Endocrinology

With a few notable exceptions, the majority of fine needle aspiration (FNA) biopsies of thyroid nodules should be delayed until the risk of COVID-19, and the burden on resources, has lessened, according to expert consensus.

copyright/Sebastian Kaulitzki/Fotolia

“Our group recommends that FNA biopsy of most asymptomatic thyroid nodules – taking into account the sonographic characteristics and patients’ clinical picture – be deferred to a later time, when risk of exposure to COVID-19 is more manageable and resource restriction is no longer a concern,” said the endocrinologists, writing in a guest editorial in Clinical Thyroidology.

All elective procedures have been canceled under guidance of the Centers for Disease Control and Prevention, in conjunction with the U.S. surgeon general, in response to the COVID-19 pandemic. However, thyroid nodule FNAs, though elective, fall into the category of being considered medically necessary and potentially prolonging life expectancy

Yet, with approximately 90% of asymptomatic thyroid nodules turning out to be benign and little evidence that early detection and treatment affects disease outcomes, there is a strong argument for deferral in most cases, stressed Ming Lee, MD, and colleagues, of the endocrinology division at Phoenix (Ariz.) Veterans Affairs Health Care System (PVAHCS), who convened a multidisciplinary meeting to address the urgent issue.

Patients should instead be interviewed by an endocrinologist (preferably via telehealth) to collect their clinical history as well as assess their perception of the disease and risk of malignancy, senior author S. Mitchell Harman, MD, chief of PVAHCS, said in an interview.

“The principal guiding factor should be the objectively assessed likelihood of malignancy of the individual patient’s nodule(s),” he said.

“In my opinion, we should also factor in the patient’s level of anxiety, since some patients are more sanguine about risk than others and our goal is to provide relief of anxiety as well as to determine need for, and course of, subsequent treatment,” Dr. Harman added. 

Vast majority of malignant thyroid nodules are DTC, which is ‘indolent’

Dr. Lee and colleagues noted that, even of the 10% of thyroid nodules that do prove to be malignant, the vast majority of these (90%) are differentiated thyroid cancers (DTC). In general, patients with DTC “follow an indolent course and have excellent outcomes.”

“There is little evidence that early detection and treatment of DTC significantly alters disease outcomes as the overall mortality rate for DTC has remained low, at around 0.5%,” they wrote.

They also noted that ultrasound features of thyroid nodules can help guide priority for the future timing of an FNA procedure, but should not be the sole basis for deciding on immediate thyroid FNA or surgery.

Exceptions to the rule

Exceptions for considering FNA include more urgent thyroid disease diagnoses, including those that are symptomatic:

Suspected medullary thyroid cancer

“Regarding medullary thyroid cancer (MTC), early diagnosis and surgery do significantly improve outcomes, therefore, delaying FNA of nodules harboring MTC could be potentially injurious,” the authors said.

They suggested, however, measuring calcitonin levels instead, which they noted “is still controversial” in the United States, but “we feel it would be justified in patients with thyroid nodules that would usually be indicated for FNA.”

Those with a family history of MTC, or nodules located in the posterior upper third of lateral lobes (the usual location of MTC), should have calcitonin levels measured.

If calcitonin levels are above 10 pg/mL, “FNA should be offered as early as possible.”

“Significantly elevated serum calcitonin levels (e.g., > 100 pg/mL) should be considered an indication for surgery without cytologic confirmation by FNA,” they added.

Anaplastic thyroid cancer

Anaplastic thyroid cancer, though rare, “is one of the few occasions when thyroid surgery should be performed on an urgent basis, as this condition can worsen very rapidly.

“Patients typically present with a rapidly enlarging thyroid mass that is associated with compressive symptoms, such as dysphagia and dyspnea,” they observed.

In this instance, although FNA is part of the preoperative work-up, it is often nondiagnostic and could require additional sampling.

“At the time of this pandemic, it is reasonable that after a multidisciplinary discussion, such patients with the appropriate clinical scenario be referred for thyroid surgery, with or without prior FNA, based on the team’s judgment,” the authors recommended.

Long-standing thyroid masses

These are usually large and/or closely associated with vital structures, such as the trachea and esophagus, and when such masses cause compressive symptoms, thyroid surgery typically is warranted.

And although prior FNA is helpful to obtain a cytologic diagnosis, as this may change the extent of surgery, it may not always be essential.

Broadly, symptomatic patients with compressive symptoms threatening vital structures can be directly referred to a surgeon, with the timing for surgery jointly decided based on the severity of symptoms, rapidity of disease progression, local COVID-19 status, and available resources.

“During the pandemic, we believe that the vast majority of thyroid FNAs should be considered optional, and extent of surgery can be determined by pathological analysis of frozen sections intraoperatively,” they wrote.

“The value of FNA in these situations is less compelling in the current COVID-19 setting, as the basis of decision for surgery has been already determined,” the authors explained.

If urgent FNA needed, screen patient for COVID-19 and use PPE

Should the need for an urgent thyroid FNA occur, patients should be screened and tested for COVID-19 by a clinician wearing personal protective equipment (PPE), said Dr. Lee and colleagues.

“It is crucial to carefully weigh the risks of COVID-19 exposure, availability of resources, and urgency of these procedures for each patient in our individual practice settings,” they noted.

As restrictions eventually loosen, precautions will still be necessary to some degree, Dr. Harman said.

“I do not consider FNA a ‘high-risk’ procedure in the era of COVID-19, since it does not routinely result in profuse aerosolization of respiratory fluids,” he said in an interview.

“However, patients do sometimes cough or choke due to pressure on the neck and the operator is, of necessity, very close to the patient’s face. Therefore, when we resume FNA, patients will be screened for symptoms of COVID-19 infection and both the operator and the patient will be masked,” Dr. Harman continued.

“We routinely wear gloves, [and] whether the operator will wear a surgical or an N95 mask, disposable gown, etc, will depend on CDC guidance and guidance received from our VA infectious disease experts as it is applied specifically to each patient evaluation.”

The authors have reported no relevant financial relationships.
 

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

With a few notable exceptions, the majority of fine needle aspiration (FNA) biopsies of thyroid nodules should be delayed until the risk of COVID-19, and the burden on resources, has lessened, according to expert consensus.

copyright/Sebastian Kaulitzki/Fotolia

“Our group recommends that FNA biopsy of most asymptomatic thyroid nodules – taking into account the sonographic characteristics and patients’ clinical picture – be deferred to a later time, when risk of exposure to COVID-19 is more manageable and resource restriction is no longer a concern,” said the endocrinologists, writing in a guest editorial in Clinical Thyroidology.

All elective procedures have been canceled under guidance of the Centers for Disease Control and Prevention, in conjunction with the U.S. surgeon general, in response to the COVID-19 pandemic. However, thyroid nodule FNAs, though elective, fall into the category of being considered medically necessary and potentially prolonging life expectancy

Yet, with approximately 90% of asymptomatic thyroid nodules turning out to be benign and little evidence that early detection and treatment affects disease outcomes, there is a strong argument for deferral in most cases, stressed Ming Lee, MD, and colleagues, of the endocrinology division at Phoenix (Ariz.) Veterans Affairs Health Care System (PVAHCS), who convened a multidisciplinary meeting to address the urgent issue.

Patients should instead be interviewed by an endocrinologist (preferably via telehealth) to collect their clinical history as well as assess their perception of the disease and risk of malignancy, senior author S. Mitchell Harman, MD, chief of PVAHCS, said in an interview.

“The principal guiding factor should be the objectively assessed likelihood of malignancy of the individual patient’s nodule(s),” he said.

“In my opinion, we should also factor in the patient’s level of anxiety, since some patients are more sanguine about risk than others and our goal is to provide relief of anxiety as well as to determine need for, and course of, subsequent treatment,” Dr. Harman added. 

Vast majority of malignant thyroid nodules are DTC, which is ‘indolent’

Dr. Lee and colleagues noted that, even of the 10% of thyroid nodules that do prove to be malignant, the vast majority of these (90%) are differentiated thyroid cancers (DTC). In general, patients with DTC “follow an indolent course and have excellent outcomes.”

“There is little evidence that early detection and treatment of DTC significantly alters disease outcomes as the overall mortality rate for DTC has remained low, at around 0.5%,” they wrote.

They also noted that ultrasound features of thyroid nodules can help guide priority for the future timing of an FNA procedure, but should not be the sole basis for deciding on immediate thyroid FNA or surgery.

Exceptions to the rule

Exceptions for considering FNA include more urgent thyroid disease diagnoses, including those that are symptomatic:

Suspected medullary thyroid cancer

“Regarding medullary thyroid cancer (MTC), early diagnosis and surgery do significantly improve outcomes, therefore, delaying FNA of nodules harboring MTC could be potentially injurious,” the authors said.

They suggested, however, measuring calcitonin levels instead, which they noted “is still controversial” in the United States, but “we feel it would be justified in patients with thyroid nodules that would usually be indicated for FNA.”

Those with a family history of MTC, or nodules located in the posterior upper third of lateral lobes (the usual location of MTC), should have calcitonin levels measured.

If calcitonin levels are above 10 pg/mL, “FNA should be offered as early as possible.”

“Significantly elevated serum calcitonin levels (e.g., > 100 pg/mL) should be considered an indication for surgery without cytologic confirmation by FNA,” they added.

Anaplastic thyroid cancer

Anaplastic thyroid cancer, though rare, “is one of the few occasions when thyroid surgery should be performed on an urgent basis, as this condition can worsen very rapidly.

“Patients typically present with a rapidly enlarging thyroid mass that is associated with compressive symptoms, such as dysphagia and dyspnea,” they observed.

In this instance, although FNA is part of the preoperative work-up, it is often nondiagnostic and could require additional sampling.

“At the time of this pandemic, it is reasonable that after a multidisciplinary discussion, such patients with the appropriate clinical scenario be referred for thyroid surgery, with or without prior FNA, based on the team’s judgment,” the authors recommended.

Long-standing thyroid masses

These are usually large and/or closely associated with vital structures, such as the trachea and esophagus, and when such masses cause compressive symptoms, thyroid surgery typically is warranted.

And although prior FNA is helpful to obtain a cytologic diagnosis, as this may change the extent of surgery, it may not always be essential.

Broadly, symptomatic patients with compressive symptoms threatening vital structures can be directly referred to a surgeon, with the timing for surgery jointly decided based on the severity of symptoms, rapidity of disease progression, local COVID-19 status, and available resources.

“During the pandemic, we believe that the vast majority of thyroid FNAs should be considered optional, and extent of surgery can be determined by pathological analysis of frozen sections intraoperatively,” they wrote.

“The value of FNA in these situations is less compelling in the current COVID-19 setting, as the basis of decision for surgery has been already determined,” the authors explained.

If urgent FNA needed, screen patient for COVID-19 and use PPE

Should the need for an urgent thyroid FNA occur, patients should be screened and tested for COVID-19 by a clinician wearing personal protective equipment (PPE), said Dr. Lee and colleagues.

“It is crucial to carefully weigh the risks of COVID-19 exposure, availability of resources, and urgency of these procedures for each patient in our individual practice settings,” they noted.

As restrictions eventually loosen, precautions will still be necessary to some degree, Dr. Harman said.

“I do not consider FNA a ‘high-risk’ procedure in the era of COVID-19, since it does not routinely result in profuse aerosolization of respiratory fluids,” he said in an interview.

“However, patients do sometimes cough or choke due to pressure on the neck and the operator is, of necessity, very close to the patient’s face. Therefore, when we resume FNA, patients will be screened for symptoms of COVID-19 infection and both the operator and the patient will be masked,” Dr. Harman continued.

“We routinely wear gloves, [and] whether the operator will wear a surgical or an N95 mask, disposable gown, etc, will depend on CDC guidance and guidance received from our VA infectious disease experts as it is applied specifically to each patient evaluation.”

The authors have reported no relevant financial relationships.
 

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

With a few notable exceptions, the majority of fine needle aspiration (FNA) biopsies of thyroid nodules should be delayed until the risk of COVID-19, and the burden on resources, has lessened, according to expert consensus.

copyright/Sebastian Kaulitzki/Fotolia

“Our group recommends that FNA biopsy of most asymptomatic thyroid nodules – taking into account the sonographic characteristics and patients’ clinical picture – be deferred to a later time, when risk of exposure to COVID-19 is more manageable and resource restriction is no longer a concern,” said the endocrinologists, writing in a guest editorial in Clinical Thyroidology.

All elective procedures have been canceled under guidance of the Centers for Disease Control and Prevention, in conjunction with the U.S. surgeon general, in response to the COVID-19 pandemic. However, thyroid nodule FNAs, though elective, fall into the category of being considered medically necessary and potentially prolonging life expectancy

Yet, with approximately 90% of asymptomatic thyroid nodules turning out to be benign and little evidence that early detection and treatment affects disease outcomes, there is a strong argument for deferral in most cases, stressed Ming Lee, MD, and colleagues, of the endocrinology division at Phoenix (Ariz.) Veterans Affairs Health Care System (PVAHCS), who convened a multidisciplinary meeting to address the urgent issue.

Patients should instead be interviewed by an endocrinologist (preferably via telehealth) to collect their clinical history as well as assess their perception of the disease and risk of malignancy, senior author S. Mitchell Harman, MD, chief of PVAHCS, said in an interview.

“The principal guiding factor should be the objectively assessed likelihood of malignancy of the individual patient’s nodule(s),” he said.

“In my opinion, we should also factor in the patient’s level of anxiety, since some patients are more sanguine about risk than others and our goal is to provide relief of anxiety as well as to determine need for, and course of, subsequent treatment,” Dr. Harman added. 

Vast majority of malignant thyroid nodules are DTC, which is ‘indolent’

Dr. Lee and colleagues noted that, even of the 10% of thyroid nodules that do prove to be malignant, the vast majority of these (90%) are differentiated thyroid cancers (DTC). In general, patients with DTC “follow an indolent course and have excellent outcomes.”

“There is little evidence that early detection and treatment of DTC significantly alters disease outcomes as the overall mortality rate for DTC has remained low, at around 0.5%,” they wrote.

They also noted that ultrasound features of thyroid nodules can help guide priority for the future timing of an FNA procedure, but should not be the sole basis for deciding on immediate thyroid FNA or surgery.

Exceptions to the rule

Exceptions for considering FNA include more urgent thyroid disease diagnoses, including those that are symptomatic:

Suspected medullary thyroid cancer

“Regarding medullary thyroid cancer (MTC), early diagnosis and surgery do significantly improve outcomes, therefore, delaying FNA of nodules harboring MTC could be potentially injurious,” the authors said.

They suggested, however, measuring calcitonin levels instead, which they noted “is still controversial” in the United States, but “we feel it would be justified in patients with thyroid nodules that would usually be indicated for FNA.”

Those with a family history of MTC, or nodules located in the posterior upper third of lateral lobes (the usual location of MTC), should have calcitonin levels measured.

If calcitonin levels are above 10 pg/mL, “FNA should be offered as early as possible.”

“Significantly elevated serum calcitonin levels (e.g., > 100 pg/mL) should be considered an indication for surgery without cytologic confirmation by FNA,” they added.

Anaplastic thyroid cancer

Anaplastic thyroid cancer, though rare, “is one of the few occasions when thyroid surgery should be performed on an urgent basis, as this condition can worsen very rapidly.

“Patients typically present with a rapidly enlarging thyroid mass that is associated with compressive symptoms, such as dysphagia and dyspnea,” they observed.

In this instance, although FNA is part of the preoperative work-up, it is often nondiagnostic and could require additional sampling.

“At the time of this pandemic, it is reasonable that after a multidisciplinary discussion, such patients with the appropriate clinical scenario be referred for thyroid surgery, with or without prior FNA, based on the team’s judgment,” the authors recommended.

Long-standing thyroid masses

These are usually large and/or closely associated with vital structures, such as the trachea and esophagus, and when such masses cause compressive symptoms, thyroid surgery typically is warranted.

And although prior FNA is helpful to obtain a cytologic diagnosis, as this may change the extent of surgery, it may not always be essential.

Broadly, symptomatic patients with compressive symptoms threatening vital structures can be directly referred to a surgeon, with the timing for surgery jointly decided based on the severity of symptoms, rapidity of disease progression, local COVID-19 status, and available resources.

“During the pandemic, we believe that the vast majority of thyroid FNAs should be considered optional, and extent of surgery can be determined by pathological analysis of frozen sections intraoperatively,” they wrote.

“The value of FNA in these situations is less compelling in the current COVID-19 setting, as the basis of decision for surgery has been already determined,” the authors explained.

If urgent FNA needed, screen patient for COVID-19 and use PPE

Should the need for an urgent thyroid FNA occur, patients should be screened and tested for COVID-19 by a clinician wearing personal protective equipment (PPE), said Dr. Lee and colleagues.

“It is crucial to carefully weigh the risks of COVID-19 exposure, availability of resources, and urgency of these procedures for each patient in our individual practice settings,” they noted.

As restrictions eventually loosen, precautions will still be necessary to some degree, Dr. Harman said.

“I do not consider FNA a ‘high-risk’ procedure in the era of COVID-19, since it does not routinely result in profuse aerosolization of respiratory fluids,” he said in an interview.

“However, patients do sometimes cough or choke due to pressure on the neck and the operator is, of necessity, very close to the patient’s face. Therefore, when we resume FNA, patients will be screened for symptoms of COVID-19 infection and both the operator and the patient will be masked,” Dr. Harman continued.

“We routinely wear gloves, [and] whether the operator will wear a surgical or an N95 mask, disposable gown, etc, will depend on CDC guidance and guidance received from our VA infectious disease experts as it is applied specifically to each patient evaluation.”

The authors have reported no relevant financial relationships.
 

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

Teprotumumab (Tepezza, Horizon Therapeutics), the first-ever medication approved specifically to treat thyroid eye disease, works in patients regardless of age, gender, and smoking status, new research finds.

The data were presented on March 31 by Raymond S. Douglas, MD, director of the thyroid eye disease program at Cedars-Sinai Medical Center, Los Angeles, during a virtual news conference held by the Endocrine Society. The study had been slated for presentation during ENDO 2020, the society’s annual meeting, which was canceled because of the COVID-19 pandemic.

Thyroid eye disease occurs in up to 50% of people with Graves disease, causing a variety of symptoms, such as eye pain, double vision, light sensitivity or difficulty closing the eye, as well as proptosis, or bulging of the eye, and vision-threatening complications. It affects more women than men, and the symptoms can lead to the progressive inability to perform important daily activities, such as driving or working.

Teprotumumab is a fully human monoclonal antibody inhibitor of the insulin-like growth factor-1 (IGF-1) receptor and was approved by the US Food and Drug Administration in January 2020. Prior to that, therapy typically involved steroids or, in severe cases, surgery.

Blocking the IGF-1 receptor leads to reduced inflammation and reversal of retro-orbital tissue expansion and hyaluronan production in the eye orbit. Teprotumumab is given as an infusion once every 3 weeks for a total of eight infusions.
 

“Exciting to have an agent” that reduces proptosis to this degree

Previously reported pooled phase 2 and phase 3 data from the randomized, placebo-controlled OPTIC trial involving 171 patients showed significantly greater reductions in proptosis, as well as diplopia, and clinical symptoms of inflammation with teprotumumab versus placebo.

“This has really been unheralded in comparison to other medical therapies previously offered,” Dr. Douglas said during the briefing.

Now, the new analysis shows that the drug works across patient subgroups, he added, highlighting in particular the fact that the agent seems to work equally well in smokers and nonsmokers. Smoking leads to a worse prognosis in thyroid eye disease.

Asked to comment, endocrinologist David C. Lieb, MD, of Eastern Virginia Medical School, Norfolk, said in an interview, “It’s reassuring that this drug appears to have benefits in reducing proptosis across multiple age groups, in both genders, and that there are also benefits seen in patients who smoke and who don’t.”

So far Dr. Lieb has two patients who have been prescribed teprotumumab by their ophthalmologists, but it’s too soon to know how they’ll respond.

