MDedge Endocrinology

Endocrinologists in Europe and the United States have come together to produce joint guidance to help clinicians manage patients who have, or are a at risk for, glucocorticoid-induced adrenal insufficiency (GC-AI).

Publication of the guidance marks the first time that the European Society of Endocrinology (ESE) and the Endocrine Society have cooperated in producing a guideline.

The guideline “Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency” is published in the May 2024 issues of the societies respective journals, the European Journal of Endocrinology and The Journal of Clinical Endocrinology & Metabolism.

Felix Beuschlein, PhD, from the ESE, who cochaired the clinical committee, told this news organization: “You would hope that this leads to a common ground for a very large number of patients.”

The risk for GC-AI is dependent on the dose, duration, and potency of the glucocorticoid; route of administration; as well as susceptibility of the individual patient. Once it develops or is suspected, careful education and management of affected patients is required.
 

Glucocorticoids Commonly Prescribed

“Glucocorticoid-induced adrenal insufficiency is actually a potential concern for a lot of patients,” coauthor Tobias Else, MD, of the department of internal medicine at the University of Michigan, Ann Arbor, explained to this news organization. “Roughly 1% of all people are being treated with glucocorticoids at any given time.”

“That’s a tremendous number, and it gives the scale of the situation,” added Dr. Beuschlein, director of the department of endocrinology, diabetology, and clinical nutrition at University Hospital Zürich in Switzerland. “Now, fortunately, only a very small proportion of patients who are treated with glucocorticoids do have endocrine problems, and this is what this guideline is actually concentrating on.”

Glucocorticoids are effective agents for treating autoimmune and inflammatory disorders. However, they can cause adverse reactions, particularly when administered at high doses and/or for a prolonged period.

Some studies have reported that even low-dose glucocorticoid use, such as prednisone at 2.5-7.5 mg/d, can increase the risk for cardiovascular disease, severe infections, hypertension, diabetes, osteoporosis, and fractures, as well as increase overall mortality with concurrent type 2 diabetes.

Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency, the guidelines stated. In general, tapering of glucocorticoids can occur more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing.

The degree and persistence of hypothalamic-pituitary-adrenal (HPA) axis suppression after glucocorticoid therapy is stopped depends on overall exposure and recovery of adrenal function. “This is a quite individual situation, as you can imagine, because it’s about sex, age, and comorbidities, the kind of glucocorticoid or other medications that you’re giving,” said Dr. Beuschlein. To cover contingencies, the paper presents tables to explain management covering various eventualities.

Leonie van Hulsteijn, MD, from the department of clinical epidemiology, Leiden University Medical Center, Leiden, the Netherlands, said: “There are so many other specialties prescribing glucocorticoids; so especially the rheumatologist, the pulmonologist, the general practitioners.”

Asked by this news organization whether the guidelines might dissuade some clinicians from offering glucocorticoids, Dr. van Hulsteijn, who contributed to the guidance, said, “I don’t think it will keep them from prescribing it, but I really hope it will make them aware if somebody, after using long-term glucocorticoids, presents with complaints of adrenal insufficiency, that they will be aware and take immediate action.”
 

Evidence Gaps

The review team took around 2.5 years to draw up the guidance amid some concerns about the quality of the evidence base, which they mainly rated as “low” or “very low.” “I think we all, going through the literature, were quite astonished at how bad the evidence is for a problem as global as that,” said Dr. Beuschlein. “But that’s how it is — sometimes, even in the absence of strong evidence, you have to give some kind of guidance.”

Nevertheless, the authors have called for more research to establish risk factors contributing to the development of and susceptibility to adrenal insufficiency, a greater understanding of glucocorticoid withdrawal, and identification of glucocorticoids retaining immunosuppressive and anti-inflammatory properties that have less effect on HPA axis suppression and an improved adverse effect profile.

Patient-facing materials on GC-AI are also in development and will be made available via the ESE Patient Zone this month.

Next year, the societies plan to publish a joint guideline on diabetes in pregnancy. That will be followed in 2026 by guidance on arginine vasopressin resistance and arginine vasopressin deficiency and a guideline on male hypogonadism in 2027.

Funding for the development of joint guidelines was provided by the societies and did not involve support from other bodies.

Dr. Beuschlein declared funding from the German Research Funding Agency, the Swiss National Science Foundation, University Medicine Zürich, the Vontobel Foundation, the Swiss Heart Foundation, and consultancy work for Bayer AG. Dr. Else declared membership of the advisory board of Merck and Company. Dr. van Hulsteijn declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

Endocrinologists in Europe and the United States have come together to produce joint guidance to help clinicians manage patients who have, or are a at risk for, glucocorticoid-induced adrenal insufficiency (GC-AI).

Publication of the guidance marks the first time that the European Society of Endocrinology (ESE) and the Endocrine Society have cooperated in producing a guideline.

The guideline “Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency” is published in the May 2024 issues of the societies respective journals, the European Journal of Endocrinology and The Journal of Clinical Endocrinology & Metabolism.

Felix Beuschlein, PhD, from the ESE, who cochaired the clinical committee, told this news organization: “You would hope that this leads to a common ground for a very large number of patients.”

The risk for GC-AI is dependent on the dose, duration, and potency of the glucocorticoid; route of administration; as well as susceptibility of the individual patient. Once it develops or is suspected, careful education and management of affected patients is required.
 

Glucocorticoids Commonly Prescribed

“Glucocorticoid-induced adrenal insufficiency is actually a potential concern for a lot of patients,” coauthor Tobias Else, MD, of the department of internal medicine at the University of Michigan, Ann Arbor, explained to this news organization. “Roughly 1% of all people are being treated with glucocorticoids at any given time.”

“That’s a tremendous number, and it gives the scale of the situation,” added Dr. Beuschlein, director of the department of endocrinology, diabetology, and clinical nutrition at University Hospital Zürich in Switzerland. “Now, fortunately, only a very small proportion of patients who are treated with glucocorticoids do have endocrine problems, and this is what this guideline is actually concentrating on.”

Glucocorticoids are effective agents for treating autoimmune and inflammatory disorders. However, they can cause adverse reactions, particularly when administered at high doses and/or for a prolonged period.

Some studies have reported that even low-dose glucocorticoid use, such as prednisone at 2.5-7.5 mg/d, can increase the risk for cardiovascular disease, severe infections, hypertension, diabetes, osteoporosis, and fractures, as well as increase overall mortality with concurrent type 2 diabetes.

Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency, the guidelines stated. In general, tapering of glucocorticoids can occur more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing.

The degree and persistence of hypothalamic-pituitary-adrenal (HPA) axis suppression after glucocorticoid therapy is stopped depends on overall exposure and recovery of adrenal function. “This is a quite individual situation, as you can imagine, because it’s about sex, age, and comorbidities, the kind of glucocorticoid or other medications that you’re giving,” said Dr. Beuschlein. To cover contingencies, the paper presents tables to explain management covering various eventualities.

Leonie van Hulsteijn, MD, from the department of clinical epidemiology, Leiden University Medical Center, Leiden, the Netherlands, said: “There are so many other specialties prescribing glucocorticoids; so especially the rheumatologist, the pulmonologist, the general practitioners.”

Asked by this news organization whether the guidelines might dissuade some clinicians from offering glucocorticoids, Dr. van Hulsteijn, who contributed to the guidance, said, “I don’t think it will keep them from prescribing it, but I really hope it will make them aware if somebody, after using long-term glucocorticoids, presents with complaints of adrenal insufficiency, that they will be aware and take immediate action.”
 

Evidence Gaps

The review team took around 2.5 years to draw up the guidance amid some concerns about the quality of the evidence base, which they mainly rated as “low” or “very low.” “I think we all, going through the literature, were quite astonished at how bad the evidence is for a problem as global as that,” said Dr. Beuschlein. “But that’s how it is — sometimes, even in the absence of strong evidence, you have to give some kind of guidance.”

Nevertheless, the authors have called for more research to establish risk factors contributing to the development of and susceptibility to adrenal insufficiency, a greater understanding of glucocorticoid withdrawal, and identification of glucocorticoids retaining immunosuppressive and anti-inflammatory properties that have less effect on HPA axis suppression and an improved adverse effect profile.

Patient-facing materials on GC-AI are also in development and will be made available via the ESE Patient Zone this month.

Next year, the societies plan to publish a joint guideline on diabetes in pregnancy. That will be followed in 2026 by guidance on arginine vasopressin resistance and arginine vasopressin deficiency and a guideline on male hypogonadism in 2027.

Funding for the development of joint guidelines was provided by the societies and did not involve support from other bodies.

Dr. Beuschlein declared funding from the German Research Funding Agency, the Swiss National Science Foundation, University Medicine Zürich, the Vontobel Foundation, the Swiss Heart Foundation, and consultancy work for Bayer AG. Dr. Else declared membership of the advisory board of Merck and Company. Dr. van Hulsteijn declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

Endocrinologists in Europe and the United States have come together to produce joint guidance to help clinicians manage patients who have, or are a at risk for, glucocorticoid-induced adrenal insufficiency (GC-AI).

Publication of the guidance marks the first time that the European Society of Endocrinology (ESE) and the Endocrine Society have cooperated in producing a guideline.

The guideline “Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency” is published in the May 2024 issues of the societies respective journals, the European Journal of Endocrinology and The Journal of Clinical Endocrinology & Metabolism.

Felix Beuschlein, PhD, from the ESE, who cochaired the clinical committee, told this news organization: “You would hope that this leads to a common ground for a very large number of patients.”

The risk for GC-AI is dependent on the dose, duration, and potency of the glucocorticoid; route of administration; as well as susceptibility of the individual patient. Once it develops or is suspected, careful education and management of affected patients is required.
 

Glucocorticoids Commonly Prescribed

“Glucocorticoid-induced adrenal insufficiency is actually a potential concern for a lot of patients,” coauthor Tobias Else, MD, of the department of internal medicine at the University of Michigan, Ann Arbor, explained to this news organization. “Roughly 1% of all people are being treated with glucocorticoids at any given time.”

“That’s a tremendous number, and it gives the scale of the situation,” added Dr. Beuschlein, director of the department of endocrinology, diabetology, and clinical nutrition at University Hospital Zürich in Switzerland. “Now, fortunately, only a very small proportion of patients who are treated with glucocorticoids do have endocrine problems, and this is what this guideline is actually concentrating on.”

Glucocorticoids are effective agents for treating autoimmune and inflammatory disorders. However, they can cause adverse reactions, particularly when administered at high doses and/or for a prolonged period.

Some studies have reported that even low-dose glucocorticoid use, such as prednisone at 2.5-7.5 mg/d, can increase the risk for cardiovascular disease, severe infections, hypertension, diabetes, osteoporosis, and fractures, as well as increase overall mortality with concurrent type 2 diabetes.

Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency, the guidelines stated. In general, tapering of glucocorticoids can occur more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing.

The degree and persistence of hypothalamic-pituitary-adrenal (HPA) axis suppression after glucocorticoid therapy is stopped depends on overall exposure and recovery of adrenal function. “This is a quite individual situation, as you can imagine, because it’s about sex, age, and comorbidities, the kind of glucocorticoid or other medications that you’re giving,” said Dr. Beuschlein. To cover contingencies, the paper presents tables to explain management covering various eventualities.

Leonie van Hulsteijn, MD, from the department of clinical epidemiology, Leiden University Medical Center, Leiden, the Netherlands, said: “There are so many other specialties prescribing glucocorticoids; so especially the rheumatologist, the pulmonologist, the general practitioners.”

Asked by this news organization whether the guidelines might dissuade some clinicians from offering glucocorticoids, Dr. van Hulsteijn, who contributed to the guidance, said, “I don’t think it will keep them from prescribing it, but I really hope it will make them aware if somebody, after using long-term glucocorticoids, presents with complaints of adrenal insufficiency, that they will be aware and take immediate action.”
 

Evidence Gaps

The review team took around 2.5 years to draw up the guidance amid some concerns about the quality of the evidence base, which they mainly rated as “low” or “very low.” “I think we all, going through the literature, were quite astonished at how bad the evidence is for a problem as global as that,” said Dr. Beuschlein. “But that’s how it is — sometimes, even in the absence of strong evidence, you have to give some kind of guidance.”

Nevertheless, the authors have called for more research to establish risk factors contributing to the development of and susceptibility to adrenal insufficiency, a greater understanding of glucocorticoid withdrawal, and identification of glucocorticoids retaining immunosuppressive and anti-inflammatory properties that have less effect on HPA axis suppression and an improved adverse effect profile.

Patient-facing materials on GC-AI are also in development and will be made available via the ESE Patient Zone this month.

Next year, the societies plan to publish a joint guideline on diabetes in pregnancy. That will be followed in 2026 by guidance on arginine vasopressin resistance and arginine vasopressin deficiency and a guideline on male hypogonadism in 2027.

Funding for the development of joint guidelines was provided by the societies and did not involve support from other bodies.

Dr. Beuschlein declared funding from the German Research Funding Agency, the Swiss National Science Foundation, University Medicine Zürich, the Vontobel Foundation, the Swiss Heart Foundation, and consultancy work for Bayer AG. Dr. Else declared membership of the advisory board of Merck and Company. Dr. van Hulsteijn declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.

At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue. 

About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.

She had three pressing questions for me:

Q: How had this happened while she had taken the birth control pills faithfully?

A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold: 

• Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
• The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
• Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.

Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?

A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.

Q: What would happen to her weight loss efforts?

A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy. 

After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful. 

*Patient’s name changed. 

A version of this article appeared on Medscape.com.

Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.

At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue. 

About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.

She had three pressing questions for me:

Q: How had this happened while she had taken the birth control pills faithfully?

A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold: 

• Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
• The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
• Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.

Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?

A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.

Q: What would happen to her weight loss efforts?

A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy. 

After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful. 

*Patient’s name changed. 

A version of this article appeared on Medscape.com.

Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.

At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue. 

About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.

She had three pressing questions for me:

Q: How had this happened while she had taken the birth control pills faithfully?

A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold: 

• Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
• The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
• Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.

Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?

A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.

Q: What would happen to her weight loss efforts?

A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy. 

