Endocrinology

ORLANDO – Use of romosozumab (Evenity) by patients with osteoporosis in various stages of renal insufficiency did not appear to affect increases in bone mineral density, the rate of new vertebral fractures, or the number of adverse events when compared with placebo, Paul D. Miller, MD, said at the annual meeting of the American Society for Bone and Mineral Research.

“Romosozumab could be considered a treatment option for osteoporotic patients with mild to moderate reductions in renal function,” said Dr. Miller, distinguished clinical professor of medicine at the University of Colorado at Denver, Aurora.

Since bisphosphonates are not recommended for use in patients with an estimated glomerular filtration rate (eGFR) of less than 30 or 35 mL/min/1.73 m², other osteoporosis treatments such as romosozumab should also be examined. “It is important to evaluate other osteoporosis treatments in this setting, particularly in the context of monoclonal antibodies, which are not cleared in the kidneys and are metabolized in the reticular endothelial system, and have no FDA ... cut-off for their use,” Dr. Miller said.

Dr. Miller and colleagues performed a post hoc analysis of patients in the FRAME study, which enrolled 3,589 patients who received a monthly dose of subcutaneous romosozumab (215 mg) and 3,591 patients who received placebo in a double-blinded study for 12 months before moving to a 12-month, open-label portion of the study where all patients received 60 mg of subcutaneous denosumab every 6 months. After 12 months, the researchers analyzed the least squares mean (LSM) percentage change in bone mineral density (BMD) at the total hip, lumbar spine, and femoral neck as well as whether patients had any new vertebral fractures or experienced adverse events from treatment.

Patients were postmenopausal women between ages 55 and 90 years with a BMD T-score between –2.5 and –3.5 at the total hip or femoral neck. Researchers divided patients into four eGFR groups based chronic kidney disease (CKD) stage: normal (90 mL/min/1.73 m² or higher; 848 patients), mild CKD (60-89 mL/min/1.73 m²; 4,939 patients), moderate CKD (30-59 mL/min/1.73 m²; 1,360 patients), and severe (15-29 mL/min/1.73 m²; 18 patients).

The LSM percentage change was 13.1% in the lumbar spine (95% confidence interval, 12.8%-13.3%) for the romosozumab group, compared with 0.4% in the placebo group (95% CI, 0.2%-0.5%). The LSM percentage change for total hip was 6.0% in the romosozumab group (95% CI, 5.9%-6.2%), compared with 0.3% in the placebo group (95% CI, 0.1%-0.4%), while the LSM percentage change for the femoral neck was 5.5% in the romosozumab group (95% CI, 5.2%-5.7%) and 0.3% in the placebo group (0.1%-0.5%).

“[The] risk of new vertebral fractures was decreased in all eGFR subgroups and did not appear to be affected by eGFR level,” he said.

Specifically, vertebral fracture incidence was 0.5% in the romosozumab group, compared with 3.0% in the placebo group, for patients with normal renal function, 0.4% in the romosozumab group, compared with 1.5% in the placebo group, for patients with mild chronic kidney disease, and 0.6% in the romosozumab group vs. 2.1% in the placebo group for patients with moderate chronic kidney disease. The incidence of adverse events, serious adverse events, and positively adjudicated cardiovascular events were similar between patients in the romosozumab group regardless of renal function status. The researchers reported 1 patient in the romosozumab group who experienced grade 2 hypocalcemia, and 14 patients in the romosozumab group who experienced mild to moderate decreases in calcium, compared with 4 patients in the placebo group.

Dr. Miller noted the study was limited by having few patients with an eGFR of less than 30 mL/min/1.73 m² and no patients with an eGFR of less than 15 mL/min/1.73 m², but said the study strengths were its large randomized nature and well-balanced baseline characteristics between each group.

This study was sponsored in part by Amgen, Astellas, and UCB Pharma. Dr. Miller reported receiving grants from Alexion, Amgen, Radius, Regeneron, UCB, and Ultragenyx. Amgen and UCB assisted in and provided financial assistance for the preparation of Dr. Miller’s presentation.

SOURCE: Miller P et al. ASBMR 2019. Abstract 1085.

ORLANDO – Use of romosozumab (Evenity) by patients with osteoporosis in various stages of renal insufficiency did not appear to affect increases in bone mineral density, the rate of new vertebral fractures, or the number of adverse events when compared with placebo, Paul D. Miller, MD, said at the annual meeting of the American Society for Bone and Mineral Research.

“Romosozumab could be considered a treatment option for osteoporotic patients with mild to moderate reductions in renal function,” said Dr. Miller, distinguished clinical professor of medicine at the University of Colorado at Denver, Aurora.

Since bisphosphonates are not recommended for use in patients with an estimated glomerular filtration rate (eGFR) of less than 30 or 35 mL/min/1.73 m², other osteoporosis treatments such as romosozumab should also be examined. “It is important to evaluate other osteoporosis treatments in this setting, particularly in the context of monoclonal antibodies, which are not cleared in the kidneys and are metabolized in the reticular endothelial system, and have no FDA ... cut-off for their use,” Dr. Miller said.

Dr. Miller and colleagues performed a post hoc analysis of patients in the FRAME study, which enrolled 3,589 patients who received a monthly dose of subcutaneous romosozumab (215 mg) and 3,591 patients who received placebo in a double-blinded study for 12 months before moving to a 12-month, open-label portion of the study where all patients received 60 mg of subcutaneous denosumab every 6 months. After 12 months, the researchers analyzed the least squares mean (LSM) percentage change in bone mineral density (BMD) at the total hip, lumbar spine, and femoral neck as well as whether patients had any new vertebral fractures or experienced adverse events from treatment.

Patients were postmenopausal women between ages 55 and 90 years with a BMD T-score between –2.5 and –3.5 at the total hip or femoral neck. Researchers divided patients into four eGFR groups based chronic kidney disease (CKD) stage: normal (90 mL/min/1.73 m² or higher; 848 patients), mild CKD (60-89 mL/min/1.73 m²; 4,939 patients), moderate CKD (30-59 mL/min/1.73 m²; 1,360 patients), and severe (15-29 mL/min/1.73 m²; 18 patients).

The LSM percentage change was 13.1% in the lumbar spine (95% confidence interval, 12.8%-13.3%) for the romosozumab group, compared with 0.4% in the placebo group (95% CI, 0.2%-0.5%). The LSM percentage change for total hip was 6.0% in the romosozumab group (95% CI, 5.9%-6.2%), compared with 0.3% in the placebo group (95% CI, 0.1%-0.4%), while the LSM percentage change for the femoral neck was 5.5% in the romosozumab group (95% CI, 5.2%-5.7%) and 0.3% in the placebo group (0.1%-0.5%).

“[The] risk of new vertebral fractures was decreased in all eGFR subgroups and did not appear to be affected by eGFR level,” he said.

Specifically, vertebral fracture incidence was 0.5% in the romosozumab group, compared with 3.0% in the placebo group, for patients with normal renal function, 0.4% in the romosozumab group, compared with 1.5% in the placebo group, for patients with mild chronic kidney disease, and 0.6% in the romosozumab group vs. 2.1% in the placebo group for patients with moderate chronic kidney disease. The incidence of adverse events, serious adverse events, and positively adjudicated cardiovascular events were similar between patients in the romosozumab group regardless of renal function status. The researchers reported 1 patient in the romosozumab group who experienced grade 2 hypocalcemia, and 14 patients in the romosozumab group who experienced mild to moderate decreases in calcium, compared with 4 patients in the placebo group.

Dr. Miller noted the study was limited by having few patients with an eGFR of less than 30 mL/min/1.73 m² and no patients with an eGFR of less than 15 mL/min/1.73 m², but said the study strengths were its large randomized nature and well-balanced baseline characteristics between each group.

This study was sponsored in part by Amgen, Astellas, and UCB Pharma. Dr. Miller reported receiving grants from Alexion, Amgen, Radius, Regeneron, UCB, and Ultragenyx. Amgen and UCB assisted in and provided financial assistance for the preparation of Dr. Miller’s presentation.

SOURCE: Miller P et al. ASBMR 2019. Abstract 1085.

ORLANDO – Use of romosozumab (Evenity) by patients with osteoporosis in various stages of renal insufficiency did not appear to affect increases in bone mineral density, the rate of new vertebral fractures, or the number of adverse events when compared with placebo, Paul D. Miller, MD, said at the annual meeting of the American Society for Bone and Mineral Research.

“Romosozumab could be considered a treatment option for osteoporotic patients with mild to moderate reductions in renal function,” said Dr. Miller, distinguished clinical professor of medicine at the University of Colorado at Denver, Aurora.

Since bisphosphonates are not recommended for use in patients with an estimated glomerular filtration rate (eGFR) of less than 30 or 35 mL/min/1.73 m², other osteoporosis treatments such as romosozumab should also be examined. “It is important to evaluate other osteoporosis treatments in this setting, particularly in the context of monoclonal antibodies, which are not cleared in the kidneys and are metabolized in the reticular endothelial system, and have no FDA ... cut-off for their use,” Dr. Miller said.

Dr. Miller and colleagues performed a post hoc analysis of patients in the FRAME study, which enrolled 3,589 patients who received a monthly dose of subcutaneous romosozumab (215 mg) and 3,591 patients who received placebo in a double-blinded study for 12 months before moving to a 12-month, open-label portion of the study where all patients received 60 mg of subcutaneous denosumab every 6 months. After 12 months, the researchers analyzed the least squares mean (LSM) percentage change in bone mineral density (BMD) at the total hip, lumbar spine, and femoral neck as well as whether patients had any new vertebral fractures or experienced adverse events from treatment.

Patients were postmenopausal women between ages 55 and 90 years with a BMD T-score between –2.5 and –3.5 at the total hip or femoral neck. Researchers divided patients into four eGFR groups based chronic kidney disease (CKD) stage: normal (90 mL/min/1.73 m² or higher; 848 patients), mild CKD (60-89 mL/min/1.73 m²; 4,939 patients), moderate CKD (30-59 mL/min/1.73 m²; 1,360 patients), and severe (15-29 mL/min/1.73 m²; 18 patients).

The LSM percentage change was 13.1% in the lumbar spine (95% confidence interval, 12.8%-13.3%) for the romosozumab group, compared with 0.4% in the placebo group (95% CI, 0.2%-0.5%). The LSM percentage change for total hip was 6.0% in the romosozumab group (95% CI, 5.9%-6.2%), compared with 0.3% in the placebo group (95% CI, 0.1%-0.4%), while the LSM percentage change for the femoral neck was 5.5% in the romosozumab group (95% CI, 5.2%-5.7%) and 0.3% in the placebo group (0.1%-0.5%).

“[The] risk of new vertebral fractures was decreased in all eGFR subgroups and did not appear to be affected by eGFR level,” he said.

Specifically, vertebral fracture incidence was 0.5% in the romosozumab group, compared with 3.0% in the placebo group, for patients with normal renal function, 0.4% in the romosozumab group, compared with 1.5% in the placebo group, for patients with mild chronic kidney disease, and 0.6% in the romosozumab group vs. 2.1% in the placebo group for patients with moderate chronic kidney disease. The incidence of adverse events, serious adverse events, and positively adjudicated cardiovascular events were similar between patients in the romosozumab group regardless of renal function status. The researchers reported 1 patient in the romosozumab group who experienced grade 2 hypocalcemia, and 14 patients in the romosozumab group who experienced mild to moderate decreases in calcium, compared with 4 patients in the placebo group.

Dr. Miller noted the study was limited by having few patients with an eGFR of less than 30 mL/min/1.73 m² and no patients with an eGFR of less than 15 mL/min/1.73 m², but said the study strengths were its large randomized nature and well-balanced baseline characteristics between each group.

This study was sponsored in part by Amgen, Astellas, and UCB Pharma. Dr. Miller reported receiving grants from Alexion, Amgen, Radius, Regeneron, UCB, and Ultragenyx. Amgen and UCB assisted in and provided financial assistance for the preparation of Dr. Miller’s presentation.

SOURCE: Miller P et al. ASBMR 2019. Abstract 1085.

ORLANDO – Reframing the decision-making process for selecting osteoporosis treatment options may help increase adherence to medication, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

“The language of this disease needs to be changed,” Deborah Gold, PhD, of Duke University, Durham, N.C., said in her presentation.

As medications for osteoporosis have changed over the decades – from estrogen in the 1940s and calcitonin in the 1970s to bisphosphonates in the 1990s – the delivery mechanisms of the drugs and the dosing intervals also have changed. However, long-term adherence to osteoporosis medication through various delivery mechanisms and doses have remained elusive, Dr. Gold said.

She cited the negative public and media response to osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF) – two rare side effects of bisphosphonate treatment – as one reason why adherence to osteoporosis medications has changed.

While the more common side effects of osteoporosis medications are manageable, the emphasis in lay press has been on “rare and frightening side effects,” she said. A 2018 study found that reports in the media “strongly influence the level of awareness of osteoporosis and fracture risk” and that a gap exists between clinical recommendations and patient perceptions (J Endocrinol Invest. 2018;41[12]:1359-64. doi: 10.1007/s40618-018-0898-9). Over the same time period, another study found that 40.2% of high-risk patients hospitalized for a hip fracture were treated with osteoporosis medications in 2002, but that number declined to 20.5% in 2011 (J Bone Miner Res. 2014;29[9]:1929-37. doi: 10.1002/jbmr.2202).

Dr. Gold advised clinicians to counter negative patient perceptions about osteoporosis treatment by explaining the risks of treatment with medications as well as the risks of not undergoing treatment for osteoporosis. “A hip fracture is a lot more likely for nontreatment than ONJ or AFF are for treatment,” she said.

Dr. Gold also described the importance of listening to patients’ preferences for treatment as well as attempting to find an appropriate treatment they are likely to continue using. “This has been shown in the literature over and over again in other diseases,” she said. If “somebody says, ‘I can’t do needles,’ you can’t prescribe a medication that goes in through a needle.”

Assuring patients that they can visit again to address issues with treatment, change medications if needed, and discuss concerns about adverse outcomes such as ONJ and AFF is also relevant. “We need to promote osteoporosis understanding – not just osteoporosis – and we need to promote treatment to multiple sources,” she said.

When osteoporosis is characterized in terms of bone mineral density, T-scores, fragility fractures, appropriate exercises, and diet, there is plenty of opportunity for confusion or misunderstanding. Accurate, plain-language information, given both verbally and in handouts, works well , according to Dr. Gold.

“Health communication services – whether we’re talking about newspapers, magazines, radio shows, television shows, or even things that come out from organizations like the NOF [National Osteoporosis Foundation] and ASBMR – need to promote accurate information and not exaggerated negatives that we hear all the time,” she said.

“Cognitive reframing is not an easy thing; there’s no question,” Dr. Gold said. “I’m not standing up here telling you we can do it tomorrow. It will be difficult. But for those of us who know this disease and know how serious it is and know what the consequences are, we need to make a positive difference.”

Dr. Gold reported being a consultant for Amgen, Eli Lilly, and Radius Pharmaceuticals.

SOURCE: Gold D. ASBMR 2019. Adherence to Osteoporosis: A Conundrum of Significant Proportions.

ORLANDO – Reframing the decision-making process for selecting osteoporosis treatment options may help increase adherence to medication, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

“The language of this disease needs to be changed,” Deborah Gold, PhD, of Duke University, Durham, N.C., said in her presentation.

As medications for osteoporosis have changed over the decades – from estrogen in the 1940s and calcitonin in the 1970s to bisphosphonates in the 1990s – the delivery mechanisms of the drugs and the dosing intervals also have changed. However, long-term adherence to osteoporosis medication through various delivery mechanisms and doses have remained elusive, Dr. Gold said.

She cited the negative public and media response to osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF) – two rare side effects of bisphosphonate treatment – as one reason why adherence to osteoporosis medications has changed.

While the more common side effects of osteoporosis medications are manageable, the emphasis in lay press has been on “rare and frightening side effects,” she said. A 2018 study found that reports in the media “strongly influence the level of awareness of osteoporosis and fracture risk” and that a gap exists between clinical recommendations and patient perceptions (J Endocrinol Invest. 2018;41[12]:1359-64. doi: 10.1007/s40618-018-0898-9). Over the same time period, another study found that 40.2% of high-risk patients hospitalized for a hip fracture were treated with osteoporosis medications in 2002, but that number declined to 20.5% in 2011 (J Bone Miner Res. 2014;29[9]:1929-37. doi: 10.1002/jbmr.2202).

