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Branding tattoo removal helps sex trafficking survivor close door on painful past
PHOENIX – When Kathy Givens walked onstage during a plenary session at the annual conference of the American Society for Laser Medicine and Surgery to reflect on her 9-month ordeal being sex trafficked in Texas more than 20 years ago, you could hear a pin drop.
“One of the scariest things about the life of sex trafficking is not knowing who’s going to be on the other side,” said Ms. Givens, who now lives in Houston. “There was some violence. There were some horrible things that happened. But you know what was really scary? When I got out. People may ask, ‘How’s that so? You escaped your trafficker. The past is behind you. Why were you afraid?’ I was afraid because I didn’t know that I had community. I didn’t know that community or that society would care about someone like me.”
She said that she found herself immobilized by fear of being shamed in society and labeled a sex trafficking victim, and wondered if she could overcome that fear and if anyone would view her as human again. Once free from her trafficker, she began a “healing journey,” which included getting married, raising four children, and re-enrolling in college with hopes of becoming a social worker. In 2020, she and her husband founded Twelve 11 Partners, an organization committed to supporting human trafficking survivors.
“I was working in the anti-trafficking field helping other survivors ... who have experienced this horrific crime,” she said. “I thought I was on my way.” But one “stain” from her sex trafficking past remained: The name of her trafficker was tattooed on her skin, “a reminder of what I’d gone through.”
Ms. Givens was eventually introduced to Paul M. Friedman, MD, the current ASLMS president and one of the that was formed in 2022. According to a survey that Dr. Friedman and colleagues presented at the 2022 annual ASLMS conference, an estimated 1 in 2 sex trafficking survivors have branding tattoos, and at least 1,000 survivors a year could benefit from removal of those tattoos.
“To date, 87 physicians in the U.S. and one in Canada have stepped forward to volunteer their services to be part of this program,” Dr. Friedman, who directs the Dermatology and Laser Surgery Center in Houston, said at this year’s meeting. “My goal is to double this number by the next annual conference,” he added, noting that trauma-informed training is part of the program, “to support the survivor experience during the treatment process.”
ASLMS is also working on this issue in partnership with the American Academy of Dermatology (AAD) Ad Hoc Task Force on Dermatological Resources for the Intervention and Prevention of Human Trafficking, which is headed by Boston dermatologist Shadi Kourosh, MD.
“Dermatologists are uniquely positioned to aid in efforts to assist those experiences in trafficking with our training to recognize and diagnose relevant signs on the skin and to assist patients with certain aspects of care and recovery including the treatment of the disease of scars and tattoos,” Dr. Friedman said. “Ultimately, we hope to create a database together to improve recognition of branding tattoos to aid in identifying sex trafficking victims.”
Ms. Givens, who sits on the U.S. Advisory Council on Human Trafficking, said that she was able to truly close the door on her sex trafficking past thanks to the tattoo removal Dr. Friedman performed as part of New Beginnings. “It means the world to me to know that I can now be an advocate for other individuals who have experienced human trafficking,” she told meeting attendees.
“Again, one of the scariest things is not knowing that you have community. I was scared of losing hope, but I’m standing here today. I have all the hope that I need. You have the power to change lives.”
PHOENIX – When Kathy Givens walked onstage during a plenary session at the annual conference of the American Society for Laser Medicine and Surgery to reflect on her 9-month ordeal being sex trafficked in Texas more than 20 years ago, you could hear a pin drop.
“One of the scariest things about the life of sex trafficking is not knowing who’s going to be on the other side,” said Ms. Givens, who now lives in Houston. “There was some violence. There were some horrible things that happened. But you know what was really scary? When I got out. People may ask, ‘How’s that so? You escaped your trafficker. The past is behind you. Why were you afraid?’ I was afraid because I didn’t know that I had community. I didn’t know that community or that society would care about someone like me.”
She said that she found herself immobilized by fear of being shamed in society and labeled a sex trafficking victim, and wondered if she could overcome that fear and if anyone would view her as human again. Once free from her trafficker, she began a “healing journey,” which included getting married, raising four children, and re-enrolling in college with hopes of becoming a social worker. In 2020, she and her husband founded Twelve 11 Partners, an organization committed to supporting human trafficking survivors.
“I was working in the anti-trafficking field helping other survivors ... who have experienced this horrific crime,” she said. “I thought I was on my way.” But one “stain” from her sex trafficking past remained: The name of her trafficker was tattooed on her skin, “a reminder of what I’d gone through.”
Ms. Givens was eventually introduced to Paul M. Friedman, MD, the current ASLMS president and one of the that was formed in 2022. According to a survey that Dr. Friedman and colleagues presented at the 2022 annual ASLMS conference, an estimated 1 in 2 sex trafficking survivors have branding tattoos, and at least 1,000 survivors a year could benefit from removal of those tattoos.
“To date, 87 physicians in the U.S. and one in Canada have stepped forward to volunteer their services to be part of this program,” Dr. Friedman, who directs the Dermatology and Laser Surgery Center in Houston, said at this year’s meeting. “My goal is to double this number by the next annual conference,” he added, noting that trauma-informed training is part of the program, “to support the survivor experience during the treatment process.”
ASLMS is also working on this issue in partnership with the American Academy of Dermatology (AAD) Ad Hoc Task Force on Dermatological Resources for the Intervention and Prevention of Human Trafficking, which is headed by Boston dermatologist Shadi Kourosh, MD.
“Dermatologists are uniquely positioned to aid in efforts to assist those experiences in trafficking with our training to recognize and diagnose relevant signs on the skin and to assist patients with certain aspects of care and recovery including the treatment of the disease of scars and tattoos,” Dr. Friedman said. “Ultimately, we hope to create a database together to improve recognition of branding tattoos to aid in identifying sex trafficking victims.”
Ms. Givens, who sits on the U.S. Advisory Council on Human Trafficking, said that she was able to truly close the door on her sex trafficking past thanks to the tattoo removal Dr. Friedman performed as part of New Beginnings. “It means the world to me to know that I can now be an advocate for other individuals who have experienced human trafficking,” she told meeting attendees.
“Again, one of the scariest things is not knowing that you have community. I was scared of losing hope, but I’m standing here today. I have all the hope that I need. You have the power to change lives.”
PHOENIX – When Kathy Givens walked onstage during a plenary session at the annual conference of the American Society for Laser Medicine and Surgery to reflect on her 9-month ordeal being sex trafficked in Texas more than 20 years ago, you could hear a pin drop.
“One of the scariest things about the life of sex trafficking is not knowing who’s going to be on the other side,” said Ms. Givens, who now lives in Houston. “There was some violence. There were some horrible things that happened. But you know what was really scary? When I got out. People may ask, ‘How’s that so? You escaped your trafficker. The past is behind you. Why were you afraid?’ I was afraid because I didn’t know that I had community. I didn’t know that community or that society would care about someone like me.”
She said that she found herself immobilized by fear of being shamed in society and labeled a sex trafficking victim, and wondered if she could overcome that fear and if anyone would view her as human again. Once free from her trafficker, she began a “healing journey,” which included getting married, raising four children, and re-enrolling in college with hopes of becoming a social worker. In 2020, she and her husband founded Twelve 11 Partners, an organization committed to supporting human trafficking survivors.
“I was working in the anti-trafficking field helping other survivors ... who have experienced this horrific crime,” she said. “I thought I was on my way.” But one “stain” from her sex trafficking past remained: The name of her trafficker was tattooed on her skin, “a reminder of what I’d gone through.”
Ms. Givens was eventually introduced to Paul M. Friedman, MD, the current ASLMS president and one of the that was formed in 2022. According to a survey that Dr. Friedman and colleagues presented at the 2022 annual ASLMS conference, an estimated 1 in 2 sex trafficking survivors have branding tattoos, and at least 1,000 survivors a year could benefit from removal of those tattoos.
“To date, 87 physicians in the U.S. and one in Canada have stepped forward to volunteer their services to be part of this program,” Dr. Friedman, who directs the Dermatology and Laser Surgery Center in Houston, said at this year’s meeting. “My goal is to double this number by the next annual conference,” he added, noting that trauma-informed training is part of the program, “to support the survivor experience during the treatment process.”
ASLMS is also working on this issue in partnership with the American Academy of Dermatology (AAD) Ad Hoc Task Force on Dermatological Resources for the Intervention and Prevention of Human Trafficking, which is headed by Boston dermatologist Shadi Kourosh, MD.
“Dermatologists are uniquely positioned to aid in efforts to assist those experiences in trafficking with our training to recognize and diagnose relevant signs on the skin and to assist patients with certain aspects of care and recovery including the treatment of the disease of scars and tattoos,” Dr. Friedman said. “Ultimately, we hope to create a database together to improve recognition of branding tattoos to aid in identifying sex trafficking victims.”
Ms. Givens, who sits on the U.S. Advisory Council on Human Trafficking, said that she was able to truly close the door on her sex trafficking past thanks to the tattoo removal Dr. Friedman performed as part of New Beginnings. “It means the world to me to know that I can now be an advocate for other individuals who have experienced human trafficking,” she told meeting attendees.
“Again, one of the scariest things is not knowing that you have community. I was scared of losing hope, but I’m standing here today. I have all the hope that I need. You have the power to change lives.”
AT ASLMS 2023
Repeated CTs in childhood linked with increased cancer risk
In a population-based case-control study that included more than 85,000 participants, researchers found a ninefold increased risk of intracranial tumors among children who received four or more CT scans.
The results “indicate that judicious CT usage and radiation-reducing techniques should be advocated,” Yu-Hsuan Joni Shao, PhD, professor of biomedical informatics at Taipei (Taiwan) Medical University, and colleagues wrote.
The study was published in the Canadian Medical Association Journal.
Dose-response relationship
The investigators used the National Health Insurance Research Database in Taiwan to identify 7,807 patients under age 25 years with intracranial tumors (grades I-IV), leukemia, non-Hodgkin lymphomas, or Hodgkin lymphomas that had been diagnosed in a 14-year span between the years 2000 and 2013. They matched each case with 10 control participants without cancer by sex, date of birth, and date of entry into the cohort.
Radiation exposure was calculated for each patient according to number and type of CT scans received and an estimated organ-specific cumulative dose based on previously published models. The investigators excluded patients from the analysis if they had a diagnosis of any malignant disease before the study period or if they had any cancer-predisposing conditions, such as Down syndrome (which entails an increased risk of leukemia) or immunodeficiency (which may require multiple CT scans).
Compared with no exposure, exposure to a single pediatric CT scan was not associated with increased cancer risk. Exposure to two to three CT scans, however, was associated with an increased risk for intracranial tumour (adjusted odds ratio, 2.36), but not for leukemia, non-Hodgkin lymphoma, or Hodgkin lymphoma. Exposure to four or more CT scans was associated with increased risk for intracranial tumor (aOR, 9.01), leukemia (aOR, 4.80), and non-Hodgkin lymphoma (aOR, 6.76), but not for Hodgkin lymphoma.
The researchers also found a dose-response relationship. Participants in the top quintile of cumulative brain radiation dose had a significantly higher risk for intracranial tumor, compared with nonexposed participants (aOR, 3.61), although this relationship was not seen with the other cancers.
Age at exposure was also a significant factor. Children exposed to four or more CT scans at or before age 6 years had the highest risk for cancer (aOR, 22.95), followed by the same number of scans in those aged 7-12 years (aOR, 5.69) and those aged 13-18 years (aOR, 3.20).
The authors noted that, although these cancers are uncommon in children, “our work reinforces the importance of radiation protection strategies, addressed by the International Atomic Energy Agency. Unnecessary CT scans should be avoided, and special attention should be paid to patients who require repeated CT scans. Parents and pediatric patients should be well informed on risks and benefits before radiological procedures and encouraged to participate in decision-making around imaging.”
True risks underestimated?
Commenting on the findings, Rebecca Smith-Bindman, MD, a radiologist at the University of California, San Francisco, and an expert on the impact of CT scans on patient outcomes, said that she trusts the authors’ overall findings. But “because of the direction of their biases,” the study design “doesn’t let me accept their conclusion that one CT does not elevate the risk.
“It’s an interesting study that found the risk of brain cancer is more than doubled in children who undergo two or more CT scans, but in many ways, their assumptions will underestimate the true risk,” said Dr. Smith-Bindman, who is a professor of epidemiology and biostatistics at UCSF. She said reasons for this include the fact that the investigators used estimated, rather than actual radiation doses; that their estimates “reflect doses far lower than we have found actually occur in clinical practice”; that they do not differentiate between a low-dose or a high-dose CT; and that that they include a long, 3-year lag during which leukemia can develop after a CT scan.
“They did a lot of really well-done adjustments to ensure that they were not overestimating risk,” said Dr. Smith-Bindman. “They made sure to delete children who had cancer susceptibility syndrome, they included a lag of 3 years, assuming that there could be hidden cancers for up to 3 years after the first imaging study when they might have had a preexisting cancer. These are decisions that ensure that any cancer risk they find is real, but it also means that the risks that are estimated are almost certainly an underestimate of the true risks.”
The study was conducted without external funding. The authors declared no relevant financial relationships. Dr. Smith-Bindman is a cofounder of Alara Imaging, a company focused on collecting and reporting radiation dose information associated with CT.
A version of this article first appeared on Medscape.com.
In a population-based case-control study that included more than 85,000 participants, researchers found a ninefold increased risk of intracranial tumors among children who received four or more CT scans.
The results “indicate that judicious CT usage and radiation-reducing techniques should be advocated,” Yu-Hsuan Joni Shao, PhD, professor of biomedical informatics at Taipei (Taiwan) Medical University, and colleagues wrote.
The study was published in the Canadian Medical Association Journal.
Dose-response relationship
The investigators used the National Health Insurance Research Database in Taiwan to identify 7,807 patients under age 25 years with intracranial tumors (grades I-IV), leukemia, non-Hodgkin lymphomas, or Hodgkin lymphomas that had been diagnosed in a 14-year span between the years 2000 and 2013. They matched each case with 10 control participants without cancer by sex, date of birth, and date of entry into the cohort.
Radiation exposure was calculated for each patient according to number and type of CT scans received and an estimated organ-specific cumulative dose based on previously published models. The investigators excluded patients from the analysis if they had a diagnosis of any malignant disease before the study period or if they had any cancer-predisposing conditions, such as Down syndrome (which entails an increased risk of leukemia) or immunodeficiency (which may require multiple CT scans).
Compared with no exposure, exposure to a single pediatric CT scan was not associated with increased cancer risk. Exposure to two to three CT scans, however, was associated with an increased risk for intracranial tumour (adjusted odds ratio, 2.36), but not for leukemia, non-Hodgkin lymphoma, or Hodgkin lymphoma. Exposure to four or more CT scans was associated with increased risk for intracranial tumor (aOR, 9.01), leukemia (aOR, 4.80), and non-Hodgkin lymphoma (aOR, 6.76), but not for Hodgkin lymphoma.
The researchers also found a dose-response relationship. Participants in the top quintile of cumulative brain radiation dose had a significantly higher risk for intracranial tumor, compared with nonexposed participants (aOR, 3.61), although this relationship was not seen with the other cancers.
Age at exposure was also a significant factor. Children exposed to four or more CT scans at or before age 6 years had the highest risk for cancer (aOR, 22.95), followed by the same number of scans in those aged 7-12 years (aOR, 5.69) and those aged 13-18 years (aOR, 3.20).
The authors noted that, although these cancers are uncommon in children, “our work reinforces the importance of radiation protection strategies, addressed by the International Atomic Energy Agency. Unnecessary CT scans should be avoided, and special attention should be paid to patients who require repeated CT scans. Parents and pediatric patients should be well informed on risks and benefits before radiological procedures and encouraged to participate in decision-making around imaging.”
True risks underestimated?
Commenting on the findings, Rebecca Smith-Bindman, MD, a radiologist at the University of California, San Francisco, and an expert on the impact of CT scans on patient outcomes, said that she trusts the authors’ overall findings. But “because of the direction of their biases,” the study design “doesn’t let me accept their conclusion that one CT does not elevate the risk.
“It’s an interesting study that found the risk of brain cancer is more than doubled in children who undergo two or more CT scans, but in many ways, their assumptions will underestimate the true risk,” said Dr. Smith-Bindman, who is a professor of epidemiology and biostatistics at UCSF. She said reasons for this include the fact that the investigators used estimated, rather than actual radiation doses; that their estimates “reflect doses far lower than we have found actually occur in clinical practice”; that they do not differentiate between a low-dose or a high-dose CT; and that that they include a long, 3-year lag during which leukemia can develop after a CT scan.
“They did a lot of really well-done adjustments to ensure that they were not overestimating risk,” said Dr. Smith-Bindman. “They made sure to delete children who had cancer susceptibility syndrome, they included a lag of 3 years, assuming that there could be hidden cancers for up to 3 years after the first imaging study when they might have had a preexisting cancer. These are decisions that ensure that any cancer risk they find is real, but it also means that the risks that are estimated are almost certainly an underestimate of the true risks.”
The study was conducted without external funding. The authors declared no relevant financial relationships. Dr. Smith-Bindman is a cofounder of Alara Imaging, a company focused on collecting and reporting radiation dose information associated with CT.
A version of this article first appeared on Medscape.com.
In a population-based case-control study that included more than 85,000 participants, researchers found a ninefold increased risk of intracranial tumors among children who received four or more CT scans.
The results “indicate that judicious CT usage and radiation-reducing techniques should be advocated,” Yu-Hsuan Joni Shao, PhD, professor of biomedical informatics at Taipei (Taiwan) Medical University, and colleagues wrote.
The study was published in the Canadian Medical Association Journal.
Dose-response relationship
The investigators used the National Health Insurance Research Database in Taiwan to identify 7,807 patients under age 25 years with intracranial tumors (grades I-IV), leukemia, non-Hodgkin lymphomas, or Hodgkin lymphomas that had been diagnosed in a 14-year span between the years 2000 and 2013. They matched each case with 10 control participants without cancer by sex, date of birth, and date of entry into the cohort.
Radiation exposure was calculated for each patient according to number and type of CT scans received and an estimated organ-specific cumulative dose based on previously published models. The investigators excluded patients from the analysis if they had a diagnosis of any malignant disease before the study period or if they had any cancer-predisposing conditions, such as Down syndrome (which entails an increased risk of leukemia) or immunodeficiency (which may require multiple CT scans).
Compared with no exposure, exposure to a single pediatric CT scan was not associated with increased cancer risk. Exposure to two to three CT scans, however, was associated with an increased risk for intracranial tumour (adjusted odds ratio, 2.36), but not for leukemia, non-Hodgkin lymphoma, or Hodgkin lymphoma. Exposure to four or more CT scans was associated with increased risk for intracranial tumor (aOR, 9.01), leukemia (aOR, 4.80), and non-Hodgkin lymphoma (aOR, 6.76), but not for Hodgkin lymphoma.
The researchers also found a dose-response relationship. Participants in the top quintile of cumulative brain radiation dose had a significantly higher risk for intracranial tumor, compared with nonexposed participants (aOR, 3.61), although this relationship was not seen with the other cancers.
