TBD Meeting (3060-21)

The phenomenon of brain fog, as described by some patients with hypothyroidism despite treatment, is often associated with fatigue and cognitive symptoms and may be relieved by a variety of pharmacologic and nonpharmacologic approaches, new research suggests.

The findings come from a survey of more than 700 patients with hypothyroidism due to thyroid surgery and/or radioactive iodine therapy (RAI) or Hashimoto’s who reported having brain fog.

The survey results were presented May 29 at the American Association of Clinical Endocrinology Virtual Annual Meeting 2021 by investigators Matthew D. Ettleson, MD, and Ava Raine, of the University of Chicago, Illinois.

Many patients with hypothyroidism continue to experience symptoms despite taking thyroid hormone replacement therapy and having normal thyroid function test results.

These symptoms can include quantifiable cognitive, quality of life, and metabolic abnormalities. However, “some patients also experience vague and difficult to quantify symptoms, which they describe as brain fog,” Ms. Raine said.

The brain fog phenomenon has been described with somewhat varying features in several different chronic conditions, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, post-menopausal syndrome, and recently, among people with “long haul” COVID-19 symptoms.

However, brain fog associated with treated hypothyroidism has not been explored in-depth, despite the fact that patients often report it, Ms. Raine noted.
 

Results will help clinicians assist patients with brain fog

Fatigue was the most prominent brain fog symptom reported in the survey, followed by forgetfulness and difficulty focusing. On the other hand, rest and relaxation were the most reported factors that alleviated symptoms, followed by thyroid hormone adjustment.

“Hopefully these findings will help clinicians to recognize and treat the symptoms of brain fog and shed light on a condition which up until now has not been very well understood,” Dr. Ettleson said.

Asked to comment, session moderator Jad G. Sfeir, MD, of the Mayo Medical School, Rochester, Minn., told this news organization: “We do see patients complain a lot about this brain fog. The question is how can I help, and what has worked for them in the past?”

“When you have symptoms that are vague, like brain fog, you don’t have a lot of objective tools to [measure], so you can’t really develop a study to see how a certain medication affects the symptoms. Relying on subjective information from patients saying what worked for them and what did not, you can draw a lot of implications to clinical practice.”

The survey results, Dr. Sfeir said, “will help direct clinicians to know what type of questions to ask patients based on the survey responses and how to make some recommendations that may help.”
 

Fatigue, memory problems, difficulty focusing characterize brain fog

The online survey was distributed to hypothyroidism support groups and through the American Thyroid Association. Of the 5,282 respondents with hypothyroidism and symptoms of brain fog, 46% (2,453) reported having experienced brain fog symptoms prior to their diagnosis of hypothyroidism.

The population analyzed for the study was the 17% (731) who reported experiencing brain fog weeks to months following a diagnosis of hypothyroidism. Of those, 33% had Hashimoto’s, 21% thyroid surgery, 11% RAI therapy, and 15.6% had both thyroid surgery and RAI.  

Brain fog symptoms were reported as occurring “frequently” by 44.5% and “all the time” by 37.0%. The composite symptom score was 22.9 out of 30.

Fatigue, or lack of energy, was the most commonly named symptom, reported by over 90% of both the thyroid surgery/RAI and Hashimoto’s groups, and as occurring “all the time” by about half in each group. Others reported by at least half of both groups included memory problems, difficulty focusing, sleep problems, and difficulties with decision-making. Other symptoms frequently cited included confusion, mood disturbance, and anxiety.

“Each ... domain was reported with some frequency by at least 85% of respondents, regardless of etiology of hypothyroidism, so it really was a high symptom burden that we were seeing, even in those whose symptoms were the least frequent,” Ms. Raine noted.

Symptom scores generally correlated with patient satisfaction scores, particularly with those of cognitive signs and difficulty focusing.
 

Lifting the fog: What do patients say helps them?

The survey asked patients what factors improved or worsened their brain fog symptoms. By far, the most frequent answer was rest/relaxation, endorsed by 58.5%. Another 10.5% listed exercise/outdoor time, but 1.5% said exercise worsened their symptoms.

Unspecified adjustments of thyroid medications were said to improve symptoms for 13.9%. Specific thyroid hormones reported to improve symptoms were liothyronine in 8.8%, desiccated thyroid extract in 3.1%, and levothyroxine in 2.7%. However, another 4.2% said thyroxine worsened their symptoms.

Healthy/nutritious diets were reported to improve symptoms by 6.3%, while consuming gluten, a high-sugar diet, and consuming alcohol were reported to worsen symptoms for 1.3%, 3.2%, and 1.3%, respectively. Caffeine was said to help for 3.1% and to harm by 0.6%.

Small numbers of patients reported improvements in symptoms with vitamins B12 and D, Adderall, or other stimulant medications, antidepressants, naltrexone, sun exposure, and blood glucose stability.

Other factors reported to worsen symptoms included menstruation, infection or other acute illness, pain, and “loud noise.”   

Dr. Ettleson pointed out, “For many of these patients [the brain fog] may have nothing to do with their thyroid. We saw a large proportion of patients who said they had symptoms well before they were ever diagnosed with hypothyroidism, and yet many patients have linked these brain fog symptoms to their thyroid.”

Nonetheless, he said, “I think it’s imperative for the clinician to at least engage in these conversations and not just stop when the thyroid function tests are normal. We have many lifestyle suggestions that have emerged from this study that I think physicians can put forward to patients who are dealing with this ... early in the process in addition to thyroid hormone adjustment, which may help some patients.”  

Dr. Ettleson, Ms. Raine, and Dr. Sfeir have reported no relevant financial relationships.

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

The phenomenon of brain fog, as described by some patients with hypothyroidism despite treatment, is often associated with fatigue and cognitive symptoms and may be relieved by a variety of pharmacologic and nonpharmacologic approaches, new research suggests.

The findings come from a survey of more than 700 patients with hypothyroidism due to thyroid surgery and/or radioactive iodine therapy (RAI) or Hashimoto’s who reported having brain fog.

The survey results were presented May 29 at the American Association of Clinical Endocrinology Virtual Annual Meeting 2021 by investigators Matthew D. Ettleson, MD, and Ava Raine, of the University of Chicago, Illinois.

Many patients with hypothyroidism continue to experience symptoms despite taking thyroid hormone replacement therapy and having normal thyroid function test results.

These symptoms can include quantifiable cognitive, quality of life, and metabolic abnormalities. However, “some patients also experience vague and difficult to quantify symptoms, which they describe as brain fog,” Ms. Raine said.

The brain fog phenomenon has been described with somewhat varying features in several different chronic conditions, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, post-menopausal syndrome, and recently, among people with “long haul” COVID-19 symptoms.

However, brain fog associated with treated hypothyroidism has not been explored in-depth, despite the fact that patients often report it, Ms. Raine noted.
 

Results will help clinicians assist patients with brain fog

Fatigue was the most prominent brain fog symptom reported in the survey, followed by forgetfulness and difficulty focusing. On the other hand, rest and relaxation were the most reported factors that alleviated symptoms, followed by thyroid hormone adjustment.

“Hopefully these findings will help clinicians to recognize and treat the symptoms of brain fog and shed light on a condition which up until now has not been very well understood,” Dr. Ettleson said.

Asked to comment, session moderator Jad G. Sfeir, MD, of the Mayo Medical School, Rochester, Minn., told this news organization: “We do see patients complain a lot about this brain fog. The question is how can I help, and what has worked for them in the past?”

“When you have symptoms that are vague, like brain fog, you don’t have a lot of objective tools to [measure], so you can’t really develop a study to see how a certain medication affects the symptoms. Relying on subjective information from patients saying what worked for them and what did not, you can draw a lot of implications to clinical practice.”

The survey results, Dr. Sfeir said, “will help direct clinicians to know what type of questions to ask patients based on the survey responses and how to make some recommendations that may help.”
 

Fatigue, memory problems, difficulty focusing characterize brain fog

The online survey was distributed to hypothyroidism support groups and through the American Thyroid Association. Of the 5,282 respondents with hypothyroidism and symptoms of brain fog, 46% (2,453) reported having experienced brain fog symptoms prior to their diagnosis of hypothyroidism.

The population analyzed for the study was the 17% (731) who reported experiencing brain fog weeks to months following a diagnosis of hypothyroidism. Of those, 33% had Hashimoto’s, 21% thyroid surgery, 11% RAI therapy, and 15.6% had both thyroid surgery and RAI.  

Brain fog symptoms were reported as occurring “frequently” by 44.5% and “all the time” by 37.0%. The composite symptom score was 22.9 out of 30.

Fatigue, or lack of energy, was the most commonly named symptom, reported by over 90% of both the thyroid surgery/RAI and Hashimoto’s groups, and as occurring “all the time” by about half in each group. Others reported by at least half of both groups included memory problems, difficulty focusing, sleep problems, and difficulties with decision-making. Other symptoms frequently cited included confusion, mood disturbance, and anxiety.

“Each ... domain was reported with some frequency by at least 85% of respondents, regardless of etiology of hypothyroidism, so it really was a high symptom burden that we were seeing, even in those whose symptoms were the least frequent,” Ms. Raine noted.

Symptom scores generally correlated with patient satisfaction scores, particularly with those of cognitive signs and difficulty focusing.
 

Lifting the fog: What do patients say helps them?

The survey asked patients what factors improved or worsened their brain fog symptoms. By far, the most frequent answer was rest/relaxation, endorsed by 58.5%. Another 10.5% listed exercise/outdoor time, but 1.5% said exercise worsened their symptoms.

Unspecified adjustments of thyroid medications were said to improve symptoms for 13.9%. Specific thyroid hormones reported to improve symptoms were liothyronine in 8.8%, desiccated thyroid extract in 3.1%, and levothyroxine in 2.7%. However, another 4.2% said thyroxine worsened their symptoms.

Healthy/nutritious diets were reported to improve symptoms by 6.3%, while consuming gluten, a high-sugar diet, and consuming alcohol were reported to worsen symptoms for 1.3%, 3.2%, and 1.3%, respectively. Caffeine was said to help for 3.1% and to harm by 0.6%.

Small numbers of patients reported improvements in symptoms with vitamins B12 and D, Adderall, or other stimulant medications, antidepressants, naltrexone, sun exposure, and blood glucose stability.

Other factors reported to worsen symptoms included menstruation, infection or other acute illness, pain, and “loud noise.”   

Dr. Ettleson pointed out, “For many of these patients [the brain fog] may have nothing to do with their thyroid. We saw a large proportion of patients who said they had symptoms well before they were ever diagnosed with hypothyroidism, and yet many patients have linked these brain fog symptoms to their thyroid.”

Nonetheless, he said, “I think it’s imperative for the clinician to at least engage in these conversations and not just stop when the thyroid function tests are normal. We have many lifestyle suggestions that have emerged from this study that I think physicians can put forward to patients who are dealing with this ... early in the process in addition to thyroid hormone adjustment, which may help some patients.”  

Dr. Ettleson, Ms. Raine, and Dr. Sfeir have reported no relevant financial relationships.

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

The phenomenon of brain fog, as described by some patients with hypothyroidism despite treatment, is often associated with fatigue and cognitive symptoms and may be relieved by a variety of pharmacologic and nonpharmacologic approaches, new research suggests.

The findings come from a survey of more than 700 patients with hypothyroidism due to thyroid surgery and/or radioactive iodine therapy (RAI) or Hashimoto’s who reported having brain fog.

The survey results were presented May 29 at the American Association of Clinical Endocrinology Virtual Annual Meeting 2021 by investigators Matthew D. Ettleson, MD, and Ava Raine, of the University of Chicago, Illinois.

Many patients with hypothyroidism continue to experience symptoms despite taking thyroid hormone replacement therapy and having normal thyroid function test results.

These symptoms can include quantifiable cognitive, quality of life, and metabolic abnormalities. However, “some patients also experience vague and difficult to quantify symptoms, which they describe as brain fog,” Ms. Raine said.

The brain fog phenomenon has been described with somewhat varying features in several different chronic conditions, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, post-menopausal syndrome, and recently, among people with “long haul” COVID-19 symptoms.

However, brain fog associated with treated hypothyroidism has not been explored in-depth, despite the fact that patients often report it, Ms. Raine noted.
 

Results will help clinicians assist patients with brain fog

Fatigue was the most prominent brain fog symptom reported in the survey, followed by forgetfulness and difficulty focusing. On the other hand, rest and relaxation were the most reported factors that alleviated symptoms, followed by thyroid hormone adjustment.

“Hopefully these findings will help clinicians to recognize and treat the symptoms of brain fog and shed light on a condition which up until now has not been very well understood,” Dr. Ettleson said.

Asked to comment, session moderator Jad G. Sfeir, MD, of the Mayo Medical School, Rochester, Minn., told this news organization: “We do see patients complain a lot about this brain fog. The question is how can I help, and what has worked for them in the past?”

“When you have symptoms that are vague, like brain fog, you don’t have a lot of objective tools to [measure], so you can’t really develop a study to see how a certain medication affects the symptoms. Relying on subjective information from patients saying what worked for them and what did not, you can draw a lot of implications to clinical practice.”

The survey results, Dr. Sfeir said, “will help direct clinicians to know what type of questions to ask patients based on the survey responses and how to make some recommendations that may help.”
 

Fatigue, memory problems, difficulty focusing characterize brain fog

The online survey was distributed to hypothyroidism support groups and through the American Thyroid Association. Of the 5,282 respondents with hypothyroidism and symptoms of brain fog, 46% (2,453) reported having experienced brain fog symptoms prior to their diagnosis of hypothyroidism.

The population analyzed for the study was the 17% (731) who reported experiencing brain fog weeks to months following a diagnosis of hypothyroidism. Of those, 33% had Hashimoto’s, 21% thyroid surgery, 11% RAI therapy, and 15.6% had both thyroid surgery and RAI.  

Brain fog symptoms were reported as occurring “frequently” by 44.5% and “all the time” by 37.0%. The composite symptom score was 22.9 out of 30.

Fatigue, or lack of energy, was the most commonly named symptom, reported by over 90% of both the thyroid surgery/RAI and Hashimoto’s groups, and as occurring “all the time” by about half in each group. Others reported by at least half of both groups included memory problems, difficulty focusing, sleep problems, and difficulties with decision-making. Other symptoms frequently cited included confusion, mood disturbance, and anxiety.

“Each ... domain was reported with some frequency by at least 85% of respondents, regardless of etiology of hypothyroidism, so it really was a high symptom burden that we were seeing, even in those whose symptoms were the least frequent,” Ms. Raine noted.

Symptom scores generally correlated with patient satisfaction scores, particularly with those of cognitive signs and difficulty focusing.
 

Lifting the fog: What do patients say helps them?

The survey asked patients what factors improved or worsened their brain fog symptoms. By far, the most frequent answer was rest/relaxation, endorsed by 58.5%. Another 10.5% listed exercise/outdoor time, but 1.5% said exercise worsened their symptoms.

Unspecified adjustments of thyroid medications were said to improve symptoms for 13.9%. Specific thyroid hormones reported to improve symptoms were liothyronine in 8.8%, desiccated thyroid extract in 3.1%, and levothyroxine in 2.7%. However, another 4.2% said thyroxine worsened their symptoms.

Healthy/nutritious diets were reported to improve symptoms by 6.3%, while consuming gluten, a high-sugar diet, and consuming alcohol were reported to worsen symptoms for 1.3%, 3.2%, and 1.3%, respectively. Caffeine was said to help for 3.1% and to harm by 0.6%.

Small numbers of patients reported improvements in symptoms with vitamins B12 and D, Adderall, or other stimulant medications, antidepressants, naltrexone, sun exposure, and blood glucose stability.

Other factors reported to worsen symptoms included menstruation, infection or other acute illness, pain, and “loud noise.”   

Dr. Ettleson pointed out, “For many of these patients [the brain fog] may have nothing to do with their thyroid. We saw a large proportion of patients who said they had symptoms well before they were ever diagnosed with hypothyroidism, and yet many patients have linked these brain fog symptoms to their thyroid.”

Nonetheless, he said, “I think it’s imperative for the clinician to at least engage in these conversations and not just stop when the thyroid function tests are normal. We have many lifestyle suggestions that have emerged from this study that I think physicians can put forward to patients who are dealing with this ... early in the process in addition to thyroid hormone adjustment, which may help some patients.”  

Dr. Ettleson, Ms. Raine, and Dr. Sfeir have reported no relevant financial relationships.

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

Two different agents showed potential for safely treating patients with hypothalamic obesity in two pilot studies with small numbers of patients.

One study prospectively randomized 21 adults with acquired hypothalamic obesity to treatment with placebo or Tesomet, a compound that combines the novel monoamine reuptake inhibitor tesofensine with metoprolol, a beta-blocker added to protect against adverse effects from tesofensine on heart rate and cardiac contractility. After 24 weeks of treatment, people on tesofensine/metoprolol had significant weight loss, compared with controls, while showing good tolerance with no significant effects on heart rate, blood pressure, or heart rhythm, Ulla Feldt-Rasmussen, MD, DMSc, reported at the annual meeting of the Endocrine Society.

The second report reviewed 18 children and adolescents with either acquired or genetic hypothalamic obesity who received open-label treatment with dextroamphetamine for an average of 20 months, and overall patients safely lost an average of 0.43 in their body mass index (BMI) standard deviation score, reported Jiska van Schaik, MD, in a separate talk at the meeting.



