The Peter Attia Drive - #230 ‒ Cardiovascular disease in women: prevention, risk factors, lipids, and more | Erin Michos, M.D.

Episode Date: November 7, 2022

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Erin Michos is an internationally-known leader in preventive cardiology and women’s cardiovascular health. In this episode, Erin discusses current trends in cardiovascular disease (CVD) through the lens of female biology and the observation that major adverse cardiac events in both sexes are on the rise. She walks through risk factors including LDL-cholesterol, apoB, and Lp(a) and makes the case for the importance of early preventative measures. She explains various interventions for reducing risk including a discussion of statins, GLP-1 agonists, PCSK9-inhibitors, and drugs that lower Lp(a). She goes in-depth on female-specific factors that contribute to CVD risk such as pregnancy, grand multiparity (having five or more children), oral contraceptives, menopause, and polycystic ovary syndrome (PCOS). Additionally, she explains her approach with patients as it relates to the use of hormone replacement therapy and provides advice for people wanting to lower risk both through lifestyle changes and medications. We discuss: Erin’s background in preventive cardiology and women’s health [2:30]; Recent trends in cardiovascular disease in women, mortality data, and how it compares to cancer [5:15]; Why early preventative measures are critical for cardiovascular disease risk [13:15]; ApoB as a causal agent of CVD, and why high apoB levels are not being aggressively treated in most cases [19:45]; The rising trend of metabolic syndrome and other factors contributing to the regression in progress of reducing cardiac events [27:00]; GLP-1 agonists—Promising drugs for treating diabetes and obesity [33:30]; Female-specific risk factors for ASCVD (pre- and post-menopause) [37:15]; Polycystic ovary syndrome (PCOS): prevalence, etiology, and impact on metabolic health, lipids and fertility [47:00]; The effect of grand multiparity (having 5+ children) on cardiovascular disease risk for women [52:30]; The impact of oral contraceptives on cardiovascular disease risk [55:00]; The effect of pregnancy on lipids and other metabolic parameters [58:45]; The undertreatment of women with familial hypercholesterolemia (FH) and how it increases lifetime risk of ASCVD [1:02:00]; How concerns around statins have contributed to undertreatment, and whether women should stop statins during pregnancy [1:09:45]; How Erin approaches the prescription of statins to patients [1:16:00]; PCSK9 inhibitors and other non-statin drugs [1:21:15]; Advice for the low- and high-risk individual [1:28:30]; The impact of nutrition, stress, and lifestyle on lipids and CVD risk [1:31:00]; Lp(a) as a risk enhancer for cardiovascular disease [1:41:15]; The effect of menopause on cardiovascular disease risk [1:50:30]; How Erin approaches decisions regarding hormone replacement therapy (HRT) for her patients [1:55:30]; The urgent need for more data on women’s health [2:03:30]; Erin’s goal of running a marathon in every state [2:09:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain

what those benefits are, or if you want to learn more now, head over to peteratia MD dot com forward slash subscribe. Now, without further delay, here's today's episode. My guess this week is Aaron Mekos. Aaron is an internationally known leader in preventative cardiology, women's cardiovascular health, and cardiovascular obstetrics. She's an associate professor of medicine in the division of cardiology at Johns Hopkins School of Medicine, the joint appointment in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health. She's also the director of Women's Cardiovascular Health and the associate director of Preventative

Cardiology with the Johns Hopkins Center of Prevention of Cardiovascular Disease. This is an episode that covers a topic that is obviously valuable to understand, given that the athletic cardiovascular disease is the number one cause of death worldwide. And while as the topic we've covered in detail in the podcast before, I think it's an important episode, because we focus this conversation around cardiovascular disease and lipids specifically through the lens of female biology. We discussed the prevalence of ASCVD in females as they age, the importance of making interventions early in life, the risk of ASCVD over the course of lifetime as opposed to the traditional view, which is to only really consider 10-year risk. We then probe the ins and outs of CVD lipids and various lipid lowering medications across a female's lifetime,

including the pre-menopausal state, changes during the perimenopausal state, pregnancy and menopausin beyond. We also touch on a number of other subjects that affect females risk of AACBD, specifically polycystic ovarian syndrome, contraceptives, GLP1 agonist, nutrition, metabolic health, familial hypercholestralemia, statins, stress, HRT, and more. So without further delay, please enjoy my conversation with Dr. Aaron Miko. Thanks so much for making time, Aaron. Look forward to this discussion we have a lot to talk about.

But before we do, there's one thing I wanted to just check going through your bio, I realize, when did you do your residency in medicine? Because you also did that at Hopkins, correct? when did you do your residency in medicine? Because you also did that at Hopkins, correct? Yes. So I've been at Hopkins 22 years. I did residency from 2000 to 2003, and then stayed on for Cardiology Fellowship, and then joined the faculty. So I've been on faculty over 15 years now.

I did my general surgery there. I was there from 01 to 06, which made me realize the probability we haven't passed each other somewhere in the emergency room during residency is exceedingly low, right? I was sure we must have interacted because I was there all during that time, overlapped with my residency and my fellowship. I always them amazed when I run into people who I know I was there, where then there are certain medicine residents I remember very well, but just by coincidence you're always in the ER together, but obviously it's a huge program. So

When you went into medicine did you know you wanted to cardiology? When I went into medicine I did in college actually didn't know that I was going to go into medicine. You know there's no doctors in my family so I I'm the first one. So I didn't really know what a career in medicine would be about. So I started out my undergrad studies at Northwestern as a molecular biology major. Through that, I interacted with so many pre-med students who are my classmates, and their enthusiasm about entering the field was really contagious. And I was doing a lot of bench science, which is really a good experience. I think anybody entering science and medicine should have some bench lab work experience.

But I began long for more direct clinical research with direct patient exposure. So kind of late, I switched to being premed kind of my last year of undergrad, and I'd actually do both the PhD in medical programs. And then when I started medical school, I really fell in love with cardiology, even as a medical student before medicine residency.

I have a real interest in diet and nutrition and exercise and lifestyle. And we think that over 90% of cardiovascular disease is due to preventable, modifiable risk factors. And there's so much we can do for prevention. And this is why I really love being a preventive cardiologist. So when I entered medicine residency, I already had my eye towards cardiology fellowship. You did the full three years of medicine and then you did three years of cards. I did four

years of cards. Oh, you did. No, I was on the slow track. You were on the slow track. I did three years of residency, which is standard. And then our Cardiology Fellowship Program was four years because we emphasized research. So I did two years of research on a T32 program and Cardiovascular epidemiology. And that's where I got my masters in health science. You said something at the outset that I completely agree with. And I feel like sometimes I'm banging my head against the wall trying to make this point.

You said, correct me if I misquote you, but something to the effect of 90% of cardiovascular disease is preventable when you consider modifiable risk factors. Was that kind of the gist of what you said? Yeah, that's the data from the inter-heart study that 90% of malchardial and barction risks was due to preventable risk factors. One of the things I tell my patients is that both in the United States and globally, AACVD is the leading cause of death. In fact, I was surprised somewhat recently, like in the last year,

to realize how much bigger the gap is between AACVD and cancer globally than in the US. It's number one in both, but you, but when you look at the entire world, I believe it's about 18.5 to 19 million deaths attributed to ASCVD versus about 10 or 11 million to cancer. It's almost 2x delta. When you take into account what you just said, that between smoking, hypertension, and controlling APOB, you could basically turn that into a disease that would barely rank on the top 10. Does it surprise you that this doesn't get more attention?

Yeah, it surprises me, and I'm also really concerned that we're reversing these trends. You know, the first statin, lobe a statin was approved in 1987. After that, along with efforts in smoking cessation and blood pressure treatment, there was a significant decline in cardiovascular disease mortality in men. During this time, unfortunately, CBD mortality was rising in women until around the year 2000 when this came to a tension that we need to prevent cardiovascular disease in women as well. And after that time, there was dramatic decline in cardiovascular disease mortality

in women and continued decline in men, but unfortunately in recent years, we are no longer making these strides and progress anymore. In fact, we're no longer even stagnated. There's been a frank uptick in cardiovascular disease mortality in both men and women due to the epidemics of obesity and diabetes and cardiac metabolic diseases. In fact, cardiovascular disease mortality is on the rise in younger women. And when you look at rates of change, the fastest growing heart disease death rate is in middle age women, age 45 to 64.

So this is a particular group that needs more focused attention. So we really need to double down on our preventive efforts. And it's really disheartening to see that we're no longer making the progress that we used to. So if these trends are not overturned, you know, heart disease is set to overtake cancer as the leading cause of death in younger women as well. I'm really glad you made that point because when you look at what these things called in our practice, we have these things called death bars, which is just an analysis that shows mortality sliced and diced in different ways

But you know sometimes a graph just says things in a way that it's harder to describe in words and One of the things that does emerge from this analysis is that in middle-age cancer is still the biggest killer and Of course overall cardiovascular disease is and and in old age, cardiovascular disease, and neurodegenerative disease dominate. But what you said is very distressing, if indeed, now cardiovascular disease would eclipse cancer in even middle age. So overall, I'm going to focus on women's health. So cardiovascular disease is the leaving cause of death in women.

Women, more often fear breast cancer, which is a terrible disease and mother had breast cancer. But far more women are likely to die of cardiovascular disease than cancer. But notably, you know, in younger individuals under the age of 65, cancer is still the leading cause of death in women. But one of my studies that we published in the European Heart Journal, we tracked death rates in younger women under the age of 65 in the US looking at CDC wonder data over a 20-year period from 1999 to 2019. And we showed during this time that actually cancer mortality

has been declining in younger women, which is a good thing. But since 2010, heart disease mortality is no longer declining and it's actually rising in these younger women at 0.5% per year. So it's actually narrowing the gap between cancer deaths and heart disease deaths in the younger female population as well. So if these trends are not overturned, as I mentioned, heart disease is set to overtake cancer as the leading cause of death in younger women, which is really discouraging considering that we have so many more tools now for prevention. And what was also really disheartening,

I don't know if you saw this, American Heart Association survey that was published in 2021, but the American Heart Association has sent out surveys over the years to women about their awareness of heart disease being the leading cause of death in women. And back in 2009, you know, 65% of women reported that they knew that heart disease was the leading cause of death. But in 2019, the more recent data, 10 years later, only 44% of women reported that heart disease was the leading cause of death in women. They were more likely to report cancer as a leading cause of death. So this lack of awareness

is very similar. It was particularly prominent among non-Hispanic black women and among Hispanic women. And also among the younger women demographic that we're talking about, who arguably we can do the most for primordial prevention would be most effective if started earlier. I also think there's kind of an emotional thing to this, which is even if you don't pose the question directly like a multiple choice question, I just find in speaking with my female patients, so young female patients, I think there's a greater fear of breast cancer than a CBD, even though the mortality from heart disease is somewhere between eight and ten times greater than that of breast cancer. It's amazing to think that they would be more

afraid of something that has a log lower difference in mortality. What do you think explains that? Again, you can answer this both through a personal lens through the experience with your mother, but also professionally given what you study. You know, I think there's still this lingering notion that somehow heart disease is a man's disease. The problem is, is women have historically been under enrolled in randomized clinical trials. So we previously had limited data on efficacy and safety of therapies in women. So both women think that they're at lower risk than they really are, but also clinicians. So clinicians, even when given the same 10-year estimated risk or burden of risk factors, clinicians are more likely to perceive women to being at lower risk, and this leads to under

treatment. And particularly, you know, I see this with women who have FH, a millihipoclustral lemia who under-treated, because on average in the non-FH population, women tend to develop cardiovascular disease about 10 years later than men, somehow thought that pre-menopausal women for reproductive years are somehow protected. But we don't see this in FH, FH affects 1 in 250 individuals. It's autosomal dominant, which means women are equally affected as men.

And it's associated with a 20-fold increase risk of CBD. Women with FH have an earlier onset of AACVD, about 20 to 30 years earlier than women without FH. And they continue to be under treated, but notably in the FH population, women have the same age, early age of onset as CBD as men do. So they are not protected. They don't have this pre-menopausal advantage. And it's still really disheartening to me to see that these women who have very high genetic risk are, I'm not being treated because of concerns about pregnancy, which you can talk about, our management around there. But it's better to even have short interruptions

and treatment than to let these women who have genetically high, very high LDLs be marinating in this atherogenesis for decades and decades untreated, which, you know, dooms them to earlier onset morbidity and mortality, if not treated. Let's put some of these numbers to folks. I don't know if these are still the correct data, but the last time I looked, this was sort of a directionally correct. We use 65 as the dividing line between quote unquote young and old.

