Pituitary, Thyroid & Adrenal Disorders

People with thyroid cancer treated with thyroidectomy have as much as a 40% increased risk of developing type 2 diabetes, regardless of their age, with the elevated risk observed with low as well as high doses of postoperative levothyroxine, new research shows.

“This is the first population-based study to demonstrate an elevated risk of type 2 diabetes in postthyroidectomy patients with thyroid cancer, compared with that in matched controls,” wrote the authors of the research, published recently in the Journal of Clinical Endocrinology & Metabolism.

“Notably, there was a U-shaped relationship between postoperative levothyroxine dosage, a surrogate marker of TSH suppression, and the risk of type 2 diabetes,” said Hye Jin Yoo, MD, of the division of endocrinology and metabolism, Korea University College of Medicine, Seoul, and colleagues.

While other studies have linked thyroidectomy for thyroid cancer with an elevated risk for other metabolic conditions, including coronary heart disease and ischemic stroke, the relatively high diabetes risk is unexpected, said Tyler Drake, MD, an endocrinologist with the Minneapolis VA Health Care System.

“A 40% increased risk of diabetes is a big surprise,” he said in an interview.

“Diabetes is very common, with about one in 10 U.S. adults having type 2 diabetes, but a 40% increased risk in thyroid cancer patients is higher than I see in my clinical practice. [However], it is important to note that the [highest] risk was predominantly among the groups on the lowest and highest doses of levothyroxine,” said Dr. Drake, assistant professor of medicine at the University of Minnesota, Minneapolis.
 

U-shaped relationship between levothyroxine dose and diabetes risk

The findings are from a study of 36,377 patients with thyroid cancer in the National Health Insurance Service (NHIS) database in Korea who had undergone a thyroidectomy between 2004 and 2013.

The patients were matched 1:1 with controls who had nonthyroid cancers. Their mean age was 46.6 years, about 30% were male, and their mean body mass index was 23.8 kg/m².

Over a mean follow-up of 6.6 years, the patients with thyroid cancer had a significantly higher risk of developing type 2 diabetes, at a rate of 47.5% (10,812) compared with 36.9% (9414; HR, 1.43; P < .001) in the control group, after adjustment for factors such as age, sex, BMI, smoking, drinking, systolic blood pressure, and fasting glucose.

The risk of type 2 diabetes among those with thyroid cancer was higher among the 83.2% of patients who underwent a total thyroidectomy compared with the 16.8% who had a unilateral lobectomy (HR, 1.06; P < .001).

In addition, those with thyroid cancer who received the lowest as well as highest dosages of levothyroxine had significantly higher risks of type 2 diabetes compared with controls (HR, 1.50 and 1.39, respectively; both P < .001).

A closer look at quartiles of levothyroxine dosing showed the first (lowest) quartile (defined as a mean levothyroxine dosage of < 101 mcg/day) was associated with an increased risk of type 2 diabetes compared with the second quartile group (101-127 mcg/day; HR, 1.45), as was the fourth quartile (≥ 150 mcg/day; HR, 1.37), while a decreased risk of type 2 diabetes was observed in the third quartile group (128-149 mcg/day versus the second quartile group; HR, 0.91).

“This result suggests a U-shaped relationship between the mean levothyroxine dosage and risk of type 2 diabetes in postthyroidectomy patients with thyroid cancer,” the authors said.

However, “consistent with previous studies, the present study showed that the highest risk of type 2 diabetes was observed in patients with thyroid cancer who were treated with the lowest mean dosage of levothyroxine,” they noted.

“This result suggests that inadequate supplementation of thyroid hormones may worsen glucose metabolism and should therefore be avoided.”
 

Potential mechanisms

Abnormal thyroid function, including hypo- and hyperthyroidism, following thyroidectomy and subsequent treatment with levothyroxine, is known to have potentially detrimental effects on glucose regulation among patients with thyroid cancer.

The potential mechanisms linking hypothyroidism with diabetes specifically include the possibility that insulin becomes unable to promote the utilization of glucose by muscles and adipose tissue. However, thyroid hormone replacement has been associated with a normalization of insulin sensitivity, the authors noted.

Meanwhile, glucose intolerance is common among patients with hyperthyroidism, largely due to an increase in hepatic glucose production, and likewise, the normalization of thyroid levels among those treated with methimazole has been linked to normalization of glucose and lipid metabolism alterations.

Dr. Drake noted that an important study limitation is that patients were analyzed based on their levothyroxine dose and not their TSH values, which the authors explain was due to the unavailability of the TSH values. 

“By looking at levothyroxine doses, and not TSH values, it is possible some patients were being improperly treated with either too much or too little levothyroxine,” Dr. Drake noted.
 

Control group should have had hypothyroidism

The findings nevertheless shed light on the risk of diabetes following thyroidectomy for thyroid cancer, Anupam Kotwal, MD, commented on the study.

“This study is significant because it addresses an important topic exploring the link between thyroid dysfunction and metabolic disease, in this case ... hypothyroidism, due to surgery for thyroid cancer and type 2 diabetes,” Dr. Kotwal, assistant professor of medicine in the division of diabetes, endocrinology & metabolism at the University of Nebraska Medical Center, Omaha, said in an interview.

In terms of other limitations, Dr. Kotwal noted that the controls did not have hypothyroidism; therefore, “from this study, it is impossible to confirm whether hypothyroidism from any cause would be associated with higher incidence of diabetes or if it is specific to thyroid surgery for thyroid cancer.

“It would have been useful to have a control group of autoimmune primary hypothyroidism to evaluate the rate of diabetes during a similar follow-up duration,” Dr. Kotwal said.

“Hence, cohort studies with more granular data such as degree of TSH suppression and having a control group of hypothyroid patients due to autoimmune thyroid disease are needed to better understand this risk.”

Dr. Kotwal and Dr. Drake have reported no relevant financial relationships.

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

People with thyroid cancer treated with thyroidectomy have as much as a 40% increased risk of developing type 2 diabetes, regardless of their age, with the elevated risk observed with low as well as high doses of postoperative levothyroxine, new research shows.

“This is the first population-based study to demonstrate an elevated risk of type 2 diabetes in postthyroidectomy patients with thyroid cancer, compared with that in matched controls,” wrote the authors of the research, published recently in the Journal of Clinical Endocrinology & Metabolism.

“Notably, there was a U-shaped relationship between postoperative levothyroxine dosage, a surrogate marker of TSH suppression, and the risk of type 2 diabetes,” said Hye Jin Yoo, MD, of the division of endocrinology and metabolism, Korea University College of Medicine, Seoul, and colleagues.

While other studies have linked thyroidectomy for thyroid cancer with an elevated risk for other metabolic conditions, including coronary heart disease and ischemic stroke, the relatively high diabetes risk is unexpected, said Tyler Drake, MD, an endocrinologist with the Minneapolis VA Health Care System.

“A 40% increased risk of diabetes is a big surprise,” he said in an interview.

“Diabetes is very common, with about one in 10 U.S. adults having type 2 diabetes, but a 40% increased risk in thyroid cancer patients is higher than I see in my clinical practice. [However], it is important to note that the [highest] risk was predominantly among the groups on the lowest and highest doses of levothyroxine,” said Dr. Drake, assistant professor of medicine at the University of Minnesota, Minneapolis.
 

U-shaped relationship between levothyroxine dose and diabetes risk

The findings are from a study of 36,377 patients with thyroid cancer in the National Health Insurance Service (NHIS) database in Korea who had undergone a thyroidectomy between 2004 and 2013.

The patients were matched 1:1 with controls who had nonthyroid cancers. Their mean age was 46.6 years, about 30% were male, and their mean body mass index was 23.8 kg/m².

Over a mean follow-up of 6.6 years, the patients with thyroid cancer had a significantly higher risk of developing type 2 diabetes, at a rate of 47.5% (10,812) compared with 36.9% (9414; HR, 1.43; P < .001) in the control group, after adjustment for factors such as age, sex, BMI, smoking, drinking, systolic blood pressure, and fasting glucose.

The risk of type 2 diabetes among those with thyroid cancer was higher among the 83.2% of patients who underwent a total thyroidectomy compared with the 16.8% who had a unilateral lobectomy (HR, 1.06; P < .001).

In addition, those with thyroid cancer who received the lowest as well as highest dosages of levothyroxine had significantly higher risks of type 2 diabetes compared with controls (HR, 1.50 and 1.39, respectively; both P < .001).

A closer look at quartiles of levothyroxine dosing showed the first (lowest) quartile (defined as a mean levothyroxine dosage of < 101 mcg/day) was associated with an increased risk of type 2 diabetes compared with the second quartile group (101-127 mcg/day; HR, 1.45), as was the fourth quartile (≥ 150 mcg/day; HR, 1.37), while a decreased risk of type 2 diabetes was observed in the third quartile group (128-149 mcg/day versus the second quartile group; HR, 0.91).

“This result suggests a U-shaped relationship between the mean levothyroxine dosage and risk of type 2 diabetes in postthyroidectomy patients with thyroid cancer,” the authors said.

However, “consistent with previous studies, the present study showed that the highest risk of type 2 diabetes was observed in patients with thyroid cancer who were treated with the lowest mean dosage of levothyroxine,” they noted.

“This result suggests that inadequate supplementation of thyroid hormones may worsen glucose metabolism and should therefore be avoided.”
 

Potential mechanisms

Abnormal thyroid function, including hypo- and hyperthyroidism, following thyroidectomy and subsequent treatment with levothyroxine, is known to have potentially detrimental effects on glucose regulation among patients with thyroid cancer.

The potential mechanisms linking hypothyroidism with diabetes specifically include the possibility that insulin becomes unable to promote the utilization of glucose by muscles and adipose tissue. However, thyroid hormone replacement has been associated with a normalization of insulin sensitivity, the authors noted.

Meanwhile, glucose intolerance is common among patients with hyperthyroidism, largely due to an increase in hepatic glucose production, and likewise, the normalization of thyroid levels among those treated with methimazole has been linked to normalization of glucose and lipid metabolism alterations.

Dr. Drake noted that an important study limitation is that patients were analyzed based on their levothyroxine dose and not their TSH values, which the authors explain was due to the unavailability of the TSH values. 

“By looking at levothyroxine doses, and not TSH values, it is possible some patients were being improperly treated with either too much or too little levothyroxine,” Dr. Drake noted.
 

Control group should have had hypothyroidism

The findings nevertheless shed light on the risk of diabetes following thyroidectomy for thyroid cancer, Anupam Kotwal, MD, commented on the study.

“This study is significant because it addresses an important topic exploring the link between thyroid dysfunction and metabolic disease, in this case ... hypothyroidism, due to surgery for thyroid cancer and type 2 diabetes,” Dr. Kotwal, assistant professor of medicine in the division of diabetes, endocrinology & metabolism at the University of Nebraska Medical Center, Omaha, said in an interview.

In terms of other limitations, Dr. Kotwal noted that the controls did not have hypothyroidism; therefore, “from this study, it is impossible to confirm whether hypothyroidism from any cause would be associated with higher incidence of diabetes or if it is specific to thyroid surgery for thyroid cancer.

“It would have been useful to have a control group of autoimmune primary hypothyroidism to evaluate the rate of diabetes during a similar follow-up duration,” Dr. Kotwal said.

“Hence, cohort studies with more granular data such as degree of TSH suppression and having a control group of hypothyroid patients due to autoimmune thyroid disease are needed to better understand this risk.”

Dr. Kotwal and Dr. Drake have reported no relevant financial relationships.

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

People with thyroid cancer treated with thyroidectomy have as much as a 40% increased risk of developing type 2 diabetes, regardless of their age, with the elevated risk observed with low as well as high doses of postoperative levothyroxine, new research shows.

“This is the first population-based study to demonstrate an elevated risk of type 2 diabetes in postthyroidectomy patients with thyroid cancer, compared with that in matched controls,” wrote the authors of the research, published recently in the Journal of Clinical Endocrinology & Metabolism.

“Notably, there was a U-shaped relationship between postoperative levothyroxine dosage, a surrogate marker of TSH suppression, and the risk of type 2 diabetes,” said Hye Jin Yoo, MD, of the division of endocrinology and metabolism, Korea University College of Medicine, Seoul, and colleagues.

While other studies have linked thyroidectomy for thyroid cancer with an elevated risk for other metabolic conditions, including coronary heart disease and ischemic stroke, the relatively high diabetes risk is unexpected, said Tyler Drake, MD, an endocrinologist with the Minneapolis VA Health Care System.

“A 40% increased risk of diabetes is a big surprise,” he said in an interview.

“Diabetes is very common, with about one in 10 U.S. adults having type 2 diabetes, but a 40% increased risk in thyroid cancer patients is higher than I see in my clinical practice. [However], it is important to note that the [highest] risk was predominantly among the groups on the lowest and highest doses of levothyroxine,” said Dr. Drake, assistant professor of medicine at the University of Minnesota, Minneapolis.
 

U-shaped relationship between levothyroxine dose and diabetes risk

The findings are from a study of 36,377 patients with thyroid cancer in the National Health Insurance Service (NHIS) database in Korea who had undergone a thyroidectomy between 2004 and 2013.

The patients were matched 1:1 with controls who had nonthyroid cancers. Their mean age was 46.6 years, about 30% were male, and their mean body mass index was 23.8 kg/m².

Over a mean follow-up of 6.6 years, the patients with thyroid cancer had a significantly higher risk of developing type 2 diabetes, at a rate of 47.5% (10,812) compared with 36.9% (9414; HR, 1.43; P < .001) in the control group, after adjustment for factors such as age, sex, BMI, smoking, drinking, systolic blood pressure, and fasting glucose.

The risk of type 2 diabetes among those with thyroid cancer was higher among the 83.2% of patients who underwent a total thyroidectomy compared with the 16.8% who had a unilateral lobectomy (HR, 1.06; P < .001).

In addition, those with thyroid cancer who received the lowest as well as highest dosages of levothyroxine had significantly higher risks of type 2 diabetes compared with controls (HR, 1.50 and 1.39, respectively; both P < .001).