Dr. Gold advised clinicians to counter negative patient perceptions about osteoporosis treatment by explaining the risks of treatment with medications as well as the risks of not undergoing treatment for osteoporosis. “A hip fracture is a lot more likely for nontreatment than ONJ or AFF are for treatment,” she said.

Dr. Gold also described the importance of listening to patients’ preferences for treatment as well as attempting to find an appropriate treatment they are likely to continue using. “This has been shown in the literature over and over again in other diseases,” she said. If “somebody says, ‘I can’t do needles,’ you can’t prescribe a medication that goes in through a needle.”

Assuring patients that they can visit again to address issues with treatment, change medications if needed, and discuss concerns about adverse outcomes such as ONJ and AFF is also relevant. “We need to promote osteoporosis understanding – not just osteoporosis – and we need to promote treatment to multiple sources,” she said.

When osteoporosis is characterized in terms of bone mineral density, T-scores, fragility fractures, appropriate exercises, and diet, there is plenty of opportunity for confusion or misunderstanding. Accurate, plain-language information, given both verbally and in handouts, works well , according to Dr. Gold.

“Health communication services – whether we’re talking about newspapers, magazines, radio shows, television shows, or even things that come out from organizations like the NOF [National Osteoporosis Foundation] and ASBMR – need to promote accurate information and not exaggerated negatives that we hear all the time,” she said.

“Cognitive reframing is not an easy thing; there’s no question,” Dr. Gold said. “I’m not standing up here telling you we can do it tomorrow. It will be difficult. But for those of us who know this disease and know how serious it is and know what the consequences are, we need to make a positive difference.”

Dr. Gold reported being a consultant for Amgen, Eli Lilly, and Radius Pharmaceuticals.

SOURCE: Gold D. ASBMR 2019. Adherence to Osteoporosis: A Conundrum of Significant Proportions.

ORLANDO – Reframing the decision-making process for selecting osteoporosis treatment options may help increase adherence to medication, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

“The language of this disease needs to be changed,” Deborah Gold, PhD, of Duke University, Durham, N.C., said in her presentation.

As medications for osteoporosis have changed over the decades – from estrogen in the 1940s and calcitonin in the 1970s to bisphosphonates in the 1990s – the delivery mechanisms of the drugs and the dosing intervals also have changed. However, long-term adherence to osteoporosis medication through various delivery mechanisms and doses have remained elusive, Dr. Gold said.

She cited the negative public and media response to osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF) – two rare side effects of bisphosphonate treatment – as one reason why adherence to osteoporosis medications has changed.

While the more common side effects of osteoporosis medications are manageable, the emphasis in lay press has been on “rare and frightening side effects,” she said. A 2018 study found that reports in the media “strongly influence the level of awareness of osteoporosis and fracture risk” and that a gap exists between clinical recommendations and patient perceptions (J Endocrinol Invest. 2018;41[12]:1359-64. doi: 10.1007/s40618-018-0898-9). Over the same time period, another study found that 40.2% of high-risk patients hospitalized for a hip fracture were treated with osteoporosis medications in 2002, but that number declined to 20.5% in 2011 (J Bone Miner Res. 2014;29[9]:1929-37. doi: 10.1002/jbmr.2202).

Dr. Gold advised clinicians to counter negative patient perceptions about osteoporosis treatment by explaining the risks of treatment with medications as well as the risks of not undergoing treatment for osteoporosis. “A hip fracture is a lot more likely for nontreatment than ONJ or AFF are for treatment,” she said.

Dr. Gold also described the importance of listening to patients’ preferences for treatment as well as attempting to find an appropriate treatment they are likely to continue using. “This has been shown in the literature over and over again in other diseases,” she said. If “somebody says, ‘I can’t do needles,’ you can’t prescribe a medication that goes in through a needle.”

Assuring patients that they can visit again to address issues with treatment, change medications if needed, and discuss concerns about adverse outcomes such as ONJ and AFF is also relevant. “We need to promote osteoporosis understanding – not just osteoporosis – and we need to promote treatment to multiple sources,” she said.

When osteoporosis is characterized in terms of bone mineral density, T-scores, fragility fractures, appropriate exercises, and diet, there is plenty of opportunity for confusion or misunderstanding. Accurate, plain-language information, given both verbally and in handouts, works well , according to Dr. Gold.

“Health communication services – whether we’re talking about newspapers, magazines, radio shows, television shows, or even things that come out from organizations like the NOF [National Osteoporosis Foundation] and ASBMR – need to promote accurate information and not exaggerated negatives that we hear all the time,” she said.

“Cognitive reframing is not an easy thing; there’s no question,” Dr. Gold said. “I’m not standing up here telling you we can do it tomorrow. It will be difficult. But for those of us who know this disease and know how serious it is and know what the consequences are, we need to make a positive difference.”

Dr. Gold reported being a consultant for Amgen, Eli Lilly, and Radius Pharmaceuticals.

SOURCE: Gold D. ASBMR 2019. Adherence to Osteoporosis: A Conundrum of Significant Proportions.

ORLANDO – The burden of osteoporosis and fragility fractures in the United States remains high, particularly in older women and minorities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

For non-Hispanic Asian, non-Hispanic white, and Hispanic patients of various ethnic groups, as well as in women and older patients, osteoporosis and fragility fractures continue to be a problem, said Nicole C. Wright, PhD, MPH, of the department of epidemiology at the University of Alabama at Birmingham.

“It remains costly; it remains associated with more health care utilization,” Dr. Wright said. “We may be seeing some declines in some fragility fractures, but [we] are seeing increases in hip fractures.”

As part of the fourth edition of the U.S. Bone and Joint Initiative publication, “The Burden of Musculoskeletal Diseases in the United States,” Dr. Wright and colleagues examined the changes in osteoporosis burden between the third and fourth editions of the publication. They used data from the National Inpatient Sample (NIS) in 2013 and 2014 as well as the National Emergency Department Sample (NEDS) of national ED visits regardless of hospital admission status. In both databases, researchers analyzed data from adults aged 50 years or older where the primary discharge ICD-9 or ICD-10 code was a diagnosis of fracture.

Using National Health and Nutrition Examination Survey data, the researchers estimated an 11.0% osteoporosis prevalence for adults aged 50 years or older overall, a 16.5% prevalence in women, and a 5.1% prevalence in men as assessed by femoral neck and lumbar spine bone mineral density. Osteoporosis was most prevalent in Asian women (40.0%) and Asian men (7.5%), while there was a difference in prevalence in patients of Hispanic race depending on their origin; for example, Puerto Rican men had a higher prevalence of osteoporosis at 8.6%, compared with Hispanic men (2.3%) and non-Hispanic white men of other races (3.9%).

Of 19.5 million hospitalizations in the NIS database between 2013 and 2014, there were approximately 540,000 fragility fractures (2.8%), of which about 300,000 were hip fractures and about 100,000 discharges were for spine fractures, Dr. Wright said. In the NEDS database, the estimate of fragility fracture prevalence was 0.9% of 46.7 million ED visits between 2013 and 2014. Fracture prevalence was increased in women and in older age, with patients aged 80 years or older and those of non-Hispanic white race having the highest prevalence of hip fracture. However, she noted that NEDS data also showed higher prevalences of wrist and humerus fractures, which are not normally fractures that a patient visits the hospital as an inpatient for. “We need both data sets to ascertain fractures in the United States,” she said.

When examining fracture site trends over time, Dr. Wright and colleagues found hip fracture prevalence increased by 3.5% between 2010 and 2014, while there was a decrease of 11.9% in the prevalence of spine fractures over the same time period.

According to data from the Medical Expenditures Panel Survey, the direct cost of osteoporosis in aggregate was $73.6 billion between 2012 and 2014, which was 118% higher than between 1998 and 2000 when the costs were $28.1 billion. The costs were spread across ambulatory care, inpatient, and prescription costs equally, the researchers said.

Although the study was limited by examining fracture prevalence rather than incidence, the potential for missing some fractures based on methodology, and limited patient characteristics and follow-up information, the goal of the presentation was to highlight the new osteoporosis prevalence data and the continued burden of the disease.

“We hope that these new prevalence estimates continue to increase the awareness of osteoporosis and prevention,” she said.

Dr. Wright reported receiving grants from Amgen and serving as an expert witness for the law firm Norton Rose Fulbright and Pfizer.

SOURCE: Wright NC et al. ASBMR 2019, Abstract 1079.

ORLANDO – The burden of osteoporosis and fragility fractures in the United States remains high, particularly in older women and minorities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

For non-Hispanic Asian, non-Hispanic white, and Hispanic patients of various ethnic groups, as well as in women and older patients, osteoporosis and fragility fractures continue to be a problem, said Nicole C. Wright, PhD, MPH, of the department of epidemiology at the University of Alabama at Birmingham.

“It remains costly; it remains associated with more health care utilization,” Dr. Wright said. “We may be seeing some declines in some fragility fractures, but [we] are seeing increases in hip fractures.”

As part of the fourth edition of the U.S. Bone and Joint Initiative publication, “The Burden of Musculoskeletal Diseases in the United States,” Dr. Wright and colleagues examined the changes in osteoporosis burden between the third and fourth editions of the publication. They used data from the National Inpatient Sample (NIS) in 2013 and 2014 as well as the National Emergency Department Sample (NEDS) of national ED visits regardless of hospital admission status. In both databases, researchers analyzed data from adults aged 50 years or older where the primary discharge ICD-9 or ICD-10 code was a diagnosis of fracture.

Using National Health and Nutrition Examination Survey data, the researchers estimated an 11.0% osteoporosis prevalence for adults aged 50 years or older overall, a 16.5% prevalence in women, and a 5.1% prevalence in men as assessed by femoral neck and lumbar spine bone mineral density. Osteoporosis was most prevalent in Asian women (40.0%) and Asian men (7.5%), while there was a difference in prevalence in patients of Hispanic race depending on their origin; for example, Puerto Rican men had a higher prevalence of osteoporosis at 8.6%, compared with Hispanic men (2.3%) and non-Hispanic white men of other races (3.9%).

Of 19.5 million hospitalizations in the NIS database between 2013 and 2014, there were approximately 540,000 fragility fractures (2.8%), of which about 300,000 were hip fractures and about 100,000 discharges were for spine fractures, Dr. Wright said. In the NEDS database, the estimate of fragility fracture prevalence was 0.9% of 46.7 million ED visits between 2013 and 2014. Fracture prevalence was increased in women and in older age, with patients aged 80 years or older and those of non-Hispanic white race having the highest prevalence of hip fracture. However, she noted that NEDS data also showed higher prevalences of wrist and humerus fractures, which are not normally fractures that a patient visits the hospital as an inpatient for. “We need both data sets to ascertain fractures in the United States,” she said.

When examining fracture site trends over time, Dr. Wright and colleagues found hip fracture prevalence increased by 3.5% between 2010 and 2014, while there was a decrease of 11.9% in the prevalence of spine fractures over the same time period.

According to data from the Medical Expenditures Panel Survey, the direct cost of osteoporosis in aggregate was $73.6 billion between 2012 and 2014, which was 118% higher than between 1998 and 2000 when the costs were $28.1 billion. The costs were spread across ambulatory care, inpatient, and prescription costs equally, the researchers said.

Although the study was limited by examining fracture prevalence rather than incidence, the potential for missing some fractures based on methodology, and limited patient characteristics and follow-up information, the goal of the presentation was to highlight the new osteoporosis prevalence data and the continued burden of the disease.

“We hope that these new prevalence estimates continue to increase the awareness of osteoporosis and prevention,” she said.

Dr. Wright reported receiving grants from Amgen and serving as an expert witness for the law firm Norton Rose Fulbright and Pfizer.

SOURCE: Wright NC et al. ASBMR 2019, Abstract 1079.

ORLANDO – The burden of osteoporosis and fragility fractures in the United States remains high, particularly in older women and minorities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

For non-Hispanic Asian, non-Hispanic white, and Hispanic patients of various ethnic groups, as well as in women and older patients, osteoporosis and fragility fractures continue to be a problem, said Nicole C. Wright, PhD, MPH, of the department of epidemiology at the University of Alabama at Birmingham.

“It remains costly; it remains associated with more health care utilization,” Dr. Wright said. “We may be seeing some declines in some fragility fractures, but [we] are seeing increases in hip fractures.”

As part of the fourth edition of the U.S. Bone and Joint Initiative publication, “The Burden of Musculoskeletal Diseases in the United States,” Dr. Wright and colleagues examined the changes in osteoporosis burden between the third and fourth editions of the publication. They used data from the National Inpatient Sample (NIS) in 2013 and 2014 as well as the National Emergency Department Sample (NEDS) of national ED visits regardless of hospital admission status. In both databases, researchers analyzed data from adults aged 50 years or older where the primary discharge ICD-9 or ICD-10 code was a diagnosis of fracture.

Using National Health and Nutrition Examination Survey data, the researchers estimated an 11.0% osteoporosis prevalence for adults aged 50 years or older overall, a 16.5% prevalence in women, and a 5.1% prevalence in men as assessed by femoral neck and lumbar spine bone mineral density. Osteoporosis was most prevalent in Asian women (40.0%) and Asian men (7.5%), while there was a difference in prevalence in patients of Hispanic race depending on their origin; for example, Puerto Rican men had a higher prevalence of osteoporosis at 8.6%, compared with Hispanic men (2.3%) and non-Hispanic white men of other races (3.9%).

Of 19.5 million hospitalizations in the NIS database between 2013 and 2014, there were approximately 540,000 fragility fractures (2.8%), of which about 300,000 were hip fractures and about 100,000 discharges were for spine fractures, Dr. Wright said. In the NEDS database, the estimate of fragility fracture prevalence was 0.9% of 46.7 million ED visits between 2013 and 2014. Fracture prevalence was increased in women and in older age, with patients aged 80 years or older and those of non-Hispanic white race having the highest prevalence of hip fracture. However, she noted that NEDS data also showed higher prevalences of wrist and humerus fractures, which are not normally fractures that a patient visits the hospital as an inpatient for. “We need both data sets to ascertain fractures in the United States,” she said.

When examining fracture site trends over time, Dr. Wright and colleagues found hip fracture prevalence increased by 3.5% between 2010 and 2014, while there was a decrease of 11.9% in the prevalence of spine fractures over the same time period.

According to data from the Medical Expenditures Panel Survey, the direct cost of osteoporosis in aggregate was $73.6 billion between 2012 and 2014, which was 118% higher than between 1998 and 2000 when the costs were $28.1 billion. The costs were spread across ambulatory care, inpatient, and prescription costs equally, the researchers said.

Although the study was limited by examining fracture prevalence rather than incidence, the potential for missing some fractures based on methodology, and limited patient characteristics and follow-up information, the goal of the presentation was to highlight the new osteoporosis prevalence data and the continued burden of the disease.

“We hope that these new prevalence estimates continue to increase the awareness of osteoporosis and prevention,” she said.

Dr. Wright reported receiving grants from Amgen and serving as an expert witness for the law firm Norton Rose Fulbright and Pfizer.

SOURCE: Wright NC et al. ASBMR 2019, Abstract 1079.

A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).

One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.

His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC) was less than 0.70, and his FEV₁ was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.

Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.

Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.

The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.

He was a retired engineer. He did not drink alcohol or use illicit drugs.

PHYSICAL EXAMINATION

On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m².

His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.

Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.

His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.

Results of initial laboratory testing are shown in Table 1.

Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.

The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.

The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.

Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:

• pH 7.35
• Partial pressure of carbon dioxide (Paco₂) 52 mm Hg
• Bicarbonate 28 mmol/L
• Partial pressure of oxygen (Pao₂) 60 mm Hg
• Oxygen saturation 90%.

HOSPITAL COURSE

On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.

At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.

Because of these episodes, the attending physician ordered thyroid function tests.

THYROID FUNCTION TESTING

1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?

• Serum thyroid-stimulating hormone (TSH) alone
• Serum TSH and total thyroxine (T₄)
• Serum TSH and total triiodothyronine (T₃)
• Serum TSH and free T₄
• Serum TSH and free T₃

There are several tests to assess thyroid function: the serum TSH, total T₄, free T₄, total T₃, and free T₃ concentrations.¹

In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T₄ and T₃, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T₄ and TSH levels.² Thus, the serum free T₄ level can remain within the normal reference range even if the TSH level is high or low. 

TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.³

TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.⁴ Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.⁴

Free vs total T₄ and T₃ levels

Serum total T₄ includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T₃. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.⁸ Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T₄ and T₃ levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T₄, is usually recommended.

