Opinion

At the close of 2024, to an odd mix of disappointment and jubilation, Cassava Sciences announced that simufilam didn’t do anything for Alzheimer’s disease.

An Alzheimer’s drug trial failing is, unfortunately, nothing new. This one, however, had more baggage behind it than most.

Like all of these things, it was worth a try. It’s an interesting molecule with a reasonable mechanism of action.

 

But the trials have been raising questions for a few years, with allegations of misconduct against the drug’s co-discoverer Hoau-Yan Wang. He’s been indicted for defrauding the National Institutes of Health of $16 million in grants related to the drug. There have been concerns over doctored images and other not-so-minor issues in trying to move simufilam forward. Cassava itself agreed to pay the Securities and Exchange Commission $40 million in 2024 to settle charges about misleading investors.

Yet, like an innocent child with criminal parents, many of us hoped that the drug would work, regardless of the ethical shenanigans behind it. On the front lines we deal with a tragic disease that robs people of what makes them human and robs the families who have to live with it.

As the wheels started to come off the bus I told a friend, “it would be really sad if this drug is THE ONE and it never gets to finish trials because of everything else.”

Now we know it isn’t. Regardless of the controversy, the final data show that simufilam is just another placebo, joining the ranks of many others in the Alzheimer’s development graveyard.

Yes, there is a vague sense of jubilation behind it. I believe in fair play, and it’s good to know that those who misled investors and falsified data were wrong and will never have their day in the sun.

At the same time, however, I’m disappointed. I’m happy that the drug at least got a chance to prove itself, but when it’s all said and done, it doesn’t do anything.

I feel bad for the innocent people in the company, who had nothing to do with the scheming and were just hoping the drug would go somewhere. The majority, if not all, of them will likely lose their jobs. Like me, they have families, bills, and mortgages.

But I’m even more disappointed for the patients and families who only wanted an effective treatment for Alzheimer’s disease, and were hoping that, regardless of its dirty laundry, simufilam would work.

They’re the ones that I, and many other neurologists, have to face every day when they ask “is there anything new out?” and we sadly shake our heads.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

At the close of 2024, to an odd mix of disappointment and jubilation, Cassava Sciences announced that simufilam didn’t do anything for Alzheimer’s disease.

An Alzheimer’s drug trial failing is, unfortunately, nothing new. This one, however, had more baggage behind it than most.

Like all of these things, it was worth a try. It’s an interesting molecule with a reasonable mechanism of action.

 

But the trials have been raising questions for a few years, with allegations of misconduct against the drug’s co-discoverer Hoau-Yan Wang. He’s been indicted for defrauding the National Institutes of Health of $16 million in grants related to the drug. There have been concerns over doctored images and other not-so-minor issues in trying to move simufilam forward. Cassava itself agreed to pay the Securities and Exchange Commission $40 million in 2024 to settle charges about misleading investors.

Yet, like an innocent child with criminal parents, many of us hoped that the drug would work, regardless of the ethical shenanigans behind it. On the front lines we deal with a tragic disease that robs people of what makes them human and robs the families who have to live with it.

As the wheels started to come off the bus I told a friend, “it would be really sad if this drug is THE ONE and it never gets to finish trials because of everything else.”

Now we know it isn’t. Regardless of the controversy, the final data show that simufilam is just another placebo, joining the ranks of many others in the Alzheimer’s development graveyard.

Yes, there is a vague sense of jubilation behind it. I believe in fair play, and it’s good to know that those who misled investors and falsified data were wrong and will never have their day in the sun.

At the same time, however, I’m disappointed. I’m happy that the drug at least got a chance to prove itself, but when it’s all said and done, it doesn’t do anything.

I feel bad for the innocent people in the company, who had nothing to do with the scheming and were just hoping the drug would go somewhere. The majority, if not all, of them will likely lose their jobs. Like me, they have families, bills, and mortgages.

But I’m even more disappointed for the patients and families who only wanted an effective treatment for Alzheimer’s disease, and were hoping that, regardless of its dirty laundry, simufilam would work.

They’re the ones that I, and many other neurologists, have to face every day when they ask “is there anything new out?” and we sadly shake our heads.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

At the close of 2024, to an odd mix of disappointment and jubilation, Cassava Sciences announced that simufilam didn’t do anything for Alzheimer’s disease.

An Alzheimer’s drug trial failing is, unfortunately, nothing new. This one, however, had more baggage behind it than most.

Like all of these things, it was worth a try. It’s an interesting molecule with a reasonable mechanism of action.

 

But the trials have been raising questions for a few years, with allegations of misconduct against the drug’s co-discoverer Hoau-Yan Wang. He’s been indicted for defrauding the National Institutes of Health of $16 million in grants related to the drug. There have been concerns over doctored images and other not-so-minor issues in trying to move simufilam forward. Cassava itself agreed to pay the Securities and Exchange Commission $40 million in 2024 to settle charges about misleading investors.

Yet, like an innocent child with criminal parents, many of us hoped that the drug would work, regardless of the ethical shenanigans behind it. On the front lines we deal with a tragic disease that robs people of what makes them human and robs the families who have to live with it.

As the wheels started to come off the bus I told a friend, “it would be really sad if this drug is THE ONE and it never gets to finish trials because of everything else.”

Now we know it isn’t. Regardless of the controversy, the final data show that simufilam is just another placebo, joining the ranks of many others in the Alzheimer’s development graveyard.

Yes, there is a vague sense of jubilation behind it. I believe in fair play, and it’s good to know that those who misled investors and falsified data were wrong and will never have their day in the sun.

At the same time, however, I’m disappointed. I’m happy that the drug at least got a chance to prove itself, but when it’s all said and done, it doesn’t do anything.

I feel bad for the innocent people in the company, who had nothing to do with the scheming and were just hoping the drug would go somewhere. The majority, if not all, of them will likely lose their jobs. Like me, they have families, bills, and mortgages.

But I’m even more disappointed for the patients and families who only wanted an effective treatment for Alzheimer’s disease, and were hoping that, regardless of its dirty laundry, simufilam would work.

They’re the ones that I, and many other neurologists, have to face every day when they ask “is there anything new out?” and we sadly shake our heads.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

This transcript has been edited for clarity. 