After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful. 

*Patient’s name changed. 

A version of this article appeared on Medscape.com.

A relatively high percentage of men in their 70s and 80s, as well those determined to have a limited life expectancy, report receiving prostate cancer screening, despite recommendations against screening for men in those age groups.

In its most recent guidance, the US Preventive Services Task Force (USPSTF) revised a previous 2012 recommendation against routine screening for prostate cancer to instead endorse individual decision-making for men aged 55 to 69 years (grade C).

In the update guidance, which was published in 2018, the task force still recommended against PSA-based screening for prostate cancer in men 70 years and older (grade D) due to a range of potential risks and harms. Guidelines from the American Urological Association and American Cancer Society have echoed that recommendation, in general agreement that men over the age of 70 or with limited life expectancy show little benefit from the screening.

To take a closer look at how commonly men are being screened for prostate cancer, based not only on their age but their estimated life expectancy, Kevin H. Kensler, ScD, of Weill Cornell Medicine, and colleagues conducted a cross-sectional study using data from the 2020 Behavioral Risk Factor Surveillance System (BRFSS).

“Our findings indicate that many males aged 70 years and older or those with a high risk of death within 10 years undergo prostate cancer screening despite the recommendation against screening in these populations by current guidelines,” the authors wrote in their paper, published in JAMA Network Open. The results underscore that “enhancements to the shared decision-making process are needed to ensure that older males who undergo screening are those who may potentially benefit,” they noted.

For the study, the authors identified 57,397 men aged 60 and older without a history of prostate cancer who reported undergoing a screening PSA test in the prior 2 years.

Using a risk factor system, mortality risk was estimated based on the scales ranging from 5.5 or less to 10.0 or greater, corresponding to the estimated 10-year mortality of less than 30% to 71% or more, respectively.

Of the men, 19.2% were aged 70 to 74 years, 13.0% were aged 75 to 79 years, and 12.3% were aged 80 years or older. The rest were 69 years or younger.

While the estimated 2-year prostate cancer screening rates were 36.3% among those aged 60 to 64 years and 42.8% for those 65 to 69 years, the rates were even higher, at 47.1%, among those aged 70 to 74 years, and similar, at 42.7%, in the 75 to 79 years of age range. Among those aged 80 years and older, 30.4% had been screened.

While the screening frequency was 43.4% among males with the greatest estimated life expectancy, a fair percentage of men, 30.4%, with the lowest life expectancy, indicative of a 71% or greater risk of death within 10 years, received prostate cancer screening.

In fact, among those with lowest life expectancy, the screening rates were greater than 20% in all age groups.
 

Screening in Older Age: Benefit in Reducing Mortality Low

Autopsy research indicates that, in fact, as many as 50% of men do have prostate cancer at age 80; however, many of those tumors are low-risk and unlikely to affect the health of the men.

If detected early, as is the intention of screening, prostate cancer can take years to advance and the likelihood of receiving any mortality benefit from continued screening in older age is low.

Furthermore, screening in older age can have implications, including a higher risk of complications following a false positive prostate biopsy that may not have been necessary in the first place, the authors explained.

“Given the long natural history of prostate cancer and lead time associated with PSA-based screening, these males [aged 70 and older or with a high risk of death within 10 years] have a low likelihood of receiving any mortality benefit from continued screening,” the authors reported.

“Yet they face the potential harms of overdiagnosis, such as complications after prostate biopsy for a false-positive screening and psychological stress associated with a cancer diagnosis.”
 

Guideline Confusion, Habit, Among Reasons for Continued Screening

Among key reasons for the continued screening of men well into old age is the fluctuating history of the guidelines, Dr. Kensler said in an interview.

“There has been considerable variation in prostate cancer screening guidelines over time and across organizations that make screening recommendations, and this has inevitably led to some confusion among clinicians,” he explained.

However, the evidence of a lack of benefit over the age of 70 is strong enough that not performing PSA-based screening among men ages 70 or older is a Healthcare Effectiveness Data and Information Set (HEDIS) measure for quality of care, he noted.

Nevertheless, “I think the trends we found in our analysis reflect that it is difficult for patients and providers to stop providing screening once they have already started it,” Dr. Kensler said.

Another motivator may be an inclination by clinicians to err on the side of caution, he added.

“For clinicians, although they may be aware of the guidelines, they may perhaps fear that they will not have offered screening to one of the older individuals who would have benefited from it even though they recognize that most would not,” Dr. Kensler noted.

Too often, however, such screenings “can lead to a cascade of other events that end up harming the patient without extending their lifespan,” he said.
 

Difficult Discussions

Complicating matters is the task of informing patients that due to their life expectancy, screening is considered to not likely be worthwhile — which may not be an easy discussion.

“For patients, hearing that they are at a stage of life where they may not benefit from screening is an unpleasant message to receive,” Dr. Kensler said.

“Having an in-depth conversation on this topic is also difficult given the many other health topics that clinicians and patients must cover during a visit.”

Ultimately, “these and other factors lead to inertia, where it is easier to stick to the status quo of continuing screening.”

The challenges underscore the need for improvements to the shared decision-making process to make sure that older men who do undergo prostrate screening will benefit, Dr. Kensler argued.

“If the guidelines are going to recommend shared decision-making, we need to provide tools to help patients and clinicians navigate these potentially difficult conversations.
 

Life Expectancy Uncertainties

Commenting on the research in an interview, Kyle Richards, MD, associate professor with the Department of Urology at the University of Wisconsin School of Medicine and Public Health, in Madison, noted that, “while most urology experts agree that we should not screen for prostate cancer in men with less than 5-10 years life expectancy, the challenge is deciding which patients have a more limited life expectancy.” 

Tools and calculators are available to try to calculate life expectancy, “but they can be cumbersome and difficult to incorporate into clinical practice,” he added.

Indeed, the difficulty in accurately estimating life expectancy is also a limitation of the study, he noted.

“The challenge with a study like this is it is very difficult to accurately estimate life expectancy,” he said. “It is easy to pick a cut point (i.e. age 70) but it is very difficult to calculate one’s life expectancy from survey data alone.” 

Another limitation is that “screening PSA testing implies that the patient is not having any symptoms, and we do not know from this study if any of these men were getting PSA checks due to some urinary symptoms or other issues,” Dr. Richards added.

“So, while the study does raise some concern about screening PSA in older men, the data source makes it quite difficult to home in on this question.”

When it can be estimated, life expectancy can indeed provide a more useful guide in assessing the options if a patient is found to have prostate cancer, Dr. Richards noted.

“If a patient has a 5- to 10-year life expectancy, and they are diagnosed with a clinically significant prostate cancer, they absolutely may still benefit from treatment,” he said.

“If they have a clinically significant prostate cancer that is unrecognized, it could metastasize and cause symptoms or lead to death, as roughly 30,000 men die from prostate cancer each year in the USA.”

However, “if a patient has a limited life expectancy of less than 5 to 10 years, don’t screen for prostate cancer,” he advised. Proper guidance should furthermore be made loud and clear in guideline recommendations.

“I do think the USPSTF and AUA need to be the primary voices educating primary care and patients regarding prostate cancer screening,” Dr. Richards said.

“We need to be smart about whom to screen, when to screen, and how often to screen. And this message needs to be heard by the primary care providers that perform the screening.”

The study was supported by the Sandra and Edward Meyer Cancer Center and a grant from the National Cancer Institute of the National Institutes of Health.

Dr. Kensler and Dr. Richards had no disclosures to report.

A relatively high percentage of men in their 70s and 80s, as well those determined to have a limited life expectancy, report receiving prostate cancer screening, despite recommendations against screening for men in those age groups.

In its most recent guidance, the US Preventive Services Task Force (USPSTF) revised a previous 2012 recommendation against routine screening for prostate cancer to instead endorse individual decision-making for men aged 55 to 69 years (grade C).

In the update guidance, which was published in 2018, the task force still recommended against PSA-based screening for prostate cancer in men 70 years and older (grade D) due to a range of potential risks and harms. Guidelines from the American Urological Association and American Cancer Society have echoed that recommendation, in general agreement that men over the age of 70 or with limited life expectancy show little benefit from the screening.

To take a closer look at how commonly men are being screened for prostate cancer, based not only on their age but their estimated life expectancy, Kevin H. Kensler, ScD, of Weill Cornell Medicine, and colleagues conducted a cross-sectional study using data from the 2020 Behavioral Risk Factor Surveillance System (BRFSS).

“Our findings indicate that many males aged 70 years and older or those with a high risk of death within 10 years undergo prostate cancer screening despite the recommendation against screening in these populations by current guidelines,” the authors wrote in their paper, published in JAMA Network Open. The results underscore that “enhancements to the shared decision-making process are needed to ensure that older males who undergo screening are those who may potentially benefit,” they noted.

For the study, the authors identified 57,397 men aged 60 and older without a history of prostate cancer who reported undergoing a screening PSA test in the prior 2 years.

Using a risk factor system, mortality risk was estimated based on the scales ranging from 5.5 or less to 10.0 or greater, corresponding to the estimated 10-year mortality of less than 30% to 71% or more, respectively.

Of the men, 19.2% were aged 70 to 74 years, 13.0% were aged 75 to 79 years, and 12.3% were aged 80 years or older. The rest were 69 years or younger.

While the estimated 2-year prostate cancer screening rates were 36.3% among those aged 60 to 64 years and 42.8% for those 65 to 69 years, the rates were even higher, at 47.1%, among those aged 70 to 74 years, and similar, at 42.7%, in the 75 to 79 years of age range. Among those aged 80 years and older, 30.4% had been screened.

While the screening frequency was 43.4% among males with the greatest estimated life expectancy, a fair percentage of men, 30.4%, with the lowest life expectancy, indicative of a 71% or greater risk of death within 10 years, received prostate cancer screening.

In fact, among those with lowest life expectancy, the screening rates were greater than 20% in all age groups.
 

Screening in Older Age: Benefit in Reducing Mortality Low

Autopsy research indicates that, in fact, as many as 50% of men do have prostate cancer at age 80; however, many of those tumors are low-risk and unlikely to affect the health of the men.

If detected early, as is the intention of screening, prostate cancer can take years to advance and the likelihood of receiving any mortality benefit from continued screening in older age is low.

Furthermore, screening in older age can have implications, including a higher risk of complications following a false positive prostate biopsy that may not have been necessary in the first place, the authors explained.

“Given the long natural history of prostate cancer and lead time associated with PSA-based screening, these males [aged 70 and older or with a high risk of death within 10 years] have a low likelihood of receiving any mortality benefit from continued screening,” the authors reported.

“Yet they face the potential harms of overdiagnosis, such as complications after prostate biopsy for a false-positive screening and psychological stress associated with a cancer diagnosis.”
 

Guideline Confusion, Habit, Among Reasons for Continued Screening

Among key reasons for the continued screening of men well into old age is the fluctuating history of the guidelines, Dr. Kensler said in an interview.

“There has been considerable variation in prostate cancer screening guidelines over time and across organizations that make screening recommendations, and this has inevitably led to some confusion among clinicians,” he explained.

However, the evidence of a lack of benefit over the age of 70 is strong enough that not performing PSA-based screening among men ages 70 or older is a Healthcare Effectiveness Data and Information Set (HEDIS) measure for quality of care, he noted.

Nevertheless, “I think the trends we found in our analysis reflect that it is difficult for patients and providers to stop providing screening once they have already started it,” Dr. Kensler said.

Another motivator may be an inclination by clinicians to err on the side of caution, he added.

“For clinicians, although they may be aware of the guidelines, they may perhaps fear that they will not have offered screening to one of the older individuals who would have benefited from it even though they recognize that most would not,” Dr. Kensler noted.

Too often, however, such screenings “can lead to a cascade of other events that end up harming the patient without extending their lifespan,” he said.
 

Difficult Discussions

Complicating matters is the task of informing patients that due to their life expectancy, screening is considered to not likely be worthwhile — which may not be an easy discussion.

“For patients, hearing that they are at a stage of life where they may not benefit from screening is an unpleasant message to receive,” Dr. Kensler said.

“Having an in-depth conversation on this topic is also difficult given the many other health topics that clinicians and patients must cover during a visit.”

Ultimately, “these and other factors lead to inertia, where it is easier to stick to the status quo of continuing screening.”

The challenges underscore the need for improvements to the shared decision-making process to make sure that older men who do undergo prostrate screening will benefit, Dr. Kensler argued.

“If the guidelines are going to recommend shared decision-making, we need to provide tools to help patients and clinicians navigate these potentially difficult conversations.
 

Life Expectancy Uncertainties

Commenting on the research in an interview, Kyle Richards, MD, associate professor with the Department of Urology at the University of Wisconsin School of Medicine and Public Health, in Madison, noted that, “while most urology experts agree that we should not screen for prostate cancer in men with less than 5-10 years life expectancy, the challenge is deciding which patients have a more limited life expectancy.” 

Tools and calculators are available to try to calculate life expectancy, “but they can be cumbersome and difficult to incorporate into clinical practice,” he added.

Indeed, the difficulty in accurately estimating life expectancy is also a limitation of the study, he noted.

“The challenge with a study like this is it is very difficult to accurately estimate life expectancy,” he said. “It is easy to pick a cut point (i.e. age 70) but it is very difficult to calculate one’s life expectancy from survey data alone.” 

Another limitation is that “screening PSA testing implies that the patient is not having any symptoms, and we do not know from this study if any of these men were getting PSA checks due to some urinary symptoms or other issues,” Dr. Richards added.

“So, while the study does raise some concern about screening PSA in older men, the data source makes it quite difficult to home in on this question.”

When it can be estimated, life expectancy can indeed provide a more useful guide in assessing the options if a patient is found to have prostate cancer, Dr. Richards noted.

“If a patient has a 5- to 10-year life expectancy, and they are diagnosed with a clinically significant prostate cancer, they absolutely may still benefit from treatment,” he said.

“If they have a clinically significant prostate cancer that is unrecognized, it could metastasize and cause symptoms or lead to death, as roughly 30,000 men die from prostate cancer each year in the USA.”