Although equilibrium dialysis is the method most likely to provide an accurate serum free T₄ measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T₄ measurement or, to a lesser degree, the free T₄ index.⁹ However, none of the currently available free T₄ tests actually measure free T₄ directly; rather, they estimate it.¹⁰

Commercial laboratories can provide a direct free T₃ estimate, but it may be less reliable than total T₃. If serum T₃ measurement is indicated, serum total T₃ is usually measured. However, total T₃ measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.¹¹ Nevertheless, serum total T₃ measurement could be useful in patients with T₃ toxicosis and in those who are acutely ill.

Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T₄ is essential to assess thyroid function. Many clinicians also measure serum total T₃.

The attending physician ordered serum TSH, free T₄, and total T₃ measurements, which yielded the following:

• TSH 0.1 mU/L (0.5–5.0)
• Total T₃ 55 ng/dL (80–180)
• Free T₄ 0.9 ng/dL (0.9–2.4).

2. Which best explains this patient’s abnormal thyroid test results?

• His acute illness
• Central hypothyroidism due to pituitary infarction
• His albuterol therapy
• Subclinical thyrotoxicosis
• Hashimoto thyroiditis

Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),^5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.¹ In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.

Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T₃, normal or low serum TSH, and normal, low, or high serum free T₄. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.¹⁶ These abnormalities with their mechanisms are shown in Table 2.^5–7 In several commercial kits, serum direct free T₄ can be falsely decreased or increased.⁸

THE DIFFERENTIAL DIAGNOSIS

Our patient had low serum TSH, low-normal serum direct free T₄, and low serum total T₃. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.¹⁷ The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.

In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.¹⁸ Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.^19,20

The serum concentration of reverse T₃ has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.²¹

GLUCOCORTICOIDS AND THYROID FUNCTION TESTS

By inhibiting D1, glucocorticoids can decrease peripheral conversion of T₄ to T₃ and thus decrease serum total T₃. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.

In one study,²² there was a significant reduction in serum total T₃ concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T₃ returned to its pretreatment level.

In another study,²³ a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T₃ in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.

Long-term glucocorticoid therapy also decreases serum total T₄ and total T₃ by lowering serum thyroid-binding globulin.²⁴

Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.^25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.²⁷

Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.²⁸ Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T₄ clearance.²⁹

While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.³⁰

In studies of propranolol, serum total T₄ concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients^31–33; serum total T₃ concentrations did not change or were decreased with 40 mg or more daily³⁴; and serum reverse T₃ concentrations were increased with daily doses of 80 mg or more.³¹ It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.

Furthermore, a significant decrease in serum total T₃ concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).^35,36

On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.³⁷

SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?

Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.

The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.

Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T₄ and total T₃ remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).^38,39

Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.⁴⁰ Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.

CASE CONTINUED

An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.

3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?

• Start levothyroxine (T₄) therapy
• Start liothyronine (T₃) therapy
• Start N-acetylcysteine therapy
• Start thyrotropin-releasing hormone therapy
• Remeasure thyroid hormones after full recovery from his acute illness

It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.⁴¹

However, current data argue against thyroid hormone therapy using T₄ or T₃ for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).⁴² Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.^41,43

Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.

Some studies showed that giving N-acetyl­cysteine, an antioxidant, increased serum T₃ and decreased serum reverse T₃ concentrations in patients with acute myocardial infarction.⁴⁴ Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.

Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T₄, and T₃ levels in critically ill patients.⁴⁵ The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.⁴⁶

Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.⁴⁷

The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.

Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.

One week later, his laboratory results were:

• TSH 11.2 mU/L (reference range 0.5–5.0)
• Free T₄ 1.2 ng/dL (0.9–2.4)
• Total T₃ 92 ng/dL (80–180).

Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.

4. Based on these last test results, which statement is correct?

• Levothyroxine therapy should be started
• His serum TSH elevation is most likely transient
• Thyroid ultrasonography is strongly indicated
• A radioactive iodine uptake study should be performed
• Measurement of thyroid-stimulating immunoglobulins is indicated

During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).⁴⁸ Normalization of the thyroid function tests including serum TSH may take several weeks⁴⁹ or months.⁵⁰ However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.⁵¹

Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.

Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)

Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.⁵² Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.

CASE CONCLUSION: BETTER, BUT STILL SMOKING

The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T₄, and total T₃ were within normal ranges. His COPD was under control, with an FEV₁ 88% of predicted.

He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.

KEY POINTS

• In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
• If thyroid function assessment is indicated for critically ill patients, serum TSH and free T₄ concentrations should be measured. Some clinicians also measure serum total T₃ level.
• Thyroid function testing in critically ill patients usually shows low serum total T₃, normal or low serum TSH, and normal or low serum free T₄.
• Many drugs can alter thyroid hormone levels.
• Thyroid hormone therapy is not recommended for critically ill patients with low T₃, low T₄, or both.
• During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
• Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
• Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.

A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).

One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.

His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC) was less than 0.70, and his FEV₁ was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.

Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.

Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.

The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.

He was a retired engineer. He did not drink alcohol or use illicit drugs.

PHYSICAL EXAMINATION

On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m².

His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.

Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.

His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.

Results of initial laboratory testing are shown in Table 1.

Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.

The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.

The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.

Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:

• pH 7.35
• Partial pressure of carbon dioxide (Paco₂) 52 mm Hg
• Bicarbonate 28 mmol/L
• Partial pressure of oxygen (Pao₂) 60 mm Hg
• Oxygen saturation 90%.

HOSPITAL COURSE

On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.

At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.

Because of these episodes, the attending physician ordered thyroid function tests.

THYROID FUNCTION TESTING

1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?

• Serum thyroid-stimulating hormone (TSH) alone
• Serum TSH and total thyroxine (T₄)
• Serum TSH and total triiodothyronine (T₃)
• Serum TSH and free T₄
• Serum TSH and free T₃

There are several tests to assess thyroid function: the serum TSH, total T₄, free T₄, total T₃, and free T₃ concentrations.¹

In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T₄ and T₃, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T₄ and TSH levels.² Thus, the serum free T₄ level can remain within the normal reference range even if the TSH level is high or low. 

TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.³

TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.⁴ Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.⁴

Free vs total T₄ and T₃ levels

Serum total T₄ includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T₃. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.⁸ Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T₄ and T₃ levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T₄, is usually recommended.

Although equilibrium dialysis is the method most likely to provide an accurate serum free T₄ measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T₄ measurement or, to a lesser degree, the free T₄ index.⁹ However, none of the currently available free T₄ tests actually measure free T₄ directly; rather, they estimate it.¹⁰

Commercial laboratories can provide a direct free T₃ estimate, but it may be less reliable than total T₃. If serum T₃ measurement is indicated, serum total T₃ is usually measured. However, total T₃ measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.¹¹ Nevertheless, serum total T₃ measurement could be useful in patients with T₃ toxicosis and in those who are acutely ill.

Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T₄ is essential to assess thyroid function. Many clinicians also measure serum total T₃.

The attending physician ordered serum TSH, free T₄, and total T₃ measurements, which yielded the following:

• TSH 0.1 mU/L (0.5–5.0)
• Total T₃ 55 ng/dL (80–180)
• Free T₄ 0.9 ng/dL (0.9–2.4).

2. Which best explains this patient’s abnormal thyroid test results?

• His acute illness
• Central hypothyroidism due to pituitary infarction
• His albuterol therapy
• Subclinical thyrotoxicosis
• Hashimoto thyroiditis

Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),^5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.¹ In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.

Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T₃, normal or low serum TSH, and normal, low, or high serum free T₄. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.¹⁶ These abnormalities with their mechanisms are shown in Table 2.^5–7 In several commercial kits, serum direct free T₄ can be falsely decreased or increased.⁸

THE DIFFERENTIAL DIAGNOSIS

Our patient had low serum TSH, low-normal serum direct free T₄, and low serum total T₃. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.¹⁷ The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.

In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.¹⁸ Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.^19,20

The serum concentration of reverse T₃ has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.²¹

GLUCOCORTICOIDS AND THYROID FUNCTION TESTS

By inhibiting D1, glucocorticoids can decrease peripheral conversion of T₄ to T₃ and thus decrease serum total T₃. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.

In one study,²² there was a significant reduction in serum total T₃ concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T₃ returned to its pretreatment level.

In another study,²³ a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T₃ in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.

Long-term glucocorticoid therapy also decreases serum total T₄ and total T₃ by lowering serum thyroid-binding globulin.²⁴

Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.^25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.²⁷

Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.²⁸ Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T₄ clearance.²⁹

While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.³⁰

In studies of propranolol, serum total T₄ concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients^31–33; serum total T₃ concentrations did not change or were decreased with 40 mg or more daily³⁴; and serum reverse T₃ concentrations were increased with daily doses of 80 mg or more.³¹ It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.

Furthermore, a significant decrease in serum total T₃ concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).^35,36

On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.³⁷

SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?

Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.

The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.

Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T₄ and total T₃ remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).^38,39

Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.⁴⁰ Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.

CASE CONTINUED

An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.

3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?

• Start levothyroxine (T₄) therapy
• Start liothyronine (T₃) therapy
• Start N-acetylcysteine therapy
• Start thyrotropin-releasing hormone therapy
• Remeasure thyroid hormones after full recovery from his acute illness

It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.⁴¹

However, current data argue against thyroid hormone therapy using T₄ or T₃ for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).⁴² Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.^41,43

Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.

Some studies showed that giving N-acetyl­cysteine, an antioxidant, increased serum T₃ and decreased serum reverse T₃ concentrations in patients with acute myocardial infarction.⁴⁴ Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.

Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T₄, and T₃ levels in critically ill patients.⁴⁵ The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.⁴⁶

Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.⁴⁷

The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.

Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.

One week later, his laboratory results were:

• TSH 11.2 mU/L (reference range 0.5–5.0)
• Free T₄ 1.2 ng/dL (0.9–2.4)
• Total T₃ 92 ng/dL (80–180).

Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.

4. Based on these last test results, which statement is correct?

• Levothyroxine therapy should be started
• His serum TSH elevation is most likely transient
• Thyroid ultrasonography is strongly indicated
• A radioactive iodine uptake study should be performed
• Measurement of thyroid-stimulating immunoglobulins is indicated

During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).⁴⁸ Normalization of the thyroid function tests including serum TSH may take several weeks⁴⁹ or months.⁵⁰ However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.⁵¹

Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.

Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)

Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.⁵² Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.

CASE CONCLUSION: BETTER, BUT STILL SMOKING

The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T₄, and total T₃ were within normal ranges. His COPD was under control, with an FEV₁ 88% of predicted.

He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.

KEY POINTS

• In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
• If thyroid function assessment is indicated for critically ill patients, serum TSH and free T₄ concentrations should be measured. Some clinicians also measure serum total T₃ level.
• Thyroid function testing in critically ill patients usually shows low serum total T₃, normal or low serum TSH, and normal or low serum free T₄.
• Many drugs can alter thyroid hormone levels.
• Thyroid hormone therapy is not recommended for critically ill patients with low T₃, low T₄, or both.
• During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
• Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
• Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.

A 66-year-old man presented to the emergency department with increasing shortness of breath and productive cough, which had begun 5 days earlier. Three years previously, he had been diagnosed with chronic obstructive pulmonary disease (COPD).

One week before the current presentation, he developed a sore throat, rhinorrhea, and nasal congestion, and the shortness of breath had started 2 days after that. Although he could speak in sentences, he was breathless even at rest. His dyspnea was associated with noisy breathing and cough productive of yellowish sputum; there was no hemoptysis. He reported fever, but he had no chills, night sweats, chest pain, or paroxysmal nocturnal dyspnea. The review of other systems was unremarkable.

His COPD was known to be mild, in Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1, group A. His postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC) was less than 0.70, and his FEV₁ was 84% of predicted. Apart from mild intermittent cough with white sputum, his COPD had been under good control with inhaled ipratropium 4 times daily and inhaled albuterol as needed. He said he did not have shortness of breath except when hurrying on level ground or walking up a slight hill (Modified Medical Research Council dyspnea scale grade 1; COPD Assessment Test score < 10). In the last 3 years, he had 2 exacerbations of COPD, 1 year apart, both requiring oral prednisone and antibiotic therapy.

Other relevant history included hypertension and dyslipidemia of 15-year duration, for which he was taking candesartan 16 mg twice daily and atorvastatin 20 mg daily. He was compliant with his medications.

Though he usually received an influenza vaccine every year, he did not get it the previous year. Also, 3 years previously, he received the 23-valent pneumococcal polysaccharide vaccine (PPSV23), and the year before that he received the pneumococcal conjugate vaccine (PCV13). In addition, he was immunized against herpes zoster and tetanus.

The patient had smoked 1 pack per day for the past 38 years. His primary care physician had advised him many times to quit smoking. He had enrolled in a smoking cessation program 2 years previously, in which he received varenicline in addition to behavioral counseling in the form of motivational interviewing and a telephone quit-line. Nevertheless, he continued to smoke.

He was a retired engineer. He did not drink alcohol or use illicit drugs.

PHYSICAL EXAMINATION

On physical examination, the patient was sitting up in bed, leaning forward. He was alert and oriented but was breathing rapidly and looked sick. He had no cyanosis, clubbing, pallor, or jaundice. His blood pressure was 145/90 mm Hg, heart rate 110 beats per minute and regular, respiratory rate 29 breaths per minute, and oral temperature 38.1°C (100.6°F). His oxygen saturation was 88% while breathing room air. His body mass index was 27.1 kg/m².

His throat was mildly congested. His neck veins were flat, and there were no carotid bruits. His thyroid examination was normal, without goiter, nodules, or tenderness.

Intercostal retractions were noted around the anterolateral costal margins. He had no chest wall deformities. Chest expansion was reduced bilaterally. There was hyperresonance bilaterally. Expiratory wheezes were heard over both lungs, without crackles.

His heart had no murmurs or added sounds. There was no lower-limb edema or swelling. The rest of his physical examination was unremarkable.

Results of initial laboratory testing are shown in Table 1.

Assessment: A 66-year-old man with GOLD grade 1, group A COPD, presenting with a severe exacerbation, most likely due to viral bronchitis.

The patient was given oxygen 28% by Venturi mask, and his oxygen saturation went up to 90%. He was started on nebulized albuterol 2.5 mg with ipratropium bromide 500 µg every 4 hours, prednisone 40 mg orally daily for 5 days, and ceftriaxone 1 g intravenously every 24 hours. The first dose of each medication was given in the emergency department.

The patient was then admitted to a progressive care unit, where he was placed on noninvasive positive pressure ventilation, continuous cardiac monitoring, and pulse oximetry. He was started on enoxaparin 40 mg subcutaneously daily to prevent venous thromboembolism, and the oral medications he had been taking at home were continued. Because he was receiving a glucocorticoid, his blood glucose was monitored in the fasting state, 2 hours after each meal, and as needed.

Two hours after he started noninvasive positive pressure ventilation, his arterial blood gases were remeasured and showed the following results:

• pH 7.35
• Partial pressure of carbon dioxide (Paco₂) 52 mm Hg
• Bicarbonate 28 mmol/L
• Partial pressure of oxygen (Pao₂) 60 mm Hg
• Oxygen saturation 90%.

HOSPITAL COURSE

On hospital day 3, his dyspnea had slightly improved. His respiratory rate was 26 to 28 breaths per minute. His oxygen saturation remained between 90% and 92%.

At 10:21 pm, his cardiac monitor showed an episode of focal atrial tachycardia at a rate of 129 beats per minute that lasted for 3 minutes and 21 seconds, terminating spontaneously. He denied any change in his clinical condition during the episode, with no chest pain, palpitation, or change in dyspnea. There was no change in his vital signs. He had another similar asymptomatic episode lasting 4 minutes and 9 seconds at 6:30 am of hospital day 4.

Because of these episodes, the attending physician ordered thyroid function tests.

THYROID FUNCTION TESTING

1. Which thyroid function test is most likely to be helpful in the assessment of this patient’s thyroid status?

• Serum thyroid-stimulating hormone (TSH) alone
• Serum TSH and total thyroxine (T₄)
• Serum TSH and total triiodothyronine (T₃)
• Serum TSH and free T₄
• Serum TSH and free T₃

There are several tests to assess thyroid function: the serum TSH, total T₄, free T₄, total T₃, and free T₃ concentrations.¹

In normal physiology, TSH from the pituitary stimulates the thyroid gland to produce and secrete T₄ and T₃, which in turn inhibit TSH secretion through negative feedback. A negative log-linear relation exists between serum free T₄ and TSH levels.² Thus, the serum free T₄ level can remain within the normal reference range even if the TSH level is high or low. 