Blood pressure. If you’re a primary care provider trying to do right by your patients, you might be understandably confused by the current mishmash of guidelines with different blood pressure targets. But as chaotic as things are, at least it’s not the 1930s, when you might hear John Hay give a lecture to the British Medical Association and say, “The greatest danger to a man with high blood pressure lies in its discovery, because then some fool is certain to try and reduce it.”

Yeah, he said that. But what happened in the 1930s stays in the 1930s. And now we can at least agree that we should be treating high blood pressure. But what’s the goal we should be aiming for? This is On Second Thought. 

We’ve come a long way since FDR was recording blood pressures of 200 and his doctor prescribed him barbiturates and massage therapy.

That s#$# don’t fly no more. Over the past hundred years, we have become much more aggressive in treating blood pressure. Remember the Oslo study? It defined mild hypertension as a blood pressure between 150 and 180 mm Hg. Now, those numbers send people screaming to the emergency room. So, let’s acknowledge that things are substantially better than they once were. Let’s agree on that and we can start to heal this nation again. 

Before we get into the numbers, when we’re treating blood pressure, let’s make a few points about measuring it. Obviously, to treat something, you have to measure it properly. Two recent trials have illustrated that these details matter a lot.

The Cuff(SZ) randomized crossover trial — and it took me a minute to realize that Cuff(SZ) meant cuff size, so bravo, Ishigami et al — showed that picking the wrong cuff size could affect BP measurements by 4.5 points if you were one size off. If you were two sizes too small, you overestimated BP by almost 20 points.

Add on here another recent study, the ARMS crossover randomized clinical trial, looking at how arm position affected BP measures. If the arm was resting on your lap or hanging by your side, that overestimated blood pressure by 4 and 6.5 points. So sometimes you have to remember the fundamentals: cuff size, arm position — it might make the difference between increasing or maintaining the patient’s meds.

But on to the main show. What numbers should we be aiming for? We no longer live in the “BP 200, the president’s going to have a stroke” world of the 1940s, and even a BP of 150 is considered quite high these days. Studies like the MRC trial, INVEST, and SPRINT have pushed BP targets ever lower. SPRINT, in particular, randomized patients to a blood pressure target under 120 systolic vs under 140 systolic, and the under-120 arm won out with fewer cardiovascular events and lower all-cause mortality.

Pretty definitive slam dunk. But the more intensive treatment came with more hypotension, syncope, and kidney injury, because there is no free lunch in medicine. And ditto with BPROAD, just published in The New England Journal of Medicine and presented at the American Heart Association annual meeting. A diabetic population randomized to 120 vs 140 as a BP target showed that more aggressive treatment was better.

Fewer cardiovascular events, like stroke, but no mortality difference, and more hypotension. So a cardiovascular benefit at the cost of more side effects. Now, like all cardiologists, my motto is “Save the heart and screw the kidney.” But if you do care about the other organs in this meat sack that we call a human body, the question you need to wrestle with is, how much do you value cardiovascular protection vs how willing are you to tolerate side effects?

Hypotension may not sound dangerous, but gravity is an unforgiving mistress. If you painstakingly compile the summary of the various BP guidelines for easy perusal, you would notice something critical: One, I have too much free time on my hands; two, the disagreements are not really all that profound.

Arguing about 120 vs 130 vs 140 is not the same as saying, “Drugs schmugs; a good massage will fix what ails you, and here are some addictive sleeping pills for good measure.” Physicians from the 1930s were a little sketchy. So much of this controversy is about how you define high-risk patients and what are the age cutoffs.

Basically, the cardiovascular guidelines say, “Treat them all and let God sort it out” because they care about cardiovascular events and are concerned about cardiovascular endpoints. Whereas general practice guidelines put more emphasis on potential side effects and admittedly tend to treat a not so high-risk population, so they have laxer targets.

A 2014 analysis from the Blood Pressure Lowering Treatment Trialists’ Collaboration [The Lancet] had a good mathematical way of explaining this problem. Now, lowering blood pressure is obviously a good thing. That prevents heart attacks, strokes, kidney failure, and all that. Please don’t let hypertension denialism become a thing.

Let’s start with the basics. Treating high blood pressure led to a 15% to 18% decrease in cardiovascular events, pretty consistently across all risk categories, and other analyses have found that every 5-point decrease in blood pressure gives you about a 10% decrease in major cardiovascular events on the relative-risk scale. 

While the benefits are pretty consistent across all groups, that difference in baseline risk translates into different absolute benefits. In the Lancet paper, when the population was divided into four different groups based on their cardiovascular risk, the absolute risk reduction in the lowest-risk group was 14 fewer cardiovascular events if you treat 1000 patients for 5 years.

With each higher-risk group, it was 20 fewer, 24 fewer, and 38 fewer. At the lowest-risk group, the number needed to treat was 71, 50, 42, and 26 fewer cardiovascular events with 5 years of treatment. 

And herein lies the secret to the disagreement: If you have a high-risk patient, there is a big benefit to bringing that blood pressure down from 135 to 130. Whereas for a low-risk patient, it probably doesn’t matter as much. And the cardiovascular benefits are going to be offset by the side effects and the risks for hypotension. 

Of course, there’s a simple solution to this dilemma: Just speak to the patient in front of you. Treat high blood pressure, and if your patient’s blood pressure drops or they get dizzy or have fainting spells, then just ease up on the meds. It’s not rocket science; it’s just cardiology. 

Arguing about five millimeters of mercury of blood pressure is probably less important from the public health perspective than the fact that tens of millions of people in the United States are unaware that they have hypertension, and even those diagnosed are being inadequately treated.

So, let’s all do better as a medical community. Nobody should have untreated hypertension in this day and age. It’s not the 1930s. 
 

Dr Labos, Cardiologist, Kirkland Medical Center, Montreal, Quebec, Canada, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Blood pressure. If you’re a primary care provider trying to do right by your patients, you might be understandably confused by the current mishmash of guidelines with different blood pressure targets. But as chaotic as things are, at least it’s not the 1930s, when you might hear John Hay give a lecture to the British Medical Association and say, “The greatest danger to a man with high blood pressure lies in its discovery, because then some fool is certain to try and reduce it.”

