Endocrinology

The annual incidence of hip fractures declined in most countries from 2005 to 2018, but this rate is projected to roughly double by 2050, according to a new study of 19 countries/regions.

The study by Chor-Wing Sing, PhD, and colleagues was presented at the annual meeting of the American Society of Bone and Mineral Research. The predicted increase in hip fractures is being driven by the aging population, with the population of those age 85 and older projected to increase 4.5-fold from 2010 to 2050, they note.

The researchers also estimate that from 2018 to 2050 the incidence of fractures will increase by 1.9-fold overall – more in men (2.4-fold) than in women (1.7-fold).

In addition, rates of use of osteoporosis drugs 1 year after a hip fracture were less than 50%, with less treatment in men. Men were also more likely than women to die within 1 year of a hip fracture.

iStock/Thinkstock

Aging will fuel rise in hip fractures; more preventive treatment needed

“Even though there is a decreasing trend of hip fracture incidence in some countries, such a percentage decrease is insufficient to offset the percentage increase in the aging population,” senior co-author Ching-Lung Cheung, PhD, associate professor in the department of pharmacology and pharmacy at the University of Hong Kong, explained to this news organization.

The takeaways from the study are that “a greater effort on fracture prevention should be made to avoid the continuous increase in the number of hip fractures,” he said.

In addition, “although initiation of anti-osteoporosis medication after hip fracture is recommended in international guidelines, the 1-year treatment rate [was] well below 50% in most of the countries and regions studied. This indicates the treatment rate is far from optimal.”

“Our study also showed that the use of anti-osteoporosis medications following a hip fracture is lower in men than in women by 30% to 67%,” he said. “Thus, more attention should be paid to preventing and treating hip fractures in men.”

“The greater increase in the projected number of hip fractures in men than in women “could be [because] osteoporosis is commonly perceived as a ‘woman’s disease,’ ” he speculated.

Invited to comment, Juliet Compston, MD, who selected the study as one of the top clinical science highlight abstracts at the ASBMR meeting, agrees that “there is substantial room for improvement” in osteoporosis treatment rates following a hip fracture “in all the regions covered by the study.”

“In addition,” she continues, “the wide variations in treatment rates can provide important lessons about the most effective models of care for people who sustain a hip fracture: for example, fracture liaison services.”

Men suffer as osteoporosis perceived to be a ‘woman’s disease’

The even lower treatment rate in men than women is “concerning and likely reflects the mistaken perception that osteoporosis is predominantly a disease affecting women,” notes Dr. Compston, emeritus professor of bone medicine, University of Cambridge, United Kingdom.  

Also invited to comment, Peter R. Ebeling, MD, outgoing president of the ASBMR, said that the projected doubling of hip fractures “is likely mainly due to aging of the population, with increasing lifespan for males in particular. However, increasing urbanization and decreasing weight-bearing exercise as a result are likely to also contribute in developing countries.”

“Unfortunately, despite the advances in treatments for osteoporosis over the last 25 years, osteoporosis treatment rates remain low, and osteoporosis remains undiagnosed in postmenopausal women and older men,” added Dr. Ebeling, from Monash University, Melbourne, who was not involved with the research.

“More targeted screening for osteoporosis would help,” he said, “as would treating patients for it following other minimal trauma fractures (vertebral, distal radius, and humerus, etc.), since if left untreated, about 50% of these patients will have hip fractures later in life.”

“Some countries may be doing better because they have health quality standards for hip fracture (for example, surgery within 24 hours, investigation, and treatment for osteoporosis). In other countries like Australia, bone density tests and treatment for osteoporosis are reimbursed, increasing their uptake.”

The public health implications of this study are “substantial” according to Dr. Compston. “People who have sustained a hip fracture are at high risk of subsequent fractures if untreated. There is a range of safe, cost-effective pharmacological therapies to reduce fracture rate, and wider use of these would have a major impact on the current and future burden imposed by hip fractures in the elderly population.”

Similarly, Dr. Ebeling noted that “prevention is important to save a huge health burden for patients and costs for society.”

“Patients with minimal trauma fractures (particularly hip or spinal fractures) should be investigated and treated for osteoporosis with care pathways established in the hospitals, reaching out to the community [fracture liaison services],” he said.

Support for these is being sought under Medicare in the United States, he noted, and bone densitometry reimbursement rates also need to be higher in the United States.
 

Projections for number of hip fractures to 2050

Previous international reviews of hip fractures have been based on heterogeneous data from more than 10 to 30 years ago, the researchers note.

They performed a retrospective cohort study using a common protocol across 19 countries/regions, as described in an article about the protocol published in BMJ Open.

They analyzed data from adults aged 50 and older who were hospitalized with a hip fracture to determine 1) the annual incidence of hip fractures in 2008-2015; 2) the uptake of drugs to treat osteoporosis at 1 year after a hip fracture; and 3) all-cause mortality at 1 year after a hip fracture.

In a second step, they estimated the number of hip fractures that would occur from 2030 to 2050, using World Bank population growth projections.

The data are from 20 health care databases from 19 countries/regions: Oceania (Australia, New Zealand), Asia (Hong Kong, Japan, Singapore, South Korea, Taiwan, and Thailand), Northern Europe (Denmark, Finland, and U.K.), Western Europe (France, Germany, Italy, The Netherlands, and Spain), and North and South America (Canada, United States, and Brazil).

The population in Japan was under age 75. U.S. data are from two databases: Medicare (age ≥ 65) and Optum.

Most databases (13) covered 90%-100% of the national population, and the rest covered 5%-70% of the population.

From 2008 to 2015, the annual incidence of hip fractures declined in 11 countries/regions (Singapore, Denmark, Hong Kong, Taiwan, Finland, U.K., Italy, Spain, United States [Medicare], Canada, and New Zealand).

“One potential reason that some countries have seen relatively large declines in hip fractures is better osteoporosis management and post-fracture care,” said Dr. Sing in a press release issued by ASBMR. “Better fall-prevention programs and clearer guidelines for clinical care have likely made a difference.”

Hip fracture incidence increased in five countries (The Netherlands, South Korea, France, Germany, and Brazil) and was stable in four countries (Australia, Japan, Thailand, and United States [Optum]).

The United Kingdom had the highest rate of osteoporosis treatment at 1-year after a hip fracture (50.3%). Rates in the other countries/regions ranged from 11.5% to 37%.

Fewer men than women were receiving drugs for osteoporosis at 1 year (range 5.1% to 38.2% versus 15.0% to 54.7%).

From 2005 to 2018, rates of osteoporosis treatment at 1 year after a hip fracture declined in six countries, increased in four countries, and were stable in five countries.

All-cause mortality within 1 year of hip fracture was higher in men than in women (range 19.2% to 35.8% versus 12.1% to 25.4%).

“Among the studied countries and regions, the U.S. ranks fifth with the highest hip fracture incidence,” Dr. Cheung replied when specifically asked about this. “The risk of hip fracture is determined by multiple factors: for example, lifestyle, diet, genetics, as well as management of osteoporosis,” he noted.

“Denmark is the only country showing no projected increase, and it is because Denmark had a continuous and remarkable decrease in the incidence of hip fractures,” he added, which “can offset the number of hip fractures contributed by the population aging.”

The study was funded by Amgen. Dr. Sing and Dr. Cheung have reported no relevant financial relationships. One of the study authors is employed by Amgen.

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

The annual incidence of hip fractures declined in most countries from 2005 to 2018, but this rate is projected to roughly double by 2050, according to a new study of 19 countries/regions.

The study by Chor-Wing Sing, PhD, and colleagues was presented at the annual meeting of the American Society of Bone and Mineral Research. The predicted increase in hip fractures is being driven by the aging population, with the population of those age 85 and older projected to increase 4.5-fold from 2010 to 2050, they note.

The researchers also estimate that from 2018 to 2050 the incidence of fractures will increase by 1.9-fold overall – more in men (2.4-fold) than in women (1.7-fold).

In addition, rates of use of osteoporosis drugs 1 year after a hip fracture were less than 50%, with less treatment in men. Men were also more likely than women to die within 1 year of a hip fracture.

iStock/Thinkstock

Aging will fuel rise in hip fractures; more preventive treatment needed

“Even though there is a decreasing trend of hip fracture incidence in some countries, such a percentage decrease is insufficient to offset the percentage increase in the aging population,” senior co-author Ching-Lung Cheung, PhD, associate professor in the department of pharmacology and pharmacy at the University of Hong Kong, explained to this news organization.

The takeaways from the study are that “a greater effort on fracture prevention should be made to avoid the continuous increase in the number of hip fractures,” he said.

In addition, “although initiation of anti-osteoporosis medication after hip fracture is recommended in international guidelines, the 1-year treatment rate [was] well below 50% in most of the countries and regions studied. This indicates the treatment rate is far from optimal.”

“Our study also showed that the use of anti-osteoporosis medications following a hip fracture is lower in men than in women by 30% to 67%,” he said. “Thus, more attention should be paid to preventing and treating hip fractures in men.”

“The greater increase in the projected number of hip fractures in men than in women “could be [because] osteoporosis is commonly perceived as a ‘woman’s disease,’ ” he speculated.

Invited to comment, Juliet Compston, MD, who selected the study as one of the top clinical science highlight abstracts at the ASBMR meeting, agrees that “there is substantial room for improvement” in osteoporosis treatment rates following a hip fracture “in all the regions covered by the study.”

“In addition,” she continues, “the wide variations in treatment rates can provide important lessons about the most effective models of care for people who sustain a hip fracture: for example, fracture liaison services.”

Men suffer as osteoporosis perceived to be a ‘woman’s disease’

The even lower treatment rate in men than women is “concerning and likely reflects the mistaken perception that osteoporosis is predominantly a disease affecting women,” notes Dr. Compston, emeritus professor of bone medicine, University of Cambridge, United Kingdom.  

Also invited to comment, Peter R. Ebeling, MD, outgoing president of the ASBMR, said that the projected doubling of hip fractures “is likely mainly due to aging of the population, with increasing lifespan for males in particular. However, increasing urbanization and decreasing weight-bearing exercise as a result are likely to also contribute in developing countries.”

“Unfortunately, despite the advances in treatments for osteoporosis over the last 25 years, osteoporosis treatment rates remain low, and osteoporosis remains undiagnosed in postmenopausal women and older men,” added Dr. Ebeling, from Monash University, Melbourne, who was not involved with the research.

