Patients with type 2 diabetes and their clinicians may not share the same priorities when it comes to choosing a second-line drug after metformin, new research suggested.

In a mixed-methods study of 40 people with type 2 diabetes and moderate heart disease risk who were asked about their goals, preferences, and priorities for glucose-lowering medications, their answers were surprisingly heterogeneous and not always aligned with those endorsed by the medical community.

Notably, most patients rated blindness and death as the most important health outcomes to avoid and efficacy in lowering blood glucose and A1c as the most important medication attributes. Avoidance of cardiovascular outcomes was ranked slightly lower. The data were published recently in Clinical Diabetes.

“We really need to ask our patients about what is important to them. That’s how you have a relationship and engage in shared decision-making,” lead author Rozalina G. McCoy, MD, Associate Division Chief for Clinical Research in the Division of Endocrinology, Diabetes, and Nutrition at the University of Maryland, Baltimore, told this news organization.

Patient education should be approached in that way, she added. “They might not think their diabetes is related to heart disease risk or that anything they do can impact it. That’s a conversation starter ... We first have to understand what motivates them and then tailor education to what is important to them,” she said.

Asked to comment, endocrinologist Cecilia C. Low Wang, MD, Professor of Medicine at the University of Colorado, Aurora, told this news organization, “the fact that death and blindness are key health outcomes in the patients surveyed indicates to me that patients place great importance on ‘irreversible’ bad outcomes. We as clinicians do not tend to discuss benefits for all-cause mortality with our diabetes medications. Maybe we should include this in our discussions.”

Dr. Low Wang also noted, as did Dr. McCoy, that the emphasis on lowering glucose reflects decades of public health messaging, and that while it’s certainly important, particularly for microvascular outcomes, it’s just one of several factors influencing cardiovascular and all-cause mortality risk.

“I think what this finding tells us is that we need to focus on a more nuanced message of improved glycemic control and reduction of risk of both micro- and macrovascular complications and weight management, healthy diet, and regular physical activity ... that it is not just glycemic control that is important but glycemic control in the context of a healthy lifestyle and good overall health,” Dr. Low Wang said.

Blindness and Death Bigger Concerns Than Heart Attack or Heart Failure

The study participants included 25 from the Mayo Health System in Rochester, Minnesota (where McCoy formerly worked), and 15 from Grady Memorial Hospital in Atlanta, Georgia. Half were White, and just over a third were Black. All had active prescriptions for a glucagon-like peptide 1 receptor agonist, sodium-glucose cotransporter 2 inhibitor, dipeptidyl peptidase 4 inhibitor, and/or a sulfonylurea.

They were first given a multistep ranking exercise regarding health outcomes and medication attributes selected from a list and then were asked to add any others that were important to them and re-ranked the entire list.

For health outcomes, the most common listed as “very important” were blindness (63%) and death (60%), followed by heart attack (48%) and heart failure (48%). Those endorsed less often were hospital admission (28%), severe hypoglycemia (25%), and pancreatitis (15%).

Dr. Low Wang noted, “Heart attack and heart failure and stroke were not far behind ... Maybe the messaging about risks of [atherosclerotic cardiovascular disease] in diabetes is working at least to some degree and in some populations.”

Combinations of outcomes selected as “very important” varied widely, with just one combination (end-stage kidney disease, heart attack, blindness, and any event causing death) endorsed by more than a single participant. This was unexpected, Dr. McCoy noted.

“Usually, a qualitative study is very small, so we thought 40 was huge and we’d see a lot of similar things, but I think the first surprising finding was just how much variability there is in what people with type 2 diabetes consider as motivating factors for choosing a diabetes medication ... So when we talk about patient-centered care and shared decision-making, that’s really important because patient priorities are very different,” she said.

For medication attributes, greater reductions in blood glucose and A1c were most often endorsed as “very important” (68%), followed by oral administration (45%) and absence of gastrointestinal side effects (38%).

Nearly half (47.5%) added one or more outcomes as important to them in deciding on a medication for type 2 diabetes. The most common had to do with affordability (n = 10), minimizing the total number of drugs (n = 3) and avoiding drowsiness (n = 2).

Dr. Low Wang said, “Some of the health outcomes we as clinicians feel are important, such as serious infection, hospitalization, kidney dysfunction or failure, and diabetic foot problems, were not felt to be as important to the patients surveyed. This could be due to other health outcomes outweighing these, or highlights the need for more focus, education, and discussion with patients.”

Five Themes Describe Patients’ Perceptions of Health Outcomes

Throughout the ranking process, a researcher asked participants (via phone or Zoom) about their reasons for ranking items as “very important” or “not very important” in choosing medications. For health outcomes, five broad themes emerged from their comments: The outcome’s severity (with permanence and potential lethality prominent), their perceived personal susceptibility to it, salience (ie, whether they knew someone who had experienced the outcome), their beliefs about causation, and about the consequences of the outcome.

With medication attributes, the medication’s ability to lower blood glucose was deemed a priority by nearly all. By contrast, there was much more variation in the responses regarding the influence of various side effects in their decision-making based on personal preferences, beliefs, and previous experiences.

This paper is one part of research funded by the Patient-Centered Outcomes Research Institute (PCORI) examining the effects of second-line glucose-lowering medications in patients with type 2 diabetes who are at moderate, rather than high, cardiovascular risk. The main paper, looking at prespecified cardiovascular outcomes, is scheduled to be published soon, Dr. McCoy said.

She’s now planning a follow-up study to look at actual outcomes for the second-line drugs based on the patients’ preferences. “We don’t have the evidence necessarily to tell our patients what is best given their specific preferences ... The question is, if our patients tell us what they want, how would that change what we recommend to them?”

The study was funded by PCORI. Dr. McCoy received support from the National Institutes of Health and AARP. She also served as a consultant to Emmi (Wolters Kluwer) for developing patient education materials related to prediabetes and diabetes. Dr. Low Wang received research support from Dexcom Inc, Virta Health, and CellResearch Corp within the past 24 months.
 

A version of this article appeared on Medscape.com.

Patients with type 2 diabetes and their clinicians may not share the same priorities when it comes to choosing a second-line drug after metformin, new research suggested.

In a mixed-methods study of 40 people with type 2 diabetes and moderate heart disease risk who were asked about their goals, preferences, and priorities for glucose-lowering medications, their answers were surprisingly heterogeneous and not always aligned with those endorsed by the medical community.

Notably, most patients rated blindness and death as the most important health outcomes to avoid and efficacy in lowering blood glucose and A1c as the most important medication attributes. Avoidance of cardiovascular outcomes was ranked slightly lower. The data were published recently in Clinical Diabetes.

“We really need to ask our patients about what is important to them. That’s how you have a relationship and engage in shared decision-making,” lead author Rozalina G. McCoy, MD, Associate Division Chief for Clinical Research in the Division of Endocrinology, Diabetes, and Nutrition at the University of Maryland, Baltimore, told this news organization.

Patient education should be approached in that way, she added. “They might not think their diabetes is related to heart disease risk or that anything they do can impact it. That’s a conversation starter ... We first have to understand what motivates them and then tailor education to what is important to them,” she said.

Asked to comment, endocrinologist Cecilia C. Low Wang, MD, Professor of Medicine at the University of Colorado, Aurora, told this news organization, “the fact that death and blindness are key health outcomes in the patients surveyed indicates to me that patients place great importance on ‘irreversible’ bad outcomes. We as clinicians do not tend to discuss benefits for all-cause mortality with our diabetes medications. Maybe we should include this in our discussions.”

Dr. Low Wang also noted, as did Dr. McCoy, that the emphasis on lowering glucose reflects decades of public health messaging, and that while it’s certainly important, particularly for microvascular outcomes, it’s just one of several factors influencing cardiovascular and all-cause mortality risk.

“I think what this finding tells us is that we need to focus on a more nuanced message of improved glycemic control and reduction of risk of both micro- and macrovascular complications and weight management, healthy diet, and regular physical activity ... that it is not just glycemic control that is important but glycemic control in the context of a healthy lifestyle and good overall health,” Dr. Low Wang said.

Blindness and Death Bigger Concerns Than Heart Attack or Heart Failure

The study participants included 25 from the Mayo Health System in Rochester, Minnesota (where McCoy formerly worked), and 15 from Grady Memorial Hospital in Atlanta, Georgia. Half were White, and just over a third were Black. All had active prescriptions for a glucagon-like peptide 1 receptor agonist, sodium-glucose cotransporter 2 inhibitor, dipeptidyl peptidase 4 inhibitor, and/or a sulfonylurea.

They were first given a multistep ranking exercise regarding health outcomes and medication attributes selected from a list and then were asked to add any others that were important to them and re-ranked the entire list.

For health outcomes, the most common listed as “very important” were blindness (63%) and death (60%), followed by heart attack (48%) and heart failure (48%). Those endorsed less often were hospital admission (28%), severe hypoglycemia (25%), and pancreatitis (15%).

