Clinical Endocrinology News

Recently, we had the opportunity to take part in a major EHR conversion project. During this “go-live,” 5 hospitals and approximately 300 ambulatory service and physician practice locations made the transition, consolidating over 100 disparate electronic systems and dozens of interfaces into one world-class medical record.

If you’ve ever been part of such an event, you know it is anything but simple. On the contrary, it requires an enormous financial investment along with years of planning, hours of meetings, and months of training. No matter how much preparation goes into it, there are sure to be bumps along the way. It is a traumatic and stressful time for all involved, but the end result is well worth the effort. Still, there are lessons to be learned and wisdom to be gleaned, and this month we’d like to share a few that we found most important. We believe that many of these are useful lessons even to those who will never live through a go-live.
 

Safety always comes first

Patient safety is a term so often used that it has a tendency to be taken for granted. Health systems build processes and procedures to ensure safety – some even win awards and recognition for their efforts. But the best (and safest) health care institutions build patient safety into their cultures. More than just being taught to use checklists or buzzwords, the staff at these institutions are encouraged to put the welfare of patients first, making all other activities secondary to this pursuit. We had the opportunity to witness the benefits of such a culture during this go-live and were incredibly impressed with the results.

To be successful in an EHR transition of any magnitude, an organization needs to hold patient safety as a core value and provide its employees with the tools to execute on that value. This enables staff to prepare adequately and to identify risks and opportunities before the conversion takes place. Once go-live occurs, staff also must feel empowered to speak up when they identify problem areas that might jeopardize patients’ care. They also must be given a clear escalation path to ensure their voices can be heard. Most importantly, everyone must understand that the electronic health record itself is just one piece of a major operational change.

As workflows are modified to adapt to the new technology, unsafe processes should be called out and fixed quickly. While the EHR may offer the latest in decision support and system integration, no advancement in technology can make up for bad outcomes, nor justify processes that lead to patient harm.
 

Training is no substitute for good support

It takes a long time to train thousands of employees, especially when that training must occur during the era of social distancing in the midst of a pandemic. Still, even in the best of times, education should be married to hands-on experience in order to have a real impact. Unfortunately, this is extremely challenging.

Trainees forget much of what they’ve learned in the weeks or months between education and go-live, so they must be given immediately accessible support to bridge the gap. This is known as “at-the-elbow” (ATE) support, and as the name implies, it consists of individuals who are familiar with the new system and are always available to end users, answering their questions and helping them navigate. Since health care never sleeps, this support needs to be offered 24/7, and it should also be flexible and plentiful.

There are many areas that will require more support than anticipated to accommodate the number of clinical and other staff who will use the system, so support staff must be nimble and available for redeployment. In addition, ensuring high-quality support is essential. As many ATE experts are hired contractors, their knowledge base and communications skills can vary widely. Accountability is key, and end users should feel empowered to identify gaps in coverage and deficits in knowledge base in the ATE.

As employees become more familiar with the new system, the need for ATE will wane, but there will still be questions that arise for many weeks to months, and new EHR users will also be added all the time. A good after–go-live support system should remain available so clinical and clerical employees can get just-in-time assistance whenever they need it.
 

Users should be given clear expectations

Clinicians going through an EHR conversion may be frustrated to discover that the data transferred from their old system into the new one is not quite what they expected. While structured elements such as allergies and immunizations may transfer, unstructured patient histories may not come over at all.

There may be gaps in data, or the opposite may even be true: an overabundance of useless information may transfer over, leaving doctors with dozens of meaningless data points to sift through and eliminate to clean up the chart. This can be extremely time-consuming and discouraging and may jeopardize the success of the go-live.

Providers deserve clear expectations prior to conversion. They should be told what will and will not transfer and be informed that there will be extra work required for documentation at the outset. They may also want the option to preemptively reduce patient volumes to accommodate the additional effort involved in preparing charts. No matter what, this will be a heavy lift, and physicians should understand the implications long before go-live to prepare accordingly.
 

Old habits die hard

One of the most common complaints we’ve heard following EHR conversions is that “things just worked better in the old system.” We always respond with a question: “Were things better, or just different?” The truth may lie somewhere in the middle, but there is no question that muscle memory develops over many years, and change is difficult no matter how much better the new system is. Still, appropriate expectations, access to just-in-time support, and a continual focus on safety will ensure that the long-term benefits of a patient-centered and integrated electronic record will far outweigh the initial challenges of go-live.

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

Recently, we had the opportunity to take part in a major EHR conversion project. During this “go-live,” 5 hospitals and approximately 300 ambulatory service and physician practice locations made the transition, consolidating over 100 disparate electronic systems and dozens of interfaces into one world-class medical record.

If you’ve ever been part of such an event, you know it is anything but simple. On the contrary, it requires an enormous financial investment along with years of planning, hours of meetings, and months of training. No matter how much preparation goes into it, there are sure to be bumps along the way. It is a traumatic and stressful time for all involved, but the end result is well worth the effort. Still, there are lessons to be learned and wisdom to be gleaned, and this month we’d like to share a few that we found most important. We believe that many of these are useful lessons even to those who will never live through a go-live.
 

Safety always comes first

Patient safety is a term so often used that it has a tendency to be taken for granted. Health systems build processes and procedures to ensure safety – some even win awards and recognition for their efforts. But the best (and safest) health care institutions build patient safety into their cultures. More than just being taught to use checklists or buzzwords, the staff at these institutions are encouraged to put the welfare of patients first, making all other activities secondary to this pursuit. We had the opportunity to witness the benefits of such a culture during this go-live and were incredibly impressed with the results.

To be successful in an EHR transition of any magnitude, an organization needs to hold patient safety as a core value and provide its employees with the tools to execute on that value. This enables staff to prepare adequately and to identify risks and opportunities before the conversion takes place. Once go-live occurs, staff also must feel empowered to speak up when they identify problem areas that might jeopardize patients’ care. They also must be given a clear escalation path to ensure their voices can be heard. Most importantly, everyone must understand that the electronic health record itself is just one piece of a major operational change.

As workflows are modified to adapt to the new technology, unsafe processes should be called out and fixed quickly. While the EHR may offer the latest in decision support and system integration, no advancement in technology can make up for bad outcomes, nor justify processes that lead to patient harm.
 

Training is no substitute for good support

It takes a long time to train thousands of employees, especially when that training must occur during the era of social distancing in the midst of a pandemic. Still, even in the best of times, education should be married to hands-on experience in order to have a real impact. Unfortunately, this is extremely challenging.

Trainees forget much of what they’ve learned in the weeks or months between education and go-live, so they must be given immediately accessible support to bridge the gap. This is known as “at-the-elbow” (ATE) support, and as the name implies, it consists of individuals who are familiar with the new system and are always available to end users, answering their questions and helping them navigate. Since health care never sleeps, this support needs to be offered 24/7, and it should also be flexible and plentiful.

There are many areas that will require more support than anticipated to accommodate the number of clinical and other staff who will use the system, so support staff must be nimble and available for redeployment. In addition, ensuring high-quality support is essential. As many ATE experts are hired contractors, their knowledge base and communications skills can vary widely. Accountability is key, and end users should feel empowered to identify gaps in coverage and deficits in knowledge base in the ATE.

As employees become more familiar with the new system, the need for ATE will wane, but there will still be questions that arise for many weeks to months, and new EHR users will also be added all the time. A good after–go-live support system should remain available so clinical and clerical employees can get just-in-time assistance whenever they need it.
 

Users should be given clear expectations

Clinicians going through an EHR conversion may be frustrated to discover that the data transferred from their old system into the new one is not quite what they expected. While structured elements such as allergies and immunizations may transfer, unstructured patient histories may not come over at all.

There may be gaps in data, or the opposite may even be true: an overabundance of useless information may transfer over, leaving doctors with dozens of meaningless data points to sift through and eliminate to clean up the chart. This can be extremely time-consuming and discouraging and may jeopardize the success of the go-live.

Providers deserve clear expectations prior to conversion. They should be told what will and will not transfer and be informed that there will be extra work required for documentation at the outset. They may also want the option to preemptively reduce patient volumes to accommodate the additional effort involved in preparing charts. No matter what, this will be a heavy lift, and physicians should understand the implications long before go-live to prepare accordingly.
 

Old habits die hard

One of the most common complaints we’ve heard following EHR conversions is that “things just worked better in the old system.” We always respond with a question: “Were things better, or just different?” The truth may lie somewhere in the middle, but there is no question that muscle memory develops over many years, and change is difficult no matter how much better the new system is. Still, appropriate expectations, access to just-in-time support, and a continual focus on safety will ensure that the long-term benefits of a patient-centered and integrated electronic record will far outweigh the initial challenges of go-live.

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

Recently, we had the opportunity to take part in a major EHR conversion project. During this “go-live,” 5 hospitals and approximately 300 ambulatory service and physician practice locations made the transition, consolidating over 100 disparate electronic systems and dozens of interfaces into one world-class medical record.

If you’ve ever been part of such an event, you know it is anything but simple. On the contrary, it requires an enormous financial investment along with years of planning, hours of meetings, and months of training. No matter how much preparation goes into it, there are sure to be bumps along the way. It is a traumatic and stressful time for all involved, but the end result is well worth the effort. Still, there are lessons to be learned and wisdom to be gleaned, and this month we’d like to share a few that we found most important. We believe that many of these are useful lessons even to those who will never live through a go-live.
 

Safety always comes first

Patient safety is a term so often used that it has a tendency to be taken for granted. Health systems build processes and procedures to ensure safety – some even win awards and recognition for their efforts. But the best (and safest) health care institutions build patient safety into their cultures. More than just being taught to use checklists or buzzwords, the staff at these institutions are encouraged to put the welfare of patients first, making all other activities secondary to this pursuit. We had the opportunity to witness the benefits of such a culture during this go-live and were incredibly impressed with the results.

To be successful in an EHR transition of any magnitude, an organization needs to hold patient safety as a core value and provide its employees with the tools to execute on that value. This enables staff to prepare adequately and to identify risks and opportunities before the conversion takes place. Once go-live occurs, staff also must feel empowered to speak up when they identify problem areas that might jeopardize patients’ care. They also must be given a clear escalation path to ensure their voices can be heard. Most importantly, everyone must understand that the electronic health record itself is just one piece of a major operational change.

As workflows are modified to adapt to the new technology, unsafe processes should be called out and fixed quickly. While the EHR may offer the latest in decision support and system integration, no advancement in technology can make up for bad outcomes, nor justify processes that lead to patient harm.
 

Training is no substitute for good support

It takes a long time to train thousands of employees, especially when that training must occur during the era of social distancing in the midst of a pandemic. Still, even in the best of times, education should be married to hands-on experience in order to have a real impact. Unfortunately, this is extremely challenging.

Trainees forget much of what they’ve learned in the weeks or months between education and go-live, so they must be given immediately accessible support to bridge the gap. This is known as “at-the-elbow” (ATE) support, and as the name implies, it consists of individuals who are familiar with the new system and are always available to end users, answering their questions and helping them navigate. Since health care never sleeps, this support needs to be offered 24/7, and it should also be flexible and plentiful.

There are many areas that will require more support than anticipated to accommodate the number of clinical and other staff who will use the system, so support staff must be nimble and available for redeployment. In addition, ensuring high-quality support is essential. As many ATE experts are hired contractors, their knowledge base and communications skills can vary widely. Accountability is key, and end users should feel empowered to identify gaps in coverage and deficits in knowledge base in the ATE.

As employees become more familiar with the new system, the need for ATE will wane, but there will still be questions that arise for many weeks to months, and new EHR users will also be added all the time. A good after–go-live support system should remain available so clinical and clerical employees can get just-in-time assistance whenever they need it.
 

Users should be given clear expectations

Clinicians going through an EHR conversion may be frustrated to discover that the data transferred from their old system into the new one is not quite what they expected. While structured elements such as allergies and immunizations may transfer, unstructured patient histories may not come over at all.

There may be gaps in data, or the opposite may even be true: an overabundance of useless information may transfer over, leaving doctors with dozens of meaningless data points to sift through and eliminate to clean up the chart. This can be extremely time-consuming and discouraging and may jeopardize the success of the go-live.

Providers deserve clear expectations prior to conversion. They should be told what will and will not transfer and be informed that there will be extra work required for documentation at the outset. They may also want the option to preemptively reduce patient volumes to accommodate the additional effort involved in preparing charts. No matter what, this will be a heavy lift, and physicians should understand the implications long before go-live to prepare accordingly.
 

Old habits die hard

One of the most common complaints we’ve heard following EHR conversions is that “things just worked better in the old system.” We always respond with a question: “Were things better, or just different?” The truth may lie somewhere in the middle, but there is no question that muscle memory develops over many years, and change is difficult no matter how much better the new system is. Still, appropriate expectations, access to just-in-time support, and a continual focus on safety will ensure that the long-term benefits of a patient-centered and integrated electronic record will far outweigh the initial challenges of go-live.

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

“I’m the first person in my circle of family and friends to participate in a clinical trial.”

Five years ago, Rhonda Long was diagnosed with cholangiocarcinoma, a rare bile duct cancer that’s seen in only about 8,000 Americans each year.

At the time, Mrs. Long, who is Black, said her doctor in Dayton, Ohio, told her she was not a candidate for surgery and suggested palliative care. After seeking a second opinion at Duke University Medical Center, Durham, N.C., where her sister worked, the 51-year-old wife and mother of two had surgery, radiation, and chemotherapy there in North Carolina. When the chemo stopped working after 3 months, her oncologist at Duke referred her to a colleague at Massachusetts General Hospital in Boston, where she was accepted into a clinical trial.

“In 2019, I traveled to Boston from Dayton, Ohio, every 3 weeks for labs and scans, to make sure that the drug wasn’t doing more harm than good, making sure that the drug as developed was maintaining, shrinking, or even eliminating the disease. Physically and financially, it takes a toll on you and loved ones.”

Her medical insurance did not cover the direct expenses from the clinical trial, and she was spending $1,000-$1,500 each trip. Sometimes they drove the 15 hours to Boston, and sometimes they flew on the cheapest flight they could find.

It’s not an unfamiliar story: people traveling, often long distances, to take part in clinical trials they hope will save their lives.

The Lazarex Cancer Foundation of Danville, Calif., helped Mrs. Long do just that.

Marya Shegog, PhD, health equity and diversity coordinator at Lazarex, said that a patient travels an average of 500 miles to participate in a trial.

The financial hurdles often prevent patients from taking part in clinical trials, Dr. Shegog said. “When you are sick, and you have a disease that may be terminal, you start thinking about setting your things in order.”

Many patients have to make a decision.

“Do I bankrupt my family on trying and hoping that this drug works and helps me live longer, or do I start setting things in order so that when I’m gone, they’re okay or at least better than if I wouldn’t have spent all the money traveling back and forth.”

Dr. Shegog, a 17-year cancer survivor, says when she was battling cervical cancer, a clinical trial was never offered or explored.

Lazarex has been helping cancer patients who have run out of options for 15 years. It identifies clinical trial opportunities and reimburses patients for all travel costs. Last year, Lazarex reimbursed more than 1,000 cancer patients. And it has supported more than 6,000 people since opening its doors.

“Lazarex exists to help remove the barriers of people not being able to participate in trials,” Dr. Shegog said. “It’s systemic that the medical system does not treat patients the same and oftentimes does not offer or make aware the opportunities for African Americans to participate.”

But now, thanks in part to COVID-19, new possibilities are taking shape. The pandemic has changed the landscape for trials, forcing many of them to go virtual, which allows patients to schedule telehealth visits and get some services like bloodwork and CT or MRI scans closer to home. Mrs. Long’s trial eventually went virtual.

“It was absolutely fantastic,” she said. “Having the trial locally, it saves us money, it saves wear and tear on my body. Being in the car, being in an airport or in a plane and in a hotel, all of that wears on you physically.”

The move to virtual studies may have lasting effects on research and treatment.

“The current pandemic has forced us to reexamine all of the traditional burdens we place on patients as it relates to receiving cancer treatment,” said Hala Borno, MD, an assistant professor of medicine at the University of California, San Francisco. “Whether they’re coming to our health care facility to see a clinician, for diagnostics such as blood draws and scans, or to receive therapy, this pandemic has challenged us to explore other possibilities that minimize the risk of exposure to SARS-CoV-2. What I find striking is that it has helped us operationalize use of telemedicine and the delivery of care closer to home.”

This is especially encouraging news for minority patients whose participation in trials has for years lagged well behind that of Whites.

But travel is not the only reason. Racial disparities in clinical trials have long been an issue that’s just another part of the implicit bias in health care.

Compared with White people, Black people are largely at higher risk for heart disease, cancer, stroke, diabetes, asthma, and even mental health problems.

And it’s not just African Americans. Asians, Hispanics, Native Americans, and Alaska Natives are all underrepresented in trials at a time when there is growing evidence that drugs may have different effects on different populations.

Dr. Borno is an oncologist who specializes in prostate cancer, a disease that she says shows a “significant disparity,” where Black men are two times more likely to die from advanced prostate cancer, compared with white men. Yet Black men make up just 3% of advanced therapeutic trials.

“A lack of diversity and inclusion in clinical trials is unacceptable,” she said. “If we continue to underrecruit racial/ethnic minorities and older adults to therapeutic clinical trials, we will not be powered to make valid conclusions regarding safety and efficacy in those patient populations. As a result, we can do harm.”

Dr. Borno said that telehealth and telemedicine are not cure-alls, and digital health solutions don’t work for all patients. Approaches, she says, must be tailored to the individual, or disparities could worsen.

In 2020, the Food and Drug Administration approved 53 new drugs. Overall, 32,000 patients took part in these trials. On average, 75% were White, 8% were Black, 6% were Asian, and 11% were Hispanic.

