The Peter Attia Drive - #230 ‒ Cardiovascular disease in women： prevention, risk factors, lipids, and more

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:47.780 here's today's episode. My guest this week is Aaron Mikos. Aaron is an internationally known

00:00:54.560 leader in preventative cardiology, women's cardiovascular health, and cardio obstetrics.

00:00:59.620 She's an associate professor of medicine in the division of cardiology at Johns Hopkins School

00:01:03.820 of Medicine, the joint appointment in the department of epidemiology at the Johns Hopkins Bloomberg

00:01:07.920 School of Public Health. She's also the director of women's cardiovascular health and the associate

00:01:12.560 director of preventative cardiology with the Johns Hopkins Center of Prevention of Cardiovascular

00:01:18.520 Disease. This is an episode that covers a topic that is obviously valuable to understand given

00:01:23.660 that atherosclerotic cardiovascular disease is the number one cause of death worldwide.

00:01:28.520 And while it's a topic we've covered in detail in the podcast before, I think it's an important

00:01:32.280 episode because we focus this conversation around cardiovascular disease and lipids specifically

00:01:37.720 through the lens of female biology. We discuss the prevalence of ASCVD in females as they age,

00:01:43.960 the importance of making interventions early in life, the risk of ASCVD over the course of lifetime

00:01:49.340 as opposed to the traditional view, which is to only really consider 10-year risk. We then probe

00:01:54.020 the ins and outs of CVD, lipids, and various lipid lowering medications across a female's lifetime,

00:01:59.180 including the premenopausal state, changes during the perimenopausal state, pregnancy, and menopause

00:02:05.540 and beyond. We also touch on a number of other subjects that affect females' risk of ASCVD,

00:02:10.640 specifically polycystic ovarian syndrome, contraceptives, GLP-1 agonists, nutrition,

00:02:15.700 metabolic health, familial hypercholesterolemia, statins, stress, HRT, and more. So without further

00:02:22.860 delay, please enjoy my conversation with Dr. Aaron Mikos.

00:02:31.880 Thanks so much for making time, Aaron. Look forward to this discussion. We have a lot to talk about,

00:02:35.900 but before we do, there's one thing I wanted to just check. Going through your bio, I realize

00:02:40.180 when did you do your residency in medicine? Because you also did that at Hopkins, correct?

00:02:45.560 Yes. So I've been at Hopkins 22 years. I did residency from 2000 to 2003, and then stayed on

00:02:54.280 for cardiology fellowship and then joined the faculty. So I've been on faculty over 15 years now.

00:03:00.580 I did my general surgery there. I was there from 01 to 06, which made me realize the probability we

00:03:07.540 haven't passed each other somewhere in the emergency room during residency is exceedingly low, right?

00:03:14.580 I'm sure we must've interacted because I was there all during that time that overlapped with my

00:03:18.940 residency and my fellowship. I always am amazed when I run into people who I know I was there with.

00:03:23.900 And there are certain medicine residents I remember very well, but just by coincidence,

00:03:27.920 you're always in the ER together, but obviously it's a huge program. So when you went into medicine,

00:03:32.860 did you know you wanted to do cardiology? When I went into medicine, I did. In college,

00:03:38.380 I actually didn't know that I was going to go into medicine. You know, there's no doctors in my

00:03:42.860 family. So I'm the first one. So I didn't really know what a career in medicine would be about.

00:03:47.400 So I started out my undergrad studies at Northwestern as a molecular biology major.

00:03:52.100 Through that, I interacted with so many pre-med students who are my classmates and their enthusiasm

00:03:57.160 about entering the field was really contagious. And I was doing a lot of bench science, which is

00:04:02.860 really a good experience. I think anybody entering science and medicine should have some bench lab

00:04:07.860 work experience, but I began to long for more direct clinical research with direct patient exposure.

00:04:13.420 So kind of late, I switched to being pre-med kind of my last year of undergrad and applied actually to

00:04:19.660 both the PhD and medical programs. And then when I started medical school, I really fell in love

00:04:25.760 in cardiology, even as a medical student before medicine residency. I have a real interest in diet and

00:04:32.300 nutrition and exercise and lifestyle. And we think that over 90% of cardiovascular disease is due to

00:04:38.740 preventable, modifiable risk factors. And there's, you know, so much we can do for prevention. And this is

00:04:45.080 why I really love being a preventive cardiologist. So when I entered medicine residency, I already had my

00:04:50.300 eye towards cardiology fellowship. You did the full three years of medicine, and then you did three

00:04:54.680 years of cards. I did four years of cards. Oh, you did? So no, I was on the slow track. You were on the slow track.

00:05:00.220 I did three years of residency, which is standard. And then our cardiology fellowship program was four

00:05:04.760 years because we emphasize research. So I did two years of research on a T32 program and cardiovascular

00:05:12.580 epidemiology. And that's where I got my master's in health science. You said something at the outset that

00:05:18.240 I completely agree with. And I feel like sometimes I'm banging my head against the wall trying to make this

00:05:26.760 point. You said, correct me if I misquote you, but something to the effect of 90% of

00:05:31.000 cardiovascular disease is preventable when you consider modifiable risk factors. Was that kind of the gist of

00:05:37.880 what you said? Yeah, that's the data from the inner heart study that 90% of myocardial infarction risk was due to

00:05:45.640 preventable risk factors. One of the things I tell my patients is that both in the United States and

00:05:52.020 globally, ASCVD is the leading cause of death. In fact, I was surprised somewhat recently, like in the

00:05:58.060 last year, to realize how much bigger the gap is between ASCVD and cancer globally than in the US.

00:06:04.240 It's number one in both. But when you look at the entire world, I believe it's about 18 and a half to

00:06:09.140 19 million deaths attributed to ASCVD versus about 10 or 11 million to cancer. It's almost 2x delta.

00:06:15.640 And when you take into account what you just said, that between smoking, hypertension, and

00:06:21.800 controlling ApoB, you could basically turn that into a disease that would barely rank on the top 10.

00:06:28.700 Does it surprise you that this doesn't get more attention?

00:06:32.040 Yeah, it surprises me. And I'm also really concerned that we're reversing these trends.

00:06:36.740 You know, the first statin, lobostatin, was approved in 1987. After that, along with efforts in smoking

00:06:43.200 cessation and blood pressure treatment, there was a significant decline in cardiovascular disease

00:06:48.160 mortality in men. During this time, unfortunately, CVD mortality was rising in women until around the

00:06:53.900 year 2000, when this came to attention that we need to prevent cardiovascular disease in women

00:06:58.320 as well. And after that time, there was dramatic decline in cardiovascular disease mortality in women

00:07:04.260 and continued decline in men. But unfortunately, in recent years, we are no longer making these strides

00:07:12.640 in progress anymore. In fact, we're no longer even stagnated. There has been a frank uptick in

00:07:18.220 cardiovascular disease mortality in both men and women due to the epidemics of obesity and diabetes

00:07:24.260 and cardiometabolic diseases. In fact, cardiovascular disease mortality is on the rise in younger women.

00:07:30.660 And when you look at rates of change, the fastest growing heart disease death rate is in middle-aged

00:07:37.000 women, age 45 to 64. So this is a particular group that needs more focused attention. So we really need

00:07:43.940 to double down on our preventive efforts. And it's really disheartening to see that we're no longer

00:07:50.000 making the progress that we used to. So if these trends are not overturned, you know, heart disease is

00:07:55.660 set to overtake cancer as the leading cause of death in younger women as well.

00:07:59.860 I'm really glad you made that point because when you look at what these things called in our

00:08:04.320 practice, we have these things called death bars, which is just an analysis that shows mortality

00:08:08.060 sliced and diced in different ways. But, you know, sometimes a graph just says things in a way that

00:08:12.760 it's harder to describe in words. And one of the things that does emerge from this analysis is that

00:08:17.560 in middle age, cancer is still the biggest killer. And of course, overall, cardiovascular disease is,

00:08:23.480 and in old age, cardiovascular disease and neurodegenerative disease dominate. But what you said

00:08:27.820 is very distressing, if indeed, now cardiovascular disease would eclipse cancer in even middle age.

00:08:35.280 So overall, I'm focused on women's health. So cardiovascular disease is the leading cause of

00:08:40.000 death in women. You know, women more often fear breast cancer, which is a terrible disease. My mother

00:08:46.220 had breast cancer. But far more women are likely to die of cardiovascular disease than cancer. But notably,

00:08:53.580 you know, in younger individuals under the age of 65, cancer is still the leading cause of death in

00:08:59.200 women. But one of my studies that we published in the European Heart Journal, we tracked death rates

00:09:05.160 in younger women under the age of 65 in the US, looking at CDC wonder data over a 20-year period from

00:09:12.180 1999 to 2019. And we showed during this time that actually cancer mortality has been declining in

00:09:19.060 younger women, which is a good thing. But since 2010, heart disease mortality is no longer declining,

00:09:26.200 and it's actually rising in these younger women at 0.5% per year. So it's actually narrowing the gap

00:09:33.160 between cancer deaths and heart disease deaths in the younger female population as well. So if these

00:09:38.980 trends are not overturned, as I mentioned, you know, heart disease is set to overtake cancer as the leading

00:09:44.200 cause of death in younger women, which is really discouraging, considering that we have so many

00:09:49.860 more tools now for prevention. And what was also really disheartening, I don't know if you saw this

00:09:54.620 American Heart Association survey that was published in 2021. But the American Heart Association has sent

00:10:01.100 out surveys over the years to women about their awareness of heart disease being the leading cause of

00:10:06.440 death in women. And back in 2009, you know, 65% of women reported that they knew that heart disease was the

00:10:13.940 leading cause of death. But in 2019, the more recent data 10 years later, only 44% of women reported

00:10:21.600 that heart disease was the leading cause of death in women, they're more likely to report cancer as a

00:10:26.200 leading cause of death. So this lack of awareness is worrisome. And it was particularly prominent among

00:10:32.220 non Hispanic black women and among Hispanic women, and also among the younger women demographic that we're

00:10:38.720 talking about, who arguably we can do the most for primordial prevention would be most

00:10:43.680 effective if started earlier. I also think there's kind of an emotional thing to this, which is even

00:10:48.800 if you don't pose the question directly, like a multiple choice question, I just find in speaking

00:10:54.740 with my female patients, so young female patients, I think there's a greater fear of breast cancer than

00:11:01.200 ASCVD, even though the mortality from heart disease is somewhere between eight and 10 times greater

00:11:08.040 than that of breast cancer. It's amazing to think that they would be more afraid of something

00:11:12.680 that has a log lower difference in mortality. What do you think explains that? Again, you can answer

00:11:19.600 this both through a personal lens through the experience with your mother, but also professionally

00:11:23.260 given what you study. You know, I think there's still this lingering notion that somehow heart

00:11:28.640 disease is a man's disease. The problem is, is women have historically been under enrolled in randomized

00:11:34.960 clinical trials. So we previously had limited data on efficacy and safety of therapies in women.

00:11:40.860 So both women think that they're at lower risk than they really are, but also clinicians. So

00:11:46.980 clinicians, even when given the same 10-year estimated risk or burden or risk factors, clinicians are more

00:11:52.560 likely to perceive women to being at lower risk. And this leads to undertreatment. And particularly,

00:12:00.300 you know, I see this with women who have FH, a middle of hypocholesterolemia, who are undertreated.

00:12:05.860 Because on average, in the non-FH population, women tend to develop cardiovascular disease about 10

00:12:13.140 years later than men, somehow thought that premenopausal women of reproductive years are

00:12:18.540 somehow protected. But we don't see this in FH. FH affects one in 250 individuals. It's autosomal

00:12:26.280 dominant, which means women are equally affected as men. And it's associated with a 20-fold increased

00:12:31.940 risk of CBD. Women with FH have an earlier onset of ASCVD about 20 to 30 years earlier than women

00:12:39.800 without FH. And they continue to be undertreated. But notably, in the FH population, women have the

00:12:46.460 same age, early age of onset as CBD as men do. So they are not protected. They don't have this

00:12:54.200 premenopausal advantage. And it's still really disheartening to me to see that these women who have

00:12:59.860 very high genetic risk are not being treated because of concerns about pregnancy, which you

00:13:06.680 can talk about our management around there. But it's better to even have short interruptions in

00:13:11.700 treatment than to let these women who have genetically high, very high LDLs be marinating in

00:13:17.980 this atherogenesis for decades and decades untreated, which dooms them to earlier onset morbidity and

00:13:25.560 mortality if not treated. Let's put some of these numbers to folks. I don't know if these are still

00:13:31.260 the correct data, but the last time I looked, this was sort of a directionally correct. We use 65 as

00:13:38.380 the dividing line between quote unquote young and old. And the data basically suggested that if you

00:13:43.720 consider all the people who are going to suffer a major adverse cardiac event in their life, and you

00:13:49.340 consider men and ask the question, what fraction of men will experience their first event? Of the men who

00:13:54.020 experience a major adverse cardiac event in life, what fraction will experience it before the age of

00:13:58.600 65? The answer was fully half. Again, this is to dispel the notion that cardiovascular disease is an

00:14:05.740 old person disease, because I don't think most people would consider someone who's 60 years old to be old

00:14:10.360 by today's standards. And even in women, to your point, who have this time shift of about one decade,

00:14:17.540 still one third of women who will experience a major adverse cardiac event in their life will do so

00:14:24.540 before the age of 65. Those were the data about five or six years ago. Do you believe that that is still

00:14:29.320 the case? Yes, unfortunately. You know, women of reproductive age are still at risk for ASCBD.

00:14:36.160 They may be lower risk on average, but they're still at risk. And they're less likely to be treated.

00:14:42.260 You know, when you look at the data from like the YUMMI, young myocardial infarction cohort,

00:14:47.660 before the onset of their myocardial infarction, you know, women were less likely to have been

00:14:51.920 treated and perceived to be at lower risk. So this is really concerning about the undertreatment of

00:14:57.680 women and this presumption that they're lower risk. We know that smoking and diabetes, in addition to

00:15:02.700 the FH, as I mentioned, also eliminate any premenopausal advantage. It's not only really the magnitude

00:15:10.400 of LDL elevation, but it's the duration of exposure. So even exposure to mild or moderately

00:15:17.160 elevated LDL for a sufficient number of years has increased the risk of ASCBD to an earlier onset

00:15:24.380 compared to individuals who have had lifetime low LDL. And so by waiting to treat individuals until

00:15:31.680 later of life, you know, you've left atherogenesis, you know, atherosclerosis propagate unchecked during

00:15:37.400 this time. It's never too late to implement prevention, but prevention is better implemented

00:15:42.200 when started earlier. Yeah, there's two ways I try to explain this to patients, and usually at least

00:15:47.160 one of them works. So sometimes patients will come in with some recollection of calculus, and you can

00:15:52.280 remind them about the area under the curve and the integral, and you can sort of explain that an

00:15:57.180 enormous driver of atherosclerosis is indeed exposure to ApoB. On my podcast, the listeners are very

00:16:03.060 astute. They understand that we're really talking about ApoB, which includes, of course, LDL, but also

00:16:07.760 VLDL, et cetera. And we say, look, it's really the time is the x-axis and ApoB concentration is the y-axis.

00:16:15.400 You want to minimize the area under that curve. And to your point, that means starting earlier and

00:16:22.120 lowering ApoB or LDL cholesterol more. And the longer you wait, the more it puts the burden on you

00:16:28.820 to really lower that ApoB. So if that doesn't resonate, I think the other way that resonates

00:16:34.600 with people is to think about saving for retirement, which is in an ideal world, you'd start

00:16:39.260 saving in your 20s. And you wouldn't have to save an enormous amount if you were saving in your 20s,

00:16:44.940 but you'd be chipping away at it and building up your coffers and generating a slow and steady

00:16:49.480 incremental return and letting the effective compounding take its toll. Of course, if you wait

00:16:55.100 until you're 40 or 50, you're going to have to be more aggressive in your savings. And you're

00:16:59.040 going to also require a higher rate of compounded return if you want to have the same amount when

00:17:04.160 you retire. And of course, if you wait until you're 60, it doesn't mean that you can't have

00:17:08.320 some sort of financial independence in your 70s, but boy, you've got to really sock away a lot of

00:17:13.300 money and you've got to really hope for some pretty impressive returns in the stock market.