“I have no first-hand experience yet, but it’s very exciting to have something to offer patients with active Graves eye disease, which causes a lot of disability for people. It makes work difficult and driving difficult. It’s exciting to have an agent that reduces proptosis to the degree that this one does because we haven’t had anything like this before,” he said.

All patient subgroups benefited in combined analysis

A total of 79 patients completed phase 2 and 76 patients completed phase 3 of the OPTIC trial.

Overall, the proportions achieving proptosis reductions of at least 2 mm without deterioration in the fellow eye at week 24 were 77.4% with teprotumumab versus 14.9% with placebo in the intention-to-treat analysis (P < .001), respectively, and 84.8% versus 17.1% in the per-protocol analysis (P < .001). The number needed to treat was 1.6.

Similar results were achieved across all subgroups of patients: those aged 65 and older versus younger than aged 65 years; male versus female; tobacco user versus nonuser; and U.S. versus E.U. study centers (all P < .001).

Overall, the average decrease in proptosis was 3.1 mm, compared to just 0.4 mm with placebo (P < .001). By subgroup, those reductions ranged from 3.55 mm for those aged 65 and older to 2.93 mm for the U.S. group.

The average proptosis reductions with teprotumumab were 2.99 mm among smokers versus 3.20 mm in nonsmokers, but responses in both groups were significant when compared with placebo.

Smoking contributes to the severity of thyroid eye disease and is associated with more optic neuropathy, poorer response to anti-inflammatory treatment, and worse outcomes, Dr. Douglas said. “Smoking appears to preferentially cause fibroblasts in the orbit to increase proinflammatory cytokines. ... It’s reassuring that this medicine does work in smokers since most other medications are much less effective in reducing inflammatory signs in smoking versus nonsmoking patients.”
 

Most adverse reactions disappeared after infusion stopped

In the pooled studies overall there were no deaths, but there were seven severe adverse events in the teprotumumab group versus one in the placebo group. Two adverse events in the teprotumumab group – diarrhea and infusion-related reaction – were considered treatment-related and led to drug discontinuation. Another adverse event, Hashimoto’s encephalopathy, was deemed possibly related to the drug and also led to discontinuation.

Treatment-emergent adverse events occurred in 79.8% of patients treated with teprotumumab versus 69.8% with placebo. Those occurring in 5% or more of patients included muscle spasms (25% vs. 7%), nausea (17% vs. 9%), alopecia (13% vs. 8%), and diarrhea (12% vs. 8%). Most were well tolerated and tended to resolve after the infusions ended, Dr. Douglas noted, adding muscle spasms tended to occur at night, improved with massage, and were not accompanied by electrolyte abnormalities.

Antidrug antibodies were detected in two teprotumumab-treated patients, one at study day 1 and another at week 3 during the 24-week treatment period. The patient with antibodies at day 1 also tested positive at week 72. “[Antidrug] antibodies appeared to be very uncommon,” Dr. Douglas noted.

The trial was sponsored by Horizon Therapeutics. Dr. Douglas is a consultant for Horizon Therapeutics and Immunovant. Dr. Lieb has reported no relevant financial relationships. The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

This article first appeared on Medscape.com.

Teprotumumab (Tepezza, Horizon Therapeutics), the first-ever medication approved specifically to treat thyroid eye disease, works in patients regardless of age, gender, and smoking status, new research finds.

The data were presented on March 31 by Raymond S. Douglas, MD, director of the thyroid eye disease program at Cedars-Sinai Medical Center, Los Angeles, during a virtual news conference held by the Endocrine Society. The study had been slated for presentation during ENDO 2020, the society’s annual meeting, which was canceled because of the COVID-19 pandemic.

Thyroid eye disease occurs in up to 50% of people with Graves disease, causing a variety of symptoms, such as eye pain, double vision, light sensitivity or difficulty closing the eye, as well as proptosis, or bulging of the eye, and vision-threatening complications. It affects more women than men, and the symptoms can lead to the progressive inability to perform important daily activities, such as driving or working.

Teprotumumab is a fully human monoclonal antibody inhibitor of the insulin-like growth factor-1 (IGF-1) receptor and was approved by the US Food and Drug Administration in January 2020. Prior to that, therapy typically involved steroids or, in severe cases, surgery.

Blocking the IGF-1 receptor leads to reduced inflammation and reversal of retro-orbital tissue expansion and hyaluronan production in the eye orbit. Teprotumumab is given as an infusion once every 3 weeks for a total of eight infusions.
 

“Exciting to have an agent” that reduces proptosis to this degree

Previously reported pooled phase 2 and phase 3 data from the randomized, placebo-controlled OPTIC trial involving 171 patients showed significantly greater reductions in proptosis, as well as diplopia, and clinical symptoms of inflammation with teprotumumab versus placebo.

“This has really been unheralded in comparison to other medical therapies previously offered,” Dr. Douglas said during the briefing.

Now, the new analysis shows that the drug works across patient subgroups, he added, highlighting in particular the fact that the agent seems to work equally well in smokers and nonsmokers. Smoking leads to a worse prognosis in thyroid eye disease.

Asked to comment, endocrinologist David C. Lieb, MD, of Eastern Virginia Medical School, Norfolk, said in an interview, “It’s reassuring that this drug appears to have benefits in reducing proptosis across multiple age groups, in both genders, and that there are also benefits seen in patients who smoke and who don’t.”

So far Dr. Lieb has two patients who have been prescribed teprotumumab by their ophthalmologists, but it’s too soon to know how they’ll respond.

“I have no first-hand experience yet, but it’s very exciting to have something to offer patients with active Graves eye disease, which causes a lot of disability for people. It makes work difficult and driving difficult. It’s exciting to have an agent that reduces proptosis to the degree that this one does because we haven’t had anything like this before,” he said.

All patient subgroups benefited in combined analysis

A total of 79 patients completed phase 2 and 76 patients completed phase 3 of the OPTIC trial.

Overall, the proportions achieving proptosis reductions of at least 2 mm without deterioration in the fellow eye at week 24 were 77.4% with teprotumumab versus 14.9% with placebo in the intention-to-treat analysis (P < .001), respectively, and 84.8% versus 17.1% in the per-protocol analysis (P < .001). The number needed to treat was 1.6.

Similar results were achieved across all subgroups of patients: those aged 65 and older versus younger than aged 65 years; male versus female; tobacco user versus nonuser; and U.S. versus E.U. study centers (all P < .001).

Overall, the average decrease in proptosis was 3.1 mm, compared to just 0.4 mm with placebo (P < .001). By subgroup, those reductions ranged from 3.55 mm for those aged 65 and older to 2.93 mm for the U.S. group.

The average proptosis reductions with teprotumumab were 2.99 mm among smokers versus 3.20 mm in nonsmokers, but responses in both groups were significant when compared with placebo.

Smoking contributes to the severity of thyroid eye disease and is associated with more optic neuropathy, poorer response to anti-inflammatory treatment, and worse outcomes, Dr. Douglas said. “Smoking appears to preferentially cause fibroblasts in the orbit to increase proinflammatory cytokines. ... It’s reassuring that this medicine does work in smokers since most other medications are much less effective in reducing inflammatory signs in smoking versus nonsmoking patients.”
 

Most adverse reactions disappeared after infusion stopped

In the pooled studies overall there were no deaths, but there were seven severe adverse events in the teprotumumab group versus one in the placebo group. Two adverse events in the teprotumumab group – diarrhea and infusion-related reaction – were considered treatment-related and led to drug discontinuation. Another adverse event, Hashimoto’s encephalopathy, was deemed possibly related to the drug and also led to discontinuation.

Treatment-emergent adverse events occurred in 79.8% of patients treated with teprotumumab versus 69.8% with placebo. Those occurring in 5% or more of patients included muscle spasms (25% vs. 7%), nausea (17% vs. 9%), alopecia (13% vs. 8%), and diarrhea (12% vs. 8%). Most were well tolerated and tended to resolve after the infusions ended, Dr. Douglas noted, adding muscle spasms tended to occur at night, improved with massage, and were not accompanied by electrolyte abnormalities.

Antidrug antibodies were detected in two teprotumumab-treated patients, one at study day 1 and another at week 3 during the 24-week treatment period. The patient with antibodies at day 1 also tested positive at week 72. “[Antidrug] antibodies appeared to be very uncommon,” Dr. Douglas noted.

The trial was sponsored by Horizon Therapeutics. Dr. Douglas is a consultant for Horizon Therapeutics and Immunovant. Dr. Lieb has reported no relevant financial relationships. The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

This article first appeared on Medscape.com.

Teprotumumab (Tepezza, Horizon Therapeutics), the first-ever medication approved specifically to treat thyroid eye disease, works in patients regardless of age, gender, and smoking status, new research finds.

The data were presented on March 31 by Raymond S. Douglas, MD, director of the thyroid eye disease program at Cedars-Sinai Medical Center, Los Angeles, during a virtual news conference held by the Endocrine Society. The study had been slated for presentation during ENDO 2020, the society’s annual meeting, which was canceled because of the COVID-19 pandemic.

Thyroid eye disease occurs in up to 50% of people with Graves disease, causing a variety of symptoms, such as eye pain, double vision, light sensitivity or difficulty closing the eye, as well as proptosis, or bulging of the eye, and vision-threatening complications. It affects more women than men, and the symptoms can lead to the progressive inability to perform important daily activities, such as driving or working.

Teprotumumab is a fully human monoclonal antibody inhibitor of the insulin-like growth factor-1 (IGF-1) receptor and was approved by the US Food and Drug Administration in January 2020. Prior to that, therapy typically involved steroids or, in severe cases, surgery.

Blocking the IGF-1 receptor leads to reduced inflammation and reversal of retro-orbital tissue expansion and hyaluronan production in the eye orbit. Teprotumumab is given as an infusion once every 3 weeks for a total of eight infusions.
 

“Exciting to have an agent” that reduces proptosis to this degree

Previously reported pooled phase 2 and phase 3 data from the randomized, placebo-controlled OPTIC trial involving 171 patients showed significantly greater reductions in proptosis, as well as diplopia, and clinical symptoms of inflammation with teprotumumab versus placebo.

“This has really been unheralded in comparison to other medical therapies previously offered,” Dr. Douglas said during the briefing.

Now, the new analysis shows that the drug works across patient subgroups, he added, highlighting in particular the fact that the agent seems to work equally well in smokers and nonsmokers. Smoking leads to a worse prognosis in thyroid eye disease.

Asked to comment, endocrinologist David C. Lieb, MD, of Eastern Virginia Medical School, Norfolk, said in an interview, “It’s reassuring that this drug appears to have benefits in reducing proptosis across multiple age groups, in both genders, and that there are also benefits seen in patients who smoke and who don’t.”

So far Dr. Lieb has two patients who have been prescribed teprotumumab by their ophthalmologists, but it’s too soon to know how they’ll respond.

“I have no first-hand experience yet, but it’s very exciting to have something to offer patients with active Graves eye disease, which causes a lot of disability for people. It makes work difficult and driving difficult. It’s exciting to have an agent that reduces proptosis to the degree that this one does because we haven’t had anything like this before,” he said.

All patient subgroups benefited in combined analysis

A total of 79 patients completed phase 2 and 76 patients completed phase 3 of the OPTIC trial.

Overall, the proportions achieving proptosis reductions of at least 2 mm without deterioration in the fellow eye at week 24 were 77.4% with teprotumumab versus 14.9% with placebo in the intention-to-treat analysis (P < .001), respectively, and 84.8% versus 17.1% in the per-protocol analysis (P < .001). The number needed to treat was 1.6.

Similar results were achieved across all subgroups of patients: those aged 65 and older versus younger than aged 65 years; male versus female; tobacco user versus nonuser; and U.S. versus E.U. study centers (all P < .001).

Overall, the average decrease in proptosis was 3.1 mm, compared to just 0.4 mm with placebo (P < .001). By subgroup, those reductions ranged from 3.55 mm for those aged 65 and older to 2.93 mm for the U.S. group.

The average proptosis reductions with teprotumumab were 2.99 mm among smokers versus 3.20 mm in nonsmokers, but responses in both groups were significant when compared with placebo.

Smoking contributes to the severity of thyroid eye disease and is associated with more optic neuropathy, poorer response to anti-inflammatory treatment, and worse outcomes, Dr. Douglas said. “Smoking appears to preferentially cause fibroblasts in the orbit to increase proinflammatory cytokines. ... It’s reassuring that this medicine does work in smokers since most other medications are much less effective in reducing inflammatory signs in smoking versus nonsmoking patients.”
 

Most adverse reactions disappeared after infusion stopped

In the pooled studies overall there were no deaths, but there were seven severe adverse events in the teprotumumab group versus one in the placebo group. Two adverse events in the teprotumumab group – diarrhea and infusion-related reaction – were considered treatment-related and led to drug discontinuation. Another adverse event, Hashimoto’s encephalopathy, was deemed possibly related to the drug and also led to discontinuation.

Treatment-emergent adverse events occurred in 79.8% of patients treated with teprotumumab versus 69.8% with placebo. Those occurring in 5% or more of patients included muscle spasms (25% vs. 7%), nausea (17% vs. 9%), alopecia (13% vs. 8%), and diarrhea (12% vs. 8%). Most were well tolerated and tended to resolve after the infusions ended, Dr. Douglas noted, adding muscle spasms tended to occur at night, improved with massage, and were not accompanied by electrolyte abnormalities.

Antidrug antibodies were detected in two teprotumumab-treated patients, one at study day 1 and another at week 3 during the 24-week treatment period. The patient with antibodies at day 1 also tested positive at week 72. “[Antidrug] antibodies appeared to be very uncommon,” Dr. Douglas noted.

The trial was sponsored by Horizon Therapeutics. Dr. Douglas is a consultant for Horizon Therapeutics and Immunovant. Dr. Lieb has reported no relevant financial relationships. The research will be published in a special supplemental issue of the Journal of the Endocrine Society. In addition to a series of news conferences on March 30-31, the society will host ENDO Online 2020 during June 8-22, which will present programming for clinicians and researchers.

This article first appeared on Medscape.com.

Testosterone normally decreases with age in men beginning in their mid-30s, with a rate of decline averaging approximately 1.6% per year. Using a cutoff of a total testosterone less than 325 ng/dL, the incidence of low testosterone is approximately 20% after age 60 years, and 30% after age 70. While the change in labs values has been reasonably validated, there is some uncertainty about whether many of the symptoms that are sometimes attributed to testosterone deficiency, including fatigue and decreased muscle mass, are actually caused by low testosterone.

Additional potential symptoms of testosterone deficiency include changes in bone mineral density, decreased libido, depression, erectile dysfunction, loss of hair, and general weakness. Since the symptoms are nonspecific, it is often unclear if someone should be tested or treated for testosterone deficiency. To address this issue, the American College of Physicians commissioned a systematic review of the evidence on testosterone-replacement therapy for age-related testosterone deficiency.¹

The evidence review of testosterone replacement in men with age-related low testosterone found the following.

• Low-certainty evidence of improvement in quality of life
• Moderate-certainty evidence of a small improvement in sexual function
• Low-certainty evidence of a small improvement in erectile function
• Low-certainty evidence showing little to no improvement in physical function
• Low-certainty evidence of a small increase to no difference in adverse cardiovascular events
• Moderate-certainty evidence of no increase in the risk for serious adverse events

The trials were not powered to assess mortality, but pool analysis showed fewer deaths among patients treated with testosterone than those who received placebo (odds ratio, 0.47; 95% confidence interval, 0.25-0.89). There were no differences in cognitive function, and the improvement in vitality and fatigue was “less than a small amount.” Evidence from an observational trial showed no increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolus or deep vein thrombosis. Of note, most studies excluded men with recent cardiovascular disease.

This evidence review led to the following recommendations.²

Recommendation 1a

Clinicians should have a discussion regarding the potential risk and benefits of treatment with the patients who have documented age-related low testosterone (testosterone levels less than 10.4 nmol/L or 300 ng/dL) and are suffering from sexual dysfunction or have a desire to enhance their sexual function.

This recommendation was based on evidence showing small improvement in sexual function and erectile dysfunction.

Recommendation 1b

For patients who opt for treatment based on recommendation 1a, clinicians should reevaluate the benefit of treatment within 12 months. If a patient is not receiving any benefit in sexual function by 12 months, it is recommended that treatment be stopped at that time.

The ACP recommendation to stop treatment if a patient lacks improvement of sexual function within 12 months stems from low or insufficient evidence regarding potential harm of treatment. If the treatment is not helping the target symptom then the benefit no longer outweighs the potential harm.

Recommendation 1c

For patients who opt for treatment based on recommendation 1a, intramuscular replacement therapy rather than transdermal replacement therapy is recommended because of substantial differences in the cost.

It is important to note that both intramuscular and transdermal testosterone applications have been associated with improvements in sexual function, without any significant differences noted in benefit or harm for the patients. This recommendation is based on a per-person per-year average cost of the intramuscular formulation – $156.32, compared with the transdermal formulation – $2,135.32.

Recommendation 2

The ACP does not endorse the use of testosterone treatment for age-related low testosterone in patients desiring improvement in physical function, mood, energy, or cognitive function.

This clear recommendation is critical, as this might be the most common reason for prescriptions of testosterone – a misplaced belief that testosterone will help general quality of life. The evidence simply does not support this effect of testosterone replacement for age-related testosterone deficiency.

The bottom line

Testosterone levels in men decrease steadily with age, with a great deal of variability. Testosterone replacement therapy may be considered for men with age-related testosterone deficiency and sexual dysfunction. Testosterone replacement therapy is not recommended as a treatment for general fatigue, weakness or with an expectation that it will improve physical function, mood, energy, or cognitive function.

Dr. Hansen is a third-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Hospital–Jefferson Health.

References

1. Diem SJ et al. Efficacy and safety of testosterone treatment in men: An evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0830.

2. Qaseem A et al. Testosterone treatment in adult men with age-related low testosterone: A clinical guideline from the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0882.

Testosterone normally decreases with age in men beginning in their mid-30s, with a rate of decline averaging approximately 1.6% per year. Using a cutoff of a total testosterone less than 325 ng/dL, the incidence of low testosterone is approximately 20% after age 60 years, and 30% after age 70. While the change in labs values has been reasonably validated, there is some uncertainty about whether many of the symptoms that are sometimes attributed to testosterone deficiency, including fatigue and decreased muscle mass, are actually caused by low testosterone.

Additional potential symptoms of testosterone deficiency include changes in bone mineral density, decreased libido, depression, erectile dysfunction, loss of hair, and general weakness. Since the symptoms are nonspecific, it is often unclear if someone should be tested or treated for testosterone deficiency. To address this issue, the American College of Physicians commissioned a systematic review of the evidence on testosterone-replacement therapy for age-related testosterone deficiency.¹

The evidence review of testosterone replacement in men with age-related low testosterone found the following.

• Low-certainty evidence of improvement in quality of life
• Moderate-certainty evidence of a small improvement in sexual function
• Low-certainty evidence of a small improvement in erectile function
• Low-certainty evidence showing little to no improvement in physical function
• Low-certainty evidence of a small increase to no difference in adverse cardiovascular events
• Moderate-certainty evidence of no increase in the risk for serious adverse events

The trials were not powered to assess mortality, but pool analysis showed fewer deaths among patients treated with testosterone than those who received placebo (odds ratio, 0.47; 95% confidence interval, 0.25-0.89). There were no differences in cognitive function, and the improvement in vitality and fatigue was “less than a small amount.” Evidence from an observational trial showed no increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolus or deep vein thrombosis. Of note, most studies excluded men with recent cardiovascular disease.

This evidence review led to the following recommendations.²

Recommendation 1a

Clinicians should have a discussion regarding the potential risk and benefits of treatment with the patients who have documented age-related low testosterone (testosterone levels less than 10.4 nmol/L or 300 ng/dL) and are suffering from sexual dysfunction or have a desire to enhance their sexual function.

