawmakers have made temporary fixes, such as a 2.93% increase in current payment that’s set to expire.
“Previous quick fixes have been insufficient — this situation requires a bold, substantial approach,” Bruce A. Scott, MD, the AMA president, said in a statement. “A Band-Aid goes only so far when the patient is in dire need.”
Dr. Scott noted that the Medicare Economic Index — a measure of practice cost inflation — is expected to rise by 3.6% in 2025.
“As a first step, Congress must enact an annual inflationary update to help physician payment rates keep pace with rising practice costs,” Steven P. Furr, MD, AAFP’s president, said in a statement released July 10. “Any payment reductions will threaten practices and exacerbate workforce shortages, preventing patients from accessing the primary care, behavioral health care, and other critical preventive services they need.”
Many medical groups, including the AMA, AAFP, and the Medical Group Management Association, are pressing Congress to pass a law that would tie the conversion factor of the physician fee schedule to inflation.
Influential advisory groups also have backed the idea of increasing the conversion factor. For example, the Medicare Payment Advisory Commission in March recommended to Congress that it increase the 2025 conversion factor, suggesting a bump of half of the projected increase in the Medicare Economic Index.
Congress seems unlikely to revamp the physician fee schedule this year, with members spending significant time away from Washington ahead of the November election.
That could make it likely that Congress’ next action on Medicare payment rates would be another short-term tweak — instead of long-lasting change.
A version of this article first appeared on Medscape.com.
Federal officials on July 11 proposed Medicare rates that effectively would cut physician pay by about 3% in 2025, touching off a fresh round of protests from medical associations.
, the Centers for Medicare & Medicaid Services said.
The American Medical Association (AMA), the American Academy of Family Physicians (AAFP) and other groups on July 10 reiterated calls on Congress to revise the law on Medicare payment for physicians and move away from short-term tweaks.
This proposed cut is mostly due to the 5-year freeze in the physician schedule base rate mandated by the 2015 Medicare Access and CHIP Reauthorization Act (MACRA). Congress designed MACRA with an aim of shifting clinicians toward programs that would peg pay increases to quality measures.
Lawmakers have since had to soften the blow of that freeze, acknowledging flaws in MACRA and inflation’s significant toll on medical practices. Yet lawmakers have made temporary fixes, such as a 2.93% increase in current payment that’s set to expire.
“Previous quick fixes have been insufficient — this situation requires a bold, substantial approach,” Bruce A. Scott, MD, the AMA president, said in a statement. “A Band-Aid goes only so far when the patient is in dire need.”
Dr. Scott noted that the Medicare Economic Index — a measure of practice cost inflation — is expected to rise by 3.6% in 2025.
“As a first step, Congress must enact an annual inflationary update to help physician payment rates keep pace with rising practice costs,” Steven P. Furr, MD, AAFP’s president, said in a statement released July 10. “Any payment reductions will threaten practices and exacerbate workforce shortages, preventing patients from accessing the primary care, behavioral health care, and other critical preventive services they need.”
Many medical groups, including the AMA, AAFP, and the Medical Group Management Association, are pressing Congress to pass a law that would tie the conversion factor of the physician fee schedule to inflation.
Influential advisory groups also have backed the idea of increasing the conversion factor. For example, the Medicare Payment Advisory Commission in March recommended to Congress that it increase the 2025 conversion factor, suggesting a bump of half of the projected increase in the Medicare Economic Index.
Congress seems unlikely to revamp the physician fee schedule this year, with members spending significant time away from Washington ahead of the November election.
That could make it likely that Congress’ next action on Medicare payment rates would be another short-term tweak — instead of long-lasting change.
A version of this article first appeared on Medscape.com.
Federal officials on July 11 proposed Medicare rates that effectively would cut physician pay by about 3% in 2025, touching off a fresh round of protests from medical associations.
, the Centers for Medicare & Medicaid Services said.
The American Medical Association (AMA), the American Academy of Family Physicians (AAFP) and other groups on July 10 reiterated calls on Congress to revise the law on Medicare payment for physicians and move away from short-term tweaks.
This proposed cut is mostly due to the 5-year freeze in the physician schedule base rate mandated by the 2015 Medicare Access and CHIP Reauthorization Act (MACRA). Congress designed MACRA with an aim of shifting clinicians toward programs that would peg pay increases to quality measures.
Lawmakers have since had to soften the blow of that freeze, acknowledging flaws in MACRA and inflation’s significant toll on medical practices. Yet lawmakers have made temporary fixes, such as a 2.93% increase in current payment that’s set to expire.
“Previous quick fixes have been insufficient — this situation requires a bold, substantial approach,” Bruce A. Scott, MD, the AMA president, said in a statement. “A Band-Aid goes only so far when the patient is in dire need.”
Dr. Scott noted that the Medicare Economic Index — a measure of practice cost inflation — is expected to rise by 3.6% in 2025.
“As a first step, Congress must enact an annual inflationary update to help physician payment rates keep pace with rising practice costs,” Steven P. Furr, MD, AAFP’s president, said in a statement released July 10. “Any payment reductions will threaten practices and exacerbate workforce shortages, preventing patients from accessing the primary care, behavioral health care, and other critical preventive services they need.”
Many medical groups, including the AMA, AAFP, and the Medical Group Management Association, are pressing Congress to pass a law that would tie the conversion factor of the physician fee schedule to inflation.
Influential advisory groups also have backed the idea of increasing the conversion factor. For example, the Medicare Payment Advisory Commission in March recommended to Congress that it increase the 2025 conversion factor, suggesting a bump of half of the projected increase in the Medicare Economic Index.
Congress seems unlikely to revamp the physician fee schedule this year, with members spending significant time away from Washington ahead of the November election.
That could make it likely that Congress’ next action on Medicare payment rates would be another short-term tweak — instead of long-lasting change.
A version of this article first appeared on Medscape.com.
Managing Agitation in Alzheimer’s Disease: Five Things to Know
Agitation is a neuropsychiatric symptom in patients with Alzheimer’s disease (AD), the most common form of dementia. The prevalence of this symptom is about 40%-65%, with the higher end of the range applying to patients who have moderate to severe dementia. . The DICE approach is a collaborative process for managing behavioral symptoms in dementia, wherein the caregiver describes the behaviors, the provider investigates the etiology, the provider and caregiver create a treatment plan, and the provider evaluates the outcome of the interventions. We use this widely adopted approach as the framework for discussing recent advances in the management of agitation.
Here are five things to know about managing agitation in AD.
1. There is a new operational definition for agitation in dementia.
Agitation in dementia is a syndrome that encompasses specific behaviors across all dementia types. The 2023 operational definition of agitation in dementia by the International Psychogeriatric Association (IPA) includes three domains: excessive motor activity (including pacing, rocking, restlessness, and performing repetitious mannerisms), verbal aggression (including using profanity, screaming, and shouting), and physical aggression (including interpersonal aggression and mishandling or destruction of property). These behaviors must be persistent or recurrent for at least 2 weeks or represent a dramatic change from the person’s baseline behavior, must be associated with excessive distress or disability beyond what is caused by the cognitive impairment itself, and result in significant impairment in at least one of the three specified functional domains. Behavioral symptoms in dementia frequently co-occur, which affects treatment and prognosis. For instance, the risk for stroke associated with antipsychotic treatments appears to be higher in dementia-related psychosis without agitation than in agitation alone or in psychosis with agitation. Therefore, the use of a rating scale such as the Neuropsychiatric Inventory–Questionnaire (NPI-Q), which takes 5 minutes or less to administer, is recommended to identify and track behavioral symptoms and caregiver distress.
2. The etiology of agitation in dementia may be multifactorial.
It is important in every case to identify all underlying etiologies so that presumed causal and/or exacerbating factors are not inadvertently missed. Agitation may be a means of communicating distress owing to unmet needs or a patient-environment mismatch (function-focused approach) or may be a direct consequence of the dementia itself (behavioral-symptom approach). These approaches are not mutually exclusive. A patient can present with agitation as a direct consequence of dementia and inadequately treated pain concurrently.
The new IPA definition specifies several exclusion criteria for agitation in dementia, including underlying medical conditions, delirium, substance use, and suboptimal care conditions. It is especially crucial to accurately identify delirium because dementia is an independent risk factor for delirium, which in turn may accelerate the progression of cognitive and functional decline. Even subsyndromal delirium in older adults leads to a higher 3-year mortality rate that is comparable to that seen in delirium. Older adults with acute-onset agitation in the context of dementia should undergo a comprehensive assessment for delirium, as agitation may be the only indication of a serious underlying medical condition.
3. Nonpharmacologic interventions should be used whenever possible.
The wider adoption of nonpharmacologic interventions in clinical practice has been greatly limited by the heterogeneity in study protocols, including in selection of participants, in the types of dementias included, and in defining and applying the intervention strategies. Nevertheless, there is general consensus that individualized behavioral strategies that build on the patients’ interests and preserved abilities are more effective, at least in the short term. Patients best suited for these interventions are those with less cognitive decline, better communication skills, less impairment in activities of daily living, and higher responsiveness. A systematic review of systematic reviews found music therapy to be the most effective intervention for reducing agitation and aggression in dementia, along with behavioral management techniques when supervised by healthcare professionals. On the other hand, physical restraints are best avoided, as their use in hospitalized patients has been associated with longer stays, higher costs, lower odds of being discharged to home, and in long-term care patients with longer stays, with increased risk for medical complications and functional decline.
4. Antidepressants are not all equally safe or efficacious in managing agitation.
In a network meta-analysis that looked at the effects of several antidepressants on agitation in dementia, citalopram had just under 95% probability of efficacy and was the only antidepressant that was significantly more efficacious than placebo. In the multicenter CitAD trial, citalopram was efficacious and well tolerated for the treatment of agitation in AD, but the mean dose of citalopram used, 30 mg/d, was higher than the maximum dose of 20 mg/d recommended by the US Food and Drug Administration (FDA) in those aged 60 years or above. The optimal candidates for citalopram were those under the age of 85 with mild to moderate AD and mild to moderate nonpsychotic agitation, and it took up to 9 weeks for it to be fully effective. Due to the risk for dose-dependent QTc prolongation with citalopram, a baseline ECG must be done, and a second ECG is recommended if a clinical decision is made to exceed the recommended maximum daily dose. In the CitAD trial, 66% of patients in the citalopram arm received cholinesterase inhibitors concurrently while 44% received memantine, so these symptomatic treatments for AD should not be stopped solely for initiating a citalopram trial.
The antiagitation effect of citalopram may well be a class effect of all selective serotonin reuptake inhibitors (SSRIs), given that there is also evidence favoring the use of sertraline and escitalopram. The S-CitAD trial, the first large, randomized controlled study of escitalopram for the treatment of agitation in dementia, is expected to announce its top-line results sometime this year. However, not all antidepressant classes appear to be equally efficacious or safe. In the large, 12-week randomized placebo-controlled trial SYMBAD, mirtazapine was not only ineffective in treating nonpsychotic agitation in AD but was also associated with a higher mortality rate that just missed statistical significance. Trazodone is also often used for treating agitation, but there is insufficient evidence regarding efficacy and a high probability of adverse effects, even at low doses.
5. Antipsychotics may be effective drugs for treating severe dementia-related agitation.
The CATIE-AD study found that the small beneficial effects of antipsychotics for treating agitation and psychosis in AD were offset by their adverse effects and high discontinuation rates, and the FDA-imposed boxed warnings in 2005 and 2008 cautioned against the use of both first- and second-generation antipsychotics to manage dementia-related psychosis owing to an increased risk for death. Subsequently, the quest for safer and more effective alternatives culminated in the FDA approval of brexpiprazole in 2023 for the treatment of agitation in AD, but the black box warning was left in place. Three randomized controlled trials found brexpiprazole to be relatively safe, with statistically significant improvement in agitation. It was especially efficacious for severe agitation, but there is controversy about whether such improvement is clinically meaningful and whether brexpiprazole is truly superior to other antipsychotics for treating dementia-related agitation. As in the previously mentioned citalopram studies, most patients in the brexpiprazole studies received the drug as an add-on to memantine and/or a cholinesterase inhibitor, and it was proven effective over a period of up to 12 weeks across the three trials. Regarding other antipsychotics, aripiprazole and risperidone have been shown to be effective in treating agitation in patients with mixed dementia, but risperidone has also been associated with the highest risk for strokes (about 80% probability). Unfortunately, an unintended consequence of the boxed warnings on antipsychotics has been an increase in off-label substitution of psychotropic drugs with unproven efficacy and a questionable safety profile, such as valproic acid preparations, that have been linked to an increased short-term risk for accelerated brain volume loss and rapid cognitive decline, as well as a higher risk for mortality.
Lisa M. Wise, assistant professor, Psychiatry, at Oregon Health & Science University, and staff psychiatrist, Department of Psychiatry, Portland VA Medical Center, Portland, Oregon, and Vimal M. Aga, adjunct assistant professor, Department of Neurology, Oregon Health & Science University, and geriatric psychiatrist, Layton Aging and Alzheimer’s Disease Center, Portland, Oregon, have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Agitation is a neuropsychiatric symptom in patients with Alzheimer’s disease (AD), the most common form of dementia. The prevalence of this symptom is about 40%-65%, with the higher end of the range applying to patients who have moderate to severe dementia. . The DICE approach is a collaborative process for managing behavioral symptoms in dementia, wherein the caregiver describes the behaviors, the provider investigates the etiology, the provider and caregiver create a treatment plan, and the provider evaluates the outcome of the interventions. We use this widely adopted approach as the framework for discussing recent advances in the management of agitation.