00:17:18.140 And so usually somewhere between those two explanations, people start to understand

00:17:22.680 what you're saying and what people like Peter Libby have said, which is it's time exposure

00:17:27.860 to ApoB. Do you get the sense that it also works that way with blood pressure and some of the other

00:17:32.440 really clear causative agents for ASCVD? Yes. You know, you wouldn't take someone who has

00:17:39.260 a younger adult who has a satanic blood pressure of 160 and say, oh, you know, your 10-year risk is

00:17:45.880 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

00:17:51.480 let this high blood pressure continue on and damage your arteries and cause, you know, silent vascular

00:17:56.620 damage. No, you would treat a 30-year-old who has elevated blood pressure. So this problem with

00:18:02.100 these 10-year risk in younger adults is that, yes, younger adults are going to have a lower

00:18:07.880 short-term risk over the next 10 years, but they have a high, you know, lifetime risk and that we do

00:18:15.240 them a disservice by ignoring these high values because they haven't crossed some kind of theoretical

00:18:21.560 10-year threshold. With the exception of guidelines say, well, FH, we would treat if it's above 190,

00:18:27.920 but a lot of patients have mild to moderate elevated cholesterol in younger age years that

00:18:34.060 is not being treated. You know, I tell my patients I'm not just concerned about preventing a heart attack

00:18:40.160 in the next 10 years. I want to prevent them from having a heart attack over the next 40 years.

00:18:45.380 And so this is where we need to have much more focus on prevention. And this does emphasize the

00:18:49.720 role of lifestyle as well and healthy dietary changes and really healthy lifestyle should really

00:18:55.280 begin in utero. You just took a real page out of Alan Snyderman's JAMA paper from a few years ago,

00:19:01.160 where he really just took aim at this ridiculous notion of 10-year risk being remotely helpful in young

00:19:08.000 people. One of the exercises I like to do with patients is take them to the MESA risk calculator

00:19:13.220 page and basically demonstrate for them how much it's driven by age. If you go to the lowest end of

00:19:19.340 that calculator, which I think is 40 or 45, there's almost no variable you can put in there that gets

00:19:26.160 you to a high enough 10-year risk that you would trigger treatment. 5% 10-year risk, okay, now we need to

00:19:33.240 act. Conversely, at a high enough age, there's almost no variable you can put in there for which

00:19:39.240 the risk is low enough. In other words, age is the biggest driver of risk. How do you think we got here?

00:19:44.360 Because you've clearly, I think, identified the jugular issue, which is the time horizon of risk.

00:19:51.780 And yet somehow, when it comes to lipids, we stick to it. And yet when it comes to smoking and blood

00:19:59.480 pressure, we don't. We treat the causative agent when we're dealing with blood pressure and smoking,

00:20:04.540 and yet we somehow ignore the causative agent of ApoB when we're talking about lipids and focus

00:20:09.720 instead on time horizon. Well, I think part of the problem is randomized clinical trials do serve as

00:20:15.240 our primary evidence base for guideline recommendations, and they're very, very important. But, you know,

00:20:20.340 randomized clinical trials are expensive. And so, you run them over, you know, generally a short time

00:20:25.940 period, you know, five years, and you want to enroll high-risk people that are going to have events over

00:20:30.940 the next five years. You really can't feasibly do a randomized clinical trial for decades and decades.

00:20:37.040 And so, by nature, these lower-risk individuals and younger adults are not included in these trials.

00:20:43.480 And then it comes down to the fact that we don't have data specifically for treatment in this

00:20:50.060 population. But I definitely hone down on lifestyle changes, particularly in younger adults. And I

00:20:56.280 think we're going to get into women-specific factors a little bit later and talk about pregnancy. But

00:21:01.140 high adverse lipid panel, elevated triglycerides, elevated total cholesterol, and chronic hypertension

00:21:07.700 and obesity, these cardiometabolic risk factors, if women are entering pregnancy in poor cardiometabolic

00:21:15.080 health, which the data shows that there's been an increase in this, you know, they're more likely to

00:21:20.040 have these adverse pregnancy outcomes like preeclampsia and gestational diabetes that not only increase

00:21:26.660 their risk of short-term complications at delivery, but also impact their risk even a decade or more after

00:21:34.140 their index pregnancy. Really, we need a shift improvement in cardiometabolic health earlier in life,

00:21:39.840 which means in young adults and women of reproductive age.

00:21:43.300 I agree with that completely. And I want to come back to it in more detail. But I still feel like there is a

00:21:49.620 double standard, going back to what we talked about earlier, in that we don't have a study that says not

00:21:57.720 smoking if you're aged 30 to 40 is going to reduce your risk of cardiovascular disease. But yet, there's not a

00:22:05.160 physician out there that doesn't recommend smoking cessation to a person the minute they pick up a

00:22:11.300 cigarette. Why? It's because we've identified causality. Once you identify causality, that's all

00:22:18.140 that matters. The same is true with blood pressure. We don't have a hypertensive study that looked at

00:22:23.840 people aged 25 to 35 or 35 to 45, where we reduced blood pressure and showed a dramatic reduction in

00:22:29.900 events because they probably weren't going to have the events in the time horizon of the study. And so the

00:22:34.640 reason it's very easy for any physician to treat hypertension in a 35-year-old is because they're

00:22:42.640 treating the causal agent. And that's where I'm frustrated, Erin, is we have the same level of

00:22:48.120 causality for ApoB. There is no ambiguity about this. And yet we somehow have this double standard

00:22:54.400 where we ignore the causal agent. I agree with you. We have overwhelming evidence that LDL is a causal

00:23:01.620 factor and atherosclerosis. We have data from observational studies, from genetic studies,

00:23:07.220 from interventional trials. It meets all the criteria for a causal factor. You just asked me

00:23:12.640 to speculate, you know, why, you know, I'm not sure why that there hasn't been a greater uptick about

00:23:18.700 treating in younger ages. And this focus on 10-year risk score, I'll point out, though, in randomized

00:23:23.300 clinical trials, none of the randomized clinical trials enrolled people on the basis of a 10-year

00:23:29.240 cut point. The pooled cohort equation has never been tested in a randomized clinical fashion about

00:23:35.380 treating people based on a pooled cohort equation cut point versus another cut point. That has never

00:23:41.000 been tested. You know, the trials have specific enrollment criteria, and they really weren't based

00:23:46.840 on 10-year risk scores. They were based on other factors. And so this over-reliance on 10-year risk

00:23:51.760 scores. But I will say that we have made some progress. And I was really pleased. I was a co-author on

00:23:57.940 the 2019 ACCHA primary prevention guidelines. We do acknowledge the limitations of these 10-year

00:24:05.080 risk scores. They can both overestimate risk in certain populations, such as older adults and

00:24:12.360 those with higher socioeconomic status. And they can underestimate risk in other populations, such as

00:24:17.740 those with more social deprivation and these other unique risk factors that are not captured in these

00:24:23.780 10-year risk scores. And so they acknowledge this. They still feel like you should do some kind of risk

00:24:28.440 assessment as a starting point. And very low-risk individuals, less than 5% 10-year risk. Lifestyle may be

00:24:34.240 enough. And high-risk individuals above 20% 10-year risk. You don't want to use your high-intensity statin to

00:24:40.020 lower LDL by 50% or more. But they do allow more room now for the borderline intermediate risk to consider

00:24:46.560 these risk-enhancing factors, of which ApoB and Lipertal A are some of them. But I also was really

00:24:52.460 pleased that they've acknowledged these female-specific factors that we'll talk more about, early

00:24:57.360 menopause and adverse pregnancy outcomes like preeclampsia. And so the presence of these risk

00:25:03.020 enhancers and those of borderline intermediate risk would favor the initiation of statins. And then if there

00:25:09.700 is still uncertainty about risk, even after you estimate 10-year risk and consider those risk-enhancing

00:25:14.140 factors, you can get a coronary artery calcium score to help refine risk a little bit better

00:25:20.580 and guide shared decision-making. So my practice, I use a lot of coronary calcium scoring, and

00:25:25.320 particularly for elevated scores, I'll even treat individuals similar to secondary prevention

00:25:30.260 population. But we know that even that doesn't work very well in the younger population that we're

00:25:35.100 talking about, less than 40, because it takes time for plaque to calcify. And so a zero calcium score

00:25:42.280 a young adult isn't as reassuring as a zero score in an older adult. You know, again, they might be

00:25:48.260 at low risk the short term for sure, but they may still have high lifetime risk.

00:25:53.440 We've gone back and forth in our practice about how to use calcium scores and I think come to the

00:25:59.180 same conclusion you have, right? Which is that in a young patient, frankly, I would say younger than

00:26:03.060 50, truthfully, I don't know that a zero calcium score tells me much. First of all, we know that 15%

00:26:08.300 of zero calcium scores are false negatives anyway. If you do a CTA, a CT angiogram, listener, you're

00:26:13.720 going to see a calcification that was missed because the CTA has much finer slices than the CAC,

00:26:18.840 or you're going to see soft plaque. In fact, one series found that I think almost 2% of zero

00:26:24.760 scores on CACs actually had hemodynamically significant lesions on CTA. Even if you put aside

00:26:31.980 the false positives or the false negatives rather, to your point, the physiology of the disease tells

00:26:37.980 us that's the wrong metric to care about. It's more interesting, I suppose, when you have perfectly

00:26:43.600 clean CTAs in 70-year-olds with hyperlipidemia to which you can say, well, look, clearly this person

00:26:50.280 has other factors that are protective. We might not understand what they are. And this is a patient in

00:26:55.000 whom aggressive treatment probably isn't necessary, especially if they don't feel, if the patient

00:27:00.040 themselves doesn't want it. So let's now talk about this thing that you've brought up on two occasions,

00:27:04.500 which I think is really important, if I'm understanding you correctly, which is if we

00:27:07.580 think about the lack of progress or the regression in progress, I guess, that's been made over the past

00:27:12.680 decade. Am I understanding you correctly that it has been less about a reduction in treatment for

00:27:19.240 the preventative measures of ASCVD and more about the increase in the background metabolic

00:27:24.840 dysfunction, or have both of these things been happening together? Well, both of these things have

00:27:29.700 been happening together. In terms of treatment, individuals are still undertreated. We see this

00:27:35.600 over and over again in registries. If you look at even the highest risk patients, that's just those

00:27:39.800 with ASCVD from the Gould Registry in the U.S. and the Santorini Registry in Europe. Patients are not at

00:27:47.200 goal with their LDL and they're undertreated. In the Gould Registry of U.S. patients with ASCVD,

00:27:53.380 more than two-thirds remained with an LDL above 70, and we can argue that maybe they should even have

00:28:00.860 their LDL as low as 55, but we even use a threshold of 70 as the goal for initiating a

00:28:07.520 non-statin therapy to a statin. Two-thirds were above this goal, and over a two-year period,

00:28:13.180 only 17% had their lipid-lowering therapy intensified. So there's this credible inertia.

00:28:18.920 So patients are not at goal. The use of combination therapy, including with PCSK9 inhibitors,

00:28:24.660 is very underutilized. There's something like 6% in this cohort. And so we're certainly not

00:28:30.500 treating with the tools that we have, which is really disheartening. But also on the backdrop of

00:28:36.560 this, we've all seen the U.S. maps about the epidemic of obesity. And along with that comes

00:28:43.360 diabetes and other disorders related to insulin resistance, including worrisome trends with

00:28:49.820 increasing maternal mortality, rising rates of gestational diabetes, which is increasing worldwide.

00:28:56.660 And so the cardiometabolic health of the U.S. population is getting worse over time. And so

00:29:01.880 we're shifting more morbidity to younger and younger age groups, which is not a good thing at all,

00:29:08.160 and likely going to affect anticipated life expectancy trends to reverse.

00:29:14.200 So Aaron, obviously these trends that you're observing, the increase in obesity, the increase

00:29:19.420 in insulin resistance, the increase in type 2 diabetes, although you didn't state it, it's

00:29:23.780 embedded within here, the increase in Nathal-D and NASH, the increase, as you said, in gestational

00:29:29.240 diabetes. I mean, all of these things are basically growing out of metabolic syndrome. You could argue

00:29:33.020 now, I don't know the latest stats, but do you know what fraction of people in the United States now

00:29:37.380 have metabolic syndrome? I don't know. I've had for metabolic syndrome, but it's huge. We know that

00:29:42.660 diabetes rates are certainly going up with over 1 in 10 U.S. adults having diabetes, and many with

00:29:49.800 diabetes don't even know that they have it. So there's a latency in diagnosis. So this is all

00:29:55.260 really alarming trends, especially when we have a lot of therapies we can do for prevention. But of

00:30:00.540 course, one of the most important prevention therapies I can prescribe for my patients is lifestyle

00:30:05.320 changes. Even modest weight loss can have pretty significant impact on triglycerides and blood

00:30:11.900 pressure reduction. So it's always important that we can talk about all the new exciting therapies we

00:30:16.820 have for weight loss, like the GLP-1 receptor agonists and the dual agonists. But really, you know,

00:30:21.500 still emphasizing healthy lifestyle from childhood is still such an important strategy for prevention.

00:30:28.180 So we know it's multifaceted. I don't think any serious commentator on this will point to one

00:30:34.400 thing and say that's the culprit for why we're seeing this epidemic. But how do you rank order

00:30:41.620 these things? So what is the causative driver in your mind for weight loss? How much of that do you

00:30:47.840 think lies at the feet of lower exercise levels versus food availability, hyperpalatability,

00:30:56.000 specific elements within the diet? How do you start to disentangle this? Because I think without some

00:31:01.880 level of granularity there, it becomes difficult to say lose weight. An overweight person shows up and

00:31:06.520 you tell them to lose weight. That's not a particularly helpful insight. So in other words, to prescribe

00:31:10.420 something insightful, we have to have some sense of what the etiology is. So how do you think about that?

00:31:16.280 First of all, I'm trying to prevent or reverse the trends of obesity on a population basis. And so we put

00:31:22.800 too much blame on the individual, but we have, you know, major societal and population problems with

00:31:28.560 the easy access to poor quality food, these highly processed foods that are extremely palatable, but

00:31:36.920 contain a lot of saturated fats and other additives and sugars. The way our jobs are structured to be

00:31:43.860 more sedentary and long commute times, you know, having access to safe places to exercise and having time

00:31:52.160 to do so. And the increased stress levels in life. I mean, there's so many social determinants of

00:31:58.880 health that have led to this problem. And there's huge parts of the country where there's food deserts,

00:32:04.480 where there's not access to fruits and vegetables or food swamps that are just really only available,

00:32:11.060 cheap and easy foods are these highly processed packaged foods. So as individuals, we do have some

00:32:16.540 responsibility for our own life choices. Larger issues should be placed in regulation and policy

00:32:22.640 on a population level. And then, you know, once an individual is already obese, it's much harder

00:32:29.060 than to lose weight. We certainly talk about lifestyle changes, but obesity is far more complicated.

00:32:35.440 There is all kinds of hormonal regulations, and it's not just as easy as calories in, calories out.

00:32:43.260 The good news for these individuals is that at least now we do have some new pharmacological

00:32:49.640 agents that are beneficial in weight loss that do not have cardiovascular harm, like some of the

00:32:57.080 older weight loss drugs, and may actually be cardiovascularly beneficial. We know the GLP-1

00:33:02.900 receptor agonist, at least in patients with type 2 diabetes, you know, reduces the risk of major adverse

00:33:07.980 cardiovascular events and stroke. And so while we do have an outcome trial ongoing right now

00:33:12.960 in persons who are overweight and obese, but without diabetes with the GLP-1 receptor agonist,

00:33:19.000 I'm anticipating this will also be beneficial for cardiovascular disease. So we have new options

00:33:23.620 to treat obesity, but really trying to focus on prevention of obesity in the first place,

00:33:29.360 because it's certainly not feasible to treat two-thirds of U.S. adults who are overweight and obese.

00:33:34.240 The statistics are astronomical and they're astounding. So we really need to focus on population

00:33:40.080 interventions. Which GLP-1 agonist are we looking at now? Is it semaglutide or chozepatide?

00:33:47.220 So they're different. So semaglutide is a GLP-1 receptor agonist. And at least in patients in type 2

00:33:53.380 diabetes, we have cardiovascular outcome data for the injectable, the subcutaneous dose. There is an

00:34:01.160 outcome data ongoing for the oral formulation, but we don't have that data yet. So usually I prescribe

00:34:08.800 the injectable form. Now, soreceptivide is the new kit on the block. It's a dual agonist, a GIP,

00:34:16.700 GLP-1 receptor agonist. This has been approved also for diabetes, although the outcome trial for diabetes

00:34:25.100 is ongoing, the surmount outcome trial. But it also has been evaluated for weight loss and really showed

00:34:33.340 dramatic weight loss, you know, up to 50 pounds in the highest dose, which is really remarkable.

