User login
In low-risk thyroid cancer, no advantage found for postsurgical iodine
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.
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.
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.
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.
FROM ENDO 2021
COVID-19 can cause atypical thyroid inflammation
Individuals who experience inflammation of the thyroid gland during acute COVID-19 illness may still have subacute thyroiditis months later, even if thyroid function has normalized, new research suggests.
Furthermore, the thyroiditis seems to be different from thyroid inflammation caused by other viruses, said Ilaria Muller, MD, PhD, when presenting her findings March 21 at the virtual ENDO 2021 meeting.
“SARS-CoV-2 seems to have multifactorial action on thyroid function,” said Dr. Muller, of the University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Italy.
In July 2020, Dr. Muller and colleagues described patients hospitalized at their institution with severe COVID-19, 15% of whom had thyrotoxicosis due to atypical subacute thyroiditis, compared with just 1% of a comparison group hospitalized in the same subintensive care units during the spring of 2019, as reported by this news organization.
The “atypical” thyroiditis that occurred in the patients with COVID-19 was not associated with neck pain and affected more men than women. Moreover, it was associated with low TSH and free-triiodothyronine (T3) levels, and normal or elevated levels of free-thyroxine (T4), which is a very different presentation to classic nonthyroidal illness syndrome (NTIS) usually seen in critically ill patients, she explained.
Although transient T4 elevations can occur in acute illness, that phenomenon is not associated with low TSH. This newly described scenario appears to be a combination of thyrotoxicosis and NTIS, Dr. Muller and colleagues had speculated last summer.
Follow patients with COVID-19 and thyroid dysfunction for a year
Now, in an assessment of 51 patients 3 months after hospitalization for moderate-to-severe COVID-19 reported by Dr. Muller at ENDO 2021, both inflammatory markers and thyroid function had normalized, yet on imaging, a third of patients still exhibited focal hypoechoic areas suggestive of thyroiditis.
Of those, two-thirds had reduced uptake on thyroid scintigraphy, but few had antithyroid autoantibodies.
“The thyroid dysfunction induced by COVID-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months,” Dr. Muller emphasized.
Asked to comment, session moderator Robert W. Lash, MD, the Endocrine Society’s chief professional & clinical affairs officer, told this news organization: “When you’re ICU-level sick, it’s not unusual to have weird thyroid tests. Some viruses cause thyroid problems as well ... What makes this different is that while a lot of thyroid inflammation is caused by antibodies, this was not.”
“It looks like this was [SARS-CoV-2] causing damage to the thyroid gland, which is interesting,” he noted, adding that the thyroid gland expresses high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), which allow SARS-CoV-2 to infect human cells.
“This is probably part of that same story,” Dr. Lash said.
For patients who had thyroid abnormalities during acute COVID-19 illness or develop symptoms that might be thyroid-related afterward, he advises: “You should keep an eye on thyroid tests. It just raises your awareness ... You might check their thyroid tests every 6 months for a year.”
Signs of focal thyroiditis despite normalized thyroid function
The 51 patients (33 men and 18 women) hospitalized with moderate-to-severe COVID-19 had no history of thyroid disease and had not been taking thyroid medications, amiodarone, or steroids before baseline TSH was measured.
From baseline to 3 months, TSH rose from 1.2 to 1.6 mIU/L, while serum concentrations of T4, T3, C-reactive protein, and full blood counts had all normalized (all P < 0.01 vs. baseline).
Thyroid ultrasound at 3 months in 49 patients showed signs of focal thyroiditis in 16 (33%).
Among 14 patients of those who further underwent thyroid 99mTc or I123 uptake scans, four (29%) were normal, eight (57%) had focally reduced uptake, and two (14%) had diffusely reduced uptake.
Of the 16 patients with focal thyroiditis, only three were positive for autoantibodies to thyroglobulin (TgAb) or thyroid peroxidase (TPOAb). All were negative for autoantibodies to the TSH receptor.
“Importantly, of the two with diffusely reduced uptake, only one was positive for TPOAb or TgAb,” Dr. Muller noted, adding, “SARS-CoV-2 disease seems to trigger some dysfunction which very likely has complex and multifactorial mechanisms.”
In response to a question about a possible role for biopsies and thyroid cytology, Dr. Muller replied: “That’s definitely the key ... So far we’re just making guesses, so the key will be cytological or histological studies to see what is really going on in the thyroid.”
“What we know is that [unlike] classical thyroiditis that has been described after viral diseases including SARS-CoV-2, these patients have a different scenario ... Probably something is going on within the thyroid with a different mechanism, so surely cytology and histology studies are what we need,” she concluded.
The study was funded by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, and by a COVID-19 research grant from the European Society of Endocrinology. Dr. Muller and Dr. Lash have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Individuals who experience inflammation of the thyroid gland during acute COVID-19 illness may still have subacute thyroiditis months later, even if thyroid function has normalized, new research suggests.
Furthermore, the thyroiditis seems to be different from thyroid inflammation caused by other viruses, said Ilaria Muller, MD, PhD, when presenting her findings March 21 at the virtual ENDO 2021 meeting.
“SARS-CoV-2 seems to have multifactorial action on thyroid function,” said Dr. Muller, of the University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Italy.
In July 2020, Dr. Muller and colleagues described patients hospitalized at their institution with severe COVID-19, 15% of whom had thyrotoxicosis due to atypical subacute thyroiditis, compared with just 1% of a comparison group hospitalized in the same subintensive care units during the spring of 2019, as reported by this news organization.
The “atypical” thyroiditis that occurred in the patients with COVID-19 was not associated with neck pain and affected more men than women. Moreover, it was associated with low TSH and free-triiodothyronine (T3) levels, and normal or elevated levels of free-thyroxine (T4), which is a very different presentation to classic nonthyroidal illness syndrome (NTIS) usually seen in critically ill patients, she explained.
Although transient T4 elevations can occur in acute illness, that phenomenon is not associated with low TSH. This newly described scenario appears to be a combination of thyrotoxicosis and NTIS, Dr. Muller and colleagues had speculated last summer.
Follow patients with COVID-19 and thyroid dysfunction for a year
Now, in an assessment of 51 patients 3 months after hospitalization for moderate-to-severe COVID-19 reported by Dr. Muller at ENDO 2021, both inflammatory markers and thyroid function had normalized, yet on imaging, a third of patients still exhibited focal hypoechoic areas suggestive of thyroiditis.
Of those, two-thirds had reduced uptake on thyroid scintigraphy, but few had antithyroid autoantibodies.
“The thyroid dysfunction induced by COVID-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months,” Dr. Muller emphasized.
Asked to comment, session moderator Robert W. Lash, MD, the Endocrine Society’s chief professional & clinical affairs officer, told this news organization: “When you’re ICU-level sick, it’s not unusual to have weird thyroid tests. Some viruses cause thyroid problems as well ... What makes this different is that while a lot of thyroid inflammation is caused by antibodies, this was not.”
“It looks like this was [SARS-CoV-2] causing damage to the thyroid gland, which is interesting,” he noted, adding that the thyroid gland expresses high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), which allow SARS-CoV-2 to infect human cells.
“This is probably part of that same story,” Dr. Lash said.
For patients who had thyroid abnormalities during acute COVID-19 illness or develop symptoms that might be thyroid-related afterward, he advises: “You should keep an eye on thyroid tests. It just raises your awareness ... You might check their thyroid tests every 6 months for a year.”
Signs of focal thyroiditis despite normalized thyroid function
The 51 patients (33 men and 18 women) hospitalized with moderate-to-severe COVID-19 had no history of thyroid disease and had not been taking thyroid medications, amiodarone, or steroids before baseline TSH was measured.
From baseline to 3 months, TSH rose from 1.2 to 1.6 mIU/L, while serum concentrations of T4, T3, C-reactive protein, and full blood counts had all normalized (all P < 0.01 vs. baseline).
Thyroid ultrasound at 3 months in 49 patients showed signs of focal thyroiditis in 16 (33%).
Among 14 patients of those who further underwent thyroid 99mTc or I123 uptake scans, four (29%) were normal, eight (57%) had focally reduced uptake, and two (14%) had diffusely reduced uptake.
Of the 16 patients with focal thyroiditis, only three were positive for autoantibodies to thyroglobulin (TgAb) or thyroid peroxidase (TPOAb). All were negative for autoantibodies to the TSH receptor.
“Importantly, of the two with diffusely reduced uptake, only one was positive for TPOAb or TgAb,” Dr. Muller noted, adding, “SARS-CoV-2 disease seems to trigger some dysfunction which very likely has complex and multifactorial mechanisms.”
In response to a question about a possible role for biopsies and thyroid cytology, Dr. Muller replied: “That’s definitely the key ... So far we’re just making guesses, so the key will be cytological or histological studies to see what is really going on in the thyroid.”
“What we know is that [unlike] classical thyroiditis that has been described after viral diseases including SARS-CoV-2, these patients have a different scenario ... Probably something is going on within the thyroid with a different mechanism, so surely cytology and histology studies are what we need,” she concluded.
The study was funded by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, and by a COVID-19 research grant from the European Society of Endocrinology. Dr. Muller and Dr. Lash have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Individuals who experience inflammation of the thyroid gland during acute COVID-19 illness may still have subacute thyroiditis months later, even if thyroid function has normalized, new research suggests.
Furthermore, the thyroiditis seems to be different from thyroid inflammation caused by other viruses, said Ilaria Muller, MD, PhD, when presenting her findings March 21 at the virtual ENDO 2021 meeting.
“SARS-CoV-2 seems to have multifactorial action on thyroid function,” said Dr. Muller, of the University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Italy.
In July 2020, Dr. Muller and colleagues described patients hospitalized at their institution with severe COVID-19, 15% of whom had thyrotoxicosis due to atypical subacute thyroiditis, compared with just 1% of a comparison group hospitalized in the same subintensive care units during the spring of 2019, as reported by this news organization.
The “atypical” thyroiditis that occurred in the patients with COVID-19 was not associated with neck pain and affected more men than women. Moreover, it was associated with low TSH and free-triiodothyronine (T3) levels, and normal or elevated levels of free-thyroxine (T4), which is a very different presentation to classic nonthyroidal illness syndrome (NTIS) usually seen in critically ill patients, she explained.
Although transient T4 elevations can occur in acute illness, that phenomenon is not associated with low TSH. This newly described scenario appears to be a combination of thyrotoxicosis and NTIS, Dr. Muller and colleagues had speculated last summer.
Follow patients with COVID-19 and thyroid dysfunction for a year
Now, in an assessment of 51 patients 3 months after hospitalization for moderate-to-severe COVID-19 reported by Dr. Muller at ENDO 2021, both inflammatory markers and thyroid function had normalized, yet on imaging, a third of patients still exhibited focal hypoechoic areas suggestive of thyroiditis.
Of those, two-thirds had reduced uptake on thyroid scintigraphy, but few had antithyroid autoantibodies.
“The thyroid dysfunction induced by COVID-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months,” Dr. Muller emphasized.
Asked to comment, session moderator Robert W. Lash, MD, the Endocrine Society’s chief professional & clinical affairs officer, told this news organization: “When you’re ICU-level sick, it’s not unusual to have weird thyroid tests. Some viruses cause thyroid problems as well ... What makes this different is that while a lot of thyroid inflammation is caused by antibodies, this was not.”
“It looks like this was [SARS-CoV-2] causing damage to the thyroid gland, which is interesting,” he noted, adding that the thyroid gland expresses high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), which allow SARS-CoV-2 to infect human cells.
“This is probably part of that same story,” Dr. Lash said.
For patients who had thyroid abnormalities during acute COVID-19 illness or develop symptoms that might be thyroid-related afterward, he advises: “You should keep an eye on thyroid tests. It just raises your awareness ... You might check their thyroid tests every 6 months for a year.”
Signs of focal thyroiditis despite normalized thyroid function
The 51 patients (33 men and 18 women) hospitalized with moderate-to-severe COVID-19 had no history of thyroid disease and had not been taking thyroid medications, amiodarone, or steroids before baseline TSH was measured.
From baseline to 3 months, TSH rose from 1.2 to 1.6 mIU/L, while serum concentrations of T4, T3, C-reactive protein, and full blood counts had all normalized (all P < 0.01 vs. baseline).
Thyroid ultrasound at 3 months in 49 patients showed signs of focal thyroiditis in 16 (33%).
Among 14 patients of those who further underwent thyroid 99mTc or I123 uptake scans, four (29%) were normal, eight (57%) had focally reduced uptake, and two (14%) had diffusely reduced uptake.
Of the 16 patients with focal thyroiditis, only three were positive for autoantibodies to thyroglobulin (TgAb) or thyroid peroxidase (TPOAb). All were negative for autoantibodies to the TSH receptor.
“Importantly, of the two with diffusely reduced uptake, only one was positive for TPOAb or TgAb,” Dr. Muller noted, adding, “SARS-CoV-2 disease seems to trigger some dysfunction which very likely has complex and multifactorial mechanisms.”
In response to a question about a possible role for biopsies and thyroid cytology, Dr. Muller replied: “That’s definitely the key ... So far we’re just making guesses, so the key will be cytological or histological studies to see what is really going on in the thyroid.”
“What we know is that [unlike] classical thyroiditis that has been described after viral diseases including SARS-CoV-2, these patients have a different scenario ... Probably something is going on within the thyroid with a different mechanism, so surely cytology and histology studies are what we need,” she concluded.
The study was funded by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, and by a COVID-19 research grant from the European Society of Endocrinology. Dr. Muller and Dr. Lash have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Combo thyroid hormones as good as levothyroxine for hypothyroidism
Patients with hypothyroidism treated with the three most common pharmacologic strategies of levothyroxine (LT4) alone, LT4 in combination with triiodothyronine (T3), or desiccated thyroid extract showed no differences in thyroid symptoms or secondary outcomes in a double-blind, randomized study.
“There are now proven good treatment options for the more than 1 in 10 patients with hypothyroidism who continue to experience symptoms of fatigue, mental fogginess, weight gain, and other symptoms despite taking levothyroxine,” first author Thanh Duc Hoang, DO, an endocrinologist at the Walter Reed National Military Medical Center, in Bethesda, Md., said in a press statement.