Here are five things to know about managing agitation in AD.
1. There is a new operational definition for agitation in dementia.
Agitation in dementia is a syndrome that encompasses specific behaviors across all dementia types. The 2023 operational definition of agitation in dementia by the International Psychogeriatric Association (IPA) includes three domains: excessive motor activity (including pacing, rocking, restlessness, and performing repetitious mannerisms), verbal aggression (including using profanity, screaming, and shouting), and physical aggression (including interpersonal aggression and mishandling or destruction of property). These behaviors must be persistent or recurrent for at least 2 weeks or represent a dramatic change from the person’s baseline behavior, must be associated with excessive distress or disability beyond what is caused by the cognitive impairment itself, and result in significant impairment in at least one of the three specified functional domains. Behavioral symptoms in dementia frequently co-occur, which affects treatment and prognosis. For instance, the risk for stroke associated with antipsychotic treatments appears to be higher in dementia-related psychosis without agitation than in agitation alone or in psychosis with agitation. Therefore, the use of a rating scale such as the Neuropsychiatric Inventory–Questionnaire (NPI-Q), which takes 5 minutes or less to administer, is recommended to identify and track behavioral symptoms and caregiver distress.
2. The etiology of agitation in dementia may be multifactorial.
It is important in every case to identify all underlying etiologies so that presumed causal and/or exacerbating factors are not inadvertently missed. Agitation may be a means of communicating distress owing to unmet needs or a patient-environment mismatch (function-focused approach) or may be a direct consequence of the dementia itself (behavioral-symptom approach). These approaches are not mutually exclusive. A patient can present with agitation as a direct consequence of dementia and inadequately treated pain concurrently.
The new IPA definition specifies several exclusion criteria for agitation in dementia, including underlying medical conditions, delirium, substance use, and suboptimal care conditions. It is especially crucial to accurately identify delirium because dementia is an independent risk factor for delirium, which in turn may accelerate the progression of cognitive and functional decline. Even subsyndromal delirium in older adults leads to a higher 3-year mortality rate that is comparable to that seen in delirium. Older adults with acute-onset agitation in the context of dementia should undergo a comprehensive assessment for delirium, as agitation may be the only indication of a serious underlying medical condition.
3. Nonpharmacologic interventions should be used whenever possible.
The wider adoption of nonpharmacologic interventions in clinical practice has been greatly limited by the heterogeneity in study protocols, including in selection of participants, in the types of dementias included, and in defining and applying the intervention strategies. Nevertheless, there is general consensus that individualized behavioral strategies that build on the patients’ interests and preserved abilities are more effective, at least in the short term. Patients best suited for these interventions are those with less cognitive decline, better communication skills, less impairment in activities of daily living, and higher responsiveness. A systematic review of systematic reviews found music therapy to be the most effective intervention for reducing agitation and aggression in dementia, along with behavioral management techniques when supervised by healthcare professionals. On the other hand, physical restraints are best avoided, as their use in hospitalized patients has been associated with longer stays, higher costs, lower odds of being discharged to home, and in long-term care patients with longer stays, with increased risk for medical complications and functional decline.
4. Antidepressants are not all equally safe or efficacious in managing agitation.
In a network meta-analysis that looked at the effects of several antidepressants on agitation in dementia, citalopram had just under 95% probability of efficacy and was the only antidepressant that was significantly more efficacious than placebo. In the multicenter CitAD trial, citalopram was efficacious and well tolerated for the treatment of agitation in AD, but the mean dose of citalopram used, 30 mg/d, was higher than the maximum dose of 20 mg/d recommended by the US Food and Drug Administration (FDA) in those aged 60 years or above. The optimal candidates for citalopram were those under the age of 85 with mild to moderate AD and mild to moderate nonpsychotic agitation, and it took up to 9 weeks for it to be fully effective. Due to the risk for dose-dependent QTc prolongation with citalopram, a baseline ECG must be done, and a second ECG is recommended if a clinical decision is made to exceed the recommended maximum daily dose. In the CitAD trial, 66% of patients in the citalopram arm received cholinesterase inhibitors concurrently while 44% received memantine, so these symptomatic treatments for AD should not be stopped solely for initiating a citalopram trial.
The antiagitation effect of citalopram may well be a class effect of all selective serotonin reuptake inhibitors (SSRIs), given that there is also evidence favoring the use of sertraline and escitalopram. The S-CitAD trial, the first large, randomized controlled study of escitalopram for the treatment of agitation in dementia, is expected to announce its top-line results sometime this year. However, not all antidepressant classes appear to be equally efficacious or safe. In the large, 12-week randomized placebo-controlled trial SYMBAD, mirtazapine was not only ineffective in treating nonpsychotic agitation in AD but was also associated with a higher mortality rate that just missed statistical significance. Trazodone is also often used for treating agitation, but there is insufficient evidence regarding efficacy and a high probability of adverse effects, even at low doses.
5. Antipsychotics may be effective drugs for treating severe dementia-related agitation.
The CATIE-AD study found that the small beneficial effects of antipsychotics for treating agitation and psychosis in AD were offset by their adverse effects and high discontinuation rates, and the FDA-imposed boxed warnings in 2005 and 2008 cautioned against the use of both first- and second-generation antipsychotics to manage dementia-related psychosis owing to an increased risk for death. Subsequently, the quest for safer and more effective alternatives culminated in the FDA approval of brexpiprazole in 2023 for the treatment of agitation in AD, but the black box warning was left in place. Three randomized controlled trials found brexpiprazole to be relatively safe, with statistically significant improvement in agitation. It was especially efficacious for severe agitation, but there is controversy about whether such improvement is clinically meaningful and whether brexpiprazole is truly superior to other antipsychotics for treating dementia-related agitation. As in the previously mentioned citalopram studies, most patients in the brexpiprazole studies received the drug as an add-on to memantine and/or a cholinesterase inhibitor, and it was proven effective over a period of up to 12 weeks across the three trials. Regarding other antipsychotics, aripiprazole and risperidone have been shown to be effective in treating agitation in patients with mixed dementia, but risperidone has also been associated with the highest risk for strokes (about 80% probability). Unfortunately, an unintended consequence of the boxed warnings on antipsychotics has been an increase in off-label substitution of psychotropic drugs with unproven efficacy and a questionable safety profile, such as valproic acid preparations, that have been linked to an increased short-term risk for accelerated brain volume loss and rapid cognitive decline, as well as a higher risk for mortality.
Lisa M. Wise, assistant professor, Psychiatry, at Oregon Health & Science University, and staff psychiatrist, Department of Psychiatry, Portland VA Medical Center, Portland, Oregon, and Vimal M. Aga, adjunct assistant professor, Department of Neurology, Oregon Health & Science University, and geriatric psychiatrist, Layton Aging and Alzheimer’s Disease Center, Portland, Oregon, have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Agitation is a neuropsychiatric symptom in patients with Alzheimer’s disease (AD), the most common form of dementia. The prevalence of this symptom is about 40%-65%, with the higher end of the range applying to patients who have moderate to severe dementia. . The DICE approach is a collaborative process for managing behavioral symptoms in dementia, wherein the caregiver describes the behaviors, the provider investigates the etiology, the provider and caregiver create a treatment plan, and the provider evaluates the outcome of the interventions. We use this widely adopted approach as the framework for discussing recent advances in the management of agitation.
Here are five things to know about managing agitation in AD.
1. There is a new operational definition for agitation in dementia.
Agitation in dementia is a syndrome that encompasses specific behaviors across all dementia types. The 2023 operational definition of agitation in dementia by the International Psychogeriatric Association (IPA) includes three domains: excessive motor activity (including pacing, rocking, restlessness, and performing repetitious mannerisms), verbal aggression (including using profanity, screaming, and shouting), and physical aggression (including interpersonal aggression and mishandling or destruction of property). These behaviors must be persistent or recurrent for at least 2 weeks or represent a dramatic change from the person’s baseline behavior, must be associated with excessive distress or disability beyond what is caused by the cognitive impairment itself, and result in significant impairment in at least one of the three specified functional domains. Behavioral symptoms in dementia frequently co-occur, which affects treatment and prognosis. For instance, the risk for stroke associated with antipsychotic treatments appears to be higher in dementia-related psychosis without agitation than in agitation alone or in psychosis with agitation. Therefore, the use of a rating scale such as the Neuropsychiatric Inventory–Questionnaire (NPI-Q), which takes 5 minutes or less to administer, is recommended to identify and track behavioral symptoms and caregiver distress.
2. The etiology of agitation in dementia may be multifactorial.
It is important in every case to identify all underlying etiologies so that presumed causal and/or exacerbating factors are not inadvertently missed. Agitation may be a means of communicating distress owing to unmet needs or a patient-environment mismatch (function-focused approach) or may be a direct consequence of the dementia itself (behavioral-symptom approach). These approaches are not mutually exclusive. A patient can present with agitation as a direct consequence of dementia and inadequately treated pain concurrently.
The new IPA definition specifies several exclusion criteria for agitation in dementia, including underlying medical conditions, delirium, substance use, and suboptimal care conditions. It is especially crucial to accurately identify delirium because dementia is an independent risk factor for delirium, which in turn may accelerate the progression of cognitive and functional decline. Even subsyndromal delirium in older adults leads to a higher 3-year mortality rate that is comparable to that seen in delirium. Older adults with acute-onset agitation in the context of dementia should undergo a comprehensive assessment for delirium, as agitation may be the only indication of a serious underlying medical condition.
3. Nonpharmacologic interventions should be used whenever possible.
The wider adoption of nonpharmacologic interventions in clinical practice has been greatly limited by the heterogeneity in study protocols, including in selection of participants, in the types of dementias included, and in defining and applying the intervention strategies. Nevertheless, there is general consensus that individualized behavioral strategies that build on the patients’ interests and preserved abilities are more effective, at least in the short term. Patients best suited for these interventions are those with less cognitive decline, better communication skills, less impairment in activities of daily living, and higher responsiveness. A systematic review of systematic reviews found music therapy to be the most effective intervention for reducing agitation and aggression in dementia, along with behavioral management techniques when supervised by healthcare professionals. On the other hand, physical restraints are best avoided, as their use in hospitalized patients has been associated with longer stays, higher costs, lower odds of being discharged to home, and in long-term care patients with longer stays, with increased risk for medical complications and functional decline.
4. Antidepressants are not all equally safe or efficacious in managing agitation.
In a network meta-analysis that looked at the effects of several antidepressants on agitation in dementia, citalopram had just under 95% probability of efficacy and was the only antidepressant that was significantly more efficacious than placebo. In the multicenter CitAD trial, citalopram was efficacious and well tolerated for the treatment of agitation in AD, but the mean dose of citalopram used, 30 mg/d, was higher than the maximum dose of 20 mg/d recommended by the US Food and Drug Administration (FDA) in those aged 60 years or above. The optimal candidates for citalopram were those under the age of 85 with mild to moderate AD and mild to moderate nonpsychotic agitation, and it took up to 9 weeks for it to be fully effective. Due to the risk for dose-dependent QTc prolongation with citalopram, a baseline ECG must be done, and a second ECG is recommended if a clinical decision is made to exceed the recommended maximum daily dose. In the CitAD trial, 66% of patients in the citalopram arm received cholinesterase inhibitors concurrently while 44% received memantine, so these symptomatic treatments for AD should not be stopped solely for initiating a citalopram trial.
The antiagitation effect of citalopram may well be a class effect of all selective serotonin reuptake inhibitors (SSRIs), given that there is also evidence favoring the use of sertraline and escitalopram. The S-CitAD trial, the first large, randomized controlled study of escitalopram for the treatment of agitation in dementia, is expected to announce its top-line results sometime this year. However, not all antidepressant classes appear to be equally efficacious or safe. In the large, 12-week randomized placebo-controlled trial SYMBAD, mirtazapine was not only ineffective in treating nonpsychotic agitation in AD but was also associated with a higher mortality rate that just missed statistical significance. Trazodone is also often used for treating agitation, but there is insufficient evidence regarding efficacy and a high probability of adverse effects, even at low doses.
5. Antipsychotics may be effective drugs for treating severe dementia-related agitation.
The CATIE-AD study found that the small beneficial effects of antipsychotics for treating agitation and psychosis in AD were offset by their adverse effects and high discontinuation rates, and the FDA-imposed boxed warnings in 2005 and 2008 cautioned against the use of both first- and second-generation antipsychotics to manage dementia-related psychosis owing to an increased risk for death. Subsequently, the quest for safer and more effective alternatives culminated in the FDA approval of brexpiprazole in 2023 for the treatment of agitation in AD, but the black box warning was left in place. Three randomized controlled trials found brexpiprazole to be relatively safe, with statistically significant improvement in agitation. It was especially efficacious for severe agitation, but there is controversy about whether such improvement is clinically meaningful and whether brexpiprazole is truly superior to other antipsychotics for treating dementia-related agitation. As in the previously mentioned citalopram studies, most patients in the brexpiprazole studies received the drug as an add-on to memantine and/or a cholinesterase inhibitor, and it was proven effective over a period of up to 12 weeks across the three trials. Regarding other antipsychotics, aripiprazole and risperidone have been shown to be effective in treating agitation in patients with mixed dementia, but risperidone has also been associated with the highest risk for strokes (about 80% probability). Unfortunately, an unintended consequence of the boxed warnings on antipsychotics has been an increase in off-label substitution of psychotropic drugs with unproven efficacy and a questionable safety profile, such as valproic acid preparations, that have been linked to an increased short-term risk for accelerated brain volume loss and rapid cognitive decline, as well as a higher risk for mortality.
