Commentary

Recently, a 40-year-old woman took to Facebook to announce that she had died.

Rachel Davies, of Wales, wrote: “If you’re reading this, then it means I’m no longer here. What a life I’ve had, and surprisingly, since cancer entered my life. When I look through my photos, I’ve done and seen so much since cancer, and probably some of my best memories are from this period. In so many ways, I have to thank it for learning how to live fully. What I wish is that everyone can experience the same but without needing cancer. Get out there, experience life fully, and wear that dress!!! I’m so sad to leave my family and friends, I wish I never had to go. I’m so grateful to have had Charlie young so that I’ve watched him grow into the man he is today. I’m unbelievably proud of him. I am thankful I had the opportunity to have Kacey and Jacob in my life. Lastly, I was blessed to meet the love of my life, my husband, and my best friend. I have no regrets, I have had a wonderful life. So to all of you, don’t be sad I’ve gone. Live your life and live it well. Love, Rachel x.”

 

I didn’t know Ms. Davies, but am likely among many who wish I had. In a terrible situation she kept trying.

She had HER2 metastatic breast cancer, which can respond to the drug Enhertu (trastuzumab). Unfortunately, she never had the chance, because it wasn’t available to her in Wales. In the United Kingdom it’s available only in Scotland.

I’m not saying it was a cure. Statistically, it likely would have bought her another 6 months of family time. But that’s still another half year.

I’m not blaming the Welsh NHS, though they made the decision not to cover it because of cost. The jobs of such committees is a thankless one, trying to decide where the limited money goes — vaccines for many children that are proven to lessen morbidity and mortality over the course of a lifetime, or to add 6 months to the lives of comparatively fewer women with HER2 metastatic breast cancer.

I’m not blaming the company that makes Enhertu, though it was the cost that kept her from getting it. Bringing a drug to market, with all the labs and clinical research behind it, ain’t cheap. If the company can’t keep the lights on they’re not going to able to develop future pharmaceuticals to help others, though I do wonder if a better price could have been negotiated. (I’m not trying to justify the salaries of insurance CEOs — don’t even get me started on those.)

Money is always limited, and human suffering is infinite. Every health care organization, public or private, has to face that simple fact. There is no right place to draw the line, so we use the greatest good for the greatest many as our best guess.

In her last post, though, Ms. Davies didn’t dwell on any of this. She reflected on her joys and blessings, and encouraged others to live life fully. Things we should all focus on.

In a world that often seems to have gone mad, it’s good to keep in mind that there is more good than bad out there. 

Thank you, Ms. Davies, for the reminder.

Allan M. Block, MD, has a solo neurology practice in Scottsdale, Arizona.

Recently, a 40-year-old woman took to Facebook to announce that she had died.

Rachel Davies, of Wales, wrote: “If you’re reading this, then it means I’m no longer here. What a life I’ve had, and surprisingly, since cancer entered my life. When I look through my photos, I’ve done and seen so much since cancer, and probably some of my best memories are from this period. In so many ways, I have to thank it for learning how to live fully. What I wish is that everyone can experience the same but without needing cancer. Get out there, experience life fully, and wear that dress!!! I’m so sad to leave my family and friends, I wish I never had to go. I’m so grateful to have had Charlie young so that I’ve watched him grow into the man he is today. I’m unbelievably proud of him. I am thankful I had the opportunity to have Kacey and Jacob in my life. Lastly, I was blessed to meet the love of my life, my husband, and my best friend. I have no regrets, I have had a wonderful life. So to all of you, don’t be sad I’ve gone. Live your life and live it well. Love, Rachel x.”

 

I didn’t know Ms. Davies, but am likely among many who wish I had. In a terrible situation she kept trying.

She had HER2 metastatic breast cancer, which can respond to the drug Enhertu (trastuzumab). Unfortunately, she never had the chance, because it wasn’t available to her in Wales. In the United Kingdom it’s available only in Scotland.

I’m not saying it was a cure. Statistically, it likely would have bought her another 6 months of family time. But that’s still another half year.

I’m not blaming the Welsh NHS, though they made the decision not to cover it because of cost. The jobs of such committees is a thankless one, trying to decide where the limited money goes — vaccines for many children that are proven to lessen morbidity and mortality over the course of a lifetime, or to add 6 months to the lives of comparatively fewer women with HER2 metastatic breast cancer.

I’m not blaming the company that makes Enhertu, though it was the cost that kept her from getting it. Bringing a drug to market, with all the labs and clinical research behind it, ain’t cheap. If the company can’t keep the lights on they’re not going to able to develop future pharmaceuticals to help others, though I do wonder if a better price could have been negotiated. (I’m not trying to justify the salaries of insurance CEOs — don’t even get me started on those.)

Money is always limited, and human suffering is infinite. Every health care organization, public or private, has to face that simple fact. There is no right place to draw the line, so we use the greatest good for the greatest many as our best guess.

In her last post, though, Ms. Davies didn’t dwell on any of this. She reflected on her joys and blessings, and encouraged others to live life fully. Things we should all focus on.

In a world that often seems to have gone mad, it’s good to keep in mind that there is more good than bad out there. 

Thank you, Ms. Davies, for the reminder.

Allan M. Block, MD, has a solo neurology practice in Scottsdale, Arizona.

Recently, a 40-year-old woman took to Facebook to announce that she had died.

Rachel Davies, of Wales, wrote: “If you’re reading this, then it means I’m no longer here. What a life I’ve had, and surprisingly, since cancer entered my life. When I look through my photos, I’ve done and seen so much since cancer, and probably some of my best memories are from this period. In so many ways, I have to thank it for learning how to live fully. What I wish is that everyone can experience the same but without needing cancer. Get out there, experience life fully, and wear that dress!!! I’m so sad to leave my family and friends, I wish I never had to go. I’m so grateful to have had Charlie young so that I’ve watched him grow into the man he is today. I’m unbelievably proud of him. I am thankful I had the opportunity to have Kacey and Jacob in my life. Lastly, I was blessed to meet the love of my life, my husband, and my best friend. I have no regrets, I have had a wonderful life. So to all of you, don’t be sad I’ve gone. Live your life and live it well. Love, Rachel x.”

 

I didn’t know Ms. Davies, but am likely among many who wish I had. In a terrible situation she kept trying.

She had HER2 metastatic breast cancer, which can respond to the drug Enhertu (trastuzumab). Unfortunately, she never had the chance, because it wasn’t available to her in Wales. In the United Kingdom it’s available only in Scotland.

I’m not saying it was a cure. Statistically, it likely would have bought her another 6 months of family time. But that’s still another half year.

I’m not blaming the Welsh NHS, though they made the decision not to cover it because of cost. The jobs of such committees is a thankless one, trying to decide where the limited money goes — vaccines for many children that are proven to lessen morbidity and mortality over the course of a lifetime, or to add 6 months to the lives of comparatively fewer women with HER2 metastatic breast cancer.

I’m not blaming the company that makes Enhertu, though it was the cost that kept her from getting it. Bringing a drug to market, with all the labs and clinical research behind it, ain’t cheap. If the company can’t keep the lights on they’re not going to able to develop future pharmaceuticals to help others, though I do wonder if a better price could have been negotiated. (I’m not trying to justify the salaries of insurance CEOs — don’t even get me started on those.)

Money is always limited, and human suffering is infinite. Every health care organization, public or private, has to face that simple fact. There is no right place to draw the line, so we use the greatest good for the greatest many as our best guess.

In her last post, though, Ms. Davies didn’t dwell on any of this. She reflected on her joys and blessings, and encouraged others to live life fully. Things we should all focus on.

In a world that often seems to have gone mad, it’s good to keep in mind that there is more good than bad out there. 

Thank you, Ms. Davies, for the reminder.

Allan M. Block, MD, has a solo neurology practice in Scottsdale, Arizona.

Cutaneous melanoma is a type of skin cancer typically associated with significant ultraviolet radiation exposure. Melanoma arises from melanocytes, cells found within the lower portion of the epidermis that make the pigment melanin.

While much less common than squamous cell carcinoma or basal cell carcinoma, melanoma is responsible for most deaths from skin cancer. In 2024, there will be more than 100,000 new cases of melanoma and over 8,000 melanoma-related deaths.¹ If localized at the time of diagnosis, survival rates are excellent. Cutaneous melanomas are more common in those with fair complexions or who have had long periods of exposure to natural or artificial sunlight.

Melanoma can also occur in mucous membranes. Mucosal melanoma is much less common than cutaneous melanoma and accounts for only a very small percentage of all new melanoma diagnoses. Unlike their cutaneous counterparts, risk factors for mucosal melanomas have yet to be identified. Although there is some disagreement on whether vulvar melanomas represent cutaneous or mucous melanomas, vulvovaginal melanomas have historically been considered to be mucosal melanomas.

Vulvovaginal melanomas are characterized by a high mortality rate, diagnostic challenges, and lack of awareness, making early detection and intervention crucial to improving patient outcomes. The 5-year overall survival rate for vulvar melanoma is 36% and for vaginal melanoma ranges between 5% and 25%.² Survival rates for vulvovaginal melanomas are lower than for other types of vulvar cancers (72%) or for cutaneous melanomas (72%-81%).²

Racial disparities in survival rates for mucosal and cutaneous melanomas were highlighted in a retrospective study using the Surveillance Epidemiology and End Results (SEER) database. Although the number of Black patients included was small, the median overall survival in that population was less than that in non-Black patients with vulvovaginal melanoma (16 vs. 39 months). Similar findings were noted in Black patients with cutaneous melanoma, compared with non-Black patients (median overall survival, 124 vs 319 months).³

One of the most significant obstacles in the diagnosis of vulvar and vaginal melanoma is its rarity. Both patients and clinicians alike may fail to recognize early warning signs. In a world where skin cancer is heavily publicized, melanoma in the genital area is not as frequently discussed or understood. Postmenopausal patients may have less regular gynecologic care, and unless they present with specific symptoms prompting an exam, melanomas can grow undetected, progressing to more advanced stages before they are discovered.

The median age of patients diagnosed with vulvar and vaginal melanomas is 67-68.^4,5 Symptoms can be subtle and nonspecific. Women with vulvar melanoma may experience symptoms that are similar to other vulvar cancers including pruritus, irritation, pain, bleeding, or a new or growing mass. While vaginal melanoma can be asymptomatic, patients frequently present with vaginal bleeding, discharge, and/or pain (including dyspareunia).

Vulvovaginal melanomas may present differently than cutaneous melanomas. Vulvar melanomas are often pigmented and frequently present as ulcerated lesions. In some cases, though, they appear amelanotic (lacking pigment), making them even harder to identify. The ABCDEs of skin cancer (asymmetry, border, color, diameter, evolving) should be applied to these lesions. Change in the size, shape, or pigment of preexisting melanosis (areas of hyperpigmentation caused by increased melanin), should raise concern for possible malignant transformation. 

Most vaginal melanomas occur within the distal third of the vagina, frequently along the anterior vaginal wall.⁶ They can be polypoid or nodular in appearance and may be ulcerated. While biopsy of any suspicious, enlarging/changing, or symptomatic lesion should be performed, it may be prudent to pause prior to biopsy of a vaginal lesion depending on its appearance. Although rare, gestational trophoblastic neoplasia (GTN) can present with vaginal metastases, and these lesions are frequently very vascular and pose a high bleeding risk if biopsied. They may look dark blue or black. If there is any concern for metastatic GTN on vaginal exam, a beta-hCG level should be obtained prior to biopsy.

Treatment of vulvovaginal melanoma may include surgical excision, systemic therapy, radiation therapy, or a combination of treatments. There is growing use of immunotherapy that mirrors cutaneous melanoma therapy.

Vulvar and vaginal melanoma represent a rare yet serious health issue for women and their impact on public health should not be underestimated. Vulvovaginal melanoma often goes unrecognized until it has reached an advanced stage. Increased awareness about these rare forms of melanoma among both patients and healthcare professionals is vital to improve early detection and treatment outcomes. With greater attention to this disease, we can strive for better diagnostic methods, more effective treatments, and ultimately, a reduction in mortality rates associated with vulvar and vaginal melanoma.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest.

References

1. National Cancer Institute. Cancer Stat Facts: Melanoma of the skin. 2024 Dec 2. Available from: https://seer.cancer.gov/statfacts/html/melan.html.

2. Piura B. Lancet Oncol. 2008 Oct;9(10):973-81. .

3. Mert I et al. Int J Gynecol Cancer. 2013;23(6):1118-25.

4. Wang D et al. Am J Cancer Res. 2020 Dec 1;10(12):4017-37.

5. Albert A et al. J Gynecol Oncol. 2020 Sep;31(5):e66.

Cutaneous melanoma is a type of skin cancer typically associated with significant ultraviolet radiation exposure. Melanoma arises from melanocytes, cells found within the lower portion of the epidermis that make the pigment melanin.

While much less common than squamous cell carcinoma or basal cell carcinoma, melanoma is responsible for most deaths from skin cancer. In 2024, there will be more than 100,000 new cases of melanoma and over 8,000 melanoma-related deaths.¹ If localized at the time of diagnosis, survival rates are excellent. Cutaneous melanomas are more common in those with fair complexions or who have had long periods of exposure to natural or artificial sunlight.

Melanoma can also occur in mucous membranes. Mucosal melanoma is much less common than cutaneous melanoma and accounts for only a very small percentage of all new melanoma diagnoses. Unlike their cutaneous counterparts, risk factors for mucosal melanomas have yet to be identified. Although there is some disagreement on whether vulvar melanomas represent cutaneous or mucous melanomas, vulvovaginal melanomas have historically been considered to be mucosal melanomas.