Age at exposure was also a significant factor. Children exposed to four or more CT scans at or before age 6 years had the highest risk for cancer (aOR, 22.95), followed by the same number of scans in those aged 7-12 years (aOR, 5.69) and those aged 13-18 years (aOR, 3.20).
The authors noted that, although these cancers are uncommon in children, “our work reinforces the importance of radiation protection strategies, addressed by the International Atomic Energy Agency. Unnecessary CT scans should be avoided, and special attention should be paid to patients who require repeated CT scans. Parents and pediatric patients should be well informed on risks and benefits before radiological procedures and encouraged to participate in decision-making around imaging.”
True risks underestimated?
Commenting on the findings, Rebecca Smith-Bindman, MD, a radiologist at the University of California, San Francisco, and an expert on the impact of CT scans on patient outcomes, said that she trusts the authors’ overall findings. But “because of the direction of their biases,” the study design “doesn’t let me accept their conclusion that one CT does not elevate the risk.
“It’s an interesting study that found the risk of brain cancer is more than doubled in children who undergo two or more CT scans, but in many ways, their assumptions will underestimate the true risk,” said Dr. Smith-Bindman, who is a professor of epidemiology and biostatistics at UCSF. She said reasons for this include the fact that the investigators used estimated, rather than actual radiation doses; that their estimates “reflect doses far lower than we have found actually occur in clinical practice”; that they do not differentiate between a low-dose or a high-dose CT; and that that they include a long, 3-year lag during which leukemia can develop after a CT scan.
“They did a lot of really well-done adjustments to ensure that they were not overestimating risk,” said Dr. Smith-Bindman. “They made sure to delete children who had cancer susceptibility syndrome, they included a lag of 3 years, assuming that there could be hidden cancers for up to 3 years after the first imaging study when they might have had a preexisting cancer. These are decisions that ensure that any cancer risk they find is real, but it also means that the risks that are estimated are almost certainly an underestimate of the true risks.”
The study was conducted without external funding. The authors declared no relevant financial relationships. Dr. Smith-Bindman is a cofounder of Alara Imaging, a company focused on collecting and reporting radiation dose information associated with CT.
A version of this article first appeared on Medscape.com.
FROM THE CANADIAN MEDICAL ASSOCIATION JOURNAL
‘Shocking’ data on what’s really in melatonin gummies
New data may explain the recent massive jump in pediatric hospitalizations.
Thenvestigators found that consuming some products as directed could expose consumers, including children, to doses that are 40-130 times greater than what’s recommended.
“The results were quite shocking,” lead researcher Pieter Cohen, MD, with Harvard Medical School, Boston, and Cambridge Health Alliance, Somerville, Mass., said in an interview.
“Melatonin gummies contained up to 347% more melatonin than what was listed on the label, and some products also contained cannabidiol; in one brand of melatonin gummies, there was zero melatonin, just CBD,” Dr. Cohen said.
The study was published online in JAMA.
530% jump in pediatric hospitalizations
Melatonin products are not approved by the Food and Drug Administration but are sold over the counter or online.
Previous research from JAMA has shown the use of melatonin has increased over the past 2 decades among people of all ages.
With increased use has come a spike in reports of melatonin overdose, calls to poison control centers, and related ED visits for children.
Federal data show the number of U.S. children who unintentionally ingested melatonin supplements jumped 530% from 2012 to 2021. More than 4,000 of the reported ingestions led to a hospital stay; 287 children required intensive care, and two children died.
It was unclear why melatonin supplements were causing these harms, which led Dr. Cohen’s team to analyze 25 unique brands of “melatonin” gummies purchased online.
One product didn’t contain any melatonin but did contain 31.3 mg of CBD.
In the remaining products, the quantity of melatonin ranged from 1.3 mg to 13.1 mg per serving. The actual quantity of melatonin ranged from 74% to 347% of the labeled quantity, the researchers found.
They note that for a young adult who takes as little as 0.1-0.3 mg of melatonin, plasma concentrations can increase into the normal night-time range.
Of the 25 products (88%) analyzed, 22 were inaccurately labeled, and only 3 (12%) contained a quantity of melatonin that was within 10% (plus or minus) of the declared quantity.
Five products listed CBD as an ingredient. The listed quantity ranged from 10.6 mg to 31.3 mg per serving, although the actual quantity of CBD ranged from 104% to 118% of the labeled quantity.
Inquire about use in kids
A limitation of the study is that only one sample of each brand was analyzed, and only gummies were analyzed. It is not known whether the results are generalizable to melatonin products sold as tablets and capsules in the United States or whether the quantity of melatonin within an individual brand may vary from batch to batch.
A recent study from Canada showed similar results. In an analysis of 16 Canadian melatonin brands, the actual dose of melatonin ranged from 17% to 478% of the declared quantity.
It’s estimated that more than 1% of all U.S. children use melatonin supplements, most commonly for sleep, stress, and relaxation.
“Given new research as to the excessive quantities of melatonin in gummies, caution should be used if considering their use,” said Dr. Cohen.
“It’s important to inquire about melatonin use when caring for children, particularly when parents express concerns about their child’s sleep,” he added.
The American Academy of Sleep Medicine recently issued a health advisory encouraging parents to talk to a health care professional before giving melatonin or any supplement to children.
Children don’t need melatonin
Commenting on the study, Michael Breus, PhD, clinical psychologist and founder of TheSleepDoctor.com, agreed that analyzing only one sample of each brand is a key limitation “because supplements are made in batches, and gummies in particular are difficult to distribute the active ingredient evenly.
“But even with that being said, 88% of them were labeled incorrectly, so even if there were a few single-sample issues, I kind of doubt its all of them,” Dr. Breus said.
“Kids as a general rule do not need melatonin. Their brains make almost four times the necessary amount already. If you start giving kids pills to help them sleep, then they start to have a pill problem, causing another issue,” Dr. Breus added.
“Most children’s falling asleep and staying sleep issues can be treated with behavioral measures like cognitive-behavioral therapy for insomnia,” he said.
The study had no specific funding. Dr. Cohen has received research support from Consumers Union and PEW Charitable Trusts and royalties from UptoDate. Dr. Breus disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
New data may explain the recent massive jump in pediatric hospitalizations.
Thenvestigators found that consuming some products as directed could expose consumers, including children, to doses that are 40-130 times greater than what’s recommended.
“The results were quite shocking,” lead researcher Pieter Cohen, MD, with Harvard Medical School, Boston, and Cambridge Health Alliance, Somerville, Mass., said in an interview.
“Melatonin gummies contained up to 347% more melatonin than what was listed on the label, and some products also contained cannabidiol; in one brand of melatonin gummies, there was zero melatonin, just CBD,” Dr. Cohen said.
The study was published online in JAMA.
530% jump in pediatric hospitalizations
Melatonin products are not approved by the Food and Drug Administration but are sold over the counter or online.
Previous research from JAMA has shown the use of melatonin has increased over the past 2 decades among people of all ages.
With increased use has come a spike in reports of melatonin overdose, calls to poison control centers, and related ED visits for children.
Federal data show the number of U.S. children who unintentionally ingested melatonin supplements jumped 530% from 2012 to 2021. More than 4,000 of the reported ingestions led to a hospital stay; 287 children required intensive care, and two children died.
It was unclear why melatonin supplements were causing these harms, which led Dr. Cohen’s team to analyze 25 unique brands of “melatonin” gummies purchased online.
One product didn’t contain any melatonin but did contain 31.3 mg of CBD.
In the remaining products, the quantity of melatonin ranged from 1.3 mg to 13.1 mg per serving. The actual quantity of melatonin ranged from 74% to 347% of the labeled quantity, the researchers found.
They note that for a young adult who takes as little as 0.1-0.3 mg of melatonin, plasma concentrations can increase into the normal night-time range.
Of the 25 products (88%) analyzed, 22 were inaccurately labeled, and only 3 (12%) contained a quantity of melatonin that was within 10% (plus or minus) of the declared quantity.
Five products listed CBD as an ingredient. The listed quantity ranged from 10.6 mg to 31.3 mg per serving, although the actual quantity of CBD ranged from 104% to 118% of the labeled quantity.
Inquire about use in kids
A limitation of the study is that only one sample of each brand was analyzed, and only gummies were analyzed. It is not known whether the results are generalizable to melatonin products sold as tablets and capsules in the United States or whether the quantity of melatonin within an individual brand may vary from batch to batch.
A recent study from Canada showed similar results. In an analysis of 16 Canadian melatonin brands, the actual dose of melatonin ranged from 17% to 478% of the declared quantity.
It’s estimated that more than 1% of all U.S. children use melatonin supplements, most commonly for sleep, stress, and relaxation.
“Given new research as to the excessive quantities of melatonin in gummies, caution should be used if considering their use,” said Dr. Cohen.
“It’s important to inquire about melatonin use when caring for children, particularly when parents express concerns about their child’s sleep,” he added.
The American Academy of Sleep Medicine recently issued a health advisory encouraging parents to talk to a health care professional before giving melatonin or any supplement to children.
Children don’t need melatonin
Commenting on the study, Michael Breus, PhD, clinical psychologist and founder of TheSleepDoctor.com, agreed that analyzing only one sample of each brand is a key limitation “because supplements are made in batches, and gummies in particular are difficult to distribute the active ingredient evenly.
“But even with that being said, 88% of them were labeled incorrectly, so even if there were a few single-sample issues, I kind of doubt its all of them,” Dr. Breus said.
“Kids as a general rule do not need melatonin. Their brains make almost four times the necessary amount already. If you start giving kids pills to help them sleep, then they start to have a pill problem, causing another issue,” Dr. Breus added.
“Most children’s falling asleep and staying sleep issues can be treated with behavioral measures like cognitive-behavioral therapy for insomnia,” he said.
The study had no specific funding. Dr. Cohen has received research support from Consumers Union and PEW Charitable Trusts and royalties from UptoDate. Dr. Breus disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
New data may explain the recent massive jump in pediatric hospitalizations.
Thenvestigators found that consuming some products as directed could expose consumers, including children, to doses that are 40-130 times greater than what’s recommended.
“The results were quite shocking,” lead researcher Pieter Cohen, MD, with Harvard Medical School, Boston, and Cambridge Health Alliance, Somerville, Mass., said in an interview.
“Melatonin gummies contained up to 347% more melatonin than what was listed on the label, and some products also contained cannabidiol; in one brand of melatonin gummies, there was zero melatonin, just CBD,” Dr. Cohen said.
The study was published online in JAMA.
530% jump in pediatric hospitalizations
Melatonin products are not approved by the Food and Drug Administration but are sold over the counter or online.
Previous research from JAMA has shown the use of melatonin has increased over the past 2 decades among people of all ages.
With increased use has come a spike in reports of melatonin overdose, calls to poison control centers, and related ED visits for children.
Federal data show the number of U.S. children who unintentionally ingested melatonin supplements jumped 530% from 2012 to 2021. More than 4,000 of the reported ingestions led to a hospital stay; 287 children required intensive care, and two children died.
It was unclear why melatonin supplements were causing these harms, which led Dr. Cohen’s team to analyze 25 unique brands of “melatonin” gummies purchased online.
One product didn’t contain any melatonin but did contain 31.3 mg of CBD.
In the remaining products, the quantity of melatonin ranged from 1.3 mg to 13.1 mg per serving. The actual quantity of melatonin ranged from 74% to 347% of the labeled quantity, the researchers found.
They note that for a young adult who takes as little as 0.1-0.3 mg of melatonin, plasma concentrations can increase into the normal night-time range.
Of the 25 products (88%) analyzed, 22 were inaccurately labeled, and only 3 (12%) contained a quantity of melatonin that was within 10% (plus or minus) of the declared quantity.
Five products listed CBD as an ingredient. The listed quantity ranged from 10.6 mg to 31.3 mg per serving, although the actual quantity of CBD ranged from 104% to 118% of the labeled quantity.
Inquire about use in kids
A limitation of the study is that only one sample of each brand was analyzed, and only gummies were analyzed. It is not known whether the results are generalizable to melatonin products sold as tablets and capsules in the United States or whether the quantity of melatonin within an individual brand may vary from batch to batch.
A recent study from Canada showed similar results. In an analysis of 16 Canadian melatonin brands, the actual dose of melatonin ranged from 17% to 478% of the declared quantity.
It’s estimated that more than 1% of all U.S. children use melatonin supplements, most commonly for sleep, stress, and relaxation.
“Given new research as to the excessive quantities of melatonin in gummies, caution should be used if considering their use,” said Dr. Cohen.
“It’s important to inquire about melatonin use when caring for children, particularly when parents express concerns about their child’s sleep,” he added.
The American Academy of Sleep Medicine recently issued a health advisory encouraging parents to talk to a health care professional before giving melatonin or any supplement to children.
Children don’t need melatonin
Commenting on the study, Michael Breus, PhD, clinical psychologist and founder of TheSleepDoctor.com, agreed that analyzing only one sample of each brand is a key limitation “because supplements are made in batches, and gummies in particular are difficult to distribute the active ingredient evenly.
“But even with that being said, 88% of them were labeled incorrectly, so even if there were a few single-sample issues, I kind of doubt its all of them,” Dr. Breus said.
“Kids as a general rule do not need melatonin. Their brains make almost four times the necessary amount already. If you start giving kids pills to help them sleep, then they start to have a pill problem, causing another issue,” Dr. Breus added.
“Most children’s falling asleep and staying sleep issues can be treated with behavioral measures like cognitive-behavioral therapy for insomnia,” he said.
The study had no specific funding. Dr. Cohen has received research support from Consumers Union and PEW Charitable Trusts and royalties from UptoDate. Dr. Breus disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA
Strong need for eating disorder screening in patients with PTSD
WASHINGTON –
“Eating-related and body-image concerns may be more prevalent than we think, and if not considered, these concerns can make psychotherapy treatment less effective,” study author Nick Powers, a doctoral student in clinical psychology, La Salle University, Philadelphia, told this news organization.
The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
Common bedfellows
Although many patients with PTSD also have an eating disorder, they are not always properly assessed for eating pathology and related functional impairment.
Some therapists don’t feel adequately equipped to target eating-related concerns in these patients and so may refer them to other providers. This, said Mr. Powers, can prolong symptoms and further distress patients.
Mr. Powers noted childhood physical or sexual abuse may affect eating patterns in patients with PTSD. “The evidence suggests these types of trauma exposure can be risk factors for the development of an eating disorder.”
Undiagnosed eating pathology may exacerbate functional impairment from PTSD and weaken the impact of evidence-based treatment.
Such patients are challenging to treat as they may not have the requisite skills to fully engage in exposure therapy, an evidence-based approach to treat PTSD, said Mr. Powers.
To determine whether PTSD would be significantly linked to greater eating disorder impairment (EDI) compared with other anxiety-related diagnoses and whether this would impair treatment, investigators studied 748 patients with an anxiety disorder who were attending a cognitive behavioral therapy (CBT) clinic. Anxiety disorders included PTSD, obsessive-compulsive disorder (OCD), social anxiety, and panic disorder.
Participants completed the 16-item Clinical Impairment Assessment (CIA) questionnaire, which includes questions about eating habits and feelings about food, body shape, and weight over the previous 4 weeks. Participants also reported anxiety symptom severity at the beginning, during, and end of treatment.
Need for better screening
Results showed that compared with those who had other anxiety disorders, patients with PTSD were three times more likely to have disordered eating (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.47-6.37; P = .003).
In addition, higher baseline CIA scores predicted poorer PTSD treatment outcome (beta = –1.4; 95% CI, –1.67 to –1.10; P < .01).
“Having higher baseline CIA scores meant that patients’ PTSD symptoms did not remit as strongly compared to those with lower scores,” said Mr. Powers.
Patients with both PTSD and an eating disorder may have difficulty with regulating emotions and tolerating distress, he said.
“They may use binge eating, purging, or food restriction as strategies to regulate emotions. These behaviors may allow patients to become numb to or avoid heightened emotions that come from having PTSD and an eating disorder.”
Prior research linked perfectionism tendencies to poorer response to PTSD treatment. Those with an eating disorder may share similar tendencies, said Mr. Powers.
“If someone is consistently thinking negatively about their eating or body to the point where it interrupts their functioning, they may not be as likely to fully engage with PTSD treatment,” he said.
Ideally, clinicians would screen all patients with PTSD for an eating disorder, said Mr. Powers. “If screening instruments aren’t feasible or available, even just inquiring about body image or history of maladaptive eating behaviors can be helpful.”
He added this could open up a conversation about a traumatic event in the patient’s past.
Confirmatory research
Commenting on the study, Karen S. Mitchell, PhD, clinical research psychologist, National Center for PTSD, VA Boston Healthcare System, and associate professor in psychiatry, Boston University, said she was “excited” to see this research.
“Very few studies have examined the impact of baseline eating disorder symptoms on PTSD treatment outcomes or vice versa,” she said.
The study findings “add to the small but growing body of evidence suggesting that comorbid PTSD and eating disorder symptoms can impact recovery from each disorder,” she said.
She noted the importance of assessing comorbidity in patients presenting for treatment and of addressing comorbidity in both eating disorders and PTSD treatment. “But we need more research on how best to do this.”
Mr. Powers and Dr. Mitchell have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
WASHINGTON –
“Eating-related and body-image concerns may be more prevalent than we think, and if not considered, these concerns can make psychotherapy treatment less effective,” study author Nick Powers, a doctoral student in clinical psychology, La Salle University, Philadelphia, told this news organization.
The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
Common bedfellows
Although many patients with PTSD also have an eating disorder, they are not always properly assessed for eating pathology and related functional impairment.
Some therapists don’t feel adequately equipped to target eating-related concerns in these patients and so may refer them to other providers. This, said Mr. Powers, can prolong symptoms and further distress patients.
Mr. Powers noted childhood physical or sexual abuse may affect eating patterns in patients with PTSD. “The evidence suggests these types of trauma exposure can be risk factors for the development of an eating disorder.”
Undiagnosed eating pathology may exacerbate functional impairment from PTSD and weaken the impact of evidence-based treatment.
Such patients are challenging to treat as they may not have the requisite skills to fully engage in exposure therapy, an evidence-based approach to treat PTSD, said Mr. Powers.
To determine whether PTSD would be significantly linked to greater eating disorder impairment (EDI) compared with other anxiety-related diagnoses and whether this would impair treatment, investigators studied 748 patients with an anxiety disorder who were attending a cognitive behavioral therapy (CBT) clinic. Anxiety disorders included PTSD, obsessive-compulsive disorder (OCD), social anxiety, and panic disorder.
Participants completed the 16-item Clinical Impairment Assessment (CIA) questionnaire, which includes questions about eating habits and feelings about food, body shape, and weight over the previous 4 weeks. Participants also reported anxiety symptom severity at the beginning, during, and end of treatment.
Need for better screening
Results showed that compared with those who had other anxiety disorders, patients with PTSD were three times more likely to have disordered eating (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.47-6.37; P = .003).
In addition, higher baseline CIA scores predicted poorer PTSD treatment outcome (beta = –1.4; 95% CI, –1.67 to –1.10; P < .01).