Dr. Low Wang noted, “Heart attack and heart failure and stroke were not far behind ... Maybe the messaging about risks of [atherosclerotic cardiovascular disease] in diabetes is working at least to some degree and in some populations.”

Combinations of outcomes selected as “very important” varied widely, with just one combination (end-stage kidney disease, heart attack, blindness, and any event causing death) endorsed by more than a single participant. This was unexpected, Dr. McCoy noted.

“Usually, a qualitative study is very small, so we thought 40 was huge and we’d see a lot of similar things, but I think the first surprising finding was just how much variability there is in what people with type 2 diabetes consider as motivating factors for choosing a diabetes medication ... So when we talk about patient-centered care and shared decision-making, that’s really important because patient priorities are very different,” she said.

For medication attributes, greater reductions in blood glucose and A1c were most often endorsed as “very important” (68%), followed by oral administration (45%) and absence of gastrointestinal side effects (38%).

Nearly half (47.5%) added one or more outcomes as important to them in deciding on a medication for type 2 diabetes. The most common had to do with affordability (n = 10), minimizing the total number of drugs (n = 3) and avoiding drowsiness (n = 2).

Dr. Low Wang said, “Some of the health outcomes we as clinicians feel are important, such as serious infection, hospitalization, kidney dysfunction or failure, and diabetic foot problems, were not felt to be as important to the patients surveyed. This could be due to other health outcomes outweighing these, or highlights the need for more focus, education, and discussion with patients.”

Five Themes Describe Patients’ Perceptions of Health Outcomes

Throughout the ranking process, a researcher asked participants (via phone or Zoom) about their reasons for ranking items as “very important” or “not very important” in choosing medications. For health outcomes, five broad themes emerged from their comments: The outcome’s severity (with permanence and potential lethality prominent), their perceived personal susceptibility to it, salience (ie, whether they knew someone who had experienced the outcome), their beliefs about causation, and about the consequences of the outcome.

With medication attributes, the medication’s ability to lower blood glucose was deemed a priority by nearly all. By contrast, there was much more variation in the responses regarding the influence of various side effects in their decision-making based on personal preferences, beliefs, and previous experiences.

This paper is one part of research funded by the Patient-Centered Outcomes Research Institute (PCORI) examining the effects of second-line glucose-lowering medications in patients with type 2 diabetes who are at moderate, rather than high, cardiovascular risk. The main paper, looking at prespecified cardiovascular outcomes, is scheduled to be published soon, Dr. McCoy said.

She’s now planning a follow-up study to look at actual outcomes for the second-line drugs based on the patients’ preferences. “We don’t have the evidence necessarily to tell our patients what is best given their specific preferences ... The question is, if our patients tell us what they want, how would that change what we recommend to them?”

The study was funded by PCORI. Dr. McCoy received support from the National Institutes of Health and AARP. She also served as a consultant to Emmi (Wolters Kluwer) for developing patient education materials related to prediabetes and diabetes. Dr. Low Wang received research support from Dexcom Inc, Virta Health, and CellResearch Corp within the past 24 months.
 

A version of this article appeared on Medscape.com.

Patients with type 2 diabetes and their clinicians may not share the same priorities when it comes to choosing a second-line drug after metformin, new research suggested.

In a mixed-methods study of 40 people with type 2 diabetes and moderate heart disease risk who were asked about their goals, preferences, and priorities for glucose-lowering medications, their answers were surprisingly heterogeneous and not always aligned with those endorsed by the medical community.

Notably, most patients rated blindness and death as the most important health outcomes to avoid and efficacy in lowering blood glucose and A1c as the most important medication attributes. Avoidance of cardiovascular outcomes was ranked slightly lower. The data were published recently in Clinical Diabetes.

“We really need to ask our patients about what is important to them. That’s how you have a relationship and engage in shared decision-making,” lead author Rozalina G. McCoy, MD, Associate Division Chief for Clinical Research in the Division of Endocrinology, Diabetes, and Nutrition at the University of Maryland, Baltimore, told this news organization.

Patient education should be approached in that way, she added. “They might not think their diabetes is related to heart disease risk or that anything they do can impact it. That’s a conversation starter ... We first have to understand what motivates them and then tailor education to what is important to them,” she said.

Asked to comment, endocrinologist Cecilia C. Low Wang, MD, Professor of Medicine at the University of Colorado, Aurora, told this news organization, “the fact that death and blindness are key health outcomes in the patients surveyed indicates to me that patients place great importance on ‘irreversible’ bad outcomes. We as clinicians do not tend to discuss benefits for all-cause mortality with our diabetes medications. Maybe we should include this in our discussions.”

Dr. Low Wang also noted, as did Dr. McCoy, that the emphasis on lowering glucose reflects decades of public health messaging, and that while it’s certainly important, particularly for microvascular outcomes, it’s just one of several factors influencing cardiovascular and all-cause mortality risk.

“I think what this finding tells us is that we need to focus on a more nuanced message of improved glycemic control and reduction of risk of both micro- and macrovascular complications and weight management, healthy diet, and regular physical activity ... that it is not just glycemic control that is important but glycemic control in the context of a healthy lifestyle and good overall health,” Dr. Low Wang said.

Blindness and Death Bigger Concerns Than Heart Attack or Heart Failure

The study participants included 25 from the Mayo Health System in Rochester, Minnesota (where McCoy formerly worked), and 15 from Grady Memorial Hospital in Atlanta, Georgia. Half were White, and just over a third were Black. All had active prescriptions for a glucagon-like peptide 1 receptor agonist, sodium-glucose cotransporter 2 inhibitor, dipeptidyl peptidase 4 inhibitor, and/or a sulfonylurea.

They were first given a multistep ranking exercise regarding health outcomes and medication attributes selected from a list and then were asked to add any others that were important to them and re-ranked the entire list.

For health outcomes, the most common listed as “very important” were blindness (63%) and death (60%), followed by heart attack (48%) and heart failure (48%). Those endorsed less often were hospital admission (28%), severe hypoglycemia (25%), and pancreatitis (15%).

Dr. Low Wang noted, “Heart attack and heart failure and stroke were not far behind ... Maybe the messaging about risks of [atherosclerotic cardiovascular disease] in diabetes is working at least to some degree and in some populations.”

Combinations of outcomes selected as “very important” varied widely, with just one combination (end-stage kidney disease, heart attack, blindness, and any event causing death) endorsed by more than a single participant. This was unexpected, Dr. McCoy noted.

“Usually, a qualitative study is very small, so we thought 40 was huge and we’d see a lot of similar things, but I think the first surprising finding was just how much variability there is in what people with type 2 diabetes consider as motivating factors for choosing a diabetes medication ... So when we talk about patient-centered care and shared decision-making, that’s really important because patient priorities are very different,” she said.

For medication attributes, greater reductions in blood glucose and A1c were most often endorsed as “very important” (68%), followed by oral administration (45%) and absence of gastrointestinal side effects (38%).

Nearly half (47.5%) added one or more outcomes as important to them in deciding on a medication for type 2 diabetes. The most common had to do with affordability (n = 10), minimizing the total number of drugs (n = 3) and avoiding drowsiness (n = 2).

Dr. Low Wang said, “Some of the health outcomes we as clinicians feel are important, such as serious infection, hospitalization, kidney dysfunction or failure, and diabetic foot problems, were not felt to be as important to the patients surveyed. This could be due to other health outcomes outweighing these, or highlights the need for more focus, education, and discussion with patients.”

Five Themes Describe Patients’ Perceptions of Health Outcomes

Throughout the ranking process, a researcher asked participants (via phone or Zoom) about their reasons for ranking items as “very important” or “not very important” in choosing medications. For health outcomes, five broad themes emerged from their comments: The outcome’s severity (with permanence and potential lethality prominent), their perceived personal susceptibility to it, salience (ie, whether they knew someone who had experienced the outcome), their beliefs about causation, and about the consequences of the outcome.

With medication attributes, the medication’s ability to lower blood glucose was deemed a priority by nearly all. By contrast, there was much more variation in the responses regarding the influence of various side effects in their decision-making based on personal preferences, beliefs, and previous experiences.

This paper is one part of research funded by the Patient-Centered Outcomes Research Institute (PCORI) examining the effects of second-line glucose-lowering medications in patients with type 2 diabetes who are at moderate, rather than high, cardiovascular risk. The main paper, looking at prespecified cardiovascular outcomes, is scheduled to be published soon, Dr. McCoy said.

She’s now planning a follow-up study to look at actual outcomes for the second-line drugs based on the patients’ preferences. “We don’t have the evidence necessarily to tell our patients what is best given their specific preferences ... The question is, if our patients tell us what they want, how would that change what we recommend to them?”

