Clinician Reviews

TOPLINE:

For relief of acute migraine, triptans, ergots, and antiemetics are two to five times more effective than ibuprofen, and acetaminophen is the least effective medication, new results from large, real-world analysis of self-reported patient data show. 

METHODOLOGY: 

• Researchers analyzed nearly 11 million migraine attack records extracted from Migraine Buddy, an e-diary smartphone app, over a 6-year period. 
• They evaluated self-reported treatment effectiveness for 25 acute migraine medications among seven classes: acetaminophen, NSAIDs, triptans, combination analgesics, ergots, antiemetics, and opioids. 
• A two-level nested multivariate logistic regression model adjusted for within-subject dependency and for concomitant medications taken within each analyzed migraine attack. 
• The final analysis included nearly 5 million medication-outcome pairs from 3.1 million migraine attacks in 278,000 medication users. 

TAKEAWAY:

• Using ibuprofen as the reference, triptans, ergots, and antiemetics were the top three medication classes with the highest effectiveness (mean odds ratios [OR] 4.80, 3.02, and 2.67, respectively). 
• The next most effective medication classes were opioids (OR, 2.49), NSAIDs other than ibuprofen (OR, 1.94), combination analgesics acetaminophen/acetylsalicylic acid/caffeine (OR, 1.69), and others (OR, 1.49).
• Acetaminophen (OR, 0.83) was considered to be the least effective.
• The most effective individual medications were eletriptan (Relpax) (OR, 6.1); zolmitriptan (Zomig) (OR, 5.7); and sumatriptan (Imitrex) (OR, 5.2).

IN PRACTICE:

“Our findings that triptans, ergots, and antiemetics are the most effective classes of medications align with the guideline recommendations and offer generalizable insights to complement clinical practice,” the authors wrote. 

laflor/gettyimages

SOURCE:

The study, with first author Chia-Chun Chiang, MD, Department of Neurology, Mayo Clinic, Rochester, Minnesota, was published online November 29 in Neurology.

LIMITATIONS:

The findings are based on subjective user-reported ratings of effectiveness and information on side effects, dosages, and formulations were not available. The newer migraine medication classes, gepants and ditans, were not included due to the relatively lower number of treated attacks. The regression model did not include age, gender, pain intensity, and other migraine-associated symptoms, which could potentially affect treatment effectiveness. 

DISCLOSURES: 

Funding for the study was provided by the Kanagawa University of Human Service research fund. A full list of author disclosures can be found with the original article.

A version of this article first appeared on Medscape.com.

TOPLINE:

For relief of acute migraine, triptans, ergots, and antiemetics are two to five times more effective than ibuprofen, and acetaminophen is the least effective medication, new results from large, real-world analysis of self-reported patient data show. 

METHODOLOGY: 

• Researchers analyzed nearly 11 million migraine attack records extracted from Migraine Buddy, an e-diary smartphone app, over a 6-year period. 
• They evaluated self-reported treatment effectiveness for 25 acute migraine medications among seven classes: acetaminophen, NSAIDs, triptans, combination analgesics, ergots, antiemetics, and opioids. 
• A two-level nested multivariate logistic regression model adjusted for within-subject dependency and for concomitant medications taken within each analyzed migraine attack. 
• The final analysis included nearly 5 million medication-outcome pairs from 3.1 million migraine attacks in 278,000 medication users. 

TAKEAWAY:

• Using ibuprofen as the reference, triptans, ergots, and antiemetics were the top three medication classes with the highest effectiveness (mean odds ratios [OR] 4.80, 3.02, and 2.67, respectively). 
• The next most effective medication classes were opioids (OR, 2.49), NSAIDs other than ibuprofen (OR, 1.94), combination analgesics acetaminophen/acetylsalicylic acid/caffeine (OR, 1.69), and others (OR, 1.49).
• Acetaminophen (OR, 0.83) was considered to be the least effective.
• The most effective individual medications were eletriptan (Relpax) (OR, 6.1); zolmitriptan (Zomig) (OR, 5.7); and sumatriptan (Imitrex) (OR, 5.2).

IN PRACTICE:

“Our findings that triptans, ergots, and antiemetics are the most effective classes of medications align with the guideline recommendations and offer generalizable insights to complement clinical practice,” the authors wrote. 

laflor/gettyimages

SOURCE:

The study, with first author Chia-Chun Chiang, MD, Department of Neurology, Mayo Clinic, Rochester, Minnesota, was published online November 29 in Neurology.

LIMITATIONS:

The findings are based on subjective user-reported ratings of effectiveness and information on side effects, dosages, and formulations were not available. The newer migraine medication classes, gepants and ditans, were not included due to the relatively lower number of treated attacks. The regression model did not include age, gender, pain intensity, and other migraine-associated symptoms, which could potentially affect treatment effectiveness. 

DISCLOSURES: 

Funding for the study was provided by the Kanagawa University of Human Service research fund. A full list of author disclosures can be found with the original article.

A version of this article first appeared on Medscape.com.

TOPLINE:

For relief of acute migraine, triptans, ergots, and antiemetics are two to five times more effective than ibuprofen, and acetaminophen is the least effective medication, new results from large, real-world analysis of self-reported patient data show. 

METHODOLOGY: 

• Researchers analyzed nearly 11 million migraine attack records extracted from Migraine Buddy, an e-diary smartphone app, over a 6-year period. 
• They evaluated self-reported treatment effectiveness for 25 acute migraine medications among seven classes: acetaminophen, NSAIDs, triptans, combination analgesics, ergots, antiemetics, and opioids. 
• A two-level nested multivariate logistic regression model adjusted for within-subject dependency and for concomitant medications taken within each analyzed migraine attack. 
• The final analysis included nearly 5 million medication-outcome pairs from 3.1 million migraine attacks in 278,000 medication users. 

TAKEAWAY:

• Using ibuprofen as the reference, triptans, ergots, and antiemetics were the top three medication classes with the highest effectiveness (mean odds ratios [OR] 4.80, 3.02, and 2.67, respectively). 
• The next most effective medication classes were opioids (OR, 2.49), NSAIDs other than ibuprofen (OR, 1.94), combination analgesics acetaminophen/acetylsalicylic acid/caffeine (OR, 1.69), and others (OR, 1.49).
• Acetaminophen (OR, 0.83) was considered to be the least effective.
• The most effective individual medications were eletriptan (Relpax) (OR, 6.1); zolmitriptan (Zomig) (OR, 5.7); and sumatriptan (Imitrex) (OR, 5.2).

IN PRACTICE:

“Our findings that triptans, ergots, and antiemetics are the most effective classes of medications align with the guideline recommendations and offer generalizable insights to complement clinical practice,” the authors wrote. 

laflor/gettyimages

SOURCE:

The study, with first author Chia-Chun Chiang, MD, Department of Neurology, Mayo Clinic, Rochester, Minnesota, was published online November 29 in Neurology.

LIMITATIONS:

The findings are based on subjective user-reported ratings of effectiveness and information on side effects, dosages, and formulations were not available. The newer migraine medication classes, gepants and ditans, were not included due to the relatively lower number of treated attacks. The regression model did not include age, gender, pain intensity, and other migraine-associated symptoms, which could potentially affect treatment effectiveness. 

DISCLOSURES: 

Funding for the study was provided by the Kanagawa University of Human Service research fund. A full list of author disclosures can be found with the original article.

A version of this article first appeared on Medscape.com.

No one planning holiday gatherings or travel wants to hear this, but the rise of a new COVID-19 variant, JN.1, is concerning experts, who say it may threaten those good times. 

The good news is recent research suggests the 2023-2024 COVID-19 vaccine appears to work against this newest variant. But so few people have gotten the latest vaccine — less than 16% of U.S. adults — that some experts suggest it’s time for the CDC to urge the public who haven’t it to do so now, so the antibodies can kick in before the festivities.

“A significant wave [of JN.1] has started here and could be blunted with a high booster rate and mitigation measures,” said Eric Topol, MD, professor and executive vice president of Scripps Research in La Jolla, CA, and editor-in-chief of Medscape, a sister site of this news organization.

COVID metrics, meanwhile, have started to climb again. Nearly 10,000 people were hospitalized for COVID in the U.S. for the week ending Nov. 25, the CDC said, a 10% increase over the previous week. 
 

Who’s Who in the Family Tree

JN.1, an Omicron subvariant, was first detected in the U.S. in September and is termed “a notable descendent lineage” of Omicron subvariant BA.2.86 by the World Health Organization. When BA.2.86, also known as Pirola, was first identified in August, it appeared very different from other variants, the CDC said. That triggered concerns it might be more infectious than previous ones, even for people with immunity from vaccination and previous infections. 

“JN.1 is Pirola’s kid,” said Rajendram Rajnarayanan, PhD, assistant dean of research and associate professor at the New York Institute of Technology at Arkansas State University, who maintains a COVID-19 variant database. The variant BA.2.86 and offspring are worrisome due to the mutations, he said.
 

How Widespread Is JN.1?

As of Nov. 27, the CDC says, BA.2.86 is projected to comprise 5%-15% of circulating variants in the U.S. “The expected public health risk of this variant, including its offshoot JN.1, is low,” the agency said.

Currently, JN.1 is reported more often in Europe, Dr. Rajnarayanan said, but some countries have better reporting data than others. “It has probably spread to every country tracking COVID,’’ he said, due to the mutations in the spike protein that make it easier for it to bind and infect.

Wastewater data suggest the variant’s rise is helping to fuel a wave, Dr. Topol said. 
 

Vaccine Effectiveness Against JN.1, Other New Variants 

The new XBB.1.5 monovalent vaccine, protects against XBB.1.5, another Omicron subvariant, but also JN.1 and other “emergent” viruses, a team of researchers reported Nov. 26 in a study on bioRxiv that has not yet been certified by peer review.

The updated vaccine, when given to uninfected people, boosted antibodies about 27-fold against XBB.1.5 and about 13- to 27-fold against JN.1 and other emergent viruses, the researchers reported.

While even primary doses of the COVID vaccine will likely help protect against the new JN.1 subvariant, “if you got the XBB.1.5 booster, it is going to be protecting you better against this new variant,” Dr. Rajnarayanan said.
 

2023-2024 Vaccine Uptake Low 

In November, the CDC posted the first detailed estimates of who did. As of Nov. 18, less than 16% of U.S. adults had, with nearly 15% saying they planned to get it.

Coverage among children is lower, with just 6.3% of children up to date on the newest vaccine and 19% of parents saying they planned to get the 2023-2024 vaccine for their children.
 

Predictions, Mitigation

While some experts say a peak due to JN.1 is expected in the weeks ahead, Dr. Topol said it’s impossible to predict exactly how JN.1 will play out.

“It’s not going to be a repeat of November 2021,” when Omicron surfaced, Dr. Rajnarayanan predicted. Within 4 weeks of the World Health Organization declaring Omicron as a virus of concern, it spread around the world.

Mitigation measures can help, Dr. Rajnarayanan said. He suggested:

Get the new vaccine, and especially encourage vulnerable family and friends to do so.

If you are gathering inside for holiday festivities, improve circulation in the house, if possible.

Wear masks in airports and on planes and other public transportation.

A version of this article appeared on WebMD.com.

No one planning holiday gatherings or travel wants to hear this, but the rise of a new COVID-19 variant, JN.1, is concerning experts, who say it may threaten those good times. 

The good news is recent research suggests the 2023-2024 COVID-19 vaccine appears to work against this newest variant. But so few people have gotten the latest vaccine — less than 16% of U.S. adults — that some experts suggest it’s time for the CDC to urge the public who haven’t it to do so now, so the antibodies can kick in before the festivities.

“A significant wave [of JN.1] has started here and could be blunted with a high booster rate and mitigation measures,” said Eric Topol, MD, professor and executive vice president of Scripps Research in La Jolla, CA, and editor-in-chief of Medscape, a sister site of this news organization.

COVID metrics, meanwhile, have started to climb again. Nearly 10,000 people were hospitalized for COVID in the U.S. for the week ending Nov. 25, the CDC said, a 10% increase over the previous week. 
 

Who’s Who in the Family Tree

JN.1, an Omicron subvariant, was first detected in the U.S. in September and is termed “a notable descendent lineage” of Omicron subvariant BA.2.86 by the World Health Organization. When BA.2.86, also known as Pirola, was first identified in August, it appeared very different from other variants, the CDC said. That triggered concerns it might be more infectious than previous ones, even for people with immunity from vaccination and previous infections. 

“JN.1 is Pirola’s kid,” said Rajendram Rajnarayanan, PhD, assistant dean of research and associate professor at the New York Institute of Technology at Arkansas State University, who maintains a COVID-19 variant database. The variant BA.2.86 and offspring are worrisome due to the mutations, he said.
 

How Widespread Is JN.1?

As of Nov. 27, the CDC says, BA.2.86 is projected to comprise 5%-15% of circulating variants in the U.S. “The expected public health risk of this variant, including its offshoot JN.1, is low,” the agency said.

Currently, JN.1 is reported more often in Europe, Dr. Rajnarayanan said, but some countries have better reporting data than others. “It has probably spread to every country tracking COVID,’’ he said, due to the mutations in the spike protein that make it easier for it to bind and infect.

Wastewater data suggest the variant’s rise is helping to fuel a wave, Dr. Topol said. 
 

Vaccine Effectiveness Against JN.1, Other New Variants 

The new XBB.1.5 monovalent vaccine, protects against XBB.1.5, another Omicron subvariant, but also JN.1 and other “emergent” viruses, a team of researchers reported Nov. 26 in a study on bioRxiv that has not yet been certified by peer review.

The updated vaccine, when given to uninfected people, boosted antibodies about 27-fold against XBB.1.5 and about 13- to 27-fold against JN.1 and other emergent viruses, the researchers reported.

While even primary doses of the COVID vaccine will likely help protect against the new JN.1 subvariant, “if you got the XBB.1.5 booster, it is going to be protecting you better against this new variant,” Dr. Rajnarayanan said.
 

2023-2024 Vaccine Uptake Low 

In November, the CDC posted the first detailed estimates of who did. As of Nov. 18, less than 16% of U.S. adults had, with nearly 15% saying they planned to get it.

Coverage among children is lower, with just 6.3% of children up to date on the newest vaccine and 19% of parents saying they planned to get the 2023-2024 vaccine for their children.
 

Predictions, Mitigation

While some experts say a peak due to JN.1 is expected in the weeks ahead, Dr. Topol said it’s impossible to predict exactly how JN.1 will play out.

“It’s not going to be a repeat of November 2021,” when Omicron surfaced, Dr. Rajnarayanan predicted. Within 4 weeks of the World Health Organization declaring Omicron as a virus of concern, it spread around the world.

Mitigation measures can help, Dr. Rajnarayanan said. He suggested:

Get the new vaccine, and especially encourage vulnerable family and friends to do so.

If you are gathering inside for holiday festivities, improve circulation in the house, if possible.

Wear masks in airports and on planes and other public transportation.

A version of this article appeared on WebMD.com.

No one planning holiday gatherings or travel wants to hear this, but the rise of a new COVID-19 variant, JN.1, is concerning experts, who say it may threaten those good times. 

The good news is recent research suggests the 2023-2024 COVID-19 vaccine appears to work against this newest variant. But so few people have gotten the latest vaccine — less than 16% of U.S. adults — that some experts suggest it’s time for the CDC to urge the public who haven’t it to do so now, so the antibodies can kick in before the festivities.

“A significant wave [of JN.1] has started here and could be blunted with a high booster rate and mitigation measures,” said Eric Topol, MD, professor and executive vice president of Scripps Research in La Jolla, CA, and editor-in-chief of Medscape, a sister site of this news organization.

COVID metrics, meanwhile, have started to climb again. Nearly 10,000 people were hospitalized for COVID in the U.S. for the week ending Nov. 25, the CDC said, a 10% increase over the previous week. 
 

Who’s Who in the Family Tree

JN.1, an Omicron subvariant, was first detected in the U.S. in September and is termed “a notable descendent lineage” of Omicron subvariant BA.2.86 by the World Health Organization. When BA.2.86, also known as Pirola, was first identified in August, it appeared very different from other variants, the CDC said. That triggered concerns it might be more infectious than previous ones, even for people with immunity from vaccination and previous infections. 

“JN.1 is Pirola’s kid,” said Rajendram Rajnarayanan, PhD, assistant dean of research and associate professor at the New York Institute of Technology at Arkansas State University, who maintains a COVID-19 variant database. The variant BA.2.86 and offspring are worrisome due to the mutations, he said.
 

How Widespread Is JN.1?

As of Nov. 27, the CDC says, BA.2.86 is projected to comprise 5%-15% of circulating variants in the U.S. “The expected public health risk of this variant, including its offshoot JN.1, is low,” the agency said.

Currently, JN.1 is reported more often in Europe, Dr. Rajnarayanan said, but some countries have better reporting data than others. “It has probably spread to every country tracking COVID,’’ he said, due to the mutations in the spike protein that make it easier for it to bind and infect.

Wastewater data suggest the variant’s rise is helping to fuel a wave, Dr. Topol said. 
 

Vaccine Effectiveness Against JN.1, Other New Variants 

The new XBB.1.5 monovalent vaccine, protects against XBB.1.5, another Omicron subvariant, but also JN.1 and other “emergent” viruses, a team of researchers reported Nov. 26 in a study on bioRxiv that has not yet been certified by peer review.