This recommendation was based on evidence showing small improvement in sexual function and erectile dysfunction.

Recommendation 1b

For patients who opt for treatment based on recommendation 1a, clinicians should reevaluate the benefit of treatment within 12 months. If a patient is not receiving any benefit in sexual function by 12 months, it is recommended that treatment be stopped at that time.

The ACP recommendation to stop treatment if a patient lacks improvement of sexual function within 12 months stems from low or insufficient evidence regarding potential harm of treatment. If the treatment is not helping the target symptom then the benefit no longer outweighs the potential harm.

Recommendation 1c

For patients who opt for treatment based on recommendation 1a, intramuscular replacement therapy rather than transdermal replacement therapy is recommended because of substantial differences in the cost.

It is important to note that both intramuscular and transdermal testosterone applications have been associated with improvements in sexual function, without any significant differences noted in benefit or harm for the patients. This recommendation is based on a per-person per-year average cost of the intramuscular formulation – $156.32, compared with the transdermal formulation – $2,135.32.

Recommendation 2

The ACP does not endorse the use of testosterone treatment for age-related low testosterone in patients desiring improvement in physical function, mood, energy, or cognitive function.

This clear recommendation is critical, as this might be the most common reason for prescriptions of testosterone – a misplaced belief that testosterone will help general quality of life. The evidence simply does not support this effect of testosterone replacement for age-related testosterone deficiency.

The bottom line

Testosterone levels in men decrease steadily with age, with a great deal of variability. Testosterone replacement therapy may be considered for men with age-related testosterone deficiency and sexual dysfunction. Testosterone replacement therapy is not recommended as a treatment for general fatigue, weakness or with an expectation that it will improve physical function, mood, energy, or cognitive function.

Dr. Hansen is a third-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Hospital–Jefferson Health.

References

1. Diem SJ et al. Efficacy and safety of testosterone treatment in men: An evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0830.

2. Qaseem A et al. Testosterone treatment in adult men with age-related low testosterone: A clinical guideline from the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0882.

Testosterone normally decreases with age in men beginning in their mid-30s, with a rate of decline averaging approximately 1.6% per year. Using a cutoff of a total testosterone less than 325 ng/dL, the incidence of low testosterone is approximately 20% after age 60 years, and 30% after age 70. While the change in labs values has been reasonably validated, there is some uncertainty about whether many of the symptoms that are sometimes attributed to testosterone deficiency, including fatigue and decreased muscle mass, are actually caused by low testosterone.

Additional potential symptoms of testosterone deficiency include changes in bone mineral density, decreased libido, depression, erectile dysfunction, loss of hair, and general weakness. Since the symptoms are nonspecific, it is often unclear if someone should be tested or treated for testosterone deficiency. To address this issue, the American College of Physicians commissioned a systematic review of the evidence on testosterone-replacement therapy for age-related testosterone deficiency.¹

The evidence review of testosterone replacement in men with age-related low testosterone found the following.

• Low-certainty evidence of improvement in quality of life
• Moderate-certainty evidence of a small improvement in sexual function
• Low-certainty evidence of a small improvement in erectile function
• Low-certainty evidence showing little to no improvement in physical function
• Low-certainty evidence of a small increase to no difference in adverse cardiovascular events
• Moderate-certainty evidence of no increase in the risk for serious adverse events

The trials were not powered to assess mortality, but pool analysis showed fewer deaths among patients treated with testosterone than those who received placebo (odds ratio, 0.47; 95% confidence interval, 0.25-0.89). There were no differences in cognitive function, and the improvement in vitality and fatigue was “less than a small amount.” Evidence from an observational trial showed no increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolus or deep vein thrombosis. Of note, most studies excluded men with recent cardiovascular disease.

This evidence review led to the following recommendations.²

Recommendation 1a

Clinicians should have a discussion regarding the potential risk and benefits of treatment with the patients who have documented age-related low testosterone (testosterone levels less than 10.4 nmol/L or 300 ng/dL) and are suffering from sexual dysfunction or have a desire to enhance their sexual function.

This recommendation was based on evidence showing small improvement in sexual function and erectile dysfunction.

Recommendation 1b

For patients who opt for treatment based on recommendation 1a, clinicians should reevaluate the benefit of treatment within 12 months. If a patient is not receiving any benefit in sexual function by 12 months, it is recommended that treatment be stopped at that time.

The ACP recommendation to stop treatment if a patient lacks improvement of sexual function within 12 months stems from low or insufficient evidence regarding potential harm of treatment. If the treatment is not helping the target symptom then the benefit no longer outweighs the potential harm.

Recommendation 1c

For patients who opt for treatment based on recommendation 1a, intramuscular replacement therapy rather than transdermal replacement therapy is recommended because of substantial differences in the cost.

It is important to note that both intramuscular and transdermal testosterone applications have been associated with improvements in sexual function, without any significant differences noted in benefit or harm for the patients. This recommendation is based on a per-person per-year average cost of the intramuscular formulation – $156.32, compared with the transdermal formulation – $2,135.32.

Recommendation 2

The ACP does not endorse the use of testosterone treatment for age-related low testosterone in patients desiring improvement in physical function, mood, energy, or cognitive function.

This clear recommendation is critical, as this might be the most common reason for prescriptions of testosterone – a misplaced belief that testosterone will help general quality of life. The evidence simply does not support this effect of testosterone replacement for age-related testosterone deficiency.

The bottom line

Testosterone levels in men decrease steadily with age, with a great deal of variability. Testosterone replacement therapy may be considered for men with age-related testosterone deficiency and sexual dysfunction. Testosterone replacement therapy is not recommended as a treatment for general fatigue, weakness or with an expectation that it will improve physical function, mood, energy, or cognitive function.

Dr. Hansen is a third-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Hospital–Jefferson Health.

References

1. Diem SJ et al. Efficacy and safety of testosterone treatment in men: An evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0830.

2. Qaseem A et al. Testosterone treatment in adult men with age-related low testosterone: A clinical guideline from the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0882.

People with hypothyroidism who choose desiccated thyroid extract (DTE) over levothyroxine alone perceive that it works better, but patients may not be aware of the risks, new research suggests.

Those were among the findings from qualitative analyses of nearly 700 online posts from three popular online hypothyroidism forums that found that 75% of patients felt they fared better on DTE than the standard therapy of levothyroxine (LT4).

A select group of patients do better on combined T4/T3

Asked to comment, endocrinologist Rachel Pessah-Pollack, MD, of New York University Langone Health, said in an interview, “Animal-derived desiccated thyroid hormone contains both T4 and T3. We typically do not recommend using this because it can vary in concentration, meaning that the actual preparation is not physiologic.”

Dr. Pessah-Pollack, a coauthor of the 2012 joint clinical practice guidelines on hypothyroidism by the American Thyroid Association and American Association of Clinical Endocrinologists, added that one of the major concerns about using DTE is the risk for iatrogenic hyperthyroidism, which could potentially lead to atrial fibrillation and fractures.

“That is one of the main factors that drive many professional societies to really use caution regarding DTE. That’s also why major societies recommend against using DTE ... based on the evidence to date,” she said.

The whole issue of “combination therapy” in hypothyroidism is contentious, however. Physicians can also prescribe a “combination” of synthetic levothyroxine (LT4) and triiodothyronine (LT3) treatment; this, along with use of DTE products, has been a subject of debate for many years.

The current (2014) American Thyroid Association guidelines do not specifically rule out use of synthetic LT4/LT3 therapy, rather they “recommend only against the routine use of combination therapy.” And although they don’t expressly endorse use of DTE, they removed a statement saying it “should not be used.”

“There is definitely a select group of patients who do better on combined T4/T3 treatment, and we’re still trying to delineate who that population is,”Dr. Pessah-Pollack said.

“As long as these patients are closely monitored and aware of the risk of hyperthyroidism and have their levels followed to ensure that they’re not hyperthyroid, in select cases this is appropriate.”

“But, first-line is ensuring that a good evaluation occurs. ... Clearly this helps us understand that we do need more studies in this area – well-designed, blinded studies to really help us get to the bottom of this controversy.”
 

Those taking DTE cite improved symptoms, well-being

Dr. Toloza and colleagues analyzed 673 posts from three online forums, WebMD (Medscape’s parent company), PatientsLikeMe, and Drugs.com, selected from an initial 1,235 posts because they included more complete information.

About half (51%, n = 257) of patients had primary hypothyroidism/Hashimoto’s thyroiditis, 25% (n = 126) had postsurgical hypothyroidism, and 16% (n = 81) had postablation hypothyroidism. Among the 172 posts in which DTE dose information was available, the mean dose was 84.1 mg/day. Treatment duration ranged widely, from 2 weeks to 45 years.

Among the posts describing the source of the DTE prescription, the initial interest was driven mainly by the patient in 54% (n = 88), while 46% (n = 74) said that a clinician drove their interest in trying DTE. (The type of clinician was not reported.)

Among posts mentioning the source of DTE, local pharmacies were the most common (63%, n = 75), followed by pharmacies outside the United States (31%, n = 37), and online (6%, n = 7).

Previous thyroid treatments were mentioned in 300 posts, of which 93% mentioned LT4 monotherapy.

Among the reasons for changing to DTE were no improvement in clinical symptoms (47%, n = 75), development of side effects (24%, n = 38), no change in overall well-being (22%, n = 36), and no changes in laboratory work-up (7%, n = 12).

Perceived benefits of DTE included improvement in clinical symptoms (56%, n = 155), change in overall well-being (34%, n = 94), possibility of reaching previous health status (7%, n = 19), and low cost, compared with previous treatment (3%, n = 8).

Specific symptoms reported to have improved included fatigue (28%, n = 43), weight gain (17%, n = 26), and neurocognitive symptoms (5%, n = 8). The average time to notice benefits with DTE was about 30 days but ranged widely from 2 days to 4 months.

The majority of posts (77%, n = 99) stated that DTE was more effective than their previous therapy, while 13% (n = 17) described it as equally effective, and 10% (n = 13) said it was less effective.

Side effects of DTE were described by 20% (n = 136), including weight loss (15%), fatigue (11%), palpitations (11%), heat intolerance (11%), sleep disturbances (10%), high blood pressure (7%), and hair loss (5%).
 

“Doctors think they know how u feel”

A qualitative analysis of the posts yielded five major themes: experience with previous therapies before starting DTE, perceived effectiveness and benefits of DTE, DTE side effects, need for individualized therapy for hypothyroidism, and barriers to obtaining DTE.

One patient posted: “Synthroid [levothyroxine] did not help ... and gives me bad side effects. ... My endocrinologist blamed all side effects on everything except the Synthroid.”

Another wrote, “It [Armour] changed my life. ...I’m glad I found a medication that makes me feel normal again. ... All have improved; moods, skin (no itching), no headaches, goiter is down.”

Others cited the lower cost of Armour compared with Synthroid.

However, some expressed negative experiences with DTE, such as, “My doctor expected that this medication would help me with brain fog, energy, and tiredness. I experienced the opposite.”

And some couldn’t obtain it. One wrote, “Doctors think they know how u feel and do not even tell you about Armour. I asked my doctor and was told there was not enough studies on it to show its effectiveness.”
 

Better evaluation, more data needed

Dr. Pessah-Pollack pointed out that the study data don’t address whether patients’ initially prescribed levothyroxine doses were optimal, and noted that sometimes changes are needed, such as during pregnancy, following weight gain, or if the patient is taking other certain medications.

“It’s unclear from patient-reported symptoms whether or not they actually had an evaluation of their thyroid levels to ensure that their dose of thyroid hormone was correct before switching over to T4/T3 replacement. ... There are many factors that need to be taken into account before we decide that the medication itself isn’t working.”

What’s sorely needed, she said, are “well-designed, blinded studies that look at this controversy.”

“Here, we don’t know why patients are feeling better. ... We need to do additional work including validated symptom questionnaires and comparing thyroid levels of patients who are on Armour thyroid with those on levothyroxine monotherapy.”

Dr. Toloza agrees: “It is not possible to say that DTE is working better for the user due to the limitations and the nature of the data used in our study.”

“However, our findings are in-line with previously published research, which has shown that a subset of patients may prefer DTE to levothyroxine and have higher satisfaction with this treatment. Nevertheless, the reason behind this is still not well understood,” and it should be further investigated.

Dr. Toloza and colleagues reported that they had no conflicts of interests. Dr. Pessah-Pollack has reported being an adviser for Boehringer Ingelheim-Eli Lilly and Radius Health, and a moderator for Sanofi.

This article first appeared on Medscape.com.

People with hypothyroidism who choose desiccated thyroid extract (DTE) over levothyroxine alone perceive that it works better, but patients may not be aware of the risks, new research suggests.

Those were among the findings from qualitative analyses of nearly 700 online posts from three popular online hypothyroidism forums that found that 75% of patients felt they fared better on DTE than the standard therapy of levothyroxine (LT4).

A select group of patients do better on combined T4/T3

Asked to comment, endocrinologist Rachel Pessah-Pollack, MD, of New York University Langone Health, said in an interview, “Animal-derived desiccated thyroid hormone contains both T4 and T3. We typically do not recommend using this because it can vary in concentration, meaning that the actual preparation is not physiologic.”

Dr. Pessah-Pollack, a coauthor of the 2012 joint clinical practice guidelines on hypothyroidism by the American Thyroid Association and American Association of Clinical Endocrinologists, added that one of the major concerns about using DTE is the risk for iatrogenic hyperthyroidism, which could potentially lead to atrial fibrillation and fractures.

“That is one of the main factors that drive many professional societies to really use caution regarding DTE. That’s also why major societies recommend against using DTE ... based on the evidence to date,” she said.

The whole issue of “combination therapy” in hypothyroidism is contentious, however. Physicians can also prescribe a “combination” of synthetic levothyroxine (LT4) and triiodothyronine (LT3) treatment; this, along with use of DTE products, has been a subject of debate for many years.

The current (2014) American Thyroid Association guidelines do not specifically rule out use of synthetic LT4/LT3 therapy, rather they “recommend only against the routine use of combination therapy.” And although they don’t expressly endorse use of DTE, they removed a statement saying it “should not be used.”

“There is definitely a select group of patients who do better on combined T4/T3 treatment, and we’re still trying to delineate who that population is,”Dr. Pessah-Pollack said.

“As long as these patients are closely monitored and aware of the risk of hyperthyroidism and have their levels followed to ensure that they’re not hyperthyroid, in select cases this is appropriate.”

“But, first-line is ensuring that a good evaluation occurs. ... Clearly this helps us understand that we do need more studies in this area – well-designed, blinded studies to really help us get to the bottom of this controversy.”
 

Those taking DTE cite improved symptoms, well-being

Dr. Toloza and colleagues analyzed 673 posts from three online forums, WebMD (Medscape’s parent company), PatientsLikeMe, and Drugs.com, selected from an initial 1,235 posts because they included more complete information.

About half (51%, n = 257) of patients had primary hypothyroidism/Hashimoto’s thyroiditis, 25% (n = 126) had postsurgical hypothyroidism, and 16% (n = 81) had postablation hypothyroidism. Among the 172 posts in which DTE dose information was available, the mean dose was 84.1 mg/day. Treatment duration ranged widely, from 2 weeks to 45 years.

Among the posts describing the source of the DTE prescription, the initial interest was driven mainly by the patient in 54% (n = 88), while 46% (n = 74) said that a clinician drove their interest in trying DTE. (The type of clinician was not reported.)

Among posts mentioning the source of DTE, local pharmacies were the most common (63%, n = 75), followed by pharmacies outside the United States (31%, n = 37), and online (6%, n = 7).

Previous thyroid treatments were mentioned in 300 posts, of which 93% mentioned LT4 monotherapy.

Among the reasons for changing to DTE were no improvement in clinical symptoms (47%, n = 75), development of side effects (24%, n = 38), no change in overall well-being (22%, n = 36), and no changes in laboratory work-up (7%, n = 12).

Perceived benefits of DTE included improvement in clinical symptoms (56%, n = 155), change in overall well-being (34%, n = 94), possibility of reaching previous health status (7%, n = 19), and low cost, compared with previous treatment (3%, n = 8).

Specific symptoms reported to have improved included fatigue (28%, n = 43), weight gain (17%, n = 26), and neurocognitive symptoms (5%, n = 8). The average time to notice benefits with DTE was about 30 days but ranged widely from 2 days to 4 months.

The majority of posts (77%, n = 99) stated that DTE was more effective than their previous therapy, while 13% (n = 17) described it as equally effective, and 10% (n = 13) said it was less effective.

Side effects of DTE were described by 20% (n = 136), including weight loss (15%), fatigue (11%), palpitations (11%), heat intolerance (11%), sleep disturbances (10%), high blood pressure (7%), and hair loss (5%).
 

“Doctors think they know how u feel”

A qualitative analysis of the posts yielded five major themes: experience with previous therapies before starting DTE, perceived effectiveness and benefits of DTE, DTE side effects, need for individualized therapy for hypothyroidism, and barriers to obtaining DTE.

One patient posted: “Synthroid [levothyroxine] did not help ... and gives me bad side effects. ... My endocrinologist blamed all side effects on everything except the Synthroid.”

Another wrote, “It [Armour] changed my life. ...I’m glad I found a medication that makes me feel normal again. ... All have improved; moods, skin (no itching), no headaches, goiter is down.”

Others cited the lower cost of Armour compared with Synthroid.

However, some expressed negative experiences with DTE, such as, “My doctor expected that this medication would help me with brain fog, energy, and tiredness. I experienced the opposite.”

And some couldn’t obtain it. One wrote, “Doctors think they know how u feel and do not even tell you about Armour. I asked my doctor and was told there was not enough studies on it to show its effectiveness.”
 

Better evaluation, more data needed

Dr. Pessah-Pollack pointed out that the study data don’t address whether patients’ initially prescribed levothyroxine doses were optimal, and noted that sometimes changes are needed, such as during pregnancy, following weight gain, or if the patient is taking other certain medications.

“It’s unclear from patient-reported symptoms whether or not they actually had an evaluation of their thyroid levels to ensure that their dose of thyroid hormone was correct before switching over to T4/T3 replacement. ... There are many factors that need to be taken into account before we decide that the medication itself isn’t working.”

What’s sorely needed, she said, are “well-designed, blinded studies that look at this controversy.”

“Here, we don’t know why patients are feeling better. ... We need to do additional work including validated symptom questionnaires and comparing thyroid levels of patients who are on Armour thyroid with those on levothyroxine monotherapy.”

Dr. Toloza agrees: “It is not possible to say that DTE is working better for the user due to the limitations and the nature of the data used in our study.”

“However, our findings are in-line with previously published research, which has shown that a subset of patients may prefer DTE to levothyroxine and have higher satisfaction with this treatment. Nevertheless, the reason behind this is still not well understood,” and it should be further investigated.

Dr. Toloza and colleagues reported that they had no conflicts of interests. Dr. Pessah-Pollack has reported being an adviser for Boehringer Ingelheim-Eli Lilly and Radius Health, and a moderator for Sanofi.

This article first appeared on Medscape.com.

People with hypothyroidism who choose desiccated thyroid extract (DTE) over levothyroxine alone perceive that it works better, but patients may not be aware of the risks, new research suggests.

Those were among the findings from qualitative analyses of nearly 700 online posts from three popular online hypothyroidism forums that found that 75% of patients felt they fared better on DTE than the standard therapy of levothyroxine (LT4).

A select group of patients do better on combined T4/T3

Asked to comment, endocrinologist Rachel Pessah-Pollack, MD, of New York University Langone Health, said in an interview, “Animal-derived desiccated thyroid hormone contains both T4 and T3. We typically do not recommend using this because it can vary in concentration, meaning that the actual preparation is not physiologic.”

Dr. Pessah-Pollack, a coauthor of the 2012 joint clinical practice guidelines on hypothyroidism by the American Thyroid Association and American Association of Clinical Endocrinologists, added that one of the major concerns about using DTE is the risk for iatrogenic hyperthyroidism, which could potentially lead to atrial fibrillation and fractures.