The study was funded by PCORI. Dr. McCoy received support from the National Institutes of Health and AARP. She also served as a consultant to Emmi (Wolters Kluwer) for developing patient education materials related to prediabetes and diabetes. Dr. Low Wang received research support from Dexcom Inc, Virta Health, and CellResearch Corp within the past 24 months.
 

A version of this article appeared on Medscape.com.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

There is insufficient evidence that drugs targeting the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway increase the risk of cardiovascular or thrombotic complications in people undergoing treatment for a variety of dermatological conditions, at least in the short term, say the authors of a new meta-analysis published in JAMA Dermatology.

Considering data on over 17,000 patients with different dermatoses from 45 placebo-controlled randomized clinical trials with an average follow up of 16 weeks, they found there was no significant increase in the occurrence of major adverse cardiovascular events (MACE) or venous thromboembolism (VTE) in people with dermatoses treated with JAK-STAT inhibitors, compared with placebo.

The I² statistic was 0.00% for both MACE and VTE comparing the two arms, indicating that the results were unlikely to be due to chance. There was no increased risk in MACE between those on placebo and those on JAK-STAT inhibitors, with a risk ratio (RR) of 0.47; or for VTE risk, with an RR of 0.46.

Similar findings were obtained when data were analyzed according to the dermatological condition being treated, mechanism of action of the medication, or whether the medication carried a boxed warning.

These data “suggest inconsistency with established sentiments,” that JAK-STAT inhibitors increase the risk for cardiovascular events, Patrick Ireland, MD, of the University of New South Wales, Randwick, Australia, and coauthors wrote in the article. “This may be owing to the limited time frames in which these rare events could be adequately captured, or the ages of enrolled patients being too young to realize the well established heightened risks of developing MACE and VTE,” they suggested.

However, the findings challenge the notion that the cardiovascular complications of these drugs are the same in all patients; dermatological use may not be associated with the same risks as with use for rheumatologic indications.
 

Class-Wide Boxed Warning

“JAK-STAT [inhibitors] have had some pretty indemnifying data against their use, with the ORAL [Surveillance] study demonstrating increased all-cause mortality, cardiovascular events, venous thromboembolism, and malignancy,” Dr. Ireland said in an interview.

ORAL Surveillance was an open-label, postmarketing trial conducted in patients with rheumatoid arthritis treated with tofacitinib or a tumor necrosis factor (TNF) inhibitor. The results led the US Food and Drug Administration to require information about the risks of serious heart-related events, cancer, blood clots, and death in a boxed warning for JAK-STAT inhibitors in 2022.

“I think it’s important to recognize that these [ORAL Surveillance participants] are very different patients to the typical dermatological patient being treated with a JAK-STAT [inhibitors], with newer studies demonstrating a much safer profile than initially thought,” Dr. Ireland said.
 

Examining Risk in Dermatological Conditions

The meta-analysis performed by Dr. Ireland and associates focused specifically on the risk for MACE and VTE in patients being treated for dermatological conditions, and included trials published up until June 2023. Only trials that had included a placebo arm were considered; pooled analyses, long-term extension trial data, post hoc analyses, and pediatric-specific trials were excluded.

Most (25) of the trials were phase 2b or phase 3 trials, 18 were phase 2 to 2b, and two were phase 1 trials. The studies included 12,996 participants, mostly with atopic dermatitis or psoriasis, who were treated with JAK-STAT inhibitors, which included baricitinib (2846 patients), tofacitinib (2470), upadacitinib (2218), abrocitinib (1904), and deucravacitinib (1492), among others. There were 4925 patients on placebo.

Overall, MACE — defined as a combined endpoint of acute myocardial infarction, stroke, cardiovascular mortality, heart failure, and unstable angina, as well as arterial embolism — occurred in 13 of the JAK-STAT inhibitor-treated patients and in four of those on placebo. VTE — defined as deep vein thrombosis, pulmonary embolism, and any unusual site thrombosis — was reported in eight JAK-STAT inhibitor-treated patients and in one patient on placebo.

The pooled incidence ratios for MACE and VTE were calculated as 0.20 per 100 person exposure years (PEY) for JAK-STAT inhibitor treatment and 0.13 PEY for placebo. The pooled RRs comparing the two treatment groups were a respective 1.13 for MACE and 2.79 for VTE, but neither RR reached statistical significance.

No difference was seen between the treatment arms in terms of treatment emergent adverse events (RR, 1.05), serious adverse events (RR, 0.92), or study discontinuation because of adverse events (RR, 0.94).
 

Reassuring Results?

Dr. Ireland and coauthors said the finding should help to reassure clinicians that the short-term use of JAK-STAT inhibitors in patients with dermatological conditions with low cardiovascular risk profiles “appears to be both safe and well tolerated.” They cautioned, however, that “clinicians must remain judicious” when using these medications for longer periods and in high-risk patient populations.

This was a pragmatic meta-analysis that provides useful information for dermatologists, Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, DC, said in an interview.

“When there are safety concerns, I think that’s where data like this are so important to not just allay the fears of practitioners, but also to arm the practitioner with information for when they discuss a possible treatment with a patient,” said Dr. Friedman, who was not involved in the study.

“What’s unique here is that they’re looking at any possible use of JAK inhibitors for dermatological disease,” so this represents patients that dermatologists would be seeing, he added.

“The limitation here is time, we only can say so much about the safety of the medication with the data that we have,” Dr. Friedman said. Almost 4 months is “a good amount of time” to know about the cardiovascular risks, he said, but added, what happens then? Will the risk increase and will patients need to be switched to another medication?

“There’s no line in the sand,” with regard to using a JAK-STAT inhibitor. “If you look at the label, they’re not meant to be used incrementally,” but as ongoing treatment, while considering the needs of the patient and the relative risks and benefits, he said.

With that in mind, “the open label extension studies for all these [JAK-STAT inhibitors] are really, really important to get a sense of ‘do new signals emerge down the road.’ ”

The meta-analysis received no commercial funding. One author of the work reported personal fees from several pharmaceutical companies which were done outside of analysis. Dr. Friedman has received research funding from or acted as a consultant for several pharmaceutical companies including, Incyte, Pfizer, Eli Lily, and AbbVie.

There is insufficient evidence that drugs targeting the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway increase the risk of cardiovascular or thrombotic complications in people undergoing treatment for a variety of dermatological conditions, at least in the short term, say the authors of a new meta-analysis published in JAMA Dermatology.

Considering data on over 17,000 patients with different dermatoses from 45 placebo-controlled randomized clinical trials with an average follow up of 16 weeks, they found there was no significant increase in the occurrence of major adverse cardiovascular events (MACE) or venous thromboembolism (VTE) in people with dermatoses treated with JAK-STAT inhibitors, compared with placebo.

The I² statistic was 0.00% for both MACE and VTE comparing the two arms, indicating that the results were unlikely to be due to chance. There was no increased risk in MACE between those on placebo and those on JAK-STAT inhibitors, with a risk ratio (RR) of 0.47; or for VTE risk, with an RR of 0.46.

Similar findings were obtained when data were analyzed according to the dermatological condition being treated, mechanism of action of the medication, or whether the medication carried a boxed warning.

These data “suggest inconsistency with established sentiments,” that JAK-STAT inhibitors increase the risk for cardiovascular events, Patrick Ireland, MD, of the University of New South Wales, Randwick, Australia, and coauthors wrote in the article. “This may be owing to the limited time frames in which these rare events could be adequately captured, or the ages of enrolled patients being too young to realize the well established heightened risks of developing MACE and VTE,” they suggested.

However, the findings challenge the notion that the cardiovascular complications of these drugs are the same in all patients; dermatological use may not be associated with the same risks as with use for rheumatologic indications.
 

Class-Wide Boxed Warning

“JAK-STAT [inhibitors] have had some pretty indemnifying data against their use, with the ORAL [Surveillance] study demonstrating increased all-cause mortality, cardiovascular events, venous thromboembolism, and malignancy,” Dr. Ireland said in an interview.

ORAL Surveillance was an open-label, postmarketing trial conducted in patients with rheumatoid arthritis treated with tofacitinib or a tumor necrosis factor (TNF) inhibitor. The results led the US Food and Drug Administration to require information about the risks of serious heart-related events, cancer, blood clots, and death in a boxed warning for JAK-STAT inhibitors in 2022.

“I think it’s important to recognize that these [ORAL Surveillance participants] are very different patients to the typical dermatological patient being treated with a JAK-STAT [inhibitors], with newer studies demonstrating a much safer profile than initially thought,” Dr. Ireland said.
 

Examining Risk in Dermatological Conditions

The meta-analysis performed by Dr. Ireland and associates focused specifically on the risk for MACE and VTE in patients being treated for dermatological conditions, and included trials published up until June 2023. Only trials that had included a placebo arm were considered; pooled analyses, long-term extension trial data, post hoc analyses, and pediatric-specific trials were excluded.