The findings were presented at the annual meeting of the Endocrine Society.
Commenting on the study, Alan P. Farwell, MD, said these new results are a valuable contribution to the understanding of treatment effects. “I think this is an interesting and important study and further studies are needed to clarify the optimal way to treat hypothyroidism,” said Dr. Farwell, who is director of endocrine clinics at Boston University.
Importantly, “the findings are different than studies where the patients are aware of what medication they are receiving,” he stressed in an interview, underscoring the importance of the double-blind design of the trial.
But Anne Cappola, MD, of the University of Pennsylvania, Philadelphia, pointed out that “the study was small and unlikely to have the statistical power to detect differences that could have been clinically important.”
Nevertheless, she too agreed that the double-blind study design is key: “My experience with patients is [the effects] are affected by patients’ perceptions about their thyroid medication. That is why studies designed so that patients do not know which treatment they are receiving are so important in this area.”
Randomized, double-blind comparison
Prior to the widespread availability of the current gold standard hypothyroidism treatment of LT4, the condition was typically treated with desiccated (animal) thyroid extract. And with many patients continuing to have a preference for this therapeutic approach, it is still commonly used.
Additionally, some patients treated with LT4 alone report greater improvements in symptoms with the addition of T3 – despite studies showing no benefits from the two together – leading to many clinicians commonly trying the combination approach.
To compare the efficacy of the three approaches in a prospective, double-blind, cross-over fashion, 75 patients received three therapeutic approaches each for 3 months: desiccated thyroid extract, an LT4/T3 combination, or LT4 alone.
After each 3-month treatment, patients completed a 36-point thyroid symptom questionnaire.
There was no significant differences in symptom relief, the primary outcome, between the three treatments (P = .32).
Overall, 45% of patients indicated they preferred desiccated thyroid as their first choice of treatment, 32% preferred LT4/T3 as their first choice, and 23% preferred LT4 alone.
For the secondary endpoints of weight, general health, depression (assessed using the Beck Depression Inventory), memory (Wechsler Memory Scale), lipids, and thyroid function, again, there were no significant differences between groups in any of the measures.
When switched to desiccated thyroid, many felt ‘much better’
A further exploratory analysis revealed that those who experienced symptoms while taking LT4 alone reported greater alleviation of symptoms with the other two treatments.
“As a whole group, there was no significant difference between the three treatment arms,” Dr. Hoang explained in an interview.
“However, with the subgroup analysis based on the scores of symptom questionnaires, we found that symptomatic patients on LT4 improved while being treated with LT4/T3 or desiccated thyroid,” he said.
Reports of improvements in switching to desiccated thyroid were notable, Dr. Hoang added. “Many patients when switched from LT4 to desiccated thyroid extract said they felt much better, [with] more energy, less mental fogginess, a better outlook, less flair of lupus symptoms, easier to lose weight, etc.”
The study also showed more patients with Hashimoto’s disease preferred desiccated thyroid extract and LT4/T3, compared with LT4 alone, however, the differences were not significant.
Treatment adjustments a helpful first step
Dr. Farwell noted that his approach when patients are still reporting symptoms despite LT4 treatment is to first try tweaking the dose.
“In my own practice, I prefer to adjust LT4 dosing first, and on occasion add T3, with a goal of getting both hormone levels in the upper half of the normal range,” he said. “I find that to be a better approach than desiccated thyroid extract. T3 should be taken twice a day due to its half-life.”
The approach is generally successful, he added. “Even those that come in asking for desiccated thyroid extract whom I am able to convince to try LT4/T3 end up being happy with their treatment in the end.
“The key is that you need to spend time discussing the options with patients and come to a consensus as to the therapy that will best resolve their symptoms and that they are most comfortable with,” he concluded.
In response to mounting evidence of different hypothyroidism treatment responses according to various subgroups of patients, experts recently called for the initiation of more thorough clinical trials on the issue of combination therapy, as recently reported by this news organization.
Dr. Hoang reported being a speaker for Acella Pharmaceuticals. Dr. Farwell and Dr. Cappola reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with hypothyroidism treated with the three most common pharmacologic strategies of levothyroxine (LT4) alone, LT4 in combination with triiodothyronine (T3), or desiccated thyroid extract showed no differences in thyroid symptoms or secondary outcomes in a double-blind, randomized study.
“There are now proven good treatment options for the more than 1 in 10 patients with hypothyroidism who continue to experience symptoms of fatigue, mental fogginess, weight gain, and other symptoms despite taking levothyroxine,” first author Thanh Duc Hoang, DO, an endocrinologist at the Walter Reed National Military Medical Center, in Bethesda, Md., said in a press statement.
The findings were presented at the annual meeting of the Endocrine Society.
Commenting on the study, Alan P. Farwell, MD, said these new results are a valuable contribution to the understanding of treatment effects. “I think this is an interesting and important study and further studies are needed to clarify the optimal way to treat hypothyroidism,” said Dr. Farwell, who is director of endocrine clinics at Boston University.
Importantly, “the findings are different than studies where the patients are aware of what medication they are receiving,” he stressed in an interview, underscoring the importance of the double-blind design of the trial.
But Anne Cappola, MD, of the University of Pennsylvania, Philadelphia, pointed out that “the study was small and unlikely to have the statistical power to detect differences that could have been clinically important.”
Nevertheless, she too agreed that the double-blind study design is key: “My experience with patients is [the effects] are affected by patients’ perceptions about their thyroid medication. That is why studies designed so that patients do not know which treatment they are receiving are so important in this area.”
Randomized, double-blind comparison
Prior to the widespread availability of the current gold standard hypothyroidism treatment of LT4, the condition was typically treated with desiccated (animal) thyroid extract. And with many patients continuing to have a preference for this therapeutic approach, it is still commonly used.
Additionally, some patients treated with LT4 alone report greater improvements in symptoms with the addition of T3 – despite studies showing no benefits from the two together – leading to many clinicians commonly trying the combination approach.
To compare the efficacy of the three approaches in a prospective, double-blind, cross-over fashion, 75 patients received three therapeutic approaches each for 3 months: desiccated thyroid extract, an LT4/T3 combination, or LT4 alone.
After each 3-month treatment, patients completed a 36-point thyroid symptom questionnaire.
There was no significant differences in symptom relief, the primary outcome, between the three treatments (P = .32).
Overall, 45% of patients indicated they preferred desiccated thyroid as their first choice of treatment, 32% preferred LT4/T3 as their first choice, and 23% preferred LT4 alone.
For the secondary endpoints of weight, general health, depression (assessed using the Beck Depression Inventory), memory (Wechsler Memory Scale), lipids, and thyroid function, again, there were no significant differences between groups in any of the measures.
When switched to desiccated thyroid, many felt ‘much better’
A further exploratory analysis revealed that those who experienced symptoms while taking LT4 alone reported greater alleviation of symptoms with the other two treatments.
“As a whole group, there was no significant difference between the three treatment arms,” Dr. Hoang explained in an interview.
“However, with the subgroup analysis based on the scores of symptom questionnaires, we found that symptomatic patients on LT4 improved while being treated with LT4/T3 or desiccated thyroid,” he said.
Reports of improvements in switching to desiccated thyroid were notable, Dr. Hoang added. “Many patients when switched from LT4 to desiccated thyroid extract said they felt much better, [with] more energy, less mental fogginess, a better outlook, less flair of lupus symptoms, easier to lose weight, etc.”
The study also showed more patients with Hashimoto’s disease preferred desiccated thyroid extract and LT4/T3, compared with LT4 alone, however, the differences were not significant.
Treatment adjustments a helpful first step
Dr. Farwell noted that his approach when patients are still reporting symptoms despite LT4 treatment is to first try tweaking the dose.
“In my own practice, I prefer to adjust LT4 dosing first, and on occasion add T3, with a goal of getting both hormone levels in the upper half of the normal range,” he said. “I find that to be a better approach than desiccated thyroid extract. T3 should be taken twice a day due to its half-life.”
The approach is generally successful, he added. “Even those that come in asking for desiccated thyroid extract whom I am able to convince to try LT4/T3 end up being happy with their treatment in the end.
“The key is that you need to spend time discussing the options with patients and come to a consensus as to the therapy that will best resolve their symptoms and that they are most comfortable with,” he concluded.
In response to mounting evidence of different hypothyroidism treatment responses according to various subgroups of patients, experts recently called for the initiation of more thorough clinical trials on the issue of combination therapy, as recently reported by this news organization.
Dr. Hoang reported being a speaker for Acella Pharmaceuticals. Dr. Farwell and Dr. Cappola reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with hypothyroidism treated with the three most common pharmacologic strategies of levothyroxine (LT4) alone, LT4 in combination with triiodothyronine (T3), or desiccated thyroid extract showed no differences in thyroid symptoms or secondary outcomes in a double-blind, randomized study.
“There are now proven good treatment options for the more than 1 in 10 patients with hypothyroidism who continue to experience symptoms of fatigue, mental fogginess, weight gain, and other symptoms despite taking levothyroxine,” first author Thanh Duc Hoang, DO, an endocrinologist at the Walter Reed National Military Medical Center, in Bethesda, Md., said in a press statement.
The findings were presented at the annual meeting of the Endocrine Society.
Commenting on the study, Alan P. Farwell, MD, said these new results are a valuable contribution to the understanding of treatment effects. “I think this is an interesting and important study and further studies are needed to clarify the optimal way to treat hypothyroidism,” said Dr. Farwell, who is director of endocrine clinics at Boston University.
Importantly, “the findings are different than studies where the patients are aware of what medication they are receiving,” he stressed in an interview, underscoring the importance of the double-blind design of the trial.
But Anne Cappola, MD, of the University of Pennsylvania, Philadelphia, pointed out that “the study was small and unlikely to have the statistical power to detect differences that could have been clinically important.”
Nevertheless, she too agreed that the double-blind study design is key: “My experience with patients is [the effects] are affected by patients’ perceptions about their thyroid medication. That is why studies designed so that patients do not know which treatment they are receiving are so important in this area.”
Randomized, double-blind comparison
Prior to the widespread availability of the current gold standard hypothyroidism treatment of LT4, the condition was typically treated with desiccated (animal) thyroid extract. And with many patients continuing to have a preference for this therapeutic approach, it is still commonly used.
Additionally, some patients treated with LT4 alone report greater improvements in symptoms with the addition of T3 – despite studies showing no benefits from the two together – leading to many clinicians commonly trying the combination approach.
To compare the efficacy of the three approaches in a prospective, double-blind, cross-over fashion, 75 patients received three therapeutic approaches each for 3 months: desiccated thyroid extract, an LT4/T3 combination, or LT4 alone.
After each 3-month treatment, patients completed a 36-point thyroid symptom questionnaire.
There was no significant differences in symptom relief, the primary outcome, between the three treatments (P = .32).
Overall, 45% of patients indicated they preferred desiccated thyroid as their first choice of treatment, 32% preferred LT4/T3 as their first choice, and 23% preferred LT4 alone.
For the secondary endpoints of weight, general health, depression (assessed using the Beck Depression Inventory), memory (Wechsler Memory Scale), lipids, and thyroid function, again, there were no significant differences between groups in any of the measures.
When switched to desiccated thyroid, many felt ‘much better’
A further exploratory analysis revealed that those who experienced symptoms while taking LT4 alone reported greater alleviation of symptoms with the other two treatments.
“As a whole group, there was no significant difference between the three treatment arms,” Dr. Hoang explained in an interview.
“However, with the subgroup analysis based on the scores of symptom questionnaires, we found that symptomatic patients on LT4 improved while being treated with LT4/T3 or desiccated thyroid,” he said.
Reports of improvements in switching to desiccated thyroid were notable, Dr. Hoang added. “Many patients when switched from LT4 to desiccated thyroid extract said they felt much better, [with] more energy, less mental fogginess, a better outlook, less flair of lupus symptoms, easier to lose weight, etc.”
The study also showed more patients with Hashimoto’s disease preferred desiccated thyroid extract and LT4/T3, compared with LT4 alone, however, the differences were not significant.
Treatment adjustments a helpful first step
Dr. Farwell noted that his approach when patients are still reporting symptoms despite LT4 treatment is to first try tweaking the dose.
“In my own practice, I prefer to adjust LT4 dosing first, and on occasion add T3, with a goal of getting both hormone levels in the upper half of the normal range,” he said. “I find that to be a better approach than desiccated thyroid extract. T3 should be taken twice a day due to its half-life.”
The approach is generally successful, he added. “Even those that come in asking for desiccated thyroid extract whom I am able to convince to try LT4/T3 end up being happy with their treatment in the end.
“The key is that you need to spend time discussing the options with patients and come to a consensus as to the therapy that will best resolve their symptoms and that they are most comfortable with,” he concluded.
In response to mounting evidence of different hypothyroidism treatment responses according to various subgroups of patients, experts recently called for the initiation of more thorough clinical trials on the issue of combination therapy, as recently reported by this news organization.
Dr. Hoang reported being a speaker for Acella Pharmaceuticals. Dr. Farwell and Dr. Cappola reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Metyrapone for Cushing’s syndrome: Safe, effective in first test
Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.
Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.
“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.
The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
Confirmation of off-label and European experience
“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.
“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.
“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.
“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.
Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.
The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).
The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.
Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.
After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.
Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.
Proper dose titration makes a difference
Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.
“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.
This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.
Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.
“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”
Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”
PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.
Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.
Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.
“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.
The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
Confirmation of off-label and European experience
“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.
“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.
“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.
“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.
Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.
The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).
The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.
Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.
After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.
Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.
Proper dose titration makes a difference
Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.
“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.
This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.
Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.
“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”
Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”
PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.
Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.
Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.
“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.
The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
Confirmation of off-label and European experience
“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.
“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.
“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.
“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.
Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.
The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).
The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.
Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.
After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.
Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.
Proper dose titration makes a difference
Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.
“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.
This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.
Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.
“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”
Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”
PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.
FROM ENDO 2021
1 in 3 on levothyroxine take meds that interfere with thyroid tests
, potentially compromising treatment decisions, new research shows.
