Clinical Endocrinology News

LISBON – Efforts are underway to better identify which individuals with so-called “prediabetes” are at greatest risk for developing type 2 diabetes and subsequent complications, and therefore merit more intensive intervention.

“Prediabetes” is the term coined to refer to either “impaired fasting glucose (IFG)” or “impaired glucose tolerance (IGT),” both denoting levels of elevated glycemia that don’t meet the thresholds for diabetes. It’s a heterogeneous group overall, and despite its name, not everyone with prediabetes will progress to develop type 2 diabetes.

There have been major increases in prediabetes in the United States and globally over the past 2 decades, epidemiologist Elizabeth Selvin, PhD, said at the recent IDF World Diabetes Congress 2022.

She noted that the concept of “prediabetes” has been controversial, previously dubbed a “dubious diagnosis” and a “boon for Pharma” in a 2019 Science article.

Others have said it’s “not a medical condition” and that it’s “an artificial category with virtually zero clinical relevance” in a press statement issued for a 2014 BMJ article.

“I don’t agree with these statements entirely but I think they speak to the confusion and tremendous controversy around the concept of prediabetes ... I think instead of calling prediabetes a ‘dubious diagnosis’ we should think of it as an opportunity,” said Dr. Selvin, of Johns Hopkins University Bloomberg School of Public Health, Baltimore.

She proposes trying to home in on those with highest risk of developing type 2 diabetes, which she suggests could be achieved by using a combination of elevated fasting glucose and an elevated A1c, although she stresses that this isn’t in any official guidance.

With the appropriate definition, people who are truly at risk for progression to type 2 diabetes can be identified so that lifestyle factors and cardiovascular risk can be addressed, and weight loss efforts implemented.

“Prevention of weight gain is ... important. That message often gets lost. Even if we can’t get people to lose weight, preventing [further] weight gain is important,” she noted.

Asked to comment, Sue Kirkman, MD, told this news organization, “The term prediabetes – or IFG or IGT or any of the ‘intermediate’ terms – is pragmatic in a way. It helps clinicians and patients understand that they are in a higher-risk category and might need intervention and likely need ongoing monitoring. But like many other risk factors [such as] blood pressure, [high] BMI, etc., the risk is not dichotomous but a continuum.

“People at the low end of the ‘intermediate’ range are not going to have much more risk compared to people who are ‘normal,’ while those at the high end of the range have very high risk,” said Dr. Kirkman, of the University of North Carolina, Chapel Hill, and a coauthor of the American Diabetes Association’s diabetes and prediabetes classifications.

“So we lose information if we just lump everyone into a single category. For individual patients, we definitely need better ways to estimate and communicate their potential risk.”


 

Currently five definitions for prediabetes: Home in on risk

The problem, Dr. Selvin explained, is that currently there are five official definitions for “prediabetes” using cutoffs for hemoglobin A1c, fasting glucose, or an oral glucose tolerance test.

Each one identifies different numbers of people with differing risk levels, ranging from a prevalence of 4.3% of the middle-aged adult population with the International Expert Committee’s definition of A1c 6.0%-6.4% to 43.5% with the American Diabetes Association’s 100-125 mg/dL fasting glucose.

“That’s an enormous difference. No wonder people are confused about who has prediabetes and what we should do about it,” Dr. Selvin said, adding that the concern about overdiagnosing “prediabetes” is even greater for older populations, in whom “it’s incredibly common to have mildly elevated glucose.”  

Hence her proposal of what she sees as an evidence-based, “really easy solution” that clinicians can use now to better identify which patients with “intermediate hyperglycemia” to be most concerned about: Use a combination of fasting glucose above 100 mg/dL and an A1c greater than 5.7%.

“If you have both fasting glucose and hemoglobin A1c, you can use them together ... This is not codified in any guidelines. You won’t see this mentioned anywhere. The guidelines are silent on what to do when some people have an elevated fasting glucose but not an elevated A1c ... but I think a simple message is that if people have both an elevated fasting glucose and an elevated A1c, that’s a very high-risk group,” she said.

On the other hand, Dr. Kirkman pointed out, “most discrepancies are near the margins, as in one test is slightly elevated and one isn’t, so those people probably are at low risk.

“It may be that both being elevated means higher risk because they have more hyperglycemia ... so it seems reasonable, but only if it changes what you tell people.”

For example, Dr. Kirkman said, “I’d tell someone with A1c of 5.8% and fasting glucose of 99 mg/dL the same thing I’d tell someone with that A1c and a glucose of 104 mg/dL – that their risk is still pretty low – and I’d recommend healthy lifestyle and weight loss if overweight either way.”

However, she also said, “Certainly people with higher glucose or A1c are at much higher risk, and same for those with both.”
 

Tie “prediabetes” definition to risk, as cardiology scores do?

Dr. Selvin also believes that risk-based definitions of prediabetes are needed. Ideally, these would incorporate demographics and clinical factors such as age and body mass index. Other biomarkers could potentially be developed and validated for inclusion in the definition, such as C-reactive protein (CRP), lipids, or even genetic/proteomic information.  

Moreover, she thinks that the definition should be tied to clinical decision-making, as is the pooled cohort equation in cardiology.

“I think we could do something very similar in prediabetes,” she suggested, adding that even simply incorporating age and BMI into the definition could help further stratify the risk level until other predictors are validated.

Dr. Kirkman said, “The concept of risk scores a la cardiology is interesting, although we’d have to make them simple and also validate them against some outcome.”

Regarding the age issue, Dr. Kirkman noted that although age wasn’t a predictor of progression to type 2 diabetes in the placebo arm of the landmark Diabetes Prevention Program (DPP) trial, “I do agree that it’s a problem that many older folks have the label of prediabetes because of a mildly elevated A1c and we know that most will never get diabetes.”

And, she noted, in the DPP people with prediabetes who had a BMI over 35 kg/m² did have significantly higher progression rates than those with lower BMI, while women with a history of gestational diabetes mellitus are also known to be at particularly high risk.
 

Whom should we throw the kitchen sink at?

Some of this discussion, Dr. Kirkman said, “is really a philosophical one, especially when you consider that lifestyle intervention has benefits for almost everyone on many short- and long-term outcomes.”

“The question is probably whom we should ‘throw the kitchen sink at,’ who should get more scalable advice that might apply to everyone regardless of glycemic levels, and whether there’s some more intermediate group that needs more of a [National Diabetes Prevention Program] approach.”

Dr. Selvin’s group is now working on gathering data to inform development of a risk-based prediabetes definition. “We have a whole research effort in this area. I hope that with some really strong data on risk in prediabetes, that can help to solve the heterogeneity issue. I’m focused on bringing evidence to bear to change the guidelines.”

In the meantime, she told this news organization, “I think there are things we can do now to provide more guidance. I get a lot of feedback from people saying things like ‘my physician told me I have prediabetes but now I don’t’ or ‘I saw in my labs that my blood sugar is elevated but my doctor never said anything.’  That’s a communications issue where we can do a better job.”

The meeting was sponsored by the International Diabetes Federation.

Dr. Selvin is deputy editor of Diabetes Care and on the editorial board of Diabetologia. She receives funding from the NIH and the Foundation for the NIH, and royalties from UpToDate for sections related to screening, diagnosis, and laboratory testing for diabetes. Dr. Kirkman reports no relevant financial relationships.

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

LISBON – Efforts are underway to better identify which individuals with so-called “prediabetes” are at greatest risk for developing type 2 diabetes and subsequent complications, and therefore merit more intensive intervention.

“Prediabetes” is the term coined to refer to either “impaired fasting glucose (IFG)” or “impaired glucose tolerance (IGT),” both denoting levels of elevated glycemia that don’t meet the thresholds for diabetes. It’s a heterogeneous group overall, and despite its name, not everyone with prediabetes will progress to develop type 2 diabetes.

There have been major increases in prediabetes in the United States and globally over the past 2 decades, epidemiologist Elizabeth Selvin, PhD, said at the recent IDF World Diabetes Congress 2022.

She noted that the concept of “prediabetes” has been controversial, previously dubbed a “dubious diagnosis” and a “boon for Pharma” in a 2019 Science article.

Others have said it’s “not a medical condition” and that it’s “an artificial category with virtually zero clinical relevance” in a press statement issued for a 2014 BMJ article.

“I don’t agree with these statements entirely but I think they speak to the confusion and tremendous controversy around the concept of prediabetes ... I think instead of calling prediabetes a ‘dubious diagnosis’ we should think of it as an opportunity,” said Dr. Selvin, of Johns Hopkins University Bloomberg School of Public Health, Baltimore.

She proposes trying to home in on those with highest risk of developing type 2 diabetes, which she suggests could be achieved by using a combination of elevated fasting glucose and an elevated A1c, although she stresses that this isn’t in any official guidance.

With the appropriate definition, people who are truly at risk for progression to type 2 diabetes can be identified so that lifestyle factors and cardiovascular risk can be addressed, and weight loss efforts implemented.

“Prevention of weight gain is ... important. That message often gets lost. Even if we can’t get people to lose weight, preventing [further] weight gain is important,” she noted.

Asked to comment, Sue Kirkman, MD, told this news organization, “The term prediabetes – or IFG or IGT or any of the ‘intermediate’ terms – is pragmatic in a way. It helps clinicians and patients understand that they are in a higher-risk category and might need intervention and likely need ongoing monitoring. But like many other risk factors [such as] blood pressure, [high] BMI, etc., the risk is not dichotomous but a continuum.

“People at the low end of the ‘intermediate’ range are not going to have much more risk compared to people who are ‘normal,’ while those at the high end of the range have very high risk,” said Dr. Kirkman, of the University of North Carolina, Chapel Hill, and a coauthor of the American Diabetes Association’s diabetes and prediabetes classifications.

“So we lose information if we just lump everyone into a single category. For individual patients, we definitely need better ways to estimate and communicate their potential risk.”


 

Currently five definitions for prediabetes: Home in on risk

The problem, Dr. Selvin explained, is that currently there are five official definitions for “prediabetes” using cutoffs for hemoglobin A1c, fasting glucose, or an oral glucose tolerance test.

Each one identifies different numbers of people with differing risk levels, ranging from a prevalence of 4.3% of the middle-aged adult population with the International Expert Committee’s definition of A1c 6.0%-6.4% to 43.5% with the American Diabetes Association’s 100-125 mg/dL fasting glucose.

“That’s an enormous difference. No wonder people are confused about who has prediabetes and what we should do about it,” Dr. Selvin said, adding that the concern about overdiagnosing “prediabetes” is even greater for older populations, in whom “it’s incredibly common to have mildly elevated glucose.”  

Hence her proposal of what she sees as an evidence-based, “really easy solution” that clinicians can use now to better identify which patients with “intermediate hyperglycemia” to be most concerned about: Use a combination of fasting glucose above 100 mg/dL and an A1c greater than 5.7%.

“If you have both fasting glucose and hemoglobin A1c, you can use them together ... This is not codified in any guidelines. You won’t see this mentioned anywhere. The guidelines are silent on what to do when some people have an elevated fasting glucose but not an elevated A1c ... but I think a simple message is that if people have both an elevated fasting glucose and an elevated A1c, that’s a very high-risk group,” she said.

On the other hand, Dr. Kirkman pointed out, “most discrepancies are near the margins, as in one test is slightly elevated and one isn’t, so those people probably are at low risk.

“It may be that both being elevated means higher risk because they have more hyperglycemia ... so it seems reasonable, but only if it changes what you tell people.”

For example, Dr. Kirkman said, “I’d tell someone with A1c of 5.8% and fasting glucose of 99 mg/dL the same thing I’d tell someone with that A1c and a glucose of 104 mg/dL – that their risk is still pretty low – and I’d recommend healthy lifestyle and weight loss if overweight either way.”

However, she also said, “Certainly people with higher glucose or A1c are at much higher risk, and same for those with both.”
 

Tie “prediabetes” definition to risk, as cardiology scores do?

Dr. Selvin also believes that risk-based definitions of prediabetes are needed. Ideally, these would incorporate demographics and clinical factors such as age and body mass index. Other biomarkers could potentially be developed and validated for inclusion in the definition, such as C-reactive protein (CRP), lipids, or even genetic/proteomic information.  

Moreover, she thinks that the definition should be tied to clinical decision-making, as is the pooled cohort equation in cardiology.

“I think we could do something very similar in prediabetes,” she suggested, adding that even simply incorporating age and BMI into the definition could help further stratify the risk level until other predictors are validated.

Dr. Kirkman said, “The concept of risk scores a la cardiology is interesting, although we’d have to make them simple and also validate them against some outcome.”

Regarding the age issue, Dr. Kirkman noted that although age wasn’t a predictor of progression to type 2 diabetes in the placebo arm of the landmark Diabetes Prevention Program (DPP) trial, “I do agree that it’s a problem that many older folks have the label of prediabetes because of a mildly elevated A1c and we know that most will never get diabetes.”

And, she noted, in the DPP people with prediabetes who had a BMI over 35 kg/m² did have significantly higher progression rates than those with lower BMI, while women with a history of gestational diabetes mellitus are also known to be at particularly high risk.
 

Whom should we throw the kitchen sink at?

Some of this discussion, Dr. Kirkman said, “is really a philosophical one, especially when you consider that lifestyle intervention has benefits for almost everyone on many short- and long-term outcomes.”

“The question is probably whom we should ‘throw the kitchen sink at,’ who should get more scalable advice that might apply to everyone regardless of glycemic levels, and whether there’s some more intermediate group that needs more of a [National Diabetes Prevention Program] approach.”

Dr. Selvin’s group is now working on gathering data to inform development of a risk-based prediabetes definition. “We have a whole research effort in this area. I hope that with some really strong data on risk in prediabetes, that can help to solve the heterogeneity issue. I’m focused on bringing evidence to bear to change the guidelines.”

In the meantime, she told this news organization, “I think there are things we can do now to provide more guidance. I get a lot of feedback from people saying things like ‘my physician told me I have prediabetes but now I don’t’ or ‘I saw in my labs that my blood sugar is elevated but my doctor never said anything.’  That’s a communications issue where we can do a better job.”

The meeting was sponsored by the International Diabetes Federation.

Dr. Selvin is deputy editor of Diabetes Care and on the editorial board of Diabetologia. She receives funding from the NIH and the Foundation for the NIH, and royalties from UpToDate for sections related to screening, diagnosis, and laboratory testing for diabetes. Dr. Kirkman reports no relevant financial relationships.

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

LISBON – Efforts are underway to better identify which individuals with so-called “prediabetes” are at greatest risk for developing type 2 diabetes and subsequent complications, and therefore merit more intensive intervention.

“Prediabetes” is the term coined to refer to either “impaired fasting glucose (IFG)” or “impaired glucose tolerance (IGT),” both denoting levels of elevated glycemia that don’t meet the thresholds for diabetes. It’s a heterogeneous group overall, and despite its name, not everyone with prediabetes will progress to develop type 2 diabetes.

There have been major increases in prediabetes in the United States and globally over the past 2 decades, epidemiologist Elizabeth Selvin, PhD, said at the recent IDF World Diabetes Congress 2022.

She noted that the concept of “prediabetes” has been controversial, previously dubbed a “dubious diagnosis” and a “boon for Pharma” in a 2019 Science article.

Others have said it’s “not a medical condition” and that it’s “an artificial category with virtually zero clinical relevance” in a press statement issued for a 2014 BMJ article.

“I don’t agree with these statements entirely but I think they speak to the confusion and tremendous controversy around the concept of prediabetes ... I think instead of calling prediabetes a ‘dubious diagnosis’ we should think of it as an opportunity,” said Dr. Selvin, of Johns Hopkins University Bloomberg School of Public Health, Baltimore.

She proposes trying to home in on those with highest risk of developing type 2 diabetes, which she suggests could be achieved by using a combination of elevated fasting glucose and an elevated A1c, although she stresses that this isn’t in any official guidance.

With the appropriate definition, people who are truly at risk for progression to type 2 diabetes can be identified so that lifestyle factors and cardiovascular risk can be addressed, and weight loss efforts implemented.

“Prevention of weight gain is ... important. That message often gets lost. Even if we can’t get people to lose weight, preventing [further] weight gain is important,” she noted.

Asked to comment, Sue Kirkman, MD, told this news organization, “The term prediabetes – or IFG or IGT or any of the ‘intermediate’ terms – is pragmatic in a way. It helps clinicians and patients understand that they are in a higher-risk category and might need intervention and likely need ongoing monitoring. But like many other risk factors [such as] blood pressure, [high] BMI, etc., the risk is not dichotomous but a continuum.

“People at the low end of the ‘intermediate’ range are not going to have much more risk compared to people who are ‘normal,’ while those at the high end of the range have very high risk,” said Dr. Kirkman, of the University of North Carolina, Chapel Hill, and a coauthor of the American Diabetes Association’s diabetes and prediabetes classifications.

“So we lose information if we just lump everyone into a single category. For individual patients, we definitely need better ways to estimate and communicate their potential risk.”


 

Currently five definitions for prediabetes: Home in on risk

The problem, Dr. Selvin explained, is that currently there are five official definitions for “prediabetes” using cutoffs for hemoglobin A1c, fasting glucose, or an oral glucose tolerance test.

Each one identifies different numbers of people with differing risk levels, ranging from a prevalence of 4.3% of the middle-aged adult population with the International Expert Committee’s definition of A1c 6.0%-6.4% to 43.5% with the American Diabetes Association’s 100-125 mg/dL fasting glucose.

“That’s an enormous difference. No wonder people are confused about who has prediabetes and what we should do about it,” Dr. Selvin said, adding that the concern about overdiagnosing “prediabetes” is even greater for older populations, in whom “it’s incredibly common to have mildly elevated glucose.”  

Hence her proposal of what she sees as an evidence-based, “really easy solution” that clinicians can use now to better identify which patients with “intermediate hyperglycemia” to be most concerned about: Use a combination of fasting glucose above 100 mg/dL and an A1c greater than 5.7%.

“If you have both fasting glucose and hemoglobin A1c, you can use them together ... This is not codified in any guidelines. You won’t see this mentioned anywhere. The guidelines are silent on what to do when some people have an elevated fasting glucose but not an elevated A1c ... but I think a simple message is that if people have both an elevated fasting glucose and an elevated A1c, that’s a very high-risk group,” she said.

On the other hand, Dr. Kirkman pointed out, “most discrepancies are near the margins, as in one test is slightly elevated and one isn’t, so those people probably are at low risk.

“It may be that both being elevated means higher risk because they have more hyperglycemia ... so it seems reasonable, but only if it changes what you tell people.”

For example, Dr. Kirkman said, “I’d tell someone with A1c of 5.8% and fasting glucose of 99 mg/dL the same thing I’d tell someone with that A1c and a glucose of 104 mg/dL – that their risk is still pretty low – and I’d recommend healthy lifestyle and weight loss if overweight either way.”

However, she also said, “Certainly people with higher glucose or A1c are at much higher risk, and same for those with both.”
 

Tie “prediabetes” definition to risk, as cardiology scores do?

Dr. Selvin also believes that risk-based definitions of prediabetes are needed. Ideally, these would incorporate demographics and clinical factors such as age and body mass index. Other biomarkers could potentially be developed and validated for inclusion in the definition, such as C-reactive protein (CRP), lipids, or even genetic/proteomic information.  

Moreover, she thinks that the definition should be tied to clinical decision-making, as is the pooled cohort equation in cardiology.

“I think we could do something very similar in prediabetes,” she suggested, adding that even simply incorporating age and BMI into the definition could help further stratify the risk level until other predictors are validated.

Dr. Kirkman said, “The concept of risk scores a la cardiology is interesting, although we’d have to make them simple and also validate them against some outcome.”

Regarding the age issue, Dr. Kirkman noted that although age wasn’t a predictor of progression to type 2 diabetes in the placebo arm of the landmark Diabetes Prevention Program (DPP) trial, “I do agree that it’s a problem that many older folks have the label of prediabetes because of a mildly elevated A1c and we know that most will never get diabetes.”

And, she noted, in the DPP people with prediabetes who had a BMI over 35 kg/m² did have significantly higher progression rates than those with lower BMI, while women with a history of gestational diabetes mellitus are also known to be at particularly high risk.
 

Whom should we throw the kitchen sink at?

Some of this discussion, Dr. Kirkman said, “is really a philosophical one, especially when you consider that lifestyle intervention has benefits for almost everyone on many short- and long-term outcomes.”

“The question is probably whom we should ‘throw the kitchen sink at,’ who should get more scalable advice that might apply to everyone regardless of glycemic levels, and whether there’s some more intermediate group that needs more of a [National Diabetes Prevention Program] approach.”

Dr. Selvin’s group is now working on gathering data to inform development of a risk-based prediabetes definition. “We have a whole research effort in this area. I hope that with some really strong data on risk in prediabetes, that can help to solve the heterogeneity issue. I’m focused on bringing evidence to bear to change the guidelines.”