Most (25) of the trials were phase 2b or phase 3 trials, 18 were phase 2 to 2b, and two were phase 1 trials. The studies included 12,996 participants, mostly with atopic dermatitis or psoriasis, who were treated with JAK-STAT inhibitors, which included baricitinib (2846 patients), tofacitinib (2470), upadacitinib (2218), abrocitinib (1904), and deucravacitinib (1492), among others. There were 4925 patients on placebo.

Overall, MACE — defined as a combined endpoint of acute myocardial infarction, stroke, cardiovascular mortality, heart failure, and unstable angina, as well as arterial embolism — occurred in 13 of the JAK-STAT inhibitor-treated patients and in four of those on placebo. VTE — defined as deep vein thrombosis, pulmonary embolism, and any unusual site thrombosis — was reported in eight JAK-STAT inhibitor-treated patients and in one patient on placebo.

The pooled incidence ratios for MACE and VTE were calculated as 0.20 per 100 person exposure years (PEY) for JAK-STAT inhibitor treatment and 0.13 PEY for placebo. The pooled RRs comparing the two treatment groups were a respective 1.13 for MACE and 2.79 for VTE, but neither RR reached statistical significance.

No difference was seen between the treatment arms in terms of treatment emergent adverse events (RR, 1.05), serious adverse events (RR, 0.92), or study discontinuation because of adverse events (RR, 0.94).
 

Reassuring Results?

Dr. Ireland and coauthors said the finding should help to reassure clinicians that the short-term use of JAK-STAT inhibitors in patients with dermatological conditions with low cardiovascular risk profiles “appears to be both safe and well tolerated.” They cautioned, however, that “clinicians must remain judicious” when using these medications for longer periods and in high-risk patient populations.

This was a pragmatic meta-analysis that provides useful information for dermatologists, Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, DC, said in an interview.

“When there are safety concerns, I think that’s where data like this are so important to not just allay the fears of practitioners, but also to arm the practitioner with information for when they discuss a possible treatment with a patient,” said Dr. Friedman, who was not involved in the study.

“What’s unique here is that they’re looking at any possible use of JAK inhibitors for dermatological disease,” so this represents patients that dermatologists would be seeing, he added.

“The limitation here is time, we only can say so much about the safety of the medication with the data that we have,” Dr. Friedman said. Almost 4 months is “a good amount of time” to know about the cardiovascular risks, he said, but added, what happens then? Will the risk increase and will patients need to be switched to another medication?

“There’s no line in the sand,” with regard to using a JAK-STAT inhibitor. “If you look at the label, they’re not meant to be used incrementally,” but as ongoing treatment, while considering the needs of the patient and the relative risks and benefits, he said.

With that in mind, “the open label extension studies for all these [JAK-STAT inhibitors] are really, really important to get a sense of ‘do new signals emerge down the road.’ ”

The meta-analysis received no commercial funding. One author of the work reported personal fees from several pharmaceutical companies which were done outside of analysis. Dr. Friedman has received research funding from or acted as a consultant for several pharmaceutical companies including, Incyte, Pfizer, Eli Lily, and AbbVie.

There is insufficient evidence that drugs targeting the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway increase the risk of cardiovascular or thrombotic complications in people undergoing treatment for a variety of dermatological conditions, at least in the short term, say the authors of a new meta-analysis published in JAMA Dermatology.

Considering data on over 17,000 patients with different dermatoses from 45 placebo-controlled randomized clinical trials with an average follow up of 16 weeks, they found there was no significant increase in the occurrence of major adverse cardiovascular events (MACE) or venous thromboembolism (VTE) in people with dermatoses treated with JAK-STAT inhibitors, compared with placebo.

The I² statistic was 0.00% for both MACE and VTE comparing the two arms, indicating that the results were unlikely to be due to chance. There was no increased risk in MACE between those on placebo and those on JAK-STAT inhibitors, with a risk ratio (RR) of 0.47; or for VTE risk, with an RR of 0.46.

Similar findings were obtained when data were analyzed according to the dermatological condition being treated, mechanism of action of the medication, or whether the medication carried a boxed warning.

These data “suggest inconsistency with established sentiments,” that JAK-STAT inhibitors increase the risk for cardiovascular events, Patrick Ireland, MD, of the University of New South Wales, Randwick, Australia, and coauthors wrote in the article. “This may be owing to the limited time frames in which these rare events could be adequately captured, or the ages of enrolled patients being too young to realize the well established heightened risks of developing MACE and VTE,” they suggested.

However, the findings challenge the notion that the cardiovascular complications of these drugs are the same in all patients; dermatological use may not be associated with the same risks as with use for rheumatologic indications.
 

Class-Wide Boxed Warning

“JAK-STAT [inhibitors] have had some pretty indemnifying data against their use, with the ORAL [Surveillance] study demonstrating increased all-cause mortality, cardiovascular events, venous thromboembolism, and malignancy,” Dr. Ireland said in an interview.

ORAL Surveillance was an open-label, postmarketing trial conducted in patients with rheumatoid arthritis treated with tofacitinib or a tumor necrosis factor (TNF) inhibitor. The results led the US Food and Drug Administration to require information about the risks of serious heart-related events, cancer, blood clots, and death in a boxed warning for JAK-STAT inhibitors in 2022.

“I think it’s important to recognize that these [ORAL Surveillance participants] are very different patients to the typical dermatological patient being treated with a JAK-STAT [inhibitors], with newer studies demonstrating a much safer profile than initially thought,” Dr. Ireland said.
 

Examining Risk in Dermatological Conditions

The meta-analysis performed by Dr. Ireland and associates focused specifically on the risk for MACE and VTE in patients being treated for dermatological conditions, and included trials published up until June 2023. Only trials that had included a placebo arm were considered; pooled analyses, long-term extension trial data, post hoc analyses, and pediatric-specific trials were excluded.

Most (25) of the trials were phase 2b or phase 3 trials, 18 were phase 2 to 2b, and two were phase 1 trials. The studies included 12,996 participants, mostly with atopic dermatitis or psoriasis, who were treated with JAK-STAT inhibitors, which included baricitinib (2846 patients), tofacitinib (2470), upadacitinib (2218), abrocitinib (1904), and deucravacitinib (1492), among others. There were 4925 patients on placebo.

Overall, MACE — defined as a combined endpoint of acute myocardial infarction, stroke, cardiovascular mortality, heart failure, and unstable angina, as well as arterial embolism — occurred in 13 of the JAK-STAT inhibitor-treated patients and in four of those on placebo. VTE — defined as deep vein thrombosis, pulmonary embolism, and any unusual site thrombosis — was reported in eight JAK-STAT inhibitor-treated patients and in one patient on placebo.

The pooled incidence ratios for MACE and VTE were calculated as 0.20 per 100 person exposure years (PEY) for JAK-STAT inhibitor treatment and 0.13 PEY for placebo. The pooled RRs comparing the two treatment groups were a respective 1.13 for MACE and 2.79 for VTE, but neither RR reached statistical significance.

No difference was seen between the treatment arms in terms of treatment emergent adverse events (RR, 1.05), serious adverse events (RR, 0.92), or study discontinuation because of adverse events (RR, 0.94).
 

Reassuring Results?

Dr. Ireland and coauthors said the finding should help to reassure clinicians that the short-term use of JAK-STAT inhibitors in patients with dermatological conditions with low cardiovascular risk profiles “appears to be both safe and well tolerated.” They cautioned, however, that “clinicians must remain judicious” when using these medications for longer periods and in high-risk patient populations.

This was a pragmatic meta-analysis that provides useful information for dermatologists, Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, DC, said in an interview.

“When there are safety concerns, I think that’s where data like this are so important to not just allay the fears of practitioners, but also to arm the practitioner with information for when they discuss a possible treatment with a patient,” said Dr. Friedman, who was not involved in the study.

“What’s unique here is that they’re looking at any possible use of JAK inhibitors for dermatological disease,” so this represents patients that dermatologists would be seeing, he added.

“The limitation here is time, we only can say so much about the safety of the medication with the data that we have,” Dr. Friedman said. Almost 4 months is “a good amount of time” to know about the cardiovascular risks, he said, but added, what happens then? Will the risk increase and will patients need to be switched to another medication?

“There’s no line in the sand,” with regard to using a JAK-STAT inhibitor. “If you look at the label, they’re not meant to be used incrementally,” but as ongoing treatment, while considering the needs of the patient and the relative risks and benefits, he said.

With that in mind, “the open label extension studies for all these [JAK-STAT inhibitors] are really, really important to get a sense of ‘do new signals emerge down the road.’ ”

The meta-analysis received no commercial funding. One author of the work reported personal fees from several pharmaceutical companies which were done outside of analysis. Dr. Friedman has received research funding from or acted as a consultant for several pharmaceutical companies including, Incyte, Pfizer, Eli Lily, and AbbVie.

The AGA Research Foundation plays an important role in medical research by providing grants to young scientists at a critical time in their career. AGA’s flagship award is the Research Scholar Award, which provides career development support for young investigators in gastroenterology and hepatology research. In the last 10 years, the AGA Research Foundation has funded 63 young scientists through a Research Scholar Award grant.