“We know from previous studies that thyroid hormone use is common in older adults and that there are a multitude of medications that can interfere with thyroid function tests in different ways,” senior author Maria Papaleontiou, MD, told Medscape Medical News.
“However, to our knowledge, the extent of concurrent use of thyroid hormone and interfering medications in older adults, age 65 years and older, has not been previously explored,” added Dr. Papaleontiou, of the Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor.
The findings were presented as a poster during virtual ENDO 2021, the Endocrine Society’s annual meeting.
Commenting on the study, Thanh Duc Hoang, DO, an endocrinologist with the Walter Reed National Military Medical Center, in Bethesda, Md., said: “It is important for clinicians to be aware of various interactions and interferences of medications affecting the accuracy of thyroid function tests.”
“If patients are not able to discontinue the medications shortly before the bloodwork, the clinicians may consider ordering different thyroid tests or assays that avoid the interferences,” he told Medscape Medical News.
32% of patients taking meds that could interfere with tests
In evaluating data on 538,137 patients treated with thyroid hormones from the Corporate Data Warehouse of the Veterans Health Administration, spanning 2004-2017, first author Rachel Beeson, MD, and colleagues with the University of Michigan found most patients in the study were men (96.5%), White (77.1%), and had two or more comorbidities (62.6%).
Of this total, 170,261 (31.6%) patients treated with thyroid hormones, over a median follow-up of 56 months, were taking at least one drug that could potentially interfere with thyroid function tests.
Among the drugs with potential thyroid test interference, about 28% of patients were taking prednisone or prednisolone, 8% were taking amiodarone, and 1.42% were taking phenytoin. Other reported drugs that could potentially interfere included carbamazepine (0.91%), phenobarbital (0.15%), lithium (0.40%), and tamoxifen (0.11%).
Multivariate analysis showed that characteristics associated with those most likely to have concurrent medication use included non-Whites (OR, 1.18 vs Whites), Hispanic ethnicity (OR 1.11 vs non-Hispanic), female sex (OR 1.12 vs males), and presence of comorbidities (eg, Charlson-Deyo comorbidity score ≥ 2, OR, 2.47 vs score of 0).
Meanwhile, older patients age 85 years and over had a lower likelihood of concurrent medications interfering with thyroid tests (OR, 0.47 vs age 65-74 years).
The findings are concerning given the wide use of levothyroxine to treat hypothyroidism, which is the most widely prescribed drug in the United States.
“Our findings not only highlight the complexity of thyroid hormone management in older adults in the context of polypharmacy and multimorbidity, but they also draw attention to vulnerable groups for this practice, which included female patients, non-Whites, patients of Hispanic ethnicity, and patients with comorbidities,” Dr. Papaleontiou said.
Nature of interference possibilities varies
Medications or supplements can interfere with thyroid function tests in a variety of ways, she explained. “Some medications could lead to a decrease in the absorption of levothyroxine, others may affect how well the pill dissolves.”
In addition, certain medications can affect the circulation of thyroid hormone in the blood and how it binds with proteins, or they can lead to decreasing thyroid hormone levels due to a variety of interactions.
And in contrast, “What is even more challenging is that some medications or supplements may appear to affect thyroid function based on lab tests when in reality they don’t actually affect thyroid function and may lead to dose adjustments unnecessarily,” Dr. Papaleontiou noted.
Recommendations to counter interference
Current recommendations to try to counter the effects of polypharmacy on thyroid treatment include advising patients to take thyroid hormones on an empty stomach at least 30-60 minutes prior to eating for optimal absorption.
If the patient is taking medications known to interfere with absorption of thyroid hormones, the recommendation is to space those out by at least 4 hours.
“The big challenge in older adults is that many of them do experience polypharmacy, being at risk for multiple drug-drug interactions,” Dr. Papaleontiou said.
“Physicians and patients should be vigilant and communicate closely every time there is initiation of a new medication or supplement to consider whether there may be interference.”
The authors have reported no relevant financial relationships. Dr. Hoang has reported being a speaker for Acella Pharmaceuticals.
A version of this article first appeared on Medscape.com.
, potentially compromising treatment decisions, new research shows.
“We know from previous studies that thyroid hormone use is common in older adults and that there are a multitude of medications that can interfere with thyroid function tests in different ways,” senior author Maria Papaleontiou, MD, told Medscape Medical News.
“However, to our knowledge, the extent of concurrent use of thyroid hormone and interfering medications in older adults, age 65 years and older, has not been previously explored,” added Dr. Papaleontiou, of the Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor.
The findings were presented as a poster during virtual ENDO 2021, the Endocrine Society’s annual meeting.
Commenting on the study, Thanh Duc Hoang, DO, an endocrinologist with the Walter Reed National Military Medical Center, in Bethesda, Md., said: “It is important for clinicians to be aware of various interactions and interferences of medications affecting the accuracy of thyroid function tests.”
“If patients are not able to discontinue the medications shortly before the bloodwork, the clinicians may consider ordering different thyroid tests or assays that avoid the interferences,” he told Medscape Medical News.
32% of patients taking meds that could interfere with tests
In evaluating data on 538,137 patients treated with thyroid hormones from the Corporate Data Warehouse of the Veterans Health Administration, spanning 2004-2017, first author Rachel Beeson, MD, and colleagues with the University of Michigan found most patients in the study were men (96.5%), White (77.1%), and had two or more comorbidities (62.6%).
Of this total, 170,261 (31.6%) patients treated with thyroid hormones, over a median follow-up of 56 months, were taking at least one drug that could potentially interfere with thyroid function tests.
Among the drugs with potential thyroid test interference, about 28% of patients were taking prednisone or prednisolone, 8% were taking amiodarone, and 1.42% were taking phenytoin. Other reported drugs that could potentially interfere included carbamazepine (0.91%), phenobarbital (0.15%), lithium (0.40%), and tamoxifen (0.11%).
Multivariate analysis showed that characteristics associated with those most likely to have concurrent medication use included non-Whites (OR, 1.18 vs Whites), Hispanic ethnicity (OR 1.11 vs non-Hispanic), female sex (OR 1.12 vs males), and presence of comorbidities (eg, Charlson-Deyo comorbidity score ≥ 2, OR, 2.47 vs score of 0).
Meanwhile, older patients age 85 years and over had a lower likelihood of concurrent medications interfering with thyroid tests (OR, 0.47 vs age 65-74 years).
The findings are concerning given the wide use of levothyroxine to treat hypothyroidism, which is the most widely prescribed drug in the United States.
“Our findings not only highlight the complexity of thyroid hormone management in older adults in the context of polypharmacy and multimorbidity, but they also draw attention to vulnerable groups for this practice, which included female patients, non-Whites, patients of Hispanic ethnicity, and patients with comorbidities,” Dr. Papaleontiou said.
Nature of interference possibilities varies
Medications or supplements can interfere with thyroid function tests in a variety of ways, she explained. “Some medications could lead to a decrease in the absorption of levothyroxine, others may affect how well the pill dissolves.”
In addition, certain medications can affect the circulation of thyroid hormone in the blood and how it binds with proteins, or they can lead to decreasing thyroid hormone levels due to a variety of interactions.
And in contrast, “What is even more challenging is that some medications or supplements may appear to affect thyroid function based on lab tests when in reality they don’t actually affect thyroid function and may lead to dose adjustments unnecessarily,” Dr. Papaleontiou noted.
Recommendations to counter interference
Current recommendations to try to counter the effects of polypharmacy on thyroid treatment include advising patients to take thyroid hormones on an empty stomach at least 30-60 minutes prior to eating for optimal absorption.
If the patient is taking medications known to interfere with absorption of thyroid hormones, the recommendation is to space those out by at least 4 hours.
“The big challenge in older adults is that many of them do experience polypharmacy, being at risk for multiple drug-drug interactions,” Dr. Papaleontiou said.
“Physicians and patients should be vigilant and communicate closely every time there is initiation of a new medication or supplement to consider whether there may be interference.”
The authors have reported no relevant financial relationships. Dr. Hoang has reported being a speaker for Acella Pharmaceuticals.
A version of this article first appeared on Medscape.com.
, potentially compromising treatment decisions, new research shows.
“We know from previous studies that thyroid hormone use is common in older adults and that there are a multitude of medications that can interfere with thyroid function tests in different ways,” senior author Maria Papaleontiou, MD, told Medscape Medical News.
“However, to our knowledge, the extent of concurrent use of thyroid hormone and interfering medications in older adults, age 65 years and older, has not been previously explored,” added Dr. Papaleontiou, of the Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor.
The findings were presented as a poster during virtual ENDO 2021, the Endocrine Society’s annual meeting.
Commenting on the study, Thanh Duc Hoang, DO, an endocrinologist with the Walter Reed National Military Medical Center, in Bethesda, Md., said: “It is important for clinicians to be aware of various interactions and interferences of medications affecting the accuracy of thyroid function tests.”
“If patients are not able to discontinue the medications shortly before the bloodwork, the clinicians may consider ordering different thyroid tests or assays that avoid the interferences,” he told Medscape Medical News.
32% of patients taking meds that could interfere with tests
In evaluating data on 538,137 patients treated with thyroid hormones from the Corporate Data Warehouse of the Veterans Health Administration, spanning 2004-2017, first author Rachel Beeson, MD, and colleagues with the University of Michigan found most patients in the study were men (96.5%), White (77.1%), and had two or more comorbidities (62.6%).
Of this total, 170,261 (31.6%) patients treated with thyroid hormones, over a median follow-up of 56 months, were taking at least one drug that could potentially interfere with thyroid function tests.
Among the drugs with potential thyroid test interference, about 28% of patients were taking prednisone or prednisolone, 8% were taking amiodarone, and 1.42% were taking phenytoin. Other reported drugs that could potentially interfere included carbamazepine (0.91%), phenobarbital (0.15%), lithium (0.40%), and tamoxifen (0.11%).
Multivariate analysis showed that characteristics associated with those most likely to have concurrent medication use included non-Whites (OR, 1.18 vs Whites), Hispanic ethnicity (OR 1.11 vs non-Hispanic), female sex (OR 1.12 vs males), and presence of comorbidities (eg, Charlson-Deyo comorbidity score ≥ 2, OR, 2.47 vs score of 0).
Meanwhile, older patients age 85 years and over had a lower likelihood of concurrent medications interfering with thyroid tests (OR, 0.47 vs age 65-74 years).
The findings are concerning given the wide use of levothyroxine to treat hypothyroidism, which is the most widely prescribed drug in the United States.
“Our findings not only highlight the complexity of thyroid hormone management in older adults in the context of polypharmacy and multimorbidity, but they also draw attention to vulnerable groups for this practice, which included female patients, non-Whites, patients of Hispanic ethnicity, and patients with comorbidities,” Dr. Papaleontiou said.
Nature of interference possibilities varies
Medications or supplements can interfere with thyroid function tests in a variety of ways, she explained. “Some medications could lead to a decrease in the absorption of levothyroxine, others may affect how well the pill dissolves.”
In addition, certain medications can affect the circulation of thyroid hormone in the blood and how it binds with proteins, or they can lead to decreasing thyroid hormone levels due to a variety of interactions.
And in contrast, “What is even more challenging is that some medications or supplements may appear to affect thyroid function based on lab tests when in reality they don’t actually affect thyroid function and may lead to dose adjustments unnecessarily,” Dr. Papaleontiou noted.
Recommendations to counter interference
Current recommendations to try to counter the effects of polypharmacy on thyroid treatment include advising patients to take thyroid hormones on an empty stomach at least 30-60 minutes prior to eating for optimal absorption.
If the patient is taking medications known to interfere with absorption of thyroid hormones, the recommendation is to space those out by at least 4 hours.
“The big challenge in older adults is that many of them do experience polypharmacy, being at risk for multiple drug-drug interactions,” Dr. Papaleontiou said.
“Physicians and patients should be vigilant and communicate closely every time there is initiation of a new medication or supplement to consider whether there may be interference.”
The authors have reported no relevant financial relationships. Dr. Hoang has reported being a speaker for Acella Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Success in achondroplasia spurs testing vosoritide in more growth disorders
On the basis of the quality of sustained bone growth achieved with vosoritide in dwarfism, studies are underway or being considered for more diseases that impair bone growth, according to discussion that followed the presentation of a phase 3 trial extension study at the annual meeting of the Endocrine Society.
After 1 year on active therapy in the randomized trial and another year in the extension study, patients in the vosoritide group had sustained growth velocity while placebo group patients who crossed over to active therapy caught up, reported Ravi Savarirayan, MD, Murdoch Children’s Research Institute, University of Melbourne, Australia.
Moreover, the quality and type of bone growth, such as the improvement in body segment ratios over the second year of the study, support a durable benefit. Dr. Savarirayan said that improvements in activities of daily living are expected from this improvement in upper-to-lower body segment ratios, as well as the growth seen in the limbs.
Currently there is no approved pharmacologic therapy for achondroplasia in the United States. Growth hormone has been approved in Japan, but Dr. Savarirayan said its effects have been limited. Surgery such as limb lengthening is another option, but this approach is not uniformly effective and carries risks.
The 52-week results from the multinational phase 3 trial with vosoritide, which stimulates bone growth, were published last year in The Lancet. In that trial, 121 patients between the ages of 5 and 18 years with achondroplasia were randomized to vosoritide at a dose of 15 μg/kg once daily or placebo.
Relative to those in the placebo arm, which did not experience any change in growth, the median growth at the end of 52 weeks was 1.75 cm/year greater (6.71 vs. 3.99 cm).
After crossover, placebo patients catch up
In the extension study, the placebo patients were crossed over to the active therapy and both groups were followed for an additional 52 weeks. Over this period, velocity declined modestly in those in the group initially randomized to vosoritide but climbed steeply in the placebo group so that rates after 1 year were nearly identical (5.57 vs. 5.65 cm, respectively).
“The results suggest this medication may well have a durable effect,” said Dr. Savarirayan, who believes that the benefit is derived from stimulation of the growth plates. Based on the very similar efficacy observed in the placebo group once switched to active therapy, the response to vosoritide appears to be predictable.