Vulvovaginal melanomas are characterized by a high mortality rate, diagnostic challenges, and lack of awareness, making early detection and intervention crucial to improving patient outcomes. The 5-year overall survival rate for vulvar melanoma is 36% and for vaginal melanoma ranges between 5% and 25%.² Survival rates for vulvovaginal melanomas are lower than for other types of vulvar cancers (72%) or for cutaneous melanomas (72%-81%).²

Racial disparities in survival rates for mucosal and cutaneous melanomas were highlighted in a retrospective study using the Surveillance Epidemiology and End Results (SEER) database. Although the number of Black patients included was small, the median overall survival in that population was less than that in non-Black patients with vulvovaginal melanoma (16 vs. 39 months). Similar findings were noted in Black patients with cutaneous melanoma, compared with non-Black patients (median overall survival, 124 vs 319 months).³

One of the most significant obstacles in the diagnosis of vulvar and vaginal melanoma is its rarity. Both patients and clinicians alike may fail to recognize early warning signs. In a world where skin cancer is heavily publicized, melanoma in the genital area is not as frequently discussed or understood. Postmenopausal patients may have less regular gynecologic care, and unless they present with specific symptoms prompting an exam, melanomas can grow undetected, progressing to more advanced stages before they are discovered.

The median age of patients diagnosed with vulvar and vaginal melanomas is 67-68.^4,5 Symptoms can be subtle and nonspecific. Women with vulvar melanoma may experience symptoms that are similar to other vulvar cancers including pruritus, irritation, pain, bleeding, or a new or growing mass. While vaginal melanoma can be asymptomatic, patients frequently present with vaginal bleeding, discharge, and/or pain (including dyspareunia).

Vulvovaginal melanomas may present differently than cutaneous melanomas. Vulvar melanomas are often pigmented and frequently present as ulcerated lesions. In some cases, though, they appear amelanotic (lacking pigment), making them even harder to identify. The ABCDEs of skin cancer (asymmetry, border, color, diameter, evolving) should be applied to these lesions. Change in the size, shape, or pigment of preexisting melanosis (areas of hyperpigmentation caused by increased melanin), should raise concern for possible malignant transformation. 

Most vaginal melanomas occur within the distal third of the vagina, frequently along the anterior vaginal wall.⁶ They can be polypoid or nodular in appearance and may be ulcerated. While biopsy of any suspicious, enlarging/changing, or symptomatic lesion should be performed, it may be prudent to pause prior to biopsy of a vaginal lesion depending on its appearance. Although rare, gestational trophoblastic neoplasia (GTN) can present with vaginal metastases, and these lesions are frequently very vascular and pose a high bleeding risk if biopsied. They may look dark blue or black. If there is any concern for metastatic GTN on vaginal exam, a beta-hCG level should be obtained prior to biopsy.

Treatment of vulvovaginal melanoma may include surgical excision, systemic therapy, radiation therapy, or a combination of treatments. There is growing use of immunotherapy that mirrors cutaneous melanoma therapy.

Vulvar and vaginal melanoma represent a rare yet serious health issue for women and their impact on public health should not be underestimated. Vulvovaginal melanoma often goes unrecognized until it has reached an advanced stage. Increased awareness about these rare forms of melanoma among both patients and healthcare professionals is vital to improve early detection and treatment outcomes. With greater attention to this disease, we can strive for better diagnostic methods, more effective treatments, and ultimately, a reduction in mortality rates associated with vulvar and vaginal melanoma.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest.

References

1. National Cancer Institute. Cancer Stat Facts: Melanoma of the skin. 2024 Dec 2. Available from: https://seer.cancer.gov/statfacts/html/melan.html.

2. Piura B. Lancet Oncol. 2008 Oct;9(10):973-81. .

3. Mert I et al. Int J Gynecol Cancer. 2013;23(6):1118-25.

4. Wang D et al. Am J Cancer Res. 2020 Dec 1;10(12):4017-37.

5. Albert A et al. J Gynecol Oncol. 2020 Sep;31(5):e66.

Cutaneous melanoma is a type of skin cancer typically associated with significant ultraviolet radiation exposure. Melanoma arises from melanocytes, cells found within the lower portion of the epidermis that make the pigment melanin.

While much less common than squamous cell carcinoma or basal cell carcinoma, melanoma is responsible for most deaths from skin cancer. In 2024, there will be more than 100,000 new cases of melanoma and over 8,000 melanoma-related deaths.¹ If localized at the time of diagnosis, survival rates are excellent. Cutaneous melanomas are more common in those with fair complexions or who have had long periods of exposure to natural or artificial sunlight.

Melanoma can also occur in mucous membranes. Mucosal melanoma is much less common than cutaneous melanoma and accounts for only a very small percentage of all new melanoma diagnoses. Unlike their cutaneous counterparts, risk factors for mucosal melanomas have yet to be identified. Although there is some disagreement on whether vulvar melanomas represent cutaneous or mucous melanomas, vulvovaginal melanomas have historically been considered to be mucosal melanomas.

Vulvovaginal melanomas are characterized by a high mortality rate, diagnostic challenges, and lack of awareness, making early detection and intervention crucial to improving patient outcomes. The 5-year overall survival rate for vulvar melanoma is 36% and for vaginal melanoma ranges between 5% and 25%.² Survival rates for vulvovaginal melanomas are lower than for other types of vulvar cancers (72%) or for cutaneous melanomas (72%-81%).²

Racial disparities in survival rates for mucosal and cutaneous melanomas were highlighted in a retrospective study using the Surveillance Epidemiology and End Results (SEER) database. Although the number of Black patients included was small, the median overall survival in that population was less than that in non-Black patients with vulvovaginal melanoma (16 vs. 39 months). Similar findings were noted in Black patients with cutaneous melanoma, compared with non-Black patients (median overall survival, 124 vs 319 months).³

One of the most significant obstacles in the diagnosis of vulvar and vaginal melanoma is its rarity. Both patients and clinicians alike may fail to recognize early warning signs. In a world where skin cancer is heavily publicized, melanoma in the genital area is not as frequently discussed or understood. Postmenopausal patients may have less regular gynecologic care, and unless they present with specific symptoms prompting an exam, melanomas can grow undetected, progressing to more advanced stages before they are discovered.

The median age of patients diagnosed with vulvar and vaginal melanomas is 67-68.^4,5 Symptoms can be subtle and nonspecific. Women with vulvar melanoma may experience symptoms that are similar to other vulvar cancers including pruritus, irritation, pain, bleeding, or a new or growing mass. While vaginal melanoma can be asymptomatic, patients frequently present with vaginal bleeding, discharge, and/or pain (including dyspareunia).

Vulvovaginal melanomas may present differently than cutaneous melanomas. Vulvar melanomas are often pigmented and frequently present as ulcerated lesions. In some cases, though, they appear amelanotic (lacking pigment), making them even harder to identify. The ABCDEs of skin cancer (asymmetry, border, color, diameter, evolving) should be applied to these lesions. Change in the size, shape, or pigment of preexisting melanosis (areas of hyperpigmentation caused by increased melanin), should raise concern for possible malignant transformation. 

Most vaginal melanomas occur within the distal third of the vagina, frequently along the anterior vaginal wall.⁶ They can be polypoid or nodular in appearance and may be ulcerated. While biopsy of any suspicious, enlarging/changing, or symptomatic lesion should be performed, it may be prudent to pause prior to biopsy of a vaginal lesion depending on its appearance. Although rare, gestational trophoblastic neoplasia (GTN) can present with vaginal metastases, and these lesions are frequently very vascular and pose a high bleeding risk if biopsied. They may look dark blue or black. If there is any concern for metastatic GTN on vaginal exam, a beta-hCG level should be obtained prior to biopsy.

Treatment of vulvovaginal melanoma may include surgical excision, systemic therapy, radiation therapy, or a combination of treatments. There is growing use of immunotherapy that mirrors cutaneous melanoma therapy.

Vulvar and vaginal melanoma represent a rare yet serious health issue for women and their impact on public health should not be underestimated. Vulvovaginal melanoma often goes unrecognized until it has reached an advanced stage. Increased awareness about these rare forms of melanoma among both patients and healthcare professionals is vital to improve early detection and treatment outcomes. With greater attention to this disease, we can strive for better diagnostic methods, more effective treatments, and ultimately, a reduction in mortality rates associated with vulvar and vaginal melanoma.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest.

References

1. National Cancer Institute. Cancer Stat Facts: Melanoma of the skin. 2024 Dec 2. Available from: https://seer.cancer.gov/statfacts/html/melan.html.

2. Piura B. Lancet Oncol. 2008 Oct;9(10):973-81. .

3. Mert I et al. Int J Gynecol Cancer. 2013;23(6):1118-25.

4. Wang D et al. Am J Cancer Res. 2020 Dec 1;10(12):4017-37.

5. Albert A et al. J Gynecol Oncol. 2020 Sep;31(5):e66.

Hatice became pregnant while working as a medical resident, and her career took a noticeable hit. Her training was downgraded, and her job applications went unanswered. This news organization spoke with her about her experiences and the disadvantages faced by young female doctors with children. 

Hatice, can you tell us about your career path?

I initially started my clinical year at a hospital in Cologne, Germany. Then, 8 months in, I got pregnant with my first child during the first COVID-19 wave. After my maternity leave, I returned to the clinic, and that’s when the problems began.

Where did the issues arise?

Suddenly, I wasn’t allowed into the operating rooms (ORs) and was instead sent to the outpatient clinic. I had to fight for every OR slot until, eventually, I said, “This can’t go on. I want to stay in the hospital and gain my surgical experience, but not if I have to keep struggling for it.”

So, initially, it was about wanting to improve the quality of your ongoing training, as they gave you no path forward for further development? And you attribute this to your maternity leave.

It wasn’t just my perception — I was told as much directly. I returned from maternity leave and was told to work in outpatients and cover shifts. I went to my supervisor and explained that I was unhappy with this. We have an OR log, and I wanted to complete my required cases. He replied, “Well, that’s your fault for getting pregnant right away.” 

In the Cologne/Düsseldorf/Bonn area, there is no shortage of doctors in training. This means that as soon as I leave, there will be new recruits. So my boss actually said to me at the time, “If you’re gone, you’re gone, then the next candidate will come along.”

 

Did you return to work part-time after your maternity leave, or full-time?

I returned full-time and took on all my usual duties. Fortunately, my husband takes on a lot at home. He spent a significant time on parental leave and has often been the one to care for our child when they’re sick. So, if you didn’t know, you wouldn’t necessarily realize at work that I have a child.

What happened next?

I discussed the situation with the senior physician responsible for the OR assignments, but she told me not to worry, as I would eventually get the required signature at the end of my training. But that wasn’t my issue — I wanted the professional training. Feeling stuck, I decided to look for other positions.

Did you apply elsewhere to improve your situation?

Yes, but most of my applications went unanswered, which I didn’t understand. When I followed up, I actually received verbal replies from three hospitals, stating, “We don’t hire women with children.”

You’ve shared your experiences publicly on social media. How has the response been? Have other female doctors had similar experiences?

I think the problem of discrimination against women with children is still taboo. You’d think, with the shortage of doctors, that jobs would be available. But I’ve heard from former classmates who now have children that they face similar career obstacles, especially in fields such as internal medicine, where fulfilling rotations is challenging owing to scheduling bias.

This raises the question of adapting working conditions. In your case, it seems that a change in employer attitudes is also needed. What’s your perspective?

It varies depending on the region. I’ve applied across Germany and found that areas outside major cities such as Cologne, Düsseldorf, and Frankfurt tend to be better. In urban centers with a large applicant pool, the atmosphere is different. In smaller areas, finding a job is easier, especially if you’re fluent in German and experienced.

Do you believe that changing the mindset of employers regarding female staff with children could happen with a generational shift?

Honestly, I doubt it. It’s not just an issue at management level — it’s also present among residents. When someone takes leave, colleagues have to cover, which leads to resentment. Yet many female residents will eventually have children themselves. And it’s often overlooked that many men now share childcare responsibilities or take parental leave. Improving staffing levels would help alleviate these pressures.

Returning to structural issues, how is your situation now — can you continue your training?

I’ve since changed positions and am very happy. I didn’t expect such a positive reception with a child in tow.

Lastly, what changes do you think are needed? Is it enough to speak out about such experiences, or are further solutions necessary?

It’s good that topics such as burnout are openly discussed now. With children, there’s a risk for burnout, as you strive to meet all expectations to avoid career setbacks. But there also needs to be an acceptance that women who are hired may become pregnant and may have more than one child. I’m hopeful that over time, this will become normalized, especially as medicine becomes a more female-dominated field.

Is there anything else you’d like to share?

I wish there were more solidarity among women. It’s disheartening to see competition and infighting. More mutual support among women would make a huge difference.

Thank you, Hatice, and best of luck in your career.

Hatice, who prefers not to disclose her last name for privacy, is a fourth-year ENT specialist in training and shares her journey as a young doctor on Instagram under the name dein.hno.arzt.

This article was translated from Coliquio using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

Hatice became pregnant while working as a medical resident, and her career took a noticeable hit. Her training was downgraded, and her job applications went unanswered. This news organization spoke with her about her experiences and the disadvantages faced by young female doctors with children. 

Hatice, can you tell us about your career path?

I initially started my clinical year at a hospital in Cologne, Germany. Then, 8 months in, I got pregnant with my first child during the first COVID-19 wave. After my maternity leave, I returned to the clinic, and that’s when the problems began.