However, “if a patient has a limited life expectancy of less than 5 to 10 years, don’t screen for prostate cancer,” he advised. Proper guidance should furthermore be made loud and clear in guideline recommendations.

“I do think the USPSTF and AUA need to be the primary voices educating primary care and patients regarding prostate cancer screening,” Dr. Richards said.

“We need to be smart about whom to screen, when to screen, and how often to screen. And this message needs to be heard by the primary care providers that perform the screening.”

The study was supported by the Sandra and Edward Meyer Cancer Center and a grant from the National Cancer Institute of the National Institutes of Health.

Dr. Kensler and Dr. Richards had no disclosures to report.

A relatively high percentage of men in their 70s and 80s, as well those determined to have a limited life expectancy, report receiving prostate cancer screening, despite recommendations against screening for men in those age groups.

In its most recent guidance, the US Preventive Services Task Force (USPSTF) revised a previous 2012 recommendation against routine screening for prostate cancer to instead endorse individual decision-making for men aged 55 to 69 years (grade C).

In the update guidance, which was published in 2018, the task force still recommended against PSA-based screening for prostate cancer in men 70 years and older (grade D) due to a range of potential risks and harms. Guidelines from the American Urological Association and American Cancer Society have echoed that recommendation, in general agreement that men over the age of 70 or with limited life expectancy show little benefit from the screening.

To take a closer look at how commonly men are being screened for prostate cancer, based not only on their age but their estimated life expectancy, Kevin H. Kensler, ScD, of Weill Cornell Medicine, and colleagues conducted a cross-sectional study using data from the 2020 Behavioral Risk Factor Surveillance System (BRFSS).

“Our findings indicate that many males aged 70 years and older or those with a high risk of death within 10 years undergo prostate cancer screening despite the recommendation against screening in these populations by current guidelines,” the authors wrote in their paper, published in JAMA Network Open. The results underscore that “enhancements to the shared decision-making process are needed to ensure that older males who undergo screening are those who may potentially benefit,” they noted.

For the study, the authors identified 57,397 men aged 60 and older without a history of prostate cancer who reported undergoing a screening PSA test in the prior 2 years.

Using a risk factor system, mortality risk was estimated based on the scales ranging from 5.5 or less to 10.0 or greater, corresponding to the estimated 10-year mortality of less than 30% to 71% or more, respectively.

Of the men, 19.2% were aged 70 to 74 years, 13.0% were aged 75 to 79 years, and 12.3% were aged 80 years or older. The rest were 69 years or younger.

While the estimated 2-year prostate cancer screening rates were 36.3% among those aged 60 to 64 years and 42.8% for those 65 to 69 years, the rates were even higher, at 47.1%, among those aged 70 to 74 years, and similar, at 42.7%, in the 75 to 79 years of age range. Among those aged 80 years and older, 30.4% had been screened.

While the screening frequency was 43.4% among males with the greatest estimated life expectancy, a fair percentage of men, 30.4%, with the lowest life expectancy, indicative of a 71% or greater risk of death within 10 years, received prostate cancer screening.

In fact, among those with lowest life expectancy, the screening rates were greater than 20% in all age groups.
 

Screening in Older Age: Benefit in Reducing Mortality Low

Autopsy research indicates that, in fact, as many as 50% of men do have prostate cancer at age 80; however, many of those tumors are low-risk and unlikely to affect the health of the men.

If detected early, as is the intention of screening, prostate cancer can take years to advance and the likelihood of receiving any mortality benefit from continued screening in older age is low.

Furthermore, screening in older age can have implications, including a higher risk of complications following a false positive prostate biopsy that may not have been necessary in the first place, the authors explained.

“Given the long natural history of prostate cancer and lead time associated with PSA-based screening, these males [aged 70 and older or with a high risk of death within 10 years] have a low likelihood of receiving any mortality benefit from continued screening,” the authors reported.

“Yet they face the potential harms of overdiagnosis, such as complications after prostate biopsy for a false-positive screening and psychological stress associated with a cancer diagnosis.”
 

Guideline Confusion, Habit, Among Reasons for Continued Screening

Among key reasons for the continued screening of men well into old age is the fluctuating history of the guidelines, Dr. Kensler said in an interview.

“There has been considerable variation in prostate cancer screening guidelines over time and across organizations that make screening recommendations, and this has inevitably led to some confusion among clinicians,” he explained.

However, the evidence of a lack of benefit over the age of 70 is strong enough that not performing PSA-based screening among men ages 70 or older is a Healthcare Effectiveness Data and Information Set (HEDIS) measure for quality of care, he noted.

Nevertheless, “I think the trends we found in our analysis reflect that it is difficult for patients and providers to stop providing screening once they have already started it,” Dr. Kensler said.

Another motivator may be an inclination by clinicians to err on the side of caution, he added.

“For clinicians, although they may be aware of the guidelines, they may perhaps fear that they will not have offered screening to one of the older individuals who would have benefited from it even though they recognize that most would not,” Dr. Kensler noted.

Too often, however, such screenings “can lead to a cascade of other events that end up harming the patient without extending their lifespan,” he said.
 

Difficult Discussions

Complicating matters is the task of informing patients that due to their life expectancy, screening is considered to not likely be worthwhile — which may not be an easy discussion.

“For patients, hearing that they are at a stage of life where they may not benefit from screening is an unpleasant message to receive,” Dr. Kensler said.

“Having an in-depth conversation on this topic is also difficult given the many other health topics that clinicians and patients must cover during a visit.”

Ultimately, “these and other factors lead to inertia, where it is easier to stick to the status quo of continuing screening.”

The challenges underscore the need for improvements to the shared decision-making process to make sure that older men who do undergo prostrate screening will benefit, Dr. Kensler argued.

“If the guidelines are going to recommend shared decision-making, we need to provide tools to help patients and clinicians navigate these potentially difficult conversations.
 

Life Expectancy Uncertainties

Commenting on the research in an interview, Kyle Richards, MD, associate professor with the Department of Urology at the University of Wisconsin School of Medicine and Public Health, in Madison, noted that, “while most urology experts agree that we should not screen for prostate cancer in men with less than 5-10 years life expectancy, the challenge is deciding which patients have a more limited life expectancy.” 

Tools and calculators are available to try to calculate life expectancy, “but they can be cumbersome and difficult to incorporate into clinical practice,” he added.

Indeed, the difficulty in accurately estimating life expectancy is also a limitation of the study, he noted.

“The challenge with a study like this is it is very difficult to accurately estimate life expectancy,” he said. “It is easy to pick a cut point (i.e. age 70) but it is very difficult to calculate one’s life expectancy from survey data alone.” 

Another limitation is that “screening PSA testing implies that the patient is not having any symptoms, and we do not know from this study if any of these men were getting PSA checks due to some urinary symptoms or other issues,” Dr. Richards added.

“So, while the study does raise some concern about screening PSA in older men, the data source makes it quite difficult to home in on this question.”

When it can be estimated, life expectancy can indeed provide a more useful guide in assessing the options if a patient is found to have prostate cancer, Dr. Richards noted.

“If a patient has a 5- to 10-year life expectancy, and they are diagnosed with a clinically significant prostate cancer, they absolutely may still benefit from treatment,” he said.

“If they have a clinically significant prostate cancer that is unrecognized, it could metastasize and cause symptoms or lead to death, as roughly 30,000 men die from prostate cancer each year in the USA.”

However, “if a patient has a limited life expectancy of less than 5 to 10 years, don’t screen for prostate cancer,” he advised. Proper guidance should furthermore be made loud and clear in guideline recommendations.

“I do think the USPSTF and AUA need to be the primary voices educating primary care and patients regarding prostate cancer screening,” Dr. Richards said.

“We need to be smart about whom to screen, when to screen, and how often to screen. And this message needs to be heard by the primary care providers that perform the screening.”

The study was supported by the Sandra and Edward Meyer Cancer Center and a grant from the National Cancer Institute of the National Institutes of Health.

Dr. Kensler and Dr. Richards had no disclosures to report.

VIENNA — With the glucagon-like peptide (GLP) 1 receptor agonist semaglutide (Wegovy) recently shown to significantly induce weight loss in people with osteoarthritis (OA) and obesity in the STEP-9 trial, could drugs traditionally used to treat type 2 diabetes be the next big thing for OA management?

“Hormone-based weight loss drugs are a game changer” for obesity management, Sébastien Czernichow, MD, PhD, said during a plenary session at the OARSI 2024 World Congress.

Sara Freeman/Medscape Medical News

Drugs such as semaglutide may also have a cardioprotective effect, reducing the risk for major adverse cardiovascular events by as much as 20% vs placebo, added Dr. Czernichow, professor of nutrition at Paris Cité University and head of the Department of Nutrition at the George Pompidou European Hospital in Paris, France.

“You have to keep in mind that the short-term side effects are mainly gastrointestinal and [are] manageable. The mid-term side effects are an increased gallbladder [disease] risk, and the long-term benefits and risks are not really well known yet,” Dr. Czernichow said. With regard to that, the effects of these drugs on lean body mass, bone health, and nutritional deficiencies need to be further evaluated and monitored.
 

Weight Loss Benefits

Weight loss is one of the cornerstones of OA management, and in addition to the weight loss seen with the GLP-1 receptor agonists, there have also been changes in body composition, Dr. Czernichow said.

In SURMOUNT-1, for example, the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide (Zepbound) was shown to significantly reduce total fat mass with a smaller decrease in total lean mass in a subanalysis.

It has been argued that effects on body composition need to be considered when evaluating new weight loss drugs, and that focusing only on the degree of weight reduction is “encouraging inaccurate measures of medication efficacy for both patients and clinicians,” Dr. Czernichow said, citing a viewpoint published in JAMA Internal Medicine.

“The real question is: Are we able to fund these drugs for everyone? Or will only the richest patients be allocated to these drugs?” Dr. Czernichow said.
 

Weight Rebound

Tonia Vincent, MBBS, PhD, professor of musculoskeletal biology and an honorary rheumatologist at The Kennedy Institute of Rheumatology at University of Oxford in England, was concerned about rebound weight gain.

“We hear a lot about this, that people stopping drugs actually get worse weight gain than before they started, and that’s a concern about a drug that is going to have a huge pressure for supply,” Dr. Vincent said following Dr. Czernichow’s presentation.

Another delegate said that calling GLP-1 receptor agonists a “game changer” for weight loss in OA was premature because long-term results are needed.

“You mentioned that the double-digit weight loss is getting very close to the results from bariatric surgery, but bariatric surgery you do once, and for these drugs, to maintain the weight loss, you need to take them continuously,” she said.
 

Weight Loss Affects Bone

Yet another delegate cautioned on the potential effects of significant weight loss on bone and cartilage. There is evidence, he said, that weight loss of 5-10 kg can significantly affect bone turnover, increasing bone resorption and thus putting patients at a risk of becoming osteopenic. “Are we looking at a new population of osteoporosis patients who may then also be at risk for fractures?” he asked.

Separately at OARSI 2024, Anne C. Bay-Jensen, PhD, chief technology officer at Nordic Bioscience in Herlev, Denmark, and colleagues reported data showing that weight loss was associated with an increase in bone and cartilage degradation.

Although Dr. Bay-Jensen and colleagues found that losing weight was associated with improved patient outcomes, there was a 1.58-fold increase in the bone resorption marker CTX-I in people who had lost weight vs a 1.37-fold gain in those whose weight remained stable and 1.11-fold increase in those who gained weight.

Moreover, there was a 1.15-fold increase in the cartilage degradation marker C2M in the weight loss group and 0.84-fold decrease in the interstitial matrix degradation marker C3M.
 

GLP-1 and Bone Effects

Another question is whether GLP-1 receptor agonists might be having direct effects on the bone that may be beneficial in OA. They might, postdoctoral researcher Eda Çiftci, PhD, of AO Research Institute Davos in Switzerland, and collaborators, said during the poster sessions at OARSI 2024.

Dr. Çiftci and researchers reported the findings of an in vitro study that looked at whether liraglutide might have anti-inflammatory and anabolic effects on a human chondrocytes model that had been treated with interleukin (IL)-1-beta to “mimic an inflammatory OA condition.”

The release of the proinflammatory cytokines IL-6 and IL-8 was reduced by treatment with liraglutide when compared with control chondrocytes. Furthermore, the expression of the proteoglycan aggrecan — important for articular cartilage function — also was preserved.

These results suggest that liraglutide does indeed have anabolic and anti-inflammatory effects, Dr. Çiftci and fellow researchers concluded.
 

New Role for Dipeptidyl Transferase Inhibitors?

Researchers are also looking at the potential role for other diabetes medications in OA management, including the dipeptidyl peptidase (DPP) 4 inhibitors.

Although these drugs are considered “weight neutral,” in vitro studies have suggested that the DPP4 enzyme may have a role to play in chondrocyte survival and inflammation, Yu-Hsiu Chen, MD, of the Tri-Service General Hospital and the National Defense Medical Center in Taipei, Taiwan, told this news organization. The DPP4 enzyme inactivates GLP-1, so there is rationale there.

“Last year, we published a paper where we found the concentration of DPP4 in the synovial fluid was correlated with radiographic change in knee OA,” Dr. Chen said. This time, “we’re trying to see if a DPP4 inhibitor can be used as a treatment.”

For their analysis, they used data on people newly diagnosed with type 2 diabetes who were and were not using DPP4 inhibitors obtained from Taiwan’s National Health Insurance Research Database. This database contains information on 99% of the Taiwanese population, Dr. Chen said.

Matching 165,333 DPP4 inhibitor users with an equal number of nonusers showed that there was a significant 58% risk reduction for developing OA with DPP4 inhibitor use (hazard ratio, 0.42; 95% CI, 0.41-0.44).

DPP4 inhibitor use was also associated with a 58% risk lower risk for total knee replacement (TKR) and a 62% lower risk for total hip replacement.

Dr. Chen and colleagues concluded: “These results strongly indicate that DPP4 inhibitors could be considered as a viable treatment approach for individuals with type 2 [diabetes mellitus] who are at risk for developing OA or [who] already have OA.”
 

Could Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Be Beneficial?