Of the 60 patients initially randomized to vosoritide, 58 entered the extension. Of the patients who did not remain in the study, two left due to discomfort from injection-site reactions. All 61 patients initially assigned to placebo crossed over.
“We did not see any evidence of tachyphylaxis in the randomized study or in the extension,” Dr. Savarirayan said.
Although two more patients initiated on vosoritide discontinued treatment before the end of 2 years, there were no new adverse events observed. Rather, injection-site pain, which self-resolved in all patients, appears to be the most significant side effect.
“In children, the daily subcutaneous injections can be an issue,” Dr. Savarirayan acknowledged.
Injection site reactions most common adverse event
In a detailed evaluation of safety in a previously published dose-finding phase 2 study, injection-site reactions were also the most common of treatment-related adverse events, but there were no episodes of anaphylaxis or other grade 3 or higher hypersensitivity reactions (N Engl J Med. 2019 Jul 4;381:25-35).
Prior to clinical trials, continuous infusion of endogenous C-type natriuretic peptide demonstrated an ability to stimulate long-bone growth in experimental studies. Vosoritide, a recombinant analogue of C-type natriuretic peptide, appears to provide the same activity but offers a longer half-life.
Based on the benefits observed in achondroplasia, other applications are now being explored.
“When you evaluate the quality of the bone growth associated with vosoritide, it is normal,” said Melita Irving, MD, a consultant in clinical genetics at the Guy’s and St .Thomas’ NHS Trust, London. Dr. Irving has been involved in other research initiatives with this therapy and she cited a variety of evidence that has supported healthy bone development, including favorable changes in markers of bone growth such as type 10 collagen.
As a result, vosoritide, which is now under review by the U.S. Food and Drug Administration for treatment of dwarfism, is being pursued for several other diseases that result in abnormal bone growth, such as hypochondroplasia. Not least, clinical studies in idiopathic short stature have reached “early stages,” Dr. Irving said.
Dr. Savarirayan and Dr. Irving report no relevant conflicts of interest.
On the basis of the quality of sustained bone growth achieved with vosoritide in dwarfism, studies are underway or being considered for more diseases that impair bone growth, according to discussion that followed the presentation of a phase 3 trial extension study at the annual meeting of the Endocrine Society.
After 1 year on active therapy in the randomized trial and another year in the extension study, patients in the vosoritide group had sustained growth velocity while placebo group patients who crossed over to active therapy caught up, reported Ravi Savarirayan, MD, Murdoch Children’s Research Institute, University of Melbourne, Australia.
Moreover, the quality and type of bone growth, such as the improvement in body segment ratios over the second year of the study, support a durable benefit. Dr. Savarirayan said that improvements in activities of daily living are expected from this improvement in upper-to-lower body segment ratios, as well as the growth seen in the limbs.
Currently there is no approved pharmacologic therapy for achondroplasia in the United States. Growth hormone has been approved in Japan, but Dr. Savarirayan said its effects have been limited. Surgery such as limb lengthening is another option, but this approach is not uniformly effective and carries risks.
The 52-week results from the multinational phase 3 trial with vosoritide, which stimulates bone growth, were published last year in The Lancet. In that trial, 121 patients between the ages of 5 and 18 years with achondroplasia were randomized to vosoritide at a dose of 15 μg/kg once daily or placebo.
Relative to those in the placebo arm, which did not experience any change in growth, the median growth at the end of 52 weeks was 1.75 cm/year greater (6.71 vs. 3.99 cm).
After crossover, placebo patients catch up
In the extension study, the placebo patients were crossed over to the active therapy and both groups were followed for an additional 52 weeks. Over this period, velocity declined modestly in those in the group initially randomized to vosoritide but climbed steeply in the placebo group so that rates after 1 year were nearly identical (5.57 vs. 5.65 cm, respectively).
“The results suggest this medication may well have a durable effect,” said Dr. Savarirayan, who believes that the benefit is derived from stimulation of the growth plates. Based on the very similar efficacy observed in the placebo group once switched to active therapy, the response to vosoritide appears to be predictable.
Of the 60 patients initially randomized to vosoritide, 58 entered the extension. Of the patients who did not remain in the study, two left due to discomfort from injection-site reactions. All 61 patients initially assigned to placebo crossed over.
“We did not see any evidence of tachyphylaxis in the randomized study or in the extension,” Dr. Savarirayan said.
Although two more patients initiated on vosoritide discontinued treatment before the end of 2 years, there were no new adverse events observed. Rather, injection-site pain, which self-resolved in all patients, appears to be the most significant side effect.
“In children, the daily subcutaneous injections can be an issue,” Dr. Savarirayan acknowledged.
Injection site reactions most common adverse event
In a detailed evaluation of safety in a previously published dose-finding phase 2 study, injection-site reactions were also the most common of treatment-related adverse events, but there were no episodes of anaphylaxis or other grade 3 or higher hypersensitivity reactions (N Engl J Med. 2019 Jul 4;381:25-35).
Prior to clinical trials, continuous infusion of endogenous C-type natriuretic peptide demonstrated an ability to stimulate long-bone growth in experimental studies. Vosoritide, a recombinant analogue of C-type natriuretic peptide, appears to provide the same activity but offers a longer half-life.
Based on the benefits observed in achondroplasia, other applications are now being explored.
“When you evaluate the quality of the bone growth associated with vosoritide, it is normal,” said Melita Irving, MD, a consultant in clinical genetics at the Guy’s and St .Thomas’ NHS Trust, London. Dr. Irving has been involved in other research initiatives with this therapy and she cited a variety of evidence that has supported healthy bone development, including favorable changes in markers of bone growth such as type 10 collagen.
As a result, vosoritide, which is now under review by the U.S. Food and Drug Administration for treatment of dwarfism, is being pursued for several other diseases that result in abnormal bone growth, such as hypochondroplasia. Not least, clinical studies in idiopathic short stature have reached “early stages,” Dr. Irving said.
Dr. Savarirayan and Dr. Irving report no relevant conflicts of interest.
On the basis of the quality of sustained bone growth achieved with vosoritide in dwarfism, studies are underway or being considered for more diseases that impair bone growth, according to discussion that followed the presentation of a phase 3 trial extension study at the annual meeting of the Endocrine Society.
After 1 year on active therapy in the randomized trial and another year in the extension study, patients in the vosoritide group had sustained growth velocity while placebo group patients who crossed over to active therapy caught up, reported Ravi Savarirayan, MD, Murdoch Children’s Research Institute, University of Melbourne, Australia.
Moreover, the quality and type of bone growth, such as the improvement in body segment ratios over the second year of the study, support a durable benefit. Dr. Savarirayan said that improvements in activities of daily living are expected from this improvement in upper-to-lower body segment ratios, as well as the growth seen in the limbs.
Currently there is no approved pharmacologic therapy for achondroplasia in the United States. Growth hormone has been approved in Japan, but Dr. Savarirayan said its effects have been limited. Surgery such as limb lengthening is another option, but this approach is not uniformly effective and carries risks.
The 52-week results from the multinational phase 3 trial with vosoritide, which stimulates bone growth, were published last year in The Lancet. In that trial, 121 patients between the ages of 5 and 18 years with achondroplasia were randomized to vosoritide at a dose of 15 μg/kg once daily or placebo.
Relative to those in the placebo arm, which did not experience any change in growth, the median growth at the end of 52 weeks was 1.75 cm/year greater (6.71 vs. 3.99 cm).
After crossover, placebo patients catch up
In the extension study, the placebo patients were crossed over to the active therapy and both groups were followed for an additional 52 weeks. Over this period, velocity declined modestly in those in the group initially randomized to vosoritide but climbed steeply in the placebo group so that rates after 1 year were nearly identical (5.57 vs. 5.65 cm, respectively).
“The results suggest this medication may well have a durable effect,” said Dr. Savarirayan, who believes that the benefit is derived from stimulation of the growth plates. Based on the very similar efficacy observed in the placebo group once switched to active therapy, the response to vosoritide appears to be predictable.
Of the 60 patients initially randomized to vosoritide, 58 entered the extension. Of the patients who did not remain in the study, two left due to discomfort from injection-site reactions. All 61 patients initially assigned to placebo crossed over.
“We did not see any evidence of tachyphylaxis in the randomized study or in the extension,” Dr. Savarirayan said.
Although two more patients initiated on vosoritide discontinued treatment before the end of 2 years, there were no new adverse events observed. Rather, injection-site pain, which self-resolved in all patients, appears to be the most significant side effect.
“In children, the daily subcutaneous injections can be an issue,” Dr. Savarirayan acknowledged.
Injection site reactions most common adverse event
In a detailed evaluation of safety in a previously published dose-finding phase 2 study, injection-site reactions were also the most common of treatment-related adverse events, but there were no episodes of anaphylaxis or other grade 3 or higher hypersensitivity reactions (N Engl J Med. 2019 Jul 4;381:25-35).
Prior to clinical trials, continuous infusion of endogenous C-type natriuretic peptide demonstrated an ability to stimulate long-bone growth in experimental studies. Vosoritide, a recombinant analogue of C-type natriuretic peptide, appears to provide the same activity but offers a longer half-life.
Based on the benefits observed in achondroplasia, other applications are now being explored.
“When you evaluate the quality of the bone growth associated with vosoritide, it is normal,” said Melita Irving, MD, a consultant in clinical genetics at the Guy’s and St .Thomas’ NHS Trust, London. Dr. Irving has been involved in other research initiatives with this therapy and she cited a variety of evidence that has supported healthy bone development, including favorable changes in markers of bone growth such as type 10 collagen.
As a result, vosoritide, which is now under review by the U.S. Food and Drug Administration for treatment of dwarfism, is being pursued for several other diseases that result in abnormal bone growth, such as hypochondroplasia. Not least, clinical studies in idiopathic short stature have reached “early stages,” Dr. Irving said.
Dr. Savarirayan and Dr. Irving report no relevant conflicts of interest.
FROM ENDO 2021
Imaging alternative to AVS could boost detection of primary aldosteronism
A noninvasive imaging method for identifying whether the source of a patient’s primary aldosteronism is from unilateral or bilateral adrenal adenomas worked as well as the standard method, invasive adrenal vein sampling, in a head-to-head comparison with 143 patients.
This noninvasive alternative, which also does not require the substantial technical expertise that AVS demands, should make assessment of adenoma laterality in patients with primary aldosteronism (PA) much more widely available and accessible, predicted Dr. Wu, a researcher at Queen Mary University of London.
“It will allow more places to do this, and I think it will definitely allow more patients to be diagnosed” with PA from a unilateral source. AVS “is a real bottleneck,” she said. “We hope metomidate, or molecular imaging using other selective radiotracers, will enable many more patients to be diagnosed and appropriately managed.” Creating new diagnostic options for patients with PA and potentially increasing the number of these patients who are surgical candidates “is the aim of this study.”
Patients with PA develop a curable form of hypertension if their excess aldosterone can be neutralized with a mineralocorticoid receptor antagonist (MRA), or even more definitively by surgical removal of the adrenal aldosteronoma generating the hormonal excess as long as the adenoma is unilateral. Conventional imaging of the adrenals with CT or MRI has proven unreliable for identifying adrenal nodules noninvasively, which has made the invasive and technically challenging standard option of AVS the only game in town.
But some endocrinologists caution that the results from this one study do not suffice to make 11C-metomidate-based PET-CT imaging a widely used alternative.
‘This is a first step.’
“This study is a first step. It will take lots more data for endocrinologists to buy into a scan over AVS,” commented David A. D’Alessio, MD, professor and chief of the division of endocrinology and metabolism at Duke University in Durham, N.C.
But Dr. D’Alessio also acknowledged the clear benefits from a safe and effective alternative to AVS.
“A reliable, less invasive, and less technical means of lateralizing excess aldosterone production would increase the number of people [with a unilateral PA source] going to surgery. The reality is that, if you are not a patient at the Mayo Clinic . . .or the National Institutes of Health, then AVS is a bit of crap shoot” that is very operator and institution dependent for its accuracy, Dr. D’Alessio said in an interview.
Metomidate specifically binds to key enzymes of the adrenal corticosteroid biosynthetic pathway, making it a precise targeting agent for a radioactive tag as documented almost a decade ago. One limitation is that this radiotracer labeling of metomidate has a 20-minute half life, which means it must be produced on site, thereby making the technology out of reach for locations that can’t set up this capability.
MATCHing imaging against AVS
To test the clinical utility of metomidate-based PET-CT directly against AVS, Dr. Wu and her associates enrolled 143 adults with confirmed PA and hypertension at two centers in London and one in Cambridge, England. The MATCH study cohort averaged 53 years of age; two-thirds were men, 58% were White, and 30% were Black. Their median blood pressure was 147/91 mm Hg, and they were maintained on a median of two antihypertensive drugs.
The researchers assessed every patient with both the imaging method and AVS, performed in random order and blindly scored. They then began each patient on a 1-month regimen with an MRA (usually spironolactone but eplerenone [Inspra] was also an option) to test the responsiveness of each patient’s hypertension to this drug class and to gauge their likely response to adrenalectomy. After the MRA test, the researchers assessed the lateralization tests and determined that 78 patients were appropriate candidates for unilateral adrenalectomy while the remaining 65 patients were not and continued on the MRA regimen. They recommended surgery if patients were clear positives by AVS, by PET-CT imaging, or both.
The study had four primary outcomes to assess the ability of the two diagnostic methods to predict the success of surgery based on four increasingly stringent postsurgical criteria calculated in hierarchical sequence: Partial or complete biochemical success, complete biochemical success, partial or complete clinical success (partial meaning any significant reduction in blood pressure), or complete clinical success (systolic pressure reduced to less than 135 mm Hg). Only one of the 78 patients treated with surgery failed to achieve at least a partial biochemical response.
For each of the four metrics, 11C-metomidate PET-CT produced point estimates of diagnostic accuracy that consistently edged out AVS. While these advantages were not large enough to meet the prespecified threshold for proving superiority, they comfortably showed the noninferiority of this imaging method compared with AVS.