In the meantime, she told this news organization, “I think there are things we can do now to provide more guidance. I get a lot of feedback from people saying things like ‘my physician told me I have prediabetes but now I don’t’ or ‘I saw in my labs that my blood sugar is elevated but my doctor never said anything.’  That’s a communications issue where we can do a better job.”

The meeting was sponsored by the International Diabetes Federation.

Dr. Selvin is deputy editor of Diabetes Care and on the editorial board of Diabetologia. She receives funding from the NIH and the Foundation for the NIH, and royalties from UpToDate for sections related to screening, diagnosis, and laboratory testing for diabetes. Dr. Kirkman reports no relevant financial relationships.

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

For many years, it has been believed that the aging process is inevitable and that age-related diseases cannot be prevented or reversed. For example, the U.S. Food and Drug Administration does not recognize aging as an indication for drug approval because there are no markers to determine whether possible treatments have a significant impact on the hallmarks of aging.

The field of geroscience aims to find ways to change this by delaying the onset of age-related diseases or by extending the life span. On May 19, 2021, experts in geroscience met virtually at a symposium of the New York Academy of Sciences. Presentations and discussions with experts in the field showed that remarkable advances have been made in understanding the mechanisms underlying biological aging. Those mechanisms contribute to the vulnerability of older adults. The presentations focused on identifying biomarkers of aging and on the search for interventions to prevent and treat age-related diseases.

Perspectives from this meeting were published in a report.
 

An abridged glossary

• Senescent cells: These are old cells with irreversibly damaged DNA; they strongly resist apoptosis. Thus, they are not eliminated and continue to secrete pathogenic proinflammatory molecules.
• Senolytics: This is a class of compounds that promote the removal of senescent cells from the body.
• Autophagy: This is a process that promotes protein degradation, which is attenuated with aging and that impedes the aggregation of proteins harmful to cell function, particularly those of the central nervous system.
• Proteostasis: This is the dynamic regulation of protein homeostasis.
• Epigenetics: This is the field of biology that studies phenotype changes that are not caused by changes in DNA sequencing and that continue to affect cellular division.
• Metabolome: This refers to small molecules that make up the building blocks of all organismal features, from cell membranes to metabolic cycles to genes and proteins.
• Translational research: This involves applying primary research results to clinical research and vice versa.

Possible research topics

Senescence not only occurs with age but also drives aging. At the meeting, evidence was provided that senescent cells may exacerbate the clinical course of older adults in cases of infections (for example, COVID-19) as they lead to cytokine storms.

Experiments on old mice that have undergone genetic modification of senescent cells or the administration of “senolytic cocktails” composed of dasatinib plus quercetin protected the animals from the effects of viral infections. This finding corroborates the idea that factors involved in biological aging increase vulnerability and could be modified through treatment.

Alzheimer’s disease is an example of the effects of cellular senescence. Senescent cells develop a senescence-associated secretory phenotype that can be toxic to neighboring healthy cells and can allow senescence to propagate within tissues. This effect makes Alzheimer’s disease an essential focal point when studying the use of senolytics. In addition, agents that stimulate autophagy may be of interest for treating degenerative diseases.
 

Assessing therapeutic effects

It may be possible to assess the therapeutic effects of drug candidates using the following biomarkers.

• Growth hormone and type 1 insulin-like growth factor (IGF-1): Older adults are often prescribed growth hormone. However, recent data suggest that doing so is not advantageous to this patient population, because it antagonizes proteostasis and other cell maintenance mechanisms in older age. Experimental studies and studies conducted on centenarians suggest that low growth hormone and IGF-1 levels contribute to longevity and may be therapeutic biomarkers.
• Epigenetics: DNA methylation is a method that offers an “epigenetic clock” to compare biological age with chronologic age. Higher epigenetic age was associated with increased mortality risk, breast cancer, and nonalcoholic fatty liver disease. Therefore, it could also be a therapeutic biomarker.
• Metabolomics: Studying metabolomes facilitates the identification of the link between genetic polymorphisms and longevity, as most polymorphisms explain less than 0.5% of longevity variations.
• New translational strategy: It is common practice to treat each age-related disease individually. An alternative strategy would be to target the hallmarks of biological aging to prevent these diseases from developing. The rate of biological aging correlates with the speed of damage accumulation at the macromolecular, organelle, and cellular levels. It also affects the capacity of the body to repair this damage. The assessment of biomarkers would make possibile research into the effects of short- and long-term treatments that minimize damage and enhance resilience related to diseases common with aging.

New translational research

The report highlights two translational research models: the in-depth study of centenarians and the analysis of how immune aging makes older adults vulnerable to COVID-19. The impact of impaired immunity on aging became particularly evident during the pandemic. However, to home in on immunity as a therapeutic target and to better understand immune resilience, the specific nature of immune and biological deficits still need to be defined.

Metformin is among the therapeutic agents under investigation in cutting-edge clinical research. Its effect on aging will be studied in the Targeting Aging with Metformin (TAME) clinical trial. This trial is the first to study aging outcomes. The goal is to create a regulatory framework that future therapies can follow to achieve FDA approval.

There are three promising therapeutic platforms among the cutting-edge research studies. The first aims to produce adenosine triphosphate, levels of which decline dramatically with aging. The second aims to promote autophagy to remove cellular waste to treat neurodegenerative diseases. The third reprograms the epigenome to a younger state.

Research on mitochondrial dysfunction is relevant because it is highly involved in age-related diseases. Mitochondrial-derived peptides could potentially serve as biomarkers of mitochondrial function in aging studies and become promising therapeutic targets in age-related diseases. One of these peptides, humanin, has been demonstrated to exert protective effects on the heart, brain, and liver. Researchers observed that mitochondrial proteins are age-dependent and are suppressed by growth hormone and IGF-1. They also found that humanin levels are correlated with endothelial function. Data from animal studies have shown that sustained humanin levels are positively linked to longevity; these findings are mirrored in data from centenarians and their offspring, who have higher levels of humanin.

The formation of a Translational Geroscience Network composed of several scientists from various institutions should accelerate the application of this understanding. Despite the ongoing investigational and clinical studies, senolytics should not be regarded as extending life span or treating certain conditions, because their full safety profiles have not yet been elucidated.
 

Conclusion

Geroscience faces challenges in dealing with age-related problems. It is hoped that these challenges will be overcome through investigational and clinical studies on the mechanisms involved in aging. In-depth study of the interactions of underlying mechanisms of aging are needed to answer the following questions:

• Is there a hierarchical relationship among these mechanisms?
• Are there organ or cell-type differences in the interactions among these mechanisms?
• Is it possible to achieve a synergistic effect through combined interventions targeting several of the processes that drive aging?

It is complicated, but researchers are starting to see the light at the end of the tunnel.

This article was translated from the Medscape Portuguese edition and a version appeared on Medscape.com.

For many years, it has been believed that the aging process is inevitable and that age-related diseases cannot be prevented or reversed. For example, the U.S. Food and Drug Administration does not recognize aging as an indication for drug approval because there are no markers to determine whether possible treatments have a significant impact on the hallmarks of aging.

The field of geroscience aims to find ways to change this by delaying the onset of age-related diseases or by extending the life span. On May 19, 2021, experts in geroscience met virtually at a symposium of the New York Academy of Sciences. Presentations and discussions with experts in the field showed that remarkable advances have been made in understanding the mechanisms underlying biological aging. Those mechanisms contribute to the vulnerability of older adults. The presentations focused on identifying biomarkers of aging and on the search for interventions to prevent and treat age-related diseases.

Perspectives from this meeting were published in a report.
 

An abridged glossary

• Senescent cells: These are old cells with irreversibly damaged DNA; they strongly resist apoptosis. Thus, they are not eliminated and continue to secrete pathogenic proinflammatory molecules.
• Senolytics: This is a class of compounds that promote the removal of senescent cells from the body.
• Autophagy: This is a process that promotes protein degradation, which is attenuated with aging and that impedes the aggregation of proteins harmful to cell function, particularly those of the central nervous system.
• Proteostasis: This is the dynamic regulation of protein homeostasis.
• Epigenetics: This is the field of biology that studies phenotype changes that are not caused by changes in DNA sequencing and that continue to affect cellular division.
• Metabolome: This refers to small molecules that make up the building blocks of all organismal features, from cell membranes to metabolic cycles to genes and proteins.
• Translational research: This involves applying primary research results to clinical research and vice versa.

Possible research topics

Senescence not only occurs with age but also drives aging. At the meeting, evidence was provided that senescent cells may exacerbate the clinical course of older adults in cases of infections (for example, COVID-19) as they lead to cytokine storms.

Experiments on old mice that have undergone genetic modification of senescent cells or the administration of “senolytic cocktails” composed of dasatinib plus quercetin protected the animals from the effects of viral infections. This finding corroborates the idea that factors involved in biological aging increase vulnerability and could be modified through treatment.

Alzheimer’s disease is an example of the effects of cellular senescence. Senescent cells develop a senescence-associated secretory phenotype that can be toxic to neighboring healthy cells and can allow senescence to propagate within tissues. This effect makes Alzheimer’s disease an essential focal point when studying the use of senolytics. In addition, agents that stimulate autophagy may be of interest for treating degenerative diseases.
 

Assessing therapeutic effects

It may be possible to assess the therapeutic effects of drug candidates using the following biomarkers.

• Growth hormone and type 1 insulin-like growth factor (IGF-1): Older adults are often prescribed growth hormone. However, recent data suggest that doing so is not advantageous to this patient population, because it antagonizes proteostasis and other cell maintenance mechanisms in older age. Experimental studies and studies conducted on centenarians suggest that low growth hormone and IGF-1 levels contribute to longevity and may be therapeutic biomarkers.
• Epigenetics: DNA methylation is a method that offers an “epigenetic clock” to compare biological age with chronologic age. Higher epigenetic age was associated with increased mortality risk, breast cancer, and nonalcoholic fatty liver disease. Therefore, it could also be a therapeutic biomarker.
• Metabolomics: Studying metabolomes facilitates the identification of the link between genetic polymorphisms and longevity, as most polymorphisms explain less than 0.5% of longevity variations.
• New translational strategy: It is common practice to treat each age-related disease individually. An alternative strategy would be to target the hallmarks of biological aging to prevent these diseases from developing. The rate of biological aging correlates with the speed of damage accumulation at the macromolecular, organelle, and cellular levels. It also affects the capacity of the body to repair this damage. The assessment of biomarkers would make possibile research into the effects of short- and long-term treatments that minimize damage and enhance resilience related to diseases common with aging.

New translational research

The report highlights two translational research models: the in-depth study of centenarians and the analysis of how immune aging makes older adults vulnerable to COVID-19. The impact of impaired immunity on aging became particularly evident during the pandemic. However, to home in on immunity as a therapeutic target and to better understand immune resilience, the specific nature of immune and biological deficits still need to be defined.

Metformin is among the therapeutic agents under investigation in cutting-edge clinical research. Its effect on aging will be studied in the Targeting Aging with Metformin (TAME) clinical trial. This trial is the first to study aging outcomes. The goal is to create a regulatory framework that future therapies can follow to achieve FDA approval.

There are three promising therapeutic platforms among the cutting-edge research studies. The first aims to produce adenosine triphosphate, levels of which decline dramatically with aging. The second aims to promote autophagy to remove cellular waste to treat neurodegenerative diseases. The third reprograms the epigenome to a younger state.

Research on mitochondrial dysfunction is relevant because it is highly involved in age-related diseases. Mitochondrial-derived peptides could potentially serve as biomarkers of mitochondrial function in aging studies and become promising therapeutic targets in age-related diseases. One of these peptides, humanin, has been demonstrated to exert protective effects on the heart, brain, and liver. Researchers observed that mitochondrial proteins are age-dependent and are suppressed by growth hormone and IGF-1. They also found that humanin levels are correlated with endothelial function. Data from animal studies have shown that sustained humanin levels are positively linked to longevity; these findings are mirrored in data from centenarians and their offspring, who have higher levels of humanin.

The formation of a Translational Geroscience Network composed of several scientists from various institutions should accelerate the application of this understanding. Despite the ongoing investigational and clinical studies, senolytics should not be regarded as extending life span or treating certain conditions, because their full safety profiles have not yet been elucidated.
 

Conclusion

Geroscience faces challenges in dealing with age-related problems. It is hoped that these challenges will be overcome through investigational and clinical studies on the mechanisms involved in aging. In-depth study of the interactions of underlying mechanisms of aging are needed to answer the following questions:

• Is there a hierarchical relationship among these mechanisms?
• Are there organ or cell-type differences in the interactions among these mechanisms?
• Is it possible to achieve a synergistic effect through combined interventions targeting several of the processes that drive aging?

It is complicated, but researchers are starting to see the light at the end of the tunnel.

This article was translated from the Medscape Portuguese edition and a version appeared on Medscape.com.

For many years, it has been believed that the aging process is inevitable and that age-related diseases cannot be prevented or reversed. For example, the U.S. Food and Drug Administration does not recognize aging as an indication for drug approval because there are no markers to determine whether possible treatments have a significant impact on the hallmarks of aging.

The field of geroscience aims to find ways to change this by delaying the onset of age-related diseases or by extending the life span. On May 19, 2021, experts in geroscience met virtually at a symposium of the New York Academy of Sciences. Presentations and discussions with experts in the field showed that remarkable advances have been made in understanding the mechanisms underlying biological aging. Those mechanisms contribute to the vulnerability of older adults. The presentations focused on identifying biomarkers of aging and on the search for interventions to prevent and treat age-related diseases.

Perspectives from this meeting were published in a report.
 

An abridged glossary

• Senescent cells: These are old cells with irreversibly damaged DNA; they strongly resist apoptosis. Thus, they are not eliminated and continue to secrete pathogenic proinflammatory molecules.
• Senolytics: This is a class of compounds that promote the removal of senescent cells from the body.
• Autophagy: This is a process that promotes protein degradation, which is attenuated with aging and that impedes the aggregation of proteins harmful to cell function, particularly those of the central nervous system.
• Proteostasis: This is the dynamic regulation of protein homeostasis.
• Epigenetics: This is the field of biology that studies phenotype changes that are not caused by changes in DNA sequencing and that continue to affect cellular division.
• Metabolome: This refers to small molecules that make up the building blocks of all organismal features, from cell membranes to metabolic cycles to genes and proteins.
• Translational research: This involves applying primary research results to clinical research and vice versa.

Possible research topics

Senescence not only occurs with age but also drives aging. At the meeting, evidence was provided that senescent cells may exacerbate the clinical course of older adults in cases of infections (for example, COVID-19) as they lead to cytokine storms.

Experiments on old mice that have undergone genetic modification of senescent cells or the administration of “senolytic cocktails” composed of dasatinib plus quercetin protected the animals from the effects of viral infections. This finding corroborates the idea that factors involved in biological aging increase vulnerability and could be modified through treatment.

Alzheimer’s disease is an example of the effects of cellular senescence. Senescent cells develop a senescence-associated secretory phenotype that can be toxic to neighboring healthy cells and can allow senescence to propagate within tissues. This effect makes Alzheimer’s disease an essential focal point when studying the use of senolytics. In addition, agents that stimulate autophagy may be of interest for treating degenerative diseases.
 

Assessing therapeutic effects

It may be possible to assess the therapeutic effects of drug candidates using the following biomarkers.

• Growth hormone and type 1 insulin-like growth factor (IGF-1): Older adults are often prescribed growth hormone. However, recent data suggest that doing so is not advantageous to this patient population, because it antagonizes proteostasis and other cell maintenance mechanisms in older age. Experimental studies and studies conducted on centenarians suggest that low growth hormone and IGF-1 levels contribute to longevity and may be therapeutic biomarkers.
• Epigenetics: DNA methylation is a method that offers an “epigenetic clock” to compare biological age with chronologic age. Higher epigenetic age was associated with increased mortality risk, breast cancer, and nonalcoholic fatty liver disease. Therefore, it could also be a therapeutic biomarker.
• Metabolomics: Studying metabolomes facilitates the identification of the link between genetic polymorphisms and longevity, as most polymorphisms explain less than 0.5% of longevity variations.
• New translational strategy: It is common practice to treat each age-related disease individually. An alternative strategy would be to target the hallmarks of biological aging to prevent these diseases from developing. The rate of biological aging correlates with the speed of damage accumulation at the macromolecular, organelle, and cellular levels. It also affects the capacity of the body to repair this damage. The assessment of biomarkers would make possibile research into the effects of short- and long-term treatments that minimize damage and enhance resilience related to diseases common with aging.

New translational research

The report highlights two translational research models: the in-depth study of centenarians and the analysis of how immune aging makes older adults vulnerable to COVID-19. The impact of impaired immunity on aging became particularly evident during the pandemic. However, to home in on immunity as a therapeutic target and to better understand immune resilience, the specific nature of immune and biological deficits still need to be defined.

Metformin is among the therapeutic agents under investigation in cutting-edge clinical research. Its effect on aging will be studied in the Targeting Aging with Metformin (TAME) clinical trial. This trial is the first to study aging outcomes. The goal is to create a regulatory framework that future therapies can follow to achieve FDA approval.

There are three promising therapeutic platforms among the cutting-edge research studies. The first aims to produce adenosine triphosphate, levels of which decline dramatically with aging. The second aims to promote autophagy to remove cellular waste to treat neurodegenerative diseases. The third reprograms the epigenome to a younger state.

Research on mitochondrial dysfunction is relevant because it is highly involved in age-related diseases. Mitochondrial-derived peptides could potentially serve as biomarkers of mitochondrial function in aging studies and become promising therapeutic targets in age-related diseases. One of these peptides, humanin, has been demonstrated to exert protective effects on the heart, brain, and liver. Researchers observed that mitochondrial proteins are age-dependent and are suppressed by growth hormone and IGF-1. They also found that humanin levels are correlated with endothelial function. Data from animal studies have shown that sustained humanin levels are positively linked to longevity; these findings are mirrored in data from centenarians and their offspring, who have higher levels of humanin.

The formation of a Translational Geroscience Network composed of several scientists from various institutions should accelerate the application of this understanding. Despite the ongoing investigational and clinical studies, senolytics should not be regarded as extending life span or treating certain conditions, because their full safety profiles have not yet been elucidated.
 

Conclusion

Geroscience faces challenges in dealing with age-related problems. It is hoped that these challenges will be overcome through investigational and clinical studies on the mechanisms involved in aging. In-depth study of the interactions of underlying mechanisms of aging are needed to answer the following questions:

• Is there a hierarchical relationship among these mechanisms?
• Are there organ or cell-type differences in the interactions among these mechanisms?
• Is it possible to achieve a synergistic effect through combined interventions targeting several of the processes that drive aging?

It is complicated, but researchers are starting to see the light at the end of the tunnel.

This article was translated from the Medscape Portuguese edition and a version appeared on Medscape.com.

The percentage of people in the U.S. getting the latest COVID-19 booster shot has crept up by single digits in the past couple months, despite health officials pleading for people to do so before the Christmas holiday. 

Now, a new poll shows why so few people are willing to roll up their sleeves again.

The most common reasons people give for not getting the latest booster shot is that they “don’t think they need one” (44%) and they “don’t think the benefits are worth it” (37%), according to poll results from the Kaiser Family Foundation. 

The data comes amid announcements by the Centers for Disease Control and Prevention that boosters reduced COVID-19 hospitalizations by up to 57% for U.S. adults and by up to 84% for people age 65 and older. Those figures are just the latest in a mountain of research reporting the public health benefits of COVID-19 vaccines.

Despite all of the statistical data, health officials’ recent vaccination campaigns have proven far from compelling. 

So far, just 15% of people age 12 and older have gotten the latest booster, and 36% of people age 65 and older have gotten it, the CDC’s vaccination trackershows.

Since the start of the pandemic, 1.1 million people in the U.S. have died from COVID-19, with the number of deaths currently rising by 400 per day, The New York Times COVID tracker shows.

Many experts continue to note the need for everyone to get booster shots regularly, but some advocate that perhaps a change in strategy is in order.

“What the administration should do is push for vaccinating people in high-risk groups, including those who are older, those who are immunocompromised and those who have comorbidities,” Paul Offitt, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, told CNN.

Federal regulators have announced they will meet Jan. 26 with a panel of vaccine advisors to examine the current recommended vaccination schedule as well as look at the effectiveness and composition of current vaccines and boosters, with an eye toward the make-up of next-generation shots.

Vaccines are the “best available protection” against hospitalization and death caused by COVID-19, said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in a statement announcing the planned meeting.

“Since the initial authorizations of these vaccines, we have learned that protection wanes over time, especially as the virus rapidly mutates and new variants and subvariants emerge,” he said. “Therefore, it’s important to continue discussions about the optimal composition of COVID-19 vaccines for primary and booster vaccination, as well as the optimal interval for booster vaccination.”