‘A supplement for lost satiety’

Patients with hypothalamic obesity face a dual problem from hypothalamic dysfunction that’s addressed by tesofensine, the weight-loss agent in Tesomet that increases hypothalamic levels of dopamine, serotonin, and noradrenaline by blocking reuptake, and thereby dulls appetite and food craving while also increasing fat metabolism, explained Dr. Feldt-Rasmussen, a professor of medical endocrinology at the University of Denmark and Rigshospitalet in Copenhagen. No treatment currently has regulatory approval for treating any form of hypothalamic obesity.

Tesofensine works as “a supplement for lost satiety, and satiety is what is lost” in patients with hypothalamic obesity as well in patients as Prader-Willi syndrome, the two disorders for which tesofensine/metoprolol is currently undergoing testing. “That’s the rationale, and it seems to work,” she declared during her talk. The formulation contains 0.5 mg tesofensine and 50 mg metoprolol administered orally once daily.

The study, run at Rigshospitalet, randomized 21 patients aged 18-75 years and with a BMI of at least 27 kg/m²who all had acquired hypothalamic obesity secondary to hypothalamic damage following cancer treatment. Patients averaged about 45 years of age, three-quarters were women, and their average BMI was about 37^, with 90% having a BMI of at least 30.

The study’s design calls for 48-week follow-up; Dr. Feldt-Rasmussen presented the interim results after 24 weeks, with 18 of the 21 enrolled patients remaining in the study through 24 weeks. Three patients dropped out because of adverse events: one in the placebo arm, and two who received tesofensine/metoprolol.

Weight dropped by an average of 6.6 kg from baseline among the 11 patients who completed 24 weeks on tesofensine/metoprolol treatment, compared with no average change from baseline among the seven patients who completed the study on placebo, a significant difference. The researchers measured a validated, composite satiety score every 4 weeks, and found significantly more improvement among patients on tesofensine/metoprolol than in those on placebo during the study’s first half, but subsequently average scores among the actively treated patients fell to the same level of modest improvement as in the placebo patients.

Despite this, average weight loss in the patients on tesofensine/metoprolol steadily increased throughout the full 24 weeks.

Safety measures of diastolic blood pressure, heart rate, and corrected QT interval showed no significant between-group difference. Systolic pressure showed a transient average rise of 4 mm Hg above baseline in the tesofensine/metoprolol group, compared with a small dip in the control patients, but by 24 weeks average systolic blood pressure had reverted closer to baseline levels in both subgroups and showed no significant between-group difference. Two patients on tesofensine/metoprolol developed serious adverse events. In one patient these were not treatment related. The other patient developed anxiety after 8 weeks that was possibly treatment related but remained on treatment. Other adverse effects on tesofensine/metoprolol included dizziness, sleep disorder, and dry mouth, but all of these were mild and patients were willing to tolerate them to achieve their weight loss, Dr. Feldt-Rasmussen said.



Repurposing an ADHD treatment

Dextroamphetamine increases satiety and boosts resting energy expenditure, and is a common treatment for attention deficit hyperactivity disorder. Dr. van Schaik and coauthors reviewed 13 children and adolescents with acquired hypothalamic obesity and 5 with genetic hypothalamic obesity who received the treatment at either of two Dutch hospitals during 2014-2020. All 18 patients went on dextroamphetamine after other interventions had failed to produce improvement, said Dr. van Schaik, a researcher at University Medical Center and Wilhelmina Children’s Hospital in Utrecht, the Netherlands. The patients averaged about 13 years of age.

In addition to an overall effect on weight across all 18 subjects, the researchers found they could subdivide the full cohort into 10 responders (56%), 4 (22%) with weight stabilization on treatment, and 4 nonresponders (22%) who continued to gain weight despite treatment. The 10 responding patients had an average drop in their BMI standard deviation score of 0.91. All 10 responders had acquired hypothalamic obesity, and they averaged a 12.5 percentage point rise in their resting energy expenditure level, compared with baseline, while on treatment. The four whose weight stabilized on treatment included three patients with genetic hypothalamic obesity. The four nonresponders split into two with acquired hypothalamic obesity and two with the genetic form.

Thirteen patients (72%) had improvements in hyperphagia, energy, and behavior, and no patient had a serious adverse effect. One patient stopped treatment after 1 month because of elevated blood pressure.

“Dextroamphetamine may be promising, especially for acquired hypothalamic obesity,” Dr. van Schaik concluded, adding that prospective, controlled assessments are needed, and that a healthy lifestyle is the foundation of hypothalamic obesity treatment.

The Tesomet study was sponsored by Saniona, the company developing Tesomet. Dr Feldt-Rasmussen is an advisor to Saniona, and some of the coauthors on the study are Saniona employees. Dr. van Schaik had no disclosures.

mzoler@mdedge.com

Two different agents showed potential for safely treating patients with hypothalamic obesity in two pilot studies with small numbers of patients.

One study prospectively randomized 21 adults with acquired hypothalamic obesity to treatment with placebo or Tesomet, a compound that combines the novel monoamine reuptake inhibitor tesofensine with metoprolol, a beta-blocker added to protect against adverse effects from tesofensine on heart rate and cardiac contractility. After 24 weeks of treatment, people on tesofensine/metoprolol had significant weight loss, compared with controls, while showing good tolerance with no significant effects on heart rate, blood pressure, or heart rhythm, Ulla Feldt-Rasmussen, MD, DMSc, reported at the annual meeting of the Endocrine Society.

The second report reviewed 18 children and adolescents with either acquired or genetic hypothalamic obesity who received open-label treatment with dextroamphetamine for an average of 20 months, and overall patients safely lost an average of 0.43 in their body mass index (BMI) standard deviation score, reported Jiska van Schaik, MD, in a separate talk at the meeting.



‘A supplement for lost satiety’

Patients with hypothalamic obesity face a dual problem from hypothalamic dysfunction that’s addressed by tesofensine, the weight-loss agent in Tesomet that increases hypothalamic levels of dopamine, serotonin, and noradrenaline by blocking reuptake, and thereby dulls appetite and food craving while also increasing fat metabolism, explained Dr. Feldt-Rasmussen, a professor of medical endocrinology at the University of Denmark and Rigshospitalet in Copenhagen. No treatment currently has regulatory approval for treating any form of hypothalamic obesity.

Tesofensine works as “a supplement for lost satiety, and satiety is what is lost” in patients with hypothalamic obesity as well in patients as Prader-Willi syndrome, the two disorders for which tesofensine/metoprolol is currently undergoing testing. “That’s the rationale, and it seems to work,” she declared during her talk. The formulation contains 0.5 mg tesofensine and 50 mg metoprolol administered orally once daily.

The study, run at Rigshospitalet, randomized 21 patients aged 18-75 years and with a BMI of at least 27 kg/m²who all had acquired hypothalamic obesity secondary to hypothalamic damage following cancer treatment. Patients averaged about 45 years of age, three-quarters were women, and their average BMI was about 37^, with 90% having a BMI of at least 30.

The study’s design calls for 48-week follow-up; Dr. Feldt-Rasmussen presented the interim results after 24 weeks, with 18 of the 21 enrolled patients remaining in the study through 24 weeks. Three patients dropped out because of adverse events: one in the placebo arm, and two who received tesofensine/metoprolol.

Weight dropped by an average of 6.6 kg from baseline among the 11 patients who completed 24 weeks on tesofensine/metoprolol treatment, compared with no average change from baseline among the seven patients who completed the study on placebo, a significant difference. The researchers measured a validated, composite satiety score every 4 weeks, and found significantly more improvement among patients on tesofensine/metoprolol than in those on placebo during the study’s first half, but subsequently average scores among the actively treated patients fell to the same level of modest improvement as in the placebo patients.

Despite this, average weight loss in the patients on tesofensine/metoprolol steadily increased throughout the full 24 weeks.

Safety measures of diastolic blood pressure, heart rate, and corrected QT interval showed no significant between-group difference. Systolic pressure showed a transient average rise of 4 mm Hg above baseline in the tesofensine/metoprolol group, compared with a small dip in the control patients, but by 24 weeks average systolic blood pressure had reverted closer to baseline levels in both subgroups and showed no significant between-group difference. Two patients on tesofensine/metoprolol developed serious adverse events. In one patient these were not treatment related. The other patient developed anxiety after 8 weeks that was possibly treatment related but remained on treatment. Other adverse effects on tesofensine/metoprolol included dizziness, sleep disorder, and dry mouth, but all of these were mild and patients were willing to tolerate them to achieve their weight loss, Dr. Feldt-Rasmussen said.



Repurposing an ADHD treatment

Dextroamphetamine increases satiety and boosts resting energy expenditure, and is a common treatment for attention deficit hyperactivity disorder. Dr. van Schaik and coauthors reviewed 13 children and adolescents with acquired hypothalamic obesity and 5 with genetic hypothalamic obesity who received the treatment at either of two Dutch hospitals during 2014-2020. All 18 patients went on dextroamphetamine after other interventions had failed to produce improvement, said Dr. van Schaik, a researcher at University Medical Center and Wilhelmina Children’s Hospital in Utrecht, the Netherlands. The patients averaged about 13 years of age.

In addition to an overall effect on weight across all 18 subjects, the researchers found they could subdivide the full cohort into 10 responders (56%), 4 (22%) with weight stabilization on treatment, and 4 nonresponders (22%) who continued to gain weight despite treatment. The 10 responding patients had an average drop in their BMI standard deviation score of 0.91. All 10 responders had acquired hypothalamic obesity, and they averaged a 12.5 percentage point rise in their resting energy expenditure level, compared with baseline, while on treatment. The four whose weight stabilized on treatment included three patients with genetic hypothalamic obesity. The four nonresponders split into two with acquired hypothalamic obesity and two with the genetic form.

Thirteen patients (72%) had improvements in hyperphagia, energy, and behavior, and no patient had a serious adverse effect. One patient stopped treatment after 1 month because of elevated blood pressure.

“Dextroamphetamine may be promising, especially for acquired hypothalamic obesity,” Dr. van Schaik concluded, adding that prospective, controlled assessments are needed, and that a healthy lifestyle is the foundation of hypothalamic obesity treatment.

The Tesomet study was sponsored by Saniona, the company developing Tesomet. Dr Feldt-Rasmussen is an advisor to Saniona, and some of the coauthors on the study are Saniona employees. Dr. van Schaik had no disclosures.

mzoler@mdedge.com

Two different agents showed potential for safely treating patients with hypothalamic obesity in two pilot studies with small numbers of patients.

One study prospectively randomized 21 adults with acquired hypothalamic obesity to treatment with placebo or Tesomet, a compound that combines the novel monoamine reuptake inhibitor tesofensine with metoprolol, a beta-blocker added to protect against adverse effects from tesofensine on heart rate and cardiac contractility. After 24 weeks of treatment, people on tesofensine/metoprolol had significant weight loss, compared with controls, while showing good tolerance with no significant effects on heart rate, blood pressure, or heart rhythm, Ulla Feldt-Rasmussen, MD, DMSc, reported at the annual meeting of the Endocrine Society.

The second report reviewed 18 children and adolescents with either acquired or genetic hypothalamic obesity who received open-label treatment with dextroamphetamine for an average of 20 months, and overall patients safely lost an average of 0.43 in their body mass index (BMI) standard deviation score, reported Jiska van Schaik, MD, in a separate talk at the meeting.



‘A supplement for lost satiety’

Patients with hypothalamic obesity face a dual problem from hypothalamic dysfunction that’s addressed by tesofensine, the weight-loss agent in Tesomet that increases hypothalamic levels of dopamine, serotonin, and noradrenaline by blocking reuptake, and thereby dulls appetite and food craving while also increasing fat metabolism, explained Dr. Feldt-Rasmussen, a professor of medical endocrinology at the University of Denmark and Rigshospitalet in Copenhagen. No treatment currently has regulatory approval for treating any form of hypothalamic obesity.

Tesofensine works as “a supplement for lost satiety, and satiety is what is lost” in patients with hypothalamic obesity as well in patients as Prader-Willi syndrome, the two disorders for which tesofensine/metoprolol is currently undergoing testing. “That’s the rationale, and it seems to work,” she declared during her talk. The formulation contains 0.5 mg tesofensine and 50 mg metoprolol administered orally once daily.

The study, run at Rigshospitalet, randomized 21 patients aged 18-75 years and with a BMI of at least 27 kg/m²who all had acquired hypothalamic obesity secondary to hypothalamic damage following cancer treatment. Patients averaged about 45 years of age, three-quarters were women, and their average BMI was about 37^, with 90% having a BMI of at least 30.

The study’s design calls for 48-week follow-up; Dr. Feldt-Rasmussen presented the interim results after 24 weeks, with 18 of the 21 enrolled patients remaining in the study through 24 weeks. Three patients dropped out because of adverse events: one in the placebo arm, and two who received tesofensine/metoprolol.

Weight dropped by an average of 6.6 kg from baseline among the 11 patients who completed 24 weeks on tesofensine/metoprolol treatment, compared with no average change from baseline among the seven patients who completed the study on placebo, a significant difference. The researchers measured a validated, composite satiety score every 4 weeks, and found significantly more improvement among patients on tesofensine/metoprolol than in those on placebo during the study’s first half, but subsequently average scores among the actively treated patients fell to the same level of modest improvement as in the placebo patients.

Despite this, average weight loss in the patients on tesofensine/metoprolol steadily increased throughout the full 24 weeks.

Safety measures of diastolic blood pressure, heart rate, and corrected QT interval showed no significant between-group difference. Systolic pressure showed a transient average rise of 4 mm Hg above baseline in the tesofensine/metoprolol group, compared with a small dip in the control patients, but by 24 weeks average systolic blood pressure had reverted closer to baseline levels in both subgroups and showed no significant between-group difference. Two patients on tesofensine/metoprolol developed serious adverse events. In one patient these were not treatment related. The other patient developed anxiety after 8 weeks that was possibly treatment related but remained on treatment. Other adverse effects on tesofensine/metoprolol included dizziness, sleep disorder, and dry mouth, but all of these were mild and patients were willing to tolerate them to achieve their weight loss, Dr. Feldt-Rasmussen said.



Repurposing an ADHD treatment

Dextroamphetamine increases satiety and boosts resting energy expenditure, and is a common treatment for attention deficit hyperactivity disorder. Dr. van Schaik and coauthors reviewed 13 children and adolescents with acquired hypothalamic obesity and 5 with genetic hypothalamic obesity who received the treatment at either of two Dutch hospitals during 2014-2020. All 18 patients went on dextroamphetamine after other interventions had failed to produce improvement, said Dr. van Schaik, a researcher at University Medical Center and Wilhelmina Children’s Hospital in Utrecht, the Netherlands. The patients averaged about 13 years of age.

In addition to an overall effect on weight across all 18 subjects, the researchers found they could subdivide the full cohort into 10 responders (56%), 4 (22%) with weight stabilization on treatment, and 4 nonresponders (22%) who continued to gain weight despite treatment. The 10 responding patients had an average drop in their BMI standard deviation score of 0.91. All 10 responders had acquired hypothalamic obesity, and they averaged a 12.5 percentage point rise in their resting energy expenditure level, compared with baseline, while on treatment. The four whose weight stabilized on treatment included three patients with genetic hypothalamic obesity. The four nonresponders split into two with acquired hypothalamic obesity and two with the genetic form.

Thirteen patients (72%) had improvements in hyperphagia, energy, and behavior, and no patient had a serious adverse effect. One patient stopped treatment after 1 month because of elevated blood pressure.

“Dextroamphetamine may be promising, especially for acquired hypothalamic obesity,” Dr. van Schaik concluded, adding that prospective, controlled assessments are needed, and that a healthy lifestyle is the foundation of hypothalamic obesity treatment.

The Tesomet study was sponsored by Saniona, the company developing Tesomet. Dr Feldt-Rasmussen is an advisor to Saniona, and some of the coauthors on the study are Saniona employees. Dr. van Schaik had no disclosures.

mzoler@mdedge.com

Girls in late stages of puberty who had elevated levels of body fat showed unusually high levels of several hormones that could contribute to an earlier age of menarche and also slow breast development, according to data from 90 girls who spanned a wide range of body fat in the first longitudinal study to examine links between fat volume, levels of reproductive hormones, and clinical manifestations of hormone action during puberty.

The results showed that girls with greater body fat had higher levels of follicle stimulating hormone, inhibin B, estrone, and certain male-like reproductive hormones, and that this pattern “is specifically tied to body fat,” said Natalie D. Shaw, MD, senior investigator for the study, reported at the annual meeting of the Endocrine Society.

“We found that total body fat is associated with the timing of menarche, as others have reported for body weight,” she noted. The new findings showed that every 1% rise in percent total body fat linked with a significant 3% rise in the likelihood of menarche, menstrual onset. In the new study the average age of menarche was 11.7 years among the overweight or obese girls and 12.8 years among those with normal weights.

But the study’s unique use of an average of about three serial ultrasound breast examinations of each subject during an average 4 years of follow-up also showed that higher levels of body fat linked with slowed breast development in later stages, specifically maturation from stage D to stages D/E and E.

For example, girls with 33% body fat spent an average of 8.2 months in stage D, which stretched to an average of 11.2 months among girls with 38% body fat, reported Madison T. Ortega, a researcher with the Pediatric Endocrinology Group of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., who presented the report at the meeting.
 

Ultrasound shows what inspection can’t

Results from “several studies have shown earlier breast development in overweight and obese girls by inspection and palpation,” but the new findings from ultrasound examination provide more nuance about the structural breast changes actually occurring in these adolescents, said Dr. Shaw, who heads the Pediatric Endocrinology Group. The current study “was not designed to capture the onset of breast development,” and “it is possible that increased androgens or insulin resistance in girls with higher body fat interferes with normal breast development,” she explained in an interview.