Here’s one stark example of the issue. In 2015, the FDA approved ixazomib (Ninlaro), a promising new drug for multiple myeloma, a blood cancer that affects Black people at disproportionately higher rates than White people. In the United States, one in five people diagnosed with multiple myeloma are Black people. They are more than twice as likely to get the disease as White people. Yet during the clinical trial of 722 participants, only 13 patients, or 1.8%, were Black.

The American Cancer Society estimates that more than 600,000 Americans will die from cancer this year. Historically, Black Americans have the highest death rate and the shortest survival of any racial or ethnic group, stemming largely, it concluded, from centuries of structural racism.

According to Jamie Freedman, MD, head of U.S. medical affairs at Genentech, a global pharmaceutical company, the lack of diversity is often tied to where studies are run.

“Companies tend to choose major academic medical centers where there is a high volume of clinical trial work. When you go to the same tried and true hospitals repeatedly, the pool of patients becomes very homogeneous and tends to be primarily white,” he said. “It’s critical to bring more trials into the community setting by including new sites that can reach underrepresented groups, and Genentech is making significant progress in that area.”

Dr. Freedman believes that, while access is a big hurdle, it doesn’t end there.

“Many patients have a lack of trust in the health care system,” he said. “There are also issues around underserved communities being able to afford quality care, so it’s important to keep time and financial burdens in mind when designing trials to help mitigate barriers such as travel, parking, time off work, and child care.”

Genentech started its diversity and inclusion effort several years ago. Dr. Freeman said that, until more trials become diverse, Black Americans will continue to pay the price. “I think they’re losing their lives in part due to lack of access to these trials. And that is why Genentech and all of us in the health care industry need to change how we design and enroll these studies. We have a long way to go, but I think the steps we’re taking are leading us in the right direction.”

Jennifer Jones-McMeans, PhD, director of global clinical affairs at Abbott Pharmaceuticals, is a clinical research scientist who has designed and led many clinical trials.

She said that Abbott is actively working on solutions.

“We have designed our trials to reduce the barriers to participation and expand access,” she said. “This can be as simple as providing transportation services or home visits for those who are housebound. We’re taking it a step further and providing home health services where someone comes to the home and provides follow-up visits there.”

They also provide interpretation services to address any language barriers.

“We are reaching out to a new set of talented investigators who work closely with underrepresented communities. They are very much wedded and supportive of the communities they treat. By working with doctors within these communities, it expands access to new therapies.”

Spokesperson Keanna Ghazvini said that Pfizer Pharmaceuticals is also committed to increasing minority participation in trials.

“We know that if historically underserved populations are left out of clinical trials, they risk not benefiting from medical breakthroughs down the line,” she said.

The National Institutes of Health’s National Library of Medicine maintains the clinicaltrials.gov database.

There, you can find information on nearly 372,000 publicly and privately supported clinical trials happening in all 50 states and 219 countries. Many are funded by the NIH, but not all of these studies have been evaluated by the U.S. government.

Andrea Denicoff, a nurse consultant at the National Cancer Institute and head of clinical trials operations for the NCI’s National Clinical Trials Network, has been involved in clinical research at the NIH for 35 years.

“It’s really important that our publicly funded trials represent the people of the country,” she said. “There are some cancers that we’re doing a good job in enrolling minorities, and other cancers we need to do a much better job in having a diverse representation in our trials.”

Ms. Denicoff believed opening trials in places where people live is key, but having a diverse clinical trials team is as important.

“We need to reinforce that cancer centers across the country have open doors, and anyone with cancer feels comfortable getting care at that center, and that also includes discussing the option to participate in clinical trials when one might be available. We know from research that when people are invited and asked about trial participation and educated about them, they’ll be much more interested in joining them.”

Ms. Denicoff said that, during the pandemic, the NCI quickly came up with guidance to allow trial sites to send patients their oral study drugs and set up virtual visits. She believes it may help increase future access.

‘Lola Fashoyin-Aje, MD, associate director for science and policy to address disparities in the Oncology Center of Excellence at the FDA, says the agency firmly believes clinical trials should represent the patients who will ultimately get the drug if it’s approved.

But the FDA’s power to require diversity in trials is limited.

“It is important to point out that there are legal constraints which limit’s FDA’s authority to require specific proportional representation in clinical trials by demographic factors,” Dr. Fashoyin-Aje said.

Still, some researchers feel the FDA should play a bigger role. The question is: Should diversity be mandated?

Rhonda Long is now back in Boston to start a new trial, with a new drug that targets her specific mutation. She will be there for 2 months. Once again, Lazarex will help cover some of the cost.

She wants people of color to understand that they are missing out on the promise of new cancer drugs and extended life.

“I feel like there’s not enough emphasis on clinical trials, I don’t believe there’s enough emphasis on second opinions, I don’t think there’s enough emphasis that medicine happens outside our borders, outside of our communities. Clinical trials that don’t have a broad range of participants, how do we know how effective they are if Black and brown people, Asian or Latin American people aren’t represented in the trial?”

And with more trials adopting virtual elements, she said it’s time for minorities to get on board.

Dr. Freedman believed the groundwork is being laid for that to happen. “I don’t think we’ll ever return back to the way we used to do things, where everything has to be done at the clinical trial site. I just don’t think we’re ever going back.”

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

“I’m the first person in my circle of family and friends to participate in a clinical trial.”

Five years ago, Rhonda Long was diagnosed with cholangiocarcinoma, a rare bile duct cancer that’s seen in only about 8,000 Americans each year.

At the time, Mrs. Long, who is Black, said her doctor in Dayton, Ohio, told her she was not a candidate for surgery and suggested palliative care. After seeking a second opinion at Duke University Medical Center, Durham, N.C., where her sister worked, the 51-year-old wife and mother of two had surgery, radiation, and chemotherapy there in North Carolina. When the chemo stopped working after 3 months, her oncologist at Duke referred her to a colleague at Massachusetts General Hospital in Boston, where she was accepted into a clinical trial.

“In 2019, I traveled to Boston from Dayton, Ohio, every 3 weeks for labs and scans, to make sure that the drug wasn’t doing more harm than good, making sure that the drug as developed was maintaining, shrinking, or even eliminating the disease. Physically and financially, it takes a toll on you and loved ones.”

Her medical insurance did not cover the direct expenses from the clinical trial, and she was spending $1,000-$1,500 each trip. Sometimes they drove the 15 hours to Boston, and sometimes they flew on the cheapest flight they could find.

It’s not an unfamiliar story: people traveling, often long distances, to take part in clinical trials they hope will save their lives.

The Lazarex Cancer Foundation of Danville, Calif., helped Mrs. Long do just that.

Marya Shegog, PhD, health equity and diversity coordinator at Lazarex, said that a patient travels an average of 500 miles to participate in a trial.

The financial hurdles often prevent patients from taking part in clinical trials, Dr. Shegog said. “When you are sick, and you have a disease that may be terminal, you start thinking about setting your things in order.”

Many patients have to make a decision.

“Do I bankrupt my family on trying and hoping that this drug works and helps me live longer, or do I start setting things in order so that when I’m gone, they’re okay or at least better than if I wouldn’t have spent all the money traveling back and forth.”

Dr. Shegog, a 17-year cancer survivor, says when she was battling cervical cancer, a clinical trial was never offered or explored.

Lazarex has been helping cancer patients who have run out of options for 15 years. It identifies clinical trial opportunities and reimburses patients for all travel costs. Last year, Lazarex reimbursed more than 1,000 cancer patients. And it has supported more than 6,000 people since opening its doors.

“Lazarex exists to help remove the barriers of people not being able to participate in trials,” Dr. Shegog said. “It’s systemic that the medical system does not treat patients the same and oftentimes does not offer or make aware the opportunities for African Americans to participate.”

But now, thanks in part to COVID-19, new possibilities are taking shape. The pandemic has changed the landscape for trials, forcing many of them to go virtual, which allows patients to schedule telehealth visits and get some services like bloodwork and CT or MRI scans closer to home. Mrs. Long’s trial eventually went virtual.

“It was absolutely fantastic,” she said. “Having the trial locally, it saves us money, it saves wear and tear on my body. Being in the car, being in an airport or in a plane and in a hotel, all of that wears on you physically.”

The move to virtual studies may have lasting effects on research and treatment.

“The current pandemic has forced us to reexamine all of the traditional burdens we place on patients as it relates to receiving cancer treatment,” said Hala Borno, MD, an assistant professor of medicine at the University of California, San Francisco. “Whether they’re coming to our health care facility to see a clinician, for diagnostics such as blood draws and scans, or to receive therapy, this pandemic has challenged us to explore other possibilities that minimize the risk of exposure to SARS-CoV-2. What I find striking is that it has helped us operationalize use of telemedicine and the delivery of care closer to home.”

This is especially encouraging news for minority patients whose participation in trials has for years lagged well behind that of Whites.

But travel is not the only reason. Racial disparities in clinical trials have long been an issue that’s just another part of the implicit bias in health care.

Compared with White people, Black people are largely at higher risk for heart disease, cancer, stroke, diabetes, asthma, and even mental health problems.

And it’s not just African Americans. Asians, Hispanics, Native Americans, and Alaska Natives are all underrepresented in trials at a time when there is growing evidence that drugs may have different effects on different populations.

Dr. Borno is an oncologist who specializes in prostate cancer, a disease that she says shows a “significant disparity,” where Black men are two times more likely to die from advanced prostate cancer, compared with white men. Yet Black men make up just 3% of advanced therapeutic trials.

“A lack of diversity and inclusion in clinical trials is unacceptable,” she said. “If we continue to underrecruit racial/ethnic minorities and older adults to therapeutic clinical trials, we will not be powered to make valid conclusions regarding safety and efficacy in those patient populations. As a result, we can do harm.”

Dr. Borno said that telehealth and telemedicine are not cure-alls, and digital health solutions don’t work for all patients. Approaches, she says, must be tailored to the individual, or disparities could worsen.

In 2020, the Food and Drug Administration approved 53 new drugs. Overall, 32,000 patients took part in these trials. On average, 75% were White, 8% were Black, 6% were Asian, and 11% were Hispanic.

Here’s one stark example of the issue. In 2015, the FDA approved ixazomib (Ninlaro), a promising new drug for multiple myeloma, a blood cancer that affects Black people at disproportionately higher rates than White people. In the United States, one in five people diagnosed with multiple myeloma are Black people. They are more than twice as likely to get the disease as White people. Yet during the clinical trial of 722 participants, only 13 patients, or 1.8%, were Black.

The American Cancer Society estimates that more than 600,000 Americans will die from cancer this year. Historically, Black Americans have the highest death rate and the shortest survival of any racial or ethnic group, stemming largely, it concluded, from centuries of structural racism.

According to Jamie Freedman, MD, head of U.S. medical affairs at Genentech, a global pharmaceutical company, the lack of diversity is often tied to where studies are run.

“Companies tend to choose major academic medical centers where there is a high volume of clinical trial work. When you go to the same tried and true hospitals repeatedly, the pool of patients becomes very homogeneous and tends to be primarily white,” he said. “It’s critical to bring more trials into the community setting by including new sites that can reach underrepresented groups, and Genentech is making significant progress in that area.”

Dr. Freedman believes that, while access is a big hurdle, it doesn’t end there.

“Many patients have a lack of trust in the health care system,” he said. “There are also issues around underserved communities being able to afford quality care, so it’s important to keep time and financial burdens in mind when designing trials to help mitigate barriers such as travel, parking, time off work, and child care.”

Genentech started its diversity and inclusion effort several years ago. Dr. Freeman said that, until more trials become diverse, Black Americans will continue to pay the price. “I think they’re losing their lives in part due to lack of access to these trials. And that is why Genentech and all of us in the health care industry need to change how we design and enroll these studies. We have a long way to go, but I think the steps we’re taking are leading us in the right direction.”

Jennifer Jones-McMeans, PhD, director of global clinical affairs at Abbott Pharmaceuticals, is a clinical research scientist who has designed and led many clinical trials.

She said that Abbott is actively working on solutions.

“We have designed our trials to reduce the barriers to participation and expand access,” she said. “This can be as simple as providing transportation services or home visits for those who are housebound. We’re taking it a step further and providing home health services where someone comes to the home and provides follow-up visits there.”

They also provide interpretation services to address any language barriers.

“We are reaching out to a new set of talented investigators who work closely with underrepresented communities. They are very much wedded and supportive of the communities they treat. By working with doctors within these communities, it expands access to new therapies.”

Spokesperson Keanna Ghazvini said that Pfizer Pharmaceuticals is also committed to increasing minority participation in trials.

“We know that if historically underserved populations are left out of clinical trials, they risk not benefiting from medical breakthroughs down the line,” she said.

The National Institutes of Health’s National Library of Medicine maintains the clinicaltrials.gov database.

There, you can find information on nearly 372,000 publicly and privately supported clinical trials happening in all 50 states and 219 countries. Many are funded by the NIH, but not all of these studies have been evaluated by the U.S. government.

Andrea Denicoff, a nurse consultant at the National Cancer Institute and head of clinical trials operations for the NCI’s National Clinical Trials Network, has been involved in clinical research at the NIH for 35 years.

“It’s really important that our publicly funded trials represent the people of the country,” she said. “There are some cancers that we’re doing a good job in enrolling minorities, and other cancers we need to do a much better job in having a diverse representation in our trials.”

Ms. Denicoff believed opening trials in places where people live is key, but having a diverse clinical trials team is as important.

“We need to reinforce that cancer centers across the country have open doors, and anyone with cancer feels comfortable getting care at that center, and that also includes discussing the option to participate in clinical trials when one might be available. We know from research that when people are invited and asked about trial participation and educated about them, they’ll be much more interested in joining them.”

Ms. Denicoff said that, during the pandemic, the NCI quickly came up with guidance to allow trial sites to send patients their oral study drugs and set up virtual visits. She believes it may help increase future access.

‘Lola Fashoyin-Aje, MD, associate director for science and policy to address disparities in the Oncology Center of Excellence at the FDA, says the agency firmly believes clinical trials should represent the patients who will ultimately get the drug if it’s approved.

But the FDA’s power to require diversity in trials is limited.

“It is important to point out that there are legal constraints which limit’s FDA’s authority to require specific proportional representation in clinical trials by demographic factors,” Dr. Fashoyin-Aje said.

Still, some researchers feel the FDA should play a bigger role. The question is: Should diversity be mandated?

Rhonda Long is now back in Boston to start a new trial, with a new drug that targets her specific mutation. She will be there for 2 months. Once again, Lazarex will help cover some of the cost.

She wants people of color to understand that they are missing out on the promise of new cancer drugs and extended life.

“I feel like there’s not enough emphasis on clinical trials, I don’t believe there’s enough emphasis on second opinions, I don’t think there’s enough emphasis that medicine happens outside our borders, outside of our communities. Clinical trials that don’t have a broad range of participants, how do we know how effective they are if Black and brown people, Asian or Latin American people aren’t represented in the trial?”

And with more trials adopting virtual elements, she said it’s time for minorities to get on board.

Dr. Freedman believed the groundwork is being laid for that to happen. “I don’t think we’ll ever return back to the way we used to do things, where everything has to be done at the clinical trial site. I just don’t think we’re ever going back.”

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

“I’m the first person in my circle of family and friends to participate in a clinical trial.”

Five years ago, Rhonda Long was diagnosed with cholangiocarcinoma, a rare bile duct cancer that’s seen in only about 8,000 Americans each year.

At the time, Mrs. Long, who is Black, said her doctor in Dayton, Ohio, told her she was not a candidate for surgery and suggested palliative care. After seeking a second opinion at Duke University Medical Center, Durham, N.C., where her sister worked, the 51-year-old wife and mother of two had surgery, radiation, and chemotherapy there in North Carolina. When the chemo stopped working after 3 months, her oncologist at Duke referred her to a colleague at Massachusetts General Hospital in Boston, where she was accepted into a clinical trial.

“In 2019, I traveled to Boston from Dayton, Ohio, every 3 weeks for labs and scans, to make sure that the drug wasn’t doing more harm than good, making sure that the drug as developed was maintaining, shrinking, or even eliminating the disease. Physically and financially, it takes a toll on you and loved ones.”

Her medical insurance did not cover the direct expenses from the clinical trial, and she was spending $1,000-$1,500 each trip. Sometimes they drove the 15 hours to Boston, and sometimes they flew on the cheapest flight they could find.

It’s not an unfamiliar story: people traveling, often long distances, to take part in clinical trials they hope will save their lives.

The Lazarex Cancer Foundation of Danville, Calif., helped Mrs. Long do just that.

Marya Shegog, PhD, health equity and diversity coordinator at Lazarex, said that a patient travels an average of 500 miles to participate in a trial.

The financial hurdles often prevent patients from taking part in clinical trials, Dr. Shegog said. “When you are sick, and you have a disease that may be terminal, you start thinking about setting your things in order.”

Many patients have to make a decision.

“Do I bankrupt my family on trying and hoping that this drug works and helps me live longer, or do I start setting things in order so that when I’m gone, they’re okay or at least better than if I wouldn’t have spent all the money traveling back and forth.”

Dr. Shegog, a 17-year cancer survivor, says when she was battling cervical cancer, a clinical trial was never offered or explored.

Lazarex has been helping cancer patients who have run out of options for 15 years. It identifies clinical trial opportunities and reimburses patients for all travel costs. Last year, Lazarex reimbursed more than 1,000 cancer patients. And it has supported more than 6,000 people since opening its doors.

“Lazarex exists to help remove the barriers of people not being able to participate in trials,” Dr. Shegog said. “It’s systemic that the medical system does not treat patients the same and oftentimes does not offer or make aware the opportunities for African Americans to participate.”

But now, thanks in part to COVID-19, new possibilities are taking shape. The pandemic has changed the landscape for trials, forcing many of them to go virtual, which allows patients to schedule telehealth visits and get some services like bloodwork and CT or MRI scans closer to home. Mrs. Long’s trial eventually went virtual.