And the data basically suggested that if you consider all the people who are going to suffer a major adverse cardiac event in their life, and you consider men and ask the question, what fraction of men will experience their first event of the men who experience a major adverse cardiac event in life? What fraction will experience it before the age of 65? The answer was fully half. Again, this is to dispel the notion that cardiovascular disease is an old person disease because I don't think most people would consider someone who's 60 years old to be old by today's standards. And even in women, to your point, who have this time shift of about one decade, still one third of women who will experience a major adverse cardiac event

in their life will do so before the age of 65. Those were the data about five or six years ago. Do you believe that that is still the case? Yes, unfortunately. Women of reproductive age are still at risk for ASCVD. They may be lower risk on average, but they're still at risk. And they're less likely to be treated. When you look at the data from like the young

and my, young myocardial function cohort before the onset of their myocardial function, you know, women were less likely to have been treated and perceived to be at lower risk. So this is really concerning about the under treatment of women and this presumption that they're lower risk. We know that smoking and diabetes, in addition to the FH, as I mentioned,

also eliminate any pre premenopausal advantage. It's not only really the magnitude of LDL elevation, but it's the duration of exposure. So, even exposure to mild or moderately elevated LDL for a sufficient number of years has increased the risk of ASCPD to an earlier onset compared to individuals who have had lifetime low LDL. And so by waiting to treat individuals until later of life, you know, you've left atherogenesis, you know, atherosclerosis, propagate unchecked during this time, is never too late to implement prevention, but prevention is better implemented when started earlier.

Yeah, there's two ways I try to explain this to patients, and usually at least one of them work. So sometimes patients will come in with some recollection of calculus, and you can remind them about the area under the curve and the integral, and you can sort of explain that an enormous driver of atherosclerosis is indeed exposure to APOB. On my podcast, the listeners of very astute, they understand that we're really talking about APOB, which includes, of course, LDL, but also the LDL, et cetera. And we say, look, it's really the time is the X axis. And APOB concentration is the Y axis.

You want to minimize the area under that curve. And to your point, that means starting earlier and lowering APOB or LDL cholesterol more. And the longer you wait, the more it puts the burden on you to really lower that APOB. So if that doesn't resonate, I think the other way that resonates with people is to think about saving for retirement, which is an ideal world you'd start saving in your 20s. And you wouldn't have to save an enormous amount if you were saving in your 20s, but you'd be chipping away at it and building up your coffers and generating a slow and steady incremental return and letting the effective compounding take its toll.

Of course, if you wait until you're 40 or 50, you're going to have to be more aggressive in your savings, and you're going to also require a higher rate of compounded return if you want to have the same amount when you retire. And of course, if you wait until you're 60, it doesn't return if you want to have the same amount when you retire. And of course, if you wait until you're 60, it doesn't mean that you can't have some sort of financial independence in your 70s. But boy, you've got to really sock away a lot of money, and you've got to really hope for some pretty impressive returns in the stock market. And so usually somewhere between those two explanations, people start to understand what you're saying and what people like Peter

Libby have said, which is it's time exposure to apobie. Do you get the sense that it also works that way with blood pressure and some of the other really clear causative agents for ASCVD? Yes, you know, you wouldn't take someone who has a younger adult who has a septal blood pressure of 160 and say, oh, you know, your 10-year risk is low in the next 10 years because you're only 30. So, you know, we're not going to treat you. We're going to let this high blood pressure continue on and damage your arteries and cause, you know, silent vascular damage. No, you would treat a 30-year-old who have elevated blood pressure. So this problem with

these 10-year risk in younger adults is that yes, younger adults are going to have a lower short-term risk of the next 10 years, but they have a high, you know, lifetime risk and that we do them a just service by ignoring these high values because they haven't crossed some kind of theoretical 10-year threshold with the exception of guidelines say, well, FH, we had treated it above 190, but a lot of patients have mild to moderate elevated cholesterol in younger age years that is not being treated. I tell my patients, I'm not just concerned about preventing a heart attack in the next 10 years. I want to prevent them from having a heart attack

over the next 40 years. And so this is where them from having a heart attack over the next 40 years. And so this is where we need to have much more focus on prevention. And this does emphasize the role of lifestyle as well and healthy dietary changes. And really, healthy lifestyle should really begin in utero. You just took a real page out of Alan Snydermann's

JAMA paper from a few years ago where he really just took aim at this ridiculous notion of 10-year risk being remotely helpful in young people. One of the exercises I like to do with patients is take them to the Mesa Risk Calculator page and basically demonstrate for them how much it's driven by age. If you go to the lowest end of that calculator, which I think is 40 or 45, There's almost no variable you can put in there that gets you to a high enough 10-year risk that you would trigger treatment 5% 10-year risk. Okay, now we need to act. Conversely, at a high enough age, there's almost no variable you can put in there

for which the risk is low enough. Another rich age is the biggest driver of risk. How do you think we got here? Because you've clearly, I think, identified the jugular issue, which is the time horizon of risk. And yet somehow, when it comes to lipids, we stick to it. And yet when it comes to smoking and blood pressure, we don't. We treat the causative agent when we're dealing with blood pressure and smoking. And yet we somehow ignore the causative agent of APOB when we're talking about lipids and focus instead on chimerizing. Well, I think part of the problem is, a randomized clinical trials,

do serve as our primary evidence base for guideline recommendations, and they're very, very important. But, you know, randomized clinical trials are expensive, and so you run them over, you know, generally a short time period, you know, five years and you want to enroll high-risk people that are going to have events over the next five years. You really can't feasibly do a randomized clinical trial for decades and decades and so by nature, these lower risk individuals and younger adults are not included in these trials, and then it comes down to the fact that we don't have data specifically for treatment in this population. But I definitely hone down on lifestyle changes, particularly in younger adults, and I think we're going to get into women

specific factors a little bit later and talk about pregnancy, but high adverse lipid panel elevated triglycerides, elevated total cholesterol and chronic hypertension and obesity, these cardiometabolic risk factors. If women are entering pregnancy at in poor cardiometabolic health, which the data shows that there's been an increase in this, you know, they're more likely to have these adverse pregnancy outcomes like preeclampsia and gestational diabetes that not only increase their risk of short-term complications at delivery, but also impact their risk even decade or more after their index pregnancy. Really, we need a shift improvement in cardiac metabolic health earlier in life, which means that in young adults and women of reproductive age.

I agree with that completely, and I want to come back to it in more detail. But I still feel like there is a double standard going back to what we talked about earlier in that we don't have a study that says not smoking if you're aged 30 to 40 is going to reduce your risk of cardiovascular disease. But yet there's not a physician out there that doesn't recommend smoking cessation to a person. The minute they pick up a cigarette, why? It's because we've identified causality. Once you identify causality, that's all that matters.

The same is true with blood pressure. We don't have a hypertensive study that looked at people age 25 to 35 or 35 to 45 where we reduced blood pressure and showed a dramatic reduction in events because they probably weren't going to have the events in the time horizon of the study. And so the reason it's very easy for any physician to treat hypertension in a 35-year-old is because they're treating the causal agent. And that's where I'm frustrated, Aaron, is we have the same level of causality for APOB. There is no ambiguity about this.

And yet we somehow have this double standard where we ignore the causal agent. I agree with you. We have overwhelming evidence that LDL is a causal factor in atherosclerosis. We have data from observational studies, from genetic studies, from interventional trials. It meets all the criteria for a causal factor. You can just ask me to speculate, you know, why, you know, I'm not sure why that there hasn't been a greater

uptick about treating in younger ages. And this focus on 10-year risk or I'll point out though and randomized clinical trials, none of the randomized clinical trials enrolled people on the basis of a 10-year cut point. The pooled cohort equation has never been tested in a randomized clinical fashion about treating people based on a pooled cohort equation cut point

versus another cut point. That was never been tested. You know, the trials have specific enrollment criteria and they really weren't based on tenure risk scores, they were based on other factors. And so this over reliance on tenure risk scores. But I will say that we have made some progress. And I was really pleased.

I was a co-author on the 2019 ACCHA Primer Prevention Guidelines. We do acknowledge the limitations of these 10-year risk scores. They can both overestimate risk in certain populations, such as older adults and those with higher socioeconomic status, and they can underestimate risk in other populations, such as those with more social deprivation and these other unique risk factors that are not captured in these 10-year risk score. And so they acknowledge this.

They still feel like you should do some kind of risk assessment as a starting point and very low risk individuals less than 5% 10-year risk. Lifestyle may be enough and high risk individuals above 20% 10-year risk. You want to use your high intensity stat and lower LDL by 50% or more. But they do allow room now for the borderline intermediate risk to consider these risk enhancing factors, of which APOB and Libertal A are some of them. But I also was really pleased that they've acknowledged

these female specific factors that we'll talk more about early menopause and adverse pregnancy outcomes like pre-clampsia. And so the presence of these risk enhancers in those of borderline intermediate risk would so the presence of these risk enhancers and there's a borderline intermediate risk, and would favor the initiation of statins. And then if there is still uncertainty about risk, even after you estimate 10-year risk and consider those risk enhancing factors, you can get a coronary artery calcium score to help refine risk a little bit better and guide

share decision making. So my practice, I use a lot of coronary calcium scoring and particularly for elevated score, I'll even treat individuals similar to secondary prevention population. But we know that even that doesn't work very well in the younger population that we're talking about less than 40 because it takes time for plaque to calcify. And so a zero calcium score, a young adult,

isn't as reassuring as a zero score and an older adult. You know, they get they might be at low risk. The short term for sure, but they may still have high lifetime risk. We've gone back and forth in our practice about how to use calcium scores. And I think come to the same conclusion you have, right, which is that in a young patient, frankly, I would say younger than 50 truthfully, I don't know that a zero calcium score tells me much. First of all, we know that 15% of zero calcium scores are false negatives anyway. If you do a CTA, a CTN, a gram listener, you're going to see

a calcification that was missed because the CTA has much finer slices than the CAC. Or you're going to see soft plaque. In fact, one series found that I think almost 2% of zero scores on CACs actually had hemodynamically significant lesions on CTA. But even if you put aside the false positives, or the false negatives, rather, to your point, the physiology of the disease tells us that's the wrong metric to care about. It's more interesting, I suppose, when you have perfectly clean CTAs in 70-year olds with hyperlippidemia to which you can say, well, look, clearly this person has other factors that are protective. We might not understand what they are. And this is a patient in whom aggressive treatment probably isn't necessary, especially if they don't

feel that if the patient themselves doesn't want it. So let's now talk about this thing that you've brought up on two occasions, which I think is really important if I'm understanding you correctly, which is if we think about the lack of progress or the regression in progress, I guess, that's been made over the past decade. Am I understanding you correctly that it has been less about a reduction in treatment for the preventative measures of AACVD and more about the increase in the background metabolic dysfunction or have both of these things been happening together. Well, both of these things have been happening together. In terms of treatment, individuals are still under treated.

We see this over and over again in registries. If you look at even the highest risk patients, that's just those with AACVD from the gold registry in the US and the Santorini registry in Europe. Patients are not at goal with their LDL and they're under treated. You know, in the gold registry of US patients with AACBD, more than two thirds remained with an LDL above 70. And we can argue that maybe they should have their LDL is low as 55, but we even use a threshold of 70 as the goal

for initiating a non-statin therapy to a statin. Two thirds were above this goal, and over a two-year period, only 17% had their lip-alowing therapy intensified. So there's this credible inertia. So patients are not at goal. The use of combination therapy, including with PCS-Canine inhibitors,

is very underutilized as something like 6% in this cohort. And so we're certainly not treating with the tools that we have, which is really disheartening. But also on the backdrop of this, we've all seen the US maps about the epidemic of obesity, and along with that comes diabetes. Another disorder is related to insulin resistance, including worrisome trends with increasing returnal mortality, rising rates of gestational diabetes, which is increasing worldwide. And so the Cardi metabolic health of the US population is getting worse over time. And so we're shifting more morbidity to younger and younger age groups, which is not a good thing at all. And likely going to affect anticipated life expectancy trends to

reverse. So where and obviously these trends that you're observing, the increase in obesity, the increase in insulin resistance, the increase in type 2 diabetes, although you didn't state it, it's embedded within here, the increase in Natholde and Nash, the increase in type 2 diabetes, although you didn't state it, it's embedded within here. The increase in Natholde and Nash, the increase, as you said, in justational diabetes. I mean, all of these things are basically growing out of metabolic syndrome. You could argue now, I don't know the latest stats, but do you know what fraction of people in the United States now have metabolic syndrome? I don't know.

I've had my head for metabolic syndrome, but it's huge. We know that diabetes rates are certainly going up with over one in 10 US adults having diabetes, and many with diabetes don't even know that they have it. So there's a latency and diagnosis. So this is all really alarming trends, especially when we have a lot of therapies we can do for prevention. But of course, one of the most important prevention therapies

I can describe for my patients is lifestyle changes. Even modest weight loss can have pretty significant impact on triglycerides and blood pressure reduction. So it's always important that we can talk about all the new exciting therapies we have for weight loss, like the GLP1 receptor agonists and the dual agonists, but really, you know, still emphasizing healthy lifestyle from childhood is still such an important strategy for prevention. So we know it's multifaceted. I don't think any serious commentator on this will point to one thing and say that's the culprit for why we're seeing this epidemic. But how do you rank order these things? So what is the causative driver in your mind for weight loss? How much of that do you think lies at the feet of lower exercise levels versus food availability,

hyperpallotability, specific elements within the diet? How do you start to disentangle this? Because I think without some level of granularity there, it becomes difficult to say lose weight. An overweight person shows up and you tell them to lose weight. That's not a particularly helpful insight. So in other words, to prescribe something insightful, we have to have some sense of what the etiology is. So how do you think about that? First of all, I'm trying to prevent or reverse the trends of obesity on a population basis. And so we put too much blame on the individual, but we have major societal and population problems with the easy access to poor quality food, these highly processed foods that are extremely palatable, but contain a lot of saturated fats and other additives and sugars.