00:34:40.520 You know, we can't compare trials head to head because they were not compared head to head. But

00:34:43.600 in the step trials with semaglutide, there was about a 30 or so pound weight loss. So trazeptivide is not

00:34:50.880 yet FDA approved for weight management, although it will likely have this indication soon. But it was,

00:34:57.640 it is approved for type 2 diabetes. Semaglutide is approved for both type 2 diabetes for reduction in

00:35:04.800 major adverse cardiovascular events. But it also has a separate weight loss indication for persons who

00:35:10.600 are obese with BMI above 30 or overweight with a BMI over 27 in the setting of one or more obesity

00:35:18.400 related cardiovascular risk factors who need additional weight management after diet and lifestyle

00:35:24.220 attempts. So we have new agents now, which is really exciting, but getting back to, we need to

00:35:29.500 do on a larger population to reverse the overall trends of obesity.

00:35:34.380 Before we leave the GLP-1 agonist and the dual receptor agonist, what is your best guess as to

00:35:39.440 the mechanism by which they also reduce cardiac events if it indeed is beyond weight loss? In other

00:35:45.000 words, do you think it's all due to the benefits of weight loss, which of course bring with it an

00:35:49.800 improvement in metabolic health? Or do you think there's something specific there that's going on?

00:35:54.220 And I would ask the same question eventually, although we don't have to discuss it now

00:35:57.380 with SGLT2 inhibitors.

00:35:59.440 The GLP-1 receptor agonist, you know, I don't know that we fully understand all of the benefits

00:36:05.380 on the mechanisms for benefits, but we know that the benefits of reducing major adverse cardiovascular

00:36:11.540 events are independent of its A1C lowering. These are interesting agents that in persons with

00:36:17.800 elevated glucose, such as diabetes, you know, they lower blood glucose. But in persons who don't have

00:36:23.940 elevated glucose, such as those who are overweight and obese, who don't have diabetes, you know, GLP-1s

00:36:29.900 don't cause hypoglycemia as solo agents. So they only lower blood glucose in a glucose dependent

00:36:36.720 fashion. But the benefit on MACE reduction, which has been shown to persons with type 2 diabetes,

00:36:42.000 is independent of A1C lowering. It may in part be related to favorable changes and other risk factors,

00:36:48.220 such as reduction in blood pressure and weight loss. There's improvement in the lipid panel.

00:36:54.180 It's being investigated also in NAFLD as well. There may be anti-inflammatory effects. There may be

00:37:02.200 anti-arthroscorotic effects. There also may be some effects, you know, in the kidney. We do see a

00:37:08.340 reduction in albinuria with these agents as well. So they're really an interesting class of drugs.

00:37:14.240 So let's now turn our attention to specifically the physiology of women as it pertains to lipids

00:37:20.880 and ASCVD. So I think we should, maybe to make it easier, at least start with premenopausal women.

00:37:27.800 What's happening in a woman's body when she's 25 that's different from a man's body when he's 25

00:37:34.360 as it pertains to sex hormones and the interaction, therefore, with lipids and other factors that

00:37:41.040 impact the simmering process of ASCVD? Sure. And first, I just wanted to give sort of a broad

00:37:47.040 statement. I'm glad that we're having this discussion about lipids in women and ASCVD in

00:37:52.420 women because there are differences. You know, women are not smaller men or have unique risk factors.

00:37:59.340 Even among traditional risk factors, diabetes and smoking confer a greater relative risk in women than

00:38:04.700 in men. And then women have unique risk factors that we'll talk more about throughout their lifespan

00:38:09.480 that men do not related to menarche when early or late and polycystic ovary syndrome and infertility,

00:38:16.140 spontaneous pregnancy loss, parity, adverse pregnancy outcomes like preeclampsia, lack of

00:38:21.860 breastfeeding and early menopause. And in addition, you know, chronic inflammatory conditions like

00:38:26.880 rheumatoid arthritis and lupus are more prevalent in women. So women have these unique risk factors that

00:38:32.660 are female specific or female predominant. And cardiovascular disease also can be different in women,

00:38:38.000 which is why we need more trials in women. You know, women are more likely to have ischemia with

00:38:43.300 non-obstructive coronary disease from coronary microvascular dysfunction or coronary vasospasm.

00:38:49.420 They're more likely to have SCAD, spontaneous coronary artery dissection, and more likely to have

00:38:54.160 stress cardiomyopathy than men. So we really need more data about treating cardiovascular disease in

00:38:59.320 women. But let's talk about the life cycle that you alluded to in the beginning with your question.

00:39:05.580 Estradiol is the predominant female sex hormone in women of reproductive age that seems to have the

00:39:13.380 beneficial effects with lowering LDL and conferring some cardiovascular protective properties.

00:39:19.500 But I should mention there's actually three types of estrogen. So estradiol, which is the predominant one

00:39:25.640 in women in childbearing age, and this is the most potent form of estrogen. So estradiol is E2.

00:39:31.300 So estriol, E3, is the main estrogen produced during pregnancy. And then estrone, E1, is the only

00:39:39.020 estrogen produced after menopause. It's also the weakest estrogen. So, you know, starting with puberty,

00:39:46.400 puberty is a process that starts in the brain. So the hypothalamus in the brain suddenly begins

00:39:52.180 secreting gonadotropin-releasing hormone, or GNRH. FSH and LH levels gradually increase during puberty,

00:39:59.780 which stimulate the follicle maturation and estrogen production and the ovaries, and also

00:40:05.440 the secondary sex characteristics like breast changes and changes in body composition. This

00:40:10.520 gets to the point where then there's the onset of menarche or the first menses. And so this is

00:40:14.600 typically, you know, around age 12. And it's important to note that, you know, I treat adult

00:40:21.220 patients, but why I even ask adult women about the onset of menarche is because both early menarche

00:40:27.080 before the age of 11 and also late menarche after the age of 17 has been associated with

00:40:33.680 increased cardiovascular disease risk later in life. And there's likely hormonal and adipokine and

00:40:40.040 cardiometabolic imprinting that's related to this. There's lots of factors related to the onset of

00:40:46.680 menarche, but both socioeconomic and environmental factors as well as genetic factors. But elevated BMI

00:40:53.360 is a risk factor for early onset menarche, which is why, again, it's so important that we think about

00:41:00.200 healthy lifestyle starting in childhood. And I'll talk a little bit now about the menstrual cycle

00:41:05.800 because many people don't know, but the lipids do change throughout the menstrual cycle. Difference in

00:41:11.720 little cholesterol, you know, as much as 10 to 12 milligrams or deciliter difference. And so while most

00:41:17.020 women are reproductive age who have lower LDL, this is not probably clinically significant in terms of

00:41:22.680 atherogenesis, it does matter when thinking about the timing of measuring a lipid panel during the

00:41:28.940 menstrual cycle. I think that's important to note. So during the menstrual cycle, you have the

00:41:35.620 hypothalamus is releasing GnRH, which causes the pituitary gland to release FSH. So FSH is acting on

00:41:43.220 the ovaries to mature the follicles, and that the follicles of the ovaries is what secretes estradiol.

00:41:49.260 And so estradiol causes the maturation of the egg and the thickening of the uterus lining

00:41:54.380 in preparation for a fertilized egg implant. And then the increased estradiol triggers the release

00:42:00.820 of LH, which induces ovulation and release of the egg. And so ovulation ends the follicular phase.

00:42:08.060 And then after ovulation, you're in the luteal phase, where estradiol with progestion prepare the

00:42:13.540 womb for implantation. But if the egg isn't fertilized, the corpus luteum, which is secreting

00:42:20.000 the progesterone, breaks down. So this leads to a drop in progesterone level in the beginning of the

00:42:25.320 menstrual period. What does this mean for lipids? So after menses, you know, total cholesterol and LDL

00:42:32.200 increase rapidly after menses. And so they really peak during this follicular phase. And then this is

00:42:38.900 followed by a decline in the luteal phase, which corresponds to the rise in the peak concentration

00:42:44.680 of estrogen and progesterone. So when estradiol is the highest in the menstrual cycle, this leads to

00:42:50.420 the fall in total cholesterol and LDL. HDL is highest around ovulation. Triglycerides didn't really have a

00:42:58.880 consistent pattern during the menstrual cycle. So there isn't specific guidance.

00:43:03.220 And sorry, just to make sure I understood that, Erin, the difference between the peak and nadir of

00:43:09.140 LDL cholesterol is about 10 to 12 milligrams per deciliter, or is that total cholesterol?

00:43:15.000 That was total cholesterol, but it mirrors the difference in LDL as well. So this was a study

00:43:22.320 that published, on average, total cholesterol may go from 158 to 168, where LDL on average went from

00:43:32.080 97 to 102. So, you know, they're not dramatic changes, which is why we don't worry about this

00:43:39.960 too much in women of reproductive ages who don't have a lipid disorder. But it's, you know, interesting

00:43:45.700 to note. But if a woman is very high risk, like has ASCBD, and we're trying to target these

00:43:52.440 really intensive thresholds, like LDL is less than 70, or even lower, it's useful to know that they do

00:43:58.860 change throughout the menstrual cycle. So while there's no specific guidance around this, you

00:44:03.100 know, I generally recommend clinicians measure the lipid panel during the menses, so that it's

00:44:09.700 ideally measured, monitored, and compared at the same time during the menstrual cycle. So usually

00:44:14.640 the menses is easiest to benchmark to. We do that when we're concerned with, as women become

00:44:20.340 perimenopausal, and we want to start getting a sense of what's happening, we always use day five.

00:44:24.840 So if the initiation of menses, even if it's spotting, is day one. But we always just pick

00:44:29.660 day five. And that way, we have a really consistent view, specifically of FSH and estradiol. Progesterone

00:44:35.560 is zero at that time. But the FSH and the estradiol really give us a sense of how close she's probably

00:44:42.520 getting to menopause. And then we correlate that with symptoms to sort of start to think about

00:44:46.800 initiating HRT. But that's a whole other topic, which I'm sure we'll get to.

00:44:50.820 You know, in terms of lipid panel, it's good to be measuring around the same time each month.

00:44:54.620 So if you're following the seriolipid panels in a woman for a reason, so timing it around

00:44:59.840 day five, especially if you're measuring other hormones. But yeah, so FSH would be at the highest

00:45:05.340 during the early follicular page and then declines after ovulation, where LH is low during the early

00:45:11.780 follicular phase and then peaks around at ovulation, which stimulates the egg to be released.

00:45:17.720 At this point in a woman's life, she still enjoys this, for all intents and purposes,

00:45:22.180 decade advantage over men in terms of ASCVD risk. So a 40-year-old woman who is still ovulating

00:45:31.640 is at a cardiovascular standpoint is a 30-year-old man. Is that directionally what we would say

00:45:38.460 prior to menopause?

00:45:40.160 Yeah. I mean, on average, and again, people are not averages, you know, people are individuals,

00:45:44.940 but on average, there is a about 10-year offset of ASCVD in women developing it later than men.

00:45:53.540 And this may be because, as we'll talk about when we get to menopause, you know, with the loss of

00:45:58.560 estradiol after menopause, LDL levels rise after menopause. And so that women may have higher LDLs a

00:46:06.500 little bit later in life. You know, many women tell me, oh, you know, I've always had good lipid levels,

00:46:11.560 and now they're higher, you know, after menopause. And so when we get back to what we started with

00:46:15.600 about the integration of duration of LDL exposure in terms of cholesterol years, they may have had

00:46:22.680 lower number of cholesterol years during their childbearing years, and then higher levels later

00:46:27.500 in life. And that might be why they have this offset. But again, we don't see this in FH, and we

00:46:32.960 don't see this as well in diabetes. And so each person is an individual. And so we do women a disservice

00:46:40.800 when we presume that all women somehow are lower risk or protected during their menopausal years,

00:46:46.400 because we started out this podcast talking about that we absolutely see myocardial events,

00:46:52.060 not just things like SCAD, but we see actual atherosclerotic myocardial infarction events

00:46:57.240 in younger women too. So they're at lower risk, but not zero risk. And so we take each person as an

00:47:04.080 individual. And then there are things we need to consider related to contraceptions and PCOS.

00:47:10.800 That can also affect the lipid profile as well. Let's take each of those then, because I think

00:47:15.320 they're both incredibly fascinating and highly prevalent. So let's start with PCOS. Tell folks

00:47:19.920 what it is, maybe what the prevalence is, what we think the etiology is, and of course what the

00:47:24.900 impact is on metabolic health and ultimately lipids. So polycystic ovary syndrome or PCOS is the most

00:47:31.820 common endocrine abnormality of women of reproductive age. Estimates are about 5% to 13% of women in the

00:47:38.400 general population, and it does affect women of all race ethnicities. It's categorized sort of by this

00:47:44.300 triad of hyperandrogenism, ovulatory dysfunction, so irregular menses or anovulatory cycles, and

00:47:52.980 polycystic ovary morphology. So just having cysts in the ovary in itself is not enough for the diagnosis.

00:47:59.520 You need to have these other criteria. It is a heterogeneous disorder in that there are

00:48:04.960 differences in risk with PCOS, but really if you talk about the classical PCOS that has the

00:48:10.680 hyperandrogen form, this seems to be the one that is the most strongly linked with cardiovascular risk

00:48:17.040 and the cardiometabolic phenotype. So we really think that insulin resistance is hallmarking under

00:48:23.640 the pathogenesis of this, that there is molecular defects and insulin activities and PCOS that leads

00:48:29.200 to impaired glucose tolerance and glucose insulin resistance and hyperinsulinemia. Studies have shown

00:48:35.860 that about 95% of obese women with PCOS and about 75% of lean women with PCOS has insulin resistance.

00:48:43.100 So there is a lean PCOS phenotype, you know, while most women with PCOS do have an elevated body mass

00:48:50.880 index, not all women have an elevated body mass index. But this insulin resistance is probably driving

00:48:57.620 a lot of the cardiometabolic complications. So elevations in blood pressure and dyslipidemia

00:49:04.220 patterns. So we see this, the triad of dyslipidemia with the elevated LDL, elevated triglycerides and low HDL,

00:49:12.440 this metabolic syndrome pattern. PCOS is associated with hypertension and incident hypertension.

00:49:18.980 And this is actually independent of BMI, but obesity increases the risk and makes the risk greater.

00:49:25.140 And there is an association not only with increased subclinical atherosclerosis. I recently published

00:49:31.080 a meta-analysis where we showed that women with PCOS were two-fold more likely to have coronary calcium.

00:49:36.600 They're also more likely to have parotid plaque. But they're also associated with increased

00:49:40.780 cardiovascular disease later in life. And the variable estimates have varied across studies.

00:49:46.360 And this is likely because how PCOS was defined and how cardiovascular disease was defined. And so

00:49:52.900 it's not quite consistent across every study, but on average, about 30% to 50% increased risk that we

00:49:59.900 saw in an umbrella review of a meta-analysis of future cardiovascular risk. Now, there's a little bit

00:50:05.780 of debate about whether PCOS is causally related to CVD. This excess risk that we see seems to be

00:50:13.940 more of women during reproductive age. Once women's already after menopause, having a prior history of

00:50:21.340 PCOS doesn't seem to confer the same level of risk. And likely because of all of the increased risk after

00:50:28.180 the menopause transition with the low estradiol and the more androgen phenotype after menopause

00:50:33.840 probably outweighs or overshadows any prior risk related to PCOS. But there does seem to be this

00:50:40.940 long-term risk. But when you look at Mendelian randomization studies, it does suggest that the

00:50:47.220 elevated testosterone, the hyperandrogen, the obesity, the higher insulin levels, insulin resistance,

00:50:52.640 and lower levels of sex hormone binding globulin do appear to have a causal relationship with PCOS

00:50:58.900 based on genetics. And so it may be that these are the mediating factors that link PCOS with future

00:51:05.840 cardiovascular disease risk. Obviously, there's an enormous impact on fertility. Are multiple

00:51:10.380 pregnancies associated with an increased risk of ASCVD or decreased risk based on the estrogen?