“It was absolutely fantastic,” she said. “Having the trial locally, it saves us money, it saves wear and tear on my body. Being in the car, being in an airport or in a plane and in a hotel, all of that wears on you physically.”

The move to virtual studies may have lasting effects on research and treatment.

“The current pandemic has forced us to reexamine all of the traditional burdens we place on patients as it relates to receiving cancer treatment,” said Hala Borno, MD, an assistant professor of medicine at the University of California, San Francisco. “Whether they’re coming to our health care facility to see a clinician, for diagnostics such as blood draws and scans, or to receive therapy, this pandemic has challenged us to explore other possibilities that minimize the risk of exposure to SARS-CoV-2. What I find striking is that it has helped us operationalize use of telemedicine and the delivery of care closer to home.”

This is especially encouraging news for minority patients whose participation in trials has for years lagged well behind that of Whites.

But travel is not the only reason. Racial disparities in clinical trials have long been an issue that’s just another part of the implicit bias in health care.

Compared with White people, Black people are largely at higher risk for heart disease, cancer, stroke, diabetes, asthma, and even mental health problems.

And it’s not just African Americans. Asians, Hispanics, Native Americans, and Alaska Natives are all underrepresented in trials at a time when there is growing evidence that drugs may have different effects on different populations.

Dr. Borno is an oncologist who specializes in prostate cancer, a disease that she says shows a “significant disparity,” where Black men are two times more likely to die from advanced prostate cancer, compared with white men. Yet Black men make up just 3% of advanced therapeutic trials.

“A lack of diversity and inclusion in clinical trials is unacceptable,” she said. “If we continue to underrecruit racial/ethnic minorities and older adults to therapeutic clinical trials, we will not be powered to make valid conclusions regarding safety and efficacy in those patient populations. As a result, we can do harm.”

Dr. Borno said that telehealth and telemedicine are not cure-alls, and digital health solutions don’t work for all patients. Approaches, she says, must be tailored to the individual, or disparities could worsen.

In 2020, the Food and Drug Administration approved 53 new drugs. Overall, 32,000 patients took part in these trials. On average, 75% were White, 8% were Black, 6% were Asian, and 11% were Hispanic.

Here’s one stark example of the issue. In 2015, the FDA approved ixazomib (Ninlaro), a promising new drug for multiple myeloma, a blood cancer that affects Black people at disproportionately higher rates than White people. In the United States, one in five people diagnosed with multiple myeloma are Black people. They are more than twice as likely to get the disease as White people. Yet during the clinical trial of 722 participants, only 13 patients, or 1.8%, were Black.

The American Cancer Society estimates that more than 600,000 Americans will die from cancer this year. Historically, Black Americans have the highest death rate and the shortest survival of any racial or ethnic group, stemming largely, it concluded, from centuries of structural racism.

According to Jamie Freedman, MD, head of U.S. medical affairs at Genentech, a global pharmaceutical company, the lack of diversity is often tied to where studies are run.

“Companies tend to choose major academic medical centers where there is a high volume of clinical trial work. When you go to the same tried and true hospitals repeatedly, the pool of patients becomes very homogeneous and tends to be primarily white,” he said. “It’s critical to bring more trials into the community setting by including new sites that can reach underrepresented groups, and Genentech is making significant progress in that area.”

Dr. Freedman believes that, while access is a big hurdle, it doesn’t end there.

“Many patients have a lack of trust in the health care system,” he said. “There are also issues around underserved communities being able to afford quality care, so it’s important to keep time and financial burdens in mind when designing trials to help mitigate barriers such as travel, parking, time off work, and child care.”

Genentech started its diversity and inclusion effort several years ago. Dr. Freeman said that, until more trials become diverse, Black Americans will continue to pay the price. “I think they’re losing their lives in part due to lack of access to these trials. And that is why Genentech and all of us in the health care industry need to change how we design and enroll these studies. We have a long way to go, but I think the steps we’re taking are leading us in the right direction.”

Jennifer Jones-McMeans, PhD, director of global clinical affairs at Abbott Pharmaceuticals, is a clinical research scientist who has designed and led many clinical trials.

She said that Abbott is actively working on solutions.

“We have designed our trials to reduce the barriers to participation and expand access,” she said. “This can be as simple as providing transportation services or home visits for those who are housebound. We’re taking it a step further and providing home health services where someone comes to the home and provides follow-up visits there.”

They also provide interpretation services to address any language barriers.

“We are reaching out to a new set of talented investigators who work closely with underrepresented communities. They are very much wedded and supportive of the communities they treat. By working with doctors within these communities, it expands access to new therapies.”

Spokesperson Keanna Ghazvini said that Pfizer Pharmaceuticals is also committed to increasing minority participation in trials.

“We know that if historically underserved populations are left out of clinical trials, they risk not benefiting from medical breakthroughs down the line,” she said.

The National Institutes of Health’s National Library of Medicine maintains the clinicaltrials.gov database.

There, you can find information on nearly 372,000 publicly and privately supported clinical trials happening in all 50 states and 219 countries. Many are funded by the NIH, but not all of these studies have been evaluated by the U.S. government.

Andrea Denicoff, a nurse consultant at the National Cancer Institute and head of clinical trials operations for the NCI’s National Clinical Trials Network, has been involved in clinical research at the NIH for 35 years.

“It’s really important that our publicly funded trials represent the people of the country,” she said. “There are some cancers that we’re doing a good job in enrolling minorities, and other cancers we need to do a much better job in having a diverse representation in our trials.”

Ms. Denicoff believed opening trials in places where people live is key, but having a diverse clinical trials team is as important.

“We need to reinforce that cancer centers across the country have open doors, and anyone with cancer feels comfortable getting care at that center, and that also includes discussing the option to participate in clinical trials when one might be available. We know from research that when people are invited and asked about trial participation and educated about them, they’ll be much more interested in joining them.”

Ms. Denicoff said that, during the pandemic, the NCI quickly came up with guidance to allow trial sites to send patients their oral study drugs and set up virtual visits. She believes it may help increase future access.

‘Lola Fashoyin-Aje, MD, associate director for science and policy to address disparities in the Oncology Center of Excellence at the FDA, says the agency firmly believes clinical trials should represent the patients who will ultimately get the drug if it’s approved.

But the FDA’s power to require diversity in trials is limited.

“It is important to point out that there are legal constraints which limit’s FDA’s authority to require specific proportional representation in clinical trials by demographic factors,” Dr. Fashoyin-Aje said.

Still, some researchers feel the FDA should play a bigger role. The question is: Should diversity be mandated?

Rhonda Long is now back in Boston to start a new trial, with a new drug that targets her specific mutation. She will be there for 2 months. Once again, Lazarex will help cover some of the cost.

She wants people of color to understand that they are missing out on the promise of new cancer drugs and extended life.

“I feel like there’s not enough emphasis on clinical trials, I don’t believe there’s enough emphasis on second opinions, I don’t think there’s enough emphasis that medicine happens outside our borders, outside of our communities. Clinical trials that don’t have a broad range of participants, how do we know how effective they are if Black and brown people, Asian or Latin American people aren’t represented in the trial?”

And with more trials adopting virtual elements, she said it’s time for minorities to get on board.

Dr. Freedman believed the groundwork is being laid for that to happen. “I don’t think we’ll ever return back to the way we used to do things, where everything has to be done at the clinical trial site. I just don’t think we’re ever going back.”

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

I recently was contacted by my nurse to schedule follow-up for a patient of mine whose routine labs sent by his cardiologist showed a blood glucose of 48 and a potassium of 5.8. He did not have diabetes, was not on any medications that could cause hyperkalemia, and most importantly he was asymptomatic when the labs were drawn.

If you are looking for zebras you might consider adrenal insufficiency, which could cause both hyperkalemia and hypoglycemia, but this would make no sense in someone asymptomatic.

This pattern is one I have seen commonly when I am on call, and I am contacted about abnormal labs. The lab reported no hemolysis seen, but this is the typical pattern seen with hemolytic specimens and/or specimens that have been held a long time before they are analyzed.

Lippi and colleagues reported on the clinically significant increase in potassium in samples that visually appeared not to be hemolyzed.¹ Hemolyzed specimens can also drop glucose values, but not as profoundly as raising potassium values. When left unprocessed, glycolysis occurs in the white blood cells of a blood sample and may consume 5%-7% of the sample’s glucose content per hour.²

Khaled and colleagues looked at the drop in glucose levels in samples over time based on what anticoagulants were used.³ They found that, at 3 hours, glucose measurements were decreased by 28.4 mg/dL when sodium citrate is used, 58 mg/dL when EDTA was used, 15.4 mg/dL when fluoride oxalate was used, and 60.2 mg/dL when no anticoagulant is used.

Low blood sugars caused by elevated WBCs in blood samples has been well described.⁴ It has been described with moderate and very high WBC counts, as well as with the leukocytosis seen with polycythemia vera.⁵ The term “leukocyte larceny” has been used to describe high WBC counts that can not only utilize glucose, but also oxygen.

Saccheti and colleagues described a patient with a WBC greater than 500,000 who had repeatedly low oxygen levels on blood gases, that did not correlate with the normal oxygen saturations measured by pulse oximetry.⁶ This same issue has been seen in patients with extreme thrombocytosis.⁷Pearl: When labs don’t make sense clinically, always look at the possibility that there may be a problem in the tube and not in the person. Especially think of this when blood samples may have been held for a long time before they are run, such as with visiting nurse visits and blood draws at shelters and nursing homes.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Lippi G et al. Clin Chem Lab Med. 2006;44(3):311-6.

2. Mikesh LM and Bruns DE. Clin Chem. 2008 May;54(5):930-2.

3. Khaled S et al. Al-Mukhtar Journal of Sciences. 2018;33(2):100-6.

4. Goodenow TJ and Malarkey WB. JAMA. 1977;237(18):1961-2.

5. R Arem et al. Arch Intern Med. 1982 Nov;142(12):2199-201.

6. Sacchetti A et al. J Emerg Med. 1990;8:567–569.

7. A Mehta et al. Eur Respir J. 2008 Feb;31(2):469-72.

I recently was contacted by my nurse to schedule follow-up for a patient of mine whose routine labs sent by his cardiologist showed a blood glucose of 48 and a potassium of 5.8. He did not have diabetes, was not on any medications that could cause hyperkalemia, and most importantly he was asymptomatic when the labs were drawn.

If you are looking for zebras you might consider adrenal insufficiency, which could cause both hyperkalemia and hypoglycemia, but this would make no sense in someone asymptomatic.

This pattern is one I have seen commonly when I am on call, and I am contacted about abnormal labs. The lab reported no hemolysis seen, but this is the typical pattern seen with hemolytic specimens and/or specimens that have been held a long time before they are analyzed.

Lippi and colleagues reported on the clinically significant increase in potassium in samples that visually appeared not to be hemolyzed.¹ Hemolyzed specimens can also drop glucose values, but not as profoundly as raising potassium values. When left unprocessed, glycolysis occurs in the white blood cells of a blood sample and may consume 5%-7% of the sample’s glucose content per hour.²

Khaled and colleagues looked at the drop in glucose levels in samples over time based on what anticoagulants were used.³ They found that, at 3 hours, glucose measurements were decreased by 28.4 mg/dL when sodium citrate is used, 58 mg/dL when EDTA was used, 15.4 mg/dL when fluoride oxalate was used, and 60.2 mg/dL when no anticoagulant is used.

Low blood sugars caused by elevated WBCs in blood samples has been well described.⁴ It has been described with moderate and very high WBC counts, as well as with the leukocytosis seen with polycythemia vera.⁵ The term “leukocyte larceny” has been used to describe high WBC counts that can not only utilize glucose, but also oxygen.

Saccheti and colleagues described a patient with a WBC greater than 500,000 who had repeatedly low oxygen levels on blood gases, that did not correlate with the normal oxygen saturations measured by pulse oximetry.⁶ This same issue has been seen in patients with extreme thrombocytosis.⁷Pearl: When labs don’t make sense clinically, always look at the possibility that there may be a problem in the tube and not in the person. Especially think of this when blood samples may have been held for a long time before they are run, such as with visiting nurse visits and blood draws at shelters and nursing homes.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Lippi G et al. Clin Chem Lab Med. 2006;44(3):311-6.

2. Mikesh LM and Bruns DE. Clin Chem. 2008 May;54(5):930-2.

3. Khaled S et al. Al-Mukhtar Journal of Sciences. 2018;33(2):100-6.

4. Goodenow TJ and Malarkey WB. JAMA. 1977;237(18):1961-2.

5. R Arem et al. Arch Intern Med. 1982 Nov;142(12):2199-201.

6. Sacchetti A et al. J Emerg Med. 1990;8:567–569.

7. A Mehta et al. Eur Respir J. 2008 Feb;31(2):469-72.

I recently was contacted by my nurse to schedule follow-up for a patient of mine whose routine labs sent by his cardiologist showed a blood glucose of 48 and a potassium of 5.8. He did not have diabetes, was not on any medications that could cause hyperkalemia, and most importantly he was asymptomatic when the labs were drawn.

If you are looking for zebras you might consider adrenal insufficiency, which could cause both hyperkalemia and hypoglycemia, but this would make no sense in someone asymptomatic.

This pattern is one I have seen commonly when I am on call, and I am contacted about abnormal labs. The lab reported no hemolysis seen, but this is the typical pattern seen with hemolytic specimens and/or specimens that have been held a long time before they are analyzed.

Lippi and colleagues reported on the clinically significant increase in potassium in samples that visually appeared not to be hemolyzed.¹ Hemolyzed specimens can also drop glucose values, but not as profoundly as raising potassium values. When left unprocessed, glycolysis occurs in the white blood cells of a blood sample and may consume 5%-7% of the sample’s glucose content per hour.²

Khaled and colleagues looked at the drop in glucose levels in samples over time based on what anticoagulants were used.³ They found that, at 3 hours, glucose measurements were decreased by 28.4 mg/dL when sodium citrate is used, 58 mg/dL when EDTA was used, 15.4 mg/dL when fluoride oxalate was used, and 60.2 mg/dL when no anticoagulant is used.

Low blood sugars caused by elevated WBCs in blood samples has been well described.⁴ It has been described with moderate and very high WBC counts, as well as with the leukocytosis seen with polycythemia vera.⁵ The term “leukocyte larceny” has been used to describe high WBC counts that can not only utilize glucose, but also oxygen.

Saccheti and colleagues described a patient with a WBC greater than 500,000 who had repeatedly low oxygen levels on blood gases, that did not correlate with the normal oxygen saturations measured by pulse oximetry.⁶ This same issue has been seen in patients with extreme thrombocytosis.⁷Pearl: When labs don’t make sense clinically, always look at the possibility that there may be a problem in the tube and not in the person. Especially think of this when blood samples may have been held for a long time before they are run, such as with visiting nurse visits and blood draws at shelters and nursing homes.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Lippi G et al. Clin Chem Lab Med. 2006;44(3):311-6.

2. Mikesh LM and Bruns DE. Clin Chem. 2008 May;54(5):930-2.

3. Khaled S et al. Al-Mukhtar Journal of Sciences. 2018;33(2):100-6.

4. Goodenow TJ and Malarkey WB. JAMA. 1977;237(18):1961-2.

5. R Arem et al. Arch Intern Med. 1982 Nov;142(12):2199-201.

6. Sacchetti A et al. J Emerg Med. 1990;8:567–569.

7. A Mehta et al. Eur Respir J. 2008 Feb;31(2):469-72.

The new SARS-CoV-2 variants are not just problems for humans. 

New research shows they can also infect animals, and for the first time, variants have been able to infect mice, a development that may complicate efforts to rein in the global spread of the virus.

In addition, two new studies have implications for pets. Veterinarians in Texas and the United Kingdom have documented infections of B.1.1.7 – the fast-spreading variant first found in the United Kingdom – in dogs and cats. The animals in the U.K. study also had heart damage, but it’s unclear if the damage was caused by the virus or was already there and was found as a result of their infections.

Animal studies of SARS-CoV-2 and its emerging variants are urgent, said Sarah Hamer, DVM, PhD, a veterinarian and epidemiologist at Texas A&M University, College Station. 

She’s part of a network of scientists who are swabbing the pets of people who are diagnosed with COVID-19 to find out how often the virus passes from people to animals.

The collaboration is part of the One Health initiative through the Centers for Disease Control and Prevention. One Health aims to tackle infectious diseases by recognizing that people can’t be fully protected from pathogens unless animals and the environment are also safeguarded. “Over 70% of emerging diseases of humans have their origins in animal populations,” Dr. Hamer said. “So if we are only focusing on studying disease as it emerges in humans and ignoring where those pathogens have been transmitted or circulating for years, then we might miss the ability to detect early emergence. We might miss the ability to control these diseases before they become problems for human health.”
 

Variants move to mice

In new work, researchers at the Institut Pasteur in Paris have shown that the B.1.351 and P.1 variants of concern, which were first identified in South Africa and Brazil, respectively, can infect mice, giving the virus a potential new host. Older versions of the virus couldn’t infect mice because they weren’t able bind to receptors on their cells. These two variants can.

On one hand, that’s a good thing, because it will help scientists more easily conduct experiments in mice. Before, if they wanted to do an experiment with SARS-CoV-2 in mice, they had to use a special strain of mouse that was bred to carry human ACE2 receptors on their lung cells. Now that mice can become naturally infected, any breed will do, making it less costly and time-consuming to study the virus in animals.

On the other hand, the idea that the virus could have more and different ways to spread isn’t good news.

“From the beginning of the epidemic and since human coronaviruses emerged from animals, it has been very important to establish in which species the virus can replicate, in particular the species that live close to humans,” said Xavier Montagutelli, DVM, PhD, head of the Mouse Genetics Laboratory at the Institut Pasteur. His study was published as a preprint ahead of peer review on BioRXIV.