Where did the issues arise?

Suddenly, I wasn’t allowed into the operating rooms (ORs) and was instead sent to the outpatient clinic. I had to fight for every OR slot until, eventually, I said, “This can’t go on. I want to stay in the hospital and gain my surgical experience, but not if I have to keep struggling for it.”

So, initially, it was about wanting to improve the quality of your ongoing training, as they gave you no path forward for further development? And you attribute this to your maternity leave.

It wasn’t just my perception — I was told as much directly. I returned from maternity leave and was told to work in outpatients and cover shifts. I went to my supervisor and explained that I was unhappy with this. We have an OR log, and I wanted to complete my required cases. He replied, “Well, that’s your fault for getting pregnant right away.” 

In the Cologne/Düsseldorf/Bonn area, there is no shortage of doctors in training. This means that as soon as I leave, there will be new recruits. So my boss actually said to me at the time, “If you’re gone, you’re gone, then the next candidate will come along.”

 

Did you return to work part-time after your maternity leave, or full-time?

I returned full-time and took on all my usual duties. Fortunately, my husband takes on a lot at home. He spent a significant time on parental leave and has often been the one to care for our child when they’re sick. So, if you didn’t know, you wouldn’t necessarily realize at work that I have a child.

What happened next?

I discussed the situation with the senior physician responsible for the OR assignments, but she told me not to worry, as I would eventually get the required signature at the end of my training. But that wasn’t my issue — I wanted the professional training. Feeling stuck, I decided to look for other positions.

Did you apply elsewhere to improve your situation?

Yes, but most of my applications went unanswered, which I didn’t understand. When I followed up, I actually received verbal replies from three hospitals, stating, “We don’t hire women with children.”

You’ve shared your experiences publicly on social media. How has the response been? Have other female doctors had similar experiences?

I think the problem of discrimination against women with children is still taboo. You’d think, with the shortage of doctors, that jobs would be available. But I’ve heard from former classmates who now have children that they face similar career obstacles, especially in fields such as internal medicine, where fulfilling rotations is challenging owing to scheduling bias.

This raises the question of adapting working conditions. In your case, it seems that a change in employer attitudes is also needed. What’s your perspective?

It varies depending on the region. I’ve applied across Germany and found that areas outside major cities such as Cologne, Düsseldorf, and Frankfurt tend to be better. In urban centers with a large applicant pool, the atmosphere is different. In smaller areas, finding a job is easier, especially if you’re fluent in German and experienced.

Do you believe that changing the mindset of employers regarding female staff with children could happen with a generational shift?

Honestly, I doubt it. It’s not just an issue at management level — it’s also present among residents. When someone takes leave, colleagues have to cover, which leads to resentment. Yet many female residents will eventually have children themselves. And it’s often overlooked that many men now share childcare responsibilities or take parental leave. Improving staffing levels would help alleviate these pressures.

Returning to structural issues, how is your situation now — can you continue your training?

I’ve since changed positions and am very happy. I didn’t expect such a positive reception with a child in tow.

Lastly, what changes do you think are needed? Is it enough to speak out about such experiences, or are further solutions necessary?

It’s good that topics such as burnout are openly discussed now. With children, there’s a risk for burnout, as you strive to meet all expectations to avoid career setbacks. But there also needs to be an acceptance that women who are hired may become pregnant and may have more than one child. I’m hopeful that over time, this will become normalized, especially as medicine becomes a more female-dominated field.

Is there anything else you’d like to share?

I wish there were more solidarity among women. It’s disheartening to see competition and infighting. More mutual support among women would make a huge difference.

Thank you, Hatice, and best of luck in your career.

Hatice, who prefers not to disclose her last name for privacy, is a fourth-year ENT specialist in training and shares her journey as a young doctor on Instagram under the name dein.hno.arzt.

This article was translated from Coliquio using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

Hatice became pregnant while working as a medical resident, and her career took a noticeable hit. Her training was downgraded, and her job applications went unanswered. This news organization spoke with her about her experiences and the disadvantages faced by young female doctors with children. 

Hatice, can you tell us about your career path?

I initially started my clinical year at a hospital in Cologne, Germany. Then, 8 months in, I got pregnant with my first child during the first COVID-19 wave. After my maternity leave, I returned to the clinic, and that’s when the problems began.

Where did the issues arise?

Suddenly, I wasn’t allowed into the operating rooms (ORs) and was instead sent to the outpatient clinic. I had to fight for every OR slot until, eventually, I said, “This can’t go on. I want to stay in the hospital and gain my surgical experience, but not if I have to keep struggling for it.”

So, initially, it was about wanting to improve the quality of your ongoing training, as they gave you no path forward for further development? And you attribute this to your maternity leave.

It wasn’t just my perception — I was told as much directly. I returned from maternity leave and was told to work in outpatients and cover shifts. I went to my supervisor and explained that I was unhappy with this. We have an OR log, and I wanted to complete my required cases. He replied, “Well, that’s your fault for getting pregnant right away.” 

In the Cologne/Düsseldorf/Bonn area, there is no shortage of doctors in training. This means that as soon as I leave, there will be new recruits. So my boss actually said to me at the time, “If you’re gone, you’re gone, then the next candidate will come along.”

 

Did you return to work part-time after your maternity leave, or full-time?

I returned full-time and took on all my usual duties. Fortunately, my husband takes on a lot at home. He spent a significant time on parental leave and has often been the one to care for our child when they’re sick. So, if you didn’t know, you wouldn’t necessarily realize at work that I have a child.

What happened next?

I discussed the situation with the senior physician responsible for the OR assignments, but she told me not to worry, as I would eventually get the required signature at the end of my training. But that wasn’t my issue — I wanted the professional training. Feeling stuck, I decided to look for other positions.

Did you apply elsewhere to improve your situation?

Yes, but most of my applications went unanswered, which I didn’t understand. When I followed up, I actually received verbal replies from three hospitals, stating, “We don’t hire women with children.”

You’ve shared your experiences publicly on social media. How has the response been? Have other female doctors had similar experiences?

I think the problem of discrimination against women with children is still taboo. You’d think, with the shortage of doctors, that jobs would be available. But I’ve heard from former classmates who now have children that they face similar career obstacles, especially in fields such as internal medicine, where fulfilling rotations is challenging owing to scheduling bias.

This raises the question of adapting working conditions. In your case, it seems that a change in employer attitudes is also needed. What’s your perspective?

It varies depending on the region. I’ve applied across Germany and found that areas outside major cities such as Cologne, Düsseldorf, and Frankfurt tend to be better. In urban centers with a large applicant pool, the atmosphere is different. In smaller areas, finding a job is easier, especially if you’re fluent in German and experienced.

Do you believe that changing the mindset of employers regarding female staff with children could happen with a generational shift?

Honestly, I doubt it. It’s not just an issue at management level — it’s also present among residents. When someone takes leave, colleagues have to cover, which leads to resentment. Yet many female residents will eventually have children themselves. And it’s often overlooked that many men now share childcare responsibilities or take parental leave. Improving staffing levels would help alleviate these pressures.

Returning to structural issues, how is your situation now — can you continue your training?

I’ve since changed positions and am very happy. I didn’t expect such a positive reception with a child in tow.

Lastly, what changes do you think are needed? Is it enough to speak out about such experiences, or are further solutions necessary?

It’s good that topics such as burnout are openly discussed now. With children, there’s a risk for burnout, as you strive to meet all expectations to avoid career setbacks. But there also needs to be an acceptance that women who are hired may become pregnant and may have more than one child. I’m hopeful that over time, this will become normalized, especially as medicine becomes a more female-dominated field.

Is there anything else you’d like to share?

I wish there were more solidarity among women. It’s disheartening to see competition and infighting. More mutual support among women would make a huge difference.

Thank you, Hatice, and best of luck in your career.

Hatice, who prefers not to disclose her last name for privacy, is a fourth-year ENT specialist in training and shares her journey as a young doctor on Instagram under the name dein.hno.arzt.

This article was translated from Coliquio using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

During a recent walk with my 6-year-old, he told me he smelled marijuana. His comment speaks to its increased (and more open) use since legalization in our state. The macho, misguided part of my dad psyche was proud of his “street cred” but the thinking part of my brain was concerned. He seemed a little young for a talk about drugs. 

I was able to provide a simple, watered-down list of reasons why he shouldn’t smoke marijuana or anything else. The “drugs are bad” aphorism sufficed for my 6-year-old but wasn’t worthy of an academic pulmonologist.

I retired from the military 2 years ago, so marijuana (I’m using the terms “marijuana” and “cannabis” interchangeably here) knowledge wasn’t required for regular practice. I recall one 60-year-old patient who reported smoking four joints a day for years. He had marked emphysema on CT, severe obstruction on spirometry, and he was functionally limited. Buttressed by scattered reports of acute lung injury caused by dabbing or marijuana vaping, this anecdotal “n of 1” led to a predictably pedantic conclusion: Smoking marijuana is bad for the lungs and preaching cessation is worth my time and effort. 

I now work in an inner-city hospital. My 6-year-old could identify the smell permeating the hallways and clinic rooms. I’ve reverted to counseling cessation using little more than my “drugs are bad” speech. When I came across a recent review in Seminars in Respiratory and Critical Care Medicine, I recognized the opportunity to read and do better. This summary is based heavily on that review.

Spoiler alert: The data aren’t great. By federal law, marijuana has been illegal in the United States since 1970, so neither funding nor recruitment has come easy. There’s lots of observational data that depend on self-report and are confounded by cigarette use. A lack of regulation results in variations in composition and concentration. In summary, though, smoking marijuana is associated with changes to the bronchial tree and respiratory symptoms, similar to those seen with chronic bronchitis. These symptoms improve with cessation. 

The relationship between marijuana and airflow obstruction and lung function is complicated. A mix of contradictory data shows a reduction in the ratio of the forced expiratory volume in the first 1 second to the forced vital capacity (FEV₁/FVC), an increase in FVC, and changes in conductance. 

Biologic plausibility, essential to bolster causality but easy to manufacture, seems intuitive for the airway changes (decreased FEV₁/FVC and conductance). The increase in FVC, explained by either the anti-inflammatory properties of delta-9-tetrahydrocannabinol (THC) or the impact from deep inhalations typical of marijuana use, is more difficult to understand. Regardless, I came away from the review less confident about marijuana’s impact on lung structure and function. 

The Seminars review also explores marijuana’s association with lung cancer, emphysema, and other structural changes seen on CT of the chest. There’s certainly noise here but the data at present are underwhelming. 

This all speaks to the general misconception I’ve had, perhaps shared by others, that the well-defined effects on the lung from tobacco abuse can be extrapolated to marijuana. In the past, I’d even gone so far as to equate a pack-year (smoking one pack of cigarettes per day for a year) to a joint-year (smoking one joint per day for a year), a rather dramatic oversimplification. While both are attempts to quantify exposure, the latter connotes far less information. The content of a joint can vary considerably in ways that the content of cigarettes does not, and there have been no formal studies of the comparative impact on the lung. 

 

Final Thoughts

The nuance here matters for several reasons. Legalization means an increase in use and presumably more open reporting by patients. In a vacuum, it seems reasonable to council cessation to reduce symptoms and because additional harms can be assumed, given what we know about smoke inhalation in general. Will cessation drive patients to an increase in tobacco use where harm is better established? 

Given its mixed effects on lung function, is it worth spending behavior change capital, the most precious of patient commodities, on marijuana counseling? Marijuana has numerous effects outside the lung that haven’t been touched on here. How should those be incorporated into our guidance? Legalization and regulation provide the opportunity to obtain the better data that are sorely needed.

Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Maryland, and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington, DC. He has disclosed the relevant financial relationships with Metapharm, CHEST College, and WebMD.

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

During a recent walk with my 6-year-old, he told me he smelled marijuana. His comment speaks to its increased (and more open) use since legalization in our state. The macho, misguided part of my dad psyche was proud of his “street cred” but the thinking part of my brain was concerned. He seemed a little young for a talk about drugs. 

I was able to provide a simple, watered-down list of reasons why he shouldn’t smoke marijuana or anything else. The “drugs are bad” aphorism sufficed for my 6-year-old but wasn’t worthy of an academic pulmonologist.

I retired from the military 2 years ago, so marijuana (I’m using the terms “marijuana” and “cannabis” interchangeably here) knowledge wasn’t required for regular practice. I recall one 60-year-old patient who reported smoking four joints a day for years. He had marked emphysema on CT, severe obstruction on spirometry, and he was functionally limited. Buttressed by scattered reports of acute lung injury caused by dabbing or marijuana vaping, this anecdotal “n of 1” led to a predictably pedantic conclusion: Smoking marijuana is bad for the lungs and preaching cessation is worth my time and effort. 

I now work in an inner-city hospital. My 6-year-old could identify the smell permeating the hallways and clinic rooms. I’ve reverted to counseling cessation using little more than my “drugs are bad” speech. When I came across a recent review in Seminars in Respiratory and Critical Care Medicine, I recognized the opportunity to read and do better. This summary is based heavily on that review.

Spoiler alert: The data aren’t great. By federal law, marijuana has been illegal in the United States since 1970, so neither funding nor recruitment has come easy. There’s lots of observational data that depend on self-report and are confounded by cigarette use. A lack of regulation results in variations in composition and concentration. In summary, though, smoking marijuana is associated with changes to the bronchial tree and respiratory symptoms, similar to those seen with chronic bronchitis. These symptoms improve with cessation. 