Lisa M. Wise, assistant professor, Psychiatry, at Oregon Health & Science University, and staff psychiatrist, Department of Psychiatry, Portland VA Medical Center, Portland, Oregon, and Vimal M. Aga, adjunct assistant professor, Department of Neurology, Oregon Health & Science University, and geriatric psychiatrist, Layton Aging and Alzheimer’s Disease Center, Portland, Oregon, have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Significant Benefit with Liver Transplantation in ACLF: CHANCE Study
MILAN —
To date, the results show that 3-month post–liver transplantation mortality rates in patients with ACLF grades 2 and 3 were only 9%, which is not significantly different than that of patients with decompensated cirrhosis, with a mortality of 7%.
“Treatment of ACLF is an unmet medical need,” said Rajiv Jalan, MD, professor of hepatology and honorary consultant in hepatology, University College London Hospitals, London, England.
These findings highlight “the inadequacy of current transplant allocation criteria for patients with ACLF 2 and 3,” which is leading to excess mortality on the wait list, he added.
Dr. Jalan presented the interim results at the European Association for the Study of the Liver (EASL) Congress 2024.
If confirmed in the full analysis, these results argue strongly for increasing access to liver transplantation and changing organ allocation for patients with ACLF 2 and 3, he said.
Organ Allocation Principally Based on MELD Scores
ACLF, which occurs in patients with cirrhosis and acutely decompensated liver disease admitted to hospital, carries a high, short-term risk for death. The risk for 28-day mortality for ACLF 2 and 3 is between 30% and 90% and characterized by multiorgan failure.
As seen in previous data, even patients on the transplant waiting list with a low Model for End-Stage Liver Disease (MELD) score have a risk for death between 20% and 30% if they are ACLF 2 and 3, Dr. Jalan said.
MELD scores do not consider the risk for death because of failure of extrahepatic organs, he added. Existing worldwide organ allocation systems are principally based on patient MELD scores or its variations; therefore, many patients die on the waiting list.
With this in mind, the CHANCE study aimed to compare 1-year graft and patient survival rates after liver transplantation in patients with ACLF 2 or 3 at the time of transplantation with patients with decompensated cirrhosis without ACLF and transplantation-free survival of patients with ACLF 2 or 3 not listed for liver transplantation.
The multicenter observational study comprised 66 liver transplant centers from 21 countries and over 500 investigators. Recruitment was closed after 1000 patients were enrolled.
Patients were aged 54-56 years, 31%-35% were women, 48%-70% had alcohol-related cirrhosis, and 19%-24% had metabolic dysfunction–associated steatohepatitis. MELD scores ranged from 25 to 36.
For the interim results, Dr. Jalan and colleagues assessed mortality on the waiting list and 3-month post–liver transplantation mortality.
Secondary endpoints included quality of life and cost of care.
Of the 823 patients in the study, they were grouped as follows: 376 patients with ACLF 2 or 3 listed for liver transplantation (group 1), 313 patients with ACLF 0 or 1 and MELD score > 20 listed for liver transplantation (group 2), and 134 patients with ACLF 2 or 3 not listed for liver transplantation (group 3).
Overall, patients in group 1 had very severe ACLF; 177 patients with ACLF 3 had three or more organ failures, Dr. Jalan noted.
“It is interesting to note that, in group 3, there is an overrepresentation of alcohol-related cirrhosis, and this might reflect a bias in transplantation,” he added.
Dr. Jalan highlighted geographical points of difference. Patients in the United States were younger, which could be important when interpreting results of post-transplantation outcomes. In Asia, the majority of the patients were men and primarily from India, where living donor transplantation is commonly performed. In Latin America, only 33% of study participants had alcohol-related cirrhosis in contrast to 67% of those in North America.
However, “comorbidities across the world were similar, and MELD scores were also similar,” Dr. Jalan said.
Death or Delisting
Between listing and transplantation, 28% of patients in group 1 either died or were delisted, compared with 16% of those in group 2. In group 3, 85% of patients who were not listed for transplantation in the first place died.
Similar to what has been seen in other studies, nearly 50% of patients with ACLF 3 but a MELD score < 25 on the wait list died or were delisted, Dr. Jalan pointed out, suggesting that these patients are disadvantaged under the current system of waiting list priority.
Geographically, deaths on the wait list were significantly higher in Latin America at 40% than in North America, Europe, and Asia at 20%, 18%, and 13%, respectively.
“This is likely due to low donation rates in Latin America,” Dr. Jalan said.
Turning to 3-month post-transplantation mortality, the rates in groups 1 and 2 were 9% and 7%, respectively.
“This demonstrates very nicely the clear benefit of transplant,” Dr. Jalan said. “The risk of death post transplant, even with ACLF 2 or 3, is not significantly different to those patients with decompensated cirrhosis.”
There was a slightly higher risk for death in patients with ACLF 3 than in those with ACLF 2 at 14% vs 7%, but “the risk of death in these patients if they don’t have transportation is 70%-80%,” he said.
Looking at 3-month post-transplantation mortality by continent, Dr. Jalan highlighted that Latin America showed 16% risk, compared with Asia, Europe, and North America that showed 12%, 7%, and 3% risk, respectively.
“This is probably multifactorial and likely to be influenced by time on the waiting list, quality of organs available, and patient demographics, among other factors,” Dr. Jalan said. When very sick people undergo transplantation, “there is a higher risk of death.”
The patients in this study have waited a long time, “which worsens their situation,” said Dr. Jalan, reinforcing his argument for changing the international organ allocation system to allow earlier access for these patients.
‘The Landscape of Organ Allocation Is Extremely Complex’
Comoderator Ana Lleo, MD, PhD, full professor of internal medicine and hepatology, Humanitas University, Milan, Italy, commented that “the number of patients included in this international study is significant,” and that the issue of mortality on the wait list is of great clinical interest.
“The landscape of organ allocation is extremely complex,” she added.
The system for liver transplantation considers a large number of clinical conditions with very diverse benefit profiles, she explained.
“While we would like to offer liver transplantation for all patients with any range of benefit, the current donations are not sufficient to cover the request,” Dr. Lleo said. “Therefore, prioritization remains key.”
The findings do illustrate the inadequacy of current transplantation allocation criteria for patients with ACLF 2 and 3, said Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College Hospital, London, England, who is also serving as vice-secretary of the EASL Governing Board.
However, “this must be balanced by the recognition that the global donor pool of organs available is a finite resource,” she said, echoing Dr. Lleo’s comments.
This calls for wider ethical discussions to avoid disadvantaging more stable, often younger patients with cirrhosis who are listed for transplantation, she added.
Dr. Jalan declared he is the inventor of Ornithine Phenylacetate, licensed by UCL to Mallinckrodt Pharma; a speaker and grant reviewer for Grifols Research Collaboration: Yaqrit; and the founder of Yaqrit, Hepyx, CyberLiver, and Gigabiome. Dr. Lleo declared that she does not have any conflicts relevant to this work but received lecture fees from Gilead, Advanz Pharma, Alfasigma, GSK, Incyte, Gore, AstraZeneca, and Ipsen and consulted for Advanz Pharma, AstraZeneca, Ipsen, GSK, and Dr Falk. Dr. Shawcross declared advisory board/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
MILAN —
To date, the results show that 3-month post–liver transplantation mortality rates in patients with ACLF grades 2 and 3 were only 9%, which is not significantly different than that of patients with decompensated cirrhosis, with a mortality of 7%.
“Treatment of ACLF is an unmet medical need,” said Rajiv Jalan, MD, professor of hepatology and honorary consultant in hepatology, University College London Hospitals, London, England.
These findings highlight “the inadequacy of current transplant allocation criteria for patients with ACLF 2 and 3,” which is leading to excess mortality on the wait list, he added.
Dr. Jalan presented the interim results at the European Association for the Study of the Liver (EASL) Congress 2024.
If confirmed in the full analysis, these results argue strongly for increasing access to liver transplantation and changing organ allocation for patients with ACLF 2 and 3, he said.
Organ Allocation Principally Based on MELD Scores
ACLF, which occurs in patients with cirrhosis and acutely decompensated liver disease admitted to hospital, carries a high, short-term risk for death. The risk for 28-day mortality for ACLF 2 and 3 is between 30% and 90% and characterized by multiorgan failure.
As seen in previous data, even patients on the transplant waiting list with a low Model for End-Stage Liver Disease (MELD) score have a risk for death between 20% and 30% if they are ACLF 2 and 3, Dr. Jalan said.
MELD scores do not consider the risk for death because of failure of extrahepatic organs, he added. Existing worldwide organ allocation systems are principally based on patient MELD scores or its variations; therefore, many patients die on the waiting list.
With this in mind, the CHANCE study aimed to compare 1-year graft and patient survival rates after liver transplantation in patients with ACLF 2 or 3 at the time of transplantation with patients with decompensated cirrhosis without ACLF and transplantation-free survival of patients with ACLF 2 or 3 not listed for liver transplantation.
The multicenter observational study comprised 66 liver transplant centers from 21 countries and over 500 investigators. Recruitment was closed after 1000 patients were enrolled.
Patients were aged 54-56 years, 31%-35% were women, 48%-70% had alcohol-related cirrhosis, and 19%-24% had metabolic dysfunction–associated steatohepatitis. MELD scores ranged from 25 to 36.
For the interim results, Dr. Jalan and colleagues assessed mortality on the waiting list and 3-month post–liver transplantation mortality.
Secondary endpoints included quality of life and cost of care.
Of the 823 patients in the study, they were grouped as follows: 376 patients with ACLF 2 or 3 listed for liver transplantation (group 1), 313 patients with ACLF 0 or 1 and MELD score > 20 listed for liver transplantation (group 2), and 134 patients with ACLF 2 or 3 not listed for liver transplantation (group 3).
Overall, patients in group 1 had very severe ACLF; 177 patients with ACLF 3 had three or more organ failures, Dr. Jalan noted.
“It is interesting to note that, in group 3, there is an overrepresentation of alcohol-related cirrhosis, and this might reflect a bias in transplantation,” he added.
Dr. Jalan highlighted geographical points of difference. Patients in the United States were younger, which could be important when interpreting results of post-transplantation outcomes. In Asia, the majority of the patients were men and primarily from India, where living donor transplantation is commonly performed. In Latin America, only 33% of study participants had alcohol-related cirrhosis in contrast to 67% of those in North America.
However, “comorbidities across the world were similar, and MELD scores were also similar,” Dr. Jalan said.
Death or Delisting
Between listing and transplantation, 28% of patients in group 1 either died or were delisted, compared with 16% of those in group 2. In group 3, 85% of patients who were not listed for transplantation in the first place died.
Similar to what has been seen in other studies, nearly 50% of patients with ACLF 3 but a MELD score < 25 on the wait list died or were delisted, Dr. Jalan pointed out, suggesting that these patients are disadvantaged under the current system of waiting list priority.
Geographically, deaths on the wait list were significantly higher in Latin America at 40% than in North America, Europe, and Asia at 20%, 18%, and 13%, respectively.
“This is likely due to low donation rates in Latin America,” Dr. Jalan said.
Turning to 3-month post-transplantation mortality, the rates in groups 1 and 2 were 9% and 7%, respectively.
“This demonstrates very nicely the clear benefit of transplant,” Dr. Jalan said. “The risk of death post transplant, even with ACLF 2 or 3, is not significantly different to those patients with decompensated cirrhosis.”
There was a slightly higher risk for death in patients with ACLF 3 than in those with ACLF 2 at 14% vs 7%, but “the risk of death in these patients if they don’t have transportation is 70%-80%,” he said.
Looking at 3-month post-transplantation mortality by continent, Dr. Jalan highlighted that Latin America showed 16% risk, compared with Asia, Europe, and North America that showed 12%, 7%, and 3% risk, respectively.
“This is probably multifactorial and likely to be influenced by time on the waiting list, quality of organs available, and patient demographics, among other factors,” Dr. Jalan said. When very sick people undergo transplantation, “there is a higher risk of death.”
The patients in this study have waited a long time, “which worsens their situation,” said Dr. Jalan, reinforcing his argument for changing the international organ allocation system to allow earlier access for these patients.
‘The Landscape of Organ Allocation Is Extremely Complex’
Comoderator Ana Lleo, MD, PhD, full professor of internal medicine and hepatology, Humanitas University, Milan, Italy, commented that “the number of patients included in this international study is significant,” and that the issue of mortality on the wait list is of great clinical interest.
“The landscape of organ allocation is extremely complex,” she added.
The system for liver transplantation considers a large number of clinical conditions with very diverse benefit profiles, she explained.
“While we would like to offer liver transplantation for all patients with any range of benefit, the current donations are not sufficient to cover the request,” Dr. Lleo said. “Therefore, prioritization remains key.”
The findings do illustrate the inadequacy of current transplantation allocation criteria for patients with ACLF 2 and 3, said Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College Hospital, London, England, who is also serving as vice-secretary of the EASL Governing Board.
However, “this must be balanced by the recognition that the global donor pool of organs available is a finite resource,” she said, echoing Dr. Lleo’s comments.
This calls for wider ethical discussions to avoid disadvantaging more stable, often younger patients with cirrhosis who are listed for transplantation, she added.
Dr. Jalan declared he is the inventor of Ornithine Phenylacetate, licensed by UCL to Mallinckrodt Pharma; a speaker and grant reviewer for Grifols Research Collaboration: Yaqrit; and the founder of Yaqrit, Hepyx, CyberLiver, and Gigabiome. Dr. Lleo declared that she does not have any conflicts relevant to this work but received lecture fees from Gilead, Advanz Pharma, Alfasigma, GSK, Incyte, Gore, AstraZeneca, and Ipsen and consulted for Advanz Pharma, AstraZeneca, Ipsen, GSK, and Dr Falk. Dr. Shawcross declared advisory board/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
MILAN —
To date, the results show that 3-month post–liver transplantation mortality rates in patients with ACLF grades 2 and 3 were only 9%, which is not significantly different than that of patients with decompensated cirrhosis, with a mortality of 7%.