For example, the PET-CT method had 43.6% accuracy for predicting a clinical cure, compared with 39.7% accuracy for AVS. For complete biochemical cure, imaging had 68.8% accuracy, compared with 62.3% for AVS, Dr. Wu reported.
Another notable finding from the study was how strongly a robust blood pressure response to spironolactone predicted the clinical outcome from surgery. Patients whose systolic blood pressure fell below 135 mm Hg on MRA treatment had a nearly 18-fold higher rate of achieving a complete clinical cure following surgery compared with patients who did not have as dramatic a blood pressure response to MRA treatment.
Woefully low rates of PA assessment
But regardless of the success that PET-CT imaging has for identifying surgical candidates, the first step is to identify patients with PA, a diagnosis that’s woefully underperformed worldwide. One example: A separate report at ENDO 2021 retrospectively reviewed nearly 12,000 patients with hypertension and an indication of PA, such as treatment-resistant hypertension or early-onset hypertension, and managed at either of two university outpatient clinics in Michigan during 2010-2019. The report documented that 3% underwent PA assessment.
Diagnosis of patients with PA “is a major problem,” noted Dr. D’Alessio. “I think of PA as an underdiagnosed and undertreated condition, with a huge impact on morbidity and mortality. Any advance in this area is likely to be useful.” But, he added, “I’m dubious whether this [new imaging approach] will increase diagnosis of PA.” What’s needed is “getting more primary care physicians to do more screening” for PA among their patients with hypertension and a suggestion of a PA cause.
“Surgical cures are glamorous, but medical management is also very effective, and we have good, inexpensive drugs to do this,” the MRAs, Dr. D’Alessio said.
The study received no commercial funding. Dr. Wu and her coauthors had no disclosures. Dr. D’Alessio has been a speaker on behalf of Novo Nordisk, a consultant to Intarcia and Lilly, and has received research funding from Lilly and Merck.
A noninvasive imaging method for identifying whether the source of a patient’s primary aldosteronism is from unilateral or bilateral adrenal adenomas worked as well as the standard method, invasive adrenal vein sampling, in a head-to-head comparison with 143 patients.
This noninvasive alternative, which also does not require the substantial technical expertise that AVS demands, should make assessment of adenoma laterality in patients with primary aldosteronism (PA) much more widely available and accessible, predicted Dr. Wu, a researcher at Queen Mary University of London.
“It will allow more places to do this, and I think it will definitely allow more patients to be diagnosed” with PA from a unilateral source. AVS “is a real bottleneck,” she said. “We hope metomidate, or molecular imaging using other selective radiotracers, will enable many more patients to be diagnosed and appropriately managed.” Creating new diagnostic options for patients with PA and potentially increasing the number of these patients who are surgical candidates “is the aim of this study.”
Patients with PA develop a curable form of hypertension if their excess aldosterone can be neutralized with a mineralocorticoid receptor antagonist (MRA), or even more definitively by surgical removal of the adrenal aldosteronoma generating the hormonal excess as long as the adenoma is unilateral. Conventional imaging of the adrenals with CT or MRI has proven unreliable for identifying adrenal nodules noninvasively, which has made the invasive and technically challenging standard option of AVS the only game in town.
But some endocrinologists caution that the results from this one study do not suffice to make 11C-metomidate-based PET-CT imaging a widely used alternative.
‘This is a first step.’
“This study is a first step. It will take lots more data for endocrinologists to buy into a scan over AVS,” commented David A. D’Alessio, MD, professor and chief of the division of endocrinology and metabolism at Duke University in Durham, N.C.
But Dr. D’Alessio also acknowledged the clear benefits from a safe and effective alternative to AVS.
“A reliable, less invasive, and less technical means of lateralizing excess aldosterone production would increase the number of people [with a unilateral PA source] going to surgery. The reality is that, if you are not a patient at the Mayo Clinic . . .or the National Institutes of Health, then AVS is a bit of crap shoot” that is very operator and institution dependent for its accuracy, Dr. D’Alessio said in an interview.
Metomidate specifically binds to key enzymes of the adrenal corticosteroid biosynthetic pathway, making it a precise targeting agent for a radioactive tag as documented almost a decade ago. One limitation is that this radiotracer labeling of metomidate has a 20-minute half life, which means it must be produced on site, thereby making the technology out of reach for locations that can’t set up this capability.
MATCHing imaging against AVS
To test the clinical utility of metomidate-based PET-CT directly against AVS, Dr. Wu and her associates enrolled 143 adults with confirmed PA and hypertension at two centers in London and one in Cambridge, England. The MATCH study cohort averaged 53 years of age; two-thirds were men, 58% were White, and 30% were Black. Their median blood pressure was 147/91 mm Hg, and they were maintained on a median of two antihypertensive drugs.
The researchers assessed every patient with both the imaging method and AVS, performed in random order and blindly scored. They then began each patient on a 1-month regimen with an MRA (usually spironolactone but eplerenone [Inspra] was also an option) to test the responsiveness of each patient’s hypertension to this drug class and to gauge their likely response to adrenalectomy. After the MRA test, the researchers assessed the lateralization tests and determined that 78 patients were appropriate candidates for unilateral adrenalectomy while the remaining 65 patients were not and continued on the MRA regimen. They recommended surgery if patients were clear positives by AVS, by PET-CT imaging, or both.
The study had four primary outcomes to assess the ability of the two diagnostic methods to predict the success of surgery based on four increasingly stringent postsurgical criteria calculated in hierarchical sequence: Partial or complete biochemical success, complete biochemical success, partial or complete clinical success (partial meaning any significant reduction in blood pressure), or complete clinical success (systolic pressure reduced to less than 135 mm Hg). Only one of the 78 patients treated with surgery failed to achieve at least a partial biochemical response.
For each of the four metrics, 11C-metomidate PET-CT produced point estimates of diagnostic accuracy that consistently edged out AVS. While these advantages were not large enough to meet the prespecified threshold for proving superiority, they comfortably showed the noninferiority of this imaging method compared with AVS.
For example, the PET-CT method had 43.6% accuracy for predicting a clinical cure, compared with 39.7% accuracy for AVS. For complete biochemical cure, imaging had 68.8% accuracy, compared with 62.3% for AVS, Dr. Wu reported.
Another notable finding from the study was how strongly a robust blood pressure response to spironolactone predicted the clinical outcome from surgery. Patients whose systolic blood pressure fell below 135 mm Hg on MRA treatment had a nearly 18-fold higher rate of achieving a complete clinical cure following surgery compared with patients who did not have as dramatic a blood pressure response to MRA treatment.
Woefully low rates of PA assessment
But regardless of the success that PET-CT imaging has for identifying surgical candidates, the first step is to identify patients with PA, a diagnosis that’s woefully underperformed worldwide. One example: A separate report at ENDO 2021 retrospectively reviewed nearly 12,000 patients with hypertension and an indication of PA, such as treatment-resistant hypertension or early-onset hypertension, and managed at either of two university outpatient clinics in Michigan during 2010-2019. The report documented that 3% underwent PA assessment.
Diagnosis of patients with PA “is a major problem,” noted Dr. D’Alessio. “I think of PA as an underdiagnosed and undertreated condition, with a huge impact on morbidity and mortality. Any advance in this area is likely to be useful.” But, he added, “I’m dubious whether this [new imaging approach] will increase diagnosis of PA.” What’s needed is “getting more primary care physicians to do more screening” for PA among their patients with hypertension and a suggestion of a PA cause.
“Surgical cures are glamorous, but medical management is also very effective, and we have good, inexpensive drugs to do this,” the MRAs, Dr. D’Alessio said.
The study received no commercial funding. Dr. Wu and her coauthors had no disclosures. Dr. D’Alessio has been a speaker on behalf of Novo Nordisk, a consultant to Intarcia and Lilly, and has received research funding from Lilly and Merck.
A noninvasive imaging method for identifying whether the source of a patient’s primary aldosteronism is from unilateral or bilateral adrenal adenomas worked as well as the standard method, invasive adrenal vein sampling, in a head-to-head comparison with 143 patients.
This noninvasive alternative, which also does not require the substantial technical expertise that AVS demands, should make assessment of adenoma laterality in patients with primary aldosteronism (PA) much more widely available and accessible, predicted Dr. Wu, a researcher at Queen Mary University of London.
“It will allow more places to do this, and I think it will definitely allow more patients to be diagnosed” with PA from a unilateral source. AVS “is a real bottleneck,” she said. “We hope metomidate, or molecular imaging using other selective radiotracers, will enable many more patients to be diagnosed and appropriately managed.” Creating new diagnostic options for patients with PA and potentially increasing the number of these patients who are surgical candidates “is the aim of this study.”
Patients with PA develop a curable form of hypertension if their excess aldosterone can be neutralized with a mineralocorticoid receptor antagonist (MRA), or even more definitively by surgical removal of the adrenal aldosteronoma generating the hormonal excess as long as the adenoma is unilateral. Conventional imaging of the adrenals with CT or MRI has proven unreliable for identifying adrenal nodules noninvasively, which has made the invasive and technically challenging standard option of AVS the only game in town.
But some endocrinologists caution that the results from this one study do not suffice to make 11C-metomidate-based PET-CT imaging a widely used alternative.
‘This is a first step.’
“This study is a first step. It will take lots more data for endocrinologists to buy into a scan over AVS,” commented David A. D’Alessio, MD, professor and chief of the division of endocrinology and metabolism at Duke University in Durham, N.C.
But Dr. D’Alessio also acknowledged the clear benefits from a safe and effective alternative to AVS.
“A reliable, less invasive, and less technical means of lateralizing excess aldosterone production would increase the number of people [with a unilateral PA source] going to surgery. The reality is that, if you are not a patient at the Mayo Clinic . . .or the National Institutes of Health, then AVS is a bit of crap shoot” that is very operator and institution dependent for its accuracy, Dr. D’Alessio said in an interview.
Metomidate specifically binds to key enzymes of the adrenal corticosteroid biosynthetic pathway, making it a precise targeting agent for a radioactive tag as documented almost a decade ago. One limitation is that this radiotracer labeling of metomidate has a 20-minute half life, which means it must be produced on site, thereby making the technology out of reach for locations that can’t set up this capability.
MATCHing imaging against AVS
To test the clinical utility of metomidate-based PET-CT directly against AVS, Dr. Wu and her associates enrolled 143 adults with confirmed PA and hypertension at two centers in London and one in Cambridge, England. The MATCH study cohort averaged 53 years of age; two-thirds were men, 58% were White, and 30% were Black. Their median blood pressure was 147/91 mm Hg, and they were maintained on a median of two antihypertensive drugs.
The researchers assessed every patient with both the imaging method and AVS, performed in random order and blindly scored. They then began each patient on a 1-month regimen with an MRA (usually spironolactone but eplerenone [Inspra] was also an option) to test the responsiveness of each patient’s hypertension to this drug class and to gauge their likely response to adrenalectomy. After the MRA test, the researchers assessed the lateralization tests and determined that 78 patients were appropriate candidates for unilateral adrenalectomy while the remaining 65 patients were not and continued on the MRA regimen. They recommended surgery if patients were clear positives by AVS, by PET-CT imaging, or both.
The study had four primary outcomes to assess the ability of the two diagnostic methods to predict the success of surgery based on four increasingly stringent postsurgical criteria calculated in hierarchical sequence: Partial or complete biochemical success, complete biochemical success, partial or complete clinical success (partial meaning any significant reduction in blood pressure), or complete clinical success (systolic pressure reduced to less than 135 mm Hg). Only one of the 78 patients treated with surgery failed to achieve at least a partial biochemical response.
For each of the four metrics, 11C-metomidate PET-CT produced point estimates of diagnostic accuracy that consistently edged out AVS. While these advantages were not large enough to meet the prespecified threshold for proving superiority, they comfortably showed the noninferiority of this imaging method compared with AVS.
For example, the PET-CT method had 43.6% accuracy for predicting a clinical cure, compared with 39.7% accuracy for AVS. For complete biochemical cure, imaging had 68.8% accuracy, compared with 62.3% for AVS, Dr. Wu reported.
Another notable finding from the study was how strongly a robust blood pressure response to spironolactone predicted the clinical outcome from surgery. Patients whose systolic blood pressure fell below 135 mm Hg on MRA treatment had a nearly 18-fold higher rate of achieving a complete clinical cure following surgery compared with patients who did not have as dramatic a blood pressure response to MRA treatment.
Woefully low rates of PA assessment
But regardless of the success that PET-CT imaging has for identifying surgical candidates, the first step is to identify patients with PA, a diagnosis that’s woefully underperformed worldwide. One example: A separate report at ENDO 2021 retrospectively reviewed nearly 12,000 patients with hypertension and an indication of PA, such as treatment-resistant hypertension or early-onset hypertension, and managed at either of two university outpatient clinics in Michigan during 2010-2019. The report documented that 3% underwent PA assessment.
Diagnosis of patients with PA “is a major problem,” noted Dr. D’Alessio. “I think of PA as an underdiagnosed and undertreated condition, with a huge impact on morbidity and mortality. Any advance in this area is likely to be useful.” But, he added, “I’m dubious whether this [new imaging approach] will increase diagnosis of PA.” What’s needed is “getting more primary care physicians to do more screening” for PA among their patients with hypertension and a suggestion of a PA cause.
“Surgical cures are glamorous, but medical management is also very effective, and we have good, inexpensive drugs to do this,” the MRAs, Dr. D’Alessio said.
The study received no commercial funding. Dr. Wu and her coauthors had no disclosures. Dr. D’Alessio has been a speaker on behalf of Novo Nordisk, a consultant to Intarcia and Lilly, and has received research funding from Lilly and Merck.
FROM ENDO 2021
Inpatient sodium imbalances linked to adverse COVID-19 outcomes
Both high and low serum sodium levels are associated with adverse outcomes for hospitalized patients with COVID-19, new research suggests.
In the retrospective study of 488 patients hospitalized with COVID-19 at one of two London hospitals between February and May 2020, hypernatremia (defined as serum sodium level >145 mmol/L) at any time point during hospital stay was associated with a threefold increase in inpatient mortality.