So, what about SGLT2 inhibitors? Do they also have a potential role to play in managing people with OA, regardless of whether there is diabetes present? Perhaps, and their effect may be even greater than what’s been observed for GLP-1 receptor agonists, as data presented by epidemiologist S. Reza Jafarzadeh, DVM, PhD, suggested.

“While GLP-1 receptor agonist drugs have been reported to reduce OA risk, largely attributed to their weight loss effect, SGLT2 inhibitors may provide a greater protective effect on OA outcomes,” said Dr. Jafarzadeh, assistant professor at Boston University.

Sara Freeman/Medscape Medical News

The congress was sponsored by the Osteoarthritis Research Society International.

Dr. Czernichow disclosed ties with BariaTek Medical, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius, Janssen, Jellynov, Lilly, Novo Nordisk, Novartis, and ViiV Healthcare. Dr. Vincent had no relevant disclosures. Dr. Bay-Jensen is the chief technology officer and director of immunoscience at Nordic Bioscience, which funded the work in the poster she presented at OARSI 2024. The work presented by Dr. Çiftci and colleagues was funded by the Eurostars-2 joint program with co-funding from the European Horizon 2020 research and innovation program. Dr. Çiftci had no personal disclosures to report. Dr. Chen’s work was supported by the government of Taiwan, and she had no financial conflicts of interest to disclose. Dr. Jafarzadeh had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com .

VIENNA — With the glucagon-like peptide (GLP) 1 receptor agonist semaglutide (Wegovy) recently shown to significantly induce weight loss in people with osteoarthritis (OA) and obesity in the STEP-9 trial, could drugs traditionally used to treat type 2 diabetes be the next big thing for OA management?

“Hormone-based weight loss drugs are a game changer” for obesity management, Sébastien Czernichow, MD, PhD, said during a plenary session at the OARSI 2024 World Congress.

Sara Freeman/Medscape Medical News

Drugs such as semaglutide may also have a cardioprotective effect, reducing the risk for major adverse cardiovascular events by as much as 20% vs placebo, added Dr. Czernichow, professor of nutrition at Paris Cité University and head of the Department of Nutrition at the George Pompidou European Hospital in Paris, France.

“You have to keep in mind that the short-term side effects are mainly gastrointestinal and [are] manageable. The mid-term side effects are an increased gallbladder [disease] risk, and the long-term benefits and risks are not really well known yet,” Dr. Czernichow said. With regard to that, the effects of these drugs on lean body mass, bone health, and nutritional deficiencies need to be further evaluated and monitored.
 

Weight Loss Benefits

Weight loss is one of the cornerstones of OA management, and in addition to the weight loss seen with the GLP-1 receptor agonists, there have also been changes in body composition, Dr. Czernichow said.

In SURMOUNT-1, for example, the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide (Zepbound) was shown to significantly reduce total fat mass with a smaller decrease in total lean mass in a subanalysis.

It has been argued that effects on body composition need to be considered when evaluating new weight loss drugs, and that focusing only on the degree of weight reduction is “encouraging inaccurate measures of medication efficacy for both patients and clinicians,” Dr. Czernichow said, citing a viewpoint published in JAMA Internal Medicine.

“The real question is: Are we able to fund these drugs for everyone? Or will only the richest patients be allocated to these drugs?” Dr. Czernichow said.
 

Weight Rebound

Tonia Vincent, MBBS, PhD, professor of musculoskeletal biology and an honorary rheumatologist at The Kennedy Institute of Rheumatology at University of Oxford in England, was concerned about rebound weight gain.

“We hear a lot about this, that people stopping drugs actually get worse weight gain than before they started, and that’s a concern about a drug that is going to have a huge pressure for supply,” Dr. Vincent said following Dr. Czernichow’s presentation.

Another delegate said that calling GLP-1 receptor agonists a “game changer” for weight loss in OA was premature because long-term results are needed.

“You mentioned that the double-digit weight loss is getting very close to the results from bariatric surgery, but bariatric surgery you do once, and for these drugs, to maintain the weight loss, you need to take them continuously,” she said.
 

Weight Loss Affects Bone

Yet another delegate cautioned on the potential effects of significant weight loss on bone and cartilage. There is evidence, he said, that weight loss of 5-10 kg can significantly affect bone turnover, increasing bone resorption and thus putting patients at a risk of becoming osteopenic. “Are we looking at a new population of osteoporosis patients who may then also be at risk for fractures?” he asked.

Separately at OARSI 2024, Anne C. Bay-Jensen, PhD, chief technology officer at Nordic Bioscience in Herlev, Denmark, and colleagues reported data showing that weight loss was associated with an increase in bone and cartilage degradation.

Although Dr. Bay-Jensen and colleagues found that losing weight was associated with improved patient outcomes, there was a 1.58-fold increase in the bone resorption marker CTX-I in people who had lost weight vs a 1.37-fold gain in those whose weight remained stable and 1.11-fold increase in those who gained weight.

Moreover, there was a 1.15-fold increase in the cartilage degradation marker C2M in the weight loss group and 0.84-fold decrease in the interstitial matrix degradation marker C3M.
 

GLP-1 and Bone Effects

Another question is whether GLP-1 receptor agonists might be having direct effects on the bone that may be beneficial in OA. They might, postdoctoral researcher Eda Çiftci, PhD, of AO Research Institute Davos in Switzerland, and collaborators, said during the poster sessions at OARSI 2024.

Dr. Çiftci and researchers reported the findings of an in vitro study that looked at whether liraglutide might have anti-inflammatory and anabolic effects on a human chondrocytes model that had been treated with interleukin (IL)-1-beta to “mimic an inflammatory OA condition.”

The release of the proinflammatory cytokines IL-6 and IL-8 was reduced by treatment with liraglutide when compared with control chondrocytes. Furthermore, the expression of the proteoglycan aggrecan — important for articular cartilage function — also was preserved.

These results suggest that liraglutide does indeed have anabolic and anti-inflammatory effects, Dr. Çiftci and fellow researchers concluded.
 

New Role for Dipeptidyl Transferase Inhibitors?

Researchers are also looking at the potential role for other diabetes medications in OA management, including the dipeptidyl peptidase (DPP) 4 inhibitors.

Although these drugs are considered “weight neutral,” in vitro studies have suggested that the DPP4 enzyme may have a role to play in chondrocyte survival and inflammation, Yu-Hsiu Chen, MD, of the Tri-Service General Hospital and the National Defense Medical Center in Taipei, Taiwan, told this news organization. The DPP4 enzyme inactivates GLP-1, so there is rationale there.

“Last year, we published a paper where we found the concentration of DPP4 in the synovial fluid was correlated with radiographic change in knee OA,” Dr. Chen said. This time, “we’re trying to see if a DPP4 inhibitor can be used as a treatment.”

For their analysis, they used data on people newly diagnosed with type 2 diabetes who were and were not using DPP4 inhibitors obtained from Taiwan’s National Health Insurance Research Database. This database contains information on 99% of the Taiwanese population, Dr. Chen said.

Matching 165,333 DPP4 inhibitor users with an equal number of nonusers showed that there was a significant 58% risk reduction for developing OA with DPP4 inhibitor use (hazard ratio, 0.42; 95% CI, 0.41-0.44).

DPP4 inhibitor use was also associated with a 58% risk lower risk for total knee replacement (TKR) and a 62% lower risk for total hip replacement.

Dr. Chen and colleagues concluded: “These results strongly indicate that DPP4 inhibitors could be considered as a viable treatment approach for individuals with type 2 [diabetes mellitus] who are at risk for developing OA or [who] already have OA.”
 

Could Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Be Beneficial?

So, what about SGLT2 inhibitors? Do they also have a potential role to play in managing people with OA, regardless of whether there is diabetes present? Perhaps, and their effect may be even greater than what’s been observed for GLP-1 receptor agonists, as data presented by epidemiologist S. Reza Jafarzadeh, DVM, PhD, suggested.

“While GLP-1 receptor agonist drugs have been reported to reduce OA risk, largely attributed to their weight loss effect, SGLT2 inhibitors may provide a greater protective effect on OA outcomes,” said Dr. Jafarzadeh, assistant professor at Boston University.

Sara Freeman/Medscape Medical News

The congress was sponsored by the Osteoarthritis Research Society International.

Dr. Czernichow disclosed ties with BariaTek Medical, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius, Janssen, Jellynov, Lilly, Novo Nordisk, Novartis, and ViiV Healthcare. Dr. Vincent had no relevant disclosures. Dr. Bay-Jensen is the chief technology officer and director of immunoscience at Nordic Bioscience, which funded the work in the poster she presented at OARSI 2024. The work presented by Dr. Çiftci and colleagues was funded by the Eurostars-2 joint program with co-funding from the European Horizon 2020 research and innovation program. Dr. Çiftci had no personal disclosures to report. Dr. Chen’s work was supported by the government of Taiwan, and she had no financial conflicts of interest to disclose. Dr. Jafarzadeh had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com .

VIENNA — With the glucagon-like peptide (GLP) 1 receptor agonist semaglutide (Wegovy) recently shown to significantly induce weight loss in people with osteoarthritis (OA) and obesity in the STEP-9 trial, could drugs traditionally used to treat type 2 diabetes be the next big thing for OA management?

“Hormone-based weight loss drugs are a game changer” for obesity management, Sébastien Czernichow, MD, PhD, said during a plenary session at the OARSI 2024 World Congress.

Sara Freeman/Medscape Medical News

Drugs such as semaglutide may also have a cardioprotective effect, reducing the risk for major adverse cardiovascular events by as much as 20% vs placebo, added Dr. Czernichow, professor of nutrition at Paris Cité University and head of the Department of Nutrition at the George Pompidou European Hospital in Paris, France.

“You have to keep in mind that the short-term side effects are mainly gastrointestinal and [are] manageable. The mid-term side effects are an increased gallbladder [disease] risk, and the long-term benefits and risks are not really well known yet,” Dr. Czernichow said. With regard to that, the effects of these drugs on lean body mass, bone health, and nutritional deficiencies need to be further evaluated and monitored.
 

Weight Loss Benefits

Weight loss is one of the cornerstones of OA management, and in addition to the weight loss seen with the GLP-1 receptor agonists, there have also been changes in body composition, Dr. Czernichow said.

In SURMOUNT-1, for example, the dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide (Zepbound) was shown to significantly reduce total fat mass with a smaller decrease in total lean mass in a subanalysis.

It has been argued that effects on body composition need to be considered when evaluating new weight loss drugs, and that focusing only on the degree of weight reduction is “encouraging inaccurate measures of medication efficacy for both patients and clinicians,” Dr. Czernichow said, citing a viewpoint published in JAMA Internal Medicine.

“The real question is: Are we able to fund these drugs for everyone? Or will only the richest patients be allocated to these drugs?” Dr. Czernichow said.
 

Weight Rebound

Tonia Vincent, MBBS, PhD, professor of musculoskeletal biology and an honorary rheumatologist at The Kennedy Institute of Rheumatology at University of Oxford in England, was concerned about rebound weight gain.

“We hear a lot about this, that people stopping drugs actually get worse weight gain than before they started, and that’s a concern about a drug that is going to have a huge pressure for supply,” Dr. Vincent said following Dr. Czernichow’s presentation.

Another delegate said that calling GLP-1 receptor agonists a “game changer” for weight loss in OA was premature because long-term results are needed.

“You mentioned that the double-digit weight loss is getting very close to the results from bariatric surgery, but bariatric surgery you do once, and for these drugs, to maintain the weight loss, you need to take them continuously,” she said.
 

Weight Loss Affects Bone

Yet another delegate cautioned on the potential effects of significant weight loss on bone and cartilage. There is evidence, he said, that weight loss of 5-10 kg can significantly affect bone turnover, increasing bone resorption and thus putting patients at a risk of becoming osteopenic. “Are we looking at a new population of osteoporosis patients who may then also be at risk for fractures?” he asked.

Separately at OARSI 2024, Anne C. Bay-Jensen, PhD, chief technology officer at Nordic Bioscience in Herlev, Denmark, and colleagues reported data showing that weight loss was associated with an increase in bone and cartilage degradation.

Although Dr. Bay-Jensen and colleagues found that losing weight was associated with improved patient outcomes, there was a 1.58-fold increase in the bone resorption marker CTX-I in people who had lost weight vs a 1.37-fold gain in those whose weight remained stable and 1.11-fold increase in those who gained weight.

Moreover, there was a 1.15-fold increase in the cartilage degradation marker C2M in the weight loss group and 0.84-fold decrease in the interstitial matrix degradation marker C3M.
 

GLP-1 and Bone Effects

Another question is whether GLP-1 receptor agonists might be having direct effects on the bone that may be beneficial in OA. They might, postdoctoral researcher Eda Çiftci, PhD, of AO Research Institute Davos in Switzerland, and collaborators, said during the poster sessions at OARSI 2024.

Dr. Çiftci and researchers reported the findings of an in vitro study that looked at whether liraglutide might have anti-inflammatory and anabolic effects on a human chondrocytes model that had been treated with interleukin (IL)-1-beta to “mimic an inflammatory OA condition.”

The release of the proinflammatory cytokines IL-6 and IL-8 was reduced by treatment with liraglutide when compared with control chondrocytes. Furthermore, the expression of the proteoglycan aggrecan — important for articular cartilage function — also was preserved.

These results suggest that liraglutide does indeed have anabolic and anti-inflammatory effects, Dr. Çiftci and fellow researchers concluded.
 

New Role for Dipeptidyl Transferase Inhibitors?

Researchers are also looking at the potential role for other diabetes medications in OA management, including the dipeptidyl peptidase (DPP) 4 inhibitors.

Although these drugs are considered “weight neutral,” in vitro studies have suggested that the DPP4 enzyme may have a role to play in chondrocyte survival and inflammation, Yu-Hsiu Chen, MD, of the Tri-Service General Hospital and the National Defense Medical Center in Taipei, Taiwan, told this news organization. The DPP4 enzyme inactivates GLP-1, so there is rationale there.

“Last year, we published a paper where we found the concentration of DPP4 in the synovial fluid was correlated with radiographic change in knee OA,” Dr. Chen said. This time, “we’re trying to see if a DPP4 inhibitor can be used as a treatment.”