Once a virus establishes itself within a population of animals, it will continue to spread and change and may eventually be passed back to humans. It’s the reason that birds and pigs are closely monitored for influenza viruses.

So far, with SARS-CoV-2, only one animal has been found to catch and spread the virus and pass it back to people – farmed mink. Researchers have also documented SARS-CoV-2 antibodies in escaped mink living near mink farms in Utah, suggesting the virus has the potential to be transmitted to wild populations.

And the move of the virus into mice suggests that SARS-CoV-2 could establish itself in a population of wild animals that live close to humans.

“At this point, we have no evidence that wild mice are infected, or can become infected from humans,” Dr. Montagutelli said. He added that his findings emphasize the need to regularly test animals for signs of the infection. He said these surveys will need to be updated as more variants emerge.

“So far, we’ve been lucky that our livestock species aren’t really susceptible to this,” said Scott Weese, DVM, a professor at Ontario Veterinary College at the University of Guelph, who studies emerging infectious diseases that pass between animals and people.

While the outbreaks on mink farms have been bad, imagine what would happen, Dr. Weese said, if the virus moved to pigs.

“If this infects a barn with a few thousand pigs – which is like the mink scenario – but we have a lot more pig farms than mink farms,” he said.

“With these variants, we have to reset,” he said. “We’ve figured all this about animals and how it spreads or how it doesn’t, but now we need to repeat all those studies to make sure it’s the same thing.”
 

Pets catch variants, too

Pets living with people who are infected with SARS-CoV-2 can catch it from their owners, and cats are particularly susceptible, Dr. Weese said. 

Contact tracing studies, which also tested animals for signs of the virus, have found that about half of cats living with infected people have signs of infection, while 20%-30% of dogs were sick.

“It’s quite common,” for pets to get COVID, Dr. Weese said.

Now, two new studies have shown that pets can also be infected by the newer B.1.1.7 variant.

The first study, from researchers at Texas A&M, documented the variant in a dog and a cat from Brazos County, Texas. Neither the older black Lab mix or the older domestic shorthair cat had symptoms of COVID-19. They were tested as part of a project funded by the CDC.

Dr. Weese said pets are at risk by people who are infected, but they don’t seem to play a big role in spreading the disease to humans. So if you have pets, there’s no reason to worry that they could bring the virus home to you. You’re more likely to be a risk to them.

The second study, from a specialty animal hospital in southeast England, documented infection by the B.1.1.7 virus variant in 11 dogs and cats. Most of the pets had unusual symptoms, including inflamed hearts and heart damage.

Dr. Weese called this study interesting and said its findings deserve more investigation, but pointed out that the study can’t determine whether the infection caused the heart damage, or whether it was already there.

“This is a human virus. There’s no doubt about it. It can affect other species, but it likes people a lot better,” he said. “If you think about the big picture and what is the potential role of animals, pets are pretty low risk.”
 

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

The new SARS-CoV-2 variants are not just problems for humans. 

New research shows they can also infect animals, and for the first time, variants have been able to infect mice, a development that may complicate efforts to rein in the global spread of the virus.

In addition, two new studies have implications for pets. Veterinarians in Texas and the United Kingdom have documented infections of B.1.1.7 – the fast-spreading variant first found in the United Kingdom – in dogs and cats. The animals in the U.K. study also had heart damage, but it’s unclear if the damage was caused by the virus or was already there and was found as a result of their infections.

Animal studies of SARS-CoV-2 and its emerging variants are urgent, said Sarah Hamer, DVM, PhD, a veterinarian and epidemiologist at Texas A&M University, College Station. 

She’s part of a network of scientists who are swabbing the pets of people who are diagnosed with COVID-19 to find out how often the virus passes from people to animals.

The collaboration is part of the One Health initiative through the Centers for Disease Control and Prevention. One Health aims to tackle infectious diseases by recognizing that people can’t be fully protected from pathogens unless animals and the environment are also safeguarded. “Over 70% of emerging diseases of humans have their origins in animal populations,” Dr. Hamer said. “So if we are only focusing on studying disease as it emerges in humans and ignoring where those pathogens have been transmitted or circulating for years, then we might miss the ability to detect early emergence. We might miss the ability to control these diseases before they become problems for human health.”
 

Variants move to mice

In new work, researchers at the Institut Pasteur in Paris have shown that the B.1.351 and P.1 variants of concern, which were first identified in South Africa and Brazil, respectively, can infect mice, giving the virus a potential new host. Older versions of the virus couldn’t infect mice because they weren’t able bind to receptors on their cells. These two variants can.

On one hand, that’s a good thing, because it will help scientists more easily conduct experiments in mice. Before, if they wanted to do an experiment with SARS-CoV-2 in mice, they had to use a special strain of mouse that was bred to carry human ACE2 receptors on their lung cells. Now that mice can become naturally infected, any breed will do, making it less costly and time-consuming to study the virus in animals.

On the other hand, the idea that the virus could have more and different ways to spread isn’t good news.

“From the beginning of the epidemic and since human coronaviruses emerged from animals, it has been very important to establish in which species the virus can replicate, in particular the species that live close to humans,” said Xavier Montagutelli, DVM, PhD, head of the Mouse Genetics Laboratory at the Institut Pasteur. His study was published as a preprint ahead of peer review on BioRXIV.

Once a virus establishes itself within a population of animals, it will continue to spread and change and may eventually be passed back to humans. It’s the reason that birds and pigs are closely monitored for influenza viruses.

So far, with SARS-CoV-2, only one animal has been found to catch and spread the virus and pass it back to people – farmed mink. Researchers have also documented SARS-CoV-2 antibodies in escaped mink living near mink farms in Utah, suggesting the virus has the potential to be transmitted to wild populations.

And the move of the virus into mice suggests that SARS-CoV-2 could establish itself in a population of wild animals that live close to humans.

“At this point, we have no evidence that wild mice are infected, or can become infected from humans,” Dr. Montagutelli said. He added that his findings emphasize the need to regularly test animals for signs of the infection. He said these surveys will need to be updated as more variants emerge.

“So far, we’ve been lucky that our livestock species aren’t really susceptible to this,” said Scott Weese, DVM, a professor at Ontario Veterinary College at the University of Guelph, who studies emerging infectious diseases that pass between animals and people.

While the outbreaks on mink farms have been bad, imagine what would happen, Dr. Weese said, if the virus moved to pigs.

“If this infects a barn with a few thousand pigs – which is like the mink scenario – but we have a lot more pig farms than mink farms,” he said.

“With these variants, we have to reset,” he said. “We’ve figured all this about animals and how it spreads or how it doesn’t, but now we need to repeat all those studies to make sure it’s the same thing.”
 

Pets catch variants, too

Pets living with people who are infected with SARS-CoV-2 can catch it from their owners, and cats are particularly susceptible, Dr. Weese said. 

Contact tracing studies, which also tested animals for signs of the virus, have found that about half of cats living with infected people have signs of infection, while 20%-30% of dogs were sick.

“It’s quite common,” for pets to get COVID, Dr. Weese said.

Now, two new studies have shown that pets can also be infected by the newer B.1.1.7 variant.

The first study, from researchers at Texas A&M, documented the variant in a dog and a cat from Brazos County, Texas. Neither the older black Lab mix or the older domestic shorthair cat had symptoms of COVID-19. They were tested as part of a project funded by the CDC.

Dr. Weese said pets are at risk by people who are infected, but they don’t seem to play a big role in spreading the disease to humans. So if you have pets, there’s no reason to worry that they could bring the virus home to you. You’re more likely to be a risk to them.

The second study, from a specialty animal hospital in southeast England, documented infection by the B.1.1.7 virus variant in 11 dogs and cats. Most of the pets had unusual symptoms, including inflamed hearts and heart damage.

Dr. Weese called this study interesting and said its findings deserve more investigation, but pointed out that the study can’t determine whether the infection caused the heart damage, or whether it was already there.

“This is a human virus. There’s no doubt about it. It can affect other species, but it likes people a lot better,” he said. “If you think about the big picture and what is the potential role of animals, pets are pretty low risk.”
 

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

The new SARS-CoV-2 variants are not just problems for humans. 

New research shows they can also infect animals, and for the first time, variants have been able to infect mice, a development that may complicate efforts to rein in the global spread of the virus.

In addition, two new studies have implications for pets. Veterinarians in Texas and the United Kingdom have documented infections of B.1.1.7 – the fast-spreading variant first found in the United Kingdom – in dogs and cats. The animals in the U.K. study also had heart damage, but it’s unclear if the damage was caused by the virus or was already there and was found as a result of their infections.

Animal studies of SARS-CoV-2 and its emerging variants are urgent, said Sarah Hamer, DVM, PhD, a veterinarian and epidemiologist at Texas A&M University, College Station. 

She’s part of a network of scientists who are swabbing the pets of people who are diagnosed with COVID-19 to find out how often the virus passes from people to animals.

The collaboration is part of the One Health initiative through the Centers for Disease Control and Prevention. One Health aims to tackle infectious diseases by recognizing that people can’t be fully protected from pathogens unless animals and the environment are also safeguarded. “Over 70% of emerging diseases of humans have their origins in animal populations,” Dr. Hamer said. “So if we are only focusing on studying disease as it emerges in humans and ignoring where those pathogens have been transmitted or circulating for years, then we might miss the ability to detect early emergence. We might miss the ability to control these diseases before they become problems for human health.”
 

Variants move to mice

In new work, researchers at the Institut Pasteur in Paris have shown that the B.1.351 and P.1 variants of concern, which were first identified in South Africa and Brazil, respectively, can infect mice, giving the virus a potential new host. Older versions of the virus couldn’t infect mice because they weren’t able bind to receptors on their cells. These two variants can.

On one hand, that’s a good thing, because it will help scientists more easily conduct experiments in mice. Before, if they wanted to do an experiment with SARS-CoV-2 in mice, they had to use a special strain of mouse that was bred to carry human ACE2 receptors on their lung cells. Now that mice can become naturally infected, any breed will do, making it less costly and time-consuming to study the virus in animals.

On the other hand, the idea that the virus could have more and different ways to spread isn’t good news.

“From the beginning of the epidemic and since human coronaviruses emerged from animals, it has been very important to establish in which species the virus can replicate, in particular the species that live close to humans,” said Xavier Montagutelli, DVM, PhD, head of the Mouse Genetics Laboratory at the Institut Pasteur. His study was published as a preprint ahead of peer review on BioRXIV.

Once a virus establishes itself within a population of animals, it will continue to spread and change and may eventually be passed back to humans. It’s the reason that birds and pigs are closely monitored for influenza viruses.

So far, with SARS-CoV-2, only one animal has been found to catch and spread the virus and pass it back to people – farmed mink. Researchers have also documented SARS-CoV-2 antibodies in escaped mink living near mink farms in Utah, suggesting the virus has the potential to be transmitted to wild populations.

And the move of the virus into mice suggests that SARS-CoV-2 could establish itself in a population of wild animals that live close to humans.

“At this point, we have no evidence that wild mice are infected, or can become infected from humans,” Dr. Montagutelli said. He added that his findings emphasize the need to regularly test animals for signs of the infection. He said these surveys will need to be updated as more variants emerge.

“So far, we’ve been lucky that our livestock species aren’t really susceptible to this,” said Scott Weese, DVM, a professor at Ontario Veterinary College at the University of Guelph, who studies emerging infectious diseases that pass between animals and people.

While the outbreaks on mink farms have been bad, imagine what would happen, Dr. Weese said, if the virus moved to pigs.

“If this infects a barn with a few thousand pigs – which is like the mink scenario – but we have a lot more pig farms than mink farms,” he said.

“With these variants, we have to reset,” he said. “We’ve figured all this about animals and how it spreads or how it doesn’t, but now we need to repeat all those studies to make sure it’s the same thing.”
 

Pets catch variants, too

Pets living with people who are infected with SARS-CoV-2 can catch it from their owners, and cats are particularly susceptible, Dr. Weese said. 

Contact tracing studies, which also tested animals for signs of the virus, have found that about half of cats living with infected people have signs of infection, while 20%-30% of dogs were sick.

“It’s quite common,” for pets to get COVID, Dr. Weese said.

Now, two new studies have shown that pets can also be infected by the newer B.1.1.7 variant.

The first study, from researchers at Texas A&M, documented the variant in a dog and a cat from Brazos County, Texas. Neither the older black Lab mix or the older domestic shorthair cat had symptoms of COVID-19. They were tested as part of a project funded by the CDC.

Dr. Weese said pets are at risk by people who are infected, but they don’t seem to play a big role in spreading the disease to humans. So if you have pets, there’s no reason to worry that they could bring the virus home to you. You’re more likely to be a risk to them.

The second study, from a specialty animal hospital in southeast England, documented infection by the B.1.1.7 virus variant in 11 dogs and cats. Most of the pets had unusual symptoms, including inflamed hearts and heart damage.

Dr. Weese called this study interesting and said its findings deserve more investigation, but pointed out that the study can’t determine whether the infection caused the heart damage, or whether it was already there.

“This is a human virus. There’s no doubt about it. It can affect other species, but it likes people a lot better,” he said. “If you think about the big picture and what is the potential role of animals, pets are pretty low risk.”
 

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

The increased risk of type 2 diabetes in women with polycystic ovary syndrome is well established, but a new analysis has shown that obesity is the major mediator and a target for preventing or reversing this comorbidity.

rumruay/Shutterstock

“Most women with PCOS are obese, complicating the effort to understand whether high rates of diabetes in this population are due to PCOS or excess weight, but our study now suggest that obesity isa targetable risk factor,” reported Panagiotis Anagnostis, MD, PhD, a reproductive endocrinologist at the Medical School of Aristotle University, Thessaloniki, Greece.

Obesity is also a known risk factor for type 2 diabetes (T2D), but there is reason to suspect that PCOS, which is associated with abnormal carbohydrate metabolism, has a direct impact on the risk of developing T2D, according to Dr. Anagnostis. It is also reasonable to expect “a synergistic deleterious effect” from PCOS and obesity on adverse changes in glucose metabolism that lead to T2D.

Even though rates of obesity among women with PCOS reach 80% in some studies, Dr. Anagnostis attempted to disentangle the relationship between obesity, PCOS, and risk of T2D using a large set of data drawn from a comprehensive search of published studies.

After screening with predefined criteria, 12 studies provided data on 224,284 women, of whom 45,361 had PCOS and 5,717 had T2D. Not least of the criteria for inclusion in this analysis, all studies stratified women as obese, defined as a body mass index (BMI) greater than 30 kg/m², or nonobese, he reported at the annual meeting of the Endocrine Society.



Diabetes risk tripled in PCOS

When compared without regard to BMI, the relative risk of having T2D among those with PCOS relative to those without this condition was more than three times greater (RR 3.13; P < .001). When women with PCOS were stratified for BMI, obesity was associated with a more than fourfold increased risk relative to controls without PCOS (RR, 4.06; P < .001).

In women who were nonobese, the risk of T2D was numerically higher for those with PCOS than those without (RR, 2.68), but it was only a trend with a large confidence interval (95% confidence interval, 0.97-7.49).

Among women with PCOS, those who were obese also had a more than fourfold and highly significant increased risk of T2D relative to those who were not obese (RR, 4.20; P < .001).

The message from these data is that obesity is a major and potentially modifiable risk factor for diabetes in women with PCOS, according to Dr. Anagnostis.

He said these data provide the basis for recommending weight loss specifically for managing this common PCOS comorbidity.

Almost the same relative risk of diabetes was derived from an analysis of a women’s health database published 2 years ago in Diabetes Care. In that study with 1,916 person-years of follow-up, the hazard ratio for T2D was also more than three times greater (HR, 3.23; P < .001) for those with PCOS relative to those without the syndrome.

However, normal BMI did not eliminate risk of developing diabetes in this study. Rather, the relative risk of T2D in women with PCOS was higher in those of normal weight, compared with those who were obese (HR, 4.68 vs. 2.36; P < .005). The investigators recommend screening all women with PCOS at least every 3 years with more frequent screening in those with risk factors.



PCOS complexity challenges simple conclusions

The complexity of disturbed metabolic pathways in patients with PCOS and obesity might explain some of the difficulty in unraveling the relationship between these two disease states and diabetes risk. In one recent review, it was suggested that obesity and PCOS share interrelated adverse effects on glucose metabolism. As a result, these associations are “more complex than a simple cause-and-effect process.” the authors of that article concluded.

Furthermore, in their examination of metabolic pathways, genetic susceptibility, and behavioral factors that might link PCOS, weight gain, and T2D, the authors did not ignore the psychological impact of PCOS in causing obesity and, as a byproduct, diabetes. These psychological factors might be relevant to treatment.

For example, depression and stress “might hamper ongoing attempts at lifestyle change and therefore effective weight loss” in at least some women, they cautioned.

However, in encouraging weight loss in overweight women with PCOS, the debate about cause of T2D might be moot in practical terms, according to Michael Dansinger, MD, founding director of the diabetes reversal program at Tufts Medical Center, Boston.

“Reducing excess body fat reduces the risk of type 2 diabetes,” Dr. Dansinger said in an interview. “Since women with obesity and PCOS are clearly at risk for future type 2 diabetes, that’s another reason to lose excess body fat through healthy eating and exercise.”

Dr. Anagnostis and Dr. Dansinger reported no relevant conflicts of interest.

The increased risk of type 2 diabetes in women with polycystic ovary syndrome is well established, but a new analysis has shown that obesity is the major mediator and a target for preventing or reversing this comorbidity.

rumruay/Shutterstock

“Most women with PCOS are obese, complicating the effort to understand whether high rates of diabetes in this population are due to PCOS or excess weight, but our study now suggest that obesity isa targetable risk factor,” reported Panagiotis Anagnostis, MD, PhD, a reproductive endocrinologist at the Medical School of Aristotle University, Thessaloniki, Greece.