Yeah, he said that. But what happened in the 1930s stays in the 1930s. And now we can at least agree that we should be treating high blood pressure. But what’s the goal we should be aiming for? This is On Second Thought. 

We’ve come a long way since FDR was recording blood pressures of 200 and his doctor prescribed him barbiturates and massage therapy.

That s#$# don’t fly no more. Over the past hundred years, we have become much more aggressive in treating blood pressure. Remember the Oslo study? It defined mild hypertension as a blood pressure between 150 and 180 mm Hg. Now, those numbers send people screaming to the emergency room. So, let’s acknowledge that things are substantially better than they once were. Let’s agree on that and we can start to heal this nation again. 

Before we get into the numbers, when we’re treating blood pressure, let’s make a few points about measuring it. Obviously, to treat something, you have to measure it properly. Two recent trials have illustrated that these details matter a lot.

The Cuff(SZ) randomized crossover trial — and it took me a minute to realize that Cuff(SZ) meant cuff size, so bravo, Ishigami et al — showed that picking the wrong cuff size could affect BP measurements by 4.5 points if you were one size off. If you were two sizes too small, you overestimated BP by almost 20 points.

Add on here another recent study, the ARMS crossover randomized clinical trial, looking at how arm position affected BP measures. If the arm was resting on your lap or hanging by your side, that overestimated blood pressure by 4 and 6.5 points. So sometimes you have to remember the fundamentals: cuff size, arm position — it might make the difference between increasing or maintaining the patient’s meds.

But on to the main show. What numbers should we be aiming for? We no longer live in the “BP 200, the president’s going to have a stroke” world of the 1940s, and even a BP of 150 is considered quite high these days. Studies like the MRC trial, INVEST, and SPRINT have pushed BP targets ever lower. SPRINT, in particular, randomized patients to a blood pressure target under 120 systolic vs under 140 systolic, and the under-120 arm won out with fewer cardiovascular events and lower all-cause mortality.

Pretty definitive slam dunk. But the more intensive treatment came with more hypotension, syncope, and kidney injury, because there is no free lunch in medicine. And ditto with BPROAD, just published in The New England Journal of Medicine and presented at the American Heart Association annual meeting. A diabetic population randomized to 120 vs 140 as a BP target showed that more aggressive treatment was better.

Fewer cardiovascular events, like stroke, but no mortality difference, and more hypotension. So a cardiovascular benefit at the cost of more side effects. Now, like all cardiologists, my motto is “Save the heart and screw the kidney.” But if you do care about the other organs in this meat sack that we call a human body, the question you need to wrestle with is, how much do you value cardiovascular protection vs how willing are you to tolerate side effects?

Hypotension may not sound dangerous, but gravity is an unforgiving mistress. If you painstakingly compile the summary of the various BP guidelines for easy perusal, you would notice something critical: One, I have too much free time on my hands; two, the disagreements are not really all that profound.

Arguing about 120 vs 130 vs 140 is not the same as saying, “Drugs schmugs; a good massage will fix what ails you, and here are some addictive sleeping pills for good measure.” Physicians from the 1930s were a little sketchy. So much of this controversy is about how you define high-risk patients and what are the age cutoffs.

Basically, the cardiovascular guidelines say, “Treat them all and let God sort it out” because they care about cardiovascular events and are concerned about cardiovascular endpoints. Whereas general practice guidelines put more emphasis on potential side effects and admittedly tend to treat a not so high-risk population, so they have laxer targets.

A 2014 analysis from the Blood Pressure Lowering Treatment Trialists’ Collaboration [The Lancet] had a good mathematical way of explaining this problem. Now, lowering blood pressure is obviously a good thing. That prevents heart attacks, strokes, kidney failure, and all that. Please don’t let hypertension denialism become a thing.

Let’s start with the basics. Treating high blood pressure led to a 15% to 18% decrease in cardiovascular events, pretty consistently across all risk categories, and other analyses have found that every 5-point decrease in blood pressure gives you about a 10% decrease in major cardiovascular events on the relative-risk scale. 

While the benefits are pretty consistent across all groups, that difference in baseline risk translates into different absolute benefits. In the Lancet paper, when the population was divided into four different groups based on their cardiovascular risk, the absolute risk reduction in the lowest-risk group was 14 fewer cardiovascular events if you treat 1000 patients for 5 years.

With each higher-risk group, it was 20 fewer, 24 fewer, and 38 fewer. At the lowest-risk group, the number needed to treat was 71, 50, 42, and 26 fewer cardiovascular events with 5 years of treatment. 

And herein lies the secret to the disagreement: If you have a high-risk patient, there is a big benefit to bringing that blood pressure down from 135 to 130. Whereas for a low-risk patient, it probably doesn’t matter as much. And the cardiovascular benefits are going to be offset by the side effects and the risks for hypotension. 

Of course, there’s a simple solution to this dilemma: Just speak to the patient in front of you. Treat high blood pressure, and if your patient’s blood pressure drops or they get dizzy or have fainting spells, then just ease up on the meds. It’s not rocket science; it’s just cardiology. 

Arguing about five millimeters of mercury of blood pressure is probably less important from the public health perspective than the fact that tens of millions of people in the United States are unaware that they have hypertension, and even those diagnosed are being inadequately treated.

So, let’s all do better as a medical community. Nobody should have untreated hypertension in this day and age. It’s not the 1930s. 
 

Dr Labos, Cardiologist, Kirkland Medical Center, Montreal, Quebec, Canada, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Blood pressure. If you’re a primary care provider trying to do right by your patients, you might be understandably confused by the current mishmash of guidelines with different blood pressure targets. But as chaotic as things are, at least it’s not the 1930s, when you might hear John Hay give a lecture to the British Medical Association and say, “The greatest danger to a man with high blood pressure lies in its discovery, because then some fool is certain to try and reduce it.”

Yeah, he said that. But what happened in the 1930s stays in the 1930s. And now we can at least agree that we should be treating high blood pressure. But what’s the goal we should be aiming for? This is On Second Thought. 