TSH assays can have different detection limits. A third-generation TSH assay with a detection limit of 0.01 mU/L is recommended for use in clinical practice.³

TSH testing alone. Given its superior sensitivity and specificity, serum TSH measurement is considered the best single test for assessing thyroid function in most cases.⁴ Nevertheless, measurement of the serum TSH level alone could be misleading in several situations, eg, hypothalamic or pituitary disorders, recent treatment of thyrotoxicosis, impaired sensitivity to thyroid hormone, and acute nonthyroidal illness.⁴

Free vs total T₄ and T₃ levels

Serum total T₄ includes a fraction that is bound, mainly to thyroxin-binding globulin, and a very small unbound (free) fraction. The same applies to T₃. Only free thyroid hormones represent the “active” fraction available for interaction with their protein receptors in the nucleus.⁸ Patients with conditions that can affect the thyroid-binding protein concentrations usually have altered serum total T₄ and T₃ levels, whereas their free hormone concentrations remain normal. Accordingly, measurement of free hormone levels, especially free T₄, is usually recommended.

Although equilibrium dialysis is the method most likely to provide an accurate serum free T₄ measurement, it is not commonly used because of its limited availability and high cost. Thus, most commercial laboratories use “direct” free T₄ measurement or, to a lesser degree, the free T₄ index.⁹ However, none of the currently available free T₄ tests actually measure free T₄ directly; rather, they estimate it.¹⁰

Commercial laboratories can provide a direct free T₃ estimate, but it may be less reliable than total T₃. If serum T₃ measurement is indicated, serum total T₃ is usually measured. However, total T₃ measurement is rarely indicated for patients with hypothyroidism because it usually remains within the normal reference range.¹¹ Nevertheless, serum total T₃ measurement could be useful in patients with T₃ toxicosis and in those who are acutely ill.

Accordingly, in acutely ill hospitalized patients like ours, measuring serum TSH using a third-generation assay and free T₄ is essential to assess thyroid function. Many clinicians also measure serum total T₃.

The attending physician ordered serum TSH, free T₄, and total T₃ measurements, which yielded the following:

• TSH 0.1 mU/L (0.5–5.0)
• Total T₃ 55 ng/dL (80–180)
• Free T₄ 0.9 ng/dL (0.9–2.4).

2. Which best explains this patient’s abnormal thyroid test results?

• His acute illness
• Central hypothyroidism due to pituitary infarction
• His albuterol therapy
• Subclinical thyrotoxicosis
• Hashimoto thyroiditis

Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),^5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.¹ In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.

Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T₃, normal or low serum TSH, and normal, low, or high serum free T₄. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.¹⁶ These abnormalities with their mechanisms are shown in Table 2.^5–7 In several commercial kits, serum direct free T₄ can be falsely decreased or increased.⁸

THE DIFFERENTIAL DIAGNOSIS

Our patient had low serum TSH, low-normal serum direct free T₄, and low serum total T₃. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.¹⁷ The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.

In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.¹⁸ Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.^19,20

The serum concentration of reverse T₃ has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.²¹

GLUCOCORTICOIDS AND THYROID FUNCTION TESTS

By inhibiting D1, glucocorticoids can decrease peripheral conversion of T₄ to T₃ and thus decrease serum total T₃. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.

In one study,²² there was a significant reduction in serum total T₃ concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T₃ returned to its pretreatment level.

In another study,²³ a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T₃ in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.

Long-term glucocorticoid therapy also decreases serum total T₄ and total T₃ by lowering serum thyroid-binding globulin.²⁴

Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.^25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.²⁷

Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.²⁸ Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T₄ clearance.²⁹

While there is general agreement that beta-adrenergic antagonists (beta-blockers) do not affect the serum TSH concentration, conflicting data have been reported concerning their effect on other thyroid function tests. This may be due to several factors, including dose, duration of therapy, the patient’s thyroid status, and differences in laboratory methodology.³⁰

In studies of propranolol, serum total T₄ concentrations did not change or were increased with daily doses of 160 mg or more in both euthyroid participants and hyperthyroid patients^31–33; serum total T₃ concentrations did not change or were decreased with 40 mg or more daily³⁴; and serum reverse T₃ concentrations were increased with daily doses of 80 mg or more.³¹ It is most likely that propranolol exerts these changes by inhibiting D1 activity in peripheral tissues.

Furthermore, a significant decrease in serum total T₃ concentrations was observed in hyperthyroid patients treated with atenolol 100 mg daily, metoprolol 100 mg daily, and alprenolol 100 mg daily, but not with sotalol 80 mg daily or nadolol (up to 240 mg daily).^35,36

On the other hand, beta-adrenergic agonists have not been reported to cause significant changes in thyroid function tests.³⁷

SUBCLINICAL THYROTOXICOSIS OR HASHIMOTO THYROIDITIS?

Our patient’s thyroid function test results are more likely due to his nonthyroidal illness and glucocorticoid therapy, as there is no clinical evidence to point to a hypothalamic-pituitary disorder accounting for true central hypothyroidism.

The other options mentioned in question 2 are unlikely to explain our patient’s thyroid function test results.

Subclinical thyrotoxicosis is characterized by suppressed serum TSH, but both serum free T₄ and total T₃ remain within the normal reference ranges. In addition, the serum TSH level may help to differentiate between thyrotoxicosis and nonthyroidal illness. In the former, serum TSH is usually suppressed (< 0.01 mU/L), whereas in the latter it is usually low but detectable (0.05– 0.3 mU/L).^38,39

Hashimoto thyroiditis is a chronic autoimmune thyroid disease characterized by diffuse lymphocytic infiltration of the thyroid gland. Almost all patients with Hashimoto thyroiditis have elevated levels of antibodies to thyroid peroxidase or thyroglobulin.⁴⁰ Clinically, patients with Hashimoto thyroiditis can either be hypothyroid or have normal thyroid function, which is not the case in our patient.

CASE CONTINUED

An endocrinologist, consulted for a second opinion, agreed that the patient’s thyroid function test results were most likely due to his nonthyroidal illness and glucocorticoid therapy.

3. In view of the endocrinologist’s opinion, which should be the next step in the management of the patient’s thyroid condition?

• Start levothyroxine (T₄) therapy
• Start liothyronine (T₃) therapy
• Start N-acetylcysteine therapy
• Start thyrotropin-releasing hormone therapy
• Remeasure thyroid hormones after full recovery from his acute illness

It is not clear whether the changes in thyroid hormone levels during an acute illness are a pathologic alteration for which thyroid hormone therapy may be beneficial, or a physiologic adaptation for which such therapy would not be indicated.⁴¹

However, current data argue against thyroid hormone therapy using T₄ or T₃ for patients with nonthyroidal illness syndrome (also called euthyroid sick syndrome).⁴² Indeed, several randomized controlled trials showed that thyroid hormone therapy is not beneficial in such patients and may be detrimental.^41,43

Therapies other than thyroid hormone have been investigated to ameliorate thyroid hormone abnormalities in patients with nonthyroidal illness. These include N-acetylcysteine, thyrotropin-releasing hormone therapy, and nutritional support.

Some studies showed that giving N-acetyl­cysteine, an antioxidant, increased serum T₃ and decreased serum reverse T₃ concentrations in patients with acute myocardial infarction.⁴⁴ Nevertheless, the mortality rate and length of hospitalization were not affected. Further studies are needed to know whether N-acetylcysteine therapy is beneficial for such patients.

Similarly, a study using a thyrotropin-releasing hormone analogue along with growth hormone-releasing peptide 2 showed an increase in serum TSH, T₄, and T₃ levels in critically ill patients.⁴⁵ The benefit of this therapy has yet to be determined. On the other hand, early nutritional support was reported to prevent thyroid hormonal changes in patients postoperatively.⁴⁶

Measuring thyroid hormone levels after full recovery is the most appropriate next step in our patient, as the changes in thyroid hormone concentrations subside as the acute illness resolves.⁴⁷

The patient continued to improve. On hospital day 6, he was feeling better but still had mild respiratory distress. There had been no further episodes of arrhythmia since day 4. His blood pressure was 136/86 mm Hg, heart rate 88 beats per minute and regular, respiratory rate 18 breaths per minute, and oral temperature 37.1°C. His oxygen saturation was 92% on room air.

Before discharge, he was encouraged to quit smoking. He was offered behavioral counseling and medication therapy, but he only said that he would think about it. He was discharged on oral cefixime for 4 more days and was instructed to switch to a long-acting bronchodilator along with his other home medications and to return in 1 week to have his thyroid hormones checked.

One week later, his laboratory results were:

• TSH 11.2 mU/L (reference range 0.5–5.0)
• Free T₄ 1.2 ng/dL (0.9–2.4)
• Total T₃ 92 ng/dL (80–180).

Clinically, the patient was euthyroid, and examination of his thyroid was unremarkable.

4. Based on these last test results, which statement is correct?

• Levothyroxine therapy should be started
• His serum TSH elevation is most likely transient
• Thyroid ultrasonography is strongly indicated
• A radioactive iodine uptake study should be performed
• Measurement of thyroid-stimulating immunoglobulins is indicated

During recovery from nonthyroidal illness, some patients may have elevated serum TSH levels that are usually transient and modest (< 20 mU/L).⁴⁸ Normalization of the thyroid function tests including serum TSH may take several weeks⁴⁹ or months.⁵⁰ However, a systematic review found that the likelihood of permanent primary hypothyroidism is high in patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness.⁵¹

Ultrasonography is useful for evaluating patients with thyroid nodules or goiter but is of little benefit for patients like ours, in whom the thyroid is normal on examination.

Similarly, a radioactive iodine uptake study is not indicated, as it is principally used to help differentiate between types of thyrotoxicosis. (Radioactive iodine is also used to treat differentiated thyroid cancer.)

Thyroid-stimulating immunoglobins are TSH receptor-stimulating antibodies that cause Graves disease. Nevertheless, measuring them is not routinely indicated for its diagnosis. However, their measurement is of significant help in the diagnosis of Graves disease if a radioactive iodine uptake study cannot be performed (as in pregnancy) and in atypical presentations such as euthyroid Graves ophthalmopathy.⁵² Other indications for thyroid-stimulating immunoglobin measurement are beyond the scope of the article. Our patient’s test results are not consistent with hyperthyroidism, so measuring thyroid-stimulating immunoglobins is not indicated.

CASE CONCLUSION: BETTER, BUT STILL SMOKING

The patient missed his 1-month clinic follow-up, but he visited the clinic for follow-up 3 months later. He was feeling well with no complaints. Test results including serum TSH, free T₄, and total T₃ were within normal ranges. His COPD was under control, with an FEV₁ 88% of predicted.

He was again encouraged to quit smoking and was offered drug therapy and behavioral counseling, but he declined. In addition, he was instructed to adhere to his annual influenza vaccination.

KEY POINTS

• In patients with acute illness, it is recommended that thyroid function not be assessed unless there is a strong indication.
• If thyroid function assessment is indicated for critically ill patients, serum TSH and free T₄ concentrations should be measured. Some clinicians also measure serum total T₃ level.
• Thyroid function testing in critically ill patients usually shows low serum total T₃, normal or low serum TSH, and normal or low serum free T₄.
• Many drugs can alter thyroid hormone levels.
• Thyroid hormone therapy is not recommended for critically ill patients with low T₃, low T₄, or both.
• During recovery from nonthyroidal illness, some patients may have mild elevation in serum TSH levels (< 20 mU/L).
• Thyroid hormone levels may take several weeks or months to return to normal after the acute illness.
• Patients with serum TSH levels higher than 20 mU/L during the recovery phase of their nonthyroidal illness are more likely to have permanent primary hypothyroidism.

People who eat red meat or processed meat should continue their current meat consumption, according to recent guidelines from an international panel that were recently published in the Annals of Internal Medicine.

Fuse/Thinkstock

This recommendation was based on the panel having found “low- to very-low-certainty evidence that diets lower in unprocessed red meat may have little or no effect on the risk for major cardiometabolic outcomes and cancer mortality and incidence.” Additionally, meta-analysis results from 23 cohort studies provided low- to very-low-certainty evidence that decreasing unprocessed red meat intake may result in a very small reduction in the risk for major cardiovascular outcomes and type 2 diabetes, with no statistically differences in all-cause mortality and cardiovascular mortality, the guidelines say.

“Our weak recommendation that people continue their current meat consumption highlights both the uncertainty associated with possible harmful effects and the very small magnitude of effect, even if the best estimates represent true causation, which we believe to be implausible,” Bradley C. Johnston, PhD, of the department of community health and epidemiology at Dalhousie University, Halifax, N.S., and colleagues wrote in their paper summarizing the panel’s guidelines.

The evidence Dr. Johnston and colleagues examined were from four systematic reviews analyzing the health effects of red meat and processed meat consumption in randomized trials and meta-analyses of cohort studies as well as one systematic review that identified how people viewed their consumption of meat and values surrounding meat consumption.

In one review of 12 randomized trials examining diets of high and low red meat consumption, a diet consisting of low red meat had little effect on cardiovascular mortality (hazard ratio, 0.98; 95% confidence interval, 0.91-1.06), cardiovascular disease (HR, 0.99; 95% CI, 0.94-1.05), all-cause mortality (0.99; 95% CI, 0.95-1.03) and total cancer mortality (HR, 0.95; 95% CI, 0.89-1.01), including on colorectal cancer or breast cancer (Zeraatkar D et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-0622). A different review of observational cohort studies with more than 1,000 participants found “very-small or possibly small decreases” in all-cause mortality, incidence, and all-cause mortality of cancer, cardiovascular mortality, nonfatal coronary heart disease and MI, and type 2 diabetes for patients who had a diet low in red meat or processed meat (Vernooij R et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-1583); a second review by Zeraatkar and colleagues of 55 observational cohort studies with more than 4 million participants found three servings of unprocessed red meat and processed meat per week was associated with a “very small reduction” in risk for MI, stroke, type 2 diabetes, cardiovascular mortality, and all-cause mortality (Zeraatkar D et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-1326). Another systematic review of 56 observational cohort studies found three servings of unprocessed red meat per week was associated with a slight reduction in overall cancer mortality (Han MA et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-0699).

The authors also performed a systematic review of participant preferences and values regarding meat consumption. The evidence from 54 qualitative studies showed omnivores preferred eating meat, considered it part of a healthy diet, “lack[ed] the skills needed” to prepare meals without meat, and were mostly unwilling to change their meat consumption (Valli C et al. Ann Intern Med. 2019. doi: 10.7326/M19-1326).

“There was a very small and often trivial absolute risk reduction based on a realistic decrease of three servings of red or processed meat per week,” Dr. Johnston and colleagues wrote in their guidelines. If the very-small exposure effect is true, given peoples’ attachment to their meat-based diet, the associated risk reduction is not likely to provide sufficient motivation to reduce consumption of red meat or processed meat in fully informed individuals, and the weak, rather than strong, recommendation is based on the large variability in peoples’ values and preferences related to meat.”

The authors noted they did not examine factors such as cost, acceptability, feasibility, equity, environmental impact, and views on animal welfare when creating the guidelines. In addition, the low level of evidence from the randomized trials and observational studies means that the potential benefits of reducing red meat or processed meat intake may not outweigh the cultural and personal preferences or quality of life issues that could arise from changing one’s diet.

“This assessment may be excessively pessimistic; indeed, we hope that is the case,” they said. “What is certain is that generating higher-quality evidence regarding the magnitude of any causal effect of meat consumption on health outcomes will test the ingenuity and imagination of health science investigators.”

Dr. El Dib reported receiving funding from the São Paulo Research Foundation, the National Council for Scientific and Technological Development, and the faculty of medicine at Dalhousie University. Dr. de Souza reports relationships with the Canadian Institutes of Health Research/Health Canada, the Canadian Foundation for Dietetic Research and the World Health Organization in the forms of personal fees, grants, and speakers bureau and board of directorship appointments. Dr. Patel reports receiving grants and person fees from the National Institutes of Health, Sanofi, the National Science Foundation, XY.health, doc.ai, Janssen, and the CDC.

SOURCE: Johnston B et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-1621.

People who eat red meat or processed meat should continue their current meat consumption, according to recent guidelines from an international panel that were recently published in the Annals of Internal Medicine.

Fuse/Thinkstock

This recommendation was based on the panel having found “low- to very-low-certainty evidence that diets lower in unprocessed red meat may have little or no effect on the risk for major cardiometabolic outcomes and cancer mortality and incidence.” Additionally, meta-analysis results from 23 cohort studies provided low- to very-low-certainty evidence that decreasing unprocessed red meat intake may result in a very small reduction in the risk for major cardiovascular outcomes and type 2 diabetes, with no statistically differences in all-cause mortality and cardiovascular mortality, the guidelines say.