A closer look at quartiles of levothyroxine dosing showed the first (lowest) quartile (defined as a mean levothyroxine dosage of < 101 mcg/day) was associated with an increased risk of type 2 diabetes compared with the second quartile group (101-127 mcg/day; HR, 1.45), as was the fourth quartile (≥ 150 mcg/day; HR, 1.37), while a decreased risk of type 2 diabetes was observed in the third quartile group (128-149 mcg/day versus the second quartile group; HR, 0.91).

“This result suggests a U-shaped relationship between the mean levothyroxine dosage and risk of type 2 diabetes in postthyroidectomy patients with thyroid cancer,” the authors said.

However, “consistent with previous studies, the present study showed that the highest risk of type 2 diabetes was observed in patients with thyroid cancer who were treated with the lowest mean dosage of levothyroxine,” they noted.

“This result suggests that inadequate supplementation of thyroid hormones may worsen glucose metabolism and should therefore be avoided.”
 

Potential mechanisms

Abnormal thyroid function, including hypo- and hyperthyroidism, following thyroidectomy and subsequent treatment with levothyroxine, is known to have potentially detrimental effects on glucose regulation among patients with thyroid cancer.

The potential mechanisms linking hypothyroidism with diabetes specifically include the possibility that insulin becomes unable to promote the utilization of glucose by muscles and adipose tissue. However, thyroid hormone replacement has been associated with a normalization of insulin sensitivity, the authors noted.

Meanwhile, glucose intolerance is common among patients with hyperthyroidism, largely due to an increase in hepatic glucose production, and likewise, the normalization of thyroid levels among those treated with methimazole has been linked to normalization of glucose and lipid metabolism alterations.

Dr. Drake noted that an important study limitation is that patients were analyzed based on their levothyroxine dose and not their TSH values, which the authors explain was due to the unavailability of the TSH values. 

“By looking at levothyroxine doses, and not TSH values, it is possible some patients were being improperly treated with either too much or too little levothyroxine,” Dr. Drake noted.
 

Control group should have had hypothyroidism

The findings nevertheless shed light on the risk of diabetes following thyroidectomy for thyroid cancer, Anupam Kotwal, MD, commented on the study.

“This study is significant because it addresses an important topic exploring the link between thyroid dysfunction and metabolic disease, in this case ... hypothyroidism, due to surgery for thyroid cancer and type 2 diabetes,” Dr. Kotwal, assistant professor of medicine in the division of diabetes, endocrinology & metabolism at the University of Nebraska Medical Center, Omaha, said in an interview.

In terms of other limitations, Dr. Kotwal noted that the controls did not have hypothyroidism; therefore, “from this study, it is impossible to confirm whether hypothyroidism from any cause would be associated with higher incidence of diabetes or if it is specific to thyroid surgery for thyroid cancer.

“It would have been useful to have a control group of autoimmune primary hypothyroidism to evaluate the rate of diabetes during a similar follow-up duration,” Dr. Kotwal said.

“Hence, cohort studies with more granular data such as degree of TSH suppression and having a control group of hypothyroid patients due to autoimmune thyroid disease are needed to better understand this risk.”

Dr. Kotwal and Dr. Drake have reported no relevant financial relationships.

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

Chronic kidney disease (CKD) had no impact on the efficacy or safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) for patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial, showing once again that agents in this class are appropriate for patients with heart failure even when their kidney function is severely compromised.

More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.

The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.

Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.

Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
 

An end to ‘renalism’

“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.   

In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).

“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.

EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.

In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.

These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.

“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.

In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
 

More CKD-independent effects of empagliflozin

Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.

In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.

“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.

At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.

Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.

EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.

EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.

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

Chronic kidney disease (CKD) had no impact on the efficacy or safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) for patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial, showing once again that agents in this class are appropriate for patients with heart failure even when their kidney function is severely compromised.

More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.

The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.

Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.

Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
 

An end to ‘renalism’

“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.   

In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).

“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.

EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.

In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.

These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.

“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.

In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
 

More CKD-independent effects of empagliflozin

Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.

In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.

“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.

At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.

Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.

EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.

EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.

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

Chronic kidney disease (CKD) had no impact on the efficacy or safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) for patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial, showing once again that agents in this class are appropriate for patients with heart failure even when their kidney function is severely compromised.

More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.

The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.

Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.

Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
 

An end to ‘renalism’

“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.   

In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).

“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.

EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.

In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.

These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.

“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.

In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
 

More CKD-independent effects of empagliflozin

Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.

In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.

“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.

At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.

Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.

EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.

EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.

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

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

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

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

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

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

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

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

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

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

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

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

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

A large international team of experts has developed two comprehensive guidelines for diagnosing, evaluating, and managing hypoparathyroidism and hyperparathyroidism, which replace guidelines issued 5 and 7 years ago.

Aliya A. Khan, MD, presented an overview of the hypoparathyroidism guidelines and John P. Bilezikian, MD, presented key aspects of the hyperparathyroidism guidelines at the American Society of Bone and Mineral Research (ASBMR) 2021 Annual Meeting.

The guidelines will be published as 17 articles in two issues of the society’s Journal of Bone and Mineral Research in 2022 – one on hypoparathyroidism and the other on hyperparathyroidism.

The work represents an “unprecedented effort” by more than 100 experts from 16 countries (United States, Canada, Australia, Brazil, China, Denmark, France, Germany, India, Italy, Israel, Lebanon, Singapore, Spain, Sweden, and the United Kingdom), Dr. Bilezikian told this news organization in an interview.

More than 100 international and national endocrine and osteoporosis organizations, societies, and patient advocacy groups from more than 50 countries have expressed interest in endorsing the guidelines.
 

Management of hypoparathyroidism

The new guidelines on hypoparathyroidism replace the guidelines issued in 2016 that were developed at the First International Conference on the Management of Hypoparathyroidism, Dr. Khan, from McMaster University, Hamilton, Ont., said in an email.

There was a need for new hypoparathyroidism guidelines, she explained, because of the better understanding of associated complications, how to predict who will develop hypoparathyroidism postoperatively (and how to prevent this), how and when to investigate a genetic cause further, when to consider parathyroid hormone (PTH) replacement therapy (and the benefits of the various molecules available today as well as those being evaluated in clinical research), and how to diagnose and manage hypoparathyroidism during pregnancy and lactation.

The experts in hypoparathyroidism were divided into four task forces that covered epidemiology and financial burden, etiology and pathophysiology, genetics and diagnosis, and patient evaluation and management.

The guidelines, developed over the past 18 months, provide detailed evidence-based graded (strong to weak) as well as ungraded (current practice) recommendations.

Summarizing a few key takeaways, Dr. Khan noted the guidelines recommend that clinicians treating patients with hypoparathyroidism should:

• Diagnose hypoparathyroidism if serum calcium corrected for albumin is low in the presence of a low or inappropriately normal PTH confirmed on two occasions 2 weeks apart (which may be supported by other specified abnormalities).
• Determine the cause for the hypoparathyroidism (which includes postsurgery, genetic variant, autoimmune, radiation, or idiopathic causes).
• Evaluate target organ damage.
• Try to achieve treatment goals and minimize risks for long-term complications.
• Consider PTH replacement therapy if patients have inadequate control, with symptoms of hypocalcemia or hypercalcemia, high phosphate, kidney disease, or high urine calcium, or poor quality of life. 

The guideline strongly recommends using PTH measurements after total thyroidectomy to try to predict which patients will develop permanent postsurgical hypoparathyroidism.

It provides a clinical approach for establishing the genetic etiology of hypoparathyroidism.

A meta-analysis of 81 studies identified that the most common symptoms/complications of chronic hypoparathyroidism were, in descending order, cataract (24%), infection (18%), nephrolithiasis, renal insufficiency, seizures, depression, ischemic heart disease, and arrhythmias.

Based on the best available evidence, the guideline advises that “clinicians need to carefully determine why a patient has hypoparathyroidism and develop an individualized treatment plan with conventional therapy consisting of calcium, active vitamin D, hydrochlorothiazide, and plain vitamin D,” Dr. Khan continued.

“If a patient has poorly controlled hypoparathyroidism with many symptoms or is not doing well, then clinicians must consider PTH replacement therapy, since this will replace the missing hormone, lower the urine calcium losses, bring the serum calcium back up to the normal reference range, and lower phosphate (which appears to be associated with kidney calcification and may also contribute to basal ganglia calcification and calcium deposits in the eye),” she noted.

The guideline also discusses the optimal way to monitor and treat patients during pregnancy, delivery, and breastfeeding to optimize outcomes for mother and baby. The key points are closer patient monitoring with normalization of calcium, urine calcium, phosphate, and vitamin D.  
 

Management of primary hyperparathyroidism

There was a need to update the previous 2014 guidelines developed at the Fourth International Workshop on the Management of Primary Hyperparathyroidism because, among other things, recent studies have provided new evidence about the different clinical phenotypes of primary hyperparathyroidism and ways the disease affects the skeleton and kidneys, Dr. Bilezikian, from the College of Physicians and Surgeons, Columbia University, New York, explained.

The experts in hyperparathyroidism were divided into four task forces that covered epidemiology, pathophysiology and genetics; classical and nonclassical disease manifestations; surgical aspects; and patient evaluation and management.

As part of these topics, the experts reviewed biochemical, skeletal, and renal findings, nonclassical features (such as neurocognitive complaints), nutritional and pharmacologic approaches, and disease course with or without surgical or medical intervention.

They made recommendations for diagnosis of hypercalcemic and normocalcemic phenotypes, differential diagnosis, evaluation of the skeleton and the kidney, indications for surgery, role of parathyroid imaging, indications for pharmacologic intervention, and monitoring.

“Consider the way this disease has appeared to change in the last 50 years,” said Dr. Bilezikian. In the 1940s, 50s, and 60s, patients with hyperparathyroidism were really sick and had severe bone disease and kidney disease. Then in the 70s, 80s, and 90s, the disease was more often discovered because of a screening test; high serum calcium was a hallmark of finding asymptomatic hyperparathyroidism.

In recent years, hyperparathyroidism is often discovered incidentally, when examining the skeleton or kidneys, he continued.

Primary hyperparathyroidism can now be subdivided into three types: patients who have target organ (kidney, bone) involvement, patients who don’t have this, and patients who have normocalcemic primary hyperparathyroidism.

The guideline discusses new medications that have become available for hyperparathyroidism, as well as surgery (the only cure), including how preoperative imaging can identify the overactive parathyroid gland, and the guidelines go into detail about how to monitor a patient and why a clinician would or would not recommend surgery, Dr. Bilezikian explained.

In the end, treatment is tailored to the individual.

Last, the guideline identifies eight areas where more research is needed.

The guidelines were funded by unrestricted educational grants from Amolyt, Ascendis, Calcilytix, and Takeda. Dr. Khan has reported participating on advisory boards for Alexion, Amgen, Amolyt, and Takeda, being a consultant for Amgen, receiving grants from Alexion, Amgen, Takeda, and Ascendis, being an investigator for Alexion, Amgen, Takeda, Ascendis, and Chugai, and being a speaker for Alexion, Amgen, Takeda, and Ultragenyx. Dr. Bilezikian has reported no relevant financial relationships.

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

A large international team of experts has developed two comprehensive guidelines for diagnosing, evaluating, and managing hypoparathyroidism and hyperparathyroidism, which replace guidelines issued 5 and 7 years ago.

Aliya A. Khan, MD, presented an overview of the hypoparathyroidism guidelines and John P. Bilezikian, MD, presented key aspects of the hyperparathyroidism guidelines at the American Society of Bone and Mineral Research (ASBMR) 2021 Annual Meeting.

The guidelines will be published as 17 articles in two issues of the society’s Journal of Bone and Mineral Research in 2022 – one on hypoparathyroidism and the other on hyperparathyroidism.

The work represents an “unprecedented effort” by more than 100 experts from 16 countries (United States, Canada, Australia, Brazil, China, Denmark, France, Germany, India, Italy, Israel, Lebanon, Singapore, Spain, Sweden, and the United Kingdom), Dr. Bilezikian told this news organization in an interview.

More than 100 international and national endocrine and osteoporosis organizations, societies, and patient advocacy groups from more than 50 countries have expressed interest in endorsing the guidelines.
 

Management of hypoparathyroidism

The new guidelines on hypoparathyroidism replace the guidelines issued in 2016 that were developed at the First International Conference on the Management of Hypoparathyroidism, Dr. Khan, from McMaster University, Hamilton, Ont., said in an email.

There was a need for new hypoparathyroidism guidelines, she explained, because of the better understanding of associated complications, how to predict who will develop hypoparathyroidism postoperatively (and how to prevent this), how and when to investigate a genetic cause further, when to consider parathyroid hormone (PTH) replacement therapy (and the benefits of the various molecules available today as well as those being evaluated in clinical research), and how to diagnose and manage hypoparathyroidism during pregnancy and lactation.

The experts in hypoparathyroidism were divided into four task forces that covered epidemiology and financial burden, etiology and pathophysiology, genetics and diagnosis, and patient evaluation and management.

The guidelines, developed over the past 18 months, provide detailed evidence-based graded (strong to weak) as well as ungraded (current practice) recommendations.

Summarizing a few key takeaways, Dr. Khan noted the guidelines recommend that clinicians treating patients with hypoparathyroidism should:

• Diagnose hypoparathyroidism if serum calcium corrected for albumin is low in the presence of a low or inappropriately normal PTH confirmed on two occasions 2 weeks apart (which may be supported by other specified abnormalities).
• Determine the cause for the hypoparathyroidism (which includes postsurgery, genetic variant, autoimmune, radiation, or idiopathic causes).
• Evaluate target organ damage.
• Try to achieve treatment goals and minimize risks for long-term complications.
• Consider PTH replacement therapy if patients have inadequate control, with symptoms of hypocalcemia or hypercalcemia, high phosphate, kidney disease, or high urine calcium, or poor quality of life. 