“Having higher baseline CIA scores meant that patients’ PTSD symptoms did not remit as strongly compared to those with lower scores,” said Mr. Powers.
Patients with both PTSD and an eating disorder may have difficulty with regulating emotions and tolerating distress, he said.
“They may use binge eating, purging, or food restriction as strategies to regulate emotions. These behaviors may allow patients to become numb to or avoid heightened emotions that come from having PTSD and an eating disorder.”
Prior research linked perfectionism tendencies to poorer response to PTSD treatment. Those with an eating disorder may share similar tendencies, said Mr. Powers.
“If someone is consistently thinking negatively about their eating or body to the point where it interrupts their functioning, they may not be as likely to fully engage with PTSD treatment,” he said.
Ideally, clinicians would screen all patients with PTSD for an eating disorder, said Mr. Powers. “If screening instruments aren’t feasible or available, even just inquiring about body image or history of maladaptive eating behaviors can be helpful.”
He added this could open up a conversation about a traumatic event in the patient’s past.
Confirmatory research
Commenting on the study, Karen S. Mitchell, PhD, clinical research psychologist, National Center for PTSD, VA Boston Healthcare System, and associate professor in psychiatry, Boston University, said she was “excited” to see this research.
“Very few studies have examined the impact of baseline eating disorder symptoms on PTSD treatment outcomes or vice versa,” she said.
The study findings “add to the small but growing body of evidence suggesting that comorbid PTSD and eating disorder symptoms can impact recovery from each disorder,” she said.
She noted the importance of assessing comorbidity in patients presenting for treatment and of addressing comorbidity in both eating disorders and PTSD treatment. “But we need more research on how best to do this.”
Mr. Powers and Dr. Mitchell have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
WASHINGTON –
“Eating-related and body-image concerns may be more prevalent than we think, and if not considered, these concerns can make psychotherapy treatment less effective,” study author Nick Powers, a doctoral student in clinical psychology, La Salle University, Philadelphia, told this news organization.
The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
Common bedfellows
Although many patients with PTSD also have an eating disorder, they are not always properly assessed for eating pathology and related functional impairment.
Some therapists don’t feel adequately equipped to target eating-related concerns in these patients and so may refer them to other providers. This, said Mr. Powers, can prolong symptoms and further distress patients.
Mr. Powers noted childhood physical or sexual abuse may affect eating patterns in patients with PTSD. “The evidence suggests these types of trauma exposure can be risk factors for the development of an eating disorder.”
Undiagnosed eating pathology may exacerbate functional impairment from PTSD and weaken the impact of evidence-based treatment.
Such patients are challenging to treat as they may not have the requisite skills to fully engage in exposure therapy, an evidence-based approach to treat PTSD, said Mr. Powers.
To determine whether PTSD would be significantly linked to greater eating disorder impairment (EDI) compared with other anxiety-related diagnoses and whether this would impair treatment, investigators studied 748 patients with an anxiety disorder who were attending a cognitive behavioral therapy (CBT) clinic. Anxiety disorders included PTSD, obsessive-compulsive disorder (OCD), social anxiety, and panic disorder.
Participants completed the 16-item Clinical Impairment Assessment (CIA) questionnaire, which includes questions about eating habits and feelings about food, body shape, and weight over the previous 4 weeks. Participants also reported anxiety symptom severity at the beginning, during, and end of treatment.
Need for better screening
Results showed that compared with those who had other anxiety disorders, patients with PTSD were three times more likely to have disordered eating (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.47-6.37; P = .003).
In addition, higher baseline CIA scores predicted poorer PTSD treatment outcome (beta = –1.4; 95% CI, –1.67 to –1.10; P < .01).
“Having higher baseline CIA scores meant that patients’ PTSD symptoms did not remit as strongly compared to those with lower scores,” said Mr. Powers.
Patients with both PTSD and an eating disorder may have difficulty with regulating emotions and tolerating distress, he said.
“They may use binge eating, purging, or food restriction as strategies to regulate emotions. These behaviors may allow patients to become numb to or avoid heightened emotions that come from having PTSD and an eating disorder.”
Prior research linked perfectionism tendencies to poorer response to PTSD treatment. Those with an eating disorder may share similar tendencies, said Mr. Powers.
“If someone is consistently thinking negatively about their eating or body to the point where it interrupts their functioning, they may not be as likely to fully engage with PTSD treatment,” he said.
Ideally, clinicians would screen all patients with PTSD for an eating disorder, said Mr. Powers. “If screening instruments aren’t feasible or available, even just inquiring about body image or history of maladaptive eating behaviors can be helpful.”
He added this could open up a conversation about a traumatic event in the patient’s past.
Confirmatory research
Commenting on the study, Karen S. Mitchell, PhD, clinical research psychologist, National Center for PTSD, VA Boston Healthcare System, and associate professor in psychiatry, Boston University, said she was “excited” to see this research.
“Very few studies have examined the impact of baseline eating disorder symptoms on PTSD treatment outcomes or vice versa,” she said.
The study findings “add to the small but growing body of evidence suggesting that comorbid PTSD and eating disorder symptoms can impact recovery from each disorder,” she said.
She noted the importance of assessing comorbidity in patients presenting for treatment and of addressing comorbidity in both eating disorders and PTSD treatment. “But we need more research on how best to do this.”
Mr. Powers and Dr. Mitchell have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ADAA 2023
Atogepant prevents episodic migraine in some difficult-to-treat cases
BOSTON – , according to findings from a study presented at the 2023 annual meeting of the American Academy of Neurology.
Initial results from the double-blind ELEVATE trial showed the oral atogepant group had significantly fewer mean monthly migraine days (MMD) compared with a placebo group. There was also a significant difference in the number of participants who achieved 50% or greater reduction in the number of mean MMDs and a significant reduction in acute medication use days compared with the placebo group, according to Patricia Pozo-Rosich, MD, PhD, a headache specialist in the neurology department and director of the headache and craniofacial pain clinical unit and the Migraine Adaptive Brain Center at the Vall d’Hebron University Hospital in Barcelona, and colleagues.
The oral calcitonin gene-related peptide (CGRP) receptor antagonist is currently approved in the United States by the Food and Drug Administration as a preventative for both episodic and chronic migraine.
Results from ELEVATE
Overall, ELEVATE’s initial efficacy analysis population consisted of 309 adults aged between 18 and 80 years from North America and Europe with episodic migraine who had 4-14 MMDs and had treatment failure with at least two classes of conventional oral medication. After a 28-day screening period, participants received either 60 mg of oral atogepant once per day (154 participants) or a placebo (155 participants). In the efficacy analysis population, 56.0% of participants had failed two oral migraine preventative medication classes, while 44.0% failed three or more classes of medication. Dr. Pozo-Rosich noted that participants were taking a number of different oral preventatives across different medication classes, including flunarizine, beta blockers, topiramate, and amitriptyline, but data are not yet available on which participants had received certain combinations of oral medications.
“[T]hese people have already taken some type of prevention, so they’re not naive patients,” she said. “They’re usually more or less well treated in the sense of having had a contact with specialists or a general neurologist, someone that actually tries to do some prevention.”
The researchers examined change from MMDs at baseline and at 12 weeks as a primary outcome, with 50% or greater MMD reduction, change in mean monthly headache days, and change in acute medication use days as secondary outcomes. Regarding the different acute medications used, Dr. Pozo-Rosich said the main three types were analgesics, nonsteroid anti-inflammatory drugs, and triptans, with participants excluded from the trial if they were taking opioids.
The results showed participants in the atogepant group had significantly fewer mean MMDs compared with the placebo group at 12 weeks compared with baseline (–4.20 vs. –1.85 days; P < .0001). Researchers also found statistically significant improvement in the atogepant group for 50% or greater reduction in MMD, change in mean monthly headache days, and change in acute medication use days across 12 weeks of treatment compared with the placebo group. While the specific data analyses for secondary outcomes were not conducted in the initial analysis, Dr. Pozo-Rosich said the numbers “correlate with the primary outcome” as seen in other migraine trials.
Compared with the placebo group, participants in the atogepant group had higher rates of constipation (10.3% vs. 2.5%), COVID-19 (9.6% vs. 8.3%), and nausea (7.1% vs. 3.2%), while the placebo group had a higher rate of nasopharyngitis (5.1% vs. 7.6%).*
Migraine is a prevalent and undertreated disease, and patients around the world with migraine are in need of treatment options that are both safe and effective, Dr. Pozo-Rosich said in an interview. “[E]ven in these hard-to-treat or difficult-to-treat migraine patients, you have a drug that works, and is safe, and well tolerated and effective,” she said.
That’s “kind of good news for all of us,” she said. Patients “need this type of good news and solution,” she explained, because they may not tolerate or have access to injectable medications. Atogepant would also give clinicians have another option to offer patients with difficult-to-treat migraine cases, she noted. “It makes life easier for many physicians and many patients for many different reasons,” she said.
Dr. Pozo-Rosich said the likely next step in the research is to conduct the main analysis as well as post hoc analyses with accumulated data from pathology trials “to understand patterns of response, understand the sustainability of the response, [and] adherence to the treatment in the long term.”
‘Exciting that it works well’ in difficult-to-treat patients
Commenting on the study, Alan M. Rapoport, MD, clinical professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, agreed that better options in migraine treatment and prevention are needed.
“We needed something that was going to be better than what we had before,” he said.
Dr. Rapoport noted the study was well designed with strongly positive results. “It looks like it’s an effective drug, and it looks really good in that it’s effective for people that have failed all these preventives that have very little hope for the future,” he said.
He specifically praised the inclusion of older participants in the population. “You never see a study on 80-year-olds,” he said, “but I like that, because they felt it would be safe. There are 80-year-old patients – fewer of them than 40-year-old patients – but there are 80-year-old patients who still have migraine, so I’m really glad they put older patients in it,” he said.
For atogepant, he noted that “some patients won’t get the side effects, and some patients will tolerate the side effects because it’s working really well.” While the study was not a head-to-head comparison against other oral migraine preventatives, he pointed out the high rate of constipation among participants in the trial setting may be a warning sign of future issues, as seen with other CGRP receptor agonists.
“I can tell you that with erenumab, the monoclonal antibody that was injected in the double-blind studies, they didn’t find any significant increase in constipation,” he explained. However, some clinicians using erenumab in the real world have reported up to 20% of their patients are constipated. “It’s not good that they’re reporting 10% are constipated” in the study, he said.
Overall, “all you can really say is it does work well,” Dr. Rapoport said. “It’s exciting that it works well in such difficult-to-treat patients, and it does come with some side effects.”
Dr. Pozo-Rosich reports serving as a consultant and developing education materials for AbbVie, Eli Lilly, Novartis, Teva Pharmaceuticals, and Pfizer. Dr. Rapoport is the editor-in-chief of Neurology Reviews; he reports being a consultant for AbbVie, the developer of atogepant. The ELEVATE trial is supported by AbbVie.
*Correction, 5/4/23: An earlier version of this article misstated the percentage of COVID-positive patients in the study population.
BOSTON – , according to findings from a study presented at the 2023 annual meeting of the American Academy of Neurology.
Initial results from the double-blind ELEVATE trial showed the oral atogepant group had significantly fewer mean monthly migraine days (MMD) compared with a placebo group. There was also a significant difference in the number of participants who achieved 50% or greater reduction in the number of mean MMDs and a significant reduction in acute medication use days compared with the placebo group, according to Patricia Pozo-Rosich, MD, PhD, a headache specialist in the neurology department and director of the headache and craniofacial pain clinical unit and the Migraine Adaptive Brain Center at the Vall d’Hebron University Hospital in Barcelona, and colleagues.
The oral calcitonin gene-related peptide (CGRP) receptor antagonist is currently approved in the United States by the Food and Drug Administration as a preventative for both episodic and chronic migraine.
Results from ELEVATE
Overall, ELEVATE’s initial efficacy analysis population consisted of 309 adults aged between 18 and 80 years from North America and Europe with episodic migraine who had 4-14 MMDs and had treatment failure with at least two classes of conventional oral medication. After a 28-day screening period, participants received either 60 mg of oral atogepant once per day (154 participants) or a placebo (155 participants). In the efficacy analysis population, 56.0% of participants had failed two oral migraine preventative medication classes, while 44.0% failed three or more classes of medication. Dr. Pozo-Rosich noted that participants were taking a number of different oral preventatives across different medication classes, including flunarizine, beta blockers, topiramate, and amitriptyline, but data are not yet available on which participants had received certain combinations of oral medications.
“[T]hese people have already taken some type of prevention, so they’re not naive patients,” she said. “They’re usually more or less well treated in the sense of having had a contact with specialists or a general neurologist, someone that actually tries to do some prevention.”
The researchers examined change from MMDs at baseline and at 12 weeks as a primary outcome, with 50% or greater MMD reduction, change in mean monthly headache days, and change in acute medication use days as secondary outcomes. Regarding the different acute medications used, Dr. Pozo-Rosich said the main three types were analgesics, nonsteroid anti-inflammatory drugs, and triptans, with participants excluded from the trial if they were taking opioids.
The results showed participants in the atogepant group had significantly fewer mean MMDs compared with the placebo group at 12 weeks compared with baseline (–4.20 vs. –1.85 days; P < .0001). Researchers also found statistically significant improvement in the atogepant group for 50% or greater reduction in MMD, change in mean monthly headache days, and change in acute medication use days across 12 weeks of treatment compared with the placebo group. While the specific data analyses for secondary outcomes were not conducted in the initial analysis, Dr. Pozo-Rosich said the numbers “correlate with the primary outcome” as seen in other migraine trials.
Compared with the placebo group, participants in the atogepant group had higher rates of constipation (10.3% vs. 2.5%), COVID-19 (9.6% vs. 8.3%), and nausea (7.1% vs. 3.2%), while the placebo group had a higher rate of nasopharyngitis (5.1% vs. 7.6%).*
Migraine is a prevalent and undertreated disease, and patients around the world with migraine are in need of treatment options that are both safe and effective, Dr. Pozo-Rosich said in an interview. “[E]ven in these hard-to-treat or difficult-to-treat migraine patients, you have a drug that works, and is safe, and well tolerated and effective,” she said.
That’s “kind of good news for all of us,” she said. Patients “need this type of good news and solution,” she explained, because they may not tolerate or have access to injectable medications. Atogepant would also give clinicians have another option to offer patients with difficult-to-treat migraine cases, she noted. “It makes life easier for many physicians and many patients for many different reasons,” she said.
Dr. Pozo-Rosich said the likely next step in the research is to conduct the main analysis as well as post hoc analyses with accumulated data from pathology trials “to understand patterns of response, understand the sustainability of the response, [and] adherence to the treatment in the long term.”
‘Exciting that it works well’ in difficult-to-treat patients
Commenting on the study, Alan M. Rapoport, MD, clinical professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, agreed that better options in migraine treatment and prevention are needed.
“We needed something that was going to be better than what we had before,” he said.
Dr. Rapoport noted the study was well designed with strongly positive results. “It looks like it’s an effective drug, and it looks really good in that it’s effective for people that have failed all these preventives that have very little hope for the future,” he said.
He specifically praised the inclusion of older participants in the population. “You never see a study on 80-year-olds,” he said, “but I like that, because they felt it would be safe. There are 80-year-old patients – fewer of them than 40-year-old patients – but there are 80-year-old patients who still have migraine, so I’m really glad they put older patients in it,” he said.
For atogepant, he noted that “some patients won’t get the side effects, and some patients will tolerate the side effects because it’s working really well.” While the study was not a head-to-head comparison against other oral migraine preventatives, he pointed out the high rate of constipation among participants in the trial setting may be a warning sign of future issues, as seen with other CGRP receptor agonists.
“I can tell you that with erenumab, the monoclonal antibody that was injected in the double-blind studies, they didn’t find any significant increase in constipation,” he explained. However, some clinicians using erenumab in the real world have reported up to 20% of their patients are constipated. “It’s not good that they’re reporting 10% are constipated” in the study, he said.
Overall, “all you can really say is it does work well,” Dr. Rapoport said. “It’s exciting that it works well in such difficult-to-treat patients, and it does come with some side effects.”
Dr. Pozo-Rosich reports serving as a consultant and developing education materials for AbbVie, Eli Lilly, Novartis, Teva Pharmaceuticals, and Pfizer. Dr. Rapoport is the editor-in-chief of Neurology Reviews; he reports being a consultant for AbbVie, the developer of atogepant. The ELEVATE trial is supported by AbbVie.
*Correction, 5/4/23: An earlier version of this article misstated the percentage of COVID-positive patients in the study population.
BOSTON – , according to findings from a study presented at the 2023 annual meeting of the American Academy of Neurology.
Initial results from the double-blind ELEVATE trial showed the oral atogepant group had significantly fewer mean monthly migraine days (MMD) compared with a placebo group. There was also a significant difference in the number of participants who achieved 50% or greater reduction in the number of mean MMDs and a significant reduction in acute medication use days compared with the placebo group, according to Patricia Pozo-Rosich, MD, PhD, a headache specialist in the neurology department and director of the headache and craniofacial pain clinical unit and the Migraine Adaptive Brain Center at the Vall d’Hebron University Hospital in Barcelona, and colleagues.
The oral calcitonin gene-related peptide (CGRP) receptor antagonist is currently approved in the United States by the Food and Drug Administration as a preventative for both episodic and chronic migraine.
Results from ELEVATE
Overall, ELEVATE’s initial efficacy analysis population consisted of 309 adults aged between 18 and 80 years from North America and Europe with episodic migraine who had 4-14 MMDs and had treatment failure with at least two classes of conventional oral medication. After a 28-day screening period, participants received either 60 mg of oral atogepant once per day (154 participants) or a placebo (155 participants). In the efficacy analysis population, 56.0% of participants had failed two oral migraine preventative medication classes, while 44.0% failed three or more classes of medication. Dr. Pozo-Rosich noted that participants were taking a number of different oral preventatives across different medication classes, including flunarizine, beta blockers, topiramate, and amitriptyline, but data are not yet available on which participants had received certain combinations of oral medications.
“[T]hese people have already taken some type of prevention, so they’re not naive patients,” she said. “They’re usually more or less well treated in the sense of having had a contact with specialists or a general neurologist, someone that actually tries to do some prevention.”
The researchers examined change from MMDs at baseline and at 12 weeks as a primary outcome, with 50% or greater MMD reduction, change in mean monthly headache days, and change in acute medication use days as secondary outcomes. Regarding the different acute medications used, Dr. Pozo-Rosich said the main three types were analgesics, nonsteroid anti-inflammatory drugs, and triptans, with participants excluded from the trial if they were taking opioids.
The results showed participants in the atogepant group had significantly fewer mean MMDs compared with the placebo group at 12 weeks compared with baseline (–4.20 vs. –1.85 days; P < .0001). Researchers also found statistically significant improvement in the atogepant group for 50% or greater reduction in MMD, change in mean monthly headache days, and change in acute medication use days across 12 weeks of treatment compared with the placebo group. While the specific data analyses for secondary outcomes were not conducted in the initial analysis, Dr. Pozo-Rosich said the numbers “correlate with the primary outcome” as seen in other migraine trials.