The way our jobs are structured to be more sedentary and more on commute times, you know, having access to safe places to exercise and having time to do so and the increased stress levels in life. I mean, there's so many social determinants of health that have led to this problem. And there's a huge part of the country where there's food deserts where there's not access to fruits and vegetables, food swamps that are just really only available, cheap and easy foods are these highly processed packaged foods. So as individuals, we do have some responsibility

of our own life choices. Larger issues should be placed in regulation and policy on a population level. And then once an individual's already obese, it's much harder than to lose weight. We certainly talk about lifestyle changes, but obesity is far more complicated. There is all kinds of hormonal regulations. And it's not just as easy as calories and calories out. The good news for these individuals is that at least now,

we do have some new pharmacological agents that are beneficial in weight loss that do not have cardiovascular harm, like some of the older weight loss drugs, and may actually be cardiovascular beneficial. We know the GLP1 receptor agonist, at least in patients with type 2 diabetes, you know, reduces the risk of major adverse cardiovascular events and stroke. And so while we do

have an outcome trial ongoing right now in persons who are overweight and obese, but without diabetes, with the GLP1 receptor agonist, I'm anticipating this will also be beneficial for cardiovascular disease. So we have new options to treat obesity, but really trying to focus on prevention of obesity in the first place, because it's certainly not feasible to treat two-thirds of US adults are overweight and obese. The statistics are astronomical and they're astounding. So we really need to focus on population interventions. Which GLP1 agonist are we looking at now? Is it semi-glutide or Chosepatide? So they're different. So semi-glutide is a GLP1 receptor agonist

and at least in patients in type 2 diabetes, we have cardiovascular outcome data for the injectable, the subcutaneous dose. There is an outcome data on going for the oral formulation, but we don't have that data yet. So usually, I prescribe the injectable form. Now, serceptivide is a new kid on the block. It's a dual agonist, a GIP, GLP-1 receptor agonist. This has been approved also for diabetes,

although the outcome trial for diabetes is ongoing, the surmount outcome trial. But it also has been evaluated for weight loss and really showed dramatic weight loss, you know, up to 50 pounds in the highest dose, which is really remarkable. You know, we can't compare trials head to head because they were not compared head to head. But in the step trials with some agglotide, there was about a 30 or so pound weight loss. So terseptibide is not yet FDA approved for weight management, although it will likely

have this indication soon, but it is approved for type 2 diabetes. Somagletide is approved for both type 2 diabetes for reduction in major adverse cardiovascular events, but it also has a separate weight loss indication for persons who are obese with BMI above 30 or overweight with a BMI over 27 in the setting of one or more obesity related cardiovascular risk factors who need additional weight management after diet and lifestyle attempts.

So we have new agents now, which is really exciting, but getting back to, we need to do in a larger population to reverse the overall trends of obesity. Before we leave the GLP1 agonist and the dual receptor agonist, what is your best guess as to the mechanism by which they also reduce cardiac events if it indeed is beyond weight loss? In other words, do you think it's all due to the benefits of weight loss, which of course bring with it an improvement in metabolic health? Or do you think there's something specific there that's going on? And I would ask the same question eventually, although we don't have to discuss it now

with SGLT2 inhibitors. The GLP1 receptor agnus, you know, I don't know that we fully understand all of the benefits, on the mechanisms for benefits. But we know that the benefits of reducing major adverse cardiovascular events are independent of its A1C lowering. And these are interesting agents that in persons with elevated glucose such as diabetes, they lower blood glucose.

But in persons who don't have elevated glucose, such as those with who are overweight and obese who don't have diabetes, and a GLP1s don't cause hypoglycemia solo agents. So they only lower blood glucose in a glucose-dependent fashion. But the benefit on mace reduction, which has been shown to persons with type 2 diabetes, is independent A-winsy lowering. It may in part be related to favorable changes and other risk factors such as reduction in blood pressure

and weight loss, there's improvement in the lipid panel as being investigated also in a naffled as well. There may be anti-inflammatory effects, there may be anti-author sciotic effects, there also may be some effects. In the kidney, we do see a reduction in albinaria with these agents as well. They're really interesting, massive drugs.

So let's now turn our attention to specifically the physiology of women as it pertains to lipids and AACVD. So I think we should maybe to make it easier, at least start with premenopausal women. What's happening in a woman's body when she's 25? That's different from a man's body when he's 25, as it pertains to sex hormones and the interaction, therefore with lipids and other factors that impact the simmering process of ASCVDD. Sure. And first I just wanted to give sort of a broad statement. I'm glad that we're having this discussion about lipids and women and ACVD women because there are differences. You know, women are

not smaller men or have unique risk factors. Even among traditional risk factors, diabetes and smoking confer a greater relative risk in women than in men. And then women have unique risk factors that we'll talk more about throughout their lifespan that men do not relate it to menarchy when early or late in polycystic ovary syndrome and infertility, spontaneous pregnancy loss, parity, adverse pregnancy outcomes like preclampsia, lack of breastfeeding and early menopause. And in addition, chronic inflammatory conditions like rheumatoid arthritis and lupus

are more prevalent in women. So women have these unique risk factors that are female specific or female predominant. And cardiovascular disease also can be different in women, which is why we need more trials in women. Women are more likely to have aschemia with non-obstructive coronary disease, from coronary microvascular dysfunction,

or coronary vasospasm, they're more likely to have scat, spontaneous coronary artery section, and more likely to have stress cardiomyopathy than men. So we really need more data about treating cardiovascular disease and women. But let's talk about the life cycle that you alluded to in the beginning with your question. Esther Dial is the predominant female sex hormone in women of reproductive age that seems to

have the beneficial effects with lowering LDL and conferring some cardiovascular protective properties. But I should mention there's actually three types of estrogen. So ester dial, which is the predominant one in women in childbearing age, and this is the most potent form of estrogen. So ester dial is E2. So estriol E3 is the main estrogen, produced during pregnancy. And then estrone E1 is the only estrogen produced

after metapause is also the weakest estrogen. So you know, starting with puberty. P puberty is a process that starts in the brain. So, the hypothalamus in the brain suddenly begins to creating granada trope and releasing hormone or GNRH. FSH and LH levels gradually increase during puberty, which stimulate the follicule maturation and estrogen production and ovaries, and also the secondary sex characteristics like breast changes and changes in body composition. This gets to the point where then there's the onset of menarchy or the first mencies.

And so this is typically around age 12, and it's important to note that I treat adult patients, but why I even ask adult women about the onset of menarchy is because both early menarchy before the age of 11 and also late menarchy after the age of 17 has been associated with increased cardiovascular disease risk later in life. hearty metabolic imprinting that's related to this. There's lots of factors related to me onset of menarchy, but both social, economic and environmental factors as well as genetic factors, but elevated BMI is a risk factor for early onset of menarchy, which is why again, it's important that we think about healthy lifestyle starting in childhood. And I'll talk a little bit now about the menstrual cycle because many people don't know, but the lipids do change throughout the menstrual cycle, difference in little cholesterol,

you know, as much as 10 to 12 milligrams or desolate or difference. And so while most women are reproductive age who have lower LDL, this is not probably clinically significant in terms of ortho-genesis, it does a matter when thinking about the timing of measuring a lipid panel during the menstrual cycle. I think that's important to note. So during the menstrual cycle, you have the hypothalamus is releasing GNRH, which causes

the pituitary gland to release FSH. So FSH is acting on the ovaries to mature the follicles, and that the follicles of the ovaries is what secretes estradiol. And so estradiol causes the maturation of the egg and the thickening of the uterus lining and preparation for a fertilized egg to implant. And then the increased estradiol triggers the release of LH, which induces ovulation and release of the egg. So ovulation ends with a flickular phase. And then after ovulation, you're in the gluteal phase, where estradiol with progestin prepare the womb for implementation.

But if the egg isn't fertilized, the corpus luteum, which is secreting the progesterone, breaks down, so this leads to a drop in progesterone level in the beginning of the menstrual period. What does this mean for lipids? So after mences, total cholesterol and LDL increase rapidly after mences, and so they really peaked during this follicular phase. And then this is followed by a decline in the ludial phase,

which corresponds to the rise in the peak concentration of estrogen of progesterone. So when esterial dial is the highest in the menstruial phase, which corresponds to the rise in the peak concentration of estrogen of progesterone. So when ester dial is the highest in the menstrual cycle, this leads to the fall in total cholesterol and LDL. HDL is highest around ovulation. triglycerides didn't really have a consistent pattern during the menstrual cycle. So there isn't specific guidance.

And sorry, just to make sure I understood that Aaron, the difference between the peak and nature of LDL cholesterol is about 10 to 12 milligrams per deciliter, or is that total cholesterol? That was total cholesterol, but it mirrors the difference in LDL as well. So this was a study that I'm publishing on average, total cholesterol, they go from 158 to 168, where LDL on average went from 97 to 102. So, you know, they're not dramatic changes, which is why we don't worry about this too much, and women of reproductive ages who don't have a lipid disorder, but it's interesting to note, but if a woman is very high risk, like has ASCBD and we're trying to target these really intensive

thresholds, like LDL's less than 70 or even lower, it's useful to know that they do change throughout the menstrual cycle. So while there's no specific guidance around this, you know, I generally recommend clinicians measure the lipid panel during the men's seas so that it's ideally measured, monitored and compared at the same time during the menstrual cycle. So usually the men's seas is easiest to benchmark to. We do that when we're concerned with as women become paramedicosal and we want to start getting a sense of what's happening. We always use day five. So if the initiation amensives, even if it's spotting is day one, but we always just pick day five. And that way we have a really consistent view, specifically of FSH and Estradile. Progesterone is zero at that time. But the FSH and the Estradile really give us a sense of how close

she's probably getting to menopause. And then we correlate that with symptoms to sort of start to think about initiating HRT. But that's a whole other topic, which I'm sure we'll get to. In terms of lipid panel, it's good to be measuring on the same time each month. So if you're following the serial lipid panels and a woman for a reason,

so time me at around day five, especially if you're measuring other hormones. But yeah, so FSA would be at the highest during the early follicular page and then declines after ovulation where LH is low during the early follicular phase and then peaks around an ovulation which stimulates the egg to be released. At this point in a woman's life, she still enjoys this for all intents and purposes decade advantage over men in terms of a CVD risk.

So a 40 year old woman who is still ovulating is at a cardiovascular standpoint is a 30 year old man. Is that directionally what we would say prior to menopause? Yeah, I mean, on average, and again, people are not averages, you know, people are individuals, but on average, there is about 10-year offset of ACVD in women developing it later than men. And this may be because we'll talk about when we get to metapause, you know, with the loss of esterdial after metapause, LDL levels rise after metapause. And so that women may have higher LDLs a little bit later in life. You know many women tell me, oh you know I've always had good lipid levels and now they're higher, you know after menopause. And so when we get back to what we started with about the integration of

duration of LDL exposure in terms of cholesterol years, they may have had lower number of cholesterol years during their childbearing years and then higher levels later in life. And that might be why they have this offset. But again, you don't see this in FH and we don't see this as well in diabetes. And so each person is an individual. And so we do women at just service when we presume that all women somehow are lower risk or protected during their menopausal years because we started out this podcast talking about that we absolutely see mild-cardial events, not just things like SCAD, but we see actual atherosclerotic mild-cardial function events in younger women too.

So they're at lower risk but not zero risk. And so we take each person as an individual. And then there are things we need to consider related to contraceptions and PCOS that can also affect the lipid profile as well. Let's take each of those then, because I think they're both incredibly fascinating and highly prevalent.

So let's start with PCOS, tell folks what it is, maybe what the prevalence is, what we think the etiology is, and of course what the impact is on metabolic health and ultimately lipids. So, polycystic ovary syndrome or PCOS is the most common intercurrent abnormality of women of reproductive age. Estimates are about 5 to 13 percent of women in the general population, and it does affect women of all race ethnicities. It's categorized sort of by this triad of hyperangrogenism, ovulatory dysfunction, so irregular men'ses or anovulatory cycles, and polycystic ovary morphology.

So just having system ovary in itself is not enough for the diagnosis. You need to have these other criteria. It is a heterogeneous disorder in that there are differences in risk with PCOS. But really, if you talk about the classical PCOS that has the hyperandrogen form, this seems to be the one that is the most strongly linked with cardiovascular risk and the cardiometabolic phenotype.

So we really think that insulin resistance is hallmarking under the pathogenesis of this, that there is molecular defects in insulin activities and PCOS that leads to impaired glucose tolerance and glucose insulin resistance and hyperinsulinemia. Studies have shown that about 95% of obese women with PCOS and about 75% of lean women with PCOS has insulin resistance. So there is a lean PCOS phenotype while most women with PCS has insulin resistance. So there is a lean PCS phenotype, you know, while most women with PCS do have an elevated body mess index, not all women have an elevated body mess index. So, elevations in blood pressure and dyslipidemia pattern.