“I want to express my sincere gratitude to the AGA Research Foundation and its benefactors. At this fragile and critical juncture, this AGA Research Scholar Award offers an unmatched opportunity to pursue the type of high-impact scientific work that allows a junior investigator such as myself to achieve the necessary momentum to create a nationally competitive research program,” states Alexander , MD, PhD, the Regent of the University of California, Los Angeles, 2023 AGA Research Scholar Award recipient.

Funded by the generosity of donors, the AGA Research Foundation’s research award program ensures that we are building a community of researchers whose work serves the greater community and benefits all our patients.

By joining others in supporting the AGA Research Foundation, you will ensure that young researchers have opportunities to continue their life-saving work. Your tax-deductible contribution supports the foundation’s research award program, including the Research Scholar Award, which ensures that studies are funded, discoveries are made, and patients are treated. Learn more or make a contribution at www.foundation.gastro.org.

The AGA Research Foundation plays an important role in medical research by providing grants to young scientists at a critical time in their career. AGA’s flagship award is the Research Scholar Award, which provides career development support for young investigators in gastroenterology and hepatology research. In the last 10 years, the AGA Research Foundation has funded 63 young scientists through a Research Scholar Award grant.

“I want to express my sincere gratitude to the AGA Research Foundation and its benefactors. At this fragile and critical juncture, this AGA Research Scholar Award offers an unmatched opportunity to pursue the type of high-impact scientific work that allows a junior investigator such as myself to achieve the necessary momentum to create a nationally competitive research program,” states Alexander , MD, PhD, the Regent of the University of California, Los Angeles, 2023 AGA Research Scholar Award recipient.

Funded by the generosity of donors, the AGA Research Foundation’s research award program ensures that we are building a community of researchers whose work serves the greater community and benefits all our patients.

By joining others in supporting the AGA Research Foundation, you will ensure that young researchers have opportunities to continue their life-saving work. Your tax-deductible contribution supports the foundation’s research award program, including the Research Scholar Award, which ensures that studies are funded, discoveries are made, and patients are treated. Learn more or make a contribution at www.foundation.gastro.org.

The AGA Research Foundation plays an important role in medical research by providing grants to young scientists at a critical time in their career. AGA’s flagship award is the Research Scholar Award, which provides career development support for young investigators in gastroenterology and hepatology research. In the last 10 years, the AGA Research Foundation has funded 63 young scientists through a Research Scholar Award grant.

“I want to express my sincere gratitude to the AGA Research Foundation and its benefactors. At this fragile and critical juncture, this AGA Research Scholar Award offers an unmatched opportunity to pursue the type of high-impact scientific work that allows a junior investigator such as myself to achieve the necessary momentum to create a nationally competitive research program,” states Alexander , MD, PhD, the Regent of the University of California, Los Angeles, 2023 AGA Research Scholar Award recipient.

Funded by the generosity of donors, the AGA Research Foundation’s research award program ensures that we are building a community of researchers whose work serves the greater community and benefits all our patients.

By joining others in supporting the AGA Research Foundation, you will ensure that young researchers have opportunities to continue their life-saving work. Your tax-deductible contribution supports the foundation’s research award program, including the Research Scholar Award, which ensures that studies are funded, discoveries are made, and patients are treated. Learn more or make a contribution at www.foundation.gastro.org.

TOPLINE:

Protein intake within 4 hours before exercise may shorten hypoglycemic episodes during moderate physical activity in teens with type 1 diabetes (T1D).

METHODOLOGY:

• For teenagers with T1D, regular physical activity improves blood sugar, insulin sensitivity, and other health measures, but the risk for hypoglycemia is a major barrier.
• In a secondary analysis of the FLEX study, researchers estimated the association between protein intake within 4 hours before moderate to vigorous physical activity bouts and glycemia during and following physical exercise.
• The final sample size included 447 bouts from 112 adolescents with T1D (median age, 14.5 years; 53.6% female) whose physical activity records and 24-hour dietary recall data were collected at baseline and 6 months.
• Data on continuous glucose monitoring (CGM) was a selection criterium and used to calculate the following measures of glycemia:
• Percentage of time above range (TAR; > 180 mg/dL)
• Percentage of time in range (TIR; 70-180 mg/dL)
• Percentage of time below range (TBR; < 70 mg/dL)

TAKEAWAY:

• There was a small reduction in TBR during physical activity in patients who consumed 10-19.9 g (−4.41%; P = .04) and more than 20 g (−4.83%; P = .02) of protein before moderate to vigorous exercise compared with those who consumed less than 10 g of protein.
• Similarly, protein intakes of 0.125-0.249 g/kg and ≥ 0.25 g/kg were associated with −5.38% (P = .01) and −4.32% (P = .03) reductions in TBR, respectively, compared with less than 0.125 g/kg of protein intake.
• However, the pre-exercise protein consumption was not associated with TAR or TIR during exercise or with any glycemic measurements (TAR, TIR, and TBR) after exercise.
• The benefits of protein intake on glycemia were observed only during moderate-intensity bouts of physical activity, which may reflect differing glycemic trajectories in more high-intensity activity.

IN PRACTICE:

“Consumption of at least 10 g or 0.125 g/kg bodyweight was associated with reduced TBR during moderate to vigorous physical activity, indicating improved safety for adolescents with T1D,” the authors wrote.

SOURCE:

This study, led by Franklin R. Muntis, PhD, Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, North Carolina, was published online in Diabetes, Obesity and Metabolism.

LIMITATIONS:

Self-reported measures of dietary intake were prone to underreporting, while moderate-to-vigorous physical activity was often overreported among adolescents. Approximately, 26% of identified bouts of moderate to vigorous physical activity were missing adequate CGM data, excluding participants from the analysis, which may have caused selection bias. There was no time-stamped insulin dosing data available.

DISCLOSURES:

The FLEX study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Protein intake within 4 hours before exercise may shorten hypoglycemic episodes during moderate physical activity in teens with type 1 diabetes (T1D).

METHODOLOGY:

• For teenagers with T1D, regular physical activity improves blood sugar, insulin sensitivity, and other health measures, but the risk for hypoglycemia is a major barrier.
• In a secondary analysis of the FLEX study, researchers estimated the association between protein intake within 4 hours before moderate to vigorous physical activity bouts and glycemia during and following physical exercise.
• The final sample size included 447 bouts from 112 adolescents with T1D (median age, 14.5 years; 53.6% female) whose physical activity records and 24-hour dietary recall data were collected at baseline and 6 months.
• Data on continuous glucose monitoring (CGM) was a selection criterium and used to calculate the following measures of glycemia:
• Percentage of time above range (TAR; > 180 mg/dL)
• Percentage of time in range (TIR; 70-180 mg/dL)
• Percentage of time below range (TBR; < 70 mg/dL)

TAKEAWAY:

• There was a small reduction in TBR during physical activity in patients who consumed 10-19.9 g (−4.41%; P = .04) and more than 20 g (−4.83%; P = .02) of protein before moderate to vigorous exercise compared with those who consumed less than 10 g of protein.
• Similarly, protein intakes of 0.125-0.249 g/kg and ≥ 0.25 g/kg were associated with −5.38% (P = .01) and −4.32% (P = .03) reductions in TBR, respectively, compared with less than 0.125 g/kg of protein intake.
• However, the pre-exercise protein consumption was not associated with TAR or TIR during exercise or with any glycemic measurements (TAR, TIR, and TBR) after exercise.
• The benefits of protein intake on glycemia were observed only during moderate-intensity bouts of physical activity, which may reflect differing glycemic trajectories in more high-intensity activity.

IN PRACTICE:

“Consumption of at least 10 g or 0.125 g/kg bodyweight was associated with reduced TBR during moderate to vigorous physical activity, indicating improved safety for adolescents with T1D,” the authors wrote.

SOURCE:

This study, led by Franklin R. Muntis, PhD, Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, North Carolina, was published online in Diabetes, Obesity and Metabolism.

LIMITATIONS:

Self-reported measures of dietary intake were prone to underreporting, while moderate-to-vigorous physical activity was often overreported among adolescents. Approximately, 26% of identified bouts of moderate to vigorous physical activity were missing adequate CGM data, excluding participants from the analysis, which may have caused selection bias. There was no time-stamped insulin dosing data available.

DISCLOSURES:

The FLEX study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Protein intake within 4 hours before exercise may shorten hypoglycemic episodes during moderate physical activity in teens with type 1 diabetes (T1D).