For their analysis, they used data on people newly diagnosed with type 2 diabetes who were and were not using DPP4 inhibitors obtained from Taiwan’s National Health Insurance Research Database. This database contains information on 99% of the Taiwanese population, Dr. Chen said.

Matching 165,333 DPP4 inhibitor users with an equal number of nonusers showed that there was a significant 58% risk reduction for developing OA with DPP4 inhibitor use (hazard ratio, 0.42; 95% CI, 0.41-0.44).

DPP4 inhibitor use was also associated with a 58% risk lower risk for total knee replacement (TKR) and a 62% lower risk for total hip replacement.

Dr. Chen and colleagues concluded: “These results strongly indicate that DPP4 inhibitors could be considered as a viable treatment approach for individuals with type 2 [diabetes mellitus] who are at risk for developing OA or [who] already have OA.”
 

Could Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Be Beneficial?

So, what about SGLT2 inhibitors? Do they also have a potential role to play in managing people with OA, regardless of whether there is diabetes present? Perhaps, and their effect may be even greater than what’s been observed for GLP-1 receptor agonists, as data presented by epidemiologist S. Reza Jafarzadeh, DVM, PhD, suggested.

“While GLP-1 receptor agonist drugs have been reported to reduce OA risk, largely attributed to their weight loss effect, SGLT2 inhibitors may provide a greater protective effect on OA outcomes,” said Dr. Jafarzadeh, assistant professor at Boston University.

Sara Freeman/Medscape Medical News

The congress was sponsored by the Osteoarthritis Research Society International.

Dr. Czernichow disclosed ties with BariaTek Medical, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius, Janssen, Jellynov, Lilly, Novo Nordisk, Novartis, and ViiV Healthcare. Dr. Vincent had no relevant disclosures. Dr. Bay-Jensen is the chief technology officer and director of immunoscience at Nordic Bioscience, which funded the work in the poster she presented at OARSI 2024. The work presented by Dr. Çiftci and colleagues was funded by the Eurostars-2 joint program with co-funding from the European Horizon 2020 research and innovation program. Dr. Çiftci had no personal disclosures to report. Dr. Chen’s work was supported by the government of Taiwan, and she had no financial conflicts of interest to disclose. Dr. Jafarzadeh had no conflicts of interest to disclose.

A version of this article appeared on Medscape.com .

DENVER — In addition to the established gastrointestinal side effects common with the highly effective anti-obesity drugs, there is growing discussion around their potential to contribute to the loss of lean mass, necessary to keep the metabolic engine running full-steam.

And although measures should be recommended to prevent those effects, experts also want to remind clinicians that the loss of lean mass is indeed expected with most weight loss interventions — when they’re successful.

“The bottom line is if you’re successful with weight loss, it’s a normal process that you’re going to lose some lean mass,” Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center in Boston, said during a presentation on the issue at Obesity Medicine 2024.

“It’s what we would expect to see if you successfully lost weight with bariatric surgery or with an intense lifestyle intervention,” said Dr. Fitch, past president of the Obesity Medicine Association.

“The difference is, there haven’t been nearly as many people being successful with weight loss with those other interventions,” she noted. “But with the popularity of the glucagon-like peptide 1 (GLP-1) medications, people are hearing this for the first time and saying, ‘Oh my gosh, 30% of the weight loss is muscle mass — that’s horrible.’ “

An underlying goal in the treatment of obesity is the reduction of fat mass, and significant fat mass reduction can provide benefits exceeding the drawbacks resulting from lean mass loss, which have been reported in clinical trials of the GLP-1s semaglutide and the dual glucose-dependent insulinotropic polypeptide tirzepatide to range from about 25% to 40%, respectively, of weight loss.

“Excess adiposity is what makes us sick — not our weight,” Dr. Fitch underscored. “The amount of fat that people are losing [with anti-obesity medications] is far more beneficial than maybe the potential that they’ve lost a little bit of lean mass,” she said.

She cited research suggesting that significant weight loss from bariatric surgery is linked to increases in life expectancy, cardiovascular risk reduction, cancer risk reduction, and a wide array of other positive effects — despite the loss of lean mass that occurs with the weight loss.

Opportunity for Awareness

The increased attention on issues of body composition accompanying weight loss importantly provides clinicians the chance to underscore to patients the importance of offsetting the loss of lean mass through strength training, nutritional choices, and other measures.

However, patients should be prepared that achieving these goals can be more challenging than expected, said Dr. Fitch.

“It can be very hard to be in an energy deficit (due to a weight loss regimen) and gain muscle mass,” she said. “When athletes are trying to gain muscle mass, they’re increasing their intake to do so. It doesn’t come naturally in today’s world.”

Nevertheless, patients can be reassured that the losses can be reversed with some effort, Dr. Fitch noted.

She cautioned that for those who succeed in building or rebuilding lean mass, the evidence may be reflected on the scale, with numbers going up, not down — something they may not wish to see.

“Patients tend to freak out when they see the scale going up after losing all of that weight, but you can reassure them that it’s okay — this is healthier weight gain.”

Special Considerations in Older Patients

Efforts at staving off lean mass loss are particularly important in older patients, who are already most vulnerable to experiencing it naturally with age, even if not on a weight loss regimen.

But Dr. Fitch offered that age does not necessarily have to be a barrier in tackling those effects.

She described two cases of treating patients in their mid-70s, a male and female, with GLP-1s for obesity. Not only were they able to achieve substantial reductions in body mass index over nearly a year on treatment, but they were also able to avoid skeletal muscle mass loss during a period when it would have likely naturally occurred.

She noted the need to augment strength training with protein intake to help build muscle, citing recommendations including consumption of 1.4-2.0 g of protein per kg of body weight for building muscle and maintaining muscle mass.

Importantly, “make sure patients aren’t too appetite suppressed so they can keep up with their nutrition,” Dr. Fitch said.

A key condition to watch for in these patients is sarcopenia. Definitions of sarcopenia vary, but it is distinguished by low skeletal muscle mass and either low muscle strength — measured, for instance, with hand grip — or low muscle performance, such as reduced walking speed or muscle power, Dr. Fitch said.

In such cases, patients may need special considerations, including avoiding significant caloric deficits and whether the risks of medication outweigh the benefits.

‘Super-Responders’ and Other Lean Mass Loss Scenarios

Further addressing the issues of body composition and weight loss at the meeting, Robert F. Kushner, MD, professor of medicine and medicine education at Northwestern University in Chicago, noted that one area of concern regarding lean mass loss is “super-responders” — patients who have exceptionally high weight loss on GLP-1s.

“We are concerned about individuals who experience very high weight loss responses to medication, [specifically] 25% or more weight loss, as well as individuals at higher risk of losing lean body mass [muscle mass], specifically people in their 50s, 60s, and 70s,” Dr. Kushner told this news organization.

“Lifestyle counseling, particularly regarding safety and body composition, is recommended in these patients,” he said, adding that in managing these patients, “the approach is to use close patient monitoring, dose reduction if needed, and emphasizing a high-protein diet accompanied by aerobic and resistance physical activity.”

Potentially dramatic lean mass loss can occur in obesity whether or not patients are on obesity medications. As evidence of this, Dr. Kushner cited a subanalysis of the Look AHEAD trial of 1019 overweight or obese patients who had a mean age of 58 years at baseline. Patients were randomized to either a physical activity and reduced calorie intervention group or simply education.

Although the results showed that fat losses in the intervention group were generally regained over 8 years, a striking, steady decline was observed in lean mass in both the intervention and control groups, including men and women.

Dr. Fitch disclosed ties to Eli Lilly, Novo Nordisk, Currax, Vivus, SideKick Health, Jenny Craig, Carmot, and Seca. Dr. Kushner is on the advisory boards of Novo Nordisk, Weight Watchers, Lilly, Boehringer Ingelheim, and Altimmune.

A version of this article appeared on Medscape.com.

DENVER — In addition to the established gastrointestinal side effects common with the highly effective anti-obesity drugs, there is growing discussion around their potential to contribute to the loss of lean mass, necessary to keep the metabolic engine running full-steam.

And although measures should be recommended to prevent those effects, experts also want to remind clinicians that the loss of lean mass is indeed expected with most weight loss interventions — when they’re successful.

“The bottom line is if you’re successful with weight loss, it’s a normal process that you’re going to lose some lean mass,” Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center in Boston, said during a presentation on the issue at Obesity Medicine 2024.

“It’s what we would expect to see if you successfully lost weight with bariatric surgery or with an intense lifestyle intervention,” said Dr. Fitch, past president of the Obesity Medicine Association.

“The difference is, there haven’t been nearly as many people being successful with weight loss with those other interventions,” she noted. “But with the popularity of the glucagon-like peptide 1 (GLP-1) medications, people are hearing this for the first time and saying, ‘Oh my gosh, 30% of the weight loss is muscle mass — that’s horrible.’ “

An underlying goal in the treatment of obesity is the reduction of fat mass, and significant fat mass reduction can provide benefits exceeding the drawbacks resulting from lean mass loss, which have been reported in clinical trials of the GLP-1s semaglutide and the dual glucose-dependent insulinotropic polypeptide tirzepatide to range from about 25% to 40%, respectively, of weight loss.

“Excess adiposity is what makes us sick — not our weight,” Dr. Fitch underscored. “The amount of fat that people are losing [with anti-obesity medications] is far more beneficial than maybe the potential that they’ve lost a little bit of lean mass,” she said.

She cited research suggesting that significant weight loss from bariatric surgery is linked to increases in life expectancy, cardiovascular risk reduction, cancer risk reduction, and a wide array of other positive effects — despite the loss of lean mass that occurs with the weight loss.

Opportunity for Awareness

The increased attention on issues of body composition accompanying weight loss importantly provides clinicians the chance to underscore to patients the importance of offsetting the loss of lean mass through strength training, nutritional choices, and other measures.

However, patients should be prepared that achieving these goals can be more challenging than expected, said Dr. Fitch.

“It can be very hard to be in an energy deficit (due to a weight loss regimen) and gain muscle mass,” she said. “When athletes are trying to gain muscle mass, they’re increasing their intake to do so. It doesn’t come naturally in today’s world.”

Nevertheless, patients can be reassured that the losses can be reversed with some effort, Dr. Fitch noted.

She cautioned that for those who succeed in building or rebuilding lean mass, the evidence may be reflected on the scale, with numbers going up, not down — something they may not wish to see.

“Patients tend to freak out when they see the scale going up after losing all of that weight, but you can reassure them that it’s okay — this is healthier weight gain.”

Special Considerations in Older Patients

Efforts at staving off lean mass loss are particularly important in older patients, who are already most vulnerable to experiencing it naturally with age, even if not on a weight loss regimen.

But Dr. Fitch offered that age does not necessarily have to be a barrier in tackling those effects.

She described two cases of treating patients in their mid-70s, a male and female, with GLP-1s for obesity. Not only were they able to achieve substantial reductions in body mass index over nearly a year on treatment, but they were also able to avoid skeletal muscle mass loss during a period when it would have likely naturally occurred.

She noted the need to augment strength training with protein intake to help build muscle, citing recommendations including consumption of 1.4-2.0 g of protein per kg of body weight for building muscle and maintaining muscle mass.

Importantly, “make sure patients aren’t too appetite suppressed so they can keep up with their nutrition,” Dr. Fitch said.

A key condition to watch for in these patients is sarcopenia. Definitions of sarcopenia vary, but it is distinguished by low skeletal muscle mass and either low muscle strength — measured, for instance, with hand grip — or low muscle performance, such as reduced walking speed or muscle power, Dr. Fitch said.

In such cases, patients may need special considerations, including avoiding significant caloric deficits and whether the risks of medication outweigh the benefits.

‘Super-Responders’ and Other Lean Mass Loss Scenarios

Further addressing the issues of body composition and weight loss at the meeting, Robert F. Kushner, MD, professor of medicine and medicine education at Northwestern University in Chicago, noted that one area of concern regarding lean mass loss is “super-responders” — patients who have exceptionally high weight loss on GLP-1s.

“We are concerned about individuals who experience very high weight loss responses to medication, [specifically] 25% or more weight loss, as well as individuals at higher risk of losing lean body mass [muscle mass], specifically people in their 50s, 60s, and 70s,” Dr. Kushner told this news organization.

“Lifestyle counseling, particularly regarding safety and body composition, is recommended in these patients,” he said, adding that in managing these patients, “the approach is to use close patient monitoring, dose reduction if needed, and emphasizing a high-protein diet accompanied by aerobic and resistance physical activity.”

Potentially dramatic lean mass loss can occur in obesity whether or not patients are on obesity medications. As evidence of this, Dr. Kushner cited a subanalysis of the Look AHEAD trial of 1019 overweight or obese patients who had a mean age of 58 years at baseline. Patients were randomized to either a physical activity and reduced calorie intervention group or simply education.

Although the results showed that fat losses in the intervention group were generally regained over 8 years, a striking, steady decline was observed in lean mass in both the intervention and control groups, including men and women.

Dr. Fitch disclosed ties to Eli Lilly, Novo Nordisk, Currax, Vivus, SideKick Health, Jenny Craig, Carmot, and Seca. Dr. Kushner is on the advisory boards of Novo Nordisk, Weight Watchers, Lilly, Boehringer Ingelheim, and Altimmune.

A version of this article appeared on Medscape.com.

DENVER — In addition to the established gastrointestinal side effects common with the highly effective anti-obesity drugs, there is growing discussion around their potential to contribute to the loss of lean mass, necessary to keep the metabolic engine running full-steam.

And although measures should be recommended to prevent those effects, experts also want to remind clinicians that the loss of lean mass is indeed expected with most weight loss interventions — when they’re successful.

“The bottom line is if you’re successful with weight loss, it’s a normal process that you’re going to lose some lean mass,” Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center in Boston, said during a presentation on the issue at Obesity Medicine 2024.

“It’s what we would expect to see if you successfully lost weight with bariatric surgery or with an intense lifestyle intervention,” said Dr. Fitch, past president of the Obesity Medicine Association.