“That is one of the main factors that drive many professional societies to really use caution regarding DTE. That’s also why major societies recommend against using DTE ... based on the evidence to date,” she said.

The whole issue of “combination therapy” in hypothyroidism is contentious, however. Physicians can also prescribe a “combination” of synthetic levothyroxine (LT4) and triiodothyronine (LT3) treatment; this, along with use of DTE products, has been a subject of debate for many years.

The current (2014) American Thyroid Association guidelines do not specifically rule out use of synthetic LT4/LT3 therapy, rather they “recommend only against the routine use of combination therapy.” And although they don’t expressly endorse use of DTE, they removed a statement saying it “should not be used.”

“There is definitely a select group of patients who do better on combined T4/T3 treatment, and we’re still trying to delineate who that population is,”Dr. Pessah-Pollack said.

“As long as these patients are closely monitored and aware of the risk of hyperthyroidism and have their levels followed to ensure that they’re not hyperthyroid, in select cases this is appropriate.”

“But, first-line is ensuring that a good evaluation occurs. ... Clearly this helps us understand that we do need more studies in this area – well-designed, blinded studies to really help us get to the bottom of this controversy.”
 

Those taking DTE cite improved symptoms, well-being

Dr. Toloza and colleagues analyzed 673 posts from three online forums, WebMD (Medscape’s parent company), PatientsLikeMe, and Drugs.com, selected from an initial 1,235 posts because they included more complete information.

About half (51%, n = 257) of patients had primary hypothyroidism/Hashimoto’s thyroiditis, 25% (n = 126) had postsurgical hypothyroidism, and 16% (n = 81) had postablation hypothyroidism. Among the 172 posts in which DTE dose information was available, the mean dose was 84.1 mg/day. Treatment duration ranged widely, from 2 weeks to 45 years.

Among the posts describing the source of the DTE prescription, the initial interest was driven mainly by the patient in 54% (n = 88), while 46% (n = 74) said that a clinician drove their interest in trying DTE. (The type of clinician was not reported.)

Among posts mentioning the source of DTE, local pharmacies were the most common (63%, n = 75), followed by pharmacies outside the United States (31%, n = 37), and online (6%, n = 7).

Previous thyroid treatments were mentioned in 300 posts, of which 93% mentioned LT4 monotherapy.

Among the reasons for changing to DTE were no improvement in clinical symptoms (47%, n = 75), development of side effects (24%, n = 38), no change in overall well-being (22%, n = 36), and no changes in laboratory work-up (7%, n = 12).

Perceived benefits of DTE included improvement in clinical symptoms (56%, n = 155), change in overall well-being (34%, n = 94), possibility of reaching previous health status (7%, n = 19), and low cost, compared with previous treatment (3%, n = 8).

Specific symptoms reported to have improved included fatigue (28%, n = 43), weight gain (17%, n = 26), and neurocognitive symptoms (5%, n = 8). The average time to notice benefits with DTE was about 30 days but ranged widely from 2 days to 4 months.

The majority of posts (77%, n = 99) stated that DTE was more effective than their previous therapy, while 13% (n = 17) described it as equally effective, and 10% (n = 13) said it was less effective.

Side effects of DTE were described by 20% (n = 136), including weight loss (15%), fatigue (11%), palpitations (11%), heat intolerance (11%), sleep disturbances (10%), high blood pressure (7%), and hair loss (5%).
 

“Doctors think they know how u feel”

A qualitative analysis of the posts yielded five major themes: experience with previous therapies before starting DTE, perceived effectiveness and benefits of DTE, DTE side effects, need for individualized therapy for hypothyroidism, and barriers to obtaining DTE.

One patient posted: “Synthroid [levothyroxine] did not help ... and gives me bad side effects. ... My endocrinologist blamed all side effects on everything except the Synthroid.”

Another wrote, “It [Armour] changed my life. ...I’m glad I found a medication that makes me feel normal again. ... All have improved; moods, skin (no itching), no headaches, goiter is down.”

Others cited the lower cost of Armour compared with Synthroid.

However, some expressed negative experiences with DTE, such as, “My doctor expected that this medication would help me with brain fog, energy, and tiredness. I experienced the opposite.”

And some couldn’t obtain it. One wrote, “Doctors think they know how u feel and do not even tell you about Armour. I asked my doctor and was told there was not enough studies on it to show its effectiveness.”
 

Better evaluation, more data needed

Dr. Pessah-Pollack pointed out that the study data don’t address whether patients’ initially prescribed levothyroxine doses were optimal, and noted that sometimes changes are needed, such as during pregnancy, following weight gain, or if the patient is taking other certain medications.

“It’s unclear from patient-reported symptoms whether or not they actually had an evaluation of their thyroid levels to ensure that their dose of thyroid hormone was correct before switching over to T4/T3 replacement. ... There are many factors that need to be taken into account before we decide that the medication itself isn’t working.”

What’s sorely needed, she said, are “well-designed, blinded studies that look at this controversy.”

“Here, we don’t know why patients are feeling better. ... We need to do additional work including validated symptom questionnaires and comparing thyroid levels of patients who are on Armour thyroid with those on levothyroxine monotherapy.”

Dr. Toloza agrees: “It is not possible to say that DTE is working better for the user due to the limitations and the nature of the data used in our study.”

“However, our findings are in-line with previously published research, which has shown that a subset of patients may prefer DTE to levothyroxine and have higher satisfaction with this treatment. Nevertheless, the reason behind this is still not well understood,” and it should be further investigated.

Dr. Toloza and colleagues reported that they had no conflicts of interests. Dr. Pessah-Pollack has reported being an adviser for Boehringer Ingelheim-Eli Lilly and Radius Health, and a moderator for Sanofi.

This article first appeared on Medscape.com.

Bone fracture in older adults is associated with greater mortality risk, but the location of the break may be a key factor, according to a new study of outcomes in a Danish database.

Over the follow-up period, those with proximal fractures – breaks in the hip, femur, pelvis, rib, clavicle, and humerus – were more likely to be hospitalized and to die, compared with their matched controls, than were those were with distal fractures in regions like the ankle, forearm, hand, or foot, where the mortality was similar to the matched controls.

“Compared with someone with similar comorbidities without a proximal fracture, there seemed to be an increased hospitalization rate for things like diabetes, heart disease, and lung disease, and then for some of those hospitalizations, there seemed to be an increased mortality, compared with people who hadn’t fractured who were hospitalized,” said Jacqueline Center, MBBS, PhD, of the Garvan Institute of Medical Research, Sydney, in an interview. The study abstract was released online by the Endocrine Society. It had been slated for presentation during ENDO 2020, the society's annual meeting, which was canceled because of the COVID-19 pandemic.*

The study included 212,498 women and 95,372 men aged over 50 years who had a fragility fracture between 2001 and 2014. The researchers excluded high-trauma fractures. They matched each fracture patient with four nonfracture patients, based on sex, age, and comorbidity status. There were 30,677 deaths among women over 384,995 person-years of follow-up, and 19,519 deaths in men over 163,482 person-years of follow-up. Women were a mean age of 72 at the time of fracture, while men were a mean age of 75.

The researchers found that proximal fractures were associated with increased risk of mortality, compared with nonfractured controls, with hazard ratios ranging between 1.5 and 4.0. Distal fractures were not associated with any increased mortality risk.

Comorbidities were common in the study population, with 75% of men and 60% of women having at least one. The risk of mortality increased with increasing numbers of comorbidities in each fracture type, but only proximal fractures were associated with an independent increase in mortality risk over and above comorbidity status.

In the 2 years following fracture, compared with matched controls, proximal fractures were associated with a greater risk of major hospital admission for conditions like cardiovascular disease, cancer, stroke, diabetes, pneumonia, and pulmonary disease. There was no significant difference between controls and those with distal fractures in hospital admission rate. The 2-year mortality risk was higher among subjects with proximal fractures, compared with patients in the no-fracture control group, regardless of whether they were admitted to the hospital, but there was no significant difference in those with distal fractures.

The differing clinical trajectories between those with proximal and distal fractures is a key finding, according to Dr. Center. The cause still isn’t clear, but she suspects that, in those patients who do badly, the fractures are either a signal that something is happening with existing comorbidities of the underlying frailty or that it may exacerbate them. Comorbidity independently and additively contributes to mortality, so that someone with a hip fracture and no comorbidities might have a similar mortality risk as someone with an upper-arm fracture and a couple of comorbidities. “I think it tells us that the person has to be treated as a whole. We need to treat the fracture to treat the underlying osteoporosis, but we also need to look closely at the person with the fracture and treat their comorbidities as well, because they seem to be more vulnerable,” Dr. Center said.

Although patients and clinicians are attuned to the concerns over hip fractures, other fractures should also be noted, according to Nelson Watts, MD, who is director of osteoporosis and bone-health services at Mercy Health in Cincinnati and was not involved in the research. “I think the message for clinicians and patients is that all of these [proximal] fractures need to be taken seriously. The good news is that that we have medications that can cut the risk of further fractures by 50%-70%,” he said in an interview.

Dr. Center has been on an advisory board for Amgen. Dr. Watts has been a speaker for Amgen and Radius and has conducted numerous clinical trials of osteoporosis drugs.

In addition to a series of news conferences, the Endocrine Society is also planning to host ENDO Online 2020 during June 8-22, which will feature on-demand and live programming for clinicians and researchers.

SOURCE: Center J et al. ENDO 2020, Abstract OR13-03.

Correction, 4/21/20: An earlier version of this article misstated when the interview with Dr. Center took place.

Bone fracture in older adults is associated with greater mortality risk, but the location of the break may be a key factor, according to a new study of outcomes in a Danish database.

Over the follow-up period, those with proximal fractures – breaks in the hip, femur, pelvis, rib, clavicle, and humerus – were more likely to be hospitalized and to die, compared with their matched controls, than were those were with distal fractures in regions like the ankle, forearm, hand, or foot, where the mortality was similar to the matched controls.

“Compared with someone with similar comorbidities without a proximal fracture, there seemed to be an increased hospitalization rate for things like diabetes, heart disease, and lung disease, and then for some of those hospitalizations, there seemed to be an increased mortality, compared with people who hadn’t fractured who were hospitalized,” said Jacqueline Center, MBBS, PhD, of the Garvan Institute of Medical Research, Sydney, in an interview. The study abstract was released online by the Endocrine Society. It had been slated for presentation during ENDO 2020, the society's annual meeting, which was canceled because of the COVID-19 pandemic.*

The study included 212,498 women and 95,372 men aged over 50 years who had a fragility fracture between 2001 and 2014. The researchers excluded high-trauma fractures. They matched each fracture patient with four nonfracture patients, based on sex, age, and comorbidity status. There were 30,677 deaths among women over 384,995 person-years of follow-up, and 19,519 deaths in men over 163,482 person-years of follow-up. Women were a mean age of 72 at the time of fracture, while men were a mean age of 75.

The researchers found that proximal fractures were associated with increased risk of mortality, compared with nonfractured controls, with hazard ratios ranging between 1.5 and 4.0. Distal fractures were not associated with any increased mortality risk.

Comorbidities were common in the study population, with 75% of men and 60% of women having at least one. The risk of mortality increased with increasing numbers of comorbidities in each fracture type, but only proximal fractures were associated with an independent increase in mortality risk over and above comorbidity status.

In the 2 years following fracture, compared with matched controls, proximal fractures were associated with a greater risk of major hospital admission for conditions like cardiovascular disease, cancer, stroke, diabetes, pneumonia, and pulmonary disease. There was no significant difference between controls and those with distal fractures in hospital admission rate. The 2-year mortality risk was higher among subjects with proximal fractures, compared with patients in the no-fracture control group, regardless of whether they were admitted to the hospital, but there was no significant difference in those with distal fractures.

The differing clinical trajectories between those with proximal and distal fractures is a key finding, according to Dr. Center. The cause still isn’t clear, but she suspects that, in those patients who do badly, the fractures are either a signal that something is happening with existing comorbidities of the underlying frailty or that it may exacerbate them. Comorbidity independently and additively contributes to mortality, so that someone with a hip fracture and no comorbidities might have a similar mortality risk as someone with an upper-arm fracture and a couple of comorbidities. “I think it tells us that the person has to be treated as a whole. We need to treat the fracture to treat the underlying osteoporosis, but we also need to look closely at the person with the fracture and treat their comorbidities as well, because they seem to be more vulnerable,” Dr. Center said.

Although patients and clinicians are attuned to the concerns over hip fractures, other fractures should also be noted, according to Nelson Watts, MD, who is director of osteoporosis and bone-health services at Mercy Health in Cincinnati and was not involved in the research. “I think the message for clinicians and patients is that all of these [proximal] fractures need to be taken seriously. The good news is that that we have medications that can cut the risk of further fractures by 50%-70%,” he said in an interview.

Dr. Center has been on an advisory board for Amgen. Dr. Watts has been a speaker for Amgen and Radius and has conducted numerous clinical trials of osteoporosis drugs.

In addition to a series of news conferences, the Endocrine Society is also planning to host ENDO Online 2020 during June 8-22, which will feature on-demand and live programming for clinicians and researchers.

SOURCE: Center J et al. ENDO 2020, Abstract OR13-03.

Correction, 4/21/20: An earlier version of this article misstated when the interview with Dr. Center took place.

Bone fracture in older adults is associated with greater mortality risk, but the location of the break may be a key factor, according to a new study of outcomes in a Danish database.

Over the follow-up period, those with proximal fractures – breaks in the hip, femur, pelvis, rib, clavicle, and humerus – were more likely to be hospitalized and to die, compared with their matched controls, than were those were with distal fractures in regions like the ankle, forearm, hand, or foot, where the mortality was similar to the matched controls.

“Compared with someone with similar comorbidities without a proximal fracture, there seemed to be an increased hospitalization rate for things like diabetes, heart disease, and lung disease, and then for some of those hospitalizations, there seemed to be an increased mortality, compared with people who hadn’t fractured who were hospitalized,” said Jacqueline Center, MBBS, PhD, of the Garvan Institute of Medical Research, Sydney, in an interview. The study abstract was released online by the Endocrine Society. It had been slated for presentation during ENDO 2020, the society's annual meeting, which was canceled because of the COVID-19 pandemic.*

The study included 212,498 women and 95,372 men aged over 50 years who had a fragility fracture between 2001 and 2014. The researchers excluded high-trauma fractures. They matched each fracture patient with four nonfracture patients, based on sex, age, and comorbidity status. There were 30,677 deaths among women over 384,995 person-years of follow-up, and 19,519 deaths in men over 163,482 person-years of follow-up. Women were a mean age of 72 at the time of fracture, while men were a mean age of 75.

The researchers found that proximal fractures were associated with increased risk of mortality, compared with nonfractured controls, with hazard ratios ranging between 1.5 and 4.0. Distal fractures were not associated with any increased mortality risk.

Comorbidities were common in the study population, with 75% of men and 60% of women having at least one. The risk of mortality increased with increasing numbers of comorbidities in each fracture type, but only proximal fractures were associated with an independent increase in mortality risk over and above comorbidity status.

In the 2 years following fracture, compared with matched controls, proximal fractures were associated with a greater risk of major hospital admission for conditions like cardiovascular disease, cancer, stroke, diabetes, pneumonia, and pulmonary disease. There was no significant difference between controls and those with distal fractures in hospital admission rate. The 2-year mortality risk was higher among subjects with proximal fractures, compared with patients in the no-fracture control group, regardless of whether they were admitted to the hospital, but there was no significant difference in those with distal fractures.

The differing clinical trajectories between those with proximal and distal fractures is a key finding, according to Dr. Center. The cause still isn’t clear, but she suspects that, in those patients who do badly, the fractures are either a signal that something is happening with existing comorbidities of the underlying frailty or that it may exacerbate them. Comorbidity independently and additively contributes to mortality, so that someone with a hip fracture and no comorbidities might have a similar mortality risk as someone with an upper-arm fracture and a couple of comorbidities. “I think it tells us that the person has to be treated as a whole. We need to treat the fracture to treat the underlying osteoporosis, but we also need to look closely at the person with the fracture and treat their comorbidities as well, because they seem to be more vulnerable,” Dr. Center said.

Although patients and clinicians are attuned to the concerns over hip fractures, other fractures should also be noted, according to Nelson Watts, MD, who is director of osteoporosis and bone-health services at Mercy Health in Cincinnati and was not involved in the research. “I think the message for clinicians and patients is that all of these [proximal] fractures need to be taken seriously. The good news is that that we have medications that can cut the risk of further fractures by 50%-70%,” he said in an interview.

Dr. Center has been on an advisory board for Amgen. Dr. Watts has been a speaker for Amgen and Radius and has conducted numerous clinical trials of osteoporosis drugs.

In addition to a series of news conferences, the Endocrine Society is also planning to host ENDO Online 2020 during June 8-22, which will feature on-demand and live programming for clinicians and researchers.

SOURCE: Center J et al. ENDO 2020, Abstract OR13-03.

Correction, 4/21/20: An earlier version of this article misstated when the interview with Dr. Center took place.

COVID-19 infection in patients with type 2 diabetes is associated with a greater increase in inflammatory and coagulation markers, compared with COVID-19 patients without diabetes, according to preliminary findings from a retrospective analysis of COVID-19 patients in Wuhan, China.

The results, though preliminary, could help explain why patients with diabetes and COVID-19 are at greater risk for more severe disease and death.

The results also suggest that more severe disease in patients with diabetes may be the result of a cytokine storm, in which the patient’s immune system overreacts to the virus and inflicts collateral damage on its own organs, according to Herbert I. Rettinger, MD, a clinical endocrinologist in Orange County, Calif., and member of the editorial advisory board for Clinical Endocrinology News. “Understanding the mechanism might help us understand the best way to treat,” COVID-19 in patients with diabetes, he said in an interview.

Dr. Rettinger, who was not involved in the research, noted that the study included only 24 patients with diabetes. Nevertheless, the finding of heightened inflammatory and coagulation markers was “fascinating.”

“This is the first paper I’ve seen [suggesting] that. I don’t know if we can extrapolate [the findings] to other populations, but if biomarkers are elevated in patients with COVID-19 and diabetes, then it’s something worth looking into, and to be aware of and cautious of. We need to pay attention to this,” he commented.

The study was led by Weina Guo and Desheng Hu at Huazhong University of Science and Technology in Wuhan, China, and published in Diabetes/Metabolism Research and Reviews.

The sample included 174 patients with COVID-19, who were treated consecutively during Feb. 10-29, 2020, at a single center. The researchers first assigned the patients to one of two groups – those with comorbid diabetes and those without. They further excluded all other comorbidities, focusing only on 26 patients with no comorbidities and 24 with only diabetes as a comorbidity, to remove all other comorbidities as possible confounding factors. Patients in the diabetes group were significantly older than those without diabetes (61 vs. 41 years, P < .01). The mortality rate was 16.5% in patients with diabetes and 0% in those without (P = .03).

COVID-19 patients with diabetes alone as a comorbidity had a greater risk for severe pneumonia, as evidenced by a higher mean CT score, compared with those without diabetes and no other comorbidities (P = .04). Patients with diabetes also had higher measures of release of tissue injury–related enzymes and were at higher risk of uncontrolled inflammation and hypercoagulable state. In particular, they had higher levels of interleukin-6 (13.7 vs. 4.1 pg/mL, respectively; P < .01), C-reactive protein (76.4 vs. 7.43 mg/L; P < .01), serum ferritin (764.8 vs. 128.9 ng/mL; P < .01), and D-dimer (1.16 vs. 0.25 mcg/mL; P < .01).

“It’s noteworthy that, for diseases that can induce a cytokine storm, IL-6 is a very good predictor of disease severity and prognosis, and its expression time is longer than other cytokines ([tumor necrosis factor] and IL-1). In addition, a significant rise in serum ferritin indicates the activation of the monocyte-macrophage system, which is a crucial part of inflammatory storm. These results indicate that patients with diabetes are susceptible to form an inflammatory storm, which eventually lead to rapid deterioration of COVID-19,” the authors wrote.