Obesity is also a known risk factor for type 2 diabetes (T2D), but there is reason to suspect that PCOS, which is associated with abnormal carbohydrate metabolism, has a direct impact on the risk of developing T2D, according to Dr. Anagnostis. It is also reasonable to expect “a synergistic deleterious effect” from PCOS and obesity on adverse changes in glucose metabolism that lead to T2D.

Even though rates of obesity among women with PCOS reach 80% in some studies, Dr. Anagnostis attempted to disentangle the relationship between obesity, PCOS, and risk of T2D using a large set of data drawn from a comprehensive search of published studies.

After screening with predefined criteria, 12 studies provided data on 224,284 women, of whom 45,361 had PCOS and 5,717 had T2D. Not least of the criteria for inclusion in this analysis, all studies stratified women as obese, defined as a body mass index (BMI) greater than 30 kg/m², or nonobese, he reported at the annual meeting of the Endocrine Society.



Diabetes risk tripled in PCOS

When compared without regard to BMI, the relative risk of having T2D among those with PCOS relative to those without this condition was more than three times greater (RR 3.13; P < .001). When women with PCOS were stratified for BMI, obesity was associated with a more than fourfold increased risk relative to controls without PCOS (RR, 4.06; P < .001).

In women who were nonobese, the risk of T2D was numerically higher for those with PCOS than those without (RR, 2.68), but it was only a trend with a large confidence interval (95% confidence interval, 0.97-7.49).

Among women with PCOS, those who were obese also had a more than fourfold and highly significant increased risk of T2D relative to those who were not obese (RR, 4.20; P < .001).

The message from these data is that obesity is a major and potentially modifiable risk factor for diabetes in women with PCOS, according to Dr. Anagnostis.

He said these data provide the basis for recommending weight loss specifically for managing this common PCOS comorbidity.

Almost the same relative risk of diabetes was derived from an analysis of a women’s health database published 2 years ago in Diabetes Care. In that study with 1,916 person-years of follow-up, the hazard ratio for T2D was also more than three times greater (HR, 3.23; P < .001) for those with PCOS relative to those without the syndrome.

However, normal BMI did not eliminate risk of developing diabetes in this study. Rather, the relative risk of T2D in women with PCOS was higher in those of normal weight, compared with those who were obese (HR, 4.68 vs. 2.36; P < .005). The investigators recommend screening all women with PCOS at least every 3 years with more frequent screening in those with risk factors.



PCOS complexity challenges simple conclusions

The complexity of disturbed metabolic pathways in patients with PCOS and obesity might explain some of the difficulty in unraveling the relationship between these two disease states and diabetes risk. In one recent review, it was suggested that obesity and PCOS share interrelated adverse effects on glucose metabolism. As a result, these associations are “more complex than a simple cause-and-effect process.” the authors of that article concluded.

Furthermore, in their examination of metabolic pathways, genetic susceptibility, and behavioral factors that might link PCOS, weight gain, and T2D, the authors did not ignore the psychological impact of PCOS in causing obesity and, as a byproduct, diabetes. These psychological factors might be relevant to treatment.

For example, depression and stress “might hamper ongoing attempts at lifestyle change and therefore effective weight loss” in at least some women, they cautioned.

However, in encouraging weight loss in overweight women with PCOS, the debate about cause of T2D might be moot in practical terms, according to Michael Dansinger, MD, founding director of the diabetes reversal program at Tufts Medical Center, Boston.

“Reducing excess body fat reduces the risk of type 2 diabetes,” Dr. Dansinger said in an interview. “Since women with obesity and PCOS are clearly at risk for future type 2 diabetes, that’s another reason to lose excess body fat through healthy eating and exercise.”

Dr. Anagnostis and Dr. Dansinger reported no relevant conflicts of interest.

The increased risk of type 2 diabetes in women with polycystic ovary syndrome is well established, but a new analysis has shown that obesity is the major mediator and a target for preventing or reversing this comorbidity.

rumruay/Shutterstock

“Most women with PCOS are obese, complicating the effort to understand whether high rates of diabetes in this population are due to PCOS or excess weight, but our study now suggest that obesity isa targetable risk factor,” reported Panagiotis Anagnostis, MD, PhD, a reproductive endocrinologist at the Medical School of Aristotle University, Thessaloniki, Greece.

Obesity is also a known risk factor for type 2 diabetes (T2D), but there is reason to suspect that PCOS, which is associated with abnormal carbohydrate metabolism, has a direct impact on the risk of developing T2D, according to Dr. Anagnostis. It is also reasonable to expect “a synergistic deleterious effect” from PCOS and obesity on adverse changes in glucose metabolism that lead to T2D.

Even though rates of obesity among women with PCOS reach 80% in some studies, Dr. Anagnostis attempted to disentangle the relationship between obesity, PCOS, and risk of T2D using a large set of data drawn from a comprehensive search of published studies.

After screening with predefined criteria, 12 studies provided data on 224,284 women, of whom 45,361 had PCOS and 5,717 had T2D. Not least of the criteria for inclusion in this analysis, all studies stratified women as obese, defined as a body mass index (BMI) greater than 30 kg/m², or nonobese, he reported at the annual meeting of the Endocrine Society.



Diabetes risk tripled in PCOS

When compared without regard to BMI, the relative risk of having T2D among those with PCOS relative to those without this condition was more than three times greater (RR 3.13; P < .001). When women with PCOS were stratified for BMI, obesity was associated with a more than fourfold increased risk relative to controls without PCOS (RR, 4.06; P < .001).

In women who were nonobese, the risk of T2D was numerically higher for those with PCOS than those without (RR, 2.68), but it was only a trend with a large confidence interval (95% confidence interval, 0.97-7.49).

Among women with PCOS, those who were obese also had a more than fourfold and highly significant increased risk of T2D relative to those who were not obese (RR, 4.20; P < .001).

The message from these data is that obesity is a major and potentially modifiable risk factor for diabetes in women with PCOS, according to Dr. Anagnostis.

He said these data provide the basis for recommending weight loss specifically for managing this common PCOS comorbidity.

Almost the same relative risk of diabetes was derived from an analysis of a women’s health database published 2 years ago in Diabetes Care. In that study with 1,916 person-years of follow-up, the hazard ratio for T2D was also more than three times greater (HR, 3.23; P < .001) for those with PCOS relative to those without the syndrome.

However, normal BMI did not eliminate risk of developing diabetes in this study. Rather, the relative risk of T2D in women with PCOS was higher in those of normal weight, compared with those who were obese (HR, 4.68 vs. 2.36; P < .005). The investigators recommend screening all women with PCOS at least every 3 years with more frequent screening in those with risk factors.



PCOS complexity challenges simple conclusions

The complexity of disturbed metabolic pathways in patients with PCOS and obesity might explain some of the difficulty in unraveling the relationship between these two disease states and diabetes risk. In one recent review, it was suggested that obesity and PCOS share interrelated adverse effects on glucose metabolism. As a result, these associations are “more complex than a simple cause-and-effect process.” the authors of that article concluded.

Furthermore, in their examination of metabolic pathways, genetic susceptibility, and behavioral factors that might link PCOS, weight gain, and T2D, the authors did not ignore the psychological impact of PCOS in causing obesity and, as a byproduct, diabetes. These psychological factors might be relevant to treatment.

For example, depression and stress “might hamper ongoing attempts at lifestyle change and therefore effective weight loss” in at least some women, they cautioned.

However, in encouraging weight loss in overweight women with PCOS, the debate about cause of T2D might be moot in practical terms, according to Michael Dansinger, MD, founding director of the diabetes reversal program at Tufts Medical Center, Boston.

“Reducing excess body fat reduces the risk of type 2 diabetes,” Dr. Dansinger said in an interview. “Since women with obesity and PCOS are clearly at risk for future type 2 diabetes, that’s another reason to lose excess body fat through healthy eating and exercise.”

Dr. Anagnostis and Dr. Dansinger reported no relevant conflicts of interest.

Individuals who experience inflammation of the thyroid gland during acute COVID-19 illness may still have subacute thyroiditis months later, even if thyroid function has normalized, new research suggests.

Furthermore, the thyroiditis seems to be different from thyroid inflammation caused by other viruses, said Ilaria Muller, MD, PhD, when presenting her findings March 21 at the virtual ENDO 2021 meeting.

“SARS-CoV-2 seems to have multifactorial action on thyroid function,” said Dr. Muller, of the University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Italy.

In July 2020, Dr. Muller and colleagues described patients hospitalized at their institution with severe COVID-19, 15% of whom had thyrotoxicosis due to atypical subacute thyroiditis, compared with just 1% of a comparison group hospitalized in the same subintensive care units during the spring of 2019, as reported by this news organization.

The “atypical” thyroiditis that occurred in the patients with COVID-19 was not associated with neck pain and affected more men than women. Moreover, it was associated with low TSH and free-triiodothyronine (T3) levels, and normal or elevated levels of free-thyroxine (T4), which is a very different presentation to classic nonthyroidal illness syndrome (NTIS) usually seen in critically ill patients, she explained.

Although transient T4 elevations can occur in acute illness, that phenomenon is not associated with low TSH. This newly described scenario appears to be a combination of thyrotoxicosis and NTIS, Dr. Muller and colleagues had speculated last summer.
 

Follow patients with COVID-19 and thyroid dysfunction for a year

Now, in an assessment of 51 patients 3 months after hospitalization for moderate-to-severe COVID-19 reported by Dr. Muller at ENDO 2021, both inflammatory markers and thyroid function had normalized, yet on imaging, a third of patients still exhibited focal hypoechoic areas suggestive of thyroiditis.

Of those, two-thirds had reduced uptake on thyroid scintigraphy, but few had antithyroid autoantibodies.

“The thyroid dysfunction induced by COVID-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months,” Dr. Muller emphasized.

Asked to comment, session moderator Robert W. Lash, MD, the Endocrine Society’s chief professional & clinical affairs officer, told this news organization: “When you’re ICU-level sick, it’s not unusual to have weird thyroid tests. Some viruses cause thyroid problems as well ... What makes this different is that while a lot of thyroid inflammation is caused by antibodies, this was not.”

“It looks like this was [SARS-CoV-2] causing damage to the thyroid gland, which is interesting,” he noted, adding that the thyroid gland expresses high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), which allow SARS-CoV-2 to infect human cells.

“This is probably part of that same story,” Dr. Lash said.  

For patients who had thyroid abnormalities during acute COVID-19 illness or develop symptoms that might be thyroid-related afterward, he advises: “You should keep an eye on thyroid tests. It just raises your awareness ... You might check their thyroid tests every 6 months for a year.”
 

Signs of focal thyroiditis despite normalized thyroid function

The 51 patients (33 men and 18 women) hospitalized with moderate-to-severe COVID-19 had no history of thyroid disease and had not been taking thyroid medications, amiodarone, or steroids before baseline TSH was measured.

From baseline to 3 months, TSH rose from 1.2 to 1.6 mIU/L, while serum concentrations of T4, T3, C-reactive protein, and full blood counts had all normalized (all P < 0.01 vs. baseline).

Thyroid ultrasound at 3 months in 49 patients showed signs of focal thyroiditis in 16 (33%).

Among 14 patients of those who further underwent thyroid 99mTc or I123 uptake scans, four (29%) were normal, eight (57%) had focally reduced uptake, and two (14%) had diffusely reduced uptake.

Of the 16 patients with focal thyroiditis, only three were positive for autoantibodies to thyroglobulin (TgAb) or thyroid peroxidase (TPOAb). All were negative for autoantibodies to the TSH receptor.

“Importantly, of the two with diffusely reduced uptake, only one was positive for TPOAb or TgAb,” Dr. Muller noted, adding, “SARS-CoV-2 disease seems to trigger some dysfunction which very likely has complex and multifactorial mechanisms.”

In response to a question about a possible role for biopsies and thyroid cytology, Dr. Muller replied: “That’s definitely the key ... So far we’re just making guesses, so the key will be cytological or histological studies to see what is really going on in the thyroid.”

“What we know is that [unlike] classical thyroiditis that has been described after viral diseases including SARS-CoV-2, these patients have a different scenario ... Probably something is going on within the thyroid with a different mechanism, so surely cytology and histology studies are what we need,” she concluded.

The study was funded by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, and by a COVID-19 research grant from the European Society of Endocrinology. Dr. Muller and Dr. Lash have reported no relevant financial relationships.

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

Individuals who experience inflammation of the thyroid gland during acute COVID-19 illness may still have subacute thyroiditis months later, even if thyroid function has normalized, new research suggests.

Furthermore, the thyroiditis seems to be different from thyroid inflammation caused by other viruses, said Ilaria Muller, MD, PhD, when presenting her findings March 21 at the virtual ENDO 2021 meeting.

“SARS-CoV-2 seems to have multifactorial action on thyroid function,” said Dr. Muller, of the University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Italy.

In July 2020, Dr. Muller and colleagues described patients hospitalized at their institution with severe COVID-19, 15% of whom had thyrotoxicosis due to atypical subacute thyroiditis, compared with just 1% of a comparison group hospitalized in the same subintensive care units during the spring of 2019, as reported by this news organization.

The “atypical” thyroiditis that occurred in the patients with COVID-19 was not associated with neck pain and affected more men than women. Moreover, it was associated with low TSH and free-triiodothyronine (T3) levels, and normal or elevated levels of free-thyroxine (T4), which is a very different presentation to classic nonthyroidal illness syndrome (NTIS) usually seen in critically ill patients, she explained.

Although transient T4 elevations can occur in acute illness, that phenomenon is not associated with low TSH. This newly described scenario appears to be a combination of thyrotoxicosis and NTIS, Dr. Muller and colleagues had speculated last summer.
 

Follow patients with COVID-19 and thyroid dysfunction for a year

Now, in an assessment of 51 patients 3 months after hospitalization for moderate-to-severe COVID-19 reported by Dr. Muller at ENDO 2021, both inflammatory markers and thyroid function had normalized, yet on imaging, a third of patients still exhibited focal hypoechoic areas suggestive of thyroiditis.

Of those, two-thirds had reduced uptake on thyroid scintigraphy, but few had antithyroid autoantibodies.

“The thyroid dysfunction induced by COVID-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months,” Dr. Muller emphasized.

Asked to comment, session moderator Robert W. Lash, MD, the Endocrine Society’s chief professional & clinical affairs officer, told this news organization: “When you’re ICU-level sick, it’s not unusual to have weird thyroid tests. Some viruses cause thyroid problems as well ... What makes this different is that while a lot of thyroid inflammation is caused by antibodies, this was not.”

“It looks like this was [SARS-CoV-2] causing damage to the thyroid gland, which is interesting,” he noted, adding that the thyroid gland expresses high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), which allow SARS-CoV-2 to infect human cells.

“This is probably part of that same story,” Dr. Lash said.  

For patients who had thyroid abnormalities during acute COVID-19 illness or develop symptoms that might be thyroid-related afterward, he advises: “You should keep an eye on thyroid tests. It just raises your awareness ... You might check their thyroid tests every 6 months for a year.”
 

Signs of focal thyroiditis despite normalized thyroid function

The 51 patients (33 men and 18 women) hospitalized with moderate-to-severe COVID-19 had no history of thyroid disease and had not been taking thyroid medications, amiodarone, or steroids before baseline TSH was measured.

From baseline to 3 months, TSH rose from 1.2 to 1.6 mIU/L, while serum concentrations of T4, T3, C-reactive protein, and full blood counts had all normalized (all P < 0.01 vs. baseline).

Thyroid ultrasound at 3 months in 49 patients showed signs of focal thyroiditis in 16 (33%).

Among 14 patients of those who further underwent thyroid 99mTc or I123 uptake scans, four (29%) were normal, eight (57%) had focally reduced uptake, and two (14%) had diffusely reduced uptake.

Of the 16 patients with focal thyroiditis, only three were positive for autoantibodies to thyroglobulin (TgAb) or thyroid peroxidase (TPOAb). All were negative for autoantibodies to the TSH receptor.

“Importantly, of the two with diffusely reduced uptake, only one was positive for TPOAb or TgAb,” Dr. Muller noted, adding, “SARS-CoV-2 disease seems to trigger some dysfunction which very likely has complex and multifactorial mechanisms.”

In response to a question about a possible role for biopsies and thyroid cytology, Dr. Muller replied: “That’s definitely the key ... So far we’re just making guesses, so the key will be cytological or histological studies to see what is really going on in the thyroid.”

“What we know is that [unlike] classical thyroiditis that has been described after viral diseases including SARS-CoV-2, these patients have a different scenario ... Probably something is going on within the thyroid with a different mechanism, so surely cytology and histology studies are what we need,” she concluded.

The study was funded by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, and by a COVID-19 research grant from the European Society of Endocrinology. Dr. Muller and Dr. Lash have reported no relevant financial relationships.

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

Individuals who experience inflammation of the thyroid gland during acute COVID-19 illness may still have subacute thyroiditis months later, even if thyroid function has normalized, new research suggests.

Furthermore, the thyroiditis seems to be different from thyroid inflammation caused by other viruses, said Ilaria Muller, MD, PhD, when presenting her findings March 21 at the virtual ENDO 2021 meeting.

“SARS-CoV-2 seems to have multifactorial action on thyroid function,” said Dr. Muller, of the University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Italy.

In July 2020, Dr. Muller and colleagues described patients hospitalized at their institution with severe COVID-19, 15% of whom had thyrotoxicosis due to atypical subacute thyroiditis, compared with just 1% of a comparison group hospitalized in the same subintensive care units during the spring of 2019, as reported by this news organization.

The “atypical” thyroiditis that occurred in the patients with COVID-19 was not associated with neck pain and affected more men than women. Moreover, it was associated with low TSH and free-triiodothyronine (T3) levels, and normal or elevated levels of free-thyroxine (T4), which is a very different presentation to classic nonthyroidal illness syndrome (NTIS) usually seen in critically ill patients, she explained.