So, we see this, the triad of dyslipidemia with the elevated LDL, elevated triglycerides and low HDL, this metabolic syndrome pattern. PCS is associated with hypertension and insinine hypertension. And this is actually independent of BMI, but obesity increases the risk and makes the risk greater. And there is an association not only with increased subclinical atherosclerosis, I recently published a meta-analysis where we showed that women with PCOS were two full of more likely to have coronary calcium,

they're also more likely to have prodid plaque. But they're also associated with increased cardiovascular disease later life. And the variable estimates have varied across studies. And this is likely because how PCOS was defined, and how cardiovascular disease was defined. And so there is not quite consistent across every study, but on average, about 30 to 50% increased risk that we saw

in an umbrella review of a meta-analysis of future cardiovascular risk. Now, there's a little bit of debate about whether PCUS is causally related to CVD. This excess risk that we see seems to be more women during reproductive age. Once women are already after menopause, having a prior history of PCUS doesn't seem to confer the same level of risk. And likely because of all of the increased risk after the metapost transition with the low-estor dial and the more androgen phenotype after metapost,

probably outweighs or overshadows any prior risk really to PCOS. But there does seem to be this long-term risk, but when you look at Mendelian randomization studies, it does suggest that the elevated testosterone, the hyperangidine, the obesity, the higher insulin levels, insulin resistance, and lower levels of sex hormone binding glibulin do appear to have a causal relationship with PCOS based on genetics.

And so maybe that these are the mediating factors that link PCOS with future cardiovascular disease risk. Obviously, there's an enormous impact on fertility. Our multiple pregnancies associated with increased risk of ASCVD or decreased risk based on the estrogen. PCOS is associated with infertility, and this is one of the mainstay of treatment of women PCOS who are not wanting to become pregnant, of course, or contraceptives to kind of reduce the hyperandrogenism. We recently

published though a study looking at national data of pregnancies at delivery and we did show that women, you know, a PCS who did become pregnant, you know, they were at greater risk for pre-clampsia and many gestational diabetes and many cardiovascular complications compared to women with PCOS. So it's important to note that not only are they at increased risk, have decreased fertility and trouble getting pregnant, that once they do become pregnant, they are at increased risk of cardiovascular complications and delivery. So it's really important with PCS again that we optimize healthier lifestyle

and weight management may be really important to mitigate some of the cardiometabolic risk and I'm interested in women who are not trying to become pregnant or not pregnant. GLP1 receptor agonist may be promising to help with the weight management and the insulin resistance. We talked about that class of drugs.

And even statin therapy, they reduce some of the testosterone or the endogen associated risk. So that's what PCOS, but I think that you asked about parity in general. So when you look at parity or the number of live bursts, there does seem to be a J-point,, J-Shape relationship with higher parity, particularly more than four or five life-bursts being associated with subsequent risk of cardiovascular disease. The reason for this is not quite known. I showed in the Mesa study that women who had aestrogrammultiparty were much more likely to be in poor cardiovascular health later in life at middle-aged, older-aged compared to less-parrased women, you know, women tend to gain weight with each pregnancy, but there

may be also dysregulation of the dipokines that sets the stage for later cardiometabolic complications. And so this is why it's really important that we try to optimize women's cardiometabolic health before pregnancy and inter-pregnancy between pregnancies to prevent these long-term complications. So I went out and tell a woman that they can't become pregnant certain number of times, but I would really try to work with them to try to optimize their cardiometabolic health. I feel like your intuition is right there, Aaron. I've always found the epidemiology on number of pregnancies and disease X to be completely full of confounders, such to the point that I think the epi provides no insight.

Whereas I think the confounder you mentioned is the most obvious one, right, which is the more pregnancies a woman has, the more likely you could believe that she's having difficulty getting back to her pre-never pregnant state of metabolic health, not just weight, but overall metabolic health. And that would strike me as a greater risk factor. Again, I one can't know this without randomization. We're obviously not going to have that. So it probably shouldn't factor into decision-making. Well, mention that there are a couple studies, so the problem is most epidemiology studies don't ask men in the parody history.

They don't ask men in these questions, you know, they only ask them of women, but there were a couple studies where they assess number of children and men. Parody is actually a risk factor for CVD and men too. So this likely gets to your point about compounding by social economic factors and cultural factors, education factors that might lead a family to have more children rather than less.

But the risk does seem to be a little greater in women suggesting that there may be some true biological effects, maybe weight mediated beyond just compounding by socioeconomic and cultural factors. Let's talk about the impact of oral contraceptives, even outside of the case of PCOS. So if you have a young woman who wants to use OCs as a form of birth control, what is the impact that that, if any, has on her lifelong risk of ASCVD via the... Let's just say she's going to go on it for a decade, age 25 to 35, and then have kids 35 to 40 and then go through menopause at 50, is there some impact that that decade being on an OCP has on her down the line? You know, women of reproductive age may be initiated on contraceptions for various reasons. So it's not just pregnancy prevention, but maybe for treatment of menstrual

cycle disorders, PCOS, acne, there's lots of reasons why they might start oral contraceptive therapy. There's the risk likely, you know, depends so much based on formulation and type. So, you know, we can't link all contraceptives in one bin. Oral combined, hormonal contraceptives, the older formulations had much higher doses of estrogen. And so estrogen can increase triglyceride levels. It can lower LDL, which is a good thing, but it can increase triglyceride levels. What's the net effect, Aaron, on APOB? Because certainly the analysis I've seen suggest that once you correct for APOB, triglycerides below 400 milligrams per deciliter really don't mean anything.

Obviously above that level, you have to start worrying about pancreatitis, but that APOB was capturing that risk. It's interesting, of course, if you're only looking at LDLC and triglyceride, it's possible that a rise in triglyceride is problematic because that could actually raise APOB, as you now have to obviously increase the potential number of both cholesterol and triglyceride trafficking particles. I'm guessing that analysis isn't done, but do you have an intuition around it? No, I mean, of course, pregnancy also increases triglyceride levels a lot too, as we'll talk about. So preventing an unwanted

pregnancy outweighs at ease, slight change in your risk for these lipid changes with oral combined contraceptives. You know, I think the changes are relatively modest, especially since we're using typically now the lower estrogen formulations because it's really the more estrogen that a combined oral hormonal contraceptive contains has the greater impact of increased triglycerides. So I don't have that number for you

because it really depends on the formulation. You know, it's unlikely to have much impact in most women, but women who already have high baseline triglycerides to begin with, it can trigger severe hyper-trianglecyroidemia above 500. So this probably would not be the agent you'd want to use if your patient already has high triglycerides. probably would not be the agent you'd want to use if your patient already had high triglycerides. Now the transdermal combined oral hormonal contraceptives, the patch, is less likely to cause clinically relevant elevations and triglycerides. There's of course other

types of contraceptives, you know, and very high-risk women with established cardiovascular disease or women who have FH, who have very high LDL levels, these Tier 1 methods, the long-acting reversible methods like the IUD and the implant are safe and effective for most women who even have, you know, our high risk who have established cardiovascular conditions. You know, the progesterone-based ones like the marina with the progesterone releasing IUDs system, you know, they can marginally, you know, lower associated with lower HDL, but usually these revert back to preinsertion levels by one year. Most of the time for the IUDs, the triglycerides and LDL and the cholesterol ratios remain pretty stable. So I really don't think that the lipid changes are so much impacted by that.

And that's why we do tend to recommend the IED for women who have FH or cardiovascular disease that are higher at risk. Let's talk a little bit about pregnancy. I guess there's two things I want to chat about. The first is obviously what's happening to a woman during pregnancy. So probably share a little bit more than my wife wishes I would. But I sort of use myself and my wife is a guinea pig from time to time and just love checking labs all the time.

During, I don't know, one of the pregnancies. Maybe it was our second child. I probably checked her, you know, did a very thorough look at her lipids and lipoproteins and everything all the way through her pregnancy. I was shocked at how much her lipids rose during pregnancy. My wife is sort of one of those people who genetically has very low burden of APOB. So her baseline LDL cholesterol is probably 60 to 70 milligrams per desoleter or HDL cholesterol might be 80, 90 milligrams per desoleter. So triglycerides

of 40 milligrams per desolate. So from a lipid lipoprotein standpoint, she's pretty uninteresting. And I want to say by the third end of second beginning of third trimester, you know, she looked like she had metabolic syndrome without the triglycerides, but just from the standpoint of of some of the other stuff, tell me what, and I know we hate talking about averages, but can you give me just sort of a general sense of what's directionally happening to a woman during pregnancy with respect to her lipids and lipoproteins? Yeah, so absolutely. There's changes in lipid panel, which is why women with

known lipid disorders are recommended to have consultation with a lipid specialist prior to pregnancy. But, you know, even at normal pregnancies,, serum total cholesterol, triglycerides, LDL cholesterol, lipoportu little A, and HDL cholesterol levels, all gradually increase and as pregnancy proceeds, they peak during the third trimester. So you can have about a 25 to 50% increase in total cholesterol can be as much as 150 to 300% increase in triglycerides that probably, you know, relative increase the most and LDL increased by 66%. And so this is normal

physiologic changes because it's, you know, designed to promote accumulation of maternal fat stores. That's going to be a source of calories for the mother and the fetus during later stages of pregnancy and lactation. You know, the cholesterol increase is needed for uteroplacental vascularization, placental steroids synthesis, placental transport function. These are important physiological effects, but these changes when someone like your wife who started out, so it sits low cholesterol levels, these are generally felt to be non-authorogenic because they really do fall precipitively to pre-pregnancy levels following delivery. So pregnancy is not a good time really to get a baseline lipid panel because it's not going to be representative of what a woman's typical lipid panel is, but in women who have concern for lipid

disorder, having a baseline lipid panel before pregnancy is helpful so that you can know what to expect. And women with FH, you know, they have the same relative increases, but they're starting with such a high baseline level that the magnitude of elevation is even greater. You know, I realize I've been the linkant in letting us talk shop a bit too much. We haven't defined FH other than to note that it's familial hyperclestralemia. We also noted, I think, the incidence or prevalence of about one in 200. But we've been a bit delinquent in giving people the magnitude of what it is.

Can you just tell folks a little bit about how high a total cholesterol or LDL cholesterol, a person with familial hyperclestralemia typically has, and what the lifetime risk of ASCVD is in that population. Yeah, I think we mentioned beginning, it's about one in 250, one in 250 people have FH and it's being autosomal dominant that women are equally affected as men.

So the FH phenotype LDL above 190, you know, there are different scoring systems that you can look with additional criteria based on family personal family history of ACVD and genetic tests are available. And there's apps that you can download to determine the likelihood that your patient has, you know, definitely a probable FH. Just even having the phenotype of having an LDL above 190, which is not all monogenic FH, that is still associated with increased lifetime risk with a 20 to 30 year earlier onset of ASCVD and females. But if they have the genetic mutation, you know, having the monogenic mutation, their increased risk is even greater than their LDL value. So that's why genetic testing is really helpful, not only for cascade effects for determining

the risk of their first degree relatives and their offspring, but also because they have a greater risk even beyond their absolute LDL value. But so 30% of women with an untreated FH will have a mild heart-owned fraction before the age of 60. And this is why it's so important that we can't ignore FH. We need to know FH. We need to screen for FH. And we need a treat FH.