“Treatment of ACLF is an unmet medical need,” said Rajiv Jalan, MD, professor of hepatology and honorary consultant in hepatology, University College London Hospitals, London, England.
These findings highlight “the inadequacy of current transplant allocation criteria for patients with ACLF 2 and 3,” which is leading to excess mortality on the wait list, he added.
Dr. Jalan presented the interim results at the European Association for the Study of the Liver (EASL) Congress 2024.
If confirmed in the full analysis, these results argue strongly for increasing access to liver transplantation and changing organ allocation for patients with ACLF 2 and 3, he said.
Organ Allocation Principally Based on MELD Scores
ACLF, which occurs in patients with cirrhosis and acutely decompensated liver disease admitted to hospital, carries a high, short-term risk for death. The risk for 28-day mortality for ACLF 2 and 3 is between 30% and 90% and characterized by multiorgan failure.
As seen in previous data, even patients on the transplant waiting list with a low Model for End-Stage Liver Disease (MELD) score have a risk for death between 20% and 30% if they are ACLF 2 and 3, Dr. Jalan said.
MELD scores do not consider the risk for death because of failure of extrahepatic organs, he added. Existing worldwide organ allocation systems are principally based on patient MELD scores or its variations; therefore, many patients die on the waiting list.
With this in mind, the CHANCE study aimed to compare 1-year graft and patient survival rates after liver transplantation in patients with ACLF 2 or 3 at the time of transplantation with patients with decompensated cirrhosis without ACLF and transplantation-free survival of patients with ACLF 2 or 3 not listed for liver transplantation.
The multicenter observational study comprised 66 liver transplant centers from 21 countries and over 500 investigators. Recruitment was closed after 1000 patients were enrolled.
Patients were aged 54-56 years, 31%-35% were women, 48%-70% had alcohol-related cirrhosis, and 19%-24% had metabolic dysfunction–associated steatohepatitis. MELD scores ranged from 25 to 36.
For the interim results, Dr. Jalan and colleagues assessed mortality on the waiting list and 3-month post–liver transplantation mortality.
Secondary endpoints included quality of life and cost of care.
Of the 823 patients in the study, they were grouped as follows: 376 patients with ACLF 2 or 3 listed for liver transplantation (group 1), 313 patients with ACLF 0 or 1 and MELD score > 20 listed for liver transplantation (group 2), and 134 patients with ACLF 2 or 3 not listed for liver transplantation (group 3).
Overall, patients in group 1 had very severe ACLF; 177 patients with ACLF 3 had three or more organ failures, Dr. Jalan noted.
“It is interesting to note that, in group 3, there is an overrepresentation of alcohol-related cirrhosis, and this might reflect a bias in transplantation,” he added.
Dr. Jalan highlighted geographical points of difference. Patients in the United States were younger, which could be important when interpreting results of post-transplantation outcomes. In Asia, the majority of the patients were men and primarily from India, where living donor transplantation is commonly performed. In Latin America, only 33% of study participants had alcohol-related cirrhosis in contrast to 67% of those in North America.
However, “comorbidities across the world were similar, and MELD scores were also similar,” Dr. Jalan said.
Death or Delisting
Between listing and transplantation, 28% of patients in group 1 either died or were delisted, compared with 16% of those in group 2. In group 3, 85% of patients who were not listed for transplantation in the first place died.
Similar to what has been seen in other studies, nearly 50% of patients with ACLF 3 but a MELD score < 25 on the wait list died or were delisted, Dr. Jalan pointed out, suggesting that these patients are disadvantaged under the current system of waiting list priority.
Geographically, deaths on the wait list were significantly higher in Latin America at 40% than in North America, Europe, and Asia at 20%, 18%, and 13%, respectively.
“This is likely due to low donation rates in Latin America,” Dr. Jalan said.
Turning to 3-month post-transplantation mortality, the rates in groups 1 and 2 were 9% and 7%, respectively.
“This demonstrates very nicely the clear benefit of transplant,” Dr. Jalan said. “The risk of death post transplant, even with ACLF 2 or 3, is not significantly different to those patients with decompensated cirrhosis.”
There was a slightly higher risk for death in patients with ACLF 3 than in those with ACLF 2 at 14% vs 7%, but “the risk of death in these patients if they don’t have transportation is 70%-80%,” he said.
Looking at 3-month post-transplantation mortality by continent, Dr. Jalan highlighted that Latin America showed 16% risk, compared with Asia, Europe, and North America that showed 12%, 7%, and 3% risk, respectively.
“This is probably multifactorial and likely to be influenced by time on the waiting list, quality of organs available, and patient demographics, among other factors,” Dr. Jalan said. When very sick people undergo transplantation, “there is a higher risk of death.”
The patients in this study have waited a long time, “which worsens their situation,” said Dr. Jalan, reinforcing his argument for changing the international organ allocation system to allow earlier access for these patients.
‘The Landscape of Organ Allocation Is Extremely Complex’
Comoderator Ana Lleo, MD, PhD, full professor of internal medicine and hepatology, Humanitas University, Milan, Italy, commented that “the number of patients included in this international study is significant,” and that the issue of mortality on the wait list is of great clinical interest.
“The landscape of organ allocation is extremely complex,” she added.
The system for liver transplantation considers a large number of clinical conditions with very diverse benefit profiles, she explained.
“While we would like to offer liver transplantation for all patients with any range of benefit, the current donations are not sufficient to cover the request,” Dr. Lleo said. “Therefore, prioritization remains key.”
The findings do illustrate the inadequacy of current transplantation allocation criteria for patients with ACLF 2 and 3, said Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College Hospital, London, England, who is also serving as vice-secretary of the EASL Governing Board.
However, “this must be balanced by the recognition that the global donor pool of organs available is a finite resource,” she said, echoing Dr. Lleo’s comments.
This calls for wider ethical discussions to avoid disadvantaging more stable, often younger patients with cirrhosis who are listed for transplantation, she added.
Dr. Jalan declared he is the inventor of Ornithine Phenylacetate, licensed by UCL to Mallinckrodt Pharma; a speaker and grant reviewer for Grifols Research Collaboration: Yaqrit; and the founder of Yaqrit, Hepyx, CyberLiver, and Gigabiome. Dr. Lleo declared that she does not have any conflicts relevant to this work but received lecture fees from Gilead, Advanz Pharma, Alfasigma, GSK, Incyte, Gore, AstraZeneca, and Ipsen and consulted for Advanz Pharma, AstraZeneca, Ipsen, GSK, and Dr Falk. Dr. Shawcross declared advisory board/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
FROM EASL 2024
‘Dramatic’ Phase 2 Results for Survodutide in MASH, Fibrosis
MILAN — , according to phase 2 results presented here at the European Association for the Study of the Liver (EASL) Congress 2024.
The data were simultaneously published in The New England Journal of Medicine .
The primary endpoint data, reported earlier this year in a press release, showed that up to 83% of participants on survodutide showed a statistically significant improvement in MASH compared with those on placebo (18.2%) based on paired biopsy results.
In addition, 75% of patients treated with survodutide experienced resolution of MASH with no worsening of fibrosis compared with 15% of patients on placebo, and in patients with F2/F3 fibrosis, 64.5% achieved improvement in fibrosis without worsening of MASH, reported Arun J. Sanyal, MD, principal study investigator and director of the Virginia Commonwealth University (VCU) Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, VCU School of Medicine, Richmond, Virginia.
What’s so amazing is that this “exceptional improvement” is after 48 weeks of therapy with a class of molecule that is already known to also have cardiometabolic benefits, Dr. Sanyal said in an interview.
“At the highest dose of survodutide [6.0 mg], two thirds of patients in whom we have biopsy data, at both the beginning and the end, actually showed fibrosis regression within 48 weeks,” he said. “This is pretty dramatic.”
Efficacy and Safety of Survodutide
A total of 293 participants with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injections of survodutide 2.4 mg (n = 73), 4.8 mg (n = 72), or 6.0 mg (n = 74) or placebo (n = 74).
Around half of study participants were women, with mean age around 50 years and a body mass index around 35 kg/m2. Overall, 26%-30% had type 2 diabetes, 24%-36% had F2 fibrosis, and 23%-30% had F3 fibrosis. The total Nonalcoholic Fatty Liver Disease Activity Score was 5.2.
After completing a 24-week rapid-dose-escalation phase, participants followed a 24-week maintenance phase. Histologic improvement (reduction) in MASH without worsening of fibrosis after 48 weeks of treatment comprised the primary endpoint, whereas a reduction in liver fat content by at least 30% and biopsy-assessed reduction in fibrosis by at least one stage were among the secondary endpoints.
The main analyses of the trial were based on two treatment sets: Actual treatment (the actual dose received at the start of the maintenance phase; per protocol) and planned treatment (the maintenance dose assigned to participants at randomization). Dr. Sanyal mainly reported results based on actual treatment, which were used for the primary analysis.
The overall primary endpoint data, including nonresponders, showed a 47% improvement in MASH in the 2.4-mg treatment group, 62% in the 4.8 mg group, and 43% in the 6.0-mg group compared with 13.5% in the placebo group (P < .001).
In addition, 50% of patients on 2.4- and 6-mg doses experienced a statistically significant improvement in fibrosis (F1-F3) without worsening of MASH. In patients with F2/F3 fibrosis, 64.5% of participants in the 6-mg survodutide group showed improvement vs 25.9% in the placebo group.
Reduction in liver fat by at least 30% was achieved by up to 87% in the 6-mg group according to MRI-estimated proton density fat fraction; when nonresponders were included, the percentage was 76.9% of the 6-mg group. Other outcomes included weight loss and reductions in A1c.
The results did not differ markedly between doses, which “is really exciting news,” Dr. Sanyal said.
Patients who are intolerant of the highest dose can switch to a lower dose without a big loss of efficacy, he said, adding that even the low dose was sufficient to get near maximal glucagon effect.
Adverse events were similar between survodutide and placebo, except for gastrointestinal events, including nausea, diarrhea, and vomiting. The occurrence of serious adverse events also was similar between survodutide and placebo.
Discontinuation due to adverse events was 20% across all the survodutide groups (with 16% due to gastrointestinal events) vs 3% in the placebo group.
Dual Agonist vs Monoagonist Therapy
The dual agonist approach may confer clinical advantages over GLP-1 receptor monoagonist pharmacotherapies for MASH.
“GLP has no receptors in the liver, so all its effects are mediated outside the liver, particularly for weight loss and improvement in metabolic status, increase in insulin secretion and sensitivity, and overall systemic glycemia,” Dr. Sanyal explained.
“People with established fibrosis take longer to respond in terms of downstream liver scarring with extrahepatic changes alone,” he added.
With “glucagon directly targeting the liver, we believe this reduces oxidative stress and possibly stimulates FGF-21 secretion [liver-derived factor that regulates lipid and glucose metabolism] in the liver, so there are likely multiple mechanisms driving the antifibrogenic benefits,” Dr. Sanyal said.
In comparison, the study authors highlighted that data on the GLP-1 receptor monoagonist semaglutide suggest a significantly higher proportion of patients on semaglutide achieve MASH resolution than those on placebo but that it does not result in “a significantly higher percentage of patients with improvement in fibrosis stage.
“It might be that it takes longer to get an effect in the liver with semaglutide,” Dr. Sanyal said.
By year-end, we’ll know how the GLP-1 alone approach (eg, semaglutide) and the dual agonist approach work, and we’ll eventually have data on triple agonists, Dr. Sanyal added.
The Burden of Liver Disease
Comoderator Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College, London, England, remarked on the importance of new drugs, including survodutide, in reducing the burden of steatotic liver disease.
Approximately one third of the world’s population and between 7% and 9% of children have steatotic liver disease, she noted. The buildup of fat causes inflammation and scarring of the liver, which may then progress to liver cirrhosis and primary liver cancers.
Survodutide offers much hope “as a drug that will reduce both liver inflammation and scarring, while also providing the benefit of improved diabetic control,” Dr. Shawcross said.
Reflecting on the dual agonism, she said that both the glucagon and GLP-1 receptors are critical to controlling metabolic functions.
Survodutide is currently being investigated in five phase 3 studies for people living with overweight and obesity, both of which are associated with MASH. There is also a trial looking at people with overweight/obesity with confirmed or presumed diagnosis of MASH, according to a company press release.
Dr. Sanyal reported grants, consultancy fees, and speaker fees from a wide range of companies working in the field of liver medicine. Dr. Shawcross reported no conflicts in relation to this drug and advisory board membership/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
MILAN — , according to phase 2 results presented here at the European Association for the Study of the Liver (EASL) Congress 2024.
The data were simultaneously published in The New England Journal of Medicine .
The primary endpoint data, reported earlier this year in a press release, showed that up to 83% of participants on survodutide showed a statistically significant improvement in MASH compared with those on placebo (18.2%) based on paired biopsy results.
In addition, 75% of patients treated with survodutide experienced resolution of MASH with no worsening of fibrosis compared with 15% of patients on placebo, and in patients with F2/F3 fibrosis, 64.5% achieved improvement in fibrosis without worsening of MASH, reported Arun J. Sanyal, MD, principal study investigator and director of the Virginia Commonwealth University (VCU) Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, VCU School of Medicine, Richmond, Virginia.