The relationship between marijuana and airflow obstruction and lung function is complicated. A mix of contradictory data shows a reduction in the ratio of the forced expiratory volume in the first 1 second to the forced vital capacity (FEV₁/FVC), an increase in FVC, and changes in conductance. 

Biologic plausibility, essential to bolster causality but easy to manufacture, seems intuitive for the airway changes (decreased FEV₁/FVC and conductance). The increase in FVC, explained by either the anti-inflammatory properties of delta-9-tetrahydrocannabinol (THC) or the impact from deep inhalations typical of marijuana use, is more difficult to understand. Regardless, I came away from the review less confident about marijuana’s impact on lung structure and function. 

The Seminars review also explores marijuana’s association with lung cancer, emphysema, and other structural changes seen on CT of the chest. There’s certainly noise here but the data at present are underwhelming. 

This all speaks to the general misconception I’ve had, perhaps shared by others, that the well-defined effects on the lung from tobacco abuse can be extrapolated to marijuana. In the past, I’d even gone so far as to equate a pack-year (smoking one pack of cigarettes per day for a year) to a joint-year (smoking one joint per day for a year), a rather dramatic oversimplification. While both are attempts to quantify exposure, the latter connotes far less information. The content of a joint can vary considerably in ways that the content of cigarettes does not, and there have been no formal studies of the comparative impact on the lung. 

 

Final Thoughts

The nuance here matters for several reasons. Legalization means an increase in use and presumably more open reporting by patients. In a vacuum, it seems reasonable to council cessation to reduce symptoms and because additional harms can be assumed, given what we know about smoke inhalation in general. Will cessation drive patients to an increase in tobacco use where harm is better established? 

Given its mixed effects on lung function, is it worth spending behavior change capital, the most precious of patient commodities, on marijuana counseling? Marijuana has numerous effects outside the lung that haven’t been touched on here. How should those be incorporated into our guidance? Legalization and regulation provide the opportunity to obtain the better data that are sorely needed.

Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Maryland, and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington, DC. He has disclosed the relevant financial relationships with Metapharm, CHEST College, and WebMD.

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

During a recent walk with my 6-year-old, he told me he smelled marijuana. His comment speaks to its increased (and more open) use since legalization in our state. The macho, misguided part of my dad psyche was proud of his “street cred” but the thinking part of my brain was concerned. He seemed a little young for a talk about drugs. 

I was able to provide a simple, watered-down list of reasons why he shouldn’t smoke marijuana or anything else. The “drugs are bad” aphorism sufficed for my 6-year-old but wasn’t worthy of an academic pulmonologist.

I retired from the military 2 years ago, so marijuana (I’m using the terms “marijuana” and “cannabis” interchangeably here) knowledge wasn’t required for regular practice. I recall one 60-year-old patient who reported smoking four joints a day for years. He had marked emphysema on CT, severe obstruction on spirometry, and he was functionally limited. Buttressed by scattered reports of acute lung injury caused by dabbing or marijuana vaping, this anecdotal “n of 1” led to a predictably pedantic conclusion: Smoking marijuana is bad for the lungs and preaching cessation is worth my time and effort. 

I now work in an inner-city hospital. My 6-year-old could identify the smell permeating the hallways and clinic rooms. I’ve reverted to counseling cessation using little more than my “drugs are bad” speech. When I came across a recent review in Seminars in Respiratory and Critical Care Medicine, I recognized the opportunity to read and do better. This summary is based heavily on that review.

Spoiler alert: The data aren’t great. By federal law, marijuana has been illegal in the United States since 1970, so neither funding nor recruitment has come easy. There’s lots of observational data that depend on self-report and are confounded by cigarette use. A lack of regulation results in variations in composition and concentration. In summary, though, smoking marijuana is associated with changes to the bronchial tree and respiratory symptoms, similar to those seen with chronic bronchitis. These symptoms improve with cessation. 

The relationship between marijuana and airflow obstruction and lung function is complicated. A mix of contradictory data shows a reduction in the ratio of the forced expiratory volume in the first 1 second to the forced vital capacity (FEV₁/FVC), an increase in FVC, and changes in conductance. 

Biologic plausibility, essential to bolster causality but easy to manufacture, seems intuitive for the airway changes (decreased FEV₁/FVC and conductance). The increase in FVC, explained by either the anti-inflammatory properties of delta-9-tetrahydrocannabinol (THC) or the impact from deep inhalations typical of marijuana use, is more difficult to understand. Regardless, I came away from the review less confident about marijuana’s impact on lung structure and function. 

The Seminars review also explores marijuana’s association with lung cancer, emphysema, and other structural changes seen on CT of the chest. There’s certainly noise here but the data at present are underwhelming. 

This all speaks to the general misconception I’ve had, perhaps shared by others, that the well-defined effects on the lung from tobacco abuse can be extrapolated to marijuana. In the past, I’d even gone so far as to equate a pack-year (smoking one pack of cigarettes per day for a year) to a joint-year (smoking one joint per day for a year), a rather dramatic oversimplification. While both are attempts to quantify exposure, the latter connotes far less information. The content of a joint can vary considerably in ways that the content of cigarettes does not, and there have been no formal studies of the comparative impact on the lung. 

 

Final Thoughts

The nuance here matters for several reasons. Legalization means an increase in use and presumably more open reporting by patients. In a vacuum, it seems reasonable to council cessation to reduce symptoms and because additional harms can be assumed, given what we know about smoke inhalation in general. Will cessation drive patients to an increase in tobacco use where harm is better established? 

Given its mixed effects on lung function, is it worth spending behavior change capital, the most precious of patient commodities, on marijuana counseling? Marijuana has numerous effects outside the lung that haven’t been touched on here. How should those be incorporated into our guidance? Legalization and regulation provide the opportunity to obtain the better data that are sorely needed.

Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Maryland, and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington, DC. He has disclosed the relevant financial relationships with Metapharm, CHEST College, and WebMD.

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

This transcript has been edited for clarity. 

I would like to briefly talk about a very interesting paper and one that probably has about as much to inform the doctor-patient relationship as any paper you can think of. 

The title itself gives you a little bit of that answer before I even discuss the outcome. The paper is “The Benefits of Quitting Smoking at Different Ages,” recently published in The American Journal of Preventive Medicine.

I’m not going to even begin to attempt to explore the statistics of the analysis, but I think the conclusions are both fascinating and important. I will read the first sentence of the results and then just comment on some of the others because there’s just so much data here and I really want to focus on the punchline. 

The results section said that, compared with people who never smoked, those who smoke currently, aged 35, 45, 55, 65, or 75, (those were all the groups they looked at), and who have smoked throughout adulthood until that age will lose an average of 9.1, 8.3, 7.3, 5.9, and 4.4 years of life, respectively — obviously, it’s a lot — if they continue to smoke for the rest of their lives. 

If somebody is smoking at age 35 and they continue to smoke, they could lose 9 years of life on average. We know that. It’s terrible. That’s why people should never smoke. Period. End of story. There’s no social value. There’s no health value of smoking. It’s a deadly recreational activity for multiple illnesses, and obviously, cancer is prominent among them.

Here’s the conclusion of the paper that I think is interesting. That doctor, whether it’s a primary care doctor, an oncologist, an ob/gyn, or a family doctor, is seeing Mr Smith or Mrs Jones in the office today, whether they know that patient well or not very well, and they’re still smoking. However, if the person we’re describing here quits smoking at these ages, how much life do they add back, compared with if they continued?

They may say: “Oh, I’ve been smoking all my life. What difference does it make? The die is cast.” Wrong! If you’ve been smoking your whole adult life — so let’s just say that you started at age 18, age 20, age 15, or even age 12 — but you quit smoking at the age of 35, you’re going to add 8 years of life on average. If you quit smoking when you’re 65, having smoked your whole adult life, you will add 1.7 years of life. That’s 1.7 years to be with your family, to be with your grandchildren, and enjoy life. If you ask, “Oh, what difference does it make?” It makes a big difference. 

I’ll share another statistic and I’ll be done. I think this is really an interesting one. The chances of gaining at least a year of life among those who quit smoking at the age of 65 was 23.4%. There is a 1 out of 4 chance that you’re going to live an additional year if you stop at age 65. Even if you stop smoking at age 75, you have a 14% chance of living at least an additional year longer than you would have if you didn’t stop smoking. 

There is much to think about here, much to consider, and much to discuss potentially with patients.

Dr. Markman is Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix. He reported conflicts of interest with GlaxoSmithKline and AstraZeneca.

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

This transcript has been edited for clarity. 

I would like to briefly talk about a very interesting paper and one that probably has about as much to inform the doctor-patient relationship as any paper you can think of. 

The title itself gives you a little bit of that answer before I even discuss the outcome. The paper is “The Benefits of Quitting Smoking at Different Ages,” recently published in The American Journal of Preventive Medicine.

I’m not going to even begin to attempt to explore the statistics of the analysis, but I think the conclusions are both fascinating and important. I will read the first sentence of the results and then just comment on some of the others because there’s just so much data here and I really want to focus on the punchline. 

The results section said that, compared with people who never smoked, those who smoke currently, aged 35, 45, 55, 65, or 75, (those were all the groups they looked at), and who have smoked throughout adulthood until that age will lose an average of 9.1, 8.3, 7.3, 5.9, and 4.4 years of life, respectively — obviously, it’s a lot — if they continue to smoke for the rest of their lives. 

If somebody is smoking at age 35 and they continue to smoke, they could lose 9 years of life on average. We know that. It’s terrible. That’s why people should never smoke. Period. End of story. There’s no social value. There’s no health value of smoking. It’s a deadly recreational activity for multiple illnesses, and obviously, cancer is prominent among them.

Here’s the conclusion of the paper that I think is interesting. That doctor, whether it’s a primary care doctor, an oncologist, an ob/gyn, or a family doctor, is seeing Mr Smith or Mrs Jones in the office today, whether they know that patient well or not very well, and they’re still smoking. However, if the person we’re describing here quits smoking at these ages, how much life do they add back, compared with if they continued?

They may say: “Oh, I’ve been smoking all my life. What difference does it make? The die is cast.” Wrong! If you’ve been smoking your whole adult life — so let’s just say that you started at age 18, age 20, age 15, or even age 12 — but you quit smoking at the age of 35, you’re going to add 8 years of life on average. If you quit smoking when you’re 65, having smoked your whole adult life, you will add 1.7 years of life. That’s 1.7 years to be with your family, to be with your grandchildren, and enjoy life. If you ask, “Oh, what difference does it make?” It makes a big difference. 

I’ll share another statistic and I’ll be done. I think this is really an interesting one. The chances of gaining at least a year of life among those who quit smoking at the age of 65 was 23.4%. There is a 1 out of 4 chance that you’re going to live an additional year if you stop at age 65. Even if you stop smoking at age 75, you have a 14% chance of living at least an additional year longer than you would have if you didn’t stop smoking. 

There is much to think about here, much to consider, and much to discuss potentially with patients.

Dr. Markman is Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix. He reported conflicts of interest with GlaxoSmithKline and AstraZeneca.

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

This transcript has been edited for clarity. 

I would like to briefly talk about a very interesting paper and one that probably has about as much to inform the doctor-patient relationship as any paper you can think of. 

The title itself gives you a little bit of that answer before I even discuss the outcome. The paper is “The Benefits of Quitting Smoking at Different Ages,” recently published in The American Journal of Preventive Medicine.

I’m not going to even begin to attempt to explore the statistics of the analysis, but I think the conclusions are both fascinating and important. I will read the first sentence of the results and then just comment on some of the others because there’s just so much data here and I really want to focus on the punchline. 

The results section said that, compared with people who never smoked, those who smoke currently, aged 35, 45, 55, 65, or 75, (those were all the groups they looked at), and who have smoked throughout adulthood until that age will lose an average of 9.1, 8.3, 7.3, 5.9, and 4.4 years of life, respectively — obviously, it’s a lot — if they continue to smoke for the rest of their lives. 

If somebody is smoking at age 35 and they continue to smoke, they could lose 9 years of life on average. We know that. It’s terrible. That’s why people should never smoke. Period. End of story. There’s no social value. There’s no health value of smoking. It’s a deadly recreational activity for multiple illnesses, and obviously, cancer is prominent among them.

Here’s the conclusion of the paper that I think is interesting. That doctor, whether it’s a primary care doctor, an oncologist, an ob/gyn, or a family doctor, is seeing Mr Smith or Mrs Jones in the office today, whether they know that patient well or not very well, and they’re still smoking. However, if the person we’re describing here quits smoking at these ages, how much life do they add back, compared with if they continued?

They may say: “Oh, I’ve been smoking all my life. What difference does it make? The die is cast.” Wrong! If you’ve been smoking your whole adult life — so let’s just say that you started at age 18, age 20, age 15, or even age 12 — but you quit smoking at the age of 35, you’re going to add 8 years of life on average. If you quit smoking when you’re 65, having smoked your whole adult life, you will add 1.7 years of life. That’s 1.7 years to be with your family, to be with your grandchildren, and enjoy life. If you ask, “Oh, what difference does it make?” It makes a big difference. 

I’ll share another statistic and I’ll be done. I think this is really an interesting one. The chances of gaining at least a year of life among those who quit smoking at the age of 65 was 23.4%. There is a 1 out of 4 chance that you’re going to live an additional year if you stop at age 65. Even if you stop smoking at age 75, you have a 14% chance of living at least an additional year longer than you would have if you didn’t stop smoking. 

There is much to think about here, much to consider, and much to discuss potentially with patients.