Women get the same onset of men that are on the female advantage. And probably because they're losing many years of statin therapy, because this concern about pregnancy and women with FH are under-treated, about pregnancy and women are with FH are under treated. I should know that when with FH don't have an increased risk of congenital malformations or pre-clampsia, which is good, they may have a slight increased risk, greater risk from aquanel friction, so we can talk about shared decision making about treatment during pregnancy

versus, you know, withholding for a short period of time during pregnancy and lactation. But interestingly, in some countries, you can actually test for the mutation in cord blood and lipid levels in children with FH are similar, whether they inherited the gene from their mother or the father. But for contraception, because of their increased risk for atherosclerosis, you know, we would want to avoid any higher estrogen compounds, either use low dose estrogen or contraceptives are preferably IUDs or barrier techniques, especially if they're over the age of 35 to kind of avoid the

estrogen oral agents, even low dose and consider the IUD for contraception. So of course, most people with FH, we don't really know the genetic cause of this. In the last I checked, there were probably more than 2,500 different genetic mutations that produce that phenotype. So this is an interesting point that there's still value in looking. In other words, just having that phenotype, how many of the genetic drivers of FH do we know and contribute to that very interesting

point you made, which is, I definitely, that specific genetic driver carries with it even greater risk than is embedded within the LDL? When I see patients clinically for evaluation of FH, I do send them, they're willing for genetic testing, you know, trying to discern whether they have the monogenic FH from a mutation in the LDL receptor or epopi or PCS canine, or spole genetic risk can have a similar phenotype to FH. We certainly want to reduce their lipids. So this comes up, you know, because we were talking about pregnancy

and you know, there had been so concerned for so long about, you know, avoiding statins and pregnancy for a while, had that category X. And so this actually led to overabundance of caution with just not treating women of reproductive age with statins at all because of fear that they might accidentally become pregnant. And then we really, of course, do them to service

of a third economy at risk for an MI before the age of 60, if they have FH and and we don't treat. Especially because now, we have more data suggesting of studies of women who did become pregnant while on statins that did not show the trotogenic effects. And so statins are probably not trotogenic. We don't have a ton of data here, which is why we still have some caution,

which most women who are planning a pregnancy, you know, we do generally still stop the statins during conception, during pregnancy, and during breastfeeding, as shorter term interruptions is better than, you know, not treating them for decades and decades, but with the removal of the strongest warning label by the FDA, this does give us some more flexible options. So in patients that very high risk, such as women who had a recent acute coronary syndrome, was part of shared decision making,

we could consider using statins during pregnancy. But we still have less data. So for most women, we're still stopping the statins. But if they do become pregnant, you know, I usually reassure them. And we just stop the statin once pregnancy is become aware. But I think there's a really interesting body of work now about whether statins can actually prevent preclampsia. So in the setting of preclampsia, there is this abnormal trophoblast invasion, and this leads to impaired spiral artery remodeling. So essentially, what's happening is there's placenta ischemia, and this sets off a whole cascade of

adverse hormonal and anti-inflammatory markers. So we have this increase in Eslip 1 and a decrease in placental growth factor, there's this increased sensitivity that angiotension 2 is other inflammatory and oxidative stress. And this sets the stage not only for complications during the pregnancy like preclampsia, but also is likely contributing to vascular damage that increase a woman's risk long term after delivery. So stethans are being investigated for know, investigated for pre-claims

supervision because we know in animal studies, they can decrease S-lit-1, they can improve an ethereal function, they can decrease inflammation and oxidative stress. So, they seem promising. There was one study that was published where they gave women for pregnant who are increased risk of preclampsia, Pravastatin starting at 35 weeks gestation and didn't show any benefit in preventing preclampsia,

but this isn't really surprising because it was just given way too late. If you know anything about the pathogenesis of preclampsia, preclampsia can generally start after 20 weeks of gestation. So you likely would have to intervene much earlier in the process. So there is a randomized clinical trial ongoing now, I'm rolling about 1,500 women who are high risk because of a prior history of pre-clampsia. And they're starting the statin, pre-glampsey versus placebo earlier around 12 weeks of gestation. So right after the first trimester,

the primary outcome is going to be a portion that developed pre-clampsia or frittino loss and maternal death. And they're looking at other things like pre-term delivery. So it'll be really interesting to see those results. We don't have those results yet, but it may be a whole pendulum switch from this absolute avoidance of statin-string pregnancy to maybe actually using statins for preeclampsia prevention if this trial is successful. Do you think broadly we're seeing a greater trend towards statin, I don't know, phobia for lack of a better word?

Well, yes, even in sort of the non-pregnant state. I meant even more broad, yeah, exactly. I meant just across all of your patients. First of all, I think there's some misconceptions out there that I still hear people cite this false statement that statins don't work in women in primary prevention. And that's completely not true. In the older studies, they just didn't enroll

enough women in trials and in primary prevention, they're at lower risk, so they're less likely to have events during the short terms of the trials. But you know, now we have enough trials, the data is in, and meta-analysis that included, you know, over 18 randomized clinical trials over 40,000 women have shown that statins benefit women in both primary and secondary prevention

without interaction by sex. So meaning in similar risk individuals, women benefit from statins just as much as men in both primary prevention where there was a 15% reduction in major adverse cardiovascular events as well as for every one million more per liter or 39 milligrams or just later lowering of LDL and in secondary prevention at a little bit greater 22% reduction as well as all cost morality was lower and women was statin. So women benefit from statins. What's the NNT on both of those, Aaron? I would have to get back to you from the meta-analysis. I don't know off hand, but of course, the NNT is going to pen on primer prevention versus secondary prevention. And of course, the women that were enrolled in these trials were at higher risk. But the important thing is that they benefited similarly to men with no effect interaction.

That's what I was kind of getting at. Was it in the ballpark of men where your primary prevention could be anywhere from 6,200 and your secondary prevention might be 30 to 50? Does that sort of, those numbers kind of ring a bell to me? That sounds about right. I just don't have that data right in front of me, but that sounds about right.

I can look that up for you. But despite the evidence clearly showing that they benefit to get back to your original question, women are less likely to be offered a stat and we saw this from the palm registry. And if offered women are more likely to decline or discontinue and the usage registry, women were 30 to 50% more likely to decline or discontinue. And the usage registry women were 30 to 50% more

likely to report, statin associated muscle symptoms, and stop statins for this reason. Even in secondary prevention, studies of individuals who have post-mial cartoil infarction, young women under the age of 55 were significantly less likely than men to be on a statin two months after their MI, you know, and these are the highest risk individuals. The reason of my and women are still less likely to be on a statin. I know one of my own studies, usually nationally representative data from the medical expenditure panel survey is weighted represent US adults with ASCVD.

So it's weighted represent 11 million women with ASCVD. Women were 45% less likely to be treated on the statin than with men. So we know there's lots of... Aaron, how much of that do you think is on the shoulders of the physician for either being ignorant or just, I guess, ignorant will be the only excuse not offering the statin versus how often is the physician doing the right thing and the patient as a woman specifically is saying, you know what, this is doing the right thing and the patient as a woman specifically is saying, you know what, this is not the right thing for me.

So the palm registry shows women are less likely to be offered and so this is on the physician side. We see this across all kinds of subgroups in both primary prevention, secondary prevention, and also whether they're treated by, you know, cardiologist or primary care, you know, women are less likely to be on a statin. But if offered, if the clinician's doing the right thing

and offer women are more likely to decline or discontinue, this is a combination of things, you know, women may still perceive themselves to be lower risk, women may be more fear adverse. They also, women are report more likely to have statin associated muscle symptoms. And so this gets down to how much is real versus the new SIBO effect.

Is it biological differences related to women's smaller body size, influenza hormones, or is that maybe women are more socialized to report symptoms or read these warning labels or a possible symptom that could happen or be more concerned. I mean, we have overwhelming data about the safety of statins. Serious muscle injury is one in a hundred thousand and randomized clinical trials. There's no difference of muscle symptoms between treated and placebo. But we know in real world practice, you know, up to 30% of statin treatedtreated patients were report muscle symptoms.

So there's this tremendous nocebo effect in trials like the SAMHSA and trial up to 90% of statin-associated symptoms was elicited by the placebo too. So patients were having symptoms on the statins, but 90% of those symptoms were also elicited on the placebo. So it really wasn't as more the act of taking the medication compared to the medication itself. So we know the no-sebo effect is real, but the problem is is that this can be challenging

to counsel, there's a lot of medical misinformation out there. And when an individual symptoms are real to them, and if they're convinced they're having these symptoms, it can be hard to break that mindset. My practice is all about building trust, and we build a relationship over time, and sometimes I start slow or do alternative doses for the other day or three times a week and trying to get individuals back on their statin and show that they tolerate them and have them take

a muscle symptom survey and show that a lot of the aches and pains that they have, you know, were unrelated to the statin. But the good news at least is that we're least in an error that we had more options than we did before. Though all individuals who have report status-associated muscle symptoms are statin intolerance, you know, really should be given a re-challenge for our highest risk patients. We have other things, Zedabai, we have the PCS-K9 inhibitors, we have Clizor and Bepidobic acid, and more things in the pipeline. So have ways to get to LDL goal if patients are willing to work with us. And while these other therapies are meant to be as an adjunct to diet and lifestyle and maximally tolerated statins,

for some patients, the maximally tolerated statin is zero statin. And so sometimes we have to move to some of these other agents to get their LDL under control. Aaron, what's your statin workflow? How do you work through a patient with a statin? So my behavior on this front has evolved a little bit in part just due to experience,

but also in part due to the arrival of these other agents that you mentioned, the big three being, is that in my PCS-Canine inhibitors and most recently, Pepandobic acid. But these days, I really find myself only fiddling with about three statins truthfully. And this excludes patients who show up on one already that they inherit, so a torvastatin or something like that.

But in terms of a naive patient, I would say it's really mostly two. It's really rizuvistatin and then patavistatin with occasional previstatin. You can imagine obviously the order in which we do that based on symptoms and need. Walk me through your thinking specifically for women. So woman comes in, doesn't have FH, family history is notable for atherosclerosis, but nothing incredibly premature before the age of 60. Her APOB is the 70th percentile, concordant with her LDL C. And after months of being your patient, she says, you know, okay, I sort of buy this thesis, which is 40 years old.

My LDL is only going to go up from here. So let's start to take preventative measurements. So this is true primary prevention in a relatively low 10 year risk patient. And you have no reason to be concerned with anything else. So what's your first line agent? What dose and how do you proceed if there are issues? The highest risk patients, look at back to your primary infreentropatients, the highest risk patients with ASCVD,

you know, we want to, I'm gonna say get as low as possible, as quickly as possible, lower for longer for faster. And so we do a lot of disservice by starting these really low dose statins, and they don't come back for six months to a year, and then they never get intensified,

and patients don't get to goal. So if the highest risk patients starting with a high intensity statin, if you start up front, that's more likely the dose that they'll stay on, and use of combination therapy early. So, you know, just like blood pressure, if it's above 160, you know, we're thinking combination therapy for blood pressure, and I have the same approach, really, for lipids, for very high risk patients, such as the ones with a recent coronary syndrome, that we know what their starting LDL is and where we want to go. And I always try to aim for at least less than 55 optimal LDLs, probably around 30 or

lower these patients. If where you need to go, high-intensity statins will lower the LDL by about 50 percent. But if you need a greater reduction, thinking about combination therapy up early, we have some data now about the safety of giving PCS-9 inhibitors, even in the hospital setting after an acute malcharnial infarction can have important changes in plaque stabilization and plaque reduction, so being very intense about those treatments. I want to make the plug about using combination earlier and more aggressively. And you're a lower risk primary prevention patient that you started with. The modern tensi-statin would be fine. I mean, it depends on their age. If it's a man over 40, or women over 50, get a coronary calcium score. You know, if they're above this 75th percentile,

also thinking high-intensity statin and naming for an LDL less than 70, which is also consideration of PCS canine inhibitors, even in primary prevention patients, if they have significant, black, you know, very high calcium scores above 300. But, you know, in a lower risk person where we're just trying to shift them some lower. And so we're just going back to that, Aaron. I know it wasn't my question, but since you brought it up, is your preferred two line out of the gate, Resuva statin, and is that amide? Is that your typical starting one, two punch? I mean, again, it depends where they are and where we start with. They're very high risk. They have A, C, B, D, and they're very high risk. You're going to go PCSK9 plus. Yeah, especially if they have elevated liportutal A, because statins, Zedemide, Bempidoc acid,

don't lower lipartutal A. So if they had an ACVD event, it used to be to get the PCS-Q9 improved that you had to be on statin and Zedemide before you could get the PCS-Q9 to prove. So I used to use both just knowing that I'm going to move to PCS-Q9. Now it's a little bit easier to get the PCS-Q9 approved even if you don't have a Zedemide on board. So these very high risk patients, because Zedemide, you know, you can lower LDL, Y, about, you know,

16 milligram for a desolate, but you want to really get the LDL way down in these very high risk patients. I'm moving pretty quickly to PCS Q9 inhibitors. But in lower risk and- Do you have a preference, by the way, between Praljuent and Repatha? You know, so they were never compared head to head. So they have a lock a map and all the rock a map had a similar 15% reduction in major adverse cardiovascular events and their respective trials, the four year odyssey trials. And they had similar reduction, like virtual a as well.

I tend to use a, I mean, I use whatever one I can get approved. So it often often depends on the patient's insurance mostly. If all things, you know, being equal and either one being approved, I probably tend to use more evalocomab because you don't have to do the dose adjustment. The sure-click pattern is really easy. We have our nurse and our clinic teaches patients and I have lots of patients on aliracomab as well. Closer in, you know, we're just starting getting experience with onboarding. Tell folks what that is.

So the PCS-K9 inhibitors that we were talking about, the Evalocamab and aliracamab are monoclonal antibodies. So PCS-K9 is a hepatic protein that's involved with LDL receptor degradation. And this was really interesting how quickly we moved from understanding from genetic studies all the way to translational studies and to the bedside. You know, we know that individuals with PCS K9 genetic mutations that were loss of function, these individuals had very low LDLs and very low risk of cardiovascular

disease at the lifetime, where gain of function PCS canine at high LDLs and increase CVD risk. So by inhibiting this protein, by inhibiting the PCS K9, it prevents the LDL receptor degradation so that there is an upregulation of LDL receptors on the surface of the hepatocyte, which leads to greater clearance of LDL at a circulation. Those were the modicule antibodies and we have not only do they lower LDL by about 50 to 60%, they also have some modest like RTA lowering or on 25%. But we have two outcome trials for your own Odyssey, for your being in stable ASCVD and Odyssey and patients with recent acute coronary citizen drum

that show that they also reduce major adverse cardiovascular events as we would anticipate. And we now have longer term data for follow up, which shows even after these trials and that earlier exposure to a Velocomab earlier exposure to a Vellacomab, to exposure to a lower LDL, has a legacy effect with continued lower risk of events. So I think that the trials were pretty short around two years and the curves were just started to separate. So I think with longer treatment, you would have had even a greater reduction.