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

The percentage of people in the U.S. getting the latest COVID-19 booster shot has crept up by single digits in the past couple months, despite health officials pleading for people to do so before the Christmas holiday. 

Now, a new poll shows why so few people are willing to roll up their sleeves again.

The most common reasons people give for not getting the latest booster shot is that they “don’t think they need one” (44%) and they “don’t think the benefits are worth it” (37%), according to poll results from the Kaiser Family Foundation. 

The data comes amid announcements by the Centers for Disease Control and Prevention that boosters reduced COVID-19 hospitalizations by up to 57% for U.S. adults and by up to 84% for people age 65 and older. Those figures are just the latest in a mountain of research reporting the public health benefits of COVID-19 vaccines.

Despite all of the statistical data, health officials’ recent vaccination campaigns have proven far from compelling. 

So far, just 15% of people age 12 and older have gotten the latest booster, and 36% of people age 65 and older have gotten it, the CDC’s vaccination trackershows.

Since the start of the pandemic, 1.1 million people in the U.S. have died from COVID-19, with the number of deaths currently rising by 400 per day, The New York Times COVID tracker shows.

Many experts continue to note the need for everyone to get booster shots regularly, but some advocate that perhaps a change in strategy is in order.

“What the administration should do is push for vaccinating people in high-risk groups, including those who are older, those who are immunocompromised and those who have comorbidities,” Paul Offitt, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, told CNN.

Federal regulators have announced they will meet Jan. 26 with a panel of vaccine advisors to examine the current recommended vaccination schedule as well as look at the effectiveness and composition of current vaccines and boosters, with an eye toward the make-up of next-generation shots.

Vaccines are the “best available protection” against hospitalization and death caused by COVID-19, said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in a statement announcing the planned meeting.

“Since the initial authorizations of these vaccines, we have learned that protection wanes over time, especially as the virus rapidly mutates and new variants and subvariants emerge,” he said. “Therefore, it’s important to continue discussions about the optimal composition of COVID-19 vaccines for primary and booster vaccination, as well as the optimal interval for booster vaccination.”

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

The percentage of people in the U.S. getting the latest COVID-19 booster shot has crept up by single digits in the past couple months, despite health officials pleading for people to do so before the Christmas holiday. 

Now, a new poll shows why so few people are willing to roll up their sleeves again.

The most common reasons people give for not getting the latest booster shot is that they “don’t think they need one” (44%) and they “don’t think the benefits are worth it” (37%), according to poll results from the Kaiser Family Foundation. 

The data comes amid announcements by the Centers for Disease Control and Prevention that boosters reduced COVID-19 hospitalizations by up to 57% for U.S. adults and by up to 84% for people age 65 and older. Those figures are just the latest in a mountain of research reporting the public health benefits of COVID-19 vaccines.

Despite all of the statistical data, health officials’ recent vaccination campaigns have proven far from compelling. 

So far, just 15% of people age 12 and older have gotten the latest booster, and 36% of people age 65 and older have gotten it, the CDC’s vaccination trackershows.

Since the start of the pandemic, 1.1 million people in the U.S. have died from COVID-19, with the number of deaths currently rising by 400 per day, The New York Times COVID tracker shows.

Many experts continue to note the need for everyone to get booster shots regularly, but some advocate that perhaps a change in strategy is in order.

“What the administration should do is push for vaccinating people in high-risk groups, including those who are older, those who are immunocompromised and those who have comorbidities,” Paul Offitt, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, told CNN.

Federal regulators have announced they will meet Jan. 26 with a panel of vaccine advisors to examine the current recommended vaccination schedule as well as look at the effectiveness and composition of current vaccines and boosters, with an eye toward the make-up of next-generation shots.

Vaccines are the “best available protection” against hospitalization and death caused by COVID-19, said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in a statement announcing the planned meeting.

“Since the initial authorizations of these vaccines, we have learned that protection wanes over time, especially as the virus rapidly mutates and new variants and subvariants emerge,” he said. “Therefore, it’s important to continue discussions about the optimal composition of COVID-19 vaccines for primary and booster vaccination, as well as the optimal interval for booster vaccination.”

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

“I could relate to many, many, many of the experiences and emotions that Charlie, which is Brendan Fraser’s character, was portraying,” Patricia Nece recalls after watching a preview copy of the new film “The Whale.”

A24

Much of the movie “rang true and hit home for me as things that I, too, had experienced,” Ms. Nece, the board of directors’ chair of the Obesity Action Coalition (OAC) and a person living with obesity, shares with this news organization.

In theaters as of December 9, The Whale chronicles the experience of a 600-lb, middle-aged man named Charlie. Throughout the film, Charlie seeks to rebuild his relationship with his estranged teenage daughter. Charlie had left his daughter and family to pursue a relationship with a man, who eventually died. As he navigates the pain surrounding his partner’s death and his lack of community, Charlie turns to food for comfort.

When the movie premiered at the Venice Film Festival, Mr. Fraser received a 6-minute standing ovation. However, activists criticized the movie for casting Fraser over an actor with obesity as well as its depiction of people with obesity.

Representatives from the National Association to Advance Fat Acceptance contend that casting an actor without obesity only contributes to ongoing bias against people of size. “Medical weight stigma and other socio-political determinants of health for people of all sizes cause far more harm to fat people than body fat does. Bias endangers fat people’s health. Anti-obesity organizations, such as those consulted with for this movie, contribute to stigma rather than reducing it as they claim,” NAAFA wrote in a statement to this news organization.

And they added that though the fat suit used in the movie may be superior to previous ones, it is still not an accurate depiction: “The creators of The Whale consider its CGI-generated fat suit to be superior to tactile fat suits, but we don’t. The issue with fat suits in Hollywood is not that they aren’t realistic enough. The issue is that they are used rather than using performers who actually live in bodies like the ones being depicted. If there is a 600-pound character in a movie, there should be a 600-pound human in that role. Rather than concentrate on the hype around the fake fat body created for The Whale, we want to see Hollywood create more opportunities for fat people across the size spectrum, both in front of the camera and behind the scenes.”
 

Prosthetics vs. reality?

Ms. Nece says she understands the controversy surrounding the use of fat suits but believes that it was not done in poor taste.

“OAC got involved with the movie after Brendan was already chosen for the part, and we never would have gotten involved with it had the prosthetics or fat suit been used to ridicule or make fun of people with obesity, which is usually the case,” she explains.

“But we knew from the start that that was never the intent of anyone involved with The Whale. And I think that’s shown by the fact that Brendan and Darren Aronofsky, the director, reached out to people who live with obesity on a daily basis to find out and learn more about it and to educate themselves about it,” Ms. Nece continues.

In a Daily Mail article, Mr. Fraser credited his son Griffin, who is autistic and obese, with helping him understand the struggles that people with obesity face.

Rachel Goldman, PhD, a clinical psychologist in private practice in New York and a professor in the psychology department at New York University, notes that there are other considerations that played into casting. “I know there was some pushback in terms of could, a say 600-lb individual, even be able to go to be on set every day and do this kind of work, and the answer is we don’t know.”

“I’m sure Darren chose Brendan for many reasons above and beyond just his body. I think that’s very important to keep in mind that just as much as representation is very important, I think it is also about finding the right person for the right role,” adds Dr. Goldman, who served as a consultant to the film.
 

Fat suits, extreme weight gains all to play a role

About 42% of adults in the United States have obesity, according to the 2017-2020 National Health and Nutrition Examination Survey, but that reality is not reflected in films or television.

A study of 1018 major television characters found that 24% of men and 14% of women had either overweight or obesity – far below the national average. And when characters with obesity are portrayed, actors often wear prosthetics, like Gwyneth Paltrow in Shallow Hal or Eddie Murphy in the Nutty Professor.

But unlike Mr. Fraser, some actors gain weight quickly instead.

This practice is unhealthy, says Jaime Almandoz, MD, an associate professor at the University of Texas Southwestern Medical Center, Dallas, and a nonsurgical weight management expert. In interviews, actors have shared how they increased calorie intake by drinking two milkshakes per day, going to fast food places regularly, or, in Mark Walhberg’s case, consuming 7,000 calories per day to gain 30 pounds for his role as boxer-turned-priest in the movie Father Stu.

This method provides their bodies with excess calories they are unable to burn off. “Then the amount of sugar and fat that streams into the blood as a result creates problems both directly and indirectly as your body tries to store it. It basically ends up using overflow warehouses for fat storage, like the liver for example, so we can create a condition called fatty liver, or in the muscle and other places, and this excess sugar and fat in the bloodstream cause several factors that are both insulin resistance causing,” Dr. Almandoz explains.

Though gaining weight helps the actor understand the character’s life experience, it may also be risky.

“To have an actor deliberately put his own health at risk and gain a certain amount of weight and whatever that might entail, one – that’s not necessarily the safest thing for that actor – but two, it’s also important to highlight the authentic experience of someone who has dealt with this chronic disease as well,” says Disha Narang, MD, a quadruple-board certified endocrinologist, obesity medicine, and culinary medicine specialist at Northwestern Medicine Lake Forest Hospital, Chicago.

These extreme fluctuations in weight may create problems. “It is typically not something we recommend because there could be metabolic damages as well as health concerns when patients are trying to gain weight quickly, just as we don’t want patients to lose weight quickly,” says Kurt Hong, MD, PhD, board-certified in internal medicine and clinical nutrition at the University of Southern California, Los Angeles.

Dr. Hong notes that it may be difficult for individuals to experience sudden weight gain because the body works hard to maintain a state of homeostasis.

“Similarly, to someone trying to gain weight you overeat, initially your body will try to again, maybe enhance its metabolic efficiency to hold the body stable,” Dr. Hong adds.

Dietary choices that may contribute to insulin resistance or promote high blood sugar can contribute to inflammation and a number of other adverse health outcomes, notes Dr. Almandoz. “The things that actors need to do in order to gain this magnitude of weight and they want to do it in the most time-effective manner is often not helpful for our bodies, it can be very problematic, the same thing goes for weight loss when actors need to lose significant amounts of weight for roles,” says Dr. Almandoz.

And Dr. Hong explained that for patients trying to lose weight, they may cut calories, but the body will try to compensate by slowing down the metabolism to keep their weight the same.
 

‘Your own worst bully’

In “The Whale,” Charlie appears to suffer from internalized weight bias, which is common to many people living with obesity, Ms. Nece says.

“Internalized weight bias is when the person of size takes all that negativity and turns it on themselves. The easiest way to describe that is to tell you that I became my own worst bully because I started believing all the negative things people said to me about my weight,” Ms. Nece adds.

Her hope is that the film will bring attention to the harm that this bias creates, especially when it derives from other people. “There’s no telling whether it will, but what Charlie experiences in bias and stigma from others clearly happens. It’s realistic. Those of us in large bodies have experienced what he is experiencing, so some people have said the movie is fat-phobic, but I see it as I can relate to those experiences because I have them too, so they are very realistic.”

Ms. Nece notes that it is important for clinicians to understand that obesity is a multifaceted and sensitive topic. “For those medical professionals who do not already know that obesity is complex, I hope the film will begin to open their eyes to the many different facets involved in obesity and their patients with obesity, I hope it will help them empathize and show compassion to their patients with obesity,” she concludes.

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

“I could relate to many, many, many of the experiences and emotions that Charlie, which is Brendan Fraser’s character, was portraying,” Patricia Nece recalls after watching a preview copy of the new film “The Whale.”

A24

Much of the movie “rang true and hit home for me as things that I, too, had experienced,” Ms. Nece, the board of directors’ chair of the Obesity Action Coalition (OAC) and a person living with obesity, shares with this news organization.

In theaters as of December 9, The Whale chronicles the experience of a 600-lb, middle-aged man named Charlie. Throughout the film, Charlie seeks to rebuild his relationship with his estranged teenage daughter. Charlie had left his daughter and family to pursue a relationship with a man, who eventually died. As he navigates the pain surrounding his partner’s death and his lack of community, Charlie turns to food for comfort.

When the movie premiered at the Venice Film Festival, Mr. Fraser received a 6-minute standing ovation. However, activists criticized the movie for casting Fraser over an actor with obesity as well as its depiction of people with obesity.

Representatives from the National Association to Advance Fat Acceptance contend that casting an actor without obesity only contributes to ongoing bias against people of size. “Medical weight stigma and other socio-political determinants of health for people of all sizes cause far more harm to fat people than body fat does. Bias endangers fat people’s health. Anti-obesity organizations, such as those consulted with for this movie, contribute to stigma rather than reducing it as they claim,” NAAFA wrote in a statement to this news organization.

And they added that though the fat suit used in the movie may be superior to previous ones, it is still not an accurate depiction: “The creators of The Whale consider its CGI-generated fat suit to be superior to tactile fat suits, but we don’t. The issue with fat suits in Hollywood is not that they aren’t realistic enough. The issue is that they are used rather than using performers who actually live in bodies like the ones being depicted. If there is a 600-pound character in a movie, there should be a 600-pound human in that role. Rather than concentrate on the hype around the fake fat body created for The Whale, we want to see Hollywood create more opportunities for fat people across the size spectrum, both in front of the camera and behind the scenes.”
 

Prosthetics vs. reality?

Ms. Nece says she understands the controversy surrounding the use of fat suits but believes that it was not done in poor taste.

“OAC got involved with the movie after Brendan was already chosen for the part, and we never would have gotten involved with it had the prosthetics or fat suit been used to ridicule or make fun of people with obesity, which is usually the case,” she explains.

“But we knew from the start that that was never the intent of anyone involved with The Whale. And I think that’s shown by the fact that Brendan and Darren Aronofsky, the director, reached out to people who live with obesity on a daily basis to find out and learn more about it and to educate themselves about it,” Ms. Nece continues.

In a Daily Mail article, Mr. Fraser credited his son Griffin, who is autistic and obese, with helping him understand the struggles that people with obesity face.

Rachel Goldman, PhD, a clinical psychologist in private practice in New York and a professor in the psychology department at New York University, notes that there are other considerations that played into casting. “I know there was some pushback in terms of could, a say 600-lb individual, even be able to go to be on set every day and do this kind of work, and the answer is we don’t know.”

“I’m sure Darren chose Brendan for many reasons above and beyond just his body. I think that’s very important to keep in mind that just as much as representation is very important, I think it is also about finding the right person for the right role,” adds Dr. Goldman, who served as a consultant to the film.
 

Fat suits, extreme weight gains all to play a role

About 42% of adults in the United States have obesity, according to the 2017-2020 National Health and Nutrition Examination Survey, but that reality is not reflected in films or television.

A study of 1018 major television characters found that 24% of men and 14% of women had either overweight or obesity – far below the national average. And when characters with obesity are portrayed, actors often wear prosthetics, like Gwyneth Paltrow in Shallow Hal or Eddie Murphy in the Nutty Professor.

But unlike Mr. Fraser, some actors gain weight quickly instead.

This practice is unhealthy, says Jaime Almandoz, MD, an associate professor at the University of Texas Southwestern Medical Center, Dallas, and a nonsurgical weight management expert. In interviews, actors have shared how they increased calorie intake by drinking two milkshakes per day, going to fast food places regularly, or, in Mark Walhberg’s case, consuming 7,000 calories per day to gain 30 pounds for his role as boxer-turned-priest in the movie Father Stu.

This method provides their bodies with excess calories they are unable to burn off. “Then the amount of sugar and fat that streams into the blood as a result creates problems both directly and indirectly as your body tries to store it. It basically ends up using overflow warehouses for fat storage, like the liver for example, so we can create a condition called fatty liver, or in the muscle and other places, and this excess sugar and fat in the bloodstream cause several factors that are both insulin resistance causing,” Dr. Almandoz explains.

Though gaining weight helps the actor understand the character’s life experience, it may also be risky.

“To have an actor deliberately put his own health at risk and gain a certain amount of weight and whatever that might entail, one – that’s not necessarily the safest thing for that actor – but two, it’s also important to highlight the authentic experience of someone who has dealt with this chronic disease as well,” says Disha Narang, MD, a quadruple-board certified endocrinologist, obesity medicine, and culinary medicine specialist at Northwestern Medicine Lake Forest Hospital, Chicago.

These extreme fluctuations in weight may create problems. “It is typically not something we recommend because there could be metabolic damages as well as health concerns when patients are trying to gain weight quickly, just as we don’t want patients to lose weight quickly,” says Kurt Hong, MD, PhD, board-certified in internal medicine and clinical nutrition at the University of Southern California, Los Angeles.

Dr. Hong notes that it may be difficult for individuals to experience sudden weight gain because the body works hard to maintain a state of homeostasis.

“Similarly, to someone trying to gain weight you overeat, initially your body will try to again, maybe enhance its metabolic efficiency to hold the body stable,” Dr. Hong adds.

Dietary choices that may contribute to insulin resistance or promote high blood sugar can contribute to inflammation and a number of other adverse health outcomes, notes Dr. Almandoz. “The things that actors need to do in order to gain this magnitude of weight and they want to do it in the most time-effective manner is often not helpful for our bodies, it can be very problematic, the same thing goes for weight loss when actors need to lose significant amounts of weight for roles,” says Dr. Almandoz.

And Dr. Hong explained that for patients trying to lose weight, they may cut calories, but the body will try to compensate by slowing down the metabolism to keep their weight the same.
 

‘Your own worst bully’

In “The Whale,” Charlie appears to suffer from internalized weight bias, which is common to many people living with obesity, Ms. Nece says.

“Internalized weight bias is when the person of size takes all that negativity and turns it on themselves. The easiest way to describe that is to tell you that I became my own worst bully because I started believing all the negative things people said to me about my weight,” Ms. Nece adds.

Her hope is that the film will bring attention to the harm that this bias creates, especially when it derives from other people. “There’s no telling whether it will, but what Charlie experiences in bias and stigma from others clearly happens. It’s realistic. Those of us in large bodies have experienced what he is experiencing, so some people have said the movie is fat-phobic, but I see it as I can relate to those experiences because I have them too, so they are very realistic.”

Ms. Nece notes that it is important for clinicians to understand that obesity is a multifaceted and sensitive topic. “For those medical professionals who do not already know that obesity is complex, I hope the film will begin to open their eyes to the many different facets involved in obesity and their patients with obesity, I hope it will help them empathize and show compassion to their patients with obesity,” she concludes.

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

“I could relate to many, many, many of the experiences and emotions that Charlie, which is Brendan Fraser’s character, was portraying,” Patricia Nece recalls after watching a preview copy of the new film “The Whale.”

A24

Much of the movie “rang true and hit home for me as things that I, too, had experienced,” Ms. Nece, the board of directors’ chair of the Obesity Action Coalition (OAC) and a person living with obesity, shares with this news organization.

In theaters as of December 9, The Whale chronicles the experience of a 600-lb, middle-aged man named Charlie. Throughout the film, Charlie seeks to rebuild his relationship with his estranged teenage daughter. Charlie had left his daughter and family to pursue a relationship with a man, who eventually died. As he navigates the pain surrounding his partner’s death and his lack of community, Charlie turns to food for comfort.

When the movie premiered at the Venice Film Festival, Mr. Fraser received a 6-minute standing ovation. However, activists criticized the movie for casting Fraser over an actor with obesity as well as its depiction of people with obesity.

Representatives from the National Association to Advance Fat Acceptance contend that casting an actor without obesity only contributes to ongoing bias against people of size. “Medical weight stigma and other socio-political determinants of health for people of all sizes cause far more harm to fat people than body fat does. Bias endangers fat people’s health. Anti-obesity organizations, such as those consulted with for this movie, contribute to stigma rather than reducing it as they claim,” NAAFA wrote in a statement to this news organization.

And they added that though the fat suit used in the movie may be superior to previous ones, it is still not an accurate depiction: “The creators of The Whale consider its CGI-generated fat suit to be superior to tactile fat suits, but we don’t. The issue with fat suits in Hollywood is not that they aren’t realistic enough. The issue is that they are used rather than using performers who actually live in bodies like the ones being depicted. If there is a 600-pound character in a movie, there should be a 600-pound human in that role. Rather than concentrate on the hype around the fake fat body created for The Whale, we want to see Hollywood create more opportunities for fat people across the size spectrum, both in front of the camera and behind the scenes.”
 

Prosthetics vs. reality?

Ms. Nece says she understands the controversy surrounding the use of fat suits but believes that it was not done in poor taste.

“OAC got involved with the movie after Brendan was already chosen for the part, and we never would have gotten involved with it had the prosthetics or fat suit been used to ridicule or make fun of people with obesity, which is usually the case,” she explains.

“But we knew from the start that that was never the intent of anyone involved with The Whale. And I think that’s shown by the fact that Brendan and Darren Aronofsky, the director, reached out to people who live with obesity on a daily basis to find out and learn more about it and to educate themselves about it,” Ms. Nece continues.