Dr. Markman is Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix. He reported conflicts of interest with GlaxoSmithKline and AstraZeneca.

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

This transcript has been edited for clarity. 

Oh, insurance claim denials. When patient care or treatment is warranted by a specific diagnosis, I wish insurers would just reimburse it without any hassle. That’s not reality. Let’s talk about insurance claim denials, how they’re rising and harming patient care, and what we can do about it. That’s kind of complicated.

Rising Trend in Claim Denials and Financial Impact

First, denials are increasing. Experian Health surveyed provider revenue cycle leaders— that’s a fancy term for people who manage billing and insurance claims — and 75% said that denials are increasing. This is up from 42% a few years ago. Those surveyed also said that reimbursement times and errors in claims are also increasing, and changes in policy are happening more frequently. This all adds to the problem. 

Aside from being time-consuming and annoying, claim denials take a toll on hospitals and patients. One analysis, which made headlines everywhere, showed that hospitals and health systems spent nearly $20 billion in 2022 trying to repeal overturned claims. This analysis was done by Premier, a health insurance performance company.

 

Breakdown of Denial Rates and Costs

Let’s do some quick whiteboard math. Health insurance companies get about 3 billion claims per year. According to surveys, about 15% of those claims are denied, so that leaves us with 450 million denied claims. Hospitals spend, on average, $43.84 per denied claim in administrative fees trying to get them overturned.

That’s about $19.7 billion spent on claim denials. Here’s the gut punch: Around 54% of those claims are ultimately paid, so that leaves us with $10.7 billion that we definitely should have saved. 

 

Common Reasons for Denials

Let’s take a look at major causes and what’s going on. 

Insurance denial rates are all over the place. It depends on state and plan. According to one analysis, the average for in-network claim denials across some states was 4% to 5%. It was 40% in Mississippi. According to HealthCare.gov, in 2021, around 17% of in-network claims were denied. 

The most common reasons were excluded services, a lack of referral or preauthorization, or a medical treatment not being deemed necessary. Then there’s the black box of “other,” just some arbitrary reason to make a claim denial. 

Many times, these denials are done by an algorithm, not by individual people. 

What’s more, a Kaiser Family Foundation analysis found that private insurers, including Medicare Advantage plans, were more likely to deny claims than public options. 

When broken down, the problem was higher among employer-sponsored and marketplace insurance, and less so with Medicare and Medicaid. 

 

Impact on Patient Care

Many consumers don’t truly understand what their health insurance covers and what’s going to be out of pocket, and many people don’t know that they have appeal rights. They don’t know who to call for help either. 

The ACA set up Consumer Assistance Programs (CAPs), which are designed to help people navigate health insurance problems. By law, private insurers have to share data with CAPs. Yet, only 3% of people who had trouble with health insurance claims called a CAP for help.

We all know some of the downstream effects of this problem. Patients may skip or delay treatments if they can’t get insurance to cover it or it’s too expensive. When post-acute care, such as transfer to a skilled nursing facility or rehab center, isn’t covered and we’re trying to discharge patients from the hospital, hospital stays become lengthened, which means they’re more expensive, and this comes with its own set of complications.

 

How Can We Address This?

I’m genuinely curious about what you all have done to efficiently address this problem. I’m looking at this publication from the American Health Information Management Association about major reasons for denial. We’ve already talked about a lack of preauthorization or procedures not being covered, but there are also reasons such as missing or incorrect information, duplicate claims, and not filing within the appropriate time.

Also, if treatments or procedures are bundled, they can’t be filed separately. 

Preventing all of this would take a large effort. Healthcare systems would have to have a dedicated team, who would understand all the major reasons for denials, identify common patterns, and then fill everything out with accurate information, with referrals, with preauthorizations, high-specificity codes, and the correct modifiers — and do all of this within the filing deadline every time. 

You would need physicians on board, but also people from IT, finance, compliance, case management, registration, and probably a bunch of other people who are already stretched too thin. 

Perhaps our government can do more to hold insurers accountable and make sure plans, such as Medicare Advantage, are holding up their end of the public health bargain.

It’s an uphill $20 billion battle, but I’m optimistic. What about you? What’s your unfiltered take on claim denials? What more can we be doing?

Dr. Patel is a clinical instructor, Department of Pediatrics, Columbia University College of Physicians and Surgeons; pediatric hospitalist, Morgan Stanley Children’s Hospital of NewYork-Presbyterian, New York City, and Benioff Children’s Hospital, University of California, San Francisco. He reported a conflict of interest with Medumo.

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

This transcript has been edited for clarity. 

Oh, insurance claim denials. When patient care or treatment is warranted by a specific diagnosis, I wish insurers would just reimburse it without any hassle. That’s not reality. Let’s talk about insurance claim denials, how they’re rising and harming patient care, and what we can do about it. That’s kind of complicated.

Rising Trend in Claim Denials and Financial Impact

First, denials are increasing. Experian Health surveyed provider revenue cycle leaders— that’s a fancy term for people who manage billing and insurance claims — and 75% said that denials are increasing. This is up from 42% a few years ago. Those surveyed also said that reimbursement times and errors in claims are also increasing, and changes in policy are happening more frequently. This all adds to the problem. 

Aside from being time-consuming and annoying, claim denials take a toll on hospitals and patients. One analysis, which made headlines everywhere, showed that hospitals and health systems spent nearly $20 billion in 2022 trying to repeal overturned claims. This analysis was done by Premier, a health insurance performance company.

 

Breakdown of Denial Rates and Costs

Let’s do some quick whiteboard math. Health insurance companies get about 3 billion claims per year. According to surveys, about 15% of those claims are denied, so that leaves us with 450 million denied claims. Hospitals spend, on average, $43.84 per denied claim in administrative fees trying to get them overturned.

That’s about $19.7 billion spent on claim denials. Here’s the gut punch: Around 54% of those claims are ultimately paid, so that leaves us with $10.7 billion that we definitely should have saved. 

 

Common Reasons for Denials

Let’s take a look at major causes and what’s going on. 

Insurance denial rates are all over the place. It depends on state and plan. According to one analysis, the average for in-network claim denials across some states was 4% to 5%. It was 40% in Mississippi. According to HealthCare.gov, in 2021, around 17% of in-network claims were denied. 

The most common reasons were excluded services, a lack of referral or preauthorization, or a medical treatment not being deemed necessary. Then there’s the black box of “other,” just some arbitrary reason to make a claim denial. 

Many times, these denials are done by an algorithm, not by individual people. 

What’s more, a Kaiser Family Foundation analysis found that private insurers, including Medicare Advantage plans, were more likely to deny claims than public options. 

When broken down, the problem was higher among employer-sponsored and marketplace insurance, and less so with Medicare and Medicaid. 

 

Impact on Patient Care

Many consumers don’t truly understand what their health insurance covers and what’s going to be out of pocket, and many people don’t know that they have appeal rights. They don’t know who to call for help either. 

The ACA set up Consumer Assistance Programs (CAPs), which are designed to help people navigate health insurance problems. By law, private insurers have to share data with CAPs. Yet, only 3% of people who had trouble with health insurance claims called a CAP for help.

We all know some of the downstream effects of this problem. Patients may skip or delay treatments if they can’t get insurance to cover it or it’s too expensive. When post-acute care, such as transfer to a skilled nursing facility or rehab center, isn’t covered and we’re trying to discharge patients from the hospital, hospital stays become lengthened, which means they’re more expensive, and this comes with its own set of complications.

 

How Can We Address This?

I’m genuinely curious about what you all have done to efficiently address this problem. I’m looking at this publication from the American Health Information Management Association about major reasons for denial. We’ve already talked about a lack of preauthorization or procedures not being covered, but there are also reasons such as missing or incorrect information, duplicate claims, and not filing within the appropriate time.

Also, if treatments or procedures are bundled, they can’t be filed separately. 

Preventing all of this would take a large effort. Healthcare systems would have to have a dedicated team, who would understand all the major reasons for denials, identify common patterns, and then fill everything out with accurate information, with referrals, with preauthorizations, high-specificity codes, and the correct modifiers — and do all of this within the filing deadline every time. 

You would need physicians on board, but also people from IT, finance, compliance, case management, registration, and probably a bunch of other people who are already stretched too thin. 

Perhaps our government can do more to hold insurers accountable and make sure plans, such as Medicare Advantage, are holding up their end of the public health bargain.

It’s an uphill $20 billion battle, but I’m optimistic. What about you? What’s your unfiltered take on claim denials? What more can we be doing?

Dr. Patel is a clinical instructor, Department of Pediatrics, Columbia University College of Physicians and Surgeons; pediatric hospitalist, Morgan Stanley Children’s Hospital of NewYork-Presbyterian, New York City, and Benioff Children’s Hospital, University of California, San Francisco. He reported a conflict of interest with Medumo.

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

This transcript has been edited for clarity. 

Oh, insurance claim denials. When patient care or treatment is warranted by a specific diagnosis, I wish insurers would just reimburse it without any hassle. That’s not reality. Let’s talk about insurance claim denials, how they’re rising and harming patient care, and what we can do about it. That’s kind of complicated.

Rising Trend in Claim Denials and Financial Impact

First, denials are increasing. Experian Health surveyed provider revenue cycle leaders— that’s a fancy term for people who manage billing and insurance claims — and 75% said that denials are increasing. This is up from 42% a few years ago. Those surveyed also said that reimbursement times and errors in claims are also increasing, and changes in policy are happening more frequently. This all adds to the problem. 

Aside from being time-consuming and annoying, claim denials take a toll on hospitals and patients. One analysis, which made headlines everywhere, showed that hospitals and health systems spent nearly $20 billion in 2022 trying to repeal overturned claims. This analysis was done by Premier, a health insurance performance company.

 

Breakdown of Denial Rates and Costs

Let’s do some quick whiteboard math. Health insurance companies get about 3 billion claims per year. According to surveys, about 15% of those claims are denied, so that leaves us with 450 million denied claims. Hospitals spend, on average, $43.84 per denied claim in administrative fees trying to get them overturned.

That’s about $19.7 billion spent on claim denials. Here’s the gut punch: Around 54% of those claims are ultimately paid, so that leaves us with $10.7 billion that we definitely should have saved. 

 

Common Reasons for Denials

Let’s take a look at major causes and what’s going on. 

Insurance denial rates are all over the place. It depends on state and plan. According to one analysis, the average for in-network claim denials across some states was 4% to 5%. It was 40% in Mississippi. According to HealthCare.gov, in 2021, around 17% of in-network claims were denied. 

The most common reasons were excluded services, a lack of referral or preauthorization, or a medical treatment not being deemed necessary. Then there’s the black box of “other,” just some arbitrary reason to make a claim denial. 

Many times, these denials are done by an algorithm, not by individual people. 

What’s more, a Kaiser Family Foundation analysis found that private insurers, including Medicare Advantage plans, were more likely to deny claims than public options. 

When broken down, the problem was higher among employer-sponsored and marketplace insurance, and less so with Medicare and Medicaid. 

 

Impact on Patient Care

Many consumers don’t truly understand what their health insurance covers and what’s going to be out of pocket, and many people don’t know that they have appeal rights. They don’t know who to call for help either. 

The ACA set up Consumer Assistance Programs (CAPs), which are designed to help people navigate health insurance problems. By law, private insurers have to share data with CAPs. Yet, only 3% of people who had trouble with health insurance claims called a CAP for help.

We all know some of the downstream effects of this problem. Patients may skip or delay treatments if they can’t get insurance to cover it or it’s too expensive. When post-acute care, such as transfer to a skilled nursing facility or rehab center, isn’t covered and we’re trying to discharge patients from the hospital, hospital stays become lengthened, which means they’re more expensive, and this comes with its own set of complications.

 

How Can We Address This?

I’m genuinely curious about what you all have done to efficiently address this problem. I’m looking at this publication from the American Health Information Management Association about major reasons for denial. We’ve already talked about a lack of preauthorization or procedures not being covered, but there are also reasons such as missing or incorrect information, duplicate claims, and not filing within the appropriate time.

Also, if treatments or procedures are bundled, they can’t be filed separately. 

Preventing all of this would take a large effort. Healthcare systems would have to have a dedicated team, who would understand all the major reasons for denials, identify common patterns, and then fill everything out with accurate information, with referrals, with preauthorizations, high-specificity codes, and the correct modifiers — and do all of this within the filing deadline every time. 

You would need physicians on board, but also people from IT, finance, compliance, case management, registration, and probably a bunch of other people who are already stretched too thin. 

Perhaps our government can do more to hold insurers accountable and make sure plans, such as Medicare Advantage, are holding up their end of the public health bargain.

It’s an uphill $20 billion battle, but I’m optimistic. What about you? What’s your unfiltered take on claim denials? What more can we be doing?

Dr. Patel is a clinical instructor, Department of Pediatrics, Columbia University College of Physicians and Surgeons; pediatric hospitalist, Morgan Stanley Children’s Hospital of NewYork-Presbyterian, New York City, and Benioff Children’s Hospital, University of California, San Francisco. He reported a conflict of interest with Medumo.

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

Every year, an estimated 45 million Americans attempt some kind of diet to shed weight, especially after the holidays. Whether or not an individual is on a successful weight loss journey, at some point they probably will experience “diet fatigue.” This is the mental and emotional exhaustion associated with engaging in dieting behaviors like calorie counting, weighing and measuring food, meal planning and prepping, and restricting certain foods. 

Diet fatigue is a huge reason (but certainly not the only reason) why diets fail, as dieters can become so burned out that they ditch their diet, return to their former eating habits, blame themselves for their diet failure, and then repeat the cycle.