We’ve come a long way since FDR was recording blood pressures of 200 and his doctor prescribed him barbiturates and massage therapy.

That s#$# don’t fly no more. Over the past hundred years, we have become much more aggressive in treating blood pressure. Remember the Oslo study? It defined mild hypertension as a blood pressure between 150 and 180 mm Hg. Now, those numbers send people screaming to the emergency room. So, let’s acknowledge that things are substantially better than they once were. Let’s agree on that and we can start to heal this nation again. 

Before we get into the numbers, when we’re treating blood pressure, let’s make a few points about measuring it. Obviously, to treat something, you have to measure it properly. Two recent trials have illustrated that these details matter a lot.

The Cuff(SZ) randomized crossover trial — and it took me a minute to realize that Cuff(SZ) meant cuff size, so bravo, Ishigami et al — showed that picking the wrong cuff size could affect BP measurements by 4.5 points if you were one size off. If you were two sizes too small, you overestimated BP by almost 20 points.

Add on here another recent study, the ARMS crossover randomized clinical trial, looking at how arm position affected BP measures. If the arm was resting on your lap or hanging by your side, that overestimated blood pressure by 4 and 6.5 points. So sometimes you have to remember the fundamentals: cuff size, arm position — it might make the difference between increasing or maintaining the patient’s meds.

But on to the main show. What numbers should we be aiming for? We no longer live in the “BP 200, the president’s going to have a stroke” world of the 1940s, and even a BP of 150 is considered quite high these days. Studies like the MRC trial, INVEST, and SPRINT have pushed BP targets ever lower. SPRINT, in particular, randomized patients to a blood pressure target under 120 systolic vs under 140 systolic, and the under-120 arm won out with fewer cardiovascular events and lower all-cause mortality.

Pretty definitive slam dunk. But the more intensive treatment came with more hypotension, syncope, and kidney injury, because there is no free lunch in medicine. And ditto with BPROAD, just published in The New England Journal of Medicine and presented at the American Heart Association annual meeting. A diabetic population randomized to 120 vs 140 as a BP target showed that more aggressive treatment was better.

Fewer cardiovascular events, like stroke, but no mortality difference, and more hypotension. So a cardiovascular benefit at the cost of more side effects. Now, like all cardiologists, my motto is “Save the heart and screw the kidney.” But if you do care about the other organs in this meat sack that we call a human body, the question you need to wrestle with is, how much do you value cardiovascular protection vs how willing are you to tolerate side effects?

Hypotension may not sound dangerous, but gravity is an unforgiving mistress. If you painstakingly compile the summary of the various BP guidelines for easy perusal, you would notice something critical: One, I have too much free time on my hands; two, the disagreements are not really all that profound.

Arguing about 120 vs 130 vs 140 is not the same as saying, “Drugs schmugs; a good massage will fix what ails you, and here are some addictive sleeping pills for good measure.” Physicians from the 1930s were a little sketchy. So much of this controversy is about how you define high-risk patients and what are the age cutoffs.

Basically, the cardiovascular guidelines say, “Treat them all and let God sort it out” because they care about cardiovascular events and are concerned about cardiovascular endpoints. Whereas general practice guidelines put more emphasis on potential side effects and admittedly tend to treat a not so high-risk population, so they have laxer targets.

A 2014 analysis from the Blood Pressure Lowering Treatment Trialists’ Collaboration [The Lancet] had a good mathematical way of explaining this problem. Now, lowering blood pressure is obviously a good thing. That prevents heart attacks, strokes, kidney failure, and all that. Please don’t let hypertension denialism become a thing.

Let’s start with the basics. Treating high blood pressure led to a 15% to 18% decrease in cardiovascular events, pretty consistently across all risk categories, and other analyses have found that every 5-point decrease in blood pressure gives you about a 10% decrease in major cardiovascular events on the relative-risk scale. 

While the benefits are pretty consistent across all groups, that difference in baseline risk translates into different absolute benefits. In the Lancet paper, when the population was divided into four different groups based on their cardiovascular risk, the absolute risk reduction in the lowest-risk group was 14 fewer cardiovascular events if you treat 1000 patients for 5 years.

With each higher-risk group, it was 20 fewer, 24 fewer, and 38 fewer. At the lowest-risk group, the number needed to treat was 71, 50, 42, and 26 fewer cardiovascular events with 5 years of treatment. 

And herein lies the secret to the disagreement: If you have a high-risk patient, there is a big benefit to bringing that blood pressure down from 135 to 130. Whereas for a low-risk patient, it probably doesn’t matter as much. And the cardiovascular benefits are going to be offset by the side effects and the risks for hypotension. 

Of course, there’s a simple solution to this dilemma: Just speak to the patient in front of you. Treat high blood pressure, and if your patient’s blood pressure drops or they get dizzy or have fainting spells, then just ease up on the meds. It’s not rocket science; it’s just cardiology. 

Arguing about five millimeters of mercury of blood pressure is probably less important from the public health perspective than the fact that tens of millions of people in the United States are unaware that they have hypertension, and even those diagnosed are being inadequately treated.

So, let’s all do better as a medical community. Nobody should have untreated hypertension in this day and age. It’s not the 1930s. 
 

Dr Labos, Cardiologist, Kirkland Medical Center, Montreal, Quebec, Canada, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

For the third straight year, firearms killed more children and teens than any other cause, including motor vehicle crashes and cancer. The population-wide toll taken by guns is equally as discouraging. Finally, this elephant in the room is getting some attention from the medical community, but the voices asking for change have most recently been coming from medical students who feel that gun violence deserves to be given a larger role in their education. It’s unclear why this plea is coming from the younger end of the medical community. It may be that, unlike most of their older instructors, these 18- to 25-year-olds have grown up under the growing threat of school shootings and become uncomfortably accustomed to active shooter drills.

Should We Look to Medical School for Answers?

There is no question that compared with the rest of this country the medical community needs to take gun violence more seriously. But, does the medical community need to take gun violence more seriously than the rest of the population? What should our response look like? To answer those questions we need to take several steps back to view the bigger picture.