00:51:15.060 PCOS is associated with infertility. And this is one of the mainstay of treatment of women with PCOS

00:51:22.360 who are not wanting to become pregnant, of course, is oral contraceptives to kind of reduce the

00:51:27.700 hyperandrogenism. We recently published, though, a study looking at national data of pregnancies at

00:51:35.320 delivery. And we did show that women, you know, PCOS who did become pregnant, you know, they were at

00:51:41.120 greater risk for preeclampsia and many gestational diabetes and many cardiovascular complications compared

00:51:47.780 to women with PCOS. So it's important to, you know, note that not only are they at increased risk,

00:51:53.760 have decreased fertility and trouble getting pregnant, that once they do become pregnant,

00:51:58.280 they are at increased risk of cardiovascular complications and delivery. So it's really

00:52:03.280 important with PCOS, again, that we optimize healthier lifestyle and weight management may be

00:52:09.300 really important to mitigate some of the cardiometabolic risk. I'm interested, you know,

00:52:14.020 on women who are not trying to become pregnant or not pregnant, GLP-1 receptor agonists may be

00:52:18.740 promising to help with the weight management and the insulin resistance. You know, we talked about

00:52:23.140 that class of drugs. And even statin therapy may reduce some of the testosterone or the androgen

00:52:29.600 associated risk. So that's with PCOS. But I think that you asked about parity in general. So when you look

00:52:36.760 at parity or the number of live births, there does seem to be a J-point, J-shaped relationship with

00:52:43.960 higher parity, particularly more than four or five live births being associated with subsequent risk

00:52:49.760 of cardiovascular disease. The reason for this is not quite known. I showed in the MESA study that

00:52:56.260 women who had histogram multiparty, you know, were much more likely to be in poor cardiovascular health

00:53:02.420 later in life at middle age to older age compared to less porous women. You know, women tend to gain

00:53:09.360 weight with each pregnancy, but there may be also dysregulation of adipokines that sets the stage for

00:53:16.980 later cardiometabolic complications. And so this is why it's really important that we try to optimize

00:53:22.200 women's cardiometabolic health before pregnancy and inter-pregnancy between pregnancies to try to

00:53:29.100 prevent these long-term complications. So I mean, I wouldn't tell a woman that they can't become

00:53:34.440 pregnant a certain number of times, but I would really try to work with them to try to optimize

00:53:39.580 their cardiometabolic health. I feel like your intuition is right there, Aaron. I've always found

00:53:43.900 the epidemiology on number of pregnancies and disease X to be completely full of confounders,

00:53:52.420 such to the point that I think the epi provides no insight. Whereas I think the confounder you mentioned

00:53:57.740 is the most obvious one, right? Which is the more pregnancies a woman has, the more likely you could

00:54:04.280 believe that she's having difficulty getting back to her pre-never-pregnant state of metabolic health,

00:54:10.760 not just weight, but overall metabolic health. And that would strike me as a greater risk factor.

00:54:15.460 Again, one can't know this without randomization. We're obviously not going to have that. So

00:54:19.820 it probably shouldn't factor into decision-making.

00:54:22.780 I will mention that there are a couple of studies. So the problem is most epidemiology studies

00:54:26.920 don't ask men parity history. They don't ask men these questions, you know, they only ask them of

00:54:31.960 women. But there were a couple of studies where they assessed number of children and men. And parity

00:54:37.120 is actually a risk factor for CBD in men too. So this likely gets to your point about confounding by

00:54:44.060 socioeconomic factors and cultural factors, education factors that might lead a family to have more

00:54:51.680 children rather than less. But the risk does seem to be a little greater in women suggesting that there

00:54:57.440 may be some true biological effects, maybe weight mediated beyond just confounding by socioeconomic

00:55:03.720 and cultural factors.

00:55:05.460 Let's talk about the impact of oral contraceptives, even outside of the case of PCOS. So if you have a

00:55:10.420 young woman who wants to use OCs as a form of birth control, what is the impact that that,

00:55:16.260 if any, has on her lifelong risk of ASCVD via the, let's just say she's going to go on it for a

00:55:22.880 decade, age 25 to 35, and then have kids 35 to 40, and then goes through menopause at 50. Is there some

00:55:30.580 impact that that decade being on an OCP has on her down the line?

00:55:36.040 You know, women of reproductive age may be initiated on contraceptions for various reasons. So it's not just

00:55:42.660 pregnancy prevention, but maybe for treatment of menstrual cycle disorders, PCOS, acne, there's lots

00:55:50.020 of reasons why they might start oral contraceptive therapy. There's the risk likely, you know, depends

00:55:57.280 so much based on formulation and type. So, you know, we can't link all contraceptives in one bin.

00:56:03.960 Oral combined hormonal contraceptives, you know, the older formulations had much higher doses of

00:56:09.280 estrogen. And so estrogen can increase triglyceride levels. It can lower LDL, which is a good thing,

00:56:16.280 but it can increase triglyceride levels. What's the net effect, Aaron, on ApoB? Because

00:56:21.200 certainly the analysis I've seen suggest that once you correct for ApoB, triglycerides below 400

00:56:27.540 milligrams per deciliter really don't mean anything. Obviously, above that level, you have to start

00:56:31.660 worrying about pancreatitis, but that ApoB was capturing that risk. And it's interesting, of course,

00:56:36.120 if you're only looking at LDL-C and triglyceride, it's possible that a rise in triglyceride is

00:56:42.200 problematic because that could actually raise ApoB as you now have to obviously increase the

00:56:47.880 potential number of both cholesterol and triglyceride trafficking particles. I'm guessing

00:56:52.680 that analysis isn't done, but do you have an intuition around it? No. I mean, of course,

00:56:56.920 pregnancy also increases triglyceride levels a lot too, as we'll talk about. So preventing an unwanted

00:57:01.700 pregnancy outweighs any slight risk for these lipid changes with oral combined contraceptives.

00:57:08.140 You know, I think the changes are relatively modest, especially since we're using typically now the

00:57:14.400 lower estrogen formulations, because it's really the more estrogen that a combined oral hormonal

00:57:20.040 contraceptive contains has the greater impact of increasing triglycerides. So I don't have that

00:57:23.740 number for you because it really depends on the formulation. You know, it's unlikely to have much

00:57:28.220 impact in most women, but women who already have high baseline triglycerides to begin with.

00:57:34.660 It can trigger severe hypertriglyceridemia above 500. So this probably would not be the agent you'd

00:57:41.780 want to use if your patient already had high triglycerides. Now, the transdermal combined

00:57:48.860 oral hormonal contraceptives, the patch, is less likely to cause clinically relevant elevations in

00:57:54.620 triglycerides. There's, of course, other types of contraceptives, you know, and very high risk

00:58:00.280 women with established cardiovascular disease or women who have FH, who have very high LDL levels.

00:58:07.240 These tier one methods, the long acting reversible methods like the IUD and the implant are safe and

00:58:13.460 effective for most women who even have, you know, are high risk who have established cardiovascular

00:58:17.540 conditions. You know, the progesterone based ones like the Mirena with the progesterone releasing IUD

00:58:25.460 system, you know, they can marginally, you know, lower, associated with lower HDL, but usually these

00:58:32.960 revert back to pre-insertion levels by one year. Most of the time for the IUDs, the triglycerides and LDL

00:58:40.500 and the cholesterol ratios remain pretty stable. So I really don't think that the lipid changes are

00:58:46.620 so much impacted by that. And that's why we do tend to recommend the IUD for women who have FH or

00:58:52.800 cardiovascular disease that are higher risk. Let's talk a little bit about pregnancy. I guess there's

00:58:56.860 two things I want to chat about. The first is obviously what's happening to a woman during

00:59:01.620 pregnancy. So probably share a little bit more than my wife wishes I would, but I sort of use myself

00:59:07.000 and my wife as a guinea pig from time to time and just love checking labs all the time. During, I don't

00:59:12.700 know, one of the pregnancies, maybe it was our second child. I probably checked her, you know,

00:59:17.180 did a very thorough look at her lipids and lipoproteins and everything all the way through

00:59:21.700 her pregnancy. I was shocked at how much her lipids rose during pregnancy. My wife is sort of one of

00:59:27.680 those people who genetically has very low burden of ApoB. So her baseline LDL cholesterol is probably 60

00:59:36.900 to 70 milligrams per deciliter. Her HDL cholesterol might be 80, 90 milligrams per deciliter. So

00:59:42.880 triglycerides of 40 milligrams per deciliter, right? So from a lipid lipoprotein standpoint,

00:59:47.740 she's pretty uninteresting. And I want to say by the third, end of second, beginning of third trimester,

00:59:54.640 you know, she looked like she had metabolic syndrome without the triglycerides. But just from

00:59:58.180 the standpoint of some of the other stuff, tell me what, and I know we hate talking about averages,

01:00:03.040 but can you give me just sort of a general sense of what's directionally happening to a woman during

01:00:08.240 pregnancy with respect to her lipids and lipoproteins? Yeah, so absolutely there's changes

01:00:13.520 in lipid panel, which is why women with known lipid disorders are recommended to have consultation

01:00:19.020 with a lipid specialist prior to pregnancy. But, you know, even at normal pregnancies, serum total

01:00:24.980 cholesterol, triglycerides, LDL cholesterol, lipoprotein little A, and HDL cholesterol levels all

01:00:32.060 gradually increase. And as pregnancy proceeds, you know, they peak during the third trimester. So

01:00:37.640 you can have about a 25 to 50% increase in total cholesterol, can be as much as 150 to 300% increase

01:00:45.100 in triglycerides, it probably, you know, relative increase the most, and LDL increased by 66%. And so

01:00:51.400 this is normal physiologic changes because it's, you know, designed to promote accumulation of maternal

01:00:58.120 fat stores. That's going to be a source of calories for the mother and the fetus during later stages of

01:01:04.200 pregnancy and lactation. You know, the cholesterol increase is needed for utero placental vascularization,

01:01:11.280 placental steroid synthesis, placental transport function. These are important physiological effects.

01:01:18.440 But these changes when someone like your wife who started out, so it's such low cholesterol levels,

01:01:23.260 these are generally felt to be non-atherogenic because they really do fall precipitately to

01:01:28.620 pre-pregnancy levels following delivery. So pregnancy is not a good time really to get a baseline lipid

01:01:35.680 panel because it's not going to be representative of what a woman's typical lipid panel is. But in women

01:01:41.580 who have concern for lipid disorder, having a baseline lipid panel before pregnancy is helpful so that you can

01:01:48.740 know what to expect. And women with FH, you know, they have the same relative increases, but they're

01:01:55.800 starting with such a high baseline level that the magnitude of elevation is even greater.

01:02:02.700 You know, I realize I've been delinquent in letting us talk shop a bit too much. We haven't defined FH,

01:02:08.340 other than to note that it's familial hypercholesterolemia. We also noted, I think, the

01:02:12.460 incidence or prevalence of about 1 in 200. But we've been a bit delinquent in giving people

01:02:17.280 the magnitude of what it is. Can you just tell folks a little bit about how high a total cholesterol

01:02:22.920 or LDL cholesterol a person with familial hypercholesterolemia typically has and what the

01:02:28.180 lifetime risk of ASCVD is in that population? Yeah, I think we mentioned at the beginning that

01:02:33.300 it's about 1 in 250, 1 in 250 people have FH and it's being autosomal dominant that women are equally

01:02:39.420 affected as men. So the FH phenotype LDL above 190, you know, there are different scoring systems that

01:02:48.940 you can look with additional criteria based on family, personal family history of ASCVD and genetic

01:02:54.840 tests are available. And there's apps that you can download to determine the likelihood that your

01:02:59.840 patient has, you know, definite or probable FH. Just even having the phenotype of having an LDL above

01:03:05.820 190, which is not all monogenic FH, that is still associated with increased lifetime risk with a

01:03:13.200 20 to 30 year earlier onset of ASCVD in females. But if they have the genetic mutation, you know,

01:03:20.640 having the monogenic mutation, their increased risk is even greater than their LDL value. So

01:03:28.560 that's why genetic testing is really helpful, not only for cascade effects for determining the risk of

01:03:35.540 their first degree relatives and their offspring, but also because they have a greater risk even

01:03:39.860 beyond their absolute LDL value. But so 30% of women with an untreated FH will have a myocardial

01:03:46.280 infarction before the age of 60. And this is why it's so important that we can't ignore FH, we need

01:03:51.400 to know FH, we need to screen for FH, and we need to treat FH. Women get the same onset as men, they don't

01:03:57.040 have the female advantage. And probably because they're losing many years of statin therapy,

01:04:01.180 because this concern about pregnancy, women with FH are undertreated. I should note that women with FH

01:04:08.160 don't have an increased risk of congenital malformations or preeclampsia, which is good, they may have a

01:04:15.000 slight increased risk, greater risk for myocardial infarction. So we can talk about shared decision

01:04:19.680 making about treatment during pregnancy versus, you know, withholding for a short period of time during

01:04:25.560 pregnancy and lactation. But interestingly, in some countries, you can actually test for

01:04:30.640 the mutation in cord blood. And lipid levels in children with FH are similar whether they inherited

01:04:37.040 the gene from their mother or the father. But for contraception, because of their increased risk

01:04:42.760 for atherosclerosis, you know, we would want to avoid any higher estrogen compounds, either use low-dose

01:04:50.200 estrogen oral contraceptives or preferably IUDs or barrier techniques, especially if they're over

01:04:56.660 the age of 35 to kind of avoid the estrogen oral agents, even low-dose, and consider the IUD for

01:05:02.820 contraception. So of course, most people with FH, we don't really know the genetic cause of this.

01:05:09.680 You know, last I checked, there were probably more than 2,500 different genetic mutations that produce

01:05:14.420 that phenotype. So this is an interesting point that there's still value in looking. In other words,

01:05:19.160 just having that phenotype, how many of the genetic drivers of FH do we know and contribute to that

01:05:25.600 very interesting point you made, which is identifying that specific genetic driver carries

01:05:30.780 with it even greater risk than is embedded within the LDL? When I see patients clinically for evaluation

01:05:35.800 of FH, I do send them if they're willing for genetic testing, you know, trying to discern whether they have

01:05:41.460 the monogenic FH from a mutation and the LDL receptor or EPOB or PCSK9. Of course, polygenetic

01:05:49.180 risk can have a similar phenotype to FH. We certainly want to reduce their lipids. So this comes up,

01:05:56.500 you know, because we were talking about pregnancy and, you know, there had been so concern for so long

01:06:01.780 about, you know, avoiding statins in pregnancy, you know, for a while it had that category X.

01:06:07.180 And so this actually led to overabundance of caution with just not treating women of reproductive age

01:06:14.960 with statins at all because of fear that they might accidentally become pregnant. And that we

01:06:20.040 really, of course, do them a disservice if a third are going to be at risk for an MI before the age of

01:06:24.580 60 if they have FH and we don't treat. Especially because now, you know, we have more data suggesting,

01:06:30.680 you know, studies of women who did become pregnant while on statins that did not show the

01:06:35.600 teratogenic effects. And so statins are probably not teratogenic. You know, we don't have a ton of

01:06:42.220 data here, which is why we still have some caution, which most women who are planning a pregnancy,

01:06:49.300 you know, we do generally still stop the statins during conception, during pregnancy, and during

01:06:54.860 breastfeeding as shorter term interruptions is better than, you know, not treating them for decades

01:07:01.660 and decades. But with the removal of the strongest warning label by the FDA, this does give us some

01:07:07.880 more flexible options. So in patients at very high risk, such as women who've had a recent acute

01:07:13.600 coronary syndrome, as part of shared decision making, we could consider using statins during

01:07:19.680 pregnancy. But, you know, we still have less data. So for most women, we're still stopping the

01:07:25.400 statins. But if they do become pregnant, you know, I usually reassure them and we just stop the

01:07:29.740 statin once pregnancy has become aware. But I think there's a really interesting body of work now

01:07:35.800 about whether statins can actually prevent preeclampsia. So in the setting of preeclampsia,

01:07:41.740 there is this abnormal trophoblast invasion, and this leads to impaired spiral artery remodeling.

01:07:49.020 So essentially what's happening is there's placenta ischemia, and this sets off a whole cascade of

01:07:54.300 adverse hormonal and anti-inflammatory markers. So we have this increase in S-flip-1 and a decrease

01:08:01.840 in placental growth factor. There's, you know, this increased sensitivity to angiotensin-2.