The guideline strongly recommends using PTH measurements after total thyroidectomy to try to predict which patients will develop permanent postsurgical hypoparathyroidism.

It provides a clinical approach for establishing the genetic etiology of hypoparathyroidism.

A meta-analysis of 81 studies identified that the most common symptoms/complications of chronic hypoparathyroidism were, in descending order, cataract (24%), infection (18%), nephrolithiasis, renal insufficiency, seizures, depression, ischemic heart disease, and arrhythmias.

Based on the best available evidence, the guideline advises that “clinicians need to carefully determine why a patient has hypoparathyroidism and develop an individualized treatment plan with conventional therapy consisting of calcium, active vitamin D, hydrochlorothiazide, and plain vitamin D,” Dr. Khan continued.

“If a patient has poorly controlled hypoparathyroidism with many symptoms or is not doing well, then clinicians must consider PTH replacement therapy, since this will replace the missing hormone, lower the urine calcium losses, bring the serum calcium back up to the normal reference range, and lower phosphate (which appears to be associated with kidney calcification and may also contribute to basal ganglia calcification and calcium deposits in the eye),” she noted.

The guideline also discusses the optimal way to monitor and treat patients during pregnancy, delivery, and breastfeeding to optimize outcomes for mother and baby. The key points are closer patient monitoring with normalization of calcium, urine calcium, phosphate, and vitamin D.  
 

Management of primary hyperparathyroidism

There was a need to update the previous 2014 guidelines developed at the Fourth International Workshop on the Management of Primary Hyperparathyroidism because, among other things, recent studies have provided new evidence about the different clinical phenotypes of primary hyperparathyroidism and ways the disease affects the skeleton and kidneys, Dr. Bilezikian, from the College of Physicians and Surgeons, Columbia University, New York, explained.

The experts in hyperparathyroidism were divided into four task forces that covered epidemiology, pathophysiology and genetics; classical and nonclassical disease manifestations; surgical aspects; and patient evaluation and management.

As part of these topics, the experts reviewed biochemical, skeletal, and renal findings, nonclassical features (such as neurocognitive complaints), nutritional and pharmacologic approaches, and disease course with or without surgical or medical intervention.

They made recommendations for diagnosis of hypercalcemic and normocalcemic phenotypes, differential diagnosis, evaluation of the skeleton and the kidney, indications for surgery, role of parathyroid imaging, indications for pharmacologic intervention, and monitoring.

“Consider the way this disease has appeared to change in the last 50 years,” said Dr. Bilezikian. In the 1940s, 50s, and 60s, patients with hyperparathyroidism were really sick and had severe bone disease and kidney disease. Then in the 70s, 80s, and 90s, the disease was more often discovered because of a screening test; high serum calcium was a hallmark of finding asymptomatic hyperparathyroidism.

In recent years, hyperparathyroidism is often discovered incidentally, when examining the skeleton or kidneys, he continued.

Primary hyperparathyroidism can now be subdivided into three types: patients who have target organ (kidney, bone) involvement, patients who don’t have this, and patients who have normocalcemic primary hyperparathyroidism.

The guideline discusses new medications that have become available for hyperparathyroidism, as well as surgery (the only cure), including how preoperative imaging can identify the overactive parathyroid gland, and the guidelines go into detail about how to monitor a patient and why a clinician would or would not recommend surgery, Dr. Bilezikian explained.

In the end, treatment is tailored to the individual.

Last, the guideline identifies eight areas where more research is needed.

The guidelines were funded by unrestricted educational grants from Amolyt, Ascendis, Calcilytix, and Takeda. Dr. Khan has reported participating on advisory boards for Alexion, Amgen, Amolyt, and Takeda, being a consultant for Amgen, receiving grants from Alexion, Amgen, Takeda, and Ascendis, being an investigator for Alexion, Amgen, Takeda, Ascendis, and Chugai, and being a speaker for Alexion, Amgen, Takeda, and Ultragenyx. Dr. Bilezikian has reported no relevant financial relationships.

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

A large international team of experts has developed two comprehensive guidelines for diagnosing, evaluating, and managing hypoparathyroidism and hyperparathyroidism, which replace guidelines issued 5 and 7 years ago.

Aliya A. Khan, MD, presented an overview of the hypoparathyroidism guidelines and John P. Bilezikian, MD, presented key aspects of the hyperparathyroidism guidelines at the American Society of Bone and Mineral Research (ASBMR) 2021 Annual Meeting.

The guidelines will be published as 17 articles in two issues of the society’s Journal of Bone and Mineral Research in 2022 – one on hypoparathyroidism and the other on hyperparathyroidism.

The work represents an “unprecedented effort” by more than 100 experts from 16 countries (United States, Canada, Australia, Brazil, China, Denmark, France, Germany, India, Italy, Israel, Lebanon, Singapore, Spain, Sweden, and the United Kingdom), Dr. Bilezikian told this news organization in an interview.

More than 100 international and national endocrine and osteoporosis organizations, societies, and patient advocacy groups from more than 50 countries have expressed interest in endorsing the guidelines.
 

Management of hypoparathyroidism

The new guidelines on hypoparathyroidism replace the guidelines issued in 2016 that were developed at the First International Conference on the Management of Hypoparathyroidism, Dr. Khan, from McMaster University, Hamilton, Ont., said in an email.

There was a need for new hypoparathyroidism guidelines, she explained, because of the better understanding of associated complications, how to predict who will develop hypoparathyroidism postoperatively (and how to prevent this), how and when to investigate a genetic cause further, when to consider parathyroid hormone (PTH) replacement therapy (and the benefits of the various molecules available today as well as those being evaluated in clinical research), and how to diagnose and manage hypoparathyroidism during pregnancy and lactation.

The experts in hypoparathyroidism were divided into four task forces that covered epidemiology and financial burden, etiology and pathophysiology, genetics and diagnosis, and patient evaluation and management.

The guidelines, developed over the past 18 months, provide detailed evidence-based graded (strong to weak) as well as ungraded (current practice) recommendations.

Summarizing a few key takeaways, Dr. Khan noted the guidelines recommend that clinicians treating patients with hypoparathyroidism should:

• Diagnose hypoparathyroidism if serum calcium corrected for albumin is low in the presence of a low or inappropriately normal PTH confirmed on two occasions 2 weeks apart (which may be supported by other specified abnormalities).
• Determine the cause for the hypoparathyroidism (which includes postsurgery, genetic variant, autoimmune, radiation, or idiopathic causes).
• Evaluate target organ damage.
• Try to achieve treatment goals and minimize risks for long-term complications.
• Consider PTH replacement therapy if patients have inadequate control, with symptoms of hypocalcemia or hypercalcemia, high phosphate, kidney disease, or high urine calcium, or poor quality of life. 

The guideline strongly recommends using PTH measurements after total thyroidectomy to try to predict which patients will develop permanent postsurgical hypoparathyroidism.

It provides a clinical approach for establishing the genetic etiology of hypoparathyroidism.

A meta-analysis of 81 studies identified that the most common symptoms/complications of chronic hypoparathyroidism were, in descending order, cataract (24%), infection (18%), nephrolithiasis, renal insufficiency, seizures, depression, ischemic heart disease, and arrhythmias.

Based on the best available evidence, the guideline advises that “clinicians need to carefully determine why a patient has hypoparathyroidism and develop an individualized treatment plan with conventional therapy consisting of calcium, active vitamin D, hydrochlorothiazide, and plain vitamin D,” Dr. Khan continued.

“If a patient has poorly controlled hypoparathyroidism with many symptoms or is not doing well, then clinicians must consider PTH replacement therapy, since this will replace the missing hormone, lower the urine calcium losses, bring the serum calcium back up to the normal reference range, and lower phosphate (which appears to be associated with kidney calcification and may also contribute to basal ganglia calcification and calcium deposits in the eye),” she noted.

The guideline also discusses the optimal way to monitor and treat patients during pregnancy, delivery, and breastfeeding to optimize outcomes for mother and baby. The key points are closer patient monitoring with normalization of calcium, urine calcium, phosphate, and vitamin D.  
 

Management of primary hyperparathyroidism

There was a need to update the previous 2014 guidelines developed at the Fourth International Workshop on the Management of Primary Hyperparathyroidism because, among other things, recent studies have provided new evidence about the different clinical phenotypes of primary hyperparathyroidism and ways the disease affects the skeleton and kidneys, Dr. Bilezikian, from the College of Physicians and Surgeons, Columbia University, New York, explained.

The experts in hyperparathyroidism were divided into four task forces that covered epidemiology, pathophysiology and genetics; classical and nonclassical disease manifestations; surgical aspects; and patient evaluation and management.

As part of these topics, the experts reviewed biochemical, skeletal, and renal findings, nonclassical features (such as neurocognitive complaints), nutritional and pharmacologic approaches, and disease course with or without surgical or medical intervention.

They made recommendations for diagnosis of hypercalcemic and normocalcemic phenotypes, differential diagnosis, evaluation of the skeleton and the kidney, indications for surgery, role of parathyroid imaging, indications for pharmacologic intervention, and monitoring.

“Consider the way this disease has appeared to change in the last 50 years,” said Dr. Bilezikian. In the 1940s, 50s, and 60s, patients with hyperparathyroidism were really sick and had severe bone disease and kidney disease. Then in the 70s, 80s, and 90s, the disease was more often discovered because of a screening test; high serum calcium was a hallmark of finding asymptomatic hyperparathyroidism.

In recent years, hyperparathyroidism is often discovered incidentally, when examining the skeleton or kidneys, he continued.

Primary hyperparathyroidism can now be subdivided into three types: patients who have target organ (kidney, bone) involvement, patients who don’t have this, and patients who have normocalcemic primary hyperparathyroidism.

The guideline discusses new medications that have become available for hyperparathyroidism, as well as surgery (the only cure), including how preoperative imaging can identify the overactive parathyroid gland, and the guidelines go into detail about how to monitor a patient and why a clinician would or would not recommend surgery, Dr. Bilezikian explained.

In the end, treatment is tailored to the individual.

Last, the guideline identifies eight areas where more research is needed.

The guidelines were funded by unrestricted educational grants from Amolyt, Ascendis, Calcilytix, and Takeda. Dr. Khan has reported participating on advisory boards for Alexion, Amgen, Amolyt, and Takeda, being a consultant for Amgen, receiving grants from Alexion, Amgen, Takeda, and Ascendis, being an investigator for Alexion, Amgen, Takeda, Ascendis, and Chugai, and being a speaker for Alexion, Amgen, Takeda, and Ultragenyx. Dr. Bilezikian has reported no relevant financial relationships.

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

As radiofrequency ablation (RFA) in the treatment of benign thyroid nodules gains favor as a noninvasive alternative to surgery in the United States, clinicians are increasingly reporting their experiences in hospital as well as outpatient settings.

And in one case, a hospital has taken the unique step of forming a multidisciplinary thyroid nodule RFA tumor board, which helps in the often tricky decision-making process that is involved.

“Our multidisciplinary RFA tumor board has been invaluable in this process, and it is the only one of its kind in the nation that I’m aware of,” James Lim, MD, of the Division of Surgical Oncology, Thyroid, and Parathyroid Center at Oregon Health Sciences University (OHSU), told this news organization.

Dr. Lim reports receiving referrals from “all avenues, some from thyroid specialists and others from nonthyroid specialists such as primary care practitioners or patient self-referrals.”

“Because of this, our centralized process of multidisciplinary review ensures that each patient is evaluated thoroughly through each thyroid specialists’ lens to optimize patient outcomes,” noted Dr. Lim, an assistant professor of endocrine surgery.

The RFA tumor board consists of experts in all specialties involved in thyroid nodule assessment and treatment, including surgeons, interventional radiologists, and endocrinologists.
 

Just because you can, doesn’t mean you should

However, there should be some caution that although there is enthusiasm regarding this noninvasive alternative to surgery, there is another option, that of mere observation, which is appropriate in many cases of thyroid nodules and should not be overlooked.

“For a number of reasons, the key to keep in mind is that, just because we can do something doesn’t mean we should,” Michael Singer, MD, director of the Division of Thyroid & Parathyroid Surgery, Department of Otolaryngology – Head and Neck Surgery, at the Henry Ford Health System, Detroit, said in an interview.

While emphasizing that he believes RFA to be a promising technology that will likely benefit patients in the future, Dr. Singer voiced concern about the approach becoming an easy choice – particularly if profit is to be had – when observation is a clear alternative. “If RFA becomes seen as an opportunity to create revenue, potential conflicts of interest may arise,” he said.

“As it is not a major procedure with a dramatic risk profile, my concern is that some clinicians [could] adopt the attitude of ‘Why not do it?’ even when the indication is minimal or nonexistent,” he added.

Dr. Lim said he agrees that “any new medical technology requires thoughtful evaluation and appropriate patient selection in order to ensure optimal patient outcomes.”

That’s where the tumor board has been especially beneficial.

“We have found great benefit in reviewing potential RFA cases in a multidisciplinary fashion within our tumor board and would recommend other institutions to consider it,” he noted. In the absence of a tumor board, “at a minimum, a thyroid specialist should be involved in the evaluation of a potential thyroid RFA patient prior to ablation treatment,” he advised.
 

Tumor board was able to identify a small subset of patients for surgery

In his research presented at the 90th Annual Meeting of the American Thyroid Association (ATA), Dr. Lim and colleagues evaluated the tumor board’s efficacy in altering diagnosis and treatment plans in a retrospective review of cases presented to the board for RFA consideration since its inception in July 2020 through June 2021.

Over the study period, 65 patients with biopsy-proven benign thyroid nodules were newly referred for RFA, with 58 referred for mass effect symptoms and seven for autonomous function.

After the multidisciplinary review, about half of the cases, 37 (56.9%), were approved for RFA.

Of the remainder, 22 (33.8%) were determined to need additional studies, just two (3.0%) were recommended for surgery, and four (6.2%) were recommended to not receive any intervention.