In a Daily Mail article, Mr. Fraser credited his son Griffin, who is autistic and obese, with helping him understand the struggles that people with obesity face.

Rachel Goldman, PhD, a clinical psychologist in private practice in New York and a professor in the psychology department at New York University, notes that there are other considerations that played into casting. “I know there was some pushback in terms of could, a say 600-lb individual, even be able to go to be on set every day and do this kind of work, and the answer is we don’t know.”

“I’m sure Darren chose Brendan for many reasons above and beyond just his body. I think that’s very important to keep in mind that just as much as representation is very important, I think it is also about finding the right person for the right role,” adds Dr. Goldman, who served as a consultant to the film.
 

Fat suits, extreme weight gains all to play a role

About 42% of adults in the United States have obesity, according to the 2017-2020 National Health and Nutrition Examination Survey, but that reality is not reflected in films or television.

A study of 1018 major television characters found that 24% of men and 14% of women had either overweight or obesity – far below the national average. And when characters with obesity are portrayed, actors often wear prosthetics, like Gwyneth Paltrow in Shallow Hal or Eddie Murphy in the Nutty Professor.

But unlike Mr. Fraser, some actors gain weight quickly instead.

This practice is unhealthy, says Jaime Almandoz, MD, an associate professor at the University of Texas Southwestern Medical Center, Dallas, and a nonsurgical weight management expert. In interviews, actors have shared how they increased calorie intake by drinking two milkshakes per day, going to fast food places regularly, or, in Mark Walhberg’s case, consuming 7,000 calories per day to gain 30 pounds for his role as boxer-turned-priest in the movie Father Stu.

This method provides their bodies with excess calories they are unable to burn off. “Then the amount of sugar and fat that streams into the blood as a result creates problems both directly and indirectly as your body tries to store it. It basically ends up using overflow warehouses for fat storage, like the liver for example, so we can create a condition called fatty liver, or in the muscle and other places, and this excess sugar and fat in the bloodstream cause several factors that are both insulin resistance causing,” Dr. Almandoz explains.

Though gaining weight helps the actor understand the character’s life experience, it may also be risky.

“To have an actor deliberately put his own health at risk and gain a certain amount of weight and whatever that might entail, one – that’s not necessarily the safest thing for that actor – but two, it’s also important to highlight the authentic experience of someone who has dealt with this chronic disease as well,” says Disha Narang, MD, a quadruple-board certified endocrinologist, obesity medicine, and culinary medicine specialist at Northwestern Medicine Lake Forest Hospital, Chicago.

These extreme fluctuations in weight may create problems. “It is typically not something we recommend because there could be metabolic damages as well as health concerns when patients are trying to gain weight quickly, just as we don’t want patients to lose weight quickly,” says Kurt Hong, MD, PhD, board-certified in internal medicine and clinical nutrition at the University of Southern California, Los Angeles.

Dr. Hong notes that it may be difficult for individuals to experience sudden weight gain because the body works hard to maintain a state of homeostasis.

“Similarly, to someone trying to gain weight you overeat, initially your body will try to again, maybe enhance its metabolic efficiency to hold the body stable,” Dr. Hong adds.

Dietary choices that may contribute to insulin resistance or promote high blood sugar can contribute to inflammation and a number of other adverse health outcomes, notes Dr. Almandoz. “The things that actors need to do in order to gain this magnitude of weight and they want to do it in the most time-effective manner is often not helpful for our bodies, it can be very problematic, the same thing goes for weight loss when actors need to lose significant amounts of weight for roles,” says Dr. Almandoz.

And Dr. Hong explained that for patients trying to lose weight, they may cut calories, but the body will try to compensate by slowing down the metabolism to keep their weight the same.
 

‘Your own worst bully’

In “The Whale,” Charlie appears to suffer from internalized weight bias, which is common to many people living with obesity, Ms. Nece says.

“Internalized weight bias is when the person of size takes all that negativity and turns it on themselves. The easiest way to describe that is to tell you that I became my own worst bully because I started believing all the negative things people said to me about my weight,” Ms. Nece adds.

Her hope is that the film will bring attention to the harm that this bias creates, especially when it derives from other people. “There’s no telling whether it will, but what Charlie experiences in bias and stigma from others clearly happens. It’s realistic. Those of us in large bodies have experienced what he is experiencing, so some people have said the movie is fat-phobic, but I see it as I can relate to those experiences because I have them too, so they are very realistic.”

Ms. Nece notes that it is important for clinicians to understand that obesity is a multifaceted and sensitive topic. “For those medical professionals who do not already know that obesity is complex, I hope the film will begin to open their eyes to the many different facets involved in obesity and their patients with obesity, I hope it will help them empathize and show compassion to their patients with obesity,” she concludes.

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

A new strategy for the management of atherosclerotic plaque as a source of major adverse cardiac events is needed with the focus shifting from the flow-limiting coronary artery luminal lesions to the overall atherosclerotic burden, be it obstructive or nonobstructive, according to a review article.

The article, by Peter H. Stone, MD, and Peter Libby, MD, Brigham and Women’s Hospital, Boston, and William E. Boden, MD, Boston University School of Medicine, was published online in JAMA Cardiology.  

The review explored new data from vascular biology, atherosclerosis imaging, natural history outcome studies, and large-scale clinical trials that support what the authors refer to as “The Plaque Hypothesis” – the idea that major adverse cardiac events such as myocardial infarction and cardiac death are triggered by destabilization of vulnerable plaque, which may be obstructive or nonobstructive.

“We need to consider embracing a new management strategy that directs our diagnostic and management focus to evaluate the entire length of the atheromatous coronary artery and broaden the target of our therapeutic intervention to include all regions of the plaque (both flow-limiting and non–flow-limiting), even those that are distant from the presumed ischemia-producing obstruction,” the authors concluded.

Dr. Stone explained to this news organization that, for several decades, the medical community has focused on plaques causing severe obstruction of coronary arteries as being responsible for major adverse cardiac events. This approach – known as the Ischemia Hypothesis – has been the accepted strategy for many years, with all guidelines advising the identification of the stenoses that cause the most obstruction for treatment with stenting.

However, the authors pointed out that a number of studies have now suggested that, while these severe obstructive stenoses cause angina, they do not seem to be responsible for the hard events of MI, acute coronary syndrome (ACS), and cardiac death. 

Several studies including the COURAGE trial and BARI-2D, and the recent ISCHEMIA trial have all failed to show a reduction in these hard endpoints by intervening on these severe obstructive lesions, Dr. Stone noted. 

“We present evidence for a new approach – that it is the composition and vascular biology of the atherosclerotic plaques that cause MI, ACS, and cardiac death, rather than simply how obstructive they are,” he said.  

Dr. Stone pointed out that plaque seen on a coronary angiogram looks at only the lumen of the artery, but plaque is primarily based in the wall of the artery, and if that plaque is inflamed it can easily be the culprit responsible for adverse events even without encroaching into the lumen.

“Our paper describes many factors which can cause plaques to destabilize and cause an ACS. These include anatomical, biochemical, and biomechanical features that together cause plaque rupture or erosion and precipitate a clinical event. It is not sufficient to just look for obstructive plaques on a coronary angiogram,” he said. “We are barking up the wrong tree. We need to look for inflamed plaque in the whole wall of the coronary arteries.”

The authors described different factors that identify a plaque at high risk of destabilization. These include a large area of vulnerable plaque, a thin-cap atheroma, a severe inflamed core, macrocalcifications, a large plaque burden, and a physical profile that would encourage a thrombus to become trapped.  

“Atherosclerotic plaques are very heterogeneous and complex structures and it is not just the mountain peaks but also the lower foothills that can precipitate a flow-limiting obstruction,” Dr. Stone noted. 

“The slope of the mountain is probably very important in the ability for a thrombus to form. If the slope is gradual there isn’t a problem. But if the slope is jagged with sharp edges this can cause a thrombus to become trapped. We need to look at the entirety of plaque and all its risk features to identify the culprit areas that could cause MI or cardiac death. These are typically not the obstructive plaques we have all been fixated on for many years,” he added. 

“We need to focus on plaque heterogeneity. Once plaque is old and just made up of scar tissue which is not inflamed it does not cause much [of] a problem – we can probably just leave it alone. Some of these obstructive plaques may cause some angina but many do not cause major cardiac events unless they have other high-risk features,” he said. 

“Cardiac events are still caused by obstruction of blood flow but that can be an abrupt process where a thrombus attaches itself to an area of destabilized plaque. These areas of plaque were not necessarily obstructing to start with. We believe that this is the explanation behind the observation that 50% of all people who have an MI (half of which are fatal) do not have symptoms beforehand,” Dr. Stone commented. 

Because these areas of destabilized plaque do not cause symptoms, he believes that vast populations of people with established cardiovascular risk factors should undergo screening. “At the moment we wait for people to experience chest pain or to have an MI – that is far too little too late.” 

To identify these areas of high-risk plaques, imaging techniques looking inside the artery wall are needed such as intravascular ultrasound. However, this is an invasive procedure, and the noninvasive coronary CT angiography also gives a good picture, so it is probably the best way to begin as a wider screening modality, with more invasive screening methods then used in those found to be at risk, Dr. Stone suggested.  

Plaques that are identified as likely to destabilize can be treated with percutaneous coronary intervention and stenting.  

While systemic therapies are useful, those currently available are not sufficient, Dr. Stone noted. For example, there are still high levels of major cardiac events in patients treated with the PCSK9 inhibitors, which bring about very large reductions in LDL cholesterol. “These therapies are beneficial, but they are not enough on their own. So, these areas of unstable plaque would need to be treated with stenting or something similar. We believe that the intervention of stenting is good but at present it is targeted at the wrong areas,” he stated.  

“Clearly what we’ve been doing – stenting only obstructive lesions – does not reduce hard clinical events. Imaging methods have improved so much in recent years that we can now identify high-risk areas of plaque. This whole field of studying the vulnerable plaque has been ongoing for many years, but it is only recently that imaging methods have become good enough to identify plaques at risk. This field is now coming of age,” he added.

The next steps are to start identifying these plaques in larger populations, more accurately characterizing those at the highest risk, and then performing randomized trials of preemptive intervention in those believed to be at highest risk, and follow up for clinical events, Dr. Stone explained.  

Advances in detecting unstable plaque may also permit early evaluation of novel therapeutics and gauge the intensity of lifestyle and disease-modifying pharmacotherapy, the authors suggested.

This work was supported in part by the National Heart, Lung, and Blood Institute, the American Heart Association, the RRM Charitable Fund, the Simard Fund, and the Schaubert Family. Dr. Libby is an unpaid consultant to or involved in clinical trials with Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, MedImmune, Merck, Norvo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; and is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Elucid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, MedImmune, Moderna, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech.

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

A new strategy for the management of atherosclerotic plaque as a source of major adverse cardiac events is needed with the focus shifting from the flow-limiting coronary artery luminal lesions to the overall atherosclerotic burden, be it obstructive or nonobstructive, according to a review article.

The article, by Peter H. Stone, MD, and Peter Libby, MD, Brigham and Women’s Hospital, Boston, and William E. Boden, MD, Boston University School of Medicine, was published online in JAMA Cardiology.  

The review explored new data from vascular biology, atherosclerosis imaging, natural history outcome studies, and large-scale clinical trials that support what the authors refer to as “The Plaque Hypothesis” – the idea that major adverse cardiac events such as myocardial infarction and cardiac death are triggered by destabilization of vulnerable plaque, which may be obstructive or nonobstructive.

“We need to consider embracing a new management strategy that directs our diagnostic and management focus to evaluate the entire length of the atheromatous coronary artery and broaden the target of our therapeutic intervention to include all regions of the plaque (both flow-limiting and non–flow-limiting), even those that are distant from the presumed ischemia-producing obstruction,” the authors concluded.

Dr. Stone explained to this news organization that, for several decades, the medical community has focused on plaques causing severe obstruction of coronary arteries as being responsible for major adverse cardiac events. This approach – known as the Ischemia Hypothesis – has been the accepted strategy for many years, with all guidelines advising the identification of the stenoses that cause the most obstruction for treatment with stenting.

However, the authors pointed out that a number of studies have now suggested that, while these severe obstructive stenoses cause angina, they do not seem to be responsible for the hard events of MI, acute coronary syndrome (ACS), and cardiac death. 

Several studies including the COURAGE trial and BARI-2D, and the recent ISCHEMIA trial have all failed to show a reduction in these hard endpoints by intervening on these severe obstructive lesions, Dr. Stone noted. 

“We present evidence for a new approach – that it is the composition and vascular biology of the atherosclerotic plaques that cause MI, ACS, and cardiac death, rather than simply how obstructive they are,” he said.  

Dr. Stone pointed out that plaque seen on a coronary angiogram looks at only the lumen of the artery, but plaque is primarily based in the wall of the artery, and if that plaque is inflamed it can easily be the culprit responsible for adverse events even without encroaching into the lumen.

“Our paper describes many factors which can cause plaques to destabilize and cause an ACS. These include anatomical, biochemical, and biomechanical features that together cause plaque rupture or erosion and precipitate a clinical event. It is not sufficient to just look for obstructive plaques on a coronary angiogram,” he said. “We are barking up the wrong tree. We need to look for inflamed plaque in the whole wall of the coronary arteries.”

The authors described different factors that identify a plaque at high risk of destabilization. These include a large area of vulnerable plaque, a thin-cap atheroma, a severe inflamed core, macrocalcifications, a large plaque burden, and a physical profile that would encourage a thrombus to become trapped.  

“Atherosclerotic plaques are very heterogeneous and complex structures and it is not just the mountain peaks but also the lower foothills that can precipitate a flow-limiting obstruction,” Dr. Stone noted. 

“The slope of the mountain is probably very important in the ability for a thrombus to form. If the slope is gradual there isn’t a problem. But if the slope is jagged with sharp edges this can cause a thrombus to become trapped. We need to look at the entirety of plaque and all its risk features to identify the culprit areas that could cause MI or cardiac death. These are typically not the obstructive plaques we have all been fixated on for many years,” he added. 

“We need to focus on plaque heterogeneity. Once plaque is old and just made up of scar tissue which is not inflamed it does not cause much [of] a problem – we can probably just leave it alone. Some of these obstructive plaques may cause some angina but many do not cause major cardiac events unless they have other high-risk features,” he said. 

“Cardiac events are still caused by obstruction of blood flow but that can be an abrupt process where a thrombus attaches itself to an area of destabilized plaque. These areas of plaque were not necessarily obstructing to start with. We believe that this is the explanation behind the observation that 50% of all people who have an MI (half of which are fatal) do not have symptoms beforehand,” Dr. Stone commented. 

Because these areas of destabilized plaque do not cause symptoms, he believes that vast populations of people with established cardiovascular risk factors should undergo screening. “At the moment we wait for people to experience chest pain or to have an MI – that is far too little too late.” 

To identify these areas of high-risk plaques, imaging techniques looking inside the artery wall are needed such as intravascular ultrasound. However, this is an invasive procedure, and the noninvasive coronary CT angiography also gives a good picture, so it is probably the best way to begin as a wider screening modality, with more invasive screening methods then used in those found to be at risk, Dr. Stone suggested.  

Plaques that are identified as likely to destabilize can be treated with percutaneous coronary intervention and stenting.  

While systemic therapies are useful, those currently available are not sufficient, Dr. Stone noted. For example, there are still high levels of major cardiac events in patients treated with the PCSK9 inhibitors, which bring about very large reductions in LDL cholesterol. “These therapies are beneficial, but they are not enough on their own. So, these areas of unstable plaque would need to be treated with stenting or something similar. We believe that the intervention of stenting is good but at present it is targeted at the wrong areas,” he stated.  

“Clearly what we’ve been doing – stenting only obstructive lesions – does not reduce hard clinical events. Imaging methods have improved so much in recent years that we can now identify high-risk areas of plaque. This whole field of studying the vulnerable plaque has been ongoing for many years, but it is only recently that imaging methods have become good enough to identify plaques at risk. This field is now coming of age,” he added.

The next steps are to start identifying these plaques in larger populations, more accurately characterizing those at the highest risk, and then performing randomized trials of preemptive intervention in those believed to be at highest risk, and follow up for clinical events, Dr. Stone explained.  

Advances in detecting unstable plaque may also permit early evaluation of novel therapeutics and gauge the intensity of lifestyle and disease-modifying pharmacotherapy, the authors suggested.

This work was supported in part by the National Heart, Lung, and Blood Institute, the American Heart Association, the RRM Charitable Fund, the Simard Fund, and the Schaubert Family. Dr. Libby is an unpaid consultant to or involved in clinical trials with Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, MedImmune, Merck, Norvo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; and is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Elucid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, MedImmune, Moderna, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech.

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

A new strategy for the management of atherosclerotic plaque as a source of major adverse cardiac events is needed with the focus shifting from the flow-limiting coronary artery luminal lesions to the overall atherosclerotic burden, be it obstructive or nonobstructive, according to a review article.

The article, by Peter H. Stone, MD, and Peter Libby, MD, Brigham and Women’s Hospital, Boston, and William E. Boden, MD, Boston University School of Medicine, was published online in JAMA Cardiology.  

The review explored new data from vascular biology, atherosclerosis imaging, natural history outcome studies, and large-scale clinical trials that support what the authors refer to as “The Plaque Hypothesis” – the idea that major adverse cardiac events such as myocardial infarction and cardiac death are triggered by destabilization of vulnerable plaque, which may be obstructive or nonobstructive.

“We need to consider embracing a new management strategy that directs our diagnostic and management focus to evaluate the entire length of the atheromatous coronary artery and broaden the target of our therapeutic intervention to include all regions of the plaque (both flow-limiting and non–flow-limiting), even those that are distant from the presumed ischemia-producing obstruction,” the authors concluded.

Dr. Stone explained to this news organization that, for several decades, the medical community has focused on plaques causing severe obstruction of coronary arteries as being responsible for major adverse cardiac events. This approach – known as the Ischemia Hypothesis – has been the accepted strategy for many years, with all guidelines advising the identification of the stenoses that cause the most obstruction for treatment with stenting.

However, the authors pointed out that a number of studies have now suggested that, while these severe obstructive stenoses cause angina, they do not seem to be responsible for the hard events of MI, acute coronary syndrome (ACS), and cardiac death. 

Several studies including the COURAGE trial and BARI-2D, and the recent ISCHEMIA trial have all failed to show a reduction in these hard endpoints by intervening on these severe obstructive lesions, Dr. Stone noted. 

“We present evidence for a new approach – that it is the composition and vascular biology of the atherosclerotic plaques that cause MI, ACS, and cardiac death, rather than simply how obstructive they are,” he said.  

Dr. Stone pointed out that plaque seen on a coronary angiogram looks at only the lumen of the artery, but plaque is primarily based in the wall of the artery, and if that plaque is inflamed it can easily be the culprit responsible for adverse events even without encroaching into the lumen.

“Our paper describes many factors which can cause plaques to destabilize and cause an ACS. These include anatomical, biochemical, and biomechanical features that together cause plaque rupture or erosion and precipitate a clinical event. It is not sufficient to just look for obstructive plaques on a coronary angiogram,” he said. “We are barking up the wrong tree. We need to look for inflamed plaque in the whole wall of the coronary arteries.”

The authors described different factors that identify a plaque at high risk of destabilization. These include a large area of vulnerable plaque, a thin-cap atheroma, a severe inflamed core, macrocalcifications, a large plaque burden, and a physical profile that would encourage a thrombus to become trapped.  

“Atherosclerotic plaques are very heterogeneous and complex structures and it is not just the mountain peaks but also the lower foothills that can precipitate a flow-limiting obstruction,” Dr. Stone noted. 

“The slope of the mountain is probably very important in the ability for a thrombus to form. If the slope is gradual there isn’t a problem. But if the slope is jagged with sharp edges this can cause a thrombus to become trapped. We need to look at the entirety of plaque and all its risk features to identify the culprit areas that could cause MI or cardiac death. These are typically not the obstructive plaques we have all been fixated on for many years,” he added. 

“We need to focus on plaque heterogeneity. Once plaque is old and just made up of scar tissue which is not inflamed it does not cause much [of] a problem – we can probably just leave it alone. Some of these obstructive plaques may cause some angina but many do not cause major cardiac events unless they have other high-risk features,” he said. 

“Cardiac events are still caused by obstruction of blood flow but that can be an abrupt process where a thrombus attaches itself to an area of destabilized plaque. These areas of plaque were not necessarily obstructing to start with. We believe that this is the explanation behind the observation that 50% of all people who have an MI (half of which are fatal) do not have symptoms beforehand,” Dr. Stone commented. 