01:08:07.680 There's other inflammatory and oxidative stress. And this sets the stage not only for complications

01:08:14.460 during the pregnancy like preeclampsia, but also is likely contributing to vascular damage that

01:08:19.980 increase a woman's risk, you know, long-term after delivery. So statins are being, you know,

01:08:25.440 investigated for preeclampsia prevention because we know in animal studies, they can decrease S-flip-1,

01:08:31.320 they can improve endothelial function, they can decrease inflammation and oxidative stress.

01:08:36.220 So they seem promising. There was one study that was published where they gave women who are pregnant

01:08:43.720 who are increased risk of preeclampsia, pravastatin starting at 35 weeks gestation,

01:08:48.880 and didn't show any benefit in preventing preeclampsia. But this isn't really surprising

01:08:54.180 because it was just given way too late. You know, if you know anything about the pathogenesis of

01:08:58.940 preeclampsia, you know, preeclampsia can generally start after 20 weeks of gestation. So you likely

01:09:04.240 would have to intervene, you know, much earlier in the process. So there is a randomized clinical trial

01:09:09.500 ongoing now, enrolling about 1,500 women who are high risk because of a prior history of preeclampsia.

01:09:15.320 And they're starting the statin, pravastatin versus placebo earlier around 12 weeks of gestation.

01:09:22.360 So right after the first trimester, the primary outcome is going to be a portion that developed

01:09:27.860 preeclampsia or protein loss and maternal death. And they're looking at other things like preterm

01:09:32.640 delivery. So it'll be really interesting to see those results. We don't have those results yet,

01:09:37.260 but it may be a whole pendulum switch from this absolute avoidance of statins during pregnancy

01:09:43.640 to maybe actually using statins for preeclampsia prevention if this trial is successful.

01:09:50.860 Do you think broadly we're seeing a greater trend towards statin, I don't know, phobia for lack of a

01:09:55.860 better word?

01:09:56.720 Well, yes, even in sort of the non-pregnant state.

01:09:59.580 I meant even more broadly. Yeah, exactly. I meant just across all of your patients.

01:10:02.540 First of all, I think there's some misconceptions out there that I still hear people cite this false

01:10:10.200 statement that statins don't work in women in primary prevention. And that's completely not

01:10:15.000 true. You know, in the older studies, they just didn't enroll enough women in trials and in primary

01:10:20.440 prevention, you know, they're at lower risk. So they're less likely to have events during the short

01:10:24.780 terms of the trials. But, you know, now we have enough trials, the data's in, and meta-analysis that

01:10:30.840 included, you know, over 18 randomized clinical trials, over 40,000 women have shown that statins

01:10:37.160 benefit women in both primary and secondary prevention without interaction by sex. So meaning

01:10:43.300 in similar risk individuals, women benefit from statins just as much as men in both primary

01:10:49.060 prevention where there was a 15% reduction in major adverse cardiovascular events, as well as for every

01:10:54.720 one millimole per liter or 39 milligrams per deciliter lowering of LDL. And in secondary prevention,

01:11:00.300 a little bit greater, 22% reduction, as well as all-cause mortality was lower in women with

01:11:05.440 statins. So women benefit from statins. What's the NNT on both of those, Erin?

01:11:10.480 I would have to get back to you from the meta-analysis. I don't know offhand, but of course,

01:11:15.100 NNT is going to depend on primary prevention versus secondary prevention. And of course, the women

01:11:19.460 that were enrolled in these trials were at higher risk. But the important thing is that they benefited

01:11:24.360 similarly to men with no effect interaction. That's what I was kind of getting at. Was it in the

01:11:30.280 ballpark of men where your primary preventions could be anywhere from 60 to 100 and your secondary

01:11:36.940 preventions might be, you know, 30 to 50? Does that sort of, those numbers kind of ring a bell to me.

01:11:43.660 That sounds about right. I just don't have that data right in front of me, but that sounds about

01:11:47.760 right. I can look that up for you. But despite the evidence clearly showing that they benefit,

01:11:52.800 to get back to your original question, women are less likely to be offered a statin. We saw this

01:11:58.000 from the palm registry, and if offered, women are more likely to decline or discontinue.

01:12:03.160 In the usage registry, women were 30 to 50% more likely to report statin-associated muscle symptoms

01:12:08.840 and stop statins for this reason. You know, even in secondary prevention, studies of individuals who

01:12:14.640 have post-myocardial infarction, you know, young women under the age of 55 were significantly less

01:12:19.940 likely than men to be on a statin, you know, two months after their MI, you know, and these are the

01:12:25.340 highest risk individuals. The reason am I, and women are still less likely to be on a statin.

01:12:29.940 I know one of my own studies, using nationally representative data from the Medical Expenditure

01:12:34.400 Panel Survey, is weighted to represent U.S. adults with ASCVD. So it's weighted to represent 11

01:12:40.420 million women with ASCVD. Women were 45% less likely to be treated on a statin than with men.

01:12:46.940 So we know there's lots of-

01:12:48.440 Erin, how much of that do you think is on the shoulders of the physician for either being

01:12:54.340 ignorant or just, I guess ignorant would be the only excuse, not offering the statin versus how

01:13:00.540 often is the physician doing the right thing and the patient, as a woman specifically, is saying,

01:13:05.340 you know what, this is not the right thing for me?

01:13:07.660 So the palm registry shows women are less likely to be offered. And so this is on the physician side.

01:13:13.260 We see this across all kinds of subgroups, both in primary prevention, secondary prevention,

01:13:19.840 and also whether they were treated by, you know, a cardiologist or primary care, you know,

01:13:24.040 women are less likely to be on a statin. But if offered, if the clinicians do the right thing and

01:13:29.440 offer, women are more likely to decline or discontinue. This is a combination of things.

01:13:34.340 You know, women may still perceive themselves to be lower risk. Women may be more fear adverse.

01:13:40.300 They also, women are report more likely to have statin-associated muscle symptoms. And so

01:13:45.680 this gets down to how much is real versus the nocebo effect. You know, is it biological differences

01:13:52.100 related to women's smaller body size, influenza hormones, or is it that maybe women are more

01:13:58.860 socialized to report symptoms or read these warning labels or, you know, or a possible symptom

01:14:05.940 that could happen or be more concerned? I mean, we have overwhelming data about the safety of

01:14:11.600 statins. Serious muscle injury is one in 100,000. In randomized clinical trials, there's no difference

01:14:17.320 of muscle symptoms between treated and placebo. But we know in real world practice, you know,

01:14:21.920 up to 30% of statin-treated patients will report muscle symptoms. So there's this tremendous

01:14:27.420 nocebo effect. In trials like the SAMSUM trial, up to 90% of statin-associated symptoms was

01:14:34.320 elicited by the placebo too. So patients were having symptoms on the statins, but 90% of those

01:14:40.620 symptoms were also elicited on the placebo. So it really wasn't as more the act of taking the

01:14:45.260 medication compared to the medication itself. So we know the nocebo effect is real, but the problem

01:14:52.080 is, is that this can be challenging to counsel. There's a lot of medical misinformation out there.

01:14:57.780 And when an individual, the symptoms are real to them, and if they're convinced they're having

01:15:02.840 these symptoms, you know, it can be hard to break that mindset. My practice is all about building

01:15:08.800 trust and, you know, we build a relationship over time. And sometimes, you know, I start slow or do

01:15:13.960 alternative doses three other day or three times a week and trying to get individuals back on their

01:15:18.880 statin and show that they tolerate them and have them take a muscle symptom survey and show that a

01:15:24.220 lot of the aches and pains that they have, you know, were unrelated to the statin. But the good news,

01:15:28.780 at least, is that we're at least in an era that we have more options than we did before.

01:15:33.680 Though all individuals who have report statin-associated muscle symptoms or statin intolerance,

01:15:38.660 you know, really should be given a re-challenge for our highest risk patients. We have other things.

01:15:43.600 Zetamine, we have the PCSK9 inhibitors, we have clizorin, bumbadoic acid, and more things in the

01:15:48.860 pipeline. So we have ways to get to LDL goal if patients are willing to work with us. And, you know,

01:15:55.540 while these other therapies are meant to be as an adjunct to diet and lifestyle and maximally

01:16:01.160 tolerated statins, for some patients, the maximally tolerated statin is zero statin. And so sometimes

01:16:07.560 we have to move to some of these other agents to get their LDL under control.

01:16:11.740 Aaron, what's your statin workflow? How do you work through a patient with a statin? So

01:16:17.200 my behavior on this front has evolved a little bit in part just due to experience, but also in part due to

01:16:24.080 the arrival of these other agents that you mentioned, the big three being ezetamide,

01:16:29.300 PCSK9 inhibitors, and most recently, bumbadoic acid. But these days, I really find myself only

01:16:34.100 fiddling with about three statins, truthfully. And this excludes patients who show up on one already

01:16:39.320 that they inherit. So a torvastatin or something like that. But in terms of a naive patient,

01:16:44.600 I would say it's really mostly two. It's really rizuvastatin and then patavastatin with occasional

01:16:49.700 prevastatin. You can imagine, obviously, the order in which we do that based on symptoms and need.

01:16:55.580 Walk me through your thinking specifically for women. So a woman comes in, doesn't have FH,

01:17:01.960 family history is notable for atherosclerosis, but nothing incredibly premature before the age of 60.

01:17:09.920 Her APOB is the 70th percentile concordant with her LDL-C. And after months of being your patient,

01:17:19.300 she says, you know, okay, I sort of buy this thesis, which is I'm 40 years old. My LDL is only going to go

01:17:26.600 up from here. So let's start to take preventative measurements. So this is true primary prevention

01:17:31.860 in a relatively low 10-year risk patient. And you have no reason to be concerned with anything else.

01:17:38.300 So what's your first line agent? What dose? And how do you proceed if there's issues?

01:17:43.160 The highest risk patients, and we'll get back to your primary prevention patients,

01:17:46.100 the highest risk patients with ASCVD, you know, we want to obviously get as low as possible,

01:17:50.600 as quickly as possible, lower for longer, for faster. And so we do a lot of disservice by starting

01:17:56.280 these really low dose statins and they don't come back for six months to a year and then they never

01:18:00.620 get intensified and patients don't get to goal. So the highest risk patients starting with a high

01:18:05.660 intensity statin, if you start up front, that's more likely the dose that they'll stay on and use

01:18:10.100 of combination therapy early. So, you know, just like blood pressure, if it's above 160, you know,

01:18:16.040 we're thinking combination therapy for blood pressure. And I have the same approach really

01:18:19.940 for lipids for very high risk patients, such as the ones with the recent coronary syndrome,

01:18:25.180 that, you know, we know what their starting LDL is and where we want to go. And I always try to aim

01:18:30.340 for at least less than 55. Optimal LDL is probably, you know, around 30 or lower in these patients.

01:18:36.180 You know, if where you need to go, high intensity statins will lower the LDL by about 50%. But if

01:18:41.320 you need a greater reduction, thinking about combination therapy early, we have some data

01:18:46.760 now about the safety of giving PCSK9 inhibitors, even in the hospital setting after an acute myocardial

01:18:52.920 infarction can have important changes in plaque stabilization and plaque reduction. So being very

01:18:58.660 intensive about those treatments, I want to make the plug about using combination earlier and more

01:19:03.680 aggressively. And your lower risk primary prevention patient that you started with,

01:19:09.080 the moderate intensity statin would be fine. I mean, it depends on their age. If it's a man over

01:19:13.460 40 or women over 50, get a coronary calcium score. You know, if they're above the 75th percentile,

01:19:19.280 also thinking high intensity statin and aiming for an LDL less than 70, which is also consideration of

01:19:26.080 PCSK9 inhibitors, even in primary prevention patients, if they have significant lack, you know,

01:19:31.820 very high calcium scores above 300. But, you know, in a lower risk person where we're just trying to

01:19:37.720 shift them some lower. And sorry, just going back to that, Erin, I know it wasn't my question,

01:19:41.860 but since you brought it up, is your preferred two line out of the gate, resuvastatin and ezetimibe?

01:19:48.600 Is that your typical starting one, two punch?

01:19:50.720 I mean, again, it depends where they are and where we start with. They're very high risk.

01:19:56.640 They have ASCVD and they're very high risk.

01:19:58.840 You're going to go PCSK9 plus.

01:20:01.000 Yeah, especially if they have elevated lipergidyl A because statins, ezetimide,

01:20:05.680 vampidoic acid don't lower lipergidyl A. So if they had an ASCVD event, it used to be to get the

01:20:11.380 PCSK9 improved that you had to be on statin and ezetimide before you could get PCSK9 approved. So I used to

01:20:17.020 use both just knowing that I'm going to move to PCSK9. Now it's a little bit easier to get the

01:20:22.120 PCSK9 approved, even if you don't have ezetimide on board. So these very high risk patients,

01:20:27.060 because ezetimide, you know, you can lower LDL by about, you know, 16 milligram per deciliter,

01:20:32.420 but you want to really get the LDL way down in these very high risk patients. I'm moving pretty

01:20:37.560 quickly to PCSK9 inhibitors, but in lower risk.

01:20:40.660 Do you have a preference, by the way, between proluent and repatha?

01:20:44.300 You know, so they were never compared head to head. So they, evalacumab and aliracumab had a

01:20:50.020 similar 15% reduction in major adverse cardiovascular events in their respective

01:20:55.380 trials, the four-year at Odyssey trials, and they had similar reduction in lipergidyl A as well.

01:21:01.080 I tend to use, I mean, I use whatever one I can get approved. So it often is, depends on the

01:21:05.900 patient's insurance mostly. If all things, you know, being equal and either one being approved,

01:21:10.660 I probably tend to use more evalacumab because you don't have to do the dose adjustment.

01:21:15.840 The SureClick patent is really easy. We have our nurse in our clinic, teaches patients, and

01:21:20.600 I have lots of patients on aliracumab as well. Closerin, you know, we're just starting getting

01:21:26.220 experience with onboarding. Tell folks what that is.

01:21:29.900 So the PCSK9 inhibitors that we were talking about, the evalacumab and aliracumab are monoclonal

01:21:36.080 antibodies. So PCSK9 is a hepatic protein that's involved with LDL receptor degradation.

01:21:45.580 And this was really interesting how quickly we moved from understanding from genetic studies

01:21:49.520 all the way to translational studies and from the bedside. You know, we know that individuals with

01:21:55.940 PCSK9 genetic mutations that were loss of function, these individuals had very low LDLs and very

01:22:05.940 low risk of cardiovascular disease of a lifetime, where gain of function PCSK9 had high LDLs and

01:22:11.920 increased CVD risk. So by inhibiting this protein, by inhibiting the PCSK9, it prevents the LDL receptor

01:22:21.080 degradation so that there is an upregulation of LDL receptors on the surface of the hepatocyte,

01:22:27.420 which leads to greater clearance of LDL out of circulation. Those were the monoclonal antibodies,

01:22:33.100 and we have, not only do they lower LDL by about 50 to 60%, they also have some modest lipopertile

01:22:40.820 A lowering around 25%. But we have two outcome trials, Fourier and Odyssey, Fourier being in stable

01:22:47.300 ASCVD and Odyssey and patients with recent acute coronary syndrome that show that they also reduce

01:22:53.260 major adverse cardiovascular events, as we would anticipate. And we now have longer term data for

01:22:59.440 follow-up, which, you know, shows even after these trials end, that earlier exposure to evalacomab to

01:23:05.880 exposure to lower LDL has a legacy effect with continued lower risk of events. So I think that

01:23:13.140 the trials were pretty short, around two years, and the curves were just starting to separate. So I think

01:23:17.080 with longer treatment, you would have had even a greater reduction. Since we're talking about women,

01:23:21.500 I will just mention, unfortunately, both of these trials, women were only about 25% of participants.

01:23:27.000 You know, women start out with higher LDLs for various reasons. You know, after menopause,

01:23:33.440 women tend to have higher LDLs compared to men, but that they had a similar reduction in LDL with

01:23:40.240 PCSK9 inhibitor therapy. In terms of MACE reduction, there was no interaction by sex, meaning that women

01:23:47.680 benefited. These high-risk women who either have ASCVD or recent acute coronary syndrome benefited to a

01:23:53.160 similar degree as men did. There was no major adverse event difference between the sexes, although women

01:23:58.740 are more likely to report injection site reactions. So those have been available for a while, and they're in the

01:24:03.700 guidelines now as an add-on to statins in high-risk patients with ASCVD or heterozygous FH who need

01:24:10.280 additional LDL lowering. I also use them in high-risk primary prevention, such as those with high calcium

01:24:15.840 scorers who need LDL lowering. But Enclosirin is the new kid on the block. So this inhibits PCSK9,

01:24:23.140 but through a different mechanism. It's a small interfering RNA, so it prevents the translation

01:24:29.880 of the PCSK9 protein from being made. We have data from the Orion 9, 10, and 11 trials, which was looking

01:24:40.200 at LDL lowering, showing that, again, you know, women had higher LDLs at baseline, but they had

01:24:46.340 similar reduction with Enclosirin. Notably, the mechanism in this little different is that, you

01:24:51.980 know, it's a subcutaneous injection, but after the first baseline in three months, it's given every six

01:24:57.020 months. So it's designed to be given in a clinic setting as opposed to monoclonal antibodies, which

01:25:02.620 people give at home. And the frequency of every six months may be attractive for adherence because you

01:25:08.960 give it in the clinic only one more time a year than a flu shot, and you can lower LDL by about 50%.