Of the 22 cases recommended for additional studies, 15 were subsequently recommended for RFA and four were recommended to receive surgery due to suspicious clinical findings.

Of those that underwent surgery, two showed thyroid cancer on final pathology.

Among the nodules recommended to RFA, the average nodule volume was 15.1 mL, whereas the average volume for those recommended for surgery was 40.9 mL (P = .08).

No significant complications occurred among patients that underwent RFA or those who had surgery.

“The tumor board’s multidisciplinary review was able to identify high-risk features in some patients with benign biopsies. This led to a change in recommendation from RFA to surgery for possible malignancy in a small subset of patients,” Dr. Lim noted.

In a separate analysis, Dr. Lim and colleagues reported that, among patients treated with RFA (with a mean baseline nodule volume of 11.9 mL), mean nodule volume was 6.4 mL after 1 month, 4.5 mL after 3 months, and 3.8 mL at 6 months, which were all significantly reduced versus baseline (P < .001). Similar improvements were also reported in symptom and cosmetic scores at each timepoint (all P < .001).

There were no cases of postprocedural hypothyroidism or symptomatic thyrotoxicosis.

Underlining that patients can expect noticeable improvement in symptom scores by their 30-day visit, Dr. Lim noted that patients should be warned of some early swelling.

“It is important to inform patients that they may have swelling of their treated nodule immediately after the procedure, but this should subside within a few days,” he said.
 

Outpatient RFA safe and efficacious

In a separate study also presented at the meeting, three practitioners described their experiences with RFA in their outpatient thyroid practices in San Antonio; Santa Monica, California; and Gettysburg, Pennsylvania.

Overall, there were 68 cases involving benign, class II thyroid nodules, and the authors reported average procedure times of under an hour, with actual RFA time varying from 7 to 22 minutes.

Of note, for nodules larger than 4.5 cm, two procedures were necessary to achieve desired results.

Excluding the larger nodules requiring more than one procedure, there was an average decrease in nodule size of 48% at 1 month and a decrease of 82% after 3 months in more than 80% of cases.

None of the cases required surgery. There were no major complications, and all patients had preserved baseline thyroid function.

“This preliminary study of 68 patients shows how thyroid RFA is safe and efficacious when performed in an endocrine outpatient office practice,” Kathleen Hands, MD, of the Thyroid Center of South Texas, and coauthors concluded.
 

Insurance coverage an issue in U.S.

Among much larger studies demonstrating the safety and efficacy of RFA for benign nodules, a study of 450 Chinese patients published in January showed RFA to be superior to conventional thyroidectomy in terms of patient satisfaction, postoperative quality of life, and shorter hospital stay, although the caveat was it took longer to achieve nodule volume reduction.

But if RFA use is to become more widespread in the United States, a key obstacle is that insurance companies generally do not cover the procedure. Although patients in Dr. Lim’s analyses did have coverage, it didn’t come easily, he said.

“Thankfully, all of our patients have been approved by insurance, and no one has had to pay by themselves, but this has sometimes required multiple appeals to the insurance company,” Dr. Lim said.

“The American Association of Endocrine Surgeons and Society of Interventional Radiology are both working towards getting this valuable treatment more readily accepted by more insurance companies,” he said.

Dr. Lim and Dr. Singer have reported no relevant financial relationships.

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

As radiofrequency ablation (RFA) in the treatment of benign thyroid nodules gains favor as a noninvasive alternative to surgery in the United States, clinicians are increasingly reporting their experiences in hospital as well as outpatient settings.

And in one case, a hospital has taken the unique step of forming a multidisciplinary thyroid nodule RFA tumor board, which helps in the often tricky decision-making process that is involved.

“Our multidisciplinary RFA tumor board has been invaluable in this process, and it is the only one of its kind in the nation that I’m aware of,” James Lim, MD, of the Division of Surgical Oncology, Thyroid, and Parathyroid Center at Oregon Health Sciences University (OHSU), told this news organization.

Dr. Lim reports receiving referrals from “all avenues, some from thyroid specialists and others from nonthyroid specialists such as primary care practitioners or patient self-referrals.”

“Because of this, our centralized process of multidisciplinary review ensures that each patient is evaluated thoroughly through each thyroid specialists’ lens to optimize patient outcomes,” noted Dr. Lim, an assistant professor of endocrine surgery.

The RFA tumor board consists of experts in all specialties involved in thyroid nodule assessment and treatment, including surgeons, interventional radiologists, and endocrinologists.
 

Just because you can, doesn’t mean you should

However, there should be some caution that although there is enthusiasm regarding this noninvasive alternative to surgery, there is another option, that of mere observation, which is appropriate in many cases of thyroid nodules and should not be overlooked.

“For a number of reasons, the key to keep in mind is that, just because we can do something doesn’t mean we should,” Michael Singer, MD, director of the Division of Thyroid & Parathyroid Surgery, Department of Otolaryngology – Head and Neck Surgery, at the Henry Ford Health System, Detroit, said in an interview.

While emphasizing that he believes RFA to be a promising technology that will likely benefit patients in the future, Dr. Singer voiced concern about the approach becoming an easy choice – particularly if profit is to be had – when observation is a clear alternative. “If RFA becomes seen as an opportunity to create revenue, potential conflicts of interest may arise,” he said.

“As it is not a major procedure with a dramatic risk profile, my concern is that some clinicians [could] adopt the attitude of ‘Why not do it?’ even when the indication is minimal or nonexistent,” he added.

Dr. Lim said he agrees that “any new medical technology requires thoughtful evaluation and appropriate patient selection in order to ensure optimal patient outcomes.”

That’s where the tumor board has been especially beneficial.

“We have found great benefit in reviewing potential RFA cases in a multidisciplinary fashion within our tumor board and would recommend other institutions to consider it,” he noted. In the absence of a tumor board, “at a minimum, a thyroid specialist should be involved in the evaluation of a potential thyroid RFA patient prior to ablation treatment,” he advised.
 

Tumor board was able to identify a small subset of patients for surgery

In his research presented at the 90th Annual Meeting of the American Thyroid Association (ATA), Dr. Lim and colleagues evaluated the tumor board’s efficacy in altering diagnosis and treatment plans in a retrospective review of cases presented to the board for RFA consideration since its inception in July 2020 through June 2021.

Over the study period, 65 patients with biopsy-proven benign thyroid nodules were newly referred for RFA, with 58 referred for mass effect symptoms and seven for autonomous function.

After the multidisciplinary review, about half of the cases, 37 (56.9%), were approved for RFA.

Of the remainder, 22 (33.8%) were determined to need additional studies, just two (3.0%) were recommended for surgery, and four (6.2%) were recommended to not receive any intervention.

Of the 22 cases recommended for additional studies, 15 were subsequently recommended for RFA and four were recommended to receive surgery due to suspicious clinical findings.

Of those that underwent surgery, two showed thyroid cancer on final pathology.

Among the nodules recommended to RFA, the average nodule volume was 15.1 mL, whereas the average volume for those recommended for surgery was 40.9 mL (P = .08).

No significant complications occurred among patients that underwent RFA or those who had surgery.

“The tumor board’s multidisciplinary review was able to identify high-risk features in some patients with benign biopsies. This led to a change in recommendation from RFA to surgery for possible malignancy in a small subset of patients,” Dr. Lim noted.

In a separate analysis, Dr. Lim and colleagues reported that, among patients treated with RFA (with a mean baseline nodule volume of 11.9 mL), mean nodule volume was 6.4 mL after 1 month, 4.5 mL after 3 months, and 3.8 mL at 6 months, which were all significantly reduced versus baseline (P < .001). Similar improvements were also reported in symptom and cosmetic scores at each timepoint (all P < .001).

There were no cases of postprocedural hypothyroidism or symptomatic thyrotoxicosis.

Underlining that patients can expect noticeable improvement in symptom scores by their 30-day visit, Dr. Lim noted that patients should be warned of some early swelling.

“It is important to inform patients that they may have swelling of their treated nodule immediately after the procedure, but this should subside within a few days,” he said.
 

Outpatient RFA safe and efficacious

In a separate study also presented at the meeting, three practitioners described their experiences with RFA in their outpatient thyroid practices in San Antonio; Santa Monica, California; and Gettysburg, Pennsylvania.

Overall, there were 68 cases involving benign, class II thyroid nodules, and the authors reported average procedure times of under an hour, with actual RFA time varying from 7 to 22 minutes.

Of note, for nodules larger than 4.5 cm, two procedures were necessary to achieve desired results.

Excluding the larger nodules requiring more than one procedure, there was an average decrease in nodule size of 48% at 1 month and a decrease of 82% after 3 months in more than 80% of cases.

None of the cases required surgery. There were no major complications, and all patients had preserved baseline thyroid function.

“This preliminary study of 68 patients shows how thyroid RFA is safe and efficacious when performed in an endocrine outpatient office practice,” Kathleen Hands, MD, of the Thyroid Center of South Texas, and coauthors concluded.
 

Insurance coverage an issue in U.S.

Among much larger studies demonstrating the safety and efficacy of RFA for benign nodules, a study of 450 Chinese patients published in January showed RFA to be superior to conventional thyroidectomy in terms of patient satisfaction, postoperative quality of life, and shorter hospital stay, although the caveat was it took longer to achieve nodule volume reduction.

But if RFA use is to become more widespread in the United States, a key obstacle is that insurance companies generally do not cover the procedure. Although patients in Dr. Lim’s analyses did have coverage, it didn’t come easily, he said.

“Thankfully, all of our patients have been approved by insurance, and no one has had to pay by themselves, but this has sometimes required multiple appeals to the insurance company,” Dr. Lim said.

“The American Association of Endocrine Surgeons and Society of Interventional Radiology are both working towards getting this valuable treatment more readily accepted by more insurance companies,” he said.

Dr. Lim and Dr. Singer have reported no relevant financial relationships.

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

As radiofrequency ablation (RFA) in the treatment of benign thyroid nodules gains favor as a noninvasive alternative to surgery in the United States, clinicians are increasingly reporting their experiences in hospital as well as outpatient settings.

And in one case, a hospital has taken the unique step of forming a multidisciplinary thyroid nodule RFA tumor board, which helps in the often tricky decision-making process that is involved.

“Our multidisciplinary RFA tumor board has been invaluable in this process, and it is the only one of its kind in the nation that I’m aware of,” James Lim, MD, of the Division of Surgical Oncology, Thyroid, and Parathyroid Center at Oregon Health Sciences University (OHSU), told this news organization.

Dr. Lim reports receiving referrals from “all avenues, some from thyroid specialists and others from nonthyroid specialists such as primary care practitioners or patient self-referrals.”

“Because of this, our centralized process of multidisciplinary review ensures that each patient is evaluated thoroughly through each thyroid specialists’ lens to optimize patient outcomes,” noted Dr. Lim, an assistant professor of endocrine surgery.

The RFA tumor board consists of experts in all specialties involved in thyroid nodule assessment and treatment, including surgeons, interventional radiologists, and endocrinologists.
 

Just because you can, doesn’t mean you should

However, there should be some caution that although there is enthusiasm regarding this noninvasive alternative to surgery, there is another option, that of mere observation, which is appropriate in many cases of thyroid nodules and should not be overlooked.

“For a number of reasons, the key to keep in mind is that, just because we can do something doesn’t mean we should,” Michael Singer, MD, director of the Division of Thyroid & Parathyroid Surgery, Department of Otolaryngology – Head and Neck Surgery, at the Henry Ford Health System, Detroit, said in an interview.

While emphasizing that he believes RFA to be a promising technology that will likely benefit patients in the future, Dr. Singer voiced concern about the approach becoming an easy choice – particularly if profit is to be had – when observation is a clear alternative. “If RFA becomes seen as an opportunity to create revenue, potential conflicts of interest may arise,” he said.

“As it is not a major procedure with a dramatic risk profile, my concern is that some clinicians [could] adopt the attitude of ‘Why not do it?’ even when the indication is minimal or nonexistent,” he added.

Dr. Lim said he agrees that “any new medical technology requires thoughtful evaluation and appropriate patient selection in order to ensure optimal patient outcomes.”

That’s where the tumor board has been especially beneficial.

“We have found great benefit in reviewing potential RFA cases in a multidisciplinary fashion within our tumor board and would recommend other institutions to consider it,” he noted. In the absence of a tumor board, “at a minimum, a thyroid specialist should be involved in the evaluation of a potential thyroid RFA patient prior to ablation treatment,” he advised.
 

Tumor board was able to identify a small subset of patients for surgery

In his research presented at the 90th Annual Meeting of the American Thyroid Association (ATA), Dr. Lim and colleagues evaluated the tumor board’s efficacy in altering diagnosis and treatment plans in a retrospective review of cases presented to the board for RFA consideration since its inception in July 2020 through June 2021.

Over the study period, 65 patients with biopsy-proven benign thyroid nodules were newly referred for RFA, with 58 referred for mass effect symptoms and seven for autonomous function.

After the multidisciplinary review, about half of the cases, 37 (56.9%), were approved for RFA.

Of the remainder, 22 (33.8%) were determined to need additional studies, just two (3.0%) were recommended for surgery, and four (6.2%) were recommended to not receive any intervention.

Of the 22 cases recommended for additional studies, 15 were subsequently recommended for RFA and four were recommended to receive surgery due to suspicious clinical findings.

Of those that underwent surgery, two showed thyroid cancer on final pathology.

Among the nodules recommended to RFA, the average nodule volume was 15.1 mL, whereas the average volume for those recommended for surgery was 40.9 mL (P = .08).

No significant complications occurred among patients that underwent RFA or those who had surgery.

“The tumor board’s multidisciplinary review was able to identify high-risk features in some patients with benign biopsies. This led to a change in recommendation from RFA to surgery for possible malignancy in a small subset of patients,” Dr. Lim noted.