Although transient T4 elevations can occur in acute illness, that phenomenon is not associated with low TSH. This newly described scenario appears to be a combination of thyrotoxicosis and NTIS, Dr. Muller and colleagues had speculated last summer.
 

Follow patients with COVID-19 and thyroid dysfunction for a year

Now, in an assessment of 51 patients 3 months after hospitalization for moderate-to-severe COVID-19 reported by Dr. Muller at ENDO 2021, both inflammatory markers and thyroid function had normalized, yet on imaging, a third of patients still exhibited focal hypoechoic areas suggestive of thyroiditis.

Of those, two-thirds had reduced uptake on thyroid scintigraphy, but few had antithyroid autoantibodies.

“The thyroid dysfunction induced by COVID-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months,” Dr. Muller emphasized.

Asked to comment, session moderator Robert W. Lash, MD, the Endocrine Society’s chief professional & clinical affairs officer, told this news organization: “When you’re ICU-level sick, it’s not unusual to have weird thyroid tests. Some viruses cause thyroid problems as well ... What makes this different is that while a lot of thyroid inflammation is caused by antibodies, this was not.”

“It looks like this was [SARS-CoV-2] causing damage to the thyroid gland, which is interesting,” he noted, adding that the thyroid gland expresses high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), which allow SARS-CoV-2 to infect human cells.

“This is probably part of that same story,” Dr. Lash said.  

For patients who had thyroid abnormalities during acute COVID-19 illness or develop symptoms that might be thyroid-related afterward, he advises: “You should keep an eye on thyroid tests. It just raises your awareness ... You might check their thyroid tests every 6 months for a year.”
 

Signs of focal thyroiditis despite normalized thyroid function

The 51 patients (33 men and 18 women) hospitalized with moderate-to-severe COVID-19 had no history of thyroid disease and had not been taking thyroid medications, amiodarone, or steroids before baseline TSH was measured.

From baseline to 3 months, TSH rose from 1.2 to 1.6 mIU/L, while serum concentrations of T4, T3, C-reactive protein, and full blood counts had all normalized (all P < 0.01 vs. baseline).

Thyroid ultrasound at 3 months in 49 patients showed signs of focal thyroiditis in 16 (33%).

Among 14 patients of those who further underwent thyroid 99mTc or I123 uptake scans, four (29%) were normal, eight (57%) had focally reduced uptake, and two (14%) had diffusely reduced uptake.

Of the 16 patients with focal thyroiditis, only three were positive for autoantibodies to thyroglobulin (TgAb) or thyroid peroxidase (TPOAb). All were negative for autoantibodies to the TSH receptor.

“Importantly, of the two with diffusely reduced uptake, only one was positive for TPOAb or TgAb,” Dr. Muller noted, adding, “SARS-CoV-2 disease seems to trigger some dysfunction which very likely has complex and multifactorial mechanisms.”

In response to a question about a possible role for biopsies and thyroid cytology, Dr. Muller replied: “That’s definitely the key ... So far we’re just making guesses, so the key will be cytological or histological studies to see what is really going on in the thyroid.”

“What we know is that [unlike] classical thyroiditis that has been described after viral diseases including SARS-CoV-2, these patients have a different scenario ... Probably something is going on within the thyroid with a different mechanism, so surely cytology and histology studies are what we need,” she concluded.

The study was funded by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, and by a COVID-19 research grant from the European Society of Endocrinology. Dr. Muller and Dr. Lash have reported no relevant financial relationships.

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

More sleep at night, fewer or no sleep problems, and low levels of professional burnout were associated with a lower risk of developing COVID-19 among health care workers considered to be at high risk for exposure to patients with COVID-19, new evidence reveals.

PRImageFactory/iStock/Getty Images

For each additional hour of sleep at night, for example, risk for COVID-19 dropped by 12% in a study of 2844 frontline health care workers.

Furthermore, those who reported experiencing work-related burnout every day were 2.6 times more likely to report having COVID-19, to report having COVID-19 for a longer time, and to experience COVID-19 of more severity.

“This study underscores the importance of non–hygiene-related risk factors for COVID-19 and supports a holistic approach to health – including optimal sleep and job stress reduction to protect our health care workers from this and future pandemics,” senior author Sara B. Seidelmann, MD, said in an interview.

“Our findings add to the literature that sleep duration at night, sleep problems, and burnout may be risk factors for viral illnesses like COVID-19,” wrote Dr. Seidelmann and colleagues.

This is the first study to link COVID-19 risk to sleep habits – including number of hours of sleep at night, daytime napping hours, and severe sleep problems – among health care workers across multiple countries.

The study was published online March 22 in BMJ Nutrition, Prevention, and Health.

The researchers surveyed health care professionals in specialties considered to place personnel at high risk for exposure to SARS-CoV-2: critical care, emergency care, and internal medicine.

The association between sleep and burnout risk factors and COVID-19 did not vary significantly by specialty. “We didn’t detect any significant interactions between age, sex, specialty, or country,” said Dr. Seidelmann, assistant professor of clinical medicine at Columbia University College of Physicians and Surgeons, New York, and an internist at Stamford (Conn.) Hospital.

In addition to the 12% lower risk associated with each additional hour of sleep at night, each 1 additional hour of daytime napping was linked with a 6% increased risk for COVID-19 in an adjusted analysis (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.01-1.12).

Daytime napping slightly increased risk for COVID-19 in five of the six countries included in the study: France, Germany, Italy, the United Kingdom, and the United States. In contrast, in Spain, napping had a nonsignificant protective effect.

The survey asked health care workers to recall nighttime sleep duration, sleep disorders, and burnout in the year prior to onset of the COVID-19 pandemic.
 

‘Significant, close contact’ with COVID-19?

Lead author Hyunju Kim, NP, Dr. Seidelmann, and colleagues conducted the population-based, case-control study from July 17 to Sept. 25, 2020. They identified health care workers from the SurveyHealthcareGlobus (SHG) network.

Of the respondents, 72% were men. The mean age of the participants was 48 years, and the study population was 77% White, 12% Asian, 6% mixed background, 2% Black, and 1% other. (The remainder preferred not to say).

The 568 health care workers considered to have COVID-19 were classified on the basis of self-reported symptoms. Control participants had no symptoms associated with COVID-19.

All 2,844 participants answered yes to a question about having “significant close contact” with COVID-19 patients in their workplace.

Compared to reporting no sleep problems, having three such problems – difficulty sleeping at night, poor sleep continuity, and frequent use of sleeping pills – was associated with 88% greater odds of COVID-19 (OR, 1.88; 95% CI, 1.17–3.01).

Having one sleep problem was not associated with COVID-19.
 

More burnout, greater risk

The health care workers reported the severity of any work-related burnout. “There was a significant dose-response relationship between frequency of burnout and COVID-19,” the researchers noted.

Those who reported having burnout rarely or weekly had a 1.3-1.4 greater chance of reporting COVID-19 compared to those who reported having no burnout, for example.

In addition, reporting a high level of burnout was linked to about three times the risk for having COVID-19 of longer duration and of greater severity.

What drives the association between sleep problems, burnout, and higher risk for COVID-19 and severe COVID-19 remains unknown.

“The mechanism underlying these associations isn’t clear, but suboptimal sleep, sleep disorders, and stress may result in immune system dysregulation, increased inflammation, and alterations in hormones such as cortisol and melatonin that may increase vulnerability to viral infections,” Dr. Seidelmann said.
 

Strengths and limitations

Using a large network of health care workers in the early phase of the pandemic is a strength of the study. How generalizable the findings are outside the SHG database of 1.5 million health care workers remains unknown.

Another limitation was reliance on self-reporting of COVID-19 patient exposure, outcomes, and covariates, which could have introduced bias.

“However,” the researchers noted, “health care workers are likely a reliable source of information.”
 

Insomnia a common challenge

A 2020 meta-analysis examined the effect of insomnia and psychological factors on COVID-19 risk among health care workers. Lead author Kavita Batra, PhD, of the University of Nevada, Las Vegas (UNLV), and colleagues found that the pooled prevalence of insomnia was almost 28%.

“The recent six-country study by Kim and colleagues also underscores this relationship between lack of sleep and having higher odds of COVID-19 infection,” Manoj Sharma, MBBS, PhD, professor of social and behavioral health in the UNLV department of environmental and occupational health, and one of the study authors, said in an interview.

More research is warranted to learn the direction of the association, he said. Does reduced sleep lower immunity and make a health care worker more susceptible to SARS-CoV-2 infection, or does the anxiety associated with COVID-19 contribute to insomnia?

“Practicing sleep hygiene is a must not only for health workers but also for everyone,” Dr. Sharma added. Recommendations include having fixed hours of going to bed, fixed hours of waking up, not overdoing naps, having at least 30 minutes of winding down before sleeping, having a dark bedroom devoid of all electronics and other disturbances, avoiding smoking, alcohol, and stimulants (such as caffeine) before sleeping, and practicing relaxation right before sleeping, he said.

“It is hard for some health care workers, especially those who work night shifts, but it must be a priority to follow as many sleep hygiene measures as possible,” Dr. Sharma said. “After all, if you do not take care of yourself how can you take care of others?”

Dr. Seidelmann, Dr. Batra, and Dr. Sharma have disclosed no relevant financial relationships.

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

More sleep at night, fewer or no sleep problems, and low levels of professional burnout were associated with a lower risk of developing COVID-19 among health care workers considered to be at high risk for exposure to patients with COVID-19, new evidence reveals.

PRImageFactory/iStock/Getty Images

For each additional hour of sleep at night, for example, risk for COVID-19 dropped by 12% in a study of 2844 frontline health care workers.

Furthermore, those who reported experiencing work-related burnout every day were 2.6 times more likely to report having COVID-19, to report having COVID-19 for a longer time, and to experience COVID-19 of more severity.

“This study underscores the importance of non–hygiene-related risk factors for COVID-19 and supports a holistic approach to health – including optimal sleep and job stress reduction to protect our health care workers from this and future pandemics,” senior author Sara B. Seidelmann, MD, said in an interview.

“Our findings add to the literature that sleep duration at night, sleep problems, and burnout may be risk factors for viral illnesses like COVID-19,” wrote Dr. Seidelmann and colleagues.

This is the first study to link COVID-19 risk to sleep habits – including number of hours of sleep at night, daytime napping hours, and severe sleep problems – among health care workers across multiple countries.

The study was published online March 22 in BMJ Nutrition, Prevention, and Health.

The researchers surveyed health care professionals in specialties considered to place personnel at high risk for exposure to SARS-CoV-2: critical care, emergency care, and internal medicine.

The association between sleep and burnout risk factors and COVID-19 did not vary significantly by specialty. “We didn’t detect any significant interactions between age, sex, specialty, or country,” said Dr. Seidelmann, assistant professor of clinical medicine at Columbia University College of Physicians and Surgeons, New York, and an internist at Stamford (Conn.) Hospital.

In addition to the 12% lower risk associated with each additional hour of sleep at night, each 1 additional hour of daytime napping was linked with a 6% increased risk for COVID-19 in an adjusted analysis (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.01-1.12).

Daytime napping slightly increased risk for COVID-19 in five of the six countries included in the study: France, Germany, Italy, the United Kingdom, and the United States. In contrast, in Spain, napping had a nonsignificant protective effect.

The survey asked health care workers to recall nighttime sleep duration, sleep disorders, and burnout in the year prior to onset of the COVID-19 pandemic.
 

‘Significant, close contact’ with COVID-19?

Lead author Hyunju Kim, NP, Dr. Seidelmann, and colleagues conducted the population-based, case-control study from July 17 to Sept. 25, 2020. They identified health care workers from the SurveyHealthcareGlobus (SHG) network.

Of the respondents, 72% were men. The mean age of the participants was 48 years, and the study population was 77% White, 12% Asian, 6% mixed background, 2% Black, and 1% other. (The remainder preferred not to say).

The 568 health care workers considered to have COVID-19 were classified on the basis of self-reported symptoms. Control participants had no symptoms associated with COVID-19.

All 2,844 participants answered yes to a question about having “significant close contact” with COVID-19 patients in their workplace.

Compared to reporting no sleep problems, having three such problems – difficulty sleeping at night, poor sleep continuity, and frequent use of sleeping pills – was associated with 88% greater odds of COVID-19 (OR, 1.88; 95% CI, 1.17–3.01).

Having one sleep problem was not associated with COVID-19.
 

More burnout, greater risk

The health care workers reported the severity of any work-related burnout. “There was a significant dose-response relationship between frequency of burnout and COVID-19,” the researchers noted.

Those who reported having burnout rarely or weekly had a 1.3-1.4 greater chance of reporting COVID-19 compared to those who reported having no burnout, for example.

In addition, reporting a high level of burnout was linked to about three times the risk for having COVID-19 of longer duration and of greater severity.

What drives the association between sleep problems, burnout, and higher risk for COVID-19 and severe COVID-19 remains unknown.

“The mechanism underlying these associations isn’t clear, but suboptimal sleep, sleep disorders, and stress may result in immune system dysregulation, increased inflammation, and alterations in hormones such as cortisol and melatonin that may increase vulnerability to viral infections,” Dr. Seidelmann said.
 

Strengths and limitations

Using a large network of health care workers in the early phase of the pandemic is a strength of the study. How generalizable the findings are outside the SHG database of 1.5 million health care workers remains unknown.

Another limitation was reliance on self-reporting of COVID-19 patient exposure, outcomes, and covariates, which could have introduced bias.

“However,” the researchers noted, “health care workers are likely a reliable source of information.”
 

Insomnia a common challenge

A 2020 meta-analysis examined the effect of insomnia and psychological factors on COVID-19 risk among health care workers. Lead author Kavita Batra, PhD, of the University of Nevada, Las Vegas (UNLV), and colleagues found that the pooled prevalence of insomnia was almost 28%.

“The recent six-country study by Kim and colleagues also underscores this relationship between lack of sleep and having higher odds of COVID-19 infection,” Manoj Sharma, MBBS, PhD, professor of social and behavioral health in the UNLV department of environmental and occupational health, and one of the study authors, said in an interview.

More research is warranted to learn the direction of the association, he said. Does reduced sleep lower immunity and make a health care worker more susceptible to SARS-CoV-2 infection, or does the anxiety associated with COVID-19 contribute to insomnia?

“Practicing sleep hygiene is a must not only for health workers but also for everyone,” Dr. Sharma added. Recommendations include having fixed hours of going to bed, fixed hours of waking up, not overdoing naps, having at least 30 minutes of winding down before sleeping, having a dark bedroom devoid of all electronics and other disturbances, avoiding smoking, alcohol, and stimulants (such as caffeine) before sleeping, and practicing relaxation right before sleeping, he said.

“It is hard for some health care workers, especially those who work night shifts, but it must be a priority to follow as many sleep hygiene measures as possible,” Dr. Sharma said. “After all, if you do not take care of yourself how can you take care of others?”

Dr. Seidelmann, Dr. Batra, and Dr. Sharma have disclosed no relevant financial relationships.

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

More sleep at night, fewer or no sleep problems, and low levels of professional burnout were associated with a lower risk of developing COVID-19 among health care workers considered to be at high risk for exposure to patients with COVID-19, new evidence reveals.

PRImageFactory/iStock/Getty Images

For each additional hour of sleep at night, for example, risk for COVID-19 dropped by 12% in a study of 2844 frontline health care workers.

Furthermore, those who reported experiencing work-related burnout every day were 2.6 times more likely to report having COVID-19, to report having COVID-19 for a longer time, and to experience COVID-19 of more severity.

“This study underscores the importance of non–hygiene-related risk factors for COVID-19 and supports a holistic approach to health – including optimal sleep and job stress reduction to protect our health care workers from this and future pandemics,” senior author Sara B. Seidelmann, MD, said in an interview.

“Our findings add to the literature that sleep duration at night, sleep problems, and burnout may be risk factors for viral illnesses like COVID-19,” wrote Dr. Seidelmann and colleagues.

This is the first study to link COVID-19 risk to sleep habits – including number of hours of sleep at night, daytime napping hours, and severe sleep problems – among health care workers across multiple countries.

The study was published online March 22 in BMJ Nutrition, Prevention, and Health.

The researchers surveyed health care professionals in specialties considered to place personnel at high risk for exposure to SARS-CoV-2: critical care, emergency care, and internal medicine.

The association between sleep and burnout risk factors and COVID-19 did not vary significantly by specialty. “We didn’t detect any significant interactions between age, sex, specialty, or country,” said Dr. Seidelmann, assistant professor of clinical medicine at Columbia University College of Physicians and Surgeons, New York, and an internist at Stamford (Conn.) Hospital.

In addition to the 12% lower risk associated with each additional hour of sleep at night, each 1 additional hour of daytime napping was linked with a 6% increased risk for COVID-19 in an adjusted analysis (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.01-1.12).

Daytime napping slightly increased risk for COVID-19 in five of the six countries included in the study: France, Germany, Italy, the United Kingdom, and the United States. In contrast, in Spain, napping had a nonsignificant protective effect.

The survey asked health care workers to recall nighttime sleep duration, sleep disorders, and burnout in the year prior to onset of the COVID-19 pandemic.
 

‘Significant, close contact’ with COVID-19?

Lead author Hyunju Kim, NP, Dr. Seidelmann, and colleagues conducted the population-based, case-control study from July 17 to Sept. 25, 2020. They identified health care workers from the SurveyHealthcareGlobus (SHG) network.

Of the respondents, 72% were men. The mean age of the participants was 48 years, and the study population was 77% White, 12% Asian, 6% mixed background, 2% Black, and 1% other. (The remainder preferred not to say).

The 568 health care workers considered to have COVID-19 were classified on the basis of self-reported symptoms. Control participants had no symptoms associated with COVID-19.

All 2,844 participants answered yes to a question about having “significant close contact” with COVID-19 patients in their workplace.