01:25:15.560 So it may be helpful for adherence. It has been approved for LDL lowering, and we're starting to

01:25:22.340 onboard it throughout the country in our clinics. But it should be noted that we don't yet have the

01:25:27.200 outcome data. The Orion 4 is the cardiovascular outcome trial that's ongoing. I anticipate with a

01:25:35.280 50% reduction in LDL that this will certainly translate into a reduction of major adverse

01:25:40.100 cardiovascular events, but we, you know, don't have that data yet. But these are all potential

01:25:45.020 options for patients that need more intensive LDL lowering. You can also mention bembedoic acid to round

01:25:51.860 out the new drugs that are available. This one also might be interesting in women. So bembedoic acid is an

01:25:57.260 oral drug. And so it blocks ATP citrase lyase, which is an enzyme in the cholesterol synthesis pathway.

01:26:05.760 So it's upstream of HMG-Coase reductase, which statins inhibit. Kind of works like in the pathway

01:26:11.280 where statins work, where it blocks cholesterol synthesis. And so by blocking cholesterol synthesis,

01:26:17.000 this leads to upregulation of the LDL receptor on the surface of the liver and more clearance of LDL

01:26:23.120 out of circulation. But what's notable about this is that prodrug,

01:26:27.040 the enzyme to activate it, it's only in the liver, not in the muscle. So it does not have the same

01:26:33.180 reported muscle symptoms that have been seen with statins. And also interestingly, it doesn't seem to

01:26:39.600 have the risk of new onset diabetes or the increase in glucose that we see with high intensity statins.

01:26:47.580 So alone, bembedoic acid lowers LDL about 18%. So kind of in your range of ezetamide,

01:26:53.680 you know, a little bit more lowering if it's used as monotherapy without statins, about 21% in statin

01:27:00.520 intolerant patients, it does come as a fixed dose combination with ezetamide. And together with

01:27:06.280 ezetamide, you see kind of greater about 36% reduction in LDL. So you're kind of getting in

01:27:12.160 the range of your moderate to high intensity statins. Notably, actually, in pooled analyses from

01:27:18.060 the clear studies, which were the studies looking at, you know, the LDL lowering effects of bembedoic

01:27:23.820 acid, we see that in ASEVD and FH patients that women seem to actually have a little bit even

01:27:30.000 greater LDL lowering with bembedoic acid than men. And they were more likely to achieve a 30% reduction

01:27:36.400 in LDL with bembedoic acid than men. Since women are more likely to have statin associated muscle

01:27:41.920 symptoms, and this agent doesn't cause that, this may be a good choice as an oral therapy for women

01:27:48.040 who can't get their LDL control on a statin or don't tolerate a statin. So just for the audience,

01:27:54.600 we don't have outcome data yet for this either. It's been approved for LDL lowering, but the big

01:27:59.820 cardiovascular outcome trial, CLEAR Outcomes, enrolled a population with statin intolerance.

01:28:05.340 And I was really pleased that nearly 50% of trial participants were women, likely because women are

01:28:10.760 more likely to have statin intolerance. So this has been closed out, and we're anticipating we may

01:28:16.020 hear the results maybe in March of 2023, hopefully. Is this secondary prevention, Erin?

01:28:22.740 No, this is high-risk patients that have statin intolerance. So high-risk primary prevention,

01:28:28.440 statin intolerance. Yes, and secondary prevention patients with statin intolerance.

01:28:32.320 I got you completely off topic from our original question, which was low to moderate risk,

01:28:37.840 low to moderate short-term risk. Obviously, long-term risk, everybody is high risk. It's

01:28:42.560 important to say that. Long time horizon, we're all high risk. Everybody gets atherosclerosis if

01:28:46.660 you live long enough. But we've got our woman whose LDL cholesterol is 130 to 140 milligrams per

01:28:51.600 deciliter, and she's in her 30s. She gets it, right? She says, look, nothing's going to happen to me in the

01:28:58.100 next decade, but I'm playing the long game here. I don't want to have atherosclerosis in my 80s.

01:29:02.160 What's your algorithm for statin choice out of the gate?

01:29:05.300 I tend to use one of the high-intensity statins that can have a little bit more potent LDL

01:29:09.740 lowering, like a Torva or Resuva. If they don't have CKD, because it's important to note that

01:29:15.680 Resuva does need to be dose-adjusted if patients have chronic kidney disease, but assuming otherwise

01:29:21.180 healthy individuals... Yeah, say she doesn't.

01:29:23.200 I use a lot of Resuva. In my experience, they tend to have a little bit less muscle-associated

01:29:28.580 symptoms. Psychologically, the doses, we do 5, 10, 20. Patients feel like they're

01:29:35.280 taking a lower dose when compared to the Atorva, you know, 20, 40, 80. You tell patients you can't

01:29:40.160 compare milligrams from one agent to another agent because they're completely different drugs.

01:29:44.960 People think they're taking lower drugs, so lower doses. So sometimes there's a lot of buy-in,

01:29:49.680 and I have a lot of patients refer to me because they're a little bit statin-reluctant or statin-hesitant.

01:29:56.260 So again, this is all in a background of lifestyle changes, but if they are concerned at all,

01:30:01.840 sometimes I use just Resuva 5. It's more about buying their trust and getting them used to the

01:30:07.600 idea of taking a statin. And we know even in statin-intolerant patients, even if we do Resuva

01:30:12.160 5 milligrams three times a week, we still can have significant LDL lowering compared to no statin at

01:30:18.080 all. So for patients that have been statin intolerant, statin-reluctant, just getting them

01:30:23.000 to take a low dose. And then seeing a little bit is believing. And so when we start getting their

01:30:27.140 numbers back and making progress, often then we can adjust up there based on how things are going.

01:30:34.120 You know, high-risk patients, you know, I start at the highest dose right out the bat.

01:30:37.460 Sometimes patients want to check vitamin D and thyroid levels and take coenzyme Q10. There really

01:30:43.920 isn't very good data that coenzyme Q10 prevents statin-associated muscle symptoms. But if my patients

01:30:50.140 want to take that because it makes them feel better, with the concept of taking a statin, I don't object to it,

01:30:55.600 but I don't actively prescribe it because there really isn't good data that it really

01:31:00.080 blocks this. The same thing with vitamin D. There really isn't good data that taking a vitamin D

01:31:05.820 supplement can prevent statin-associated muscle symptoms. But many patients, you know, want to

01:31:11.460 take that. And, you know, my philosophy is if I could get them on the statin and get their LDL

01:31:16.000 lowering, you know, I'm willing to work with them on some of these other things, really trying to get

01:31:20.640 their buy-in to get them on a therapy that will lower their LDL. And it's really important that I

01:31:25.520 do refer them to our, we have a preventive cardiology nurse who discusses nutrition because I don't

01:31:30.160 want them to think that I don't value diet and lifestyle. You know, we know that a lot of lipids is

01:31:35.820 predominantly genetically determined, but there is influence in diet. And I want to emphasize to my

01:31:41.000 patients that this is really a combination approach and that I do take diet and lifestyle, you know, very

01:31:46.340 seriously as well.

01:31:47.220 What type of an impact do you think you can see with manipulating diet, presumably mostly through

01:31:53.820 the types of fats they're consuming, but more broadly, is there how aggressively can you use

01:32:00.140 dietary manipulation, especially in a woman who, for whatever reason, be it pregnancy or just

01:32:05.740 reluctance, is hoping to minimize, if not avoid the use of lipid lowering medication?

01:32:11.120 You know, about three fourths or 80% of LDL is synthesized by the liver. So there's, you know,

01:32:18.000 is a strong genetic component. I have lots of patients that are strict vegan and do everything

01:32:23.240 right. And they still have high cholesterol and they get so frustrated. And I, you know, this is

01:32:27.440 genetically determined. And if they had a bad diet, their numbers would be so much worse. And so

01:32:32.860 it's important to note all the good things that they're doing for their diet, but also acknowledge

01:32:38.280 that sometimes they're going to need a little help with pharmacotherapy because of the strong

01:32:41.580 genetic determination. But, you know, around the other 20% is influenced by diet. So diet does

01:32:47.900 matter, particularly in younger adults, when we're thinking about adolescents and young adults,

01:32:53.020 you know, especially when they start earlier in life, if we can shift everybody a little bit lower

01:32:57.520 in their LDL by following a healthy diet, really, since, you know, early childhood, if we can shift

01:33:03.100 everybody lower on LDL, this will reduce the total burden of years with LDL elevation.

01:33:08.280 So, you know, we counsel about reduction in saturated fats and focusing on the healthier

01:33:12.740 fats, the polyunsaturated and the monounsaturated fats, increasing fiber, fruits, vegetables,

01:33:19.780 whole grains into their diet, really trying to avoid processed foods, which are the worst,

01:33:25.720 especially processed meats. There are some patients that have already have a CBD and they don't want to

01:33:31.820 take a medicine. And, you know, at this point it's like too late, you know, diet's important,

01:33:35.840 but you already have plaque in your arteries. You're pretty far along in the process and we

01:33:41.120 need to do everything to prevent further progression and even reverse. And we know from,

01:33:46.580 you know, the IVA studies that high intensity statins and significant LDL lowering can cause

01:33:53.400 atheroma volume regression. So it's really a combination of pharmacotherapy and lifestyle

01:33:59.340 changes. But for a very low risk young adult, I push as hard as we can with healthier lifestyle

01:34:05.700 changes. You know, it's sort of funny. I've gone back and forth on this stuff so much, Aaron, and I

01:34:09.840 probably sound like a heretic at the moment, but I just sort of went through and reviewed as many of

01:34:15.400 the Cochrane collaboration meta-analyses as I could sort of stomach on all of the different fatty acid

01:34:22.620 impacts on cardiovascular disease. So if you look at the Cochrane collaboration in 2019,

01:34:27.860 that looks at the role of PUFAs and then the one in 2020 that looks at the SFA substitution with PUFA

01:34:33.620 and MUFA. And if I came away from this with anything, it's that I don't know how much any

01:34:38.520 of that stuff matters once you're in energy balance. In other words, in the context of over nutrition,

01:34:44.340 I think it all is bad. In the context of adequate nutrition, the ambiguity in these data were enormous.

01:34:53.380 And, you know, I was left basically thinking, look, on the basis of PREDIMED and the Leone heart study,

01:35:03.520 in addition to some epidemiology, MUFA is probably the most important fatty acid. And therefore, let's just

01:35:10.040 call it 50% of your fat intake should probably be MUFA. And, you know, probably after that looks like PUFA

01:35:18.420 is a little bit better than SFA, but I certainly couldn't find a shred of evidence to suggest that

01:35:24.460 aggressive restriction of SFA was in any way protective. Now, of course, the opposite, which

01:35:30.540 was you do see people that are consuming massive amounts of saturated fat and who have incredible

01:35:36.240 hyper-beta lipoproteinemia. You know, I think that's a clear problem. But, you know, when I think about

01:35:43.300 all of the lifestyle factors, I wonder if the one that gets the least attention that has the greatest

01:35:48.940 impact is stress, you know, because we don't have a pill for it. We can offset the harm of nutrition

01:35:56.060 so much easier with pharmacotherapy. And yet a person walking around with simmering hypercortisolemia

01:36:03.340 and the effect that that's having on their endothelium and, you know, their sympathetic nervous system,

01:36:09.200 I feel like that's the one that I wish we had a better handle on as far as how to help people.

01:36:14.660 Because again, we don't have a pill right outside of blood pressure management. We don't really have

01:36:18.960 a pill for that. What are your thoughts on the role of stress? It's such a dumb buzzword that I hate it,

01:36:25.140 but I really think physiologically it's problematic. Well, first of all, you know, I didn't say about

01:36:29.820 aggressively low saturated fat diet. The guidelines, the HAACC guidelines really are talking more of a

01:36:35.960 moderate fat intake diet. And really a Mediterranean style pattern, as you alluded to, is what I recommend

01:36:41.200 to my patients. You know, maybe I'm biased because I'm half Italian, I'm married to a Greek, but we do

01:36:45.940 have both observational data and clinical trial data. A Mediterranean style diet is pretty palatable and

01:36:51.880 it's pretty easy to follow without getting too crazy. And it's, you know, generally low in saturated fats

01:36:58.260 and generally higher in the unsaturated fats, lots of fruits and vegetables, but it's also the

01:37:03.800 Mediterranean lifestyle with increased physical activity, more social connection and reduced stress. And I'll add

01:37:11.200 in there the importance of physical activity. Although exercise maybe has less impact on lipids per se than

01:37:17.380 diet, it has significant impact on overall cardiovascular risk with both helping with weight maintenance, but

01:37:24.420 also increased levels of fitness is being more fit is one of the strongest favorable factors for lower

01:37:30.880 cardiovascular risk. So I definitely encourage regular physical activity as well. So I do think

01:37:36.120 mental health is very important that we also address you can't talk about cardiovascular health without

01:37:40.660 talking about mental health. And I was a co author on the American Heart Association statement that came

01:37:47.280 out last year about the mind heart body connection where we really talk about both positive psychological

01:37:53.160 factors and negative psychological factors both influence cardiovascular health, both in indirect ways,

01:38:00.640 and direct ways. So what do I mean? So in indirect ways, so individuals with more negative psychological

01:38:06.520 factors like anxiety, stress, depression, anger, you know, they might be more likely to have poor coping

01:38:12.800 habits, such as they might be eating more poorly and not getting physical activity and having more smoking

01:38:19.400 or more alcohol intake, you know, and less follow up with preventive interventions. So it's sort of the

01:38:26.120 indirect mechanisms where the positive psychological factors as individuals may be more likely if they

01:38:31.860 have a sense of purpose and more optimism to be, you know, eat healthy and exercise and take their

01:38:37.800 medications at fault with preventive visits. But there also may be direct mechanisms as well, that stress

01:38:44.560 leads to activation of the sympathetic nervous system, increasing heart rate, increasing blood pressure,

01:38:50.760 increasing release of stress hormones like cortisol that can lead to more insulin resistance, more fat

01:38:57.420 deposition and the visceral cavities, and more low grade chronic inflammation. And we know that

01:39:03.700 inflammation can also be a trigger for plaque rupture. So I do think it's important that we think about the

01:39:10.020 whole person. And you know, we can make all these recommendations about managing their lipids and things. But if we

01:39:15.640 don't take into account some of the challenges that they have in their personal lives and social

01:39:20.600 determinants of health, you know, we may not be able to effectively deliver preventive interventions.

01:39:26.380 Completely agree with everything you said. And sorry, I didn't mean to apply that you were suggesting a low

01:39:31.060 saturated fat diet. I was sort of saying that more just as broadly, you kind of hear these extreme

01:39:35.380 views. I guess what I'm getting at building on what you would say is when I think of the five

01:39:40.800 pillars through which we can impact a person's health. So nutrition, exercise, sleep, emotional

01:39:48.280 and mental health, and pharmacotherapy, the lowest impact in my view on cardiovascular disease is

01:39:54.320 through nutrition. I think the other four trumpet all day, every day, and twice on Sundays. I don't

01:39:59.860 even think it's close. And the reason I mentioned this, and the reason I'm on my soapbox about this,

01:40:05.700 is I think the general public seems to think that nutrition is the most important lever in

01:40:10.340 controlling the cardiovascular disease risk. I see this a lot, right? I see the person who

01:40:15.100 ostensibly is eating, quote unquote, a healthy diet. And yet they still have these biomarkers

01:40:20.620 that are horrible. And or they even have evidence of clinical disease. They have a calcification on

01:40:26.200 their calcium score. They have soft plaque on their CTA. And they sort of say, but look, doctor,

01:40:30.840 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

01:40:35.660 want to say to them, no, you don't even have it close to under control. And your diet's not even

01:40:39.040 remotely helpful at controlling this. And if it is, it's, it's rearranging the deck chairs on the

01:40:43.580 Titanic at this point. Those other four things are going to move the needle far more in different

01:40:48.660 amounts in different people. There are some people for whom I think, you know, the stress thing

01:40:51.760 doesn't play a role. And there are other people for whom I think it plays an enormous role. And

01:40:55.240 every time I'm in Europe, I come to the same conclusion you do, which is especially in amazing

01:40:59.380 places like Italy, which is hands down my favorite place in Europe. They're way more active,

01:41:03.860 they eat less, and they just don't give a damn. Like there's just a sense of it's all okay.