They also cited previous findings suggesting that coronavirus might exacerbate, or even cause, diabetes by seriously damaging islets (Acta Diabetol. 2010;47[3]:193-9). “Since viral infection may cause sharp fluctuation of the blood glucose levels of diabetes patients, which adversely affect the recovery of patients, there is reason to suspect that diabetes combined with SARS-CoV-2 pneumonia may form a vicious circle,” they wrote.

That’s one more reason to carefully monitor diabetes patients, said Dr. Rettinger. “Those patients who are able to make insulin might not be able to do so with the infection, and that may last a while, and they may require insulin. You want to keep a watch on things, and if oral agents are not working well, you want to go to insulin as quickly as you can. Probably diabetics should be way more careful and maybe visit the emergency department at earlier than a nondiabetic would.”

Raghavendra Mirmira, MD, PhD, who conducts translational research on diabetes and insulin production, said that the finding was not a complete surprise to him. “With a lot of diseases, having diabetes as a comorbidity can mean worse outcomes, and that’s certainly true of influenza. It was true for the other COVID-like illnesses, such as SARS and MERS,” Dr. Mirmira, who was not involved in the research, said in an interview.

If the findings hold up in larger numbers of patients and across multiple centers, they have the potential to inform patient management, said Dr. Mirmira, director of the Translational Research Center in the department of medicine at the University of Chicago. That will be especially true as data from long-term follow-up of become available. Elevated values in some biomarkers might dictate a patient be sent straight to the ICU or dictate admission to the hospital rather than being sent home, or it could assist patient selection for some of the new therapies that physicians hope will become available.

“The more information we get [about] total outcome, the more informed we’d be about who would benefit from some of the therapies that are in clinical trials now,” he said. Still, it will be a challenge to prove causation, because patients with diabetes have unique clinical characteristics that could also be the source of the difference.

Dr. Mirmira noted that patients with diabetes only were 20 years older on average than those with no comorbidities. “It’s really hard to know if what you’re looking at for the worse outcomes for people with diabetes is because they were older, and we know that older people tend to do much worse with COVID than younger people.” Ideally, patients would also be matched by age, but there are not enough data to do that yet.

The study was funded by the China National Natural Science Foundation. The authors reported no conflicts of interest. Dr. Rettinger has no relevant financial disclosures. Dr. Mirmira is on scientific advisory boards for Veralox Therapeutics, Sigilon Therapeutics, the Indiana Biosciences Research Institute, and the Juvenile Diabetes Research Foundation.
 

SOURCE: Guo W et al. Diabetes Metab Res Rev. 2020 Mar 31. doi: 10.1002/dmrr.3319.

COVID-19 infection in patients with type 2 diabetes is associated with a greater increase in inflammatory and coagulation markers, compared with COVID-19 patients without diabetes, according to preliminary findings from a retrospective analysis of COVID-19 patients in Wuhan, China.

The results, though preliminary, could help explain why patients with diabetes and COVID-19 are at greater risk for more severe disease and death.

The results also suggest that more severe disease in patients with diabetes may be the result of a cytokine storm, in which the patient’s immune system overreacts to the virus and inflicts collateral damage on its own organs, according to Herbert I. Rettinger, MD, a clinical endocrinologist in Orange County, Calif., and member of the editorial advisory board for Clinical Endocrinology News. “Understanding the mechanism might help us understand the best way to treat,” COVID-19 in patients with diabetes, he said in an interview.

Dr. Rettinger, who was not involved in the research, noted that the study included only 24 patients with diabetes. Nevertheless, the finding of heightened inflammatory and coagulation markers was “fascinating.”

“This is the first paper I’ve seen [suggesting] that. I don’t know if we can extrapolate [the findings] to other populations, but if biomarkers are elevated in patients with COVID-19 and diabetes, then it’s something worth looking into, and to be aware of and cautious of. We need to pay attention to this,” he commented.

The study was led by Weina Guo and Desheng Hu at Huazhong University of Science and Technology in Wuhan, China, and published in Diabetes/Metabolism Research and Reviews.

The sample included 174 patients with COVID-19, who were treated consecutively during Feb. 10-29, 2020, at a single center. The researchers first assigned the patients to one of two groups – those with comorbid diabetes and those without. They further excluded all other comorbidities, focusing only on 26 patients with no comorbidities and 24 with only diabetes as a comorbidity, to remove all other comorbidities as possible confounding factors. Patients in the diabetes group were significantly older than those without diabetes (61 vs. 41 years, P < .01). The mortality rate was 16.5% in patients with diabetes and 0% in those without (P = .03).

COVID-19 patients with diabetes alone as a comorbidity had a greater risk for severe pneumonia, as evidenced by a higher mean CT score, compared with those without diabetes and no other comorbidities (P = .04). Patients with diabetes also had higher measures of release of tissue injury–related enzymes and were at higher risk of uncontrolled inflammation and hypercoagulable state. In particular, they had higher levels of interleukin-6 (13.7 vs. 4.1 pg/mL, respectively; P < .01), C-reactive protein (76.4 vs. 7.43 mg/L; P < .01), serum ferritin (764.8 vs. 128.9 ng/mL; P < .01), and D-dimer (1.16 vs. 0.25 mcg/mL; P < .01).

“It’s noteworthy that, for diseases that can induce a cytokine storm, IL-6 is a very good predictor of disease severity and prognosis, and its expression time is longer than other cytokines ([tumor necrosis factor] and IL-1). In addition, a significant rise in serum ferritin indicates the activation of the monocyte-macrophage system, which is a crucial part of inflammatory storm. These results indicate that patients with diabetes are susceptible to form an inflammatory storm, which eventually lead to rapid deterioration of COVID-19,” the authors wrote.

They also cited previous findings suggesting that coronavirus might exacerbate, or even cause, diabetes by seriously damaging islets (Acta Diabetol. 2010;47[3]:193-9). “Since viral infection may cause sharp fluctuation of the blood glucose levels of diabetes patients, which adversely affect the recovery of patients, there is reason to suspect that diabetes combined with SARS-CoV-2 pneumonia may form a vicious circle,” they wrote.

That’s one more reason to carefully monitor diabetes patients, said Dr. Rettinger. “Those patients who are able to make insulin might not be able to do so with the infection, and that may last a while, and they may require insulin. You want to keep a watch on things, and if oral agents are not working well, you want to go to insulin as quickly as you can. Probably diabetics should be way more careful and maybe visit the emergency department at earlier than a nondiabetic would.”

Raghavendra Mirmira, MD, PhD, who conducts translational research on diabetes and insulin production, said that the finding was not a complete surprise to him. “With a lot of diseases, having diabetes as a comorbidity can mean worse outcomes, and that’s certainly true of influenza. It was true for the other COVID-like illnesses, such as SARS and MERS,” Dr. Mirmira, who was not involved in the research, said in an interview.

If the findings hold up in larger numbers of patients and across multiple centers, they have the potential to inform patient management, said Dr. Mirmira, director of the Translational Research Center in the department of medicine at the University of Chicago. That will be especially true as data from long-term follow-up of become available. Elevated values in some biomarkers might dictate a patient be sent straight to the ICU or dictate admission to the hospital rather than being sent home, or it could assist patient selection for some of the new therapies that physicians hope will become available.

“The more information we get [about] total outcome, the more informed we’d be about who would benefit from some of the therapies that are in clinical trials now,” he said. Still, it will be a challenge to prove causation, because patients with diabetes have unique clinical characteristics that could also be the source of the difference.

Dr. Mirmira noted that patients with diabetes only were 20 years older on average than those with no comorbidities. “It’s really hard to know if what you’re looking at for the worse outcomes for people with diabetes is because they were older, and we know that older people tend to do much worse with COVID than younger people.” Ideally, patients would also be matched by age, but there are not enough data to do that yet.

The study was funded by the China National Natural Science Foundation. The authors reported no conflicts of interest. Dr. Rettinger has no relevant financial disclosures. Dr. Mirmira is on scientific advisory boards for Veralox Therapeutics, Sigilon Therapeutics, the Indiana Biosciences Research Institute, and the Juvenile Diabetes Research Foundation.
 

SOURCE: Guo W et al. Diabetes Metab Res Rev. 2020 Mar 31. doi: 10.1002/dmrr.3319.

COVID-19 infection in patients with type 2 diabetes is associated with a greater increase in inflammatory and coagulation markers, compared with COVID-19 patients without diabetes, according to preliminary findings from a retrospective analysis of COVID-19 patients in Wuhan, China.

The results, though preliminary, could help explain why patients with diabetes and COVID-19 are at greater risk for more severe disease and death.

The results also suggest that more severe disease in patients with diabetes may be the result of a cytokine storm, in which the patient’s immune system overreacts to the virus and inflicts collateral damage on its own organs, according to Herbert I. Rettinger, MD, a clinical endocrinologist in Orange County, Calif., and member of the editorial advisory board for Clinical Endocrinology News. “Understanding the mechanism might help us understand the best way to treat,” COVID-19 in patients with diabetes, he said in an interview.

Dr. Rettinger, who was not involved in the research, noted that the study included only 24 patients with diabetes. Nevertheless, the finding of heightened inflammatory and coagulation markers was “fascinating.”

“This is the first paper I’ve seen [suggesting] that. I don’t know if we can extrapolate [the findings] to other populations, but if biomarkers are elevated in patients with COVID-19 and diabetes, then it’s something worth looking into, and to be aware of and cautious of. We need to pay attention to this,” he commented.

The study was led by Weina Guo and Desheng Hu at Huazhong University of Science and Technology in Wuhan, China, and published in Diabetes/Metabolism Research and Reviews.

The sample included 174 patients with COVID-19, who were treated consecutively during Feb. 10-29, 2020, at a single center. The researchers first assigned the patients to one of two groups – those with comorbid diabetes and those without. They further excluded all other comorbidities, focusing only on 26 patients with no comorbidities and 24 with only diabetes as a comorbidity, to remove all other comorbidities as possible confounding factors. Patients in the diabetes group were significantly older than those without diabetes (61 vs. 41 years, P < .01). The mortality rate was 16.5% in patients with diabetes and 0% in those without (P = .03).

COVID-19 patients with diabetes alone as a comorbidity had a greater risk for severe pneumonia, as evidenced by a higher mean CT score, compared with those without diabetes and no other comorbidities (P = .04). Patients with diabetes also had higher measures of release of tissue injury–related enzymes and were at higher risk of uncontrolled inflammation and hypercoagulable state. In particular, they had higher levels of interleukin-6 (13.7 vs. 4.1 pg/mL, respectively; P < .01), C-reactive protein (76.4 vs. 7.43 mg/L; P < .01), serum ferritin (764.8 vs. 128.9 ng/mL; P < .01), and D-dimer (1.16 vs. 0.25 mcg/mL; P < .01).

“It’s noteworthy that, for diseases that can induce a cytokine storm, IL-6 is a very good predictor of disease severity and prognosis, and its expression time is longer than other cytokines ([tumor necrosis factor] and IL-1). In addition, a significant rise in serum ferritin indicates the activation of the monocyte-macrophage system, which is a crucial part of inflammatory storm. These results indicate that patients with diabetes are susceptible to form an inflammatory storm, which eventually lead to rapid deterioration of COVID-19,” the authors wrote.

They also cited previous findings suggesting that coronavirus might exacerbate, or even cause, diabetes by seriously damaging islets (Acta Diabetol. 2010;47[3]:193-9). “Since viral infection may cause sharp fluctuation of the blood glucose levels of diabetes patients, which adversely affect the recovery of patients, there is reason to suspect that diabetes combined with SARS-CoV-2 pneumonia may form a vicious circle,” they wrote.

That’s one more reason to carefully monitor diabetes patients, said Dr. Rettinger. “Those patients who are able to make insulin might not be able to do so with the infection, and that may last a while, and they may require insulin. You want to keep a watch on things, and if oral agents are not working well, you want to go to insulin as quickly as you can. Probably diabetics should be way more careful and maybe visit the emergency department at earlier than a nondiabetic would.”

Raghavendra Mirmira, MD, PhD, who conducts translational research on diabetes and insulin production, said that the finding was not a complete surprise to him. “With a lot of diseases, having diabetes as a comorbidity can mean worse outcomes, and that’s certainly true of influenza. It was true for the other COVID-like illnesses, such as SARS and MERS,” Dr. Mirmira, who was not involved in the research, said in an interview.

If the findings hold up in larger numbers of patients and across multiple centers, they have the potential to inform patient management, said Dr. Mirmira, director of the Translational Research Center in the department of medicine at the University of Chicago. That will be especially true as data from long-term follow-up of become available. Elevated values in some biomarkers might dictate a patient be sent straight to the ICU or dictate admission to the hospital rather than being sent home, or it could assist patient selection for some of the new therapies that physicians hope will become available.

“The more information we get [about] total outcome, the more informed we’d be about who would benefit from some of the therapies that are in clinical trials now,” he said. Still, it will be a challenge to prove causation, because patients with diabetes have unique clinical characteristics that could also be the source of the difference.

Dr. Mirmira noted that patients with diabetes only were 20 years older on average than those with no comorbidities. “It’s really hard to know if what you’re looking at for the worse outcomes for people with diabetes is because they were older, and we know that older people tend to do much worse with COVID than younger people.” Ideally, patients would also be matched by age, but there are not enough data to do that yet.

The study was funded by the China National Natural Science Foundation. The authors reported no conflicts of interest. Dr. Rettinger has no relevant financial disclosures. Dr. Mirmira is on scientific advisory boards for Veralox Therapeutics, Sigilon Therapeutics, the Indiana Biosciences Research Institute, and the Juvenile Diabetes Research Foundation.
 

SOURCE: Guo W et al. Diabetes Metab Res Rev. 2020 Mar 31. doi: 10.1002/dmrr.3319.

Average measures of bone mineral density were similar for individuals with high-trauma and low-trauma fractures, and both were significantly distinct from those with no fracture history, based on data from a cohort study of adults aged 40 years and older.

©eranicle/Thinkstock

In the past, low-trauma fractures have typically been associated with osteoporosis, wrote William D. Leslie, MD, of the University of Manitoba, Canada, and his colleagues. However, features distinguishing between low- and high-trauma fractures are often arbitrary and “empirical data have questioned whether distinguishing low-trauma from high-trauma fractures is clinically useful for purposes of risk assessment and treatment,” they wrote.

In a study published in Osteoporosis International, the researchers reviewed data from 64,626 individuals with no prior fracture, 858 with high-trauma fractures, and 14,758 with low-trauma fractures. Overall, the average BMD Z-scores for individuals with no previous fracture were slightly positive, while those with either a high-trauma or low-trauma fracture were negative. The scores for individuals with high-trauma fractures or major osteoporotic fractures were similar to those with low-trauma fractures, and significantly lower (P less than .001) than among individuals with no prior fractures.

The study population included adults aged 40 years and older with baseline DXA scans between Jan. 1, 1996, and Mar. 31, 2016. Those with high-trauma fractures were younger than those with low-trauma fractures (65 years vs. 67 years), and fewer individuals with high-trauma fractures were women (77% vs. 87%).

Both high-trauma and low-trauma fractures were similarly and significantly associated with increased risk for incident major osteoporotic fractures (adjusted hazard ratios 1.31 and 1.55, respectively).

The study findings were limited by several factors including incomplete data on external injury codes, the retrospective study design, and the lack of analysis of the time since prior fractures, the researchers noted. However, the results were strengthened by the large sample size, long-term follow-up, and large numbers of incident fractures, they wrote.

The results support data from previous studies and support “the inclusion of high-trauma clinical fractures in clinical assessment for underlying osteoporosis and in the evaluation for intervention to reduce future fracture risk,” they wrote.

In an accompanying editorial, Steven R. Cummings, MD, of California Pacific Medical Center Research Institute, San Francisco, and Richard Eastell, MD, of the University of Sheffield, England, wrote that the practice of rating fractures according to degree of trauma should be eliminated.

“The study adds evidence to the case that it is time to abandon the mistaken beliefs that fractures rated as high trauma are not associated with decreased BMD, indicate no higher risk of subsequent fracture, or are less likely to be prevented by treatments for osteoporosis,” they wrote.

Describing some fractures as due to trauma reinforces the mistaken belief that the fractures are simply due to the trauma, not decreased bone strength, they noted.

“Indeed, we recommend that people stop attempting to rate or record degree of trauma because such ratings are at best inaccurate and would promote the continued neglect of those patients who are misclassified as having fractures that do not warrant evaluation and treatment,” they concluded.

The study received no outside funding. Dr. Leslie, the study’s first author, reported having no financial conflicts to disclose.

Dr. Cummings disclosed consultancy and grant funding from Amgen and Radius. Dr. Eastell disclosed consultancy funding from IDS, Roche Diagnostics, GSK Nutrition, FNIH, Mereo, Lilly, Sandoz, Nittobo, Abbvie, Samsung, and Haoma Medica and grant funding from Nittobo, IDS, Roche, Amgen, and Alexion.

SOURCE: Leslie WD et al. Osteroporos Int. 2020 Mar 16. doi: 10.1007/s00198-019-05274-2.

Average measures of bone mineral density were similar for individuals with high-trauma and low-trauma fractures, and both were significantly distinct from those with no fracture history, based on data from a cohort study of adults aged 40 years and older.

©eranicle/Thinkstock

In the past, low-trauma fractures have typically been associated with osteoporosis, wrote William D. Leslie, MD, of the University of Manitoba, Canada, and his colleagues. However, features distinguishing between low- and high-trauma fractures are often arbitrary and “empirical data have questioned whether distinguishing low-trauma from high-trauma fractures is clinically useful for purposes of risk assessment and treatment,” they wrote.

In a study published in Osteoporosis International, the researchers reviewed data from 64,626 individuals with no prior fracture, 858 with high-trauma fractures, and 14,758 with low-trauma fractures. Overall, the average BMD Z-scores for individuals with no previous fracture were slightly positive, while those with either a high-trauma or low-trauma fracture were negative. The scores for individuals with high-trauma fractures or major osteoporotic fractures were similar to those with low-trauma fractures, and significantly lower (P less than .001) than among individuals with no prior fractures.

The study population included adults aged 40 years and older with baseline DXA scans between Jan. 1, 1996, and Mar. 31, 2016. Those with high-trauma fractures were younger than those with low-trauma fractures (65 years vs. 67 years), and fewer individuals with high-trauma fractures were women (77% vs. 87%).

Both high-trauma and low-trauma fractures were similarly and significantly associated with increased risk for incident major osteoporotic fractures (adjusted hazard ratios 1.31 and 1.55, respectively).

The study findings were limited by several factors including incomplete data on external injury codes, the retrospective study design, and the lack of analysis of the time since prior fractures, the researchers noted. However, the results were strengthened by the large sample size, long-term follow-up, and large numbers of incident fractures, they wrote.

The results support data from previous studies and support “the inclusion of high-trauma clinical fractures in clinical assessment for underlying osteoporosis and in the evaluation for intervention to reduce future fracture risk,” they wrote.

In an accompanying editorial, Steven R. Cummings, MD, of California Pacific Medical Center Research Institute, San Francisco, and Richard Eastell, MD, of the University of Sheffield, England, wrote that the practice of rating fractures according to degree of trauma should be eliminated.

“The study adds evidence to the case that it is time to abandon the mistaken beliefs that fractures rated as high trauma are not associated with decreased BMD, indicate no higher risk of subsequent fracture, or are less likely to be prevented by treatments for osteoporosis,” they wrote.

Describing some fractures as due to trauma reinforces the mistaken belief that the fractures are simply due to the trauma, not decreased bone strength, they noted.

“Indeed, we recommend that people stop attempting to rate or record degree of trauma because such ratings are at best inaccurate and would promote the continued neglect of those patients who are misclassified as having fractures that do not warrant evaluation and treatment,” they concluded.