The updated vaccine, when given to uninfected people, boosted antibodies about 27-fold against XBB.1.5 and about 13- to 27-fold against JN.1 and other emergent viruses, the researchers reported.

While even primary doses of the COVID vaccine will likely help protect against the new JN.1 subvariant, “if you got the XBB.1.5 booster, it is going to be protecting you better against this new variant,” Dr. Rajnarayanan said.
 

2023-2024 Vaccine Uptake Low 

In November, the CDC posted the first detailed estimates of who did. As of Nov. 18, less than 16% of U.S. adults had, with nearly 15% saying they planned to get it.

Coverage among children is lower, with just 6.3% of children up to date on the newest vaccine and 19% of parents saying they planned to get the 2023-2024 vaccine for their children.
 

Predictions, Mitigation

While some experts say a peak due to JN.1 is expected in the weeks ahead, Dr. Topol said it’s impossible to predict exactly how JN.1 will play out.

“It’s not going to be a repeat of November 2021,” when Omicron surfaced, Dr. Rajnarayanan predicted. Within 4 weeks of the World Health Organization declaring Omicron as a virus of concern, it spread around the world.

Mitigation measures can help, Dr. Rajnarayanan said. He suggested:

Get the new vaccine, and especially encourage vulnerable family and friends to do so.

If you are gathering inside for holiday festivities, improve circulation in the house, if possible.

Wear masks in airports and on planes and other public transportation.

A version of this article appeared on WebMD.com.

Pediatricians commonly are asked to see infants presenting with symptoms of colic. The frequent and intense crying associated with colic is understandably quite distressing to parents, who often worry about a serious underlying medical cause. There also is the stress of trying to soothe an irritable infant who often does not seem to respond to the typical interventions.

Conventional wisdom about colic has been that the behaviors are the result of some gastrointestinal problem that, while not perfectly understood, tends to be mercifully self-limited and not predictive of future medical or mental health problems. This perspective then leads to pediatricians typically offering mainly sympathy and reassurance at these visits.

A new study,¹ however, challenges some of this traditional thinking. The data come from a remarkable longitudinal study called the Generation R Study (R being Rotterdam in the Netherlands) that has prospectively studied a group of nearly 5,000 children from before birth into adolescence. Colic symptoms were briefly assessed when infants were about 3 months old and emotional-behavioral problems have been prospectively measured at multiple time points subsequently using well-validated rating scales.

Dr. Rettew

The main finding of the study was excessive crying in infancy actually was significantly associated with higher levels of emotional-behavioral problems later in childhood and, to a lesser extent, in adolescence. This held for both internalizing problems (like anxiety and depressive symptoms) and externalizing problems (like defiance and aggressive behavior). At age 10, participants also underwent an MRI scan and those who were excessive criers as infants were found to have a smaller amygdala, a region known for being important in regulating emotions.

The authors concluded that colicky behavior in infancy may reflect some underlying temperamental vulnerabilities and may have more predictive value than previously thought. The connection between excessive crying and a measurable brain region difference later in life is also interesting, although these kinds of brain imaging findings have been notoriously difficult to interpret clinically.

Overall, this is a solid study that deserves to be considered. Colic may reflect a bit more than most of us have been taught and shouldn’t necessarily be “shrugged off,” as the authors state in their discussion.

At the same time, however, it is important not to overinterpret the findings. The magnitude of the effects were on the small side (about 0.2 of a standard deviation) and most children with excessive crying in early infancy did not manifest high levels of mental health problems later in life. The mothers of high crying infants also had slightly higher levels of mental health problems themselves so there could be other mechanisms at work here, such as genetic differences between the two groups.

So how could a pediatrician best use this new information without taking things too far? Regardless of the question of whether the excessive crying infancy is a true risk factor for later behavior problems (in the causal sense) or whether it represents more of a marker for something else, its presence so early in life offers an opportunity. Primary care clinicians would still likely want to provide the reassurance that has typically been given in these visits but perhaps with the caveat that some of these kids go on to struggle a bit more with mental health and that they might benefit from some additional support. We are not talking about prophylactic medications here, but something like additional parenting skills. Especially if you, as the pediatrician, suspect that the parents might benefit from expanding their parenting toolkit already, here is a nice opportunity to invite them to learn some new approaches and skills — framed in a way that focuses on the temperament of the child rather than any “deficits” you perceive in the parents. Some parents may be more receptive and less defensive to the idea of participating in parent training under the framework that they are doing this because they have a temperamentally more challenging child (rather than feeling that they are deficient in basic parenting skills).

It’s always a good idea to know about what resources are available in the community when it comes to teaching parenting skills. In addition to scientifically supported books and podcasts, there has been a steady increase in reliable websites, apps, and other digital platforms related to parenting, as well as standard in-person groups and classes. This could also be a great use of an integrated behavioral health professional for practices fortunate enough to have one.

In summary, there is some new evidence that colic can represent a little more than “just gas,” and while we shouldn’t take this one study to the extreme, there may be some good opportunities here to discuss and support good parenting practices in general.

Dr. Rettew is a child and adolescent psychiatrist with Lane County Behavioral Health in Eugene, Ore., and Oregon Health & Science University, Portland. His latest book is “Parenting Made Complicated: What Science Really Knows about the Greatest Debates of Early Childhood.” You can follow him on Twitter and Facebook @PediPsych.

Reference

1. Sammallahti S et al. Excessive crying, behavior problems, and amygdala volume: A study from infancy to adolescence. J Am Acad Child Adolesc Psychiatry. 2023 Jun;62(6):675-83. doi: 10.1016/j.jaac.2023.01.014.

Pediatricians commonly are asked to see infants presenting with symptoms of colic. The frequent and intense crying associated with colic is understandably quite distressing to parents, who often worry about a serious underlying medical cause. There also is the stress of trying to soothe an irritable infant who often does not seem to respond to the typical interventions.

Conventional wisdom about colic has been that the behaviors are the result of some gastrointestinal problem that, while not perfectly understood, tends to be mercifully self-limited and not predictive of future medical or mental health problems. This perspective then leads to pediatricians typically offering mainly sympathy and reassurance at these visits.

A new study,¹ however, challenges some of this traditional thinking. The data come from a remarkable longitudinal study called the Generation R Study (R being Rotterdam in the Netherlands) that has prospectively studied a group of nearly 5,000 children from before birth into adolescence. Colic symptoms were briefly assessed when infants were about 3 months old and emotional-behavioral problems have been prospectively measured at multiple time points subsequently using well-validated rating scales.

Dr. Rettew

The main finding of the study was excessive crying in infancy actually was significantly associated with higher levels of emotional-behavioral problems later in childhood and, to a lesser extent, in adolescence. This held for both internalizing problems (like anxiety and depressive symptoms) and externalizing problems (like defiance and aggressive behavior). At age 10, participants also underwent an MRI scan and those who were excessive criers as infants were found to have a smaller amygdala, a region known for being important in regulating emotions.

The authors concluded that colicky behavior in infancy may reflect some underlying temperamental vulnerabilities and may have more predictive value than previously thought. The connection between excessive crying and a measurable brain region difference later in life is also interesting, although these kinds of brain imaging findings have been notoriously difficult to interpret clinically.

Overall, this is a solid study that deserves to be considered. Colic may reflect a bit more than most of us have been taught and shouldn’t necessarily be “shrugged off,” as the authors state in their discussion.

At the same time, however, it is important not to overinterpret the findings. The magnitude of the effects were on the small side (about 0.2 of a standard deviation) and most children with excessive crying in early infancy did not manifest high levels of mental health problems later in life. The mothers of high crying infants also had slightly higher levels of mental health problems themselves so there could be other mechanisms at work here, such as genetic differences between the two groups.

So how could a pediatrician best use this new information without taking things too far? Regardless of the question of whether the excessive crying infancy is a true risk factor for later behavior problems (in the causal sense) or whether it represents more of a marker for something else, its presence so early in life offers an opportunity. Primary care clinicians would still likely want to provide the reassurance that has typically been given in these visits but perhaps with the caveat that some of these kids go on to struggle a bit more with mental health and that they might benefit from some additional support. We are not talking about prophylactic medications here, but something like additional parenting skills. Especially if you, as the pediatrician, suspect that the parents might benefit from expanding their parenting toolkit already, here is a nice opportunity to invite them to learn some new approaches and skills — framed in a way that focuses on the temperament of the child rather than any “deficits” you perceive in the parents. Some parents may be more receptive and less defensive to the idea of participating in parent training under the framework that they are doing this because they have a temperamentally more challenging child (rather than feeling that they are deficient in basic parenting skills).

It’s always a good idea to know about what resources are available in the community when it comes to teaching parenting skills. In addition to scientifically supported books and podcasts, there has been a steady increase in reliable websites, apps, and other digital platforms related to parenting, as well as standard in-person groups and classes. This could also be a great use of an integrated behavioral health professional for practices fortunate enough to have one.

In summary, there is some new evidence that colic can represent a little more than “just gas,” and while we shouldn’t take this one study to the extreme, there may be some good opportunities here to discuss and support good parenting practices in general.

Dr. Rettew is a child and adolescent psychiatrist with Lane County Behavioral Health in Eugene, Ore., and Oregon Health & Science University, Portland. His latest book is “Parenting Made Complicated: What Science Really Knows about the Greatest Debates of Early Childhood.” You can follow him on Twitter and Facebook @PediPsych.

Reference

1. Sammallahti S et al. Excessive crying, behavior problems, and amygdala volume: A study from infancy to adolescence. J Am Acad Child Adolesc Psychiatry. 2023 Jun;62(6):675-83. doi: 10.1016/j.jaac.2023.01.014.

Pediatricians commonly are asked to see infants presenting with symptoms of colic. The frequent and intense crying associated with colic is understandably quite distressing to parents, who often worry about a serious underlying medical cause. There also is the stress of trying to soothe an irritable infant who often does not seem to respond to the typical interventions.

Conventional wisdom about colic has been that the behaviors are the result of some gastrointestinal problem that, while not perfectly understood, tends to be mercifully self-limited and not predictive of future medical or mental health problems. This perspective then leads to pediatricians typically offering mainly sympathy and reassurance at these visits.

A new study,¹ however, challenges some of this traditional thinking. The data come from a remarkable longitudinal study called the Generation R Study (R being Rotterdam in the Netherlands) that has prospectively studied a group of nearly 5,000 children from before birth into adolescence. Colic symptoms were briefly assessed when infants were about 3 months old and emotional-behavioral problems have been prospectively measured at multiple time points subsequently using well-validated rating scales.

Dr. Rettew

The main finding of the study was excessive crying in infancy actually was significantly associated with higher levels of emotional-behavioral problems later in childhood and, to a lesser extent, in adolescence. This held for both internalizing problems (like anxiety and depressive symptoms) and externalizing problems (like defiance and aggressive behavior). At age 10, participants also underwent an MRI scan and those who were excessive criers as infants were found to have a smaller amygdala, a region known for being important in regulating emotions.

The authors concluded that colicky behavior in infancy may reflect some underlying temperamental vulnerabilities and may have more predictive value than previously thought. The connection between excessive crying and a measurable brain region difference later in life is also interesting, although these kinds of brain imaging findings have been notoriously difficult to interpret clinically.

Overall, this is a solid study that deserves to be considered. Colic may reflect a bit more than most of us have been taught and shouldn’t necessarily be “shrugged off,” as the authors state in their discussion.

At the same time, however, it is important not to overinterpret the findings. The magnitude of the effects were on the small side (about 0.2 of a standard deviation) and most children with excessive crying in early infancy did not manifest high levels of mental health problems later in life. The mothers of high crying infants also had slightly higher levels of mental health problems themselves so there could be other mechanisms at work here, such as genetic differences between the two groups.

So how could a pediatrician best use this new information without taking things too far? Regardless of the question of whether the excessive crying infancy is a true risk factor for later behavior problems (in the causal sense) or whether it represents more of a marker for something else, its presence so early in life offers an opportunity. Primary care clinicians would still likely want to provide the reassurance that has typically been given in these visits but perhaps with the caveat that some of these kids go on to struggle a bit more with mental health and that they might benefit from some additional support. We are not talking about prophylactic medications here, but something like additional parenting skills. Especially if you, as the pediatrician, suspect that the parents might benefit from expanding their parenting toolkit already, here is a nice opportunity to invite them to learn some new approaches and skills — framed in a way that focuses on the temperament of the child rather than any “deficits” you perceive in the parents. Some parents may be more receptive and less defensive to the idea of participating in parent training under the framework that they are doing this because they have a temperamentally more challenging child (rather than feeling that they are deficient in basic parenting skills).

It’s always a good idea to know about what resources are available in the community when it comes to teaching parenting skills. In addition to scientifically supported books and podcasts, there has been a steady increase in reliable websites, apps, and other digital platforms related to parenting, as well as standard in-person groups and classes. This could also be a great use of an integrated behavioral health professional for practices fortunate enough to have one.

In summary, there is some new evidence that colic can represent a little more than “just gas,” and while we shouldn’t take this one study to the extreme, there may be some good opportunities here to discuss and support good parenting practices in general.

Dr. Rettew is a child and adolescent psychiatrist with Lane County Behavioral Health in Eugene, Ore., and Oregon Health & Science University, Portland. His latest book is “Parenting Made Complicated: What Science Really Knows about the Greatest Debates of Early Childhood.” You can follow him on Twitter and Facebook @PediPsych.

Reference

1. Sammallahti S et al. Excessive crying, behavior problems, and amygdala volume: A study from infancy to adolescence. J Am Acad Child Adolesc Psychiatry. 2023 Jun;62(6):675-83. doi: 10.1016/j.jaac.2023.01.014.

MADRID — The role of vitamin D in the risk for overweight and obesity has been the subject of multiple studies. Though there’s still not enough evidence to reach a decisive conclusion, several ongoing debates are setting the stage for future research.

Irene Bretón, MD, PhD, discussed these debates in a presentation titled “Vitamin D Deficiency and Obesity: Cause or Consequence?” delivered at the 64th Congress of the Spanish Society of Endocrinology and Nutrition (SEEN). Dr. Bretón is president of the Foundation of the Spanish Society of Endocrinology and Nutrition.

“Vitamin D deficiency can arise from different causes. The percentage that can be attributed to solar radiation is extremely variable. Some studies put it at 80%, while others suggest lower figures. Many diseases have also been associated with vitamin D deficiency or with low vitamin D levels (which are not always at the level of deficiency). Nonetheless, we still have a lot to learn about these associations,” she said.

Dr. Bretón pointed out that many of these studies overlook parathyroid hormone testing. “I also think it’s more appropriate to discuss nutritional status of vitamin D as opposed to serum levels, because these data can be misleading. It would be interesting to focus more on vitamin D metabolism and not just plasma levels.”
 

Vitamin Deficiency 

To answer whether obesity and its complications could be related to low vitamin D levels, Dr. Bretón pointed to this vitamin’s profile in various regions of the world and called attention to the fact that none of the studies on this topic include populations with roughly adequate levels of this vitamin.

“This highlights the prevalence of vitamin D deficiency worldwide. It affects approximately 50% of the population, has been described in all age groups, and affects both men and women — particularly pregnant women and those in menopause — and older adults,” said Dr. Bretón.

She also cited the figures backing this fact: 88% have 25-hydroxyvitamin D levels < 30 ng/mL, 37% have levels < 20 ng/mL, and 7% have levels < 10 ng/mL.

“These percentages have brought us to consider their potential link to the current obesity epidemic. Studies in humans have observed a relationship between low plasma levels and markers for obesity and adiposity. Free 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D are known to be reduced in obesity, and treatments to correct vitamin D deficiency are less effective in people with the disease,” she noted.

Regarding the impact in “the opposite direction,” that is, whether obesity affects the nutritional status of vitamin D, Bretón explained that observational studies have generally found a relationship between overweight and obesity and lower plasma levels of vitamin D. “Data from these studies show that each kg/m² increase in [body mass index (BMI)] is associated with a 1.15% decrease in 25-hydroxyvitamin D. These studies also show that the prevalence of vitamin D deficiency is 35% higher in patients with obesity and 24% higher in those that are overweight compared with individuals of normal weight. A relationship has been observed between vitamin D deficiency and body fat percentage in men and women and in all age groups,” explained Dr. Bretón.

Dr. Bretón noted that the diseases most closely associated with obesity are type 2 diabetes, hypertension, ischemic heart disease, cancer (colon, breast, prostate, and ovarian), inflammatory liver disease, asthma, and inflammatory diseases.
 

Mechanisms Involved

Dr. Bretón reviewed the latest evidence on the mechanisms involved in the relationship between obesity and vitamin D deficiency. “People with obesity may experience less solar exposure (more of their body is covered, or they spend more time indoors), but reduced exposure to the sun is known to have less of an influence on vitamin D levels. Studies where people were given radiation to test how their plasma levels of vitamin D respond have found that there is a smaller effect in people with obesity, and that the effect is inversely correlated with BMI: the higher the BMI, the less vitamin D levels increase under exposure to solar radiation.”

Another mechanism is sequestration in adipose tissue, which is the largest reservoir of vitamin D in the body. Nevertheless, factors such as vitamin D concentration in this tissue, regulation of local metabolism, and vitamin uptake and release are less understood. It is therefore unclear whether this mechanism acts to regulate plasma levels.

“This is why severe vitamin D deficiencies (and deficiencies of other fat-soluble vitamins) that occur after bariatric surgery are often not seen in the first year after surgery but develop much later, when the vitamin that has accumulated in adipose tissue is released as weight is lost,” said Dr. Bretón.