In a separate analysis, Dr. Lim and colleagues reported that, among patients treated with RFA (with a mean baseline nodule volume of 11.9 mL), mean nodule volume was 6.4 mL after 1 month, 4.5 mL after 3 months, and 3.8 mL at 6 months, which were all significantly reduced versus baseline (P < .001). Similar improvements were also reported in symptom and cosmetic scores at each timepoint (all P < .001).

There were no cases of postprocedural hypothyroidism or symptomatic thyrotoxicosis.

Underlining that patients can expect noticeable improvement in symptom scores by their 30-day visit, Dr. Lim noted that patients should be warned of some early swelling.

“It is important to inform patients that they may have swelling of their treated nodule immediately after the procedure, but this should subside within a few days,” he said.
 

Outpatient RFA safe and efficacious

In a separate study also presented at the meeting, three practitioners described their experiences with RFA in their outpatient thyroid practices in San Antonio; Santa Monica, California; and Gettysburg, Pennsylvania.

Overall, there were 68 cases involving benign, class II thyroid nodules, and the authors reported average procedure times of under an hour, with actual RFA time varying from 7 to 22 minutes.

Of note, for nodules larger than 4.5 cm, two procedures were necessary to achieve desired results.

Excluding the larger nodules requiring more than one procedure, there was an average decrease in nodule size of 48% at 1 month and a decrease of 82% after 3 months in more than 80% of cases.

None of the cases required surgery. There were no major complications, and all patients had preserved baseline thyroid function.

“This preliminary study of 68 patients shows how thyroid RFA is safe and efficacious when performed in an endocrine outpatient office practice,” Kathleen Hands, MD, of the Thyroid Center of South Texas, and coauthors concluded.
 

Insurance coverage an issue in U.S.

Among much larger studies demonstrating the safety and efficacy of RFA for benign nodules, a study of 450 Chinese patients published in January showed RFA to be superior to conventional thyroidectomy in terms of patient satisfaction, postoperative quality of life, and shorter hospital stay, although the caveat was it took longer to achieve nodule volume reduction.

But if RFA use is to become more widespread in the United States, a key obstacle is that insurance companies generally do not cover the procedure. Although patients in Dr. Lim’s analyses did have coverage, it didn’t come easily, he said.

“Thankfully, all of our patients have been approved by insurance, and no one has had to pay by themselves, but this has sometimes required multiple appeals to the insurance company,” Dr. Lim said.

“The American Association of Endocrine Surgeons and Society of Interventional Radiology are both working towards getting this valuable treatment more readily accepted by more insurance companies,” he said.

Dr. Lim and Dr. Singer have reported no relevant financial relationships.

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

Patients with comorbid anxiety and mood disorders who have reduced, albeit “normal” serum levels of thyroid-stimulating hormone (TSH) may be at increased risk for suicidal ideation, new research suggests.

In a cross-sectional study, clinical data on diagnosis, medication use, and symptom scores were gathered, along with assessments of blood levels of thyroid axis hormones, in patients with both anxiety and mood disorders.

After investigators accounted for age, gender, symptoms, medication use, and other potential confounders, patients with suicidal ideation were 54% less likely to have higher TSH levels. There was no association found with other thyroid hormones.

Based on the results, the assessment of thyroid hormone levels “may be important for suicide prevention and might allow clinicians to evaluate the potential of the suicidal ideation risk in individuals with [anxiety and mood disorders],” co-investigator Vilma Liaugaudaite, PhD student, Neuroscience Institute of the Lithuanian University of Health Sciences, Palanga, and colleagues note.

The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Complex mechanism’

Ms. Liaugaudaite told this news organization that thyroid hormones are known to have a “profound” effect on mood and behavior.

Recent studies show “various degrees of hypothalamic-pituitary-thyroid axis dysregulation are associated with suicidal behavior” in patients with depression, she added.

Noting that disturbances in the serotonin system “constitute the most common biochemical abnormality associated with suicidal behavior,” Ms. Liaugaudaite said it is thought thyroid hormones “are involved in a complex compensatory mechanism to correct reduced central 5-hydroxytryptamine activity” via lower TSH levels.

In addition, hypersecretion of thyrotropin-releasing hormone, which stimulates the release of TSH, “has been considered a compensatory mechanism to maintain normal thyroid hormone secretion and normalize serotonin activity in depressed patients,” she said.

To investigate associations between thyroid axis hormones and suicidality in individuals with comorbid anxiety and mood disorders, the researchers assessed consecutive patients attending a stress disorders clinic.

Sociodemographic and clinical information was gathered, and patients completed the Mini International Neuropsychiatric Interview, the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) scale.

Fasting blood samples were also tested for free thyroxine (FT4), free triiodothyronine (FT3), and TSH levels.

Significant association

Seventy-seven patients aged 18 to 73 years participated in the study. Of these, 59 were women. Suicidal ideation was identified in 42 participants. Serum FT4, FT3, and TSH levels were within the normal range.

Badmanproduction/Thinkstock

There were no significant differences between patients with and without suicidal ideation in terms of age, gender, education, obesity, smoking, and medication use.

Suicidal ideation was associated with higher scores on the PHQ-9 (15.5 vs. 13.3; P = .085), and with lower TSH levels (1.54 IU/L vs. 2.04 IU/L; P = .092).

The association between serum TSH levels and suicidal ideation was significant after multivariate logistic regression analysis accounted for age, gender, PHQ-9 and GAD-7 scores, education, body mass index, smoking, and use of antidepressants, tranquilizers, mood stabilizers, and neuroleptics.

Specifically, patients with suicidal ideation were significantly less likely to have higher TSH levels than those without, at an odds ratio of 0.46 (P = .027).

There were no significant associations between serum FT4 and FT3 levels and suicidal ideation.


 

Interesting, but preliminary

Commenting on the findings, Sanjeev Sockalingam, MD, vice chair and professor of psychiatry at the University of Toronto, said it is an “interesting study” because the literature on trying to identify individuals at risk for suicidal ideation or behaviors is “quite mixed, in terms of the results.”

However, it was a cross-sectional study with a relatively small sample size, and studies of this nature typically include patients with hypothyroidism “who end up having suicidal thoughts,” said Dr. Sockalingam, who was not involved with the research.

“I do wonder, given the sample size and patient population, if there may be other factors that may have been related to this,” he added.

Dr. Sockalingam noted that he would like to see more data on the medications the patients were taking, and he underlined that the thyroid levels were in the normal range, “so it’s a bit difficult to untangle what that means in terms of these subtle changes in thyroid levels.”

Robert Levitan, MD, Cameron Wilson Chair in Depression Research at the Centre for Addiction and Mental Health, Toronto, also emphasized that the thyroid levels were in the normal range.

He commented that it therefore “seems unlikely that there’s going to be some biological effect that’s going to affect the brain in a significant enough way” to influence suicidal ideation.

Dr. Levitan continued, “What’s probably happening is there’s some other clinical issue here that they just haven’t picked up on that’s leading in one direction to the suicidal ideation and perhaps affecting the TSH to some extent.”

Although the study is, therefore, “preliminary,” the findings are nevertheless “interesting,” he concluded.

The study received no funding. Ms. Liaugaudaite, Dr. Sockalingam, and Dr. Levitan have disclosed no relevant financial relationships.

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

Patients with comorbid anxiety and mood disorders who have reduced, albeit “normal” serum levels of thyroid-stimulating hormone (TSH) may be at increased risk for suicidal ideation, new research suggests.

In a cross-sectional study, clinical data on diagnosis, medication use, and symptom scores were gathered, along with assessments of blood levels of thyroid axis hormones, in patients with both anxiety and mood disorders.

After investigators accounted for age, gender, symptoms, medication use, and other potential confounders, patients with suicidal ideation were 54% less likely to have higher TSH levels. There was no association found with other thyroid hormones.

Based on the results, the assessment of thyroid hormone levels “may be important for suicide prevention and might allow clinicians to evaluate the potential of the suicidal ideation risk in individuals with [anxiety and mood disorders],” co-investigator Vilma Liaugaudaite, PhD student, Neuroscience Institute of the Lithuanian University of Health Sciences, Palanga, and colleagues note.

The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Complex mechanism’

Ms. Liaugaudaite told this news organization that thyroid hormones are known to have a “profound” effect on mood and behavior.

Recent studies show “various degrees of hypothalamic-pituitary-thyroid axis dysregulation are associated with suicidal behavior” in patients with depression, she added.

Noting that disturbances in the serotonin system “constitute the most common biochemical abnormality associated with suicidal behavior,” Ms. Liaugaudaite said it is thought thyroid hormones “are involved in a complex compensatory mechanism to correct reduced central 5-hydroxytryptamine activity” via lower TSH levels.

In addition, hypersecretion of thyrotropin-releasing hormone, which stimulates the release of TSH, “has been considered a compensatory mechanism to maintain normal thyroid hormone secretion and normalize serotonin activity in depressed patients,” she said.

To investigate associations between thyroid axis hormones and suicidality in individuals with comorbid anxiety and mood disorders, the researchers assessed consecutive patients attending a stress disorders clinic.

Sociodemographic and clinical information was gathered, and patients completed the Mini International Neuropsychiatric Interview, the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) scale.

Fasting blood samples were also tested for free thyroxine (FT4), free triiodothyronine (FT3), and TSH levels.

Significant association

Seventy-seven patients aged 18 to 73 years participated in the study. Of these, 59 were women. Suicidal ideation was identified in 42 participants. Serum FT4, FT3, and TSH levels were within the normal range.

Badmanproduction/Thinkstock

There were no significant differences between patients with and without suicidal ideation in terms of age, gender, education, obesity, smoking, and medication use.

Suicidal ideation was associated with higher scores on the PHQ-9 (15.5 vs. 13.3; P = .085), and with lower TSH levels (1.54 IU/L vs. 2.04 IU/L; P = .092).

The association between serum TSH levels and suicidal ideation was significant after multivariate logistic regression analysis accounted for age, gender, PHQ-9 and GAD-7 scores, education, body mass index, smoking, and use of antidepressants, tranquilizers, mood stabilizers, and neuroleptics.

Specifically, patients with suicidal ideation were significantly less likely to have higher TSH levels than those without, at an odds ratio of 0.46 (P = .027).

There were no significant associations between serum FT4 and FT3 levels and suicidal ideation.


 

Interesting, but preliminary

Commenting on the findings, Sanjeev Sockalingam, MD, vice chair and professor of psychiatry at the University of Toronto, said it is an “interesting study” because the literature on trying to identify individuals at risk for suicidal ideation or behaviors is “quite mixed, in terms of the results.”

However, it was a cross-sectional study with a relatively small sample size, and studies of this nature typically include patients with hypothyroidism “who end up having suicidal thoughts,” said Dr. Sockalingam, who was not involved with the research.

“I do wonder, given the sample size and patient population, if there may be other factors that may have been related to this,” he added.

Dr. Sockalingam noted that he would like to see more data on the medications the patients were taking, and he underlined that the thyroid levels were in the normal range, “so it’s a bit difficult to untangle what that means in terms of these subtle changes in thyroid levels.”

Robert Levitan, MD, Cameron Wilson Chair in Depression Research at the Centre for Addiction and Mental Health, Toronto, also emphasized that the thyroid levels were in the normal range.

He commented that it therefore “seems unlikely that there’s going to be some biological effect that’s going to affect the brain in a significant enough way” to influence suicidal ideation.

Dr. Levitan continued, “What’s probably happening is there’s some other clinical issue here that they just haven’t picked up on that’s leading in one direction to the suicidal ideation and perhaps affecting the TSH to some extent.”

Although the study is, therefore, “preliminary,” the findings are nevertheless “interesting,” he concluded.

The study received no funding. Ms. Liaugaudaite, Dr. Sockalingam, and Dr. Levitan have disclosed no relevant financial relationships.

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

Patients with comorbid anxiety and mood disorders who have reduced, albeit “normal” serum levels of thyroid-stimulating hormone (TSH) may be at increased risk for suicidal ideation, new research suggests.

In a cross-sectional study, clinical data on diagnosis, medication use, and symptom scores were gathered, along with assessments of blood levels of thyroid axis hormones, in patients with both anxiety and mood disorders.

After investigators accounted for age, gender, symptoms, medication use, and other potential confounders, patients with suicidal ideation were 54% less likely to have higher TSH levels. There was no association found with other thyroid hormones.

Based on the results, the assessment of thyroid hormone levels “may be important for suicide prevention and might allow clinicians to evaluate the potential of the suicidal ideation risk in individuals with [anxiety and mood disorders],” co-investigator Vilma Liaugaudaite, PhD student, Neuroscience Institute of the Lithuanian University of Health Sciences, Palanga, and colleagues note.

The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Complex mechanism’

Ms. Liaugaudaite told this news organization that thyroid hormones are known to have a “profound” effect on mood and behavior.

Recent studies show “various degrees of hypothalamic-pituitary-thyroid axis dysregulation are associated with suicidal behavior” in patients with depression, she added.

Noting that disturbances in the serotonin system “constitute the most common biochemical abnormality associated with suicidal behavior,” Ms. Liaugaudaite said it is thought thyroid hormones “are involved in a complex compensatory mechanism to correct reduced central 5-hydroxytryptamine activity” via lower TSH levels.

In addition, hypersecretion of thyrotropin-releasing hormone, which stimulates the release of TSH, “has been considered a compensatory mechanism to maintain normal thyroid hormone secretion and normalize serotonin activity in depressed patients,” she said.

To investigate associations between thyroid axis hormones and suicidality in individuals with comorbid anxiety and mood disorders, the researchers assessed consecutive patients attending a stress disorders clinic.

Sociodemographic and clinical information was gathered, and patients completed the Mini International Neuropsychiatric Interview, the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) scale.

Fasting blood samples were also tested for free thyroxine (FT4), free triiodothyronine (FT3), and TSH levels.

Significant association

Seventy-seven patients aged 18 to 73 years participated in the study. Of these, 59 were women. Suicidal ideation was identified in 42 participants. Serum FT4, FT3, and TSH levels were within the normal range.

Badmanproduction/Thinkstock

There were no significant differences between patients with and without suicidal ideation in terms of age, gender, education, obesity, smoking, and medication use.