What’s so amazing is that this “exceptional improvement” is after 48 weeks of therapy with a class of molecule that is already known to also have cardiometabolic benefits, Dr. Sanyal said in an interview.
“At the highest dose of survodutide [6.0 mg], two thirds of patients in whom we have biopsy data, at both the beginning and the end, actually showed fibrosis regression within 48 weeks,” he said. “This is pretty dramatic.”
Efficacy and Safety of Survodutide
A total of 293 participants with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injections of survodutide 2.4 mg (n = 73), 4.8 mg (n = 72), or 6.0 mg (n = 74) or placebo (n = 74).
Around half of study participants were women, with mean age around 50 years and a body mass index around 35 kg/m2. Overall, 26%-30% had type 2 diabetes, 24%-36% had F2 fibrosis, and 23%-30% had F3 fibrosis. The total Nonalcoholic Fatty Liver Disease Activity Score was 5.2.
After completing a 24-week rapid-dose-escalation phase, participants followed a 24-week maintenance phase. Histologic improvement (reduction) in MASH without worsening of fibrosis after 48 weeks of treatment comprised the primary endpoint, whereas a reduction in liver fat content by at least 30% and biopsy-assessed reduction in fibrosis by at least one stage were among the secondary endpoints.
The main analyses of the trial were based on two treatment sets: Actual treatment (the actual dose received at the start of the maintenance phase; per protocol) and planned treatment (the maintenance dose assigned to participants at randomization). Dr. Sanyal mainly reported results based on actual treatment, which were used for the primary analysis.
The overall primary endpoint data, including nonresponders, showed a 47% improvement in MASH in the 2.4-mg treatment group, 62% in the 4.8 mg group, and 43% in the 6.0-mg group compared with 13.5% in the placebo group (P < .001).
In addition, 50% of patients on 2.4- and 6-mg doses experienced a statistically significant improvement in fibrosis (F1-F3) without worsening of MASH. In patients with F2/F3 fibrosis, 64.5% of participants in the 6-mg survodutide group showed improvement vs 25.9% in the placebo group.
Reduction in liver fat by at least 30% was achieved by up to 87% in the 6-mg group according to MRI-estimated proton density fat fraction; when nonresponders were included, the percentage was 76.9% of the 6-mg group. Other outcomes included weight loss and reductions in A1c.
The results did not differ markedly between doses, which “is really exciting news,” Dr. Sanyal said.
Patients who are intolerant of the highest dose can switch to a lower dose without a big loss of efficacy, he said, adding that even the low dose was sufficient to get near maximal glucagon effect.
Adverse events were similar between survodutide and placebo, except for gastrointestinal events, including nausea, diarrhea, and vomiting. The occurrence of serious adverse events also was similar between survodutide and placebo.
Discontinuation due to adverse events was 20% across all the survodutide groups (with 16% due to gastrointestinal events) vs 3% in the placebo group.
Dual Agonist vs Monoagonist Therapy
The dual agonist approach may confer clinical advantages over GLP-1 receptor monoagonist pharmacotherapies for MASH.
“GLP has no receptors in the liver, so all its effects are mediated outside the liver, particularly for weight loss and improvement in metabolic status, increase in insulin secretion and sensitivity, and overall systemic glycemia,” Dr. Sanyal explained.
“People with established fibrosis take longer to respond in terms of downstream liver scarring with extrahepatic changes alone,” he added.
With “glucagon directly targeting the liver, we believe this reduces oxidative stress and possibly stimulates FGF-21 secretion [liver-derived factor that regulates lipid and glucose metabolism] in the liver, so there are likely multiple mechanisms driving the antifibrogenic benefits,” Dr. Sanyal said.
In comparison, the study authors highlighted that data on the GLP-1 receptor monoagonist semaglutide suggest a significantly higher proportion of patients on semaglutide achieve MASH resolution than those on placebo but that it does not result in “a significantly higher percentage of patients with improvement in fibrosis stage.
“It might be that it takes longer to get an effect in the liver with semaglutide,” Dr. Sanyal said.
By year-end, we’ll know how the GLP-1 alone approach (eg, semaglutide) and the dual agonist approach work, and we’ll eventually have data on triple agonists, Dr. Sanyal added.
The Burden of Liver Disease
Comoderator Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College, London, England, remarked on the importance of new drugs, including survodutide, in reducing the burden of steatotic liver disease.
Approximately one third of the world’s population and between 7% and 9% of children have steatotic liver disease, she noted. The buildup of fat causes inflammation and scarring of the liver, which may then progress to liver cirrhosis and primary liver cancers.
Survodutide offers much hope “as a drug that will reduce both liver inflammation and scarring, while also providing the benefit of improved diabetic control,” Dr. Shawcross said.
Reflecting on the dual agonism, she said that both the glucagon and GLP-1 receptors are critical to controlling metabolic functions.
Survodutide is currently being investigated in five phase 3 studies for people living with overweight and obesity, both of which are associated with MASH. There is also a trial looking at people with overweight/obesity with confirmed or presumed diagnosis of MASH, according to a company press release.
Dr. Sanyal reported grants, consultancy fees, and speaker fees from a wide range of companies working in the field of liver medicine. Dr. Shawcross reported no conflicts in relation to this drug and advisory board membership/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
MILAN — , according to phase 2 results presented here at the European Association for the Study of the Liver (EASL) Congress 2024.
The data were simultaneously published in The New England Journal of Medicine .
The primary endpoint data, reported earlier this year in a press release, showed that up to 83% of participants on survodutide showed a statistically significant improvement in MASH compared with those on placebo (18.2%) based on paired biopsy results.
In addition, 75% of patients treated with survodutide experienced resolution of MASH with no worsening of fibrosis compared with 15% of patients on placebo, and in patients with F2/F3 fibrosis, 64.5% achieved improvement in fibrosis without worsening of MASH, reported Arun J. Sanyal, MD, principal study investigator and director of the Virginia Commonwealth University (VCU) Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, VCU School of Medicine, Richmond, Virginia.
What’s so amazing is that this “exceptional improvement” is after 48 weeks of therapy with a class of molecule that is already known to also have cardiometabolic benefits, Dr. Sanyal said in an interview.
“At the highest dose of survodutide [6.0 mg], two thirds of patients in whom we have biopsy data, at both the beginning and the end, actually showed fibrosis regression within 48 weeks,” he said. “This is pretty dramatic.”
Efficacy and Safety of Survodutide
A total of 293 participants with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injections of survodutide 2.4 mg (n = 73), 4.8 mg (n = 72), or 6.0 mg (n = 74) or placebo (n = 74).
Around half of study participants were women, with mean age around 50 years and a body mass index around 35 kg/m2. Overall, 26%-30% had type 2 diabetes, 24%-36% had F2 fibrosis, and 23%-30% had F3 fibrosis. The total Nonalcoholic Fatty Liver Disease Activity Score was 5.2.
After completing a 24-week rapid-dose-escalation phase, participants followed a 24-week maintenance phase. Histologic improvement (reduction) in MASH without worsening of fibrosis after 48 weeks of treatment comprised the primary endpoint, whereas a reduction in liver fat content by at least 30% and biopsy-assessed reduction in fibrosis by at least one stage were among the secondary endpoints.
The main analyses of the trial were based on two treatment sets: Actual treatment (the actual dose received at the start of the maintenance phase; per protocol) and planned treatment (the maintenance dose assigned to participants at randomization). Dr. Sanyal mainly reported results based on actual treatment, which were used for the primary analysis.
The overall primary endpoint data, including nonresponders, showed a 47% improvement in MASH in the 2.4-mg treatment group, 62% in the 4.8 mg group, and 43% in the 6.0-mg group compared with 13.5% in the placebo group (P < .001).
In addition, 50% of patients on 2.4- and 6-mg doses experienced a statistically significant improvement in fibrosis (F1-F3) without worsening of MASH. In patients with F2/F3 fibrosis, 64.5% of participants in the 6-mg survodutide group showed improvement vs 25.9% in the placebo group.
Reduction in liver fat by at least 30% was achieved by up to 87% in the 6-mg group according to MRI-estimated proton density fat fraction; when nonresponders were included, the percentage was 76.9% of the 6-mg group. Other outcomes included weight loss and reductions in A1c.
The results did not differ markedly between doses, which “is really exciting news,” Dr. Sanyal said.
Patients who are intolerant of the highest dose can switch to a lower dose without a big loss of efficacy, he said, adding that even the low dose was sufficient to get near maximal glucagon effect.
Adverse events were similar between survodutide and placebo, except for gastrointestinal events, including nausea, diarrhea, and vomiting. The occurrence of serious adverse events also was similar between survodutide and placebo.
Discontinuation due to adverse events was 20% across all the survodutide groups (with 16% due to gastrointestinal events) vs 3% in the placebo group.
Dual Agonist vs Monoagonist Therapy
The dual agonist approach may confer clinical advantages over GLP-1 receptor monoagonist pharmacotherapies for MASH.
“GLP has no receptors in the liver, so all its effects are mediated outside the liver, particularly for weight loss and improvement in metabolic status, increase in insulin secretion and sensitivity, and overall systemic glycemia,” Dr. Sanyal explained.
“People with established fibrosis take longer to respond in terms of downstream liver scarring with extrahepatic changes alone,” he added.
With “glucagon directly targeting the liver, we believe this reduces oxidative stress and possibly stimulates FGF-21 secretion [liver-derived factor that regulates lipid and glucose metabolism] in the liver, so there are likely multiple mechanisms driving the antifibrogenic benefits,” Dr. Sanyal said.
In comparison, the study authors highlighted that data on the GLP-1 receptor monoagonist semaglutide suggest a significantly higher proportion of patients on semaglutide achieve MASH resolution than those on placebo but that it does not result in “a significantly higher percentage of patients with improvement in fibrosis stage.
“It might be that it takes longer to get an effect in the liver with semaglutide,” Dr. Sanyal said.
By year-end, we’ll know how the GLP-1 alone approach (eg, semaglutide) and the dual agonist approach work, and we’ll eventually have data on triple agonists, Dr. Sanyal added.
The Burden of Liver Disease
Comoderator Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College, London, England, remarked on the importance of new drugs, including survodutide, in reducing the burden of steatotic liver disease.
Approximately one third of the world’s population and between 7% and 9% of children have steatotic liver disease, she noted. The buildup of fat causes inflammation and scarring of the liver, which may then progress to liver cirrhosis and primary liver cancers.
Survodutide offers much hope “as a drug that will reduce both liver inflammation and scarring, while also providing the benefit of improved diabetic control,” Dr. Shawcross said.
Reflecting on the dual agonism, she said that both the glucagon and GLP-1 receptors are critical to controlling metabolic functions.
Survodutide is currently being investigated in five phase 3 studies for people living with overweight and obesity, both of which are associated with MASH. There is also a trial looking at people with overweight/obesity with confirmed or presumed diagnosis of MASH, according to a company press release.
Dr. Sanyal reported grants, consultancy fees, and speaker fees from a wide range of companies working in the field of liver medicine. Dr. Shawcross reported no conflicts in relation to this drug and advisory board membership/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
FROM EASL 2024
Weakness on one side of the body
FHM is a rare phenotype of migraine with aura with a characteristic presentation of motor aura. Motor aura presents as unilateral muscle weakness that tends to be felt first in the hands or arm and may spread to the face. To date, three distinct types have been identified by mutations in one of three genes. Type 1 is the most common and is associated with mutations in the gene CACNA1A. Mutations in ATP1A2 underlie type 2 FHM, and mutations in SCN1A underlie type 3 FHM.
FHM is distinguished from other hemiplegic migraine by family history of one or more affected first- or second-degree relatives. Genetic studies have shown FHM to have autosomal dominant inheritance. From half to three quarters of patients with FHM will have one of the more than 30 identified mutations on CACNA1A that diagnose type 1 FHM. These mutations affect transmission of glutamate in the neurons and neuronal reactions, increasing the susceptibility to cortical spreading depression associated with migraine. Mutations in ATP1A2 are found in about 20% of patients with FHM (type 2). More than 80 individual mutations have been identified, which alter sodium-potassium metabolism in neurons. About 5% of patients have type 3 FHM, associated with mutations in SCN1A that create gain of function or loss of function in neuronal voltage-gated sodium channels. Studies of other possible genes and mutations in relation to FHM, including PRRT2, are ongoing, but to date the associations are not clearly established.
Patients with FHM may also report sensory symptoms, visual disturbances, or aphasia. FHM generally affects people in their teens and twenties (women more than men) and has an estimated prevalence of 0.003% of the population. On average, patients report having two to three attacks per year, and some patients go for extended periods without a recurrent attack. Motor aura may occur on the same or opposite side of the body as headache and may alternate affected sides with each attack. Differential diagnoses that should be ruled out include transient ischemic attacks, infections (eg, meningitis, encephalitis), tumors, seizures, other inherited disorders, and metabolic issues.
Like other forms of migraine with aura, FHM is treated with abortive and/or preventive medications. Given the rarity of FHM, there are few studies specifically in families with this phenotype. Patients should be counseled on trigger avoidance to limit exposure. Acute treatment includes nonsteroidal anti-inflammatory drugs, acetaminophen, and other nonopioid pain relievers. The class of calcitonin gene-related peptide (CGRP) antagonists (rimegepant, ubrogepant, zavegepant) may be considered. However, with FHM, medications associated with ischemia must be avoided. As such, triptans and ergotamines are generally contraindicated, as are beta-blockers. Patients with FHM and more frequent or severe attacks may be considered for preventive treatment to improve function and quality of life and avoid reliance on acute therapies. Options include CGRP monoclonal antibodies (mAbs), administered subcutaneously or by intravenous infusion, and onabotulinumtoxinA injection. Current CGRP mAbs include eptinezumab, erenumab, fremanezumab, and galcanezumab. Combined CGRP mAb therapy with onabotulinumtoxinA may be an effective alternative for patients with resistant FHM.
Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.
Heidi Moawad, MD, has disclosed no relevant financial relationships.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
FHM is a rare phenotype of migraine with aura with a characteristic presentation of motor aura. Motor aura presents as unilateral muscle weakness that tends to be felt first in the hands or arm and may spread to the face. To date, three distinct types have been identified by mutations in one of three genes. Type 1 is the most common and is associated with mutations in the gene CACNA1A. Mutations in ATP1A2 underlie type 2 FHM, and mutations in SCN1A underlie type 3 FHM.
FHM is distinguished from other hemiplegic migraine by family history of one or more affected first- or second-degree relatives. Genetic studies have shown FHM to have autosomal dominant inheritance. From half to three quarters of patients with FHM will have one of the more than 30 identified mutations on CACNA1A that diagnose type 1 FHM. These mutations affect transmission of glutamate in the neurons and neuronal reactions, increasing the susceptibility to cortical spreading depression associated with migraine. Mutations in ATP1A2 are found in about 20% of patients with FHM (type 2). More than 80 individual mutations have been identified, which alter sodium-potassium metabolism in neurons. About 5% of patients have type 3 FHM, associated with mutations in SCN1A that create gain of function or loss of function in neuronal voltage-gated sodium channels. Studies of other possible genes and mutations in relation to FHM, including PRRT2, are ongoing, but to date the associations are not clearly established.
Patients with FHM may also report sensory symptoms, visual disturbances, or aphasia. FHM generally affects people in their teens and twenties (women more than men) and has an estimated prevalence of 0.003% of the population. On average, patients report having two to three attacks per year, and some patients go for extended periods without a recurrent attack. Motor aura may occur on the same or opposite side of the body as headache and may alternate affected sides with each attack. Differential diagnoses that should be ruled out include transient ischemic attacks, infections (eg, meningitis, encephalitis), tumors, seizures, other inherited disorders, and metabolic issues.
Like other forms of migraine with aura, FHM is treated with abortive and/or preventive medications. Given the rarity of FHM, there are few studies specifically in families with this phenotype. Patients should be counseled on trigger avoidance to limit exposure. Acute treatment includes nonsteroidal anti-inflammatory drugs, acetaminophen, and other nonopioid pain relievers. The class of calcitonin gene-related peptide (CGRP) antagonists (rimegepant, ubrogepant, zavegepant) may be considered. However, with FHM, medications associated with ischemia must be avoided. As such, triptans and ergotamines are generally contraindicated, as are beta-blockers. Patients with FHM and more frequent or severe attacks may be considered for preventive treatment to improve function and quality of life and avoid reliance on acute therapies. Options include CGRP monoclonal antibodies (mAbs), administered subcutaneously or by intravenous infusion, and onabotulinumtoxinA injection. Current CGRP mAbs include eptinezumab, erenumab, fremanezumab, and galcanezumab. Combined CGRP mAb therapy with onabotulinumtoxinA may be an effective alternative for patients with resistant FHM.
Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.
Heidi Moawad, MD, has disclosed no relevant financial relationships.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
FHM is a rare phenotype of migraine with aura with a characteristic presentation of motor aura. Motor aura presents as unilateral muscle weakness that tends to be felt first in the hands or arm and may spread to the face. To date, three distinct types have been identified by mutations in one of three genes. Type 1 is the most common and is associated with mutations in the gene CACNA1A. Mutations in ATP1A2 underlie type 2 FHM, and mutations in SCN1A underlie type 3 FHM.
FHM is distinguished from other hemiplegic migraine by family history of one or more affected first- or second-degree relatives. Genetic studies have shown FHM to have autosomal dominant inheritance. From half to three quarters of patients with FHM will have one of the more than 30 identified mutations on CACNA1A that diagnose type 1 FHM. These mutations affect transmission of glutamate in the neurons and neuronal reactions, increasing the susceptibility to cortical spreading depression associated with migraine. Mutations in ATP1A2 are found in about 20% of patients with FHM (type 2). More than 80 individual mutations have been identified, which alter sodium-potassium metabolism in neurons. About 5% of patients have type 3 FHM, associated with mutations in SCN1A that create gain of function or loss of function in neuronal voltage-gated sodium channels. Studies of other possible genes and mutations in relation to FHM, including PRRT2, are ongoing, but to date the associations are not clearly established.
Patients with FHM may also report sensory symptoms, visual disturbances, or aphasia. FHM generally affects people in their teens and twenties (women more than men) and has an estimated prevalence of 0.003% of the population. On average, patients report having two to three attacks per year, and some patients go for extended periods without a recurrent attack. Motor aura may occur on the same or opposite side of the body as headache and may alternate affected sides with each attack. Differential diagnoses that should be ruled out include transient ischemic attacks, infections (eg, meningitis, encephalitis), tumors, seizures, other inherited disorders, and metabolic issues.
Like other forms of migraine with aura, FHM is treated with abortive and/or preventive medications. Given the rarity of FHM, there are few studies specifically in families with this phenotype. Patients should be counseled on trigger avoidance to limit exposure. Acute treatment includes nonsteroidal anti-inflammatory drugs, acetaminophen, and other nonopioid pain relievers. The class of calcitonin gene-related peptide (CGRP) antagonists (rimegepant, ubrogepant, zavegepant) may be considered. However, with FHM, medications associated with ischemia must be avoided. As such, triptans and ergotamines are generally contraindicated, as are beta-blockers. Patients with FHM and more frequent or severe attacks may be considered for preventive treatment to improve function and quality of life and avoid reliance on acute therapies. Options include CGRP monoclonal antibodies (mAbs), administered subcutaneously or by intravenous infusion, and onabotulinumtoxinA injection. Current CGRP mAbs include eptinezumab, erenumab, fremanezumab, and galcanezumab. Combined CGRP mAb therapy with onabotulinumtoxinA may be an effective alternative for patients with resistant FHM.
Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.
Heidi Moawad, MD, has disclosed no relevant financial relationships.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
The patient is 35-year-old woman presenting for recurrent, unilateral headaches associated with weakness in the hand, arm, or face on one side of the body. The patient says this weakness sometimes occurs on the right side and other times on the left, often with a tingling sensation in the affected side, and is followed by an intense headache lasting for several hours.
She notes that the headaches started after recovery from a mild case of COVID. Over the past 2 years, five attacks have occurred, all following a similar pattern. With each attack, the motor weakness fully resolved with resolution of the headache. Two of the headaches were preceded by visual disturbances that resolved with headache onset.
Physical exam reveals an apparently healthy woman without fever or respiratory symptoms. Weight, blood pressure, and heart rate are within healthy ranges. All lab work is within normal ranges. Her facial appearance is normal at presentation, but she shows a photo taken during her last attack, in which she shows left side facial paralysis. Family history includes her mother with hemiplegic migraine and father with type 2 diabetes. You suspect familial hemiplegic migraine (FHM) and order genetic testing.
Announcing Our 2024 AGA Council Chair and Section Leaders
Meet Our New Chair
Douglas J. Robertson, MD, MPH, AGAFAGA Institute Council Chair
VA Medical Center, White River Junction, Vermont
Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
Dr. Robertson will serve as council chair for 3 years (May 2024-May 2027; DDW 2025, 2026 and 2027).
Section Leadership
, the driving force behind AGA’s programming at Digestive Disease Week (DDW). We welcome 8 members into their new roles as section vice chairs, joining the existing 17 Council members. Each new vice chair will serve a 2-year term that began immediately following this year’s DDW meeting and extends through DDW 2026. Following their term as vice chair, they will move into the role of section chair for an additional 2 years through DDW 2028. 
We are also pleased to announce the members joining nominating committees during the 2026 nomination/election cycle. The chairs of the nominating committee will be the immediate past section chairs, whom we also recognize and thank for their service and dedication to the section and the council.
Basic & Clinical Intestinal Disorders (BCID)
Uma Sundaram, MDVice chair
Marshall University School of Medicine, Huntington, West Virginia
Nominating committee members
- Colleen Renee Kelly, MD, AGAF, Chair
- Amy C. Engevik, PhD, Medical University of South Carolina
- Ravinder Gill, PhD, University of Illinois at Chicago
- Madhusudan Grover, MD, Mayo Clinic, Rochester, Minnesota
- Lisa L. Strate, MD, Harborview Medical Center, Seattle
Clinical Practice (CP)
Linda Anh Nguyen, MDVice Chair
Stanford (Calif.) University School of Medicine
Nominating committee members
- Gary W. Falk, MD, MS, AGAF, Chair
- Megan Adams, MD, JD, MSc, VA Ann Arbor Healthcare System Endoscopy Unit
- Mohammad Bilal, MD, Minneapolis VA Health Care System
- Carolyn Newberry, MD, Weill Cornell Medical Center, New York
- Adam Weizman, MD, MSc, Mount Sinai Hospital, Toronto
Endoscopy, Technology & Imaging (ETI)
Vivek Kaul, MD, AGAFVice Chair
University of Rochester (N.Y.) Medical Center
Nominating committee members
- Irving Waxman, MD, Chair
- Sushovan Guha, MD, PhD, University of Texas at Houston
- Pichamol Jirapinyo, MD, MPH, Brigham and Women’s Hospital, Boston
- Vladimir Kushnir, MD, Washington University St. Louis Barnes–Jewish West County Hospital
- Andrew C. Storm, MD, Mayo Clinic, Rochester, Minnesota
Immunology, Microbiology & Inflammatory Bowel Diseases (IMIBD)
Florian Rieder, MDVice Chair
Cleveland Clinic Foundation
Nominating committee members
- Fernando S. Velayos, MD, AGAF, Chair
- Brigid S. Boland, MD, University of California, San Diego
- Karen L. Edelblum, PhD, Icahn School of Medicine at Mount Sinai, New York
- Michael Kattah, MD, PhD, UCSF Gastroenterology
- Andres J. Yarur, MD, Cedars Sinai Medical Center. Los Angeles
Liver & Biliary (LB)
Don Rockey, MDVice Chair
Medical University of South Carolina, Charleston
Nominating committee members
- Gyongyi Szabo, MD, PhD, AGAF, Chair
- Brett Fortune, MD, MSc, Montefiore Medical Center
- Ruben Hernaez, MD, MPH, PhD, Baylor College of Medicine, Houston
- Cynthia Ann Moylan, MD, MHS, MS, Duke University, Durham, North Carolina
- Douglas A. Simonetto, MD, Mayo Clinic, Rochester, Minnesota
Microbiome & Microbial Therapy (MMT)
Jessica Allegretti, MD, MPHVice Chair
Brigham and Women’s Hospital, Boston
Nominating committee members
- Purna C. Kashyap, MBBS, AGAF, Chair
- Melinda Engevik, PhD, Medical University of South Carolina
- Christian Jobin, PhD, University of Florida
- Vanessa Leone, PhD, The University of Wisconsin–Madison
- Jun Yu, MD, PhD, The Chinese University of Hong Kong
Obesity, Metabolism & Nutrition (OMN)
Berkeley M. Limketkai, MD, PhDVice Chair
University of California Los Angeles
Nominating committee members
- Andres Jose Acosta, MD, PhD, Chair
- Barham K. Abu Dayyeh, MD, MPH, Mayo Clinic, Rochester, Minnesota
- Alan L. Buchman, MD, MSPH, University of Illinois at Chicago
- Octavia Pickett-Blakely, MD, MHS, Hospital of the University of Pennsylvania
- Robert Shulman, MD, Texas Children’s Hospital, Baylor College of Medicine
Pediatric Gastroenterology & Developmental Biology (PGDB)
Kelli L. VanDussen, PhDVice Chair
Cincinnati Children’s Hospital Medical Center
Meet Our New Chair
Douglas J. Robertson, MD, MPH, AGAFAGA Institute Council Chair
VA Medical Center, White River Junction, Vermont
Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
Dr. Robertson will serve as council chair for 3 years (May 2024-May 2027; DDW 2025, 2026 and 2027).
Section Leadership
, the driving force behind AGA’s programming at Digestive Disease Week (DDW). We welcome 8 members into their new roles as section vice chairs, joining the existing 17 Council members. Each new vice chair will serve a 2-year term that began immediately following this year’s DDW meeting and extends through DDW 2026. Following their term as vice chair, they will move into the role of section chair for an additional 2 years through DDW 2028.
We are also pleased to announce the members joining nominating committees during the 2026 nomination/election cycle. The chairs of the nominating committee will be the immediate past section chairs, whom we also recognize and thank for their service and dedication to the section and the council.