“On the other hand, the volumetric dilution in blood that occurs in relation to total body fat content may explain the variability of plasma levels and the response to treatment. Predictive equations have been described,” she explained.
 

The Prenatal Stage

Dr. Bretón mentioned that the best setting for studying the impact of vitamin D and preventing future obesity is during the initial stages of life, when adipogenesis and fetal programming are occurring.

“Studies in animals have shown how maternal vitamin D deficiency (due to nongenetic or nonepigenetic mechanisms) leads to changes in adipogenesis and programming of adipose reserves. A fetal or perinatal environment with low vitamin D levels programs all these mechanisms differently, and not just adipogenesis and adipocyte differentiation in utero,” she added.

Various mechanisms involved in vitamin D deficiency as a cause of obesity are currently being studied in the prenatal setting. One such mechanism is the interaction between the vitamin D receptor and 1 alpha–hydroxylase, which are present in the adipose tissue and help modulate lipid metabolism.

“The vitamin D receptor is particularly expressed in the early stages of adipocyte differentiation, but its expression drops off as the differentiation process continues. Vitamin D receptor knockout mice have a slender phenotype and are resistant to diet-induced obesity. They also accumulate less fat with age and a high-fat diet,” explained Dr. Bretón.

“However, vitamin D also influences the production of inflammatory adipokines in these early stages of life. It specifically plays a central role in modulating the inflammatory response in adipose tissue. These anti-inflammatory effects appear to be mediated by inhibition of [NF–kappa B] and MAPK signaling pathways. All of this suggests that vitamin D influences both adipogenesis and how the adipose tissue functions,” she added.
 

Weight Loss 

When considering the link between vitamin D and obesity in the context of weight loss, Dr. Bretón explained that studies in this area suggest that weight loss per se is not sufficient to increase serum 25-hydroxyvitamin D. Rather, increased synthesis by the skin or increased dietary intake are the most relevant factors for the nutritional status of this vitamin.

“A recent systematic review looking at the relationship between vitamin D levels and weight loss via caloric restriction and exercise showed a small but significant effect in the sense that weight loss increases vitamin D levels. However, other meta-analyses have not found significant results in this area,” she said.

“In my opinion, these results depend on how long the intervention is performed. If a lot of weight is lost in a short time frame, vitamin D is released into the adipose tissue, a process that doesn’t have any significant impact on the nutritional status of this vitamin. Generally, the effect of this relationship is small (1.5 ng/mL) and of little clinical relevance. Moreover, many systematic reviews have analyzed this relationship following bariatric surgery and have also come up with inconclusive results,” Dr. Bretón added.

What role do treatments play in correcting vitamin D deficiency? Dr. Bretón explained that studies that have examined how fortified foods affect obesity show that though these foods don’t cause significant weight changes, they do affect fat mass and waist circumference. This finding suggests that fortified foods have some impact, not necessarily on weight but perhaps on adiposity.

“To rightly value all this data, one has to pay special attention to the environment and the context where the research took place (children or adults, baseline vitamin D levels, and so on). If fortified foods are directly supplemented with cholecalciferol, the results are very inconsistent. We therefore cannot say that treatment with vitamin D can reduce body weight and adiposity,” she said.

When it comes to the complications from obesity, studies of vitamin D supplementation, cancer, and cardiovascular disease did not find any beneficial effect on preventing these pathologies.

For obesity’s impact on vitamin D supplementation, it is known that the levels achieved are lower in patients with obesity compared with patients of normal weight. “Compared with other interventions, however, these levels (15.27 ng/mL) are clinically relevant,” she noted.
 

Future Directions

Dr. Bretón explained that all this evidence has revealed many debates regarding the association of vitamin D levels with obesity. “For example, it appears that obesity could predict low vitamin D levels (not necessarily a deficiency). In turn, these low levels could cause obesity, especially during embryonic development, when programming of adipocyte physiology is taking place.”

Dr. Bretón sees many confounding factors that will need to be elucidated in the future. “One factor is that we aren’t sure whether the patient we’re seeing has vitamin D deficiency or if other factors are in play, like time since weight loss, laboratory technique used to measure vitamin D, nutritional status, geographic location, time of year when the test is performed, et cetera. You also have to assess other factors having to do with obesity, like how adiposity is being measured and whether BMI reflects that adiposity.”

Last, the expert reviewed the major research efforts underway that are based on evidence that vitamin D is associated with insulin resistance. Studies are being performed on pancreatic function, the role of vitamin D levels in ovarian physiology related to insulin resistance (specifically, the role of hyperandrogenism), adipose tissue (vitamin D receptor expression, volumetric dilution), and other components of metabolic syndrome to determine how this vitamin’s status influences the renin-angiotensin system, apoptosis, and cardiovascular risk.

“There is also plenty of research going on surrounding metabolic liver disease, which has a lot to do with the microbiota. So, they’re studying the relationship between vitamin D and dysbiosis, especially regarding local immunomodulation in the gut in relation to the microbiota,” she added.

Another area of research is cancer, focusing primarily on analyzing the nutritional status of vitamin D in relation to the microbiome and how this status may affect the therapeutic effect of chemotherapy and radiation therapy. “It would be interesting to find out whether the effect of immunotherapy varies depending on the patient’s vitamin D status,” concluded Dr. Bretón.

Dr. Bretón’s lecture at the 64th Congress of the SEEN was sponsored by the Foundation for Analysis and Social Studies (FAES).

This article was translated from the Medscape Spanish edition.  A version of this article appeared on Medscape.com.

MADRID — The role of vitamin D in the risk for overweight and obesity has been the subject of multiple studies. Though there’s still not enough evidence to reach a decisive conclusion, several ongoing debates are setting the stage for future research.

Irene Bretón, MD, PhD, discussed these debates in a presentation titled “Vitamin D Deficiency and Obesity: Cause or Consequence?” delivered at the 64th Congress of the Spanish Society of Endocrinology and Nutrition (SEEN). Dr. Bretón is president of the Foundation of the Spanish Society of Endocrinology and Nutrition.

“Vitamin D deficiency can arise from different causes. The percentage that can be attributed to solar radiation is extremely variable. Some studies put it at 80%, while others suggest lower figures. Many diseases have also been associated with vitamin D deficiency or with low vitamin D levels (which are not always at the level of deficiency). Nonetheless, we still have a lot to learn about these associations,” she said.

Dr. Bretón pointed out that many of these studies overlook parathyroid hormone testing. “I also think it’s more appropriate to discuss nutritional status of vitamin D as opposed to serum levels, because these data can be misleading. It would be interesting to focus more on vitamin D metabolism and not just plasma levels.”
 

Vitamin Deficiency 

To answer whether obesity and its complications could be related to low vitamin D levels, Dr. Bretón pointed to this vitamin’s profile in various regions of the world and called attention to the fact that none of the studies on this topic include populations with roughly adequate levels of this vitamin.

“This highlights the prevalence of vitamin D deficiency worldwide. It affects approximately 50% of the population, has been described in all age groups, and affects both men and women — particularly pregnant women and those in menopause — and older adults,” said Dr. Bretón.

She also cited the figures backing this fact: 88% have 25-hydroxyvitamin D levels < 30 ng/mL, 37% have levels < 20 ng/mL, and 7% have levels < 10 ng/mL.

“These percentages have brought us to consider their potential link to the current obesity epidemic. Studies in humans have observed a relationship between low plasma levels and markers for obesity and adiposity. Free 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D are known to be reduced in obesity, and treatments to correct vitamin D deficiency are less effective in people with the disease,” she noted.

Regarding the impact in “the opposite direction,” that is, whether obesity affects the nutritional status of vitamin D, Bretón explained that observational studies have generally found a relationship between overweight and obesity and lower plasma levels of vitamin D. “Data from these studies show that each kg/m² increase in [body mass index (BMI)] is associated with a 1.15% decrease in 25-hydroxyvitamin D. These studies also show that the prevalence of vitamin D deficiency is 35% higher in patients with obesity and 24% higher in those that are overweight compared with individuals of normal weight. A relationship has been observed between vitamin D deficiency and body fat percentage in men and women and in all age groups,” explained Dr. Bretón.

Dr. Bretón noted that the diseases most closely associated with obesity are type 2 diabetes, hypertension, ischemic heart disease, cancer (colon, breast, prostate, and ovarian), inflammatory liver disease, asthma, and inflammatory diseases.
 

Mechanisms Involved

Dr. Bretón reviewed the latest evidence on the mechanisms involved in the relationship between obesity and vitamin D deficiency. “People with obesity may experience less solar exposure (more of their body is covered, or they spend more time indoors), but reduced exposure to the sun is known to have less of an influence on vitamin D levels. Studies where people were given radiation to test how their plasma levels of vitamin D respond have found that there is a smaller effect in people with obesity, and that the effect is inversely correlated with BMI: the higher the BMI, the less vitamin D levels increase under exposure to solar radiation.”

Another mechanism is sequestration in adipose tissue, which is the largest reservoir of vitamin D in the body. Nevertheless, factors such as vitamin D concentration in this tissue, regulation of local metabolism, and vitamin uptake and release are less understood. It is therefore unclear whether this mechanism acts to regulate plasma levels.

“This is why severe vitamin D deficiencies (and deficiencies of other fat-soluble vitamins) that occur after bariatric surgery are often not seen in the first year after surgery but develop much later, when the vitamin that has accumulated in adipose tissue is released as weight is lost,” said Dr. Bretón.

“On the other hand, the volumetric dilution in blood that occurs in relation to total body fat content may explain the variability of plasma levels and the response to treatment. Predictive equations have been described,” she explained.
 

The Prenatal Stage

Dr. Bretón mentioned that the best setting for studying the impact of vitamin D and preventing future obesity is during the initial stages of life, when adipogenesis and fetal programming are occurring.

“Studies in animals have shown how maternal vitamin D deficiency (due to nongenetic or nonepigenetic mechanisms) leads to changes in adipogenesis and programming of adipose reserves. A fetal or perinatal environment with low vitamin D levels programs all these mechanisms differently, and not just adipogenesis and adipocyte differentiation in utero,” she added.

Various mechanisms involved in vitamin D deficiency as a cause of obesity are currently being studied in the prenatal setting. One such mechanism is the interaction between the vitamin D receptor and 1 alpha–hydroxylase, which are present in the adipose tissue and help modulate lipid metabolism.

“The vitamin D receptor is particularly expressed in the early stages of adipocyte differentiation, but its expression drops off as the differentiation process continues. Vitamin D receptor knockout mice have a slender phenotype and are resistant to diet-induced obesity. They also accumulate less fat with age and a high-fat diet,” explained Dr. Bretón.

“However, vitamin D also influences the production of inflammatory adipokines in these early stages of life. It specifically plays a central role in modulating the inflammatory response in adipose tissue. These anti-inflammatory effects appear to be mediated by inhibition of [NF–kappa B] and MAPK signaling pathways. All of this suggests that vitamin D influences both adipogenesis and how the adipose tissue functions,” she added.
 

Weight Loss 

When considering the link between vitamin D and obesity in the context of weight loss, Dr. Bretón explained that studies in this area suggest that weight loss per se is not sufficient to increase serum 25-hydroxyvitamin D. Rather, increased synthesis by the skin or increased dietary intake are the most relevant factors for the nutritional status of this vitamin.

“A recent systematic review looking at the relationship between vitamin D levels and weight loss via caloric restriction and exercise showed a small but significant effect in the sense that weight loss increases vitamin D levels. However, other meta-analyses have not found significant results in this area,” she said.

“In my opinion, these results depend on how long the intervention is performed. If a lot of weight is lost in a short time frame, vitamin D is released into the adipose tissue, a process that doesn’t have any significant impact on the nutritional status of this vitamin. Generally, the effect of this relationship is small (1.5 ng/mL) and of little clinical relevance. Moreover, many systematic reviews have analyzed this relationship following bariatric surgery and have also come up with inconclusive results,” Dr. Bretón added.

What role do treatments play in correcting vitamin D deficiency? Dr. Bretón explained that studies that have examined how fortified foods affect obesity show that though these foods don’t cause significant weight changes, they do affect fat mass and waist circumference. This finding suggests that fortified foods have some impact, not necessarily on weight but perhaps on adiposity.

“To rightly value all this data, one has to pay special attention to the environment and the context where the research took place (children or adults, baseline vitamin D levels, and so on). If fortified foods are directly supplemented with cholecalciferol, the results are very inconsistent. We therefore cannot say that treatment with vitamin D can reduce body weight and adiposity,” she said.

When it comes to the complications from obesity, studies of vitamin D supplementation, cancer, and cardiovascular disease did not find any beneficial effect on preventing these pathologies.

For obesity’s impact on vitamin D supplementation, it is known that the levels achieved are lower in patients with obesity compared with patients of normal weight. “Compared with other interventions, however, these levels (15.27 ng/mL) are clinically relevant,” she noted.
 

Future Directions

Dr. Bretón explained that all this evidence has revealed many debates regarding the association of vitamin D levels with obesity. “For example, it appears that obesity could predict low vitamin D levels (not necessarily a deficiency). In turn, these low levels could cause obesity, especially during embryonic development, when programming of adipocyte physiology is taking place.”

Dr. Bretón sees many confounding factors that will need to be elucidated in the future. “One factor is that we aren’t sure whether the patient we’re seeing has vitamin D deficiency or if other factors are in play, like time since weight loss, laboratory technique used to measure vitamin D, nutritional status, geographic location, time of year when the test is performed, et cetera. You also have to assess other factors having to do with obesity, like how adiposity is being measured and whether BMI reflects that adiposity.”

Last, the expert reviewed the major research efforts underway that are based on evidence that vitamin D is associated with insulin resistance. Studies are being performed on pancreatic function, the role of vitamin D levels in ovarian physiology related to insulin resistance (specifically, the role of hyperandrogenism), adipose tissue (vitamin D receptor expression, volumetric dilution), and other components of metabolic syndrome to determine how this vitamin’s status influences the renin-angiotensin system, apoptosis, and cardiovascular risk.

“There is also plenty of research going on surrounding metabolic liver disease, which has a lot to do with the microbiota. So, they’re studying the relationship between vitamin D and dysbiosis, especially regarding local immunomodulation in the gut in relation to the microbiota,” she added.

Another area of research is cancer, focusing primarily on analyzing the nutritional status of vitamin D in relation to the microbiome and how this status may affect the therapeutic effect of chemotherapy and radiation therapy. “It would be interesting to find out whether the effect of immunotherapy varies depending on the patient’s vitamin D status,” concluded Dr. Bretón.

Dr. Bretón’s lecture at the 64th Congress of the SEEN was sponsored by the Foundation for Analysis and Social Studies (FAES).

This article was translated from the Medscape Spanish edition.  A version of this article appeared on Medscape.com.

MADRID — The role of vitamin D in the risk for overweight and obesity has been the subject of multiple studies. Though there’s still not enough evidence to reach a decisive conclusion, several ongoing debates are setting the stage for future research.

Irene Bretón, MD, PhD, discussed these debates in a presentation titled “Vitamin D Deficiency and Obesity: Cause or Consequence?” delivered at the 64th Congress of the Spanish Society of Endocrinology and Nutrition (SEEN). Dr. Bretón is president of the Foundation of the Spanish Society of Endocrinology and Nutrition.

“Vitamin D deficiency can arise from different causes. The percentage that can be attributed to solar radiation is extremely variable. Some studies put it at 80%, while others suggest lower figures. Many diseases have also been associated with vitamin D deficiency or with low vitamin D levels (which are not always at the level of deficiency). Nonetheless, we still have a lot to learn about these associations,” she said.

Dr. Bretón pointed out that many of these studies overlook parathyroid hormone testing. “I also think it’s more appropriate to discuss nutritional status of vitamin D as opposed to serum levels, because these data can be misleading. It would be interesting to focus more on vitamin D metabolism and not just plasma levels.”
 

Vitamin Deficiency 

To answer whether obesity and its complications could be related to low vitamin D levels, Dr. Bretón pointed to this vitamin’s profile in various regions of the world and called attention to the fact that none of the studies on this topic include populations with roughly adequate levels of this vitamin.

“This highlights the prevalence of vitamin D deficiency worldwide. It affects approximately 50% of the population, has been described in all age groups, and affects both men and women — particularly pregnant women and those in menopause — and older adults,” said Dr. Bretón.

She also cited the figures backing this fact: 88% have 25-hydroxyvitamin D levels < 30 ng/mL, 37% have levels < 20 ng/mL, and 7% have levels < 10 ng/mL.

“These percentages have brought us to consider their potential link to the current obesity epidemic. Studies in humans have observed a relationship between low plasma levels and markers for obesity and adiposity. Free 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D are known to be reduced in obesity, and treatments to correct vitamin D deficiency are less effective in people with the disease,” she noted.

Regarding the impact in “the opposite direction,” that is, whether obesity affects the nutritional status of vitamin D, Bretón explained that observational studies have generally found a relationship between overweight and obesity and lower plasma levels of vitamin D. “Data from these studies show that each kg/m² increase in [body mass index (BMI)] is associated with a 1.15% decrease in 25-hydroxyvitamin D. These studies also show that the prevalence of vitamin D deficiency is 35% higher in patients with obesity and 24% higher in those that are overweight compared with individuals of normal weight. A relationship has been observed between vitamin D deficiency and body fat percentage in men and women and in all age groups,” explained Dr. Bretón.