Is the medical community more responsible for this current situation than any other segment of the population? Do physicians bear any more culpability than publishers who sell gun-related magazines? Since its inception pediatrics has taken on the role of advocate for children and their health and well-being. But, is there more we can and should do other than turn up the volume on our advocacy? 

While still taking the longer view, let’s ask ourselves what the role of medical school should be. Not just with respect to gun violence but in producing physicians and healthcare providers. We are approaching a crisis in primary care as it loses appeal with physicians at both ends of the age continuum. It could be because it pays poorly — certainly in relation to the cost of medical school — or because the awareness that if done well primary care requires a commitment that is difficult to square with many individuals’ lifestyle expectations. 

Is the traditional medical school the right place to be training primary care providers? Medical school is currently aimed at broad and deep exposure. The student will be exposed to the all the diseases to which he or she might be seeing anywhere in the world and at the same time will have learned the mechanisms down to the cellular level that lies behind that pathology. Does a primary care pediatrician practicing in a small city or suburbia need that depth of training? He or she might benefit from some breadth. But maybe it should be focused on socioeconomic and geographic population the doctor is likely to see. This is particularly true for gun-related deaths.

Returning our attention to gun violence and its relation to healthcare, let’s ask ourselves what role the traditional medical school should play. Should it be a breeding ground for gun control advocates? When physicians speak people tend to listen but our effectiveness on issues such as immunizations and gun control has not been what many have hoped for. The supply of guns available to the public in this country is staggering and certainly contributes to gun-related injuries and death. However, I’m afraid that making a significant dent in that supply, given our political history and current climate, is an issue whose ship has sailed.

On the other hand, as gun advocates are often quoted as saying, “it’s not guns that kill, it’s people.” We don’t need to go into to the fallacy of this argument, but it gives us a starting point from which a medical school might focus its efforts on addressing the fallout from gun violence. A curriculum that begins with a presentation of the grizzly statistics and moves on to research about gun-related mental health issues and the social environments that breed violence makes good sense. Recanting the depressing history of how our society got to this place, in which guns outnumber people, should be part of the undergraduate curriculum.

Addressing the specifics of gun safety and suicide prevention in general with families and individuals would be more appropriate during clinical specialty training. 

How big a chunk of the curriculum should be committed to gun violence and its fallout? Some of the call for change seems to be suggesting a semester-long course. However, we must accept the reality that instructional time in medical school is a finite asset. Although gunshots are the leading cause of death in children, how effective will even the most cleverly crafted curriculum be in moving the needle on the embarrassing data?

Given what is known about the problem, a day, or at most a week would be sufficient in class time. This could include personal presentations by victims or family members. I’m sure there are some who would see that as insufficient. But I see it as realistic. For the large urban schools, observing an evening shift in the trauma unit of an ER could be a potent addition.

Beyond this, a commitment by the school to host seminars and workshops devoted to gun violence could be an important component. It might also be helpful for a school or training program to promote the habit of whenever an instructor is introducing a potentially fatal disease to the students for the first time, he or she would begin with “To put this in perspective, you should remember that xxx thousand children die of gunshot wounds every year.” 

Unfortunately, like obesity, gun-related deaths and injuries are the result of our society’s failure to muster the political will to act in our best interest as a nation. The medical community is left to clean up the collateral damage. There is always more that we could do, but we must be thoughtful in how we invest our energies in the effort.

Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com. 

For the third straight year, firearms killed more children and teens than any other cause, including motor vehicle crashes and cancer. The population-wide toll taken by guns is equally as discouraging. Finally, this elephant in the room is getting some attention from the medical community, but the voices asking for change have most recently been coming from medical students who feel that gun violence deserves to be given a larger role in their education. It’s unclear why this plea is coming from the younger end of the medical community. It may be that, unlike most of their older instructors, these 18- to 25-year-olds have grown up under the growing threat of school shootings and become uncomfortably accustomed to active shooter drills.

Should We Look to Medical School for Answers?

There is no question that compared with the rest of this country the medical community needs to take gun violence more seriously. But, does the medical community need to take gun violence more seriously than the rest of the population? What should our response look like? To answer those questions we need to take several steps back to view the bigger picture.

Is the medical community more responsible for this current situation than any other segment of the population? Do physicians bear any more culpability than publishers who sell gun-related magazines? Since its inception pediatrics has taken on the role of advocate for children and their health and well-being. But, is there more we can and should do other than turn up the volume on our advocacy? 

While still taking the longer view, let’s ask ourselves what the role of medical school should be. Not just with respect to gun violence but in producing physicians and healthcare providers. We are approaching a crisis in primary care as it loses appeal with physicians at both ends of the age continuum. It could be because it pays poorly — certainly in relation to the cost of medical school — or because the awareness that if done well primary care requires a commitment that is difficult to square with many individuals’ lifestyle expectations. 

Is the traditional medical school the right place to be training primary care providers? Medical school is currently aimed at broad and deep exposure. The student will be exposed to the all the diseases to which he or she might be seeing anywhere in the world and at the same time will have learned the mechanisms down to the cellular level that lies behind that pathology. Does a primary care pediatrician practicing in a small city or suburbia need that depth of training? He or she might benefit from some breadth. But maybe it should be focused on socioeconomic and geographic population the doctor is likely to see. This is particularly true for gun-related deaths.

Returning our attention to gun violence and its relation to healthcare, let’s ask ourselves what role the traditional medical school should play. Should it be a breeding ground for gun control advocates? When physicians speak people tend to listen but our effectiveness on issues such as immunizations and gun control has not been what many have hoped for. The supply of guns available to the public in this country is staggering and certainly contributes to gun-related injuries and death. However, I’m afraid that making a significant dent in that supply, given our political history and current climate, is an issue whose ship has sailed.

On the other hand, as gun advocates are often quoted as saying, “it’s not guns that kill, it’s people.” We don’t need to go into to the fallacy of this argument, but it gives us a starting point from which a medical school might focus its efforts on addressing the fallout from gun violence. A curriculum that begins with a presentation of the grizzly statistics and moves on to research about gun-related mental health issues and the social environments that breed violence makes good sense. Recanting the depressing history of how our society got to this place, in which guns outnumber people, should be part of the undergraduate curriculum.