“The difference is, there haven’t been nearly as many people being successful with weight loss with those other interventions,” she noted. “But with the popularity of the glucagon-like peptide 1 (GLP-1) medications, people are hearing this for the first time and saying, ‘Oh my gosh, 30% of the weight loss is muscle mass — that’s horrible.’ “

An underlying goal in the treatment of obesity is the reduction of fat mass, and significant fat mass reduction can provide benefits exceeding the drawbacks resulting from lean mass loss, which have been reported in clinical trials of the GLP-1s semaglutide and the dual glucose-dependent insulinotropic polypeptide tirzepatide to range from about 25% to 40%, respectively, of weight loss.

“Excess adiposity is what makes us sick — not our weight,” Dr. Fitch underscored. “The amount of fat that people are losing [with anti-obesity medications] is far more beneficial than maybe the potential that they’ve lost a little bit of lean mass,” she said.

She cited research suggesting that significant weight loss from bariatric surgery is linked to increases in life expectancy, cardiovascular risk reduction, cancer risk reduction, and a wide array of other positive effects — despite the loss of lean mass that occurs with the weight loss.

Opportunity for Awareness

The increased attention on issues of body composition accompanying weight loss importantly provides clinicians the chance to underscore to patients the importance of offsetting the loss of lean mass through strength training, nutritional choices, and other measures.

However, patients should be prepared that achieving these goals can be more challenging than expected, said Dr. Fitch.

“It can be very hard to be in an energy deficit (due to a weight loss regimen) and gain muscle mass,” she said. “When athletes are trying to gain muscle mass, they’re increasing their intake to do so. It doesn’t come naturally in today’s world.”

Nevertheless, patients can be reassured that the losses can be reversed with some effort, Dr. Fitch noted.

She cautioned that for those who succeed in building or rebuilding lean mass, the evidence may be reflected on the scale, with numbers going up, not down — something they may not wish to see.

“Patients tend to freak out when they see the scale going up after losing all of that weight, but you can reassure them that it’s okay — this is healthier weight gain.”

Special Considerations in Older Patients

Efforts at staving off lean mass loss are particularly important in older patients, who are already most vulnerable to experiencing it naturally with age, even if not on a weight loss regimen.

But Dr. Fitch offered that age does not necessarily have to be a barrier in tackling those effects.

She described two cases of treating patients in their mid-70s, a male and female, with GLP-1s for obesity. Not only were they able to achieve substantial reductions in body mass index over nearly a year on treatment, but they were also able to avoid skeletal muscle mass loss during a period when it would have likely naturally occurred.

She noted the need to augment strength training with protein intake to help build muscle, citing recommendations including consumption of 1.4-2.0 g of protein per kg of body weight for building muscle and maintaining muscle mass.

Importantly, “make sure patients aren’t too appetite suppressed so they can keep up with their nutrition,” Dr. Fitch said.

A key condition to watch for in these patients is sarcopenia. Definitions of sarcopenia vary, but it is distinguished by low skeletal muscle mass and either low muscle strength — measured, for instance, with hand grip — or low muscle performance, such as reduced walking speed or muscle power, Dr. Fitch said.

In such cases, patients may need special considerations, including avoiding significant caloric deficits and whether the risks of medication outweigh the benefits.

‘Super-Responders’ and Other Lean Mass Loss Scenarios

Further addressing the issues of body composition and weight loss at the meeting, Robert F. Kushner, MD, professor of medicine and medicine education at Northwestern University in Chicago, noted that one area of concern regarding lean mass loss is “super-responders” — patients who have exceptionally high weight loss on GLP-1s.

“We are concerned about individuals who experience very high weight loss responses to medication, [specifically] 25% or more weight loss, as well as individuals at higher risk of losing lean body mass [muscle mass], specifically people in their 50s, 60s, and 70s,” Dr. Kushner told this news organization.

“Lifestyle counseling, particularly regarding safety and body composition, is recommended in these patients,” he said, adding that in managing these patients, “the approach is to use close patient monitoring, dose reduction if needed, and emphasizing a high-protein diet accompanied by aerobic and resistance physical activity.”

Potentially dramatic lean mass loss can occur in obesity whether or not patients are on obesity medications. As evidence of this, Dr. Kushner cited a subanalysis of the Look AHEAD trial of 1019 overweight or obese patients who had a mean age of 58 years at baseline. Patients were randomized to either a physical activity and reduced calorie intervention group or simply education.

Although the results showed that fat losses in the intervention group were generally regained over 8 years, a striking, steady decline was observed in lean mass in both the intervention and control groups, including men and women.

Dr. Fitch disclosed ties to Eli Lilly, Novo Nordisk, Currax, Vivus, SideKick Health, Jenny Craig, Carmot, and Seca. Dr. Kushner is on the advisory boards of Novo Nordisk, Weight Watchers, Lilly, Boehringer Ingelheim, and Altimmune.

A version of this article appeared on Medscape.com.

Observational studies on red meat consumption and lifespan are prime examples of attempts to find signal in a sea of noise. 

Randomized controlled trials are the best way to sort cause from mere correlation. But these are not possible in most matters of food consumption. So, we look back and observe groups with different exposures.

My most frequent complaint about these nonrandom comparison studies has been the chance that the two groups differ in important ways, and it’s these differences — not the food in question — that account for the disparate outcomes.

But selection biases are only one issue. There is also the matter of analytic flexibility. Observational studies are born from large databases. Researchers have many choices in how to analyze all these data.

A few years ago, Brian Nosek, PhD, and colleagues elegantly showed that analytic choices can affect results. His Many Analysts, One Data Set study had little uptake in the medical community, perhaps because he studied a social science question.
 

Multiple Ways to Slice the Data

Recently, a group from McMaster University, led by Dena Zeraatkar, PhD, has confirmed the analytic choices problem, using the question of red meat consumption and mortality. 

Their idea was simple: Because there are many plausible and defensible ways to analyze a dataset, we should not choose one method; rather, we should choose thousands, combine the results, and see where the truth lies. 

You might wonder how there could be thousands of ways to analyze a dataset. I surely did. 

The answer stems from the choices that researchers face. For instance, there is the selection of eligible participants, the choice of analytic model (logistic, Poisson, etc.), and covariates for which to adjust. Think exponents when combining possible choices.

Dr. Zeraatkar and colleagues are research methodologists, so, sadly, they are comfortable with the clunky name of this approach: specification curve analysis. Don’t be deterred. It means that they analyze the data in thousands of ways using computers. Each way is a specification. In the end, the specifications give rise to a curve of hazard ratios for red meat and mortality. Another name for this approach is multiverse analysis.

For their paper in the Journal of Clinical Epidemiology, aptly named “Grilling the Data,” they didn’t just conjure up the many analytic ways to study the red meat–mortality question. Instead, they used a published systematic review of 15 studies on unprocessed red meat and early mortality. The studies included in this review reported 70 unique ways to analyze the association. 
 

Is Red Meat Good or Bad?

Their first finding was that this analysis yielded widely disparate effect estimates, from 0.63 (reduced risk for early death) to 2.31 (a higher risk). The median hazard ratio was 1.14 with an interquartile range (IQR) of 1.02-1.23. One might conclude from this that eating red meat is associated with a slightly higher risk for early mortality. 

Their second step was to calculate how many ways (specifications) there were to analyze the data by totaling all possible combinations of choices in the 70 ways found in the systematic review. 

They calculated a total of 10 quadrillion possible unique analyses. A quadrillion is 1 with 15 zeros. Computing power cannot handle that amount of analyses yet. So, they generated 20 random unique combinations of covariates, which narrowed the number of analyses to about 1400. About 200 of these were excluded due to implausibly wide confidence intervals. 

Voilà. They now had about 1200 different ways to analyze a dataset; they chose an NHANES longitudinal cohort study from 2007-2014. They deemed each of the more than 1200 approaches plausible because they were derived from peer-reviewed papers written by experts in epidemiology. 
 

Specification Curve Analyses Results 

Each analysis (or specification) yielded a hazard ratio for red meat exposure and death.

• The median HR was 0.94 (IQR, 0.83-1.05) for the effect of red meat on all-cause mortality — ie, not significant.
• The range of hazard ratios was large. They went from 0.51 — a 49% reduced risk for early mortality — to 1.75: a 75% increase in early mortality.
• Among all analyses, 36% yielded hazard ratios above 1.0 and 64% less than 1.0.
• As for statistical significance, defined as P ≤.05, only 4% (or 48 specifications) met this threshold. Zeraatkar reminded me that this is what you’d expect if unprocessed red meat has no effect on longevity.
• Of the 48 analyses deemed statistically significant, 40 indicated that red meat consumption reduced early death and eight indicated that eating red meat led to higher mortality.
• Nearly half the analyses yielded unexciting point estimates, with hazard ratios between 0.90 and 1.10.

Paradigm Changing 

As a user of evidence, I find this a potentially paradigm-changing study. Observational studies far outnumber randomized trials. For many medical questions, observational data are all we have. 

Now think about every observational study published. The authors tell you — post hoc — which method they used to analyze the data. The key point is that it is one method. 

Dr. Zeraatkar and colleagues have shown that there are thousands of plausible ways to analyze the data, and this can lead to very different findings. In the specific question of red meat and mortality, their many analyses yielded a null result. 

Now imagine other cases where the researchers did many analyses of a dataset and chose to publish only the significant ones. Observational studies are rarely preregistered, so a reader cannot know how a result would vary depending on analytic choices. A specification curve analysis of a dataset provides a much broader picture. In the case of red meat, you see some significant results, but the vast majority hover around null. 

What about the difficulty in analyzing a dataset 1000 different ways? Dr. Zeraatkar told me that it is harder than just choosing one method, but it’s not impossible. 

The main barrier to adopting this multiverse approach to data, she noted, was not the extra work but the entrenched belief among researchers that there is a best way to analyze data. 

I hope you read this paper and think about it every time you read an observational study that finds a positive or negative association between two things. Ask: What if the researchers were as careful as Dr. Zeraatkar and colleagues and did multiple different analyses? Would the finding hold up to a series of plausible analytic choices? 

Nutritional epidemiology would benefit greatly from this approach. But so would any observational study of an exposure and outcome. I suspect that the number of “positive” associations would diminish. And that would not be a bad thing.

 

Dr. Mandrola, a clinical electrophysiologist at Baptist Medical Associates, Louisville, Kentucky, disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Observational studies on red meat consumption and lifespan are prime examples of attempts to find signal in a sea of noise. 

Randomized controlled trials are the best way to sort cause from mere correlation. But these are not possible in most matters of food consumption. So, we look back and observe groups with different exposures.

My most frequent complaint about these nonrandom comparison studies has been the chance that the two groups differ in important ways, and it’s these differences — not the food in question — that account for the disparate outcomes.

But selection biases are only one issue. There is also the matter of analytic flexibility. Observational studies are born from large databases. Researchers have many choices in how to analyze all these data.

A few years ago, Brian Nosek, PhD, and colleagues elegantly showed that analytic choices can affect results. His Many Analysts, One Data Set study had little uptake in the medical community, perhaps because he studied a social science question.
 

Multiple Ways to Slice the Data

Recently, a group from McMaster University, led by Dena Zeraatkar, PhD, has confirmed the analytic choices problem, using the question of red meat consumption and mortality. 

Their idea was simple: Because there are many plausible and defensible ways to analyze a dataset, we should not choose one method; rather, we should choose thousands, combine the results, and see where the truth lies. 

You might wonder how there could be thousands of ways to analyze a dataset. I surely did. 

The answer stems from the choices that researchers face. For instance, there is the selection of eligible participants, the choice of analytic model (logistic, Poisson, etc.), and covariates for which to adjust. Think exponents when combining possible choices.

Dr. Zeraatkar and colleagues are research methodologists, so, sadly, they are comfortable with the clunky name of this approach: specification curve analysis. Don’t be deterred. It means that they analyze the data in thousands of ways using computers. Each way is a specification. In the end, the specifications give rise to a curve of hazard ratios for red meat and mortality. Another name for this approach is multiverse analysis.

For their paper in the Journal of Clinical Epidemiology, aptly named “Grilling the Data,” they didn’t just conjure up the many analytic ways to study the red meat–mortality question. Instead, they used a published systematic review of 15 studies on unprocessed red meat and early mortality. The studies included in this review reported 70 unique ways to analyze the association. 
 

Is Red Meat Good or Bad?

Their first finding was that this analysis yielded widely disparate effect estimates, from 0.63 (reduced risk for early death) to 2.31 (a higher risk). The median hazard ratio was 1.14 with an interquartile range (IQR) of 1.02-1.23. One might conclude from this that eating red meat is associated with a slightly higher risk for early mortality. 

Their second step was to calculate how many ways (specifications) there were to analyze the data by totaling all possible combinations of choices in the 70 ways found in the systematic review. 

They calculated a total of 10 quadrillion possible unique analyses. A quadrillion is 1 with 15 zeros. Computing power cannot handle that amount of analyses yet. So, they generated 20 random unique combinations of covariates, which narrowed the number of analyses to about 1400. About 200 of these were excluded due to implausibly wide confidence intervals. 

Voilà. They now had about 1200 different ways to analyze a dataset; they chose an NHANES longitudinal cohort study from 2007-2014. They deemed each of the more than 1200 approaches plausible because they were derived from peer-reviewed papers written by experts in epidemiology. 
 

Specification Curve Analyses Results 

Each analysis (or specification) yielded a hazard ratio for red meat exposure and death.

• The median HR was 0.94 (IQR, 0.83-1.05) for the effect of red meat on all-cause mortality — ie, not significant.
• The range of hazard ratios was large. They went from 0.51 — a 49% reduced risk for early mortality — to 1.75: a 75% increase in early mortality.
• Among all analyses, 36% yielded hazard ratios above 1.0 and 64% less than 1.0.
• As for statistical significance, defined as P ≤.05, only 4% (or 48 specifications) met this threshold. Zeraatkar reminded me that this is what you’d expect if unprocessed red meat has no effect on longevity.
• Of the 48 analyses deemed statistically significant, 40 indicated that red meat consumption reduced early death and eight indicated that eating red meat led to higher mortality.
• Nearly half the analyses yielded unexciting point estimates, with hazard ratios between 0.90 and 1.10.