Compared to reporting no sleep problems, having three such problems – difficulty sleeping at night, poor sleep continuity, and frequent use of sleeping pills – was associated with 88% greater odds of COVID-19 (OR, 1.88; 95% CI, 1.17–3.01).

Having one sleep problem was not associated with COVID-19.
 

More burnout, greater risk

The health care workers reported the severity of any work-related burnout. “There was a significant dose-response relationship between frequency of burnout and COVID-19,” the researchers noted.

Those who reported having burnout rarely or weekly had a 1.3-1.4 greater chance of reporting COVID-19 compared to those who reported having no burnout, for example.

In addition, reporting a high level of burnout was linked to about three times the risk for having COVID-19 of longer duration and of greater severity.

What drives the association between sleep problems, burnout, and higher risk for COVID-19 and severe COVID-19 remains unknown.

“The mechanism underlying these associations isn’t clear, but suboptimal sleep, sleep disorders, and stress may result in immune system dysregulation, increased inflammation, and alterations in hormones such as cortisol and melatonin that may increase vulnerability to viral infections,” Dr. Seidelmann said.
 

Strengths and limitations

Using a large network of health care workers in the early phase of the pandemic is a strength of the study. How generalizable the findings are outside the SHG database of 1.5 million health care workers remains unknown.

Another limitation was reliance on self-reporting of COVID-19 patient exposure, outcomes, and covariates, which could have introduced bias.

“However,” the researchers noted, “health care workers are likely a reliable source of information.”
 

Insomnia a common challenge

A 2020 meta-analysis examined the effect of insomnia and psychological factors on COVID-19 risk among health care workers. Lead author Kavita Batra, PhD, of the University of Nevada, Las Vegas (UNLV), and colleagues found that the pooled prevalence of insomnia was almost 28%.

“The recent six-country study by Kim and colleagues also underscores this relationship between lack of sleep and having higher odds of COVID-19 infection,” Manoj Sharma, MBBS, PhD, professor of social and behavioral health in the UNLV department of environmental and occupational health, and one of the study authors, said in an interview.

More research is warranted to learn the direction of the association, he said. Does reduced sleep lower immunity and make a health care worker more susceptible to SARS-CoV-2 infection, or does the anxiety associated with COVID-19 contribute to insomnia?

“Practicing sleep hygiene is a must not only for health workers but also for everyone,” Dr. Sharma added. Recommendations include having fixed hours of going to bed, fixed hours of waking up, not overdoing naps, having at least 30 minutes of winding down before sleeping, having a dark bedroom devoid of all electronics and other disturbances, avoiding smoking, alcohol, and stimulants (such as caffeine) before sleeping, and practicing relaxation right before sleeping, he said.

“It is hard for some health care workers, especially those who work night shifts, but it must be a priority to follow as many sleep hygiene measures as possible,” Dr. Sharma said. “After all, if you do not take care of yourself how can you take care of others?”

Dr. Seidelmann, Dr. Batra, and Dr. Sharma have disclosed no relevant financial relationships.

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

Patients with hypothyroidism treated with the three most common pharmacologic strategies of levothyroxine (LT4) alone, LT4 in combination with triiodothyronine (T3), or desiccated thyroid extract showed no differences in thyroid symptoms or secondary outcomes in a double-blind, randomized study.

Sebastian Kaulitzki/Fotolia

“There are now proven good treatment options for the more than 1 in 10 patients with hypothyroidism who continue to experience symptoms of fatigue, mental fogginess, weight gain, and other symptoms despite taking levothyroxine,” first author Thanh Duc Hoang, DO, an endocrinologist at the Walter Reed National Military Medical Center, in Bethesda, Md., said in a press statement.

The findings were presented at the annual meeting of the Endocrine Society.

Commenting on the study, Alan P. Farwell, MD, said these new results are a valuable contribution to the understanding of treatment effects. “I think this is an interesting and important study and further studies are needed to clarify the optimal way to treat hypothyroidism,” said Dr. Farwell, who is director of endocrine clinics at Boston University.

Importantly, “the findings are different than studies where the patients are aware of what medication they are receiving,” he stressed in an interview, underscoring the importance of the double-blind design of the trial.

But Anne Cappola, MD, of the University of Pennsylvania, Philadelphia, pointed out that “the study was small and unlikely to have the statistical power to detect differences that could have been clinically important.”

Nevertheless, she too agreed that the double-blind study design is key: “My experience with patients is [the effects] are affected by patients’ perceptions about their thyroid medication. That is why studies designed so that patients do not know which treatment they are receiving are so important in this area.”
 

Randomized, double-blind comparison

Prior to the widespread availability of the current gold standard hypothyroidism treatment of LT4, the condition was typically treated with desiccated (animal) thyroid extract. And with many patients continuing to have a preference for this therapeutic approach, it is still commonly used.

Additionally, some patients treated with LT4 alone report greater improvements in symptoms with the addition of T3 – despite studies showing no benefits from the two together – leading to many clinicians commonly trying the combination approach.

To compare the efficacy of the three approaches in a prospective, double-blind, cross-over fashion, 75 patients received three therapeutic approaches each for 3 months: desiccated thyroid extract, an LT4/T3 combination, or LT4 alone.

After each 3-month treatment, patients completed a 36-point thyroid symptom questionnaire.

There was no significant differences in symptom relief, the primary outcome, between the three treatments (P = .32).

Overall, 45% of patients indicated they preferred desiccated thyroid as their first choice of treatment, 32% preferred LT4/T3 as their first choice, and 23% preferred LT4 alone.

For the secondary endpoints of weight, general health, depression (assessed using the Beck Depression Inventory), memory (Wechsler Memory Scale), lipids, and thyroid function, again, there were no significant differences between groups in any of the measures.
 

When switched to desiccated thyroid, many felt ‘much better’

A further exploratory analysis revealed that those who experienced symptoms while taking LT4 alone reported greater alleviation of symptoms with the other two treatments.

“As a whole group, there was no significant difference between the three treatment arms,” Dr. Hoang explained in an interview.

“However, with the subgroup analysis based on the scores of symptom questionnaires, we found that symptomatic patients on LT4 improved while being treated with LT4/T3 or desiccated thyroid,” he said.

Reports of improvements in switching to desiccated thyroid were notable, Dr. Hoang added. “Many patients when switched from LT4 to desiccated thyroid extract said they felt much better, [with] more energy, less mental fogginess, a better outlook, less flair of lupus symptoms, easier to lose weight, etc.”

The study also showed more patients with Hashimoto’s disease preferred desiccated thyroid extract and LT4/T3, compared with LT4 alone, however, the differences were not significant.
 

Treatment adjustments a helpful first step

Dr. Farwell noted that his approach when patients are still reporting symptoms despite LT4 treatment is to first try tweaking the dose.

“In my own practice, I prefer to adjust LT4 dosing first, and on occasion add T3, with a goal of getting both hormone levels in the upper half of the normal range,” he said. “I find that to be a better approach than desiccated thyroid extract. T3 should be taken twice a day due to its half-life.”

The approach is generally successful, he added. “Even those that come in asking for desiccated thyroid extract whom I am able to convince to try LT4/T3 end up being happy with their treatment in the end.

“The key is that you need to spend time discussing the options with patients and come to a consensus as to the therapy that will best resolve their symptoms and that they are most comfortable with,” he concluded.

In response to mounting evidence of different hypothyroidism treatment responses according to various subgroups of patients, experts recently called for the initiation of more thorough clinical trials on the issue of combination therapy, as recently reported by this news organization.

Dr. Hoang reported being a speaker for Acella Pharmaceuticals. Dr. Farwell and Dr. Cappola reported no relevant financial relationships.

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

Patients with hypothyroidism treated with the three most common pharmacologic strategies of levothyroxine (LT4) alone, LT4 in combination with triiodothyronine (T3), or desiccated thyroid extract showed no differences in thyroid symptoms or secondary outcomes in a double-blind, randomized study.

Sebastian Kaulitzki/Fotolia

“There are now proven good treatment options for the more than 1 in 10 patients with hypothyroidism who continue to experience symptoms of fatigue, mental fogginess, weight gain, and other symptoms despite taking levothyroxine,” first author Thanh Duc Hoang, DO, an endocrinologist at the Walter Reed National Military Medical Center, in Bethesda, Md., said in a press statement.

The findings were presented at the annual meeting of the Endocrine Society.

Commenting on the study, Alan P. Farwell, MD, said these new results are a valuable contribution to the understanding of treatment effects. “I think this is an interesting and important study and further studies are needed to clarify the optimal way to treat hypothyroidism,” said Dr. Farwell, who is director of endocrine clinics at Boston University.

Importantly, “the findings are different than studies where the patients are aware of what medication they are receiving,” he stressed in an interview, underscoring the importance of the double-blind design of the trial.

But Anne Cappola, MD, of the University of Pennsylvania, Philadelphia, pointed out that “the study was small and unlikely to have the statistical power to detect differences that could have been clinically important.”

Nevertheless, she too agreed that the double-blind study design is key: “My experience with patients is [the effects] are affected by patients’ perceptions about their thyroid medication. That is why studies designed so that patients do not know which treatment they are receiving are so important in this area.”
 

Randomized, double-blind comparison

Prior to the widespread availability of the current gold standard hypothyroidism treatment of LT4, the condition was typically treated with desiccated (animal) thyroid extract. And with many patients continuing to have a preference for this therapeutic approach, it is still commonly used.

Additionally, some patients treated with LT4 alone report greater improvements in symptoms with the addition of T3 – despite studies showing no benefits from the two together – leading to many clinicians commonly trying the combination approach.

To compare the efficacy of the three approaches in a prospective, double-blind, cross-over fashion, 75 patients received three therapeutic approaches each for 3 months: desiccated thyroid extract, an LT4/T3 combination, or LT4 alone.

After each 3-month treatment, patients completed a 36-point thyroid symptom questionnaire.

There was no significant differences in symptom relief, the primary outcome, between the three treatments (P = .32).

Overall, 45% of patients indicated they preferred desiccated thyroid as their first choice of treatment, 32% preferred LT4/T3 as their first choice, and 23% preferred LT4 alone.

For the secondary endpoints of weight, general health, depression (assessed using the Beck Depression Inventory), memory (Wechsler Memory Scale), lipids, and thyroid function, again, there were no significant differences between groups in any of the measures.
 

When switched to desiccated thyroid, many felt ‘much better’

A further exploratory analysis revealed that those who experienced symptoms while taking LT4 alone reported greater alleviation of symptoms with the other two treatments.

“As a whole group, there was no significant difference between the three treatment arms,” Dr. Hoang explained in an interview.

“However, with the subgroup analysis based on the scores of symptom questionnaires, we found that symptomatic patients on LT4 improved while being treated with LT4/T3 or desiccated thyroid,” he said.

Reports of improvements in switching to desiccated thyroid were notable, Dr. Hoang added. “Many patients when switched from LT4 to desiccated thyroid extract said they felt much better, [with] more energy, less mental fogginess, a better outlook, less flair of lupus symptoms, easier to lose weight, etc.”

The study also showed more patients with Hashimoto’s disease preferred desiccated thyroid extract and LT4/T3, compared with LT4 alone, however, the differences were not significant.
 

Treatment adjustments a helpful first step

Dr. Farwell noted that his approach when patients are still reporting symptoms despite LT4 treatment is to first try tweaking the dose.

“In my own practice, I prefer to adjust LT4 dosing first, and on occasion add T3, with a goal of getting both hormone levels in the upper half of the normal range,” he said. “I find that to be a better approach than desiccated thyroid extract. T3 should be taken twice a day due to its half-life.”

The approach is generally successful, he added. “Even those that come in asking for desiccated thyroid extract whom I am able to convince to try LT4/T3 end up being happy with their treatment in the end.

“The key is that you need to spend time discussing the options with patients and come to a consensus as to the therapy that will best resolve their symptoms and that they are most comfortable with,” he concluded.

In response to mounting evidence of different hypothyroidism treatment responses according to various subgroups of patients, experts recently called for the initiation of more thorough clinical trials on the issue of combination therapy, as recently reported by this news organization.

Dr. Hoang reported being a speaker for Acella Pharmaceuticals. Dr. Farwell and Dr. Cappola reported no relevant financial relationships.

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

Patients with hypothyroidism treated with the three most common pharmacologic strategies of levothyroxine (LT4) alone, LT4 in combination with triiodothyronine (T3), or desiccated thyroid extract showed no differences in thyroid symptoms or secondary outcomes in a double-blind, randomized study.

Sebastian Kaulitzki/Fotolia

“There are now proven good treatment options for the more than 1 in 10 patients with hypothyroidism who continue to experience symptoms of fatigue, mental fogginess, weight gain, and other symptoms despite taking levothyroxine,” first author Thanh Duc Hoang, DO, an endocrinologist at the Walter Reed National Military Medical Center, in Bethesda, Md., said in a press statement.

The findings were presented at the annual meeting of the Endocrine Society.

Commenting on the study, Alan P. Farwell, MD, said these new results are a valuable contribution to the understanding of treatment effects. “I think this is an interesting and important study and further studies are needed to clarify the optimal way to treat hypothyroidism,” said Dr. Farwell, who is director of endocrine clinics at Boston University.

Importantly, “the findings are different than studies where the patients are aware of what medication they are receiving,” he stressed in an interview, underscoring the importance of the double-blind design of the trial.

But Anne Cappola, MD, of the University of Pennsylvania, Philadelphia, pointed out that “the study was small and unlikely to have the statistical power to detect differences that could have been clinically important.”

Nevertheless, she too agreed that the double-blind study design is key: “My experience with patients is [the effects] are affected by patients’ perceptions about their thyroid medication. That is why studies designed so that patients do not know which treatment they are receiving are so important in this area.”
 

Randomized, double-blind comparison

Prior to the widespread availability of the current gold standard hypothyroidism treatment of LT4, the condition was typically treated with desiccated (animal) thyroid extract. And with many patients continuing to have a preference for this therapeutic approach, it is still commonly used.

Additionally, some patients treated with LT4 alone report greater improvements in symptoms with the addition of T3 – despite studies showing no benefits from the two together – leading to many clinicians commonly trying the combination approach.

To compare the efficacy of the three approaches in a prospective, double-blind, cross-over fashion, 75 patients received three therapeutic approaches each for 3 months: desiccated thyroid extract, an LT4/T3 combination, or LT4 alone.

After each 3-month treatment, patients completed a 36-point thyroid symptom questionnaire.

There was no significant differences in symptom relief, the primary outcome, between the three treatments (P = .32).

Overall, 45% of patients indicated they preferred desiccated thyroid as their first choice of treatment, 32% preferred LT4/T3 as their first choice, and 23% preferred LT4 alone.

For the secondary endpoints of weight, general health, depression (assessed using the Beck Depression Inventory), memory (Wechsler Memory Scale), lipids, and thyroid function, again, there were no significant differences between groups in any of the measures.
 

When switched to desiccated thyroid, many felt ‘much better’

A further exploratory analysis revealed that those who experienced symptoms while taking LT4 alone reported greater alleviation of symptoms with the other two treatments.

“As a whole group, there was no significant difference between the three treatment arms,” Dr. Hoang explained in an interview.

“However, with the subgroup analysis based on the scores of symptom questionnaires, we found that symptomatic patients on LT4 improved while being treated with LT4/T3 or desiccated thyroid,” he said.

Reports of improvements in switching to desiccated thyroid were notable, Dr. Hoang added. “Many patients when switched from LT4 to desiccated thyroid extract said they felt much better, [with] more energy, less mental fogginess, a better outlook, less flair of lupus symptoms, easier to lose weight, etc.”

The study also showed more patients with Hashimoto’s disease preferred desiccated thyroid extract and LT4/T3, compared with LT4 alone, however, the differences were not significant.
 

Treatment adjustments a helpful first step

Dr. Farwell noted that his approach when patients are still reporting symptoms despite LT4 treatment is to first try tweaking the dose.

“In my own practice, I prefer to adjust LT4 dosing first, and on occasion add T3, with a goal of getting both hormone levels in the upper half of the normal range,” he said. “I find that to be a better approach than desiccated thyroid extract. T3 should be taken twice a day due to its half-life.”

The approach is generally successful, he added. “Even those that come in asking for desiccated thyroid extract whom I am able to convince to try LT4/T3 end up being happy with their treatment in the end.

“The key is that you need to spend time discussing the options with patients and come to a consensus as to the therapy that will best resolve their symptoms and that they are most comfortable with,” he concluded.

In response to mounting evidence of different hypothyroidism treatment responses according to various subgroups of patients, experts recently called for the initiation of more thorough clinical trials on the issue of combination therapy, as recently reported by this news organization.

Dr. Hoang reported being a speaker for Acella Pharmaceuticals. Dr. Farwell and Dr. Cappola reported no relevant financial relationships.

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

A new study shows apolipoprotein B (apoB) and non-HDL cholesterol – but not LDL cholesterol – are associated with increased risk for all-cause mortality and myocardial infarction in patients taking statins.

Bruce Jancin/Frontline Medical News

Moreover, apoB was a more accurate marker of all-cause mortality risk than non-HDL or LDL cholesterol and was more accurate at identifying MI risk than LDL cholesterol.

“Any patient that comes to a doctor for evaluation, if statin treatment is sufficient, the doctor should look not only at LDL cholesterol but HDL cholesterol and apoB, if its available – that is the take-home message,” senior author Børge Grønne Nordestgaard, MD, DMSC, University of Copenhagen, said in an interview.

The findings are very relevant to clinical practice because international guidelines focus on LDL cholesterol and “many doctors are brainwashed that that is the only thing they should look at, just to keep LDL cholesterol down,” he said. “I’ve worked for years with triglyceride lipoproteins, what I call remnant cholesterol, and I think that the risk is very high also when you have high remnant cholesterol.”

Previous work has shown that apoB and non-HDL cholesterol better reflect atherosclerotic cardiovascular disease risk than LDL cholesterol. This is the first study, however, to show that elevated apoB and non-HDL cholesterol are associated with a higher risk for all-cause death in statin-treated patients with low LDL cholesterol, Dr. Nordestgaard noted.