Compared with the placebo group, participants in the atogepant group had higher rates of constipation (10.3% vs. 2.5%), COVID-19 (9.6% vs. 8.3%), and nausea (7.1% vs. 3.2%), while the placebo group had a higher rate of nasopharyngitis (5.1% vs. 7.6%).*
Migraine is a prevalent and undertreated disease, and patients around the world with migraine are in need of treatment options that are both safe and effective, Dr. Pozo-Rosich said in an interview. “[E]ven in these hard-to-treat or difficult-to-treat migraine patients, you have a drug that works, and is safe, and well tolerated and effective,” she said.
That’s “kind of good news for all of us,” she said. Patients “need this type of good news and solution,” she explained, because they may not tolerate or have access to injectable medications. Atogepant would also give clinicians have another option to offer patients with difficult-to-treat migraine cases, she noted. “It makes life easier for many physicians and many patients for many different reasons,” she said.
Dr. Pozo-Rosich said the likely next step in the research is to conduct the main analysis as well as post hoc analyses with accumulated data from pathology trials “to understand patterns of response, understand the sustainability of the response, [and] adherence to the treatment in the long term.”
‘Exciting that it works well’ in difficult-to-treat patients
Commenting on the study, Alan M. Rapoport, MD, clinical professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, agreed that better options in migraine treatment and prevention are needed.
“We needed something that was going to be better than what we had before,” he said.
Dr. Rapoport noted the study was well designed with strongly positive results. “It looks like it’s an effective drug, and it looks really good in that it’s effective for people that have failed all these preventives that have very little hope for the future,” he said.
He specifically praised the inclusion of older participants in the population. “You never see a study on 80-year-olds,” he said, “but I like that, because they felt it would be safe. There are 80-year-old patients – fewer of them than 40-year-old patients – but there are 80-year-old patients who still have migraine, so I’m really glad they put older patients in it,” he said.
For atogepant, he noted that “some patients won’t get the side effects, and some patients will tolerate the side effects because it’s working really well.” While the study was not a head-to-head comparison against other oral migraine preventatives, he pointed out the high rate of constipation among participants in the trial setting may be a warning sign of future issues, as seen with other CGRP receptor agonists.
“I can tell you that with erenumab, the monoclonal antibody that was injected in the double-blind studies, they didn’t find any significant increase in constipation,” he explained. However, some clinicians using erenumab in the real world have reported up to 20% of their patients are constipated. “It’s not good that they’re reporting 10% are constipated” in the study, he said.
Overall, “all you can really say is it does work well,” Dr. Rapoport said. “It’s exciting that it works well in such difficult-to-treat patients, and it does come with some side effects.”
Dr. Pozo-Rosich reports serving as a consultant and developing education materials for AbbVie, Eli Lilly, Novartis, Teva Pharmaceuticals, and Pfizer. Dr. Rapoport is the editor-in-chief of Neurology Reviews; he reports being a consultant for AbbVie, the developer of atogepant. The ELEVATE trial is supported by AbbVie.
*Correction, 5/4/23: An earlier version of this article misstated the percentage of COVID-positive patients in the study population.
FROM AAN 2023
New ABIM fees to stay listed as ‘board certified’ irk physicians
Abdul Moiz Hafiz, MD, was flabbergasted when he received a phone call from his institution’s credentialing office telling him that he was not certified for interventional cardiology – even though he had passed that exam in 2016.
Dr. Hafiz, who directs the Advanced Structural Heart Disease Program at Southern Illinois University, phoned the American Board of Internal Medicine (ABIM), where he learned that to restore his credentials, he would need to pay $1,225 in maintenance of certification (MOC) fees.
Like Dr. Hafiz,
Even doctors who are participating in mandatory continuing education outside the ABIM’s auspices are finding themselves listed as “not certified.” Some physicians learned of the policy change only after applying for hospital privileges or for jobs that require ABIM certification.
Now that increasing numbers of physicians are employed by hospitals and health care organizations that require ABIM certification, many doctors have no option but to pony up the fees if they want to continue to practice medicine.
“We have no say in the matter,” said Dr. Hafiz, “and there’s no appeal process.”
The change affects nearly 330,000 physicians. Responses to the policy on Twitter included accusations of extortion and denunciations of the ABIM’s “money grab policies.”
Sunil Rao, MD, director of interventional cardiology at NYU Langone Health and president of the Society for Cardiovascular Angiography and Interventions (SCAI), has heard from many SCAI members who had experiences similar to Dr. Hafiz’s. While Dr. Rao describes some of the Twitter outrage as “emotional,” he does acknowledge that the ABIM’s moves appear to be financially motivated.
“The issue here was that as soon as they paid the fee, all of a sudden, ABIM flipped the switch and said they were certified,” he said. “It certainly sounds like a purely financial kind of structure.”
Richard Baron, MD, president and CEO of the ABIM, said doctors are misunderstanding the policy change.
“No doctor loses certification solely for failure to pay fees,” Dr. Baron told this news organization. “What caused them to be reported as not certified was that we didn’t have evidence that they had met program requirements. They could say, ‘But I did meet program requirements, you just didn’t know it.’ To which our answer would be, for us to know it, we have to process them. And our policy is that we don’t process them unless you are current on your fees.”
This is not the first time ABIM policies have alienated physicians.
Last year, the ABIM raised its MOC fees from $165 to $220. That also prompted a wave of outrage. Other grievances go further back. At one time, being board certified was a lifetime credential. However, in 1990 the ABIM made periodic recertification mandatory.
The process, which came to be known as “maintenance of certification,” had to be completed every 10 years, and fees were charged for each certification. At that point, said Dr. Baron, the relationship between the ABIM and physicians changed from a one-time interaction to a career-long relationship. He advises doctors to check in periodically on their portal page at the ABIM or download the app so they will always know their status.
Many physicians would prefer not to be bound to a lifetime relationship with the ABIM. There is an alternative licensing board, the National Board of Physicians and Surgeons (NBPAS), but it is accepted by only a limited number of hospitals.
“Until the NBPAS gains wide recognition,” said Dr. Hafiz, “the ABIM is going to continue to have basically a monopoly over the market.”
The value of MOC itself has been called into question. “There are no direct data supporting the value of the MOC process in either improving care, making patient care safer, or making patient care higher quality,” said Dr. Rao. This feeds frustration in a clinical community already dealing with onerous training requirements and expensive board certification exams and adds to the perception that it is a purely financial transaction, he said. (Studies examining whether the MOC system improves patient care have shown mixed results.)
The true value of the ABIM to physicians, Dr. Baron contends, is that the organization is an independent third party that differentiates those doctors from people who don’t have their skills, training, and expertise. “In these days, where anyone can be an ‘expert’ on the Internet, that’s more valuable than ever before,” he said.
A version of this article first appeared on Medscape.com.
Abdul Moiz Hafiz, MD, was flabbergasted when he received a phone call from his institution’s credentialing office telling him that he was not certified for interventional cardiology – even though he had passed that exam in 2016.
Dr. Hafiz, who directs the Advanced Structural Heart Disease Program at Southern Illinois University, phoned the American Board of Internal Medicine (ABIM), where he learned that to restore his credentials, he would need to pay $1,225 in maintenance of certification (MOC) fees.
Like Dr. Hafiz,
Even doctors who are participating in mandatory continuing education outside the ABIM’s auspices are finding themselves listed as “not certified.” Some physicians learned of the policy change only after applying for hospital privileges or for jobs that require ABIM certification.
Now that increasing numbers of physicians are employed by hospitals and health care organizations that require ABIM certification, many doctors have no option but to pony up the fees if they want to continue to practice medicine.
“We have no say in the matter,” said Dr. Hafiz, “and there’s no appeal process.”
The change affects nearly 330,000 physicians. Responses to the policy on Twitter included accusations of extortion and denunciations of the ABIM’s “money grab policies.”
Sunil Rao, MD, director of interventional cardiology at NYU Langone Health and president of the Society for Cardiovascular Angiography and Interventions (SCAI), has heard from many SCAI members who had experiences similar to Dr. Hafiz’s. While Dr. Rao describes some of the Twitter outrage as “emotional,” he does acknowledge that the ABIM’s moves appear to be financially motivated.
“The issue here was that as soon as they paid the fee, all of a sudden, ABIM flipped the switch and said they were certified,” he said. “It certainly sounds like a purely financial kind of structure.”
Richard Baron, MD, president and CEO of the ABIM, said doctors are misunderstanding the policy change.
“No doctor loses certification solely for failure to pay fees,” Dr. Baron told this news organization. “What caused them to be reported as not certified was that we didn’t have evidence that they had met program requirements. They could say, ‘But I did meet program requirements, you just didn’t know it.’ To which our answer would be, for us to know it, we have to process them. And our policy is that we don’t process them unless you are current on your fees.”
This is not the first time ABIM policies have alienated physicians.
Last year, the ABIM raised its MOC fees from $165 to $220. That also prompted a wave of outrage. Other grievances go further back. At one time, being board certified was a lifetime credential. However, in 1990 the ABIM made periodic recertification mandatory.
The process, which came to be known as “maintenance of certification,” had to be completed every 10 years, and fees were charged for each certification. At that point, said Dr. Baron, the relationship between the ABIM and physicians changed from a one-time interaction to a career-long relationship. He advises doctors to check in periodically on their portal page at the ABIM or download the app so they will always know their status.
Many physicians would prefer not to be bound to a lifetime relationship with the ABIM. There is an alternative licensing board, the National Board of Physicians and Surgeons (NBPAS), but it is accepted by only a limited number of hospitals.
“Until the NBPAS gains wide recognition,” said Dr. Hafiz, “the ABIM is going to continue to have basically a monopoly over the market.”
The value of MOC itself has been called into question. “There are no direct data supporting the value of the MOC process in either improving care, making patient care safer, or making patient care higher quality,” said Dr. Rao. This feeds frustration in a clinical community already dealing with onerous training requirements and expensive board certification exams and adds to the perception that it is a purely financial transaction, he said. (Studies examining whether the MOC system improves patient care have shown mixed results.)
The true value of the ABIM to physicians, Dr. Baron contends, is that the organization is an independent third party that differentiates those doctors from people who don’t have their skills, training, and expertise. “In these days, where anyone can be an ‘expert’ on the Internet, that’s more valuable than ever before,” he said.
A version of this article first appeared on Medscape.com.
Abdul Moiz Hafiz, MD, was flabbergasted when he received a phone call from his institution’s credentialing office telling him that he was not certified for interventional cardiology – even though he had passed that exam in 2016.
Dr. Hafiz, who directs the Advanced Structural Heart Disease Program at Southern Illinois University, phoned the American Board of Internal Medicine (ABIM), where he learned that to restore his credentials, he would need to pay $1,225 in maintenance of certification (MOC) fees.
Like Dr. Hafiz,
Even doctors who are participating in mandatory continuing education outside the ABIM’s auspices are finding themselves listed as “not certified.” Some physicians learned of the policy change only after applying for hospital privileges or for jobs that require ABIM certification.
Now that increasing numbers of physicians are employed by hospitals and health care organizations that require ABIM certification, many doctors have no option but to pony up the fees if they want to continue to practice medicine.
“We have no say in the matter,” said Dr. Hafiz, “and there’s no appeal process.”
The change affects nearly 330,000 physicians. Responses to the policy on Twitter included accusations of extortion and denunciations of the ABIM’s “money grab policies.”
Sunil Rao, MD, director of interventional cardiology at NYU Langone Health and president of the Society for Cardiovascular Angiography and Interventions (SCAI), has heard from many SCAI members who had experiences similar to Dr. Hafiz’s. While Dr. Rao describes some of the Twitter outrage as “emotional,” he does acknowledge that the ABIM’s moves appear to be financially motivated.
“The issue here was that as soon as they paid the fee, all of a sudden, ABIM flipped the switch and said they were certified,” he said. “It certainly sounds like a purely financial kind of structure.”
Richard Baron, MD, president and CEO of the ABIM, said doctors are misunderstanding the policy change.
“No doctor loses certification solely for failure to pay fees,” Dr. Baron told this news organization. “What caused them to be reported as not certified was that we didn’t have evidence that they had met program requirements. They could say, ‘But I did meet program requirements, you just didn’t know it.’ To which our answer would be, for us to know it, we have to process them. And our policy is that we don’t process them unless you are current on your fees.”
This is not the first time ABIM policies have alienated physicians.
Last year, the ABIM raised its MOC fees from $165 to $220. That also prompted a wave of outrage. Other grievances go further back. At one time, being board certified was a lifetime credential. However, in 1990 the ABIM made periodic recertification mandatory.
The process, which came to be known as “maintenance of certification,” had to be completed every 10 years, and fees were charged for each certification. At that point, said Dr. Baron, the relationship between the ABIM and physicians changed from a one-time interaction to a career-long relationship. He advises doctors to check in periodically on their portal page at the ABIM or download the app so they will always know their status.
Many physicians would prefer not to be bound to a lifetime relationship with the ABIM. There is an alternative licensing board, the National Board of Physicians and Surgeons (NBPAS), but it is accepted by only a limited number of hospitals.
“Until the NBPAS gains wide recognition,” said Dr. Hafiz, “the ABIM is going to continue to have basically a monopoly over the market.”
The value of MOC itself has been called into question. “There are no direct data supporting the value of the MOC process in either improving care, making patient care safer, or making patient care higher quality,” said Dr. Rao. This feeds frustration in a clinical community already dealing with onerous training requirements and expensive board certification exams and adds to the perception that it is a purely financial transaction, he said. (Studies examining whether the MOC system improves patient care have shown mixed results.)
The true value of the ABIM to physicians, Dr. Baron contends, is that the organization is an independent third party that differentiates those doctors from people who don’t have their skills, training, and expertise. “In these days, where anyone can be an ‘expert’ on the Internet, that’s more valuable than ever before,” he said.
A version of this article first appeared on Medscape.com.
BMI is a flawed measure of obesity. What are alternatives?
“BMI is trash. Full stop.” This controversial tweet, which received thousands of likes and retweets, was cited in a recent article by one doctor on when physicians might stop using body mass index (BMI) to diagnose obesity.
BMI has for years been the consensus default method for assessing whether a person is overweight or has obesity, and is still widely used as the gatekeeper metric for treatment eligibility for certain weight-loss agents and bariatric surgery.
an important determinant of the cardiometabolic consequences of fat.
Alternative metrics include waist circumference and/or waist-to-height ratio (WHtR); imaging methods such as CT, MRI, and dual-energy x-ray absorptiometry (DXA); and bioelectrical impedance to assess fat volume and location. All have made some inroads on the tight grip BMI has had on obesity assessment.
Chances are, however, that BMI will not fade away anytime soon given how entrenched it has become in clinical practice and for insurance coverage, as well as its relative simplicity and precision.
“BMI is embedded in a wide range of guidelines on the use of medications and surgery. It’s embedded in Food and Drug Administration regulations and for billing and insurance coverage. It would take extremely strong data and years of work to undo the infrastructure built around BMI and replace it with something else. I don’t see that happening [anytime soon],” commented Daniel H. Bessesen, MD, a professor at the University of Colorado at Denver, Aurora, and chief of endocrinology for Denver Health.
“It would be almost impossible to replace all the studies that have used BMI with investigations using some other measure,” he said.
BMI Is ‘imperfect’
The entrenched position of BMI as the go-to metric doesn’t keep detractors from weighing in. As noted in a commentary on current clinical challenges surrounding obesity recently published in Annals of Internal Medicine, the journal’s editor-in-chief, Christine Laine, MD, and senior deputy editor Christina C. Wee, MD, listed six top issues clinicians must deal with, one of which, they say, is the need for a better measure of obesity than BMI.
“Unfortunately, BMI is an imperfect measure of body composition that differs with ethnicity, sex, body frame, and muscle mass,” noted Dr. Laine and Dr. Wee.
BMI is based on a person’s weight in kilograms divided by the square of their height in meters. A “healthy” BMI is between 18.5 and 24.9 kg/m2, overweight is 25-29.9, and 30 or greater is considered to represent obesity. However, certain ethnic groups have lower cutoffs for overweight or obesity because of evidence that such individuals can be at higher risk of obesity-related comorbidities at lower BMIs.
“BMI was chosen as the initial screening tool [for obesity] not because anyone thought it was perfect or the best measure but because of its simplicity. All you need is height, weight, and a calculator,” Dr. Wee said in an interview.
Numerous online calculators are available, including one from the Centers for Disease Control and Prevention where height in feet and inches and weight in pounds can be entered to generate the BMI.
BMI is also inherently limited by being “a proxy for adiposity” and not a direct measure, added Dr. Wee, who is also director of the Obesity Research Program of Beth Israel Deaconess Medical Center, Boston.
As such, BMI can’t distinguish between fat and muscle because it relies on weight only to gauge adiposity, noted Tiffany Powell-Wiley, MD, an obesity researcher at the National Heart, Lung, and Blood Institute in Bethesda, Md. Another shortcoming of BMI is that it “is good for distinguishing population-level risk for cardiovascular disease and other chronic diseases, but it does not help as much for distinguishing risk at an individual level,” she said in an interview.
These and other drawbacks have prompted researchers to look for other useful metrics. WHtR, for example, has recently made headway as a potential BMI alternative or complement.
The case for WHtR
Concern about overreliance on BMI despite its limitations is not new. In 2015, an American Heart Association scientific statement from the group’s Obesity Committee concluded that “BMI alone, even with lower thresholds, is a useful but not an ideal tool for identification of obesity or assessment of cardiovascular risk,” especially for people from Asian, Black, Hispanic, and Pacific Islander populations.
The writing panel also recommended that clinicians measure waist circumference annually and use that information along with BMI “to better gauge cardiovascular risk in diverse populations.”
Momentum for moving beyond BMI alone has continued to build following the AHA statement.
In September 2022, the National Institute for Health and Care Excellence, which sets policies for the United Kingdom’s National Health Service, revised its guidancefor assessment and management of people with obesity. The updated guidance recommends that when clinicians assess “adults with BMI below 35 kg/m2, measure and use their WHtR, as well as their BMI, as a practical estimate of central adiposity and use these measurements to help to assess and predict health risks.”
NICE released an extensive literature review with the revision, and based on the evidence, said that “using waist-to-height ratio as well as BMI would help give a practical estimate of central adiposity in adults with BMI under 35 kg/m2. This would in turn help professionals assess and predict health risks.”
However, the review added that, “because people with a BMI over 35 kg/m2 are always likely to have a high WHtR, the committee recognized that it may not be a useful addition for predicting health risks in this group.” The 2022 NICE review also said that it is “important to estimate central adiposity when assessing future health risks, including for people whose BMI is in the healthy-weight category.”
This new emphasis by NICE on measuring and using WHtR as part of obesity assessment “represents an important change in population health policy,” commented Dr. Powell-Wiley. “I expect more professional organizations will endorse use of waist circumference or waist-to-height ratio now that NICE has taken this step,” she predicted.
Waist circumference and WHtR may become standard measures of adiposity in clinical practice over the next 5-10 years.