Paradigm Changing 

As a user of evidence, I find this a potentially paradigm-changing study. Observational studies far outnumber randomized trials. For many medical questions, observational data are all we have. 

Now think about every observational study published. The authors tell you — post hoc — which method they used to analyze the data. The key point is that it is one method. 

Dr. Zeraatkar and colleagues have shown that there are thousands of plausible ways to analyze the data, and this can lead to very different findings. In the specific question of red meat and mortality, their many analyses yielded a null result. 

Now imagine other cases where the researchers did many analyses of a dataset and chose to publish only the significant ones. Observational studies are rarely preregistered, so a reader cannot know how a result would vary depending on analytic choices. A specification curve analysis of a dataset provides a much broader picture. In the case of red meat, you see some significant results, but the vast majority hover around null. 

What about the difficulty in analyzing a dataset 1000 different ways? Dr. Zeraatkar told me that it is harder than just choosing one method, but it’s not impossible. 

The main barrier to adopting this multiverse approach to data, she noted, was not the extra work but the entrenched belief among researchers that there is a best way to analyze data. 

I hope you read this paper and think about it every time you read an observational study that finds a positive or negative association between two things. Ask: What if the researchers were as careful as Dr. Zeraatkar and colleagues and did multiple different analyses? Would the finding hold up to a series of plausible analytic choices? 

Nutritional epidemiology would benefit greatly from this approach. But so would any observational study of an exposure and outcome. I suspect that the number of “positive” associations would diminish. And that would not be a bad thing.

 

Dr. Mandrola, a clinical electrophysiologist at Baptist Medical Associates, Louisville, Kentucky, disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Observational studies on red meat consumption and lifespan are prime examples of attempts to find signal in a sea of noise. 

Randomized controlled trials are the best way to sort cause from mere correlation. But these are not possible in most matters of food consumption. So, we look back and observe groups with different exposures.

My most frequent complaint about these nonrandom comparison studies has been the chance that the two groups differ in important ways, and it’s these differences — not the food in question — that account for the disparate outcomes.

But selection biases are only one issue. There is also the matter of analytic flexibility. Observational studies are born from large databases. Researchers have many choices in how to analyze all these data.

A few years ago, Brian Nosek, PhD, and colleagues elegantly showed that analytic choices can affect results. His Many Analysts, One Data Set study had little uptake in the medical community, perhaps because he studied a social science question.
 

Multiple Ways to Slice the Data

Recently, a group from McMaster University, led by Dena Zeraatkar, PhD, has confirmed the analytic choices problem, using the question of red meat consumption and mortality. 

Their idea was simple: Because there are many plausible and defensible ways to analyze a dataset, we should not choose one method; rather, we should choose thousands, combine the results, and see where the truth lies. 

You might wonder how there could be thousands of ways to analyze a dataset. I surely did. 

The answer stems from the choices that researchers face. For instance, there is the selection of eligible participants, the choice of analytic model (logistic, Poisson, etc.), and covariates for which to adjust. Think exponents when combining possible choices.

Dr. Zeraatkar and colleagues are research methodologists, so, sadly, they are comfortable with the clunky name of this approach: specification curve analysis. Don’t be deterred. It means that they analyze the data in thousands of ways using computers. Each way is a specification. In the end, the specifications give rise to a curve of hazard ratios for red meat and mortality. Another name for this approach is multiverse analysis.

For their paper in the Journal of Clinical Epidemiology, aptly named “Grilling the Data,” they didn’t just conjure up the many analytic ways to study the red meat–mortality question. Instead, they used a published systematic review of 15 studies on unprocessed red meat and early mortality. The studies included in this review reported 70 unique ways to analyze the association. 
 

Is Red Meat Good or Bad?

Their first finding was that this analysis yielded widely disparate effect estimates, from 0.63 (reduced risk for early death) to 2.31 (a higher risk). The median hazard ratio was 1.14 with an interquartile range (IQR) of 1.02-1.23. One might conclude from this that eating red meat is associated with a slightly higher risk for early mortality. 

Their second step was to calculate how many ways (specifications) there were to analyze the data by totaling all possible combinations of choices in the 70 ways found in the systematic review. 

They calculated a total of 10 quadrillion possible unique analyses. A quadrillion is 1 with 15 zeros. Computing power cannot handle that amount of analyses yet. So, they generated 20 random unique combinations of covariates, which narrowed the number of analyses to about 1400. About 200 of these were excluded due to implausibly wide confidence intervals. 

Voilà. They now had about 1200 different ways to analyze a dataset; they chose an NHANES longitudinal cohort study from 2007-2014. They deemed each of the more than 1200 approaches plausible because they were derived from peer-reviewed papers written by experts in epidemiology. 
 

Specification Curve Analyses Results 

Each analysis (or specification) yielded a hazard ratio for red meat exposure and death.

• The median HR was 0.94 (IQR, 0.83-1.05) for the effect of red meat on all-cause mortality — ie, not significant.
• The range of hazard ratios was large. They went from 0.51 — a 49% reduced risk for early mortality — to 1.75: a 75% increase in early mortality.
• Among all analyses, 36% yielded hazard ratios above 1.0 and 64% less than 1.0.
• As for statistical significance, defined as P ≤.05, only 4% (or 48 specifications) met this threshold. Zeraatkar reminded me that this is what you’d expect if unprocessed red meat has no effect on longevity.
• Of the 48 analyses deemed statistically significant, 40 indicated that red meat consumption reduced early death and eight indicated that eating red meat led to higher mortality.
• Nearly half the analyses yielded unexciting point estimates, with hazard ratios between 0.90 and 1.10.

Paradigm Changing 

As a user of evidence, I find this a potentially paradigm-changing study. Observational studies far outnumber randomized trials. For many medical questions, observational data are all we have. 

Now think about every observational study published. The authors tell you — post hoc — which method they used to analyze the data. The key point is that it is one method. 

Dr. Zeraatkar and colleagues have shown that there are thousands of plausible ways to analyze the data, and this can lead to very different findings. In the specific question of red meat and mortality, their many analyses yielded a null result. 

Now imagine other cases where the researchers did many analyses of a dataset and chose to publish only the significant ones. Observational studies are rarely preregistered, so a reader cannot know how a result would vary depending on analytic choices. A specification curve analysis of a dataset provides a much broader picture. In the case of red meat, you see some significant results, but the vast majority hover around null. 

What about the difficulty in analyzing a dataset 1000 different ways? Dr. Zeraatkar told me that it is harder than just choosing one method, but it’s not impossible. 

The main barrier to adopting this multiverse approach to data, she noted, was not the extra work but the entrenched belief among researchers that there is a best way to analyze data. 

I hope you read this paper and think about it every time you read an observational study that finds a positive or negative association between two things. Ask: What if the researchers were as careful as Dr. Zeraatkar and colleagues and did multiple different analyses? Would the finding hold up to a series of plausible analytic choices? 

Nutritional epidemiology would benefit greatly from this approach. But so would any observational study of an exposure and outcome. I suspect that the number of “positive” associations would diminish. And that would not be a bad thing.

 

Dr. Mandrola, a clinical electrophysiologist at Baptist Medical Associates, Louisville, Kentucky, disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

BERLIN — To date, mRNA vaccines have had their largest global presence in combating the COVID-19 pandemic. Intensive research is underway on many other potential applications for this vaccine technology, which suggests a promising future. Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.

To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
 

Instability Challenge

Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.

With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
 

Improved Scalability

“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”

Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.

In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.

Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.

Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
 

Cancer Immunotherapy

Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.

Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.

The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
 

Genetic Engineering

Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.

Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.

In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.

Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
 

Research in Infections

Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.

“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”

“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”

Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.

An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
 

Elaborate Purification Process

Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.

These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”

Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
 

Prevention and Therapy

In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.

“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.

“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Physicians are leaving healthcare in droves, “not because they don’t want to practice ... but because the system is making it more and more difficult for them to care for their patients,” Bruce Scott, MD, president-elect of the American Medical Association (AMA), said at a press conference May 9 at the National Rural Health Association’s Annual Conference in New Orleans. 

He said that shrinking reimbursement rates and excessive administrative tasks are pushing doctors out of the workforce, exacerbating physician shortages in rural locations where 46 million Americans live. 

Rural areas have about one tenth of the specialists that urban areas do, and 65% of rural communities do not have enough primary care doctors, according to federal data. A recent Centers for Disease Control and Prevention report found that people living in rural areas are more likely to die early from preventable causes than their urban counterparts, said Dr. Scott. 

He said the AMA wants Congress to pass legislation to incentivize more physicians to work in rural areas and expand the number of rural and primary care residency spots. Historically, 80% of residents practice within 80 miles of where they complete residency, he said. 

Dr. Scott also hopes Congress will revise the J-1 visa rules to allow qualified international medical graduates to continue to practice in the United States. He’d like to see the pandemic telehealth flexibilities made permanent because these loosened guidelines greatly improved care access for rural areas in recent years. 

Lower Pay Affects Care in Rural, Urban Areas

Decreased reimbursements also have hit rural and urban doctors in independent practice particularly hard, Dr. Scott said. When adjusted for inflation, the current Medicare payment rate for physicians has dropped 29% since 2001, he said. Now that commercial payers tie their reimbursement models to the Medicare rate, physicians are experiencing “severe” financial stress amid rising practice costs and student loan debt. 

He shared anecdotes about how these issues have affected his private otolaryngology practice in Louisville, Kentucky, a state where more than 2 million people live in federally designated primary care professional shortage areas. 

“A major insurance company that controls over 60% of the private payer market in rural Kentucky [recently] offered us ... surgical rates less than they paid us 6 years ago,” he said. 

Dr. Scott said physicians must make difficult choices. “Do we not invest in the latest physical equipment? Do we reduce our number of employees? Do we perhaps stop accepting new Medicare patients?”

He noted that physicians now spend twice as much time on prior authorizations and other administrative tasks as they do on direct patient care. According to a 2022 AMA survey, 33% of physicians reported that the cumbersome prior authorization process led to a serious adverse event for a patient. Eighty percent reported it caused their patient to forgo treatment altogether.

Dr. Scott, who will be sworn in as AMA president in June, said he experiences the frustration daily. 

“I have to get on the phone and justify to an insurance person who rarely has gone to medical school, has never seen the patient, and heck, in my case, sometimes they can’t even say otolaryngology, much less tell me what the appropriate care is for my patient,” he said.

When asked about the impact of private equity in healthcare, Dr. Scott said there is room for all different modes of practice, but private equity could bring a unique benefit. 

“They have deeper pockets to potentially invest in telehealth technology, AI, and better computer systems,” he said. 

But, he said, some private equity-owned systems have abandoned rural areas, and in other regions they “push the physicians to move faster, see more patients, and do the things that are profit-driven.

“The key is to continue to provide ... quality medical care that is determined by an individual physician in consultation with the patient.”
 

A version of this article appeared on Medscape.com.

Physicians are leaving healthcare in droves, “not because they don’t want to practice ... but because the system is making it more and more difficult for them to care for their patients,” Bruce Scott, MD, president-elect of the American Medical Association (AMA), said at a press conference May 9 at the National Rural Health Association’s Annual Conference in New Orleans. 

He said that shrinking reimbursement rates and excessive administrative tasks are pushing doctors out of the workforce, exacerbating physician shortages in rural locations where 46 million Americans live. 

Rural areas have about one tenth of the specialists that urban areas do, and 65% of rural communities do not have enough primary care doctors, according to federal data. A recent Centers for Disease Control and Prevention report found that people living in rural areas are more likely to die early from preventable causes than their urban counterparts, said Dr. Scott. 

He said the AMA wants Congress to pass legislation to incentivize more physicians to work in rural areas and expand the number of rural and primary care residency spots. Historically, 80% of residents practice within 80 miles of where they complete residency, he said. 

Dr. Scott also hopes Congress will revise the J-1 visa rules to allow qualified international medical graduates to continue to practice in the United States. He’d like to see the pandemic telehealth flexibilities made permanent because these loosened guidelines greatly improved care access for rural areas in recent years. 

Lower Pay Affects Care in Rural, Urban Areas

Decreased reimbursements also have hit rural and urban doctors in independent practice particularly hard, Dr. Scott said. When adjusted for inflation, the current Medicare payment rate for physicians has dropped 29% since 2001, he said. Now that commercial payers tie their reimbursement models to the Medicare rate, physicians are experiencing “severe” financial stress amid rising practice costs and student loan debt. 

He shared anecdotes about how these issues have affected his private otolaryngology practice in Louisville, Kentucky, a state where more than 2 million people live in federally designated primary care professional shortage areas. 

“A major insurance company that controls over 60% of the private payer market in rural Kentucky [recently] offered us ... surgical rates less than they paid us 6 years ago,” he said. 

Dr. Scott said physicians must make difficult choices. “Do we not invest in the latest physical equipment? Do we reduce our number of employees? Do we perhaps stop accepting new Medicare patients?”

He noted that physicians now spend twice as much time on prior authorizations and other administrative tasks as they do on direct patient care. According to a 2022 AMA survey, 33% of physicians reported that the cumbersome prior authorization process led to a serious adverse event for a patient. Eighty percent reported it caused their patient to forgo treatment altogether.

Dr. Scott, who will be sworn in as AMA president in June, said he experiences the frustration daily. 

“I have to get on the phone and justify to an insurance person who rarely has gone to medical school, has never seen the patient, and heck, in my case, sometimes they can’t even say otolaryngology, much less tell me what the appropriate care is for my patient,” he said.

When asked about the impact of private equity in healthcare, Dr. Scott said there is room for all different modes of practice, but private equity could bring a unique benefit. 

“They have deeper pockets to potentially invest in telehealth technology, AI, and better computer systems,” he said. 

But, he said, some private equity-owned systems have abandoned rural areas, and in other regions they “push the physicians to move faster, see more patients, and do the things that are profit-driven.

“The key is to continue to provide ... quality medical care that is determined by an individual physician in consultation with the patient.”
 

A version of this article appeared on Medscape.com.

Physicians are leaving healthcare in droves, “not because they don’t want to practice ... but because the system is making it more and more difficult for them to care for their patients,” Bruce Scott, MD, president-elect of the American Medical Association (AMA), said at a press conference May 9 at the National Rural Health Association’s Annual Conference in New Orleans. 