Addressing the specifics of gun safety and suicide prevention in general with families and individuals would be more appropriate during clinical specialty training. 

How big a chunk of the curriculum should be committed to gun violence and its fallout? Some of the call for change seems to be suggesting a semester-long course. However, we must accept the reality that instructional time in medical school is a finite asset. Although gunshots are the leading cause of death in children, how effective will even the most cleverly crafted curriculum be in moving the needle on the embarrassing data?

Given what is known about the problem, a day, or at most a week would be sufficient in class time. This could include personal presentations by victims or family members. I’m sure there are some who would see that as insufficient. But I see it as realistic. For the large urban schools, observing an evening shift in the trauma unit of an ER could be a potent addition.

Beyond this, a commitment by the school to host seminars and workshops devoted to gun violence could be an important component. It might also be helpful for a school or training program to promote the habit of whenever an instructor is introducing a potentially fatal disease to the students for the first time, he or she would begin with “To put this in perspective, you should remember that xxx thousand children die of gunshot wounds every year.” 

Unfortunately, like obesity, gun-related deaths and injuries are the result of our society’s failure to muster the political will to act in our best interest as a nation. The medical community is left to clean up the collateral damage. There is always more that we could do, but we must be thoughtful in how we invest our energies in the effort.

Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com. 

For the third straight year, firearms killed more children and teens than any other cause, including motor vehicle crashes and cancer. The population-wide toll taken by guns is equally as discouraging. Finally, this elephant in the room is getting some attention from the medical community, but the voices asking for change have most recently been coming from medical students who feel that gun violence deserves to be given a larger role in their education. It’s unclear why this plea is coming from the younger end of the medical community. It may be that, unlike most of their older instructors, these 18- to 25-year-olds have grown up under the growing threat of school shootings and become uncomfortably accustomed to active shooter drills.

Should We Look to Medical School for Answers?

There is no question that compared with the rest of this country the medical community needs to take gun violence more seriously. But, does the medical community need to take gun violence more seriously than the rest of the population? What should our response look like? To answer those questions we need to take several steps back to view the bigger picture.

Is the medical community more responsible for this current situation than any other segment of the population? Do physicians bear any more culpability than publishers who sell gun-related magazines? Since its inception pediatrics has taken on the role of advocate for children and their health and well-being. But, is there more we can and should do other than turn up the volume on our advocacy? 

While still taking the longer view, let’s ask ourselves what the role of medical school should be. Not just with respect to gun violence but in producing physicians and healthcare providers. We are approaching a crisis in primary care as it loses appeal with physicians at both ends of the age continuum. It could be because it pays poorly — certainly in relation to the cost of medical school — or because the awareness that if done well primary care requires a commitment that is difficult to square with many individuals’ lifestyle expectations. 

Is the traditional medical school the right place to be training primary care providers? Medical school is currently aimed at broad and deep exposure. The student will be exposed to the all the diseases to which he or she might be seeing anywhere in the world and at the same time will have learned the mechanisms down to the cellular level that lies behind that pathology. Does a primary care pediatrician practicing in a small city or suburbia need that depth of training? He or she might benefit from some breadth. But maybe it should be focused on socioeconomic and geographic population the doctor is likely to see. This is particularly true for gun-related deaths.

Returning our attention to gun violence and its relation to healthcare, let’s ask ourselves what role the traditional medical school should play. Should it be a breeding ground for gun control advocates? When physicians speak people tend to listen but our effectiveness on issues such as immunizations and gun control has not been what many have hoped for. The supply of guns available to the public in this country is staggering and certainly contributes to gun-related injuries and death. However, I’m afraid that making a significant dent in that supply, given our political history and current climate, is an issue whose ship has sailed.

On the other hand, as gun advocates are often quoted as saying, “it’s not guns that kill, it’s people.” We don’t need to go into to the fallacy of this argument, but it gives us a starting point from which a medical school might focus its efforts on addressing the fallout from gun violence. A curriculum that begins with a presentation of the grizzly statistics and moves on to research about gun-related mental health issues and the social environments that breed violence makes good sense. Recanting the depressing history of how our society got to this place, in which guns outnumber people, should be part of the undergraduate curriculum.

Addressing the specifics of gun safety and suicide prevention in general with families and individuals would be more appropriate during clinical specialty training. 

How big a chunk of the curriculum should be committed to gun violence and its fallout? Some of the call for change seems to be suggesting a semester-long course. However, we must accept the reality that instructional time in medical school is a finite asset. Although gunshots are the leading cause of death in children, how effective will even the most cleverly crafted curriculum be in moving the needle on the embarrassing data?

Given what is known about the problem, a day, or at most a week would be sufficient in class time. This could include personal presentations by victims or family members. I’m sure there are some who would see that as insufficient. But I see it as realistic. For the large urban schools, observing an evening shift in the trauma unit of an ER could be a potent addition.

Beyond this, a commitment by the school to host seminars and workshops devoted to gun violence could be an important component. It might also be helpful for a school or training program to promote the habit of whenever an instructor is introducing a potentially fatal disease to the students for the first time, he or she would begin with “To put this in perspective, you should remember that xxx thousand children die of gunshot wounds every year.” 

Unfortunately, like obesity, gun-related deaths and injuries are the result of our society’s failure to muster the political will to act in our best interest as a nation. The medical community is left to clean up the collateral damage. There is always more that we could do, but we must be thoughtful in how we invest our energies in the effort.

Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com. 

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.

Earlier in December, the Supreme Court heard the first oral arguments in United States v. Skrmetti, a critical case challenging gender-affirming bans for minors in Tennessee. The case has garnered national attention as it is the first case the Supreme Court has undertaken regarding gender-affirming care and the first time an openly transgender attorney presented a case to the high court. The ruling will have nationwide implications as it can single-handedly decide the fate of gender-affirming care for minors, and potentially adults. Even though the final verdict may not come out until June of 2025, the conservative majority of justices seems poised to uphold the Tennessee ban.¹ In what is possibly a harbinger of the US ruling, the United Kingdom announced an indefinite ban on gender-affirming care for minors the week after the oral arguments in this case were heard.2

While the legal arguments in the Skrmetti case hinge on sex discrimination and the Equal Protection Clause of the Fourteenth Amendment, the more fundamental argument centers around the question of what is in the best interest of the minor. I’d like to delve deeper into this question as our responsibility as physicians is to the health and well-being of our patients, not partisan politics. 