Suicidal ideation was associated with higher scores on the PHQ-9 (15.5 vs. 13.3; P = .085), and with lower TSH levels (1.54 IU/L vs. 2.04 IU/L; P = .092).

The association between serum TSH levels and suicidal ideation was significant after multivariate logistic regression analysis accounted for age, gender, PHQ-9 and GAD-7 scores, education, body mass index, smoking, and use of antidepressants, tranquilizers, mood stabilizers, and neuroleptics.

Specifically, patients with suicidal ideation were significantly less likely to have higher TSH levels than those without, at an odds ratio of 0.46 (P = .027).

There were no significant associations between serum FT4 and FT3 levels and suicidal ideation.


 

Interesting, but preliminary

Commenting on the findings, Sanjeev Sockalingam, MD, vice chair and professor of psychiatry at the University of Toronto, said it is an “interesting study” because the literature on trying to identify individuals at risk for suicidal ideation or behaviors is “quite mixed, in terms of the results.”

However, it was a cross-sectional study with a relatively small sample size, and studies of this nature typically include patients with hypothyroidism “who end up having suicidal thoughts,” said Dr. Sockalingam, who was not involved with the research.

“I do wonder, given the sample size and patient population, if there may be other factors that may have been related to this,” he added.

Dr. Sockalingam noted that he would like to see more data on the medications the patients were taking, and he underlined that the thyroid levels were in the normal range, “so it’s a bit difficult to untangle what that means in terms of these subtle changes in thyroid levels.”

Robert Levitan, MD, Cameron Wilson Chair in Depression Research at the Centre for Addiction and Mental Health, Toronto, also emphasized that the thyroid levels were in the normal range.

He commented that it therefore “seems unlikely that there’s going to be some biological effect that’s going to affect the brain in a significant enough way” to influence suicidal ideation.

Dr. Levitan continued, “What’s probably happening is there’s some other clinical issue here that they just haven’t picked up on that’s leading in one direction to the suicidal ideation and perhaps affecting the TSH to some extent.”

Although the study is, therefore, “preliminary,” the findings are nevertheless “interesting,” he concluded.

The study received no funding. Ms. Liaugaudaite, Dr. Sockalingam, and Dr. Levitan have disclosed no relevant financial relationships.

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

Daily exposure to phthalates, which are synthetic chemicals founds in many consumer products, may lead to hundreds of thousands of early deaths each year among older adults in the United States, according to a new study published Oct. 12, 2021, in the peer-reviewed journal Environmental Pollution.

The chemicals are found in hundreds of types of products, including children’s toys, food storage containers, makeup, perfume, and shampoo. In the study, those with the highest levels of phthalates had a greater risk of death from any cause, especially heart disease.

“This study adds to the growing database on the impact of plastics on the human body and bolsters public health and business cases for reducing or eliminating the use of plastics,” Leonardo Trasande, MD, the lead author and a professor of environmental medicine and population health at New York University Langone Health, told CNN.

Dr. Trasande and colleagues measured the urine concentration of phthalates in more than 5,000 adults aged 55-64 and compared the levels with the risk of early death over an average of 10 years. The research team controlled for preexisting heart diseases, diabetes, cancer, poor eating habits, physical activity, body mass, and other known hormone disruptors such as bisphenol A, or BPA, an industrial chemical that’s been used since the 1950s to make certain plastics and resins, according to the Mayo Clinic

The research team found that phthalates could contribute to 91,000-107,000 premature deaths per year in the United States. These early deaths could cost the nation $40 billion to $47 billion each year in lost economic productivity.

Phthalates interrupt the body’s endocrine system and hormone production. Previous studies have found that the chemicals are linked with developmental, reproductive, and immune system problems, according to NYU Langone Health. They’ve also been linked with asthma, childhood obesity, heart issues, and cancer.

“These chemicals have a rap sheet,” Dr. Trasande told CNN. “And the fact of the matter is that when you look at the entire body of evidence, it provides a haunting pattern of concern.”

Phthalates are often called “everywhere chemicals” because they are so common, CNN reported. Also called “plasticizers,” they are added to products to make them more durable, including PVC plumbing, vinyl flooring, medical tubing, garden hoses, food packaging, detergents, clothing, furniture, and automotive materials.

People are often exposed when they breathe contaminated air or consume food that comes into contact with the chemical, according to the Centers for Disease Control and Prevention. Children may be exposed by touching plastic items and putting their hands in their mouth.

Dr. Trasande told CNN that it’s possible to lessen exposure to phthalates and other endocrine disruptors such as BPA by using unscented lotions, laundry detergents, and cleaning supplies, as well as substituting glass, stainless steel, ceramic, and wood for plastic food storage.

“First, avoid plastics as much as you can. Never put plastic containers in the microwave or dishwasher, where the heat can break down the linings so they might be absorbed more readily,” he said. “In addition, cooking at home and reducing your use of processed foods can reduce the levels of the chemical exposures you come in contact with.”

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

Daily exposure to phthalates, which are synthetic chemicals founds in many consumer products, may lead to hundreds of thousands of early deaths each year among older adults in the United States, according to a new study published Oct. 12, 2021, in the peer-reviewed journal Environmental Pollution.

The chemicals are found in hundreds of types of products, including children’s toys, food storage containers, makeup, perfume, and shampoo. In the study, those with the highest levels of phthalates had a greater risk of death from any cause, especially heart disease.

“This study adds to the growing database on the impact of plastics on the human body and bolsters public health and business cases for reducing or eliminating the use of plastics,” Leonardo Trasande, MD, the lead author and a professor of environmental medicine and population health at New York University Langone Health, told CNN.

Dr. Trasande and colleagues measured the urine concentration of phthalates in more than 5,000 adults aged 55-64 and compared the levels with the risk of early death over an average of 10 years. The research team controlled for preexisting heart diseases, diabetes, cancer, poor eating habits, physical activity, body mass, and other known hormone disruptors such as bisphenol A, or BPA, an industrial chemical that’s been used since the 1950s to make certain plastics and resins, according to the Mayo Clinic

The research team found that phthalates could contribute to 91,000-107,000 premature deaths per year in the United States. These early deaths could cost the nation $40 billion to $47 billion each year in lost economic productivity.

Phthalates interrupt the body’s endocrine system and hormone production. Previous studies have found that the chemicals are linked with developmental, reproductive, and immune system problems, according to NYU Langone Health. They’ve also been linked with asthma, childhood obesity, heart issues, and cancer.

“These chemicals have a rap sheet,” Dr. Trasande told CNN. “And the fact of the matter is that when you look at the entire body of evidence, it provides a haunting pattern of concern.”

Phthalates are often called “everywhere chemicals” because they are so common, CNN reported. Also called “plasticizers,” they are added to products to make them more durable, including PVC plumbing, vinyl flooring, medical tubing, garden hoses, food packaging, detergents, clothing, furniture, and automotive materials.

People are often exposed when they breathe contaminated air or consume food that comes into contact with the chemical, according to the Centers for Disease Control and Prevention. Children may be exposed by touching plastic items and putting their hands in their mouth.

Dr. Trasande told CNN that it’s possible to lessen exposure to phthalates and other endocrine disruptors such as BPA by using unscented lotions, laundry detergents, and cleaning supplies, as well as substituting glass, stainless steel, ceramic, and wood for plastic food storage.

“First, avoid plastics as much as you can. Never put plastic containers in the microwave or dishwasher, where the heat can break down the linings so they might be absorbed more readily,” he said. “In addition, cooking at home and reducing your use of processed foods can reduce the levels of the chemical exposures you come in contact with.”

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

Daily exposure to phthalates, which are synthetic chemicals founds in many consumer products, may lead to hundreds of thousands of early deaths each year among older adults in the United States, according to a new study published Oct. 12, 2021, in the peer-reviewed journal Environmental Pollution.

The chemicals are found in hundreds of types of products, including children’s toys, food storage containers, makeup, perfume, and shampoo. In the study, those with the highest levels of phthalates had a greater risk of death from any cause, especially heart disease.

“This study adds to the growing database on the impact of plastics on the human body and bolsters public health and business cases for reducing or eliminating the use of plastics,” Leonardo Trasande, MD, the lead author and a professor of environmental medicine and population health at New York University Langone Health, told CNN.

Dr. Trasande and colleagues measured the urine concentration of phthalates in more than 5,000 adults aged 55-64 and compared the levels with the risk of early death over an average of 10 years. The research team controlled for preexisting heart diseases, diabetes, cancer, poor eating habits, physical activity, body mass, and other known hormone disruptors such as bisphenol A, or BPA, an industrial chemical that’s been used since the 1950s to make certain plastics and resins, according to the Mayo Clinic

The research team found that phthalates could contribute to 91,000-107,000 premature deaths per year in the United States. These early deaths could cost the nation $40 billion to $47 billion each year in lost economic productivity.

Phthalates interrupt the body’s endocrine system and hormone production. Previous studies have found that the chemicals are linked with developmental, reproductive, and immune system problems, according to NYU Langone Health. They’ve also been linked with asthma, childhood obesity, heart issues, and cancer.

“These chemicals have a rap sheet,” Dr. Trasande told CNN. “And the fact of the matter is that when you look at the entire body of evidence, it provides a haunting pattern of concern.”

Phthalates are often called “everywhere chemicals” because they are so common, CNN reported. Also called “plasticizers,” they are added to products to make them more durable, including PVC plumbing, vinyl flooring, medical tubing, garden hoses, food packaging, detergents, clothing, furniture, and automotive materials.

People are often exposed when they breathe contaminated air or consume food that comes into contact with the chemical, according to the Centers for Disease Control and Prevention. Children may be exposed by touching plastic items and putting their hands in their mouth.

Dr. Trasande told CNN that it’s possible to lessen exposure to phthalates and other endocrine disruptors such as BPA by using unscented lotions, laundry detergents, and cleaning supplies, as well as substituting glass, stainless steel, ceramic, and wood for plastic food storage.

“First, avoid plastics as much as you can. Never put plastic containers in the microwave or dishwasher, where the heat can break down the linings so they might be absorbed more readily,” he said. “In addition, cooking at home and reducing your use of processed foods can reduce the levels of the chemical exposures you come in contact with.”

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

Treatment of Graves’ orbitopathy with statins in combination with glucocorticoids shows benefits among people with – and even without – high cholesterol, results from a new randomized clinical trial show.

RogerAshford/Thinkstock

“Our results [indicate] that adding atorvastatin to intravenous glucocorticoids seems to potentiate the effects of glucocorticoids,” senior author Michelle Marino, MD, associate professor of endocrinology in the department of clinical and experimental medicine at the University of Pisa, Italy, told this news organization.

“At least in hypercholesterolemic patients with moderate to severe and active Graves’ orbitopathy, atorvastatin should be considered in addition to intravenous glucocorticoids,” Dr. Marino said.

The study was presented by first author Giulia Lanzolla, MD, also of the University of Pisa and University Hospital of Pisa, at the virtual annual meeting of the American Thyroid Association.

Hypercholesterolemia, well known to promote systemic inflammation, has been previously linked to Graves’ orbitopathy, and the use of statins has also been shown to possibly provide a protective effect in the risk of developing the thyroid eye disease.

Furthermore, patients with Graves’ orbitopathy and high cholesterol levels, compared with those with normal cholesterol, have been shown to have poorer responses to treatment with glucocorticoids, which have long been the first line of treatment.

Asked for comment on the findings, Marius Stan, MD, a consultant in the division of endocrinology, diabetes, metabolism, and nutrition, Mayo Clinic, Rochester, Minn., said he didn’t think the outcome measure used – a composite of a variety of measures of thyroid eye disease – was best to truly understand the benefits.
 

Statins for Graves’ orbitopathy (STAGO) study details

For a better understanding of the effects with and without the addition of statins in a randomized trial, Dr. Lanzolla and colleagues enrolled 88 patients with high cholesterol and moderate to severe active Graves’ orbitopathy in the phase 2 STAGO trial.

Patients were randomized to two groups of 44 patients each to receive treatment either with intravenous (IV) methylprednisolone at 500 mg per week for 6 weeks, followed by 250 mg per week for another 6 weeks, in combination with atorvastatin 20 mg daily for 12 weeks, or methylprednisolone alone for 12 weeks.

The primary endpoint was a composite of Graves orbitopathy outcomes and included measures of exophthalmos, clinical activity score, eyelid aperture, diplopia, and visual acuity, as assessed in the modified intention-to-treat population.

The trial met the primary composite endpoint, with 51.2% of those treated with statins achieving the outcome (21 of 41) versus 28.2% (11 of 39) of those treated with glucocorticoids alone (odds ratio, 2.76; P = .03).

The study also achieved secondary outcomes, with 43.9% in the statin group having a response to treatment at 12 weeks versus 23% in the glucocorticoid group (OR 2.60; P = .05). The statin group also had a greater improvement in quality of life measures (P = .03).

The glucocorticoid-only group meanwhile had a significantly greater rate of Graves orbitopathy relapse at 24 weeks, with six relapses versus none in the statin group (15.3% vs. 0.0%; OR 0.06; P = .01).

There were no significant differences in low-density lipoprotein (LDL) cholesterol between those who did and did not respond to treatment in the statin group.

The most likely explanation for those findings is that “atorvastatin acts through its pleiotropic action, resulting in an anti-inflammatory effect,” Dr. Marino said.

“In addition, the effect may be related to the capability of statins to inhibit fibroblast proliferation,” Dr. Marino added.

“Total cholesterol had a behavior similar to LDL cholesterol, [while] HDL cholesterol did not change across the study.”

There were no major adverse events related to atorvastatin, with one patient in each group requiring treatment discontinuation.

In the rapidly evolving landscape of treatments for Graves’ orbitopathy, including the recent Food and Drug Administration approval for teprotumumab in thyroid eye disease, the potential role of statins remains to be seen, Dr. Marino noted.