Because these areas of destabilized plaque do not cause symptoms, he believes that vast populations of people with established cardiovascular risk factors should undergo screening. “At the moment we wait for people to experience chest pain or to have an MI – that is far too little too late.” 

To identify these areas of high-risk plaques, imaging techniques looking inside the artery wall are needed such as intravascular ultrasound. However, this is an invasive procedure, and the noninvasive coronary CT angiography also gives a good picture, so it is probably the best way to begin as a wider screening modality, with more invasive screening methods then used in those found to be at risk, Dr. Stone suggested.  

Plaques that are identified as likely to destabilize can be treated with percutaneous coronary intervention and stenting.  

While systemic therapies are useful, those currently available are not sufficient, Dr. Stone noted. For example, there are still high levels of major cardiac events in patients treated with the PCSK9 inhibitors, which bring about very large reductions in LDL cholesterol. “These therapies are beneficial, but they are not enough on their own. So, these areas of unstable plaque would need to be treated with stenting or something similar. We believe that the intervention of stenting is good but at present it is targeted at the wrong areas,” he stated.  

“Clearly what we’ve been doing – stenting only obstructive lesions – does not reduce hard clinical events. Imaging methods have improved so much in recent years that we can now identify high-risk areas of plaque. This whole field of studying the vulnerable plaque has been ongoing for many years, but it is only recently that imaging methods have become good enough to identify plaques at risk. This field is now coming of age,” he added.

The next steps are to start identifying these plaques in larger populations, more accurately characterizing those at the highest risk, and then performing randomized trials of preemptive intervention in those believed to be at highest risk, and follow up for clinical events, Dr. Stone explained.  

Advances in detecting unstable plaque may also permit early evaluation of novel therapeutics and gauge the intensity of lifestyle and disease-modifying pharmacotherapy, the authors suggested.

This work was supported in part by the National Heart, Lung, and Blood Institute, the American Heart Association, the RRM Charitable Fund, the Simard Fund, and the Schaubert Family. Dr. Libby is an unpaid consultant to or involved in clinical trials with Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, MedImmune, Merck, Norvo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; and is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Elucid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, MedImmune, Moderna, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech.

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

Short bursts of activity are approximately as effective for general health as longer sessions, especially for those who are mainly sedentary, according to several recently published studies.

If your fitness goals are greater, and you want to build muscle strength and endurance, compete in a 5K, or just look better in your swimsuit, you will need to do more. But for basic health, it appears that short bursts can help, the new research papers and experts suggest.

“Whether you accumulate activity in many short bouts versus one extended bout, the general health benefits tend to be similar,” Amanda Paluch, PhD, a physical activity epidemiologist at the University of Massachusetts, Amherst, said in an interview.

Current public health recommendations from the Centers for Disease Control and Prevention suggest doing at least 150 minutes of moderate intensity physical activity per week for health benefits, but this activity can be accumulated in any way over the week, she noted. Previous versions of the CDC guidelines on exercise suggested that physical activity bouts should be at least 10 minutes each, but the latest version of the guidelines acknowledges that bursts of less than 10 minutes may be beneficial.

However, “the activity or fitness level at which someone starts and the specific health goals matter,” Dr. Paluch continued. “Short bouts may be particularly beneficial for those least active to get moving more to improve their general wellness.”

The current federal physical activity guidelines are still worth striving for, and patients can work their way to this goal, accumulating 150 or more minutes in a way that works best for them, she added.

“There is a lack of research directly comparing individuals who consistently accumulate their activity in many short bouts versus single bouts over an extended period of time,” Dr. Paluch noted. From a public health perspective, since both short and long bouts have health benefits, the best physical activity is what fits into your life and helps build a lifelong habit.

The benefits of exercise for cardiovascular health are well documented. A review from Circulation published in 2003 summarized the benefits of regular physical activity on measures of cardiovascular health including reduction in body weight, blood pressure, and bad cholesterol, while increasing insulin sensitivity, good cholesterol, and muscular strength and function. In that review, author Jonathan N. Myers, PhD, now of Stanford (Calif.) University, noted that “one need not be a marathon runner or an elite athlete to derive significant benefits from physical activity.” In fact, “the greatest gains in terms of mortality are achieved when an individual goes from being sedentary to becoming moderately active.”

A recent large, population-based study showed the value of short bursts of exercise for those previously sedentary. In this study, published in Nature Medicine, a team in Australia used wearable fitness trackers to measure the health benefits of what researchers have named “vigorous intermittent lifestyle physical activity” or VILPA.

Some examples of VILPA include power walking on the way to work, climbing stairs, or even running around with your kids on the playground.

Specifically, individuals who engaged in the median VILPA frequency of three bursts of vigorous activity lasting 1-2 minutes showed a 38%-40% reduction in all-cause mortality risk and cancer mortality risk, and a 48%-49% reduction in cardiovascular mortality risk.

The researchers repeated their analysis for a group of 62,344 adults from the UK Biobank who reported regular vigorous physical activity (VPA). They found similar effects on mortality, based on 1,552 deaths reported.

These results suggest that VILPA may be a reasonable physical activity target, especially for people not able or willing to exercise more formally or intensely, the researchers noted.

“We have known for a long time that leisure-time exercise often reaches vigorous intensity and has many health benefits, but we understand less about the health potential of daily movement, especially activities done as part of daily living that reach vigorous intensity,” lead author Emmanuel Stamatakis, PhD, professor of physical activity, lifestyle and population health at the University of Sydney’s Charles Perkins Centre, said in an interview.

“As long as the heart rate goes up for a minute or 2 it will likely be vigorous activity,” Dr. Stamatakis said in an interview. “It is also important that clinicians effectively communicate how patients can know that they are reaching vigorous intensity,” he said.

Signs of vigorous intensity include increased heart rate and getting out of breath after about 20-40 seconds from the start of the VILPA burst. After about a minute of VILPA, the person doing it should be too out of breath to speak more than a few words comfortably, he said.
 

Data support value of any and all exercise

The Nature Medicine study supports other recent research showing the value of short, intense bursts of physical activity. A pair of recent studies also used fitness trackers to measure activity in adults and assess the benefits on outcomes including death and heart disease.

One of these studies, which was published in the European Heart Journal, also used fitness trackers to measure physical activity at moderate and vigorous levels. The researchers found that individuals who performed at least 20% of their physical activity at a moderate to high level, such as by doing brisk walking in lieu of strolling had a significantly lower risk of heart disease than those whose daily activity included less than 20% at a moderate or intense level.

In another study from the European Heart Journal, researchers found that short bursts of vigorous physical activity of 2 minutes or less adding up to 15-20 minutes per week was enough to reduce mortality by as much as 40%.

Plus, a meta-analysis published in the Lancet showed a decrease in all-cause mortality with an increase in the number of daily steps, although the impact of stepping rate on mortality was inconsistent.

“Many studies have investigated the health benefits of physical activity, but not the importance of these difficult-to-capture VILPA bouts that accrue during the course of normal activities of daily living,” Lee Stoner, PhD, an exercise physiologist and director of the Cardiometabolic Lab at the University of North Carolina at Chapel Hill, said in an interview.

Dr. Stoner, who was not involved in the Nature Medicine study, said he was not surprised by the overall finding that doing short bursts of activity impacted mortality and cardiovascular disease, but was slightly surprised by the strength of the evidence.

“The referent group in the Nature Medicine study were those accruing no VILPA”, likely meaning they were very inactive,” Dr. Stoner said and added that he thinks this demonstrates the value of VILPA.

Even without immediately meeting the specific numbers recommended by the CDC, “any physical activity is better than none, especially if vigorous, and VILPA can be built into normal daily routines,” Dr. Stoner added.
 

What’s missing in short bursts?

Short bursts of activity do have their limits when it comes to overall fitness, said Dr. Stoner.

“Endurance will not be improved as much through short bursts, because such activities are unlikely to be as effective at empowering the mitochondria – the batteries keeping our cells running, including skeletal muscle cells,” he said. “Additionally, the vigorous bouts are unlikely to be as effective at improving muscular strength and endurance. For this, it is recommended that we engage each muscle group in strengthening exercises two times per week.”

However, Dr. Stoner agreed that prescribing short bursts of intense activity as part of daily living may be a great way to get people started with exercise.

“The key is to remove barriers to physical activity pursuit, then focusing on long-term routine rather than short-term gain,” he said. “Individuals are better served if they focus on goals other than weight loss, for which physical activity or exercise may not be the solution. Rather, being physically active can improve vigor, make daily activities simpler, and improve cognitive abilities,” and any physical activity is one of the most effective solutions for regulating blood glucose levels and improving cardiovascular risk factors.
 

Make it routine – and fun

To benefit from physical activity, cultivating and sustaining a long-term routine is key, said Dr. Stoner, whose research has focused on sedentary behavior and cardiovascular disease. Whatever the activity is, shorter bursts, or longer bouts or both, it is essential that individuals figure out activities that they enjoy if they want to create sustained behavior, and thus health change, Gabriel Zieff, MA, a doctoral candidate in Dr. Stoner’s Cardiometabolic Lab, who conducts studies on exercise, noted in an interview.

“We exercise enthusiasts and researchers are often hyperfocused on whether this duration or that duration is better, whether this intensity or that intensity is better,” but at the end of the day, it is the enjoyment factor that often predicts sustained behavior change, and should be part of discussions with patients to help reduce sedentary behavior and promote activity, Mr. Zieff said.
 

Short bouts can encourage hesitant exercisers

“To best support health, clinicians should consider taking a few seconds to ask patients about their physical activity levels,” said Dr. Paluch, who was the lead author on the Lancet meta-analysis of daily steps. In that study, Dr. Paluch and colleagues found that taking more steps each day was associated with a progressively lower risk of all-cause mortality. However, that study did not measure step rate.

Clinicians can emphasize that health benefits do not require an hour-long exercise routine and special equipment, and moving more, even in shorts bursts of activity can have meaningful associations with health, particularly for those who are less active, she said.

The recent studies on short bursts of activity agree that “some physical activity is better than none and adults should move more throughout the day in whatever way makes sense to them and fits best into their lives,” said Dr. Paluch. “For example, opting for the stairs instead of the elevator, a brisk walk to the bus stop, a short game of hide and seek with the children or grandchildren – anything that gets your body moving more, even if briefly. Making simple lifestyle changes is often easier in small bites. In time, this can grow into long-term habits, ultimately leading to an overall active lifestyle that supports living healthier for longer.”

The Nature Medicine study was supported by the Australian National Health and Medical Research Council. Several coauthors were supported by the Wellcome Trust, the National Institute for Health Research Oxford Biomedical Research Centre, Novo Nordisk, the British Heart Foundation Centre of Research Excellence, the Alan Turing Institute, the British Heart Foundation, and Health Data Research UK, an initiative funded by UK Research and Innovation. Dr. Paluch and Dr. Stoner had no financial conflicts to disclose.

Short bursts of activity are approximately as effective for general health as longer sessions, especially for those who are mainly sedentary, according to several recently published studies.

If your fitness goals are greater, and you want to build muscle strength and endurance, compete in a 5K, or just look better in your swimsuit, you will need to do more. But for basic health, it appears that short bursts can help, the new research papers and experts suggest.

“Whether you accumulate activity in many short bouts versus one extended bout, the general health benefits tend to be similar,” Amanda Paluch, PhD, a physical activity epidemiologist at the University of Massachusetts, Amherst, said in an interview.

Current public health recommendations from the Centers for Disease Control and Prevention suggest doing at least 150 minutes of moderate intensity physical activity per week for health benefits, but this activity can be accumulated in any way over the week, she noted. Previous versions of the CDC guidelines on exercise suggested that physical activity bouts should be at least 10 minutes each, but the latest version of the guidelines acknowledges that bursts of less than 10 minutes may be beneficial.

However, “the activity or fitness level at which someone starts and the specific health goals matter,” Dr. Paluch continued. “Short bouts may be particularly beneficial for those least active to get moving more to improve their general wellness.”

The current federal physical activity guidelines are still worth striving for, and patients can work their way to this goal, accumulating 150 or more minutes in a way that works best for them, she added.

“There is a lack of research directly comparing individuals who consistently accumulate their activity in many short bouts versus single bouts over an extended period of time,” Dr. Paluch noted. From a public health perspective, since both short and long bouts have health benefits, the best physical activity is what fits into your life and helps build a lifelong habit.

The benefits of exercise for cardiovascular health are well documented. A review from Circulation published in 2003 summarized the benefits of regular physical activity on measures of cardiovascular health including reduction in body weight, blood pressure, and bad cholesterol, while increasing insulin sensitivity, good cholesterol, and muscular strength and function. In that review, author Jonathan N. Myers, PhD, now of Stanford (Calif.) University, noted that “one need not be a marathon runner or an elite athlete to derive significant benefits from physical activity.” In fact, “the greatest gains in terms of mortality are achieved when an individual goes from being sedentary to becoming moderately active.”

A recent large, population-based study showed the value of short bursts of exercise for those previously sedentary. In this study, published in Nature Medicine, a team in Australia used wearable fitness trackers to measure the health benefits of what researchers have named “vigorous intermittent lifestyle physical activity” or VILPA.

Some examples of VILPA include power walking on the way to work, climbing stairs, or even running around with your kids on the playground.

Specifically, individuals who engaged in the median VILPA frequency of three bursts of vigorous activity lasting 1-2 minutes showed a 38%-40% reduction in all-cause mortality risk and cancer mortality risk, and a 48%-49% reduction in cardiovascular mortality risk.

The researchers repeated their analysis for a group of 62,344 adults from the UK Biobank who reported regular vigorous physical activity (VPA). They found similar effects on mortality, based on 1,552 deaths reported.

These results suggest that VILPA may be a reasonable physical activity target, especially for people not able or willing to exercise more formally or intensely, the researchers noted.

“We have known for a long time that leisure-time exercise often reaches vigorous intensity and has many health benefits, but we understand less about the health potential of daily movement, especially activities done as part of daily living that reach vigorous intensity,” lead author Emmanuel Stamatakis, PhD, professor of physical activity, lifestyle and population health at the University of Sydney’s Charles Perkins Centre, said in an interview.

“As long as the heart rate goes up for a minute or 2 it will likely be vigorous activity,” Dr. Stamatakis said in an interview. “It is also important that clinicians effectively communicate how patients can know that they are reaching vigorous intensity,” he said.

Signs of vigorous intensity include increased heart rate and getting out of breath after about 20-40 seconds from the start of the VILPA burst. After about a minute of VILPA, the person doing it should be too out of breath to speak more than a few words comfortably, he said.
 

Data support value of any and all exercise

The Nature Medicine study supports other recent research showing the value of short, intense bursts of physical activity. A pair of recent studies also used fitness trackers to measure activity in adults and assess the benefits on outcomes including death and heart disease.

One of these studies, which was published in the European Heart Journal, also used fitness trackers to measure physical activity at moderate and vigorous levels. The researchers found that individuals who performed at least 20% of their physical activity at a moderate to high level, such as by doing brisk walking in lieu of strolling had a significantly lower risk of heart disease than those whose daily activity included less than 20% at a moderate or intense level.

In another study from the European Heart Journal, researchers found that short bursts of vigorous physical activity of 2 minutes or less adding up to 15-20 minutes per week was enough to reduce mortality by as much as 40%.

Plus, a meta-analysis published in the Lancet showed a decrease in all-cause mortality with an increase in the number of daily steps, although the impact of stepping rate on mortality was inconsistent.

“Many studies have investigated the health benefits of physical activity, but not the importance of these difficult-to-capture VILPA bouts that accrue during the course of normal activities of daily living,” Lee Stoner, PhD, an exercise physiologist and director of the Cardiometabolic Lab at the University of North Carolina at Chapel Hill, said in an interview.

Dr. Stoner, who was not involved in the Nature Medicine study, said he was not surprised by the overall finding that doing short bursts of activity impacted mortality and cardiovascular disease, but was slightly surprised by the strength of the evidence.

“The referent group in the Nature Medicine study were those accruing no VILPA”, likely meaning they were very inactive,” Dr. Stoner said and added that he thinks this demonstrates the value of VILPA.

Even without immediately meeting the specific numbers recommended by the CDC, “any physical activity is better than none, especially if vigorous, and VILPA can be built into normal daily routines,” Dr. Stoner added.
 

What’s missing in short bursts?

Short bursts of activity do have their limits when it comes to overall fitness, said Dr. Stoner.

“Endurance will not be improved as much through short bursts, because such activities are unlikely to be as effective at empowering the mitochondria – the batteries keeping our cells running, including skeletal muscle cells,” he said. “Additionally, the vigorous bouts are unlikely to be as effective at improving muscular strength and endurance. For this, it is recommended that we engage each muscle group in strengthening exercises two times per week.”

However, Dr. Stoner agreed that prescribing short bursts of intense activity as part of daily living may be a great way to get people started with exercise.

“The key is to remove barriers to physical activity pursuit, then focusing on long-term routine rather than short-term gain,” he said. “Individuals are better served if they focus on goals other than weight loss, for which physical activity or exercise may not be the solution. Rather, being physically active can improve vigor, make daily activities simpler, and improve cognitive abilities,” and any physical activity is one of the most effective solutions for regulating blood glucose levels and improving cardiovascular risk factors.
 

Make it routine – and fun

To benefit from physical activity, cultivating and sustaining a long-term routine is key, said Dr. Stoner, whose research has focused on sedentary behavior and cardiovascular disease. Whatever the activity is, shorter bursts, or longer bouts or both, it is essential that individuals figure out activities that they enjoy if they want to create sustained behavior, and thus health change, Gabriel Zieff, MA, a doctoral candidate in Dr. Stoner’s Cardiometabolic Lab, who conducts studies on exercise, noted in an interview.

“We exercise enthusiasts and researchers are often hyperfocused on whether this duration or that duration is better, whether this intensity or that intensity is better,” but at the end of the day, it is the enjoyment factor that often predicts sustained behavior change, and should be part of discussions with patients to help reduce sedentary behavior and promote activity, Mr. Zieff said.
 

Short bouts can encourage hesitant exercisers

“To best support health, clinicians should consider taking a few seconds to ask patients about their physical activity levels,” said Dr. Paluch, who was the lead author on the Lancet meta-analysis of daily steps. In that study, Dr. Paluch and colleagues found that taking more steps each day was associated with a progressively lower risk of all-cause mortality. However, that study did not measure step rate.

Clinicians can emphasize that health benefits do not require an hour-long exercise routine and special equipment, and moving more, even in shorts bursts of activity can have meaningful associations with health, particularly for those who are less active, she said.

The recent studies on short bursts of activity agree that “some physical activity is better than none and adults should move more throughout the day in whatever way makes sense to them and fits best into their lives,” said Dr. Paluch. “For example, opting for the stairs instead of the elevator, a brisk walk to the bus stop, a short game of hide and seek with the children or grandchildren – anything that gets your body moving more, even if briefly. Making simple lifestyle changes is often easier in small bites. In time, this can grow into long-term habits, ultimately leading to an overall active lifestyle that supports living healthier for longer.”

The Nature Medicine study was supported by the Australian National Health and Medical Research Council. Several coauthors were supported by the Wellcome Trust, the National Institute for Health Research Oxford Biomedical Research Centre, Novo Nordisk, the British Heart Foundation Centre of Research Excellence, the Alan Turing Institute, the British Heart Foundation, and Health Data Research UK, an initiative funded by UK Research and Innovation. Dr. Paluch and Dr. Stoner had no financial conflicts to disclose.

Short bursts of activity are approximately as effective for general health as longer sessions, especially for those who are mainly sedentary, according to several recently published studies.

If your fitness goals are greater, and you want to build muscle strength and endurance, compete in a 5K, or just look better in your swimsuit, you will need to do more. But for basic health, it appears that short bursts can help, the new research papers and experts suggest.

“Whether you accumulate activity in many short bouts versus one extended bout, the general health benefits tend to be similar,” Amanda Paluch, PhD, a physical activity epidemiologist at the University of Massachusetts, Amherst, said in an interview.

Current public health recommendations from the Centers for Disease Control and Prevention suggest doing at least 150 minutes of moderate intensity physical activity per week for health benefits, but this activity can be accumulated in any way over the week, she noted. Previous versions of the CDC guidelines on exercise suggested that physical activity bouts should be at least 10 minutes each, but the latest version of the guidelines acknowledges that bursts of less than 10 minutes may be beneficial.

However, “the activity or fitness level at which someone starts and the specific health goals matter,” Dr. Paluch continued. “Short bouts may be particularly beneficial for those least active to get moving more to improve their general wellness.”

The current federal physical activity guidelines are still worth striving for, and patients can work their way to this goal, accumulating 150 or more minutes in a way that works best for them, she added.

“There is a lack of research directly comparing individuals who consistently accumulate their activity in many short bouts versus single bouts over an extended period of time,” Dr. Paluch noted. From a public health perspective, since both short and long bouts have health benefits, the best physical activity is what fits into your life and helps build a lifelong habit.