Alison* became my client just as her diet fatigue was starting to settle in. She had already lost 25 pounds in the prior 6 months while in a coaching program that focused primarily on hitting calorie and macro targets. She had been following an extremely high-protein regimen that relied heavily on animal sources and protein powders. I’m not against using powders to supplement protein needs, but in Alison’s case, she was consuming a powder-and-milk concoction twice per day in place of a meal with actual food. Not only had she become plain sick of the powder, but she was also concerned that all the protein was pushing vegetables off her plate. Alison had been following this plan quite strictly but admitted to indulging in weekend sweets. She recognized that this occasional indulgence could quickly morph into a full-on habit and undo her progress. While Alison had not yet reached her goal weight, we both agreed that she needed to change up her eating routine. 

Getting a patient through diet fatigue involves identifying which dieting behaviors are causing them the most angst and then guiding them toward a more sustainable approach that provides a similar benefit. For example, many dieters develop a huge disdain for calorie tracking, which they most often describe as tedious. One alternative to tracking calories is food journaling, which encourages accountability and mindfulness but is not as time-consuming as plugging every single ingredient you ingest into an app. Alison, however, didn’t have a problem with tracking, nor with weighing her food (as a Type A personality, she preferred having this kind of control). But she was clearly lacking a few things in her previous diet: variety, fiber, and flavor. In short, Alison was not enjoying her food — hence, her increased desire for treats on weekends, which she saw as a kind of reward for “being good” all week. 

To keep Alison from slipping into a weekend bingeing pattern, we discussed a few tweaks to her regimen. First, we had to ditch the protein powder in favor of balanced meals. I recommended reducing her daily protein target, which I felt was unnecessarily high. This provided some wiggle room to add a well-rounded dinner. I encouraged her to start adding spices and herbs to make dishes more exciting. 

Finally — and this one might be controversial — I encouraged Alison to actually plan for a weekly indulgence. In my experience working in the weight management space, complete restriction of a desired food always backfires, so it made sense for Alison to simply build the chocolate into her plan in a reasonable way. 

I’m confident that Alison will reach her weight loss goal (and keep the weight off) if food continues to bring her pleasure. When it comes to weight loss, I believe that if the solution is temporary, success will also be temporary. As a dietitian, preaching sustainable, long-term habit changes is my priority, not just because it’s responsible, but because it’s the only approach that truly works.

*Patient’s name changed to protect privacy. 

Ms. Hanks is a registered dietitian at Well by Messer in New York City. She disclosed no relevant conflicts of interest.

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

Every year, an estimated 45 million Americans attempt some kind of diet to shed weight, especially after the holidays. Whether or not an individual is on a successful weight loss journey, at some point they probably will experience “diet fatigue.” This is the mental and emotional exhaustion associated with engaging in dieting behaviors like calorie counting, weighing and measuring food, meal planning and prepping, and restricting certain foods. 

Diet fatigue is a huge reason (but certainly not the only reason) why diets fail, as dieters can become so burned out that they ditch their diet, return to their former eating habits, blame themselves for their diet failure, and then repeat the cycle.

Alison* became my client just as her diet fatigue was starting to settle in. She had already lost 25 pounds in the prior 6 months while in a coaching program that focused primarily on hitting calorie and macro targets. She had been following an extremely high-protein regimen that relied heavily on animal sources and protein powders. I’m not against using powders to supplement protein needs, but in Alison’s case, she was consuming a powder-and-milk concoction twice per day in place of a meal with actual food. Not only had she become plain sick of the powder, but she was also concerned that all the protein was pushing vegetables off her plate. Alison had been following this plan quite strictly but admitted to indulging in weekend sweets. She recognized that this occasional indulgence could quickly morph into a full-on habit and undo her progress. While Alison had not yet reached her goal weight, we both agreed that she needed to change up her eating routine. 

Getting a patient through diet fatigue involves identifying which dieting behaviors are causing them the most angst and then guiding them toward a more sustainable approach that provides a similar benefit. For example, many dieters develop a huge disdain for calorie tracking, which they most often describe as tedious. One alternative to tracking calories is food journaling, which encourages accountability and mindfulness but is not as time-consuming as plugging every single ingredient you ingest into an app. Alison, however, didn’t have a problem with tracking, nor with weighing her food (as a Type A personality, she preferred having this kind of control). But she was clearly lacking a few things in her previous diet: variety, fiber, and flavor. In short, Alison was not enjoying her food — hence, her increased desire for treats on weekends, which she saw as a kind of reward for “being good” all week. 

To keep Alison from slipping into a weekend bingeing pattern, we discussed a few tweaks to her regimen. First, we had to ditch the protein powder in favor of balanced meals. I recommended reducing her daily protein target, which I felt was unnecessarily high. This provided some wiggle room to add a well-rounded dinner. I encouraged her to start adding spices and herbs to make dishes more exciting. 

Finally — and this one might be controversial — I encouraged Alison to actually plan for a weekly indulgence. In my experience working in the weight management space, complete restriction of a desired food always backfires, so it made sense for Alison to simply build the chocolate into her plan in a reasonable way. 

I’m confident that Alison will reach her weight loss goal (and keep the weight off) if food continues to bring her pleasure. When it comes to weight loss, I believe that if the solution is temporary, success will also be temporary. As a dietitian, preaching sustainable, long-term habit changes is my priority, not just because it’s responsible, but because it’s the only approach that truly works.

*Patient’s name changed to protect privacy. 

Ms. Hanks is a registered dietitian at Well by Messer in New York City. She disclosed no relevant conflicts of interest.

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

Every year, an estimated 45 million Americans attempt some kind of diet to shed weight, especially after the holidays. Whether or not an individual is on a successful weight loss journey, at some point they probably will experience “diet fatigue.” This is the mental and emotional exhaustion associated with engaging in dieting behaviors like calorie counting, weighing and measuring food, meal planning and prepping, and restricting certain foods. 

Diet fatigue is a huge reason (but certainly not the only reason) why diets fail, as dieters can become so burned out that they ditch their diet, return to their former eating habits, blame themselves for their diet failure, and then repeat the cycle.

Alison* became my client just as her diet fatigue was starting to settle in. She had already lost 25 pounds in the prior 6 months while in a coaching program that focused primarily on hitting calorie and macro targets. She had been following an extremely high-protein regimen that relied heavily on animal sources and protein powders. I’m not against using powders to supplement protein needs, but in Alison’s case, she was consuming a powder-and-milk concoction twice per day in place of a meal with actual food. Not only had she become plain sick of the powder, but she was also concerned that all the protein was pushing vegetables off her plate. Alison had been following this plan quite strictly but admitted to indulging in weekend sweets. She recognized that this occasional indulgence could quickly morph into a full-on habit and undo her progress. While Alison had not yet reached her goal weight, we both agreed that she needed to change up her eating routine. 

Getting a patient through diet fatigue involves identifying which dieting behaviors are causing them the most angst and then guiding them toward a more sustainable approach that provides a similar benefit. For example, many dieters develop a huge disdain for calorie tracking, which they most often describe as tedious. One alternative to tracking calories is food journaling, which encourages accountability and mindfulness but is not as time-consuming as plugging every single ingredient you ingest into an app. Alison, however, didn’t have a problem with tracking, nor with weighing her food (as a Type A personality, she preferred having this kind of control). But she was clearly lacking a few things in her previous diet: variety, fiber, and flavor. In short, Alison was not enjoying her food — hence, her increased desire for treats on weekends, which she saw as a kind of reward for “being good” all week. 

To keep Alison from slipping into a weekend bingeing pattern, we discussed a few tweaks to her regimen. First, we had to ditch the protein powder in favor of balanced meals. I recommended reducing her daily protein target, which I felt was unnecessarily high. This provided some wiggle room to add a well-rounded dinner. I encouraged her to start adding spices and herbs to make dishes more exciting. 

Finally — and this one might be controversial — I encouraged Alison to actually plan for a weekly indulgence. In my experience working in the weight management space, complete restriction of a desired food always backfires, so it made sense for Alison to simply build the chocolate into her plan in a reasonable way. 

I’m confident that Alison will reach her weight loss goal (and keep the weight off) if food continues to bring her pleasure. When it comes to weight loss, I believe that if the solution is temporary, success will also be temporary. As a dietitian, preaching sustainable, long-term habit changes is my priority, not just because it’s responsible, but because it’s the only approach that truly works.

*Patient’s name changed to protect privacy. 

Ms. Hanks is a registered dietitian at Well by Messer in New York City. She disclosed no relevant conflicts of interest.

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

This transcript has been edited for clarity. 

Michelle L. O’Donoghue, MD, MPH: I’m here at the American Heart Association Scientific Sessions. It’s a very exciting meeting, but one of the interesting topics that we’re going to be talking about is lipoprotein(a) [Lp(a)] . It’s definitely one of the hottest sessions of the meeting.

Joining me to discuss this topic is Dr Steve Nicholls, who is arguably one of the leading experts in the world on lipids. He’s a professor of medicine at Monash University in Australia. Welcome. Thanks, Steve. 

Stephen J. Nicholls, MBBS, PhD: Thanks for having me. 

O’Donoghue: There are two phase 2 studies that we’ll circle back to that are being presented here at the American Heart Association meeting. These are for novel therapeutics that lower Lp(a). Perhaps taking a step back, we know that there’s a large body of evidence to support the concept that Lp(a) plays a causal role in heart disease and atherogenesis, but to date we haven’t had any effective therapies to really lower it.

Thinking about the therapeutics specifically that are on the horizon, perhaps we could start there. Which one is furthest along in development, and how does that look in terms of its ability to lower Lp(a)?

 

Pelacarsen, an ASO

Nicholls: Most of the therapies are injectable. Most of them are nucleic acid–based therapies, and the one that’s most advanced is an agent called pelacarsen. Pelacarsen is an antisense oligonucleotide (ASO), and it has gone all the way through its early phase 2 studies. It has a fully enrolled cardiovascular outcome trial.

We’re all eagerly awaiting the results of that study sometime in the next year or so. That will be the first large-scale clinical trial that will give us some clinical validation to ask the question of whether substantive lowering of Lp(a) will lower cardiovascular risk, with an agent that in early studies looks like it lowers Lp(a) about 80%.

O’Donoghue: Which is tremendous, because again, we really don’t have any effective therapies right now. I guess one of the big questions is, how much do we need to lower Lp(a) for that to translate into meaningful clinical benefit? What’s your sense there? 

Nicholls: Well, we simply don’t know. We’ve tried to look to genetics to try and give us some sort of sense in terms of what that looks like. Lp(a) is a little tricky because the assays and the numbers that get spit out can be tricky in terms of trying to compare apples and apples in different studies. 

We think that it’s probably at least a 50- to 75-mg/dL lowering of Lp(a) using the old units. We think that pelacarsen would hit that, and so our hope is that that would translate to a 15%-20% reduction in major cardiovascular events, but again, we’ve never asked this question before. 

We have data from PCSK9 inhibitor trials showing that lesser reductions in Lp(a) of 25%-30% with both evolocumab and alirocumab contributed to the clinical benefit that we saw in those studies. Those agents were really good at lowering low-density lipoprotein (LDL) cholesterol, but Lp(a) lowering seemed to matter. One would be very hopeful that if a 25%-30% lowering of Lp(a) is useful, then an 80% or greater lowering of Lp(a) should be really useful. 

 

The siRNAs

O’Donoghue: In addition to the ASO pelacarsen that you mentioned, there are several therapeutics in the pipeline, including three small interfering (si) RNAs that are at least in phase 2 and phase 3 testing at this point in time. There’s olpasiran, which in phase 2 testing led to more than a 95% reduction in Lp(a), and then lepodisiran , which has now moved into phase 3  testing, albeit we haven’t seen yet the phase 2  results. 

What is your sense of lepodisiran and its efficacy? 

Nicholls: What’s been really quite striking about the siRNAs is the even more profound degree of lowering of Lp(a) that we’re seeing. We’re seeing 90% and greater lowering of Lp(a) in all of those programs. We’re seeing some differences between the programs in terms of the durability of that effect. 

I think it would be fair to say that with zerlasiran we’re starting to see perhaps that lowering effect starts to taper off a little bit more quickly than the other two. I think that may have some implications in terms of what dosing regimens may look like in the future. 

Even so, we’re talking about therapies that may be dosed 3- to 6-monthly, or even with the potential for being less frequent than that with lepodisiran. Again, I think the phase 2 data will be really important in terms of giving us more information.

O’Donoghue: For the lepodisiran results, I was really quite struck that even though it was small numbers, single dose administered, it really looked like the duration of effect persisted at the higher doses up to about a year. 

Nicholls: It looks pretty promising. We’ve launched the ACCLAIM study, the large cardiovascular outcome trial of lepodisiran, with a 6-monthly regimen. We are hopeful that more information may be able to give us the opportunity for even less frequent administration. 

That has really important implications for patients where adherence is a particular issue. They may just simply want to come into the clinic. You know, once or twice a year, very much like we’re seeing with inclisiran, and that may be a really effective approach for many patients. 

O’Donoghue: You alluded to the zerlasiran results, which were presented here at the American Heart Association meeting, and that even though it led to a robust reduction in Lp(a), it looked like the durability component was maybe a little bit shorter than for some of the other siRNAs that are currently being evaluated.

What’s your sense of that? 

Nicholls: It probably is. The implications clinically, at least in an outcome trial when they ultimately get to that point, probably aren’t that important. They’ll probably just have slightly more frequent administration. That may become a bigger issue when it gets out into the clinic.