“More targeted screening for osteoporosis would help,” he said, “as would treating patients for it following other minimal trauma fractures (vertebral, distal radius, and humerus, etc.), since if left untreated, about 50% of these patients will have hip fractures later in life.”

“Some countries may be doing better because they have health quality standards for hip fracture (for example, surgery within 24 hours, investigation, and treatment for osteoporosis). In other countries like Australia, bone density tests and treatment for osteoporosis are reimbursed, increasing their uptake.”

The public health implications of this study are “substantial” according to Dr. Compston. “People who have sustained a hip fracture are at high risk of subsequent fractures if untreated. There is a range of safe, cost-effective pharmacological therapies to reduce fracture rate, and wider use of these would have a major impact on the current and future burden imposed by hip fractures in the elderly population.”

Similarly, Dr. Ebeling noted that “prevention is important to save a huge health burden for patients and costs for society.”

“Patients with minimal trauma fractures (particularly hip or spinal fractures) should be investigated and treated for osteoporosis with care pathways established in the hospitals, reaching out to the community [fracture liaison services],” he said.

Support for these is being sought under Medicare in the United States, he noted, and bone densitometry reimbursement rates also need to be higher in the United States.
 

Projections for number of hip fractures to 2050

Previous international reviews of hip fractures have been based on heterogeneous data from more than 10 to 30 years ago, the researchers note.

They performed a retrospective cohort study using a common protocol across 19 countries/regions, as described in an article about the protocol published in BMJ Open.

They analyzed data from adults aged 50 and older who were hospitalized with a hip fracture to determine 1) the annual incidence of hip fractures in 2008-2015; 2) the uptake of drugs to treat osteoporosis at 1 year after a hip fracture; and 3) all-cause mortality at 1 year after a hip fracture.

In a second step, they estimated the number of hip fractures that would occur from 2030 to 2050, using World Bank population growth projections.

The data are from 20 health care databases from 19 countries/regions: Oceania (Australia, New Zealand), Asia (Hong Kong, Japan, Singapore, South Korea, Taiwan, and Thailand), Northern Europe (Denmark, Finland, and U.K.), Western Europe (France, Germany, Italy, The Netherlands, and Spain), and North and South America (Canada, United States, and Brazil).

The population in Japan was under age 75. U.S. data are from two databases: Medicare (age ≥ 65) and Optum.

Most databases (13) covered 90%-100% of the national population, and the rest covered 5%-70% of the population.

From 2008 to 2015, the annual incidence of hip fractures declined in 11 countries/regions (Singapore, Denmark, Hong Kong, Taiwan, Finland, U.K., Italy, Spain, United States [Medicare], Canada, and New Zealand).

“One potential reason that some countries have seen relatively large declines in hip fractures is better osteoporosis management and post-fracture care,” said Dr. Sing in a press release issued by ASBMR. “Better fall-prevention programs and clearer guidelines for clinical care have likely made a difference.”

Hip fracture incidence increased in five countries (The Netherlands, South Korea, France, Germany, and Brazil) and was stable in four countries (Australia, Japan, Thailand, and United States [Optum]).

The United Kingdom had the highest rate of osteoporosis treatment at 1-year after a hip fracture (50.3%). Rates in the other countries/regions ranged from 11.5% to 37%.

Fewer men than women were receiving drugs for osteoporosis at 1 year (range 5.1% to 38.2% versus 15.0% to 54.7%).

From 2005 to 2018, rates of osteoporosis treatment at 1 year after a hip fracture declined in six countries, increased in four countries, and were stable in five countries.

All-cause mortality within 1 year of hip fracture was higher in men than in women (range 19.2% to 35.8% versus 12.1% to 25.4%).

“Among the studied countries and regions, the U.S. ranks fifth with the highest hip fracture incidence,” Dr. Cheung replied when specifically asked about this. “The risk of hip fracture is determined by multiple factors: for example, lifestyle, diet, genetics, as well as management of osteoporosis,” he noted.

“Denmark is the only country showing no projected increase, and it is because Denmark had a continuous and remarkable decrease in the incidence of hip fractures,” he added, which “can offset the number of hip fractures contributed by the population aging.”

The study was funded by Amgen. Dr. Sing and Dr. Cheung have reported no relevant financial relationships. One of the study authors is employed by Amgen.

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

The annual incidence of hip fractures declined in most countries from 2005 to 2018, but this rate is projected to roughly double by 2050, according to a new study of 19 countries/regions.

The study by Chor-Wing Sing, PhD, and colleagues was presented at the annual meeting of the American Society of Bone and Mineral Research. The predicted increase in hip fractures is being driven by the aging population, with the population of those age 85 and older projected to increase 4.5-fold from 2010 to 2050, they note.

The researchers also estimate that from 2018 to 2050 the incidence of fractures will increase by 1.9-fold overall – more in men (2.4-fold) than in women (1.7-fold).

In addition, rates of use of osteoporosis drugs 1 year after a hip fracture were less than 50%, with less treatment in men. Men were also more likely than women to die within 1 year of a hip fracture.

iStock/Thinkstock

Aging will fuel rise in hip fractures; more preventive treatment needed

“Even though there is a decreasing trend of hip fracture incidence in some countries, such a percentage decrease is insufficient to offset the percentage increase in the aging population,” senior co-author Ching-Lung Cheung, PhD, associate professor in the department of pharmacology and pharmacy at the University of Hong Kong, explained to this news organization.

The takeaways from the study are that “a greater effort on fracture prevention should be made to avoid the continuous increase in the number of hip fractures,” he said.

In addition, “although initiation of anti-osteoporosis medication after hip fracture is recommended in international guidelines, the 1-year treatment rate [was] well below 50% in most of the countries and regions studied. This indicates the treatment rate is far from optimal.”

“Our study also showed that the use of anti-osteoporosis medications following a hip fracture is lower in men than in women by 30% to 67%,” he said. “Thus, more attention should be paid to preventing and treating hip fractures in men.”

“The greater increase in the projected number of hip fractures in men than in women “could be [because] osteoporosis is commonly perceived as a ‘woman’s disease,’ ” he speculated.

Invited to comment, Juliet Compston, MD, who selected the study as one of the top clinical science highlight abstracts at the ASBMR meeting, agrees that “there is substantial room for improvement” in osteoporosis treatment rates following a hip fracture “in all the regions covered by the study.”

“In addition,” she continues, “the wide variations in treatment rates can provide important lessons about the most effective models of care for people who sustain a hip fracture: for example, fracture liaison services.”

Men suffer as osteoporosis perceived to be a ‘woman’s disease’

The even lower treatment rate in men than women is “concerning and likely reflects the mistaken perception that osteoporosis is predominantly a disease affecting women,” notes Dr. Compston, emeritus professor of bone medicine, University of Cambridge, United Kingdom.  

Also invited to comment, Peter R. Ebeling, MD, outgoing president of the ASBMR, said that the projected doubling of hip fractures “is likely mainly due to aging of the population, with increasing lifespan for males in particular. However, increasing urbanization and decreasing weight-bearing exercise as a result are likely to also contribute in developing countries.”

“Unfortunately, despite the advances in treatments for osteoporosis over the last 25 years, osteoporosis treatment rates remain low, and osteoporosis remains undiagnosed in postmenopausal women and older men,” added Dr. Ebeling, from Monash University, Melbourne, who was not involved with the research.

“More targeted screening for osteoporosis would help,” he said, “as would treating patients for it following other minimal trauma fractures (vertebral, distal radius, and humerus, etc.), since if left untreated, about 50% of these patients will have hip fractures later in life.”

“Some countries may be doing better because they have health quality standards for hip fracture (for example, surgery within 24 hours, investigation, and treatment for osteoporosis). In other countries like Australia, bone density tests and treatment for osteoporosis are reimbursed, increasing their uptake.”

The public health implications of this study are “substantial” according to Dr. Compston. “People who have sustained a hip fracture are at high risk of subsequent fractures if untreated. There is a range of safe, cost-effective pharmacological therapies to reduce fracture rate, and wider use of these would have a major impact on the current and future burden imposed by hip fractures in the elderly population.”

Similarly, Dr. Ebeling noted that “prevention is important to save a huge health burden for patients and costs for society.”

“Patients with minimal trauma fractures (particularly hip or spinal fractures) should be investigated and treated for osteoporosis with care pathways established in the hospitals, reaching out to the community [fracture liaison services],” he said.

Support for these is being sought under Medicare in the United States, he noted, and bone densitometry reimbursement rates also need to be higher in the United States.
 

Projections for number of hip fractures to 2050

Previous international reviews of hip fractures have been based on heterogeneous data from more than 10 to 30 years ago, the researchers note.

They performed a retrospective cohort study using a common protocol across 19 countries/regions, as described in an article about the protocol published in BMJ Open.

They analyzed data from adults aged 50 and older who were hospitalized with a hip fracture to determine 1) the annual incidence of hip fractures in 2008-2015; 2) the uptake of drugs to treat osteoporosis at 1 year after a hip fracture; and 3) all-cause mortality at 1 year after a hip fracture.

In a second step, they estimated the number of hip fractures that would occur from 2030 to 2050, using World Bank population growth projections.

The data are from 20 health care databases from 19 countries/regions: Oceania (Australia, New Zealand), Asia (Hong Kong, Japan, Singapore, South Korea, Taiwan, and Thailand), Northern Europe (Denmark, Finland, and U.K.), Western Europe (France, Germany, Italy, The Netherlands, and Spain), and North and South America (Canada, United States, and Brazil).

The population in Japan was under age 75. U.S. data are from two databases: Medicare (age ≥ 65) and Optum.

Most databases (13) covered 90%-100% of the national population, and the rest covered 5%-70% of the population.

From 2008 to 2015, the annual incidence of hip fractures declined in 11 countries/regions (Singapore, Denmark, Hong Kong, Taiwan, Finland, U.K., Italy, Spain, United States [Medicare], Canada, and New Zealand).

“One potential reason that some countries have seen relatively large declines in hip fractures is better osteoporosis management and post-fracture care,” said Dr. Sing in a press release issued by ASBMR. “Better fall-prevention programs and clearer guidelines for clinical care have likely made a difference.”

Hip fracture incidence increased in five countries (The Netherlands, South Korea, France, Germany, and Brazil) and was stable in four countries (Australia, Japan, Thailand, and United States [Optum]).

The United Kingdom had the highest rate of osteoporosis treatment at 1-year after a hip fracture (50.3%). Rates in the other countries/regions ranged from 11.5% to 37%.