The benefits of exercise for cardiovascular health are well documented. A review from Circulation published in 2003 summarized the benefits of regular physical activity on measures of cardiovascular health including reduction in body weight, blood pressure, and bad cholesterol, while increasing insulin sensitivity, good cholesterol, and muscular strength and function. In that review, author Jonathan N. Myers, PhD, now of Stanford (Calif.) University, noted that “one need not be a marathon runner or an elite athlete to derive significant benefits from physical activity.” In fact, “the greatest gains in terms of mortality are achieved when an individual goes from being sedentary to becoming moderately active.”

A recent large, population-based study showed the value of short bursts of exercise for those previously sedentary. In this study, published in Nature Medicine, a team in Australia used wearable fitness trackers to measure the health benefits of what researchers have named “vigorous intermittent lifestyle physical activity” or VILPA.

Some examples of VILPA include power walking on the way to work, climbing stairs, or even running around with your kids on the playground.

Specifically, individuals who engaged in the median VILPA frequency of three bursts of vigorous activity lasting 1-2 minutes showed a 38%-40% reduction in all-cause mortality risk and cancer mortality risk, and a 48%-49% reduction in cardiovascular mortality risk.

The researchers repeated their analysis for a group of 62,344 adults from the UK Biobank who reported regular vigorous physical activity (VPA). They found similar effects on mortality, based on 1,552 deaths reported.

These results suggest that VILPA may be a reasonable physical activity target, especially for people not able or willing to exercise more formally or intensely, the researchers noted.

“We have known for a long time that leisure-time exercise often reaches vigorous intensity and has many health benefits, but we understand less about the health potential of daily movement, especially activities done as part of daily living that reach vigorous intensity,” lead author Emmanuel Stamatakis, PhD, professor of physical activity, lifestyle and population health at the University of Sydney’s Charles Perkins Centre, said in an interview.

“As long as the heart rate goes up for a minute or 2 it will likely be vigorous activity,” Dr. Stamatakis said in an interview. “It is also important that clinicians effectively communicate how patients can know that they are reaching vigorous intensity,” he said.

Signs of vigorous intensity include increased heart rate and getting out of breath after about 20-40 seconds from the start of the VILPA burst. After about a minute of VILPA, the person doing it should be too out of breath to speak more than a few words comfortably, he said.
 

Data support value of any and all exercise

The Nature Medicine study supports other recent research showing the value of short, intense bursts of physical activity. A pair of recent studies also used fitness trackers to measure activity in adults and assess the benefits on outcomes including death and heart disease.

One of these studies, which was published in the European Heart Journal, also used fitness trackers to measure physical activity at moderate and vigorous levels. The researchers found that individuals who performed at least 20% of their physical activity at a moderate to high level, such as by doing brisk walking in lieu of strolling had a significantly lower risk of heart disease than those whose daily activity included less than 20% at a moderate or intense level.

In another study from the European Heart Journal, researchers found that short bursts of vigorous physical activity of 2 minutes or less adding up to 15-20 minutes per week was enough to reduce mortality by as much as 40%.

Plus, a meta-analysis published in the Lancet showed a decrease in all-cause mortality with an increase in the number of daily steps, although the impact of stepping rate on mortality was inconsistent.

“Many studies have investigated the health benefits of physical activity, but not the importance of these difficult-to-capture VILPA bouts that accrue during the course of normal activities of daily living,” Lee Stoner, PhD, an exercise physiologist and director of the Cardiometabolic Lab at the University of North Carolina at Chapel Hill, said in an interview.

Dr. Stoner, who was not involved in the Nature Medicine study, said he was not surprised by the overall finding that doing short bursts of activity impacted mortality and cardiovascular disease, but was slightly surprised by the strength of the evidence.

“The referent group in the Nature Medicine study were those accruing no VILPA”, likely meaning they were very inactive,” Dr. Stoner said and added that he thinks this demonstrates the value of VILPA.

Even without immediately meeting the specific numbers recommended by the CDC, “any physical activity is better than none, especially if vigorous, and VILPA can be built into normal daily routines,” Dr. Stoner added.
 

What’s missing in short bursts?

Short bursts of activity do have their limits when it comes to overall fitness, said Dr. Stoner.

“Endurance will not be improved as much through short bursts, because such activities are unlikely to be as effective at empowering the mitochondria – the batteries keeping our cells running, including skeletal muscle cells,” he said. “Additionally, the vigorous bouts are unlikely to be as effective at improving muscular strength and endurance. For this, it is recommended that we engage each muscle group in strengthening exercises two times per week.”

However, Dr. Stoner agreed that prescribing short bursts of intense activity as part of daily living may be a great way to get people started with exercise.

“The key is to remove barriers to physical activity pursuit, then focusing on long-term routine rather than short-term gain,” he said. “Individuals are better served if they focus on goals other than weight loss, for which physical activity or exercise may not be the solution. Rather, being physically active can improve vigor, make daily activities simpler, and improve cognitive abilities,” and any physical activity is one of the most effective solutions for regulating blood glucose levels and improving cardiovascular risk factors.
 

Make it routine – and fun

To benefit from physical activity, cultivating and sustaining a long-term routine is key, said Dr. Stoner, whose research has focused on sedentary behavior and cardiovascular disease. Whatever the activity is, shorter bursts, or longer bouts or both, it is essential that individuals figure out activities that they enjoy if they want to create sustained behavior, and thus health change, Gabriel Zieff, MA, a doctoral candidate in Dr. Stoner’s Cardiometabolic Lab, who conducts studies on exercise, noted in an interview.

“We exercise enthusiasts and researchers are often hyperfocused on whether this duration or that duration is better, whether this intensity or that intensity is better,” but at the end of the day, it is the enjoyment factor that often predicts sustained behavior change, and should be part of discussions with patients to help reduce sedentary behavior and promote activity, Mr. Zieff said.
 

Short bouts can encourage hesitant exercisers

“To best support health, clinicians should consider taking a few seconds to ask patients about their physical activity levels,” said Dr. Paluch, who was the lead author on the Lancet meta-analysis of daily steps. In that study, Dr. Paluch and colleagues found that taking more steps each day was associated with a progressively lower risk of all-cause mortality. However, that study did not measure step rate.

Clinicians can emphasize that health benefits do not require an hour-long exercise routine and special equipment, and moving more, even in shorts bursts of activity can have meaningful associations with health, particularly for those who are less active, she said.

The recent studies on short bursts of activity agree that “some physical activity is better than none and adults should move more throughout the day in whatever way makes sense to them and fits best into their lives,” said Dr. Paluch. “For example, opting for the stairs instead of the elevator, a brisk walk to the bus stop, a short game of hide and seek with the children or grandchildren – anything that gets your body moving more, even if briefly. Making simple lifestyle changes is often easier in small bites. In time, this can grow into long-term habits, ultimately leading to an overall active lifestyle that supports living healthier for longer.”

The Nature Medicine study was supported by the Australian National Health and Medical Research Council. Several coauthors were supported by the Wellcome Trust, the National Institute for Health Research Oxford Biomedical Research Centre, Novo Nordisk, the British Heart Foundation Centre of Research Excellence, the Alan Turing Institute, the British Heart Foundation, and Health Data Research UK, an initiative funded by UK Research and Innovation. Dr. Paluch and Dr. Stoner had no financial conflicts to disclose.

Fitbit users who took 10,700 steps a day had a 44% lower risk of developing type 2 diabetes than those who only took 6,000 steps a day, regardless of age, sex, or body mass index, in an almost 4-year study.

The protective effect of daily step count on type 2 diabetes risk remained after adjusting for smoking and sedentary time.

Taking more steps per day was also associated with less risk of developing type 2 diabetes in different subgroups of physical activity intensity.

“Our data shows the importance of moving your body every day to lower your risk of [type 2] diabetes,” said the lead author of the research, Andrew S. Perry, MD. The findings were published online in the Journal of Clinical Endocrinology & Metabolism.
 

Despite low baseline risk, benefit from increased physical activity

The study was conducted in more than 5,000 participants in the National Institutes of Health’s All of Us research program who had a median age of 51 and were generally overweight (median BMI 27.8 kg/m²). Three quarters were women and 89% were White.

It used an innovative approach in a real-world population, said Dr. Perry, of Vanderbilt University Medical Center in Nashville, Tenn.

The individuals in this cohort had relatively few risk factors, so it was not surprising that the incidence of type 2 diabetes overall was low (2%), the researchers note. “Yet, despite being low risk, we still detected a signal of benefit from increased” physical activity, Dr. Perry and colleagues write.

The individuals had a median of 16 very active minutes/day, which corresponds to 112 very active minutes/week (ie, less than the guideline-recommended 150 minutes of physical activity/week).

“These results indicate that amounts of physical activity are correlated with lower risk of [type 2] diabetes, regardless of the intensity level, and even at amounts less than current guidelines recommend,” the researchers summarize.
 

Physical activity tracked over close to 4 years

Prior studies of the relationship between physical activity and type 2 diabetes risk relied primarily on questionnaires that asked people about physical activity at one point in time.

The researchers aimed to examine this association over time, in a contemporary cohort of Fitbit users who participated in the All of Us program.

From 12,781 participants with Fitbit data between 2010 and 2021, they identified 5,677 individuals who were at least 18 years old and had linked electronic health record data, no diabetes at baseline, at least 15 days of Fitbit data in the initial monitoring period, and at least 180 days of follow-up.

The Fitbit counts steps, and it also uses an algorithm to quantify physical activity intensity as lightly active (1.5-3 metabolic equivalent task (METs), fairly active (3-6 METs), and very active (> 6 METs).

During a median 3.8-year follow-up, participants made a median of 7,924 steps/day and were “fairly active” for a median of 16 minutes/day.

They found 97 new cases of type 2 diabetes over a follow-up of 4 years in the dataset.

The predicted cumulative incidence of type 2 diabetes at 5 years was 0.8% for individuals who walked 13,245 steps/day (90th percentile) vs. 2.3% for those who walked 4,301 steps/day (10th percentile).

“We hope to study more diverse populations in future studies to confirm the generalizability of these findings,” Dr. Perry said.

This study received funding from the National Heart, Lung, and Blood Institute. Dr. Perry reports no relevant financial relationships. Disclosures for the other authors are listed with the original article.

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

Fitbit users who took 10,700 steps a day had a 44% lower risk of developing type 2 diabetes than those who only took 6,000 steps a day, regardless of age, sex, or body mass index, in an almost 4-year study.

The protective effect of daily step count on type 2 diabetes risk remained after adjusting for smoking and sedentary time.

Taking more steps per day was also associated with less risk of developing type 2 diabetes in different subgroups of physical activity intensity.

“Our data shows the importance of moving your body every day to lower your risk of [type 2] diabetes,” said the lead author of the research, Andrew S. Perry, MD. The findings were published online in the Journal of Clinical Endocrinology & Metabolism.
 

Despite low baseline risk, benefit from increased physical activity

The study was conducted in more than 5,000 participants in the National Institutes of Health’s All of Us research program who had a median age of 51 and were generally overweight (median BMI 27.8 kg/m²). Three quarters were women and 89% were White.

It used an innovative approach in a real-world population, said Dr. Perry, of Vanderbilt University Medical Center in Nashville, Tenn.

The individuals in this cohort had relatively few risk factors, so it was not surprising that the incidence of type 2 diabetes overall was low (2%), the researchers note. “Yet, despite being low risk, we still detected a signal of benefit from increased” physical activity, Dr. Perry and colleagues write.

The individuals had a median of 16 very active minutes/day, which corresponds to 112 very active minutes/week (ie, less than the guideline-recommended 150 minutes of physical activity/week).

“These results indicate that amounts of physical activity are correlated with lower risk of [type 2] diabetes, regardless of the intensity level, and even at amounts less than current guidelines recommend,” the researchers summarize.
 

Physical activity tracked over close to 4 years

Prior studies of the relationship between physical activity and type 2 diabetes risk relied primarily on questionnaires that asked people about physical activity at one point in time.

The researchers aimed to examine this association over time, in a contemporary cohort of Fitbit users who participated in the All of Us program.

From 12,781 participants with Fitbit data between 2010 and 2021, they identified 5,677 individuals who were at least 18 years old and had linked electronic health record data, no diabetes at baseline, at least 15 days of Fitbit data in the initial monitoring period, and at least 180 days of follow-up.

The Fitbit counts steps, and it also uses an algorithm to quantify physical activity intensity as lightly active (1.5-3 metabolic equivalent task (METs), fairly active (3-6 METs), and very active (> 6 METs).

During a median 3.8-year follow-up, participants made a median of 7,924 steps/day and were “fairly active” for a median of 16 minutes/day.

They found 97 new cases of type 2 diabetes over a follow-up of 4 years in the dataset.

The predicted cumulative incidence of type 2 diabetes at 5 years was 0.8% for individuals who walked 13,245 steps/day (90th percentile) vs. 2.3% for those who walked 4,301 steps/day (10th percentile).

“We hope to study more diverse populations in future studies to confirm the generalizability of these findings,” Dr. Perry said.

This study received funding from the National Heart, Lung, and Blood Institute. Dr. Perry reports no relevant financial relationships. Disclosures for the other authors are listed with the original article.

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

Fitbit users who took 10,700 steps a day had a 44% lower risk of developing type 2 diabetes than those who only took 6,000 steps a day, regardless of age, sex, or body mass index, in an almost 4-year study.

The protective effect of daily step count on type 2 diabetes risk remained after adjusting for smoking and sedentary time.

Taking more steps per day was also associated with less risk of developing type 2 diabetes in different subgroups of physical activity intensity.

“Our data shows the importance of moving your body every day to lower your risk of [type 2] diabetes,” said the lead author of the research, Andrew S. Perry, MD. The findings were published online in the Journal of Clinical Endocrinology & Metabolism.
 

Despite low baseline risk, benefit from increased physical activity

The study was conducted in more than 5,000 participants in the National Institutes of Health’s All of Us research program who had a median age of 51 and were generally overweight (median BMI 27.8 kg/m²). Three quarters were women and 89% were White.

It used an innovative approach in a real-world population, said Dr. Perry, of Vanderbilt University Medical Center in Nashville, Tenn.

The individuals in this cohort had relatively few risk factors, so it was not surprising that the incidence of type 2 diabetes overall was low (2%), the researchers note. “Yet, despite being low risk, we still detected a signal of benefit from increased” physical activity, Dr. Perry and colleagues write.

The individuals had a median of 16 very active minutes/day, which corresponds to 112 very active minutes/week (ie, less than the guideline-recommended 150 minutes of physical activity/week).

“These results indicate that amounts of physical activity are correlated with lower risk of [type 2] diabetes, regardless of the intensity level, and even at amounts less than current guidelines recommend,” the researchers summarize.
 

Physical activity tracked over close to 4 years

Prior studies of the relationship between physical activity and type 2 diabetes risk relied primarily on questionnaires that asked people about physical activity at one point in time.

The researchers aimed to examine this association over time, in a contemporary cohort of Fitbit users who participated in the All of Us program.

From 12,781 participants with Fitbit data between 2010 and 2021, they identified 5,677 individuals who were at least 18 years old and had linked electronic health record data, no diabetes at baseline, at least 15 days of Fitbit data in the initial monitoring period, and at least 180 days of follow-up.

The Fitbit counts steps, and it also uses an algorithm to quantify physical activity intensity as lightly active (1.5-3 metabolic equivalent task (METs), fairly active (3-6 METs), and very active (> 6 METs).

During a median 3.8-year follow-up, participants made a median of 7,924 steps/day and were “fairly active” for a median of 16 minutes/day.

They found 97 new cases of type 2 diabetes over a follow-up of 4 years in the dataset.

The predicted cumulative incidence of type 2 diabetes at 5 years was 0.8% for individuals who walked 13,245 steps/day (90th percentile) vs. 2.3% for those who walked 4,301 steps/day (10th percentile).

“We hope to study more diverse populations in future studies to confirm the generalizability of these findings,” Dr. Perry said.

This study received funding from the National Heart, Lung, and Blood Institute. Dr. Perry reports no relevant financial relationships. Disclosures for the other authors are listed with the original article.

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

It’s a story perhaps more appropriate for Halloween than for the festive holiday season, given its scary implications. Four Omicron subvariants of the virus that causes COVID-19 will be the most common strains going from person to person in the winter of 2022-2023, new research predicts.

Not too dire so far, until the researchers’ other findings are considered.

The BQ.1, BQ1.1, XBB, and XBB.1 subvariants are the most resistant to neutralizing antibodies, researcher Qian Wang, PhD, and colleagues wrote in a study published online in the journal Cell. This means people have no or “markedly reduced” protection against infection from these four strains, even if they’ve already had COVID-19 or are vaccinated and boosted multiple times, including with a bivalent vaccine.

On top of that, all available monoclonal antibody treatments are mostly or completely ineffective against these subvariants.

What does that mean for the immediate future? The findings are definitely “worrisome,” said Eric Topol, MD, founder and director of the Scripps Translational Research Institute in La Jolla, Calif.

But evidence from other countries, specifically Singapore and France, show that at least two of these variants turned out not to be as damaging as expected, likely because of high numbers of people vaccinated or who survived previous infections, he said.

Still, there is little to celebrate in the new findings, except that COVID-19 vaccinations and prior infections can still reduce the risk for serious outcomes such as hospitalization and death, the researchers wrote.

In fact, Centers for Disease Control and Prevention data released on Dec. 16 shows that people who have received four shots of the original COVID-19 vaccines as well as the bivalent booster were 57% less likely to visit an urgent care clinic or emergency room, regardless of age. 

It comes at a time when BQ.1 and BQ.1.1 account for about 70% of the circulating variants, data show. In addition, hospitalizations are up 18% over the past 2 weeks and COVID-19 deaths are up 50% nationwide, The New York Times reported.

Globally, in many places, an “immunity wall” that has been built, Dr. Topol said. That may not be the case in the United States.  

“The problem in the United States, making it harder to predict, is that we have a very low rate of recent boosters, in the past 6 months, especially in seniors,” he said. For example, only 36% of Americans aged 65 years and older, the group with highest risk, have received an updated bivalent booster.
 

An evolving virus

The subvariants are successfully replacing BA.5, which reigned as one of the most common Omicron variants over the past year. The latest CDC data show that BA.5 now accounts for only about 10% of the circulating virus. The researchers wrote: “This rapid replacement of virus strains is raising the specter of yet another wave of infections in the coming months.”

BQ.1 and BQ.1.1 evolved directly from BA.5 – adding more and some novel mutations to the SARS-CoV-2 virus. XBB and XBB.1 are the “offspring” of a combination of two other strains, known as BJ.1 and BA.2.75.

The story sounds familiar to the researchers. “The rapid rise of these subvariants and their extensive array of spike mutations are reminiscent of the appearance of the first Omicron variant last year, thus raising concerns that they may further compromise the efficacy of current COVID-19 vaccines and monoclonal antibody therapeutics,” they wrote. “We now report findings that indicate that such concerns are, sadly, justified, especially so for the XBB and XBB.1 subvariants.”

To figure out how effective existing antibodies could be against these newer subvariants, Dr. Wang and colleagues used blood samples from five groups of people. They tested serum from people who had three doses of the original COVID-19 vaccine, four doses of the original vaccine, those who received a bivalent booster, people who experienced a breakthrough infection with the BA.2 Omicron variant, and those who had a breakthrough with a BA.4 or BA.5 variant.

Adding the new subvariants to these serum samples revealed that the existing antibodies in the blood were ineffective at wiping out or neutralizing BQ.1, BQ.1.1, XBB, and XBB.1.

The BQ.1 subvariant was six times more resistant to antibodies than BA.5, its parent strain, and XBB.1 was 63 times more resistant compared with its predecessor, BA.2.

This shift in the ability of vaccines to stop the subvariants “is particularly concerning,” the researchers wrote.
 

Wiping out treatments too

Dr. Wang and colleagues also tested how well a panel of 23 different monoclonal antibody drugs might work against the four subvariants. The therapies all worked well against the original Omicron variant and included some approved for use through the Food and Drug Administration emergency use authorization (EUA) program at the time of the study.

They found that 19 of these 23 monoclonal antibodies lost effectiveness “greatly or completely” against XBB and XBB.1, for example.

This is not the first time that monoclonal antibody therapies have gone from effective to ineffective. Previous variants have come out that no longer responded to treatment with bamlanivimab, etesevimab, imdevimab, casirivimab, tixagevimab, cilgavimab, and sotrovimab. Bebtelovimab now joins this list and is no longer available from Eli Lilly under EUA because of this lack of effectiveness.

The lack of an effective monoclonal antibody treatment “poses a serious problem for millions of immunocompromised individuals who do not respond robustly to COVID-19 vaccines,” the researchers wrote, adding that “the urgent need to develop active monoclonal antibodies for clinical use is obvious.”