The nice thing is that if all of these agents appear to be effective, are well tolerated, and get out to the clinic, then clinicians and patients are going to have a lot of choice. 

O’Donoghue: I think more competition is always good news for the field, ultimately. I think to your point, especially for a drug that might be self-administered, ultimately, whether it’s once a month or once every 3 months, it doesn’t probably make much difference. I think different choices are needed for different patients. 

Perhaps that’s a perfect segue to talk about the oral Lp(a) inhibitor that is also being developed. You presented these results for muvalaplin. 

 

Muvalaplin, an Oral Small Molecule

Nicholls: In terms of frequency of administration, we’re talking about a daily oral therapeutic. For patients who don’t want an injectable and are happy to take a tablet every day, muvalaplin has the potential to be a really good option for them. 

Muvalaplin is an oral small-molecule inhibitor. It essentially prevents apolipoprotein(a) [apo(a)] from binding to apolipoprotein B (apo B). We presented phase 1 data  at the European Society of Cardiology meeting last year, showing probably Lp(a) lowering on the order of about 65%. Here, we’re going to show that that’s a little bit more. It looks like it’s probably at least 70% lowering using a standard Lp(a) assay. Using an assay that looks specifically at intact Lp(a) particles, it’s probably well in excess of 80%.

Those are really good results. The safety and tolerability with muvalaplin look really good. Again, we’ll need to see that agent move forward into a large outcome trial and we’ve yet to hear about that, at least for now. 

O’Donoghue: It’s an interesting challenge that you faced in terms of the assay because, as you say, it really disrupts the apo(a) from binding to the apo B particle, and hence, a traditional assay that just measures apo(a), regardless of whether or not it’s bound to an apo B particle, may be a conservative estimate.

Nicholls: It may, in particular, because we know that apo(a) ultimately then binds to the drug. That assay is measuring what we think is nonfunctional apo(a) in addition to functional apo(a). It’s measuring functional apo(a) that’s still on an actual Lp(a) particle, but if it’s bound to muvalaplin, we think to some degree that’s probably unfair to count that. That’s why trying to develop other assays to try and understand the full effect of the drug is really important in terms of trying to understand how we develop that and move that forward.

O’Donoghue: Is there any evidence yet that the apo(a) particle that is not bound to apo B is in fact nonfunctional as you described it? 

Nicholls: We think that’s likely to be the case, but I think there continues to be research in that space to try and settle that question once and for all. 

O’Donoghue: Again, I think it’s a really exciting time in this field. Right now, we have three ongoing phase 3 trials. We have the pelacarsen trial that is still in follow-up, and fingers crossed, maybe will report out next year. Olpasiran is also in phase 3 testing, completed enrollment, and also is in the follow-up period. We also have lepodisiran, the ACCLAIM trial, as you mentioned. For people who are perhaps watching and looking to enroll their patients, this trial is still ongoing right now in terms of enrollment. 

Nicholls: It is, and what’s nice about the ACCLAIM study is that it includes both primary and secondary prevention patients. For the first time in a big outcome trial, patients with high Lp(a) levels but who have yet to have a clinical event can actually get into a clinical trial.

I’m sure, like you, my clinic is full of patients with high Lp(a) who are really desperate to get into these trials. Many of those primary prevention patients just simply haven’t qualified, so that’s really good news. 

The step beyond that, if we’re talking about even less frequent administration, is gene editing. We’re seeing those studies with CRISPR move forward to try to evaluate whether a single gene-editing approach at Lp(a) will be all that you need, which is even a more amazing concept, but that’s a study that needs more work. 

O’Donoghue: An exciting space though, for sure. As a final thought, you mentioned the patients in your clinic who you have identified as having high Lp(a). What are you doing right now in your practice for managing those patients? I think there are many practitioners out there who struggle with whether they should really measure their patients’ Lp(a), and whether they want to know that information.

Nicholls: Yeah, it’s really hard. The answer is yes, we do want to know it. We know it’s a great risk enhancer. We know that a patient with a high Lp(a) is somebody whom I want to more intensively treat their other risk factors. I’m aiming for a lower LDL. I’m being much tighter with blood pressure control.

I think there’s some argument from observational data at least that aspirin remains a consideration, particularly in patients where you think there’s a particularly high risk associated with that high Lp(a). I think there are things we absolutely can do today, but we can’t do anything if you don’t know the numbers.

It starts with testing, and then we can move on to what we can do today, and then hopefully in the not-too-distant future, we’ll have specific therapies that really enable for us to address Lp(a) quite definitively. 

O’Donoghue: Thanks again for taking the time. This was a very helpful discussion.

 

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. Dr O’Donoghue, Senior Investigator, TIMI Study Group; Associate Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts, disclosed ties to Janssen; Novartis; CVS Minute Clinic; Merck & Co.; GlaxoSmithKline; Eisai Inc.; AstraZeneca Pharmaceuticals LP; Janssen Pharmaceuticals; Medicines Company; and Amgen. The opinions expressed in this article do not necessarily reflect the views and opinions of Brigham and Women’s Hospital. Stephen J. Nicholls, MBBS, PhD, Director, Victorian Heart Institute, Monash University; Director, Victorian Heart Hospital, Monash Health, Melbourne, Australia, has disclosed ties with Akcea Therapeutics; Amgen; AstraZeneca; Boehringer Ingelheim; CSL Behring; Eli Lilly and Company; Esperion Therapeutics; Kowa Pharmaceuticals; Merck; Novo Nordisk; Pfizer; Sanofi Regeneron; Daichii Sankyo; Vaxxinity; Cyclarity; CSL Sequirus; Takeda; Anthera Pharmaceuticals; Cerenis Therapeutics; Infraredx; New Amsterdam Pharma; Novartis; and Resverlogix.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Michelle L. O’Donoghue, MD, MPH: I’m here at the American Heart Association Scientific Sessions. It’s a very exciting meeting, but one of the interesting topics that we’re going to be talking about is lipoprotein(a) [Lp(a)] . It’s definitely one of the hottest sessions of the meeting.

Joining me to discuss this topic is Dr Steve Nicholls, who is arguably one of the leading experts in the world on lipids. He’s a professor of medicine at Monash University in Australia. Welcome. Thanks, Steve. 

Stephen J. Nicholls, MBBS, PhD: Thanks for having me. 

O’Donoghue: There are two phase 2 studies that we’ll circle back to that are being presented here at the American Heart Association meeting. These are for novel therapeutics that lower Lp(a). Perhaps taking a step back, we know that there’s a large body of evidence to support the concept that Lp(a) plays a causal role in heart disease and atherogenesis, but to date we haven’t had any effective therapies to really lower it.

Thinking about the therapeutics specifically that are on the horizon, perhaps we could start there. Which one is furthest along in development, and how does that look in terms of its ability to lower Lp(a)?

 

Pelacarsen, an ASO

Nicholls: Most of the therapies are injectable. Most of them are nucleic acid–based therapies, and the one that’s most advanced is an agent called pelacarsen. Pelacarsen is an antisense oligonucleotide (ASO), and it has gone all the way through its early phase 2 studies. It has a fully enrolled cardiovascular outcome trial.

We’re all eagerly awaiting the results of that study sometime in the next year or so. That will be the first large-scale clinical trial that will give us some clinical validation to ask the question of whether substantive lowering of Lp(a) will lower cardiovascular risk, with an agent that in early studies looks like it lowers Lp(a) about 80%.

O’Donoghue: Which is tremendous, because again, we really don’t have any effective therapies right now. I guess one of the big questions is, how much do we need to lower Lp(a) for that to translate into meaningful clinical benefit? What’s your sense there? 

Nicholls: Well, we simply don’t know. We’ve tried to look to genetics to try and give us some sort of sense in terms of what that looks like. Lp(a) is a little tricky because the assays and the numbers that get spit out can be tricky in terms of trying to compare apples and apples in different studies. 

We think that it’s probably at least a 50- to 75-mg/dL lowering of Lp(a) using the old units. We think that pelacarsen would hit that, and so our hope is that that would translate to a 15%-20% reduction in major cardiovascular events, but again, we’ve never asked this question before. 

We have data from PCSK9 inhibitor trials showing that lesser reductions in Lp(a) of 25%-30% with both evolocumab and alirocumab contributed to the clinical benefit that we saw in those studies. Those agents were really good at lowering low-density lipoprotein (LDL) cholesterol, but Lp(a) lowering seemed to matter. One would be very hopeful that if a 25%-30% lowering of Lp(a) is useful, then an 80% or greater lowering of Lp(a) should be really useful. 

 

The siRNAs

O’Donoghue: In addition to the ASO pelacarsen that you mentioned, there are several therapeutics in the pipeline, including three small interfering (si) RNAs that are at least in phase 2 and phase 3 testing at this point in time. There’s olpasiran, which in phase 2 testing led to more than a 95% reduction in Lp(a), and then lepodisiran , which has now moved into phase 3  testing, albeit we haven’t seen yet the phase 2  results. 

What is your sense of lepodisiran and its efficacy? 

Nicholls: What’s been really quite striking about the siRNAs is the even more profound degree of lowering of Lp(a) that we’re seeing. We’re seeing 90% and greater lowering of Lp(a) in all of those programs. We’re seeing some differences between the programs in terms of the durability of that effect. 

I think it would be fair to say that with zerlasiran we’re starting to see perhaps that lowering effect starts to taper off a little bit more quickly than the other two. I think that may have some implications in terms of what dosing regimens may look like in the future. 

Even so, we’re talking about therapies that may be dosed 3- to 6-monthly, or even with the potential for being less frequent than that with lepodisiran. Again, I think the phase 2 data will be really important in terms of giving us more information.

O’Donoghue: For the lepodisiran results, I was really quite struck that even though it was small numbers, single dose administered, it really looked like the duration of effect persisted at the higher doses up to about a year. 

Nicholls: It looks pretty promising. We’ve launched the ACCLAIM study, the large cardiovascular outcome trial of lepodisiran, with a 6-monthly regimen. We are hopeful that more information may be able to give us the opportunity for even less frequent administration. 

That has really important implications for patients where adherence is a particular issue. They may just simply want to come into the clinic. You know, once or twice a year, very much like we’re seeing with inclisiran, and that may be a really effective approach for many patients. 

O’Donoghue: You alluded to the zerlasiran results, which were presented here at the American Heart Association meeting, and that even though it led to a robust reduction in Lp(a), it looked like the durability component was maybe a little bit shorter than for some of the other siRNAs that are currently being evaluated.

What’s your sense of that? 

Nicholls: It probably is. The implications clinically, at least in an outcome trial when they ultimately get to that point, probably aren’t that important. They’ll probably just have slightly more frequent administration. That may become a bigger issue when it gets out into the clinic.

The nice thing is that if all of these agents appear to be effective, are well tolerated, and get out to the clinic, then clinicians and patients are going to have a lot of choice. 

O’Donoghue: I think more competition is always good news for the field, ultimately. I think to your point, especially for a drug that might be self-administered, ultimately, whether it’s once a month or once every 3 months, it doesn’t probably make much difference. I think different choices are needed for different patients. 

Perhaps that’s a perfect segue to talk about the oral Lp(a) inhibitor that is also being developed. You presented these results for muvalaplin. 

 

Muvalaplin, an Oral Small Molecule

Nicholls: In terms of frequency of administration, we’re talking about a daily oral therapeutic. For patients who don’t want an injectable and are happy to take a tablet every day, muvalaplin has the potential to be a really good option for them. 

Muvalaplin is an oral small-molecule inhibitor. It essentially prevents apolipoprotein(a) [apo(a)] from binding to apolipoprotein B (apo B). We presented phase 1 data  at the European Society of Cardiology meeting last year, showing probably Lp(a) lowering on the order of about 65%. Here, we’re going to show that that’s a little bit more. It looks like it’s probably at least 70% lowering using a standard Lp(a) assay. Using an assay that looks specifically at intact Lp(a) particles, it’s probably well in excess of 80%.

Those are really good results. The safety and tolerability with muvalaplin look really good. Again, we’ll need to see that agent move forward into a large outcome trial and we’ve yet to hear about that, at least for now. 

O’Donoghue: It’s an interesting challenge that you faced in terms of the assay because, as you say, it really disrupts the apo(a) from binding to the apo B particle, and hence, a traditional assay that just measures apo(a), regardless of whether or not it’s bound to an apo B particle, may be a conservative estimate.

Nicholls: It may, in particular, because we know that apo(a) ultimately then binds to the drug. That assay is measuring what we think is nonfunctional apo(a) in addition to functional apo(a). It’s measuring functional apo(a) that’s still on an actual Lp(a) particle, but if it’s bound to muvalaplin, we think to some degree that’s probably unfair to count that. That’s why trying to develop other assays to try and understand the full effect of the drug is really important in terms of trying to understand how we develop that and move that forward.

O’Donoghue: Is there any evidence yet that the apo(a) particle that is not bound to apo B is in fact nonfunctional as you described it? 

Nicholls: We think that’s likely to be the case, but I think there continues to be research in that space to try and settle that question once and for all. 

O’Donoghue: Again, I think it’s a really exciting time in this field. Right now, we have three ongoing phase 3 trials. We have the pelacarsen trial that is still in follow-up, and fingers crossed, maybe will report out next year. Olpasiran is also in phase 3 testing, completed enrollment, and also is in the follow-up period. We also have lepodisiran, the ACCLAIM trial, as you mentioned. For people who are perhaps watching and looking to enroll their patients, this trial is still ongoing right now in terms of enrollment. 