 

It is essential that we do not allow our personal views to cloud our ability to objectively analyze scientific data and prohibit individuals from accessing the health care from which they’d benefit. Conversely, we should not allow social pressure and ideologic principles interfere with our ability to challenge and regulate emerging treatments.

The answer to the question, “what is in the best interest of a minor?” is somewhat rhetorical. But in the most basic of senses, minors deserve equal protection under the law, a safe environment, good nutrition, healthcare, and an education. Regardless of our beliefs, we would all probably agree that minors should be protected and cared for but disagree about the ways in which we do so. This discrepancy is painfully evident if you dissect legislation as it pertains to these fundamental rights. It should come as no surprise that legislation is often contradictory. 

For example, firearm-related injury is now the leading cause of death among minors in the United States.³ It is a public health crisis no different from childhood obesity or substance abuse in adolescents. Despite this fact, politicians are reluctant, and in many cases, downright defiant, about tightening restrictions on firearms. Yet, it is these same politicians who cite that we must “protect our children,” from beneficial gender-affirming medical interventions.

Most major medical organizations, including the American Academy of Pediatrics, the American Medical Association, and the American College of Obstetricians and Gynecologists, support gender-affirming care for minors. Current research into medical care of minors, which includes puberty blockers, hormone treatments, and in rare cases, surgery, demonstrates improvement in mental health outcomes like depression, anxiety, and suicidal ideation.⁴

Critics of this type of care of minors often cite small sample sizes, selection bias, and lack of long-term data, which raise concerns about the long-term impacts of these treatments. This apprehension is not entirely unfounded as there are fewer clinical trials and studies gender-affirming care than in other fields of medicine. As with all emerging medical fields, research is needed and gender-affirming care for minors is no exception. It is unlikely bans will enhance larger clinical trials but will instead further isolate these already marginalized individuals. 

Unlike in the United Kingdom, the legislators in states with bans in effect seem to have little interest in understanding gender-affirming care in this demographic. Instead, they have imposed penalties on parents who seek this type of care from other states and the providers who treat their children. The most insidious consequence of the Tennessee ban, if upheld, is the federally sanctioned interference in the ability of parents to make health care decisions for their child with a medical provider. 

Such a move sets a dangerous precedent for politicians to target other forms of healthcare and other marginalized communities. As the ruling pertains to gender-affirming care, politicians and most attorneys are not well-versed in the medical issues in the field. Nor is it in their purview to be. During oral arguments, the Supreme Court Justices were understandably unfamiliar with the medical nuances of this type of treatment. As someone who has met with various politicians to discuss gender-affirming medicine and surgery for adults, I can say that they have very little knowledge. Therefore, isn’t the argument even stronger to leave medical decisions to parents, providers, and patients rather than uninformed policymakers?

References

1. Cole D et al. CNN. Takeaways from the historic transgender care arguments at the Supreme Court. 2024 Dec 4.

CNN.com/2024/12/04/politics/transgender-care-bans-scotus-takeaways/index.html. 

2. Triggle N. BBC. Puberty blockers for under-18s banned indefinitely. BBC. 2024 Dec 11. BBC.com/news/articles/cly2z0gx3p5o. 

3. Wilson RF et al. MMWR Morb Mortal Wkly Rep. 2023;72(5):1338-1345.

4. Coleman E et al. Int J Transgender Health. 2022;23(suppl 1):S1-S259.

Earlier in December, the Supreme Court heard the first oral arguments in United States v. Skrmetti, a critical case challenging gender-affirming bans for minors in Tennessee. The case has garnered national attention as it is the first case the Supreme Court has undertaken regarding gender-affirming care and the first time an openly transgender attorney presented a case to the high court. The ruling will have nationwide implications as it can single-handedly decide the fate of gender-affirming care for minors, and potentially adults. Even though the final verdict may not come out until June of 2025, the conservative majority of justices seems poised to uphold the Tennessee ban.¹ In what is possibly a harbinger of the US ruling, the United Kingdom announced an indefinite ban on gender-affirming care for minors the week after the oral arguments in this case were heard.2

While the legal arguments in the Skrmetti case hinge on sex discrimination and the Equal Protection Clause of the Fourteenth Amendment, the more fundamental argument centers around the question of what is in the best interest of the minor. I’d like to delve deeper into this question as our responsibility as physicians is to the health and well-being of our patients, not partisan politics. 

 

It is essential that we do not allow our personal views to cloud our ability to objectively analyze scientific data and prohibit individuals from accessing the health care from which they’d benefit. Conversely, we should not allow social pressure and ideologic principles interfere with our ability to challenge and regulate emerging treatments.

The answer to the question, “what is in the best interest of a minor?” is somewhat rhetorical. But in the most basic of senses, minors deserve equal protection under the law, a safe environment, good nutrition, healthcare, and an education. Regardless of our beliefs, we would all probably agree that minors should be protected and cared for but disagree about the ways in which we do so. This discrepancy is painfully evident if you dissect legislation as it pertains to these fundamental rights. It should come as no surprise that legislation is often contradictory. 

For example, firearm-related injury is now the leading cause of death among minors in the United States.³ It is a public health crisis no different from childhood obesity or substance abuse in adolescents. Despite this fact, politicians are reluctant, and in many cases, downright defiant, about tightening restrictions on firearms. Yet, it is these same politicians who cite that we must “protect our children,” from beneficial gender-affirming medical interventions.

Most major medical organizations, including the American Academy of Pediatrics, the American Medical Association, and the American College of Obstetricians and Gynecologists, support gender-affirming care for minors. Current research into medical care of minors, which includes puberty blockers, hormone treatments, and in rare cases, surgery, demonstrates improvement in mental health outcomes like depression, anxiety, and suicidal ideation.⁴

Critics of this type of care of minors often cite small sample sizes, selection bias, and lack of long-term data, which raise concerns about the long-term impacts of these treatments. This apprehension is not entirely unfounded as there are fewer clinical trials and studies gender-affirming care than in other fields of medicine. As with all emerging medical fields, research is needed and gender-affirming care for minors is no exception. It is unlikely bans will enhance larger clinical trials but will instead further isolate these already marginalized individuals. 