Fewer men than women were receiving drugs for osteoporosis at 1 year (range 5.1% to 38.2% versus 15.0% to 54.7%).

From 2005 to 2018, rates of osteoporosis treatment at 1 year after a hip fracture declined in six countries, increased in four countries, and were stable in five countries.

All-cause mortality within 1 year of hip fracture was higher in men than in women (range 19.2% to 35.8% versus 12.1% to 25.4%).

“Among the studied countries and regions, the U.S. ranks fifth with the highest hip fracture incidence,” Dr. Cheung replied when specifically asked about this. “The risk of hip fracture is determined by multiple factors: for example, lifestyle, diet, genetics, as well as management of osteoporosis,” he noted.

“Denmark is the only country showing no projected increase, and it is because Denmark had a continuous and remarkable decrease in the incidence of hip fractures,” he added, which “can offset the number of hip fractures contributed by the population aging.”

The study was funded by Amgen. Dr. Sing and Dr. Cheung have reported no relevant financial relationships. One of the study authors is employed by Amgen.

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

The Crystal Bone (Amgen) novel algorithm predicted 2-year risk of osteoporotic fractures in a large dataset with an accuracy that was consistent with FRAX 10-year risk predictions, researchers report.  

The algorithm was built using machine learning and artificial intelligence to predict fracture risk based on International Classification of Diseases (ICD) codes, as described in an article published in the Journal of Medical Internet Research.

The current validation study was presented September 9 as a poster at the annual meeting of the American Society for Bone and Mineral Research.

The scientists validated the algorithm in more than 100,000 patients aged 50 and older (that is, at risk of fracture) who were part of the Reliant Medical Group dataset (a subset of Optum Care).

Importantly, the algorithm predicted increased fracture in many patients who did not have a diagnosis of osteoporosis.

The next steps are validation in other datasets to support the generalizability of Crystal Bone across U.S. health care systems, Elinor Mody, MD, Reliant Medical Group, and colleagues report.

“Implementation research, in which patients identified by Crystal Bone undergo a bone health assessment and receive ongoing management, will help inform the clinical utility of this novel algorithm,” they conclude.

At the poster session, Tina Kelley, Optum Life Sciences, explained: “It’s a screening tool that says: ‘These are your patients that maybe you should spend a little extra time with, ask a few extra questions.’ ”

However, further study is needed before it should be used in clinical practice, she emphasized to this news organization.

‘A very useful advance’ but needs further validation

Invited to comment, Peter R. Ebeling, MD, outgoing president of the ASBMR, noted that “many clinicians now use FRAX to calculate absolute fracture risk and select patients who should initiate anti-osteoporosis drugs.”

With FRAX, clinicians input a patient’s age, sex, weight, height, previous fracture, [history of] parent with fractured hip, current smoking status, glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol (3 units/day or more), and bone mineral density (by DXA at the femoral neck) into the tool, to obtain a 10-year probability of fracture.

“Crystal Bone takes a different approach,” Dr. Ebeling, from Monash University, Melbourne, who was not involved with the research but who disclosed receiving funding from Amgen, told this news organization in an email.

The algorithm uses electronic health records (EHRs) to identify patients who are likely to have a fracture within the next 2 years, he explained, based on diagnoses and medications associated with osteoporosis and fractures. These include ICD-10 codes for fractures at various sites and secondary causes of osteoporosis (such as rheumatoid and other inflammatory arthritis, chronic obstructive pulmonary disease, asthma, celiac disease, and inflammatory bowel disease).

“This is a very useful advance,” Dr. Ebeling summarized, “in that it would alert the clinician to patients in their practice who have a high fracture risk and need to be investigated for osteoporosis and initiated on treatment. Otherwise, the patients would be missed, as currently often occurs.”

“It would need to be adaptable to other [EMR] systems and to be validated in a large separate population to be ready to enter clinical practice,” he said, “but these data look very promising with a good [positive predictive value (PPV)].”

Similarly, Juliet Compston, MD, said: “It provides a novel, fully automated approach to population-based screening for osteoporosis using EHRs to identify people at high imminent risk of fracture.”

Dr. Compston, emeritus professor of bone medicine, University of Cambridge, England, who was not involved with the research but who also disclosed being a consultant for Amgen, selected the study as one of the top clinical science highlights abstracts at the meeting.

“The algorithm looks at ICD codes for previous history of fracture, medications that have adverse effects on bone – for example glucocorticoids, aromatase inhibitors, and anti-androgens – as well as chronic diseases that increase the risk of fracture,” she explained.

“FRAX is the most commonly used tool to estimate fracture probability in clinical practice and to guide treatment decisions,” she noted. However, “currently it requires human input of data into the FRAX website and is generally only performed on individuals who are selected on the basis of clinical risk factors.”

“The Crystal Bone algorithm offers the potential for fully automated population-based screening in older adults to identify those at high risk of fracture, for whom effective therapies are available to reduce fracture risk,” she summarized.

“It needs further validation,” she noted, “and implementation into clinical practice requires the availability of high-quality EHRs.”
 

Algorithm validated in 106,328 patients aged 50 and older

Despite guidelines that recommend screening for osteoporosis in women aged 65 and older, men older than 70, and adults aged 50-79 with risk factors, real-world data suggest such screening is low, the researchers note.

The current validation study identified 106,328 patients aged 50 and older who had at least 2 years of consecutive medical history with the Reliant Medical Group from December 2014 to November 2020 as well as at least two EHR codes.

The accuracy of predicting a fracture within 2 years, expressed as area under the receiver operating characteristic (AUROC), was 0.77, where 1 is perfect, 0.5 is no better than random selection, 0.7 to 0.8 is acceptable, and 0.8 to 0.9 indicates excellent predictive accuracy.

In the entire Optum Reliant population older than 50, the risk of fracture within 2 years was 1.95%.

The algorithm identified four groups with a greater risk: 19,100 patients had a threefold higher risk of fracture within 2 years, 9,246 patients had a fourfold higher risk, 3,533 patients had a sevenfold higher risk, and 1,735 patients had a ninefold higher risk.

Many of these patients had no prior diagnosis of osteoporosis

For example, in the 19,100 patients with a threefold greater risk of fracture in 2 years, 69% of patients had not been diagnosed with osteoporosis (49% of them had no history of fracture and 20% did have a history of fracture).

The algorithm had a positive predictive value of 6%-18%, a negative predictive value of 98%-99%, a specificity of 81%-98%, and a sensitivity of 18%-59%, for the four groups.

The study was funded by Amgen. Dr. Mody and another author are Reliant Medical Group employees. Ms. Kelley and another author are Optum Life Sciences employees. One author is an employee at Landing AI. Two authors are Amgen employees and own Amgen stock. Dr. Ebeling has disclosed receiving research funding from Amgen, Sanofi, and Alexion, and his institution has received honoraria from Amgen and Kyowa Kirin. Dr. Compston has disclosed receiving speaking and consultancy fees from Amgen and UCB.

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

The Crystal Bone (Amgen) novel algorithm predicted 2-year risk of osteoporotic fractures in a large dataset with an accuracy that was consistent with FRAX 10-year risk predictions, researchers report.  

The algorithm was built using machine learning and artificial intelligence to predict fracture risk based on International Classification of Diseases (ICD) codes, as described in an article published in the Journal of Medical Internet Research.

The current validation study was presented September 9 as a poster at the annual meeting of the American Society for Bone and Mineral Research.

The scientists validated the algorithm in more than 100,000 patients aged 50 and older (that is, at risk of fracture) who were part of the Reliant Medical Group dataset (a subset of Optum Care).

Importantly, the algorithm predicted increased fracture in many patients who did not have a diagnosis of osteoporosis.

The next steps are validation in other datasets to support the generalizability of Crystal Bone across U.S. health care systems, Elinor Mody, MD, Reliant Medical Group, and colleagues report.

“Implementation research, in which patients identified by Crystal Bone undergo a bone health assessment and receive ongoing management, will help inform the clinical utility of this novel algorithm,” they conclude.

At the poster session, Tina Kelley, Optum Life Sciences, explained: “It’s a screening tool that says: ‘These are your patients that maybe you should spend a little extra time with, ask a few extra questions.’ ”

However, further study is needed before it should be used in clinical practice, she emphasized to this news organization.

‘A very useful advance’ but needs further validation

Invited to comment, Peter R. Ebeling, MD, outgoing president of the ASBMR, noted that “many clinicians now use FRAX to calculate absolute fracture risk and select patients who should initiate anti-osteoporosis drugs.”

With FRAX, clinicians input a patient’s age, sex, weight, height, previous fracture, [history of] parent with fractured hip, current smoking status, glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol (3 units/day or more), and bone mineral density (by DXA at the femoral neck) into the tool, to obtain a 10-year probability of fracture.

“Crystal Bone takes a different approach,” Dr. Ebeling, from Monash University, Melbourne, who was not involved with the research but who disclosed receiving funding from Amgen, told this news organization in an email.

The algorithm uses electronic health records (EHRs) to identify patients who are likely to have a fracture within the next 2 years, he explained, based on diagnoses and medications associated with osteoporosis and fractures. These include ICD-10 codes for fractures at various sites and secondary causes of osteoporosis (such as rheumatoid and other inflammatory arthritis, chronic obstructive pulmonary disease, asthma, celiac disease, and inflammatory bowel disease).

“This is a very useful advance,” Dr. Ebeling summarized, “in that it would alert the clinician to patients in their practice who have a high fracture risk and need to be investigated for osteoporosis and initiated on treatment. Otherwise, the patients would be missed, as currently often occurs.”

“It would need to be adaptable to other [EMR] systems and to be validated in a large separate population to be ready to enter clinical practice,” he said, “but these data look very promising with a good [positive predictive value (PPV)].”

Similarly, Juliet Compston, MD, said: “It provides a novel, fully automated approach to population-based screening for osteoporosis using EHRs to identify people at high imminent risk of fracture.”

Dr. Compston, emeritus professor of bone medicine, University of Cambridge, England, who was not involved with the research but who also disclosed being a consultant for Amgen, selected the study as one of the top clinical science highlights abstracts at the meeting.

“The algorithm looks at ICD codes for previous history of fracture, medications that have adverse effects on bone – for example glucocorticoids, aromatase inhibitors, and anti-androgens – as well as chronic diseases that increase the risk of fracture,” she explained.

“FRAX is the most commonly used tool to estimate fracture probability in clinical practice and to guide treatment decisions,” she noted. However, “currently it requires human input of data into the FRAX website and is generally only performed on individuals who are selected on the basis of clinical risk factors.”