The recent move by NICE to highlight a complementary role for WHtR “is another acknowledgment that BMI is an imperfect tool for stratifying cardiometabolic risk in a diverse population, especially in people with lower BMIs” because of its variability, commented Jamie Almandoz, MD, medical director of the weight wellness program at UT Southwestern Medical Center, Dallas.
WHtR vs. BMI
Another recent step forward for WHtR came with the publication of a post hoc analysis of data collected in the PARADIGM-HF trial, a study that had the primary purpose of comparing two medications for improving outcomes in more than 8,000 patients with heart failure with reduced ejection fraction.
The new analysis showed that “two indices that incorporate waist circumference and height, but not weight, showed a clearer association between greater adiposity and a higher risk of heart failure hospitalization,” compared with BMI.
WHtR was one of the two indices identified as being a better correlate for the adverse effect of excess adiposity compared with BMI.
The authors of the post hoc analysis did not design their analysis to compare WHtR with BMI. Instead, their goal was to better understand what’s known as the “obesity paradox” in people with heart failure with reduced ejection fraction: The recurring observation that, when these patients with heart failure have lower BMIs they fare worse, with higher rates of mortality and adverse cardiovascular outcomes, compared with patients with higher BMIs.
The new analysis showed that this paradox disappeared when WHtR was substituted for BMI as the obesity metric.
This “provides meaningful data about the superiority of WHtR, compared with BMI, for predicting heart failure outcomes,” said Dr. Powell-Wiley, although she cautioned that the analysis was limited by scant data in diverse populations and did not look at other important cardiovascular disease outcomes. While Dr. Powell-Wiley does not think that WHtR needs assessment in a prospective, controlled trial, she called for analysis of pooled prospective studies with more diverse populations to better document the advantages of WHtR over BMI.
The PARADIGM-HF post hoc analysis shows again how flawed BMI is for health assessment and the relative importance of an individualized understanding of a person’s body composition, Dr. Almandoz said in an interview. “As we collect more data, there is increasing awareness of how imperfect BMI is.”
Measuring waist circumference is tricky
Although WHtR looks promising as a substitute for or add-on to BMI, it has its own limitations, particularly the challenge of accurately measuring waist circumference.
Measuring waist circumference “not only takes more time but requires the assessor to be well trained about where to put the tape measure and making sure it’s measured at the same place each time,” even when different people take serial measurements from individual patients, noted Dr. Wee. Determining waist circumference can also be technically difficult when done on larger people, she added, and collectively these challenges make waist circumference “less reproducible from measurement to measurement.”
“It’s relatively clear how to standardize measurement of weight and height, but there is a huge amount of variability when the waist is measured,” agreed Dr. Almandoz. “And waist circumference also differs by ethnicity, race, sex, and body frame. There are significant differences in waist circumference levels that associate with increased health risks” between, for example, White and South Asian people.
Another limitation of waist circumference and WHtR is that they “cannot differentiate between visceral and abdominal subcutaneous adipose tissue, which are vastly different regarding cardiometabolic risk, commented Ian Neeland, MD, director of cardiovascular prevention at the University Hospitals Harrington Heart & Vascular Institute, Cleveland.
The imaging option
“Waist-to-height ratio is not the ultimate answer,” Dr. Neeland said in an interview. He instead endorsed “advanced imaging for body fat distribution,” such as CT or MRI scans, as his pick for what should be the standard obesity metric, “given that it is much more specific and actionable for both risk assessment and response to therapy. I expect slow but steady advancements that move away from BMI cutoffs, for example for bariatric surgery, given that BMI is an imprecise and crude tool.”
But although imaging with methods like CT and MRI may provide the best accuracy and precision for tracking the volume of a person’s cardiometabolically dangerous fat, they are also hampered by relatively high cost and, for CT and DXA, the issue of radiation exposure.
“CT, MRI, and DXA scans give more in-depth assessment of body composition, but should we expose people to the radiation and the cost?” Dr. Almandoz wondered.
“Height, weight, and waist circumference cost nothing to obtain,” creating a big relative disadvantage for imaging, said Naveed Sattar, MD, professor of metabolic medicine at the University of Glasgow.
“Data would need to show that imaging gives clinicians substantially more information about future risk” to justify its price, Dr. Sattar emphasized.
BMI’s limits mean adding on
Regardless of whichever alternatives to BMI end up getting used most, experts generally agree that BMI alone is looking increasingly inadequate.
“Over the next 5 years, BMI will come to be seen as a screening tool that categorizes people into general risk groups” that also needs “other metrics and variables, such as age, race, ethnicity, family history, blood glucose, and blood pressure to better describe health risk in an individual,” predicted Dr. Bessesen.
The endorsement of WHtR by NICE “will lead to more research into how to incorporate WHtR into routine practice. We need more evidence to translate what NICE said into practice,” said Dr. Sattar. “I don’t think we’ll see a shift away from BMI, but we’ll add alternative measures that are particularly useful in certain patients.”
“Because we live in diverse societies, we need to individualize risk assessment and couple that with technology that makes analysis of body composition more accessible,” agreed Dr. Almandoz. He noted that the UT Southwestern weight wellness program where he practices has, for about the past decade, routinely collected waist circumference and bioelectrical impedance data as well as BMI on all people seen in the practice for obesity concerns. Making these additional measurements on a routine basis also helps strengthen patient engagement.
“We get into trouble when we make rigid health policy and clinical decisions based on BMI alone without looking at the patient holistically,” said Dr. Wee. “Patients are more than arbitrary numbers, and clinicians should make clinical decisions based on the totality of evidence for each individual patient.”
Dr. Bessesen, Dr. Wee, Dr. Powell-Wiley, and Dr. Almandoz reported no relevant financial relationships. Dr. Neeland has reported being a consultant for Merck. Dr. Sattar has reported being a consultant or speaker for Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, MSD, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi.
A version of this article originally appeared on Medscape.com.
“BMI is trash. Full stop.” This controversial tweet, which received thousands of likes and retweets, was cited in a recent article by one doctor on when physicians might stop using body mass index (BMI) to diagnose obesity.
BMI has for years been the consensus default method for assessing whether a person is overweight or has obesity, and is still widely used as the gatekeeper metric for treatment eligibility for certain weight-loss agents and bariatric surgery.
an important determinant of the cardiometabolic consequences of fat.
Alternative metrics include waist circumference and/or waist-to-height ratio (WHtR); imaging methods such as CT, MRI, and dual-energy x-ray absorptiometry (DXA); and bioelectrical impedance to assess fat volume and location. All have made some inroads on the tight grip BMI has had on obesity assessment.
Chances are, however, that BMI will not fade away anytime soon given how entrenched it has become in clinical practice and for insurance coverage, as well as its relative simplicity and precision.
“BMI is embedded in a wide range of guidelines on the use of medications and surgery. It’s embedded in Food and Drug Administration regulations and for billing and insurance coverage. It would take extremely strong data and years of work to undo the infrastructure built around BMI and replace it with something else. I don’t see that happening [anytime soon],” commented Daniel H. Bessesen, MD, a professor at the University of Colorado at Denver, Aurora, and chief of endocrinology for Denver Health.
“It would be almost impossible to replace all the studies that have used BMI with investigations using some other measure,” he said.
BMI Is ‘imperfect’
The entrenched position of BMI as the go-to metric doesn’t keep detractors from weighing in. As noted in a commentary on current clinical challenges surrounding obesity recently published in Annals of Internal Medicine, the journal’s editor-in-chief, Christine Laine, MD, and senior deputy editor Christina C. Wee, MD, listed six top issues clinicians must deal with, one of which, they say, is the need for a better measure of obesity than BMI.
“Unfortunately, BMI is an imperfect measure of body composition that differs with ethnicity, sex, body frame, and muscle mass,” noted Dr. Laine and Dr. Wee.
BMI is based on a person’s weight in kilograms divided by the square of their height in meters. A “healthy” BMI is between 18.5 and 24.9 kg/m2, overweight is 25-29.9, and 30 or greater is considered to represent obesity. However, certain ethnic groups have lower cutoffs for overweight or obesity because of evidence that such individuals can be at higher risk of obesity-related comorbidities at lower BMIs.
“BMI was chosen as the initial screening tool [for obesity] not because anyone thought it was perfect or the best measure but because of its simplicity. All you need is height, weight, and a calculator,” Dr. Wee said in an interview.
Numerous online calculators are available, including one from the Centers for Disease Control and Prevention where height in feet and inches and weight in pounds can be entered to generate the BMI.
BMI is also inherently limited by being “a proxy for adiposity” and not a direct measure, added Dr. Wee, who is also director of the Obesity Research Program of Beth Israel Deaconess Medical Center, Boston.
As such, BMI can’t distinguish between fat and muscle because it relies on weight only to gauge adiposity, noted Tiffany Powell-Wiley, MD, an obesity researcher at the National Heart, Lung, and Blood Institute in Bethesda, Md. Another shortcoming of BMI is that it “is good for distinguishing population-level risk for cardiovascular disease and other chronic diseases, but it does not help as much for distinguishing risk at an individual level,” she said in an interview.
These and other drawbacks have prompted researchers to look for other useful metrics. WHtR, for example, has recently made headway as a potential BMI alternative or complement.
The case for WHtR
Concern about overreliance on BMI despite its limitations is not new. In 2015, an American Heart Association scientific statement from the group’s Obesity Committee concluded that “BMI alone, even with lower thresholds, is a useful but not an ideal tool for identification of obesity or assessment of cardiovascular risk,” especially for people from Asian, Black, Hispanic, and Pacific Islander populations.
The writing panel also recommended that clinicians measure waist circumference annually and use that information along with BMI “to better gauge cardiovascular risk in diverse populations.”
Momentum for moving beyond BMI alone has continued to build following the AHA statement.
In September 2022, the National Institute for Health and Care Excellence, which sets policies for the United Kingdom’s National Health Service, revised its guidancefor assessment and management of people with obesity. The updated guidance recommends that when clinicians assess “adults with BMI below 35 kg/m2, measure and use their WHtR, as well as their BMI, as a practical estimate of central adiposity and use these measurements to help to assess and predict health risks.”
NICE released an extensive literature review with the revision, and based on the evidence, said that “using waist-to-height ratio as well as BMI would help give a practical estimate of central adiposity in adults with BMI under 35 kg/m2. This would in turn help professionals assess and predict health risks.”
However, the review added that, “because people with a BMI over 35 kg/m2 are always likely to have a high WHtR, the committee recognized that it may not be a useful addition for predicting health risks in this group.” The 2022 NICE review also said that it is “important to estimate central adiposity when assessing future health risks, including for people whose BMI is in the healthy-weight category.”
This new emphasis by NICE on measuring and using WHtR as part of obesity assessment “represents an important change in population health policy,” commented Dr. Powell-Wiley. “I expect more professional organizations will endorse use of waist circumference or waist-to-height ratio now that NICE has taken this step,” she predicted.
Waist circumference and WHtR may become standard measures of adiposity in clinical practice over the next 5-10 years.
The recent move by NICE to highlight a complementary role for WHtR “is another acknowledgment that BMI is an imperfect tool for stratifying cardiometabolic risk in a diverse population, especially in people with lower BMIs” because of its variability, commented Jamie Almandoz, MD, medical director of the weight wellness program at UT Southwestern Medical Center, Dallas.
WHtR vs. BMI
Another recent step forward for WHtR came with the publication of a post hoc analysis of data collected in the PARADIGM-HF trial, a study that had the primary purpose of comparing two medications for improving outcomes in more than 8,000 patients with heart failure with reduced ejection fraction.
The new analysis showed that “two indices that incorporate waist circumference and height, but not weight, showed a clearer association between greater adiposity and a higher risk of heart failure hospitalization,” compared with BMI.
WHtR was one of the two indices identified as being a better correlate for the adverse effect of excess adiposity compared with BMI.
The authors of the post hoc analysis did not design their analysis to compare WHtR with BMI. Instead, their goal was to better understand what’s known as the “obesity paradox” in people with heart failure with reduced ejection fraction: The recurring observation that, when these patients with heart failure have lower BMIs they fare worse, with higher rates of mortality and adverse cardiovascular outcomes, compared with patients with higher BMIs.
The new analysis showed that this paradox disappeared when WHtR was substituted for BMI as the obesity metric.
This “provides meaningful data about the superiority of WHtR, compared with BMI, for predicting heart failure outcomes,” said Dr. Powell-Wiley, although she cautioned that the analysis was limited by scant data in diverse populations and did not look at other important cardiovascular disease outcomes. While Dr. Powell-Wiley does not think that WHtR needs assessment in a prospective, controlled trial, she called for analysis of pooled prospective studies with more diverse populations to better document the advantages of WHtR over BMI.
The PARADIGM-HF post hoc analysis shows again how flawed BMI is for health assessment and the relative importance of an individualized understanding of a person’s body composition, Dr. Almandoz said in an interview. “As we collect more data, there is increasing awareness of how imperfect BMI is.”
Measuring waist circumference is tricky
Although WHtR looks promising as a substitute for or add-on to BMI, it has its own limitations, particularly the challenge of accurately measuring waist circumference.
Measuring waist circumference “not only takes more time but requires the assessor to be well trained about where to put the tape measure and making sure it’s measured at the same place each time,” even when different people take serial measurements from individual patients, noted Dr. Wee. Determining waist circumference can also be technically difficult when done on larger people, she added, and collectively these challenges make waist circumference “less reproducible from measurement to measurement.”
“It’s relatively clear how to standardize measurement of weight and height, but there is a huge amount of variability when the waist is measured,” agreed Dr. Almandoz. “And waist circumference also differs by ethnicity, race, sex, and body frame. There are significant differences in waist circumference levels that associate with increased health risks” between, for example, White and South Asian people.
Another limitation of waist circumference and WHtR is that they “cannot differentiate between visceral and abdominal subcutaneous adipose tissue, which are vastly different regarding cardiometabolic risk, commented Ian Neeland, MD, director of cardiovascular prevention at the University Hospitals Harrington Heart & Vascular Institute, Cleveland.
The imaging option
“Waist-to-height ratio is not the ultimate answer,” Dr. Neeland said in an interview. He instead endorsed “advanced imaging for body fat distribution,” such as CT or MRI scans, as his pick for what should be the standard obesity metric, “given that it is much more specific and actionable for both risk assessment and response to therapy. I expect slow but steady advancements that move away from BMI cutoffs, for example for bariatric surgery, given that BMI is an imprecise and crude tool.”
But although imaging with methods like CT and MRI may provide the best accuracy and precision for tracking the volume of a person’s cardiometabolically dangerous fat, they are also hampered by relatively high cost and, for CT and DXA, the issue of radiation exposure.
“CT, MRI, and DXA scans give more in-depth assessment of body composition, but should we expose people to the radiation and the cost?” Dr. Almandoz wondered.
“Height, weight, and waist circumference cost nothing to obtain,” creating a big relative disadvantage for imaging, said Naveed Sattar, MD, professor of metabolic medicine at the University of Glasgow.
“Data would need to show that imaging gives clinicians substantially more information about future risk” to justify its price, Dr. Sattar emphasized.
BMI’s limits mean adding on
Regardless of whichever alternatives to BMI end up getting used most, experts generally agree that BMI alone is looking increasingly inadequate.
“Over the next 5 years, BMI will come to be seen as a screening tool that categorizes people into general risk groups” that also needs “other metrics and variables, such as age, race, ethnicity, family history, blood glucose, and blood pressure to better describe health risk in an individual,” predicted Dr. Bessesen.
The endorsement of WHtR by NICE “will lead to more research into how to incorporate WHtR into routine practice. We need more evidence to translate what NICE said into practice,” said Dr. Sattar. “I don’t think we’ll see a shift away from BMI, but we’ll add alternative measures that are particularly useful in certain patients.”
“Because we live in diverse societies, we need to individualize risk assessment and couple that with technology that makes analysis of body composition more accessible,” agreed Dr. Almandoz. He noted that the UT Southwestern weight wellness program where he practices has, for about the past decade, routinely collected waist circumference and bioelectrical impedance data as well as BMI on all people seen in the practice for obesity concerns. Making these additional measurements on a routine basis also helps strengthen patient engagement.
“We get into trouble when we make rigid health policy and clinical decisions based on BMI alone without looking at the patient holistically,” said Dr. Wee. “Patients are more than arbitrary numbers, and clinicians should make clinical decisions based on the totality of evidence for each individual patient.”
Dr. Bessesen, Dr. Wee, Dr. Powell-Wiley, and Dr. Almandoz reported no relevant financial relationships. Dr. Neeland has reported being a consultant for Merck. Dr. Sattar has reported being a consultant or speaker for Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, MSD, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi.
A version of this article originally appeared on Medscape.com.
“BMI is trash. Full stop.” This controversial tweet, which received thousands of likes and retweets, was cited in a recent article by one doctor on when physicians might stop using body mass index (BMI) to diagnose obesity.
BMI has for years been the consensus default method for assessing whether a person is overweight or has obesity, and is still widely used as the gatekeeper metric for treatment eligibility for certain weight-loss agents and bariatric surgery.
an important determinant of the cardiometabolic consequences of fat.
Alternative metrics include waist circumference and/or waist-to-height ratio (WHtR); imaging methods such as CT, MRI, and dual-energy x-ray absorptiometry (DXA); and bioelectrical impedance to assess fat volume and location. All have made some inroads on the tight grip BMI has had on obesity assessment.
Chances are, however, that BMI will not fade away anytime soon given how entrenched it has become in clinical practice and for insurance coverage, as well as its relative simplicity and precision.
“BMI is embedded in a wide range of guidelines on the use of medications and surgery. It’s embedded in Food and Drug Administration regulations and for billing and insurance coverage. It would take extremely strong data and years of work to undo the infrastructure built around BMI and replace it with something else. I don’t see that happening [anytime soon],” commented Daniel H. Bessesen, MD, a professor at the University of Colorado at Denver, Aurora, and chief of endocrinology for Denver Health.
“It would be almost impossible to replace all the studies that have used BMI with investigations using some other measure,” he said.
BMI Is ‘imperfect’
The entrenched position of BMI as the go-to metric doesn’t keep detractors from weighing in. As noted in a commentary on current clinical challenges surrounding obesity recently published in Annals of Internal Medicine, the journal’s editor-in-chief, Christine Laine, MD, and senior deputy editor Christina C. Wee, MD, listed six top issues clinicians must deal with, one of which, they say, is the need for a better measure of obesity than BMI.
“Unfortunately, BMI is an imperfect measure of body composition that differs with ethnicity, sex, body frame, and muscle mass,” noted Dr. Laine and Dr. Wee.
BMI is based on a person’s weight in kilograms divided by the square of their height in meters. A “healthy” BMI is between 18.5 and 24.9 kg/m2, overweight is 25-29.9, and 30 or greater is considered to represent obesity. However, certain ethnic groups have lower cutoffs for overweight or obesity because of evidence that such individuals can be at higher risk of obesity-related comorbidities at lower BMIs.
“BMI was chosen as the initial screening tool [for obesity] not because anyone thought it was perfect or the best measure but because of its simplicity. All you need is height, weight, and a calculator,” Dr. Wee said in an interview.