“Our weak recommendation that people continue their current meat consumption highlights both the uncertainty associated with possible harmful effects and the very small magnitude of effect, even if the best estimates represent true causation, which we believe to be implausible,” Bradley C. Johnston, PhD, of the department of community health and epidemiology at Dalhousie University, Halifax, N.S., and colleagues wrote in their paper summarizing the panel’s guidelines.

The evidence Dr. Johnston and colleagues examined were from four systematic reviews analyzing the health effects of red meat and processed meat consumption in randomized trials and meta-analyses of cohort studies as well as one systematic review that identified how people viewed their consumption of meat and values surrounding meat consumption.

In one review of 12 randomized trials examining diets of high and low red meat consumption, a diet consisting of low red meat had little effect on cardiovascular mortality (hazard ratio, 0.98; 95% confidence interval, 0.91-1.06), cardiovascular disease (HR, 0.99; 95% CI, 0.94-1.05), all-cause mortality (0.99; 95% CI, 0.95-1.03) and total cancer mortality (HR, 0.95; 95% CI, 0.89-1.01), including on colorectal cancer or breast cancer (Zeraatkar D et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-0622). A different review of observational cohort studies with more than 1,000 participants found “very-small or possibly small decreases” in all-cause mortality, incidence, and all-cause mortality of cancer, cardiovascular mortality, nonfatal coronary heart disease and MI, and type 2 diabetes for patients who had a diet low in red meat or processed meat (Vernooij R et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-1583); a second review by Zeraatkar and colleagues of 55 observational cohort studies with more than 4 million participants found three servings of unprocessed red meat and processed meat per week was associated with a “very small reduction” in risk for MI, stroke, type 2 diabetes, cardiovascular mortality, and all-cause mortality (Zeraatkar D et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-1326). Another systematic review of 56 observational cohort studies found three servings of unprocessed red meat per week was associated with a slight reduction in overall cancer mortality (Han MA et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-0699).

The authors also performed a systematic review of participant preferences and values regarding meat consumption. The evidence from 54 qualitative studies showed omnivores preferred eating meat, considered it part of a healthy diet, “lack[ed] the skills needed” to prepare meals without meat, and were mostly unwilling to change their meat consumption (Valli C et al. Ann Intern Med. 2019. doi: 10.7326/M19-1326).

“There was a very small and often trivial absolute risk reduction based on a realistic decrease of three servings of red or processed meat per week,” Dr. Johnston and colleagues wrote in their guidelines. If the very-small exposure effect is true, given peoples’ attachment to their meat-based diet, the associated risk reduction is not likely to provide sufficient motivation to reduce consumption of red meat or processed meat in fully informed individuals, and the weak, rather than strong, recommendation is based on the large variability in peoples’ values and preferences related to meat.”

The authors noted they did not examine factors such as cost, acceptability, feasibility, equity, environmental impact, and views on animal welfare when creating the guidelines. In addition, the low level of evidence from the randomized trials and observational studies means that the potential benefits of reducing red meat or processed meat intake may not outweigh the cultural and personal preferences or quality of life issues that could arise from changing one’s diet.

“This assessment may be excessively pessimistic; indeed, we hope that is the case,” they said. “What is certain is that generating higher-quality evidence regarding the magnitude of any causal effect of meat consumption on health outcomes will test the ingenuity and imagination of health science investigators.”

Dr. El Dib reported receiving funding from the São Paulo Research Foundation, the National Council for Scientific and Technological Development, and the faculty of medicine at Dalhousie University. Dr. de Souza reports relationships with the Canadian Institutes of Health Research/Health Canada, the Canadian Foundation for Dietetic Research and the World Health Organization in the forms of personal fees, grants, and speakers bureau and board of directorship appointments. Dr. Patel reports receiving grants and person fees from the National Institutes of Health, Sanofi, the National Science Foundation, XY.health, doc.ai, Janssen, and the CDC.

SOURCE: Johnston B et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-1621.

People who eat red meat or processed meat should continue their current meat consumption, according to recent guidelines from an international panel that were recently published in the Annals of Internal Medicine.

Fuse/Thinkstock

This recommendation was based on the panel having found “low- to very-low-certainty evidence that diets lower in unprocessed red meat may have little or no effect on the risk for major cardiometabolic outcomes and cancer mortality and incidence.” Additionally, meta-analysis results from 23 cohort studies provided low- to very-low-certainty evidence that decreasing unprocessed red meat intake may result in a very small reduction in the risk for major cardiovascular outcomes and type 2 diabetes, with no statistically differences in all-cause mortality and cardiovascular mortality, the guidelines say.

“Our weak recommendation that people continue their current meat consumption highlights both the uncertainty associated with possible harmful effects and the very small magnitude of effect, even if the best estimates represent true causation, which we believe to be implausible,” Bradley C. Johnston, PhD, of the department of community health and epidemiology at Dalhousie University, Halifax, N.S., and colleagues wrote in their paper summarizing the panel’s guidelines.

The evidence Dr. Johnston and colleagues examined were from four systematic reviews analyzing the health effects of red meat and processed meat consumption in randomized trials and meta-analyses of cohort studies as well as one systematic review that identified how people viewed their consumption of meat and values surrounding meat consumption.

In one review of 12 randomized trials examining diets of high and low red meat consumption, a diet consisting of low red meat had little effect on cardiovascular mortality (hazard ratio, 0.98; 95% confidence interval, 0.91-1.06), cardiovascular disease (HR, 0.99; 95% CI, 0.94-1.05), all-cause mortality (0.99; 95% CI, 0.95-1.03) and total cancer mortality (HR, 0.95; 95% CI, 0.89-1.01), including on colorectal cancer or breast cancer (Zeraatkar D et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-0622). A different review of observational cohort studies with more than 1,000 participants found “very-small or possibly small decreases” in all-cause mortality, incidence, and all-cause mortality of cancer, cardiovascular mortality, nonfatal coronary heart disease and MI, and type 2 diabetes for patients who had a diet low in red meat or processed meat (Vernooij R et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-1583); a second review by Zeraatkar and colleagues of 55 observational cohort studies with more than 4 million participants found three servings of unprocessed red meat and processed meat per week was associated with a “very small reduction” in risk for MI, stroke, type 2 diabetes, cardiovascular mortality, and all-cause mortality (Zeraatkar D et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-1326). Another systematic review of 56 observational cohort studies found three servings of unprocessed red meat per week was associated with a slight reduction in overall cancer mortality (Han MA et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-0699).

The authors also performed a systematic review of participant preferences and values regarding meat consumption. The evidence from 54 qualitative studies showed omnivores preferred eating meat, considered it part of a healthy diet, “lack[ed] the skills needed” to prepare meals without meat, and were mostly unwilling to change their meat consumption (Valli C et al. Ann Intern Med. 2019. doi: 10.7326/M19-1326).

“There was a very small and often trivial absolute risk reduction based on a realistic decrease of three servings of red or processed meat per week,” Dr. Johnston and colleagues wrote in their guidelines. If the very-small exposure effect is true, given peoples’ attachment to their meat-based diet, the associated risk reduction is not likely to provide sufficient motivation to reduce consumption of red meat or processed meat in fully informed individuals, and the weak, rather than strong, recommendation is based on the large variability in peoples’ values and preferences related to meat.”

The authors noted they did not examine factors such as cost, acceptability, feasibility, equity, environmental impact, and views on animal welfare when creating the guidelines. In addition, the low level of evidence from the randomized trials and observational studies means that the potential benefits of reducing red meat or processed meat intake may not outweigh the cultural and personal preferences or quality of life issues that could arise from changing one’s diet.

“This assessment may be excessively pessimistic; indeed, we hope that is the case,” they said. “What is certain is that generating higher-quality evidence regarding the magnitude of any causal effect of meat consumption on health outcomes will test the ingenuity and imagination of health science investigators.”

Dr. El Dib reported receiving funding from the São Paulo Research Foundation, the National Council for Scientific and Technological Development, and the faculty of medicine at Dalhousie University. Dr. de Souza reports relationships with the Canadian Institutes of Health Research/Health Canada, the Canadian Foundation for Dietetic Research and the World Health Organization in the forms of personal fees, grants, and speakers bureau and board of directorship appointments. Dr. Patel reports receiving grants and person fees from the National Institutes of Health, Sanofi, the National Science Foundation, XY.health, doc.ai, Janssen, and the CDC.

SOURCE: Johnston B et al. Ann Intern Med. 2019 Oct 1. doi: 10.7326/M19-1621.

The Food and Drug Administration has approved canagliflozin (Invokana) for the treatment of diabetic kidney disease and for reduction of the risk of hospitalization for heart failure in patients with type 2 diabetes and diabetic kidney disease, which makes it the first drug indicated for diabetic kidney disease treatment in 20 years.

FDA approval, which was announced in a press release by Janssen, the drug’s manufacturer, is based on results from the phase 3 CREDENCE trial. In that study patients with type 2 diabetes and chronic diabetic kidney disease received either 100 mg canagliflozin or placebo. Patients who received canagliflozin experienced a 30% reduction in the risk of the primary composite endpoint, which included end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. The risk of secondary outcomes were also reduced in patients receiving canagliflozin, including a 39% reduction in the risk of hospitalization for heart failure.

The most common adverse events associated with canagliflozin, according to the label, are female genital mycotic infections, urinary tract infection, and increased urination. Serious adverse events associated with canagliflozin include ketoacidosis, kidney problems, serious urinary tract infections, hypoglycemia, necrotizing fasciitis, serious allergic reaction, and bone fractures.

“The real battle to turn the tide on kidney disease is in early detection and slowing its progression so that patients stay healthier and fewer patients reach kidney failure,” LaVerne A. Burton, president and CEO of the American Kidney Fund, said in the press release. “We are so grateful that advances in kidney disease research are producing treatment options that help to slow the progression of diabetic kidney disease and reduce the risk of hospitalization for heart failure.”

Find the full press release on the Janssen website.

[email protected]

The Food and Drug Administration has approved canagliflozin (Invokana) for the treatment of diabetic kidney disease and for reduction of the risk of hospitalization for heart failure in patients with type 2 diabetes and diabetic kidney disease, which makes it the first drug indicated for diabetic kidney disease treatment in 20 years.

FDA approval, which was announced in a press release by Janssen, the drug’s manufacturer, is based on results from the phase 3 CREDENCE trial. In that study patients with type 2 diabetes and chronic diabetic kidney disease received either 100 mg canagliflozin or placebo. Patients who received canagliflozin experienced a 30% reduction in the risk of the primary composite endpoint, which included end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. The risk of secondary outcomes were also reduced in patients receiving canagliflozin, including a 39% reduction in the risk of hospitalization for heart failure.

The most common adverse events associated with canagliflozin, according to the label, are female genital mycotic infections, urinary tract infection, and increased urination. Serious adverse events associated with canagliflozin include ketoacidosis, kidney problems, serious urinary tract infections, hypoglycemia, necrotizing fasciitis, serious allergic reaction, and bone fractures.

“The real battle to turn the tide on kidney disease is in early detection and slowing its progression so that patients stay healthier and fewer patients reach kidney failure,” LaVerne A. Burton, president and CEO of the American Kidney Fund, said in the press release. “We are so grateful that advances in kidney disease research are producing treatment options that help to slow the progression of diabetic kidney disease and reduce the risk of hospitalization for heart failure.”

Find the full press release on the Janssen website.

[email protected]

The Food and Drug Administration has approved canagliflozin (Invokana) for the treatment of diabetic kidney disease and for reduction of the risk of hospitalization for heart failure in patients with type 2 diabetes and diabetic kidney disease, which makes it the first drug indicated for diabetic kidney disease treatment in 20 years.

FDA approval, which was announced in a press release by Janssen, the drug’s manufacturer, is based on results from the phase 3 CREDENCE trial. In that study patients with type 2 diabetes and chronic diabetic kidney disease received either 100 mg canagliflozin or placebo. Patients who received canagliflozin experienced a 30% reduction in the risk of the primary composite endpoint, which included end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. The risk of secondary outcomes were also reduced in patients receiving canagliflozin, including a 39% reduction in the risk of hospitalization for heart failure.

The most common adverse events associated with canagliflozin, according to the label, are female genital mycotic infections, urinary tract infection, and increased urination. Serious adverse events associated with canagliflozin include ketoacidosis, kidney problems, serious urinary tract infections, hypoglycemia, necrotizing fasciitis, serious allergic reaction, and bone fractures.

“The real battle to turn the tide on kidney disease is in early detection and slowing its progression so that patients stay healthier and fewer patients reach kidney failure,” LaVerne A. Burton, president and CEO of the American Kidney Fund, said in the press release. “We are so grateful that advances in kidney disease research are producing treatment options that help to slow the progression of diabetic kidney disease and reduce the risk of hospitalization for heart failure.”

Find the full press release on the Janssen website.

[email protected]

ORLANDO – Supplemental vitamin D₃ in healthy older men and women did not significantly affect areal bone mineral density in the whole body, femoral neck, total hip, or spine after 2 years of daily use, according to data presented at the annual meeting of the American Society for Bone and Mineral Research.

“Participants may have already reached the vitamin D level needed for bone health,” Meryl S. LeBoff, MD, of Brigham and Women’s Hospital in Boston, said in her presentation.

Dr. LeBoff presented results from 771 patients (mean age, 63.8 years) in the Bone Health Subcohort of VITAL (Vitamin D and OmegA-3 TriaL) who were not on any bone active medications and were randomized to receive daily vitamin D₃ at a dose of 2,000 IU or placebo. Patients received bone imaging at baseline and at 2 years; areal bone mineral density (aBMD) of the whole body, femoral neck, total hip, and spine was assessed via dual x-ray absorptiometry scan. Total 25-hydroxyvitamin D (25[OH]D) levels were measured via liquid chromatography tandem mass spectrometry, and free 25(OH)D levels were measured via the ELISA assay. The baseline characteristics of the vitamin D₃ supplementation and placebo groups were similar. Overall, 52% of patients had osteopenia and 10.4% had osteoporosis.

Between baseline and 2 years, the vitamin D group’s total 25(OH)D levels increased from a mean 27.0 ng/mL to 39.5 ng/mL (46%) and the free 25(OH)D levels increased from 5.8 pg/mL to 9.0 pg/mL (55%), whereas levels in the placebo stayed the same. The researchers found no significant absolute percentage changes over 2 years in aBMD of the whole body (P = .60), femoral neck (P = .16), total hip (P = .23) and spine (P = .55), compared with patients in the placebo group.

In a secondary analysis, Dr. LeBoff and colleagues found no benefit to volumetric BMD (vBMD) of the radius and the tibia at 2 years, and the results persisted after they performed a sensitivity analysis. Adverse events, such as hypercalciuria, kidney stones, and gastrointestinal symptoms, were not significantly different in the vitamin D group, compared with the placebo group.

Dr. LeBoff noted among the limitations of the study that it evaluated one dose level of vitamin D and was not designed to determine whether vitamin D supplementation was effective in people with vitamin D insufficiency, and the results are not generalizable to patients with osteoporosis or osteomalacia. Future studies should also examine whether free 25(OH)D levels can be used to detect which patients can benefit from vitamin D supplementation, she added.
 

Risk of falls

In a separate abstract, which Dr. LeBoff presented in a different session, 12,927 patients who received vitamin D supplementation for 5 years, were studied for risk of falls, compared with 12,994 individuals in a placebo group. At baseline, 33.3% of patients had fallen at least once in the previous year, and overall 6,605 patients reported 13,235 falls. At 5.3 years of follow-up, there were no significant differences in number of falls between groups, falls leading to injury, and falls leading to a doctor or a hospital visit.

There are ongoing parallel studies examining the incidence of fractures between groups in the total population of the VITAL study (25,871 participants); bone turnover markers; bone microarchitecture measurements through high-resolution peripheral quantitative computed tomography; and examining the connection between free 25(OH)D, parathyroid hormone, and vitamin D binding protein, said Dr. LeBoff.

The study was funded in part by grants from the National Cancer Institute, the National Heart, Lung and Blood Institute, the Office of Dietary Supplements, the National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health. Dr. LeBoff reported receiving grants from the National Institute of Arthritis Musculoskeletal and Skin Diseases. Two authors reported nonfinancial support Pharmavite LLC of Northridge, Calif., Pronova BioPharma of Norway and BASF, and Quest Diagnostics. The remaining authors reported no conflicts of interest.

SOURCE: LeBoff M et al. ASBMR 2019, Abstracts 1046 and 1057.