“The authors showed that the timing and progress of early stages of puberty were not earlier in overweight or obese girls. Luteinizing hormone, the indicator of neuroendocrine pubertal onset, and timing of early stages of breast development were the same in all weight groups. The authors also discovered falsely advanced Turner breast stage designations with ultrasonography in some girls with obesity. This might suggest that prior findings in epidemiologic studies of an earlier start to puberty based mostly on breast development stages identified by self-reported inspection and, rarely, palpation, may have been biased by breast adipose tissue,” said Christine M. Burt Solorzano, MD, a pediatric endocrinologist at the University of Virginia in Charlottesville, who was not involved in the study.

“Development of increased follicle-stimulating hormone in late puberty suggests that pubertal tempo, not onset, may be increased in girls with obesity, and goes along with earlier menarche. Their finding of increased androgen levels during mid to late puberty with obesity are consistent with prior findings,” including work published Dr. Burt Solorzano and her associates, she noted. “Delayed timing of advanced breast morphology was unexpected and may reflect relatively lower levels of progesterone in girls with obesity,” a hormone necessary for later stages of breast maturation.

The findings “reinforce that early breast development in the setting of obesity may in fact reflect adipose tissue and not be a true representation of neuroendocrine precocious puberty,” Dr. Burt Solorzano said in an interview. The findings “also suggest that pubertal initiation may not happen earlier in girls with obesity, as has been thought, but rather the tempo of puberty may be more rapid, leading to earlier menarche.”

A possible step toward PCOS

The long-term clinical consequences of the hormonal state linked with overweight and obesity “are unknown,” said Dr. Shaw. However, she and her coworkers followed a few of their subjects with elevated testosterone levels during midpuberty, and several developed signs of early polycystic ovarian syndrome (PCOS) such as irregular menstrual cycles, acne, and hirsutism. “It may be possible to identify girls at high risk for PCOS before menarche,” she suggested.

Dr. Burt Solorzano agreed that delayed breast development in girls with high levels of body fat may reflect inadequate progesterone production, which when coupled with an obesity-related excess level of androgens could put girls at risk for chronic anovulation and later PCOS.

“Weight management during childhood and early puberty may mitigate the adverse effects of obesity on pubertal progression and avoid some of the lifetime complications related to early menarche,” Dr. Burt Solorzano said.

The Body Weight and Puberty Study enrolled 36 girls who were overweight or obese and 54 girls with normal weight. They averaged 11 years of age, with a range of 8.2-14.7 years. Average percent body fat was 41% among the overweight or obese girls and 27% among those with normal weight. The results reported by Ms. Ortega also appeared in a report published Feb 22, 2021 (J Clin Endocrinol Metab. doi: 10.1210/clinem/dgab092).

Dr. Shaw, Ms. Ortega, and Dr. Burt Solorzano had no disclosures.

mzoler@mdedge.com

Girls in late stages of puberty who had elevated levels of body fat showed unusually high levels of several hormones that could contribute to an earlier age of menarche and also slow breast development, according to data from 90 girls who spanned a wide range of body fat in the first longitudinal study to examine links between fat volume, levels of reproductive hormones, and clinical manifestations of hormone action during puberty.

The results showed that girls with greater body fat had higher levels of follicle stimulating hormone, inhibin B, estrone, and certain male-like reproductive hormones, and that this pattern “is specifically tied to body fat,” said Natalie D. Shaw, MD, senior investigator for the study, reported at the annual meeting of the Endocrine Society.

“We found that total body fat is associated with the timing of menarche, as others have reported for body weight,” she noted. The new findings showed that every 1% rise in percent total body fat linked with a significant 3% rise in the likelihood of menarche, menstrual onset. In the new study the average age of menarche was 11.7 years among the overweight or obese girls and 12.8 years among those with normal weights.

But the study’s unique use of an average of about three serial ultrasound breast examinations of each subject during an average 4 years of follow-up also showed that higher levels of body fat linked with slowed breast development in later stages, specifically maturation from stage D to stages D/E and E.

For example, girls with 33% body fat spent an average of 8.2 months in stage D, which stretched to an average of 11.2 months among girls with 38% body fat, reported Madison T. Ortega, a researcher with the Pediatric Endocrinology Group of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., who presented the report at the meeting.
 

Ultrasound shows what inspection can’t

Results from “several studies have shown earlier breast development in overweight and obese girls by inspection and palpation,” but the new findings from ultrasound examination provide more nuance about the structural breast changes actually occurring in these adolescents, said Dr. Shaw, who heads the Pediatric Endocrinology Group. The current study “was not designed to capture the onset of breast development,” and “it is possible that increased androgens or insulin resistance in girls with higher body fat interferes with normal breast development,” she explained in an interview.

“The authors showed that the timing and progress of early stages of puberty were not earlier in overweight or obese girls. Luteinizing hormone, the indicator of neuroendocrine pubertal onset, and timing of early stages of breast development were the same in all weight groups. The authors also discovered falsely advanced Turner breast stage designations with ultrasonography in some girls with obesity. This might suggest that prior findings in epidemiologic studies of an earlier start to puberty based mostly on breast development stages identified by self-reported inspection and, rarely, palpation, may have been biased by breast adipose tissue,” said Christine M. Burt Solorzano, MD, a pediatric endocrinologist at the University of Virginia in Charlottesville, who was not involved in the study.

“Development of increased follicle-stimulating hormone in late puberty suggests that pubertal tempo, not onset, may be increased in girls with obesity, and goes along with earlier menarche. Their finding of increased androgen levels during mid to late puberty with obesity are consistent with prior findings,” including work published Dr. Burt Solorzano and her associates, she noted. “Delayed timing of advanced breast morphology was unexpected and may reflect relatively lower levels of progesterone in girls with obesity,” a hormone necessary for later stages of breast maturation.

The findings “reinforce that early breast development in the setting of obesity may in fact reflect adipose tissue and not be a true representation of neuroendocrine precocious puberty,” Dr. Burt Solorzano said in an interview. The findings “also suggest that pubertal initiation may not happen earlier in girls with obesity, as has been thought, but rather the tempo of puberty may be more rapid, leading to earlier menarche.”

A possible step toward PCOS

The long-term clinical consequences of the hormonal state linked with overweight and obesity “are unknown,” said Dr. Shaw. However, she and her coworkers followed a few of their subjects with elevated testosterone levels during midpuberty, and several developed signs of early polycystic ovarian syndrome (PCOS) such as irregular menstrual cycles, acne, and hirsutism. “It may be possible to identify girls at high risk for PCOS before menarche,” she suggested.

Dr. Burt Solorzano agreed that delayed breast development in girls with high levels of body fat may reflect inadequate progesterone production, which when coupled with an obesity-related excess level of androgens could put girls at risk for chronic anovulation and later PCOS.

“Weight management during childhood and early puberty may mitigate the adverse effects of obesity on pubertal progression and avoid some of the lifetime complications related to early menarche,” Dr. Burt Solorzano said.

The Body Weight and Puberty Study enrolled 36 girls who were overweight or obese and 54 girls with normal weight. They averaged 11 years of age, with a range of 8.2-14.7 years. Average percent body fat was 41% among the overweight or obese girls and 27% among those with normal weight. The results reported by Ms. Ortega also appeared in a report published Feb 22, 2021 (J Clin Endocrinol Metab. doi: 10.1210/clinem/dgab092).

Dr. Shaw, Ms. Ortega, and Dr. Burt Solorzano had no disclosures.

mzoler@mdedge.com

Girls in late stages of puberty who had elevated levels of body fat showed unusually high levels of several hormones that could contribute to an earlier age of menarche and also slow breast development, according to data from 90 girls who spanned a wide range of body fat in the first longitudinal study to examine links between fat volume, levels of reproductive hormones, and clinical manifestations of hormone action during puberty.

The results showed that girls with greater body fat had higher levels of follicle stimulating hormone, inhibin B, estrone, and certain male-like reproductive hormones, and that this pattern “is specifically tied to body fat,” said Natalie D. Shaw, MD, senior investigator for the study, reported at the annual meeting of the Endocrine Society.

“We found that total body fat is associated with the timing of menarche, as others have reported for body weight,” she noted. The new findings showed that every 1% rise in percent total body fat linked with a significant 3% rise in the likelihood of menarche, menstrual onset. In the new study the average age of menarche was 11.7 years among the overweight or obese girls and 12.8 years among those with normal weights.

But the study’s unique use of an average of about three serial ultrasound breast examinations of each subject during an average 4 years of follow-up also showed that higher levels of body fat linked with slowed breast development in later stages, specifically maturation from stage D to stages D/E and E.

For example, girls with 33% body fat spent an average of 8.2 months in stage D, which stretched to an average of 11.2 months among girls with 38% body fat, reported Madison T. Ortega, a researcher with the Pediatric Endocrinology Group of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., who presented the report at the meeting.
 

Ultrasound shows what inspection can’t

Results from “several studies have shown earlier breast development in overweight and obese girls by inspection and palpation,” but the new findings from ultrasound examination provide more nuance about the structural breast changes actually occurring in these adolescents, said Dr. Shaw, who heads the Pediatric Endocrinology Group. The current study “was not designed to capture the onset of breast development,” and “it is possible that increased androgens or insulin resistance in girls with higher body fat interferes with normal breast development,” she explained in an interview.

“The authors showed that the timing and progress of early stages of puberty were not earlier in overweight or obese girls. Luteinizing hormone, the indicator of neuroendocrine pubertal onset, and timing of early stages of breast development were the same in all weight groups. The authors also discovered falsely advanced Turner breast stage designations with ultrasonography in some girls with obesity. This might suggest that prior findings in epidemiologic studies of an earlier start to puberty based mostly on breast development stages identified by self-reported inspection and, rarely, palpation, may have been biased by breast adipose tissue,” said Christine M. Burt Solorzano, MD, a pediatric endocrinologist at the University of Virginia in Charlottesville, who was not involved in the study.

“Development of increased follicle-stimulating hormone in late puberty suggests that pubertal tempo, not onset, may be increased in girls with obesity, and goes along with earlier menarche. Their finding of increased androgen levels during mid to late puberty with obesity are consistent with prior findings,” including work published Dr. Burt Solorzano and her associates, she noted. “Delayed timing of advanced breast morphology was unexpected and may reflect relatively lower levels of progesterone in girls with obesity,” a hormone necessary for later stages of breast maturation.

The findings “reinforce that early breast development in the setting of obesity may in fact reflect adipose tissue and not be a true representation of neuroendocrine precocious puberty,” Dr. Burt Solorzano said in an interview. The findings “also suggest that pubertal initiation may not happen earlier in girls with obesity, as has been thought, but rather the tempo of puberty may be more rapid, leading to earlier menarche.”

A possible step toward PCOS

The long-term clinical consequences of the hormonal state linked with overweight and obesity “are unknown,” said Dr. Shaw. However, she and her coworkers followed a few of their subjects with elevated testosterone levels during midpuberty, and several developed signs of early polycystic ovarian syndrome (PCOS) such as irregular menstrual cycles, acne, and hirsutism. “It may be possible to identify girls at high risk for PCOS before menarche,” she suggested.

Dr. Burt Solorzano agreed that delayed breast development in girls with high levels of body fat may reflect inadequate progesterone production, which when coupled with an obesity-related excess level of androgens could put girls at risk for chronic anovulation and later PCOS.

“Weight management during childhood and early puberty may mitigate the adverse effects of obesity on pubertal progression and avoid some of the lifetime complications related to early menarche,” Dr. Burt Solorzano said.

The Body Weight and Puberty Study enrolled 36 girls who were overweight or obese and 54 girls with normal weight. They averaged 11 years of age, with a range of 8.2-14.7 years. Average percent body fat was 41% among the overweight or obese girls and 27% among those with normal weight. The results reported by Ms. Ortega also appeared in a report published Feb 22, 2021 (J Clin Endocrinol Metab. doi: 10.1210/clinem/dgab092).

Dr. Shaw, Ms. Ortega, and Dr. Burt Solorzano had no disclosures.

mzoler@mdedge.com

Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”

Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest study in scale and scope of Cushing’s syndrome mortality

Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).

This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).

The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing perioperative mortality: Consider thromboprophylaxis

Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

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

Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”

Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest study in scale and scope of Cushing’s syndrome mortality

Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).

This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).

The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing perioperative mortality: Consider thromboprophylaxis

Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

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

Excess mortality among people with endogenous Cushing’s syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality – defined as the ratio of the number of deaths from CS divided by the total number of CS patients – was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS, compared with those with Cushing’s disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Dr. Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population ... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told this news organization that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet ... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing’s was unexpectedly high despite patients with adrenal cancer being excluded.”

Dr. Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.”

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing’s treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications ... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest study in scale and scope of Cushing’s syndrome mortality

Endogenous Cushing’s syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing’s disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing’s syndrome). Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing’s disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing’s syndrome,” Dr. Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15-7.84).

This SMR was higher among patients with adrenal Cushing’s syndrome (3.3) versus Cushing’s disease (2.8) (P = .003) and among patients who had active disease (5.7) versus those whose disease was in remission (2.3) (P < .001).

The SMR was also worse among patients with Cushing’s disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing perioperative mortality: Consider thromboprophylaxis

Dr. Fleseriu told this news organization that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Dr. Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing’s syndrome and balanced with individual bleeding risk,” Dr. Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Dr. Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Dr. Limumpornpetch has disclosed no relevant financial relationships. Dr. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

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

Incorporation of a nonintensive fitness intervention for women with obesity into a standard fertility treatment program could be cost effective, a new analysis finds.

Financial data for the Canadian Fit-for-Fertility program were presented March 20 at the annual meeting of the Endocrine Society by Matea Belan, PhD, of the division of endocrinology at the University of Sherbrooke (Que.).

Women with obesity and infertility are typically advised to lose 5%-10% of their body weight as first-line fertility treatment, as doing so has been shown to increase rates of ovulation and pregnancy. But most established fertility treatment programs don’t incorporate organized lifestyle modification interventions, Dr. Belan explained during a press briefing.

“Mostly they’re just given general advice, not resources. It’s up to the woman to seek help for lifestyle. Our idea is to give them access to intervention that’s integrated into the setting of a fertility clinic,” she said.

Primary results from the Fit-for-Fertility program, including significant weight loss and a 40% increased live birth rate at 18 months, compared with standard fertility treatment, were presented at ENDO 2019 and reported at the time by this news organization.

In the new analysis, the cost in Canadian dollars per additional newborn achieved with the Fit-for-Fertility program was similar to the willingness-to-pay for in vitro fertilization from a health system perspective.

The final goal, lead investigator Jean-Patrice Baillargeon, MD, said in an interview, “would be to convince stakeholders, and mainly the provincial government, to cover the costs of our lifestyle program. This would not be more costly than funding IVF, but [would provide] more long-term benefits for the whole family and the offspring.”

Chloe A. Zera, MD, said in an interview that she supports the idea in principle, but is concerned that, in the U.S. health care system, women don’t always have access to fertility and obesity treatments to begin with.

“There’s a huge equity issue. People with Medicaid don’t necessarily get coverage for IVF. ... Even many commercially insured people are paying out of pocket, which can be $10,000 to $15,000 for a cycle just for the medications, so the cost to patients on the individual level is huge,” said Dr. Zera, who is associate professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston.

She added: “I’m prolifestyle modification. I’m also proequity in health care delivery so I would want to make sure that the way it’s delivered incorporates that as a consideration. ... Is that money better spent on primary prevention of obesity and access to basic services and basic reproductive health care for everybody?”
 

Primary results: Improvements in overall and spontaneous pregnancy rates

The study included 130 women with infertility and a body mass index of at least 30 kg/m2 (mean, 40), of whom 65 were randomized to the Fit-for-Fitness program and 65 to standard fertility treatment that did not include a lifestyle intervention, although those women could consult professionals on their own. The women in the lifestyle intervention group had to stop medical fertility treatments for the first 6 months but could use them thereafter while the controls continued to use them throughout.

Based on motivational interviewing, the program focused on womens’ individual likes and dislikes, experiences, and perceived capacities, aiming to improve healthful habits gradually and with “low intensity” so as to maintain them in the long run.

The program combined individual sessions with a nutritionist and kinesiologist every 6 weeks and 12 mandatory group sessions. The women were asked to reduce their total caloric intake by about 500 calories/day but weren’t asked to change their diets. They were also advised to increase physical activity by about 150 minutes/week.

“We want to keep it sustainable in time, so they don’t have a relapse when they become pregnant, and to help the newborn and spouse too. It’s about improving and maintaining habits,” Dr. Belan explained during the briefing.

At 6 months, mean weight changes were –3.4% versus –0.89% for the intervention versus control groups (P = .003).

“What is important for women with obesity and infertility is to improve their lifestyle, both physical activity and nutrition, even if the weight loss is minimal,” noted Dr. Baillargeon, professor of medicine, health sciences research and physiology, also at the University of Sherbrooke.

A total of 46 intervention and 52 control patients finished the 18-month study. Pregnancies occurred in 61% of the intervention group versus 39% of the controls, while spontaneous pregnancies – among those not using medical fertility treatments – occurred in 33.3% versus 12.3% (P = .009).

The primary outcome, live births at 18 months, occurred in 51.0% of the intervention group versus 36.8% of controls, which wasn’t a statistically significant difference, but was “highly clinically significant,” Dr. Belan said.
 

Cost per additional newborn similar to IVF

Costs (in Canadian dollars) considered in the analysis included those related to the management of infertility, obesity, pregnancy, and childbirth. The incremental cost-effectiveness ratios, a standard cost-effectiveness measure, per live birth were $24,393 from a societal perspective, $12,633 for the health system, and $5,980 for the patient.