As we're talking about women, I will just mention, I'm fortunate both of these trials, women were only about 25% of participants. Women start out with higher LDLs for various reasons. After menopause, women tend to have higher LDLs compared to men, but that they had a similar reduction in LDL with PCIS-Canine inhibitor therapy. In terms of MACE reduction, there was no interaction by sex, meaning that women benefited, these high risk women who either have AACVD

or RescQ Corner Syndrome benefited to a similar degree as men did. There was no major adverse event difference between the sexes of the women or more likely to report injection site reactions. So those have been available for a while and they're in the guidelines now as an add-on to statins in high-risk patients with AACVD or

hetersigas FH who need additional LDL lowering. I also use them in high-risk primary prevention such as those with high calcium scores who need LDL lowering. But in CloserIn is the new kit on the block. So this inhibits PCS-K9 but through a different mechanism it's a small interfering RNA, so it prevents the translation of the PCSK9 protein from being made. We have data from the Ryan 9, 10, and 11 trials, which was looking at LDL lowering, showing that again, women had higher LDLs at baseline, but they had similar reduction within Closarin. Notably, the mechanism in this little difference is that it's subcutaneous injection, but after

the first baseline in three months, it's given every six months. So it's designed to be given in a clinic setting as opposed to monoclonal antibodies, which people give at home. And the frequency of every six months may be attractive for adherence because you give it in the clinic only one more time a year than a flu shot and you can lower LDL by about 50%.

So it may be helpful for adherence. It has been approved for LDL lowering and we're starting to onboard it throughout the country and our clinics, but should be noted that we don't yet have the outcome data, the Orion 4 is the cardiovascular outcome trial that's ongoing. I anticipate with a 50% reduction in LDL that this will certainly translate into reduction in major adverse cardiovascular events, but we don't have that data yet. But these are all potential options for patients

that need more intensive LDL lowering. You can also mention Bepidoric Acid to round out the new drugs that are available. This one also might be interesting in women. So Bepidoric Acids is an oral drug. And so it locks ATP Citrus Lice, which is an enzyme in the cholesterol synthesis pathway. So it's upstream of HMG coase reductase, which statins inhibit.

It kind of works like in the pathway where statins work, where it blocks cholesterol synthesis. And so by blocking cholesterol synthesis, this leads to upregulation of the LDL receptor on the surface of the liver and more clearance of LDL out of circulation. But what's notable about this is that pro-drug, the enzyme to activate it's only of the liver and more clearance of LDL out of circulation. But what's notable about this is that prodrug, the enzyme to activate it's only in the liver, not in the muscle. So it does not have the same reported muscle symptoms that have been seen with statins.

And also interestingly, it doesn't seem to have the risk of new onset diabetes or the increase in glucose that we see with high intensity statins. So alone, Bepidoic acid lowers LDL about 18%. So kind of in your range of a Zedamide, you know a little bit more lowering if it's used as monotherapy without statins, about 21% in statin intolerant patients. It does come as a fixed dose combination with a zedamide. And together with a zedamide, you see kind of greater about 36% reduction in LDL. So you're kind of getting in the range of your moderate to high intensity statins. Notably, actually in pooled

analyses from the clear studies, which were the studies looking at, you know, the LDL lowering effects of Bempidoc acid, we see that in ASED and FH patients that women seem to actually have a little bit even greater LDL lowering with lymphedoag acid than men, and they were more likely to achieve a 30% reduction in LDL with lymphedoag acid than men. Since women are more likely to have stat associated muscle symptoms, and this agent doesn't cause that. This may be a good choice as an oral therapy for women who can't get their LDL control on a statin or taller to statin.

So just for the audience, we don't have outcome data yet for this either. It's been approved for LDL lowering, but the big cardiovascular outcome trial clear outcomes enrolled a population with statin intolerance. And I was really pleased that nearly 50% of trial participants were women, likely because women are more likely to have statin tolerance. So this has been closed out and we're anticipating we may hear the results maybe in March of 2023, hopefully. Is this secondary prevention area?

No, this is high risk patients. They're have statin intolerance. So high risk primary prevention statin intolerant? Yes. And second prevention patients with statin intolerance. I got you completely off topic from our original question, which was low to moderate risk, low to moderate short-term risk. Obviously long-term risk, everybody is high risk. It's important to say that long time horizon where all high risk. Everybody gets at-risk grosses if you live long enough. But we've got our woman who's LDL cholesterol is 130 to 140 milligrams per desk a liter.

And she's in her 30s, she gets it, right? She says, look, nothing's gonna happen to me in the next decade, but I'm playing the long game here. I don't wanna have at-risk grosses in my 80s. What's your algorithm for statinin choice out of the gate? I tend to use one of the high and tensile statins that can, you know, a bit more potent LDL lowering, like a torva or a rizuba.

So if they don't have CKD, because it's important to note that rizuba does need to be dose-suggested if patients have chronic kidney disease, but assuming, you know, otherwise healthy individuals. Yeah, say she doesn't. I use a lot of rizuba. In my experience, they tend to have a little bit less muscle-sociated symptoms.

Psychologically, the doses, we do 5, 10, 20, patients feel like they're taking a lower dose when compared to the Adorva in a 20, 40, 80. Don't patient you can't compare milligrams from one agent to another agent because they're completely different drugs. People think they're completely different drugs. People think they're taking lower drugs, so lower doses.

So sometimes there's a lot of buy-in and I have a lot of patients refer to me because if they're a little bit statin-relectorin or statin-hezidin, so again, this is all in a background of lifestyle changes, but if they are concerned at all, sometimes I use just Resuba 5, it's more about buying their trust and getting them. You see the idea of taking a statin.

And we know even in statin and tolerate patients, even if we do RZUVA-5 milligrams three times a week, we still can have, if again, LDL lower and compared to no statin at all. So for patients that have been statin and taller or statin-relected, just getting them to take a low dose. And then seeing a little bit as believing. And so when we think about getting their numbers back and making progress often, then we can adjust up there based on how things are going, you know,

high-risk patients, you know, I started the highest dose right out the bat. Sometimes patients, I don't know, check vitamin D and thyroid levels and it co-ins on Q10. There really isn't very good data that co-inzyme Q10 prevents statin-associate muscle symptoms. But if my patients want to take that, has it make some feel better? I'm with the concept taking a stat and I don't object to it,

but I don't actively prescribe it because it really isn't good data that it really locks this. The same thing with vitamin D, there really isn't good data that taking a vitamin D supplement can prevent statin associated muscle symptoms by many patients. You know, I want to take that and, you know, my philosophy is if I could get them on the statin and at their LDL lowering, you know, I'm willing to work with them on some of these

other things, really trying to get their buy-in to get them on a therapy that will lower their LDL. And it's really important that I do refer them to our, we have a preventic cardiology nurse who discuss this nutrition, has I don't want them to think that I don't value diet and lifestyle. You know, we know that a lot of lipids

is predominantly genetically determined, but there is influence in diet and I want to emphasize to my patients that this is really a combination approach and that I do take diet and lifestyle, you know, very seriously as well. What type of an impact do you think you can see with manipulating diet, presumably mostly through the types of fats they're consuming, but more broadly, is there how aggressively can you use dietary manipulation, especially in a woman who, for whatever reason, be it pregnancy or just reluctance is hoping to minimize, if not avoid, the use of lipid lowering medication. No, about three, four, or 80% of LDL is synthesized by the liver, so there's, you know, is a strong

genetic component. I have lots of patients that are strict vegan and do everything right, and they still have high cholesterol, and they still have high cholesterol and they get so frustrated. And this is genetically determined. And if they had a bad diet, their numbers would be so much worse. And so it's important to note all the good things

that they're doing for the diet, but also acknowledge that sometimes they're gonna need a little help with pharmacotherapy because of the strong genetic determination. But around the other 20% is influenced by diets. So, diet does matter, particularly in young adults, we're thinking about adolescents in young adults, especially when they start earlier in life, if we can shift everybody a little bit lower in their LDL by following a healthy diet, really, since early childhood,

if we can shift everybody lower on LDL, this will reduce the total burden of years with LDL elevation. So we counsel about reduction in saturated fats and focusing on the healthier fats, the polyunsaturated, and the monoinsaturated fats, increasing fiber, fruit, vegetables, whole grains into their diet. I'm really trying to avoid processed foods, which are the worst, especially processed meats. There are some patients that have already have a CBD, and they don't want to take a medicine.

And at this point, it's too late. Diet's important, but you already have plaque in your arteries. You're pretty far along in the process. And we need to do everything to prevent further progression and even reverse. And we know from the IVIS studies that high intensity statins and significant LDL lowering can cause atthroma volume regression. So it's really a combination of pharmacotherapy and lifestyle changes.

But for a very low-risk young adult, I pushed as hard as we can with healthier lifestyle changes. You know, it's sort of funny. I've gone back and forth on this stuff so much, Aaron, and I probably sound like a heretic at the moment, but I just sort of went through and reviewed as many of the Cochrane collaboration meta-analyses as I could sort of stomach on all of the different fatty acid impacts on cardiovascular disease. So if you look at the Cochrane collaboration in 2019, that looks at the role of poofas and then the one in 2020 that looks at the SFA substitution with poofa and moofa. And if I came away from this with anything, it's that I don't know how much any of that stuff matters once you're in energy balance.

In other words, in the context of overnutrition, I think it all is bad. In the context of adequate nutrition, the ambiguity in these data were enormous. And, you know, I was left basically thinking, look, on the basis of predomed and the leone, heart study, in addition to some epidemiology, Mufas, probably the most important fatty acid. And therefore, let's just call it 50% of your fat intake should probably be Mufa. And you know, probably after that looks like Pufas a little bit better than SFA, but I certainly couldn't find a shred of evidence to suggest that aggressive restriction of SFA

was in any way protective. Now, of course, the opposite, which was you do see people that are consuming massive amounts of saturated fat and who have incredible hyperbeta, lipoproteinemia, you know, I think that's a clear problem. But, you know, when I think about all of the lifestyle factors, I wonder if the one that gets the least attention that has the greatest impact is stress. You know, because we don't have a pill for it, we can offset the harm of nutrition so much easier with pharmacotherapy. And yet, a person walking around with simmering hypercordislemia and the effect that that's having on their endothelium and, you know, their sympathetic nervous system, I feel like that's the one that I wish we had a

better handle on as far as how to help people. Because again, we don't have a pill right outside of blood pressure management. We don't really have a pill for that. What are your thoughts on the role of stress? It's such a dumb buzzword that I hate it, but I really think physiologically it's problematic. Well, first of all, I didn't say about aggressively low saturated fat diet. The guidelines, the HAACC guidelines, really, are talking more of a moderate fat intake diet.

And really, a Mediterranean-style pattern, as you alluded to, is what I recommend to my patients, maybe I'm biased, because I'm half Italian, I'm married to a Greek, but we do have both observational data and clinical trial data. Metatronial style diet is pretty palatable and it's pretty easy to follow without getting too crazy. And it's, you know, generally low in saturated fats and generally higher in the unsaturated

fats, lots of fruits and vegetables, but it's also the Mediterranean lifestyle with increased physical activity, more social connection and reduced stress. And I'll add in there the importance of physical activity, although exercise maybe has less impact on lipids per se than diet, it has significant impact on overall cardiovascular risk with both helping with weight maintenance, but also increased levels of fitness is being more fit as one of the strongest, favorable factors for lower cardiovascular risks. So I definitely encourage regular physical activity as well. So I do think mental health is very important that we also address.

You can't talk about cardiovascular health without talking about mental health. And I was a co-author on the American Heart Association statement that came out last year about the mind heart body connection, where we really talk about both positive psychological factors and negative psychological factors, both influence cardiovascular health, both in indirect ways and direct ways. So what do I mean? So in indirect ways, so individuals with more negative psychological factors like anxiety, stress, depression, anger, you know, they might be more likely to have poor coping habits such as they might be eating more poorly and

not getting physical activity and having more smoking or more alcohol intake, you know, and less follow up with preventive interventions. So it's sort of the indirect mechanisms where the positive psychological factors as individuals may be more likely if they have a sense of purpose and more optimism to be, you know, eat healthy and exercise and take their medications apart with preventive visits.

But there also may be direct mechanisms as well that stress leads to activation of the sympathetic nervous system, increasing heart rate, increasing blood pressure, increasing release of stress hormones like cortisol that can lead to more insulin resistance, more fat deposition, and the visceral cavities, and more low grade chronic inflammation. And we know that inflammation can also be a trigger for plaque rupture. So I do think it's important that we think about the whole person, and we can make all these recommendations about managing their lipids and things, but if we don't take into account some of the challenges that they have in their personal lives,

and social determinants of health, we may not be able to effectively deliver preventive interventions. Completely agree with everything you said. And sorry, didn't mean to apply that you were suggesting a low saturated fat diet. I was sort of saying that more just as broadly, you kind of hear these extreme views. I guess what I'm getting at building on what you would say is when I think of the five pillars through which we can impact a person's health. So nutrition, exercise, sleep, emotional and mental health, and pharmacotherapy.