“Graves’ orbitopathy is a rather complex disease, and in its mild to moderate forms it is very rare for a patient to require only a single treatment,” Dr. Marino explained. “Rehabilitative surgery is needed quite often once the disease is inactive.”

The authors noted that a composite overall Graves’ orbitopathy outcome was used as the primary endpoint because the alternative of a change in single eye features may not reflect a true modification of Graves’ orbitopathy and could be affected by a number of unrelated factors.

“By contrast, the composite evaluation offers a more realistic picture,” the authors wrote in the article, which was published in The Lancet Diabetes and Endocrinology.  
 

Composite outcome not best way of assessing effects of statins

Dr. Stan extrapolated on his criticism of the trial.

“The study has interesting results but fails to show that any particular eye feature is benefited by the combination therapy, showing only the composite outcome to be improved,” he told this news organization.

“Unfortunately, that is hard to extrapolate to patient care, where one or another of Graves’ orbitopathy features are present and are the intended target of therapy,” he said.

Dr. Stan added that IV glucocorticoids are meanwhile also changing the landscape of treatment of thyroid eye disease.

“This ... current plan is to recommend a more individualized approach, depending on what is the main problem for that thyroid eye disease case,” he explained.

Dr. Marino noted that the authors are planning a double-blind, placebo-controlled phase 3 clinical trial of the statin/glucocorticoid combination to include patients regardless of their cholesterol levels.

The study received funding from Associazione Allievi Endocrinologia Pisana. The authors have reported no relevant financial relationships. Dr. Stan is on the advisory board for Horizon Pharma/Immunovant and provides general consulting for VasaraGen/Septerna and ValenzaBio/Medicxi.

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

Treatment of Graves’ orbitopathy with statins in combination with glucocorticoids shows benefits among people with – and even without – high cholesterol, results from a new randomized clinical trial show.

RogerAshford/Thinkstock

“Our results [indicate] that adding atorvastatin to intravenous glucocorticoids seems to potentiate the effects of glucocorticoids,” senior author Michelle Marino, MD, associate professor of endocrinology in the department of clinical and experimental medicine at the University of Pisa, Italy, told this news organization.

“At least in hypercholesterolemic patients with moderate to severe and active Graves’ orbitopathy, atorvastatin should be considered in addition to intravenous glucocorticoids,” Dr. Marino said.

The study was presented by first author Giulia Lanzolla, MD, also of the University of Pisa and University Hospital of Pisa, at the virtual annual meeting of the American Thyroid Association.

Hypercholesterolemia, well known to promote systemic inflammation, has been previously linked to Graves’ orbitopathy, and the use of statins has also been shown to possibly provide a protective effect in the risk of developing the thyroid eye disease.

Furthermore, patients with Graves’ orbitopathy and high cholesterol levels, compared with those with normal cholesterol, have been shown to have poorer responses to treatment with glucocorticoids, which have long been the first line of treatment.

Asked for comment on the findings, Marius Stan, MD, a consultant in the division of endocrinology, diabetes, metabolism, and nutrition, Mayo Clinic, Rochester, Minn., said he didn’t think the outcome measure used – a composite of a variety of measures of thyroid eye disease – was best to truly understand the benefits.
 

Statins for Graves’ orbitopathy (STAGO) study details

For a better understanding of the effects with and without the addition of statins in a randomized trial, Dr. Lanzolla and colleagues enrolled 88 patients with high cholesterol and moderate to severe active Graves’ orbitopathy in the phase 2 STAGO trial.

Patients were randomized to two groups of 44 patients each to receive treatment either with intravenous (IV) methylprednisolone at 500 mg per week for 6 weeks, followed by 250 mg per week for another 6 weeks, in combination with atorvastatin 20 mg daily for 12 weeks, or methylprednisolone alone for 12 weeks.

The primary endpoint was a composite of Graves orbitopathy outcomes and included measures of exophthalmos, clinical activity score, eyelid aperture, diplopia, and visual acuity, as assessed in the modified intention-to-treat population.

The trial met the primary composite endpoint, with 51.2% of those treated with statins achieving the outcome (21 of 41) versus 28.2% (11 of 39) of those treated with glucocorticoids alone (odds ratio, 2.76; P = .03).

The study also achieved secondary outcomes, with 43.9% in the statin group having a response to treatment at 12 weeks versus 23% in the glucocorticoid group (OR 2.60; P = .05). The statin group also had a greater improvement in quality of life measures (P = .03).

The glucocorticoid-only group meanwhile had a significantly greater rate of Graves orbitopathy relapse at 24 weeks, with six relapses versus none in the statin group (15.3% vs. 0.0%; OR 0.06; P = .01).

There were no significant differences in low-density lipoprotein (LDL) cholesterol between those who did and did not respond to treatment in the statin group.

The most likely explanation for those findings is that “atorvastatin acts through its pleiotropic action, resulting in an anti-inflammatory effect,” Dr. Marino said.

“In addition, the effect may be related to the capability of statins to inhibit fibroblast proliferation,” Dr. Marino added.

“Total cholesterol had a behavior similar to LDL cholesterol, [while] HDL cholesterol did not change across the study.”

There were no major adverse events related to atorvastatin, with one patient in each group requiring treatment discontinuation.

In the rapidly evolving landscape of treatments for Graves’ orbitopathy, including the recent Food and Drug Administration approval for teprotumumab in thyroid eye disease, the potential role of statins remains to be seen, Dr. Marino noted.

“Graves’ orbitopathy is a rather complex disease, and in its mild to moderate forms it is very rare for a patient to require only a single treatment,” Dr. Marino explained. “Rehabilitative surgery is needed quite often once the disease is inactive.”

The authors noted that a composite overall Graves’ orbitopathy outcome was used as the primary endpoint because the alternative of a change in single eye features may not reflect a true modification of Graves’ orbitopathy and could be affected by a number of unrelated factors.

“By contrast, the composite evaluation offers a more realistic picture,” the authors wrote in the article, which was published in The Lancet Diabetes and Endocrinology.  
 

Composite outcome not best way of assessing effects of statins

Dr. Stan extrapolated on his criticism of the trial.

“The study has interesting results but fails to show that any particular eye feature is benefited by the combination therapy, showing only the composite outcome to be improved,” he told this news organization.

“Unfortunately, that is hard to extrapolate to patient care, where one or another of Graves’ orbitopathy features are present and are the intended target of therapy,” he said.

Dr. Stan added that IV glucocorticoids are meanwhile also changing the landscape of treatment of thyroid eye disease.

“This ... current plan is to recommend a more individualized approach, depending on what is the main problem for that thyroid eye disease case,” he explained.

Dr. Marino noted that the authors are planning a double-blind, placebo-controlled phase 3 clinical trial of the statin/glucocorticoid combination to include patients regardless of their cholesterol levels.

The study received funding from Associazione Allievi Endocrinologia Pisana. The authors have reported no relevant financial relationships. Dr. Stan is on the advisory board for Horizon Pharma/Immunovant and provides general consulting for VasaraGen/Septerna and ValenzaBio/Medicxi.

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

Treatment of Graves’ orbitopathy with statins in combination with glucocorticoids shows benefits among people with – and even without – high cholesterol, results from a new randomized clinical trial show.

RogerAshford/Thinkstock

“Our results [indicate] that adding atorvastatin to intravenous glucocorticoids seems to potentiate the effects of glucocorticoids,” senior author Michelle Marino, MD, associate professor of endocrinology in the department of clinical and experimental medicine at the University of Pisa, Italy, told this news organization.

“At least in hypercholesterolemic patients with moderate to severe and active Graves’ orbitopathy, atorvastatin should be considered in addition to intravenous glucocorticoids,” Dr. Marino said.

The study was presented by first author Giulia Lanzolla, MD, also of the University of Pisa and University Hospital of Pisa, at the virtual annual meeting of the American Thyroid Association.

Hypercholesterolemia, well known to promote systemic inflammation, has been previously linked to Graves’ orbitopathy, and the use of statins has also been shown to possibly provide a protective effect in the risk of developing the thyroid eye disease.

Furthermore, patients with Graves’ orbitopathy and high cholesterol levels, compared with those with normal cholesterol, have been shown to have poorer responses to treatment with glucocorticoids, which have long been the first line of treatment.

Asked for comment on the findings, Marius Stan, MD, a consultant in the division of endocrinology, diabetes, metabolism, and nutrition, Mayo Clinic, Rochester, Minn., said he didn’t think the outcome measure used – a composite of a variety of measures of thyroid eye disease – was best to truly understand the benefits.
 

Statins for Graves’ orbitopathy (STAGO) study details

For a better understanding of the effects with and without the addition of statins in a randomized trial, Dr. Lanzolla and colleagues enrolled 88 patients with high cholesterol and moderate to severe active Graves’ orbitopathy in the phase 2 STAGO trial.

Patients were randomized to two groups of 44 patients each to receive treatment either with intravenous (IV) methylprednisolone at 500 mg per week for 6 weeks, followed by 250 mg per week for another 6 weeks, in combination with atorvastatin 20 mg daily for 12 weeks, or methylprednisolone alone for 12 weeks.

The primary endpoint was a composite of Graves orbitopathy outcomes and included measures of exophthalmos, clinical activity score, eyelid aperture, diplopia, and visual acuity, as assessed in the modified intention-to-treat population.

The trial met the primary composite endpoint, with 51.2% of those treated with statins achieving the outcome (21 of 41) versus 28.2% (11 of 39) of those treated with glucocorticoids alone (odds ratio, 2.76; P = .03).

The study also achieved secondary outcomes, with 43.9% in the statin group having a response to treatment at 12 weeks versus 23% in the glucocorticoid group (OR 2.60; P = .05). The statin group also had a greater improvement in quality of life measures (P = .03).

The glucocorticoid-only group meanwhile had a significantly greater rate of Graves orbitopathy relapse at 24 weeks, with six relapses versus none in the statin group (15.3% vs. 0.0%; OR 0.06; P = .01).

There were no significant differences in low-density lipoprotein (LDL) cholesterol between those who did and did not respond to treatment in the statin group.

The most likely explanation for those findings is that “atorvastatin acts through its pleiotropic action, resulting in an anti-inflammatory effect,” Dr. Marino said.

“In addition, the effect may be related to the capability of statins to inhibit fibroblast proliferation,” Dr. Marino added.

“Total cholesterol had a behavior similar to LDL cholesterol, [while] HDL cholesterol did not change across the study.”

There were no major adverse events related to atorvastatin, with one patient in each group requiring treatment discontinuation.

In the rapidly evolving landscape of treatments for Graves’ orbitopathy, including the recent Food and Drug Administration approval for teprotumumab in thyroid eye disease, the potential role of statins remains to be seen, Dr. Marino noted.

“Graves’ orbitopathy is a rather complex disease, and in its mild to moderate forms it is very rare for a patient to require only a single treatment,” Dr. Marino explained. “Rehabilitative surgery is needed quite often once the disease is inactive.”

The authors noted that a composite overall Graves’ orbitopathy outcome was used as the primary endpoint because the alternative of a change in single eye features may not reflect a true modification of Graves’ orbitopathy and could be affected by a number of unrelated factors.

“By contrast, the composite evaluation offers a more realistic picture,” the authors wrote in the article, which was published in The Lancet Diabetes and Endocrinology.  
 

Composite outcome not best way of assessing effects of statins

Dr. Stan extrapolated on his criticism of the trial.

“The study has interesting results but fails to show that any particular eye feature is benefited by the combination therapy, showing only the composite outcome to be improved,” he told this news organization.

“Unfortunately, that is hard to extrapolate to patient care, where one or another of Graves’ orbitopathy features are present and are the intended target of therapy,” he said.

Dr. Stan added that IV glucocorticoids are meanwhile also changing the landscape of treatment of thyroid eye disease.

“This ... current plan is to recommend a more individualized approach, depending on what is the main problem for that thyroid eye disease case,” he explained.

Dr. Marino noted that the authors are planning a double-blind, placebo-controlled phase 3 clinical trial of the statin/glucocorticoid combination to include patients regardless of their cholesterol levels.

The study received funding from Associazione Allievi Endocrinologia Pisana. The authors have reported no relevant financial relationships. Dr. Stan is on the advisory board for Horizon Pharma/Immunovant and provides general consulting for VasaraGen/Septerna and ValenzaBio/Medicxi.

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

The attraction of reproductive endocrinology and infertility (REI), personally, is the hormonal interplay of the hypothalamus and pituitary with the end organs that are intimately involved in female reproduction. While the sex hormone–producing organs, such as the ovaries and adrenal glands, are directly related to reproductive function, the thyroid gland is typically overlooked until dysfunction occurs, resulting in ovulation dysfunction and pregnancy complications, namely miscarriage and preterm labor. This month we address thyroid function, given its vital role for fertility and pregnancy health and the fetus’ reliance on maternal thyroid hormone during the first trimester to ensure normal neurologic development.

Thyroid disease is the second most common endocrine disorder affecting women of reproductive age; the first being polycystic ovary syndrome (PCOS). Thyroid dysfunction can impair ovulation and, consequently, fertility. Hyperthyroidism is found in approximately 2.3% of women presenting with fertility problems, compared with 1.5% of women in the general population. Hypothyroidism affects 0.5% of women of reproductive age and has been shown to result in impaired reproductive outcomes, including miscarriage, along with adverse obstetric and fetal outcomes. Subclinical hypothyroidism (SCH), defined as an elevated thyroid-stimulating hormone (TSH) level with a normal free T4, has an incidence of 4%-8% in the reproductive-age population. While there is fair evidence SCH increases miscarriage, treatment may result in improved outcomes.

The prevalence of thyroid autoimmunity (TAI) among women of reproductive age is 8%-14% worldwide and it is increased in the infertility population. TAI, defined as the presence of thyroid peroxidase and thyroglobulin antibodies, has been shown to be associated with a reduced live birth rate, increase in preterm birth, and a two- to threefold increase in miscarriage.