Nicholls: It is, and what’s nice about the ACCLAIM study is that it includes both primary and secondary prevention patients. For the first time in a big outcome trial, patients with high Lp(a) levels but who have yet to have a clinical event can actually get into a clinical trial.

I’m sure, like you, my clinic is full of patients with high Lp(a) who are really desperate to get into these trials. Many of those primary prevention patients just simply haven’t qualified, so that’s really good news. 

The step beyond that, if we’re talking about even less frequent administration, is gene editing. We’re seeing those studies with CRISPR move forward to try to evaluate whether a single gene-editing approach at Lp(a) will be all that you need, which is even a more amazing concept, but that’s a study that needs more work. 

O’Donoghue: An exciting space though, for sure. As a final thought, you mentioned the patients in your clinic who you have identified as having high Lp(a). What are you doing right now in your practice for managing those patients? I think there are many practitioners out there who struggle with whether they should really measure their patients’ Lp(a), and whether they want to know that information.

Nicholls: Yeah, it’s really hard. The answer is yes, we do want to know it. We know it’s a great risk enhancer. We know that a patient with a high Lp(a) is somebody whom I want to more intensively treat their other risk factors. I’m aiming for a lower LDL. I’m being much tighter with blood pressure control.

I think there’s some argument from observational data at least that aspirin remains a consideration, particularly in patients where you think there’s a particularly high risk associated with that high Lp(a). I think there are things we absolutely can do today, but we can’t do anything if you don’t know the numbers.

It starts with testing, and then we can move on to what we can do today, and then hopefully in the not-too-distant future, we’ll have specific therapies that really enable for us to address Lp(a) quite definitively. 

O’Donoghue: Thanks again for taking the time. This was a very helpful discussion.

 

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. Dr O’Donoghue, Senior Investigator, TIMI Study Group; Associate Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts, disclosed ties to Janssen; Novartis; CVS Minute Clinic; Merck & Co.; GlaxoSmithKline; Eisai Inc.; AstraZeneca Pharmaceuticals LP; Janssen Pharmaceuticals; Medicines Company; and Amgen. The opinions expressed in this article do not necessarily reflect the views and opinions of Brigham and Women’s Hospital. Stephen J. Nicholls, MBBS, PhD, Director, Victorian Heart Institute, Monash University; Director, Victorian Heart Hospital, Monash Health, Melbourne, Australia, has disclosed ties with Akcea Therapeutics; Amgen; AstraZeneca; Boehringer Ingelheim; CSL Behring; Eli Lilly and Company; Esperion Therapeutics; Kowa Pharmaceuticals; Merck; Novo Nordisk; Pfizer; Sanofi Regeneron; Daichii Sankyo; Vaxxinity; Cyclarity; CSL Sequirus; Takeda; Anthera Pharmaceuticals; Cerenis Therapeutics; Infraredx; New Amsterdam Pharma; Novartis; and Resverlogix.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Michelle L. O’Donoghue, MD, MPH: I’m here at the American Heart Association Scientific Sessions. It’s a very exciting meeting, but one of the interesting topics that we’re going to be talking about is lipoprotein(a) [Lp(a)] . It’s definitely one of the hottest sessions of the meeting.

Joining me to discuss this topic is Dr Steve Nicholls, who is arguably one of the leading experts in the world on lipids. He’s a professor of medicine at Monash University in Australia. Welcome. Thanks, Steve. 

Stephen J. Nicholls, MBBS, PhD: Thanks for having me. 

O’Donoghue: There are two phase 2 studies that we’ll circle back to that are being presented here at the American Heart Association meeting. These are for novel therapeutics that lower Lp(a). Perhaps taking a step back, we know that there’s a large body of evidence to support the concept that Lp(a) plays a causal role in heart disease and atherogenesis, but to date we haven’t had any effective therapies to really lower it.

Thinking about the therapeutics specifically that are on the horizon, perhaps we could start there. Which one is furthest along in development, and how does that look in terms of its ability to lower Lp(a)?

 

Pelacarsen, an ASO

Nicholls: Most of the therapies are injectable. Most of them are nucleic acid–based therapies, and the one that’s most advanced is an agent called pelacarsen. Pelacarsen is an antisense oligonucleotide (ASO), and it has gone all the way through its early phase 2 studies. It has a fully enrolled cardiovascular outcome trial.

We’re all eagerly awaiting the results of that study sometime in the next year or so. That will be the first large-scale clinical trial that will give us some clinical validation to ask the question of whether substantive lowering of Lp(a) will lower cardiovascular risk, with an agent that in early studies looks like it lowers Lp(a) about 80%.

O’Donoghue: Which is tremendous, because again, we really don’t have any effective therapies right now. I guess one of the big questions is, how much do we need to lower Lp(a) for that to translate into meaningful clinical benefit? What’s your sense there? 

Nicholls: Well, we simply don’t know. We’ve tried to look to genetics to try and give us some sort of sense in terms of what that looks like. Lp(a) is a little tricky because the assays and the numbers that get spit out can be tricky in terms of trying to compare apples and apples in different studies. 

We think that it’s probably at least a 50- to 75-mg/dL lowering of Lp(a) using the old units. We think that pelacarsen would hit that, and so our hope is that that would translate to a 15%-20% reduction in major cardiovascular events, but again, we’ve never asked this question before. 

We have data from PCSK9 inhibitor trials showing that lesser reductions in Lp(a) of 25%-30% with both evolocumab and alirocumab contributed to the clinical benefit that we saw in those studies. Those agents were really good at lowering low-density lipoprotein (LDL) cholesterol, but Lp(a) lowering seemed to matter. One would be very hopeful that if a 25%-30% lowering of Lp(a) is useful, then an 80% or greater lowering of Lp(a) should be really useful. 

 

The siRNAs

O’Donoghue: In addition to the ASO pelacarsen that you mentioned, there are several therapeutics in the pipeline, including three small interfering (si) RNAs that are at least in phase 2 and phase 3 testing at this point in time. There’s olpasiran, which in phase 2 testing led to more than a 95% reduction in Lp(a), and then lepodisiran , which has now moved into phase 3  testing, albeit we haven’t seen yet the phase 2  results. 

What is your sense of lepodisiran and its efficacy? 

Nicholls: What’s been really quite striking about the siRNAs is the even more profound degree of lowering of Lp(a) that we’re seeing. We’re seeing 90% and greater lowering of Lp(a) in all of those programs. We’re seeing some differences between the programs in terms of the durability of that effect. 

I think it would be fair to say that with zerlasiran we’re starting to see perhaps that lowering effect starts to taper off a little bit more quickly than the other two. I think that may have some implications in terms of what dosing regimens may look like in the future. 

Even so, we’re talking about therapies that may be dosed 3- to 6-monthly, or even with the potential for being less frequent than that with lepodisiran. Again, I think the phase 2 data will be really important in terms of giving us more information.

O’Donoghue: For the lepodisiran results, I was really quite struck that even though it was small numbers, single dose administered, it really looked like the duration of effect persisted at the higher doses up to about a year. 

Nicholls: It looks pretty promising. We’ve launched the ACCLAIM study, the large cardiovascular outcome trial of lepodisiran, with a 6-monthly regimen. We are hopeful that more information may be able to give us the opportunity for even less frequent administration. 

That has really important implications for patients where adherence is a particular issue. They may just simply want to come into the clinic. You know, once or twice a year, very much like we’re seeing with inclisiran, and that may be a really effective approach for many patients. 

O’Donoghue: You alluded to the zerlasiran results, which were presented here at the American Heart Association meeting, and that even though it led to a robust reduction in Lp(a), it looked like the durability component was maybe a little bit shorter than for some of the other siRNAs that are currently being evaluated.

What’s your sense of that? 

Nicholls: It probably is. The implications clinically, at least in an outcome trial when they ultimately get to that point, probably aren’t that important. They’ll probably just have slightly more frequent administration. That may become a bigger issue when it gets out into the clinic.

The nice thing is that if all of these agents appear to be effective, are well tolerated, and get out to the clinic, then clinicians and patients are going to have a lot of choice. 

O’Donoghue: I think more competition is always good news for the field, ultimately. I think to your point, especially for a drug that might be self-administered, ultimately, whether it’s once a month or once every 3 months, it doesn’t probably make much difference. I think different choices are needed for different patients. 

Perhaps that’s a perfect segue to talk about the oral Lp(a) inhibitor that is also being developed. You presented these results for muvalaplin. 

 

Muvalaplin, an Oral Small Molecule

Nicholls: In terms of frequency of administration, we’re talking about a daily oral therapeutic. For patients who don’t want an injectable and are happy to take a tablet every day, muvalaplin has the potential to be a really good option for them. 

Muvalaplin is an oral small-molecule inhibitor. It essentially prevents apolipoprotein(a) [apo(a)] from binding to apolipoprotein B (apo B). We presented phase 1 data  at the European Society of Cardiology meeting last year, showing probably Lp(a) lowering on the order of about 65%. Here, we’re going to show that that’s a little bit more. It looks like it’s probably at least 70% lowering using a standard Lp(a) assay. Using an assay that looks specifically at intact Lp(a) particles, it’s probably well in excess of 80%.

Those are really good results. The safety and tolerability with muvalaplin look really good. Again, we’ll need to see that agent move forward into a large outcome trial and we’ve yet to hear about that, at least for now. 

O’Donoghue: It’s an interesting challenge that you faced in terms of the assay because, as you say, it really disrupts the apo(a) from binding to the apo B particle, and hence, a traditional assay that just measures apo(a), regardless of whether or not it’s bound to an apo B particle, may be a conservative estimate.

Nicholls: It may, in particular, because we know that apo(a) ultimately then binds to the drug. That assay is measuring what we think is nonfunctional apo(a) in addition to functional apo(a). It’s measuring functional apo(a) that’s still on an actual Lp(a) particle, but if it’s bound to muvalaplin, we think to some degree that’s probably unfair to count that. That’s why trying to develop other assays to try and understand the full effect of the drug is really important in terms of trying to understand how we develop that and move that forward.

O’Donoghue: Is there any evidence yet that the apo(a) particle that is not bound to apo B is in fact nonfunctional as you described it? 

Nicholls: We think that’s likely to be the case, but I think there continues to be research in that space to try and settle that question once and for all. 

O’Donoghue: Again, I think it’s a really exciting time in this field. Right now, we have three ongoing phase 3 trials. We have the pelacarsen trial that is still in follow-up, and fingers crossed, maybe will report out next year. Olpasiran is also in phase 3 testing, completed enrollment, and also is in the follow-up period. We also have lepodisiran, the ACCLAIM trial, as you mentioned. For people who are perhaps watching and looking to enroll their patients, this trial is still ongoing right now in terms of enrollment. 

Nicholls: It is, and what’s nice about the ACCLAIM study is that it includes both primary and secondary prevention patients. For the first time in a big outcome trial, patients with high Lp(a) levels but who have yet to have a clinical event can actually get into a clinical trial.

I’m sure, like you, my clinic is full of patients with high Lp(a) who are really desperate to get into these trials. Many of those primary prevention patients just simply haven’t qualified, so that’s really good news. 

The step beyond that, if we’re talking about even less frequent administration, is gene editing. We’re seeing those studies with CRISPR move forward to try to evaluate whether a single gene-editing approach at Lp(a) will be all that you need, which is even a more amazing concept, but that’s a study that needs more work. 

O’Donoghue: An exciting space though, for sure. As a final thought, you mentioned the patients in your clinic who you have identified as having high Lp(a). What are you doing right now in your practice for managing those patients? I think there are many practitioners out there who struggle with whether they should really measure their patients’ Lp(a), and whether they want to know that information.

Nicholls: Yeah, it’s really hard. The answer is yes, we do want to know it. We know it’s a great risk enhancer. We know that a patient with a high Lp(a) is somebody whom I want to more intensively treat their other risk factors. I’m aiming for a lower LDL. I’m being much tighter with blood pressure control.

I think there’s some argument from observational data at least that aspirin remains a consideration, particularly in patients where you think there’s a particularly high risk associated with that high Lp(a). I think there are things we absolutely can do today, but we can’t do anything if you don’t know the numbers.

It starts with testing, and then we can move on to what we can do today, and then hopefully in the not-too-distant future, we’ll have specific therapies that really enable for us to address Lp(a) quite definitively. 

O’Donoghue: Thanks again for taking the time. This was a very helpful discussion.

 

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates. Dr O’Donoghue, Senior Investigator, TIMI Study Group; Associate Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts, disclosed ties to Janssen; Novartis; CVS Minute Clinic; Merck & Co.; GlaxoSmithKline; Eisai Inc.; AstraZeneca Pharmaceuticals LP; Janssen Pharmaceuticals; Medicines Company; and Amgen. The opinions expressed in this article do not necessarily reflect the views and opinions of Brigham and Women’s Hospital. Stephen J. Nicholls, MBBS, PhD, Director, Victorian Heart Institute, Monash University; Director, Victorian Heart Hospital, Monash Health, Melbourne, Australia, has disclosed ties with Akcea Therapeutics; Amgen; AstraZeneca; Boehringer Ingelheim; CSL Behring; Eli Lilly and Company; Esperion Therapeutics; Kowa Pharmaceuticals; Merck; Novo Nordisk; Pfizer; Sanofi Regeneron; Daichii Sankyo; Vaxxinity; Cyclarity; CSL Sequirus; Takeda; Anthera Pharmaceuticals; Cerenis Therapeutics; Infraredx; New Amsterdam Pharma; Novartis; and Resverlogix.

A version of this article appeared on Medscape.com.