“The Crystal Bone algorithm offers the potential for fully automated population-based screening in older adults to identify those at high risk of fracture, for whom effective therapies are available to reduce fracture risk,” she summarized.

“It needs further validation,” she noted, “and implementation into clinical practice requires the availability of high-quality EHRs.”
 

Algorithm validated in 106,328 patients aged 50 and older

Despite guidelines that recommend screening for osteoporosis in women aged 65 and older, men older than 70, and adults aged 50-79 with risk factors, real-world data suggest such screening is low, the researchers note.

The current validation study identified 106,328 patients aged 50 and older who had at least 2 years of consecutive medical history with the Reliant Medical Group from December 2014 to November 2020 as well as at least two EHR codes.

The accuracy of predicting a fracture within 2 years, expressed as area under the receiver operating characteristic (AUROC), was 0.77, where 1 is perfect, 0.5 is no better than random selection, 0.7 to 0.8 is acceptable, and 0.8 to 0.9 indicates excellent predictive accuracy.

In the entire Optum Reliant population older than 50, the risk of fracture within 2 years was 1.95%.

The algorithm identified four groups with a greater risk: 19,100 patients had a threefold higher risk of fracture within 2 years, 9,246 patients had a fourfold higher risk, 3,533 patients had a sevenfold higher risk, and 1,735 patients had a ninefold higher risk.

Many of these patients had no prior diagnosis of osteoporosis

For example, in the 19,100 patients with a threefold greater risk of fracture in 2 years, 69% of patients had not been diagnosed with osteoporosis (49% of them had no history of fracture and 20% did have a history of fracture).

The algorithm had a positive predictive value of 6%-18%, a negative predictive value of 98%-99%, a specificity of 81%-98%, and a sensitivity of 18%-59%, for the four groups.

The study was funded by Amgen. Dr. Mody and another author are Reliant Medical Group employees. Ms. Kelley and another author are Optum Life Sciences employees. One author is an employee at Landing AI. Two authors are Amgen employees and own Amgen stock. Dr. Ebeling has disclosed receiving research funding from Amgen, Sanofi, and Alexion, and his institution has received honoraria from Amgen and Kyowa Kirin. Dr. Compston has disclosed receiving speaking and consultancy fees from Amgen and UCB.

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

The Crystal Bone (Amgen) novel algorithm predicted 2-year risk of osteoporotic fractures in a large dataset with an accuracy that was consistent with FRAX 10-year risk predictions, researchers report.  

The algorithm was built using machine learning and artificial intelligence to predict fracture risk based on International Classification of Diseases (ICD) codes, as described in an article published in the Journal of Medical Internet Research.

The current validation study was presented September 9 as a poster at the annual meeting of the American Society for Bone and Mineral Research.

The scientists validated the algorithm in more than 100,000 patients aged 50 and older (that is, at risk of fracture) who were part of the Reliant Medical Group dataset (a subset of Optum Care).

Importantly, the algorithm predicted increased fracture in many patients who did not have a diagnosis of osteoporosis.

The next steps are validation in other datasets to support the generalizability of Crystal Bone across U.S. health care systems, Elinor Mody, MD, Reliant Medical Group, and colleagues report.

“Implementation research, in which patients identified by Crystal Bone undergo a bone health assessment and receive ongoing management, will help inform the clinical utility of this novel algorithm,” they conclude.

At the poster session, Tina Kelley, Optum Life Sciences, explained: “It’s a screening tool that says: ‘These are your patients that maybe you should spend a little extra time with, ask a few extra questions.’ ”

However, further study is needed before it should be used in clinical practice, she emphasized to this news organization.

‘A very useful advance’ but needs further validation

Invited to comment, Peter R. Ebeling, MD, outgoing president of the ASBMR, noted that “many clinicians now use FRAX to calculate absolute fracture risk and select patients who should initiate anti-osteoporosis drugs.”

With FRAX, clinicians input a patient’s age, sex, weight, height, previous fracture, [history of] parent with fractured hip, current smoking status, glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol (3 units/day or more), and bone mineral density (by DXA at the femoral neck) into the tool, to obtain a 10-year probability of fracture.

“Crystal Bone takes a different approach,” Dr. Ebeling, from Monash University, Melbourne, who was not involved with the research but who disclosed receiving funding from Amgen, told this news organization in an email.

The algorithm uses electronic health records (EHRs) to identify patients who are likely to have a fracture within the next 2 years, he explained, based on diagnoses and medications associated with osteoporosis and fractures. These include ICD-10 codes for fractures at various sites and secondary causes of osteoporosis (such as rheumatoid and other inflammatory arthritis, chronic obstructive pulmonary disease, asthma, celiac disease, and inflammatory bowel disease).

“This is a very useful advance,” Dr. Ebeling summarized, “in that it would alert the clinician to patients in their practice who have a high fracture risk and need to be investigated for osteoporosis and initiated on treatment. Otherwise, the patients would be missed, as currently often occurs.”

“It would need to be adaptable to other [EMR] systems and to be validated in a large separate population to be ready to enter clinical practice,” he said, “but these data look very promising with a good [positive predictive value (PPV)].”

Similarly, Juliet Compston, MD, said: “It provides a novel, fully automated approach to population-based screening for osteoporosis using EHRs to identify people at high imminent risk of fracture.”

Dr. Compston, emeritus professor of bone medicine, University of Cambridge, England, who was not involved with the research but who also disclosed being a consultant for Amgen, selected the study as one of the top clinical science highlights abstracts at the meeting.

“The algorithm looks at ICD codes for previous history of fracture, medications that have adverse effects on bone – for example glucocorticoids, aromatase inhibitors, and anti-androgens – as well as chronic diseases that increase the risk of fracture,” she explained.

“FRAX is the most commonly used tool to estimate fracture probability in clinical practice and to guide treatment decisions,” she noted. However, “currently it requires human input of data into the FRAX website and is generally only performed on individuals who are selected on the basis of clinical risk factors.”

“The Crystal Bone algorithm offers the potential for fully automated population-based screening in older adults to identify those at high risk of fracture, for whom effective therapies are available to reduce fracture risk,” she summarized.

“It needs further validation,” she noted, “and implementation into clinical practice requires the availability of high-quality EHRs.”
 

Algorithm validated in 106,328 patients aged 50 and older

Despite guidelines that recommend screening for osteoporosis in women aged 65 and older, men older than 70, and adults aged 50-79 with risk factors, real-world data suggest such screening is low, the researchers note.

The current validation study identified 106,328 patients aged 50 and older who had at least 2 years of consecutive medical history with the Reliant Medical Group from December 2014 to November 2020 as well as at least two EHR codes.

The accuracy of predicting a fracture within 2 years, expressed as area under the receiver operating characteristic (AUROC), was 0.77, where 1 is perfect, 0.5 is no better than random selection, 0.7 to 0.8 is acceptable, and 0.8 to 0.9 indicates excellent predictive accuracy.

In the entire Optum Reliant population older than 50, the risk of fracture within 2 years was 1.95%.

The algorithm identified four groups with a greater risk: 19,100 patients had a threefold higher risk of fracture within 2 years, 9,246 patients had a fourfold higher risk, 3,533 patients had a sevenfold higher risk, and 1,735 patients had a ninefold higher risk.

Many of these patients had no prior diagnosis of osteoporosis

For example, in the 19,100 patients with a threefold greater risk of fracture in 2 years, 69% of patients had not been diagnosed with osteoporosis (49% of them had no history of fracture and 20% did have a history of fracture).

The algorithm had a positive predictive value of 6%-18%, a negative predictive value of 98%-99%, a specificity of 81%-98%, and a sensitivity of 18%-59%, for the four groups.

The study was funded by Amgen. Dr. Mody and another author are Reliant Medical Group employees. Ms. Kelley and another author are Optum Life Sciences employees. One author is an employee at Landing AI. Two authors are Amgen employees and own Amgen stock. Dr. Ebeling has disclosed receiving research funding from Amgen, Sanofi, and Alexion, and his institution has received honoraria from Amgen and Kyowa Kirin. Dr. Compston has disclosed receiving speaking and consultancy fees from Amgen and UCB.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Certain ultraprocessed foods – especially candy, prepackaged pastries, and frozen desserts – could be “gateway foods” for adolescents, leading them to increase their intake of other unhealthy foods, a new study suggests.

“For teens, gateway ultraprocessed foods (candy, store pastries, frozen desserts) should be prioritized for preventive dietary interventions as they increase intake across all other UPFs,” lead researcher Maria Balhara said in an interview.

“The good news,” said Ms. Balhara, is that even small changes, such as reducing how often gateway foods are consumed, may reduce overall intake of unhealthy foods and have a “big impact” on overall health.

Ms. Balhara has a unique perspective on adolescent eating habits: She’s 16 years old, from Florida, and conducted the study while dual-enrolled at Broward College and Cooper City High School.

Her study was released Sept. 7 ahead of presentation at the American Heart Association Hypertension Scientific Sessions 2022 in San Diego.
 

Blame the pandemic?

Over the past 30 years, there’s been a steady increase in consumption of UPFs worldwide, coupled with mounting evidence that diets rich in UPFs raise the risk for several chronic diseases, including weight gain, hypertension, and increased risk for heart disease and premature death.

For her research, Ms. Balhara asked 315 teenagers (42% male) from 12 high schools in South Florida how often they consumed UPFs over two time periods – before COVID in 2019 and after COVID restrictions were eased in 2022 – using a survey that she developed called the Processed Intake Evaluation (PIE).

More than 2 in 5 teens (43%) increased their consumption of UPFs between 2019 and 2022.

During this time, increased consumption of frozen desserts was associated with an 11% increase in consumption of all other UPFs, whereas increased consumption of prepackaged pastries and candy was associated with a 12% and 31%, respectively, increase in consumption of all other UPFs, Ms. Balhara found.

Encouragingly, 57% of teens decreased their consumption of UPFs between 2019 and 2022.

During this time, decreased consumption of processed meats was associated with an 8% decrease in consumption of all other UPFs, whereas decreased consumption of white bread and biscuits was associated with a 9% and 10%, respectively, decrease in consumption of all other UPFs.

The results provide initial evidence for a new “gateway food model,” Ms. Balhara told this news organization, in which certain UPFs, when increased, drive overall consumption of all UPFs among teens.

Limitations of the study include the self-reported dietary data and the fact that the PIE survey has not been validated.
 