METHODOLOGY:

• For teenagers with T1D, regular physical activity improves blood sugar, insulin sensitivity, and other health measures, but the risk for hypoglycemia is a major barrier.
• In a secondary analysis of the FLEX study, researchers estimated the association between protein intake within 4 hours before moderate to vigorous physical activity bouts and glycemia during and following physical exercise.
• The final sample size included 447 bouts from 112 adolescents with T1D (median age, 14.5 years; 53.6% female) whose physical activity records and 24-hour dietary recall data were collected at baseline and 6 months.
• Data on continuous glucose monitoring (CGM) was a selection criterium and used to calculate the following measures of glycemia:
• Percentage of time above range (TAR; > 180 mg/dL)
• Percentage of time in range (TIR; 70-180 mg/dL)
• Percentage of time below range (TBR; < 70 mg/dL)

TAKEAWAY:

• There was a small reduction in TBR during physical activity in patients who consumed 10-19.9 g (−4.41%; P = .04) and more than 20 g (−4.83%; P = .02) of protein before moderate to vigorous exercise compared with those who consumed less than 10 g of protein.
• Similarly, protein intakes of 0.125-0.249 g/kg and ≥ 0.25 g/kg were associated with −5.38% (P = .01) and −4.32% (P = .03) reductions in TBR, respectively, compared with less than 0.125 g/kg of protein intake.
• However, the pre-exercise protein consumption was not associated with TAR or TIR during exercise or with any glycemic measurements (TAR, TIR, and TBR) after exercise.
• The benefits of protein intake on glycemia were observed only during moderate-intensity bouts of physical activity, which may reflect differing glycemic trajectories in more high-intensity activity.

IN PRACTICE:

“Consumption of at least 10 g or 0.125 g/kg bodyweight was associated with reduced TBR during moderate to vigorous physical activity, indicating improved safety for adolescents with T1D,” the authors wrote.

SOURCE:

This study, led by Franklin R. Muntis, PhD, Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, North Carolina, was published online in Diabetes, Obesity and Metabolism.

LIMITATIONS:

Self-reported measures of dietary intake were prone to underreporting, while moderate-to-vigorous physical activity was often overreported among adolescents. Approximately, 26% of identified bouts of moderate to vigorous physical activity were missing adequate CGM data, excluding participants from the analysis, which may have caused selection bias. There was no time-stamped insulin dosing data available.

DISCLOSURES:

The FLEX study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

People with polycystic ovary syndrome (PCOS) may score lower on cognitive tests than people without the condition, a research showed. They also may have worse integrity of brain tissue as evident on an MRI.

METHODOLOGY:

• Researchers used data from the Coronary Artery Risk Development in Young Adults Women’s Study; individuals were 18-30 years old at the beginning of the study and were followed over 30 years.
• A little over 900 women were included in the study, of which 66 had PCOS, which was defined as having elevated androgen levels or self-reported hirsutism and irregular menstrual cycles more than 32 days apart.
• Study participants completed tests measuring verbal learning and memory, processing speed and executive function, attention and cognitive control, and semantics and attention.
• Researchers analyzed brain white matter integrity for 291 of the individuals, including 25 with PCOS, who underwent MRI.

TAKEAWAY:

• Individuals with PCOS had worse memory, attention, and verbal ability scores than those without the disorder.
• MRI scans showed that those with PCOS had lower white matter integrity, an indicator of cognitive deficits, including poorer decision-making abilities.
• Those in the PCOS group were more likely to be White and have diabetes than those in the control group.

IN PRACTICE:

“This report of midlife cognition in PCOS raises a new concern about another potential comorbidity for individuals with this common disorder; given that up to 10% of women may be affected by PCOS, these results have important implications for public health at large,” the authors concluded.

SOURCE:

Heather G. Huddleston, MD, director of the PCOS Clinic at the UCSF Health, San Francisco, California, is the lead author of the study published in Neurology.

LIMITATIONS:

PCOS was determined on the basis of serum androgen levels and self-reporting of hirsutism and oligomenorrhea, so some cases may have been misclassified without the official diagnosis of a clinician.

DISCLOSURES:

The authors did not report any relevant financial conflicts. The study was funded by a grant from the University of California, San Francisco, California.

A version of this article appeared on Medscape.com.

TOPLINE:

People with polycystic ovary syndrome (PCOS) may score lower on cognitive tests than people without the condition, a research showed. They also may have worse integrity of brain tissue as evident on an MRI.

METHODOLOGY:

• Researchers used data from the Coronary Artery Risk Development in Young Adults Women’s Study; individuals were 18-30 years old at the beginning of the study and were followed over 30 years.
• A little over 900 women were included in the study, of which 66 had PCOS, which was defined as having elevated androgen levels or self-reported hirsutism and irregular menstrual cycles more than 32 days apart.
• Study participants completed tests measuring verbal learning and memory, processing speed and executive function, attention and cognitive control, and semantics and attention.
• Researchers analyzed brain white matter integrity for 291 of the individuals, including 25 with PCOS, who underwent MRI.

TAKEAWAY:

• Individuals with PCOS had worse memory, attention, and verbal ability scores than those without the disorder.
• MRI scans showed that those with PCOS had lower white matter integrity, an indicator of cognitive deficits, including poorer decision-making abilities.
• Those in the PCOS group were more likely to be White and have diabetes than those in the control group.

IN PRACTICE:

“This report of midlife cognition in PCOS raises a new concern about another potential comorbidity for individuals with this common disorder; given that up to 10% of women may be affected by PCOS, these results have important implications for public health at large,” the authors concluded.

SOURCE:

Heather G. Huddleston, MD, director of the PCOS Clinic at the UCSF Health, San Francisco, California, is the lead author of the study published in Neurology.

LIMITATIONS:

PCOS was determined on the basis of serum androgen levels and self-reporting of hirsutism and oligomenorrhea, so some cases may have been misclassified without the official diagnosis of a clinician.

DISCLOSURES:

The authors did not report any relevant financial conflicts. The study was funded by a grant from the University of California, San Francisco, California.

A version of this article appeared on Medscape.com.

TOPLINE:

People with polycystic ovary syndrome (PCOS) may score lower on cognitive tests than people without the condition, a research showed. They also may have worse integrity of brain tissue as evident on an MRI.

METHODOLOGY:

• Researchers used data from the Coronary Artery Risk Development in Young Adults Women’s Study; individuals were 18-30 years old at the beginning of the study and were followed over 30 years.
• A little over 900 women were included in the study, of which 66 had PCOS, which was defined as having elevated androgen levels or self-reported hirsutism and irregular menstrual cycles more than 32 days apart.
• Study participants completed tests measuring verbal learning and memory, processing speed and executive function, attention and cognitive control, and semantics and attention.
• Researchers analyzed brain white matter integrity for 291 of the individuals, including 25 with PCOS, who underwent MRI.

TAKEAWAY:

• Individuals with PCOS had worse memory, attention, and verbal ability scores than those without the disorder.
• MRI scans showed that those with PCOS had lower white matter integrity, an indicator of cognitive deficits, including poorer decision-making abilities.
• Those in the PCOS group were more likely to be White and have diabetes than those in the control group.

IN PRACTICE:

“This report of midlife cognition in PCOS raises a new concern about another potential comorbidity for individuals with this common disorder; given that up to 10% of women may be affected by PCOS, these results have important implications for public health at large,” the authors concluded.

SOURCE:

Heather G. Huddleston, MD, director of the PCOS Clinic at the UCSF Health, San Francisco, California, is the lead author of the study published in Neurology.

LIMITATIONS:

PCOS was determined on the basis of serum androgen levels and self-reporting of hirsutism and oligomenorrhea, so some cases may have been misclassified without the official diagnosis of a clinician.

DISCLOSURES:

The authors did not report any relevant financial conflicts. The study was funded by a grant from the University of California, San Francisco, California.

A version of this article appeared on Medscape.com.

TOPLINE:

Higher scores on the dietary inflammatory index in patients with knee osteoarthritis (KOA) were associated with an increased risk of experiencing greater pain over 10 years of follow-up.

METHODOLOGY:

• The researchers recruited 944 adults aged 50-80 years from the community; the mean age at baseline was 62.9 years, 51% were female, the mean body mass index was 27.9 kg/m2, and 60% had radiographic KOA at baseline.
• Magnetic resonance imaging was used to identify structural changes in the knee based on cartilage volume and bone marrow lesions at baseline and follow-up; knee pain was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index pain questionnaire.
• Dietary inflammation was measured using energy-adjusted dietary inflammatory index (E-DII) scores based on nutritional information from the Food-Frequency Questionnaire (FFQ).

TAKEAWAY: 

• Over a follow-up period of 10.7 years, higher E-DII scores were positively associated with increased pain scores (beta = 0.21) after adjustment for age, sex, body mass index, steps per day, education, emotional problems, employment status, comorbidities, and radiographic KOA.
• E-DII scores were not associated with tibial cartilage volume loss or overall bone marrow loss.
• Patients with higher E-DII scores had a significantly higher risk of being on a moderate pain trajectory (relative risk ratio, 1.19), compared with those who followed a minimal pain trajectory over the follow-up period.