Because the $12,633 health system cost per additional newborn with the Fit-for-Fertility program is similar to the health system’s willingness-to-pay for IVF of up to $15,000, a lifestyle intervention could be considered cost-efficient compared with the standard of care, Dr. Belan said.

“We think that the Fit-for-Fertility program could be deemed cost effective and could represent an interesting alternative to the usual standard of care for women with obesity seeking fertility treatments,” she commented.

The Canadian Institutes of Health Research is funding a larger randomized, controlled trial of the program at six Canadian centers to validate these results.

Dr. Belan, Dr. Baillargeon, and Dr. Zera reported no relevant financial relationships.

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

Incorporation of a nonintensive fitness intervention for women with obesity into a standard fertility treatment program could be cost effective, a new analysis finds.

Financial data for the Canadian Fit-for-Fertility program were presented March 20 at the annual meeting of the Endocrine Society by Matea Belan, PhD, of the division of endocrinology at the University of Sherbrooke (Que.).

Women with obesity and infertility are typically advised to lose 5%-10% of their body weight as first-line fertility treatment, as doing so has been shown to increase rates of ovulation and pregnancy. But most established fertility treatment programs don’t incorporate organized lifestyle modification interventions, Dr. Belan explained during a press briefing.

“Mostly they’re just given general advice, not resources. It’s up to the woman to seek help for lifestyle. Our idea is to give them access to intervention that’s integrated into the setting of a fertility clinic,” she said.

Primary results from the Fit-for-Fertility program, including significant weight loss and a 40% increased live birth rate at 18 months, compared with standard fertility treatment, were presented at ENDO 2019 and reported at the time by this news organization.

In the new analysis, the cost in Canadian dollars per additional newborn achieved with the Fit-for-Fertility program was similar to the willingness-to-pay for in vitro fertilization from a health system perspective.

The final goal, lead investigator Jean-Patrice Baillargeon, MD, said in an interview, “would be to convince stakeholders, and mainly the provincial government, to cover the costs of our lifestyle program. This would not be more costly than funding IVF, but [would provide] more long-term benefits for the whole family and the offspring.”

Chloe A. Zera, MD, said in an interview that she supports the idea in principle, but is concerned that, in the U.S. health care system, women don’t always have access to fertility and obesity treatments to begin with.

“There’s a huge equity issue. People with Medicaid don’t necessarily get coverage for IVF. ... Even many commercially insured people are paying out of pocket, which can be $10,000 to $15,000 for a cycle just for the medications, so the cost to patients on the individual level is huge,” said Dr. Zera, who is associate professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston.

She added: “I’m prolifestyle modification. I’m also proequity in health care delivery so I would want to make sure that the way it’s delivered incorporates that as a consideration. ... Is that money better spent on primary prevention of obesity and access to basic services and basic reproductive health care for everybody?”
 

Primary results: Improvements in overall and spontaneous pregnancy rates

The study included 130 women with infertility and a body mass index of at least 30 kg/m2 (mean, 40), of whom 65 were randomized to the Fit-for-Fitness program and 65 to standard fertility treatment that did not include a lifestyle intervention, although those women could consult professionals on their own. The women in the lifestyle intervention group had to stop medical fertility treatments for the first 6 months but could use them thereafter while the controls continued to use them throughout.

Based on motivational interviewing, the program focused on womens’ individual likes and dislikes, experiences, and perceived capacities, aiming to improve healthful habits gradually and with “low intensity” so as to maintain them in the long run.

The program combined individual sessions with a nutritionist and kinesiologist every 6 weeks and 12 mandatory group sessions. The women were asked to reduce their total caloric intake by about 500 calories/day but weren’t asked to change their diets. They were also advised to increase physical activity by about 150 minutes/week.

“We want to keep it sustainable in time, so they don’t have a relapse when they become pregnant, and to help the newborn and spouse too. It’s about improving and maintaining habits,” Dr. Belan explained during the briefing.

At 6 months, mean weight changes were –3.4% versus –0.89% for the intervention versus control groups (P = .003).

“What is important for women with obesity and infertility is to improve their lifestyle, both physical activity and nutrition, even if the weight loss is minimal,” noted Dr. Baillargeon, professor of medicine, health sciences research and physiology, also at the University of Sherbrooke.

A total of 46 intervention and 52 control patients finished the 18-month study. Pregnancies occurred in 61% of the intervention group versus 39% of the controls, while spontaneous pregnancies – among those not using medical fertility treatments – occurred in 33.3% versus 12.3% (P = .009).

The primary outcome, live births at 18 months, occurred in 51.0% of the intervention group versus 36.8% of controls, which wasn’t a statistically significant difference, but was “highly clinically significant,” Dr. Belan said.
 

Cost per additional newborn similar to IVF

Costs (in Canadian dollars) considered in the analysis included those related to the management of infertility, obesity, pregnancy, and childbirth. The incremental cost-effectiveness ratios, a standard cost-effectiveness measure, per live birth were $24,393 from a societal perspective, $12,633 for the health system, and $5,980 for the patient.

Because the $12,633 health system cost per additional newborn with the Fit-for-Fertility program is similar to the health system’s willingness-to-pay for IVF of up to $15,000, a lifestyle intervention could be considered cost-efficient compared with the standard of care, Dr. Belan said.

“We think that the Fit-for-Fertility program could be deemed cost effective and could represent an interesting alternative to the usual standard of care for women with obesity seeking fertility treatments,” she commented.

The Canadian Institutes of Health Research is funding a larger randomized, controlled trial of the program at six Canadian centers to validate these results.

Dr. Belan, Dr. Baillargeon, and Dr. Zera reported no relevant financial relationships.

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

Incorporation of a nonintensive fitness intervention for women with obesity into a standard fertility treatment program could be cost effective, a new analysis finds.

Financial data for the Canadian Fit-for-Fertility program were presented March 20 at the annual meeting of the Endocrine Society by Matea Belan, PhD, of the division of endocrinology at the University of Sherbrooke (Que.).

Women with obesity and infertility are typically advised to lose 5%-10% of their body weight as first-line fertility treatment, as doing so has been shown to increase rates of ovulation and pregnancy. But most established fertility treatment programs don’t incorporate organized lifestyle modification interventions, Dr. Belan explained during a press briefing.

“Mostly they’re just given general advice, not resources. It’s up to the woman to seek help for lifestyle. Our idea is to give them access to intervention that’s integrated into the setting of a fertility clinic,” she said.

Primary results from the Fit-for-Fertility program, including significant weight loss and a 40% increased live birth rate at 18 months, compared with standard fertility treatment, were presented at ENDO 2019 and reported at the time by this news organization.

In the new analysis, the cost in Canadian dollars per additional newborn achieved with the Fit-for-Fertility program was similar to the willingness-to-pay for in vitro fertilization from a health system perspective.

The final goal, lead investigator Jean-Patrice Baillargeon, MD, said in an interview, “would be to convince stakeholders, and mainly the provincial government, to cover the costs of our lifestyle program. This would not be more costly than funding IVF, but [would provide] more long-term benefits for the whole family and the offspring.”

Chloe A. Zera, MD, said in an interview that she supports the idea in principle, but is concerned that, in the U.S. health care system, women don’t always have access to fertility and obesity treatments to begin with.

“There’s a huge equity issue. People with Medicaid don’t necessarily get coverage for IVF. ... Even many commercially insured people are paying out of pocket, which can be $10,000 to $15,000 for a cycle just for the medications, so the cost to patients on the individual level is huge,” said Dr. Zera, who is associate professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston.

She added: “I’m prolifestyle modification. I’m also proequity in health care delivery so I would want to make sure that the way it’s delivered incorporates that as a consideration. ... Is that money better spent on primary prevention of obesity and access to basic services and basic reproductive health care for everybody?”
 

Primary results: Improvements in overall and spontaneous pregnancy rates

The study included 130 women with infertility and a body mass index of at least 30 kg/m2 (mean, 40), of whom 65 were randomized to the Fit-for-Fitness program and 65 to standard fertility treatment that did not include a lifestyle intervention, although those women could consult professionals on their own. The women in the lifestyle intervention group had to stop medical fertility treatments for the first 6 months but could use them thereafter while the controls continued to use them throughout.

Based on motivational interviewing, the program focused on womens’ individual likes and dislikes, experiences, and perceived capacities, aiming to improve healthful habits gradually and with “low intensity” so as to maintain them in the long run.

The program combined individual sessions with a nutritionist and kinesiologist every 6 weeks and 12 mandatory group sessions. The women were asked to reduce their total caloric intake by about 500 calories/day but weren’t asked to change their diets. They were also advised to increase physical activity by about 150 minutes/week.

“We want to keep it sustainable in time, so they don’t have a relapse when they become pregnant, and to help the newborn and spouse too. It’s about improving and maintaining habits,” Dr. Belan explained during the briefing.

At 6 months, mean weight changes were –3.4% versus –0.89% for the intervention versus control groups (P = .003).

“What is important for women with obesity and infertility is to improve their lifestyle, both physical activity and nutrition, even if the weight loss is minimal,” noted Dr. Baillargeon, professor of medicine, health sciences research and physiology, also at the University of Sherbrooke.

A total of 46 intervention and 52 control patients finished the 18-month study. Pregnancies occurred in 61% of the intervention group versus 39% of the controls, while spontaneous pregnancies – among those not using medical fertility treatments – occurred in 33.3% versus 12.3% (P = .009).

The primary outcome, live births at 18 months, occurred in 51.0% of the intervention group versus 36.8% of controls, which wasn’t a statistically significant difference, but was “highly clinically significant,” Dr. Belan said.
 

Cost per additional newborn similar to IVF

Costs (in Canadian dollars) considered in the analysis included those related to the management of infertility, obesity, pregnancy, and childbirth. The incremental cost-effectiveness ratios, a standard cost-effectiveness measure, per live birth were $24,393 from a societal perspective, $12,633 for the health system, and $5,980 for the patient.

Because the $12,633 health system cost per additional newborn with the Fit-for-Fertility program is similar to the health system’s willingness-to-pay for IVF of up to $15,000, a lifestyle intervention could be considered cost-efficient compared with the standard of care, Dr. Belan said.

“We think that the Fit-for-Fertility program could be deemed cost effective and could represent an interesting alternative to the usual standard of care for women with obesity seeking fertility treatments,” she commented.

The Canadian Institutes of Health Research is funding a larger randomized, controlled trial of the program at six Canadian centers to validate these results.

Dr. Belan, Dr. Baillargeon, and Dr. Zera reported no relevant financial relationships.

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

Cardiovascular and metabolic risk factors are increased among transgender youths, compared with youths who are not transgender. Elevations in lipid levels and body mass index (BMI) also occur in adult transgender patients, new research shows.

“This is the first study of its size in the United States of which we are aware that looks at the odds of youth with a diagnosis of gender dysphoria having medical diagnoses that relate to overall metabolic and cardiovascular health,” first author Anna Valentine, MD, of Children’s Hospital Colorado, Aurora, said in a press statement.

Although previous studies have shown that among transgender adults, BMI is higher and there is an increased risk for cardiovascular events, such as stroke or heart attack, compared with nontransgender people, research on adolescent transgender patients has been lacking.

With a recent survey showing that nearly 2% of adolescents identify as transgender, interest in health outcomes among younger patients is high.

To investigate, Dr. Valentine, and colleagues evaluated data from the PEDSnet pediatric database on 4,177 youths who had received a diagnosis of gender dysphoria. The participants had been enrolled at six sites from 2009 to 2019. The researchers compared these patients in a ratio of 1:4 with 16,664 control persons who had not been diagnosed with gender dysphoria. They reported their findings as a poster at the annual meeting of the Endocrine Society.

For the propensity-score analysis, participants were matched according to year of birth, age at last visit, site, race, ethnicity, insurance status, and duration in the database.

In both the transgender and control groups, about 66% were female at birth, 73% were White, and 9% Hispanic. For both groups, the average age was 16.2 years at the last visit. The average duration in the database was 7 years.
 

Study didn’t distinguish between those receiving and those not receiving gender-affirming hormones

In the retrospective study, among those who identified as transgender, the rates of diagnoses of dyslipidemia (odds ratio, 1.6; P < .0001) and metabolic syndrome (OR, 1.9; P = .0086) were significantly higher, compared with those without gender dysphoria.

Among the transgender male patients (born female) but not transgender female patients (born male), rates of diagnoses of overweight/obesity (OR, 1.7; P < .0001) and polycystic ovary syndrome were higher (OR, 1.9, P = .0006), compared with controls.

Gender-affirming hormone therapy, such as with testosterone or estradiol, is among the suspected culprits for the cardiovascular effects. However, importantly, this study did not differentiate between patients who had received estradiol or testosterone for gender affirmation and those who had not, Dr. Valentine said.

“We don’t know [whether gender-affirming hormone therapy is a cause], as we have not looked at this yet,” she said in an interview. “We are looking at that in our next analyses and will be including that in our future publication.

“We’ll also be looking at the relationship between having overweight/obesity and the other diagnoses that influence cardiovascular health (high blood pressure, liver dysfunction, and abnormal cholesterol), as that could certainly be playing a role as well,” she said.

For many transgender patients, gender-affirming hormone therapy is lifelong. One question that needs to be evaluated concerns whether the dose of such therapy has a role on cardiovascular effects and if so, whether adjustments could be made without compromising the therapeutic effect, Dr. Valentine noted.

“This is an important question, and future research is needed to evaluate whether doses [of gender-affirming hormones] are related to cardiometabolic outcomes,” she said.

Potential confounders in the study include the fact that rates of overweight and obesity are higher among youths with gender dysphoria. This can in itself can increase the risk for other disorders, Dr. Valentine noted.

Furthermore, rates of mental health comorbidities are higher among youths with gender dysphoria. One consequence of this may be that they engage in less physical activity, she said.
 

Hormone therapy, health care disparities, or both could explain risk

In commenting on the study, Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery, the Mount Sinai Health System, New York, said that although similar cardiovascular effects are known to occur in transgender adults as well, they may or may not be hormone related. Other factors can increase the risk.

“With transgender adults, any differences in lipids or cardiac risk factors relative to cisgender people might be attributable either to hormone therapy or to health care disparities,” he said in an interview.

“The data are mixed. It may be that most differences relate to lack of access to care and to mistreatment by society,” he said. “Even studies that focus on hormones see a worsened situation for trans women versus trans men.”

Other recent research that shows potential cardiovascular effects among adult transgender men includes a study of more than 1,000 transgender men (born female) who received testosterone. That study, which was also presented at the ENDO meeting and was reported by this news organization, found an increased risk for high hematocrit levels, which could lead to a thrombotic event.

However, a study published in Pediatrics, which was also reported by this news organization, that included 611 transgender youths who had taken gender-affirming hormone therapy for more than a year found no increased risk for thrombosis, even in the presence of thrombosis risk factors, including obesity, tobacco use, and family history of thrombosis. However, the senior author of that study pointed out that the duration of follow-up in that study was relatively short, which may have been why they did not find an increased risk for thrombosis.

Dr. Safer noted that transgender youths and adults alike face a host of cultural factors that could play a role in increased cardiovascular risks.

“For adults, the major candidate explanations for worse BMI and cardiac risk factors are societal mistreatment, and for trans women specifically, progestins. For youth, the major candidate explanations are societal mistreatment and lack of access to athletics,” he said.

The authors and Dr. Safer disclosed no relevant financial relationships.

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

Cardiovascular and metabolic risk factors are increased among transgender youths, compared with youths who are not transgender. Elevations in lipid levels and body mass index (BMI) also occur in adult transgender patients, new research shows.

“This is the first study of its size in the United States of which we are aware that looks at the odds of youth with a diagnosis of gender dysphoria having medical diagnoses that relate to overall metabolic and cardiovascular health,” first author Anna Valentine, MD, of Children’s Hospital Colorado, Aurora, said in a press statement.

Although previous studies have shown that among transgender adults, BMI is higher and there is an increased risk for cardiovascular events, such as stroke or heart attack, compared with nontransgender people, research on adolescent transgender patients has been lacking.

With a recent survey showing that nearly 2% of adolescents identify as transgender, interest in health outcomes among younger patients is high.

To investigate, Dr. Valentine, and colleagues evaluated data from the PEDSnet pediatric database on 4,177 youths who had received a diagnosis of gender dysphoria. The participants had been enrolled at six sites from 2009 to 2019. The researchers compared these patients in a ratio of 1:4 with 16,664 control persons who had not been diagnosed with gender dysphoria. They reported their findings as a poster at the annual meeting of the Endocrine Society.

For the propensity-score analysis, participants were matched according to year of birth, age at last visit, site, race, ethnicity, insurance status, and duration in the database.

In both the transgender and control groups, about 66% were female at birth, 73% were White, and 9% Hispanic. For both groups, the average age was 16.2 years at the last visit. The average duration in the database was 7 years.
 

Study didn’t distinguish between those receiving and those not receiving gender-affirming hormones

In the retrospective study, among those who identified as transgender, the rates of diagnoses of dyslipidemia (odds ratio, 1.6; P < .0001) and metabolic syndrome (OR, 1.9; P = .0086) were significantly higher, compared with those without gender dysphoria.

Among the transgender male patients (born female) but not transgender female patients (born male), rates of diagnoses of overweight/obesity (OR, 1.7; P < .0001) and polycystic ovary syndrome were higher (OR, 1.9, P = .0006), compared with controls.

Gender-affirming hormone therapy, such as with testosterone or estradiol, is among the suspected culprits for the cardiovascular effects. However, importantly, this study did not differentiate between patients who had received estradiol or testosterone for gender affirmation and those who had not, Dr. Valentine said.