Not all UPFs are bad

“I commend Ms. Balhara for her project, which highlights the importance of establishing good dietary patterns early in life,” Donna K. Arnett, PhD, past president of the AHA, said in a news release.

“The relationship between poor dietary quality and cardiovascular risk factors is well-established. While this is a small, preliminary study, it’s an important topic to continue to investigate and help us understand ways we can influence dietary behaviors to promote optimal cardiovascular health for all ages,” said Dr. Arnett, executive vice president for academic affairs and provost at the University of South Carolina, Columbia.

Offering perspective on the study, Taylor C. Wallace, PhD, with the department of nutrition and food studies, George Mason University, Fairfax, Va., made the point that “food processing and ultraprocessed foods aren’t the problem. The problem is the types of ultraprocessed foods on the market that people consume.”

“Remember, non-fat, vitamin D fortified yogurt is also ‘ultra-processed,’ and it’s very healthy,” he told this news organization.

Dr. Wallace said that it’s no surprise that teens increased their intake of UPFs during the pandemic.

“Of course, people increased processed food intake during the pandemic. Processed foods are shelf stable at a time when grocery stores were running out of things and supply chains weren’t able to keep up. Also, many were depressed and use food to indulge,” he noted.

The study had no funding. Ms. Balhara has no relevant disclosures. Dr. Wallace is principal and CEO of Think Healthy Group; chief food and nutrition scientist with Produce for Better Health Foundation; editor, Journal of Dietary Supplements; deputy editor, Journal of the American College of Nutrition; nutrition section editor, Annals of Medicine; and an advisory board member with Forbes Health.

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

Certain ultraprocessed foods – especially candy, prepackaged pastries, and frozen desserts – could be “gateway foods” for adolescents, leading them to increase their intake of other unhealthy foods, a new study suggests.

“For teens, gateway ultraprocessed foods (candy, store pastries, frozen desserts) should be prioritized for preventive dietary interventions as they increase intake across all other UPFs,” lead researcher Maria Balhara said in an interview.

“The good news,” said Ms. Balhara, is that even small changes, such as reducing how often gateway foods are consumed, may reduce overall intake of unhealthy foods and have a “big impact” on overall health.

Ms. Balhara has a unique perspective on adolescent eating habits: She’s 16 years old, from Florida, and conducted the study while dual-enrolled at Broward College and Cooper City High School.

Her study was released Sept. 7 ahead of presentation at the American Heart Association Hypertension Scientific Sessions 2022 in San Diego.
 

Blame the pandemic?

Over the past 30 years, there’s been a steady increase in consumption of UPFs worldwide, coupled with mounting evidence that diets rich in UPFs raise the risk for several chronic diseases, including weight gain, hypertension, and increased risk for heart disease and premature death.

For her research, Ms. Balhara asked 315 teenagers (42% male) from 12 high schools in South Florida how often they consumed UPFs over two time periods – before COVID in 2019 and after COVID restrictions were eased in 2022 – using a survey that she developed called the Processed Intake Evaluation (PIE).

More than 2 in 5 teens (43%) increased their consumption of UPFs between 2019 and 2022.

During this time, increased consumption of frozen desserts was associated with an 11% increase in consumption of all other UPFs, whereas increased consumption of prepackaged pastries and candy was associated with a 12% and 31%, respectively, increase in consumption of all other UPFs, Ms. Balhara found.

Encouragingly, 57% of teens decreased their consumption of UPFs between 2019 and 2022.

During this time, decreased consumption of processed meats was associated with an 8% decrease in consumption of all other UPFs, whereas decreased consumption of white bread and biscuits was associated with a 9% and 10%, respectively, decrease in consumption of all other UPFs.

The results provide initial evidence for a new “gateway food model,” Ms. Balhara told this news organization, in which certain UPFs, when increased, drive overall consumption of all UPFs among teens.

Limitations of the study include the self-reported dietary data and the fact that the PIE survey has not been validated.
 

Not all UPFs are bad

“I commend Ms. Balhara for her project, which highlights the importance of establishing good dietary patterns early in life,” Donna K. Arnett, PhD, past president of the AHA, said in a news release.

“The relationship between poor dietary quality and cardiovascular risk factors is well-established. While this is a small, preliminary study, it’s an important topic to continue to investigate and help us understand ways we can influence dietary behaviors to promote optimal cardiovascular health for all ages,” said Dr. Arnett, executive vice president for academic affairs and provost at the University of South Carolina, Columbia.

Offering perspective on the study, Taylor C. Wallace, PhD, with the department of nutrition and food studies, George Mason University, Fairfax, Va., made the point that “food processing and ultraprocessed foods aren’t the problem. The problem is the types of ultraprocessed foods on the market that people consume.”

“Remember, non-fat, vitamin D fortified yogurt is also ‘ultra-processed,’ and it’s very healthy,” he told this news organization.

Dr. Wallace said that it’s no surprise that teens increased their intake of UPFs during the pandemic.

“Of course, people increased processed food intake during the pandemic. Processed foods are shelf stable at a time when grocery stores were running out of things and supply chains weren’t able to keep up. Also, many were depressed and use food to indulge,” he noted.

The study had no funding. Ms. Balhara has no relevant disclosures. Dr. Wallace is principal and CEO of Think Healthy Group; chief food and nutrition scientist with Produce for Better Health Foundation; editor, Journal of Dietary Supplements; deputy editor, Journal of the American College of Nutrition; nutrition section editor, Annals of Medicine; and an advisory board member with Forbes Health.

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

Certain ultraprocessed foods – especially candy, prepackaged pastries, and frozen desserts – could be “gateway foods” for adolescents, leading them to increase their intake of other unhealthy foods, a new study suggests.

“For teens, gateway ultraprocessed foods (candy, store pastries, frozen desserts) should be prioritized for preventive dietary interventions as they increase intake across all other UPFs,” lead researcher Maria Balhara said in an interview.

“The good news,” said Ms. Balhara, is that even small changes, such as reducing how often gateway foods are consumed, may reduce overall intake of unhealthy foods and have a “big impact” on overall health.

Ms. Balhara has a unique perspective on adolescent eating habits: She’s 16 years old, from Florida, and conducted the study while dual-enrolled at Broward College and Cooper City High School.

Her study was released Sept. 7 ahead of presentation at the American Heart Association Hypertension Scientific Sessions 2022 in San Diego.
 

Blame the pandemic?

Over the past 30 years, there’s been a steady increase in consumption of UPFs worldwide, coupled with mounting evidence that diets rich in UPFs raise the risk for several chronic diseases, including weight gain, hypertension, and increased risk for heart disease and premature death.

For her research, Ms. Balhara asked 315 teenagers (42% male) from 12 high schools in South Florida how often they consumed UPFs over two time periods – before COVID in 2019 and after COVID restrictions were eased in 2022 – using a survey that she developed called the Processed Intake Evaluation (PIE).

More than 2 in 5 teens (43%) increased their consumption of UPFs between 2019 and 2022.

During this time, increased consumption of frozen desserts was associated with an 11% increase in consumption of all other UPFs, whereas increased consumption of prepackaged pastries and candy was associated with a 12% and 31%, respectively, increase in consumption of all other UPFs, Ms. Balhara found.

Encouragingly, 57% of teens decreased their consumption of UPFs between 2019 and 2022.

During this time, decreased consumption of processed meats was associated with an 8% decrease in consumption of all other UPFs, whereas decreased consumption of white bread and biscuits was associated with a 9% and 10%, respectively, decrease in consumption of all other UPFs.

The results provide initial evidence for a new “gateway food model,” Ms. Balhara told this news organization, in which certain UPFs, when increased, drive overall consumption of all UPFs among teens.

Limitations of the study include the self-reported dietary data and the fact that the PIE survey has not been validated.
 

Not all UPFs are bad

“I commend Ms. Balhara for her project, which highlights the importance of establishing good dietary patterns early in life,” Donna K. Arnett, PhD, past president of the AHA, said in a news release.

“The relationship between poor dietary quality and cardiovascular risk factors is well-established. While this is a small, preliminary study, it’s an important topic to continue to investigate and help us understand ways we can influence dietary behaviors to promote optimal cardiovascular health for all ages,” said Dr. Arnett, executive vice president for academic affairs and provost at the University of South Carolina, Columbia.

Offering perspective on the study, Taylor C. Wallace, PhD, with the department of nutrition and food studies, George Mason University, Fairfax, Va., made the point that “food processing and ultraprocessed foods aren’t the problem. The problem is the types of ultraprocessed foods on the market that people consume.”

“Remember, non-fat, vitamin D fortified yogurt is also ‘ultra-processed,’ and it’s very healthy,” he told this news organization.

Dr. Wallace said that it’s no surprise that teens increased their intake of UPFs during the pandemic.

“Of course, people increased processed food intake during the pandemic. Processed foods are shelf stable at a time when grocery stores were running out of things and supply chains weren’t able to keep up. Also, many were depressed and use food to indulge,” he noted.

The study had no funding. Ms. Balhara has no relevant disclosures. Dr. Wallace is principal and CEO of Think Healthy Group; chief food and nutrition scientist with Produce for Better Health Foundation; editor, Journal of Dietary Supplements; deputy editor, Journal of the American College of Nutrition; nutrition section editor, Annals of Medicine; and an advisory board member with Forbes Health.

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

New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

The first major revision in the systematic description of ovulatory disorders in nearly 50 years has been proposed by a consensus of experts organized by the International Federation of Gynecology and Obstetrics.

“The FIGO HyPO-P system for the classification of ovulatory disorders is submitted for consideration as a worldwide standard,” according to the writing committee, who published their methodology and their proposed applications in the International Journal of Gynecology and Obstetrics.

The classification system was created to replace the much-modified World Health Organization system first described in 1973. Since that time, many modifications have been proposed to accommodate advances in imaging and new information about underlying pathologies, but there has been no subsequent authoritative reference with these modifications or any other newer organizing system.

The new system “provides a different structure for determining the diagnosis. Blood tests are not a necessary first step,” explained Malcolm G. Munro, MD, clinical professor, department of obstetrics and gynecology, University of California, Los Angeles. Dr. Munro was the first author of the publication.

The classification system “is not as focused on the specific steps for investigation of ovulatory dysfunction as much as it explains how to structure an investigation of the girl or woman with an ovulatory disorder and then how to characterize the underlying cause,” Dr. Munro said in an interview. “It is designed to allow everyone, whether clinicians, researchers, or patients, to speak the same language.”
 