Hyponatremia (serum sodium level <135 mmol/L) was associated with twice the likelihood of requiring advanced ventilatory support. In-hospital mortality was also increased among patients with hypovolemic hyponatremia.
“Serum sodium values could be used in clinical practice to identify patients with COVID-19 at high risk of poor outcomes who would benefit from more intensive monitoring and judicious rehydration,” Ploutarchos Tzoulis, MD, PhD, and colleagues wrote in their article, which was published online on Feb. 24, 2021, in the Journal of Clinical Endocrinology and Metabolism.
The findings will be presented at the upcoming news conference held by the Endocrine Society
Should sodium be included in a risk calculator for COVID-19?
Dr. Tzoulis, professor of endocrinology at the University College London Medical School, said in an interview that “sodium could be incorporated in risk calculators across other routine biomarkers, such as white cell count, lymphocytes, and CRP [C-reactive protein], in order to provide a tool for dynamic risk stratification throughout the clinical course of COVID-19 and assist clinical decision-making.”
Moreover, he said, “we should follow less conservative strategies in the rate and amount of fluid resuscitation in order to prevent hypernatremia, which is induced by negative fluid balance and can often be iatrogenic.”
Asked to comment, Steven Q. Simpson, MD, professor of medicine in the division of pulmonary, critical care, and sleep medicine at the University of Kansas, Kansas City, said that the article is missing key results that would assist in interpreting of the findings.
“Data regarding diuretic use and sparing of fluid administration are not in the paper. ... It is simply not possible to tell whether serum sodium is a ‘predictor’ ... or if it is a side effect of other issues or actions taken by physicians in patients who are progressing poorly.
“To say that sodium needs to be included in a risk calculator is to subtly suggest that there is some causal association with mortality, and that has quite clearly not been established,” stressed Dr. Simpson, who is president of the American College of Chest Physicians but was not speaking for the organization.
He added: “The data are interesting, but not actionable. It is common practice in critical care medicine to adjust water and salt intake to maintain serum sodium within the normal range, so the paper really doesn’t change any behavior.”
Dr. Tzoulis said in an interview that, despite not having electronic medical record data on diuretic use or fluid input and output, “our acute physicians and intensivists at both study sites have been adamant that they’ve not routinely used diuretics in COVID-19 patients. Diuretics have been sparingly used in our cohort, and also the frequency of pulmonary edema was reported as below 5%.”
Regarding volume of fluid intake, Dr. Tzoulis noted, “At our hospital sites, the strategy has been that of cautious fluid resuscitation. In fact, the amount of fluid given has been reported by our physicians and intensivists as ‘on purpose much more conservative than the usual one adopted in patients with community-acquired pneumonia at risk of respiratory failure.’ ”
Hyper- and hyponatremia linked to adverse COVID-19 outcomes
In the study, 5.3% of the 488 patients had hypernatremia at hospital presentation, and 24.6% had hyponatremia. Of note, only 19% of those with hyponatremia underwent laboratory workup to determine the etiology. Of those, three quarters had hypovolemic hyponatremia, determined on the basis of a urinary sodium cutoff of 30 mmol/L.
The total in-hospital mortality rate was 31.1%. There was a strong, although nonsignificant, trend toward higher mortality in association with sodium status at admission. Death rates were 28.4%, 30.8%, and 46.1% for those who were normonatremic, hyponatremic, and hypernatremic, respectively (P = .07). Baseline serum sodium levels didn’t differ between survivors (137 mmol/L) and nonsurvivors (138 mmol/L).
In multivariable analysis, the occurrence of hypernatremia at any point during the first 5 days in the hospital was among three independent risk factors for higher in-hospital mortality (adjusted hazard ratio, 2.74; P = .02). The other risk factors were older age and higher CRP level.
Overall, hyponatremia was not associated with death (P = .41).
During hospitalization, 37.9% of patients remained normonatremic; 36.9% experienced hyponatremia; 10.9% had hypernatremia; and 14.3% had both conditions at some point during their stay.
In-hospital mortality was 21% among those with normonatremia, compared with 56.6% for those with hypernatremia (odds ratio, 3.05; P = .0038) and 45.7% for those with both (OR, 2.25; P < .0001).
The 28.3% mortality rate in the overall group that experienced hyponatremia didn’t differ significantly from the 21.1% in the normonatremic group (OR, 1.34; P = .16). However, the death rate was 40.9% among the subgroup that developed hypovolemic hyponatremia, significantly higher than the normonatremic group (OR, 2.59, P = .0017).
The incidence of hyponatremia decreased from 24.6% at admission to 14.1% 5 days later, whereas the frequency of hypernatremia rose from 5.3% to 13.8%.
Key finding: Link between hospital-acquired hypernatremia and death
“The key novel finding of our study was that hospital-acquired hypernatremia, rather than hypernatremia at admission, was a predictor for in-hospital mortality, with the worst prognosis being reported in patients with the largest increase in serum sodium in the first 5 days of hospitalization,” noted Dr. Tzoulis and colleagues.
Hypernatremia was present in 29.6% of nonsurvivors, compared with 5.2% in survivors.
Among 120 patients with hyponatremia at admission, 31.7% received advanced respiratory support, compared with 17.5% and 7.7% of those with normonatremia or hypernatremia, respectively (OR, 2.18; P = .0011).
In contrast, there was no difference in the proportions needing ventilatory support between those with hypernatremia and those with normonatremia (16.7% vs. 12.4%; OR, 1.44; P = .39).
Acute kidney injury occurred in 181 patients (37.1%). It was not related to serum sodium concentration at any time point.
Dr. Tzoulis and Dr. Simpson disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Both high and low serum sodium levels are associated with adverse outcomes for hospitalized patients with COVID-19, new research suggests.
In the retrospective study of 488 patients hospitalized with COVID-19 at one of two London hospitals between February and May 2020, hypernatremia (defined as serum sodium level >145 mmol/L) at any time point during hospital stay was associated with a threefold increase in inpatient mortality.
Hyponatremia (serum sodium level <135 mmol/L) was associated with twice the likelihood of requiring advanced ventilatory support. In-hospital mortality was also increased among patients with hypovolemic hyponatremia.
“Serum sodium values could be used in clinical practice to identify patients with COVID-19 at high risk of poor outcomes who would benefit from more intensive monitoring and judicious rehydration,” Ploutarchos Tzoulis, MD, PhD, and colleagues wrote in their article, which was published online on Feb. 24, 2021, in the Journal of Clinical Endocrinology and Metabolism.
The findings will be presented at the upcoming news conference held by the Endocrine Society
Should sodium be included in a risk calculator for COVID-19?
Dr. Tzoulis, professor of endocrinology at the University College London Medical School, said in an interview that “sodium could be incorporated in risk calculators across other routine biomarkers, such as white cell count, lymphocytes, and CRP [C-reactive protein], in order to provide a tool for dynamic risk stratification throughout the clinical course of COVID-19 and assist clinical decision-making.”
Moreover, he said, “we should follow less conservative strategies in the rate and amount of fluid resuscitation in order to prevent hypernatremia, which is induced by negative fluid balance and can often be iatrogenic.”
Asked to comment, Steven Q. Simpson, MD, professor of medicine in the division of pulmonary, critical care, and sleep medicine at the University of Kansas, Kansas City, said that the article is missing key results that would assist in interpreting of the findings.
“Data regarding diuretic use and sparing of fluid administration are not in the paper. ... It is simply not possible to tell whether serum sodium is a ‘predictor’ ... or if it is a side effect of other issues or actions taken by physicians in patients who are progressing poorly.
“To say that sodium needs to be included in a risk calculator is to subtly suggest that there is some causal association with mortality, and that has quite clearly not been established,” stressed Dr. Simpson, who is president of the American College of Chest Physicians but was not speaking for the organization.
He added: “The data are interesting, but not actionable. It is common practice in critical care medicine to adjust water and salt intake to maintain serum sodium within the normal range, so the paper really doesn’t change any behavior.”
Dr. Tzoulis said in an interview that, despite not having electronic medical record data on diuretic use or fluid input and output, “our acute physicians and intensivists at both study sites have been adamant that they’ve not routinely used diuretics in COVID-19 patients. Diuretics have been sparingly used in our cohort, and also the frequency of pulmonary edema was reported as below 5%.”
Regarding volume of fluid intake, Dr. Tzoulis noted, “At our hospital sites, the strategy has been that of cautious fluid resuscitation. In fact, the amount of fluid given has been reported by our physicians and intensivists as ‘on purpose much more conservative than the usual one adopted in patients with community-acquired pneumonia at risk of respiratory failure.’ ”
Hyper- and hyponatremia linked to adverse COVID-19 outcomes
In the study, 5.3% of the 488 patients had hypernatremia at hospital presentation, and 24.6% had hyponatremia. Of note, only 19% of those with hyponatremia underwent laboratory workup to determine the etiology. Of those, three quarters had hypovolemic hyponatremia, determined on the basis of a urinary sodium cutoff of 30 mmol/L.
The total in-hospital mortality rate was 31.1%. There was a strong, although nonsignificant, trend toward higher mortality in association with sodium status at admission. Death rates were 28.4%, 30.8%, and 46.1% for those who were normonatremic, hyponatremic, and hypernatremic, respectively (P = .07). Baseline serum sodium levels didn’t differ between survivors (137 mmol/L) and nonsurvivors (138 mmol/L).
In multivariable analysis, the occurrence of hypernatremia at any point during the first 5 days in the hospital was among three independent risk factors for higher in-hospital mortality (adjusted hazard ratio, 2.74; P = .02). The other risk factors were older age and higher CRP level.
Overall, hyponatremia was not associated with death (P = .41).
During hospitalization, 37.9% of patients remained normonatremic; 36.9% experienced hyponatremia; 10.9% had hypernatremia; and 14.3% had both conditions at some point during their stay.
In-hospital mortality was 21% among those with normonatremia, compared with 56.6% for those with hypernatremia (odds ratio, 3.05; P = .0038) and 45.7% for those with both (OR, 2.25; P < .0001).
The 28.3% mortality rate in the overall group that experienced hyponatremia didn’t differ significantly from the 21.1% in the normonatremic group (OR, 1.34; P = .16). However, the death rate was 40.9% among the subgroup that developed hypovolemic hyponatremia, significantly higher than the normonatremic group (OR, 2.59, P = .0017).
The incidence of hyponatremia decreased from 24.6% at admission to 14.1% 5 days later, whereas the frequency of hypernatremia rose from 5.3% to 13.8%.
Key finding: Link between hospital-acquired hypernatremia and death
“The key novel finding of our study was that hospital-acquired hypernatremia, rather than hypernatremia at admission, was a predictor for in-hospital mortality, with the worst prognosis being reported in patients with the largest increase in serum sodium in the first 5 days of hospitalization,” noted Dr. Tzoulis and colleagues.
Hypernatremia was present in 29.6% of nonsurvivors, compared with 5.2% in survivors.
Among 120 patients with hyponatremia at admission, 31.7% received advanced respiratory support, compared with 17.5% and 7.7% of those with normonatremia or hypernatremia, respectively (OR, 2.18; P = .0011).
In contrast, there was no difference in the proportions needing ventilatory support between those with hypernatremia and those with normonatremia (16.7% vs. 12.4%; OR, 1.44; P = .39).
Acute kidney injury occurred in 181 patients (37.1%). It was not related to serum sodium concentration at any time point.
Dr. Tzoulis and Dr. Simpson disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Both high and low serum sodium levels are associated with adverse outcomes for hospitalized patients with COVID-19, new research suggests.
In the retrospective study of 488 patients hospitalized with COVID-19 at one of two London hospitals between February and May 2020, hypernatremia (defined as serum sodium level >145 mmol/L) at any time point during hospital stay was associated with a threefold increase in inpatient mortality.
Hyponatremia (serum sodium level <135 mmol/L) was associated with twice the likelihood of requiring advanced ventilatory support. In-hospital mortality was also increased among patients with hypovolemic hyponatremia.
“Serum sodium values could be used in clinical practice to identify patients with COVID-19 at high risk of poor outcomes who would benefit from more intensive monitoring and judicious rehydration,” Ploutarchos Tzoulis, MD, PhD, and colleagues wrote in their article, which was published online on Feb. 24, 2021, in the Journal of Clinical Endocrinology and Metabolism.
The findings will be presented at the upcoming news conference held by the Endocrine Society
Should sodium be included in a risk calculator for COVID-19?
Dr. Tzoulis, professor of endocrinology at the University College London Medical School, said in an interview that “sodium could be incorporated in risk calculators across other routine biomarkers, such as white cell count, lymphocytes, and CRP [C-reactive protein], in order to provide a tool for dynamic risk stratification throughout the clinical course of COVID-19 and assist clinical decision-making.”
Moreover, he said, “we should follow less conservative strategies in the rate and amount of fluid resuscitation in order to prevent hypernatremia, which is induced by negative fluid balance and can often be iatrogenic.”
Asked to comment, Steven Q. Simpson, MD, professor of medicine in the division of pulmonary, critical care, and sleep medicine at the University of Kansas, Kansas City, said that the article is missing key results that would assist in interpreting of the findings.
“Data regarding diuretic use and sparing of fluid administration are not in the paper. ... It is simply not possible to tell whether serum sodium is a ‘predictor’ ... or if it is a side effect of other issues or actions taken by physicians in patients who are progressing poorly.
“To say that sodium needs to be included in a risk calculator is to subtly suggest that there is some causal association with mortality, and that has quite clearly not been established,” stressed Dr. Simpson, who is president of the American College of Chest Physicians but was not speaking for the organization.
He added: “The data are interesting, but not actionable. It is common practice in critical care medicine to adjust water and salt intake to maintain serum sodium within the normal range, so the paper really doesn’t change any behavior.”
Dr. Tzoulis said in an interview that, despite not having electronic medical record data on diuretic use or fluid input and output, “our acute physicians and intensivists at both study sites have been adamant that they’ve not routinely used diuretics in COVID-19 patients. Diuretics have been sparingly used in our cohort, and also the frequency of pulmonary edema was reported as below 5%.”