The lowest impact, in my view, on cardiovascular disease is through nutrition. I think the other four trumpet all day, every day, and twice on Sundays. I don't even think it's close. And the reason I mention this, and the reason I'm on my soapbox about this, is I think the general public seems to think that nutrition is the most important lever in controlling

cardiovascular disease risk. I see this a lot, right? I see the person who ostensibly is eating, quote, unquote, a healthy diet, and yet they still have these biomarkers that are horrible, and or they even have evidence of clinical disease. They have a calcipation on their calcium score. They have soft plaque on their CTA and they sort of say, but look, doctor, I eat this, you know, I'm on this diet or that diet and clearly I've got it under control. And I sort of want to say to them, no, you don't even have it close to under control.

And your diet's not even remotely helpful at controlling this. And if it is, it's rearranging the textures on the Titanic at this point. Those other four things are going to move the needle far more in different amounts in different people. There are some people for whom I think, you know, the stressed thing doesn't play a role. And there are other people for whom I think it plays an enormous role. And every time I'm in Europe, I come to the same conclusion you do, which is especially in amazing places like Italy, which is hands down my favorite place in Europe, They're way more active, they eat less, and they just don't give a damn. Like, there's just a sense of it's all okay.

They're not so wound up the way we are. And I think that counts for, I don't know. I think that's 90% of it right there. Let's shift gears for a second. Let's talk about LP Little A. It's come up a number of times. And obviously the listeners on this podcast know the ins and outs of LP Little A. We've got a number of guests to talk about it.

But we've never spoken about it through two lenses. One is specifically through the lens of women versus men, anything we need to know. And also, I want to now talk about the role of LP Little A. You already alluded to it in pregnancy. You know, it isn't a cute phase reactant in a way. So you wouldn't surprise me that LP Little A goes it in pregnancy. You know, it isn't a cute phase reactant in a way. So you wouldn't surprise me that L.P. little A goes up during pregnancy. But I also want to talk about what happens

after menopause if anything. Sure. I'll talk about that. And then I do want to talk more about menopause. Because I think we talked about menstrual cycles and premenopause and PCOS and pregnancy. And then we didn't get to really dive into menopause. So, yeah, so I want to go back up.

That's where I want to go next. So, yeah, I want to go from this directly into metapause in the HRT as well, but I wanted to just close the loop on L.P. little A. So, Lifer protein little A. So I know you've talked about this a lot, but just in case there's any new listeners, I'll just briefly recap. It's an L.D.L. like particle that's comprised both of an APO B, which is, you know, Mark of the bad moieties. So it shares protein with other athergenic lipoproteins.

And then it also has an APO lipoprotein A moiety. And that's what distinguish lipotryl A from LDL. And this APO A is kind of unique because it has these 10 subdomains and these cringle four domains. And the cringle four two can expand two to 40 times. And so that's leads to a lot of heterogeneity in the population. You know, 80% or more of individuals actually carry two different isoforms of APOA, you know, one inherited from each parent. And so it's important to recognize this heterogeneity in the multiple isoforms because this accounts for

some of the differences in cardiovascular risk that we see by race ethnicity with higher lipotal A levels being seen in black and South Asian individuals compared to white individuals. But in terms of women, there are sex differences. So, lipotal A generally is 5% to 10% higher in women than in men, but there's changes over the life course where lipotal A is relatively constant in men, wherein women tends to increase after menopause. So it does increase during pregnancy, normal pregnancy between 10 to 35 weeks with about a doubling of the value during pregnancy.

And we think since the levels fall back to their pre-pregnancy baseline after delivery, that the short increase is probably not ather not authentic, but it does rise during pregnancy. So why don't we care about liporetile A? Well, it's pro-authorgenic, pro-inflammatory and pro-phromotic, and it's associated with cardiovascular risk. And as likely from Mendelian Ramanemization studies, you know, causally related to both ASCBD as well as calcific erotic stenosis. And even in individuals who have LDLs less than 70, like in the Copenhagen general population study, a liporectal A above 50 milligrams per deciliter is still associated with risk of cardiovascular beds. So it's still associated with risk, even when the LDL is low. And you really need to measure

it because if you think your LDL is low, you may be missing some residual risk, depending on whether lipotryl A is making up a significant component of that. And so Mendelian randomization studies do suggest that it is causally associated with cardiovascular risk in women, but the impact of therapies and lower liposol A and what that translates into actually lowering cardiovascular risk is a little bit uncertain. Right now we have a ferrisis for an option for patients with very high liposol A who have progressive cardiovascular disease. As I mentioned, the model clint of antibodies of a lock-emab and all the rack-emab as well

as in Closering can lower lipigil A about 20 to 25%. And it seems that actually in those trials that individuals who had the higher Lepigil A levels actually derive the greatest benefit from those therapies. So it is something that if somebody is elevated, Lepigil A kind of think about moving quickly to PCSK9, if they have another indication such as elevated LDL. And the reason why to measure it, we talked about it being a risk enhancer, but also because of these exciting new therapies that are being studied right now in trials, the Pelocarsin, which is an antisensit a nucleotide targeting and leperchial A and opusarine,

which is a small interfering RNA, also targeting the synthesis of leperchial A. And there's some other ones being studied as well, another small interfering RNA. So we'll have to see, you know, there's a cardiovascular outcome trial and going right now for Pelocarsin, the horizon trial,

to determine how much does lowering leperchial A actually translate into reduction in mace, and that one is trial is enrolling high risk secondary prevention population with elevated liporital A. Any concern that we're going to see a rebound increase in LDL with an anti-sensalagonucleotide, so when you knock out LPLital A, all of those additional LDLs that would have been L little A's just become LPL. So your APO B concentration stays the same, even though you've shifted the distribution

from between LP little A and LDL. I mean, I think this is why we need the trials. So with LDL, there is a pretty linear relationship that we can anticipate with the degree of LDL lowering, you know, by one millimil per liter or 30 net milling runs for desolate or with reduction in major adverse cardiovascular events being 20 to 30 percent. And this is why therapies like Bempidoic acid and Clisering got approved based on their LDL lowering properties, even without outcome data, because we have a pretty good sense of what lowering LDL

is associated with reduced events. We really don't have that data for Libertual A, other than modeling data. Certainly, it's associated with increased risk, but some modeling data says, you might need to reduce Libertual A as much as 50 to 100 milligrams per deciliter to have a meaningful reduction, A and CBD in the short term. And other therapies, for example, Nyson lower's liporchial A, but was not shown to have clinical benefit in two outcome studies. I'll be at those studies, didn't enroll based on liporchial A,

but we're not using Nyson. Same thing with hormone replacement therapy. Estrogen therapy, a hormone replacement therapy, does lower, as associated with lower lip therapy. Estrogen therapy, a hormone replacement therapy, does lower, as associated with lower liporja-a levels, but we're not recommending it for the sole purpose of liporja-a, because particularly in high risk individuals with ASCVD, or who, multirispectors, or many years out

from the menopause transition, this therapy has been associated with increased cardiovascular risk. So, you know, we really need the data. We know that these agents, Pelocarsin and Opusyrin, can reduce lipotel A by, you know, 80 to 90%, which is remarkable, considering, you know, statins, bempidoc acid, azenomide, you know, don't lower it at all. A statins may even increase it, you know, PCSK9 is only lower by 25%. So that's remarkable that we now have therapies

that work in terms of lowering a- but what does that mean in terms of vet reduction? And I think we've been burned from other studies like the C-TIP inhibitor and other studies that biomarker data is not enough and that you actually have to show that it can meaningfully actually reduce risk and so maybe Offsetting some of the LDL increase may be offset any reduction in benefit the other thing

I think which warrants further study is in epidemiology studies of very low liposal A levels Maybe associated with increased risk of diabetes. So what does that mean if you lower to very low liposal A level? But I don't know so we really need the trial data. Super interesting. I feel like Tom Deisbring recently sent me an analysis of Odyssey, which demonstrated that the greater the reduction in LP little A through the use of Praluewind, the greater the reduction in Mace. Am I remembering that correctly?

Yeah, so both in forrier and Odyssey, individuals who experienced the greatest reduction in Libertual A had greater relative at absolute reduction in Mace, major adverse cardiovascular events. So it seems to be that lower in Libertual A, may in part be an important mediator in the benefits that we see with these agents that it may just not be all due to their LDL lowering effects, but maybe also due to the

L-A lowering effects. So that's very encouraging when we think about these new agents, but you know this is modeling, post-talk analysis from these trials, and the PCS came nine inhibitors also lowered LDL. So when you now think about agents that really only target liposal A, is that gonna be sufficient enough to have a meaningful, significant reduction in major adverse cardiovascular events?

I mean, I'm hopeful, I'm really hopeful because I think it's causal. We know it's associated with risk. I'm really excited about the therapies in this area, but gotta show me the data. I gotta see the outcome data results. Well, let's talk about menopause. I'm amazed it's taken us this long into a podcast to get to it because it's such an important issue. It plays such a huge role in women's health, whether it be dementia, sarcopenia, osteopenia, you name it, but I don't think I've done a dedicated

podcast where we look at the effects of menopause on ASEVD. We've certainly danced around it today and we've shown our hands a little bit here, which is this is an accelerator of risk. Can you say a little bit more about why? Is there anything more to it than simply the loss of estradial leading to an increase in LDL? And if so, what's the actual mechanism by which that's happening? You know, we started off the program talking about hormone levels. So estrogen levels start dropping during parimenopause. And parimenopause can actually last several years before menopause. Metapause is one of those things you don't really know.

It's happened until it's after it's happened because it is officially sort of diagnosed when you haven't had a menstrual cycle for 12 months, which usually happens around age 51, but earlier onset of metapause, before age 45 or before age 40 is associated with increased cardiovascular risk. You know, with the primary estrogen of women are reproductive age, estradiol, and drops dramatically. And then there are the changes to estrone E1, which is the weakest type of estrogen formed in the adrenal glands and other adipose tissues.

By the way, Aaron, am I remembering my biochemistry correctly? Estrone exists in three variants, or it can be converted into four hydroxy, eight hydroxy and 16 hydroxy or two four and eight hydroxy, 16 hydroxy estrone. Is that ring a bell at all? And the reason I only bring it up is I feel like one of those was more thought to be involved in the creation of breast cancer. I'm not sure I can speak on that. I'm mostly familiar with just the three major subtypes, the E2 estradiol, the E1 and the E3, among estrone types. I apologize.

I don't know that data, except that it's a very weak type of estrogen. And so essentially, you know, women after metapause really have very low levels of estrogen. In fact, women after metapause have lower levels of estrogen than men do. Men have higher estrogen levels because of, they have much higher testosterone levels and they have increased peripheral conversion of testosterone estradiol. So actually men have higher estradiol levels than women after menopause.

Do you know my other favorite stat? That's a great one, by the way. The other favorite stat of mine is that even pre-menopause women have higher testosterone than estrogen if you actually convert the units to the same units. Some people think after metapause the ovaries are just not active anymore, but that's not true. Actually after metapause the ovaries continue to just don't make a survival, but they continue to produce androids to known and testosterone, so they keep making androgens, and really up to significant amounts until age 80.

And these androgens are what get converted and fat muscle tissue into estrone. So I mentioned this because a lot of my research has been about sex hormone levels after menopause, and we've previously shown that postmenopausal women who have higher androgen levels, who have higher testosterone to estrogen ratios, you know, had a more male-like pattern.

You know, they had greater risk of developing ASCVD and heart failure over the next 12 years. And this was even after we adjusted for risk factors like blood pressure, lipids, and diabetes. And we did a number of studies as well in the Mesa study, the multi-ethic study of other scroces, but we also showed that women with higher endrogens had more coronary artery calcium progression.

They had worse endylphilial reactivity. They had increase in concentric remodeling. All this adverse cardiovascular phenotype. And also, as I mentioned, we started out talking about PCOS earlier, but in PCOS, the risk here phenotype is the hyperandrogenism state and testosterone and interesting known and higher LH levels in PCOS as a marker PCOS. So getting back to menopause, a lot of things happen related to these hormonal changes. You have more visceral fat, deposition, and the abdomen, and more insulin

resistance. And this leads to this dyslipidemia pattern of increased triglycerides, increased LDL, and decreased HDL. There's more endothelial dysfunction, increased blood pressure, increased sympathetic tone. So we're a lot of cardiovascular risk and women is more linear with aging. So for the most part, blood pressure and diabetes risk tends to be more of an aging effect, rather than an over-effect.

Lippitz is one thing that really seems to be an over-effect that we do see relatively acute changes in the lipid panel following the final menstrual period with this rise in total cholesterol and LDL. I think we alluded to earlier that this may be one of the reasons that women tend to have risk a little bit later in life. And after metapause, it's because they tend to have this more dyslipidemia pattern a little bit later in life.