New system employs four categories

The four primary categories provide just the first level of classification. The next step is encapsulated in the GAIN-FIT-PIE acronym, which frames the presumed or documented categories of etiologies for the primary categories. GAIN stands for genetic, autoimmune, iatrogenic, or neoplasm etiologies. FIT stands for functional, infectious/inflammatory, or trauma and vascular etiologies. PIE stands for physiological, idiopathic, and endocrine etiologies.

By this methodology, a patient with irregular menses, galactorrhea, and elevated prolactin and an MRI showing a pituitary tumor would be identified a type 2-N, signifying pituitary (type 2) involvement with a neoplasm (N).

A third level of classification permits specific diagnostic entities to be named, allowing the patient in the example above to receive a diagnosis of a prolactin-secreting adenoma.

Not all etiologies can be identified with current diagnostic studies, even assuming clinicians have access to the resources, such as advanced imaging, that will increase diagnostic yield. As a result, the authors acknowledged that the classification system will be “aspirational” in at least some patients, but the structure of this system is expected to lead to greater precision in understanding the causes and defining features of ovulatory disorders, which, in turn, might facilitate new research initiatives.

In the published report, diagnostic protocols based on symptoms were described as being “beyond the spectrum” of this initial description. Rather, Dr. Munro explained that the most important contribution of this new classification system are standardization and communication. The system will be amenable for educating trainees and patients, for communicating between clinicians, and as a framework for research where investigators focus on more homogeneous populations of patients.

“There are many causes of ovulatory disorders that are not related to ovarian function. This is one message. Another is that ovulatory disorders are not binary. They occur on a spectrum. These range from transient instances of delayed or failed ovulation to chronic anovulation,” he said.

The new system is “ a welcome update,” according to Mark P. Trolice, MD, director of the IVF Center and professor of obstetrics and gynecology at the University of Central Florida, both in Orlando.

Dr. Trolice pointed to the clinical value of placing PCOS in a separate category. He noted that it affects 8%-13% of women, making it the most common single cause of ovulatory dysfunction.

“Another area that required clarification from prior WHO classifications was hyperprolactinemia, which is now placed in the type II category,” Dr. Trolice said in an interview.

Better terminology can help address a complex set of disorders with multiple causes and variable manifestations.

“In the evaluation of ovulation dysfunction, it is important to remember that regular menstrual intervals do not ensure ovulation,” Dr. Trolice pointed out. Even though a serum progesterone level of higher than 3 ng/mL is one of the simplest laboratory markers for ovulation, this level, he noted, “can vary through the luteal phase and even throughout the day.”

The proposed classification system, while providing a framework for describing ovulatory disorders, is designed to be adaptable, permitting advances in the understanding of the causes of ovulatory dysfunction, in the diagnosis of the causes, and in the treatments to be incorporated.

“No system should be considered permanent,” according to Dr. Munro and his coauthors. “Review and careful modification and revision should be carried out regularly.”

Dr. Munro reports financial relationships with AbbVie, American Regent, Daiichi Sankyo, Hologic, Myovant, and Pharmacosmos. Dr. Trolice reports no potential conflicts of interest.
 

The first major revision in the systematic description of ovulatory disorders in nearly 50 years has been proposed by a consensus of experts organized by the International Federation of Gynecology and Obstetrics.

“The FIGO HyPO-P system for the classification of ovulatory disorders is submitted for consideration as a worldwide standard,” according to the writing committee, who published their methodology and their proposed applications in the International Journal of Gynecology and Obstetrics.

The classification system was created to replace the much-modified World Health Organization system first described in 1973. Since that time, many modifications have been proposed to accommodate advances in imaging and new information about underlying pathologies, but there has been no subsequent authoritative reference with these modifications or any other newer organizing system.

The new system “provides a different structure for determining the diagnosis. Blood tests are not a necessary first step,” explained Malcolm G. Munro, MD, clinical professor, department of obstetrics and gynecology, University of California, Los Angeles. Dr. Munro was the first author of the publication.

The classification system “is not as focused on the specific steps for investigation of ovulatory dysfunction as much as it explains how to structure an investigation of the girl or woman with an ovulatory disorder and then how to characterize the underlying cause,” Dr. Munro said in an interview. “It is designed to allow everyone, whether clinicians, researchers, or patients, to speak the same language.”
 

New system employs four categories

The four primary categories provide just the first level of classification. The next step is encapsulated in the GAIN-FIT-PIE acronym, which frames the presumed or documented categories of etiologies for the primary categories. GAIN stands for genetic, autoimmune, iatrogenic, or neoplasm etiologies. FIT stands for functional, infectious/inflammatory, or trauma and vascular etiologies. PIE stands for physiological, idiopathic, and endocrine etiologies.

By this methodology, a patient with irregular menses, galactorrhea, and elevated prolactin and an MRI showing a pituitary tumor would be identified a type 2-N, signifying pituitary (type 2) involvement with a neoplasm (N).

A third level of classification permits specific diagnostic entities to be named, allowing the patient in the example above to receive a diagnosis of a prolactin-secreting adenoma.

Not all etiologies can be identified with current diagnostic studies, even assuming clinicians have access to the resources, such as advanced imaging, that will increase diagnostic yield. As a result, the authors acknowledged that the classification system will be “aspirational” in at least some patients, but the structure of this system is expected to lead to greater precision in understanding the causes and defining features of ovulatory disorders, which, in turn, might facilitate new research initiatives.

In the published report, diagnostic protocols based on symptoms were described as being “beyond the spectrum” of this initial description. Rather, Dr. Munro explained that the most important contribution of this new classification system are standardization and communication. The system will be amenable for educating trainees and patients, for communicating between clinicians, and as a framework for research where investigators focus on more homogeneous populations of patients.

“There are many causes of ovulatory disorders that are not related to ovarian function. This is one message. Another is that ovulatory disorders are not binary. They occur on a spectrum. These range from transient instances of delayed or failed ovulation to chronic anovulation,” he said.

The new system is “ a welcome update,” according to Mark P. Trolice, MD, director of the IVF Center and professor of obstetrics and gynecology at the University of Central Florida, both in Orlando.

Dr. Trolice pointed to the clinical value of placing PCOS in a separate category. He noted that it affects 8%-13% of women, making it the most common single cause of ovulatory dysfunction.

“Another area that required clarification from prior WHO classifications was hyperprolactinemia, which is now placed in the type II category,” Dr. Trolice said in an interview.

Better terminology can help address a complex set of disorders with multiple causes and variable manifestations.

“In the evaluation of ovulation dysfunction, it is important to remember that regular menstrual intervals do not ensure ovulation,” Dr. Trolice pointed out. Even though a serum progesterone level of higher than 3 ng/mL is one of the simplest laboratory markers for ovulation, this level, he noted, “can vary through the luteal phase and even throughout the day.”

The proposed classification system, while providing a framework for describing ovulatory disorders, is designed to be adaptable, permitting advances in the understanding of the causes of ovulatory dysfunction, in the diagnosis of the causes, and in the treatments to be incorporated.

“No system should be considered permanent,” according to Dr. Munro and his coauthors. “Review and careful modification and revision should be carried out regularly.”

Dr. Munro reports financial relationships with AbbVie, American Regent, Daiichi Sankyo, Hologic, Myovant, and Pharmacosmos. Dr. Trolice reports no potential conflicts of interest.
 

The first major revision in the systematic description of ovulatory disorders in nearly 50 years has been proposed by a consensus of experts organized by the International Federation of Gynecology and Obstetrics.

“The FIGO HyPO-P system for the classification of ovulatory disorders is submitted for consideration as a worldwide standard,” according to the writing committee, who published their methodology and their proposed applications in the International Journal of Gynecology and Obstetrics.

The classification system was created to replace the much-modified World Health Organization system first described in 1973. Since that time, many modifications have been proposed to accommodate advances in imaging and new information about underlying pathologies, but there has been no subsequent authoritative reference with these modifications or any other newer organizing system.

The new system “provides a different structure for determining the diagnosis. Blood tests are not a necessary first step,” explained Malcolm G. Munro, MD, clinical professor, department of obstetrics and gynecology, University of California, Los Angeles. Dr. Munro was the first author of the publication.

The classification system “is not as focused on the specific steps for investigation of ovulatory dysfunction as much as it explains how to structure an investigation of the girl or woman with an ovulatory disorder and then how to characterize the underlying cause,” Dr. Munro said in an interview. “It is designed to allow everyone, whether clinicians, researchers, or patients, to speak the same language.”
 

New system employs four categories

The four primary categories provide just the first level of classification. The next step is encapsulated in the GAIN-FIT-PIE acronym, which frames the presumed or documented categories of etiologies for the primary categories. GAIN stands for genetic, autoimmune, iatrogenic, or neoplasm etiologies. FIT stands for functional, infectious/inflammatory, or trauma and vascular etiologies. PIE stands for physiological, idiopathic, and endocrine etiologies.

By this methodology, a patient with irregular menses, galactorrhea, and elevated prolactin and an MRI showing a pituitary tumor would be identified a type 2-N, signifying pituitary (type 2) involvement with a neoplasm (N).

A third level of classification permits specific diagnostic entities to be named, allowing the patient in the example above to receive a diagnosis of a prolactin-secreting adenoma.

Not all etiologies can be identified with current diagnostic studies, even assuming clinicians have access to the resources, such as advanced imaging, that will increase diagnostic yield. As a result, the authors acknowledged that the classification system will be “aspirational” in at least some patients, but the structure of this system is expected to lead to greater precision in understanding the causes and defining features of ovulatory disorders, which, in turn, might facilitate new research initiatives.

In the published report, diagnostic protocols based on symptoms were described as being “beyond the spectrum” of this initial description. Rather, Dr. Munro explained that the most important contribution of this new classification system are standardization and communication. The system will be amenable for educating trainees and patients, for communicating between clinicians, and as a framework for research where investigators focus on more homogeneous populations of patients.

“There are many causes of ovulatory disorders that are not related to ovarian function. This is one message. Another is that ovulatory disorders are not binary. They occur on a spectrum. These range from transient instances of delayed or failed ovulation to chronic anovulation,” he said.

The new system is “ a welcome update,” according to Mark P. Trolice, MD, director of the IVF Center and professor of obstetrics and gynecology at the University of Central Florida, both in Orlando.

Dr. Trolice pointed to the clinical value of placing PCOS in a separate category. He noted that it affects 8%-13% of women, making it the most common single cause of ovulatory dysfunction.

“Another area that required clarification from prior WHO classifications was hyperprolactinemia, which is now placed in the type II category,” Dr. Trolice said in an interview.