“We don’t know [whether gender-affirming hormone therapy is a cause], as we have not looked at this yet,” she said in an interview. “We are looking at that in our next analyses and will be including that in our future publication.

“We’ll also be looking at the relationship between having overweight/obesity and the other diagnoses that influence cardiovascular health (high blood pressure, liver dysfunction, and abnormal cholesterol), as that could certainly be playing a role as well,” she said.

For many transgender patients, gender-affirming hormone therapy is lifelong. One question that needs to be evaluated concerns whether the dose of such therapy has a role on cardiovascular effects and if so, whether adjustments could be made without compromising the therapeutic effect, Dr. Valentine noted.

“This is an important question, and future research is needed to evaluate whether doses [of gender-affirming hormones] are related to cardiometabolic outcomes,” she said.

Potential confounders in the study include the fact that rates of overweight and obesity are higher among youths with gender dysphoria. This can in itself can increase the risk for other disorders, Dr. Valentine noted.

Furthermore, rates of mental health comorbidities are higher among youths with gender dysphoria. One consequence of this may be that they engage in less physical activity, she said.
 

Hormone therapy, health care disparities, or both could explain risk

In commenting on the study, Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery, the Mount Sinai Health System, New York, said that although similar cardiovascular effects are known to occur in transgender adults as well, they may or may not be hormone related. Other factors can increase the risk.

“With transgender adults, any differences in lipids or cardiac risk factors relative to cisgender people might be attributable either to hormone therapy or to health care disparities,” he said in an interview.

“The data are mixed. It may be that most differences relate to lack of access to care and to mistreatment by society,” he said. “Even studies that focus on hormones see a worsened situation for trans women versus trans men.”

Other recent research that shows potential cardiovascular effects among adult transgender men includes a study of more than 1,000 transgender men (born female) who received testosterone. That study, which was also presented at the ENDO meeting and was reported by this news organization, found an increased risk for high hematocrit levels, which could lead to a thrombotic event.

However, a study published in Pediatrics, which was also reported by this news organization, that included 611 transgender youths who had taken gender-affirming hormone therapy for more than a year found no increased risk for thrombosis, even in the presence of thrombosis risk factors, including obesity, tobacco use, and family history of thrombosis. However, the senior author of that study pointed out that the duration of follow-up in that study was relatively short, which may have been why they did not find an increased risk for thrombosis.

Dr. Safer noted that transgender youths and adults alike face a host of cultural factors that could play a role in increased cardiovascular risks.

“For adults, the major candidate explanations for worse BMI and cardiac risk factors are societal mistreatment, and for trans women specifically, progestins. For youth, the major candidate explanations are societal mistreatment and lack of access to athletics,” he said.

The authors and Dr. Safer disclosed no relevant financial relationships.

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

Cardiovascular and metabolic risk factors are increased among transgender youths, compared with youths who are not transgender. Elevations in lipid levels and body mass index (BMI) also occur in adult transgender patients, new research shows.

“This is the first study of its size in the United States of which we are aware that looks at the odds of youth with a diagnosis of gender dysphoria having medical diagnoses that relate to overall metabolic and cardiovascular health,” first author Anna Valentine, MD, of Children’s Hospital Colorado, Aurora, said in a press statement.

Although previous studies have shown that among transgender adults, BMI is higher and there is an increased risk for cardiovascular events, such as stroke or heart attack, compared with nontransgender people, research on adolescent transgender patients has been lacking.

With a recent survey showing that nearly 2% of adolescents identify as transgender, interest in health outcomes among younger patients is high.

To investigate, Dr. Valentine, and colleagues evaluated data from the PEDSnet pediatric database on 4,177 youths who had received a diagnosis of gender dysphoria. The participants had been enrolled at six sites from 2009 to 2019. The researchers compared these patients in a ratio of 1:4 with 16,664 control persons who had not been diagnosed with gender dysphoria. They reported their findings as a poster at the annual meeting of the Endocrine Society.

For the propensity-score analysis, participants were matched according to year of birth, age at last visit, site, race, ethnicity, insurance status, and duration in the database.

In both the transgender and control groups, about 66% were female at birth, 73% were White, and 9% Hispanic. For both groups, the average age was 16.2 years at the last visit. The average duration in the database was 7 years.
 

Study didn’t distinguish between those receiving and those not receiving gender-affirming hormones

In the retrospective study, among those who identified as transgender, the rates of diagnoses of dyslipidemia (odds ratio, 1.6; P < .0001) and metabolic syndrome (OR, 1.9; P = .0086) were significantly higher, compared with those without gender dysphoria.

Among the transgender male patients (born female) but not transgender female patients (born male), rates of diagnoses of overweight/obesity (OR, 1.7; P < .0001) and polycystic ovary syndrome were higher (OR, 1.9, P = .0006), compared with controls.

Gender-affirming hormone therapy, such as with testosterone or estradiol, is among the suspected culprits for the cardiovascular effects. However, importantly, this study did not differentiate between patients who had received estradiol or testosterone for gender affirmation and those who had not, Dr. Valentine said.

“We don’t know [whether gender-affirming hormone therapy is a cause], as we have not looked at this yet,” she said in an interview. “We are looking at that in our next analyses and will be including that in our future publication.

“We’ll also be looking at the relationship between having overweight/obesity and the other diagnoses that influence cardiovascular health (high blood pressure, liver dysfunction, and abnormal cholesterol), as that could certainly be playing a role as well,” she said.

For many transgender patients, gender-affirming hormone therapy is lifelong. One question that needs to be evaluated concerns whether the dose of such therapy has a role on cardiovascular effects and if so, whether adjustments could be made without compromising the therapeutic effect, Dr. Valentine noted.

“This is an important question, and future research is needed to evaluate whether doses [of gender-affirming hormones] are related to cardiometabolic outcomes,” she said.

Potential confounders in the study include the fact that rates of overweight and obesity are higher among youths with gender dysphoria. This can in itself can increase the risk for other disorders, Dr. Valentine noted.

Furthermore, rates of mental health comorbidities are higher among youths with gender dysphoria. One consequence of this may be that they engage in less physical activity, she said.
 

Hormone therapy, health care disparities, or both could explain risk

In commenting on the study, Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery, the Mount Sinai Health System, New York, said that although similar cardiovascular effects are known to occur in transgender adults as well, they may or may not be hormone related. Other factors can increase the risk.

“With transgender adults, any differences in lipids or cardiac risk factors relative to cisgender people might be attributable either to hormone therapy or to health care disparities,” he said in an interview.

“The data are mixed. It may be that most differences relate to lack of access to care and to mistreatment by society,” he said. “Even studies that focus on hormones see a worsened situation for trans women versus trans men.”

Other recent research that shows potential cardiovascular effects among adult transgender men includes a study of more than 1,000 transgender men (born female) who received testosterone. That study, which was also presented at the ENDO meeting and was reported by this news organization, found an increased risk for high hematocrit levels, which could lead to a thrombotic event.

However, a study published in Pediatrics, which was also reported by this news organization, that included 611 transgender youths who had taken gender-affirming hormone therapy for more than a year found no increased risk for thrombosis, even in the presence of thrombosis risk factors, including obesity, tobacco use, and family history of thrombosis. However, the senior author of that study pointed out that the duration of follow-up in that study was relatively short, which may have been why they did not find an increased risk for thrombosis.

Dr. Safer noted that transgender youths and adults alike face a host of cultural factors that could play a role in increased cardiovascular risks.

“For adults, the major candidate explanations for worse BMI and cardiac risk factors are societal mistreatment, and for trans women specifically, progestins. For youth, the major candidate explanations are societal mistreatment and lack of access to athletics,” he said.

The authors and Dr. Safer disclosed no relevant financial relationships.

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

Children and adolescents with Prader-Willi syndrome (PWS) who received three daily, intranasal doses of carbetocin, an investigational, long-acting oxytocin analogue, had significant improvement in hyperphagia and anxiety during 8 weeks on treatment, compared with placebo in a multicenter, phase 3 trial with 119 patients.

The treatment also appeared safe during up to 56 additional weeks on active treatment, with no serious adverse effects nor “unexpected” events, and once completing the study about 95% of enrolled patients opted to remain on active treatment, Cheri L. Deal, MD, PhD, said at the annual meeting of the Endocrine Society.

Based on “the significant results for the placebo-controlled period, as well as for those finishing the 56-week extension, we may well have a new armament for helping these kids and their families deal with the unrelenting hunger of patients with PWS as well as some of the behavioral symptoms,” Dr. Deal, chief of endocrinology and diabetes at the Sainte-Justine Mother-Child University of Montreal Hospital, said in an interview. No treatment currently has labeling for addressing the hyperphagia or anxiety that is characteristic and often problematic for children and adolescents with PWS, an autosomal dominant genetic disease with an incidence of about 1 in 15,000 births and an estimated U.S. prevalence of about 9,000 cases, or about 1 case for every 37,000 people.
 

‘Gorgeous’ safety

“The results looked pretty positive, and we’re encouraged by what appears to be a good safety profile, so overall I think the PWS community is very excited by the results and is very interested in getting access to this drug,” commented Theresa V. Strong, PhD, director of research programs for the Foundation for Prader-Willi Research in Walnut, Calif., a group not involved with the study. Currently, “we have no effective treatments for these difficult behaviors” of hyperphagia and anxiety. Surveys and studies run by the foundation have documented that hyperphagia and anxiety “were the two most important symptoms that families would like to see treated,” Dr. Strong added in an interview.

PWS “is complex and affects almost every aspect of the lives of affected people and their families. Any treatment that can chip away at some of the problems these patients have can be a huge benefit to the patients and their families,” said Jennifer L. Miller, MD, a professor of pediatric endocrinology at the University of Florida, Gainesville, and a coinvestigator on the study.

But the finding that carbetocin appeared to address, at least in part, this unmet need while compiling a safety record that Dr. Miller called “gorgeous” and “remarkable,” also came with a few limitations.
 

Fewer patients than planned, and muddled outcomes

The CARE-PWS trial aimed to enroll 175 patients, but fell short once the COVID-19 pandemic hit. Plus the trial had two prespecified primary endpoints – improvements in a measure of hyperphagia, and in a measure of obsessive and compulsive behaviors – specifically in the 40 patients who received the higher of the two dosages studied, 9.6 mg t.i.d. intranasally. Neither endpoint showed significant improvement among the patients on this dosage, compared with the 40 patients who received placebo, although both outcomes trended in the right direction in the actively treated patients.

The study’s positive results came in a secondary treatment group, 39 patients who received 3.2 mg t.i.d., also intranasally. This subgroup had significant benefit, compared with placebo, for reducing hyperphagia symptoms as measured on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score. After the first 8 weeks on treatment, patients on the lower carbetocin dosage had an average reduction in their HQ-CT score of greater than 5 points, more than double the reduction seen among control patients who received placebo.

Those on the 3.2-mg t.i.d. dosage also showed significant improvements, compared with placebo, for anxiety, measured by the PWS Anxiety and Distress Questionnaire Total Score, as well as on measures of clinical global impression of severity, and of clinical global impression of change. Like the higher-dosage patients the lower-dosage subgroup did not show a significant difference compared with placebo for the other primary endpoint, change in obsessive and compulsive behaviors as measured by the Children’s Yale-Brown Obsessive-Compulsive Scale Total Score, although also like the higher dosage the effect from the lower dosage trended toward benefit.

A further limitation was that, at the time of her report, presented in abstract OR16-3 at the meeting, Dr. Deal could only present complete 64-week follow-up for 72 patients, although this reassuringly showed that, as time on the 9.6-mg t.i.d. dosage continued beyond 8 weeks, patients gradually improved their HQ-CT response so that by 64 weeks on treatment their hyperphagia score had improved as much as in the patients who received the lower dosage.

In short, documented benefits occurred on the lower dosage, especially for clinically meaningful symptoms like hyperphagia and anxiety, but the study’s overall results were not fully consistent by statistical criteria.

Benefiting an unmet need?

“While it is regrettable that we did not get to 175 patients because of COVID-19, the dataset is significant enough for me to feel that the FDA [Food and Drug Administration] needs to take a very serious look and consider approval,” Dr. Deal said in an interview. “Once safety is assured, which I think it is, I can only hope that regulatory officials understand their unmet needs of this rare disease community and will allow the drug to move to the next stage.”

“This is a very rare disease, and having families participate in trials is really challenging,” especially while the COVID-19 pandemic continues, Dr. Strong said. For the pediatric and adolescent patients targeted in this study “it will take a while for COVID to go away and for families to feel safe again being in a trial, so a real concern is that a need for more clinical trials is not terribly feasible now. Given that the safety profile looked good and one dose seemed to have good efficacy, as long as the long-term data continue to look good we’d love for the FDA to look at the existing data and see whether there is a path forward.”

Dr. Miller highlighted the limitations of what the CARE-PWS findings show.

“Given that it was only an 8-week trial of drug against placebo, and the fact that the primary outcomes weren’t met for the higher dose, my thought is that potentially we need to study more patients for a longer period at the 3.2-mg dose,” she said. She acknowledged that the metric used in the study to assess obsessive and compulsive behaviors is “very difficult” to apply to patients with PWS because of uncertainties in scoring obsessions in patients “who are not very good at telling you what they’re thinking.” Plus, “it’s absolutely not a problem that we did not see an effect on obsession and compulsions if the treatment potentially improves anxiety and hyperphagia, which are very common.” A treatment that reliably reduces these symptoms “would be amazing,” Dr. Miller added.

“PWS is very rare, so it’s very hard to do trials. Maybe the FDA will approve carbetocin because it was safe and gave a signal of efficacy at the lower dose. But my thought is that additional treatment trials are needed with only the lower dose and with longer duration,” she said.

CARE-PWS enrolled patients with nutritional phase 3 PWS who were aged 7-18 years at any of 24 sites in the United States, Canada, or Australia during 2018-2020. They averaged about 12 years of age, and 56% were girls.

The most common adverse effect from carbetocin was flushing, occurring in 14% of those on the lower dose and 21% on the higher dose, but not in any placebo patient. Other adverse effects more common on the lower dose than in the placebo group included headache in 16%, and diarrhea in 9%.

Carbetocin is not only long-lasting in circulation, it also has better affinity for oxytocin receptors than for vasopressin receptors, reducing the potential for causing hyponatremia. The idea to use it in patients with PWS followed prior studies with oxytocin, which had shown dopamine interactions that reduced anxiety and influenced food ingestion behavior. Brain autopsy studies had shown that patients with Prader-Willi syndrome have substantially fewer neurons than usual producing oxytocin. Treatment with intranasal carbetocin had shown efficacy for improving hyperphagia and behavior in a controlled phase 2 study with 37 patients.

Carbetocin is approved for use in reducing excessive bleeding after childbirth, particularly cesarean, in more than 20 countries outside the United States.

CARE-PWS was sponsored by Levo Therapeutics, the company developing carbetocin. Dr. Deal has been an adviser to Levo Therapeutics. Dr. Strong is an employee of the Foundation for Prader-Willi Research, which has received support from Levo Therapeutics as well as from other drug companies, but which receives most of its funding from individuals. Dr. Miller has received research funding from Levo Therapeutics and also from Harmony Biosciences, Rhythm Pharmaceuticals, and Soleno Therapeutics.

mzoler@mdedge.com

Children and adolescents with Prader-Willi syndrome (PWS) who received three daily, intranasal doses of carbetocin, an investigational, long-acting oxytocin analogue, had significant improvement in hyperphagia and anxiety during 8 weeks on treatment, compared with placebo in a multicenter, phase 3 trial with 119 patients.

The treatment also appeared safe during up to 56 additional weeks on active treatment, with no serious adverse effects nor “unexpected” events, and once completing the study about 95% of enrolled patients opted to remain on active treatment, Cheri L. Deal, MD, PhD, said at the annual meeting of the Endocrine Society.

Based on “the significant results for the placebo-controlled period, as well as for those finishing the 56-week extension, we may well have a new armament for helping these kids and their families deal with the unrelenting hunger of patients with PWS as well as some of the behavioral symptoms,” Dr. Deal, chief of endocrinology and diabetes at the Sainte-Justine Mother-Child University of Montreal Hospital, said in an interview. No treatment currently has labeling for addressing the hyperphagia or anxiety that is characteristic and often problematic for children and adolescents with PWS, an autosomal dominant genetic disease with an incidence of about 1 in 15,000 births and an estimated U.S. prevalence of about 9,000 cases, or about 1 case for every 37,000 people.
 

‘Gorgeous’ safety

“The results looked pretty positive, and we’re encouraged by what appears to be a good safety profile, so overall I think the PWS community is very excited by the results and is very interested in getting access to this drug,” commented Theresa V. Strong, PhD, director of research programs for the Foundation for Prader-Willi Research in Walnut, Calif., a group not involved with the study. Currently, “we have no effective treatments for these difficult behaviors” of hyperphagia and anxiety. Surveys and studies run by the foundation have documented that hyperphagia and anxiety “were the two most important symptoms that families would like to see treated,” Dr. Strong added in an interview.

PWS “is complex and affects almost every aspect of the lives of affected people and their families. Any treatment that can chip away at some of the problems these patients have can be a huge benefit to the patients and their families,” said Jennifer L. Miller, MD, a professor of pediatric endocrinology at the University of Florida, Gainesville, and a coinvestigator on the study.

But the finding that carbetocin appeared to address, at least in part, this unmet need while compiling a safety record that Dr. Miller called “gorgeous” and “remarkable,” also came with a few limitations.
 