Numerous online calculators are available, including one from the Centers for Disease Control and Prevention where height in feet and inches and weight in pounds can be entered to generate the BMI.
BMI is also inherently limited by being “a proxy for adiposity” and not a direct measure, added Dr. Wee, who is also director of the Obesity Research Program of Beth Israel Deaconess Medical Center, Boston.
As such, BMI can’t distinguish between fat and muscle because it relies on weight only to gauge adiposity, noted Tiffany Powell-Wiley, MD, an obesity researcher at the National Heart, Lung, and Blood Institute in Bethesda, Md. Another shortcoming of BMI is that it “is good for distinguishing population-level risk for cardiovascular disease and other chronic diseases, but it does not help as much for distinguishing risk at an individual level,” she said in an interview.
These and other drawbacks have prompted researchers to look for other useful metrics. WHtR, for example, has recently made headway as a potential BMI alternative or complement.
The case for WHtR
Concern about overreliance on BMI despite its limitations is not new. In 2015, an American Heart Association scientific statement from the group’s Obesity Committee concluded that “BMI alone, even with lower thresholds, is a useful but not an ideal tool for identification of obesity or assessment of cardiovascular risk,” especially for people from Asian, Black, Hispanic, and Pacific Islander populations.
The writing panel also recommended that clinicians measure waist circumference annually and use that information along with BMI “to better gauge cardiovascular risk in diverse populations.”
Momentum for moving beyond BMI alone has continued to build following the AHA statement.
In September 2022, the National Institute for Health and Care Excellence, which sets policies for the United Kingdom’s National Health Service, revised its guidancefor assessment and management of people with obesity. The updated guidance recommends that when clinicians assess “adults with BMI below 35 kg/m2, measure and use their WHtR, as well as their BMI, as a practical estimate of central adiposity and use these measurements to help to assess and predict health risks.”
NICE released an extensive literature review with the revision, and based on the evidence, said that “using waist-to-height ratio as well as BMI would help give a practical estimate of central adiposity in adults with BMI under 35 kg/m2. This would in turn help professionals assess and predict health risks.”
However, the review added that, “because people with a BMI over 35 kg/m2 are always likely to have a high WHtR, the committee recognized that it may not be a useful addition for predicting health risks in this group.” The 2022 NICE review also said that it is “important to estimate central adiposity when assessing future health risks, including for people whose BMI is in the healthy-weight category.”
This new emphasis by NICE on measuring and using WHtR as part of obesity assessment “represents an important change in population health policy,” commented Dr. Powell-Wiley. “I expect more professional organizations will endorse use of waist circumference or waist-to-height ratio now that NICE has taken this step,” she predicted.
Waist circumference and WHtR may become standard measures of adiposity in clinical practice over the next 5-10 years.
The recent move by NICE to highlight a complementary role for WHtR “is another acknowledgment that BMI is an imperfect tool for stratifying cardiometabolic risk in a diverse population, especially in people with lower BMIs” because of its variability, commented Jamie Almandoz, MD, medical director of the weight wellness program at UT Southwestern Medical Center, Dallas.
WHtR vs. BMI
Another recent step forward for WHtR came with the publication of a post hoc analysis of data collected in the PARADIGM-HF trial, a study that had the primary purpose of comparing two medications for improving outcomes in more than 8,000 patients with heart failure with reduced ejection fraction.
The new analysis showed that “two indices that incorporate waist circumference and height, but not weight, showed a clearer association between greater adiposity and a higher risk of heart failure hospitalization,” compared with BMI.
WHtR was one of the two indices identified as being a better correlate for the adverse effect of excess adiposity compared with BMI.
The authors of the post hoc analysis did not design their analysis to compare WHtR with BMI. Instead, their goal was to better understand what’s known as the “obesity paradox” in people with heart failure with reduced ejection fraction: The recurring observation that, when these patients with heart failure have lower BMIs they fare worse, with higher rates of mortality and adverse cardiovascular outcomes, compared with patients with higher BMIs.
The new analysis showed that this paradox disappeared when WHtR was substituted for BMI as the obesity metric.
This “provides meaningful data about the superiority of WHtR, compared with BMI, for predicting heart failure outcomes,” said Dr. Powell-Wiley, although she cautioned that the analysis was limited by scant data in diverse populations and did not look at other important cardiovascular disease outcomes. While Dr. Powell-Wiley does not think that WHtR needs assessment in a prospective, controlled trial, she called for analysis of pooled prospective studies with more diverse populations to better document the advantages of WHtR over BMI.
The PARADIGM-HF post hoc analysis shows again how flawed BMI is for health assessment and the relative importance of an individualized understanding of a person’s body composition, Dr. Almandoz said in an interview. “As we collect more data, there is increasing awareness of how imperfect BMI is.”
Measuring waist circumference is tricky
Although WHtR looks promising as a substitute for or add-on to BMI, it has its own limitations, particularly the challenge of accurately measuring waist circumference.
Measuring waist circumference “not only takes more time but requires the assessor to be well trained about where to put the tape measure and making sure it’s measured at the same place each time,” even when different people take serial measurements from individual patients, noted Dr. Wee. Determining waist circumference can also be technically difficult when done on larger people, she added, and collectively these challenges make waist circumference “less reproducible from measurement to measurement.”
“It’s relatively clear how to standardize measurement of weight and height, but there is a huge amount of variability when the waist is measured,” agreed Dr. Almandoz. “And waist circumference also differs by ethnicity, race, sex, and body frame. There are significant differences in waist circumference levels that associate with increased health risks” between, for example, White and South Asian people.
Another limitation of waist circumference and WHtR is that they “cannot differentiate between visceral and abdominal subcutaneous adipose tissue, which are vastly different regarding cardiometabolic risk, commented Ian Neeland, MD, director of cardiovascular prevention at the University Hospitals Harrington Heart & Vascular Institute, Cleveland.
The imaging option
“Waist-to-height ratio is not the ultimate answer,” Dr. Neeland said in an interview. He instead endorsed “advanced imaging for body fat distribution,” such as CT or MRI scans, as his pick for what should be the standard obesity metric, “given that it is much more specific and actionable for both risk assessment and response to therapy. I expect slow but steady advancements that move away from BMI cutoffs, for example for bariatric surgery, given that BMI is an imprecise and crude tool.”
But although imaging with methods like CT and MRI may provide the best accuracy and precision for tracking the volume of a person’s cardiometabolically dangerous fat, they are also hampered by relatively high cost and, for CT and DXA, the issue of radiation exposure.
“CT, MRI, and DXA scans give more in-depth assessment of body composition, but should we expose people to the radiation and the cost?” Dr. Almandoz wondered.
“Height, weight, and waist circumference cost nothing to obtain,” creating a big relative disadvantage for imaging, said Naveed Sattar, MD, professor of metabolic medicine at the University of Glasgow.
“Data would need to show that imaging gives clinicians substantially more information about future risk” to justify its price, Dr. Sattar emphasized.
BMI’s limits mean adding on
Regardless of whichever alternatives to BMI end up getting used most, experts generally agree that BMI alone is looking increasingly inadequate.
“Over the next 5 years, BMI will come to be seen as a screening tool that categorizes people into general risk groups” that also needs “other metrics and variables, such as age, race, ethnicity, family history, blood glucose, and blood pressure to better describe health risk in an individual,” predicted Dr. Bessesen.
The endorsement of WHtR by NICE “will lead to more research into how to incorporate WHtR into routine practice. We need more evidence to translate what NICE said into practice,” said Dr. Sattar. “I don’t think we’ll see a shift away from BMI, but we’ll add alternative measures that are particularly useful in certain patients.”
“Because we live in diverse societies, we need to individualize risk assessment and couple that with technology that makes analysis of body composition more accessible,” agreed Dr. Almandoz. He noted that the UT Southwestern weight wellness program where he practices has, for about the past decade, routinely collected waist circumference and bioelectrical impedance data as well as BMI on all people seen in the practice for obesity concerns. Making these additional measurements on a routine basis also helps strengthen patient engagement.
“We get into trouble when we make rigid health policy and clinical decisions based on BMI alone without looking at the patient holistically,” said Dr. Wee. “Patients are more than arbitrary numbers, and clinicians should make clinical decisions based on the totality of evidence for each individual patient.”
Dr. Bessesen, Dr. Wee, Dr. Powell-Wiley, and Dr. Almandoz reported no relevant financial relationships. Dr. Neeland has reported being a consultant for Merck. Dr. Sattar has reported being a consultant or speaker for Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, MSD, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi.
A version of this article originally appeared on Medscape.com.
Disrupted gut microbiome a key driver of major depression?
Investigators found that MDD had specific metabolic “signatures” consisting of 124 metabolites that spanned energy and lipid pathways, with some involving the tricarboxylic acid cycle in particular. These changes in metabolites were consistent with differences in composition of several gut microbiota.
The researchers found that fatty acids and intermediate and very large lipoproteins changed in association with the depressive disease process. However, high-density lipoproteins and metabolites in the tricarboxylic acid cycle did not.
“As we wait to establish causal influences through clinical trials, clinicians should advise patients suffering from mood disorders to modify their diet by increasing the intake of fresh fruits, vegetables, and whole grains, as these provide the required fuel/fiber to the gut microbiota for their enrichment, and more short-chain fatty acids are produced for the optimal functioning of the body,” study investigator Najaf Amin, PhD, DSc, senior researcher, Nuffield Department of Population Health, Oxford University, England, told this news organization.
“At the same time, patients should be advised to minimize the intake of sugars and processed foods, which are known to have an inverse impact on the gut microbiome and are associated with higher inflammation,” she said.
The study was published online in JAMA Psychiatry.
MDD poorly understood
Although most antidepressants target the monoamine pathway, “evidence is increasing for a more complex interplay of multiple pathways involving a wide range of metabolic alterations spanning energy and lipid metabolism,” the authors wrote.
Previous research using the Nightingale proton nuclear magnetic resonance (NMR) metabolomics platform showed a “shift” toward decreased levels of high-density lipoproteins (HDLs) and increased levels of very low-density lipoproteins (VLDLs) and triglycerides among patients with depression.
The gut microbiome, which is primarily modulated by diet, “has been shown to be a major determinant of circulating lipids, specifically triglycerides and HDLs, and to regulate mitochondrial function,” the investigators noted. Patients with MDD are known to have disruptions in the gut microbiome.
The gut microbiome may “explain part of the shift in VLDL and HDL levels observed in patients with depression and if the metabolic signatures of the disease based on Nightingale metabolites can be used as a tool to infer the association between gut microbiome and depression.”
Dr. Amin called depression “one of the most poorly understood diseases, as underlying mechanisms remain elusive.”
Large-scale genetic studies “have shown that the contribution of genetics to depression is modest,” she continued. On the other hand, initial animal studies suggest the gut microbiome “may potentially have a causal influence on depression.”
Several studies have evaluated the influence of gut microbiome on depression, “but, due to small sample sizes and inadequate control for confounding factors, most of their findings were not reproducible.”
Harnessing the power of the UK Biobank, the investigators studied 58,257 individuals who were between the ages of 37 and 73 years at recruitment. They used data on NMR spectroscopy–based plasma metabolites in depression. Individuals who didn’t report depression at baseline served as controls.
Logistic regression analysis was used to test the association of metabolite levels with depression in four models, each with an increasing number of covariates.
To identify patterns of correlation in the “metabolic signatures of MDD and the human gut biome,” they regressed the metabolic signatures of MDD on the metabolic signatures of the gut microbiota and then regressed the metabolic signature of gut microbiota on the metabolic signatures of MDD.
Bidirectional 2-sample Mendelian randomization was used to ascertain the direction of the association observed between metabolites and MDD.
Individuals with lifetime and recurrent MDD were compared with controls (6,811 vs. 51,446 and 4,370 vs. 62,508, respectively).
Participants with lifetime MDD were significantly younger (median [IQR] age, 56 [49-62] years vs. 58 [51-64] years) and were more likely to be female in comparison with controls (54% vs. 35%).
‘Novel findings’
In the fully adjusted analysis, metabolic signatures of MDD were found to consist of 124 metabolites that spanned energy and lipid metabolism pathways.
The investigators noted that these “novel findings” included 49 metabolites encompassing those involved in the tricarboxylic acid cycle – citrate and pyruvate.
The findings revealed that fatty acids and intermediate and VLDL changed in association with the disease process. On the other hand, HDL and the metabolites in the tricarboxylic acid cycle did not.
“We observed that the genera Sellimonas, Eggerthella, Hungatella, and Lachnoclostridium were more abundant, while genera Ruminococcaceae ... Coprococcus, Lachnospiraceae ... Eubacterium ventriosum, Subdoligranulum, and family Ruminococcaceae were depleted in the guts of individuals with more symptoms of depression,” said Dr. Amin. “Of these, genus Eggerthella showed statistical evidence of being involved in the causal pathway.”
These microbes are involved in the synthesis of important neurotransmitters, such as gamma aminobutyric acid, butyrate, glutamate, and serotonin, she noted.
Butyrate produced by the gut can cross the blood-brain barrier, enter the brain, and affect transcriptional and translational activity or be used by the cells for generating energy, she added. “So basically, butyrate can influence depression through several routes – i.e., via immune regulation, genomic transcript/translation, and/or affecting energy metabolism.”
No causality
Commenting on the study, Emeran Mayer, MD, distinguished research professor of medicine, G. Oppenheimer Center for Neurobiology of Stress and Resilience and UCLA Brain Gut Microbiome Center, called it the “largest, most comprehensive and best validated association study to date providing further evidence for an association between gut microbial taxa, previously identified in patients with MDD, blood metabolites (generated by host and by microbes) and questionnaire data.”
However, “despite its strengths, the study does not allow [us] to identify a causal role of the microbiome alterations in the observed microbial and metabolic changes (fatty acids, Krebs cycle components),” cautioned Dr. Mayer, who was not involved with the study.
Moreover, “causality of gut microbial changes on the behavioral phenotype of depression cannot been inferred,” he concluded.
Metabolomics data were provided by the Alzheimer’s Disease Metabolomics Consortium. The study was funded wholly or in part by grants from the National Institute on Aging and Foundation for the National Institutes of Health. It was further supported by a grant from ZonMW Memorabel. Dr. Amin reports no relevant financial relationships. The other authors’ disclosures are listed oin the original article. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.
A version of this article originally appeared on Medscape.com.
Investigators found that MDD had specific metabolic “signatures” consisting of 124 metabolites that spanned energy and lipid pathways, with some involving the tricarboxylic acid cycle in particular. These changes in metabolites were consistent with differences in composition of several gut microbiota.
The researchers found that fatty acids and intermediate and very large lipoproteins changed in association with the depressive disease process. However, high-density lipoproteins and metabolites in the tricarboxylic acid cycle did not.
“As we wait to establish causal influences through clinical trials, clinicians should advise patients suffering from mood disorders to modify their diet by increasing the intake of fresh fruits, vegetables, and whole grains, as these provide the required fuel/fiber to the gut microbiota for their enrichment, and more short-chain fatty acids are produced for the optimal functioning of the body,” study investigator Najaf Amin, PhD, DSc, senior researcher, Nuffield Department of Population Health, Oxford University, England, told this news organization.
“At the same time, patients should be advised to minimize the intake of sugars and processed foods, which are known to have an inverse impact on the gut microbiome and are associated with higher inflammation,” she said.
The study was published online in JAMA Psychiatry.
MDD poorly understood
Although most antidepressants target the monoamine pathway, “evidence is increasing for a more complex interplay of multiple pathways involving a wide range of metabolic alterations spanning energy and lipid metabolism,” the authors wrote.
Previous research using the Nightingale proton nuclear magnetic resonance (NMR) metabolomics platform showed a “shift” toward decreased levels of high-density lipoproteins (HDLs) and increased levels of very low-density lipoproteins (VLDLs) and triglycerides among patients with depression.
The gut microbiome, which is primarily modulated by diet, “has been shown to be a major determinant of circulating lipids, specifically triglycerides and HDLs, and to regulate mitochondrial function,” the investigators noted. Patients with MDD are known to have disruptions in the gut microbiome.
The gut microbiome may “explain part of the shift in VLDL and HDL levels observed in patients with depression and if the metabolic signatures of the disease based on Nightingale metabolites can be used as a tool to infer the association between gut microbiome and depression.”
Dr. Amin called depression “one of the most poorly understood diseases, as underlying mechanisms remain elusive.”
Large-scale genetic studies “have shown that the contribution of genetics to depression is modest,” she continued. On the other hand, initial animal studies suggest the gut microbiome “may potentially have a causal influence on depression.”
Several studies have evaluated the influence of gut microbiome on depression, “but, due to small sample sizes and inadequate control for confounding factors, most of their findings were not reproducible.”
Harnessing the power of the UK Biobank, the investigators studied 58,257 individuals who were between the ages of 37 and 73 years at recruitment. They used data on NMR spectroscopy–based plasma metabolites in depression. Individuals who didn’t report depression at baseline served as controls.
Logistic regression analysis was used to test the association of metabolite levels with depression in four models, each with an increasing number of covariates.
To identify patterns of correlation in the “metabolic signatures of MDD and the human gut biome,” they regressed the metabolic signatures of MDD on the metabolic signatures of the gut microbiota and then regressed the metabolic signature of gut microbiota on the metabolic signatures of MDD.
Bidirectional 2-sample Mendelian randomization was used to ascertain the direction of the association observed between metabolites and MDD.
Individuals with lifetime and recurrent MDD were compared with controls (6,811 vs. 51,446 and 4,370 vs. 62,508, respectively).
Participants with lifetime MDD were significantly younger (median [IQR] age, 56 [49-62] years vs. 58 [51-64] years) and were more likely to be female in comparison with controls (54% vs. 35%).
‘Novel findings’
In the fully adjusted analysis, metabolic signatures of MDD were found to consist of 124 metabolites that spanned energy and lipid metabolism pathways.
The investigators noted that these “novel findings” included 49 metabolites encompassing those involved in the tricarboxylic acid cycle – citrate and pyruvate.
The findings revealed that fatty acids and intermediate and VLDL changed in association with the disease process. On the other hand, HDL and the metabolites in the tricarboxylic acid cycle did not.
“We observed that the genera Sellimonas, Eggerthella, Hungatella, and Lachnoclostridium were more abundant, while genera Ruminococcaceae ... Coprococcus, Lachnospiraceae ... Eubacterium ventriosum, Subdoligranulum, and family Ruminococcaceae were depleted in the guts of individuals with more symptoms of depression,” said Dr. Amin. “Of these, genus Eggerthella showed statistical evidence of being involved in the causal pathway.”
These microbes are involved in the synthesis of important neurotransmitters, such as gamma aminobutyric acid, butyrate, glutamate, and serotonin, she noted.
Butyrate produced by the gut can cross the blood-brain barrier, enter the brain, and affect transcriptional and translational activity or be used by the cells for generating energy, she added. “So basically, butyrate can influence depression through several routes – i.e., via immune regulation, genomic transcript/translation, and/or affecting energy metabolism.”