01:41:11.440 They're not so wound up the way we are. And I think that counts for, I don't know. I think that's

01:41:17.880 90% of it right there. Let's shift gears for a second. Let's talk about LP little a. It's come up

01:41:22.580 a number of times. And obviously the listeners on this podcast know the ins and outs of LP little a.

01:41:27.520 We've had a number of guests talk about it, but we've never spoken about it through two lenses.

01:41:31.820 One is specifically through the lens of women versus men, anything we need to know.

01:41:37.400 And also I want to now talk about the role of LP little a. You already alluded to it in pregnancy.

01:41:42.340 You know, it is an acute phase reactant in a way. So you wouldn't surprise me that LP little a goes

01:41:46.780 up during pregnancy, but I also want to talk about what happens after menopause, if anything.

01:41:51.080 Sure. I'll talk about that. And then I do want to talk more about menopause because I think we

01:41:54.500 talked about menstrual cycles and premenopause and PCOS and pregnancy, and then we didn't get to really

01:42:00.180 dive into menopause. So yes, I want to go back. That's where I want to go next. So yeah, I want

01:42:04.480 to go from this directly into menopause and then HRT as well, but I wanted to just close the loop on

01:42:08.700 LP little a. So lipoprotein little a. So I know you've talked about this a lot, but just in case

01:42:14.980 there's any new listeners, I'll just briefly recap. It's an LDL like particle that's comprised both of

01:42:21.800 an APO B, which is, you know, a marker of the bad moieties. So it shares protein with other

01:42:27.360 atherogenic lipoproteins. And then it also has an APO lipoprotein A moiety, and that's what

01:42:33.660 distinguished lipoprotein A from LDL. And this APO A is kind of unique because it has these 10

01:42:39.980 subdomains of these Kringle 4 domains and the Kringle 4 too can expand two to 40 times. And so

01:42:46.080 this leads to a lot of heterogeneity in the population. You know, 80% or more of individuals

01:42:52.140 actually carry two different isoforms of APO A, you know, one inherited from each parent. And so

01:42:57.680 it's important to recognize this heterogeneity in the multiple isoforms because this accounts for

01:43:01.920 some of the differences in cardiovascular risk that we see by race, ethnicity, with higher

01:43:06.800 lipoprotein A levels being seen in Black and South Asian individuals compared to white

01:43:11.640 individuals. But in terms of women, there are sex differences. So lipoprotein A

01:43:16.060 generally is 5 to 10% higher in women than in men. But there's changes over the life course where

01:43:22.680 lipoprotein A is relatively constant in men, where in women, it tends to increase after menopause.

01:43:28.860 So it does increase during pregnancy, normal pregnancy between 10 to 35 weeks with about a doubling

01:43:34.860 of the value during pregnancy. And we think since the levels fall back to their pre-pregnancy baseline

01:43:41.860 after delivery, that the short increase is probably not atherogenic, but it does rise during pregnancy.

01:43:48.320 So why do we, you know, care about lipoprotein A? Well, it's pro-atherogenic, pro-inflammatory,

01:43:53.640 and pro-thrombotic, and it's associated with cardiovascular risk. And as likely from

01:43:58.860 endelior randomization studies, you know, causally related to both ASCVD as well as calcific

01:44:04.420 aortic stenosis. And even in individuals who have LDLs less than 70, like in the Copenhagen

01:44:10.620 general population study, a lipoprotein A above 50 milligrams per deciliter is still associated with

01:44:16.980 risk of cardiovascular meds. So it's still associated with risk, even when the LDL is low,

01:44:21.700 and you really need to, you know, measure it because, you know, if you think your LDL is low,

01:44:27.340 you may be missing some residual risk depending on, you know, whether lipoprotein A is making up a

01:44:32.520 significant component of that. And so mendelior randomization studies do suggest that it is

01:44:37.960 causally associated with cardiovascular risk in women, but the impact of therapies and lowering

01:44:45.900 lipoprotein A and what that translates into actually lowering cardiovascular risk, you know,

01:44:50.920 is a little bit uncertain. You know, right now we have apheresis for an option for patients with

01:44:56.160 very high lipoprotein A who have progressive cardiovascular disease. As we mentioned, the

01:45:00.400 monoclonal antibodies of alacumab and aliracumab, as well as in clozarin, can lower lipoprotein A

01:45:05.100 about 20 to 25%. And it seems that actually in those trials that individuals who had the higher

01:45:12.120 lipoprotein A levels actually derive the greatest benefit from those therapies. So it is something

01:45:17.640 that, you know, if somebody is elevated lipoprotein A, kind of think about moving quickly to PCSK9

01:45:23.520 if they have another indication such as elevated LDL. And the reason, you know, why to measure it,

01:45:29.460 we talked about it being a risk enhancer, but also because of these exciting new therapies that

01:45:34.680 are being studied right now in trials, the pellicarsin, which is an antisense alliglionucleotide

01:45:41.420 targeting lipoprotein A, and oposarin, which is a small interfering RNA, also targeting the synthesis

01:45:49.620 of lipoprotein A. And there's some other ones being studied as well, another small interfering RNA.

01:45:55.260 So we'll have to see, you know, there's a cardiovascular outcome trial I'm going right

01:45:58.520 now for pellicarsin, the HORIZON trial, to determine how much does lowering lipoprotein A

01:46:04.260 actually translate into reduction in MACE. And that one trial is enrolling a high-risk secondary

01:46:10.220 prevention population with elevated lipoprotein A.

01:46:12.980 Any concern that we're going to see a rebound increase in LDL with an antisense oligonucleotide?

01:46:18.900 So when you knock out LP little a, all of those additional LDLs that would have been LP little

01:46:25.960 a has just become LPL. So your ApoB concentration stays the same, even though you've shifted the

01:46:32.820 distribution from between LP little a and LDL?

01:46:36.780 I mean, I think this is why we need the trials. So with LDL, there's a pretty linear relationship

01:46:42.900 that we can anticipate with the degree of LDL lowering, you know, by one millimole per liter

01:46:48.520 or 39 milligrams per deciliter with reduction in major adverse cardiovascular events being

01:46:53.220 20 to 30%. And this is why therapies like memphedoic acid and glycerin got approved based on their LDL

01:46:59.660 lowering properties, even without outcome data, because we have a pretty good sense of what lowering

01:47:04.580 LDL is associated with reduced events. We really don't have that data for lipoprotein A other than

01:47:11.060 modeling data. Certainly it's associated with increased risk, but, you know, some modeling

01:47:16.480 data says, you know, you might need to reduce lipoprotein A as much as 50 to 100 milligrams

01:47:20.900 per deciliter to have a meaningful reduction to ASCVD in the short term. And other therapies,

01:47:26.220 for example, you know, niacin lowers lipoprotein A, but was not shown to have clinical benefit

01:47:32.740 in two outcome studies, albeit those studies didn't, you know, enroll based on lipoprotein A,

01:47:37.800 but, you know, we're not using niacin. Same thing with hormone replacement therapy,

01:47:42.260 estrogen therapy or hormone replacement therapy does lower, is associated with lower lipoprotein A

01:47:47.520 levels, but we're not recommending it for the sole purpose of lipoprotein A because particularly in

01:47:53.320 high risk individuals with ASCVD or who multiple risk factors are many years out from the menopause

01:48:00.680 transition, this therapy has been associated with increased cardiovascular risk. So, you know,

01:48:05.400 we really need the data. We know that these agents, pelicarsin and opacirin can reduce lipoprotein A

01:48:12.680 by, you know, 80 to 90%, which is remarkable considering, you know, statins, bemphedoic acid,

01:48:18.660 azetamide, you know, don't lower it at all. Statins may even increase it. You know, PCSK9 is only

01:48:24.140 lower it by 25%. So that's remarkable that we now have therapies that work in terms of lowering

01:48:29.000 lipoprotein A. But what does that mean in terms of event reduction? And I think we've been burned

01:48:34.260 from other studies like the CTIP inhibitor and other studies that biomarker data is sometimes not

01:48:40.520 enough and that you actually have to show that it can meaningfully actually reduce risk. And so maybe

01:48:45.780 offsetting some of the LDL increase, maybe offset any reduction in benefit. The other thing I think

01:48:52.600 which warrants further study is in epidemiology studies of very low lipoprotein A levels, maybe

01:48:58.380 associated with increased risk of diabetes. So what does that mean if you lower it to very low

01:49:02.940 lipoprotein A level? I don't know. So we really need the trial data. Super interesting. I feel like

01:49:08.300 Tom Dayspring recently sent me an analysis of Odyssey, which demonstrated that the greater the

01:49:14.580 reduction in LP little A through the use of Prowl-U-Wend, the greater the reduction in MACE.

01:49:20.740 Am I remembering that correctly? Yeah. So both in Fourier and Odyssey, individuals who experienced the

01:49:28.620 greatest reduction in lipoprotein A had greater relative and absolute reduction in MACE, major

01:49:35.620 adverse cardiovascular events. So it seems to be that lowering lipoprotein A may in part be an

01:49:43.600 important mediator in the benefits that we see with these agents. And it may just not be all due to

01:49:49.440 their LDL lowering effects, but maybe also due to lipoprotein A lowering effects. So that's very

01:49:54.260 encouraging when we think about these new agents. But you know, this is modeling post hoc analysis from

01:50:01.740 these trials and the PCSK9 inhibitors also lowered LDL. So when you now think about agents that really

01:50:09.780 only target lipoprotein A, is that going to be sufficient enough to have a meaningful, significant

01:50:15.580 reduction in major adverse cardiovascular events? I mean, I'm hopeful. I'm really hopeful because I think

01:50:20.060 it's causal. We know it's associated with risk. I'm really excited about the therapies in this area,

01:50:25.440 but got to show me the data. I got to see the outcome data results. Well, let's talk about

01:50:29.580 menopause. You know, I'm amazed it's taken us this long into a podcast to get to it because it's such

01:50:35.280 an important issue. It plays such a huge role in women's health, whether it be dementia, sarcopenia,

01:50:42.720 osteopenia, you name it. But I don't think I've done a dedicated podcast where we look at the effects of

01:50:49.540 menopause on ASCVD. We've certainly danced around it today and we've shown our hands a little bit

01:50:56.080 here, which is this is an accelerator of risk. Can you say a little bit more about why? Is there

01:51:00.760 anything more to it than simply the loss of estradiol leading to an increase in LDL? And if so,

01:51:07.320 what's the actual mechanism by which that's happening? You know, we started off the program

01:51:10.880 talking about hormone levels. So estrogen levels start dropping during perimenopause. And perimenopause

01:51:17.600 can actually last several years before menopause. Menopause is one of those things you don't really

01:51:22.700 know it's happened until it's after it's happened because it is officially sort of diagnosed when you

01:51:28.540 haven't had a menstrual cycle for 12 months, which usually happens around age 51. But earlier onset of

01:51:37.200 menopause before the age of 45 or before the age of 40 is associated with increased cardiovascular risk.

01:51:42.740 With the primary estrogen of women of reproductive age, estradiol drops dramatically. And then there's

01:51:50.240 the changes to estrone E1, which is the weakest type of estrogen formed in the adrenal glands and other

01:51:56.760 adipose tissues. By the way, Erin, am I remembering my biochemistry correctly? Estrone exists in three

01:52:04.820 variants or it can be converted into four hydroxy, eight hydroxy and 16 hydroxy or two, four and eight

01:52:12.240 16 hydroxy estrone. Does that ring a bell at all? And the reason I only bring it up is I feel like

01:52:16.820 one of those was more thought to be involved in the creation of breast cancer.

01:52:22.620 I'm not sure I can speak on that. I'm mostly familiar with just the three major subtypes,

01:52:27.400 the E2 estradiol, the E1 and the E3 among estrone types. I apologize. I don't know that data except

01:52:35.520 that it's a very weak type of estrogen. And so essentially, you know, women after menopause

01:52:41.720 really have very low levels of estrogen. In fact, women after menopause have lower levels of estrogen

01:52:47.600 than men do. Men have higher estrogen levels because they have much higher testosterone levels and they

01:52:53.600 have increased peripheral conversion of testosterone estradiol. So actually, men have higher estradiol

01:52:58.880 levels than women after menopause. Do you know my other favorite stat? That's a great one, by the way.

01:53:03.620 The other favorite stat of mine is that even pre-menopause, women have higher testosterone than estrogen

01:53:08.740 if you actually convert the units to the same units. I think some people think after menopause,

01:53:14.420 the ovaries are just not active anymore. But that's not true, actually. After menopause, the ovaries

01:53:19.620 continue to just don't make estradiol, but they continue to produce androstenone and testosterone.

01:53:24.940 So they keep making androgens really up to significant amounts until age 80. And these

01:53:30.180 androgens are what get converted in fat and muscle tissue into estrone. So I mentioned this because a

01:53:35.760 lot of my research has been about sex hormone levels after menopause. And we've previously shown

01:53:41.000 that post-menopausal women who have higher androgen levels, who have higher testosterone to estrogen

01:53:47.240 ratios, you know, had a more male-like pattern, you know, they had greater risk of developing

01:53:52.340 ASCVD and heart failure over the next 12 years. And this was even after we adjusted for risk factors

01:53:57.920 like blood pressure and lipids and diabetes. And we did a number of studies as well in the MESA study,

01:54:03.220 the multi-ethic study of atherosclerosis, but we also showed that women with higher androgens had more

01:54:08.280 coronary artery calcium progression. They had worse endothelial reactivity. They had increase in

01:54:15.360 concentric remodeling, you know, all this adverse cardiovascular phenotype. And also, as I mentioned,

01:54:21.100 we started out talking about PCOS earlier, but in PCOS, the riskier phenotype is the hyperandrogenism

01:54:28.640 state and, you know, testosterone and androstenone and higher LH levels in PCOS as a marker PCOS.

01:54:36.760 So getting back to menopause, a lot of things happen related to these hormonal changes. You have more

01:54:41.540 visceral fat deposition in the abdomen and more insulin resistance. And this leads to this

01:54:47.700 dyslipidemia pattern of increased triglycerides, increased LDL and decreased HDL. There's more

01:54:54.460 endothelial dysfunction, increased blood pressure, increased sympathetic tone. So where a lot of

01:54:59.440 cardiovascular risk in women is more linear with aging. So for the most part, you know, blood pressure

01:55:04.820 and diabetes risk tends to be more of an aging effect rather than ovary effect. Lipids is one

01:55:11.340 thing that really seems to be an ovary effect that we do see, you know, relatively acute changes

01:55:16.620 in the lipid panel following the final menstrual period with this rise in total cholesterol and LDL.

01:55:23.160 I think we alluded to earlier that it's maybe one of the reasons that women tend to have risk a little

01:55:28.640 bit later in life and after menopause is because they tend to have this more dyslipidemia pattern a little

01:55:33.520 bit later in life. Now, this pattern, this increased risk, you know, had led this whole body of work

01:55:39.840 about, well, if these changes are harmful, maybe giving menopause hormone therapy would be beneficial.

01:55:45.740 And of course, you know, we did this for years. My mother used to be on hormone therapy. This is all,

01:55:50.460 you know, well before the Women's Health Initiative study because we just felt that, you know, oh, well,

01:55:55.040 you must give these hormones back. There are favorable and unfavorable changes that we see with hormone

01:56:01.560 therapy, especially this combined therapy. So some of the favorable therapy changes, if you do give women

01:56:07.160 estrogen, you will lower their LDL and it can increase the HDL and estrogen can have...

01:56:13.200 And are you talking about oral estrogen or topical estrogen?