Fewer patients than planned, and muddled outcomes

The CARE-PWS trial aimed to enroll 175 patients, but fell short once the COVID-19 pandemic hit. Plus the trial had two prespecified primary endpoints – improvements in a measure of hyperphagia, and in a measure of obsessive and compulsive behaviors – specifically in the 40 patients who received the higher of the two dosages studied, 9.6 mg t.i.d. intranasally. Neither endpoint showed significant improvement among the patients on this dosage, compared with the 40 patients who received placebo, although both outcomes trended in the right direction in the actively treated patients.

The study’s positive results came in a secondary treatment group, 39 patients who received 3.2 mg t.i.d., also intranasally. This subgroup had significant benefit, compared with placebo, for reducing hyperphagia symptoms as measured on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score. After the first 8 weeks on treatment, patients on the lower carbetocin dosage had an average reduction in their HQ-CT score of greater than 5 points, more than double the reduction seen among control patients who received placebo.

Those on the 3.2-mg t.i.d. dosage also showed significant improvements, compared with placebo, for anxiety, measured by the PWS Anxiety and Distress Questionnaire Total Score, as well as on measures of clinical global impression of severity, and of clinical global impression of change. Like the higher-dosage patients the lower-dosage subgroup did not show a significant difference compared with placebo for the other primary endpoint, change in obsessive and compulsive behaviors as measured by the Children’s Yale-Brown Obsessive-Compulsive Scale Total Score, although also like the higher dosage the effect from the lower dosage trended toward benefit.

A further limitation was that, at the time of her report, presented in abstract OR16-3 at the meeting, Dr. Deal could only present complete 64-week follow-up for 72 patients, although this reassuringly showed that, as time on the 9.6-mg t.i.d. dosage continued beyond 8 weeks, patients gradually improved their HQ-CT response so that by 64 weeks on treatment their hyperphagia score had improved as much as in the patients who received the lower dosage.

In short, documented benefits occurred on the lower dosage, especially for clinically meaningful symptoms like hyperphagia and anxiety, but the study’s overall results were not fully consistent by statistical criteria.

Benefiting an unmet need?

“While it is regrettable that we did not get to 175 patients because of COVID-19, the dataset is significant enough for me to feel that the FDA [Food and Drug Administration] needs to take a very serious look and consider approval,” Dr. Deal said in an interview. “Once safety is assured, which I think it is, I can only hope that regulatory officials understand their unmet needs of this rare disease community and will allow the drug to move to the next stage.”

“This is a very rare disease, and having families participate in trials is really challenging,” especially while the COVID-19 pandemic continues, Dr. Strong said. For the pediatric and adolescent patients targeted in this study “it will take a while for COVID to go away and for families to feel safe again being in a trial, so a real concern is that a need for more clinical trials is not terribly feasible now. Given that the safety profile looked good and one dose seemed to have good efficacy, as long as the long-term data continue to look good we’d love for the FDA to look at the existing data and see whether there is a path forward.”

Dr. Miller highlighted the limitations of what the CARE-PWS findings show.

“Given that it was only an 8-week trial of drug against placebo, and the fact that the primary outcomes weren’t met for the higher dose, my thought is that potentially we need to study more patients for a longer period at the 3.2-mg dose,” she said. She acknowledged that the metric used in the study to assess obsessive and compulsive behaviors is “very difficult” to apply to patients with PWS because of uncertainties in scoring obsessions in patients “who are not very good at telling you what they’re thinking.” Plus, “it’s absolutely not a problem that we did not see an effect on obsession and compulsions if the treatment potentially improves anxiety and hyperphagia, which are very common.” A treatment that reliably reduces these symptoms “would be amazing,” Dr. Miller added.

“PWS is very rare, so it’s very hard to do trials. Maybe the FDA will approve carbetocin because it was safe and gave a signal of efficacy at the lower dose. But my thought is that additional treatment trials are needed with only the lower dose and with longer duration,” she said.

CARE-PWS enrolled patients with nutritional phase 3 PWS who were aged 7-18 years at any of 24 sites in the United States, Canada, or Australia during 2018-2020. They averaged about 12 years of age, and 56% were girls.

The most common adverse effect from carbetocin was flushing, occurring in 14% of those on the lower dose and 21% on the higher dose, but not in any placebo patient. Other adverse effects more common on the lower dose than in the placebo group included headache in 16%, and diarrhea in 9%.

Carbetocin is not only long-lasting in circulation, it also has better affinity for oxytocin receptors than for vasopressin receptors, reducing the potential for causing hyponatremia. The idea to use it in patients with PWS followed prior studies with oxytocin, which had shown dopamine interactions that reduced anxiety and influenced food ingestion behavior. Brain autopsy studies had shown that patients with Prader-Willi syndrome have substantially fewer neurons than usual producing oxytocin. Treatment with intranasal carbetocin had shown efficacy for improving hyperphagia and behavior in a controlled phase 2 study with 37 patients.

Carbetocin is approved for use in reducing excessive bleeding after childbirth, particularly cesarean, in more than 20 countries outside the United States.

CARE-PWS was sponsored by Levo Therapeutics, the company developing carbetocin. Dr. Deal has been an adviser to Levo Therapeutics. Dr. Strong is an employee of the Foundation for Prader-Willi Research, which has received support from Levo Therapeutics as well as from other drug companies, but which receives most of its funding from individuals. Dr. Miller has received research funding from Levo Therapeutics and also from Harmony Biosciences, Rhythm Pharmaceuticals, and Soleno Therapeutics.

mzoler@mdedge.com

Children and adolescents with Prader-Willi syndrome (PWS) who received three daily, intranasal doses of carbetocin, an investigational, long-acting oxytocin analogue, had significant improvement in hyperphagia and anxiety during 8 weeks on treatment, compared with placebo in a multicenter, phase 3 trial with 119 patients.

The treatment also appeared safe during up to 56 additional weeks on active treatment, with no serious adverse effects nor “unexpected” events, and once completing the study about 95% of enrolled patients opted to remain on active treatment, Cheri L. Deal, MD, PhD, said at the annual meeting of the Endocrine Society.

Based on “the significant results for the placebo-controlled period, as well as for those finishing the 56-week extension, we may well have a new armament for helping these kids and their families deal with the unrelenting hunger of patients with PWS as well as some of the behavioral symptoms,” Dr. Deal, chief of endocrinology and diabetes at the Sainte-Justine Mother-Child University of Montreal Hospital, said in an interview. No treatment currently has labeling for addressing the hyperphagia or anxiety that is characteristic and often problematic for children and adolescents with PWS, an autosomal dominant genetic disease with an incidence of about 1 in 15,000 births and an estimated U.S. prevalence of about 9,000 cases, or about 1 case for every 37,000 people.
 

‘Gorgeous’ safety

“The results looked pretty positive, and we’re encouraged by what appears to be a good safety profile, so overall I think the PWS community is very excited by the results and is very interested in getting access to this drug,” commented Theresa V. Strong, PhD, director of research programs for the Foundation for Prader-Willi Research in Walnut, Calif., a group not involved with the study. Currently, “we have no effective treatments for these difficult behaviors” of hyperphagia and anxiety. Surveys and studies run by the foundation have documented that hyperphagia and anxiety “were the two most important symptoms that families would like to see treated,” Dr. Strong added in an interview.

PWS “is complex and affects almost every aspect of the lives of affected people and their families. Any treatment that can chip away at some of the problems these patients have can be a huge benefit to the patients and their families,” said Jennifer L. Miller, MD, a professor of pediatric endocrinology at the University of Florida, Gainesville, and a coinvestigator on the study.

But the finding that carbetocin appeared to address, at least in part, this unmet need while compiling a safety record that Dr. Miller called “gorgeous” and “remarkable,” also came with a few limitations.
 

Fewer patients than planned, and muddled outcomes

The CARE-PWS trial aimed to enroll 175 patients, but fell short once the COVID-19 pandemic hit. Plus the trial had two prespecified primary endpoints – improvements in a measure of hyperphagia, and in a measure of obsessive and compulsive behaviors – specifically in the 40 patients who received the higher of the two dosages studied, 9.6 mg t.i.d. intranasally. Neither endpoint showed significant improvement among the patients on this dosage, compared with the 40 patients who received placebo, although both outcomes trended in the right direction in the actively treated patients.

The study’s positive results came in a secondary treatment group, 39 patients who received 3.2 mg t.i.d., also intranasally. This subgroup had significant benefit, compared with placebo, for reducing hyperphagia symptoms as measured on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score. After the first 8 weeks on treatment, patients on the lower carbetocin dosage had an average reduction in their HQ-CT score of greater than 5 points, more than double the reduction seen among control patients who received placebo.

Those on the 3.2-mg t.i.d. dosage also showed significant improvements, compared with placebo, for anxiety, measured by the PWS Anxiety and Distress Questionnaire Total Score, as well as on measures of clinical global impression of severity, and of clinical global impression of change. Like the higher-dosage patients the lower-dosage subgroup did not show a significant difference compared with placebo for the other primary endpoint, change in obsessive and compulsive behaviors as measured by the Children’s Yale-Brown Obsessive-Compulsive Scale Total Score, although also like the higher dosage the effect from the lower dosage trended toward benefit.

A further limitation was that, at the time of her report, presented in abstract OR16-3 at the meeting, Dr. Deal could only present complete 64-week follow-up for 72 patients, although this reassuringly showed that, as time on the 9.6-mg t.i.d. dosage continued beyond 8 weeks, patients gradually improved their HQ-CT response so that by 64 weeks on treatment their hyperphagia score had improved as much as in the patients who received the lower dosage.

In short, documented benefits occurred on the lower dosage, especially for clinically meaningful symptoms like hyperphagia and anxiety, but the study’s overall results were not fully consistent by statistical criteria.

Benefiting an unmet need?

“While it is regrettable that we did not get to 175 patients because of COVID-19, the dataset is significant enough for me to feel that the FDA [Food and Drug Administration] needs to take a very serious look and consider approval,” Dr. Deal said in an interview. “Once safety is assured, which I think it is, I can only hope that regulatory officials understand their unmet needs of this rare disease community and will allow the drug to move to the next stage.”

“This is a very rare disease, and having families participate in trials is really challenging,” especially while the COVID-19 pandemic continues, Dr. Strong said. For the pediatric and adolescent patients targeted in this study “it will take a while for COVID to go away and for families to feel safe again being in a trial, so a real concern is that a need for more clinical trials is not terribly feasible now. Given that the safety profile looked good and one dose seemed to have good efficacy, as long as the long-term data continue to look good we’d love for the FDA to look at the existing data and see whether there is a path forward.”

Dr. Miller highlighted the limitations of what the CARE-PWS findings show.

“Given that it was only an 8-week trial of drug against placebo, and the fact that the primary outcomes weren’t met for the higher dose, my thought is that potentially we need to study more patients for a longer period at the 3.2-mg dose,” she said. She acknowledged that the metric used in the study to assess obsessive and compulsive behaviors is “very difficult” to apply to patients with PWS because of uncertainties in scoring obsessions in patients “who are not very good at telling you what they’re thinking.” Plus, “it’s absolutely not a problem that we did not see an effect on obsession and compulsions if the treatment potentially improves anxiety and hyperphagia, which are very common.” A treatment that reliably reduces these symptoms “would be amazing,” Dr. Miller added.

“PWS is very rare, so it’s very hard to do trials. Maybe the FDA will approve carbetocin because it was safe and gave a signal of efficacy at the lower dose. But my thought is that additional treatment trials are needed with only the lower dose and with longer duration,” she said.

CARE-PWS enrolled patients with nutritional phase 3 PWS who were aged 7-18 years at any of 24 sites in the United States, Canada, or Australia during 2018-2020. They averaged about 12 years of age, and 56% were girls.

The most common adverse effect from carbetocin was flushing, occurring in 14% of those on the lower dose and 21% on the higher dose, but not in any placebo patient. Other adverse effects more common on the lower dose than in the placebo group included headache in 16%, and diarrhea in 9%.

Carbetocin is not only long-lasting in circulation, it also has better affinity for oxytocin receptors than for vasopressin receptors, reducing the potential for causing hyponatremia. The idea to use it in patients with PWS followed prior studies with oxytocin, which had shown dopamine interactions that reduced anxiety and influenced food ingestion behavior. Brain autopsy studies had shown that patients with Prader-Willi syndrome have substantially fewer neurons than usual producing oxytocin. Treatment with intranasal carbetocin had shown efficacy for improving hyperphagia and behavior in a controlled phase 2 study with 37 patients.

Carbetocin is approved for use in reducing excessive bleeding after childbirth, particularly cesarean, in more than 20 countries outside the United States.

CARE-PWS was sponsored by Levo Therapeutics, the company developing carbetocin. Dr. Deal has been an adviser to Levo Therapeutics. Dr. Strong is an employee of the Foundation for Prader-Willi Research, which has received support from Levo Therapeutics as well as from other drug companies, but which receives most of its funding from individuals. Dr. Miller has received research funding from Levo Therapeutics and also from Harmony Biosciences, Rhythm Pharmaceuticals, and Soleno Therapeutics.

mzoler@mdedge.com

After 3 years of follow-up in patients with low-risk differentiated thyroid cancer (DTC), there is no significant difference in the rate of tumor-related events in those treated with postsurgical radioactive iodine (RAI) relative to those who are not, according to a randomized phase 3 trial.

SciePro/Science Source

The controversy about whether postoperative RAI is beneficial or an overtreatment in low-risk DTC has persisted for years, but it can now be addressed with level one data, according to Sophie Leboulleux, MD, PhD, who heads the thyroid cancer division at Gustave Roussy Cancer Institute, Villejuif, France.

The trial, called ESTIMABL2, included 776 low-risk DTC patients managed at 35 participating treatment centers in France. Two to five months after surgery, patients were randomized to receive RAI or to follow-up without RAI if there were no suspicious findings, such as changes in lateral neck lymph nodes, on ultrasonography.

Three years after randomization in 729 evaluable patients, tumor-related effects occurred in 4.1% of those randomized to RAI and 4.9% of those randomized to follow-up without RAI.

“Thus, 95.1% of patients in the followed group and 95.9% in the RAI group had no event over 3 years of follow-up. The difference of 0.8% was noninferior by the prespecified definition,” Dr. Leboulleux reported at the annual meeting of the Endocrine Society.
 

The 0.8% difference in events is noninferior

The prespecified definition was a less than 5% difference in events at the end of 5 years. The 0.8% difference in this study was comfortably within the 95% confidence interval (–3.3%-1.8%).

On yearly evaluations under levothyroxine treatment, events were defined as an indication for treatment, whether surgery or RAI administration if there was abnormal RAI intake on the posttherapeutic whole-body scan or elevated thyroglobulin or thyroglobulin antibodies. In the latter case, this was an event even in the absence of abnormal neck ultrasonography.

“Elevated thyroglobulin levels on levothyroxine treatment were defined as greater than 2 ng/mL in the group that did not received RAI and greater than 1 ng/mL in the group that did,” Dr. Leboulleux reported.

Thyroglobulin antibodies were considered elevated with a greater than 50% increase over the upper limit of normal on two consecutive determinations 6 months apart, Dr. Leboulleux said. The same or similar definitions of an event have been used previously.

Of the study population, 83% were women and almost all (96%) had papillary DTC. The mean age was 52 years. Of the tumors, 81.1% were T1b, of which more than half were unevaluable for node status and about 40% were node negative. The remaining tumors were grade T1a, of which about two-thirds had unevaluable node status and the remainder were confirmed node negative.
 

Prior studies also question RAI benefit

Several retrospective studies have also failed to associated RAI with a significant protection against thyroid events in low-risk DTC. In the most recent guidelines, the American Thoracic Society recommended against routine use of RAI following surgery in low-risk DTC patients. However, these guidelines acknowledged this is a “weak recommendation” based on “low-quality evidence.”

Recurrence rates following surgery in low-risk DTC are not zero. According to a review article coauthored by Dr. Leboulleux, these may occur in up to 3% of patients. This measurable risk might explain why many published retrospective data suggest low-risk DTC patients are continuing to receive postsurgical RAI. In one, using data taken from the Surveillance, Epidemiology, and End Results (SEER) database, nearly 25% of 17,286 low-risk papillary thyroid cancers had received postsurgical RAI.

The ESTIMABL2 trial is one of two randomized studies launched over the last several years to address the controversy regarding postsurgical RAI in low-risk DTC with prospective randomized data. The ongoing IoN trial is the other. The researchers plan a much longer follow-up, with data not expected until 2031.

In fact, one criticism of the ESTIMABL2 is “the low event rate and relatively short follow-up,” reported Megan Haymart, MD, a professor in the division of metabolism, endocrinology, and diabetes at the University of Michigan, Ann Arbor.

“The strengths of this study include the involvement of 35 French centers, the use of a cohort that is representative of the distribution of low-risk thyroid cancer at large, and the use of biochemical markers during follow-up,” Dr. Haymart said in an interview.

Ultimately, despite the limited follow-up, “this is a clinically important study as it supports the recent paradigm shift towards less use of RAI for low-risk thyroid cancer,” she said.

Dr. Leboulleux and Dr. Haymart report no relevant conflicts of interest.

After 3 years of follow-up in patients with low-risk differentiated thyroid cancer (DTC), there is no significant difference in the rate of tumor-related events in those treated with postsurgical radioactive iodine (RAI) relative to those who are not, according to a randomized phase 3 trial.

SciePro/Science Source

The controversy about whether postoperative RAI is beneficial or an overtreatment in low-risk DTC has persisted for years, but it can now be addressed with level one data, according to Sophie Leboulleux, MD, PhD, who heads the thyroid cancer division at Gustave Roussy Cancer Institute, Villejuif, France.