Basic & Clinical Intestinal Disorders (BCID)
Uma Sundaram, MDVice chair
Marshall University School of Medicine, Huntington, West Virginia
Nominating committee members
- Colleen Renee Kelly, MD, AGAF, Chair
- Amy C. Engevik, PhD, Medical University of South Carolina
- Ravinder Gill, PhD, University of Illinois at Chicago
- Madhusudan Grover, MD, Mayo Clinic, Rochester, Minnesota
- Lisa L. Strate, MD, Harborview Medical Center, Seattle
Clinical Practice (CP)
Linda Anh Nguyen, MDVice Chair
Stanford (Calif.) University School of Medicine
Nominating committee members
- Gary W. Falk, MD, MS, AGAF, Chair
- Megan Adams, MD, JD, MSc, VA Ann Arbor Healthcare System Endoscopy Unit
- Mohammad Bilal, MD, Minneapolis VA Health Care System
- Carolyn Newberry, MD, Weill Cornell Medical Center, New York
- Adam Weizman, MD, MSc, Mount Sinai Hospital, Toronto
Endoscopy, Technology & Imaging (ETI)
Vivek Kaul, MD, AGAFVice Chair
University of Rochester (N.Y.) Medical Center
Nominating committee members
- Irving Waxman, MD, Chair
- Sushovan Guha, MD, PhD, University of Texas at Houston
- Pichamol Jirapinyo, MD, MPH, Brigham and Women’s Hospital, Boston
- Vladimir Kushnir, MD, Washington University St. Louis Barnes–Jewish West County Hospital
- Andrew C. Storm, MD, Mayo Clinic, Rochester, Minnesota
Immunology, Microbiology & Inflammatory Bowel Diseases (IMIBD)
Florian Rieder, MDVice Chair
Cleveland Clinic Foundation
Nominating committee members
- Fernando S. Velayos, MD, AGAF, Chair
- Brigid S. Boland, MD, University of California, San Diego
- Karen L. Edelblum, PhD, Icahn School of Medicine at Mount Sinai, New York
- Michael Kattah, MD, PhD, UCSF Gastroenterology
- Andres J. Yarur, MD, Cedars Sinai Medical Center. Los Angeles
Liver & Biliary (LB)
Don Rockey, MDVice Chair
Medical University of South Carolina, Charleston
Nominating committee members
- Gyongyi Szabo, MD, PhD, AGAF, Chair
- Brett Fortune, MD, MSc, Montefiore Medical Center
- Ruben Hernaez, MD, MPH, PhD, Baylor College of Medicine, Houston
- Cynthia Ann Moylan, MD, MHS, MS, Duke University, Durham, North Carolina
- Douglas A. Simonetto, MD, Mayo Clinic, Rochester, Minnesota
Microbiome & Microbial Therapy (MMT)
Jessica Allegretti, MD, MPHVice Chair
Brigham and Women’s Hospital, Boston
Nominating committee members
- Purna C. Kashyap, MBBS, AGAF, Chair
- Melinda Engevik, PhD, Medical University of South Carolina
- Christian Jobin, PhD, University of Florida
- Vanessa Leone, PhD, The University of Wisconsin–Madison
- Jun Yu, MD, PhD, The Chinese University of Hong Kong
Obesity, Metabolism & Nutrition (OMN)
Berkeley M. Limketkai, MD, PhDVice Chair
University of California Los Angeles
Nominating committee members
- Andres Jose Acosta, MD, PhD, Chair
- Barham K. Abu Dayyeh, MD, MPH, Mayo Clinic, Rochester, Minnesota
- Alan L. Buchman, MD, MSPH, University of Illinois at Chicago
- Octavia Pickett-Blakely, MD, MHS, Hospital of the University of Pennsylvania
- Robert Shulman, MD, Texas Children’s Hospital, Baylor College of Medicine
Pediatric Gastroenterology & Developmental Biology (PGDB)
Kelli L. VanDussen, PhDVice Chair
Cincinnati Children’s Hospital Medical Center
Meet Our New Chair
Douglas J. Robertson, MD, MPH, AGAFAGA Institute Council Chair
VA Medical Center, White River Junction, Vermont
Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
Dr. Robertson will serve as council chair for 3 years (May 2024-May 2027; DDW 2025, 2026 and 2027).
Section Leadership
, the driving force behind AGA’s programming at Digestive Disease Week (DDW). We welcome 8 members into their new roles as section vice chairs, joining the existing 17 Council members. Each new vice chair will serve a 2-year term that began immediately following this year’s DDW meeting and extends through DDW 2026. Following their term as vice chair, they will move into the role of section chair for an additional 2 years through DDW 2028.
We are also pleased to announce the members joining nominating committees during the 2026 nomination/election cycle. The chairs of the nominating committee will be the immediate past section chairs, whom we also recognize and thank for their service and dedication to the section and the council.
Basic & Clinical Intestinal Disorders (BCID)
Uma Sundaram, MDVice chair
Marshall University School of Medicine, Huntington, West Virginia
Nominating committee members
- Colleen Renee Kelly, MD, AGAF, Chair
- Amy C. Engevik, PhD, Medical University of South Carolina
- Ravinder Gill, PhD, University of Illinois at Chicago
- Madhusudan Grover, MD, Mayo Clinic, Rochester, Minnesota
- Lisa L. Strate, MD, Harborview Medical Center, Seattle
Clinical Practice (CP)
Linda Anh Nguyen, MDVice Chair
Stanford (Calif.) University School of Medicine
Nominating committee members
- Gary W. Falk, MD, MS, AGAF, Chair
- Megan Adams, MD, JD, MSc, VA Ann Arbor Healthcare System Endoscopy Unit
- Mohammad Bilal, MD, Minneapolis VA Health Care System
- Carolyn Newberry, MD, Weill Cornell Medical Center, New York
- Adam Weizman, MD, MSc, Mount Sinai Hospital, Toronto
Endoscopy, Technology & Imaging (ETI)
Vivek Kaul, MD, AGAFVice Chair
University of Rochester (N.Y.) Medical Center
Nominating committee members
- Irving Waxman, MD, Chair
- Sushovan Guha, MD, PhD, University of Texas at Houston
- Pichamol Jirapinyo, MD, MPH, Brigham and Women’s Hospital, Boston
- Vladimir Kushnir, MD, Washington University St. Louis Barnes–Jewish West County Hospital
- Andrew C. Storm, MD, Mayo Clinic, Rochester, Minnesota
Immunology, Microbiology & Inflammatory Bowel Diseases (IMIBD)
Florian Rieder, MDVice Chair
Cleveland Clinic Foundation
Nominating committee members
- Fernando S. Velayos, MD, AGAF, Chair
- Brigid S. Boland, MD, University of California, San Diego
- Karen L. Edelblum, PhD, Icahn School of Medicine at Mount Sinai, New York
- Michael Kattah, MD, PhD, UCSF Gastroenterology
- Andres J. Yarur, MD, Cedars Sinai Medical Center. Los Angeles
Liver & Biliary (LB)
Don Rockey, MDVice Chair
Medical University of South Carolina, Charleston
Nominating committee members
- Gyongyi Szabo, MD, PhD, AGAF, Chair
- Brett Fortune, MD, MSc, Montefiore Medical Center
- Ruben Hernaez, MD, MPH, PhD, Baylor College of Medicine, Houston
- Cynthia Ann Moylan, MD, MHS, MS, Duke University, Durham, North Carolina
- Douglas A. Simonetto, MD, Mayo Clinic, Rochester, Minnesota
Microbiome & Microbial Therapy (MMT)
Jessica Allegretti, MD, MPHVice Chair
Brigham and Women’s Hospital, Boston
Nominating committee members
- Purna C. Kashyap, MBBS, AGAF, Chair
- Melinda Engevik, PhD, Medical University of South Carolina
- Christian Jobin, PhD, University of Florida
- Vanessa Leone, PhD, The University of Wisconsin–Madison
- Jun Yu, MD, PhD, The Chinese University of Hong Kong
Obesity, Metabolism & Nutrition (OMN)
Berkeley M. Limketkai, MD, PhDVice Chair
University of California Los Angeles
Nominating committee members
- Andres Jose Acosta, MD, PhD, Chair
- Barham K. Abu Dayyeh, MD, MPH, Mayo Clinic, Rochester, Minnesota
- Alan L. Buchman, MD, MSPH, University of Illinois at Chicago
- Octavia Pickett-Blakely, MD, MHS, Hospital of the University of Pennsylvania
- Robert Shulman, MD, Texas Children’s Hospital, Baylor College of Medicine
Pediatric Gastroenterology & Developmental Biology (PGDB)
Kelli L. VanDussen, PhDVice Chair
Cincinnati Children’s Hospital Medical Center
Dupilumab Safe, Effective Over 5 Years in Moderate to Severe Atopic Dermatitis
TOPLINE:
Over 5 years, dupilumab demonstrated acceptable safety and sustained efficacy, with significant improvements in the signs and symptoms of AD, in the treatment of moderate to severe atopic dermatitis (AD).
METHODOLOGY:
- The phase 3 multinational LIBERTY AD open-label extension study evaluated the safety and efficacy of dupilumab in 2677 adults with moderate to severe AD who had previously participated in dupilumab trials over 5 years; 334 patients (12.5%) completed treatment up to 5 years.
- Patients started with subcutaneous dupilumab, initially dosed weekly after a loading dose, then every 2 weeks in 2019.
- The primary outcomes were the incidence and rate of treatment-emergent adverse events (TEAEs).
TAKEAWAY:
- Overall, 14,717 TEAEs were reported over 5 years. The exposure-adjusted incidence rate decreased over time and was 252.48 events per 100 patient-years.
- The most common TEAEs were nasopharyngitis (28.9%), worsening AD (16.7%), upper respiratory tract infection (13.6%), conjunctivitis (10.3%), allergic conjunctivitis (9%), headache (8.1%), oral herpes (7.5%), and injection-site reactions (5.2%).
- Serious and severe TEAE rates were 10.6% and 10.0%, respectively. Exposure-adjusted incidence rates were 6.66 and 6.71 events per 100 patient-years, respectively.
- At week 260, 67.5% of patients had achieved clear or almost clear skin according to the Investigator’s Global Assessment, and 88.9% experienced a 75% or greater improvement in the Eczema Area and Severity Index.
IN PRACTICE:
“Safety and efficacy results from up to 5 years of dupilumab treatment in the LIBERTY AD open-label extension study support dupilumab as a continuous long-term treatment for adults with moderate to severe AD,” the authors concluded.
SOURCE:
The study was led by Lisa A. Beck, MD, University of Rochester, Rochester, New York, and was published online in JAMA Dermatology.
LIMITATIONS:
Study limitations included the absence of a placebo arm and treatment interruptions stemming from protocol changes. The number of patients who received biweekly doses was small. The early conclusion of the trial by the sponsor because of regulatory approval also resulted in a lower number of patients at later stages.
DISCLOSURES:
This study was funded by dupilumab manufacturers Sanofi and Regeneron Pharmaceuticals. Several authors declared ties with various pharmaceutical companies including Sanofi and Regeneron, and several authors were employees of Sanofi or Regeneron. No disclosures were reported by other authors.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
Over 5 years, dupilumab demonstrated acceptable safety and sustained efficacy, with significant improvements in the signs and symptoms of AD, in the treatment of moderate to severe atopic dermatitis (AD).
METHODOLOGY:
- The phase 3 multinational LIBERTY AD open-label extension study evaluated the safety and efficacy of dupilumab in 2677 adults with moderate to severe AD who had previously participated in dupilumab trials over 5 years; 334 patients (12.5%) completed treatment up to 5 years.
- Patients started with subcutaneous dupilumab, initially dosed weekly after a loading dose, then every 2 weeks in 2019.
- The primary outcomes were the incidence and rate of treatment-emergent adverse events (TEAEs).
TAKEAWAY:
- Overall, 14,717 TEAEs were reported over 5 years. The exposure-adjusted incidence rate decreased over time and was 252.48 events per 100 patient-years.
- The most common TEAEs were nasopharyngitis (28.9%), worsening AD (16.7%), upper respiratory tract infection (13.6%), conjunctivitis (10.3%), allergic conjunctivitis (9%), headache (8.1%), oral herpes (7.5%), and injection-site reactions (5.2%).
- Serious and severe TEAE rates were 10.6% and 10.0%, respectively. Exposure-adjusted incidence rates were 6.66 and 6.71 events per 100 patient-years, respectively.
- At week 260, 67.5% of patients had achieved clear or almost clear skin according to the Investigator’s Global Assessment, and 88.9% experienced a 75% or greater improvement in the Eczema Area and Severity Index.
IN PRACTICE:
“Safety and efficacy results from up to 5 years of dupilumab treatment in the LIBERTY AD open-label extension study support dupilumab as a continuous long-term treatment for adults with moderate to severe AD,” the authors concluded.
SOURCE:
The study was led by Lisa A. Beck, MD, University of Rochester, Rochester, New York, and was published online in JAMA Dermatology.
LIMITATIONS:
Study limitations included the absence of a placebo arm and treatment interruptions stemming from protocol changes. The number of patients who received biweekly doses was small. The early conclusion of the trial by the sponsor because of regulatory approval also resulted in a lower number of patients at later stages.
DISCLOSURES:
This study was funded by dupilumab manufacturers Sanofi and Regeneron Pharmaceuticals. Several authors declared ties with various pharmaceutical companies including Sanofi and Regeneron, and several authors were employees of Sanofi or Regeneron. No disclosures were reported by other authors.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
Over 5 years, dupilumab demonstrated acceptable safety and sustained efficacy, with significant improvements in the signs and symptoms of AD, in the treatment of moderate to severe atopic dermatitis (AD).
METHODOLOGY:
- The phase 3 multinational LIBERTY AD open-label extension study evaluated the safety and efficacy of dupilumab in 2677 adults with moderate to severe AD who had previously participated in dupilumab trials over 5 years; 334 patients (12.5%) completed treatment up to 5 years.
- Patients started with subcutaneous dupilumab, initially dosed weekly after a loading dose, then every 2 weeks in 2019.
- The primary outcomes were the incidence and rate of treatment-emergent adverse events (TEAEs).
TAKEAWAY:
- Overall, 14,717 TEAEs were reported over 5 years. The exposure-adjusted incidence rate decreased over time and was 252.48 events per 100 patient-years.