He said that shrinking reimbursement rates and excessive administrative tasks are pushing doctors out of the workforce, exacerbating physician shortages in rural locations where 46 million Americans live. 

Rural areas have about one tenth of the specialists that urban areas do, and 65% of rural communities do not have enough primary care doctors, according to federal data. A recent Centers for Disease Control and Prevention report found that people living in rural areas are more likely to die early from preventable causes than their urban counterparts, said Dr. Scott. 

He said the AMA wants Congress to pass legislation to incentivize more physicians to work in rural areas and expand the number of rural and primary care residency spots. Historically, 80% of residents practice within 80 miles of where they complete residency, he said. 

Dr. Scott also hopes Congress will revise the J-1 visa rules to allow qualified international medical graduates to continue to practice in the United States. He’d like to see the pandemic telehealth flexibilities made permanent because these loosened guidelines greatly improved care access for rural areas in recent years. 

Lower Pay Affects Care in Rural, Urban Areas

Decreased reimbursements also have hit rural and urban doctors in independent practice particularly hard, Dr. Scott said. When adjusted for inflation, the current Medicare payment rate for physicians has dropped 29% since 2001, he said. Now that commercial payers tie their reimbursement models to the Medicare rate, physicians are experiencing “severe” financial stress amid rising practice costs and student loan debt. 

He shared anecdotes about how these issues have affected his private otolaryngology practice in Louisville, Kentucky, a state where more than 2 million people live in federally designated primary care professional shortage areas. 

“A major insurance company that controls over 60% of the private payer market in rural Kentucky [recently] offered us ... surgical rates less than they paid us 6 years ago,” he said. 

Dr. Scott said physicians must make difficult choices. “Do we not invest in the latest physical equipment? Do we reduce our number of employees? Do we perhaps stop accepting new Medicare patients?”

He noted that physicians now spend twice as much time on prior authorizations and other administrative tasks as they do on direct patient care. According to a 2022 AMA survey, 33% of physicians reported that the cumbersome prior authorization process led to a serious adverse event for a patient. Eighty percent reported it caused their patient to forgo treatment altogether.

Dr. Scott, who will be sworn in as AMA president in June, said he experiences the frustration daily. 

“I have to get on the phone and justify to an insurance person who rarely has gone to medical school, has never seen the patient, and heck, in my case, sometimes they can’t even say otolaryngology, much less tell me what the appropriate care is for my patient,” he said.

When asked about the impact of private equity in healthcare, Dr. Scott said there is room for all different modes of practice, but private equity could bring a unique benefit. 

“They have deeper pockets to potentially invest in telehealth technology, AI, and better computer systems,” he said. 

But, he said, some private equity-owned systems have abandoned rural areas, and in other regions they “push the physicians to move faster, see more patients, and do the things that are profit-driven.

“The key is to continue to provide ... quality medical care that is determined by an individual physician in consultation with the patient.”
 

A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

Like it or not, artificial intelligence (AI) is coming to medicine. For many physicians — maybe you — it’s already here.

More than a third of physicians use AI in their practice. And the vast majority of healthcare companies — 94%, according to Morgan Stanley — use some kind of AI machine learning.

“It’s incumbent on physicians, as well as physicians in training, to become familiar with at least the basics [of AI],” said internist Matthew DeCamp, MD, PhD, an associate professor in the Center for Bioethics and Humanities at the University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Understanding AI can help you leverage it safely and effectively — plus “make better-informed decisions about whether or not to use it in [your] practice,” Dr. DeCamp said.

“Frankly, the people who are deciding whether to implement algorithms in our day-to-day lives are oftentimes not physicians,” noted Ravi B. Parikh, MD, an assistant professor at the University of Pennsylvania and director of augmented and artificial intelligence at the Penn Center for Cancer Care Innovation, Philadelphia. Yet, physicians are most qualified to assess an AI tool’s usefulness in clinical practice.

That brings us to the best starting place for your AI education: Your own institution. Find out what AI tools your organization is implementing — and how you can influence them.

“Getting involved with our hospital data governance is the best way not only to learn practically what these AI tools do but also to influence the development process in positive ways,” Dr. Parikh said.

From there, consider the following resources to enhance your AI knowledge.
 

Get a Lay of the Land: Free Primers

Many clinical societies and interest groups have put out AI primers, an easy way to get a broad overview of the technology. The following were recommended or developed by the experts we spoke to, and all are free:

• The American Medical Association’s (AMA’s) framework for advancing healthcare AI lays out actionable guidance. Ask three key questions, the AMA recommends: Does it work? Does it work for my patients? Does it improve health outcomes?
• The Coalition for Health AI’s Blueprint for Trustworthy AI Implementation Guidance and Assurance for Healthcare provides a high-level summary of how to evaluate AI in healthcare, plus steps for implementing it. AI systems should be useful, safe, accountable, explainable, fair, and secure, the report asserted.
• The National Academy of Medicine’s draft code of conduct for AI in healthcare proposes core principles and commitments. These “reflect simple guideposts to guide and gauge behavior in a complex system and provide a starting point for real-time decision-making,” the report said.
• Health AI Partnership — a collaboration of Duke Health and Microsoft — outlines eight key decision points to consider at any stage of AI implementation, whether you’re still planning how to use it or you’ve started but want to improve it. The site also provides a breakdown of standards by regulatory agencies, organizations, and oversight bodies — so you can make sure your practices align with their guidance.

Make the Most of Conferences

Next time you’re at a conference, check the agenda for sessions on AI. “For someone who’s interested in this, I would be looking for content in my next national meeting because, undoubtedly, it’s going to be there,” said Dr. DeCamp. In a fast-moving field like AI, it’s a great way to get fresh, up-to-the-moment insights.

Listen to This Podcast

The New England Journal of Medicine’s free monthly podcast AI Grand Rounds is made for researchers and clinicians. Available on Apple, Spotify, and YouTube, the pod is good for “someone who’s looking to see both where the field is going [and to hear] a retrospective on big-name papers,” said Dr. Parikh . Episodes run for about an hour.

To learn about the challenges of applying AI to biology: Listen to Daphne Koller, PhD, founder of AI-driven drug discovery and development company insitro. For insights on the potential of AI in medicine, tune into the one with Eric Horvitz, MD, PhD, Microsoft’s chief scientific officer.
 

Consider a Class

Look for courses that focus on AI applications in clinical practice rather than a deep dive into theory. (You need to understand how these tools will influence your work, not the intricacies of large language model development.) Be wary of corporate-funded training that centers on one product , which could present conflicts of interest, said Dr. DeCamp. See the chart for courses that meet these criteria.

A version of this article appeared on Medscape.com.

Like it or not, artificial intelligence (AI) is coming to medicine. For many physicians — maybe you — it’s already here.

More than a third of physicians use AI in their practice. And the vast majority of healthcare companies — 94%, according to Morgan Stanley — use some kind of AI machine learning.

“It’s incumbent on physicians, as well as physicians in training, to become familiar with at least the basics [of AI],” said internist Matthew DeCamp, MD, PhD, an associate professor in the Center for Bioethics and Humanities at the University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Understanding AI can help you leverage it safely and effectively — plus “make better-informed decisions about whether or not to use it in [your] practice,” Dr. DeCamp said.

“Frankly, the people who are deciding whether to implement algorithms in our day-to-day lives are oftentimes not physicians,” noted Ravi B. Parikh, MD, an assistant professor at the University of Pennsylvania and director of augmented and artificial intelligence at the Penn Center for Cancer Care Innovation, Philadelphia. Yet, physicians are most qualified to assess an AI tool’s usefulness in clinical practice.

That brings us to the best starting place for your AI education: Your own institution. Find out what AI tools your organization is implementing — and how you can influence them.

“Getting involved with our hospital data governance is the best way not only to learn practically what these AI tools do but also to influence the development process in positive ways,” Dr. Parikh said.

From there, consider the following resources to enhance your AI knowledge.
 

Get a Lay of the Land: Free Primers

Many clinical societies and interest groups have put out AI primers, an easy way to get a broad overview of the technology. The following were recommended or developed by the experts we spoke to, and all are free:

• The American Medical Association’s (AMA’s) framework for advancing healthcare AI lays out actionable guidance. Ask three key questions, the AMA recommends: Does it work? Does it work for my patients? Does it improve health outcomes?
• The Coalition for Health AI’s Blueprint for Trustworthy AI Implementation Guidance and Assurance for Healthcare provides a high-level summary of how to evaluate AI in healthcare, plus steps for implementing it. AI systems should be useful, safe, accountable, explainable, fair, and secure, the report asserted.
• The National Academy of Medicine’s draft code of conduct for AI in healthcare proposes core principles and commitments. These “reflect simple guideposts to guide and gauge behavior in a complex system and provide a starting point for real-time decision-making,” the report said.
• Health AI Partnership — a collaboration of Duke Health and Microsoft — outlines eight key decision points to consider at any stage of AI implementation, whether you’re still planning how to use it or you’ve started but want to improve it. The site also provides a breakdown of standards by regulatory agencies, organizations, and oversight bodies — so you can make sure your practices align with their guidance.

Make the Most of Conferences

Next time you’re at a conference, check the agenda for sessions on AI. “For someone who’s interested in this, I would be looking for content in my next national meeting because, undoubtedly, it’s going to be there,” said Dr. DeCamp. In a fast-moving field like AI, it’s a great way to get fresh, up-to-the-moment insights.

Listen to This Podcast

The New England Journal of Medicine’s free monthly podcast AI Grand Rounds is made for researchers and clinicians. Available on Apple, Spotify, and YouTube, the pod is good for “someone who’s looking to see both where the field is going [and to hear] a retrospective on big-name papers,” said Dr. Parikh . Episodes run for about an hour.

To learn about the challenges of applying AI to biology: Listen to Daphne Koller, PhD, founder of AI-driven drug discovery and development company insitro. For insights on the potential of AI in medicine, tune into the one with Eric Horvitz, MD, PhD, Microsoft’s chief scientific officer.
 

Consider a Class

Look for courses that focus on AI applications in clinical practice rather than a deep dive into theory. (You need to understand how these tools will influence your work, not the intricacies of large language model development.) Be wary of corporate-funded training that centers on one product , which could present conflicts of interest, said Dr. DeCamp. See the chart for courses that meet these criteria.

A version of this article appeared on Medscape.com.

Like it or not, artificial intelligence (AI) is coming to medicine. For many physicians — maybe you — it’s already here.

More than a third of physicians use AI in their practice. And the vast majority of healthcare companies — 94%, according to Morgan Stanley — use some kind of AI machine learning.

“It’s incumbent on physicians, as well as physicians in training, to become familiar with at least the basics [of AI],” said internist Matthew DeCamp, MD, PhD, an associate professor in the Center for Bioethics and Humanities at the University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Understanding AI can help you leverage it safely and effectively — plus “make better-informed decisions about whether or not to use it in [your] practice,” Dr. DeCamp said.

“Frankly, the people who are deciding whether to implement algorithms in our day-to-day lives are oftentimes not physicians,” noted Ravi B. Parikh, MD, an assistant professor at the University of Pennsylvania and director of augmented and artificial intelligence at the Penn Center for Cancer Care Innovation, Philadelphia. Yet, physicians are most qualified to assess an AI tool’s usefulness in clinical practice.

That brings us to the best starting place for your AI education: Your own institution. Find out what AI tools your organization is implementing — and how you can influence them.

“Getting involved with our hospital data governance is the best way not only to learn practically what these AI tools do but also to influence the development process in positive ways,” Dr. Parikh said.

From there, consider the following resources to enhance your AI knowledge.
 

Get a Lay of the Land: Free Primers

Many clinical societies and interest groups have put out AI primers, an easy way to get a broad overview of the technology. The following were recommended or developed by the experts we spoke to, and all are free:

• The American Medical Association’s (AMA’s) framework for advancing healthcare AI lays out actionable guidance. Ask three key questions, the AMA recommends: Does it work? Does it work for my patients? Does it improve health outcomes?
• The Coalition for Health AI’s Blueprint for Trustworthy AI Implementation Guidance and Assurance for Healthcare provides a high-level summary of how to evaluate AI in healthcare, plus steps for implementing it. AI systems should be useful, safe, accountable, explainable, fair, and secure, the report asserted.
• The National Academy of Medicine’s draft code of conduct for AI in healthcare proposes core principles and commitments. These “reflect simple guideposts to guide and gauge behavior in a complex system and provide a starting point for real-time decision-making,” the report said.
• Health AI Partnership — a collaboration of Duke Health and Microsoft — outlines eight key decision points to consider at any stage of AI implementation, whether you’re still planning how to use it or you’ve started but want to improve it. The site also provides a breakdown of standards by regulatory agencies, organizations, and oversight bodies — so you can make sure your practices align with their guidance.

Make the Most of Conferences

Next time you’re at a conference, check the agenda for sessions on AI. “For someone who’s interested in this, I would be looking for content in my next national meeting because, undoubtedly, it’s going to be there,” said Dr. DeCamp. In a fast-moving field like AI, it’s a great way to get fresh, up-to-the-moment insights.

Listen to This Podcast

The New England Journal of Medicine’s free monthly podcast AI Grand Rounds is made for researchers and clinicians. Available on Apple, Spotify, and YouTube, the pod is good for “someone who’s looking to see both where the field is going [and to hear] a retrospective on big-name papers,” said Dr. Parikh . Episodes run for about an hour.

To learn about the challenges of applying AI to biology: Listen to Daphne Koller, PhD, founder of AI-driven drug discovery and development company insitro. For insights on the potential of AI in medicine, tune into the one with Eric Horvitz, MD, PhD, Microsoft’s chief scientific officer.
 

Consider a Class

Look for courses that focus on AI applications in clinical practice rather than a deep dive into theory. (You need to understand how these tools will influence your work, not the intricacies of large language model development.) Be wary of corporate-funded training that centers on one product , which could present conflicts of interest, said Dr. DeCamp. See the chart for courses that meet these criteria.

A version of this article appeared on Medscape.com.