The study received no outside funding. Dr. Leslie, the study’s first author, reported having no financial conflicts to disclose.

Dr. Cummings disclosed consultancy and grant funding from Amgen and Radius. Dr. Eastell disclosed consultancy funding from IDS, Roche Diagnostics, GSK Nutrition, FNIH, Mereo, Lilly, Sandoz, Nittobo, Abbvie, Samsung, and Haoma Medica and grant funding from Nittobo, IDS, Roche, Amgen, and Alexion.

SOURCE: Leslie WD et al. Osteroporos Int. 2020 Mar 16. doi: 10.1007/s00198-019-05274-2.

Average measures of bone mineral density were similar for individuals with high-trauma and low-trauma fractures, and both were significantly distinct from those with no fracture history, based on data from a cohort study of adults aged 40 years and older.

©eranicle/Thinkstock

In the past, low-trauma fractures have typically been associated with osteoporosis, wrote William D. Leslie, MD, of the University of Manitoba, Canada, and his colleagues. However, features distinguishing between low- and high-trauma fractures are often arbitrary and “empirical data have questioned whether distinguishing low-trauma from high-trauma fractures is clinically useful for purposes of risk assessment and treatment,” they wrote.

In a study published in Osteoporosis International, the researchers reviewed data from 64,626 individuals with no prior fracture, 858 with high-trauma fractures, and 14,758 with low-trauma fractures. Overall, the average BMD Z-scores for individuals with no previous fracture were slightly positive, while those with either a high-trauma or low-trauma fracture were negative. The scores for individuals with high-trauma fractures or major osteoporotic fractures were similar to those with low-trauma fractures, and significantly lower (P less than .001) than among individuals with no prior fractures.

The study population included adults aged 40 years and older with baseline DXA scans between Jan. 1, 1996, and Mar. 31, 2016. Those with high-trauma fractures were younger than those with low-trauma fractures (65 years vs. 67 years), and fewer individuals with high-trauma fractures were women (77% vs. 87%).

Both high-trauma and low-trauma fractures were similarly and significantly associated with increased risk for incident major osteoporotic fractures (adjusted hazard ratios 1.31 and 1.55, respectively).

The study findings were limited by several factors including incomplete data on external injury codes, the retrospective study design, and the lack of analysis of the time since prior fractures, the researchers noted. However, the results were strengthened by the large sample size, long-term follow-up, and large numbers of incident fractures, they wrote.

The results support data from previous studies and support “the inclusion of high-trauma clinical fractures in clinical assessment for underlying osteoporosis and in the evaluation for intervention to reduce future fracture risk,” they wrote.

In an accompanying editorial, Steven R. Cummings, MD, of California Pacific Medical Center Research Institute, San Francisco, and Richard Eastell, MD, of the University of Sheffield, England, wrote that the practice of rating fractures according to degree of trauma should be eliminated.

“The study adds evidence to the case that it is time to abandon the mistaken beliefs that fractures rated as high trauma are not associated with decreased BMD, indicate no higher risk of subsequent fracture, or are less likely to be prevented by treatments for osteoporosis,” they wrote.

Describing some fractures as due to trauma reinforces the mistaken belief that the fractures are simply due to the trauma, not decreased bone strength, they noted.

“Indeed, we recommend that people stop attempting to rate or record degree of trauma because such ratings are at best inaccurate and would promote the continued neglect of those patients who are misclassified as having fractures that do not warrant evaluation and treatment,” they concluded.

The study received no outside funding. Dr. Leslie, the study’s first author, reported having no financial conflicts to disclose.

Dr. Cummings disclosed consultancy and grant funding from Amgen and Radius. Dr. Eastell disclosed consultancy funding from IDS, Roche Diagnostics, GSK Nutrition, FNIH, Mereo, Lilly, Sandoz, Nittobo, Abbvie, Samsung, and Haoma Medica and grant funding from Nittobo, IDS, Roche, Amgen, and Alexion.

SOURCE: Leslie WD et al. Osteroporos Int. 2020 Mar 16. doi: 10.1007/s00198-019-05274-2.

Nearly one in five individuals with cancer who are treated with immune checkpoint inhibitors develop thyroid dysfunction, new research suggests.

Sebastian Kaulitzki/Fotolia

Immune checkpoint inhibitors have revolutionized the treatment of many different types of cancers, but can also trigger a variety of immune-related adverse effects. As these drugs become more widely used, rates of these events appear to be more common in the real-world compared with clinical trial settings.

In their new study, Zoe Quandt, MD, of the University of California, San Francisco (UCSF), and colleagues specifically looked at thyroid dysfunction in their own institution’s EHR data and found more than double the rate of hypothyroidism and more than triple the rate of hyperthyroidism, compared with rates in published trials.

Moreover, in contrast to previous studies that have found differences in thyroid dysfunction by checkpoint inhibitor type, Dr. Quandt and colleagues instead found significant differences by cancer type.

Dr. Quandt presented the findings during a virtual press briefing held March 31originally scheduled for ENDO 2020.

“Thyroid dysfunction following checkpoint inhibitor therapy appears to be much more common than was previously reported in clinical trials, and this is one of the first studies to show differences by cancer type rather than by checkpoint inhibitor type,” Dr. Quandt said during the presentation.

However, she also cautioned that there’s “a lot more research to be done to validate case definitions and validate these findings.”

Asked to comment, endocrinologist David C. Lieb, MD, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said in an interview, “These drugs are becoming so much more commonly used, so it’s not surprising that we’re seeing more endocrine complications, especially thyroid disease.”

“Endocrinologists need to work closely with oncologists to make sure patients are being screened and followed appropriately.”

‘A much higher percentage than we were expecting’

Dr. Quandt’s study included 1,146 individuals treated with checkpoint inhibitors at UCSF during 2012-2018 who did not have thyroid cancer or preexisting thyroid dysfunction.

Pembrolizumab (Keytruda) was the most common treatment (45%), followed by nivolumab (Opdivo) (20%). Less than 10% of patients received atezolizumab (Tecentriq), durvalumab (Imfizi), ipilimumab (Yervoy) monotherapy, combined ipilimumab/nivolumab, or other combinations of checkpoint inhibitors.

A total of 19.1% developed thyroid disease, with 13.4% having hypothyroidism and 9.5% hyperthyroidism. These figures far exceed those found in a recent meta-analysis of 38 randomized clinical trials of checkpoint inhibitors that included 7551 patients.

“Using this approach, we found a much higher percentage of patients who developed thyroid dysfunction than we were expecting,” Dr. Quandt said.

In both cases, the two categories – hypothyroidism and hyperthyroidism – aren’t mutually exclusive as hypothyroidism can arise de novo or subsequent to hyperthyroidism.

Dr Lieb commented, “It would be interesting to see what the causes of hyperthyroidism are – thyroiditis or Graves disease.”

Dr. Quandt mentioned a possible reason for the large difference between clinical trial and real-world data.

“Once we’re actually using these drugs outside of clinical trials, some of the restrictions about using them in people with other autoimmune diseases have been lifted, so my guess is that as we give them to a broader population we’re seeing more of these [adverse effects],” she suggested.

Also, “In the initial trials, people weren’t quite as aware of the possibilities of these side effects, so now we’re doing many more labs. Patients get thyroid function tests with every infusion, so I think we’re probably catching more patients who develop disease.”
 

Differences by cancer type, not checkpoint inhibitor type

And in a new twist, Dr. Quandt found that, in contrast to the differences seen by checkpoint inhibitor type in randomized trials, “surprisingly, we found that this difference did not reach statistical significance.”

“Instead, we saw that cancer type was associated with development of thyroid dysfunction, even after taking checkpoint inhibitor type into account.”

The percentages of patients who developed thyroid dysfunction ranged from 9.7% of those with glioblastoma to 40.0% of those with renal cell carcinoma.

The reason for this is not clear, said Dr. Quandt in an interview.

One possibility relates to other treatments patients with cancer also receive. In renal cell carcinoma, for example, patients also are treated with tyrosine kinase inhibitors, which can also cause thyroid dysfunction, so they may be more susceptible. Or there may be shared antigens activating the immune system.

“That’s definitely one of the questions we’re looking at,” she said.

Dr. Quandt and Dr. Lieb have reported no relevant financial relationships.

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

Nearly one in five individuals with cancer who are treated with immune checkpoint inhibitors develop thyroid dysfunction, new research suggests.

Sebastian Kaulitzki/Fotolia

Immune checkpoint inhibitors have revolutionized the treatment of many different types of cancers, but can also trigger a variety of immune-related adverse effects. As these drugs become more widely used, rates of these events appear to be more common in the real-world compared with clinical trial settings.

In their new study, Zoe Quandt, MD, of the University of California, San Francisco (UCSF), and colleagues specifically looked at thyroid dysfunction in their own institution’s EHR data and found more than double the rate of hypothyroidism and more than triple the rate of hyperthyroidism, compared with rates in published trials.

Moreover, in contrast to previous studies that have found differences in thyroid dysfunction by checkpoint inhibitor type, Dr. Quandt and colleagues instead found significant differences by cancer type.

Dr. Quandt presented the findings during a virtual press briefing held March 31originally scheduled for ENDO 2020.

“Thyroid dysfunction following checkpoint inhibitor therapy appears to be much more common than was previously reported in clinical trials, and this is one of the first studies to show differences by cancer type rather than by checkpoint inhibitor type,” Dr. Quandt said during the presentation.

However, she also cautioned that there’s “a lot more research to be done to validate case definitions and validate these findings.”

Asked to comment, endocrinologist David C. Lieb, MD, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said in an interview, “These drugs are becoming so much more commonly used, so it’s not surprising that we’re seeing more endocrine complications, especially thyroid disease.”

“Endocrinologists need to work closely with oncologists to make sure patients are being screened and followed appropriately.”

‘A much higher percentage than we were expecting’

Dr. Quandt’s study included 1,146 individuals treated with checkpoint inhibitors at UCSF during 2012-2018 who did not have thyroid cancer or preexisting thyroid dysfunction.

Pembrolizumab (Keytruda) was the most common treatment (45%), followed by nivolumab (Opdivo) (20%). Less than 10% of patients received atezolizumab (Tecentriq), durvalumab (Imfizi), ipilimumab (Yervoy) monotherapy, combined ipilimumab/nivolumab, or other combinations of checkpoint inhibitors.

A total of 19.1% developed thyroid disease, with 13.4% having hypothyroidism and 9.5% hyperthyroidism. These figures far exceed those found in a recent meta-analysis of 38 randomized clinical trials of checkpoint inhibitors that included 7551 patients.

“Using this approach, we found a much higher percentage of patients who developed thyroid dysfunction than we were expecting,” Dr. Quandt said.

In both cases, the two categories – hypothyroidism and hyperthyroidism – aren’t mutually exclusive as hypothyroidism can arise de novo or subsequent to hyperthyroidism.

Dr Lieb commented, “It would be interesting to see what the causes of hyperthyroidism are – thyroiditis or Graves disease.”

Dr. Quandt mentioned a possible reason for the large difference between clinical trial and real-world data.

“Once we’re actually using these drugs outside of clinical trials, some of the restrictions about using them in people with other autoimmune diseases have been lifted, so my guess is that as we give them to a broader population we’re seeing more of these [adverse effects],” she suggested.

Also, “In the initial trials, people weren’t quite as aware of the possibilities of these side effects, so now we’re doing many more labs. Patients get thyroid function tests with every infusion, so I think we’re probably catching more patients who develop disease.”
 

Differences by cancer type, not checkpoint inhibitor type

And in a new twist, Dr. Quandt found that, in contrast to the differences seen by checkpoint inhibitor type in randomized trials, “surprisingly, we found that this difference did not reach statistical significance.”

“Instead, we saw that cancer type was associated with development of thyroid dysfunction, even after taking checkpoint inhibitor type into account.”

The percentages of patients who developed thyroid dysfunction ranged from 9.7% of those with glioblastoma to 40.0% of those with renal cell carcinoma.

The reason for this is not clear, said Dr. Quandt in an interview.

One possibility relates to other treatments patients with cancer also receive. In renal cell carcinoma, for example, patients also are treated with tyrosine kinase inhibitors, which can also cause thyroid dysfunction, so they may be more susceptible. Or there may be shared antigens activating the immune system.

“That’s definitely one of the questions we’re looking at,” she said.

Dr. Quandt and Dr. Lieb have reported no relevant financial relationships.

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

Nearly one in five individuals with cancer who are treated with immune checkpoint inhibitors develop thyroid dysfunction, new research suggests.

Sebastian Kaulitzki/Fotolia

Immune checkpoint inhibitors have revolutionized the treatment of many different types of cancers, but can also trigger a variety of immune-related adverse effects. As these drugs become more widely used, rates of these events appear to be more common in the real-world compared with clinical trial settings.

In their new study, Zoe Quandt, MD, of the University of California, San Francisco (UCSF), and colleagues specifically looked at thyroid dysfunction in their own institution’s EHR data and found more than double the rate of hypothyroidism and more than triple the rate of hyperthyroidism, compared with rates in published trials.

Moreover, in contrast to previous studies that have found differences in thyroid dysfunction by checkpoint inhibitor type, Dr. Quandt and colleagues instead found significant differences by cancer type.

Dr. Quandt presented the findings during a virtual press briefing held March 31originally scheduled for ENDO 2020.

“Thyroid dysfunction following checkpoint inhibitor therapy appears to be much more common than was previously reported in clinical trials, and this is one of the first studies to show differences by cancer type rather than by checkpoint inhibitor type,” Dr. Quandt said during the presentation.

However, she also cautioned that there’s “a lot more research to be done to validate case definitions and validate these findings.”

Asked to comment, endocrinologist David C. Lieb, MD, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said in an interview, “These drugs are becoming so much more commonly used, so it’s not surprising that we’re seeing more endocrine complications, especially thyroid disease.”

“Endocrinologists need to work closely with oncologists to make sure patients are being screened and followed appropriately.”

‘A much higher percentage than we were expecting’

Dr. Quandt’s study included 1,146 individuals treated with checkpoint inhibitors at UCSF during 2012-2018 who did not have thyroid cancer or preexisting thyroid dysfunction.

Pembrolizumab (Keytruda) was the most common treatment (45%), followed by nivolumab (Opdivo) (20%). Less than 10% of patients received atezolizumab (Tecentriq), durvalumab (Imfizi), ipilimumab (Yervoy) monotherapy, combined ipilimumab/nivolumab, or other combinations of checkpoint inhibitors.

A total of 19.1% developed thyroid disease, with 13.4% having hypothyroidism and 9.5% hyperthyroidism. These figures far exceed those found in a recent meta-analysis of 38 randomized clinical trials of checkpoint inhibitors that included 7551 patients.

“Using this approach, we found a much higher percentage of patients who developed thyroid dysfunction than we were expecting,” Dr. Quandt said.

In both cases, the two categories – hypothyroidism and hyperthyroidism – aren’t mutually exclusive as hypothyroidism can arise de novo or subsequent to hyperthyroidism.

Dr Lieb commented, “It would be interesting to see what the causes of hyperthyroidism are – thyroiditis or Graves disease.”

Dr. Quandt mentioned a possible reason for the large difference between clinical trial and real-world data.

“Once we’re actually using these drugs outside of clinical trials, some of the restrictions about using them in people with other autoimmune diseases have been lifted, so my guess is that as we give them to a broader population we’re seeing more of these [adverse effects],” she suggested.

Also, “In the initial trials, people weren’t quite as aware of the possibilities of these side effects, so now we’re doing many more labs. Patients get thyroid function tests with every infusion, so I think we’re probably catching more patients who develop disease.”
 

Differences by cancer type, not checkpoint inhibitor type

And in a new twist, Dr. Quandt found that, in contrast to the differences seen by checkpoint inhibitor type in randomized trials, “surprisingly, we found that this difference did not reach statistical significance.”

“Instead, we saw that cancer type was associated with development of thyroid dysfunction, even after taking checkpoint inhibitor type into account.”

The percentages of patients who developed thyroid dysfunction ranged from 9.7% of those with glioblastoma to 40.0% of those with renal cell carcinoma.

The reason for this is not clear, said Dr. Quandt in an interview.

One possibility relates to other treatments patients with cancer also receive. In renal cell carcinoma, for example, patients also are treated with tyrosine kinase inhibitors, which can also cause thyroid dysfunction, so they may be more susceptible. Or there may be shared antigens activating the immune system.

“That’s definitely one of the questions we’re looking at,” she said.

Dr. Quandt and Dr. Lieb have reported no relevant financial relationships.

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

AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.

DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.

The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.

Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.

“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.

[email protected]

AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.

DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.

The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.

Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.

“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.

[email protected]

AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.

DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.

The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.

Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.

“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.

[email protected]

From Northwell Health System, Lake Success, NY.

Abstract

• Objective: To explore factors associated with lower-extremity amputation (LEA) in patients with diabetic foot ulcers using data from the Online Wound Electronic Medical Record Database.
• Design: Retrospective analysis of medical records.
• Setting and participants: Data from 169 individuals with previously diagnosed diabetes mellitus who received wound care for a 6-month period within a span of 2 years was analyzed. A baseline evaluation was obtained and wound(s) were treated, managed, and monitored. Treatment continued until the patient healed, required an LEA, or phased out of the study, neither healing nor undergoing an amputation. Of the 149 patients who completed the study, 38 had healed ulcers, 14 underwent amputation, and 97 neither healed nor underwent an amputation. All patients were treated under the care of vascular and/or podiatric surgeons.
• Measurements: Variables included wound status (healed, amputated, and unhealed/non-amputated); size of wound area; age, gender, race, and ethnicity; white blood cell (WBC) count, hemoglobin A1c (HbA1c), blood glucose, and body mass index (BMI); and presence of osteomyelitis, gangrene, and peripheral vascular disease.
• Results: As compared to the healed and unhealed/non-amputated group, the group of patients who underwent LEA was older and had higher percentages of males, Hispanics, and African Americans; had a higher WBC count, larger wound area, and higher rates of wound infection, osteomyelitis, and neuropathy; and had lower average values of HbA1c, blood glucose, and BMI and a lower rate of peripheral vascular disease.
• Conclusion: The association between HbA1c and LEA highlights a window of relative safety among an at-risk population. By identifying and focusing on factors associated with LEA, health care professionals may be able to decrease the prevalence of LEA in patients with diabetes.

Keywords: diabetic foot ulcer; lower-extremity amputation; risk factors; HbA1c.

An estimated 30.3 million people, or 9.4% of the US population, has diabetes. In 2014, approximately 108,000 amputations were performed on adults with diagnosed diabetes.¹ Furthermore, patients with diabetes have a 10-fold increased risk for lower-extremity amputation (LEA), as compared with patients without diabetes.² The frequency of amputations in the diabetic population is a public health crisis.

Amputation has significant, life-altering consequences. Patients who undergo LEA often face debilitation in their daily activities and must undergo intense rehabilitation to learn basic tasks. Amputations can also impact individuals’ psychological well-being as they come to terms with their altered body and may face challenges in self-perception, confidence, self-esteem, work life, and relationships. In addition, the mortality rate for patients with diabetes 5 years after undergoing LEA is 30%.² However, public health studies estimate that more than half of LEAs in patients with diabetes are preventable.³

Although studies have explored the relationship between diabetes and LEA, few have sought to identify factors directly correlated with wound care. In the United States, patients with diabetic ulcerations are typically treated in wound care facilities; however, previous studies have concentrated on the conditions that lead to the formation of an ulcer or amputation, viewing amputation and ulcer as 2 separate entities. Our study took into account systemic variables, patient demographics, and specific wound characteristics to explore factors associated with LEA in a high-risk group of patients with diabetes. This study was designed to assess ailments that are prevalent in patients who require a LEA.