ORLANDO – Supplemental vitamin D₃ in healthy older men and women did not significantly affect areal bone mineral density in the whole body, femoral neck, total hip, or spine after 2 years of daily use, according to data presented at the annual meeting of the American Society for Bone and Mineral Research.

“Participants may have already reached the vitamin D level needed for bone health,” Meryl S. LeBoff, MD, of Brigham and Women’s Hospital in Boston, said in her presentation.

Dr. LeBoff presented results from 771 patients (mean age, 63.8 years) in the Bone Health Subcohort of VITAL (Vitamin D and OmegA-3 TriaL) who were not on any bone active medications and were randomized to receive daily vitamin D₃ at a dose of 2,000 IU or placebo. Patients received bone imaging at baseline and at 2 years; areal bone mineral density (aBMD) of the whole body, femoral neck, total hip, and spine was assessed via dual x-ray absorptiometry scan. Total 25-hydroxyvitamin D (25[OH]D) levels were measured via liquid chromatography tandem mass spectrometry, and free 25(OH)D levels were measured via the ELISA assay. The baseline characteristics of the vitamin D₃ supplementation and placebo groups were similar. Overall, 52% of patients had osteopenia and 10.4% had osteoporosis.

Between baseline and 2 years, the vitamin D group’s total 25(OH)D levels increased from a mean 27.0 ng/mL to 39.5 ng/mL (46%) and the free 25(OH)D levels increased from 5.8 pg/mL to 9.0 pg/mL (55%), whereas levels in the placebo stayed the same. The researchers found no significant absolute percentage changes over 2 years in aBMD of the whole body (P = .60), femoral neck (P = .16), total hip (P = .23) and spine (P = .55), compared with patients in the placebo group.

In a secondary analysis, Dr. LeBoff and colleagues found no benefit to volumetric BMD (vBMD) of the radius and the tibia at 2 years, and the results persisted after they performed a sensitivity analysis. Adverse events, such as hypercalciuria, kidney stones, and gastrointestinal symptoms, were not significantly different in the vitamin D group, compared with the placebo group.

Dr. LeBoff noted among the limitations of the study that it evaluated one dose level of vitamin D and was not designed to determine whether vitamin D supplementation was effective in people with vitamin D insufficiency, and the results are not generalizable to patients with osteoporosis or osteomalacia. Future studies should also examine whether free 25(OH)D levels can be used to detect which patients can benefit from vitamin D supplementation, she added.
 

Risk of falls

In a separate abstract, which Dr. LeBoff presented in a different session, 12,927 patients who received vitamin D supplementation for 5 years, were studied for risk of falls, compared with 12,994 individuals in a placebo group. At baseline, 33.3% of patients had fallen at least once in the previous year, and overall 6,605 patients reported 13,235 falls. At 5.3 years of follow-up, there were no significant differences in number of falls between groups, falls leading to injury, and falls leading to a doctor or a hospital visit.

There are ongoing parallel studies examining the incidence of fractures between groups in the total population of the VITAL study (25,871 participants); bone turnover markers; bone microarchitecture measurements through high-resolution peripheral quantitative computed tomography; and examining the connection between free 25(OH)D, parathyroid hormone, and vitamin D binding protein, said Dr. LeBoff.

The study was funded in part by grants from the National Cancer Institute, the National Heart, Lung and Blood Institute, the Office of Dietary Supplements, the National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health. Dr. LeBoff reported receiving grants from the National Institute of Arthritis Musculoskeletal and Skin Diseases. Two authors reported nonfinancial support Pharmavite LLC of Northridge, Calif., Pronova BioPharma of Norway and BASF, and Quest Diagnostics. The remaining authors reported no conflicts of interest.

SOURCE: LeBoff M et al. ASBMR 2019, Abstracts 1046 and 1057.

ORLANDO – Supplemental vitamin D₃ in healthy older men and women did not significantly affect areal bone mineral density in the whole body, femoral neck, total hip, or spine after 2 years of daily use, according to data presented at the annual meeting of the American Society for Bone and Mineral Research.

“Participants may have already reached the vitamin D level needed for bone health,” Meryl S. LeBoff, MD, of Brigham and Women’s Hospital in Boston, said in her presentation.

Dr. LeBoff presented results from 771 patients (mean age, 63.8 years) in the Bone Health Subcohort of VITAL (Vitamin D and OmegA-3 TriaL) who were not on any bone active medications and were randomized to receive daily vitamin D₃ at a dose of 2,000 IU or placebo. Patients received bone imaging at baseline and at 2 years; areal bone mineral density (aBMD) of the whole body, femoral neck, total hip, and spine was assessed via dual x-ray absorptiometry scan. Total 25-hydroxyvitamin D (25[OH]D) levels were measured via liquid chromatography tandem mass spectrometry, and free 25(OH)D levels were measured via the ELISA assay. The baseline characteristics of the vitamin D₃ supplementation and placebo groups were similar. Overall, 52% of patients had osteopenia and 10.4% had osteoporosis.

Between baseline and 2 years, the vitamin D group’s total 25(OH)D levels increased from a mean 27.0 ng/mL to 39.5 ng/mL (46%) and the free 25(OH)D levels increased from 5.8 pg/mL to 9.0 pg/mL (55%), whereas levels in the placebo stayed the same. The researchers found no significant absolute percentage changes over 2 years in aBMD of the whole body (P = .60), femoral neck (P = .16), total hip (P = .23) and spine (P = .55), compared with patients in the placebo group.

In a secondary analysis, Dr. LeBoff and colleagues found no benefit to volumetric BMD (vBMD) of the radius and the tibia at 2 years, and the results persisted after they performed a sensitivity analysis. Adverse events, such as hypercalciuria, kidney stones, and gastrointestinal symptoms, were not significantly different in the vitamin D group, compared with the placebo group.

Dr. LeBoff noted among the limitations of the study that it evaluated one dose level of vitamin D and was not designed to determine whether vitamin D supplementation was effective in people with vitamin D insufficiency, and the results are not generalizable to patients with osteoporosis or osteomalacia. Future studies should also examine whether free 25(OH)D levels can be used to detect which patients can benefit from vitamin D supplementation, she added.
 

Risk of falls

In a separate abstract, which Dr. LeBoff presented in a different session, 12,927 patients who received vitamin D supplementation for 5 years, were studied for risk of falls, compared with 12,994 individuals in a placebo group. At baseline, 33.3% of patients had fallen at least once in the previous year, and overall 6,605 patients reported 13,235 falls. At 5.3 years of follow-up, there were no significant differences in number of falls between groups, falls leading to injury, and falls leading to a doctor or a hospital visit.

There are ongoing parallel studies examining the incidence of fractures between groups in the total population of the VITAL study (25,871 participants); bone turnover markers; bone microarchitecture measurements through high-resolution peripheral quantitative computed tomography; and examining the connection between free 25(OH)D, parathyroid hormone, and vitamin D binding protein, said Dr. LeBoff.

The study was funded in part by grants from the National Cancer Institute, the National Heart, Lung and Blood Institute, the Office of Dietary Supplements, the National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health. Dr. LeBoff reported receiving grants from the National Institute of Arthritis Musculoskeletal and Skin Diseases. Two authors reported nonfinancial support Pharmavite LLC of Northridge, Calif., Pronova BioPharma of Norway and BASF, and Quest Diagnostics. The remaining authors reported no conflicts of interest.

SOURCE: LeBoff M et al. ASBMR 2019, Abstracts 1046 and 1057.

PHILADELPHIA – For patients with high-risk diabetes, a novel, machine learning–derived risk score based on 10 common clinical variables can identify those facing a heart failure risk of up to nearly 20% over the ensuing 5 years, an investigator said at the annual meeting of the Heart Failure Society of America.

The risk score, dubbed WATCH-DM, has greater accuracy in predicting incident heart failure than traditional risk-based models, and requires no specific cardiovascular biomarkers or imaging, according to Muthiah Vaduganathan, MD, MPH, a cardiologist at Brigham and Women’s Hospital and faculty at Harvard Medical School in Boston.

The tool may help inform risk-based monitoring and introduction of sodium-glucose transporter 2 (SGLT2) inhibitors, which have been shown in multiple clinical trials to prevent heart failure in at-risk patients with type 2 diabetes mellitus (T2DM), Dr. Vaduganathan said.

“Patients identified at high risk based on WATCH-DM should be strongly considered for initiation of SGLT2 inhibitors in clinical practice,” Dr. Vaduganathan said in an interview.

WATCH-DM is available online at cvriskscores.com. Work is underway to integrate the tool into electronic health record systems at Brigham and Women’s Hospital and at the University of Texas Southwestern Medical Center in Dallas. “I expect that to be launched in the next year,” he said.

The WATCH-DM score was developed based on data from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, including 8,756 T2DM patients with inadequate glycemic control at high cardiovascular risk and no heart failure at baseline.

Starting with 147 variables, the investigators used a decision-tree machine learning approach to identify predictors of heart failure.

“What machine learning does is automate the variable selection process, as a form of artificial intelligence,” Dr. Vaduganathan said.

The WATCH-DM risk score was based on the 10 best-performing predictors as selected by machine learning, including body mass index, age, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, serum creatinine, high-density lipoprotein cholesterol, QRS duration, prior myocardial infarction, and prior coronary artery bypass grafting.

The 5-year risk of heart failure was just 1.1% for patients with WATCH-DM scores in the lowest quintile, increasing in a graded fashion to nearly 20% (17.4%) in the highest quintile, study results show.

Findings of the study were simultaneously published in the journal Diabetes Care.

Dr. Vaduganathan said he is supported by an award from Harvard Catalyst. He provided disclosures related to Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim (advisory boards), and with Novartis and the National Institutes of Health (participation on clinical endpoint committees).

SOURCE: HFSA 2019; Segar MW, Vaduganathan M et al. Diabetes Care. doi: 10.2337/dc19-0587.

PHILADELPHIA – For patients with high-risk diabetes, a novel, machine learning–derived risk score based on 10 common clinical variables can identify those facing a heart failure risk of up to nearly 20% over the ensuing 5 years, an investigator said at the annual meeting of the Heart Failure Society of America.

The risk score, dubbed WATCH-DM, has greater accuracy in predicting incident heart failure than traditional risk-based models, and requires no specific cardiovascular biomarkers or imaging, according to Muthiah Vaduganathan, MD, MPH, a cardiologist at Brigham and Women’s Hospital and faculty at Harvard Medical School in Boston.

The tool may help inform risk-based monitoring and introduction of sodium-glucose transporter 2 (SGLT2) inhibitors, which have been shown in multiple clinical trials to prevent heart failure in at-risk patients with type 2 diabetes mellitus (T2DM), Dr. Vaduganathan said.

“Patients identified at high risk based on WATCH-DM should be strongly considered for initiation of SGLT2 inhibitors in clinical practice,” Dr. Vaduganathan said in an interview.

WATCH-DM is available online at cvriskscores.com. Work is underway to integrate the tool into electronic health record systems at Brigham and Women’s Hospital and at the University of Texas Southwestern Medical Center in Dallas. “I expect that to be launched in the next year,” he said.

The WATCH-DM score was developed based on data from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, including 8,756 T2DM patients with inadequate glycemic control at high cardiovascular risk and no heart failure at baseline.

Starting with 147 variables, the investigators used a decision-tree machine learning approach to identify predictors of heart failure.

“What machine learning does is automate the variable selection process, as a form of artificial intelligence,” Dr. Vaduganathan said.

The WATCH-DM risk score was based on the 10 best-performing predictors as selected by machine learning, including body mass index, age, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, serum creatinine, high-density lipoprotein cholesterol, QRS duration, prior myocardial infarction, and prior coronary artery bypass grafting.

The 5-year risk of heart failure was just 1.1% for patients with WATCH-DM scores in the lowest quintile, increasing in a graded fashion to nearly 20% (17.4%) in the highest quintile, study results show.

Findings of the study were simultaneously published in the journal Diabetes Care.

Dr. Vaduganathan said he is supported by an award from Harvard Catalyst. He provided disclosures related to Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim (advisory boards), and with Novartis and the National Institutes of Health (participation on clinical endpoint committees).

SOURCE: HFSA 2019; Segar MW, Vaduganathan M et al. Diabetes Care. doi: 10.2337/dc19-0587.

PHILADELPHIA – For patients with high-risk diabetes, a novel, machine learning–derived risk score based on 10 common clinical variables can identify those facing a heart failure risk of up to nearly 20% over the ensuing 5 years, an investigator said at the annual meeting of the Heart Failure Society of America.

The risk score, dubbed WATCH-DM, has greater accuracy in predicting incident heart failure than traditional risk-based models, and requires no specific cardiovascular biomarkers or imaging, according to Muthiah Vaduganathan, MD, MPH, a cardiologist at Brigham and Women’s Hospital and faculty at Harvard Medical School in Boston.

The tool may help inform risk-based monitoring and introduction of sodium-glucose transporter 2 (SGLT2) inhibitors, which have been shown in multiple clinical trials to prevent heart failure in at-risk patients with type 2 diabetes mellitus (T2DM), Dr. Vaduganathan said.

“Patients identified at high risk based on WATCH-DM should be strongly considered for initiation of SGLT2 inhibitors in clinical practice,” Dr. Vaduganathan said in an interview.

WATCH-DM is available online at cvriskscores.com. Work is underway to integrate the tool into electronic health record systems at Brigham and Women’s Hospital and at the University of Texas Southwestern Medical Center in Dallas. “I expect that to be launched in the next year,” he said.

The WATCH-DM score was developed based on data from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, including 8,756 T2DM patients with inadequate glycemic control at high cardiovascular risk and no heart failure at baseline.

Starting with 147 variables, the investigators used a decision-tree machine learning approach to identify predictors of heart failure.

“What machine learning does is automate the variable selection process, as a form of artificial intelligence,” Dr. Vaduganathan said.

The WATCH-DM risk score was based on the 10 best-performing predictors as selected by machine learning, including body mass index, age, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, serum creatinine, high-density lipoprotein cholesterol, QRS duration, prior myocardial infarction, and prior coronary artery bypass grafting.

The 5-year risk of heart failure was just 1.1% for patients with WATCH-DM scores in the lowest quintile, increasing in a graded fashion to nearly 20% (17.4%) in the highest quintile, study results show.

Findings of the study were simultaneously published in the journal Diabetes Care.

Dr. Vaduganathan said he is supported by an award from Harvard Catalyst. He provided disclosures related to Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim (advisory boards), and with Novartis and the National Institutes of Health (participation on clinical endpoint committees).

SOURCE: HFSA 2019; Segar MW, Vaduganathan M et al. Diabetes Care. doi: 10.2337/dc19-0587.

ORLANDO – The use of a teleconferencing program to share knowledge about osteoporosis has helped health care professionals learn about the disease and may potentially reduce the osteoporosis treatment gap in underserved communities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

The concept, called “technology-enabled collaborative learning,” is intended to address the problem of there being not enough specialists to see patients who need treatment, and the ineffectiveness of educating primary care providers in how to treat complex medical conditions, E. Michael Lewiecki, MD, the director of the New Mexico Clinical Research & Osteoporosis Center said in his presentation.

“Primary care doctors are busy,” said Dr. Lewiecki. “They have limited time taking care of patients. They don’t have the time or often the skills to manage patients who have any questions or concerns about osteoporosis and treatments for osteoporosis.”

One solution, he said, is to find health care professionals in underserved communities who are already interested in and motivated to learn more about osteoporosis, turn them into near-experts on osteoporosis for their patients as well as in their own community.

Dr. Lewiecki proposed the Extension for Community Healthcare Outcomes (ECHO), or Project ECHO, an initiative out of the University of New Mexico School of Medicine, as a potential answer. Project ECHO uses videoconferencing to connect experts in a therapeutic area, with Bone Health TeleECHO focusing on raising knowledge of osteoporosis for its participants. “The idea of ECHO is to be a force multiplier to educate health care professionals, each of whom takes care of many patients, and to have many ECHO programs around the world in convenient time zones and convenient languages for people who are interested in participating,” said Dr. Lewiecki.

The idea began when a gastroenterologist at Dr. Lewiecki’s own center was frustrated that patients were not seeking treatment for hepatitis C because of time or travel issues. In response, a pilot program for Project ECHO was developed through a collaboration between the University of New Mexico Health Sciences Center and the Osteoporosis Foundation of New Mexico where gastroenterologists at University of New Mexico connected with primary care providers across the state, sharing information about hepatitis C and discussing case studies. The results of the pilot program were published in the New England Journal of Medicine and showed a similar rate of sustained viral response between patients treated at the University of New Mexico clinic (84 of 146 patients; 57.5%) and at 21 ECHO clinics (152 of 261 patients; 58.2%) (Arora S et al. N Eng J Med. 2011. doi: 10.1056/NEJMoa1009370).