01:56:16.180 Systemic estrogen, which is oral and to some degree transdermal. Vaginal estrogens don't have much systemic

01:56:24.100 absorption. So they're a really good option for women, you know, I'll talk about which women to use hormone

01:56:29.380 therapy in, but for women who just have the genital urinary symptoms, even in women with cardiovascular

01:56:34.820 disease or history of stroke, or you can use vaginal estrogens safely. And sometimes I think

01:56:41.320 there's this concern about using them in high-risk women, but you can use the vaginal estrogen. So I'm

01:56:45.340 really talking about oral estrogens here. They dilate the blood vessels through a nitric oxide effect,

01:56:50.660 which, you know, may be all cardioprotective, but keep in mind, estrogens also have unfavorable

01:56:55.240 properties. So we know that estrogens can increase CRP. So women have higher CRP levels and estrogens

01:57:01.960 are prothrombotic. I mean, this is why there is some increased risk with oral contraceptives,

01:57:07.540 particularly in women who are older of reproductive age and combined with smoking and also during

01:57:13.040 pregnancy, that estrogens can increase prothrombin, decrease antithrombin-3. And we also talked about

01:57:19.620 the estrogen effects with triglycerides. Same thing with oral contraceptives, which have higher estrogen levels

01:57:25.240 hormone therapy, all could increase triglycerides. So in higher risk women, particularly those that

01:57:31.960 are farther out from the menopause transition or those with established cardiovascular disease,

01:57:37.520 these adverse changes, you know, may outweigh any favorable benefits. And that's why probably the

01:57:45.200 Women's Health Initiative, who had the mean age of 63, most of these women were quite far from the

01:57:50.760 menopause transition. And the Women's Health Initiative also used an oral conjugated equine

01:57:56.200 estrogen with progestin formulation that we saw, you know, an increased risk, including a twofold

01:58:02.060 increased risk of venous thromboembolism. So this is why, you know, the guidelines all changed and we

01:58:07.320 don't recommend hormone therapy for the sole purpose of cardiovascular disease prevention, because we have

01:58:12.260 many other things we can use for prevention like statins. But, you know, the pendulum doesn't have to

01:58:16.940 swing so far away that if you look at sub-analyses of these trials of women that were closer to the

01:58:24.300 menopause transition, younger women, we didn't see this excess harm. And so while a lot of women are

01:58:30.860 quite symptomatic at menopause, you know, vasomotor symptoms can be very disabling for many women with

01:58:38.200 the hot flashes and the brain fog. In fact, vasomotor symptoms in and of themselves when frequent or

01:58:43.760 persistent are associated with cardiovascular risk. And so for symptomatic women who are under the age

01:58:49.200 of 60 or within 10 years of menopause who have symptomatic menopause, menopausal hot flashes or

01:58:54.960 night sweats, you know, consider a hormone therapy. Women who go through menopause early, if they don't

01:59:00.380 have other contraindications, menopausal hormone therapy is recommended to at least the natural age

01:59:04.780 of menopause or age 51. But generally, we're not recommending it if a woman's more than 10 years out

01:59:10.280 for menopause or over age 65. This is where the increased risks are emerging in these trials.

01:59:15.940 And we want to avoid oral estrogens in women with a history of cardiovascular disease, blood clots,

01:59:21.740 high triglycerides, gallbladder disease, or prior breast and intermetial cancer, particularly the

01:59:26.460 oral estrogens. There's probably a little bit less risk with transdermal estrogens, which are still

01:59:31.500 systemic, but they don't have the first pass effect. But I, you know, very work really closely with our

01:59:36.700 menopause clinic as part of doing a cardiovascular risk assessment prior to use of menopausal hormone

01:59:40.680 therapy. So when risk is uncertain, you know, I get a coronary calcium score to make sure that they

01:59:46.400 don't have any calcified plaque. Their score is zero. I feel pretty comfortable with using hormone

01:59:52.620 therapy in them for treatment of their vasomotor symptoms. But if they have significant atherosclerotic

01:59:57.500 disease, you know, I tend to not recommend it. And again, if they're only having genital urinary

02:00:03.460 symptoms, topical estrogen is fine, you know, the risk, you really probably depends on a lot of

02:00:08.920 factors. It depends on when you start the hormone replacement, you know, your age at initiation,

02:00:15.060 how many years you've been since menopause, your menopause age, how long you take the therapy,

02:00:20.940 the duration, the type of therapy, the dose, and the route of administration.

02:00:26.240 And probably your incoming health. The other thing I'm hearing here, Erin, is this is another

02:00:30.840 reason for young women, women who are in their thirties for whom menopause isn't even on the

02:00:36.300 radar. This is another reason to be as healthy as possible and to do as much preventative work as

02:00:42.680 possible. Because if for no other reason, it gives you more optionality in menopause.

02:00:47.680 My calculus on this is looking at a few things and, you know, obviously quality of life is one. Bone

02:00:53.640 health is another. Muscle mass, brain health is a huge one. So I'm kind of looking at it as

02:01:00.760 heart health is not even on the radar. Because to your point, we have so many better tools

02:01:06.360 to reduce the risk of ASCVD that we don't need to rely on estradiol as one of those tools. It's

02:01:13.140 basically a pea shooter in a bazooka fight when we have big, big guns to reduce the risk of

02:01:18.100 cardiovascular disease. So while we're really asking of HRT is to not hurt somebody, while we let it do

02:01:24.620 its bazooka-like work, which is going to be on the brain, bone health, vasomotor symptoms, eventually

02:01:32.200 vaginal atrophy and things like that, for which we don't have alternatives. And so to your point,

02:01:38.500 the difference between a 50-year-old woman who shows up with a beautiful CTA that's crystal clear,

02:01:44.280 where we're going to have no ambiguity about this line of treatment, versus a woman who shows up with

02:01:49.180 the worrisome CTA. And yeah, maybe even if we go to a transdermal, there's going to be more

02:01:55.180 hesitation, there's going to be more concern. And maybe that slight increase in risk, if it exists,

02:02:00.360 is something we now have to weigh in the balance. Again, it all comes back, in my mind, listening to

02:02:04.940 you to prevention is the key. It's just start early and be aggressive. And all you do is give

02:02:10.180 yourself more options later in life. Yeah, absolutely. The risk is in women with

02:02:15.460 established cardiovascular disease. So trying to prevent that plaque, you know, in the first place,

02:02:20.640 you know, if there's no atherosclerosis, then the evasive dilatory effects and the lowering of LDL,

02:02:28.260 you know, may be helpful in preventing the initiation of atherosclerosis. But, you know,

02:02:33.860 women who already has disease, then the slight increase in inflammatory markers, a prothrombotic

02:02:38.780 effect, you know, may tip them over to having a vascular event. So all unfavorable about improving

02:02:44.160 cardiovascular health earlier in life, you know, the really how we live the first half of our lives

02:02:48.640 really influences our freedom from morbidity and mortality, the second half of our lives.

02:02:53.520 Any relationship with progesterone and lipids, once we get into that menopausal state, obviously,

02:02:59.540 women who are on estrogen need to either take oral progesterone, usually these days, it's done

02:03:05.620 micronized, or we're even seeing them use progesterone coated IUDs if they can't. But let's

02:03:10.900 just talk about this systemic progesterone. Does that have any bearing, positive or negative?

02:03:16.100 Yes. I mean, we have to use progesterone if they have an intact uterus. This may influence some of

02:03:24.080 the, you know, again, we're not using these for cardiovascular benefit, but, you know, whether it

02:03:28.780 offsets the benefit that we see from the estrogen. You mentioned, again, something at the outside of

02:03:34.420 the podcast, which I think is an enormous problem in all of medicine, which is the disproportionate

02:03:40.620 shortcoming or shortfall rather of women in clinical trials, women as subjects. You said

02:03:47.820 something funny earlier that's only funny because it's not true, which is women are not little men.

02:03:52.760 Do you see that changing? I guess I'd just ask you to sort of think about it in your field. I don't

02:03:56.400 expect you to speak about it in terms of fields in oncology or things like that. But when you think

02:04:00.620 about cardiovascular medicine, be it on the lipid side, the hypertensive side, all fronts of

02:04:05.600 cardiovascular medicine, are we seeing a more equal, i.e. 50-50 distribution of patients into

02:04:12.080 clinical trials today? Or are we still seeing it be more male-focused and therefore more underpowered

02:04:18.060 to understand the effective interventions on women? So for background, you know, women have been

02:04:23.240 historically under-enrolled in cardiovascular clinical trials, usually only 25 to 30% of trials.

02:04:28.680 You know, I previously published analysis or reviewed the literature of lipid-lowering trials

02:04:33.560 between 1990 and 2018. So this was just through 2018, so it doesn't reflect the more recent trials.

02:04:39.660 But we showed the overall representation of women was only 29% in those trials.

02:04:44.480 Now, for some things like acute coronary syndrome, you know, the prevalence is less common in women

02:04:49.460 than in men. So we benchmarked it to something called a participation to prevalence ratio,

02:04:54.380 where a ratio of one would be adequately representation to their prevalence of the

02:05:01.060 disease in the population. And we showed that, you know, women were underrepresented with a

02:05:06.900 prevalence to participation ratio, you know, generally, you know, 0.5 or less, meaning that

02:05:11.940 even though if they had lower burden of disease, they were still under-enrolled in trials related to

02:05:17.120 this. We showed also another analysis looking at cardiometabolic drugs through 2017 that had

02:05:24.420 gotten FDA approval for new molecular entities. And again, showed women only made up like 36% of those

02:05:30.220 trials. And in an editorial we wrote, we looked at all kinds of different things, stroke, acute coronary

02:05:35.240 syndrome, heart failure, hypertension, and women throughout all these disease entities were

02:05:39.920 under-enrolled in trials. Some things are getting better. I mean, there are, you know, I mentioned

02:05:44.800 clear outcomes, which is nearly half the participants are women. I think this is because it's enrolling a

02:05:49.800 statin intolerant population. There was some of the GLP-1 studies like Rewind, which studied

02:05:56.320 delaglutide, that was largely a primary prevention trial that had like 46% women. So those were

02:06:02.620 encouraging. So I think there's some examples of some improvement, but women still, for the most part,

02:06:08.800 you know, we still see trial after trial being published, presented at ESC or AHA, ACC, and we're like,

02:06:14.800 who are the women? Why are women continually to be under-enrolled? And one of the things I'm

02:06:19.780 passionate about is I think that there's unfortunately an under-involvement of clinical

02:06:24.520 trial leadership. These steering committees of these trials have a dearth of women cardiovascular

02:06:28.940 investigators. There was a paper a couple of years ago that looked at major cardiovascular trials,

02:06:34.360 you know, published in the leading journals, New England Journal, JAMA, Lancet, you know, only 10%

02:06:38.820 of trial leadership committees were women, and more than half, about 56% of these trial leadership

02:06:45.860 committees had no female representation on the trial. One of the trial steering committee were

02:06:50.840 women investigators, and less than 10% had a woman in the first or last author position,

02:06:56.380 you know, which would indicate a senior leadership position. We know from other studies that the

02:07:01.800 likelihood that a study will report a sex and gender-specific analysis actually is, you know,

02:07:06.980 increased when there's more women authors of the study and more first and last authors women. I

02:07:12.320 think women tend to publish more about science related to women. So I do think it matters. There

02:07:17.440 is some data from my work and some other work from other authors that have shown a modest correlation.

02:07:24.280 It's not perfect, but a correlation between the proportion of women authors, the trial steering

02:07:30.300 committees, and enrollment of women participants in trials. For example, we did this for AFib,

02:07:35.700 and we showed that for every 1% increase in women authors, there was a 19% higher enrollment of

02:07:41.580 women participants in the trials. I mean, there's a lot that we can do to tackle this. One of them

02:07:47.940 is having more representation and by diversifying study team and investigators. I think also we need

02:07:54.480 to include more patients in trial designs, include more women in trial designs, patient-centered designs.

02:08:00.240 We hear that women are approached, but often are declined participating in trials. And I think

02:08:06.260 women tend to be a little bit more risk adverse. And this is where it's really important to provide

02:08:11.400 education, dispel misconceptions, emphasize the benefits. Even if we don't know if a drug is going

02:08:17.660 to be beneficial or not, there's a lot of benefits with being part of a trial because you have more

02:08:22.560 access to gold standard care and more access to study investigators. And it's really important to

02:08:28.060 include women in the design and try to understand some of these design issues, which may be not so

02:08:34.580 obvious, you know, such as making sure there's no hidden costs that often people are paid for the

02:08:40.480 drug or device, but there can be things related to transportation or time off work or providing,

02:08:46.120 you know, for childcare or other responsibilities. By having more flexible follow-up, more pragmatic trials

02:08:52.100 or having a follow-up being online or by phone or by PCP, that may get over some of the barriers to

02:08:59.240 enrolling women in the trials, which I think can be really helpful. And making sure that the study

02:09:04.120 designs are not so restrictive in terms of the inclusion-exclusion criteria, that we shouldn't just

02:09:09.580 exclude women of childbearing age. If they have a plan for preventing pregnancy, have an adequate

02:09:16.520 contraception, you know, women should be eligible for these trials. Not to mention, we actually need more

02:09:21.980 trials in pregnant women too. It's just so important to understand what works and what's safe. And so

02:09:27.180 there's a lot of barriers to overcome. And these barriers need to be both with trial teams and trial

02:09:33.180 designs, with the funding agencies, institutions, and even the journals that publish these trials

02:09:39.140 should be questioning why there's not enough women in the trial. So we all need to do better.

02:09:43.520 Randomized clinical trials is our largest evidence base. And we want to make sure that something is

02:09:49.000 efficacious, but safe in women, and that women benefit to a similar degree as men do.

02:09:54.200 Karen, you've run how many marathons?

02:09:56.520 Oh, slowly. I'm very talented at it, but I've done like 38 marathons. And I was trying to do one

02:10:02.640 in every state as a goal. I'm really slow at running. So my only goal for these is just

02:10:07.500 finishing as an accomplishment in and of itself.

02:10:10.080 Are those 38 in 38 different states?

02:10:13.240 I've done about 36 states. And then there was a couple of states like Maryland where I live that

02:10:18.300 I've repeated more than once.

02:10:20.620 Is that still a goal? You still want those other 14 states?

02:10:23.680 Yeah. So of course I had taken a little bit, you know, I set back during the COVID. I had four

02:10:29.820 marathons planned for 2020 and they all got canceled due to COVID. And without a marathon on the calendar,

02:10:36.380 I got a little bit out of the habit of running with these long distances because I didn't really

02:10:41.260 run by myself. I do it for the social support with my running groups. And so without people or groups to

02:10:46.820 run with. And then in 2021, you know, the marathon I registered for was canceled as well. And so I've

02:10:52.660 gotten sort of out of it for a while, but I...

02:10:55.600 It's really good that we're canceling outdoor exercise during COVID because I can't...

02:10:59.980 Well, it's back now. So events are back. So I am registered for a marathon in

02:11:06.240 October next month. It'll be my first marathon again in three years. So I'm hoping to get state

02:11:11.080 37.

02:11:11.820 Which state?

02:11:12.660 It's New Jersey and most of the East Coast, but this one I haven't done yet. And I've been

02:11:16.960 back doing other races. I just did a 12 miler here in Baltimore on Saturday last weekend. So

02:11:23.400 races are back and they're fun. And I just like participating. You know, you don't have to be

02:11:28.040 good at a hobby to enjoy it. So I'll never in any age groups or probably never qualify for Boston,

02:11:34.100 but you know, sometimes it's just the act of doing something and setting goals for yourself.

02:11:38.360 And I love it. It's just, it's fun.

02:11:40.840 That's fantastic. Well, I have such fond memories of Baltimore. My wife is from there,

02:11:45.340 so there's an additional fondness to it. But I guess more than anything, it's the time I spent

02:11:49.280 there. It's great to catch up with you and it brings back memories by proxy at a minimum.

02:11:53.700 I want to thank you for your time, Erin. This was really insightful. I learned a lot. I think this is

02:11:57.800 a podcast where obviously women will have learned a lot, but hopefully men as well. Because

02:12:01.620 if you're a man listening to this, you certainly know a woman and therefore you should be just as

02:12:06.180 concerned with her risk of cardiovascular disease as your own. Thank you very much for

02:12:10.120 this input, making the time and your continued work.

02:12:13.480 Thank you for having me on your podcast.

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02:14:47.540 Thank you, everyone.

02:15:02.400 Thank you.

02:15:02.760 Thank you.

02:15:04.200 Thank you.

The Peter Attia Drive - November 07, 2022

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

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