Regarding volume of fluid intake, Dr. Tzoulis noted, “At our hospital sites, the strategy has been that of cautious fluid resuscitation. In fact, the amount of fluid given has been reported by our physicians and intensivists as ‘on purpose much more conservative than the usual one adopted in patients with community-acquired pneumonia at risk of respiratory failure.’ ”
Hyper- and hyponatremia linked to adverse COVID-19 outcomes
In the study, 5.3% of the 488 patients had hypernatremia at hospital presentation, and 24.6% had hyponatremia. Of note, only 19% of those with hyponatremia underwent laboratory workup to determine the etiology. Of those, three quarters had hypovolemic hyponatremia, determined on the basis of a urinary sodium cutoff of 30 mmol/L.
The total in-hospital mortality rate was 31.1%. There was a strong, although nonsignificant, trend toward higher mortality in association with sodium status at admission. Death rates were 28.4%, 30.8%, and 46.1% for those who were normonatremic, hyponatremic, and hypernatremic, respectively (P = .07). Baseline serum sodium levels didn’t differ between survivors (137 mmol/L) and nonsurvivors (138 mmol/L).
In multivariable analysis, the occurrence of hypernatremia at any point during the first 5 days in the hospital was among three independent risk factors for higher in-hospital mortality (adjusted hazard ratio, 2.74; P = .02). The other risk factors were older age and higher CRP level.
Overall, hyponatremia was not associated with death (P = .41).
During hospitalization, 37.9% of patients remained normonatremic; 36.9% experienced hyponatremia; 10.9% had hypernatremia; and 14.3% had both conditions at some point during their stay.
In-hospital mortality was 21% among those with normonatremia, compared with 56.6% for those with hypernatremia (odds ratio, 3.05; P = .0038) and 45.7% for those with both (OR, 2.25; P < .0001).
The 28.3% mortality rate in the overall group that experienced hyponatremia didn’t differ significantly from the 21.1% in the normonatremic group (OR, 1.34; P = .16). However, the death rate was 40.9% among the subgroup that developed hypovolemic hyponatremia, significantly higher than the normonatremic group (OR, 2.59, P = .0017).
The incidence of hyponatremia decreased from 24.6% at admission to 14.1% 5 days later, whereas the frequency of hypernatremia rose from 5.3% to 13.8%.
Key finding: Link between hospital-acquired hypernatremia and death
“The key novel finding of our study was that hospital-acquired hypernatremia, rather than hypernatremia at admission, was a predictor for in-hospital mortality, with the worst prognosis being reported in patients with the largest increase in serum sodium in the first 5 days of hospitalization,” noted Dr. Tzoulis and colleagues.
Hypernatremia was present in 29.6% of nonsurvivors, compared with 5.2% in survivors.
Among 120 patients with hyponatremia at admission, 31.7% received advanced respiratory support, compared with 17.5% and 7.7% of those with normonatremia or hypernatremia, respectively (OR, 2.18; P = .0011).
In contrast, there was no difference in the proportions needing ventilatory support between those with hypernatremia and those with normonatremia (16.7% vs. 12.4%; OR, 1.44; P = .39).
Acute kidney injury occurred in 181 patients (37.1%). It was not related to serum sodium concentration at any time point.
Dr. Tzoulis and Dr. Simpson disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A third discontinuing levothyroxine have normal thyroid levels
Approximately a third of patients treated for hypothyroidism continue to maintain normal thyroid levels after discontinuing thyroid hormone replacement therapy.
Those who were treated for overt hypothyroidism were less likely to maintain normal hormone levels than those with subclinical disease, the new meta-analysis shows.
“This analysis is the first to summarize the limited evidence regarding successful thyroid hormone discontinuation, but unfortunately more research is needed to develop an evidenced-based strategy for deprescribing thyroid hormone replacement,” Nydia Burgos, MD, and colleagues write in their article published online in Thyroid.
Nevertheless, the main findings were somewhat surprising, Dr. Burgos of the division of endocrinology, diabetes and metabolism, University of Puerto Rico, told this news organization.
“I expected that a considerable portion of patients would remain euthyroid, but up to a third of patients was an impressive number,” she said.
The finding could be an indicator of people who may not have had much benefit from the treatment in the first place, she noted.
“The truth of the matter is that levothyroxine (LT4) is among the top-prescribed drugs in the United States, and every day in clinics we encounter patients that were started on thyroid hormone replacement therapy for unclear reasons, as a therapeutic trial that was never reassessed, or as treatment for subclinical hypothyroidism without having convincing criteria for treatment,” she observed.
Meta-analysis of 17 studies examining LT4 discontinuation
Known to be highly effective in the treatment of overt hypothyroidism, LT4 is often prescribed long term; however, it is also commonly prescribed for patients with subclinical hypothyroidism, despite research suggesting no benefits in these patients.
With a guideline panel underscoring the lack of evidence and issuing a “strong recommendation” in May 2019 against treatment with thyroid hormones in adults with subclinical hypothyroidism (elevated thyroid-stimulating hormone [TSH] levels and normal free T4 levels), clinicians may increasingly be considering discontinuation strategies.
To examine the evidence to date on the clinical outcomes of discontinuing LT4, Dr. Burgos and colleagues conducted a meta-analysis in which they identified 17 observational studies that met the inclusion criteria. Of a total of 1,103 patients in the studies, 86% were women. Most studies included only adults.
With a median follow-up of 5 years, the pooled estimate of patients maintaining euthyroidism after treatment discontinuation was 37.2%.
The estimated rate of remaining euthyroid was significantly lower among those with overt hypothyroidism (11.8%) compared with those with subclinical hypothyroidism (35.6%).
Meanwhile, as many as 65.8% of patients ended up restarting thyroid hormone treatment during the follow-up period, according to pooled estimates, and the rate was as high as 87.2% in patients with overt hypothyroidism. The mean increase in TSH from time of LT4 discontinuation to follow-up was 9.4 mIU/L.
Among specific factors shown to be linked to a lower likelihood of euthyroidism at follow-up were inconsistent echogenicity on thyroid ultrasound, elevated TSH (8-9 mIU/L), and the presence of thyroid antibodies.
Only a few of the studies evaluated thyroid hormones other than synthetic LT4 (such as the commonly used desiccated thyroid), and so the analysis did not compare differences between therapies, Dr. Burgos noted.
Despite the lack of evidence of benefits of LT4 treatment for subclinical hypothyroidism, the finding that, even among those patients, approximately two-thirds were not euthyroid at follow-up was not unexpected, she added.
“I am not surprised that, even in the subclinical hypothyroidism group about two-thirds of participants were not euthyroid, because when looking at the natural history of subclinical hypothyroidism in other studies, only a fifth had normalized thyroid hormone tests, while the majority continue with mild subclinical hypothyroidism and a fifth progress to overt hypothyroidism,” she explained.
More work needed to determine best way to taper down LT4
The specific regimens for discontinuing LT4 were detailed in only three studies and reflected varying approaches, ranging from tapering down the dose over 2 weeks to reducing the dose over several more weeks, or even months, Dr. Burgos noted
“We need more studies to figure out which tapering regimen will promote a more favorable outcome,” she said.
“The ideal regimen will be one in which patients can comply with follow-up visits and have thyroid function testing done before symptoms of hypothyroidism develop.”
In addition to likely offering no benefit to people with subclinical hypothyroidism, other reasons for discontinuing LT4 in patients who are considered appropriate candidates include concerns about side effects in older patients.
The authors say there is evidence indicating that as many as 50% of patients older than 65 who take thyroid hormones develop iatrogenic hyperthyroidism, which can have detrimental effects including an increased risk for cardiac arrhythmias, angina pectoris, bone loss, and fractures.
Collaborative approach to ‘deprescribing’ suggested
To get patients off LT4, the authors suggest a collaborative approach of “deprescribing,” whereby the health care professional supervises with a goal of managing polypharmacy and improving outcomes.
“This systematic process starts with an accurate evaluation of the medication list, followed by identification of potentially inappropriate medications, collaboration between patients and clinicians to decide whether deprescribing would be appropriate, and establishing a supportive plan to safely deprescribe the medication,” they write.
When decision-making is shared, patients are more likely to consider discontinuation if they understand why the medication is inappropriate, have their concerns related to the discontinuation addressed, understand the process, and feel that they have the support of the clinical team, the authors conclude.
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Approximately a third of patients treated for hypothyroidism continue to maintain normal thyroid levels after discontinuing thyroid hormone replacement therapy.
Those who were treated for overt hypothyroidism were less likely to maintain normal hormone levels than those with subclinical disease, the new meta-analysis shows.
“This analysis is the first to summarize the limited evidence regarding successful thyroid hormone discontinuation, but unfortunately more research is needed to develop an evidenced-based strategy for deprescribing thyroid hormone replacement,” Nydia Burgos, MD, and colleagues write in their article published online in Thyroid.
Nevertheless, the main findings were somewhat surprising, Dr. Burgos of the division of endocrinology, diabetes and metabolism, University of Puerto Rico, told this news organization.
“I expected that a considerable portion of patients would remain euthyroid, but up to a third of patients was an impressive number,” she said.
The finding could be an indicator of people who may not have had much benefit from the treatment in the first place, she noted.
“The truth of the matter is that levothyroxine (LT4) is among the top-prescribed drugs in the United States, and every day in clinics we encounter patients that were started on thyroid hormone replacement therapy for unclear reasons, as a therapeutic trial that was never reassessed, or as treatment for subclinical hypothyroidism without having convincing criteria for treatment,” she observed.
Meta-analysis of 17 studies examining LT4 discontinuation
Known to be highly effective in the treatment of overt hypothyroidism, LT4 is often prescribed long term; however, it is also commonly prescribed for patients with subclinical hypothyroidism, despite research suggesting no benefits in these patients.
With a guideline panel underscoring the lack of evidence and issuing a “strong recommendation” in May 2019 against treatment with thyroid hormones in adults with subclinical hypothyroidism (elevated thyroid-stimulating hormone [TSH] levels and normal free T4 levels), clinicians may increasingly be considering discontinuation strategies.
To examine the evidence to date on the clinical outcomes of discontinuing LT4, Dr. Burgos and colleagues conducted a meta-analysis in which they identified 17 observational studies that met the inclusion criteria. Of a total of 1,103 patients in the studies, 86% were women. Most studies included only adults.
With a median follow-up of 5 years, the pooled estimate of patients maintaining euthyroidism after treatment discontinuation was 37.2%.
The estimated rate of remaining euthyroid was significantly lower among those with overt hypothyroidism (11.8%) compared with those with subclinical hypothyroidism (35.6%).
Meanwhile, as many as 65.8% of patients ended up restarting thyroid hormone treatment during the follow-up period, according to pooled estimates, and the rate was as high as 87.2% in patients with overt hypothyroidism. The mean increase in TSH from time of LT4 discontinuation to follow-up was 9.4 mIU/L.
Among specific factors shown to be linked to a lower likelihood of euthyroidism at follow-up were inconsistent echogenicity on thyroid ultrasound, elevated TSH (8-9 mIU/L), and the presence of thyroid antibodies.
Only a few of the studies evaluated thyroid hormones other than synthetic LT4 (such as the commonly used desiccated thyroid), and so the analysis did not compare differences between therapies, Dr. Burgos noted.
Despite the lack of evidence of benefits of LT4 treatment for subclinical hypothyroidism, the finding that, even among those patients, approximately two-thirds were not euthyroid at follow-up was not unexpected, she added.
“I am not surprised that, even in the subclinical hypothyroidism group about two-thirds of participants were not euthyroid, because when looking at the natural history of subclinical hypothyroidism in other studies, only a fifth had normalized thyroid hormone tests, while the majority continue with mild subclinical hypothyroidism and a fifth progress to overt hypothyroidism,” she explained.
More work needed to determine best way to taper down LT4
The specific regimens for discontinuing LT4 were detailed in only three studies and reflected varying approaches, ranging from tapering down the dose over 2 weeks to reducing the dose over several more weeks, or even months, Dr. Burgos noted
“We need more studies to figure out which tapering regimen will promote a more favorable outcome,” she said.
“The ideal regimen will be one in which patients can comply with follow-up visits and have thyroid function testing done before symptoms of hypothyroidism develop.”
In addition to likely offering no benefit to people with subclinical hypothyroidism, other reasons for discontinuing LT4 in patients who are considered appropriate candidates include concerns about side effects in older patients.
The authors say there is evidence indicating that as many as 50% of patients older than 65 who take thyroid hormones develop iatrogenic hyperthyroidism, which can have detrimental effects including an increased risk for cardiac arrhythmias, angina pectoris, bone loss, and fractures.
Collaborative approach to ‘deprescribing’ suggested
To get patients off LT4, the authors suggest a collaborative approach of “deprescribing,” whereby the health care professional supervises with a goal of managing polypharmacy and improving outcomes.
“This systematic process starts with an accurate evaluation of the medication list, followed by identification of potentially inappropriate medications, collaboration between patients and clinicians to decide whether deprescribing would be appropriate, and establishing a supportive plan to safely deprescribe the medication,” they write.
When decision-making is shared, patients are more likely to consider discontinuation if they understand why the medication is inappropriate, have their concerns related to the discontinuation addressed, understand the process, and feel that they have the support of the clinical team, the authors conclude.
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Approximately a third of patients treated for hypothyroidism continue to maintain normal thyroid levels after discontinuing thyroid hormone replacement therapy.
Those who were treated for overt hypothyroidism were less likely to maintain normal hormone levels than those with subclinical disease, the new meta-analysis shows.
“This analysis is the first to summarize the limited evidence regarding successful thyroid hormone discontinuation, but unfortunately more research is needed to develop an evidenced-based strategy for deprescribing thyroid hormone replacement,” Nydia Burgos, MD, and colleagues write in their article published online in Thyroid.
Nevertheless, the main findings were somewhat surprising, Dr. Burgos of the division of endocrinology, diabetes and metabolism, University of Puerto Rico, told this news organization.
“I expected that a considerable portion of patients would remain euthyroid, but up to a third of patients was an impressive number,” she said.
The finding could be an indicator of people who may not have had much benefit from the treatment in the first place, she noted.