Methods

Patients and Setting

A total of 169 patients who were treated at the Comprehensive Wound Healing and Hyperbaric Center (Lake Success, NY), a tertiary facility of the Northwell Health system, participated in this retrospective study. The data for this study were obtained in conjunction with the development of the New York University School of Medicine’s Online Wound Electronic Medical Record to Decrease Limb Amputations in Persons with Diabetes (OWEMR) database. The OWEMR collects individual patient data from satellite locations across the country. Using this database, researchers can analyze similarities and differences between patients who undergo LEA.

This study utilized patient data specific to the Northwell Health facility. All of the patients in our study were enrolled under the criteria of the OWEMR database. In order to be included in the OWEMR database, patients had to be diagnosed with type 1 or type 2 diabetes; have a break in the skin ≥ 0.5 cm²; be 18 years of age or older; and have a measured hemoglobin A1c (HbA1c) value within the past 120 days. Study patients signed an informed consent and committed to being available for follow-up visits to the wound care facility for 6 months after entering the study. Patients were enrolled between 2012 and 2014, and each patient was monitored for a period of 6 months within this time period. Participants were treated with current standards of care using diet, lifestyle, and pharmacologic interventions. This study was approved by the Northwell Health System Institutional Review Board Human Research Protection Program (Manhasset, NY).

Data Collection

On their first visit to the facility, patients were given a physical examination and initial interview regarding their medical history. Clinicians were required to select 1 ulcer that would be examined for the duration of the study. The selection of the ulcer was based on a point system that awarded points for pedal pulses, the ability to be probed to the bone, the location of the ulcer (ie, located on the foot rather than a toe), and the presence of multiple ulcerations. The ulcer with the highest score was selected for the study. If numerous ulcers were evaluated with the same score, the largest and deepest was selected. Wagner classification of the wound was recorded at baseline and taken at each subsequent patient visit. In addition, peripheral sensation was assessed for signs of neuropathy using Semmes-Weinstein monofilament testing.

Once selected, the wound was clinically evaluated, samples for culture were obtained, and blood tests were performed to detect the presence of wound infection. The patient’s blood was drawn for a full laboratory analysis, including white blood cell (WBC) count and measurement of blood glucose and HbA1c levels. Bone biopsy, magnetic resonance imaging, and bone scans were used to detect the presence of osteomyelitis at the discretion of the health care provider. Wounds suspected of infection, underlying osteomyelitis, or gangrene at baseline were excluded. Patients would then return for follow-up visits at least once every 6 weeks, plus or minus 2 weeks, for a maximum of 6 months.

Statistical Analysis

Utilizing SAS version 9.3 (Cary, NC), descriptive statistics (minimum, maximum, mean, median, and SD) were calculated for the following variables: age, WBC count, wound area, HbA1c, blood glucose, and body mass index (BMI). These variables were collected for each patient as per the OWEMR protocol and provided a basis for which to compare patients who underwent amputation and those who did not. Twenty patients were lost to follow-up, and therefore we altered the window of our statistics from 6 months to 3 months to provide the most accurate data, as 6-month follow-up data were limited. The patients were classified into the following categories: healed, amputated, and unhealed/non-amputated. Descriptive statistics were calculated for these 3 groups, analyzing the same variables (age, WBC count, wound area, HbA1c, blood glucose, and BMI). Additional statistical computations were utilized in order to show the prevalence and frequency of our categorical variables: gender, race, ethnicity, osteomyelitis, gangrene, and peripheral vascular disease. The baseline values of WBC count, HbA1c, wound area, and BMI of the 3 groups were analyzed with descriptive statistics for comparison. A multinomial logistic regression was then performed using a 3-level outcome variable: healed, amputated, or unhealed/non-amputated. Each predictor variable was analyzed independently due to the small sample size.

Results

Of the 169 registered patients treated at the Northwell Health facility, all qualified for the OWEMR study and met the study criteria. In the original 169 patients, there were 19 amputations: 6 toe, 6 trans-metatarsal, 6 below knee, and 1 above knee (Table 1).

The descriptive statistics of 149 patients grouped into 3 categories (healed, amputated, unhealed/non-amputated) are shown in Table 2.

The results of the logistic regression exploring the differences between the amputation and healed groups and the unhealed/non-amputated group are shown in Table 3. The amputation group had a higher mean age and WBC count and greater wound area. Increased age was determined to be a significant predictor of the odds of amputation (P = 0.0089). For each year increase in age, the odds of amputation increased by 6.5% (odds ratio, 1.07 [95% confidence interval {CI}, 1.02-1.12]). Patients in the amputation group were more likely to be male, Hispanic, and African American and to have wound infections and comorbidities (osteomyelitis, neuropathy, and gangrene).

The presence of gangrene was significantly associated with LEA (P = 0.03). Specifically, the odds of patients without gangrene undergoing a LEA were substantially lower compared with their counterparts with gangrene (odds ratio, 0.17; 95% CI, 0.04-0.68; P = 0.0131). However, the presence of gangrene was not associated with the odds of healing compared with the odds of neither healing nor undergoing amputation (P = 0.84; not shown in Table 3).

The amputation group had lower mean values for HbA1c, BMI, and blood glucose levels and a lower rate of peripheral vascular disease. Only the relationship between lower HbA1c and increased odds of amputation versus not healing/non-amputation was found to be statistically significant (95% CI, 0.27-0.78; P = 0.009).

Discussion

This retrospective study was undertaken to evaluate factors associated with LEA in patients with diabetic foot ulcers. Patients with diabetes being treated at a wound care facility often require continuous surgical and metabolic intervention to promote optimal healing: drainage, surgical debridement, irrigation, culturing for infection, and monitoring of blood glucose levels. This treatment requires strict compliance with medical directions and, oftentimes, additional care, such as home-care nursing visits, to maintain a curative environment for the wound. Frequently, wounds on the lower extremity further complicate the healing process by reducing the patient’s mobility and daily life. Due to these factors, many patients progress to LEA. The link between diabetic ulcers and amputation has already been well described in previous studies, with studies showing that history of diabetic foot ulcer significantly predisposes an individual to LEA.⁴ However, few studies have further investigated demographic factors associated with risk for an amputation. Our study analyzed several categories of patient data taken from a baseline visit. We found that those with highly elevated HbA1c values were less likely to have an amputation than persons with relatively lower levels, a finding that is contrary to previous studies.

Our study’s findings suggest a higher risk for LEA with increased age. The amputation group was, on average, 7 years older than the other 2 groups. A recent study showed that risk for amputation is directly correlated to patient age, as is the mortality rate after undergoing LEA (2.3%; P < 0.05).⁵ Our study found that with each increase in age of 1 year, the odds of amputation increased by 6.5%. However, recent evidence on LEA risk and aging suggests that age is of less consequence than the duration of diabetes. One study found that the propensity to develop diabetic foot ulcers increases with the duration of diabetes.⁶ The same study found that prevalence of ulceration was correlated with age, but the relationship between age and LEA was less significant. A follow-up study for LEA could be done to examine the role of disease duration versus age in LEA.

A consensus among previous studies is that men have a higher risk for LEA.^5,7 Men comprised the majority in all 3 groups in our study. In addition, the amputation group in our study had the lowest BMI. Higher BMI generally is associated with an increased risk for health complications. However, a past study conducted in Taiwan reported that obese patients with diabetes were less likely to undergo LEA than those within the normal range for BMI.⁸ Neither study suggests that obesity is a deterrent for LEA, but both studies may suggest that risk of amputation may approach a maximum frequency at a specific BMI range, and then decrease. This unconfirmed “cyclic” relationship should be evaluated further in a larger sample size.

Most patients in our analysis were Caucasian, followed by African American and South Asian. African Americans were the only racial group with an increased frequency in the amputation group. This finding is supported by a previous study that found that the rate of LEA among patients with diabetes in low-income, predominantly African-American neighborhoods was nearly double that in wealthier, predominantly Caucasian areas.⁹ A potential problem in the comparison between our data with previous studies is that the studies did not analyze patients with our inclusion criteria. All patients with diabetes in previous investigations were grouped by race, but were not necessarily required to have 1 or more ulcers. Multiple ulcers may predispose an individual to a greater risk for amputation.

Multinomial logistic regression did not suggest an association between initial size of a patient’s wound and the risk of amputation. However, the descriptive data suggests a trend. Patients who did not heal or require an amputation had the largest average wound area. This finding is not surprising in that our study followed individuals for only 3 months. Many wounds require a long course of treatment, especially in patients with diabetes, who may have poor vascularization. However, in comparison to the healed patients, the patients who required an amputation had a larger average wound area. A larger wound requires a plentiful vascular supply for the delivery of clotting factors and nutrients to the damaged area. As wound size increases, an individual’s body must transmit an increased quantity of these factors and nutrients for the regeneration of tissue. In addition, wounds that possess a larger surface area require more debridement and present a greater opportunity for infection. This may also foreshadow a longer, more costly course of treatment. Additionally, individuals coping with large ulcerations are burdened by more elaborate and complex wound dressings.

Elevated levels of HbA1c are associated with increased adverse effects of diabetes, including end-stage renal disease, neuropathy, and infection.¹⁰ In a previous study, the risk for amputation was 1.2 times higher in patients with elevated HbA1c.¹¹ In contrast, our study suggested the odds of LEA versus not healing/not undergoing amputation decreased as HbA1c increased. As a patient’s HbA1c level increased by a value of 1, their odds for LEA decreased by 54.3%. This finding contradicts prior studies that have found a positive association between HbA1c and LEA risk, including a study where each percentage increase in HbA1c correlated with a 13% to 15% increased risk of LEA.¹² The finding that patients who underwent amputation in our study had lower levels of HbA1c and blood glucose cannot be fully explained. The maximum HbA1c value in the amputated group was 7.9%. The average values for healed patients and those who underwent LEA were 8.75% and 6.77%, respectively.

Blood glucose levels were also found to be the lowest in the amputated group in our study (mean, 149.29 mg/dL vs 163.19 mg/dL in the healed group). Similar results were found in a Brazilian study, in which patients who did not require amputation had higher HbA1c levels. This study also found an association between blood glucose levels above 200 mg/dL and amputations.³ These findings provide interesting opportunities for repeat studies, preferably with a larger number of participants.

Our study is limited by the small sample size. The sample population had to be reduced, as many patients were lost to follow-up. Although this paring down of the sample size can introduce bias, we are confident that our study is representative of the demographic of patients treated in our facility. The loss of patients to follow-up in turn caused the window of analysis to be narrowed, as long-term outcome data were not available. A multisite study observing various population samples can better explore the relationship between HbA1c and risk of amputation.

This retrospective study exploring factors associated with LEA was unique in that all our participants had 1 or more diabetic foot ulcerations, and thus already had an extremely high risk for amputation, in contrast to previous studies that followed persons at risk for developing diabetic foot ulcerations. In contrast to several previous studies, we found that the risk for amputation actually decreased as baseline measurements of HbA1c increased. The results of this study offer many opportunities for future investigations, preferably with a larger sample size. By further isolating and scrutinizing specific factors associated with LEA, researchers can help clinicians focus on providing wound care that promotes limb salvage.

Corresponding author: Alisha Oropallo, MD, MS, Northwell Health Comprehensive Wound Care Healing Center and Hyperbarics, 1999 Marcus Avenue, Suite M6, Lake Success, NY 11042; [email protected].

Financial disclosures: Funding for this research was provided by a multi-institutional AHRQ governmental grant.

From Northwell Health System, Lake Success, NY.

Abstract

• Objective: To explore factors associated with lower-extremity amputation (LEA) in patients with diabetic foot ulcers using data from the Online Wound Electronic Medical Record Database.
• Design: Retrospective analysis of medical records.
• Setting and participants: Data from 169 individuals with previously diagnosed diabetes mellitus who received wound care for a 6-month period within a span of 2 years was analyzed. A baseline evaluation was obtained and wound(s) were treated, managed, and monitored. Treatment continued until the patient healed, required an LEA, or phased out of the study, neither healing nor undergoing an amputation. Of the 149 patients who completed the study, 38 had healed ulcers, 14 underwent amputation, and 97 neither healed nor underwent an amputation. All patients were treated under the care of vascular and/or podiatric surgeons.
• Measurements: Variables included wound status (healed, amputated, and unhealed/non-amputated); size of wound area; age, gender, race, and ethnicity; white blood cell (WBC) count, hemoglobin A1c (HbA1c), blood glucose, and body mass index (BMI); and presence of osteomyelitis, gangrene, and peripheral vascular disease.
• Results: As compared to the healed and unhealed/non-amputated group, the group of patients who underwent LEA was older and had higher percentages of males, Hispanics, and African Americans; had a higher WBC count, larger wound area, and higher rates of wound infection, osteomyelitis, and neuropathy; and had lower average values of HbA1c, blood glucose, and BMI and a lower rate of peripheral vascular disease.
• Conclusion: The association between HbA1c and LEA highlights a window of relative safety among an at-risk population. By identifying and focusing on factors associated with LEA, health care professionals may be able to decrease the prevalence of LEA in patients with diabetes.

Keywords: diabetic foot ulcer; lower-extremity amputation; risk factors; HbA1c.

An estimated 30.3 million people, or 9.4% of the US population, has diabetes. In 2014, approximately 108,000 amputations were performed on adults with diagnosed diabetes.¹ Furthermore, patients with diabetes have a 10-fold increased risk for lower-extremity amputation (LEA), as compared with patients without diabetes.² The frequency of amputations in the diabetic population is a public health crisis.

Amputation has significant, life-altering consequences. Patients who undergo LEA often face debilitation in their daily activities and must undergo intense rehabilitation to learn basic tasks. Amputations can also impact individuals’ psychological well-being as they come to terms with their altered body and may face challenges in self-perception, confidence, self-esteem, work life, and relationships. In addition, the mortality rate for patients with diabetes 5 years after undergoing LEA is 30%.² However, public health studies estimate that more than half of LEAs in patients with diabetes are preventable.³

Although studies have explored the relationship between diabetes and LEA, few have sought to identify factors directly correlated with wound care. In the United States, patients with diabetic ulcerations are typically treated in wound care facilities; however, previous studies have concentrated on the conditions that lead to the formation of an ulcer or amputation, viewing amputation and ulcer as 2 separate entities. Our study took into account systemic variables, patient demographics, and specific wound characteristics to explore factors associated with LEA in a high-risk group of patients with diabetes. This study was designed to assess ailments that are prevalent in patients who require a LEA.

Methods

Patients and Setting

A total of 169 patients who were treated at the Comprehensive Wound Healing and Hyperbaric Center (Lake Success, NY), a tertiary facility of the Northwell Health system, participated in this retrospective study. The data for this study were obtained in conjunction with the development of the New York University School of Medicine’s Online Wound Electronic Medical Record to Decrease Limb Amputations in Persons with Diabetes (OWEMR) database. The OWEMR collects individual patient data from satellite locations across the country. Using this database, researchers can analyze similarities and differences between patients who undergo LEA.

This study utilized patient data specific to the Northwell Health facility. All of the patients in our study were enrolled under the criteria of the OWEMR database. In order to be included in the OWEMR database, patients had to be diagnosed with type 1 or type 2 diabetes; have a break in the skin ≥ 0.5 cm²; be 18 years of age or older; and have a measured hemoglobin A1c (HbA1c) value within the past 120 days. Study patients signed an informed consent and committed to being available for follow-up visits to the wound care facility for 6 months after entering the study. Patients were enrolled between 2012 and 2014, and each patient was monitored for a period of 6 months within this time period. Participants were treated with current standards of care using diet, lifestyle, and pharmacologic interventions. This study was approved by the Northwell Health System Institutional Review Board Human Research Protection Program (Manhasset, NY).

Data Collection

On their first visit to the facility, patients were given a physical examination and initial interview regarding their medical history. Clinicians were required to select 1 ulcer that would be examined for the duration of the study. The selection of the ulcer was based on a point system that awarded points for pedal pulses, the ability to be probed to the bone, the location of the ulcer (ie, located on the foot rather than a toe), and the presence of multiple ulcerations. The ulcer with the highest score was selected for the study. If numerous ulcers were evaluated with the same score, the largest and deepest was selected. Wagner classification of the wound was recorded at baseline and taken at each subsequent patient visit. In addition, peripheral sensation was assessed for signs of neuropathy using Semmes-Weinstein monofilament testing.

Once selected, the wound was clinically evaluated, samples for culture were obtained, and blood tests were performed to detect the presence of wound infection. The patient’s blood was drawn for a full laboratory analysis, including white blood cell (WBC) count and measurement of blood glucose and HbA1c levels. Bone biopsy, magnetic resonance imaging, and bone scans were used to detect the presence of osteomyelitis at the discretion of the health care provider. Wounds suspected of infection, underlying osteomyelitis, or gangrene at baseline were excluded. Patients would then return for follow-up visits at least once every 6 weeks, plus or minus 2 weeks, for a maximum of 6 months.

Statistical Analysis

Utilizing SAS version 9.3 (Cary, NC), descriptive statistics (minimum, maximum, mean, median, and SD) were calculated for the following variables: age, WBC count, wound area, HbA1c, blood glucose, and body mass index (BMI). These variables were collected for each patient as per the OWEMR protocol and provided a basis for which to compare patients who underwent amputation and those who did not. Twenty patients were lost to follow-up, and therefore we altered the window of our statistics from 6 months to 3 months to provide the most accurate data, as 6-month follow-up data were limited. The patients were classified into the following categories: healed, amputated, and unhealed/non-amputated. Descriptive statistics were calculated for these 3 groups, analyzing the same variables (age, WBC count, wound area, HbA1c, blood glucose, and BMI). Additional statistical computations were utilized in order to show the prevalence and frequency of our categorical variables: gender, race, ethnicity, osteomyelitis, gangrene, and peripheral vascular disease. The baseline values of WBC count, HbA1c, wound area, and BMI of the 3 groups were analyzed with descriptive statistics for comparison. A multinomial logistic regression was then performed using a 3-level outcome variable: healed, amputated, or unhealed/non-amputated. Each predictor variable was analyzed independently due to the small sample size.

Results

Of the 169 registered patients treated at the Northwell Health facility, all qualified for the OWEMR study and met the study criteria. In the original 169 patients, there were 19 amputations: 6 toe, 6 trans-metatarsal, 6 below knee, and 1 above knee (Table 1).

The descriptive statistics of 149 patients grouped into 3 categories (healed, amputated, unhealed/non-amputated) are shown in Table 2.

The results of the logistic regression exploring the differences between the amputation and healed groups and the unhealed/non-amputated group are shown in Table 3. The amputation group had a higher mean age and WBC count and greater wound area. Increased age was determined to be a significant predictor of the odds of amputation (P = 0.0089). For each year increase in age, the odds of amputation increased by 6.5% (odds ratio, 1.07 [95% confidence interval {CI}, 1.02-1.12]). Patients in the amputation group were more likely to be male, Hispanic, and African American and to have wound infections and comorbidities (osteomyelitis, neuropathy, and gangrene).

The presence of gangrene was significantly associated with LEA (P = 0.03). Specifically, the odds of patients without gangrene undergoing a LEA were substantially lower compared with their counterparts with gangrene (odds ratio, 0.17; 95% CI, 0.04-0.68; P = 0.0131). However, the presence of gangrene was not associated with the odds of healing compared with the odds of neither healing nor undergoing amputation (P = 0.84; not shown in Table 3).

The amputation group had lower mean values for HbA1c, BMI, and blood glucose levels and a lower rate of peripheral vascular disease. Only the relationship between lower HbA1c and increased odds of amputation versus not healing/non-amputation was found to be statistically significant (95% CI, 0.27-0.78; P = 0.009).

Discussion

This retrospective study was undertaken to evaluate factors associated with LEA in patients with diabetic foot ulcers. Patients with diabetes being treated at a wound care facility often require continuous surgical and metabolic intervention to promote optimal healing: drainage, surgical debridement, irrigation, culturing for infection, and monitoring of blood glucose levels. This treatment requires strict compliance with medical directions and, oftentimes, additional care, such as home-care nursing visits, to maintain a curative environment for the wound. Frequently, wounds on the lower extremity further complicate the healing process by reducing the patient’s mobility and daily life. Due to these factors, many patients progress to LEA. The link between diabetic ulcers and amputation has already been well described in previous studies, with studies showing that history of diabetic foot ulcer significantly predisposes an individual to LEA.⁴ However, few studies have further investigated demographic factors associated with risk for an amputation. Our study analyzed several categories of patient data taken from a baseline visit. We found that those with highly elevated HbA1c values were less likely to have an amputation than persons with relatively lower levels, a finding that is contrary to previous studies.