Better terminology can help address a complex set of disorders with multiple causes and variable manifestations.

“In the evaluation of ovulation dysfunction, it is important to remember that regular menstrual intervals do not ensure ovulation,” Dr. Trolice pointed out. Even though a serum progesterone level of higher than 3 ng/mL is one of the simplest laboratory markers for ovulation, this level, he noted, “can vary through the luteal phase and even throughout the day.”

The proposed classification system, while providing a framework for describing ovulatory disorders, is designed to be adaptable, permitting advances in the understanding of the causes of ovulatory dysfunction, in the diagnosis of the causes, and in the treatments to be incorporated.

“No system should be considered permanent,” according to Dr. Munro and his coauthors. “Review and careful modification and revision should be carried out regularly.”

Dr. Munro reports financial relationships with AbbVie, American Regent, Daiichi Sankyo, Hologic, Myovant, and Pharmacosmos. Dr. Trolice reports no potential conflicts of interest.
 

A new study provides more evidence that people with thyroid autoimmunity are more likely than are others to develop papillary thyroid cancer (odds ratio [OR] = 1.90, 95% confidence interval [CI], 1.33-2.70), although the overall risk remains very low. 
Researchers aren't recommending routine screening in all patients with thyroid autoimmunity, but they're calling for more research into whether it's a good idea in severe cases. "This is the one circumstance where screening for subclinical disease could make sense," said Donald McLeod, MPH, PhD, an epidemiologist at Royal Brisbane & Women's Hospital in Australia and lead author of the study, published in the Journal of Clinical Oncology. "However, more research is needed because our study is the first to show this result, and we need to prove that screening would make a difference to the prognosis of these patients." 
According to Dr. McLeod, "doctors and patients have been wondering about the connection between thyroid autoimmunity and thyroid cancer for many years. In fact, the first report was in 1955. While the association was plausible, all previous studies had potential for biases that could have influenced the results." 
For example, he said, multiple studies didn't control for confounders, while others didn't account for the possibility that cancer could have triggered an immune response. "Other case-control studies could have been affected by selection bias, where a diagnosis of thyroid autoimmunity leads to thyroid cancer identification and entry into the study," he said. "Finally, medical surveillance of people diagnosed with thyroid autoimmunity could lead to overdiagnosis, where small, subclinical cancers are diagnosed in those patients but not identified in people who are not under medical follow-up." 
For the new retrospective case-control study, researchers compared 451 active-duty members of the U.S. military who developed papillary thyroid cancer from the period of 1996-2014 to matched controls (61% of all subjects were men and the mean age was 36). Those with cancer had their serum collected 3-5 years and 7-10 years before the date of diagnosis - the index date for all subjects. Some of those considered to have thyroid autoimmunity had conditions such as Graves' disease and Hashimoto's thyroiditis. 
"Eighty-five percent of cases (379 of 451) had a thyroid-related diagnosis recorded ... before their index date, compared with 5% of controls," the researchers reported. "Most cases (80%) had classical papillary thyroid cancer, with the rest having the follicular variant of papillary thyroid cancer."  
After adjustment to account for various confounders, those who were positive for thyroid peroxidase antibodies 7-10 years prior to the index date were more likely to have developed thyroid cancer (OR = 1.90, 95% CI, 1.33-2.70). "The results could not be fully explained by diagnosis of thyroid autoimmunity," the researchers reported, "although when autoimmunity had been identified, thyroid cancers were diagnosed at a very early stage." 
Two groups - those with the highest thyroid antibody levels and women - faced the greatest risk, Dr. McLeod said. The results regarding women were the most surprising in the study, he said. "This is the first time this has been found. We think this result needs to be confirmed. If true, it could explain why women have a three-times-higher risk of thyroid cancer than men." 
The overall incidence of thyroid cancer in the U.S. was estimated at 13.49 per 100,000 person-years in 2018, with women (76% of cases) and Whites (81%) accounting for the majority. Rates have nearly doubled since 2000. The authors of a 2022 report that disclosed these numbers suggest the rise is due to overdiagnosis of small tumors. 
It's not clear why thyroid autoimmunity and thyroid cancer may be linked. "Chronic inflammation from thyroid autoimmunity could cause thyroid cancer, as chronic inflammation in other organs precedes cancers at those sites," Dr. McLeod said. "Alternatively, thyroid autoimmunity could appear to be associated with thyroid cancer because of biases inherent in previous studies, including previous diagnosis of autoimmunity. Thyroid cancer could also induce an immune response, which mimics thyroid autoimmunity and could bias assessment." 
As for screening of patients with thyroid autoimmunity, "the main danger is that you will commonly identify small thyroid cancers that would never become clinically apparent," he said. "This leads to unnecessary treatments that can cause complications and give people a cancer label, which can also cause harm. Diagnosis and treatment guidelines recommend against screening the general population for this reason." 
Many of those with thyroid autoimmunity developed small cancers, he said, most likely "detected from ultrasound being performed because autoimmune thyroid disease was known. If all patients with thyroid autoimmunity were screened for thyroid cancer, the likelihood is that many people's cancers would be overdiagnosed." 
The study was funded by the Walton Family Foundation. Dr. McLeod reports no disclosures. Some of the authors report various relationships with industry.

A new study provides more evidence that people with thyroid autoimmunity are more likely than are others to develop papillary thyroid cancer (odds ratio [OR] = 1.90, 95% confidence interval [CI], 1.33-2.70), although the overall risk remains very low. 
Researchers aren't recommending routine screening in all patients with thyroid autoimmunity, but they're calling for more research into whether it's a good idea in severe cases. "This is the one circumstance where screening for subclinical disease could make sense," said Donald McLeod, MPH, PhD, an epidemiologist at Royal Brisbane & Women's Hospital in Australia and lead author of the study, published in the Journal of Clinical Oncology. "However, more research is needed because our study is the first to show this result, and we need to prove that screening would make a difference to the prognosis of these patients." 
According to Dr. McLeod, "doctors and patients have been wondering about the connection between thyroid autoimmunity and thyroid cancer for many years. In fact, the first report was in 1955. While the association was plausible, all previous studies had potential for biases that could have influenced the results." 
For example, he said, multiple studies didn't control for confounders, while others didn't account for the possibility that cancer could have triggered an immune response. "Other case-control studies could have been affected by selection bias, where a diagnosis of thyroid autoimmunity leads to thyroid cancer identification and entry into the study," he said. "Finally, medical surveillance of people diagnosed with thyroid autoimmunity could lead to overdiagnosis, where small, subclinical cancers are diagnosed in those patients but not identified in people who are not under medical follow-up." 
For the new retrospective case-control study, researchers compared 451 active-duty members of the U.S. military who developed papillary thyroid cancer from the period of 1996-2014 to matched controls (61% of all subjects were men and the mean age was 36). Those with cancer had their serum collected 3-5 years and 7-10 years before the date of diagnosis - the index date for all subjects. Some of those considered to have thyroid autoimmunity had conditions such as Graves' disease and Hashimoto's thyroiditis. 
"Eighty-five percent of cases (379 of 451) had a thyroid-related diagnosis recorded ... before their index date, compared with 5% of controls," the researchers reported. "Most cases (80%) had classical papillary thyroid cancer, with the rest having the follicular variant of papillary thyroid cancer."  
After adjustment to account for various confounders, those who were positive for thyroid peroxidase antibodies 7-10 years prior to the index date were more likely to have developed thyroid cancer (OR = 1.90, 95% CI, 1.33-2.70). "The results could not be fully explained by diagnosis of thyroid autoimmunity," the researchers reported, "although when autoimmunity had been identified, thyroid cancers were diagnosed at a very early stage." 
Two groups - those with the highest thyroid antibody levels and women - faced the greatest risk, Dr. McLeod said. The results regarding women were the most surprising in the study, he said. "This is the first time this has been found. We think this result needs to be confirmed. If true, it could explain why women have a three-times-higher risk of thyroid cancer than men." 
The overall incidence of thyroid cancer in the U.S. was estimated at 13.49 per 100,000 person-years in 2018, with women (76% of cases) and Whites (81%) accounting for the majority. Rates have nearly doubled since 2000. The authors of a 2022 report that disclosed these numbers suggest the rise is due to overdiagnosis of small tumors. 
It's not clear why thyroid autoimmunity and thyroid cancer may be linked. "Chronic inflammation from thyroid autoimmunity could cause thyroid cancer, as chronic inflammation in other organs precedes cancers at those sites," Dr. McLeod said. "Alternatively, thyroid autoimmunity could appear to be associated with thyroid cancer because of biases inherent in previous studies, including previous diagnosis of autoimmunity. Thyroid cancer could also induce an immune response, which mimics thyroid autoimmunity and could bias assessment." 
As for screening of patients with thyroid autoimmunity, "the main danger is that you will commonly identify small thyroid cancers that would never become clinically apparent," he said. "This leads to unnecessary treatments that can cause complications and give people a cancer label, which can also cause harm. Diagnosis and treatment guidelines recommend against screening the general population for this reason." 
Many of those with thyroid autoimmunity developed small cancers, he said, most likely "detected from ultrasound being performed because autoimmune thyroid disease was known. If all patients with thyroid autoimmunity were screened for thyroid cancer, the likelihood is that many people's cancers would be overdiagnosed." 
The study was funded by the Walton Family Foundation. Dr. McLeod reports no disclosures. Some of the authors report various relationships with industry.