A limitation of the study is that the work is done in blood samples. The effectiveness of COVID-19 vaccination against the BQ and XBB subvariants should be evaluated in people in clinical studies, the authors noted.

Also, the current study looked at how well antibodies could neutralize the viral strains, but future research, they added, should look at how well “cellular immunity” or other aspects of the immune system might protect people.

Going forward, the challenge remains to develop vaccines and treatments that offer broad protection as the coronavirus continues to evolve.

In an alarming ending, the researchers wrote: “We have collectively chased after SARS-CoV-2 variants for over 2 years, and yet, the virus continues to evolve and evade.”

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

It’s a story perhaps more appropriate for Halloween than for the festive holiday season, given its scary implications. Four Omicron subvariants of the virus that causes COVID-19 will be the most common strains going from person to person in the winter of 2022-2023, new research predicts.

Not too dire so far, until the researchers’ other findings are considered.

The BQ.1, BQ1.1, XBB, and XBB.1 subvariants are the most resistant to neutralizing antibodies, researcher Qian Wang, PhD, and colleagues wrote in a study published online in the journal Cell. This means people have no or “markedly reduced” protection against infection from these four strains, even if they’ve already had COVID-19 or are vaccinated and boosted multiple times, including with a bivalent vaccine.

On top of that, all available monoclonal antibody treatments are mostly or completely ineffective against these subvariants.

What does that mean for the immediate future? The findings are definitely “worrisome,” said Eric Topol, MD, founder and director of the Scripps Translational Research Institute in La Jolla, Calif.

But evidence from other countries, specifically Singapore and France, show that at least two of these variants turned out not to be as damaging as expected, likely because of high numbers of people vaccinated or who survived previous infections, he said.

Still, there is little to celebrate in the new findings, except that COVID-19 vaccinations and prior infections can still reduce the risk for serious outcomes such as hospitalization and death, the researchers wrote.

In fact, Centers for Disease Control and Prevention data released on Dec. 16 shows that people who have received four shots of the original COVID-19 vaccines as well as the bivalent booster were 57% less likely to visit an urgent care clinic or emergency room, regardless of age. 

It comes at a time when BQ.1 and BQ.1.1 account for about 70% of the circulating variants, data show. In addition, hospitalizations are up 18% over the past 2 weeks and COVID-19 deaths are up 50% nationwide, The New York Times reported.

Globally, in many places, an “immunity wall” that has been built, Dr. Topol said. That may not be the case in the United States.  

“The problem in the United States, making it harder to predict, is that we have a very low rate of recent boosters, in the past 6 months, especially in seniors,” he said. For example, only 36% of Americans aged 65 years and older, the group with highest risk, have received an updated bivalent booster.
 

An evolving virus

The subvariants are successfully replacing BA.5, which reigned as one of the most common Omicron variants over the past year. The latest CDC data show that BA.5 now accounts for only about 10% of the circulating virus. The researchers wrote: “This rapid replacement of virus strains is raising the specter of yet another wave of infections in the coming months.”

BQ.1 and BQ.1.1 evolved directly from BA.5 – adding more and some novel mutations to the SARS-CoV-2 virus. XBB and XBB.1 are the “offspring” of a combination of two other strains, known as BJ.1 and BA.2.75.

The story sounds familiar to the researchers. “The rapid rise of these subvariants and their extensive array of spike mutations are reminiscent of the appearance of the first Omicron variant last year, thus raising concerns that they may further compromise the efficacy of current COVID-19 vaccines and monoclonal antibody therapeutics,” they wrote. “We now report findings that indicate that such concerns are, sadly, justified, especially so for the XBB and XBB.1 subvariants.”

To figure out how effective existing antibodies could be against these newer subvariants, Dr. Wang and colleagues used blood samples from five groups of people. They tested serum from people who had three doses of the original COVID-19 vaccine, four doses of the original vaccine, those who received a bivalent booster, people who experienced a breakthrough infection with the BA.2 Omicron variant, and those who had a breakthrough with a BA.4 or BA.5 variant.

Adding the new subvariants to these serum samples revealed that the existing antibodies in the blood were ineffective at wiping out or neutralizing BQ.1, BQ.1.1, XBB, and XBB.1.

The BQ.1 subvariant was six times more resistant to antibodies than BA.5, its parent strain, and XBB.1 was 63 times more resistant compared with its predecessor, BA.2.

This shift in the ability of vaccines to stop the subvariants “is particularly concerning,” the researchers wrote.
 

Wiping out treatments too

Dr. Wang and colleagues also tested how well a panel of 23 different monoclonal antibody drugs might work against the four subvariants. The therapies all worked well against the original Omicron variant and included some approved for use through the Food and Drug Administration emergency use authorization (EUA) program at the time of the study.

They found that 19 of these 23 monoclonal antibodies lost effectiveness “greatly or completely” against XBB and XBB.1, for example.

This is not the first time that monoclonal antibody therapies have gone from effective to ineffective. Previous variants have come out that no longer responded to treatment with bamlanivimab, etesevimab, imdevimab, casirivimab, tixagevimab, cilgavimab, and sotrovimab. Bebtelovimab now joins this list and is no longer available from Eli Lilly under EUA because of this lack of effectiveness.

The lack of an effective monoclonal antibody treatment “poses a serious problem for millions of immunocompromised individuals who do not respond robustly to COVID-19 vaccines,” the researchers wrote, adding that “the urgent need to develop active monoclonal antibodies for clinical use is obvious.”

A limitation of the study is that the work is done in blood samples. The effectiveness of COVID-19 vaccination against the BQ and XBB subvariants should be evaluated in people in clinical studies, the authors noted.

Also, the current study looked at how well antibodies could neutralize the viral strains, but future research, they added, should look at how well “cellular immunity” or other aspects of the immune system might protect people.

Going forward, the challenge remains to develop vaccines and treatments that offer broad protection as the coronavirus continues to evolve.

In an alarming ending, the researchers wrote: “We have collectively chased after SARS-CoV-2 variants for over 2 years, and yet, the virus continues to evolve and evade.”

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

It’s a story perhaps more appropriate for Halloween than for the festive holiday season, given its scary implications. Four Omicron subvariants of the virus that causes COVID-19 will be the most common strains going from person to person in the winter of 2022-2023, new research predicts.

Not too dire so far, until the researchers’ other findings are considered.

The BQ.1, BQ1.1, XBB, and XBB.1 subvariants are the most resistant to neutralizing antibodies, researcher Qian Wang, PhD, and colleagues wrote in a study published online in the journal Cell. This means people have no or “markedly reduced” protection against infection from these four strains, even if they’ve already had COVID-19 or are vaccinated and boosted multiple times, including with a bivalent vaccine.

On top of that, all available monoclonal antibody treatments are mostly or completely ineffective against these subvariants.

What does that mean for the immediate future? The findings are definitely “worrisome,” said Eric Topol, MD, founder and director of the Scripps Translational Research Institute in La Jolla, Calif.

But evidence from other countries, specifically Singapore and France, show that at least two of these variants turned out not to be as damaging as expected, likely because of high numbers of people vaccinated or who survived previous infections, he said.

Still, there is little to celebrate in the new findings, except that COVID-19 vaccinations and prior infections can still reduce the risk for serious outcomes such as hospitalization and death, the researchers wrote.

In fact, Centers for Disease Control and Prevention data released on Dec. 16 shows that people who have received four shots of the original COVID-19 vaccines as well as the bivalent booster were 57% less likely to visit an urgent care clinic or emergency room, regardless of age. 

It comes at a time when BQ.1 and BQ.1.1 account for about 70% of the circulating variants, data show. In addition, hospitalizations are up 18% over the past 2 weeks and COVID-19 deaths are up 50% nationwide, The New York Times reported.

Globally, in many places, an “immunity wall” that has been built, Dr. Topol said. That may not be the case in the United States.  

“The problem in the United States, making it harder to predict, is that we have a very low rate of recent boosters, in the past 6 months, especially in seniors,” he said. For example, only 36% of Americans aged 65 years and older, the group with highest risk, have received an updated bivalent booster.
 

An evolving virus

The subvariants are successfully replacing BA.5, which reigned as one of the most common Omicron variants over the past year. The latest CDC data show that BA.5 now accounts for only about 10% of the circulating virus. The researchers wrote: “This rapid replacement of virus strains is raising the specter of yet another wave of infections in the coming months.”

BQ.1 and BQ.1.1 evolved directly from BA.5 – adding more and some novel mutations to the SARS-CoV-2 virus. XBB and XBB.1 are the “offspring” of a combination of two other strains, known as BJ.1 and BA.2.75.

The story sounds familiar to the researchers. “The rapid rise of these subvariants and their extensive array of spike mutations are reminiscent of the appearance of the first Omicron variant last year, thus raising concerns that they may further compromise the efficacy of current COVID-19 vaccines and monoclonal antibody therapeutics,” they wrote. “We now report findings that indicate that such concerns are, sadly, justified, especially so for the XBB and XBB.1 subvariants.”

To figure out how effective existing antibodies could be against these newer subvariants, Dr. Wang and colleagues used blood samples from five groups of people. They tested serum from people who had three doses of the original COVID-19 vaccine, four doses of the original vaccine, those who received a bivalent booster, people who experienced a breakthrough infection with the BA.2 Omicron variant, and those who had a breakthrough with a BA.4 or BA.5 variant.

Adding the new subvariants to these serum samples revealed that the existing antibodies in the blood were ineffective at wiping out or neutralizing BQ.1, BQ.1.1, XBB, and XBB.1.

The BQ.1 subvariant was six times more resistant to antibodies than BA.5, its parent strain, and XBB.1 was 63 times more resistant compared with its predecessor, BA.2.

This shift in the ability of vaccines to stop the subvariants “is particularly concerning,” the researchers wrote.
 

Wiping out treatments too

Dr. Wang and colleagues also tested how well a panel of 23 different monoclonal antibody drugs might work against the four subvariants. The therapies all worked well against the original Omicron variant and included some approved for use through the Food and Drug Administration emergency use authorization (EUA) program at the time of the study.

They found that 19 of these 23 monoclonal antibodies lost effectiveness “greatly or completely” against XBB and XBB.1, for example.

This is not the first time that monoclonal antibody therapies have gone from effective to ineffective. Previous variants have come out that no longer responded to treatment with bamlanivimab, etesevimab, imdevimab, casirivimab, tixagevimab, cilgavimab, and sotrovimab. Bebtelovimab now joins this list and is no longer available from Eli Lilly under EUA because of this lack of effectiveness.

The lack of an effective monoclonal antibody treatment “poses a serious problem for millions of immunocompromised individuals who do not respond robustly to COVID-19 vaccines,” the researchers wrote, adding that “the urgent need to develop active monoclonal antibodies for clinical use is obvious.”

A limitation of the study is that the work is done in blood samples. The effectiveness of COVID-19 vaccination against the BQ and XBB subvariants should be evaluated in people in clinical studies, the authors noted.

Also, the current study looked at how well antibodies could neutralize the viral strains, but future research, they added, should look at how well “cellular immunity” or other aspects of the immune system might protect people.

Going forward, the challenge remains to develop vaccines and treatments that offer broad protection as the coronavirus continues to evolve.

In an alarming ending, the researchers wrote: “We have collectively chased after SARS-CoV-2 variants for over 2 years, and yet, the virus continues to evolve and evade.”

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

Congenital hypothyroidism is one of the most common preventable causes of intellectual disabilities worldwide, but newborn screening has not been established in all countries.

Additionally, screening alone is not enough to prevent adverse outcomes in children, write authors of a technical report published online in Pediatrics (Jan. 2023;151[1]:e2022060420).

Susan R. Rose, MD, with the division of endocrinology at Cincinnati Children’s Hospital Medical Center in Ohio, led the work group that updated guidance for screening and management of congenital hypothyroidism. The group worked in conjunction with the American Academy of Pediatrics Section on Endocrinology, the AAP Council on Genetics, the Pediatric Endocrine Society, and the American Thyroid Association.

In addition to screening, timely diagnosis, effective treatment, and follow-up are important.

Tests don’t always tell the full story with congenital hypothyroidism.

“Physicians need to consider hypothyroidism in the face of clinical symptoms, even if newborn screening thyroid test results are normal,” the authors write.

They add that newborn screening for congenital hypothyroidism followed by prompt levothyroxine therapy can prevent severe intellectual disability, psychomotor dysfunction, and impaired growth.

Incidence of congenital hypothyroidism ranges from approximately 1 in 2,000 to 1 in 4,000 newborn infants in countries that have newborn screening data, according to the report.

Following are highlights of the guidance:
 

Clinical signs

Symptoms and signs include large posterior fontanelle, lethargy, large tongue, prolonged jaundice, umbilical hernia, constipation, and/or hypothermia. With these signs, measuring serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) is indicated, regardless of screening results.

Newborn screening in first days

Population screening is cost effective when performed by state or other public health laboratories working with hospitals or birthing centers in their area, the authors write.

Multidisciplinary teams are best able to conduct comprehensive care when cases are detected.

The screening includes a dried blood spot from a heel stick on an approved paper card using appropriate collection methods. The blood spots are then sent to the laboratory. The preferred age for collecting the specimen is 48-72 hours of age.

That timing may be difficult, the authors note, as 90% of infants in the United States and Europe are discharged before 48 hours, but taking the specimen before discharge is important to avoid missing the early diagnosis.

“However, collection of the NBS [newborn screening] specimen before 48 hours of age, and particularly before 24 hours of age, necessitates the use of age-specific TSH reference ranges or repeat screening, particularly to avoid false-positive results,” the authors note.

If a newborn infant is transferred to another hospital, communication about the screening is critical.
 

Testing strategies

Three test strategies are used for screening: a primary TSH – reflex T4 measurement; primary T4 – reflex TSH measurement; and combined T4 and TSH measurement.

“All three test strategies detect moderate to severe primary congenital hypothyroidism with similar accuracy,” the authors write.

Most newborn screening programs in the United States and worldwide use a primary TSH test strategy.
 

Multiple births, same-sex twins

The incidence of congenital hypothyroidism appears to be higher with multiple births (1:876 in twin births and 1:575 in higher-order multiple births in one study). Another study showed the incidence of congenital hypothyroidism in same-sex twins to be 1 in 593, compared with 1 in 3,060 in different-sex twins.

“Most twin pairs (> 95%) are discordant for congenital hypothyroidism,” the authors write. “However, in monozygotic twins who share placental circulation, blood from a euthyroid fetal twin with normal thyroid hormone levels may cross to a fetal twin with congenital hypothyroidism, temporarily correcting the hypothyroidism and preventing its detection by newborn screening at 24-72 hours of life. Thus, all monozygotic twins, or same-sex twins for whom zygosity is unknown, should undergo repeat newborn screening around 2 weeks of age.”
 

Down syndrome

Congenital hypothyroidism incidence in infants with trisomy 21 (Down syndrome) is high and ranges from 1% to 12% in various reports. The infants tend to have lower T4 concentrations and higher TSH concentrations than do infants without trisomy. Down syndrome is associated with other comorbidities, including congenital heart disease, “that may further increase the risk of abnormal newborn screening results because of acute illness or excess iodine exposure,” the authors write.

Even infants with Down syndrome who don’t have congenital hypothyroidism are still at significant risk of developing primary hypothyroidism in their first year (approximately 7% in one prospective study).

“Therefore, in these infants, a second newborn screening should be performed at 2-4 weeks of life and serum TSH should be measured at 6 and 12 months of life,” the authors say.
 

Communication with primary care provider

Direct communication between the newborn screening program and the primary care physician is important for appropriate follow-up. Consulting a pediatric endocrinologist can speed diagnosis and management.

Serum confirmation after abnormal screening

The next step if any child’s screening results suggest congenital hypothyroidism is to perform a physical exam (for goiter, lingual thyroid gland, and/or physical signs of hypothyroidism) and to measure the concentrations of TSH and FT4 (or total T4) in the blood.

For confirmation of abnormal screening results, the authors say, measurement of FT4 is preferred over measuring total T4.
 

Interpreting serum confirmation

Some interpretations are clear cut: “Elevated TSH with low FT4 on the confirmatory serum testing indicates overt primary hypothyroidism,” the authors write.

But there are various other outcomes with more controversy.

Elevated TSH and normal FT4, for instance, is known as hyperthyrotropinemia or subclinical hypothyroidism and represents a mild primary thyroid abnormality.

In this scenario, there is controversy regarding the need for L-T4 therapy because there are few and conflicting studies regarding how mild congenital hypothyroidism affects cognitive development.

“[E]xpert opinion suggests that persistent TSH elevation > 10 mIU/L is an indication to initiate L-T4 treatment,” the authors write.

Normal TSH and low T4 is seen in patients with central hypothyroidism, prematurity, low birth weight, acute illness, or thyroxine-binding globulin deficiency.

“The concept that central hypothyroidism is usually mild appears unfounded: A study from the Netherlands found that mean pretreatment serum FT4 levels in central congenital hypothyroidism were similar to those of patients with moderately severe primary congenital hypothyroidism. Therefore, L-T4 treatment of central congenital hypothyroidism is indicated.”
 

Imaging

Routine thyroid imaging is controversial for patients with congenital hypothyroidism. In most cases, it won’t alter clinical management before age 3 years.

Thyroid ultrasonography can find thyroid tissue without radiation exposure and can be performed at any time after a congenital hypothyroidism diagnosis.

“Ultrasonography has lower sensitivity than scintigraphy for detecting ectopic thyroid tissue, the most common cause of congenital hypothyroidism, although its sensitivity is improved by the use of color Doppler,” the authors write.

Infants with normal thyroid imaging at birth may have transient hypothyroidism. In these patients, reevaluation of thyroid hormone therapy after 3 years of age to assess for persistent hypothyroidism may be beneficial.
 

Treatment

Congenital hypothyroidism is treated with enteral L-T4 at a starting dose of 10-15 mcg/kg per day, given once a day.

L-T4 tablets are the treatment of choice and generic tablets are fine for most children, the authors write, adding that a brand name formulation may be more consistent and better for children with severe congenital hypothyroidism.

An oral solution of L-T4 has been approved by the U.S. Food and Drug Administration for use in children.

“[H]owever, limited experience with its use showed that dosing may not be equivalent to dosing with tablet formulations,” the guidance states.

The goal of initial L-T4 therapy is to normalize serum FT4 and TSH levels as quickly as possible. The outlook is poorer for infants whose hypothyroidism is detected later in life, who receive inadequate doses of L-T4, or who have more severe forms.

Age-specific TSH reference ranges vary by laboratory, but recent studies indicate the top limit of normal TSH in infants in the first 3 months of life is 4.1-4.8 mIU/L.

“[T]herefore, TSH values above 5 mIU/L generally are abnormal if observed after 3 months of age. Whether overtreatment (defined by elevated serum FT4) is harmful remains unclear and evidence is conflicting,” the authors write.
 

Monitoring

In the near-term follow-up, close laboratory monitoring is necessary during L-T4 treatment to maintain blood TSH and FT4 in the target ranges. Studies support measuring those levels every 1-2 months in the first 6 months of life for children with congenital hypothyroidism, every 2-3 months in the second 6 months, and then every 3-4 months between 1 and 3 years of age.

In long-term follow-up, attention to behavioral and cognitive development is important, because children with congenital hypothyroidism may be at higher risk for neurocognitive and socioemotional dysfunction compared with their peers, even with adequate treatment of congenital hypothyroidism. Hearing deficits are reported in about 10% of children with congenital hypothyroidism.
 

Developmental outcomes

When L-T4 therapy is maintained and TSH and FT4 are within target range, growth and adult height are generally normal in children with congenital hypothyroidism.

In contrast, the neurodevelopmental prognosis is less certain when treatment starts late.

“[I]nfants with severe congenital hypothyroidism and intrauterine hypothyroidism (as indicated by retarded skeletal maturation at birth) may have low-to-normal intelligence,” the report states. “Similarly, although more than 80% of infants given L-T4 replacement therapy before 3 months of age have an intelligence [quotient] greater than 85, 77% of these infants show signs of cognitive impairment in arithmetic ability, speech, or fine motor coordination later in life.”

If a child is properly treated for congenital hypothyroidism but growth or development is abnormal, testing for other illness, hearing deficit, or other hormone deficiency is needed, the report states.

The authors report no relevant financial relationships.

Congenital hypothyroidism is one of the most common preventable causes of intellectual disabilities worldwide, but newborn screening has not been established in all countries.

Additionally, screening alone is not enough to prevent adverse outcomes in children, write authors of a technical report published online in Pediatrics (Jan. 2023;151[1]:e2022060420).