Now, this pattern, this increased risk, you know, had led this whole body of work about, well, these changes are harmful, maybe giving menopause hormone therapy would be beneficial. And of course, we did this for years. My mother used to be in hormone therapy. This is all well before the women's health initiative study, because we just felt that, you know, oh, well, you must give these hormones back.

There are favorable and unfavorable changes that we see with hormone therapy, basically this combined therapy. So some of the favorable therapy changes that you do give hormone therapy, basically this combined therapy. So some of the favorable therapy changes if you do give women estrogen, you will lower their LDL and increase CHDL and estrogen can have. And are you talking about oral estrogen or topical estrogen?

Systemic estrogen, which is oral and to some degree, transdermal. Vaginal estrogens don't have much systemic absorption. So, they're a really good option for women, you know, talk about which women to use hormone therapy in, but for women who just have the genital urinary symptoms, even a women with cardiovascular disease or history of stroke, or you can use vaginal estrogens safely.

And sometimes I think there's this concern about using them in high-risk women, but you can use the vaginal estrogen. So I'm really talking about oral estrogens here. They dilate the blood vessels through a nitric oxide effect, which you know, maybe all cardioprotective, but keep in mind estrogens also have unfavorable properties. So we know that estrogens can increase CRP, so women of higher CRP levels and estrogens are pro-thrombotic. I mean, this is why there is some increased risk with oral contraceptives, particularly in women who are older, reproductive age, and combined with smoking, and also during pregnancy, that estrogens

can increase pro-thrombin, decrease anti-thrombin-3. And we also talked about the estrogen-infects with triglycerides, same thing with oral contraceptives, which have higher estrogen levels, hormone therapy, all could increase triglycerides. So in higher risk women, particularly those that are farther out from the menopause transition or those with established cardiovascular disease, these adverse changes may outweigh any favorable benefits. And that's why probably the Women's Health Initiative

who had the mean age of 63, most of these women were quite far from the menopause transition. And the Women's Health Initiative also used an oral conjugated equine estrogen with progestin formulation that we saw an increased risk, including a two-fold increased risk of venous thrombloembolism. So this is why the guidelines all

changed and we don't recommend hormone therapy for the sole purpose of cardiovascular disease prevention because we have many other things we can use for prevention like statins. But the pendulum doesn't have to swing so far away that you look at subanalyses of these trials of women that were closer to the menopause transition younger women, we didn't see this excess harm. And so while a lot of women are quite symptomatic at menopause, you know, vasomotor symptoms

can be very disabling for many women with the hot flashes and the brain fog. In fact, vasomotor symptoms in of themselves when frequent or persistent are associated with cardiovascular risk. And so for symptomatic women who are under the age of 60 or within 10 years of metapause, who have symptomatic metapause, metapausal hot flashes or night sweats, consider hormone therapy. Women who go through metapause early, if they don't have other contraintacations, metapausal hormone therapy is recommended to at least the natural age of menopause or age 51.

But generally, we're not recommending it if a woman's more than 10 years out for menopause or over age 65. This is where the increased risks are emerging in these trials. And we want to avoid oral estrogens in women with a history of cardiovascular disease, blood clots, high triglycerides, gallbladder disease, or prior breast intermeachal cancer,

particularly the oral estrogens. There's probably a little bit less risk with transdermal estrogens, which are still systemic, but they don't have the first pass effect. But I, you know, I'm very work really closely with our menopause clinic as part of it, doing cardiovascular risk assessment prior to use of menopausal hormone therapy.

So when risk is uncertain, you know, I get a coronary calcium score to make sure that they don't have any calcified plaque. Their score is zero. I feel pretty comfortable with using hormone therapy in them for treatment of their vasemotor symptoms. But if they have significant auto-spotic disease, you know, I tend to not recommend it.

And again, if they're only having genital urinary symptoms, topical estrogen's fine, you know, the risk, you really probably depends on a lot of factors. It depends on when you start the hormone replacement, you know, your age at initiation. How many years you've been since menopause, your menopause age, how long you take the therapy, the duration, the type of therapy, the dose, and the route of administration. And probably your incoming health. The other thing I'm hearing here, Aaron, is this is another reason for young women, women in their 30s for whom menopause isn't even on the radar. This is another reason to be as healthy as possible and to do as much preventative work as possible.

Because if for no other reason, it gives you more optionality and menopause. My calculus on this is looking at a few things, and obviously quality of life is one, bone health is another, muscle mass, brain health is a huge one. So I'm kind of looking at it as heart health is not even on the radar, because to your point, we have so many better tools to reduce the risk of AACVD

that we don't need to rely on estradiol as one of those tools. It's basically a pea shooter and a bazooka fight. When we have big, big guns to reduce the risk of cardiovascular disease. So while we're really asking of HRTist to not hurt somebody, while we let it do its bazooka-like work, which

is going to be on the brain, bone health, vasomotor symptoms, eventually vaginal atrophy and things like that, for which we don't have alternatives. And so to your point, the difference between a 50-year-old woman who shows up with a beautiful CTA that's crystal clear, where we're going to have no ambiguity about this line of treatment versus a woman who shows up with a worry some CTA. And yeah, maybe even if we go to a trans dermal, there's going to be more hesitation, there's going to be more concern. And maybe that slight increase in risk, if it exists, is something we now have to weigh in the balance. Again, it all comes back in my mind listening to you to prevention is the key. It's it all comes back in my mind listening to you

to prevention is the key. It's just start early and be aggressive. And all you do is give yourself more options later in life. Yeah, absolutely. The risk is in women with established cardiovascular disease. So trying to prevent that plaque in the first place, you know, if there's no atherosclerosis, then the the vase of delitory effects and the lowering of LDL

may be helpful in preventing the initiation of atherosclerosis. But a woman who already has disease, and the slight increase in inflammatory markers, a pro-pharmotic effect may tip them over to having a faster event. So all in favourable about improving cardiovascular health earlier in life, you know, the really how we live the first half of our lives really influences our freedom from morbidity and mortality the second half of our lives. Any relationship with progesterone and lipids once we get into that menopausal state, obviously women who are on estrogen need to either take oral progesterone, usually these days it's done micronized, or we're even seeing them use progesterone coated IUDs

if they can't, but let's just talk about this systemic progesterone. Does that have any bearing positive or negative? Yes, I mean, we have to use progesterone if they have an intact mutorous. This may influence some of the, you know, again, we're not using these for cardiovascular benefit, but, you know, whether it offsets the benefit that we see from the estrogen. You mentioned, again, something at the outside of the podcast, which I think is an enormous

problem in all of medicine, which is the disproportionate shortcoming or shortfall rather of women in clinical trials, women as subjects. You said something funny earlier that's only funny because it's not true, which is women or not little men. Do you see that changing? I guess I just asked you to sort of think about it in your field. I don't expect you to speak about it in terms of fields and oncology or things like that. But when you think about cardiovascular medicine, be it on the lipid side, the hypertensive side, all fronts of cardiovascular medicine, are we seeing a more equal IE 50-50 distribution of

patients into clinical trials today, or are we still seeing it be more male-focused and therefore more underpowered to understand the effective interventions on women? So, for background, women areerralled in cardiovascular clinical trials, usually only 25 to 30% of trials. I previously published analysis, reviewed the literature of lipid lowering trials between 1990 and 2018. So this was just through 2018, so it doesn't reflect the more recent trials. But we showed the overall representation of women was only 29% in those trials.

Now for some things like a QCornary syndrome, you know, the prevalence is less common in women than in men. So we benchmarked it to something called a participation of prevalence ratio, where a ratio of one would be adequately representation to their prevalence of the disease in the population. And we showed that women were underrepresented with a prevalence, such a participation ratio, generally, 0.5 or less, meaning that even though if they had lower burden of disease, they were still under enrolled in trials related to this.

We showed also another analysis looking at cardiometabolic drugs through 2017 that had gotten FDA approval for new molecular entities. And again, it showed women only made up like 36% of those trials. And then in editorial we wrote, we looked at all kinds of different things, stroke, a coroner syndrome, heart failure, hypertension, and women throughout all these disease entities were under enrolled in trials.

Some things are getting better. I mean, there are, you know, I mentioned clear outcomes, which is nearly half the participants are women. I think this is because it's enrolling a statin intolerant population. There was some of the GLP1 studies like Rwine, which studied delaglitide. That was largely a primary prevention trial that had like 46 percent women. So those were encouraging. So I think there's some examples of some improvement, but women still, for the most part, we still see trial after trial being published, presented at ESC or HACC, and we're like,

where are the women? Why are women continually to be under enrolled? And one of the things I'm passionate about is I think that there's unfortunately an under-envolvement of clinical trial leadership. These steering committees of these trials have a birth of women cardiovascular investigators. There was a paper a couple years ago that looked at major cardiovascular trials, you know, published in the leading journals, New England Journal, Jamma Lancet. You know, only 10% of trial

leaderships, committees, were women, and more than half, about 56% of these trial leadership committees had no female representation on the trial. One of the trial steering committee were women investigators, and less than 10% had a woman in the first or last author position, which would indicate a senior leadership position. We know from other studies that the likelihood that a study will report a sex and gender-specific analysis actually is increased when there's more women authors of the study and more person-last-authors women. I think women tend to publish more about science related to women. So I do think it matters. There is some data from my work and some other work from other authors that have shown

a modest correlation. It's not perfect, but a correlation between the proportion of women authors, the trial, steering committees, and enrollment of women participants in trials. For example, we did this for A-Fib, and we showed that for every 1% increase in women authors, there was a 19% higher enrollment of women participants in the trials. I mean, there's a lot that we can do to tackle this. One of them is having more representation by diversifying study team and investigators. I think also we need to include more patients in trial designs, include more women in trial

designs, patient centered designs. We hear that women are approached, but often are decline participating in trials. I think women tend to be a little bit more risk adverse. This is where it's really important to provide education, to spell misconceptions, emphasize the benefits. Even if we don't know if a drug is going to be beneficial or not, there's a lot of benefits with being part of a trial because you have more access to gold standard care and more access to study investigators.

It's really important to include women in the design and try to understand some of these design issues, which may be not so obvious, you know, such as making sure there's no hidden costs that often people are paid for the drug or device, but there can be things related to transportation or time off work or providing, for childcare or other responsibilities, by having more flexible follow-up, more pragmatic trials or having your fall-up being online or by phone or by PCP, that may get over some

of the barriers to enrolling women in the trials, which I think can be really helpful. And making sure that the study designs are not so restrictive in terms of the inclusion exclusion criteria, that we shouldn't just exclude women of childbearing age, if they have a plan for preventing pregnancy, have an adequate contraception, women should be eligible for these trials.

Not to mention, we actually need more trials in pregnant women too. It's just important to understand what works and what's safe. And so there's a lot of barriers to overcome and this barriers need to be both with trial teams and trial designs, with the funding agencies, institutions, and even the journals that publish these trials should be questioning, well, there's not enough women in the trial. So we all need to do better. Randomized clinical trials is our largest evidence base and we want to make sure that something is efficacious but safe

in women and that women benefit to a similar degree as men do. Karen, you've run how many marathons? Oh, slowly. I'm already talented at it, but I've done like 38 marathons and I was trying to do one in every state as a goal. I'm really slow at running, so my only goal for these is just finishing as an accomplishment in and of myself. Are those 38 in 38 different states? I've done about 36 states, and then there was a couple states,

like Maryland, where I live that I've repeated more than once. Is that still a goal? You still want those other 14 states? Yeah, so of course I had taken a little bit, you know, I set back during the COVID. I had four marathons planned for 2020 and they all got canceled due to COVID. And without a marathon on the calendar, I got a little bit out of the habit of running with these long distances because I didn't really run by myself. I do it for the social support with my

running groups. And so without people or groups to run with. And then in 2021, you know, the marathon I registered for was canceled as well. And so I've gotten sort of out of it for a while, but I... It's really good that we're canceling outdoor exercise during COVID because I can. Well, it's back now. So events are back. So I am registered for a marathon in October next month. It'll be my first marathon again in three years. So I'm hoping to get state 37. Which state?

It's New Jersey, and most of the East Coast for this one I haven't done yet. And I've been back doing other races. I just did a 12 mileer here in Baltimore on Saturday last weekend. So races are back and they're fun and I just like participating, you know, you don't have to be good at a hobby, do enjoy it. So I'll never have many age groups or probably never qualify for Boston, but you know, sometimes it's just the act of doing something and

setting goals for yourself. And I love it. It's just fun. That's fantastic. Well, I have such fun memories of Baltimore. My wife is from there, so there's an additional fondness to it. But I guess more than anything, it's the time I spent there. It's great to catch up with you and it brings back memories by proxy at a minimum. I want to thank you for your time here. And this was really insightful. I learned a lot.

I think this is a podcast where obviously women will have learned a lot, but hopefully men as well, because if you're a man listening to this, you certainly know a woman. And therefore, you should be as concerned with her risk of cardiovascular diseases your own. Thank you very much for this input making the time and your continued work. Thank you for having me on your podcast.

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