A new study provides more evidence that people with thyroid autoimmunity are more likely than are others to develop papillary thyroid cancer (odds ratio [OR] = 1.90, 95% confidence interval [CI], 1.33-2.70), although the overall risk remains very low. 
Researchers aren't recommending routine screening in all patients with thyroid autoimmunity, but they're calling for more research into whether it's a good idea in severe cases. "This is the one circumstance where screening for subclinical disease could make sense," said Donald McLeod, MPH, PhD, an epidemiologist at Royal Brisbane & Women's Hospital in Australia and lead author of the study, published in the Journal of Clinical Oncology. "However, more research is needed because our study is the first to show this result, and we need to prove that screening would make a difference to the prognosis of these patients." 
According to Dr. McLeod, "doctors and patients have been wondering about the connection between thyroid autoimmunity and thyroid cancer for many years. In fact, the first report was in 1955. While the association was plausible, all previous studies had potential for biases that could have influenced the results." 
For example, he said, multiple studies didn't control for confounders, while others didn't account for the possibility that cancer could have triggered an immune response. "Other case-control studies could have been affected by selection bias, where a diagnosis of thyroid autoimmunity leads to thyroid cancer identification and entry into the study," he said. "Finally, medical surveillance of people diagnosed with thyroid autoimmunity could lead to overdiagnosis, where small, subclinical cancers are diagnosed in those patients but not identified in people who are not under medical follow-up." 
For the new retrospective case-control study, researchers compared 451 active-duty members of the U.S. military who developed papillary thyroid cancer from the period of 1996-2014 to matched controls (61% of all subjects were men and the mean age was 36). Those with cancer had their serum collected 3-5 years and 7-10 years before the date of diagnosis - the index date for all subjects. Some of those considered to have thyroid autoimmunity had conditions such as Graves' disease and Hashimoto's thyroiditis. 
"Eighty-five percent of cases (379 of 451) had a thyroid-related diagnosis recorded ... before their index date, compared with 5% of controls," the researchers reported. "Most cases (80%) had classical papillary thyroid cancer, with the rest having the follicular variant of papillary thyroid cancer."  
After adjustment to account for various confounders, those who were positive for thyroid peroxidase antibodies 7-10 years prior to the index date were more likely to have developed thyroid cancer (OR = 1.90, 95% CI, 1.33-2.70). "The results could not be fully explained by diagnosis of thyroid autoimmunity," the researchers reported, "although when autoimmunity had been identified, thyroid cancers were diagnosed at a very early stage." 
Two groups - those with the highest thyroid antibody levels and women - faced the greatest risk, Dr. McLeod said. The results regarding women were the most surprising in the study, he said. "This is the first time this has been found. We think this result needs to be confirmed. If true, it could explain why women have a three-times-higher risk of thyroid cancer than men." 
The overall incidence of thyroid cancer in the U.S. was estimated at 13.49 per 100,000 person-years in 2018, with women (76% of cases) and Whites (81%) accounting for the majority. Rates have nearly doubled since 2000. The authors of a 2022 report that disclosed these numbers suggest the rise is due to overdiagnosis of small tumors. 
It's not clear why thyroid autoimmunity and thyroid cancer may be linked. "Chronic inflammation from thyroid autoimmunity could cause thyroid cancer, as chronic inflammation in other organs precedes cancers at those sites," Dr. McLeod said. "Alternatively, thyroid autoimmunity could appear to be associated with thyroid cancer because of biases inherent in previous studies, including previous diagnosis of autoimmunity. Thyroid cancer could also induce an immune response, which mimics thyroid autoimmunity and could bias assessment." 
As for screening of patients with thyroid autoimmunity, "the main danger is that you will commonly identify small thyroid cancers that would never become clinically apparent," he said. "This leads to unnecessary treatments that can cause complications and give people a cancer label, which can also cause harm. Diagnosis and treatment guidelines recommend against screening the general population for this reason." 
Many of those with thyroid autoimmunity developed small cancers, he said, most likely "detected from ultrasound being performed because autoimmune thyroid disease was known. If all patients with thyroid autoimmunity were screened for thyroid cancer, the likelihood is that many people's cancers would be overdiagnosed." 
The study was funded by the Walton Family Foundation. Dr. McLeod reports no disclosures. Some of the authors report various relationships with industry.

To address current gaps in expert guidance on newer nonstatin agents, the American College of Cardiology has issued an expert consensus decision pathway on the role of nonstatin therapies in LDL cholesterol lowering for risk reduction in atherosclerotic cardiovascular disease (ASCVD).

Since the publication of the most recent AHA/ACC cholesterol guidelines in 2018, a number of newer nonstatin medications have become available for management of lipid-associated risk, including bempedoic acid, inclisiran, evinacumab, and icosapent ethyl.

These medications were not addressed in the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol.

The 53-page document – 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk – was published online in the Journal of the American College of Cardiology.

The new expert consensus document provides guidance for clinicians until the next formal guidelines are produced, Donald Lloyd-Jones, MD, chair of the writing committee, told this news organization.

• In what patient populations should newer nonstatin therapies be considered?
• In what situations should newer nonstatin therapies be considered?
• If newer nonstatin therapies are to be added, which therapies should be considered and in what order to maximize patient benefit and preference?

The document provides algorithms that endorse the four evidence-based patient groups identified in the 2018 guidelines and assumes that the patient is currently taking or has attempted to take a statin, given that that is the most effective initial therapy, the writing group says.

“The algorithms have been streamlined for ease of use by clinicians to help them identify who may need adjunctive nonstatin medications, to provide thresholds for consideration of those medications, and to provide a prioritization of those medications based on the strength of available evidence of efficacy,” said Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago.

“We hope that these pathways will assist the decision-making process for clinicians and patients,” he added.

He also noted that statins remain the “most important first-line therapy for reducing ASCVD risk, because of their efficacy, safety, and low cost. However, for some patients, there are now options if statins do not fully achieve the goals for reducing ASCVD risk or if statins are not tolerated at effective doses.”

“The new expert consensus document highlights that higher-risk patients should be considered more often for adjunctive therapy and provides user-friendly decision pathways to assist in considering the reasonable choices available under different clinical scenarios,” Dr. Lloyd-Jones said.

The document has been endorsed by the National Lipid Association.

This research had no commercial funding. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

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

To address current gaps in expert guidance on newer nonstatin agents, the American College of Cardiology has issued an expert consensus decision pathway on the role of nonstatin therapies in LDL cholesterol lowering for risk reduction in atherosclerotic cardiovascular disease (ASCVD).

Since the publication of the most recent AHA/ACC cholesterol guidelines in 2018, a number of newer nonstatin medications have become available for management of lipid-associated risk, including bempedoic acid, inclisiran, evinacumab, and icosapent ethyl.

These medications were not addressed in the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol.

The 53-page document – 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk – was published online in the Journal of the American College of Cardiology.

The new expert consensus document provides guidance for clinicians until the next formal guidelines are produced, Donald Lloyd-Jones, MD, chair of the writing committee, told this news organization.

• In what patient populations should newer nonstatin therapies be considered?
• In what situations should newer nonstatin therapies be considered?
• If newer nonstatin therapies are to be added, which therapies should be considered and in what order to maximize patient benefit and preference?

The document provides algorithms that endorse the four evidence-based patient groups identified in the 2018 guidelines and assumes that the patient is currently taking or has attempted to take a statin, given that that is the most effective initial therapy, the writing group says.

“The algorithms have been streamlined for ease of use by clinicians to help them identify who may need adjunctive nonstatin medications, to provide thresholds for consideration of those medications, and to provide a prioritization of those medications based on the strength of available evidence of efficacy,” said Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago.

“We hope that these pathways will assist the decision-making process for clinicians and patients,” he added.

He also noted that statins remain the “most important first-line therapy for reducing ASCVD risk, because of their efficacy, safety, and low cost. However, for some patients, there are now options if statins do not fully achieve the goals for reducing ASCVD risk or if statins are not tolerated at effective doses.”

“The new expert consensus document highlights that higher-risk patients should be considered more often for adjunctive therapy and provides user-friendly decision pathways to assist in considering the reasonable choices available under different clinical scenarios,” Dr. Lloyd-Jones said.

The document has been endorsed by the National Lipid Association.

This research had no commercial funding. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

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

To address current gaps in expert guidance on newer nonstatin agents, the American College of Cardiology has issued an expert consensus decision pathway on the role of nonstatin therapies in LDL cholesterol lowering for risk reduction in atherosclerotic cardiovascular disease (ASCVD).

Since the publication of the most recent AHA/ACC cholesterol guidelines in 2018, a number of newer nonstatin medications have become available for management of lipid-associated risk, including bempedoic acid, inclisiran, evinacumab, and icosapent ethyl.

These medications were not addressed in the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol.

The 53-page document – 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk – was published online in the Journal of the American College of Cardiology.

The new expert consensus document provides guidance for clinicians until the next formal guidelines are produced, Donald Lloyd-Jones, MD, chair of the writing committee, told this news organization.

• In what patient populations should newer nonstatin therapies be considered?
• In what situations should newer nonstatin therapies be considered?
• If newer nonstatin therapies are to be added, which therapies should be considered and in what order to maximize patient benefit and preference?

The document provides algorithms that endorse the four evidence-based patient groups identified in the 2018 guidelines and assumes that the patient is currently taking or has attempted to take a statin, given that that is the most effective initial therapy, the writing group says.

“The algorithms have been streamlined for ease of use by clinicians to help them identify who may need adjunctive nonstatin medications, to provide thresholds for consideration of those medications, and to provide a prioritization of those medications based on the strength of available evidence of efficacy,” said Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago.

“We hope that these pathways will assist the decision-making process for clinicians and patients,” he added.

He also noted that statins remain the “most important first-line therapy for reducing ASCVD risk, because of their efficacy, safety, and low cost. However, for some patients, there are now options if statins do not fully achieve the goals for reducing ASCVD risk or if statins are not tolerated at effective doses.”

“The new expert consensus document highlights that higher-risk patients should be considered more often for adjunctive therapy and provides user-friendly decision pathways to assist in considering the reasonable choices available under different clinical scenarios,” Dr. Lloyd-Jones said.

The document has been endorsed by the National Lipid Association.

This research had no commercial funding. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

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

Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.

Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”

One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.

Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.

Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.

“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
 

The hypothalamic-pituitary-gonadal axis

In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.

“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.

The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.

But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.

But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
 

Remaining chicken-and-egg questions

A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.

It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”

Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.

“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.

Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.

Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.

Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.

These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
 

Recent and upcoming changes in treatment

Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.

In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.

“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.

Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.

“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”

Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.

And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.

Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.

“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”

This story was updated on Sept. 6, 2022.

Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.

Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”

One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.

Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.

Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.

“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
 

The hypothalamic-pituitary-gonadal axis

In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.

“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.

The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.

But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.

But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
 

Remaining chicken-and-egg questions

A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.

It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”

Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.

“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.

Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.

Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.

Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.

These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
 

Recent and upcoming changes in treatment

Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.

In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.

“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.

Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.

“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”

Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.

And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.

Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.

“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”

This story was updated on Sept. 6, 2022.

Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.

Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”

One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.

Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.

Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.

“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
 

The hypothalamic-pituitary-gonadal axis

In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.

“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.

The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.

But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.

But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
 

Remaining chicken-and-egg questions

A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.

It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”

Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.

“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.

Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.

Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.

Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.

These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
 

Recent and upcoming changes in treatment

Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.

In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.

“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.

Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.

“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”

Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.

And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.

Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.

“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”

This story was updated on Sept. 6, 2022.