“ECHO expands the capacity to deliver best practice medical care through collegial, interactive, case-based discussions with minimal disruption to the office routine,” said Dr. Lewiecki. “Patients benefit from better care, closer to home, with greater convenience and lower cost than referral to a medical center. And the potential is to reduce the osteoporosis treatment gap by having many ECHOs starting up in many places in the world.”

Today, the ECHO program is in 37 countries, with 322 ECHO hubs and 677 ECHO programs. The top three specialties are endocrinology, orthopedics, and rheumatology; 51% of ECHO participants are primary care providers, 24% are advanced care providers, and 19% are health care providers such as nutritionists, physical therapists, and other providers that have an interest in bone health.

In survey results adapted from a 2017 study from his own group, Dr. Lewiecki showed that 263 health care professionals who participated in Bone Health TeleECHO rated themselves as more confident in 20 different domains of osteoporosis treatment, such as secondary osteoporosis and anabolic therapy, after 21 months of using the ECHO program (Lewiecki EM et al. J Endocr Soc. 2017. doi: 10.1210/js.2017-00361). However, he admitted that showing fracture prevention outcomes at these ECHO centers has proven more difficult.

“Of course, we’re all interested in outcomes. The ultimate outcome here is preventing fractures, but it is extraordinarily difficult to design a study to actually show that we’re reducing fractures, but certainly self-confidence in managing osteoporosis has improved,” he said.

There have also been some misconceptions of the Project ECHO. The program is not only for beginners or primary care providers, said Dr. Lewiecki. It is also not limited to providers in rural areas, as the program has many participants at urban centers, he added.

“We are a virtual community of practice. It’s a collegial relationship,” he said. “It’s really recapitulating the way that we learned during our postgraduate training: When we see a patient, we present the case to our attending, the attending pontificates a little bit, we bounce things off of one another, and we go back and then we do some different things with our patients. And that’s exactly what we do with Echo. It makes learning fun again.”

Dr. Lewiecki challenged the attendees in the room who are already experts in osteoporosis to help share their knowledge of the disease to help other health care professionals learn more about how to better care for their patients. “If you have a passion for teaching, if you want to share knowledge and you’re willing to devote a little bit of your time to doing that and reaching out to more people, this is the way that you can do it.”

Dr. Lewiecki reports research grant support from Amgen, consulting fees from Alexion, Amgen, Radius, Shire, and Ultragenyx, speaking fees from Alexion, Radius, and Shire, and is an advisory board member with the National Osteoporosis Foundation, International Society for Clinical Densitometry, and the Osteoporosis Foundation of New Mexico.

SOURCE: Lewiecki ME. ASBMR 2019. Symposia: Cutting Edge Concepts: Novel Approaches to Reducing Fractures. Bone Health TeleECHO.

ORLANDO – The use of a teleconferencing program to share knowledge about osteoporosis has helped health care professionals learn about the disease and may potentially reduce the osteoporosis treatment gap in underserved communities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

The concept, called “technology-enabled collaborative learning,” is intended to address the problem of there being not enough specialists to see patients who need treatment, and the ineffectiveness of educating primary care providers in how to treat complex medical conditions, E. Michael Lewiecki, MD, the director of the New Mexico Clinical Research & Osteoporosis Center said in his presentation.

“Primary care doctors are busy,” said Dr. Lewiecki. “They have limited time taking care of patients. They don’t have the time or often the skills to manage patients who have any questions or concerns about osteoporosis and treatments for osteoporosis.”

One solution, he said, is to find health care professionals in underserved communities who are already interested in and motivated to learn more about osteoporosis, turn them into near-experts on osteoporosis for their patients as well as in their own community.

Dr. Lewiecki proposed the Extension for Community Healthcare Outcomes (ECHO), or Project ECHO, an initiative out of the University of New Mexico School of Medicine, as a potential answer. Project ECHO uses videoconferencing to connect experts in a therapeutic area, with Bone Health TeleECHO focusing on raising knowledge of osteoporosis for its participants. “The idea of ECHO is to be a force multiplier to educate health care professionals, each of whom takes care of many patients, and to have many ECHO programs around the world in convenient time zones and convenient languages for people who are interested in participating,” said Dr. Lewiecki.

The idea began when a gastroenterologist at Dr. Lewiecki’s own center was frustrated that patients were not seeking treatment for hepatitis C because of time or travel issues. In response, a pilot program for Project ECHO was developed through a collaboration between the University of New Mexico Health Sciences Center and the Osteoporosis Foundation of New Mexico where gastroenterologists at University of New Mexico connected with primary care providers across the state, sharing information about hepatitis C and discussing case studies. The results of the pilot program were published in the New England Journal of Medicine and showed a similar rate of sustained viral response between patients treated at the University of New Mexico clinic (84 of 146 patients; 57.5%) and at 21 ECHO clinics (152 of 261 patients; 58.2%) (Arora S et al. N Eng J Med. 2011. doi: 10.1056/NEJMoa1009370).

“ECHO expands the capacity to deliver best practice medical care through collegial, interactive, case-based discussions with minimal disruption to the office routine,” said Dr. Lewiecki. “Patients benefit from better care, closer to home, with greater convenience and lower cost than referral to a medical center. And the potential is to reduce the osteoporosis treatment gap by having many ECHOs starting up in many places in the world.”

Today, the ECHO program is in 37 countries, with 322 ECHO hubs and 677 ECHO programs. The top three specialties are endocrinology, orthopedics, and rheumatology; 51% of ECHO participants are primary care providers, 24% are advanced care providers, and 19% are health care providers such as nutritionists, physical therapists, and other providers that have an interest in bone health.

In survey results adapted from a 2017 study from his own group, Dr. Lewiecki showed that 263 health care professionals who participated in Bone Health TeleECHO rated themselves as more confident in 20 different domains of osteoporosis treatment, such as secondary osteoporosis and anabolic therapy, after 21 months of using the ECHO program (Lewiecki EM et al. J Endocr Soc. 2017. doi: 10.1210/js.2017-00361). However, he admitted that showing fracture prevention outcomes at these ECHO centers has proven more difficult.

“Of course, we’re all interested in outcomes. The ultimate outcome here is preventing fractures, but it is extraordinarily difficult to design a study to actually show that we’re reducing fractures, but certainly self-confidence in managing osteoporosis has improved,” he said.

There have also been some misconceptions of the Project ECHO. The program is not only for beginners or primary care providers, said Dr. Lewiecki. It is also not limited to providers in rural areas, as the program has many participants at urban centers, he added.

“We are a virtual community of practice. It’s a collegial relationship,” he said. “It’s really recapitulating the way that we learned during our postgraduate training: When we see a patient, we present the case to our attending, the attending pontificates a little bit, we bounce things off of one another, and we go back and then we do some different things with our patients. And that’s exactly what we do with Echo. It makes learning fun again.”

Dr. Lewiecki challenged the attendees in the room who are already experts in osteoporosis to help share their knowledge of the disease to help other health care professionals learn more about how to better care for their patients. “If you have a passion for teaching, if you want to share knowledge and you’re willing to devote a little bit of your time to doing that and reaching out to more people, this is the way that you can do it.”

Dr. Lewiecki reports research grant support from Amgen, consulting fees from Alexion, Amgen, Radius, Shire, and Ultragenyx, speaking fees from Alexion, Radius, and Shire, and is an advisory board member with the National Osteoporosis Foundation, International Society for Clinical Densitometry, and the Osteoporosis Foundation of New Mexico.

SOURCE: Lewiecki ME. ASBMR 2019. Symposia: Cutting Edge Concepts: Novel Approaches to Reducing Fractures. Bone Health TeleECHO.

ORLANDO – The use of a teleconferencing program to share knowledge about osteoporosis has helped health care professionals learn about the disease and may potentially reduce the osteoporosis treatment gap in underserved communities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

The concept, called “technology-enabled collaborative learning,” is intended to address the problem of there being not enough specialists to see patients who need treatment, and the ineffectiveness of educating primary care providers in how to treat complex medical conditions, E. Michael Lewiecki, MD, the director of the New Mexico Clinical Research & Osteoporosis Center said in his presentation.

“Primary care doctors are busy,” said Dr. Lewiecki. “They have limited time taking care of patients. They don’t have the time or often the skills to manage patients who have any questions or concerns about osteoporosis and treatments for osteoporosis.”

One solution, he said, is to find health care professionals in underserved communities who are already interested in and motivated to learn more about osteoporosis, turn them into near-experts on osteoporosis for their patients as well as in their own community.

Dr. Lewiecki proposed the Extension for Community Healthcare Outcomes (ECHO), or Project ECHO, an initiative out of the University of New Mexico School of Medicine, as a potential answer. Project ECHO uses videoconferencing to connect experts in a therapeutic area, with Bone Health TeleECHO focusing on raising knowledge of osteoporosis for its participants. “The idea of ECHO is to be a force multiplier to educate health care professionals, each of whom takes care of many patients, and to have many ECHO programs around the world in convenient time zones and convenient languages for people who are interested in participating,” said Dr. Lewiecki.

The idea began when a gastroenterologist at Dr. Lewiecki’s own center was frustrated that patients were not seeking treatment for hepatitis C because of time or travel issues. In response, a pilot program for Project ECHO was developed through a collaboration between the University of New Mexico Health Sciences Center and the Osteoporosis Foundation of New Mexico where gastroenterologists at University of New Mexico connected with primary care providers across the state, sharing information about hepatitis C and discussing case studies. The results of the pilot program were published in the New England Journal of Medicine and showed a similar rate of sustained viral response between patients treated at the University of New Mexico clinic (84 of 146 patients; 57.5%) and at 21 ECHO clinics (152 of 261 patients; 58.2%) (Arora S et al. N Eng J Med. 2011. doi: 10.1056/NEJMoa1009370).

“ECHO expands the capacity to deliver best practice medical care through collegial, interactive, case-based discussions with minimal disruption to the office routine,” said Dr. Lewiecki. “Patients benefit from better care, closer to home, with greater convenience and lower cost than referral to a medical center. And the potential is to reduce the osteoporosis treatment gap by having many ECHOs starting up in many places in the world.”

Today, the ECHO program is in 37 countries, with 322 ECHO hubs and 677 ECHO programs. The top three specialties are endocrinology, orthopedics, and rheumatology; 51% of ECHO participants are primary care providers, 24% are advanced care providers, and 19% are health care providers such as nutritionists, physical therapists, and other providers that have an interest in bone health.

In survey results adapted from a 2017 study from his own group, Dr. Lewiecki showed that 263 health care professionals who participated in Bone Health TeleECHO rated themselves as more confident in 20 different domains of osteoporosis treatment, such as secondary osteoporosis and anabolic therapy, after 21 months of using the ECHO program (Lewiecki EM et al. J Endocr Soc. 2017. doi: 10.1210/js.2017-00361). However, he admitted that showing fracture prevention outcomes at these ECHO centers has proven more difficult.

“Of course, we’re all interested in outcomes. The ultimate outcome here is preventing fractures, but it is extraordinarily difficult to design a study to actually show that we’re reducing fractures, but certainly self-confidence in managing osteoporosis has improved,” he said.

There have also been some misconceptions of the Project ECHO. The program is not only for beginners or primary care providers, said Dr. Lewiecki. It is also not limited to providers in rural areas, as the program has many participants at urban centers, he added.

“We are a virtual community of practice. It’s a collegial relationship,” he said. “It’s really recapitulating the way that we learned during our postgraduate training: When we see a patient, we present the case to our attending, the attending pontificates a little bit, we bounce things off of one another, and we go back and then we do some different things with our patients. And that’s exactly what we do with Echo. It makes learning fun again.”

Dr. Lewiecki challenged the attendees in the room who are already experts in osteoporosis to help share their knowledge of the disease to help other health care professionals learn more about how to better care for their patients. “If you have a passion for teaching, if you want to share knowledge and you’re willing to devote a little bit of your time to doing that and reaching out to more people, this is the way that you can do it.”

Dr. Lewiecki reports research grant support from Amgen, consulting fees from Alexion, Amgen, Radius, Shire, and Ultragenyx, speaking fees from Alexion, Radius, and Shire, and is an advisory board member with the National Osteoporosis Foundation, International Society for Clinical Densitometry, and the Osteoporosis Foundation of New Mexico.

SOURCE: Lewiecki ME. ASBMR 2019. Symposia: Cutting Edge Concepts: Novel Approaches to Reducing Fractures. Bone Health TeleECHO.

A new international position statement on testosterone therapy for women concludes that a trial of testosterone is appropriate for postmenopausal women with hypoactive sexual desire dysfunction (HSDD) and that its use for any other condition, symptom, or reason is not supported by available evidence.

The seven-page position statement, developed by an international task force of experts from the Endocrine Society, the American College of Gynecologists and Obstetricians, and multiple other medical societies, also emphasized that blood concentrations of testosterone should approximate premenopausal physiological conditions.

“When testosterone therapy is given, the resultant blood levels should not be above those seen in healthy young women,” said lead author Susan Ruth Davis, PhD, MBBS, of Monash University in Melbourne, Australia, in a press release issued by the Endocrine Society. Dr. Davis is president of the International Menopause Society, which coordinated the panel.

The statement was published in the Journal of Clinical Endocrinology & Metabolism and three other medical journals.

Margaret E. Wierman, MD, who represented the Endocrine Society on the task force, said in an interview that there has been “growing concern about testosterone being prescribed for a variety of signs and symptoms without data to support” such use. At the same time, there is significant concern about the ongoing lack of approved formulations licensed specifically for women, she said.

In part, the statement is about a renewed “call to industry to make some [female-specific] formulations so that we can examine other potential roles of testosterone in women,” said Dr. Wierman, professor of medicine and physiology at the University of Colorado at Denver, Aurora, and chief of endocrinology at the Rocky Mountain Regional Veterans Affairs Medical Center in Aurora.

“Testosterone may be useful [for indications other than HSDD], but we don’t know. There may be no [breast or cardiovascular disease risk], but we don’t know,” she said. “And without a formulation to study potential benefits and risks, it’s good to be cautious. It’s good to really outline where we have data and where we don’t.”

The Endocrine Society’s 2014 clinical practice guideline on androgen therapy in women, for which Dr. Wierman was the lead author, also recommended against the off-label use of testosterone for sexual dysfunction other than HSDD or for any other reason, such as cognitive, cardiovascular, metabolic, or bone health. As with the new statement, the society’s position statement was guided by an international, multisociety task force, albeit a smaller one.

For the new global position statement, the task force’s review of evidence includes a recently published systematic review and meta-analysis of randomized controlled trial data – of at least 12 weeks’ duration – on the use of testosterone for sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. Some of the data from the randomized controlled trials were unpublished.

The meta-analysis, led by Dr. Davis and published in July in the Lancet Diabetes & Endocrinology, found that, compared with placebo or a comparator (such as estrogen, with or without progesterone), testosterone in either oral or transdermal form significantly improved sexual function in postmenopausal women. However, data about the effects of testosterone for other indications, its long-term safety, and its use in premenopausal women, were insufficient for drawing any conclusions (Lancet Diabetes Endocrinol. 2019 Jul 25. doi: 10.1016/S2213-8587[19]30189-5).

In addition, testosterone administered orally – but not nonorally (patch or cream) – was associated with adverse lipid profiles, Dr. Davis and her colleagues reported.

Another systematic review and meta-analysis, published in Fertility and Sterility in 2017 and included in the task force’s evidence review, focused specifically on transdermal testosterone for menopausal women with HSDD, with or without estrogen and progestin therapy. It also showed short-term efficacy in terms of improvement in sexual function, as well as short-term safety (Fertil Steril. 2017;107(2):475-82).

The new position statement warns about the lack of long-term safety data, stating that “safety data for testosterone in physiologic doses are not available beyond 24 months of treatment.”

In the short term, testosterone therapy for postmenopausal women (in doses approximating testosterone concentrations for premenopausal women), is associated with mild increases in acne and body/facial hair growth in some women, but not with alopecia, clitoromegaly, or voice change. Short-term transdermal therapy also does not seem to affect breast cancer risk or have any significant effects on lipid profiles, the statement says.