“The truth of the matter is that levothyroxine (LT4) is among the top-prescribed drugs in the United States, and every day in clinics we encounter patients that were started on thyroid hormone replacement therapy for unclear reasons, as a therapeutic trial that was never reassessed, or as treatment for subclinical hypothyroidism without having convincing criteria for treatment,” she observed.
Meta-analysis of 17 studies examining LT4 discontinuation
Known to be highly effective in the treatment of overt hypothyroidism, LT4 is often prescribed long term; however, it is also commonly prescribed for patients with subclinical hypothyroidism, despite research suggesting no benefits in these patients.
With a guideline panel underscoring the lack of evidence and issuing a “strong recommendation” in May 2019 against treatment with thyroid hormones in adults with subclinical hypothyroidism (elevated thyroid-stimulating hormone [TSH] levels and normal free T4 levels), clinicians may increasingly be considering discontinuation strategies.
To examine the evidence to date on the clinical outcomes of discontinuing LT4, Dr. Burgos and colleagues conducted a meta-analysis in which they identified 17 observational studies that met the inclusion criteria. Of a total of 1,103 patients in the studies, 86% were women. Most studies included only adults.
With a median follow-up of 5 years, the pooled estimate of patients maintaining euthyroidism after treatment discontinuation was 37.2%.
The estimated rate of remaining euthyroid was significantly lower among those with overt hypothyroidism (11.8%) compared with those with subclinical hypothyroidism (35.6%).
Meanwhile, as many as 65.8% of patients ended up restarting thyroid hormone treatment during the follow-up period, according to pooled estimates, and the rate was as high as 87.2% in patients with overt hypothyroidism. The mean increase in TSH from time of LT4 discontinuation to follow-up was 9.4 mIU/L.
Among specific factors shown to be linked to a lower likelihood of euthyroidism at follow-up were inconsistent echogenicity on thyroid ultrasound, elevated TSH (8-9 mIU/L), and the presence of thyroid antibodies.
Only a few of the studies evaluated thyroid hormones other than synthetic LT4 (such as the commonly used desiccated thyroid), and so the analysis did not compare differences between therapies, Dr. Burgos noted.
Despite the lack of evidence of benefits of LT4 treatment for subclinical hypothyroidism, the finding that, even among those patients, approximately two-thirds were not euthyroid at follow-up was not unexpected, she added.
“I am not surprised that, even in the subclinical hypothyroidism group about two-thirds of participants were not euthyroid, because when looking at the natural history of subclinical hypothyroidism in other studies, only a fifth had normalized thyroid hormone tests, while the majority continue with mild subclinical hypothyroidism and a fifth progress to overt hypothyroidism,” she explained.
More work needed to determine best way to taper down LT4
The specific regimens for discontinuing LT4 were detailed in only three studies and reflected varying approaches, ranging from tapering down the dose over 2 weeks to reducing the dose over several more weeks, or even months, Dr. Burgos noted
“We need more studies to figure out which tapering regimen will promote a more favorable outcome,” she said.
“The ideal regimen will be one in which patients can comply with follow-up visits and have thyroid function testing done before symptoms of hypothyroidism develop.”
In addition to likely offering no benefit to people with subclinical hypothyroidism, other reasons for discontinuing LT4 in patients who are considered appropriate candidates include concerns about side effects in older patients.
The authors say there is evidence indicating that as many as 50% of patients older than 65 who take thyroid hormones develop iatrogenic hyperthyroidism, which can have detrimental effects including an increased risk for cardiac arrhythmias, angina pectoris, bone loss, and fractures.
Collaborative approach to ‘deprescribing’ suggested
To get patients off LT4, the authors suggest a collaborative approach of “deprescribing,” whereby the health care professional supervises with a goal of managing polypharmacy and improving outcomes.
“This systematic process starts with an accurate evaluation of the medication list, followed by identification of potentially inappropriate medications, collaboration between patients and clinicians to decide whether deprescribing would be appropriate, and establishing a supportive plan to safely deprescribe the medication,” they write.
When decision-making is shared, patients are more likely to consider discontinuation if they understand why the medication is inappropriate, have their concerns related to the discontinuation addressed, understand the process, and feel that they have the support of the clinical team, the authors conclude.
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
New technique uses voice to evaluate thyroid nodules
However, it has not yet been tested for cancer detection.
The new approach involves holding a linear ultrasound probe to the throat of the patient, who is then requested to vocalize an “eee” sound at 150 Hz. A loudspeaker plays a 150-Hz sound to guide the patient.
The vocal vibrations generated, called shear waves, are detected by the probe as they pass through the thyroid. Software the researchers developed calculates the velocity of the shear waves, which move faster through stiffer tissue. The software produces a stiffness map that is then superimposed onto a gray-scale (B mode) thyroid image from the ultrasound.
Cancerous tissue is stiffer than healthy tissue and benign nodules, so shear waves pass through it more quickly, the researchers explained. Areas of particular stiffness that are revealed by the test are a concern.
The study was published online Jan. 12 in Applied Physics Letters.
The new approach is a noninvasive method that “would reduce the stress of patients during their medical exams. Having to sing during a medical exam can perhaps help release some of the nervous tension even more,” lead investigator Steve Beuve, PhD, of the Université de Tours (France), said in a press release. The main benefit of this technique is that it is “quick and easy,” he added. Data acquisition takes about a second, and no specialized equipment is required. Imaging can be rendered by any Doppler ultrasound set at an ultrafast frame rate to track the shear waves. The computer program automatically calculates wave velocity through various parts of the thyroid.
The technique, dubbed vocal passive elastography (VPE), has not yet been tested to see how well it distinguishes cancerous from benign thyroid nodules.
“We want to cooperate with physicians to propose protocols to verify [VPE’s] relevance,” Dr. Beuve said.
Because no data are currently available on how accurate VPE is in diagnosing malignant nodules, it is not possible to comment on its potential usefulness, Aya Kamaya, MD, a radiology professor at Stanford (Calif.) University Medical Center, said in an interview.
Ultrasound elastography for diagnosing thyroid disease has been in development for years. More than 100 reports have been published in the medical literature since 2005. Various devices are available commercially, but for now, elastography for thyroid nodules remains investigational, she said.
Another expert who was approached for comment was more critical.
Lisa Orloff, MD, a professor and director of endocrine head and neck surgery and the thyroid tumor program at Stanford University, noted that, in general, “elastography has not gained more traction in thyroid evaluation to date because it does not appear to reduce the need for [fine-needle aspiration] of suspicious nodules based on gray-scale ultrasound alone, without elastography.”
As for the French report, she said that “while the voice might be a convenient shear wave source, I am very skeptical at many levels. I get the impression that [this is] a laboratory-based concept that is fraught with confounding factors in attempting real-world application.
“One concern is that the thyroid gland and nodule stiffness are affected by factors including underlying goiter, autoimmune disease, fluid content of nodules, calcifications, and other variables that can be present in benign or malignant conditions. And there are so many variables that would affect an individual patient’s ability (or not) to phonate at 150 Hz,” Dr. Orloff said.
VPE is an extension of passive elastography, which extracts elasticity data from the natural vibrations caused by the heart, blood pulsatility, and muscle activity, the authors explained. The team turned to vocalization at 150 Hz in part to overcome the physiological background noise in the thyroid from carotid pulsation at about 1-10 Hz.
The group is exploring vocalizations at other frequencies and is working to improve the computer program interface. They are also exploring VPE for other organs, including the brain.
The source of funding for the study and the authors’ relevant financial relationships were not reported.
A version of this article first appeared on Medscape.com.
However, it has not yet been tested for cancer detection.
The new approach involves holding a linear ultrasound probe to the throat of the patient, who is then requested to vocalize an “eee” sound at 150 Hz. A loudspeaker plays a 150-Hz sound to guide the patient.
The vocal vibrations generated, called shear waves, are detected by the probe as they pass through the thyroid. Software the researchers developed calculates the velocity of the shear waves, which move faster through stiffer tissue. The software produces a stiffness map that is then superimposed onto a gray-scale (B mode) thyroid image from the ultrasound.
Cancerous tissue is stiffer than healthy tissue and benign nodules, so shear waves pass through it more quickly, the researchers explained. Areas of particular stiffness that are revealed by the test are a concern.
The study was published online Jan. 12 in Applied Physics Letters.
The new approach is a noninvasive method that “would reduce the stress of patients during their medical exams. Having to sing during a medical exam can perhaps help release some of the nervous tension even more,” lead investigator Steve Beuve, PhD, of the Université de Tours (France), said in a press release. The main benefit of this technique is that it is “quick and easy,” he added. Data acquisition takes about a second, and no specialized equipment is required. Imaging can be rendered by any Doppler ultrasound set at an ultrafast frame rate to track the shear waves. The computer program automatically calculates wave velocity through various parts of the thyroid.
The technique, dubbed vocal passive elastography (VPE), has not yet been tested to see how well it distinguishes cancerous from benign thyroid nodules.
“We want to cooperate with physicians to propose protocols to verify [VPE’s] relevance,” Dr. Beuve said.
Because no data are currently available on how accurate VPE is in diagnosing malignant nodules, it is not possible to comment on its potential usefulness, Aya Kamaya, MD, a radiology professor at Stanford (Calif.) University Medical Center, said in an interview.
Ultrasound elastography for diagnosing thyroid disease has been in development for years. More than 100 reports have been published in the medical literature since 2005. Various devices are available commercially, but for now, elastography for thyroid nodules remains investigational, she said.
Another expert who was approached for comment was more critical.
Lisa Orloff, MD, a professor and director of endocrine head and neck surgery and the thyroid tumor program at Stanford University, noted that, in general, “elastography has not gained more traction in thyroid evaluation to date because it does not appear to reduce the need for [fine-needle aspiration] of suspicious nodules based on gray-scale ultrasound alone, without elastography.”
As for the French report, she said that “while the voice might be a convenient shear wave source, I am very skeptical at many levels. I get the impression that [this is] a laboratory-based concept that is fraught with confounding factors in attempting real-world application.
“One concern is that the thyroid gland and nodule stiffness are affected by factors including underlying goiter, autoimmune disease, fluid content of nodules, calcifications, and other variables that can be present in benign or malignant conditions. And there are so many variables that would affect an individual patient’s ability (or not) to phonate at 150 Hz,” Dr. Orloff said.
VPE is an extension of passive elastography, which extracts elasticity data from the natural vibrations caused by the heart, blood pulsatility, and muscle activity, the authors explained. The team turned to vocalization at 150 Hz in part to overcome the physiological background noise in the thyroid from carotid pulsation at about 1-10 Hz.
The group is exploring vocalizations at other frequencies and is working to improve the computer program interface. They are also exploring VPE for other organs, including the brain.
The source of funding for the study and the authors’ relevant financial relationships were not reported.
A version of this article first appeared on Medscape.com.
However, it has not yet been tested for cancer detection.
The new approach involves holding a linear ultrasound probe to the throat of the patient, who is then requested to vocalize an “eee” sound at 150 Hz. A loudspeaker plays a 150-Hz sound to guide the patient.
The vocal vibrations generated, called shear waves, are detected by the probe as they pass through the thyroid. Software the researchers developed calculates the velocity of the shear waves, which move faster through stiffer tissue. The software produces a stiffness map that is then superimposed onto a gray-scale (B mode) thyroid image from the ultrasound.
Cancerous tissue is stiffer than healthy tissue and benign nodules, so shear waves pass through it more quickly, the researchers explained. Areas of particular stiffness that are revealed by the test are a concern.
The study was published online Jan. 12 in Applied Physics Letters.
The new approach is a noninvasive method that “would reduce the stress of patients during their medical exams. Having to sing during a medical exam can perhaps help release some of the nervous tension even more,” lead investigator Steve Beuve, PhD, of the Université de Tours (France), said in a press release. The main benefit of this technique is that it is “quick and easy,” he added. Data acquisition takes about a second, and no specialized equipment is required. Imaging can be rendered by any Doppler ultrasound set at an ultrafast frame rate to track the shear waves. The computer program automatically calculates wave velocity through various parts of the thyroid.
The technique, dubbed vocal passive elastography (VPE), has not yet been tested to see how well it distinguishes cancerous from benign thyroid nodules.
“We want to cooperate with physicians to propose protocols to verify [VPE’s] relevance,” Dr. Beuve said.
Because no data are currently available on how accurate VPE is in diagnosing malignant nodules, it is not possible to comment on its potential usefulness, Aya Kamaya, MD, a radiology professor at Stanford (Calif.) University Medical Center, said in an interview.
Ultrasound elastography for diagnosing thyroid disease has been in development for years. More than 100 reports have been published in the medical literature since 2005. Various devices are available commercially, but for now, elastography for thyroid nodules remains investigational, she said.
Another expert who was approached for comment was more critical.
Lisa Orloff, MD, a professor and director of endocrine head and neck surgery and the thyroid tumor program at Stanford University, noted that, in general, “elastography has not gained more traction in thyroid evaluation to date because it does not appear to reduce the need for [fine-needle aspiration] of suspicious nodules based on gray-scale ultrasound alone, without elastography.”
As for the French report, she said that “while the voice might be a convenient shear wave source, I am very skeptical at many levels. I get the impression that [this is] a laboratory-based concept that is fraught with confounding factors in attempting real-world application.
“One concern is that the thyroid gland and nodule stiffness are affected by factors including underlying goiter, autoimmune disease, fluid content of nodules, calcifications, and other variables that can be present in benign or malignant conditions. And there are so many variables that would affect an individual patient’s ability (or not) to phonate at 150 Hz,” Dr. Orloff said.
VPE is an extension of passive elastography, which extracts elasticity data from the natural vibrations caused by the heart, blood pulsatility, and muscle activity, the authors explained. The team turned to vocalization at 150 Hz in part to overcome the physiological background noise in the thyroid from carotid pulsation at about 1-10 Hz.
The group is exploring vocalizations at other frequencies and is working to improve the computer program interface. They are also exploring VPE for other organs, including the brain.
The source of funding for the study and the authors’ relevant financial relationships were not reported.
A version of this article first appeared on Medscape.com.