IN PRACTICE:

“An anti-inflammatory diet may reduce pain among KOA patients. Future trials investigating the potential of an anti-inflammatory diet for pain relief in KOA are warranted,” the researchers wrote. 

SOURCE:

The lead author on the study was Canchen Ma, PhD, of the University of Tasmania, Hobart, Australia. The study was published online in Arthritis Care & Research. 

LIMITATIONS:

The study used a relatively small number of nutrients from the FFQ to calculate the E-DII scores; participants also exhibited a narrower range of E-DII scores than previous studies. The researchers were unable to account for pharmacologic or preventive treatments. 

DISCLOSURES:

The study was supported by the National Health and Medical Research Council of Australia (NHMRC) and Arthritis Australia. Several authors received support from the National Heart Foundation Fellowship, the NHMRC Leadership Fellowship, the NHMRC Practitioner Fellowship, and the NHMRC Early Career Fellowship. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Higher scores on the dietary inflammatory index in patients with knee osteoarthritis (KOA) were associated with an increased risk of experiencing greater pain over 10 years of follow-up.

METHODOLOGY:

• The researchers recruited 944 adults aged 50-80 years from the community; the mean age at baseline was 62.9 years, 51% were female, the mean body mass index was 27.9 kg/m2, and 60% had radiographic KOA at baseline.
• Magnetic resonance imaging was used to identify structural changes in the knee based on cartilage volume and bone marrow lesions at baseline and follow-up; knee pain was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index pain questionnaire.
• Dietary inflammation was measured using energy-adjusted dietary inflammatory index (E-DII) scores based on nutritional information from the Food-Frequency Questionnaire (FFQ).

TAKEAWAY: 

• Over a follow-up period of 10.7 years, higher E-DII scores were positively associated with increased pain scores (beta = 0.21) after adjustment for age, sex, body mass index, steps per day, education, emotional problems, employment status, comorbidities, and radiographic KOA.
• E-DII scores were not associated with tibial cartilage volume loss or overall bone marrow loss.
• Patients with higher E-DII scores had a significantly higher risk of being on a moderate pain trajectory (relative risk ratio, 1.19), compared with those who followed a minimal pain trajectory over the follow-up period.

IN PRACTICE:

“An anti-inflammatory diet may reduce pain among KOA patients. Future trials investigating the potential of an anti-inflammatory diet for pain relief in KOA are warranted,” the researchers wrote. 

SOURCE:

The lead author on the study was Canchen Ma, PhD, of the University of Tasmania, Hobart, Australia. The study was published online in Arthritis Care & Research. 

LIMITATIONS:

The study used a relatively small number of nutrients from the FFQ to calculate the E-DII scores; participants also exhibited a narrower range of E-DII scores than previous studies. The researchers were unable to account for pharmacologic or preventive treatments. 

DISCLOSURES:

The study was supported by the National Health and Medical Research Council of Australia (NHMRC) and Arthritis Australia. Several authors received support from the National Heart Foundation Fellowship, the NHMRC Leadership Fellowship, the NHMRC Practitioner Fellowship, and the NHMRC Early Career Fellowship. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Higher scores on the dietary inflammatory index in patients with knee osteoarthritis (KOA) were associated with an increased risk of experiencing greater pain over 10 years of follow-up.

METHODOLOGY:

• The researchers recruited 944 adults aged 50-80 years from the community; the mean age at baseline was 62.9 years, 51% were female, the mean body mass index was 27.9 kg/m2, and 60% had radiographic KOA at baseline.
• Magnetic resonance imaging was used to identify structural changes in the knee based on cartilage volume and bone marrow lesions at baseline and follow-up; knee pain was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index pain questionnaire.
• Dietary inflammation was measured using energy-adjusted dietary inflammatory index (E-DII) scores based on nutritional information from the Food-Frequency Questionnaire (FFQ).

TAKEAWAY: 

• Over a follow-up period of 10.7 years, higher E-DII scores were positively associated with increased pain scores (beta = 0.21) after adjustment for age, sex, body mass index, steps per day, education, emotional problems, employment status, comorbidities, and radiographic KOA.
• E-DII scores were not associated with tibial cartilage volume loss or overall bone marrow loss.
• Patients with higher E-DII scores had a significantly higher risk of being on a moderate pain trajectory (relative risk ratio, 1.19), compared with those who followed a minimal pain trajectory over the follow-up period.

IN PRACTICE:

“An anti-inflammatory diet may reduce pain among KOA patients. Future trials investigating the potential of an anti-inflammatory diet for pain relief in KOA are warranted,” the researchers wrote. 

SOURCE:

The lead author on the study was Canchen Ma, PhD, of the University of Tasmania, Hobart, Australia. The study was published online in Arthritis Care & Research. 

LIMITATIONS:

The study used a relatively small number of nutrients from the FFQ to calculate the E-DII scores; participants also exhibited a narrower range of E-DII scores than previous studies. The researchers were unable to account for pharmacologic or preventive treatments. 

DISCLOSURES:

The study was supported by the National Health and Medical Research Council of Australia (NHMRC) and Arthritis Australia. Several authors received support from the National Heart Foundation Fellowship, the NHMRC Leadership Fellowship, the NHMRC Practitioner Fellowship, and the NHMRC Early Career Fellowship. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

According to a rule issued by CMS, starting in 2026, health plans must decide on prior authorization requests within 72 hours for an expedited request or 7 days for non-urgent appeals.

The rule also requires plans to provide a detailed rationale for a denial and include metrics on denials and approvals.

AGA and our allies in the physician community have aggressively advocated that Congress and the Administration address prior auth, which slows patient access to care and contributes to physician burnout.

The rule applies to Medicare, Medicare Advantage (MA), Medicaid, Children’s Health Insurance Plans (CHIP), and qualified health plans on the exchange.

Thank you to our advocates who called on policymakers to take action to ensure patients receive care in a timely manner.

According to a rule issued by CMS, starting in 2026, health plans must decide on prior authorization requests within 72 hours for an expedited request or 7 days for non-urgent appeals.

The rule also requires plans to provide a detailed rationale for a denial and include metrics on denials and approvals.

AGA and our allies in the physician community have aggressively advocated that Congress and the Administration address prior auth, which slows patient access to care and contributes to physician burnout.

The rule applies to Medicare, Medicare Advantage (MA), Medicaid, Children’s Health Insurance Plans (CHIP), and qualified health plans on the exchange.

Thank you to our advocates who called on policymakers to take action to ensure patients receive care in a timely manner.

According to a rule issued by CMS, starting in 2026, health plans must decide on prior authorization requests within 72 hours for an expedited request or 7 days for non-urgent appeals.

The rule also requires plans to provide a detailed rationale for a denial and include metrics on denials and approvals.

AGA and our allies in the physician community have aggressively advocated that Congress and the Administration address prior auth, which slows patient access to care and contributes to physician burnout.

The rule applies to Medicare, Medicare Advantage (MA), Medicaid, Children’s Health Insurance Plans (CHIP), and qualified health plans on the exchange.

Thank you to our advocates who called on policymakers to take action to ensure patients receive care in a timely manner.

As the number of women in gastroenterology grows, so does AGA’s portfolio of programs focused on maximizing the role of women in GI.

“Women continue to face unique barriers to leadership including gender bias, lack of role models, maternal discrimination, and lack of equal consideration for opportunities,” notes AGA President Barbara Jung, MD, AGAF. “AGA sits in a unique position where we can influence changes in academia and practice to improve the field for all women and particularly enhance women leaders.”

A tangible way AGA supports female leadership and career advancement is the Women in GI Regional Workshops. Throughout 2024, these workshops provide opportunities for networking, business and financial education training, burnout prevention strategies, and career advice.

American Gastroenterological Association

Bigger picture, AGA’s Gender Equity Framework paints a compelling vision for the future in six domains:

• Bias & gender disparities: Academic institutions, healthcare systems, and practices establish regular systems of equity reviews and eradicate institutional gender disparities and bias.
• Leadership & career advancement: Equitable access to leadership in the field and professional GI societies for the benefit of medicine, research, and patient care.
• Wellness & balance: Women in GI experience balanced integration of family, work, community, health, and professional growth.
• Retention & recruitment: GI is the leading specialty for women in medicine and a sustainable career where women grow and thrive.
• Mentorship & sponsorship: The benefits of mentorship and sponsorship are universally recognized and incentivized in GI institutions and practices.
• Recognition: Equitable recognition of the achievements and contributions of women in GI.

In the coming years, AGA committees will collaborate with the AGA Women’s Committee to achieve the vision laid out in the AGA Gender Equity Framework. Thank you to the AGA Women’s Committee, which created the framework, under the leadership of chair Aimee Lucas, MD, MS, AGAF, and within the auspices of the AGA Equity Project (gastro.org/equity).

As the number of women in gastroenterology grows, so does AGA’s portfolio of programs focused on maximizing the role of women in GI.