Dr. Bretón noted that the diseases most closely associated with obesity are type 2 diabetes, hypertension, ischemic heart disease, cancer (colon, breast, prostate, and ovarian), inflammatory liver disease, asthma, and inflammatory diseases.
 

Mechanisms Involved

Dr. Bretón reviewed the latest evidence on the mechanisms involved in the relationship between obesity and vitamin D deficiency. “People with obesity may experience less solar exposure (more of their body is covered, or they spend more time indoors), but reduced exposure to the sun is known to have less of an influence on vitamin D levels. Studies where people were given radiation to test how their plasma levels of vitamin D respond have found that there is a smaller effect in people with obesity, and that the effect is inversely correlated with BMI: the higher the BMI, the less vitamin D levels increase under exposure to solar radiation.”

Another mechanism is sequestration in adipose tissue, which is the largest reservoir of vitamin D in the body. Nevertheless, factors such as vitamin D concentration in this tissue, regulation of local metabolism, and vitamin uptake and release are less understood. It is therefore unclear whether this mechanism acts to regulate plasma levels.

“This is why severe vitamin D deficiencies (and deficiencies of other fat-soluble vitamins) that occur after bariatric surgery are often not seen in the first year after surgery but develop much later, when the vitamin that has accumulated in adipose tissue is released as weight is lost,” said Dr. Bretón.

“On the other hand, the volumetric dilution in blood that occurs in relation to total body fat content may explain the variability of plasma levels and the response to treatment. Predictive equations have been described,” she explained.
 

The Prenatal Stage

Dr. Bretón mentioned that the best setting for studying the impact of vitamin D and preventing future obesity is during the initial stages of life, when adipogenesis and fetal programming are occurring.

“Studies in animals have shown how maternal vitamin D deficiency (due to nongenetic or nonepigenetic mechanisms) leads to changes in adipogenesis and programming of adipose reserves. A fetal or perinatal environment with low vitamin D levels programs all these mechanisms differently, and not just adipogenesis and adipocyte differentiation in utero,” she added.

Various mechanisms involved in vitamin D deficiency as a cause of obesity are currently being studied in the prenatal setting. One such mechanism is the interaction between the vitamin D receptor and 1 alpha–hydroxylase, which are present in the adipose tissue and help modulate lipid metabolism.

“The vitamin D receptor is particularly expressed in the early stages of adipocyte differentiation, but its expression drops off as the differentiation process continues. Vitamin D receptor knockout mice have a slender phenotype and are resistant to diet-induced obesity. They also accumulate less fat with age and a high-fat diet,” explained Dr. Bretón.

“However, vitamin D also influences the production of inflammatory adipokines in these early stages of life. It specifically plays a central role in modulating the inflammatory response in adipose tissue. These anti-inflammatory effects appear to be mediated by inhibition of [NF–kappa B] and MAPK signaling pathways. All of this suggests that vitamin D influences both adipogenesis and how the adipose tissue functions,” she added.
 

Weight Loss 

When considering the link between vitamin D and obesity in the context of weight loss, Dr. Bretón explained that studies in this area suggest that weight loss per se is not sufficient to increase serum 25-hydroxyvitamin D. Rather, increased synthesis by the skin or increased dietary intake are the most relevant factors for the nutritional status of this vitamin.

“A recent systematic review looking at the relationship between vitamin D levels and weight loss via caloric restriction and exercise showed a small but significant effect in the sense that weight loss increases vitamin D levels. However, other meta-analyses have not found significant results in this area,” she said.

“In my opinion, these results depend on how long the intervention is performed. If a lot of weight is lost in a short time frame, vitamin D is released into the adipose tissue, a process that doesn’t have any significant impact on the nutritional status of this vitamin. Generally, the effect of this relationship is small (1.5 ng/mL) and of little clinical relevance. Moreover, many systematic reviews have analyzed this relationship following bariatric surgery and have also come up with inconclusive results,” Dr. Bretón added.

What role do treatments play in correcting vitamin D deficiency? Dr. Bretón explained that studies that have examined how fortified foods affect obesity show that though these foods don’t cause significant weight changes, they do affect fat mass and waist circumference. This finding suggests that fortified foods have some impact, not necessarily on weight but perhaps on adiposity.

“To rightly value all this data, one has to pay special attention to the environment and the context where the research took place (children or adults, baseline vitamin D levels, and so on). If fortified foods are directly supplemented with cholecalciferol, the results are very inconsistent. We therefore cannot say that treatment with vitamin D can reduce body weight and adiposity,” she said.

When it comes to the complications from obesity, studies of vitamin D supplementation, cancer, and cardiovascular disease did not find any beneficial effect on preventing these pathologies.

For obesity’s impact on vitamin D supplementation, it is known that the levels achieved are lower in patients with obesity compared with patients of normal weight. “Compared with other interventions, however, these levels (15.27 ng/mL) are clinically relevant,” she noted.
 

Future Directions

Dr. Bretón explained that all this evidence has revealed many debates regarding the association of vitamin D levels with obesity. “For example, it appears that obesity could predict low vitamin D levels (not necessarily a deficiency). In turn, these low levels could cause obesity, especially during embryonic development, when programming of adipocyte physiology is taking place.”

Dr. Bretón sees many confounding factors that will need to be elucidated in the future. “One factor is that we aren’t sure whether the patient we’re seeing has vitamin D deficiency or if other factors are in play, like time since weight loss, laboratory technique used to measure vitamin D, nutritional status, geographic location, time of year when the test is performed, et cetera. You also have to assess other factors having to do with obesity, like how adiposity is being measured and whether BMI reflects that adiposity.”

Last, the expert reviewed the major research efforts underway that are based on evidence that vitamin D is associated with insulin resistance. Studies are being performed on pancreatic function, the role of vitamin D levels in ovarian physiology related to insulin resistance (specifically, the role of hyperandrogenism), adipose tissue (vitamin D receptor expression, volumetric dilution), and other components of metabolic syndrome to determine how this vitamin’s status influences the renin-angiotensin system, apoptosis, and cardiovascular risk.

“There is also plenty of research going on surrounding metabolic liver disease, which has a lot to do with the microbiota. So, they’re studying the relationship between vitamin D and dysbiosis, especially regarding local immunomodulation in the gut in relation to the microbiota,” she added.

Another area of research is cancer, focusing primarily on analyzing the nutritional status of vitamin D in relation to the microbiome and how this status may affect the therapeutic effect of chemotherapy and radiation therapy. “It would be interesting to find out whether the effect of immunotherapy varies depending on the patient’s vitamin D status,” concluded Dr. Bretón.

Dr. Bretón’s lecture at the 64th Congress of the SEEN was sponsored by the Foundation for Analysis and Social Studies (FAES).

This article was translated from the Medscape Spanish edition.  A version of this article appeared on Medscape.com.

Though many people remain on the fence about getting the latest COVID vaccine booster, new research suggests a strong argument for getting the shot this winter: It sharply reduces the risk for COVID. 

Researchers found that getting vaccinated led to a 69% reduction in long-COVID risk among adults who received three vaccines before being infected. The risk reduction was 37% for those who received two doses. Experts say the research provides a strong argument for getting the vaccine, noting that about 10% of people infected with COVID go on to have long COVID, which can be debilitating for one quarter of those with long-lasting symptoms.

The data come from a systematic literature review and meta-analysis published in October in Antimicrobial Stewardship & Epidemiology. Researchers examined 32 studies published between December 2019 and June 2023, involving 775,931 adults. Twenty-four studies, encompassing 620,221 individuals, were included in the meta-analysis. 

“The body of evidence from all these different studies converge on one single reality — that vaccines reduce the risk of long COVID, and people who keep up to date on their vaccinations also fared better than people who got it once or twice and didn’t follow up,” said Ziyad Al-Aly, MD, a clinical epidemiologist at Washington University in St Louis. 

Researchers have reported similar results for children. The National Institutes of Health RECOVER Initiative team found that vaccines are up to 42% effective in preventing long COVID in children, said Dr. Carlos Oliveira, MD, a pediatric infectious diseases specialist and Yale researcher who contributed to the study, which is in preprint. 

Vaccines also protect children from multisystem inflammatory syndrome, a condition that can happen after COVID, as well as protect against other COVID-related problems, such as missed school days, Oliveira said. “Even if the vaccine doesn’t completely stop long COVID, it’s still good for kids to get vaccinated for all these other reasons.” 

However, uptake for the latest boosters has been slow: the Centers for Disease Control and Prevention reported that by mid-November, less than 16% of people aged 18 years or older had received a shot. For children, the number was closer to 6%. A recent Kaiser Family Foundation survey found that booster rates for adults are similar to what it was 1 year ago. 

The survey results suggest that people are no longer as worried about COVID, which is why there is less concerned about keeping up with boosters. Though the current mutation of the virus is not as debilitating as its predecessors, long COVID continues to be a problem: as of January 2023, 28% of people who had contracted the virus had experienced long-COVID symptoms. And though the mechanisms are still not fully understood, and researchers have yet to agree on a definition of long COVID, they are certain about this much: The best way to avoid it is to avoid getting infected to begin with. 

The lack of a diagnostic test for long COVID and the fact that the symptoms mimic those of other diseases lead to inconsistency that can make studies hard to replicate. In the papers reviewed for the Antimicrobial Stewardship & Epidemiology study, long COVID was defined as having symptoms lasting from more than 4 weeks to more than 6 months. Alexandre Marra, MD, the lead author and a researcher at the Hospital Israelita Albert Einstein, in São Paulo, Brazil, and at the University of Iowa, said that a clear standard definition is needed to better understand the actual prevalence and evaluate vaccine effectiveness. 

Al-Aly noted that there is a logical explanation for one finding in the paper: The percentage of individuals who had COVID and reported that long-COVID symptoms declined from 19% in June 2022 to 11% in January 2023. 

Because a pandemic is a dynamic event, constantly producing different variants with different phenotypes, the prevalence of disease is naturally going to be affected. “People who got infected early in the pandemic may have a different long COVID profile and long COVID risk than people who got infected in the second or third year of the pandemic,” Al-Aly said. 

Most of the studies reported data from before the Omicron-variant era. Only eight reported data during that era. Omicron was not as lethal as previous variants, and consequently, fewer patients developed long COVID during that time. 

One of those who did is Yeng Chang, age 40 years, a family doctor who lives in Sherwood Park, Alberta, Canada. Chang developed long COVID during fall 2022 after getting the virus in June. By then, she’d been vaccinated three times, but she isn’t surprised that she got sick because each vaccine she had was developed before Omicron.

“When I had COVID I was really sick, but I was well enough to stay home,” she said. “I think if I didn’t have my immunizations, I might have been hospitalized, and I don’t know what would have happened.” 

Long COVID has left Chang with brain fog, fatigue, and a lack of physical stamina that forced her to pause her medical practice. For the past year and a half, she’s spent more time as a patient than a physician. 

Chang had her fifth COVID vaccination in the fall and recommends that others do the same. “The booster you got however many years ago was effective for the COVID of that time but there is a new COVID now. You can’t just say, ‘I had one and I’m fine forever.’” 
 

A version of this article appeared on Medscape.com.

Though many people remain on the fence about getting the latest COVID vaccine booster, new research suggests a strong argument for getting the shot this winter: It sharply reduces the risk for COVID. 

Researchers found that getting vaccinated led to a 69% reduction in long-COVID risk among adults who received three vaccines before being infected. The risk reduction was 37% for those who received two doses. Experts say the research provides a strong argument for getting the vaccine, noting that about 10% of people infected with COVID go on to have long COVID, which can be debilitating for one quarter of those with long-lasting symptoms.

The data come from a systematic literature review and meta-analysis published in October in Antimicrobial Stewardship & Epidemiology. Researchers examined 32 studies published between December 2019 and June 2023, involving 775,931 adults. Twenty-four studies, encompassing 620,221 individuals, were included in the meta-analysis. 

“The body of evidence from all these different studies converge on one single reality — that vaccines reduce the risk of long COVID, and people who keep up to date on their vaccinations also fared better than people who got it once or twice and didn’t follow up,” said Ziyad Al-Aly, MD, a clinical epidemiologist at Washington University in St Louis. 

Researchers have reported similar results for children. The National Institutes of Health RECOVER Initiative team found that vaccines are up to 42% effective in preventing long COVID in children, said Dr. Carlos Oliveira, MD, a pediatric infectious diseases specialist and Yale researcher who contributed to the study, which is in preprint. 

Vaccines also protect children from multisystem inflammatory syndrome, a condition that can happen after COVID, as well as protect against other COVID-related problems, such as missed school days, Oliveira said. “Even if the vaccine doesn’t completely stop long COVID, it’s still good for kids to get vaccinated for all these other reasons.” 

However, uptake for the latest boosters has been slow: the Centers for Disease Control and Prevention reported that by mid-November, less than 16% of people aged 18 years or older had received a shot. For children, the number was closer to 6%. A recent Kaiser Family Foundation survey found that booster rates for adults are similar to what it was 1 year ago. 

The survey results suggest that people are no longer as worried about COVID, which is why there is less concerned about keeping up with boosters. Though the current mutation of the virus is not as debilitating as its predecessors, long COVID continues to be a problem: as of January 2023, 28% of people who had contracted the virus had experienced long-COVID symptoms. And though the mechanisms are still not fully understood, and researchers have yet to agree on a definition of long COVID, they are certain about this much: The best way to avoid it is to avoid getting infected to begin with. 

The lack of a diagnostic test for long COVID and the fact that the symptoms mimic those of other diseases lead to inconsistency that can make studies hard to replicate. In the papers reviewed for the Antimicrobial Stewardship & Epidemiology study, long COVID was defined as having symptoms lasting from more than 4 weeks to more than 6 months. Alexandre Marra, MD, the lead author and a researcher at the Hospital Israelita Albert Einstein, in São Paulo, Brazil, and at the University of Iowa, said that a clear standard definition is needed to better understand the actual prevalence and evaluate vaccine effectiveness. 

Al-Aly noted that there is a logical explanation for one finding in the paper: The percentage of individuals who had COVID and reported that long-COVID symptoms declined from 19% in June 2022 to 11% in January 2023. 

Because a pandemic is a dynamic event, constantly producing different variants with different phenotypes, the prevalence of disease is naturally going to be affected. “People who got infected early in the pandemic may have a different long COVID profile and long COVID risk than people who got infected in the second or third year of the pandemic,” Al-Aly said. 

Most of the studies reported data from before the Omicron-variant era. Only eight reported data during that era. Omicron was not as lethal as previous variants, and consequently, fewer patients developed long COVID during that time. 

One of those who did is Yeng Chang, age 40 years, a family doctor who lives in Sherwood Park, Alberta, Canada. Chang developed long COVID during fall 2022 after getting the virus in June. By then, she’d been vaccinated three times, but she isn’t surprised that she got sick because each vaccine she had was developed before Omicron.

“When I had COVID I was really sick, but I was well enough to stay home,” she said. “I think if I didn’t have my immunizations, I might have been hospitalized, and I don’t know what would have happened.” 

Long COVID has left Chang with brain fog, fatigue, and a lack of physical stamina that forced her to pause her medical practice. For the past year and a half, she’s spent more time as a patient than a physician. 

Chang had her fifth COVID vaccination in the fall and recommends that others do the same. “The booster you got however many years ago was effective for the COVID of that time but there is a new COVID now. You can’t just say, ‘I had one and I’m fine forever.’” 
 

A version of this article appeared on Medscape.com.

Though many people remain on the fence about getting the latest COVID vaccine booster, new research suggests a strong argument for getting the shot this winter: It sharply reduces the risk for COVID. 

Researchers found that getting vaccinated led to a 69% reduction in long-COVID risk among adults who received three vaccines before being infected. The risk reduction was 37% for those who received two doses. Experts say the research provides a strong argument for getting the vaccine, noting that about 10% of people infected with COVID go on to have long COVID, which can be debilitating for one quarter of those with long-lasting symptoms.

The data come from a systematic literature review and meta-analysis published in October in Antimicrobial Stewardship & Epidemiology. Researchers examined 32 studies published between December 2019 and June 2023, involving 775,931 adults. Twenty-four studies, encompassing 620,221 individuals, were included in the meta-analysis. 

“The body of evidence from all these different studies converge on one single reality — that vaccines reduce the risk of long COVID, and people who keep up to date on their vaccinations also fared better than people who got it once or twice and didn’t follow up,” said Ziyad Al-Aly, MD, a clinical epidemiologist at Washington University in St Louis. 

Researchers have reported similar results for children. The National Institutes of Health RECOVER Initiative team found that vaccines are up to 42% effective in preventing long COVID in children, said Dr. Carlos Oliveira, MD, a pediatric infectious diseases specialist and Yale researcher who contributed to the study, which is in preprint. 

Vaccines also protect children from multisystem inflammatory syndrome, a condition that can happen after COVID, as well as protect against other COVID-related problems, such as missed school days, Oliveira said. “Even if the vaccine doesn’t completely stop long COVID, it’s still good for kids to get vaccinated for all these other reasons.” 

However, uptake for the latest boosters has been slow: the Centers for Disease Control and Prevention reported that by mid-November, less than 16% of people aged 18 years or older had received a shot. For children, the number was closer to 6%. A recent Kaiser Family Foundation survey found that booster rates for adults are similar to what it was 1 year ago. 