The investigators compared outcomes among 13,015 statin-treated participants in the Copenhagen General Population Study using median baseline values of 92 mg/dL for apoB, 3.1 mmol/L (120 mg/dL) for non-HDL cholesterol, and 2.3 mmol/L (89 mg/dL) for LDL cholesterol. Over a median follow-up of 8 years, there were 2,499 deaths and 537 MIs.

As reported in the Journal of the American College of Cardiology, discordant apoB above the median with LDL cholesterol below was associated with a 21% increased risk for all-cause mortality (hazard ratio, 1.21; 95% confidence interval, 1.07-1.36) and 49% increased risk for MI (HR, 1.49; 95% CI, 1.15-1.92), compared with concordant apoB and LDL cholesterol below the medians.

Similar results were found for discordant non-HDL cholesterol above the median with low LDL cholesterol for all-cause mortality (HR, 1.18; 95% CI, 1.02-1.36) and MI (1.78; 95% CI, 1.35-2.34).

No such associations with mortality or MI were observed when LDL cholesterol was above the median and apoB or non-HDL below.

Additional analyses showed that high apoB with low non-HDL cholesterol was associated with a higher risk for all-cause mortality (HR, 1.21; 95% CI, 1.03-1.41), whereas high non-HDL cholesterol with low apoB was associated with a lower risk (HR, 0.75; 95% CI, 0.62-0.92).

Current guidelines define apoB greater than 130 mg/dL as a risk modifier in patients not using statins but, the authors wrote, “based on our results, the threshold for apoB as a risk modifier in statin-treated patients should be closer to 92 mg/dL than to 130 mg/dL.”

In an accompanying editorial, Neil J. Stone, MD, and Donald Lloyd-Jones, MD, both from Northwestern University, Chicago, said that American and European guidelines acknowledge the usefulness of apoB and non-HDL cholesterol in their risk algorithms and as possible targets to indicate efficacy, but don’t give a strong recommendation for apoB to assess residual risk.

“This paper suggests that, in the next iteration, we’ve got to give a stronger thought to measuring apoB for residual risk in those with secondary prevention,” Dr. Stone, vice chair of the 2018 American Heart Association/ACC cholesterol guidelines, said in an interview.

“The whole part of the guidelines was not to focus on any one number but to focus on the clinical risk as a whole,” he said. “You can enlarge your understanding of the patient by looking at their non-HDL, which you have anyway, and in certain circumstances, for example, people with metabolic syndrome, diabetes, obesity, or high triglycerides, those people might very well benefit from an apoB to further understand their risk. This paper simply highlights that and, therefore, was very valuable.”

Dr. Stone and Dr. Lloyd-Jones, however, pointed out that statin use was self-reported and information was lacking on adherence, dose intensity, and the amount of LDL cholesterol lowering from baseline. LDL cholesterol levels were also above current recommendations for optimizing risk reduction. “If statin dosing and LDL [cholesterol] were not optimized already, then there may have been ‘room’ for non-HDL [cholesterol] and apoB to add value in understanding residual risk,” they wrote.

The editorialists suggested that sequential use, rather than regular use, of apoB and non-HDL cholesterol may be best and that incorporating this information may be particularly beneficial for patients with metabolic disorders and elevated triglycerides after statin therapy.

“Maybe this paper is a wake-up call that there are other markers out there that can tell you that you still have higher risk and need to tighten up lifestyle and maybe be more adherent,” Dr. Stone said. “I think this is a wonderful chance to say that preventive cardiology isn’t just ‘set it and forget it’.”

C. Noel Bairey Merz, MD, who coauthored the 2018 cholesterol guidelines, agreed there’s “an overexuberant focus on LDL [cholesterol] for residual risk” and highlighted a recent systematic review of statins, ezetimibe, and PCSK9 cardiovascular outcomes trials that showed very little gain from aggressively driving down LDL below 100 mg/dL, unless the patient is at extremely high risk.

“If I, as a treating cardiologist who spends a lot of time on lipids, had a patient on a high-intensity statin and they didn’t drop [their LDL cholesterol] 50% and I already had them going to cardiac rehab and they were already losing weight, would I measure apoB? Yeah, I might, to motivate them to do more or to take Vascepa,” she said.

“This study is a useful addition to a relatively important problem, which is residual risk, and really supports personalized or precision medicine,” added Bairey Merz, MD, Cedars-Sinai Medical Center, Los Angeles. “But now we have to do the work and do an intervention trial in these people and see whether these markers make a difference.”

The study was supported by Herlev and Gentofte Hospital’s Research Fund and the department of clinical biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital. Dr. Nordestgaard has had consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amarin, Amgen, Esperion, Kowa, Novartis, Novo Nordisk, and Silence Therapeutics. All other authors, Dr. Stone, and Dr. Lloyd-Jones reported no conflicts. Dr. Merz reported no relevant disclosures.

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

A new study shows apolipoprotein B (apoB) and non-HDL cholesterol – but not LDL cholesterol – are associated with increased risk for all-cause mortality and myocardial infarction in patients taking statins.

Bruce Jancin/Frontline Medical News

Moreover, apoB was a more accurate marker of all-cause mortality risk than non-HDL or LDL cholesterol and was more accurate at identifying MI risk than LDL cholesterol.

“Any patient that comes to a doctor for evaluation, if statin treatment is sufficient, the doctor should look not only at LDL cholesterol but HDL cholesterol and apoB, if its available – that is the take-home message,” senior author Børge Grønne Nordestgaard, MD, DMSC, University of Copenhagen, said in an interview.

The findings are very relevant to clinical practice because international guidelines focus on LDL cholesterol and “many doctors are brainwashed that that is the only thing they should look at, just to keep LDL cholesterol down,” he said. “I’ve worked for years with triglyceride lipoproteins, what I call remnant cholesterol, and I think that the risk is very high also when you have high remnant cholesterol.”

Previous work has shown that apoB and non-HDL cholesterol better reflect atherosclerotic cardiovascular disease risk than LDL cholesterol. This is the first study, however, to show that elevated apoB and non-HDL cholesterol are associated with a higher risk for all-cause death in statin-treated patients with low LDL cholesterol, Dr. Nordestgaard noted.

The investigators compared outcomes among 13,015 statin-treated participants in the Copenhagen General Population Study using median baseline values of 92 mg/dL for apoB, 3.1 mmol/L (120 mg/dL) for non-HDL cholesterol, and 2.3 mmol/L (89 mg/dL) for LDL cholesterol. Over a median follow-up of 8 years, there were 2,499 deaths and 537 MIs.

As reported in the Journal of the American College of Cardiology, discordant apoB above the median with LDL cholesterol below was associated with a 21% increased risk for all-cause mortality (hazard ratio, 1.21; 95% confidence interval, 1.07-1.36) and 49% increased risk for MI (HR, 1.49; 95% CI, 1.15-1.92), compared with concordant apoB and LDL cholesterol below the medians.

Similar results were found for discordant non-HDL cholesterol above the median with low LDL cholesterol for all-cause mortality (HR, 1.18; 95% CI, 1.02-1.36) and MI (1.78; 95% CI, 1.35-2.34).

No such associations with mortality or MI were observed when LDL cholesterol was above the median and apoB or non-HDL below.

Additional analyses showed that high apoB with low non-HDL cholesterol was associated with a higher risk for all-cause mortality (HR, 1.21; 95% CI, 1.03-1.41), whereas high non-HDL cholesterol with low apoB was associated with a lower risk (HR, 0.75; 95% CI, 0.62-0.92).

Current guidelines define apoB greater than 130 mg/dL as a risk modifier in patients not using statins but, the authors wrote, “based on our results, the threshold for apoB as a risk modifier in statin-treated patients should be closer to 92 mg/dL than to 130 mg/dL.”

In an accompanying editorial, Neil J. Stone, MD, and Donald Lloyd-Jones, MD, both from Northwestern University, Chicago, said that American and European guidelines acknowledge the usefulness of apoB and non-HDL cholesterol in their risk algorithms and as possible targets to indicate efficacy, but don’t give a strong recommendation for apoB to assess residual risk.

“This paper suggests that, in the next iteration, we’ve got to give a stronger thought to measuring apoB for residual risk in those with secondary prevention,” Dr. Stone, vice chair of the 2018 American Heart Association/ACC cholesterol guidelines, said in an interview.

“The whole part of the guidelines was not to focus on any one number but to focus on the clinical risk as a whole,” he said. “You can enlarge your understanding of the patient by looking at their non-HDL, which you have anyway, and in certain circumstances, for example, people with metabolic syndrome, diabetes, obesity, or high triglycerides, those people might very well benefit from an apoB to further understand their risk. This paper simply highlights that and, therefore, was very valuable.”

Dr. Stone and Dr. Lloyd-Jones, however, pointed out that statin use was self-reported and information was lacking on adherence, dose intensity, and the amount of LDL cholesterol lowering from baseline. LDL cholesterol levels were also above current recommendations for optimizing risk reduction. “If statin dosing and LDL [cholesterol] were not optimized already, then there may have been ‘room’ for non-HDL [cholesterol] and apoB to add value in understanding residual risk,” they wrote.

The editorialists suggested that sequential use, rather than regular use, of apoB and non-HDL cholesterol may be best and that incorporating this information may be particularly beneficial for patients with metabolic disorders and elevated triglycerides after statin therapy.

“Maybe this paper is a wake-up call that there are other markers out there that can tell you that you still have higher risk and need to tighten up lifestyle and maybe be more adherent,” Dr. Stone said. “I think this is a wonderful chance to say that preventive cardiology isn’t just ‘set it and forget it’.”

C. Noel Bairey Merz, MD, who coauthored the 2018 cholesterol guidelines, agreed there’s “an overexuberant focus on LDL [cholesterol] for residual risk” and highlighted a recent systematic review of statins, ezetimibe, and PCSK9 cardiovascular outcomes trials that showed very little gain from aggressively driving down LDL below 100 mg/dL, unless the patient is at extremely high risk.

“If I, as a treating cardiologist who spends a lot of time on lipids, had a patient on a high-intensity statin and they didn’t drop [their LDL cholesterol] 50% and I already had them going to cardiac rehab and they were already losing weight, would I measure apoB? Yeah, I might, to motivate them to do more or to take Vascepa,” she said.

“This study is a useful addition to a relatively important problem, which is residual risk, and really supports personalized or precision medicine,” added Bairey Merz, MD, Cedars-Sinai Medical Center, Los Angeles. “But now we have to do the work and do an intervention trial in these people and see whether these markers make a difference.”

The study was supported by Herlev and Gentofte Hospital’s Research Fund and the department of clinical biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital. Dr. Nordestgaard has had consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amarin, Amgen, Esperion, Kowa, Novartis, Novo Nordisk, and Silence Therapeutics. All other authors, Dr. Stone, and Dr. Lloyd-Jones reported no conflicts. Dr. Merz reported no relevant disclosures.

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

A new study shows apolipoprotein B (apoB) and non-HDL cholesterol – but not LDL cholesterol – are associated with increased risk for all-cause mortality and myocardial infarction in patients taking statins.

Bruce Jancin/Frontline Medical News

Moreover, apoB was a more accurate marker of all-cause mortality risk than non-HDL or LDL cholesterol and was more accurate at identifying MI risk than LDL cholesterol.

“Any patient that comes to a doctor for evaluation, if statin treatment is sufficient, the doctor should look not only at LDL cholesterol but HDL cholesterol and apoB, if its available – that is the take-home message,” senior author Børge Grønne Nordestgaard, MD, DMSC, University of Copenhagen, said in an interview.

The findings are very relevant to clinical practice because international guidelines focus on LDL cholesterol and “many doctors are brainwashed that that is the only thing they should look at, just to keep LDL cholesterol down,” he said. “I’ve worked for years with triglyceride lipoproteins, what I call remnant cholesterol, and I think that the risk is very high also when you have high remnant cholesterol.”

Previous work has shown that apoB and non-HDL cholesterol better reflect atherosclerotic cardiovascular disease risk than LDL cholesterol. This is the first study, however, to show that elevated apoB and non-HDL cholesterol are associated with a higher risk for all-cause death in statin-treated patients with low LDL cholesterol, Dr. Nordestgaard noted.

The investigators compared outcomes among 13,015 statin-treated participants in the Copenhagen General Population Study using median baseline values of 92 mg/dL for apoB, 3.1 mmol/L (120 mg/dL) for non-HDL cholesterol, and 2.3 mmol/L (89 mg/dL) for LDL cholesterol. Over a median follow-up of 8 years, there were 2,499 deaths and 537 MIs.

As reported in the Journal of the American College of Cardiology, discordant apoB above the median with LDL cholesterol below was associated with a 21% increased risk for all-cause mortality (hazard ratio, 1.21; 95% confidence interval, 1.07-1.36) and 49% increased risk for MI (HR, 1.49; 95% CI, 1.15-1.92), compared with concordant apoB and LDL cholesterol below the medians.

Similar results were found for discordant non-HDL cholesterol above the median with low LDL cholesterol for all-cause mortality (HR, 1.18; 95% CI, 1.02-1.36) and MI (1.78; 95% CI, 1.35-2.34).

No such associations with mortality or MI were observed when LDL cholesterol was above the median and apoB or non-HDL below.

Additional analyses showed that high apoB with low non-HDL cholesterol was associated with a higher risk for all-cause mortality (HR, 1.21; 95% CI, 1.03-1.41), whereas high non-HDL cholesterol with low apoB was associated with a lower risk (HR, 0.75; 95% CI, 0.62-0.92).

Current guidelines define apoB greater than 130 mg/dL as a risk modifier in patients not using statins but, the authors wrote, “based on our results, the threshold for apoB as a risk modifier in statin-treated patients should be closer to 92 mg/dL than to 130 mg/dL.”

In an accompanying editorial, Neil J. Stone, MD, and Donald Lloyd-Jones, MD, both from Northwestern University, Chicago, said that American and European guidelines acknowledge the usefulness of apoB and non-HDL cholesterol in their risk algorithms and as possible targets to indicate efficacy, but don’t give a strong recommendation for apoB to assess residual risk.

“This paper suggests that, in the next iteration, we’ve got to give a stronger thought to measuring apoB for residual risk in those with secondary prevention,” Dr. Stone, vice chair of the 2018 American Heart Association/ACC cholesterol guidelines, said in an interview.

“The whole part of the guidelines was not to focus on any one number but to focus on the clinical risk as a whole,” he said. “You can enlarge your understanding of the patient by looking at their non-HDL, which you have anyway, and in certain circumstances, for example, people with metabolic syndrome, diabetes, obesity, or high triglycerides, those people might very well benefit from an apoB to further understand their risk. This paper simply highlights that and, therefore, was very valuable.”

Dr. Stone and Dr. Lloyd-Jones, however, pointed out that statin use was self-reported and information was lacking on adherence, dose intensity, and the amount of LDL cholesterol lowering from baseline. LDL cholesterol levels were also above current recommendations for optimizing risk reduction. “If statin dosing and LDL [cholesterol] were not optimized already, then there may have been ‘room’ for non-HDL [cholesterol] and apoB to add value in understanding residual risk,” they wrote.

The editorialists suggested that sequential use, rather than regular use, of apoB and non-HDL cholesterol may be best and that incorporating this information may be particularly beneficial for patients with metabolic disorders and elevated triglycerides after statin therapy.

“Maybe this paper is a wake-up call that there are other markers out there that can tell you that you still have higher risk and need to tighten up lifestyle and maybe be more adherent,” Dr. Stone said. “I think this is a wonderful chance to say that preventive cardiology isn’t just ‘set it and forget it’.”

C. Noel Bairey Merz, MD, who coauthored the 2018 cholesterol guidelines, agreed there’s “an overexuberant focus on LDL [cholesterol] for residual risk” and highlighted a recent systematic review of statins, ezetimibe, and PCSK9 cardiovascular outcomes trials that showed very little gain from aggressively driving down LDL below 100 mg/dL, unless the patient is at extremely high risk.

“If I, as a treating cardiologist who spends a lot of time on lipids, had a patient on a high-intensity statin and they didn’t drop [their LDL cholesterol] 50% and I already had them going to cardiac rehab and they were already losing weight, would I measure apoB? Yeah, I might, to motivate them to do more or to take Vascepa,” she said.

“This study is a useful addition to a relatively important problem, which is residual risk, and really supports personalized or precision medicine,” added Bairey Merz, MD, Cedars-Sinai Medical Center, Los Angeles. “But now we have to do the work and do an intervention trial in these people and see whether these markers make a difference.”

The study was supported by Herlev and Gentofte Hospital’s Research Fund and the department of clinical biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital. Dr. Nordestgaard has had consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amarin, Amgen, Esperion, Kowa, Novartis, Novo Nordisk, and Silence Therapeutics. All other authors, Dr. Stone, and Dr. Lloyd-Jones reported no conflicts. Dr. Merz reported no relevant disclosures.

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

Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.

Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.

“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.

The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
 

Confirmation of off-label and European experience

“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.

“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.

“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.

“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.

Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.

The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).

The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.

Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.

After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.

Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.

Proper dose titration makes a difference

Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.

“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.

This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.

Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.

“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”

Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”

PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.

mzoler@mdedge.com

Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.

Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.

“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.

The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
 

Confirmation of off-label and European experience

“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.

“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.

“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.

“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.

Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.

The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).

The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.

Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.

After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.

Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.

Proper dose titration makes a difference

Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.

“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.

This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.

Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.

“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”

Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”

PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.

mzoler@mdedge.com

Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.

Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.

“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.

The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
 

Confirmation of off-label and European experience

“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.

“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.

“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.

“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.

Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.

The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).

The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.

Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.

After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.

Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.

Proper dose titration makes a difference

Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.

“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.

This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.

Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.

“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”

Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”

PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.

mzoler@mdedge.com