Our study’s findings suggest a higher risk for LEA with increased age. The amputation group was, on average, 7 years older than the other 2 groups. A recent study showed that risk for amputation is directly correlated to patient age, as is the mortality rate after undergoing LEA (2.3%; P < 0.05).⁵ Our study found that with each increase in age of 1 year, the odds of amputation increased by 6.5%. However, recent evidence on LEA risk and aging suggests that age is of less consequence than the duration of diabetes. One study found that the propensity to develop diabetic foot ulcers increases with the duration of diabetes.⁶ The same study found that prevalence of ulceration was correlated with age, but the relationship between age and LEA was less significant. A follow-up study for LEA could be done to examine the role of disease duration versus age in LEA.

A consensus among previous studies is that men have a higher risk for LEA.^5,7 Men comprised the majority in all 3 groups in our study. In addition, the amputation group in our study had the lowest BMI. Higher BMI generally is associated with an increased risk for health complications. However, a past study conducted in Taiwan reported that obese patients with diabetes were less likely to undergo LEA than those within the normal range for BMI.⁸ Neither study suggests that obesity is a deterrent for LEA, but both studies may suggest that risk of amputation may approach a maximum frequency at a specific BMI range, and then decrease. This unconfirmed “cyclic” relationship should be evaluated further in a larger sample size.

Most patients in our analysis were Caucasian, followed by African American and South Asian. African Americans were the only racial group with an increased frequency in the amputation group. This finding is supported by a previous study that found that the rate of LEA among patients with diabetes in low-income, predominantly African-American neighborhoods was nearly double that in wealthier, predominantly Caucasian areas.⁹ A potential problem in the comparison between our data with previous studies is that the studies did not analyze patients with our inclusion criteria. All patients with diabetes in previous investigations were grouped by race, but were not necessarily required to have 1 or more ulcers. Multiple ulcers may predispose an individual to a greater risk for amputation.

Multinomial logistic regression did not suggest an association between initial size of a patient’s wound and the risk of amputation. However, the descriptive data suggests a trend. Patients who did not heal or require an amputation had the largest average wound area. This finding is not surprising in that our study followed individuals for only 3 months. Many wounds require a long course of treatment, especially in patients with diabetes, who may have poor vascularization. However, in comparison to the healed patients, the patients who required an amputation had a larger average wound area. A larger wound requires a plentiful vascular supply for the delivery of clotting factors and nutrients to the damaged area. As wound size increases, an individual’s body must transmit an increased quantity of these factors and nutrients for the regeneration of tissue. In addition, wounds that possess a larger surface area require more debridement and present a greater opportunity for infection. This may also foreshadow a longer, more costly course of treatment. Additionally, individuals coping with large ulcerations are burdened by more elaborate and complex wound dressings.

Elevated levels of HbA1c are associated with increased adverse effects of diabetes, including end-stage renal disease, neuropathy, and infection.¹⁰ In a previous study, the risk for amputation was 1.2 times higher in patients with elevated HbA1c.¹¹ In contrast, our study suggested the odds of LEA versus not healing/not undergoing amputation decreased as HbA1c increased. As a patient’s HbA1c level increased by a value of 1, their odds for LEA decreased by 54.3%. This finding contradicts prior studies that have found a positive association between HbA1c and LEA risk, including a study where each percentage increase in HbA1c correlated with a 13% to 15% increased risk of LEA.¹² The finding that patients who underwent amputation in our study had lower levels of HbA1c and blood glucose cannot be fully explained. The maximum HbA1c value in the amputated group was 7.9%. The average values for healed patients and those who underwent LEA were 8.75% and 6.77%, respectively.

Blood glucose levels were also found to be the lowest in the amputated group in our study (mean, 149.29 mg/dL vs 163.19 mg/dL in the healed group). Similar results were found in a Brazilian study, in which patients who did not require amputation had higher HbA1c levels. This study also found an association between blood glucose levels above 200 mg/dL and amputations.³ These findings provide interesting opportunities for repeat studies, preferably with a larger number of participants.

Our study is limited by the small sample size. The sample population had to be reduced, as many patients were lost to follow-up. Although this paring down of the sample size can introduce bias, we are confident that our study is representative of the demographic of patients treated in our facility. The loss of patients to follow-up in turn caused the window of analysis to be narrowed, as long-term outcome data were not available. A multisite study observing various population samples can better explore the relationship between HbA1c and risk of amputation.

This retrospective study exploring factors associated with LEA was unique in that all our participants had 1 or more diabetic foot ulcerations, and thus already had an extremely high risk for amputation, in contrast to previous studies that followed persons at risk for developing diabetic foot ulcerations. In contrast to several previous studies, we found that the risk for amputation actually decreased as baseline measurements of HbA1c increased. The results of this study offer many opportunities for future investigations, preferably with a larger sample size. By further isolating and scrutinizing specific factors associated with LEA, researchers can help clinicians focus on providing wound care that promotes limb salvage.

Corresponding author: Alisha Oropallo, MD, MS, Northwell Health Comprehensive Wound Care Healing Center and Hyperbarics, 1999 Marcus Avenue, Suite M6, Lake Success, NY 11042; [email protected].

Financial disclosures: Funding for this research was provided by a multi-institutional AHRQ governmental grant.

From Northwell Health System, Lake Success, NY.

Abstract

• Objective: To explore factors associated with lower-extremity amputation (LEA) in patients with diabetic foot ulcers using data from the Online Wound Electronic Medical Record Database.
• Design: Retrospective analysis of medical records.
• Setting and participants: Data from 169 individuals with previously diagnosed diabetes mellitus who received wound care for a 6-month period within a span of 2 years was analyzed. A baseline evaluation was obtained and wound(s) were treated, managed, and monitored. Treatment continued until the patient healed, required an LEA, or phased out of the study, neither healing nor undergoing an amputation. Of the 149 patients who completed the study, 38 had healed ulcers, 14 underwent amputation, and 97 neither healed nor underwent an amputation. All patients were treated under the care of vascular and/or podiatric surgeons.
• Measurements: Variables included wound status (healed, amputated, and unhealed/non-amputated); size of wound area; age, gender, race, and ethnicity; white blood cell (WBC) count, hemoglobin A1c (HbA1c), blood glucose, and body mass index (BMI); and presence of osteomyelitis, gangrene, and peripheral vascular disease.
• Results: As compared to the healed and unhealed/non-amputated group, the group of patients who underwent LEA was older and had higher percentages of males, Hispanics, and African Americans; had a higher WBC count, larger wound area, and higher rates of wound infection, osteomyelitis, and neuropathy; and had lower average values of HbA1c, blood glucose, and BMI and a lower rate of peripheral vascular disease.
• Conclusion: The association between HbA1c and LEA highlights a window of relative safety among an at-risk population. By identifying and focusing on factors associated with LEA, health care professionals may be able to decrease the prevalence of LEA in patients with diabetes.

Keywords: diabetic foot ulcer; lower-extremity amputation; risk factors; HbA1c.

An estimated 30.3 million people, or 9.4% of the US population, has diabetes. In 2014, approximately 108,000 amputations were performed on adults with diagnosed diabetes.¹ Furthermore, patients with diabetes have a 10-fold increased risk for lower-extremity amputation (LEA), as compared with patients without diabetes.² The frequency of amputations in the diabetic population is a public health crisis.

Amputation has significant, life-altering consequences. Patients who undergo LEA often face debilitation in their daily activities and must undergo intense rehabilitation to learn basic tasks. Amputations can also impact individuals’ psychological well-being as they come to terms with their altered body and may face challenges in self-perception, confidence, self-esteem, work life, and relationships. In addition, the mortality rate for patients with diabetes 5 years after undergoing LEA is 30%.² However, public health studies estimate that more than half of LEAs in patients with diabetes are preventable.³

Although studies have explored the relationship between diabetes and LEA, few have sought to identify factors directly correlated with wound care. In the United States, patients with diabetic ulcerations are typically treated in wound care facilities; however, previous studies have concentrated on the conditions that lead to the formation of an ulcer or amputation, viewing amputation and ulcer as 2 separate entities. Our study took into account systemic variables, patient demographics, and specific wound characteristics to explore factors associated with LEA in a high-risk group of patients with diabetes. This study was designed to assess ailments that are prevalent in patients who require a LEA.

Methods

Patients and Setting

A total of 169 patients who were treated at the Comprehensive Wound Healing and Hyperbaric Center (Lake Success, NY), a tertiary facility of the Northwell Health system, participated in this retrospective study. The data for this study were obtained in conjunction with the development of the New York University School of Medicine’s Online Wound Electronic Medical Record to Decrease Limb Amputations in Persons with Diabetes (OWEMR) database. The OWEMR collects individual patient data from satellite locations across the country. Using this database, researchers can analyze similarities and differences between patients who undergo LEA.

This study utilized patient data specific to the Northwell Health facility. All of the patients in our study were enrolled under the criteria of the OWEMR database. In order to be included in the OWEMR database, patients had to be diagnosed with type 1 or type 2 diabetes; have a break in the skin ≥ 0.5 cm²; be 18 years of age or older; and have a measured hemoglobin A1c (HbA1c) value within the past 120 days. Study patients signed an informed consent and committed to being available for follow-up visits to the wound care facility for 6 months after entering the study. Patients were enrolled between 2012 and 2014, and each patient was monitored for a period of 6 months within this time period. Participants were treated with current standards of care using diet, lifestyle, and pharmacologic interventions. This study was approved by the Northwell Health System Institutional Review Board Human Research Protection Program (Manhasset, NY).

Data Collection

On their first visit to the facility, patients were given a physical examination and initial interview regarding their medical history. Clinicians were required to select 1 ulcer that would be examined for the duration of the study. The selection of the ulcer was based on a point system that awarded points for pedal pulses, the ability to be probed to the bone, the location of the ulcer (ie, located on the foot rather than a toe), and the presence of multiple ulcerations. The ulcer with the highest score was selected for the study. If numerous ulcers were evaluated with the same score, the largest and deepest was selected. Wagner classification of the wound was recorded at baseline and taken at each subsequent patient visit. In addition, peripheral sensation was assessed for signs of neuropathy using Semmes-Weinstein monofilament testing.

Once selected, the wound was clinically evaluated, samples for culture were obtained, and blood tests were performed to detect the presence of wound infection. The patient’s blood was drawn for a full laboratory analysis, including white blood cell (WBC) count and measurement of blood glucose and HbA1c levels. Bone biopsy, magnetic resonance imaging, and bone scans were used to detect the presence of osteomyelitis at the discretion of the health care provider. Wounds suspected of infection, underlying osteomyelitis, or gangrene at baseline were excluded. Patients would then return for follow-up visits at least once every 6 weeks, plus or minus 2 weeks, for a maximum of 6 months.

Statistical Analysis

Utilizing SAS version 9.3 (Cary, NC), descriptive statistics (minimum, maximum, mean, median, and SD) were calculated for the following variables: age, WBC count, wound area, HbA1c, blood glucose, and body mass index (BMI). These variables were collected for each patient as per the OWEMR protocol and provided a basis for which to compare patients who underwent amputation and those who did not. Twenty patients were lost to follow-up, and therefore we altered the window of our statistics from 6 months to 3 months to provide the most accurate data, as 6-month follow-up data were limited. The patients were classified into the following categories: healed, amputated, and unhealed/non-amputated. Descriptive statistics were calculated for these 3 groups, analyzing the same variables (age, WBC count, wound area, HbA1c, blood glucose, and BMI). Additional statistical computations were utilized in order to show the prevalence and frequency of our categorical variables: gender, race, ethnicity, osteomyelitis, gangrene, and peripheral vascular disease. The baseline values of WBC count, HbA1c, wound area, and BMI of the 3 groups were analyzed with descriptive statistics for comparison. A multinomial logistic regression was then performed using a 3-level outcome variable: healed, amputated, or unhealed/non-amputated. Each predictor variable was analyzed independently due to the small sample size.

Results

Of the 169 registered patients treated at the Northwell Health facility, all qualified for the OWEMR study and met the study criteria. In the original 169 patients, there were 19 amputations: 6 toe, 6 trans-metatarsal, 6 below knee, and 1 above knee (Table 1).

The descriptive statistics of 149 patients grouped into 3 categories (healed, amputated, unhealed/non-amputated) are shown in Table 2.

The results of the logistic regression exploring the differences between the amputation and healed groups and the unhealed/non-amputated group are shown in Table 3. The amputation group had a higher mean age and WBC count and greater wound area. Increased age was determined to be a significant predictor of the odds of amputation (P = 0.0089). For each year increase in age, the odds of amputation increased by 6.5% (odds ratio, 1.07 [95% confidence interval {CI}, 1.02-1.12]). Patients in the amputation group were more likely to be male, Hispanic, and African American and to have wound infections and comorbidities (osteomyelitis, neuropathy, and gangrene).

The presence of gangrene was significantly associated with LEA (P = 0.03). Specifically, the odds of patients without gangrene undergoing a LEA were substantially lower compared with their counterparts with gangrene (odds ratio, 0.17; 95% CI, 0.04-0.68; P = 0.0131). However, the presence of gangrene was not associated with the odds of healing compared with the odds of neither healing nor undergoing amputation (P = 0.84; not shown in Table 3).

The amputation group had lower mean values for HbA1c, BMI, and blood glucose levels and a lower rate of peripheral vascular disease. Only the relationship between lower HbA1c and increased odds of amputation versus not healing/non-amputation was found to be statistically significant (95% CI, 0.27-0.78; P = 0.009).

Discussion

This retrospective study was undertaken to evaluate factors associated with LEA in patients with diabetic foot ulcers. Patients with diabetes being treated at a wound care facility often require continuous surgical and metabolic intervention to promote optimal healing: drainage, surgical debridement, irrigation, culturing for infection, and monitoring of blood glucose levels. This treatment requires strict compliance with medical directions and, oftentimes, additional care, such as home-care nursing visits, to maintain a curative environment for the wound. Frequently, wounds on the lower extremity further complicate the healing process by reducing the patient’s mobility and daily life. Due to these factors, many patients progress to LEA. The link between diabetic ulcers and amputation has already been well described in previous studies, with studies showing that history of diabetic foot ulcer significantly predisposes an individual to LEA.⁴ However, few studies have further investigated demographic factors associated with risk for an amputation. Our study analyzed several categories of patient data taken from a baseline visit. We found that those with highly elevated HbA1c values were less likely to have an amputation than persons with relatively lower levels, a finding that is contrary to previous studies.

Our study’s findings suggest a higher risk for LEA with increased age. The amputation group was, on average, 7 years older than the other 2 groups. A recent study showed that risk for amputation is directly correlated to patient age, as is the mortality rate after undergoing LEA (2.3%; P < 0.05).⁵ Our study found that with each increase in age of 1 year, the odds of amputation increased by 6.5%. However, recent evidence on LEA risk and aging suggests that age is of less consequence than the duration of diabetes. One study found that the propensity to develop diabetic foot ulcers increases with the duration of diabetes.⁶ The same study found that prevalence of ulceration was correlated with age, but the relationship between age and LEA was less significant. A follow-up study for LEA could be done to examine the role of disease duration versus age in LEA.

A consensus among previous studies is that men have a higher risk for LEA.^5,7 Men comprised the majority in all 3 groups in our study. In addition, the amputation group in our study had the lowest BMI. Higher BMI generally is associated with an increased risk for health complications. However, a past study conducted in Taiwan reported that obese patients with diabetes were less likely to undergo LEA than those within the normal range for BMI.⁸ Neither study suggests that obesity is a deterrent for LEA, but both studies may suggest that risk of amputation may approach a maximum frequency at a specific BMI range, and then decrease. This unconfirmed “cyclic” relationship should be evaluated further in a larger sample size.

Most patients in our analysis were Caucasian, followed by African American and South Asian. African Americans were the only racial group with an increased frequency in the amputation group. This finding is supported by a previous study that found that the rate of LEA among patients with diabetes in low-income, predominantly African-American neighborhoods was nearly double that in wealthier, predominantly Caucasian areas.⁹ A potential problem in the comparison between our data with previous studies is that the studies did not analyze patients with our inclusion criteria. All patients with diabetes in previous investigations were grouped by race, but were not necessarily required to have 1 or more ulcers. Multiple ulcers may predispose an individual to a greater risk for amputation.

Multinomial logistic regression did not suggest an association between initial size of a patient’s wound and the risk of amputation. However, the descriptive data suggests a trend. Patients who did not heal or require an amputation had the largest average wound area. This finding is not surprising in that our study followed individuals for only 3 months. Many wounds require a long course of treatment, especially in patients with diabetes, who may have poor vascularization. However, in comparison to the healed patients, the patients who required an amputation had a larger average wound area. A larger wound requires a plentiful vascular supply for the delivery of clotting factors and nutrients to the damaged area. As wound size increases, an individual’s body must transmit an increased quantity of these factors and nutrients for the regeneration of tissue. In addition, wounds that possess a larger surface area require more debridement and present a greater opportunity for infection. This may also foreshadow a longer, more costly course of treatment. Additionally, individuals coping with large ulcerations are burdened by more elaborate and complex wound dressings.

Elevated levels of HbA1c are associated with increased adverse effects of diabetes, including end-stage renal disease, neuropathy, and infection.¹⁰ In a previous study, the risk for amputation was 1.2 times higher in patients with elevated HbA1c.¹¹ In contrast, our study suggested the odds of LEA versus not healing/not undergoing amputation decreased as HbA1c increased. As a patient’s HbA1c level increased by a value of 1, their odds for LEA decreased by 54.3%. This finding contradicts prior studies that have found a positive association between HbA1c and LEA risk, including a study where each percentage increase in HbA1c correlated with a 13% to 15% increased risk of LEA.¹² The finding that patients who underwent amputation in our study had lower levels of HbA1c and blood glucose cannot be fully explained. The maximum HbA1c value in the amputated group was 7.9%. The average values for healed patients and those who underwent LEA were 8.75% and 6.77%, respectively.

Blood glucose levels were also found to be the lowest in the amputated group in our study (mean, 149.29 mg/dL vs 163.19 mg/dL in the healed group). Similar results were found in a Brazilian study, in which patients who did not require amputation had higher HbA1c levels. This study also found an association between blood glucose levels above 200 mg/dL and amputations.³ These findings provide interesting opportunities for repeat studies, preferably with a larger number of participants.

Our study is limited by the small sample size. The sample population had to be reduced, as many patients were lost to follow-up. Although this paring down of the sample size can introduce bias, we are confident that our study is representative of the demographic of patients treated in our facility. The loss of patients to follow-up in turn caused the window of analysis to be narrowed, as long-term outcome data were not available. A multisite study observing various population samples can better explore the relationship between HbA1c and risk of amputation.

This retrospective study exploring factors associated with LEA was unique in that all our participants had 1 or more diabetic foot ulcerations, and thus already had an extremely high risk for amputation, in contrast to previous studies that followed persons at risk for developing diabetic foot ulcerations. In contrast to several previous studies, we found that the risk for amputation actually decreased as baseline measurements of HbA1c increased. The results of this study offer many opportunities for future investigations, preferably with a larger sample size. By further isolating and scrutinizing specific factors associated with LEA, researchers can help clinicians focus on providing wound care that promotes limb salvage.

Corresponding author: Alisha Oropallo, MD, MS, Northwell Health Comprehensive Wound Care Healing Center and Hyperbarics, 1999 Marcus Avenue, Suite M6, Lake Success, NY 11042; [email protected].

Financial disclosures: Funding for this research was provided by a multi-institutional AHRQ governmental grant.