The survey results suggest that people are no longer as worried about COVID, which is why there is less concerned about keeping up with boosters. Though the current mutation of the virus is not as debilitating as its predecessors, long COVID continues to be a problem: as of January 2023, 28% of people who had contracted the virus had experienced long-COVID symptoms. And though the mechanisms are still not fully understood, and researchers have yet to agree on a definition of long COVID, they are certain about this much: The best way to avoid it is to avoid getting infected to begin with. 

The lack of a diagnostic test for long COVID and the fact that the symptoms mimic those of other diseases lead to inconsistency that can make studies hard to replicate. In the papers reviewed for the Antimicrobial Stewardship & Epidemiology study, long COVID was defined as having symptoms lasting from more than 4 weeks to more than 6 months. Alexandre Marra, MD, the lead author and a researcher at the Hospital Israelita Albert Einstein, in São Paulo, Brazil, and at the University of Iowa, said that a clear standard definition is needed to better understand the actual prevalence and evaluate vaccine effectiveness. 

Al-Aly noted that there is a logical explanation for one finding in the paper: The percentage of individuals who had COVID and reported that long-COVID symptoms declined from 19% in June 2022 to 11% in January 2023. 

Because a pandemic is a dynamic event, constantly producing different variants with different phenotypes, the prevalence of disease is naturally going to be affected. “People who got infected early in the pandemic may have a different long COVID profile and long COVID risk than people who got infected in the second or third year of the pandemic,” Al-Aly said. 

Most of the studies reported data from before the Omicron-variant era. Only eight reported data during that era. Omicron was not as lethal as previous variants, and consequently, fewer patients developed long COVID during that time. 

One of those who did is Yeng Chang, age 40 years, a family doctor who lives in Sherwood Park, Alberta, Canada. Chang developed long COVID during fall 2022 after getting the virus in June. By then, she’d been vaccinated three times, but she isn’t surprised that she got sick because each vaccine she had was developed before Omicron.

“When I had COVID I was really sick, but I was well enough to stay home,” she said. “I think if I didn’t have my immunizations, I might have been hospitalized, and I don’t know what would have happened.” 

Long COVID has left Chang with brain fog, fatigue, and a lack of physical stamina that forced her to pause her medical practice. For the past year and a half, she’s spent more time as a patient than a physician. 

Chang had her fifth COVID vaccination in the fall and recommends that others do the same. “The booster you got however many years ago was effective for the COVID of that time but there is a new COVID now. You can’t just say, ‘I had one and I’m fine forever.’” 
 

A version of this article appeared on Medscape.com.

Long-term data showed negligible differences in mortality among hypertensive adults treated with thiazide-type diuretics, calcium channel blockers, or angiotensin-converting enzyme inhibitors in a review of nearly 33,000 individuals published in JAMA Network Open.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study was designed to compare initial antihypertensive treatments with a calcium channel blocker (CCB; amlodipine), an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) or an alpha-blocker (doxazosin), and a thiazide-type diuretic (chlorthalidone).

The composite primary outcome was fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI), but long-term data were lacking, wrote Jose-Miguel Yamal, PhD, of University of Texas Health Science Center at Houston, and colleagues. A previous study with 8-13 years of follow-up showed no significant differences in mortality between the treatment groups, the researchers noted.

In the current study, a prespecified secondary analysis of ALLHAT, the researchers added 11 more years of data for a total of 19-24 years of follow-up after randomization.

In the original ALLHAT, 32,804 adults aged 55 years and older with a diagnosis of hypertension and at least one additional coronary heart disease risk factor were followed for 4-8 years for all-cause mortality. A subgroup of 22,754 were followed for fatal or nonfatal cardiovascular disease (CVD) for a mean of 13.7 years, with a maximum of 23.9 years.

The study occurred from Feb. 23, 1994, to Dec. 31, 2017. The participants were randomized to receive a thiazide-type diuretic (15,002 patients), a CCB (8,898 patients), or an ACE inhibitor (8,904 patients).

The primary outcome was CVD mortality; secondary outcomes included all-cause mortality, combined fatal and nonfatal CVD (CVD morbidity), and both morbidity and mortality for coronary heart disease, stroke, heart failure, end-stage renal disease, and cancer.

At 23 years, CVD mortality rates per 100 persons were 23.7, 21.6, and 23.8 in the diuretic, CCB, and ACE inhibitor groups, respectively. The adjusted hazard ratios were 0.97 for CCB vs. diuretics and 1.06 for ACE inhibitors vs. diuretics.

Although the risk of stroke mortality and of combined fatal and nonfatal hospitalized stroke was higher in the ACE inhibitor group compared with the diuretic group (adjusted hazard ratios 1.19 and 1.11, respectively), this increase was no longer significant after adjustment for multiple comparisons. “In contrast to the in-trial and 8-year to 13-year analyses, we now observed that the lisinopril group had an increased risk of kidney disease mortality that emerged after approximately 13 years after randomization, but this effect was attenuated after adjustment for baseline variables,” the researchers wrote in their discussion.

The findings were limited by several factors including the potential effect of unblinding if participants stopped the randomized drug, and by the lack of morbidity and mortality data on Canadian participants, Veterans Affairs participants, and those with no Medicare number, the researchers noted. Other limitations included the lack of data on posttrial medication use, blood pressure, and laboratory findings, they said.

However, the results over the follow-up period of up to 23 years supported those of the larger ALLHAT study, with similar outcomes among the drugs, and with 11 years of passive follow-up, “the results for lisinopril vs. chlorthalidone for stroke and stroke mortality are almost the same,” they concluded.
 

Findings support current practice, but new drug data are needed

The current study was important to determine whether there was a significant difference in long-term morbidity and mortality between patients treated with thiazide diuretics, calcium channel blockers and ACE inhibitors, Noel Deep, MD, said in an interview.

“Previously reported data had indicated no significant differences between patients randomized to one of these three classes of antihypertensive medications during the trial period or at 8-13 years post trial,” said Dr. Deep, a general internist in private practice in Antigo, Wisc., who was not involved in the study. Dr. Deep is chief medical officer and a staff physician at Aspirus Langlade Hospital in Antigo.

“This study reinforces the previously noted benefits of the three classes of antihypertensive medications, as well as the higher rates of cardiovascular disease and stroke in the ACE inhibitor arm,” he said.

In clinical practice, the results suggest that thiazide diuretics should be considered first-line agents for management of hypertension based on their noninferiority compared with ACE inhibitors and CCBs, and lower risk of stroke compared with ACE inhibitors, Dr. Deep said in an interview. “All three classes of antihypertensive medications are equally efficacious in blood pressure control and preventing all-cause mortality,” he said.

More research is needed in the wake of the introduction of other classes of antihypertensives since the original ALLHAT trial, Dr. Deep said. “It would be beneficial to assess the relative benefit/risks of those medications compared to the thiazide diuretics, and I would also look at studies comparing beta blockers to the thiazide diuretics,” he said. The question remains as to whether outcomes were affected by patients’ use of other classes of antihypertensives after the trial period, he said.

The study was supported by the National Institute on Aging of the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose and serves on the editorial advisory board of Internal Medicine News.

Long-term data showed negligible differences in mortality among hypertensive adults treated with thiazide-type diuretics, calcium channel blockers, or angiotensin-converting enzyme inhibitors in a review of nearly 33,000 individuals published in JAMA Network Open.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study was designed to compare initial antihypertensive treatments with a calcium channel blocker (CCB; amlodipine), an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) or an alpha-blocker (doxazosin), and a thiazide-type diuretic (chlorthalidone).

The composite primary outcome was fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI), but long-term data were lacking, wrote Jose-Miguel Yamal, PhD, of University of Texas Health Science Center at Houston, and colleagues. A previous study with 8-13 years of follow-up showed no significant differences in mortality between the treatment groups, the researchers noted.

In the current study, a prespecified secondary analysis of ALLHAT, the researchers added 11 more years of data for a total of 19-24 years of follow-up after randomization.

In the original ALLHAT, 32,804 adults aged 55 years and older with a diagnosis of hypertension and at least one additional coronary heart disease risk factor were followed for 4-8 years for all-cause mortality. A subgroup of 22,754 were followed for fatal or nonfatal cardiovascular disease (CVD) for a mean of 13.7 years, with a maximum of 23.9 years.

The study occurred from Feb. 23, 1994, to Dec. 31, 2017. The participants were randomized to receive a thiazide-type diuretic (15,002 patients), a CCB (8,898 patients), or an ACE inhibitor (8,904 patients).

The primary outcome was CVD mortality; secondary outcomes included all-cause mortality, combined fatal and nonfatal CVD (CVD morbidity), and both morbidity and mortality for coronary heart disease, stroke, heart failure, end-stage renal disease, and cancer.

At 23 years, CVD mortality rates per 100 persons were 23.7, 21.6, and 23.8 in the diuretic, CCB, and ACE inhibitor groups, respectively. The adjusted hazard ratios were 0.97 for CCB vs. diuretics and 1.06 for ACE inhibitors vs. diuretics.

Although the risk of stroke mortality and of combined fatal and nonfatal hospitalized stroke was higher in the ACE inhibitor group compared with the diuretic group (adjusted hazard ratios 1.19 and 1.11, respectively), this increase was no longer significant after adjustment for multiple comparisons. “In contrast to the in-trial and 8-year to 13-year analyses, we now observed that the lisinopril group had an increased risk of kidney disease mortality that emerged after approximately 13 years after randomization, but this effect was attenuated after adjustment for baseline variables,” the researchers wrote in their discussion.

The findings were limited by several factors including the potential effect of unblinding if participants stopped the randomized drug, and by the lack of morbidity and mortality data on Canadian participants, Veterans Affairs participants, and those with no Medicare number, the researchers noted. Other limitations included the lack of data on posttrial medication use, blood pressure, and laboratory findings, they said.

However, the results over the follow-up period of up to 23 years supported those of the larger ALLHAT study, with similar outcomes among the drugs, and with 11 years of passive follow-up, “the results for lisinopril vs. chlorthalidone for stroke and stroke mortality are almost the same,” they concluded.
 

Findings support current practice, but new drug data are needed

The current study was important to determine whether there was a significant difference in long-term morbidity and mortality between patients treated with thiazide diuretics, calcium channel blockers and ACE inhibitors, Noel Deep, MD, said in an interview.

“Previously reported data had indicated no significant differences between patients randomized to one of these three classes of antihypertensive medications during the trial period or at 8-13 years post trial,” said Dr. Deep, a general internist in private practice in Antigo, Wisc., who was not involved in the study. Dr. Deep is chief medical officer and a staff physician at Aspirus Langlade Hospital in Antigo.

“This study reinforces the previously noted benefits of the three classes of antihypertensive medications, as well as the higher rates of cardiovascular disease and stroke in the ACE inhibitor arm,” he said.

In clinical practice, the results suggest that thiazide diuretics should be considered first-line agents for management of hypertension based on their noninferiority compared with ACE inhibitors and CCBs, and lower risk of stroke compared with ACE inhibitors, Dr. Deep said in an interview. “All three classes of antihypertensive medications are equally efficacious in blood pressure control and preventing all-cause mortality,” he said.

More research is needed in the wake of the introduction of other classes of antihypertensives since the original ALLHAT trial, Dr. Deep said. “It would be beneficial to assess the relative benefit/risks of those medications compared to the thiazide diuretics, and I would also look at studies comparing beta blockers to the thiazide diuretics,” he said. The question remains as to whether outcomes were affected by patients’ use of other classes of antihypertensives after the trial period, he said.

The study was supported by the National Institute on Aging of the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose and serves on the editorial advisory board of Internal Medicine News.

Long-term data showed negligible differences in mortality among hypertensive adults treated with thiazide-type diuretics, calcium channel blockers, or angiotensin-converting enzyme inhibitors in a review of nearly 33,000 individuals published in JAMA Network Open.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study was designed to compare initial antihypertensive treatments with a calcium channel blocker (CCB; amlodipine), an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) or an alpha-blocker (doxazosin), and a thiazide-type diuretic (chlorthalidone).

The composite primary outcome was fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI), but long-term data were lacking, wrote Jose-Miguel Yamal, PhD, of University of Texas Health Science Center at Houston, and colleagues. A previous study with 8-13 years of follow-up showed no significant differences in mortality between the treatment groups, the researchers noted.

In the current study, a prespecified secondary analysis of ALLHAT, the researchers added 11 more years of data for a total of 19-24 years of follow-up after randomization.

In the original ALLHAT, 32,804 adults aged 55 years and older with a diagnosis of hypertension and at least one additional coronary heart disease risk factor were followed for 4-8 years for all-cause mortality. A subgroup of 22,754 were followed for fatal or nonfatal cardiovascular disease (CVD) for a mean of 13.7 years, with a maximum of 23.9 years.

The study occurred from Feb. 23, 1994, to Dec. 31, 2017. The participants were randomized to receive a thiazide-type diuretic (15,002 patients), a CCB (8,898 patients), or an ACE inhibitor (8,904 patients).

The primary outcome was CVD mortality; secondary outcomes included all-cause mortality, combined fatal and nonfatal CVD (CVD morbidity), and both morbidity and mortality for coronary heart disease, stroke, heart failure, end-stage renal disease, and cancer.

At 23 years, CVD mortality rates per 100 persons were 23.7, 21.6, and 23.8 in the diuretic, CCB, and ACE inhibitor groups, respectively. The adjusted hazard ratios were 0.97 for CCB vs. diuretics and 1.06 for ACE inhibitors vs. diuretics.

Although the risk of stroke mortality and of combined fatal and nonfatal hospitalized stroke was higher in the ACE inhibitor group compared with the diuretic group (adjusted hazard ratios 1.19 and 1.11, respectively), this increase was no longer significant after adjustment for multiple comparisons. “In contrast to the in-trial and 8-year to 13-year analyses, we now observed that the lisinopril group had an increased risk of kidney disease mortality that emerged after approximately 13 years after randomization, but this effect was attenuated after adjustment for baseline variables,” the researchers wrote in their discussion.

The findings were limited by several factors including the potential effect of unblinding if participants stopped the randomized drug, and by the lack of morbidity and mortality data on Canadian participants, Veterans Affairs participants, and those with no Medicare number, the researchers noted. Other limitations included the lack of data on posttrial medication use, blood pressure, and laboratory findings, they said.

However, the results over the follow-up period of up to 23 years supported those of the larger ALLHAT study, with similar outcomes among the drugs, and with 11 years of passive follow-up, “the results for lisinopril vs. chlorthalidone for stroke and stroke mortality are almost the same,” they concluded.
 

Findings support current practice, but new drug data are needed

The current study was important to determine whether there was a significant difference in long-term morbidity and mortality between patients treated with thiazide diuretics, calcium channel blockers and ACE inhibitors, Noel Deep, MD, said in an interview.

“Previously reported data had indicated no significant differences between patients randomized to one of these three classes of antihypertensive medications during the trial period or at 8-13 years post trial,” said Dr. Deep, a general internist in private practice in Antigo, Wisc., who was not involved in the study. Dr. Deep is chief medical officer and a staff physician at Aspirus Langlade Hospital in Antigo.

“This study reinforces the previously noted benefits of the three classes of antihypertensive medications, as well as the higher rates of cardiovascular disease and stroke in the ACE inhibitor arm,” he said.

In clinical practice, the results suggest that thiazide diuretics should be considered first-line agents for management of hypertension based on their noninferiority compared with ACE inhibitors and CCBs, and lower risk of stroke compared with ACE inhibitors, Dr. Deep said in an interview. “All three classes of antihypertensive medications are equally efficacious in blood pressure control and preventing all-cause mortality,” he said.

More research is needed in the wake of the introduction of other classes of antihypertensives since the original ALLHAT trial, Dr. Deep said. “It would be beneficial to assess the relative benefit/risks of those medications compared to the thiazide diuretics, and I would also look at studies comparing beta blockers to the thiazide diuretics,” he said. The question remains as to whether outcomes were affected by patients’ use of other classes of antihypertensives after the trial period, he said.

The study was supported by the National Institute on Aging of the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose and serves on the editorial advisory board of Internal Medicine News.

Patients receiving semaglutide for weight loss show a significantly higher rate of continuing the medication at 1 year compared with less effective anti-obesity drugs. However, even among those patients, continuation declines to fewer than half of patients.

“We now have effective US Food and Drug Administration–approved anti-obesity medications; [however], this study shows that in a real-world setting, the vast majority of patients discontinued their prescription fills within the first year,” said first author Hamlet Gasoyan, PhD, lead author of the study and a researcher with Cleveland Clinic’s Center for Value-Based Care Research, said in a press statement.

The study was published online in the journal Obesity.

While breakthrough drugs such as glucagon-like peptide-1 (GLP-1) receptor agonists have shown high efficacy in achieving weight loss while providing a host of other health benefits, their discontinuation has been shown to potentially result in a rapid regaining of weight that was lost, as well as a reversal of the other health benefits, such as cardiometabolic improvements, the study authors wrote.

To evaluate rates of persistence with those along with other weight loss medications and factors associated with discontinuation, Dr. Gasoyan and colleagues conducted a retrospective cohort study, identifying 1911 patients with obesity, who had an initial anti-obesity medication prescription filled between 2015 and 2022 at Cleveland Clinic centers in Ohio and Florida. 

Over the study period, 25% of patients filled a prescription for semaglutide, 34% for naltrexone-bupropion, 26% for phentermine-topiramate, 14% for liraglutide, and 0.9% for orlistat.