“Women continue to face unique barriers to leadership including gender bias, lack of role models, maternal discrimination, and lack of equal consideration for opportunities,” notes AGA President Barbara Jung, MD, AGAF. “AGA sits in a unique position where we can influence changes in academia and practice to improve the field for all women and particularly enhance women leaders.”

A tangible way AGA supports female leadership and career advancement is the Women in GI Regional Workshops. Throughout 2024, these workshops provide opportunities for networking, business and financial education training, burnout prevention strategies, and career advice.

American Gastroenterological Association

Bigger picture, AGA’s Gender Equity Framework paints a compelling vision for the future in six domains:

• Bias & gender disparities: Academic institutions, healthcare systems, and practices establish regular systems of equity reviews and eradicate institutional gender disparities and bias.
• Leadership & career advancement: Equitable access to leadership in the field and professional GI societies for the benefit of medicine, research, and patient care.
• Wellness & balance: Women in GI experience balanced integration of family, work, community, health, and professional growth.
• Retention & recruitment: GI is the leading specialty for women in medicine and a sustainable career where women grow and thrive.
• Mentorship & sponsorship: The benefits of mentorship and sponsorship are universally recognized and incentivized in GI institutions and practices.
• Recognition: Equitable recognition of the achievements and contributions of women in GI.

In the coming years, AGA committees will collaborate with the AGA Women’s Committee to achieve the vision laid out in the AGA Gender Equity Framework. Thank you to the AGA Women’s Committee, which created the framework, under the leadership of chair Aimee Lucas, MD, MS, AGAF, and within the auspices of the AGA Equity Project (gastro.org/equity).

As the number of women in gastroenterology grows, so does AGA’s portfolio of programs focused on maximizing the role of women in GI.

“Women continue to face unique barriers to leadership including gender bias, lack of role models, maternal discrimination, and lack of equal consideration for opportunities,” notes AGA President Barbara Jung, MD, AGAF. “AGA sits in a unique position where we can influence changes in academia and practice to improve the field for all women and particularly enhance women leaders.”

A tangible way AGA supports female leadership and career advancement is the Women in GI Regional Workshops. Throughout 2024, these workshops provide opportunities for networking, business and financial education training, burnout prevention strategies, and career advice.

American Gastroenterological Association

Bigger picture, AGA’s Gender Equity Framework paints a compelling vision for the future in six domains:

• Bias & gender disparities: Academic institutions, healthcare systems, and practices establish regular systems of equity reviews and eradicate institutional gender disparities and bias.
• Leadership & career advancement: Equitable access to leadership in the field and professional GI societies for the benefit of medicine, research, and patient care.
• Wellness & balance: Women in GI experience balanced integration of family, work, community, health, and professional growth.
• Retention & recruitment: GI is the leading specialty for women in medicine and a sustainable career where women grow and thrive.
• Mentorship & sponsorship: The benefits of mentorship and sponsorship are universally recognized and incentivized in GI institutions and practices.
• Recognition: Equitable recognition of the achievements and contributions of women in GI.

In the coming years, AGA committees will collaborate with the AGA Women’s Committee to achieve the vision laid out in the AGA Gender Equity Framework. Thank you to the AGA Women’s Committee, which created the framework, under the leadership of chair Aimee Lucas, MD, MS, AGAF, and within the auspices of the AGA Equity Project (gastro.org/equity).

TOPLINE:

Gabapentinoid use significantly increased the risk for exacerbations in adults with chronic obstructive pulmonary disease (COPD).

METHODOLOGY:

• Previous research has prompted warnings from North American and European health agencies of severe exacerbations associated with gabapentinoid use by patients with COPD.
• The researchers compared data from patients with COPD in Canadian databases between 1994 and 2015 who were new to gabapentinoids and matched them to patients who did not use gabapentinoids.
• The primary outcome was exacerbation of COPD that required hospitalization in a propensity score-matched study. 

TAKEAWAY:

• The study population included 356 epilepsy patients, 9411 neuropathic pain patients, and 3737 patients with other chronic pain.
• Use of gabapentinoids was significantly associated with an overall increased risk for severe COPD exacerbation (hazard ratio, 1.49) compared with nonuse.
• Gabapentinoid use was associated with a significantly increased COPD exacerbation risk for each group of users compared with nonusers, with hazard ratios of 1.58, 1.35, and 1.49 for epilepsy, neuropathic pain, and other chronic pain, respectively.

IN PRACTICE:

“This study supports the warnings from regulatory agencies and highlights the importance of considering this potential risk when prescribing gabapentin and pregabalin to patients with COPD,” the researchers wrote. 

SOURCE:

The lead author on the study was Alvi A. Rahman, MSc, of Jewish General Hospital, Montreal. The study was published online on January 16, 2024, in Annals of Internal Medicine. 

LIMITATIONS:

A lack of data on smoking status and other residual confounding factors limited the study findings. 

DISCLOSURES:

The study was supported by the Canadian Institutes of Health Research and the Canadian Lung Association. Mr. Rahman had no financial conflicts to disclose, but some coauthors disclosed consulting and advisory relationships with various companies, including Merck, Pfizer, Seqirus, Boehringer-Ingelheim, and Novartis outside of the current work.

A version of this article appeared on Medscape.com.

TOPLINE:

Gabapentinoid use significantly increased the risk for exacerbations in adults with chronic obstructive pulmonary disease (COPD).

METHODOLOGY:

• Previous research has prompted warnings from North American and European health agencies of severe exacerbations associated with gabapentinoid use by patients with COPD.
• The researchers compared data from patients with COPD in Canadian databases between 1994 and 2015 who were new to gabapentinoids and matched them to patients who did not use gabapentinoids.
• The primary outcome was exacerbation of COPD that required hospitalization in a propensity score-matched study. 

TAKEAWAY:

• The study population included 356 epilepsy patients, 9411 neuropathic pain patients, and 3737 patients with other chronic pain.
• Use of gabapentinoids was significantly associated with an overall increased risk for severe COPD exacerbation (hazard ratio, 1.49) compared with nonuse.
• Gabapentinoid use was associated with a significantly increased COPD exacerbation risk for each group of users compared with nonusers, with hazard ratios of 1.58, 1.35, and 1.49 for epilepsy, neuropathic pain, and other chronic pain, respectively.

IN PRACTICE:

“This study supports the warnings from regulatory agencies and highlights the importance of considering this potential risk when prescribing gabapentin and pregabalin to patients with COPD,” the researchers wrote. 

SOURCE:

The lead author on the study was Alvi A. Rahman, MSc, of Jewish General Hospital, Montreal. The study was published online on January 16, 2024, in Annals of Internal Medicine. 

LIMITATIONS:

A lack of data on smoking status and other residual confounding factors limited the study findings. 

DISCLOSURES:

The study was supported by the Canadian Institutes of Health Research and the Canadian Lung Association. Mr. Rahman had no financial conflicts to disclose, but some coauthors disclosed consulting and advisory relationships with various companies, including Merck, Pfizer, Seqirus, Boehringer-Ingelheim, and Novartis outside of the current work.

A version of this article appeared on Medscape.com.

TOPLINE:

Gabapentinoid use significantly increased the risk for exacerbations in adults with chronic obstructive pulmonary disease (COPD).

METHODOLOGY:

• Previous research has prompted warnings from North American and European health agencies of severe exacerbations associated with gabapentinoid use by patients with COPD.
• The researchers compared data from patients with COPD in Canadian databases between 1994 and 2015 who were new to gabapentinoids and matched them to patients who did not use gabapentinoids.
• The primary outcome was exacerbation of COPD that required hospitalization in a propensity score-matched study. 

TAKEAWAY:

• The study population included 356 epilepsy patients, 9411 neuropathic pain patients, and 3737 patients with other chronic pain.
• Use of gabapentinoids was significantly associated with an overall increased risk for severe COPD exacerbation (hazard ratio, 1.49) compared with nonuse.
• Gabapentinoid use was associated with a significantly increased COPD exacerbation risk for each group of users compared with nonusers, with hazard ratios of 1.58, 1.35, and 1.49 for epilepsy, neuropathic pain, and other chronic pain, respectively.

IN PRACTICE:

“This study supports the warnings from regulatory agencies and highlights the importance of considering this potential risk when prescribing gabapentin and pregabalin to patients with COPD,” the researchers wrote. 

SOURCE:

The lead author on the study was Alvi A. Rahman, MSc, of Jewish General Hospital, Montreal. The study was published online on January 16, 2024, in Annals of Internal Medicine. 

LIMITATIONS:

A lack of data on smoking status and other residual confounding factors limited the study findings. 

DISCLOSURES:

The study was supported by the Canadian Institutes of Health Research and the Canadian Lung Association. Mr. Rahman had no financial conflicts to disclose, but some coauthors disclosed consulting and advisory relationships with various companies, including Merck, Pfizer, Seqirus, Boehringer-Ingelheim, and Novartis outside of the current work.

A version of this article appeared on Medscape.com.