No causality
Commenting on the study, Emeran Mayer, MD, distinguished research professor of medicine, G. Oppenheimer Center for Neurobiology of Stress and Resilience and UCLA Brain Gut Microbiome Center, called it the “largest, most comprehensive and best validated association study to date providing further evidence for an association between gut microbial taxa, previously identified in patients with MDD, blood metabolites (generated by host and by microbes) and questionnaire data.”
However, “despite its strengths, the study does not allow [us] to identify a causal role of the microbiome alterations in the observed microbial and metabolic changes (fatty acids, Krebs cycle components),” cautioned Dr. Mayer, who was not involved with the study.
Moreover, “causality of gut microbial changes on the behavioral phenotype of depression cannot been inferred,” he concluded.
Metabolomics data were provided by the Alzheimer’s Disease Metabolomics Consortium. The study was funded wholly or in part by grants from the National Institute on Aging and Foundation for the National Institutes of Health. It was further supported by a grant from ZonMW Memorabel. Dr. Amin reports no relevant financial relationships. The other authors’ disclosures are listed oin the original article. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.
A version of this article originally appeared on Medscape.com.
Investigators found that MDD had specific metabolic “signatures” consisting of 124 metabolites that spanned energy and lipid pathways, with some involving the tricarboxylic acid cycle in particular. These changes in metabolites were consistent with differences in composition of several gut microbiota.
The researchers found that fatty acids and intermediate and very large lipoproteins changed in association with the depressive disease process. However, high-density lipoproteins and metabolites in the tricarboxylic acid cycle did not.
“As we wait to establish causal influences through clinical trials, clinicians should advise patients suffering from mood disorders to modify their diet by increasing the intake of fresh fruits, vegetables, and whole grains, as these provide the required fuel/fiber to the gut microbiota for their enrichment, and more short-chain fatty acids are produced for the optimal functioning of the body,” study investigator Najaf Amin, PhD, DSc, senior researcher, Nuffield Department of Population Health, Oxford University, England, told this news organization.
“At the same time, patients should be advised to minimize the intake of sugars and processed foods, which are known to have an inverse impact on the gut microbiome and are associated with higher inflammation,” she said.
The study was published online in JAMA Psychiatry.
MDD poorly understood
Although most antidepressants target the monoamine pathway, “evidence is increasing for a more complex interplay of multiple pathways involving a wide range of metabolic alterations spanning energy and lipid metabolism,” the authors wrote.
Previous research using the Nightingale proton nuclear magnetic resonance (NMR) metabolomics platform showed a “shift” toward decreased levels of high-density lipoproteins (HDLs) and increased levels of very low-density lipoproteins (VLDLs) and triglycerides among patients with depression.
The gut microbiome, which is primarily modulated by diet, “has been shown to be a major determinant of circulating lipids, specifically triglycerides and HDLs, and to regulate mitochondrial function,” the investigators noted. Patients with MDD are known to have disruptions in the gut microbiome.
The gut microbiome may “explain part of the shift in VLDL and HDL levels observed in patients with depression and if the metabolic signatures of the disease based on Nightingale metabolites can be used as a tool to infer the association between gut microbiome and depression.”
Dr. Amin called depression “one of the most poorly understood diseases, as underlying mechanisms remain elusive.”
Large-scale genetic studies “have shown that the contribution of genetics to depression is modest,” she continued. On the other hand, initial animal studies suggest the gut microbiome “may potentially have a causal influence on depression.”
Several studies have evaluated the influence of gut microbiome on depression, “but, due to small sample sizes and inadequate control for confounding factors, most of their findings were not reproducible.”
Harnessing the power of the UK Biobank, the investigators studied 58,257 individuals who were between the ages of 37 and 73 years at recruitment. They used data on NMR spectroscopy–based plasma metabolites in depression. Individuals who didn’t report depression at baseline served as controls.
Logistic regression analysis was used to test the association of metabolite levels with depression in four models, each with an increasing number of covariates.
To identify patterns of correlation in the “metabolic signatures of MDD and the human gut biome,” they regressed the metabolic signatures of MDD on the metabolic signatures of the gut microbiota and then regressed the metabolic signature of gut microbiota on the metabolic signatures of MDD.
Bidirectional 2-sample Mendelian randomization was used to ascertain the direction of the association observed between metabolites and MDD.
Individuals with lifetime and recurrent MDD were compared with controls (6,811 vs. 51,446 and 4,370 vs. 62,508, respectively).
Participants with lifetime MDD were significantly younger (median [IQR] age, 56 [49-62] years vs. 58 [51-64] years) and were more likely to be female in comparison with controls (54% vs. 35%).
‘Novel findings’
In the fully adjusted analysis, metabolic signatures of MDD were found to consist of 124 metabolites that spanned energy and lipid metabolism pathways.
The investigators noted that these “novel findings” included 49 metabolites encompassing those involved in the tricarboxylic acid cycle – citrate and pyruvate.
The findings revealed that fatty acids and intermediate and VLDL changed in association with the disease process. On the other hand, HDL and the metabolites in the tricarboxylic acid cycle did not.
“We observed that the genera Sellimonas, Eggerthella, Hungatella, and Lachnoclostridium were more abundant, while genera Ruminococcaceae ... Coprococcus, Lachnospiraceae ... Eubacterium ventriosum, Subdoligranulum, and family Ruminococcaceae were depleted in the guts of individuals with more symptoms of depression,” said Dr. Amin. “Of these, genus Eggerthella showed statistical evidence of being involved in the causal pathway.”
These microbes are involved in the synthesis of important neurotransmitters, such as gamma aminobutyric acid, butyrate, glutamate, and serotonin, she noted.
Butyrate produced by the gut can cross the blood-brain barrier, enter the brain, and affect transcriptional and translational activity or be used by the cells for generating energy, she added. “So basically, butyrate can influence depression through several routes – i.e., via immune regulation, genomic transcript/translation, and/or affecting energy metabolism.”
No causality
Commenting on the study, Emeran Mayer, MD, distinguished research professor of medicine, G. Oppenheimer Center for Neurobiology of Stress and Resilience and UCLA Brain Gut Microbiome Center, called it the “largest, most comprehensive and best validated association study to date providing further evidence for an association between gut microbial taxa, previously identified in patients with MDD, blood metabolites (generated by host and by microbes) and questionnaire data.”
However, “despite its strengths, the study does not allow [us] to identify a causal role of the microbiome alterations in the observed microbial and metabolic changes (fatty acids, Krebs cycle components),” cautioned Dr. Mayer, who was not involved with the study.
Moreover, “causality of gut microbial changes on the behavioral phenotype of depression cannot been inferred,” he concluded.
Metabolomics data were provided by the Alzheimer’s Disease Metabolomics Consortium. The study was funded wholly or in part by grants from the National Institute on Aging and Foundation for the National Institutes of Health. It was further supported by a grant from ZonMW Memorabel. Dr. Amin reports no relevant financial relationships. The other authors’ disclosures are listed oin the original article. Dr. Mayer is a scientific advisory board member of Danone, Axial Therapeutics, Viome, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, and APC Microbiome Ireland.
A version of this article originally appeared on Medscape.com.
FROM JAMA PSYCHIATRY
Walnuts linked to improved attention, psychological maturity in teens
, new research shows. Adolescents who consumed walnuts for at least 100 days showed improved sustained attention and fluid intelligence as well as a reduction in symptoms of attension deficit hyperactivity disorder, compared with matched controls who did not consume the nuts. However, there were no statistically significant changes between the groups in other parameters, such as working memory and executive function.
Clinicians should advise adolescents “to eat a handful of walnuts three times a week for the rest of their lives. They may have a healthier brain with better cognitive function,” said senior investigator Jordi Julvez, PhD, group leader at the Institute of Health Research Pere Virgili, Barcelona, and associated researcher at the Barcelona Institute for Global Health.
The study was published online in eClinicalMedicine.
Rich source of omega-3s
Adolescence is “a period of refinement of brain connectivity and complex behaviors,” the investigators noted.
Previous research suggests polyunsaturated fatty acids are key in central nervous system architecture and function during times of neural development, with three specific PUFAs playing an “essential developmental role.”
Two omega-3 fatty acids – docosahexaenoic acid and eicosapentaenoic acid – are PUFAs that must be obtained through diet, mainly from seafood. Walnuts are “among the richest sources” of plant-derived omega-3 fatty acids, particularly alpha-linolenic acid (ALA), a precursor for longer-chain EPA and DHA.
ALA independently “has positive effects on brain function and plasticity,” the authors wrote. In addition, walnut constituents – particularly polyphenols and other bioactive compounds – “may act synergistically with ALA to foster brain health.”
Earlier small studies have found positive associations between walnut consumption and cognitive function in children, adolescents, and young adults, but to date, no randomized controlled trial has focused on the effect of walnut consumption on adolescent neuropsychological function.
The researchers studied 771 healthy adolescents (aged 11-16 years, mean age 14) drawn from 12 Spanish high schools. Participants were instructed to follow healthy eating recommendations and were randomly assigned 1:1 to the intervention (n = 386) or the control group (n = 385).
At baseline and after 6 months, they completed neuropsychological tests and behavioral rating scales. The Attention Network Test assessed attention, and the N-back test was used to assess working memory. The Tests of Primary Mental Abilities assessed fluid intelligence. Risky decision-making was tested using the Roulettes Task.
Fruit and nuts
Participants also completed the Strengths and Difficulties Questionnaire, which provided a total score of problem behavior. Teachers filled out the ADHD DSM-IV form list to provide additional information about ADHD behaviors.
The intervention group received 30 grams/day of raw California walnut kernels to incorporate into their daily diet. It is estimated that this walnut contains about 9 g of ALA per 100 g.
All participants received a seasonal fruit calendar and were asked to eat at least one piece of seasonal fruit daily.
Parents reported their child’s daily walnut consumption, with adherence defined as 100 or more days of eating walnuts during the 6-month period.
All main analyses were based on an intention-to-treat method (participants were analyzed according to their original group assignment, regardless of their adherence to the intervention).
The researchers also conducted a secondary per-protocol analysis, comparing the intervention and control groups to estimate the effect if all participants had adhered to their assigned intervention. They censored data for participants who reported eating walnuts for less than 100 days during the 6-month trial period.
Secondary outcomes included changes in height, weight, waist circumference, and BMI, as well as red blood cell proportions of omega-3 fatty acids (DHA, EPA, and ALA) at baseline and after 6 months.
Adherence counts
Most participants had “medium” or “high” levels of adherence to the Mediterranean diet, with “no meaningful differences” at baseline between the intervention and control groups in lifestyle characteristics or mean scores in all primary endpoints.
In the ITT analysis, there were no statistically significant differences in primary outcomes between the groups following the intervention. As for secondary outcomes, the RBC ALA significantly increased in the walnuts group but not the control group (coefficient, 0.04%; 95% confidence interval, 0.03%-0.06%; P < .0001).
However, there were differences in primary outcomes between the groups in the per-protocol analysis: The adherence-adjusted effect on improvement in attention score was −11.26 ms; 95% CI, −19.92 to −2.60; P = .011) for the intervention versus the control group.
The per-protocol analysis showed other differences: an improvement in fluid intelligence score (1.78; 95% CI, 0.90 - 2.67; P < .0001) and a reduction in ADHD symptom score (−2.18; 95% CI, −3.70 to −0.67; P = .0050).
“Overall, no significant differences were found in the intervention group in relation to the control group,” Dr. Julvez said in a news release. “But if the adherence factor is considered, then positive results are observed, since participants who most closely followed the guidelines – in terms of the recommended dose of walnuts and the number of days of consumption – did show improvements in the neuropsychological functions evaluated.”
Adolescence “is a time of great biological changes. Hormonal transformation occurs, which in turn is responsible for stimulating the synaptic growth of the frontal lobe,” he continued, adding that this brain region “enables neuropsychological maturation of more complex emotional and cognitive functions.”
“Neurons that are well nourished with these types of fatty acids will be able to grow and form new, stronger synapses,” he said.
Food as medicine
Uma Naidoo, MD, director of nutritional and lifestyle psychiatry at Massachusetts General Hospital, Boston, “commends” the researchers for conducting an RCT with a “robust” sample size and said she is “excited to see research like this furthering functional nutrition for mental health,” as she believes that “food is medicine.”
Dr. Naidoo, a professional chef, nutritional biologist, and author of the book “This Is Your Brain on Food,” said the findings “align” with her own approach to nutritional psychiatry and are also “in line” with her clinical practice.
However, although these results are “promising,” more research is needed across more diverse populations to “make sure these results are truly generalizable,” said Dr. Naidoo, a faculty member at Harvard Medical School, Boston, who was not involved with the study.
She “envisions a future where the research is so advanced that we can ‘dose’ these healthy whole foods for specific psychiatric symptoms and conditions.”
This study was supported by Instituto de Salud Carlos III (co-funded by European Union Regional Development Fund “A way to make Europe”). The California Walnut Commission has given support by supplying the walnuts for free for the Walnuts Smart Snack Dietary Intervention Trial. Dr. Julvez holds a Miguel Servet-II contract awarded by the Instituto de Salud Carlos III (co-funded by European Union Social Fund). The other authors’ disclosures are listed in the original article. Dr. Naidoo reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. Adolescents who consumed walnuts for at least 100 days showed improved sustained attention and fluid intelligence as well as a reduction in symptoms of attension deficit hyperactivity disorder, compared with matched controls who did not consume the nuts. However, there were no statistically significant changes between the groups in other parameters, such as working memory and executive function.
Clinicians should advise adolescents “to eat a handful of walnuts three times a week for the rest of their lives. They may have a healthier brain with better cognitive function,” said senior investigator Jordi Julvez, PhD, group leader at the Institute of Health Research Pere Virgili, Barcelona, and associated researcher at the Barcelona Institute for Global Health.
The study was published online in eClinicalMedicine.
Rich source of omega-3s
Adolescence is “a period of refinement of brain connectivity and complex behaviors,” the investigators noted.
Previous research suggests polyunsaturated fatty acids are key in central nervous system architecture and function during times of neural development, with three specific PUFAs playing an “essential developmental role.”
Two omega-3 fatty acids – docosahexaenoic acid and eicosapentaenoic acid – are PUFAs that must be obtained through diet, mainly from seafood. Walnuts are “among the richest sources” of plant-derived omega-3 fatty acids, particularly alpha-linolenic acid (ALA), a precursor for longer-chain EPA and DHA.
ALA independently “has positive effects on brain function and plasticity,” the authors wrote. In addition, walnut constituents – particularly polyphenols and other bioactive compounds – “may act synergistically with ALA to foster brain health.”
Earlier small studies have found positive associations between walnut consumption and cognitive function in children, adolescents, and young adults, but to date, no randomized controlled trial has focused on the effect of walnut consumption on adolescent neuropsychological function.
The researchers studied 771 healthy adolescents (aged 11-16 years, mean age 14) drawn from 12 Spanish high schools. Participants were instructed to follow healthy eating recommendations and were randomly assigned 1:1 to the intervention (n = 386) or the control group (n = 385).
At baseline and after 6 months, they completed neuropsychological tests and behavioral rating scales. The Attention Network Test assessed attention, and the N-back test was used to assess working memory. The Tests of Primary Mental Abilities assessed fluid intelligence. Risky decision-making was tested using the Roulettes Task.
Fruit and nuts
Participants also completed the Strengths and Difficulties Questionnaire, which provided a total score of problem behavior. Teachers filled out the ADHD DSM-IV form list to provide additional information about ADHD behaviors.
The intervention group received 30 grams/day of raw California walnut kernels to incorporate into their daily diet. It is estimated that this walnut contains about 9 g of ALA per 100 g.
All participants received a seasonal fruit calendar and were asked to eat at least one piece of seasonal fruit daily.
Parents reported their child’s daily walnut consumption, with adherence defined as 100 or more days of eating walnuts during the 6-month period.
All main analyses were based on an intention-to-treat method (participants were analyzed according to their original group assignment, regardless of their adherence to the intervention).
The researchers also conducted a secondary per-protocol analysis, comparing the intervention and control groups to estimate the effect if all participants had adhered to their assigned intervention. They censored data for participants who reported eating walnuts for less than 100 days during the 6-month trial period.
Secondary outcomes included changes in height, weight, waist circumference, and BMI, as well as red blood cell proportions of omega-3 fatty acids (DHA, EPA, and ALA) at baseline and after 6 months.
Adherence counts
Most participants had “medium” or “high” levels of adherence to the Mediterranean diet, with “no meaningful differences” at baseline between the intervention and control groups in lifestyle characteristics or mean scores in all primary endpoints.
In the ITT analysis, there were no statistically significant differences in primary outcomes between the groups following the intervention. As for secondary outcomes, the RBC ALA significantly increased in the walnuts group but not the control group (coefficient, 0.04%; 95% confidence interval, 0.03%-0.06%; P < .0001).
However, there were differences in primary outcomes between the groups in the per-protocol analysis: The adherence-adjusted effect on improvement in attention score was −11.26 ms; 95% CI, −19.92 to −2.60; P = .011) for the intervention versus the control group.
The per-protocol analysis showed other differences: an improvement in fluid intelligence score (1.78; 95% CI, 0.90 - 2.67; P < .0001) and a reduction in ADHD symptom score (−2.18; 95% CI, −3.70 to −0.67; P = .0050).
“Overall, no significant differences were found in the intervention group in relation to the control group,” Dr. Julvez said in a news release. “But if the adherence factor is considered, then positive results are observed, since participants who most closely followed the guidelines – in terms of the recommended dose of walnuts and the number of days of consumption – did show improvements in the neuropsychological functions evaluated.”
Adolescence “is a time of great biological changes. Hormonal transformation occurs, which in turn is responsible for stimulating the synaptic growth of the frontal lobe,” he continued, adding that this brain region “enables neuropsychological maturation of more complex emotional and cognitive functions.”
“Neurons that are well nourished with these types of fatty acids will be able to grow and form new, stronger synapses,” he said.
Food as medicine
Uma Naidoo, MD, director of nutritional and lifestyle psychiatry at Massachusetts General Hospital, Boston, “commends” the researchers for conducting an RCT with a “robust” sample size and said she is “excited to see research like this furthering functional nutrition for mental health,” as she believes that “food is medicine.”
Dr. Naidoo, a professional chef, nutritional biologist, and author of the book “This Is Your Brain on Food,” said the findings “align” with her own approach to nutritional psychiatry and are also “in line” with her clinical practice.
However, although these results are “promising,” more research is needed across more diverse populations to “make sure these results are truly generalizable,” said Dr. Naidoo, a faculty member at Harvard Medical School, Boston, who was not involved with the study.
She “envisions a future where the research is so advanced that we can ‘dose’ these healthy whole foods for specific psychiatric symptoms and conditions.”
This study was supported by Instituto de Salud Carlos III (co-funded by European Union Regional Development Fund “A way to make Europe”). The California Walnut Commission has given support by supplying the walnuts for free for the Walnuts Smart Snack Dietary Intervention Trial. Dr. Julvez holds a Miguel Servet-II contract awarded by the Instituto de Salud Carlos III (co-funded by European Union Social Fund). The other authors’ disclosures are listed in the original article. Dr. Naidoo reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. Adolescents who consumed walnuts for at least 100 days showed improved sustained attention and fluid intelligence as well as a reduction in symptoms of attension deficit hyperactivity disorder, compared with matched controls who did not consume the nuts. However, there were no statistically significant changes between the groups in other parameters, such as working memory and executive function.