The patients had a median baseline BMI of 38, with obesity defined as a BMI of 30 or higher.
 

Medication Continuation Drops After 3 Months

With a median follow-up time of 2.4 years, the rate of persistence to the medications overall dropped from 44% at 3 months to 33% at 6 months and just 19% at 12 months. 

In a multivariate analysis, semaglutide was associated with the highest odds of 1-year persistence (adjusted odds ratio [AOR], 4.26), while naltrexone-bupropion had the lowest odds (AOR, 0.68), compared with phentermine-topiramate. The other agents did not have significantly different odds of persistence.

Semaglutide and liraglutide also had the highest persistence rates overall, including at 3 months (63% and 52%, respectively) and 6 months (56% and 37%, respectively).

Those with higher weight loss at 6 months had a higher likelihood of remaining on the weight loss medication at 1 year, with a 1% increase in weight loss at 6 months associated with 6% increased odds of still being persistent at year 1 (adjusted odds ratio, 1.06).

Those who did continue medications at 1 year had a mean of 10% weight loss at 12 months compared with just 2% among individuals who were not persistent (P <.001).

Most patients (84%) in the study were privately insured, and weight loss drug adherence varied significantly based on the insurance carrier. 

Studies demonstrating the effects of discontinuing treatment with semaglutide include the STEP 1 trial extension, which showed that 1 year after discontinuation of treatment and lifestyle intervention, participants regained two thirds of their lost weight on average, and the cardiometabolic improvements with the weight loss were reversed.

In light of those findings, “the current scientific knowledge favors using anti-obesity medications longer term for weight loss maintenance if they are well-tolerated and have resulted in clinically meaningful weight loss,” Dr. Gasoyan told this news organization. 

Paradoxically, the possible regaining of weight could be a factor in some insurers denying longer-term coverage, he noted.
 

Discontinuing Medications Means Regaining Appetite

Anne Peters, MD, a professor of medicine at USC’s Keck School of Medicine in Los Angeles and director of the USC Clinical Diabetes Programs, underscored that the possibility of regaining weight with discontinuation of GLP-1 receptor agonists is indeed “a big concern because your appetite comes back in spades when you take away the effect of these hormones,” she told this news organization. “For that reason, I don’t ever tell people to stop cold turkey.”

Regarding the question of how long patients should remain on the medications, Peters said the scenario might be compared to the need for patients with type 1 diabetes to be on insulin, which is a gut hormone.

“These medications are also gut hormones, and some patients may need to also be on them for life to maintain the benefits,” she said. 

“If a patient for some reason wishes to come off of the medication, for instance in order to be on less medicine, I have them titrate down and usually there will be a dose where they actually need only a small dose.

“I even have some patients who just take semaglutide once a month who are able to manage to maintain their weight loss,” Dr. Peters noted. 

“But the whole goal in people who are overweight or obese is to establish a new set point and maintain whatever that new target weight is.”

Dr. Peters agreed that the loss of insurance coverage for the medications can throw a big wrench into that maintenance, presenting adverse effects of its own by causing a lack of treatment continuity. 

“When you lose weight, you lose lean body mass and fat mass, but when you regain, it’s primary fat mass, so if you go on and off these drugs, it can contribute to a loss of lean mass. Therefore, these drugs should not be taken if someone is going to go on and off them repeatedly.” 

The study received funding from the National Cancer Institute. Dr. Peters has consulted for Eli Lilly in the past.

A version of this article appeared on Medscape.com.

Patients receiving semaglutide for weight loss show a significantly higher rate of continuing the medication at 1 year compared with less effective anti-obesity drugs. However, even among those patients, continuation declines to fewer than half of patients.

“We now have effective US Food and Drug Administration–approved anti-obesity medications; [however], this study shows that in a real-world setting, the vast majority of patients discontinued their prescription fills within the first year,” said first author Hamlet Gasoyan, PhD, lead author of the study and a researcher with Cleveland Clinic’s Center for Value-Based Care Research, said in a press statement.

The study was published online in the journal Obesity.

While breakthrough drugs such as glucagon-like peptide-1 (GLP-1) receptor agonists have shown high efficacy in achieving weight loss while providing a host of other health benefits, their discontinuation has been shown to potentially result in a rapid regaining of weight that was lost, as well as a reversal of the other health benefits, such as cardiometabolic improvements, the study authors wrote.

To evaluate rates of persistence with those along with other weight loss medications and factors associated with discontinuation, Dr. Gasoyan and colleagues conducted a retrospective cohort study, identifying 1911 patients with obesity, who had an initial anti-obesity medication prescription filled between 2015 and 2022 at Cleveland Clinic centers in Ohio and Florida. 

Over the study period, 25% of patients filled a prescription for semaglutide, 34% for naltrexone-bupropion, 26% for phentermine-topiramate, 14% for liraglutide, and 0.9% for orlistat.

The patients had a median baseline BMI of 38, with obesity defined as a BMI of 30 or higher.
 

Medication Continuation Drops After 3 Months

With a median follow-up time of 2.4 years, the rate of persistence to the medications overall dropped from 44% at 3 months to 33% at 6 months and just 19% at 12 months. 

In a multivariate analysis, semaglutide was associated with the highest odds of 1-year persistence (adjusted odds ratio [AOR], 4.26), while naltrexone-bupropion had the lowest odds (AOR, 0.68), compared with phentermine-topiramate. The other agents did not have significantly different odds of persistence.

Semaglutide and liraglutide also had the highest persistence rates overall, including at 3 months (63% and 52%, respectively) and 6 months (56% and 37%, respectively).

Those with higher weight loss at 6 months had a higher likelihood of remaining on the weight loss medication at 1 year, with a 1% increase in weight loss at 6 months associated with 6% increased odds of still being persistent at year 1 (adjusted odds ratio, 1.06).

Those who did continue medications at 1 year had a mean of 10% weight loss at 12 months compared with just 2% among individuals who were not persistent (P <.001).

Most patients (84%) in the study were privately insured, and weight loss drug adherence varied significantly based on the insurance carrier. 

Studies demonstrating the effects of discontinuing treatment with semaglutide include the STEP 1 trial extension, which showed that 1 year after discontinuation of treatment and lifestyle intervention, participants regained two thirds of their lost weight on average, and the cardiometabolic improvements with the weight loss were reversed.

In light of those findings, “the current scientific knowledge favors using anti-obesity medications longer term for weight loss maintenance if they are well-tolerated and have resulted in clinically meaningful weight loss,” Dr. Gasoyan told this news organization. 

Paradoxically, the possible regaining of weight could be a factor in some insurers denying longer-term coverage, he noted.
 

Discontinuing Medications Means Regaining Appetite

Anne Peters, MD, a professor of medicine at USC’s Keck School of Medicine in Los Angeles and director of the USC Clinical Diabetes Programs, underscored that the possibility of regaining weight with discontinuation of GLP-1 receptor agonists is indeed “a big concern because your appetite comes back in spades when you take away the effect of these hormones,” she told this news organization. “For that reason, I don’t ever tell people to stop cold turkey.”

Regarding the question of how long patients should remain on the medications, Peters said the scenario might be compared to the need for patients with type 1 diabetes to be on insulin, which is a gut hormone.

“These medications are also gut hormones, and some patients may need to also be on them for life to maintain the benefits,” she said. 

“If a patient for some reason wishes to come off of the medication, for instance in order to be on less medicine, I have them titrate down and usually there will be a dose where they actually need only a small dose.

“I even have some patients who just take semaglutide once a month who are able to manage to maintain their weight loss,” Dr. Peters noted. 

“But the whole goal in people who are overweight or obese is to establish a new set point and maintain whatever that new target weight is.”

Dr. Peters agreed that the loss of insurance coverage for the medications can throw a big wrench into that maintenance, presenting adverse effects of its own by causing a lack of treatment continuity. 

“When you lose weight, you lose lean body mass and fat mass, but when you regain, it’s primary fat mass, so if you go on and off these drugs, it can contribute to a loss of lean mass. Therefore, these drugs should not be taken if someone is going to go on and off them repeatedly.” 

The study received funding from the National Cancer Institute. Dr. Peters has consulted for Eli Lilly in the past.

A version of this article appeared on Medscape.com.

Patients receiving semaglutide for weight loss show a significantly higher rate of continuing the medication at 1 year compared with less effective anti-obesity drugs. However, even among those patients, continuation declines to fewer than half of patients.

“We now have effective US Food and Drug Administration–approved anti-obesity medications; [however], this study shows that in a real-world setting, the vast majority of patients discontinued their prescription fills within the first year,” said first author Hamlet Gasoyan, PhD, lead author of the study and a researcher with Cleveland Clinic’s Center for Value-Based Care Research, said in a press statement.

The study was published online in the journal Obesity.

While breakthrough drugs such as glucagon-like peptide-1 (GLP-1) receptor agonists have shown high efficacy in achieving weight loss while providing a host of other health benefits, their discontinuation has been shown to potentially result in a rapid regaining of weight that was lost, as well as a reversal of the other health benefits, such as cardiometabolic improvements, the study authors wrote.

To evaluate rates of persistence with those along with other weight loss medications and factors associated with discontinuation, Dr. Gasoyan and colleagues conducted a retrospective cohort study, identifying 1911 patients with obesity, who had an initial anti-obesity medication prescription filled between 2015 and 2022 at Cleveland Clinic centers in Ohio and Florida. 

Over the study period, 25% of patients filled a prescription for semaglutide, 34% for naltrexone-bupropion, 26% for phentermine-topiramate, 14% for liraglutide, and 0.9% for orlistat.

The patients had a median baseline BMI of 38, with obesity defined as a BMI of 30 or higher.
 

Medication Continuation Drops After 3 Months

With a median follow-up time of 2.4 years, the rate of persistence to the medications overall dropped from 44% at 3 months to 33% at 6 months and just 19% at 12 months. 

In a multivariate analysis, semaglutide was associated with the highest odds of 1-year persistence (adjusted odds ratio [AOR], 4.26), while naltrexone-bupropion had the lowest odds (AOR, 0.68), compared with phentermine-topiramate. The other agents did not have significantly different odds of persistence.

Semaglutide and liraglutide also had the highest persistence rates overall, including at 3 months (63% and 52%, respectively) and 6 months (56% and 37%, respectively).

Those with higher weight loss at 6 months had a higher likelihood of remaining on the weight loss medication at 1 year, with a 1% increase in weight loss at 6 months associated with 6% increased odds of still being persistent at year 1 (adjusted odds ratio, 1.06).

Those who did continue medications at 1 year had a mean of 10% weight loss at 12 months compared with just 2% among individuals who were not persistent (P <.001).

Most patients (84%) in the study were privately insured, and weight loss drug adherence varied significantly based on the insurance carrier. 

Studies demonstrating the effects of discontinuing treatment with semaglutide include the STEP 1 trial extension, which showed that 1 year after discontinuation of treatment and lifestyle intervention, participants regained two thirds of their lost weight on average, and the cardiometabolic improvements with the weight loss were reversed.

In light of those findings, “the current scientific knowledge favors using anti-obesity medications longer term for weight loss maintenance if they are well-tolerated and have resulted in clinically meaningful weight loss,” Dr. Gasoyan told this news organization. 

Paradoxically, the possible regaining of weight could be a factor in some insurers denying longer-term coverage, he noted.
 

Discontinuing Medications Means Regaining Appetite

Anne Peters, MD, a professor of medicine at USC’s Keck School of Medicine in Los Angeles and director of the USC Clinical Diabetes Programs, underscored that the possibility of regaining weight with discontinuation of GLP-1 receptor agonists is indeed “a big concern because your appetite comes back in spades when you take away the effect of these hormones,” she told this news organization. “For that reason, I don’t ever tell people to stop cold turkey.”

Regarding the question of how long patients should remain on the medications, Peters said the scenario might be compared to the need for patients with type 1 diabetes to be on insulin, which is a gut hormone.

“These medications are also gut hormones, and some patients may need to also be on them for life to maintain the benefits,” she said. 

“If a patient for some reason wishes to come off of the medication, for instance in order to be on less medicine, I have them titrate down and usually there will be a dose where they actually need only a small dose.

“I even have some patients who just take semaglutide once a month who are able to manage to maintain their weight loss,” Dr. Peters noted. 

“But the whole goal in people who are overweight or obese is to establish a new set point and maintain whatever that new target weight is.”

Dr. Peters agreed that the loss of insurance coverage for the medications can throw a big wrench into that maintenance, presenting adverse effects of its own by causing a lack of treatment continuity. 

“When you lose weight, you lose lean body mass and fat mass, but when you regain, it’s primary fat mass, so if you go on and off these drugs, it can contribute to a loss of lean mass. Therefore, these drugs should not be taken if someone is going to go on and off them repeatedly.” 

The study received funding from the National Cancer Institute. Dr. Peters has consulted for Eli Lilly in the past.

A version of this article appeared on Medscape.com.

TOPLINE: 

Compared with a healthy omnivore diet, a healthy vegan diet led to significant improvement in  low-density lipoprotein cholesterol (LDL-C) as well as fasting insulin and weight loss in a randomized controlled trial of identical twins. 

METHODOLOGY:  

• Researchers randomly assigned 22 pairs of healthy adult identical twins (34 women, mean age 39 years, mean body mass index 25.9) to a healthy vegan or omnivore diet (1 twin per pair) for 8 weeks.
• For the first 4 weeks, diet-specific meals were provided via a meal delivery service. For the final 4 weeks, participants prepared their own diet-appropriate meals/snacks.
• The primary outcome was change in LDL-C; secondary outcomes included changes in body weight and fasting insulin. 

TAKEAWAY:

• After 8 weeks, twins eating a vegan diet showed a significant mean decrease of 13.9 mg/dL in LDL-C compared with twins eating an omnivorous diet.
• The vegan diet also led to a significant mean decrease of 2.9 Times New RomanμIU/mL in fasting insulin and 1.9 kg in body weight after 8 weeks compared with the omnivore diet, although weight loss was observed in both diet groups. 
• The vegan diet group also had a larger but nonsignificant absolute median decrease in fasting HDL-C  triglycerides , vitamin B12, glucose, and trimethylamine N-oxide levels at 8 weeks.

IN PRACTICE: 

“Our results corroborate a previous finding showing that eating a vegan diet can improve cardiovascular health. Clinicians may consider recommending plant-based diets to reduce cardiometabolic risk factors, as well as aligning with environmental benefits,” the researchers concluded. 

SOURCE: 

The study, with first author Matthew J. Landry, PhD, RDN, Stanford Prevention Research Center, Stanford University School of Medicine, California, was published online November 30 in  JAMA Network Open. 

LIMITATIONS: 

The adult twin population was generally healthy and findings may not be generalizable to other populations. The sample size was small, and the duration of intervention was short and there was no follow-up period, which limits insights on stability and sustainability of the diets. 

DISCLOSURES: 

Funding was provided by the Vogt Foundation, and grants from Stanford University and the National Heart, Lung, and Blood Institute. Dr. Landry has no relevant disclosures. One author reported receiving funding from Beyond Meat outside of this study. 

A version of this article appeared on Medscape.com.

TOPLINE: 

Compared with a healthy omnivore diet, a healthy vegan diet led to significant improvement in  low-density lipoprotein cholesterol (LDL-C) as well as fasting insulin and weight loss in a randomized controlled trial of identical twins. 

METHODOLOGY:  

• Researchers randomly assigned 22 pairs of healthy adult identical twins (34 women, mean age 39 years, mean body mass index 25.9) to a healthy vegan or omnivore diet (1 twin per pair) for 8 weeks.
• For the first 4 weeks, diet-specific meals were provided via a meal delivery service. For the final 4 weeks, participants prepared their own diet-appropriate meals/snacks.
• The primary outcome was change in LDL-C; secondary outcomes included changes in body weight and fasting insulin. 

TAKEAWAY:

• After 8 weeks, twins eating a vegan diet showed a significant mean decrease of 13.9 mg/dL in LDL-C compared with twins eating an omnivorous diet.
• The vegan diet also led to a significant mean decrease of 2.9 Times New RomanμIU/mL in fasting insulin and 1.9 kg in body weight after 8 weeks compared with the omnivore diet, although weight loss was observed in both diet groups. 
• The vegan diet group also had a larger but nonsignificant absolute median decrease in fasting HDL-C  triglycerides , vitamin B12, glucose, and trimethylamine N-oxide levels at 8 weeks.

IN PRACTICE: 

“Our results corroborate a previous finding showing that eating a vegan diet can improve cardiovascular health. Clinicians may consider recommending plant-based diets to reduce cardiometabolic risk factors, as well as aligning with environmental benefits,” the researchers concluded. 

SOURCE: 

The study, with first author Matthew J. Landry, PhD, RDN, Stanford Prevention Research Center, Stanford University School of Medicine, California, was published online November 30 in  JAMA Network Open. 

LIMITATIONS: 

The adult twin population was generally healthy and findings may not be generalizable to other populations. The sample size was small, and the duration of intervention was short and there was no follow-up period, which limits insights on stability and sustainability of the diets. 

DISCLOSURES: 

Funding was provided by the Vogt Foundation, and grants from Stanford University and the National Heart, Lung, and Blood Institute. Dr. Landry has no relevant disclosures. One author reported receiving funding from Beyond Meat outside of this study. 

A version of this article appeared on Medscape.com.

TOPLINE: 

Compared with a healthy omnivore diet, a healthy vegan diet led to significant improvement in  low-density lipoprotein cholesterol (LDL-C) as well as fasting insulin and weight loss in a randomized controlled trial of identical twins. 