The trial, called ESTIMABL2, included 776 low-risk DTC patients managed at 35 participating treatment centers in France. Two to five months after surgery, patients were randomized to receive RAI or to follow-up without RAI if there were no suspicious findings, such as changes in lateral neck lymph nodes, on ultrasonography.

Three years after randomization in 729 evaluable patients, tumor-related effects occurred in 4.1% of those randomized to RAI and 4.9% of those randomized to follow-up without RAI.

“Thus, 95.1% of patients in the followed group and 95.9% in the RAI group had no event over 3 years of follow-up. The difference of 0.8% was noninferior by the prespecified definition,” Dr. Leboulleux reported at the annual meeting of the Endocrine Society.
 

The 0.8% difference in events is noninferior

The prespecified definition was a less than 5% difference in events at the end of 5 years. The 0.8% difference in this study was comfortably within the 95% confidence interval (–3.3%-1.8%).

On yearly evaluations under levothyroxine treatment, events were defined as an indication for treatment, whether surgery or RAI administration if there was abnormal RAI intake on the posttherapeutic whole-body scan or elevated thyroglobulin or thyroglobulin antibodies. In the latter case, this was an event even in the absence of abnormal neck ultrasonography.

“Elevated thyroglobulin levels on levothyroxine treatment were defined as greater than 2 ng/mL in the group that did not received RAI and greater than 1 ng/mL in the group that did,” Dr. Leboulleux reported.

Thyroglobulin antibodies were considered elevated with a greater than 50% increase over the upper limit of normal on two consecutive determinations 6 months apart, Dr. Leboulleux said. The same or similar definitions of an event have been used previously.

Of the study population, 83% were women and almost all (96%) had papillary DTC. The mean age was 52 years. Of the tumors, 81.1% were T1b, of which more than half were unevaluable for node status and about 40% were node negative. The remaining tumors were grade T1a, of which about two-thirds had unevaluable node status and the remainder were confirmed node negative.
 

Prior studies also question RAI benefit

Several retrospective studies have also failed to associated RAI with a significant protection against thyroid events in low-risk DTC. In the most recent guidelines, the American Thoracic Society recommended against routine use of RAI following surgery in low-risk DTC patients. However, these guidelines acknowledged this is a “weak recommendation” based on “low-quality evidence.”

Recurrence rates following surgery in low-risk DTC are not zero. According to a review article coauthored by Dr. Leboulleux, these may occur in up to 3% of patients. This measurable risk might explain why many published retrospective data suggest low-risk DTC patients are continuing to receive postsurgical RAI. In one, using data taken from the Surveillance, Epidemiology, and End Results (SEER) database, nearly 25% of 17,286 low-risk papillary thyroid cancers had received postsurgical RAI.

The ESTIMABL2 trial is one of two randomized studies launched over the last several years to address the controversy regarding postsurgical RAI in low-risk DTC with prospective randomized data. The ongoing IoN trial is the other. The researchers plan a much longer follow-up, with data not expected until 2031.

In fact, one criticism of the ESTIMABL2 is “the low event rate and relatively short follow-up,” reported Megan Haymart, MD, a professor in the division of metabolism, endocrinology, and diabetes at the University of Michigan, Ann Arbor.

“The strengths of this study include the involvement of 35 French centers, the use of a cohort that is representative of the distribution of low-risk thyroid cancer at large, and the use of biochemical markers during follow-up,” Dr. Haymart said in an interview.

Ultimately, despite the limited follow-up, “this is a clinically important study as it supports the recent paradigm shift towards less use of RAI for low-risk thyroid cancer,” she said.

Dr. Leboulleux and Dr. Haymart report no relevant conflicts of interest.

After 3 years of follow-up in patients with low-risk differentiated thyroid cancer (DTC), there is no significant difference in the rate of tumor-related events in those treated with postsurgical radioactive iodine (RAI) relative to those who are not, according to a randomized phase 3 trial.

SciePro/Science Source

The controversy about whether postoperative RAI is beneficial or an overtreatment in low-risk DTC has persisted for years, but it can now be addressed with level one data, according to Sophie Leboulleux, MD, PhD, who heads the thyroid cancer division at Gustave Roussy Cancer Institute, Villejuif, France.

The trial, called ESTIMABL2, included 776 low-risk DTC patients managed at 35 participating treatment centers in France. Two to five months after surgery, patients were randomized to receive RAI or to follow-up without RAI if there were no suspicious findings, such as changes in lateral neck lymph nodes, on ultrasonography.

Three years after randomization in 729 evaluable patients, tumor-related effects occurred in 4.1% of those randomized to RAI and 4.9% of those randomized to follow-up without RAI.

“Thus, 95.1% of patients in the followed group and 95.9% in the RAI group had no event over 3 years of follow-up. The difference of 0.8% was noninferior by the prespecified definition,” Dr. Leboulleux reported at the annual meeting of the Endocrine Society.
 

The 0.8% difference in events is noninferior

The prespecified definition was a less than 5% difference in events at the end of 5 years. The 0.8% difference in this study was comfortably within the 95% confidence interval (–3.3%-1.8%).

On yearly evaluations under levothyroxine treatment, events were defined as an indication for treatment, whether surgery or RAI administration if there was abnormal RAI intake on the posttherapeutic whole-body scan or elevated thyroglobulin or thyroglobulin antibodies. In the latter case, this was an event even in the absence of abnormal neck ultrasonography.

“Elevated thyroglobulin levels on levothyroxine treatment were defined as greater than 2 ng/mL in the group that did not received RAI and greater than 1 ng/mL in the group that did,” Dr. Leboulleux reported.

Thyroglobulin antibodies were considered elevated with a greater than 50% increase over the upper limit of normal on two consecutive determinations 6 months apart, Dr. Leboulleux said. The same or similar definitions of an event have been used previously.

Of the study population, 83% were women and almost all (96%) had papillary DTC. The mean age was 52 years. Of the tumors, 81.1% were T1b, of which more than half were unevaluable for node status and about 40% were node negative. The remaining tumors were grade T1a, of which about two-thirds had unevaluable node status and the remainder were confirmed node negative.
 

Prior studies also question RAI benefit

Several retrospective studies have also failed to associated RAI with a significant protection against thyroid events in low-risk DTC. In the most recent guidelines, the American Thoracic Society recommended against routine use of RAI following surgery in low-risk DTC patients. However, these guidelines acknowledged this is a “weak recommendation” based on “low-quality evidence.”

Recurrence rates following surgery in low-risk DTC are not zero. According to a review article coauthored by Dr. Leboulleux, these may occur in up to 3% of patients. This measurable risk might explain why many published retrospective data suggest low-risk DTC patients are continuing to receive postsurgical RAI. In one, using data taken from the Surveillance, Epidemiology, and End Results (SEER) database, nearly 25% of 17,286 low-risk papillary thyroid cancers had received postsurgical RAI.

The ESTIMABL2 trial is one of two randomized studies launched over the last several years to address the controversy regarding postsurgical RAI in low-risk DTC with prospective randomized data. The ongoing IoN trial is the other. The researchers plan a much longer follow-up, with data not expected until 2031.

In fact, one criticism of the ESTIMABL2 is “the low event rate and relatively short follow-up,” reported Megan Haymart, MD, a professor in the division of metabolism, endocrinology, and diabetes at the University of Michigan, Ann Arbor.

“The strengths of this study include the involvement of 35 French centers, the use of a cohort that is representative of the distribution of low-risk thyroid cancer at large, and the use of biochemical markers during follow-up,” Dr. Haymart said in an interview.

Ultimately, despite the limited follow-up, “this is a clinically important study as it supports the recent paradigm shift towards less use of RAI for low-risk thyroid cancer,” she said.

Dr. Leboulleux and Dr. Haymart report no relevant conflicts of interest.

Weekly injections with the GLP-1 receptor agonist semaglutide helped people maintain, and even increase, their initial weight loss on the agent when they continued treatment beyond 20 weeks in results from an international, multicenter trial with 803 randomized subjects.

The study “reflects what we always see in practice, that when people lose weight their body then fights to regain it. The results underscore this” by showing what happens when people stop the drug, Domenica M. Rubino, MD, reported at the annual meeting of the Endocrine Society.

The STEP 4 study began with 902 obese or higher-risk people with an average body mass index of about 38 kg/m² who underwent a 20-week, open-label, run-in phase of weekly subcutaneous injections of semaglutide (Ozempic), during which all subjects gradually up-titrated to the study’s maintenance dosage of 2.4 mg/week and allowing investigators to weed out intolerant, noncompliant, or nonresponsive people. After this phase excluded 99 subjects from continuing, and documented that the remaining 803 patients had already lost an average of 11% of their starting weight, the core of the study kicked in by randomizing them 2:1 to either maintain their weekly semaglutide injections for another 48 weeks or change to placebo injections.

After 48 more weeks, the 535 people who continued active semaglutide treatment lost on average an additional 8% of their weight. Meanwhile, the 268 who switched to placebo gained 7% of the weight they had reached at the 20-week point, for a significant between-group weight-loss difference of about 15% for the study’s primary endpoint. Those maintained on semaglutide for the full 68 weeks had a cumulative average weight loss of about 17%, compared with when they first began treatment, Dr. Rubino said. Concurrently with her report, the results also appeared in an article published online in JAMA.

“It’s reassuring that people who remain on this treatment can sustain weight losses of 15%, and in some cases 20% or more. That’s huge,” Dr. Rubino said in an interview. . After 68 weeks, 40% of the people who maintained their semaglutide treatment had lost at least 20% of their weight, compared with when they first started treatment.

“Preventing weight regain following initial weight loss is a well-known major challenge for people who lose weight,” commented John Clark III, MD, PhD, a weight management specialist at the University of Texas Southwestern Medical Center in Dallas who was not involved with the study. The findings from STEP 4 will be “helpful to have a discussion [with weight-loss patients] about the risks and benefits of continuing to take this medication longer than just a few months and if they want to continue taking the medication after they reach their goal weight,” Dr. Clark noted in an interview. “This new information reinforces that treatment continues to be effective after the short term.”

“This is obesity 101. If a treatment is provided that targets mechanisms of obesity, and then the treatment stops, we should not be surprised that weight regain occurs,” commented Ania M. Jastreboff, MD, PhD, codirector of the Yale Center for Weight Management in New Haven, Conn. “It’s tragic to see patients who, after successful weight loss, suffer regain because the treatment by which they lost weight stopped,” she said in an interview.

The STEP 4 study ran at 73 centers in 10 countries during 2018-2020. It enrolled adults without diabetes and with a BMI of at least 30, or at least 27 if they also had at least one weight-related comorbidity such as hypertension, dyslipidemia, or obstructive sleep apnea. Participants averaged about 47 years of age, almost 80% were women, and about 84% were White, including 8% of Hispanic or Latinx ethnicity.

The adverse-event profile was consistent with findings from trials where semaglutide treated hyperglycemia in patients with type 2 diabetes (semaglutide at a maximum once-weekly dosage of 1 mg has Food and Drug Administration approval for controlling hyperglycemia in patients with type 2 diabetes), as well results from other semaglutide studies and from studies of other agents in the GLP-1 receptor agonist class.

In STEP 4 9% of patients who received semaglutide during the randomized phase and 7% of those randomized to placebo had a serious adverse reaction, and about 2% of those in both treatment arms stopped treatment because of an adverse event. The most common adverse events on semaglutide were gastrointestinal, with diarrhea in 14%, nausea in 14%, constipation in 12%, and vomiting in 10%.

These GI effects are often mitigated by slower dose escalation, eating smaller amounts of food at a time, and not eating beyond the point of feeling full, noted Dr. Jastreboff.

The STEP 4 results follow prior reports from three other large trials – STEP 1, STEP 2, and STEP 3 – that studied the weight-loss effects of weekly semaglutide treatment in adults using varying enrollment criteria and treatment designs. “We’ve seen very consistent results [across all four studies] for efficacy and safety,” said Dr. Rubino, who owns and directs the Washington Center for Weight Management & Research in Arlington, Va.

NovoNordisk, the company that markets semaglutide, submitted data from all four studies to the FDA late last year in an application for a new label for a weight loss indication at the 2.4-mg/week dosage. The company has said it expects an agency decision by June 2021.

Dr. Rubino has been an adviser and consultant to and a speaker on behalf of Novo Nordisk, and she has also been an investigator for studies sponsored by AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr. Clark had no disclosures. Dr. Jastreboff is consultant for and has received research funding from NovoNordisk, and she has also been a consultant to and/or received research from Eli Lilly and Boehringer Ingelheim.

mzoler@mdedge.com

Weekly injections with the GLP-1 receptor agonist semaglutide helped people maintain, and even increase, their initial weight loss on the agent when they continued treatment beyond 20 weeks in results from an international, multicenter trial with 803 randomized subjects.

The study “reflects what we always see in practice, that when people lose weight their body then fights to regain it. The results underscore this” by showing what happens when people stop the drug, Domenica M. Rubino, MD, reported at the annual meeting of the Endocrine Society.

The STEP 4 study began with 902 obese or higher-risk people with an average body mass index of about 38 kg/m² who underwent a 20-week, open-label, run-in phase of weekly subcutaneous injections of semaglutide (Ozempic), during which all subjects gradually up-titrated to the study’s maintenance dosage of 2.4 mg/week and allowing investigators to weed out intolerant, noncompliant, or nonresponsive people. After this phase excluded 99 subjects from continuing, and documented that the remaining 803 patients had already lost an average of 11% of their starting weight, the core of the study kicked in by randomizing them 2:1 to either maintain their weekly semaglutide injections for another 48 weeks or change to placebo injections.

After 48 more weeks, the 535 people who continued active semaglutide treatment lost on average an additional 8% of their weight. Meanwhile, the 268 who switched to placebo gained 7% of the weight they had reached at the 20-week point, for a significant between-group weight-loss difference of about 15% for the study’s primary endpoint. Those maintained on semaglutide for the full 68 weeks had a cumulative average weight loss of about 17%, compared with when they first began treatment, Dr. Rubino said. Concurrently with her report, the results also appeared in an article published online in JAMA.

“It’s reassuring that people who remain on this treatment can sustain weight losses of 15%, and in some cases 20% or more. That’s huge,” Dr. Rubino said in an interview. . After 68 weeks, 40% of the people who maintained their semaglutide treatment had lost at least 20% of their weight, compared with when they first started treatment.

“Preventing weight regain following initial weight loss is a well-known major challenge for people who lose weight,” commented John Clark III, MD, PhD, a weight management specialist at the University of Texas Southwestern Medical Center in Dallas who was not involved with the study. The findings from STEP 4 will be “helpful to have a discussion [with weight-loss patients] about the risks and benefits of continuing to take this medication longer than just a few months and if they want to continue taking the medication after they reach their goal weight,” Dr. Clark noted in an interview. “This new information reinforces that treatment continues to be effective after the short term.”

“This is obesity 101. If a treatment is provided that targets mechanisms of obesity, and then the treatment stops, we should not be surprised that weight regain occurs,” commented Ania M. Jastreboff, MD, PhD, codirector of the Yale Center for Weight Management in New Haven, Conn. “It’s tragic to see patients who, after successful weight loss, suffer regain because the treatment by which they lost weight stopped,” she said in an interview.

The STEP 4 study ran at 73 centers in 10 countries during 2018-2020. It enrolled adults without diabetes and with a BMI of at least 30, or at least 27 if they also had at least one weight-related comorbidity such as hypertension, dyslipidemia, or obstructive sleep apnea. Participants averaged about 47 years of age, almost 80% were women, and about 84% were White, including 8% of Hispanic or Latinx ethnicity.

The adverse-event profile was consistent with findings from trials where semaglutide treated hyperglycemia in patients with type 2 diabetes (semaglutide at a maximum once-weekly dosage of 1 mg has Food and Drug Administration approval for controlling hyperglycemia in patients with type 2 diabetes), as well results from other semaglutide studies and from studies of other agents in the GLP-1 receptor agonist class.

In STEP 4 9% of patients who received semaglutide during the randomized phase and 7% of those randomized to placebo had a serious adverse reaction, and about 2% of those in both treatment arms stopped treatment because of an adverse event. The most common adverse events on semaglutide were gastrointestinal, with diarrhea in 14%, nausea in 14%, constipation in 12%, and vomiting in 10%.

These GI effects are often mitigated by slower dose escalation, eating smaller amounts of food at a time, and not eating beyond the point of feeling full, noted Dr. Jastreboff.

The STEP 4 results follow prior reports from three other large trials – STEP 1, STEP 2, and STEP 3 – that studied the weight-loss effects of weekly semaglutide treatment in adults using varying enrollment criteria and treatment designs. “We’ve seen very consistent results [across all four studies] for efficacy and safety,” said Dr. Rubino, who owns and directs the Washington Center for Weight Management & Research in Arlington, Va.

NovoNordisk, the company that markets semaglutide, submitted data from all four studies to the FDA late last year in an application for a new label for a weight loss indication at the 2.4-mg/week dosage. The company has said it expects an agency decision by June 2021.

Dr. Rubino has been an adviser and consultant to and a speaker on behalf of Novo Nordisk, and she has also been an investigator for studies sponsored by AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr. Clark had no disclosures. Dr. Jastreboff is consultant for and has received research funding from NovoNordisk, and she has also been a consultant to and/or received research from Eli Lilly and Boehringer Ingelheim.

mzoler@mdedge.com

Weekly injections with the GLP-1 receptor agonist semaglutide helped people maintain, and even increase, their initial weight loss on the agent when they continued treatment beyond 20 weeks in results from an international, multicenter trial with 803 randomized subjects.