- The most common TEAEs were nasopharyngitis (28.9%), worsening AD (16.7%), upper respiratory tract infection (13.6%), conjunctivitis (10.3%), allergic conjunctivitis (9%), headache (8.1%), oral herpes (7.5%), and injection-site reactions (5.2%).
- Serious and severe TEAE rates were 10.6% and 10.0%, respectively. Exposure-adjusted incidence rates were 6.66 and 6.71 events per 100 patient-years, respectively.
- At week 260, 67.5% of patients had achieved clear or almost clear skin according to the Investigator’s Global Assessment, and 88.9% experienced a 75% or greater improvement in the Eczema Area and Severity Index.
IN PRACTICE:
“Safety and efficacy results from up to 5 years of dupilumab treatment in the LIBERTY AD open-label extension study support dupilumab as a continuous long-term treatment for adults with moderate to severe AD,” the authors concluded.
SOURCE:
The study was led by Lisa A. Beck, MD, University of Rochester, Rochester, New York, and was published online in JAMA Dermatology.
LIMITATIONS:
Study limitations included the absence of a placebo arm and treatment interruptions stemming from protocol changes. The number of patients who received biweekly doses was small. The early conclusion of the trial by the sponsor because of regulatory approval also resulted in a lower number of patients at later stages.
DISCLOSURES:
This study was funded by dupilumab manufacturers Sanofi and Regeneron Pharmaceuticals. Several authors declared ties with various pharmaceutical companies including Sanofi and Regeneron, and several authors were employees of Sanofi or Regeneron. No disclosures were reported by other authors.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Eosinophilic Esophagitis Often Persists Despite Treatment
based on a recent retrospective study.
Challenging patient journeys were common across age groups, with a range of ongoing symptoms and histological abnormalities supporting high unmet need among patients with EoE, lead author Olulade Ayodele, MBBS, MPH, of Takeda Development Center Americas and colleagues reported.
“Recent studies have found that patients with EoE experience a complicated journey to diagnosis and a substantial disease burden, which requires significant healthcare resource utilization,” the investigators wrote in Gastro Hep Advances . “Reasons for this may include delays in diagnosis owing to nonspecific symptoms, adaptive behaviors, progression of silent disease, lack of adequate follow-up or referral, or suboptimal treatment after diagnosis.”Two medications are currently Food and Drug administration approved for EoE: dupilumab, a biologic for patients aged 1 year and older, and budesonide oral suspension, a topical corticosteroid for patients aged 11 years and older.
The investigators noted that “biologic therapies may not always be selected as first-line treatment, and are often associated with high costs”; however, the effects of real-world treatment decisions like these are poorly documented, prompting the present study.
The final dataset comprised 613 patients with newly diagnosed EoE treated in a rural integrated healthcare system, all of whom had at least 12 months of data before and after a predetermined index date. Individuals were stratified by age, including 182 children, 146 adolescents, 244 adults, and 41 older adults.
Signs and symptoms of EoE frequently worsened after the index date, including dysphagia (34.6% before, 49.9% after), abdominal pain (33.0% before, 48.1% after), and nausea/vomiting (20.1% before, 31.5% after).
At baseline, 80.5% of endoscopies were abnormal and 87.9% of patients had more than 15 eosinophils/high-power field. These parameters improved post index; however, 3 years later, 62.3% of patients still had abnormal endoscopic appearance and 51.2% had abnormal histologic activity.
Before and after index, the most prescribed treatments were corticosteroids (47.3% before, 87.9% after) and proton pump inhibitors (51.1% before, 96.1% after).
After index, 44.0% of patients discontinued their first-line treatment, and 13.9% experienced disease progression.
“We found that a substantial portion of patients with EoE received variable medical treatments, and did not report undergoing follow-up care, consulting with specialists, or routinely undergoing endoscopy with biopsy after diagnosis; the reasons for this are unknown, but experiences do not appear to be consistent with current guideline recommendations,” Dr. Ayodele and colleagues wrote.
They also noted substantial healthcare resource utilization; more than half of the patients visited emergency departments, and nearly one in five were admitted as inpatients.
“Our findings outline the persistent disease activity and difficult therapeutic journeys faced by patients with EoE irrespective of their age, as well as the substantial disease burden,” the investigators concluded. “These data highlight the potential unmet medical need of patients with EoE in the United States.”The study was funded by Shire Human Genetic Therapies, a member of the Takeda group of companies. The investigators disclosed additional relationships with RTI Health Solutions and Receptos/Celgene.
In a large, retrospective, real-world cohort study, investigators examined the patient journey in 613 child, adolescent, and adult patients with eosinophilic esophagitis (EoE) via healthcare claims database and electronic medical record data. As we enter into an exciting era in novel biologic therapies in EoE, the article provides comprehensive and reliable information in several critical and actionable areas with respect to EoE diagnosis and management.
The study highlights the heterogeneity of the patient experience in EoE and suggests that improvements in the reliability and precision of EoE care models will impact healthcare utilization. In particular, the findings support the need for structured and systematic mechanisms for appropriate follow-up after the index diagnosis and increased use and continued development of novel therapies.
Anand Jain, MD, is assistant professor in the Division of Digestive Diseases at Emory University School of Medicine, Atlanta, Georgia. Ravinder Mittal, MD, AGAF, is professor in the Division of Gastroenterology at the University of California, San Diego, and staff physician at the San Diego VA Hospital. They report no conflicts of interest.
In a large, retrospective, real-world cohort study, investigators examined the patient journey in 613 child, adolescent, and adult patients with eosinophilic esophagitis (EoE) via healthcare claims database and electronic medical record data. As we enter into an exciting era in novel biologic therapies in EoE, the article provides comprehensive and reliable information in several critical and actionable areas with respect to EoE diagnosis and management.
The study highlights the heterogeneity of the patient experience in EoE and suggests that improvements in the reliability and precision of EoE care models will impact healthcare utilization. In particular, the findings support the need for structured and systematic mechanisms for appropriate follow-up after the index diagnosis and increased use and continued development of novel therapies.
Anand Jain, MD, is assistant professor in the Division of Digestive Diseases at Emory University School of Medicine, Atlanta, Georgia. Ravinder Mittal, MD, AGAF, is professor in the Division of Gastroenterology at the University of California, San Diego, and staff physician at the San Diego VA Hospital. They report no conflicts of interest.
In a large, retrospective, real-world cohort study, investigators examined the patient journey in 613 child, adolescent, and adult patients with eosinophilic esophagitis (EoE) via healthcare claims database and electronic medical record data. As we enter into an exciting era in novel biologic therapies in EoE, the article provides comprehensive and reliable information in several critical and actionable areas with respect to EoE diagnosis and management.
The study highlights the heterogeneity of the patient experience in EoE and suggests that improvements in the reliability and precision of EoE care models will impact healthcare utilization. In particular, the findings support the need for structured and systematic mechanisms for appropriate follow-up after the index diagnosis and increased use and continued development of novel therapies.
Anand Jain, MD, is assistant professor in the Division of Digestive Diseases at Emory University School of Medicine, Atlanta, Georgia. Ravinder Mittal, MD, AGAF, is professor in the Division of Gastroenterology at the University of California, San Diego, and staff physician at the San Diego VA Hospital. They report no conflicts of interest.
based on a recent retrospective study.
Challenging patient journeys were common across age groups, with a range of ongoing symptoms and histological abnormalities supporting high unmet need among patients with EoE, lead author Olulade Ayodele, MBBS, MPH, of Takeda Development Center Americas and colleagues reported.
“Recent studies have found that patients with EoE experience a complicated journey to diagnosis and a substantial disease burden, which requires significant healthcare resource utilization,” the investigators wrote in Gastro Hep Advances . “Reasons for this may include delays in diagnosis owing to nonspecific symptoms, adaptive behaviors, progression of silent disease, lack of adequate follow-up or referral, or suboptimal treatment after diagnosis.”Two medications are currently Food and Drug administration approved for EoE: dupilumab, a biologic for patients aged 1 year and older, and budesonide oral suspension, a topical corticosteroid for patients aged 11 years and older.
The investigators noted that “biologic therapies may not always be selected as first-line treatment, and are often associated with high costs”; however, the effects of real-world treatment decisions like these are poorly documented, prompting the present study.
The final dataset comprised 613 patients with newly diagnosed EoE treated in a rural integrated healthcare system, all of whom had at least 12 months of data before and after a predetermined index date. Individuals were stratified by age, including 182 children, 146 adolescents, 244 adults, and 41 older adults.
Signs and symptoms of EoE frequently worsened after the index date, including dysphagia (34.6% before, 49.9% after), abdominal pain (33.0% before, 48.1% after), and nausea/vomiting (20.1% before, 31.5% after).
At baseline, 80.5% of endoscopies were abnormal and 87.9% of patients had more than 15 eosinophils/high-power field. These parameters improved post index; however, 3 years later, 62.3% of patients still had abnormal endoscopic appearance and 51.2% had abnormal histologic activity.
Before and after index, the most prescribed treatments were corticosteroids (47.3% before, 87.9% after) and proton pump inhibitors (51.1% before, 96.1% after).
After index, 44.0% of patients discontinued their first-line treatment, and 13.9% experienced disease progression.
“We found that a substantial portion of patients with EoE received variable medical treatments, and did not report undergoing follow-up care, consulting with specialists, or routinely undergoing endoscopy with biopsy after diagnosis; the reasons for this are unknown, but experiences do not appear to be consistent with current guideline recommendations,” Dr. Ayodele and colleagues wrote.
They also noted substantial healthcare resource utilization; more than half of the patients visited emergency departments, and nearly one in five were admitted as inpatients.
“Our findings outline the persistent disease activity and difficult therapeutic journeys faced by patients with EoE irrespective of their age, as well as the substantial disease burden,” the investigators concluded. “These data highlight the potential unmet medical need of patients with EoE in the United States.”The study was funded by Shire Human Genetic Therapies, a member of the Takeda group of companies. The investigators disclosed additional relationships with RTI Health Solutions and Receptos/Celgene.
based on a recent retrospective study.
Challenging patient journeys were common across age groups, with a range of ongoing symptoms and histological abnormalities supporting high unmet need among patients with EoE, lead author Olulade Ayodele, MBBS, MPH, of Takeda Development Center Americas and colleagues reported.
“Recent studies have found that patients with EoE experience a complicated journey to diagnosis and a substantial disease burden, which requires significant healthcare resource utilization,” the investigators wrote in Gastro Hep Advances . “Reasons for this may include delays in diagnosis owing to nonspecific symptoms, adaptive behaviors, progression of silent disease, lack of adequate follow-up or referral, or suboptimal treatment after diagnosis.”Two medications are currently Food and Drug administration approved for EoE: dupilumab, a biologic for patients aged 1 year and older, and budesonide oral suspension, a topical corticosteroid for patients aged 11 years and older.
The investigators noted that “biologic therapies may not always be selected as first-line treatment, and are often associated with high costs”; however, the effects of real-world treatment decisions like these are poorly documented, prompting the present study.
The final dataset comprised 613 patients with newly diagnosed EoE treated in a rural integrated healthcare system, all of whom had at least 12 months of data before and after a predetermined index date. Individuals were stratified by age, including 182 children, 146 adolescents, 244 adults, and 41 older adults.
Signs and symptoms of EoE frequently worsened after the index date, including dysphagia (34.6% before, 49.9% after), abdominal pain (33.0% before, 48.1% after), and nausea/vomiting (20.1% before, 31.5% after).
At baseline, 80.5% of endoscopies were abnormal and 87.9% of patients had more than 15 eosinophils/high-power field. These parameters improved post index; however, 3 years later, 62.3% of patients still had abnormal endoscopic appearance and 51.2% had abnormal histologic activity.
Before and after index, the most prescribed treatments were corticosteroids (47.3% before, 87.9% after) and proton pump inhibitors (51.1% before, 96.1% after).
After index, 44.0% of patients discontinued their first-line treatment, and 13.9% experienced disease progression.
“We found that a substantial portion of patients with EoE received variable medical treatments, and did not report undergoing follow-up care, consulting with specialists, or routinely undergoing endoscopy with biopsy after diagnosis; the reasons for this are unknown, but experiences do not appear to be consistent with current guideline recommendations,” Dr. Ayodele and colleagues wrote.
They also noted substantial healthcare resource utilization; more than half of the patients visited emergency departments, and nearly one in five were admitted as inpatients.
“Our findings outline the persistent disease activity and difficult therapeutic journeys faced by patients with EoE irrespective of their age, as well as the substantial disease burden,” the investigators concluded. “These data highlight the potential unmet medical need of patients with EoE in the United States.”The study was funded by Shire Human Genetic Therapies, a member of the Takeda group of companies. The investigators disclosed additional relationships with RTI Health Solutions and Receptos/Celgene.
FROM GASTRO HEP ADVANCES
Eribulin Similar to Taxane When Paired With Dual HER2 Blockade in BC
The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.
“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.
“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.
“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.
“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
Study Results and Methods
The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.
They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m2 on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.
Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.
For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.
The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.
Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).
In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).
“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.
Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
Findings Are a ‘Clinical Pearl’
Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.
Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).
Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.
“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”
Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.
The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.
“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.
“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.
“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.
“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
Study Results and Methods
The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.
They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m2 on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.
Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.
For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.
The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.
Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).
In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).
“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.
Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
Findings Are a ‘Clinical Pearl’
Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.
Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).
Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.
“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”
Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.
The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.
“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.
“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.
“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.
“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
Study Results and Methods
The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.
They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m2 on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.
Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.
For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.
The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.
Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).
In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).
“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.
Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
Findings Are a ‘Clinical Pearl’
Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.
Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).
Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.
“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”
Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.
FROM ASCO 2024