METHODOLOGY:  

• Researchers randomly assigned 22 pairs of healthy adult identical twins (34 women, mean age 39 years, mean body mass index 25.9) to a healthy vegan or omnivore diet (1 twin per pair) for 8 weeks.
• For the first 4 weeks, diet-specific meals were provided via a meal delivery service. For the final 4 weeks, participants prepared their own diet-appropriate meals/snacks.
• The primary outcome was change in LDL-C; secondary outcomes included changes in body weight and fasting insulin. 

TAKEAWAY:

• After 8 weeks, twins eating a vegan diet showed a significant mean decrease of 13.9 mg/dL in LDL-C compared with twins eating an omnivorous diet.
• The vegan diet also led to a significant mean decrease of 2.9 Times New RomanμIU/mL in fasting insulin and 1.9 kg in body weight after 8 weeks compared with the omnivore diet, although weight loss was observed in both diet groups. 
• The vegan diet group also had a larger but nonsignificant absolute median decrease in fasting HDL-C  triglycerides , vitamin B12, glucose, and trimethylamine N-oxide levels at 8 weeks.

IN PRACTICE: 

“Our results corroborate a previous finding showing that eating a vegan diet can improve cardiovascular health. Clinicians may consider recommending plant-based diets to reduce cardiometabolic risk factors, as well as aligning with environmental benefits,” the researchers concluded. 

SOURCE: 

The study, with first author Matthew J. Landry, PhD, RDN, Stanford Prevention Research Center, Stanford University School of Medicine, California, was published online November 30 in  JAMA Network Open. 

LIMITATIONS: 

The adult twin population was generally healthy and findings may not be generalizable to other populations. The sample size was small, and the duration of intervention was short and there was no follow-up period, which limits insights on stability and sustainability of the diets. 

DISCLOSURES: 

Funding was provided by the Vogt Foundation, and grants from Stanford University and the National Heart, Lung, and Blood Institute. Dr. Landry has no relevant disclosures. One author reported receiving funding from Beyond Meat outside of this study. 

A version of this article appeared on Medscape.com.

PHILADELPHIA — Promise that the unmet need for more effective pulmonary artery hypertension treatments may soon be met was in strong evidence in research into three strategies presented at this year’s recent American Heart Association scientific sessions; one was based on an ancient Chinese herb epimedium (yin yang huo or horny goat weed) commonly used for treating sexual dysfunction and directly related to the phosphodiesterase inhibitors sildenafil, vardenafil, and tadalafil (sold as Viagra, Levitra, and Cialis). A second studied sotatercept, an investigational, potential first-in-class activin signaling inhibitor biologic, and a third evaluated physically ablating the baroreceptor nerves that stimulate vasoconstriction of the pulmonary artery via catheter-based techniques.

Until as recently as the late 1970s, a pulmonary arterial hypertension diagnosis was a uniformly fatal one.¹ While targeted therapies have since improved prognosis, pulmonary arterial hypertension remains a chronic and progressive disorder of the pulmonary vasculature with significant morbidity and mortality associated with pulmonary and right ventricle remodeling, and leads toward heart failure and death. The complex underlying pathogenesis was divided into six groups by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, and includes as its most common features pulmonary artery endothelial cell dysfunction, pulmonary artery smooth muscle cell proliferation and migration, and dysregulated fibroblast activity leading to dysregulated vasoconstriction, micro and in-situ vascular thrombosis, vascular fibrosis and pathogenic remodeling of pulmonary vessels.¹ The threshold mean arterial pressure (mPAP) for pulmonary arterial hypertension was defined by the 6th [WSPH] at mPAP ≥ 20 mm Hg, twice the upper limit of a normal mPAP of 14.0 ± 3.3 mm Hg as reported by Kovacs et al. in 2018.²

Pathways for current therapies

Current drugs for pulmonary arterial hypertension focus on three signaling pathways, including the endothelin receptor, prostacyclin and nitric oxide pathways, stated Zhi-Cheng Jing, MD, professor of medicine, head of the cardiology department at Peking Union Medical College Hospital, Peking, China. While the phosphodiesterase 5 inhibitors sildenafil and tadalafil, which target the nitric oxide pathway, came into wide use after Food and Drug Administration approval, the need for higher PDE5-selectivity remains, Dr. Jing said. Structurally modified from the active ingredient in epimedium, TPN171H is an investigational PDE5 inhibitor which has shown several favorable features: a greater PDE5 selectivity than both sildenafil and tadalafil in vitro, an ability to decrease right ventricular systolic pressure and alleviate arterial remodeling in animal studies, and safety and tolerability in healthy human subjects.

The current randomized, double-blind, placebo-and active-controlled phase IIa study assessed the hemodynamic impact of a single oral dose of TPN171H in 60 pulmonary arterial hypertension patients (mean age ~34 years, 83.3% female), all with negative vasodilation test results and in WHO class 2 or 3. Only patients aged 18-75 years with group 1 pulmonary arterial hypertension of idiopathic, connective tissue disorder, or repaired congenital heart defects etiology were included. Patients were divided into six groups: placebo, TPN171H at 2.5, 5, and 10 milligrams, and tadalafil at 20 and 40 milligrams.

For the primary endpoint of maximum decrease in pulmonary vascular resistance (PVR), significant reductions vs. placebo were found only for the TPN171H 5-mg group (–41.2% vs. –24.4%; P = .008) and for the 20-mg (–39.8%) and 40-mg (–37.6%) tadalafil groups (both P < .05). What was not seen in the tadalafil groups, but was evident in the TPN171H 5-mg group, was a significant reduction in the secondary endpoint of PVR/SVR (systolic vascular resistance) at 2, 3, and 5 hours (all P < .05). “As we know,” Dr. Jing said in an interview, “the PDE5 inhibitor functions as a vasodilator, having an impact on both pulmonary circulation and systemic circulation. So, to evaluate the  selectivity for pulmonary circulation is crucial when exploring a novel drug for pulmonary arterial hypertension. The change of PVR/SVR ratio from baseline is an indicator for selectivity for pulmonary circulation and implies that TPN171H has good PDE5 selectivity in the pulmonary vasculature,” Dr. Jing said.

TPN171H was well tolerated with no serious adverse effects (vomiting 10% and headache 10% were most common with no discontinuations).
 

TGF-signaling pathway

A meta-analysis of randomized controlled trials of sotatercept, an investigational fusion protein under priority FDA review that modulates the TGF-beta superfamily signaling pathway, looked at PVR, pulmonary arterial pressure (PAP), right arterial pressure (RAP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). A literature search by corresponding author Vamsikalyan Borra, MD, Knapp Medical Center, Weslaco, Texas, and colleagues identified two trials (STELLAR and PULSAR) comprising 429 patients with pulmonary arterial hypertension. The experimental arms (sotatercept) had 237 patients (mean age ~49 years, ~82% female) and the placebo arm had 192 patients (mean age ~47 years, ~80% female).

A pooled analysis showed significant reductions with sotatercept in PVR (standardization mean difference [SMD] = –1.00, 95% confidence interval [CI] = –1.2, –.79, P < .001), PAP (SMD = –1.34, 95% CI = 1.6, –1.08, P < .001), RAP (SMD = –0.66, 95% CI = –0.93, –0.39, P < .001), and the levels of NT-proBNP (SMD = –0.64, 95% CI = –1.01, –0.27, P < .001) at 24 weeks from baseline. The sotatercept safety profile was favorable, with lower overall incidence of adverse events (84.8% vs. 87.5%) and fewer adverse events leading to death (0.4% vs. 3.1%) compared with placebo. Further investigation is needed, however, according to Dr. Borra, into the higher frequency of reported thrombocytopenia (71.7% vs. 20.8%) with sotatercept. “Our findings,” Dr. Borra said in a poster session, “suggest that sotatercept is an effective treatment option for pulmonary arterial hypertension, with the potential to improve both pulmonary and cardiac function.”
 

Denervation technique

Catheter-based ablation techniques, most commonly using thermal energy, target the afferent and efferent fibers of the baroreceptor reflex in the main pulmonary artery trunk and bifurcation involved in elevated pulmonary artery pressure. Mounica Vorla, MD, Carle Foundation Hospital, Urbana, Illinois, and colleagues conducted an updated systematic review and meta-analysis of the safety and efficacy of pulmonary artery denervation (PADN) for pulmonary arterial hypertension in seven clinical trials with 506 patients with moderate-severe pulmonary arterial hypertension conducted from 2013 to 2022.

Compared with placebo, PADN treatment was associated with a significant reduction in mean pulmonary artery pressure (weighted mean difference [WMD] = –6.9 mm Hg; 95% CI = –9.7, –4.1; P < .01; I2 = 61) and pulmonary vascular resistance (WMD = –3.2; 95% CI = –5.4, –0.9; P = .005). PADN improvements in cardiac output were also statistically significant (WMD = 0.3; 95% CI = 0.07, 0.6; P = .012), with numerical improvement in 6-minute walking distance (WMD = 67.7; 95% CI = –3.73, 139.2; P = .06) in the PADN group. Side effects were less common in the PADN group as compared with the placebo group, Dr. Vorla reported. She concluded, “This updated meta-analysis supports PADN as a safe and efficacious therapy for severe pulmonary arterial hypertension.” The authors noted limitations imposed by the small sample size, large data heterogeneity, and medium-quality literature. Larger randomized, controlled trials with clinical endpoints comparing PADN with optimal medical therapy are needed, they stated.
 

References

1. Shah AJ et al. New Drugs and Therapies in Pulmonary Arterial Hypertension. Int J Mol Sci. 2023 Mar 19;24(6):5850. doi: 10.3390/ijms24065850. PMID: 36982922; PMCID: PMC10058689.

2. Kovacs G et al. Pulmonary Vascular Involvement in Chronic Obstructive Pulmonary Disease. Is There a Pulmonary Vascular Phenotype? Am J Respir Crit Care Med. 2018 Oct 15;198(8):1000-11. doi: 10.1164/rccm.201801-0095PP. PMID: 29746142.

PHILADELPHIA — Promise that the unmet need for more effective pulmonary artery hypertension treatments may soon be met was in strong evidence in research into three strategies presented at this year’s recent American Heart Association scientific sessions; one was based on an ancient Chinese herb epimedium (yin yang huo or horny goat weed) commonly used for treating sexual dysfunction and directly related to the phosphodiesterase inhibitors sildenafil, vardenafil, and tadalafil (sold as Viagra, Levitra, and Cialis). A second studied sotatercept, an investigational, potential first-in-class activin signaling inhibitor biologic, and a third evaluated physically ablating the baroreceptor nerves that stimulate vasoconstriction of the pulmonary artery via catheter-based techniques.

Until as recently as the late 1970s, a pulmonary arterial hypertension diagnosis was a uniformly fatal one.¹ While targeted therapies have since improved prognosis, pulmonary arterial hypertension remains a chronic and progressive disorder of the pulmonary vasculature with significant morbidity and mortality associated with pulmonary and right ventricle remodeling, and leads toward heart failure and death. The complex underlying pathogenesis was divided into six groups by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, and includes as its most common features pulmonary artery endothelial cell dysfunction, pulmonary artery smooth muscle cell proliferation and migration, and dysregulated fibroblast activity leading to dysregulated vasoconstriction, micro and in-situ vascular thrombosis, vascular fibrosis and pathogenic remodeling of pulmonary vessels.¹ The threshold mean arterial pressure (mPAP) for pulmonary arterial hypertension was defined by the 6th [WSPH] at mPAP ≥ 20 mm Hg, twice the upper limit of a normal mPAP of 14.0 ± 3.3 mm Hg as reported by Kovacs et al. in 2018.²

Pathways for current therapies

Current drugs for pulmonary arterial hypertension focus on three signaling pathways, including the endothelin receptor, prostacyclin and nitric oxide pathways, stated Zhi-Cheng Jing, MD, professor of medicine, head of the cardiology department at Peking Union Medical College Hospital, Peking, China. While the phosphodiesterase 5 inhibitors sildenafil and tadalafil, which target the nitric oxide pathway, came into wide use after Food and Drug Administration approval, the need for higher PDE5-selectivity remains, Dr. Jing said. Structurally modified from the active ingredient in epimedium, TPN171H is an investigational PDE5 inhibitor which has shown several favorable features: a greater PDE5 selectivity than both sildenafil and tadalafil in vitro, an ability to decrease right ventricular systolic pressure and alleviate arterial remodeling in animal studies, and safety and tolerability in healthy human subjects.

The current randomized, double-blind, placebo-and active-controlled phase IIa study assessed the hemodynamic impact of a single oral dose of TPN171H in 60 pulmonary arterial hypertension patients (mean age ~34 years, 83.3% female), all with negative vasodilation test results and in WHO class 2 or 3. Only patients aged 18-75 years with group 1 pulmonary arterial hypertension of idiopathic, connective tissue disorder, or repaired congenital heart defects etiology were included. Patients were divided into six groups: placebo, TPN171H at 2.5, 5, and 10 milligrams, and tadalafil at 20 and 40 milligrams.

For the primary endpoint of maximum decrease in pulmonary vascular resistance (PVR), significant reductions vs. placebo were found only for the TPN171H 5-mg group (–41.2% vs. –24.4%; P = .008) and for the 20-mg (–39.8%) and 40-mg (–37.6%) tadalafil groups (both P < .05). What was not seen in the tadalafil groups, but was evident in the TPN171H 5-mg group, was a significant reduction in the secondary endpoint of PVR/SVR (systolic vascular resistance) at 2, 3, and 5 hours (all P < .05). “As we know,” Dr. Jing said in an interview, “the PDE5 inhibitor functions as a vasodilator, having an impact on both pulmonary circulation and systemic circulation. So, to evaluate the  selectivity for pulmonary circulation is crucial when exploring a novel drug for pulmonary arterial hypertension. The change of PVR/SVR ratio from baseline is an indicator for selectivity for pulmonary circulation and implies that TPN171H has good PDE5 selectivity in the pulmonary vasculature,” Dr. Jing said.

TPN171H was well tolerated with no serious adverse effects (vomiting 10% and headache 10% were most common with no discontinuations).
 

TGF-signaling pathway

A meta-analysis of randomized controlled trials of sotatercept, an investigational fusion protein under priority FDA review that modulates the TGF-beta superfamily signaling pathway, looked at PVR, pulmonary arterial pressure (PAP), right arterial pressure (RAP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). A literature search by corresponding author Vamsikalyan Borra, MD, Knapp Medical Center, Weslaco, Texas, and colleagues identified two trials (STELLAR and PULSAR) comprising 429 patients with pulmonary arterial hypertension. The experimental arms (sotatercept) had 237 patients (mean age ~49 years, ~82% female) and the placebo arm had 192 patients (mean age ~47 years, ~80% female).

A pooled analysis showed significant reductions with sotatercept in PVR (standardization mean difference [SMD] = –1.00, 95% confidence interval [CI] = –1.2, –.79, P < .001), PAP (SMD = –1.34, 95% CI = 1.6, –1.08, P < .001), RAP (SMD = –0.66, 95% CI = –0.93, –0.39, P < .001), and the levels of NT-proBNP (SMD = –0.64, 95% CI = –1.01, –0.27, P < .001) at 24 weeks from baseline. The sotatercept safety profile was favorable, with lower overall incidence of adverse events (84.8% vs. 87.5%) and fewer adverse events leading to death (0.4% vs. 3.1%) compared with placebo. Further investigation is needed, however, according to Dr. Borra, into the higher frequency of reported thrombocytopenia (71.7% vs. 20.8%) with sotatercept. “Our findings,” Dr. Borra said in a poster session, “suggest that sotatercept is an effective treatment option for pulmonary arterial hypertension, with the potential to improve both pulmonary and cardiac function.”
 

Denervation technique

Catheter-based ablation techniques, most commonly using thermal energy, target the afferent and efferent fibers of the baroreceptor reflex in the main pulmonary artery trunk and bifurcation involved in elevated pulmonary artery pressure. Mounica Vorla, MD, Carle Foundation Hospital, Urbana, Illinois, and colleagues conducted an updated systematic review and meta-analysis of the safety and efficacy of pulmonary artery denervation (PADN) for pulmonary arterial hypertension in seven clinical trials with 506 patients with moderate-severe pulmonary arterial hypertension conducted from 2013 to 2022.

Compared with placebo, PADN treatment was associated with a significant reduction in mean pulmonary artery pressure (weighted mean difference [WMD] = –6.9 mm Hg; 95% CI = –9.7, –4.1; P < .01; I2 = 61) and pulmonary vascular resistance (WMD = –3.2; 95% CI = –5.4, –0.9; P = .005). PADN improvements in cardiac output were also statistically significant (WMD = 0.3; 95% CI = 0.07, 0.6; P = .012), with numerical improvement in 6-minute walking distance (WMD = 67.7; 95% CI = –3.73, 139.2; P = .06) in the PADN group. Side effects were less common in the PADN group as compared with the placebo group, Dr. Vorla reported. She concluded, “This updated meta-analysis supports PADN as a safe and efficacious therapy for severe pulmonary arterial hypertension.” The authors noted limitations imposed by the small sample size, large data heterogeneity, and medium-quality literature. Larger randomized, controlled trials with clinical endpoints comparing PADN with optimal medical therapy are needed, they stated.
 