The study “reflects what we always see in practice, that when people lose weight their body then fights to regain it. The results underscore this” by showing what happens when people stop the drug, Domenica M. Rubino, MD, reported at the annual meeting of the Endocrine Society.

The STEP 4 study began with 902 obese or higher-risk people with an average body mass index of about 38 kg/m² who underwent a 20-week, open-label, run-in phase of weekly subcutaneous injections of semaglutide (Ozempic), during which all subjects gradually up-titrated to the study’s maintenance dosage of 2.4 mg/week and allowing investigators to weed out intolerant, noncompliant, or nonresponsive people. After this phase excluded 99 subjects from continuing, and documented that the remaining 803 patients had already lost an average of 11% of their starting weight, the core of the study kicked in by randomizing them 2:1 to either maintain their weekly semaglutide injections for another 48 weeks or change to placebo injections.

After 48 more weeks, the 535 people who continued active semaglutide treatment lost on average an additional 8% of their weight. Meanwhile, the 268 who switched to placebo gained 7% of the weight they had reached at the 20-week point, for a significant between-group weight-loss difference of about 15% for the study’s primary endpoint. Those maintained on semaglutide for the full 68 weeks had a cumulative average weight loss of about 17%, compared with when they first began treatment, Dr. Rubino said. Concurrently with her report, the results also appeared in an article published online in JAMA.

“It’s reassuring that people who remain on this treatment can sustain weight losses of 15%, and in some cases 20% or more. That’s huge,” Dr. Rubino said in an interview. . After 68 weeks, 40% of the people who maintained their semaglutide treatment had lost at least 20% of their weight, compared with when they first started treatment.

“Preventing weight regain following initial weight loss is a well-known major challenge for people who lose weight,” commented John Clark III, MD, PhD, a weight management specialist at the University of Texas Southwestern Medical Center in Dallas who was not involved with the study. The findings from STEP 4 will be “helpful to have a discussion [with weight-loss patients] about the risks and benefits of continuing to take this medication longer than just a few months and if they want to continue taking the medication after they reach their goal weight,” Dr. Clark noted in an interview. “This new information reinforces that treatment continues to be effective after the short term.”

“This is obesity 101. If a treatment is provided that targets mechanisms of obesity, and then the treatment stops, we should not be surprised that weight regain occurs,” commented Ania M. Jastreboff, MD, PhD, codirector of the Yale Center for Weight Management in New Haven, Conn. “It’s tragic to see patients who, after successful weight loss, suffer regain because the treatment by which they lost weight stopped,” she said in an interview.

The STEP 4 study ran at 73 centers in 10 countries during 2018-2020. It enrolled adults without diabetes and with a BMI of at least 30, or at least 27 if they also had at least one weight-related comorbidity such as hypertension, dyslipidemia, or obstructive sleep apnea. Participants averaged about 47 years of age, almost 80% were women, and about 84% were White, including 8% of Hispanic or Latinx ethnicity.

The adverse-event profile was consistent with findings from trials where semaglutide treated hyperglycemia in patients with type 2 diabetes (semaglutide at a maximum once-weekly dosage of 1 mg has Food and Drug Administration approval for controlling hyperglycemia in patients with type 2 diabetes), as well results from other semaglutide studies and from studies of other agents in the GLP-1 receptor agonist class.

In STEP 4 9% of patients who received semaglutide during the randomized phase and 7% of those randomized to placebo had a serious adverse reaction, and about 2% of those in both treatment arms stopped treatment because of an adverse event. The most common adverse events on semaglutide were gastrointestinal, with diarrhea in 14%, nausea in 14%, constipation in 12%, and vomiting in 10%.

These GI effects are often mitigated by slower dose escalation, eating smaller amounts of food at a time, and not eating beyond the point of feeling full, noted Dr. Jastreboff.

The STEP 4 results follow prior reports from three other large trials – STEP 1, STEP 2, and STEP 3 – that studied the weight-loss effects of weekly semaglutide treatment in adults using varying enrollment criteria and treatment designs. “We’ve seen very consistent results [across all four studies] for efficacy and safety,” said Dr. Rubino, who owns and directs the Washington Center for Weight Management & Research in Arlington, Va.

NovoNordisk, the company that markets semaglutide, submitted data from all four studies to the FDA late last year in an application for a new label for a weight loss indication at the 2.4-mg/week dosage. The company has said it expects an agency decision by June 2021.

Dr. Rubino has been an adviser and consultant to and a speaker on behalf of Novo Nordisk, and she has also been an investigator for studies sponsored by AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr. Clark had no disclosures. Dr. Jastreboff is consultant for and has received research funding from NovoNordisk, and she has also been a consultant to and/or received research from Eli Lilly and Boehringer Ingelheim.

mzoler@mdedge.com

Amid a substantial expansion of therapies in several drug classes for the treatment of osteoporosis, there has been a notable increase in the prescription of denosumab for patients with a cancer-related indication.

ogichobanov/iStock/Getty Images Plus

In an analysis of claims data from January 2009 to March 2020, the bisphosphonate alendronate represented more than 50% of all prescriptions for bone-directed therapies, but growth in the use of the monoclonal antibody denosumab overall and in cancer-related indications particularly was steady throughout the study period.

“In the malignancy cohort, alendronate and zoledronic acid were each used in approximately 30% of individuals at the onset of the study, but use of both then declined,” Sara Cromer, MD, reported at the annual meeting of the Endocrine Society.

For malignancy-based prescriptions, denosumab surpassed either bisphosphonate by 2013 and then continued to rise.

Denosumab use “reached approximately 50% of all bone-directed medication use in the malignancy cohort” by the end of the study period, said Dr. Cromer, a clinical research fellow in endocrinology at Massachusetts General Hospital, Boston.

The claims data for this analysis was drawn from the Clinformatics Data Mart. The analysis was restricted to individuals aged older than 50 years who received a prescription for a bone-directed therapy. The 15.48 million prescriptions evaluated were drawn from 1.46 million unique individuals. The mean age was 69 years, and 89% of those prescribed a drug were women.
 

Oncologic indications one of two tracked cohorts

In the context of a large expansion of treatment options in several drug classes for osteoporosis, the objective of this claims analysis was to document trends in treatment choice, according to Dr. Cromer. She and her coinvestigators looked at prescriptions overall as well as in two cohorts defined by ICD codes. One included patients prescribed a prescription by an oncologist. The other included everyone else.

When all prescriptions for bone-directed therapy were evaluated over the study period, alendronate was the most commonly prescribed therapy, and its use increased over time. Prescriptions of zoledronic acid also rose, doubling over the study period, but use was very low in the beginning and it never climbed above 5%.

The proportion of prescriptions written for bisphosphonates other than alendronate and zoledronic acid “declined steadily” over the study period, Dr. Cromer reported.

Denosumab, a monoclonal antibody that targets a step in the process important to maturation of osteoclasts, was approved in 2010. It accounted for 10% of all prescriptions for osteoporosis by 2015 and 15% by 2018. It was still rising through the end of the study period.

In contrast, prescriptions of raloxifene, a selective estrogen receptor modulator, began to decline after 2013. In general, the rates of prescriptions for other agents, including some of the more recently approved drugs, such as teriparatide, abaloparatide, and romosozumab, changed very little over the study period. None of these therapies ever represented more than 2% of prescriptions.

When looking at the cohort of patients who received a bone-directed reason for a noncancer indication, the trends “paralleled those in the all-user analysis,” Dr. Cromer reported.
 

Denosumab use greater in privately insured

In the malignancy cohort, the decline in the use of bisphosphonates and the rise in the use of denosumab were most pronounced in patients who were privately insured. The increased use of denosumab over the study period “outpaced gains in use of other agents despite guidelines,” said Dr. Cromer, referring to the those issued by the Endocrine Society in 2019 .

In those guidelines, written for management of postmenopausal women at high risk of fractures, bisphosphonates are recommended for initial treatment while denosumab is recommended as an alternative. However, those guidelines do not provide specific recommendations for therapies directed at osteoporosis associated with cancer.

Guidelines for this population exist, including one published by the American Society of Clinical Oncology in 2019.

In the ASCO guidelines, oral bisphosphonates, intravenous bisphosphonates, and subcutaneous denosumab were all identified as “efficacious options,” according to Charles L. Shapiro, MD, director of breast cancer translational research, Mount Sinai Health System, New York.

Specifically, “all three of them work to reduce fractures and improve bone density in women with breast cancer in whom you are trying to prevent or treat osteoporosis,” Dr. Shapiro said in an interview.

There might be relative advantages for one therapy over another in specific subgroups defined by type of cancer or stage of cancer, but trials are not definitive for such outcomes as overall survival. Citing one comparative study associating denosumab with an 18% delay to first skeletal event in women with metastatic breast cancer, Dr. Shapiro observed, “I personally don’t consider an 18% delay [for this outcome] to be that clinically meaningful.”

Although major guidelines from ASCO have not so far favored denosumab over any bisphosphonate in routine care, Dr. Shapiro did not rule out the possibility that future studies will show differences.

Dr. Comer and Dr. Shapiro reported no relevant conflicts of interest.

Amid a substantial expansion of therapies in several drug classes for the treatment of osteoporosis, there has been a notable increase in the prescription of denosumab for patients with a cancer-related indication.

ogichobanov/iStock/Getty Images Plus

In an analysis of claims data from January 2009 to March 2020, the bisphosphonate alendronate represented more than 50% of all prescriptions for bone-directed therapies, but growth in the use of the monoclonal antibody denosumab overall and in cancer-related indications particularly was steady throughout the study period.

“In the malignancy cohort, alendronate and zoledronic acid were each used in approximately 30% of individuals at the onset of the study, but use of both then declined,” Sara Cromer, MD, reported at the annual meeting of the Endocrine Society.

For malignancy-based prescriptions, denosumab surpassed either bisphosphonate by 2013 and then continued to rise.

Denosumab use “reached approximately 50% of all bone-directed medication use in the malignancy cohort” by the end of the study period, said Dr. Cromer, a clinical research fellow in endocrinology at Massachusetts General Hospital, Boston.

The claims data for this analysis was drawn from the Clinformatics Data Mart. The analysis was restricted to individuals aged older than 50 years who received a prescription for a bone-directed therapy. The 15.48 million prescriptions evaluated were drawn from 1.46 million unique individuals. The mean age was 69 years, and 89% of those prescribed a drug were women.
 

Oncologic indications one of two tracked cohorts

In the context of a large expansion of treatment options in several drug classes for osteoporosis, the objective of this claims analysis was to document trends in treatment choice, according to Dr. Cromer. She and her coinvestigators looked at prescriptions overall as well as in two cohorts defined by ICD codes. One included patients prescribed a prescription by an oncologist. The other included everyone else.

When all prescriptions for bone-directed therapy were evaluated over the study period, alendronate was the most commonly prescribed therapy, and its use increased over time. Prescriptions of zoledronic acid also rose, doubling over the study period, but use was very low in the beginning and it never climbed above 5%.

The proportion of prescriptions written for bisphosphonates other than alendronate and zoledronic acid “declined steadily” over the study period, Dr. Cromer reported.

Denosumab, a monoclonal antibody that targets a step in the process important to maturation of osteoclasts, was approved in 2010. It accounted for 10% of all prescriptions for osteoporosis by 2015 and 15% by 2018. It was still rising through the end of the study period.

In contrast, prescriptions of raloxifene, a selective estrogen receptor modulator, began to decline after 2013. In general, the rates of prescriptions for other agents, including some of the more recently approved drugs, such as teriparatide, abaloparatide, and romosozumab, changed very little over the study period. None of these therapies ever represented more than 2% of prescriptions.

When looking at the cohort of patients who received a bone-directed reason for a noncancer indication, the trends “paralleled those in the all-user analysis,” Dr. Cromer reported.
 

Denosumab use greater in privately insured

In the malignancy cohort, the decline in the use of bisphosphonates and the rise in the use of denosumab were most pronounced in patients who were privately insured. The increased use of denosumab over the study period “outpaced gains in use of other agents despite guidelines,” said Dr. Cromer, referring to the those issued by the Endocrine Society in 2019 .

In those guidelines, written for management of postmenopausal women at high risk of fractures, bisphosphonates are recommended for initial treatment while denosumab is recommended as an alternative. However, those guidelines do not provide specific recommendations for therapies directed at osteoporosis associated with cancer.

Guidelines for this population exist, including one published by the American Society of Clinical Oncology in 2019.

In the ASCO guidelines, oral bisphosphonates, intravenous bisphosphonates, and subcutaneous denosumab were all identified as “efficacious options,” according to Charles L. Shapiro, MD, director of breast cancer translational research, Mount Sinai Health System, New York.

Specifically, “all three of them work to reduce fractures and improve bone density in women with breast cancer in whom you are trying to prevent or treat osteoporosis,” Dr. Shapiro said in an interview.

There might be relative advantages for one therapy over another in specific subgroups defined by type of cancer or stage of cancer, but trials are not definitive for such outcomes as overall survival. Citing one comparative study associating denosumab with an 18% delay to first skeletal event in women with metastatic breast cancer, Dr. Shapiro observed, “I personally don’t consider an 18% delay [for this outcome] to be that clinically meaningful.”

Although major guidelines from ASCO have not so far favored denosumab over any bisphosphonate in routine care, Dr. Shapiro did not rule out the possibility that future studies will show differences.

Dr. Comer and Dr. Shapiro reported no relevant conflicts of interest.

Amid a substantial expansion of therapies in several drug classes for the treatment of osteoporosis, there has been a notable increase in the prescription of denosumab for patients with a cancer-related indication.

ogichobanov/iStock/Getty Images Plus

In an analysis of claims data from January 2009 to March 2020, the bisphosphonate alendronate represented more than 50% of all prescriptions for bone-directed therapies, but growth in the use of the monoclonal antibody denosumab overall and in cancer-related indications particularly was steady throughout the study period.

“In the malignancy cohort, alendronate and zoledronic acid were each used in approximately 30% of individuals at the onset of the study, but use of both then declined,” Sara Cromer, MD, reported at the annual meeting of the Endocrine Society.

For malignancy-based prescriptions, denosumab surpassed either bisphosphonate by 2013 and then continued to rise.

Denosumab use “reached approximately 50% of all bone-directed medication use in the malignancy cohort” by the end of the study period, said Dr. Cromer, a clinical research fellow in endocrinology at Massachusetts General Hospital, Boston.

The claims data for this analysis was drawn from the Clinformatics Data Mart. The analysis was restricted to individuals aged older than 50 years who received a prescription for a bone-directed therapy. The 15.48 million prescriptions evaluated were drawn from 1.46 million unique individuals. The mean age was 69 years, and 89% of those prescribed a drug were women.
 

Oncologic indications one of two tracked cohorts

In the context of a large expansion of treatment options in several drug classes for osteoporosis, the objective of this claims analysis was to document trends in treatment choice, according to Dr. Cromer. She and her coinvestigators looked at prescriptions overall as well as in two cohorts defined by ICD codes. One included patients prescribed a prescription by an oncologist. The other included everyone else.

When all prescriptions for bone-directed therapy were evaluated over the study period, alendronate was the most commonly prescribed therapy, and its use increased over time. Prescriptions of zoledronic acid also rose, doubling over the study period, but use was very low in the beginning and it never climbed above 5%.

The proportion of prescriptions written for bisphosphonates other than alendronate and zoledronic acid “declined steadily” over the study period, Dr. Cromer reported.

Denosumab, a monoclonal antibody that targets a step in the process important to maturation of osteoclasts, was approved in 2010. It accounted for 10% of all prescriptions for osteoporosis by 2015 and 15% by 2018. It was still rising through the end of the study period.

In contrast, prescriptions of raloxifene, a selective estrogen receptor modulator, began to decline after 2013. In general, the rates of prescriptions for other agents, including some of the more recently approved drugs, such as teriparatide, abaloparatide, and romosozumab, changed very little over the study period. None of these therapies ever represented more than 2% of prescriptions.

When looking at the cohort of patients who received a bone-directed reason for a noncancer indication, the trends “paralleled those in the all-user analysis,” Dr. Cromer reported.
 

Denosumab use greater in privately insured

In the malignancy cohort, the decline in the use of bisphosphonates and the rise in the use of denosumab were most pronounced in patients who were privately insured. The increased use of denosumab over the study period “outpaced gains in use of other agents despite guidelines,” said Dr. Cromer, referring to the those issued by the Endocrine Society in 2019 .

In those guidelines, written for management of postmenopausal women at high risk of fractures, bisphosphonates are recommended for initial treatment while denosumab is recommended as an alternative. However, those guidelines do not provide specific recommendations for therapies directed at osteoporosis associated with cancer.

Guidelines for this population exist, including one published by the American Society of Clinical Oncology in 2019.

In the ASCO guidelines, oral bisphosphonates, intravenous bisphosphonates, and subcutaneous denosumab were all identified as “efficacious options,” according to Charles L. Shapiro, MD, director of breast cancer translational research, Mount Sinai Health System, New York.

Specifically, “all three of them work to reduce fractures and improve bone density in women with breast cancer in whom you are trying to prevent or treat osteoporosis,” Dr. Shapiro said in an interview.

There might be relative advantages for one therapy over another in specific subgroups defined by type of cancer or stage of cancer, but trials are not definitive for such outcomes as overall survival. Citing one comparative study associating denosumab with an 18% delay to first skeletal event in women with metastatic breast cancer, Dr. Shapiro observed, “I personally don’t consider an 18% delay [for this outcome] to be that clinically meaningful.”

Although major guidelines from ASCO have not so far favored denosumab over any bisphosphonate in routine care, Dr. Shapiro did not rule out the possibility that future studies will show differences.

Dr. Comer and Dr. Shapiro reported no relevant conflicts of interest.