The endocrinologic “pendulum” of guidance regarding the effect on and management of thyroid function regarding fertility, pregnancy, and baby has conflicting results. Controlled ovarian hyperstimulation for in vitro fertilization appears to alter TSH levels and levothyroxine requirements increase in the first trimester by approximately 50%. The controversy lies in which population of women should be tested for TAI, which TSH level is acceptable, and how to manage, if at all, euthyroid women with TAI or women with SCH who are trying to conceive. Ultimately, which women would benefit from levothyroxine while trying to conceive and during pregnancy?
 

Summary of salient studies

• In a meta-analysis, untreated women with SCH had a higher prevalence of miscarriage, compared with euthyroid women (RR, 1.90). Miscarriage rates were even higher in SCH with TIA, compared with women with SCH. The authors recommend “early treatments to avoid adverse pregnancy outcomes and complications.”
• A randomized controlled trial from China studied women who were euthyroid with TAI undergoing IVF. The authors demonstrated levothyroxine did not reduce miscarriage rates or increase live birth rates. To dive further into their cohort, the authors addressed whether TSH above 2.5 mIU/L or above 4 mIU/L (per the American Society for Reproductive Medicine cutoff values) impaired reproductive outcome and found no benefit of levothyroxine in any subgroup. This is consistent with other studies that showed no detrimental effect on pregnancy outcome with TSH levels above 2.5 mIU/L in the normal range and no reduction in miscarriage with the addition of levothyroxine.
• An observational cohort study of IVF patients that underwent preimplantation genetic testing for aneuploidy did not demonstrate an association between chromosomally normal embryos that miscarried and maternal antithyroid antibodies in recurrent miscarriage patients.
• A double-blind, placebo-controlled trial on the use of levothyroxine in euthyroid women with TAI did not result in a higher rate of live births, lower rate of pregnancy loss, or preterm birth, compared with placebo.

Consensus statements

• The American Society for Reproductive Medicine considers it reasonable to test infertile women trying to conceive and to treat SCH with levothyroxine to maintain a TSH less than 2.5 mIU/L and within the normal range. Women who have TAI and TSH greater than 2.5 mIU/L can be considered for treatment with levothyroxine.
• The Endocrine Society recommends levothyroxine in women with SCH who have TAI.
• The American Thyroid Association guideline recommends women with SCH who are undergoing IVF be treated with levothyroxine to achieve a TSH concentration less than 2.5mIU/L.
• The 2011 guidelines of the American Thyroid Association and the 2012 guidelines of the Endocrine Society recommended the specific reference ranges for TSH in the early, middle, and late stages of pregnancy as 0.1-2.5 mIU/L, 0.2-3.0 mIU/L, and 0.3-3.0 mIU/L, respectively.
• The American College of Obstetricians & Gynecologists recommend avoiding universal thyroid screening in pregnancy since “identification and treatment of maternal subclinical hypothyroidism has not been shown to result in improved pregnancy outcomes and neurocognitive function in offspring.”

Conclusion

The 2019 Cochrane Database states there are no clear conclusions regarding treatment with levothyroxine in euthyroid TAI or SCH because of the low quality of evidence reported. While TAI and SCH have been associated with pregnancy complications, there is no apparent benefit of levothyroxine in women with TAI or TSH levels between 2.5 and 4 mIU/L.

So, the conundrum is which preconception women to test and how to manage nonovert thyroid disease. For now, it is reasonable to obtain a serum TSH on all women desiring fertility, to treat SCH with levothyroxine to maintain TSH less than 2.5 mIU/L in the normal range, and to adjust levothyroxine accordingly throughout pregnancy.

Dr. Trolice is director of fertility at CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no disclosures. Email him at [email protected].

The attraction of reproductive endocrinology and infertility (REI), personally, is the hormonal interplay of the hypothalamus and pituitary with the end organs that are intimately involved in female reproduction. While the sex hormone–producing organs, such as the ovaries and adrenal glands, are directly related to reproductive function, the thyroid gland is typically overlooked until dysfunction occurs, resulting in ovulation dysfunction and pregnancy complications, namely miscarriage and preterm labor. This month we address thyroid function, given its vital role for fertility and pregnancy health and the fetus’ reliance on maternal thyroid hormone during the first trimester to ensure normal neurologic development.

Thyroid disease is the second most common endocrine disorder affecting women of reproductive age; the first being polycystic ovary syndrome (PCOS). Thyroid dysfunction can impair ovulation and, consequently, fertility. Hyperthyroidism is found in approximately 2.3% of women presenting with fertility problems, compared with 1.5% of women in the general population. Hypothyroidism affects 0.5% of women of reproductive age and has been shown to result in impaired reproductive outcomes, including miscarriage, along with adverse obstetric and fetal outcomes. Subclinical hypothyroidism (SCH), defined as an elevated thyroid-stimulating hormone (TSH) level with a normal free T4, has an incidence of 4%-8% in the reproductive-age population. While there is fair evidence SCH increases miscarriage, treatment may result in improved outcomes.

The prevalence of thyroid autoimmunity (TAI) among women of reproductive age is 8%-14% worldwide and it is increased in the infertility population. TAI, defined as the presence of thyroid peroxidase and thyroglobulin antibodies, has been shown to be associated with a reduced live birth rate, increase in preterm birth, and a two- to threefold increase in miscarriage.

The endocrinologic “pendulum” of guidance regarding the effect on and management of thyroid function regarding fertility, pregnancy, and baby has conflicting results. Controlled ovarian hyperstimulation for in vitro fertilization appears to alter TSH levels and levothyroxine requirements increase in the first trimester by approximately 50%. The controversy lies in which population of women should be tested for TAI, which TSH level is acceptable, and how to manage, if at all, euthyroid women with TAI or women with SCH who are trying to conceive. Ultimately, which women would benefit from levothyroxine while trying to conceive and during pregnancy?
 

Summary of salient studies

• In a meta-analysis, untreated women with SCH had a higher prevalence of miscarriage, compared with euthyroid women (RR, 1.90). Miscarriage rates were even higher in SCH with TIA, compared with women with SCH. The authors recommend “early treatments to avoid adverse pregnancy outcomes and complications.”
• A randomized controlled trial from China studied women who were euthyroid with TAI undergoing IVF. The authors demonstrated levothyroxine did not reduce miscarriage rates or increase live birth rates. To dive further into their cohort, the authors addressed whether TSH above 2.5 mIU/L or above 4 mIU/L (per the American Society for Reproductive Medicine cutoff values) impaired reproductive outcome and found no benefit of levothyroxine in any subgroup. This is consistent with other studies that showed no detrimental effect on pregnancy outcome with TSH levels above 2.5 mIU/L in the normal range and no reduction in miscarriage with the addition of levothyroxine.
• An observational cohort study of IVF patients that underwent preimplantation genetic testing for aneuploidy did not demonstrate an association between chromosomally normal embryos that miscarried and maternal antithyroid antibodies in recurrent miscarriage patients.
• A double-blind, placebo-controlled trial on the use of levothyroxine in euthyroid women with TAI did not result in a higher rate of live births, lower rate of pregnancy loss, or preterm birth, compared with placebo.

Consensus statements

• The American Society for Reproductive Medicine considers it reasonable to test infertile women trying to conceive and to treat SCH with levothyroxine to maintain a TSH less than 2.5 mIU/L and within the normal range. Women who have TAI and TSH greater than 2.5 mIU/L can be considered for treatment with levothyroxine.
• The Endocrine Society recommends levothyroxine in women with SCH who have TAI.
• The American Thyroid Association guideline recommends women with SCH who are undergoing IVF be treated with levothyroxine to achieve a TSH concentration less than 2.5mIU/L.
• The 2011 guidelines of the American Thyroid Association and the 2012 guidelines of the Endocrine Society recommended the specific reference ranges for TSH in the early, middle, and late stages of pregnancy as 0.1-2.5 mIU/L, 0.2-3.0 mIU/L, and 0.3-3.0 mIU/L, respectively.
• The American College of Obstetricians & Gynecologists recommend avoiding universal thyroid screening in pregnancy since “identification and treatment of maternal subclinical hypothyroidism has not been shown to result in improved pregnancy outcomes and neurocognitive function in offspring.”

Conclusion

The 2019 Cochrane Database states there are no clear conclusions regarding treatment with levothyroxine in euthyroid TAI or SCH because of the low quality of evidence reported. While TAI and SCH have been associated with pregnancy complications, there is no apparent benefit of levothyroxine in women with TAI or TSH levels between 2.5 and 4 mIU/L.

So, the conundrum is which preconception women to test and how to manage nonovert thyroid disease. For now, it is reasonable to obtain a serum TSH on all women desiring fertility, to treat SCH with levothyroxine to maintain TSH less than 2.5 mIU/L in the normal range, and to adjust levothyroxine accordingly throughout pregnancy.

Dr. Trolice is director of fertility at CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no disclosures. Email him at [email protected].

The attraction of reproductive endocrinology and infertility (REI), personally, is the hormonal interplay of the hypothalamus and pituitary with the end organs that are intimately involved in female reproduction. While the sex hormone–producing organs, such as the ovaries and adrenal glands, are directly related to reproductive function, the thyroid gland is typically overlooked until dysfunction occurs, resulting in ovulation dysfunction and pregnancy complications, namely miscarriage and preterm labor. This month we address thyroid function, given its vital role for fertility and pregnancy health and the fetus’ reliance on maternal thyroid hormone during the first trimester to ensure normal neurologic development.

Thyroid disease is the second most common endocrine disorder affecting women of reproductive age; the first being polycystic ovary syndrome (PCOS). Thyroid dysfunction can impair ovulation and, consequently, fertility. Hyperthyroidism is found in approximately 2.3% of women presenting with fertility problems, compared with 1.5% of women in the general population. Hypothyroidism affects 0.5% of women of reproductive age and has been shown to result in impaired reproductive outcomes, including miscarriage, along with adverse obstetric and fetal outcomes. Subclinical hypothyroidism (SCH), defined as an elevated thyroid-stimulating hormone (TSH) level with a normal free T4, has an incidence of 4%-8% in the reproductive-age population. While there is fair evidence SCH increases miscarriage, treatment may result in improved outcomes.

The prevalence of thyroid autoimmunity (TAI) among women of reproductive age is 8%-14% worldwide and it is increased in the infertility population. TAI, defined as the presence of thyroid peroxidase and thyroglobulin antibodies, has been shown to be associated with a reduced live birth rate, increase in preterm birth, and a two- to threefold increase in miscarriage.

The endocrinologic “pendulum” of guidance regarding the effect on and management of thyroid function regarding fertility, pregnancy, and baby has conflicting results. Controlled ovarian hyperstimulation for in vitro fertilization appears to alter TSH levels and levothyroxine requirements increase in the first trimester by approximately 50%. The controversy lies in which population of women should be tested for TAI, which TSH level is acceptable, and how to manage, if at all, euthyroid women with TAI or women with SCH who are trying to conceive. Ultimately, which women would benefit from levothyroxine while trying to conceive and during pregnancy?
 

Summary of salient studies

• In a meta-analysis, untreated women with SCH had a higher prevalence of miscarriage, compared with euthyroid women (RR, 1.90). Miscarriage rates were even higher in SCH with TIA, compared with women with SCH. The authors recommend “early treatments to avoid adverse pregnancy outcomes and complications.”
• A randomized controlled trial from China studied women who were euthyroid with TAI undergoing IVF. The authors demonstrated levothyroxine did not reduce miscarriage rates or increase live birth rates. To dive further into their cohort, the authors addressed whether TSH above 2.5 mIU/L or above 4 mIU/L (per the American Society for Reproductive Medicine cutoff values) impaired reproductive outcome and found no benefit of levothyroxine in any subgroup. This is consistent with other studies that showed no detrimental effect on pregnancy outcome with TSH levels above 2.5 mIU/L in the normal range and no reduction in miscarriage with the addition of levothyroxine.
• An observational cohort study of IVF patients that underwent preimplantation genetic testing for aneuploidy did not demonstrate an association between chromosomally normal embryos that miscarried and maternal antithyroid antibodies in recurrent miscarriage patients.
• A double-blind, placebo-controlled trial on the use of levothyroxine in euthyroid women with TAI did not result in a higher rate of live births, lower rate of pregnancy loss, or preterm birth, compared with placebo.

Consensus statements

• The American Society for Reproductive Medicine considers it reasonable to test infertile women trying to conceive and to treat SCH with levothyroxine to maintain a TSH less than 2.5 mIU/L and within the normal range. Women who have TAI and TSH greater than 2.5 mIU/L can be considered for treatment with levothyroxine.
• The Endocrine Society recommends levothyroxine in women with SCH who have TAI.
• The American Thyroid Association guideline recommends women with SCH who are undergoing IVF be treated with levothyroxine to achieve a TSH concentration less than 2.5mIU/L.
• The 2011 guidelines of the American Thyroid Association and the 2012 guidelines of the Endocrine Society recommended the specific reference ranges for TSH in the early, middle, and late stages of pregnancy as 0.1-2.5 mIU/L, 0.2-3.0 mIU/L, and 0.3-3.0 mIU/L, respectively.
• The American College of Obstetricians & Gynecologists recommend avoiding universal thyroid screening in pregnancy since “identification and treatment of maternal subclinical hypothyroidism has not been shown to result in improved pregnancy outcomes and neurocognitive function in offspring.”

Conclusion

The 2019 Cochrane Database states there are no clear conclusions regarding treatment with levothyroxine in euthyroid TAI or SCH because of the low quality of evidence reported. While TAI and SCH have been associated with pregnancy complications, there is no apparent benefit of levothyroxine in women with TAI or TSH levels between 2.5 and 4 mIU/L.

So, the conundrum is which preconception women to test and how to manage nonovert thyroid disease. For now, it is reasonable to obtain a serum TSH on all women desiring fertility, to treat SCH with levothyroxine to maintain TSH less than 2.5 mIU/L in the normal range, and to adjust levothyroxine accordingly throughout pregnancy.

Dr. Trolice is director of fertility at CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no disclosures. Email him at [email protected].