Unlike in the United Kingdom, the legislators in states with bans in effect seem to have little interest in understanding gender-affirming care in this demographic. Instead, they have imposed penalties on parents who seek this type of care from other states and the providers who treat their children. The most insidious consequence of the Tennessee ban, if upheld, is the federally sanctioned interference in the ability of parents to make health care decisions for their child with a medical provider. 

Such a move sets a dangerous precedent for politicians to target other forms of healthcare and other marginalized communities. As the ruling pertains to gender-affirming care, politicians and most attorneys are not well-versed in the medical issues in the field. Nor is it in their purview to be. During oral arguments, the Supreme Court Justices were understandably unfamiliar with the medical nuances of this type of treatment. As someone who has met with various politicians to discuss gender-affirming medicine and surgery for adults, I can say that they have very little knowledge. Therefore, isn’t the argument even stronger to leave medical decisions to parents, providers, and patients rather than uninformed policymakers?

References

1. Cole D et al. CNN. Takeaways from the historic transgender care arguments at the Supreme Court. 2024 Dec 4.

CNN.com/2024/12/04/politics/transgender-care-bans-scotus-takeaways/index.html. 

2. Triggle N. BBC. Puberty blockers for under-18s banned indefinitely. BBC. 2024 Dec 11. BBC.com/news/articles/cly2z0gx3p5o. 

3. Wilson RF et al. MMWR Morb Mortal Wkly Rep. 2023;72(5):1338-1345.

4. Coleman E et al. Int J Transgender Health. 2022;23(suppl 1):S1-S259.

Earlier in December, the Supreme Court heard the first oral arguments in United States v. Skrmetti, a critical case challenging gender-affirming bans for minors in Tennessee. The case has garnered national attention as it is the first case the Supreme Court has undertaken regarding gender-affirming care and the first time an openly transgender attorney presented a case to the high court. The ruling will have nationwide implications as it can single-handedly decide the fate of gender-affirming care for minors, and potentially adults. Even though the final verdict may not come out until June of 2025, the conservative majority of justices seems poised to uphold the Tennessee ban.¹ In what is possibly a harbinger of the US ruling, the United Kingdom announced an indefinite ban on gender-affirming care for minors the week after the oral arguments in this case were heard.2

While the legal arguments in the Skrmetti case hinge on sex discrimination and the Equal Protection Clause of the Fourteenth Amendment, the more fundamental argument centers around the question of what is in the best interest of the minor. I’d like to delve deeper into this question as our responsibility as physicians is to the health and well-being of our patients, not partisan politics. 

 

It is essential that we do not allow our personal views to cloud our ability to objectively analyze scientific data and prohibit individuals from accessing the health care from which they’d benefit. Conversely, we should not allow social pressure and ideologic principles interfere with our ability to challenge and regulate emerging treatments.

The answer to the question, “what is in the best interest of a minor?” is somewhat rhetorical. But in the most basic of senses, minors deserve equal protection under the law, a safe environment, good nutrition, healthcare, and an education. Regardless of our beliefs, we would all probably agree that minors should be protected and cared for but disagree about the ways in which we do so. This discrepancy is painfully evident if you dissect legislation as it pertains to these fundamental rights. It should come as no surprise that legislation is often contradictory. 

For example, firearm-related injury is now the leading cause of death among minors in the United States.³ It is a public health crisis no different from childhood obesity or substance abuse in adolescents. Despite this fact, politicians are reluctant, and in many cases, downright defiant, about tightening restrictions on firearms. Yet, it is these same politicians who cite that we must “protect our children,” from beneficial gender-affirming medical interventions.

Most major medical organizations, including the American Academy of Pediatrics, the American Medical Association, and the American College of Obstetricians and Gynecologists, support gender-affirming care for minors. Current research into medical care of minors, which includes puberty blockers, hormone treatments, and in rare cases, surgery, demonstrates improvement in mental health outcomes like depression, anxiety, and suicidal ideation.⁴

Critics of this type of care of minors often cite small sample sizes, selection bias, and lack of long-term data, which raise concerns about the long-term impacts of these treatments. This apprehension is not entirely unfounded as there are fewer clinical trials and studies gender-affirming care than in other fields of medicine. As with all emerging medical fields, research is needed and gender-affirming care for minors is no exception. It is unlikely bans will enhance larger clinical trials but will instead further isolate these already marginalized individuals. 

Unlike in the United Kingdom, the legislators in states with bans in effect seem to have little interest in understanding gender-affirming care in this demographic. Instead, they have imposed penalties on parents who seek this type of care from other states and the providers who treat their children. The most insidious consequence of the Tennessee ban, if upheld, is the federally sanctioned interference in the ability of parents to make health care decisions for their child with a medical provider. 

Such a move sets a dangerous precedent for politicians to target other forms of healthcare and other marginalized communities. As the ruling pertains to gender-affirming care, politicians and most attorneys are not well-versed in the medical issues in the field. Nor is it in their purview to be. During oral arguments, the Supreme Court Justices were understandably unfamiliar with the medical nuances of this type of treatment. As someone who has met with various politicians to discuss gender-affirming medicine and surgery for adults, I can say that they have very little knowledge. Therefore, isn’t the argument even stronger to leave medical decisions to parents, providers, and patients rather than uninformed policymakers?

References

1. Cole D et al. CNN. Takeaways from the historic transgender care arguments at the Supreme Court. 2024 Dec 4.

CNN.com/2024/12/04/politics/transgender-care-bans-scotus-takeaways/index.html. 

2. Triggle N. BBC. Puberty blockers for under-18s banned indefinitely. BBC. 2024 Dec 11. BBC.com/news/articles/cly2z0gx3p5o. 

3. Wilson RF et al. MMWR Morb Mortal Wkly Rep. 2023;72(5):1338-1345.

4. Coleman E et al. Int J Transgender Health. 2022;23(suppl 1):S1-S259.

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.

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.

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.