The panel points out, however, that randomized controlled trials with testosterone therapy have excluded women who are at high risk of cardiometabolic disease, and that women with a previous diagnosis of breast cancer have also been excluded from randomized trials of testosterone in women with HSDD. This is a “big issue,” said Dr. Wierman, and means that recommendations regarding the effect of testosterone in postmenopausal women with HSDD may not be generalizable to possible at-risk subpopulations.

The panel endorsed testosterone therapy specifically for women with HSDD because most of the studies reporting on sexual function have recruited women with diagnosed HSDD. Demonstrated benefits of testosterone in these cases include improved sexual desire, arousal, orgasm, and pleasure, and reduced concerns and distress about sex. HSDD should be diagnosed after formal biopsychosocial assessment, the statement notes.

“We don’t completely understand the control of sexual function in women, but it’s very dependent on estrogen status. And it’s also dependent on psychosocial factors, emotional health, relationship issues, and physical issues,” Dr. Wierman said in the interview.

“In practice, we look at all these issues, and we first optimize estrogen status. Once that’s done, and we’ve looked at all the other components of sexual function, then we can consider off-label use of testosterone,” she said. “If there’s no response in 3-6 months, we stop it.”

Testosterone levels do not correlate with sexual dysfunction, Dr. Wierman emphasized, and direct assays for the measurement of total and free testosterone are unreliable. The statement acknowledges that but still recommends measurement of testosterone using direct assays, in cases in which liquid/gas chromatography and tandem mass spectrometry assay (which has “high accuracy and reproducibility”) are not available. This is “to exclude high baseline concentrations and also to exclude supraphysiological concentrations during treatment,” the panel said.

Most endocrinologists and other experts who prescribe testosterone therapy for women use an approved male formulation off label and adjust it – an approach that the panel says is reasonable as long as hormone concentrations are “maintained in the physiologic female range.”

Compounded “bioidentical” testosterone therapy “cannot be recommended for the treatment of HSDD because of the lack of evidence for safety and efficacy,” the statement says.

“A big concern of many endocrinologists,” Dr. Wierman added, “is the recent explosion of using pharmacological levels of both estrogen and testosterone in either [injections] or pellets.” The Endocrine Society and other societies have alerted the Food and Drug Administration to “this new cottage industry, which may have significant side effects and risks for our patients,” she said.
Dr. Wierman reported received funding from Corcept Therapeutics, Novartis, and the Cancer League of Colorado, and honoraria or consultation fees from Pfizer to review ASPIRE grant applications for studies of acromegaly as well as Endocrine Society honorarium for teaching in the Endocrine Board Review and Clinical Endocrine Update. Dr. Davis reported receiving funding from a National Health and Medical Research Council Project Grant, a National Breast Foundation accelerator grant, and the Grollo-Ruzenne Foundation, as well as honoraria from Besins and Pfizer Australia. She has been a consultant to Besins Healthcare, Mayne Pharmaceuticals, Lawley Pharmaceuticals, and Que Oncology. Disclosures for other authors of the position statement are listed with the statement.

SOURCE: Davis SR et al. J Clin Endocrinol Metab. 2019 Sep 2. doi: 10.1210/jc.2019-01603.
 

A new international position statement on testosterone therapy for women concludes that a trial of testosterone is appropriate for postmenopausal women with hypoactive sexual desire dysfunction (HSDD) and that its use for any other condition, symptom, or reason is not supported by available evidence.

The seven-page position statement, developed by an international task force of experts from the Endocrine Society, the American College of Gynecologists and Obstetricians, and multiple other medical societies, also emphasized that blood concentrations of testosterone should approximate premenopausal physiological conditions.

“When testosterone therapy is given, the resultant blood levels should not be above those seen in healthy young women,” said lead author Susan Ruth Davis, PhD, MBBS, of Monash University in Melbourne, Australia, in a press release issued by the Endocrine Society. Dr. Davis is president of the International Menopause Society, which coordinated the panel.

The statement was published in the Journal of Clinical Endocrinology & Metabolism and three other medical journals.

Margaret E. Wierman, MD, who represented the Endocrine Society on the task force, said in an interview that there has been “growing concern about testosterone being prescribed for a variety of signs and symptoms without data to support” such use. At the same time, there is significant concern about the ongoing lack of approved formulations licensed specifically for women, she said.

In part, the statement is about a renewed “call to industry to make some [female-specific] formulations so that we can examine other potential roles of testosterone in women,” said Dr. Wierman, professor of medicine and physiology at the University of Colorado at Denver, Aurora, and chief of endocrinology at the Rocky Mountain Regional Veterans Affairs Medical Center in Aurora.

“Testosterone may be useful [for indications other than HSDD], but we don’t know. There may be no [breast or cardiovascular disease risk], but we don’t know,” she said. “And without a formulation to study potential benefits and risks, it’s good to be cautious. It’s good to really outline where we have data and where we don’t.”

The Endocrine Society’s 2014 clinical practice guideline on androgen therapy in women, for which Dr. Wierman was the lead author, also recommended against the off-label use of testosterone for sexual dysfunction other than HSDD or for any other reason, such as cognitive, cardiovascular, metabolic, or bone health. As with the new statement, the society’s position statement was guided by an international, multisociety task force, albeit a smaller one.

For the new global position statement, the task force’s review of evidence includes a recently published systematic review and meta-analysis of randomized controlled trial data – of at least 12 weeks’ duration – on the use of testosterone for sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. Some of the data from the randomized controlled trials were unpublished.

The meta-analysis, led by Dr. Davis and published in July in the Lancet Diabetes & Endocrinology, found that, compared with placebo or a comparator (such as estrogen, with or without progesterone), testosterone in either oral or transdermal form significantly improved sexual function in postmenopausal women. However, data about the effects of testosterone for other indications, its long-term safety, and its use in premenopausal women, were insufficient for drawing any conclusions (Lancet Diabetes Endocrinol. 2019 Jul 25. doi: 10.1016/S2213-8587[19]30189-5).

In addition, testosterone administered orally – but not nonorally (patch or cream) – was associated with adverse lipid profiles, Dr. Davis and her colleagues reported.

Another systematic review and meta-analysis, published in Fertility and Sterility in 2017 and included in the task force’s evidence review, focused specifically on transdermal testosterone for menopausal women with HSDD, with or without estrogen and progestin therapy. It also showed short-term efficacy in terms of improvement in sexual function, as well as short-term safety (Fertil Steril. 2017;107(2):475-82).

The new position statement warns about the lack of long-term safety data, stating that “safety data for testosterone in physiologic doses are not available beyond 24 months of treatment.”

In the short term, testosterone therapy for postmenopausal women (in doses approximating testosterone concentrations for premenopausal women), is associated with mild increases in acne and body/facial hair growth in some women, but not with alopecia, clitoromegaly, or voice change. Short-term transdermal therapy also does not seem to affect breast cancer risk or have any significant effects on lipid profiles, the statement says.

The panel points out, however, that randomized controlled trials with testosterone therapy have excluded women who are at high risk of cardiometabolic disease, and that women with a previous diagnosis of breast cancer have also been excluded from randomized trials of testosterone in women with HSDD. This is a “big issue,” said Dr. Wierman, and means that recommendations regarding the effect of testosterone in postmenopausal women with HSDD may not be generalizable to possible at-risk subpopulations.

The panel endorsed testosterone therapy specifically for women with HSDD because most of the studies reporting on sexual function have recruited women with diagnosed HSDD. Demonstrated benefits of testosterone in these cases include improved sexual desire, arousal, orgasm, and pleasure, and reduced concerns and distress about sex. HSDD should be diagnosed after formal biopsychosocial assessment, the statement notes.

“We don’t completely understand the control of sexual function in women, but it’s very dependent on estrogen status. And it’s also dependent on psychosocial factors, emotional health, relationship issues, and physical issues,” Dr. Wierman said in the interview.

“In practice, we look at all these issues, and we first optimize estrogen status. Once that’s done, and we’ve looked at all the other components of sexual function, then we can consider off-label use of testosterone,” she said. “If there’s no response in 3-6 months, we stop it.”

Testosterone levels do not correlate with sexual dysfunction, Dr. Wierman emphasized, and direct assays for the measurement of total and free testosterone are unreliable. The statement acknowledges that but still recommends measurement of testosterone using direct assays, in cases in which liquid/gas chromatography and tandem mass spectrometry assay (which has “high accuracy and reproducibility”) are not available. This is “to exclude high baseline concentrations and also to exclude supraphysiological concentrations during treatment,” the panel said.

Most endocrinologists and other experts who prescribe testosterone therapy for women use an approved male formulation off label and adjust it – an approach that the panel says is reasonable as long as hormone concentrations are “maintained in the physiologic female range.”

Compounded “bioidentical” testosterone therapy “cannot be recommended for the treatment of HSDD because of the lack of evidence for safety and efficacy,” the statement says.

“A big concern of many endocrinologists,” Dr. Wierman added, “is the recent explosion of using pharmacological levels of both estrogen and testosterone in either [injections] or pellets.” The Endocrine Society and other societies have alerted the Food and Drug Administration to “this new cottage industry, which may have significant side effects and risks for our patients,” she said.
Dr. Wierman reported received funding from Corcept Therapeutics, Novartis, and the Cancer League of Colorado, and honoraria or consultation fees from Pfizer to review ASPIRE grant applications for studies of acromegaly as well as Endocrine Society honorarium for teaching in the Endocrine Board Review and Clinical Endocrine Update. Dr. Davis reported receiving funding from a National Health and Medical Research Council Project Grant, a National Breast Foundation accelerator grant, and the Grollo-Ruzenne Foundation, as well as honoraria from Besins and Pfizer Australia. She has been a consultant to Besins Healthcare, Mayne Pharmaceuticals, Lawley Pharmaceuticals, and Que Oncology. Disclosures for other authors of the position statement are listed with the statement.

SOURCE: Davis SR et al. J Clin Endocrinol Metab. 2019 Sep 2. doi: 10.1210/jc.2019-01603.
 

A new international position statement on testosterone therapy for women concludes that a trial of testosterone is appropriate for postmenopausal women with hypoactive sexual desire dysfunction (HSDD) and that its use for any other condition, symptom, or reason is not supported by available evidence.

The seven-page position statement, developed by an international task force of experts from the Endocrine Society, the American College of Gynecologists and Obstetricians, and multiple other medical societies, also emphasized that blood concentrations of testosterone should approximate premenopausal physiological conditions.

“When testosterone therapy is given, the resultant blood levels should not be above those seen in healthy young women,” said lead author Susan Ruth Davis, PhD, MBBS, of Monash University in Melbourne, Australia, in a press release issued by the Endocrine Society. Dr. Davis is president of the International Menopause Society, which coordinated the panel.

The statement was published in the Journal of Clinical Endocrinology & Metabolism and three other medical journals.

Margaret E. Wierman, MD, who represented the Endocrine Society on the task force, said in an interview that there has been “growing concern about testosterone being prescribed for a variety of signs and symptoms without data to support” such use. At the same time, there is significant concern about the ongoing lack of approved formulations licensed specifically for women, she said.

In part, the statement is about a renewed “call to industry to make some [female-specific] formulations so that we can examine other potential roles of testosterone in women,” said Dr. Wierman, professor of medicine and physiology at the University of Colorado at Denver, Aurora, and chief of endocrinology at the Rocky Mountain Regional Veterans Affairs Medical Center in Aurora.

“Testosterone may be useful [for indications other than HSDD], but we don’t know. There may be no [breast or cardiovascular disease risk], but we don’t know,” she said. “And without a formulation to study potential benefits and risks, it’s good to be cautious. It’s good to really outline where we have data and where we don’t.”

The Endocrine Society’s 2014 clinical practice guideline on androgen therapy in women, for which Dr. Wierman was the lead author, also recommended against the off-label use of testosterone for sexual dysfunction other than HSDD or for any other reason, such as cognitive, cardiovascular, metabolic, or bone health. As with the new statement, the society’s position statement was guided by an international, multisociety task force, albeit a smaller one.

For the new global position statement, the task force’s review of evidence includes a recently published systematic review and meta-analysis of randomized controlled trial data – of at least 12 weeks’ duration – on the use of testosterone for sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. Some of the data from the randomized controlled trials were unpublished.

The meta-analysis, led by Dr. Davis and published in July in the Lancet Diabetes & Endocrinology, found that, compared with placebo or a comparator (such as estrogen, with or without progesterone), testosterone in either oral or transdermal form significantly improved sexual function in postmenopausal women. However, data about the effects of testosterone for other indications, its long-term safety, and its use in premenopausal women, were insufficient for drawing any conclusions (Lancet Diabetes Endocrinol. 2019 Jul 25. doi: 10.1016/S2213-8587[19]30189-5).

In addition, testosterone administered orally – but not nonorally (patch or cream) – was associated with adverse lipid profiles, Dr. Davis and her colleagues reported.

Another systematic review and meta-analysis, published in Fertility and Sterility in 2017 and included in the task force’s evidence review, focused specifically on transdermal testosterone for menopausal women with HSDD, with or without estrogen and progestin therapy. It also showed short-term efficacy in terms of improvement in sexual function, as well as short-term safety (Fertil Steril. 2017;107(2):475-82).

The new position statement warns about the lack of long-term safety data, stating that “safety data for testosterone in physiologic doses are not available beyond 24 months of treatment.”

In the short term, testosterone therapy for postmenopausal women (in doses approximating testosterone concentrations for premenopausal women), is associated with mild increases in acne and body/facial hair growth in some women, but not with alopecia, clitoromegaly, or voice change. Short-term transdermal therapy also does not seem to affect breast cancer risk or have any significant effects on lipid profiles, the statement says.

The panel points out, however, that randomized controlled trials with testosterone therapy have excluded women who are at high risk of cardiometabolic disease, and that women with a previous diagnosis of breast cancer have also been excluded from randomized trials of testosterone in women with HSDD. This is a “big issue,” said Dr. Wierman, and means that recommendations regarding the effect of testosterone in postmenopausal women with HSDD may not be generalizable to possible at-risk subpopulations.

The panel endorsed testosterone therapy specifically for women with HSDD because most of the studies reporting on sexual function have recruited women with diagnosed HSDD. Demonstrated benefits of testosterone in these cases include improved sexual desire, arousal, orgasm, and pleasure, and reduced concerns and distress about sex. HSDD should be diagnosed after formal biopsychosocial assessment, the statement notes.

“We don’t completely understand the control of sexual function in women, but it’s very dependent on estrogen status. And it’s also dependent on psychosocial factors, emotional health, relationship issues, and physical issues,” Dr. Wierman said in the interview.

“In practice, we look at all these issues, and we first optimize estrogen status. Once that’s done, and we’ve looked at all the other components of sexual function, then we can consider off-label use of testosterone,” she said. “If there’s no response in 3-6 months, we stop it.”

Testosterone levels do not correlate with sexual dysfunction, Dr. Wierman emphasized, and direct assays for the measurement of total and free testosterone are unreliable. The statement acknowledges that but still recommends measurement of testosterone using direct assays, in cases in which liquid/gas chromatography and tandem mass spectrometry assay (which has “high accuracy and reproducibility”) are not available. This is “to exclude high baseline concentrations and also to exclude supraphysiological concentrations during treatment,” the panel said.

Most endocrinologists and other experts who prescribe testosterone therapy for women use an approved male formulation off label and adjust it – an approach that the panel says is reasonable as long as hormone concentrations are “maintained in the physiologic female range.”

Compounded “bioidentical” testosterone therapy “cannot be recommended for the treatment of HSDD because of the lack of evidence for safety and efficacy,” the statement says.

“A big concern of many endocrinologists,” Dr. Wierman added, “is the recent explosion of using pharmacological levels of both estrogen and testosterone in either [injections] or pellets.” The Endocrine Society and other societies have alerted the Food and Drug Administration to “this new cottage industry, which may have significant side effects and risks for our patients,” she said.
Dr. Wierman reported received funding from Corcept Therapeutics, Novartis, and the Cancer League of Colorado, and honoraria or consultation fees from Pfizer to review ASPIRE grant applications for studies of acromegaly as well as Endocrine Society honorarium for teaching in the Endocrine Board Review and Clinical Endocrine Update. Dr. Davis reported receiving funding from a National Health and Medical Research Council Project Grant, a National Breast Foundation accelerator grant, and the Grollo-Ruzenne Foundation, as well as honoraria from Besins and Pfizer Australia. She has been a consultant to Besins Healthcare, Mayne Pharmaceuticals, Lawley Pharmaceuticals, and Que Oncology. Disclosures for other authors of the position statement are listed with the statement.

SOURCE: Davis SR et al. J Clin Endocrinol Metab. 2019 Sep 2. doi: 10.1210/jc.2019-01603.