Susan R. Rose, MD, with the division of endocrinology at Cincinnati Children’s Hospital Medical Center in Ohio, led the work group that updated guidance for screening and management of congenital hypothyroidism. The group worked in conjunction with the American Academy of Pediatrics Section on Endocrinology, the AAP Council on Genetics, the Pediatric Endocrine Society, and the American Thyroid Association.

In addition to screening, timely diagnosis, effective treatment, and follow-up are important.

Tests don’t always tell the full story with congenital hypothyroidism.

“Physicians need to consider hypothyroidism in the face of clinical symptoms, even if newborn screening thyroid test results are normal,” the authors write.

They add that newborn screening for congenital hypothyroidism followed by prompt levothyroxine therapy can prevent severe intellectual disability, psychomotor dysfunction, and impaired growth.

Incidence of congenital hypothyroidism ranges from approximately 1 in 2,000 to 1 in 4,000 newborn infants in countries that have newborn screening data, according to the report.

Following are highlights of the guidance:
 

Clinical signs

Symptoms and signs include large posterior fontanelle, lethargy, large tongue, prolonged jaundice, umbilical hernia, constipation, and/or hypothermia. With these signs, measuring serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) is indicated, regardless of screening results.

Newborn screening in first days

Population screening is cost effective when performed by state or other public health laboratories working with hospitals or birthing centers in their area, the authors write.

Multidisciplinary teams are best able to conduct comprehensive care when cases are detected.

The screening includes a dried blood spot from a heel stick on an approved paper card using appropriate collection methods. The blood spots are then sent to the laboratory. The preferred age for collecting the specimen is 48-72 hours of age.

That timing may be difficult, the authors note, as 90% of infants in the United States and Europe are discharged before 48 hours, but taking the specimen before discharge is important to avoid missing the early diagnosis.

“However, collection of the NBS [newborn screening] specimen before 48 hours of age, and particularly before 24 hours of age, necessitates the use of age-specific TSH reference ranges or repeat screening, particularly to avoid false-positive results,” the authors note.

If a newborn infant is transferred to another hospital, communication about the screening is critical.
 

Testing strategies

Three test strategies are used for screening: a primary TSH – reflex T4 measurement; primary T4 – reflex TSH measurement; and combined T4 and TSH measurement.

“All three test strategies detect moderate to severe primary congenital hypothyroidism with similar accuracy,” the authors write.

Most newborn screening programs in the United States and worldwide use a primary TSH test strategy.
 

Multiple births, same-sex twins

The incidence of congenital hypothyroidism appears to be higher with multiple births (1:876 in twin births and 1:575 in higher-order multiple births in one study). Another study showed the incidence of congenital hypothyroidism in same-sex twins to be 1 in 593, compared with 1 in 3,060 in different-sex twins.

“Most twin pairs (> 95%) are discordant for congenital hypothyroidism,” the authors write. “However, in monozygotic twins who share placental circulation, blood from a euthyroid fetal twin with normal thyroid hormone levels may cross to a fetal twin with congenital hypothyroidism, temporarily correcting the hypothyroidism and preventing its detection by newborn screening at 24-72 hours of life. Thus, all monozygotic twins, or same-sex twins for whom zygosity is unknown, should undergo repeat newborn screening around 2 weeks of age.”
 

Down syndrome

Congenital hypothyroidism incidence in infants with trisomy 21 (Down syndrome) is high and ranges from 1% to 12% in various reports. The infants tend to have lower T4 concentrations and higher TSH concentrations than do infants without trisomy. Down syndrome is associated with other comorbidities, including congenital heart disease, “that may further increase the risk of abnormal newborn screening results because of acute illness or excess iodine exposure,” the authors write.

Even infants with Down syndrome who don’t have congenital hypothyroidism are still at significant risk of developing primary hypothyroidism in their first year (approximately 7% in one prospective study).

“Therefore, in these infants, a second newborn screening should be performed at 2-4 weeks of life and serum TSH should be measured at 6 and 12 months of life,” the authors say.
 

Communication with primary care provider

Direct communication between the newborn screening program and the primary care physician is important for appropriate follow-up. Consulting a pediatric endocrinologist can speed diagnosis and management.

Serum confirmation after abnormal screening

The next step if any child’s screening results suggest congenital hypothyroidism is to perform a physical exam (for goiter, lingual thyroid gland, and/or physical signs of hypothyroidism) and to measure the concentrations of TSH and FT4 (or total T4) in the blood.

For confirmation of abnormal screening results, the authors say, measurement of FT4 is preferred over measuring total T4.
 

Interpreting serum confirmation

Some interpretations are clear cut: “Elevated TSH with low FT4 on the confirmatory serum testing indicates overt primary hypothyroidism,” the authors write.

But there are various other outcomes with more controversy.

Elevated TSH and normal FT4, for instance, is known as hyperthyrotropinemia or subclinical hypothyroidism and represents a mild primary thyroid abnormality.

In this scenario, there is controversy regarding the need for L-T4 therapy because there are few and conflicting studies regarding how mild congenital hypothyroidism affects cognitive development.

“[E]xpert opinion suggests that persistent TSH elevation > 10 mIU/L is an indication to initiate L-T4 treatment,” the authors write.

Normal TSH and low T4 is seen in patients with central hypothyroidism, prematurity, low birth weight, acute illness, or thyroxine-binding globulin deficiency.

“The concept that central hypothyroidism is usually mild appears unfounded: A study from the Netherlands found that mean pretreatment serum FT4 levels in central congenital hypothyroidism were similar to those of patients with moderately severe primary congenital hypothyroidism. Therefore, L-T4 treatment of central congenital hypothyroidism is indicated.”
 

Imaging

Routine thyroid imaging is controversial for patients with congenital hypothyroidism. In most cases, it won’t alter clinical management before age 3 years.

Thyroid ultrasonography can find thyroid tissue without radiation exposure and can be performed at any time after a congenital hypothyroidism diagnosis.

“Ultrasonography has lower sensitivity than scintigraphy for detecting ectopic thyroid tissue, the most common cause of congenital hypothyroidism, although its sensitivity is improved by the use of color Doppler,” the authors write.

Infants with normal thyroid imaging at birth may have transient hypothyroidism. In these patients, reevaluation of thyroid hormone therapy after 3 years of age to assess for persistent hypothyroidism may be beneficial.
 

Treatment

Congenital hypothyroidism is treated with enteral L-T4 at a starting dose of 10-15 mcg/kg per day, given once a day.

L-T4 tablets are the treatment of choice and generic tablets are fine for most children, the authors write, adding that a brand name formulation may be more consistent and better for children with severe congenital hypothyroidism.

An oral solution of L-T4 has been approved by the U.S. Food and Drug Administration for use in children.

“[H]owever, limited experience with its use showed that dosing may not be equivalent to dosing with tablet formulations,” the guidance states.

The goal of initial L-T4 therapy is to normalize serum FT4 and TSH levels as quickly as possible. The outlook is poorer for infants whose hypothyroidism is detected later in life, who receive inadequate doses of L-T4, or who have more severe forms.

Age-specific TSH reference ranges vary by laboratory, but recent studies indicate the top limit of normal TSH in infants in the first 3 months of life is 4.1-4.8 mIU/L.

“[T]herefore, TSH values above 5 mIU/L generally are abnormal if observed after 3 months of age. Whether overtreatment (defined by elevated serum FT4) is harmful remains unclear and evidence is conflicting,” the authors write.
 

Monitoring

In the near-term follow-up, close laboratory monitoring is necessary during L-T4 treatment to maintain blood TSH and FT4 in the target ranges. Studies support measuring those levels every 1-2 months in the first 6 months of life for children with congenital hypothyroidism, every 2-3 months in the second 6 months, and then every 3-4 months between 1 and 3 years of age.

In long-term follow-up, attention to behavioral and cognitive development is important, because children with congenital hypothyroidism may be at higher risk for neurocognitive and socioemotional dysfunction compared with their peers, even with adequate treatment of congenital hypothyroidism. Hearing deficits are reported in about 10% of children with congenital hypothyroidism.
 

Developmental outcomes

When L-T4 therapy is maintained and TSH and FT4 are within target range, growth and adult height are generally normal in children with congenital hypothyroidism.

In contrast, the neurodevelopmental prognosis is less certain when treatment starts late.

“[I]nfants with severe congenital hypothyroidism and intrauterine hypothyroidism (as indicated by retarded skeletal maturation at birth) may have low-to-normal intelligence,” the report states. “Similarly, although more than 80% of infants given L-T4 replacement therapy before 3 months of age have an intelligence [quotient] greater than 85, 77% of these infants show signs of cognitive impairment in arithmetic ability, speech, or fine motor coordination later in life.”

If a child is properly treated for congenital hypothyroidism but growth or development is abnormal, testing for other illness, hearing deficit, or other hormone deficiency is needed, the report states.

The authors report no relevant financial relationships.

Congenital hypothyroidism is one of the most common preventable causes of intellectual disabilities worldwide, but newborn screening has not been established in all countries.

Additionally, screening alone is not enough to prevent adverse outcomes in children, write authors of a technical report published online in Pediatrics (Jan. 2023;151[1]:e2022060420).

Susan R. Rose, MD, with the division of endocrinology at Cincinnati Children’s Hospital Medical Center in Ohio, led the work group that updated guidance for screening and management of congenital hypothyroidism. The group worked in conjunction with the American Academy of Pediatrics Section on Endocrinology, the AAP Council on Genetics, the Pediatric Endocrine Society, and the American Thyroid Association.

In addition to screening, timely diagnosis, effective treatment, and follow-up are important.

Tests don’t always tell the full story with congenital hypothyroidism.

“Physicians need to consider hypothyroidism in the face of clinical symptoms, even if newborn screening thyroid test results are normal,” the authors write.

They add that newborn screening for congenital hypothyroidism followed by prompt levothyroxine therapy can prevent severe intellectual disability, psychomotor dysfunction, and impaired growth.

Incidence of congenital hypothyroidism ranges from approximately 1 in 2,000 to 1 in 4,000 newborn infants in countries that have newborn screening data, according to the report.

Following are highlights of the guidance:
 

Clinical signs

Symptoms and signs include large posterior fontanelle, lethargy, large tongue, prolonged jaundice, umbilical hernia, constipation, and/or hypothermia. With these signs, measuring serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) is indicated, regardless of screening results.

Newborn screening in first days

Population screening is cost effective when performed by state or other public health laboratories working with hospitals or birthing centers in their area, the authors write.

Multidisciplinary teams are best able to conduct comprehensive care when cases are detected.

The screening includes a dried blood spot from a heel stick on an approved paper card using appropriate collection methods. The blood spots are then sent to the laboratory. The preferred age for collecting the specimen is 48-72 hours of age.

That timing may be difficult, the authors note, as 90% of infants in the United States and Europe are discharged before 48 hours, but taking the specimen before discharge is important to avoid missing the early diagnosis.

“However, collection of the NBS [newborn screening] specimen before 48 hours of age, and particularly before 24 hours of age, necessitates the use of age-specific TSH reference ranges or repeat screening, particularly to avoid false-positive results,” the authors note.

If a newborn infant is transferred to another hospital, communication about the screening is critical.
 

Testing strategies

Three test strategies are used for screening: a primary TSH – reflex T4 measurement; primary T4 – reflex TSH measurement; and combined T4 and TSH measurement.

“All three test strategies detect moderate to severe primary congenital hypothyroidism with similar accuracy,” the authors write.

Most newborn screening programs in the United States and worldwide use a primary TSH test strategy.
 

Multiple births, same-sex twins

The incidence of congenital hypothyroidism appears to be higher with multiple births (1:876 in twin births and 1:575 in higher-order multiple births in one study). Another study showed the incidence of congenital hypothyroidism in same-sex twins to be 1 in 593, compared with 1 in 3,060 in different-sex twins.

“Most twin pairs (> 95%) are discordant for congenital hypothyroidism,” the authors write. “However, in monozygotic twins who share placental circulation, blood from a euthyroid fetal twin with normal thyroid hormone levels may cross to a fetal twin with congenital hypothyroidism, temporarily correcting the hypothyroidism and preventing its detection by newborn screening at 24-72 hours of life. Thus, all monozygotic twins, or same-sex twins for whom zygosity is unknown, should undergo repeat newborn screening around 2 weeks of age.”
 

Down syndrome

Congenital hypothyroidism incidence in infants with trisomy 21 (Down syndrome) is high and ranges from 1% to 12% in various reports. The infants tend to have lower T4 concentrations and higher TSH concentrations than do infants without trisomy. Down syndrome is associated with other comorbidities, including congenital heart disease, “that may further increase the risk of abnormal newborn screening results because of acute illness or excess iodine exposure,” the authors write.

Even infants with Down syndrome who don’t have congenital hypothyroidism are still at significant risk of developing primary hypothyroidism in their first year (approximately 7% in one prospective study).

“Therefore, in these infants, a second newborn screening should be performed at 2-4 weeks of life and serum TSH should be measured at 6 and 12 months of life,” the authors say.
 

Communication with primary care provider

Direct communication between the newborn screening program and the primary care physician is important for appropriate follow-up. Consulting a pediatric endocrinologist can speed diagnosis and management.

Serum confirmation after abnormal screening

The next step if any child’s screening results suggest congenital hypothyroidism is to perform a physical exam (for goiter, lingual thyroid gland, and/or physical signs of hypothyroidism) and to measure the concentrations of TSH and FT4 (or total T4) in the blood.

For confirmation of abnormal screening results, the authors say, measurement of FT4 is preferred over measuring total T4.
 

Interpreting serum confirmation

Some interpretations are clear cut: “Elevated TSH with low FT4 on the confirmatory serum testing indicates overt primary hypothyroidism,” the authors write.

But there are various other outcomes with more controversy.

Elevated TSH and normal FT4, for instance, is known as hyperthyrotropinemia or subclinical hypothyroidism and represents a mild primary thyroid abnormality.

In this scenario, there is controversy regarding the need for L-T4 therapy because there are few and conflicting studies regarding how mild congenital hypothyroidism affects cognitive development.

“[E]xpert opinion suggests that persistent TSH elevation > 10 mIU/L is an indication to initiate L-T4 treatment,” the authors write.

Normal TSH and low T4 is seen in patients with central hypothyroidism, prematurity, low birth weight, acute illness, or thyroxine-binding globulin deficiency.

“The concept that central hypothyroidism is usually mild appears unfounded: A study from the Netherlands found that mean pretreatment serum FT4 levels in central congenital hypothyroidism were similar to those of patients with moderately severe primary congenital hypothyroidism. Therefore, L-T4 treatment of central congenital hypothyroidism is indicated.”
 

Imaging

Routine thyroid imaging is controversial for patients with congenital hypothyroidism. In most cases, it won’t alter clinical management before age 3 years.

Thyroid ultrasonography can find thyroid tissue without radiation exposure and can be performed at any time after a congenital hypothyroidism diagnosis.

“Ultrasonography has lower sensitivity than scintigraphy for detecting ectopic thyroid tissue, the most common cause of congenital hypothyroidism, although its sensitivity is improved by the use of color Doppler,” the authors write.

Infants with normal thyroid imaging at birth may have transient hypothyroidism. In these patients, reevaluation of thyroid hormone therapy after 3 years of age to assess for persistent hypothyroidism may be beneficial.
 

Treatment

Congenital hypothyroidism is treated with enteral L-T4 at a starting dose of 10-15 mcg/kg per day, given once a day.

L-T4 tablets are the treatment of choice and generic tablets are fine for most children, the authors write, adding that a brand name formulation may be more consistent and better for children with severe congenital hypothyroidism.

An oral solution of L-T4 has been approved by the U.S. Food and Drug Administration for use in children.

“[H]owever, limited experience with its use showed that dosing may not be equivalent to dosing with tablet formulations,” the guidance states.

The goal of initial L-T4 therapy is to normalize serum FT4 and TSH levels as quickly as possible. The outlook is poorer for infants whose hypothyroidism is detected later in life, who receive inadequate doses of L-T4, or who have more severe forms.

Age-specific TSH reference ranges vary by laboratory, but recent studies indicate the top limit of normal TSH in infants in the first 3 months of life is 4.1-4.8 mIU/L.

“[T]herefore, TSH values above 5 mIU/L generally are abnormal if observed after 3 months of age. Whether overtreatment (defined by elevated serum FT4) is harmful remains unclear and evidence is conflicting,” the authors write.
 

Monitoring

In the near-term follow-up, close laboratory monitoring is necessary during L-T4 treatment to maintain blood TSH and FT4 in the target ranges. Studies support measuring those levels every 1-2 months in the first 6 months of life for children with congenital hypothyroidism, every 2-3 months in the second 6 months, and then every 3-4 months between 1 and 3 years of age.

In long-term follow-up, attention to behavioral and cognitive development is important, because children with congenital hypothyroidism may be at higher risk for neurocognitive and socioemotional dysfunction compared with their peers, even with adequate treatment of congenital hypothyroidism. Hearing deficits are reported in about 10% of children with congenital hypothyroidism.
 

Developmental outcomes

When L-T4 therapy is maintained and TSH and FT4 are within target range, growth and adult height are generally normal in children with congenital hypothyroidism.

In contrast, the neurodevelopmental prognosis is less certain when treatment starts late.

“[I]nfants with severe congenital hypothyroidism and intrauterine hypothyroidism (as indicated by retarded skeletal maturation at birth) may have low-to-normal intelligence,” the report states. “Similarly, although more than 80% of infants given L-T4 replacement therapy before 3 months of age have an intelligence [quotient] greater than 85, 77% of these infants show signs of cognitive impairment in arithmetic ability, speech, or fine motor coordination later in life.”

If a child is properly treated for congenital hypothyroidism but growth or development is abnormal, testing for other illness, hearing deficit, or other hormone deficiency is needed, the report states.

The authors report no relevant financial relationships.

The U.S. Centers for Disease Control and Prevention has issued extended growth charts to help doctors and researchers better understand patterns of development for the most overweight children and adolescents.

In 2017-2018, more than 4.5 million U.S. youth met the criteria for severe obesity – defined as 120% of the 95th percentile, or 35 kg/m² or greater – according to the CDC.

The new growth charts will not replace the current charts but extend beyond the 97th percentile for body mass index. Formerly, data were extrapolated for anything over the 95th percentile based on evidence from 1963 to 1980, when obesity rates were lower.

The extended growth charts are based on data collected between 1988 and 2015 from young children and adolescents with obesity.

Experts said the expanded charts will allow researchers and clinicians to track the effects of interventions for obesity whether they involve an increase in physical activity, a decrease in consumption, or other interventions. The corresponding z-score charts also are provided.

Physicians should still use the CDC’s BMI-for-age growth charts from 2000 for pediatric patients with BMIs under the 95th percentile. The agency said it does not intend to update those charts.

The definitions of overweight, obesity, and severe obesity remain unchanged.
 

The U.S. Centers for Disease Control and Prevention has issued extended growth charts to help doctors and researchers better understand patterns of development for the most overweight children and adolescents.

In 2017-2018, more than 4.5 million U.S. youth met the criteria for severe obesity – defined as 120% of the 95th percentile, or 35 kg/m² or greater – according to the CDC.

The new growth charts will not replace the current charts but extend beyond the 97th percentile for body mass index. Formerly, data were extrapolated for anything over the 95th percentile based on evidence from 1963 to 1980, when obesity rates were lower.

The extended growth charts are based on data collected between 1988 and 2015 from young children and adolescents with obesity.

Experts said the expanded charts will allow researchers and clinicians to track the effects of interventions for obesity whether they involve an increase in physical activity, a decrease in consumption, or other interventions. The corresponding z-score charts also are provided.

Physicians should still use the CDC’s BMI-for-age growth charts from 2000 for pediatric patients with BMIs under the 95th percentile. The agency said it does not intend to update those charts.

The definitions of overweight, obesity, and severe obesity remain unchanged.
 

The U.S. Centers for Disease Control and Prevention has issued extended growth charts to help doctors and researchers better understand patterns of development for the most overweight children and adolescents.

In 2017-2018, more than 4.5 million U.S. youth met the criteria for severe obesity – defined as 120% of the 95th percentile, or 35 kg/m² or greater – according to the CDC.

The new growth charts will not replace the current charts but extend beyond the 97th percentile for body mass index. Formerly, data were extrapolated for anything over the 95th percentile based on evidence from 1963 to 1980, when obesity rates were lower.

The extended growth charts are based on data collected between 1988 and 2015 from young children and adolescents with obesity.

Experts said the expanded charts will allow researchers and clinicians to track the effects of interventions for obesity whether they involve an increase in physical activity, a decrease in consumption, or other interventions. The corresponding z-score charts also are provided.

Physicians should still use the CDC’s BMI-for-age growth charts from 2000 for pediatric patients with BMIs under the 95th percentile. The agency said it does not intend to update those charts.

The definitions of overweight, obesity, and severe obesity remain unchanged.