References

1. Shah AJ et al. New Drugs and Therapies in Pulmonary Arterial Hypertension. Int J Mol Sci. 2023 Mar 19;24(6):5850. doi: 10.3390/ijms24065850. PMID: 36982922; PMCID: PMC10058689.

2. Kovacs G et al. Pulmonary Vascular Involvement in Chronic Obstructive Pulmonary Disease. Is There a Pulmonary Vascular Phenotype? Am J Respir Crit Care Med. 2018 Oct 15;198(8):1000-11. doi: 10.1164/rccm.201801-0095PP. PMID: 29746142.

PHILADELPHIA — Promise that the unmet need for more effective pulmonary artery hypertension treatments may soon be met was in strong evidence in research into three strategies presented at this year’s recent American Heart Association scientific sessions; one was based on an ancient Chinese herb epimedium (yin yang huo or horny goat weed) commonly used for treating sexual dysfunction and directly related to the phosphodiesterase inhibitors sildenafil, vardenafil, and tadalafil (sold as Viagra, Levitra, and Cialis). A second studied sotatercept, an investigational, potential first-in-class activin signaling inhibitor biologic, and a third evaluated physically ablating the baroreceptor nerves that stimulate vasoconstriction of the pulmonary artery via catheter-based techniques.

Until as recently as the late 1970s, a pulmonary arterial hypertension diagnosis was a uniformly fatal one.¹ While targeted therapies have since improved prognosis, pulmonary arterial hypertension remains a chronic and progressive disorder of the pulmonary vasculature with significant morbidity and mortality associated with pulmonary and right ventricle remodeling, and leads toward heart failure and death. The complex underlying pathogenesis was divided into six groups by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, and includes as its most common features pulmonary artery endothelial cell dysfunction, pulmonary artery smooth muscle cell proliferation and migration, and dysregulated fibroblast activity leading to dysregulated vasoconstriction, micro and in-situ vascular thrombosis, vascular fibrosis and pathogenic remodeling of pulmonary vessels.¹ The threshold mean arterial pressure (mPAP) for pulmonary arterial hypertension was defined by the 6th [WSPH] at mPAP ≥ 20 mm Hg, twice the upper limit of a normal mPAP of 14.0 ± 3.3 mm Hg as reported by Kovacs et al. in 2018.²

Pathways for current therapies

Current drugs for pulmonary arterial hypertension focus on three signaling pathways, including the endothelin receptor, prostacyclin and nitric oxide pathways, stated Zhi-Cheng Jing, MD, professor of medicine, head of the cardiology department at Peking Union Medical College Hospital, Peking, China. While the phosphodiesterase 5 inhibitors sildenafil and tadalafil, which target the nitric oxide pathway, came into wide use after Food and Drug Administration approval, the need for higher PDE5-selectivity remains, Dr. Jing said. Structurally modified from the active ingredient in epimedium, TPN171H is an investigational PDE5 inhibitor which has shown several favorable features: a greater PDE5 selectivity than both sildenafil and tadalafil in vitro, an ability to decrease right ventricular systolic pressure and alleviate arterial remodeling in animal studies, and safety and tolerability in healthy human subjects.

The current randomized, double-blind, placebo-and active-controlled phase IIa study assessed the hemodynamic impact of a single oral dose of TPN171H in 60 pulmonary arterial hypertension patients (mean age ~34 years, 83.3% female), all with negative vasodilation test results and in WHO class 2 or 3. Only patients aged 18-75 years with group 1 pulmonary arterial hypertension of idiopathic, connective tissue disorder, or repaired congenital heart defects etiology were included. Patients were divided into six groups: placebo, TPN171H at 2.5, 5, and 10 milligrams, and tadalafil at 20 and 40 milligrams.

For the primary endpoint of maximum decrease in pulmonary vascular resistance (PVR), significant reductions vs. placebo were found only for the TPN171H 5-mg group (–41.2% vs. –24.4%; P = .008) and for the 20-mg (–39.8%) and 40-mg (–37.6%) tadalafil groups (both P < .05). What was not seen in the tadalafil groups, but was evident in the TPN171H 5-mg group, was a significant reduction in the secondary endpoint of PVR/SVR (systolic vascular resistance) at 2, 3, and 5 hours (all P < .05). “As we know,” Dr. Jing said in an interview, “the PDE5 inhibitor functions as a vasodilator, having an impact on both pulmonary circulation and systemic circulation. So, to evaluate the  selectivity for pulmonary circulation is crucial when exploring a novel drug for pulmonary arterial hypertension. The change of PVR/SVR ratio from baseline is an indicator for selectivity for pulmonary circulation and implies that TPN171H has good PDE5 selectivity in the pulmonary vasculature,” Dr. Jing said.

TPN171H was well tolerated with no serious adverse effects (vomiting 10% and headache 10% were most common with no discontinuations).
 

TGF-signaling pathway

A meta-analysis of randomized controlled trials of sotatercept, an investigational fusion protein under priority FDA review that modulates the TGF-beta superfamily signaling pathway, looked at PVR, pulmonary arterial pressure (PAP), right arterial pressure (RAP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). A literature search by corresponding author Vamsikalyan Borra, MD, Knapp Medical Center, Weslaco, Texas, and colleagues identified two trials (STELLAR and PULSAR) comprising 429 patients with pulmonary arterial hypertension. The experimental arms (sotatercept) had 237 patients (mean age ~49 years, ~82% female) and the placebo arm had 192 patients (mean age ~47 years, ~80% female).

A pooled analysis showed significant reductions with sotatercept in PVR (standardization mean difference [SMD] = –1.00, 95% confidence interval [CI] = –1.2, –.79, P < .001), PAP (SMD = –1.34, 95% CI = 1.6, –1.08, P < .001), RAP (SMD = –0.66, 95% CI = –0.93, –0.39, P < .001), and the levels of NT-proBNP (SMD = –0.64, 95% CI = –1.01, –0.27, P < .001) at 24 weeks from baseline. The sotatercept safety profile was favorable, with lower overall incidence of adverse events (84.8% vs. 87.5%) and fewer adverse events leading to death (0.4% vs. 3.1%) compared with placebo. Further investigation is needed, however, according to Dr. Borra, into the higher frequency of reported thrombocytopenia (71.7% vs. 20.8%) with sotatercept. “Our findings,” Dr. Borra said in a poster session, “suggest that sotatercept is an effective treatment option for pulmonary arterial hypertension, with the potential to improve both pulmonary and cardiac function.”
 

Denervation technique

Catheter-based ablation techniques, most commonly using thermal energy, target the afferent and efferent fibers of the baroreceptor reflex in the main pulmonary artery trunk and bifurcation involved in elevated pulmonary artery pressure. Mounica Vorla, MD, Carle Foundation Hospital, Urbana, Illinois, and colleagues conducted an updated systematic review and meta-analysis of the safety and efficacy of pulmonary artery denervation (PADN) for pulmonary arterial hypertension in seven clinical trials with 506 patients with moderate-severe pulmonary arterial hypertension conducted from 2013 to 2022.

Compared with placebo, PADN treatment was associated with a significant reduction in mean pulmonary artery pressure (weighted mean difference [WMD] = –6.9 mm Hg; 95% CI = –9.7, –4.1; P < .01; I2 = 61) and pulmonary vascular resistance (WMD = –3.2; 95% CI = –5.4, –0.9; P = .005). PADN improvements in cardiac output were also statistically significant (WMD = 0.3; 95% CI = 0.07, 0.6; P = .012), with numerical improvement in 6-minute walking distance (WMD = 67.7; 95% CI = –3.73, 139.2; P = .06) in the PADN group. Side effects were less common in the PADN group as compared with the placebo group, Dr. Vorla reported. She concluded, “This updated meta-analysis supports PADN as a safe and efficacious therapy for severe pulmonary arterial hypertension.” The authors noted limitations imposed by the small sample size, large data heterogeneity, and medium-quality literature. Larger randomized, controlled trials with clinical endpoints comparing PADN with optimal medical therapy are needed, they stated.
 

References

1. Shah AJ et al. New Drugs and Therapies in Pulmonary Arterial Hypertension. Int J Mol Sci. 2023 Mar 19;24(6):5850. doi: 10.3390/ijms24065850. PMID: 36982922; PMCID: PMC10058689.

2. Kovacs G et al. Pulmonary Vascular Involvement in Chronic Obstructive Pulmonary Disease. Is There a Pulmonary Vascular Phenotype? Am J Respir Crit Care Med. 2018 Oct 15;198(8):1000-11. doi: 10.1164/rccm.201801-0095PP. PMID: 29746142.

In a letter dated Nov. 30, 2023, the Food and Drug Administration informed isotretinoin manufacturers that they have 6 months to make five changes to existing iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) requirements for the acne drug isotretinoin.

The development follows a March 2023 joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee about iPLEDGE REMS requirements, which included feedback from patients and dermatologists and recommendations for changes to the REMS program, aimed at minimizing the burden of the program on patients, pharmacies, and prescribers while continuing to maintain safe use of the highly teratogenic drug for patients.

The five changes include the following:

• Remove the requirement that pregnancy tests must be performed in a specially certified (i.e., Clinical Laboratory Improvement Amendments [CLIA]) laboratory. In the opinion of John S. Barbieri, MD, MBA, director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, this change “may make it easier to perform pregnancy tests in a clinic setting without needing to send the patient to a separate lab,” he said in an interview.
• Allow prescribers the option of using home pregnancy testing for their patients during and after isotretinoin treatment. Prescribers who rely on the patient to perform a home pregnancy test need to take steps to minimize patients falsifying the results of these tests. According to Dr. Barbieri, this means that two pregnancy tests prior to starting isotretinoin must be done in a lab or office setting. “However, all the pregnancy tests on therapy can be either in a medical setting or using a home pregnancy test,” he told this news organization. “This option facilitates the use of telemedicine so that patients would not need to come in; they can just share a pregnancy test with their name and date with their dermatologist.”
• Remove the waiting period requirement — also known as the “19-day lockout” — for patients if they do not obtain isotretinoin within the first 7-day prescription window. According to Dr. Barbieri, this change helps to ensure that patients can begin isotretinoin in a timely manner. “Insurance and pharmacy delays that are no fault of the patient can commonly cause missed initial window periods,” he said. “Allowing for immediate repeat of a pregnancy test to start a new window period, rather than requiring the patient to wait 19 more days, can ensure patient safety and pregnancy prevention without negatively impacting access.”
• Revise the pregnancy registry requirement to remove the objective to document the pregnancy and fetal outcomes for each pregnancy.
• Revise the requirement for prescribers to document patient counseling in patients who cannot become pregnant from monthly to only at enrollment. Dr. Barbieri characterized this change as “major” and said that it could eliminate the need for monthly visits for persons of non–childbearing potential. “This could substantially reduce logistical burdens for patients and reduce wait times to see a dermatologist,” he said.

Future changes to iPLEDGE that Dr. Barbieri would like to see include allowing for home pregnancy tests prior to starting therapy — particularly the test after the 30-day window period. “In addition, it would be good to be able to reduce the 30-day waiting period prior to therapy to something shorter,” such as 14 days, which would still “reliably exclude pregnancy, particularly for those on stable long-acting reversible contraception,” he said. There are also opportunities to improve the iPLEDGE website functionality and to ensure that the website is accessible to patients with limited English proficiency, he added.

He also recommended greater transparency by the Isotretinoin Products Manufacturers Group and inclusion of input from diverse stakeholders such as dermatologists, patients, and pharmacists.

Dr. Barbieri reported personal fees from Dexcel Pharma.

In a letter dated Nov. 30, 2023, the Food and Drug Administration informed isotretinoin manufacturers that they have 6 months to make five changes to existing iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) requirements for the acne drug isotretinoin.

The development follows a March 2023 joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee about iPLEDGE REMS requirements, which included feedback from patients and dermatologists and recommendations for changes to the REMS program, aimed at minimizing the burden of the program on patients, pharmacies, and prescribers while continuing to maintain safe use of the highly teratogenic drug for patients.

The five changes include the following:

• Remove the requirement that pregnancy tests must be performed in a specially certified (i.e., Clinical Laboratory Improvement Amendments [CLIA]) laboratory. In the opinion of John S. Barbieri, MD, MBA, director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, this change “may make it easier to perform pregnancy tests in a clinic setting without needing to send the patient to a separate lab,” he said in an interview.
• Allow prescribers the option of using home pregnancy testing for their patients during and after isotretinoin treatment. Prescribers who rely on the patient to perform a home pregnancy test need to take steps to minimize patients falsifying the results of these tests. According to Dr. Barbieri, this means that two pregnancy tests prior to starting isotretinoin must be done in a lab or office setting. “However, all the pregnancy tests on therapy can be either in a medical setting or using a home pregnancy test,” he told this news organization. “This option facilitates the use of telemedicine so that patients would not need to come in; they can just share a pregnancy test with their name and date with their dermatologist.”
• Remove the waiting period requirement — also known as the “19-day lockout” — for patients if they do not obtain isotretinoin within the first 7-day prescription window. According to Dr. Barbieri, this change helps to ensure that patients can begin isotretinoin in a timely manner. “Insurance and pharmacy delays that are no fault of the patient can commonly cause missed initial window periods,” he said. “Allowing for immediate repeat of a pregnancy test to start a new window period, rather than requiring the patient to wait 19 more days, can ensure patient safety and pregnancy prevention without negatively impacting access.”
• Revise the pregnancy registry requirement to remove the objective to document the pregnancy and fetal outcomes for each pregnancy.
• Revise the requirement for prescribers to document patient counseling in patients who cannot become pregnant from monthly to only at enrollment. Dr. Barbieri characterized this change as “major” and said that it could eliminate the need for monthly visits for persons of non–childbearing potential. “This could substantially reduce logistical burdens for patients and reduce wait times to see a dermatologist,” he said.

Future changes to iPLEDGE that Dr. Barbieri would like to see include allowing for home pregnancy tests prior to starting therapy — particularly the test after the 30-day window period. “In addition, it would be good to be able to reduce the 30-day waiting period prior to therapy to something shorter,” such as 14 days, which would still “reliably exclude pregnancy, particularly for those on stable long-acting reversible contraception,” he said. There are also opportunities to improve the iPLEDGE website functionality and to ensure that the website is accessible to patients with limited English proficiency, he added.

He also recommended greater transparency by the Isotretinoin Products Manufacturers Group and inclusion of input from diverse stakeholders such as dermatologists, patients, and pharmacists.

Dr. Barbieri reported personal fees from Dexcel Pharma.

In a letter dated Nov. 30, 2023, the Food and Drug Administration informed isotretinoin manufacturers that they have 6 months to make five changes to existing iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) requirements for the acne drug isotretinoin.

The development follows a March 2023 joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee about iPLEDGE REMS requirements, which included feedback from patients and dermatologists and recommendations for changes to the REMS program, aimed at minimizing the burden of the program on patients, pharmacies, and prescribers while continuing to maintain safe use of the highly teratogenic drug for patients.

The five changes include the following:

• Remove the requirement that pregnancy tests must be performed in a specially certified (i.e., Clinical Laboratory Improvement Amendments [CLIA]) laboratory. In the opinion of John S. Barbieri, MD, MBA, director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, this change “may make it easier to perform pregnancy tests in a clinic setting without needing to send the patient to a separate lab,” he said in an interview.
• Allow prescribers the option of using home pregnancy testing for their patients during and after isotretinoin treatment. Prescribers who rely on the patient to perform a home pregnancy test need to take steps to minimize patients falsifying the results of these tests. According to Dr. Barbieri, this means that two pregnancy tests prior to starting isotretinoin must be done in a lab or office setting. “However, all the pregnancy tests on therapy can be either in a medical setting or using a home pregnancy test,” he told this news organization. “This option facilitates the use of telemedicine so that patients would not need to come in; they can just share a pregnancy test with their name and date with their dermatologist.”
• Remove the waiting period requirement — also known as the “19-day lockout” — for patients if they do not obtain isotretinoin within the first 7-day prescription window. According to Dr. Barbieri, this change helps to ensure that patients can begin isotretinoin in a timely manner. “Insurance and pharmacy delays that are no fault of the patient can commonly cause missed initial window periods,” he said. “Allowing for immediate repeat of a pregnancy test to start a new window period, rather than requiring the patient to wait 19 more days, can ensure patient safety and pregnancy prevention without negatively impacting access.”
• Revise the pregnancy registry requirement to remove the objective to document the pregnancy and fetal outcomes for each pregnancy.
• Revise the requirement for prescribers to document patient counseling in patients who cannot become pregnant from monthly to only at enrollment. Dr. Barbieri characterized this change as “major” and said that it could eliminate the need for monthly visits for persons of non–childbearing potential. “This could substantially reduce logistical burdens for patients and reduce wait times to see a dermatologist,” he said.

Future changes to iPLEDGE that Dr. Barbieri would like to see include allowing for home pregnancy tests prior to starting therapy — particularly the test after the 30-day window period. “In addition, it would be good to be able to reduce the 30-day waiting period prior to therapy to something shorter,” such as 14 days, which would still “reliably exclude pregnancy, particularly for those on stable long-acting reversible contraception,” he said. There are also opportunities to improve the iPLEDGE website functionality and to ensure that the website is accessible to patients with limited English proficiency, he added.

He also recommended greater transparency by the Isotretinoin Products Manufacturers Group and inclusion of input from diverse stakeholders such as dermatologists, patients, and pharmacists.

Dr. Barbieri reported personal fees from Dexcel Pharma.