Clinicians should advise adolescents “to eat a handful of walnuts three times a week for the rest of their lives. They may have a healthier brain with better cognitive function,” said senior investigator Jordi Julvez, PhD, group leader at the Institute of Health Research Pere Virgili, Barcelona, and associated researcher at the Barcelona Institute for Global Health.
The study was published online in eClinicalMedicine.
Rich source of omega-3s
Adolescence is “a period of refinement of brain connectivity and complex behaviors,” the investigators noted.
Previous research suggests polyunsaturated fatty acids are key in central nervous system architecture and function during times of neural development, with three specific PUFAs playing an “essential developmental role.”
Two omega-3 fatty acids – docosahexaenoic acid and eicosapentaenoic acid – are PUFAs that must be obtained through diet, mainly from seafood. Walnuts are “among the richest sources” of plant-derived omega-3 fatty acids, particularly alpha-linolenic acid (ALA), a precursor for longer-chain EPA and DHA.
ALA independently “has positive effects on brain function and plasticity,” the authors wrote. In addition, walnut constituents – particularly polyphenols and other bioactive compounds – “may act synergistically with ALA to foster brain health.”
Earlier small studies have found positive associations between walnut consumption and cognitive function in children, adolescents, and young adults, but to date, no randomized controlled trial has focused on the effect of walnut consumption on adolescent neuropsychological function.
The researchers studied 771 healthy adolescents (aged 11-16 years, mean age 14) drawn from 12 Spanish high schools. Participants were instructed to follow healthy eating recommendations and were randomly assigned 1:1 to the intervention (n = 386) or the control group (n = 385).
At baseline and after 6 months, they completed neuropsychological tests and behavioral rating scales. The Attention Network Test assessed attention, and the N-back test was used to assess working memory. The Tests of Primary Mental Abilities assessed fluid intelligence. Risky decision-making was tested using the Roulettes Task.
Fruit and nuts
Participants also completed the Strengths and Difficulties Questionnaire, which provided a total score of problem behavior. Teachers filled out the ADHD DSM-IV form list to provide additional information about ADHD behaviors.
The intervention group received 30 grams/day of raw California walnut kernels to incorporate into their daily diet. It is estimated that this walnut contains about 9 g of ALA per 100 g.
All participants received a seasonal fruit calendar and were asked to eat at least one piece of seasonal fruit daily.
Parents reported their child’s daily walnut consumption, with adherence defined as 100 or more days of eating walnuts during the 6-month period.
All main analyses were based on an intention-to-treat method (participants were analyzed according to their original group assignment, regardless of their adherence to the intervention).
The researchers also conducted a secondary per-protocol analysis, comparing the intervention and control groups to estimate the effect if all participants had adhered to their assigned intervention. They censored data for participants who reported eating walnuts for less than 100 days during the 6-month trial period.
Secondary outcomes included changes in height, weight, waist circumference, and BMI, as well as red blood cell proportions of omega-3 fatty acids (DHA, EPA, and ALA) at baseline and after 6 months.
Adherence counts
Most participants had “medium” or “high” levels of adherence to the Mediterranean diet, with “no meaningful differences” at baseline between the intervention and control groups in lifestyle characteristics or mean scores in all primary endpoints.
In the ITT analysis, there were no statistically significant differences in primary outcomes between the groups following the intervention. As for secondary outcomes, the RBC ALA significantly increased in the walnuts group but not the control group (coefficient, 0.04%; 95% confidence interval, 0.03%-0.06%; P < .0001).
However, there were differences in primary outcomes between the groups in the per-protocol analysis: The adherence-adjusted effect on improvement in attention score was −11.26 ms; 95% CI, −19.92 to −2.60; P = .011) for the intervention versus the control group.
The per-protocol analysis showed other differences: an improvement in fluid intelligence score (1.78; 95% CI, 0.90 - 2.67; P < .0001) and a reduction in ADHD symptom score (−2.18; 95% CI, −3.70 to −0.67; P = .0050).
“Overall, no significant differences were found in the intervention group in relation to the control group,” Dr. Julvez said in a news release. “But if the adherence factor is considered, then positive results are observed, since participants who most closely followed the guidelines – in terms of the recommended dose of walnuts and the number of days of consumption – did show improvements in the neuropsychological functions evaluated.”
Adolescence “is a time of great biological changes. Hormonal transformation occurs, which in turn is responsible for stimulating the synaptic growth of the frontal lobe,” he continued, adding that this brain region “enables neuropsychological maturation of more complex emotional and cognitive functions.”
“Neurons that are well nourished with these types of fatty acids will be able to grow and form new, stronger synapses,” he said.
Food as medicine
Uma Naidoo, MD, director of nutritional and lifestyle psychiatry at Massachusetts General Hospital, Boston, “commends” the researchers for conducting an RCT with a “robust” sample size and said she is “excited to see research like this furthering functional nutrition for mental health,” as she believes that “food is medicine.”
Dr. Naidoo, a professional chef, nutritional biologist, and author of the book “This Is Your Brain on Food,” said the findings “align” with her own approach to nutritional psychiatry and are also “in line” with her clinical practice.
However, although these results are “promising,” more research is needed across more diverse populations to “make sure these results are truly generalizable,” said Dr. Naidoo, a faculty member at Harvard Medical School, Boston, who was not involved with the study.
She “envisions a future where the research is so advanced that we can ‘dose’ these healthy whole foods for specific psychiatric symptoms and conditions.”
This study was supported by Instituto de Salud Carlos III (co-funded by European Union Regional Development Fund “A way to make Europe”). The California Walnut Commission has given support by supplying the walnuts for free for the Walnuts Smart Snack Dietary Intervention Trial. Dr. Julvez holds a Miguel Servet-II contract awarded by the Instituto de Salud Carlos III (co-funded by European Union Social Fund). The other authors’ disclosures are listed in the original article. Dr. Naidoo reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ECLINICALMEDICINE
Meta-analysis examines cancer risk concern for JAK inhibitors
MANCHESTER, ENGLAND – Janus kinase (JAK) inhibitors may be associated with a higher risk for cancer relative to tumor necrosis factor (TNF) inhibitors, according to a meta-analysis reported at the annual meeting of the British Society for Rheumatology.
Looking at all phase 2, 3, and 4 trials and long-term extension studies across the indications of rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease, and atopic dermatitis, the risk ratio for any cancer developing was 1.63 when compared with anti-TNF therapy (95% confidence interval, 1.27-2.09).
By comparison, JAK inhibitor use was not significantly associated with any greater risk for cancer than methotrexate (RR, 1.06; 95% confidence interval, 0.58-1.94) or placebo (RR, 1.16; 95% CI, 0.75-1.80).
“Our data suggests that rather than JAK inhibitors necessarily being harmful, it could be more a case of TNF inhibitors being protective,” said Christopher Stovin, MBChB, a specialist registrar in rheumatology at the Princess Royal University Hospital, King’s College Hospital NHS Trust, London.
“We should stress that these are rare events in our study, roughly around 1 in every 100 patient-years of exposure,” Dr. Stovin said.
“Despite having over 80,000 years of patient exposure, the median follow-up duration for JAK inhibitors was still only 118 weeks, which for cancers [that] obviously have long latency periods is still a relatively small duration of time,” the researcher added.
“People worry about the drugs. But there is a possibility that [a] disturbed immune system plays a role per se in development of cancers,” consultant rheumatologist Anurag Bharadwaj, MD, DM, said in an interview.
“Although there are studies which attribute increased risk of cancer to different DMARDs [disease-modifying antirheumatic drugs] and biologics like TNF, but on other hand, it’s maybe that we are giving these drugs to patients who have got more serious immunological disease,” suggested Bharadwaj, who serves as the clinical lead for rheumatology at Basildon (England) Hospital, Mid & South Essex Foundation Trust.
“So, a possibility may be that the more severe or the more active the immunological inflammatory disease, the higher the chance of cancer, and these are the patients who go for the stronger medications,” Dr. Bharadwaj said.
There is an “immunological window of opportunity” when treating these inflammatory diseases, said Dr. Bharadwaj, noting that the first few months of treatment are vital. “For all immunological diseases, the more quickly you bring the immunological abnormality down, the chances of long-term complications go down, including [possibly that the] chances of cancer go down, chances of cardiovascular disease go down, and chances of lung disease go down. Hit it early, hit it hard.”
Concern over a possible higher risk for cancer with JAK inhibitors than with TNF inhibitors was raised following the release of data from the ORAL Surveillance trial, a postmarketing trial of tofacitinib (Xeljanz) that had been mandated by the Food and Drug Administration.
“This was a study looking at the coprimary endpoints of malignancy and major adverse cardiovascular events, and it was enriched with patients over the age of 50, with one additional cardiac risk factor, designed to amplify the detection of these rare events,” Dr. Stovin said.
“There was a signal of an increased risk of malignancy in the tofacitinib group, and this led to the FDA issuing a [boxed warning for all licensed JAK inhibitors] at that time,” he added.
Dr. Stovin and colleagues aimed to determine what, if any, cancer risk was associated with all available JAK inhibitors relative to placebo, TNF inhibitors, and methotrexate.
In all, data from 62 randomized controlled trials and 14 long-term extension studies were included in the meta-analysis, accounting for 82,366 patient years of follow-up. The JAK inhibitors analyzed included tofacitinib, baricitinib (Olumiant), upadacitinib (Rinvoq), filgotinib (Jyseleca), and peficitinib (Smyraf). (Filgotinib and peficitinib have not been approved by the FDA.)
The researchers performed sensitivity analyses that excluded cancers detected within the first 6 months of treatment, the use of higher than licensed JAK inhibitor doses, and patients with non-rheumatoid arthritis diagnoses, but the results remained largely unchanged, Dr. Stovin reported.
“Perhaps not surprisingly, when we removed ORAL Surveillance” from the analysis comparing JAK inhibitors and TNF inhibitors, “we lost statistical significance,” he said.
“Longitudinal observational data is needed but currently remains limited,” Dr. Stovin concluded.
Dr. Stovin and Dr. Bharadwaj reported no relevant financial relationships. The meta-analysis was independently supported. Dr. Bharadwaj was not involved in the study and provided comment ahead of the presentation.
A version of this article first appeared on Medscape.com.
MANCHESTER, ENGLAND – Janus kinase (JAK) inhibitors may be associated with a higher risk for cancer relative to tumor necrosis factor (TNF) inhibitors, according to a meta-analysis reported at the annual meeting of the British Society for Rheumatology.
Looking at all phase 2, 3, and 4 trials and long-term extension studies across the indications of rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease, and atopic dermatitis, the risk ratio for any cancer developing was 1.63 when compared with anti-TNF therapy (95% confidence interval, 1.27-2.09).
By comparison, JAK inhibitor use was not significantly associated with any greater risk for cancer than methotrexate (RR, 1.06; 95% confidence interval, 0.58-1.94) or placebo (RR, 1.16; 95% CI, 0.75-1.80).
“Our data suggests that rather than JAK inhibitors necessarily being harmful, it could be more a case of TNF inhibitors being protective,” said Christopher Stovin, MBChB, a specialist registrar in rheumatology at the Princess Royal University Hospital, King’s College Hospital NHS Trust, London.
“We should stress that these are rare events in our study, roughly around 1 in every 100 patient-years of exposure,” Dr. Stovin said.
“Despite having over 80,000 years of patient exposure, the median follow-up duration for JAK inhibitors was still only 118 weeks, which for cancers [that] obviously have long latency periods is still a relatively small duration of time,” the researcher added.
“People worry about the drugs. But there is a possibility that [a] disturbed immune system plays a role per se in development of cancers,” consultant rheumatologist Anurag Bharadwaj, MD, DM, said in an interview.
“Although there are studies which attribute increased risk of cancer to different DMARDs [disease-modifying antirheumatic drugs] and biologics like TNF, but on other hand, it’s maybe that we are giving these drugs to patients who have got more serious immunological disease,” suggested Bharadwaj, who serves as the clinical lead for rheumatology at Basildon (England) Hospital, Mid & South Essex Foundation Trust.
“So, a possibility may be that the more severe or the more active the immunological inflammatory disease, the higher the chance of cancer, and these are the patients who go for the stronger medications,” Dr. Bharadwaj said.
There is an “immunological window of opportunity” when treating these inflammatory diseases, said Dr. Bharadwaj, noting that the first few months of treatment are vital. “For all immunological diseases, the more quickly you bring the immunological abnormality down, the chances of long-term complications go down, including [possibly that the] chances of cancer go down, chances of cardiovascular disease go down, and chances of lung disease go down. Hit it early, hit it hard.”
Concern over a possible higher risk for cancer with JAK inhibitors than with TNF inhibitors was raised following the release of data from the ORAL Surveillance trial, a postmarketing trial of tofacitinib (Xeljanz) that had been mandated by the Food and Drug Administration.
“This was a study looking at the coprimary endpoints of malignancy and major adverse cardiovascular events, and it was enriched with patients over the age of 50, with one additional cardiac risk factor, designed to amplify the detection of these rare events,” Dr. Stovin said.
“There was a signal of an increased risk of malignancy in the tofacitinib group, and this led to the FDA issuing a [boxed warning for all licensed JAK inhibitors] at that time,” he added.
Dr. Stovin and colleagues aimed to determine what, if any, cancer risk was associated with all available JAK inhibitors relative to placebo, TNF inhibitors, and methotrexate.
In all, data from 62 randomized controlled trials and 14 long-term extension studies were included in the meta-analysis, accounting for 82,366 patient years of follow-up. The JAK inhibitors analyzed included tofacitinib, baricitinib (Olumiant), upadacitinib (Rinvoq), filgotinib (Jyseleca), and peficitinib (Smyraf). (Filgotinib and peficitinib have not been approved by the FDA.)
The researchers performed sensitivity analyses that excluded cancers detected within the first 6 months of treatment, the use of higher than licensed JAK inhibitor doses, and patients with non-rheumatoid arthritis diagnoses, but the results remained largely unchanged, Dr. Stovin reported.
“Perhaps not surprisingly, when we removed ORAL Surveillance” from the analysis comparing JAK inhibitors and TNF inhibitors, “we lost statistical significance,” he said.
“Longitudinal observational data is needed but currently remains limited,” Dr. Stovin concluded.
Dr. Stovin and Dr. Bharadwaj reported no relevant financial relationships. The meta-analysis was independently supported. Dr. Bharadwaj was not involved in the study and provided comment ahead of the presentation.
A version of this article first appeared on Medscape.com.
MANCHESTER, ENGLAND – Janus kinase (JAK) inhibitors may be associated with a higher risk for cancer relative to tumor necrosis factor (TNF) inhibitors, according to a meta-analysis reported at the annual meeting of the British Society for Rheumatology.
Looking at all phase 2, 3, and 4 trials and long-term extension studies across the indications of rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease, and atopic dermatitis, the risk ratio for any cancer developing was 1.63 when compared with anti-TNF therapy (95% confidence interval, 1.27-2.09).
By comparison, JAK inhibitor use was not significantly associated with any greater risk for cancer than methotrexate (RR, 1.06; 95% confidence interval, 0.58-1.94) or placebo (RR, 1.16; 95% CI, 0.75-1.80).
“Our data suggests that rather than JAK inhibitors necessarily being harmful, it could be more a case of TNF inhibitors being protective,” said Christopher Stovin, MBChB, a specialist registrar in rheumatology at the Princess Royal University Hospital, King’s College Hospital NHS Trust, London.
“We should stress that these are rare events in our study, roughly around 1 in every 100 patient-years of exposure,” Dr. Stovin said.
“Despite having over 80,000 years of patient exposure, the median follow-up duration for JAK inhibitors was still only 118 weeks, which for cancers [that] obviously have long latency periods is still a relatively small duration of time,” the researcher added.
“People worry about the drugs. But there is a possibility that [a] disturbed immune system plays a role per se in development of cancers,” consultant rheumatologist Anurag Bharadwaj, MD, DM, said in an interview.
“Although there are studies which attribute increased risk of cancer to different DMARDs [disease-modifying antirheumatic drugs] and biologics like TNF, but on other hand, it’s maybe that we are giving these drugs to patients who have got more serious immunological disease,” suggested Bharadwaj, who serves as the clinical lead for rheumatology at Basildon (England) Hospital, Mid & South Essex Foundation Trust.
“So, a possibility may be that the more severe or the more active the immunological inflammatory disease, the higher the chance of cancer, and these are the patients who go for the stronger medications,” Dr. Bharadwaj said.
There is an “immunological window of opportunity” when treating these inflammatory diseases, said Dr. Bharadwaj, noting that the first few months of treatment are vital. “For all immunological diseases, the more quickly you bring the immunological abnormality down, the chances of long-term complications go down, including [possibly that the] chances of cancer go down, chances of cardiovascular disease go down, and chances of lung disease go down. Hit it early, hit it hard.”
Concern over a possible higher risk for cancer with JAK inhibitors than with TNF inhibitors was raised following the release of data from the ORAL Surveillance trial, a postmarketing trial of tofacitinib (Xeljanz) that had been mandated by the Food and Drug Administration.
“This was a study looking at the coprimary endpoints of malignancy and major adverse cardiovascular events, and it was enriched with patients over the age of 50, with one additional cardiac risk factor, designed to amplify the detection of these rare events,” Dr. Stovin said.
“There was a signal of an increased risk of malignancy in the tofacitinib group, and this led to the FDA issuing a [boxed warning for all licensed JAK inhibitors] at that time,” he added.
Dr. Stovin and colleagues aimed to determine what, if any, cancer risk was associated with all available JAK inhibitors relative to placebo, TNF inhibitors, and methotrexate.
In all, data from 62 randomized controlled trials and 14 long-term extension studies were included in the meta-analysis, accounting for 82,366 patient years of follow-up. The JAK inhibitors analyzed included tofacitinib, baricitinib (Olumiant), upadacitinib (Rinvoq), filgotinib (Jyseleca), and peficitinib (Smyraf). (Filgotinib and peficitinib have not been approved by the FDA.)
The researchers performed sensitivity analyses that excluded cancers detected within the first 6 months of treatment, the use of higher than licensed JAK inhibitor doses, and patients with non-rheumatoid arthritis diagnoses, but the results remained largely unchanged, Dr. Stovin reported.
“Perhaps not surprisingly, when we removed ORAL Surveillance” from the analysis comparing JAK inhibitors and TNF inhibitors, “we lost statistical significance,” he said.
“Longitudinal observational data is needed but currently remains limited,” Dr. Stovin concluded.
Dr. Stovin and Dr. Bharadwaj reported no relevant financial relationships. The meta-analysis was independently supported. Dr. Bharadwaj was not involved in the study and provided comment ahead of the presentation.
A version of this article first appeared on Medscape.com.
AT BSR 2023