Good afternoon. Welcome to the session, Cardiovascular Risk and Polycystic Ovarian Syndrome, When to Screen and How to Treat. My name is Alice Chang and I am an associate professor in the Division of Endocrinology at Mayo Clinic in Rochester, Minnesota. I will be serving as your moderator today. It is my honor to introduce Dr. Margaret Lippincott who will be speaking to us on this subject. She's a physician scientist in the Reproductive Endocrine Unit of the Department of Medicine at the Mass General Hospital. She's an instructor of medicine at Harvard Medical School and assistant in medicine at MGH. She received her medical degree from Duke University School of Medicine, trained in internal medicine at Beth Israel Medical Center, and completed her fellowship in endocrinology at MGH. In the clinic, Dr. Lippincott sees both men and women with a broad variety of reproductive problems, including women with polycystic ovarian syndrome. As a researcher, Dr. Lippincott uses physiologic tools, genetics, and in vitro modeling to better understand how the brain controls reproduction and the metabolic role of reproductive peptides across the reproductive lifespan in pregnancy and gender biology. Hello and welcome to this session here and ACE for cardiovascular risk and polycystic ovarian syndrome. When to screen and how to treat. My name is Meg. I'm a reproductive endocrinologist, and I was thrilled to get the invitation to share this with you today. I have no conflicts of interest. Because the outline of this talk, we're going to talk about how PCOS is related to cardiovascular disease, how and when cardiovascular disease risk should be assessed in women with PCOS, and how and when should women with PCOS be treated for primary prevention of cardiovascular disease. First, how is PCOS related to cardiovascular disease? First, just as a reminder, polycystic ovarian syndrome is a diagnosis that you get by meeting two of the three following criteria. You can have clinical or biochemical hyperandrogenism, that's elevated testosterone or DHEAS, acne, piercitism, or female pattern hair loss. You can have oligo and ovulation, that is typically menstrual cycles less than 21 days or greater than 35 days, or you can have documentation of failure to ovulate by a low mid-luteal progesterone. Finally, you can have polycystic ovarian morphology. The criteria for meeting this is highly dependent on ultrasound technology and on patient age, as there are many more follicles and the ovary is much larger at the beginning of the reproductive life cycle than at the end of the reproductive life cycle. If someone meets two of these three following criteria, then you can say they have PCOS, assuming you have ruled out any other disease that could be contributing, because this is a diagnosis of exclusion. Amongst those individuals with PCOS, what can we say about what PCOS is? PCOS is a polygenic disease. What that means is that there are many genetic variants that confer a risk for developing PCOS. What does this look like? What I'm showing you here is a Manhattan plot. On the bottom are all of the chromosomes in the genome. What you can see is multiple genes coded in red that cross the genome-wide significance threshold, suggesting that these are single nucleotide polymorphisms tied to specific genes that contribute to the development of polycystic ovarian syndrome. We can take all of these single nucleotide polymorphisms, and we can ask a very simple question, and that is, what else do these genetic variants confer a risk for? When we ask that question, we find that they confer a risk for earlier age of menarche, increased BMI as both a child and an adult, and increased fasting insulin, which could be seen as a marker of insulin resistance. This should all seem very familiar because although none of these are part of the diagnostic criteria for polycystic ovarian syndrome, it's incredibly common that we see these in our patients. But these genetic variants also confer risk for increased triglycerides, risk for type 2 diabetes, and a risk for coronary artery disease. This means that exactly the same genetics that result in one of your patients developing PCOS, also can contribute to their development of obesity, of hyperlipidemia, of type 2 diabetes, and of coronary artery disease. We can see this if we flip this around and look at the phenotype of women with a genetic risk for PCOS. How do we do that? We create a predictive risk score that's based on the PCOS GWAS loci that I just showed you on the previous slide. You then conduct what's known as a phenome-wide association study or a PHEWAS to determine what phenotypic traits are related to this predictive risk score. I am showing you an example of this here. This is a PHEWAS Manhattan plot of the predictive risk score. The phenomes of about 50,000 female participants from 12 EHRs, electronic health rectors, linked biobanks nationwide through the eMERGE consortium. What you can clearly see is that women with a genetic risk for PCOS also have obesity and morbid obesity, type 2 diabetes, hypercholesterolemia, essential hypertension, and sleep apnea. They also happen to have polycystic ovaries. What this means is that there's a very complex relationship between PCOS as a diagnosis and some of the other phenotypes we see in our women with PCOS. I think one of the most common questions that I get is, well, how does testosterone factor into all of this? We can actually look at that. We can look at the role of testosterone in PCOS. In this case, we can take a genome-wide association study of sex hormone traits out of the UK biobank, where we are looking at testosterone, SHBG, and estradiol. In this case, we're doing sex-specific, so just for males or just for females, Mendelian randomization analysis. A Mendelian randomization analysis allows us to isolate the causal effect of particular genetic changes in the genome. In this case, they found that bioavailable testosterone is causal in the development of both type 2 diabetes and PCOS in women, but not type 2 diabetes in men. What this means is that there is an increased odds ratio of about 1.5-1.7 per unit higher of bioavailable testosterone. It also happened to find that it was also causal for higher fasting insulin levels. What this tells you is, well, if we're here to talk about PCOS and cardiovascular disease, what we can say is that the genetics that underlie PCOS also underlie cardiovascular disease. There's a direct risk relationship. There's also several indirect risk relationships. If we look at the ASCVD risk calculator, which calculates your risk for cardiovascular disease based on blood pressure, cholesterol, and diabetes parameters, what we can find is both cholesterol levels and diabetes are directly, yet again, have shared genetics with PCOS. The phenotype of women with PCOS genetics is to have elevated blood pressure. We can go even further and look at AHA and ACC risk-enhancing factors for cardiovascular disease. Here you again see the impact of genetics. Metabolic syndrome, four of the five components in metabolic syndrome, increased waist circumference, elevated triglycerides, elevated blood pressure, and elevated glucose, all are either phenotypically related or genetically related to the underlying genetics of PCOS. Then we also have primary hypertriglyceridemia. We can go even further and note that there are additional risk factors for cardiovascular disease that are tied to PCOS, which include obesity, early menarche, and insulin resistance. This type of complex genetic relationship likely explains why when we are looking at either observational or case control studies trying to establish the relationship between PCOS and cardiovascular disease, there is a mix of both positive and negative findings. Often because what these studies are trying to do is they're trying to control for other risk factors for cardiovascular disease that we now know, from looking at the genetics, have a shared genetic basis with PCOS. How do we take this information and move forward? How and when should cardiovascular disease risk be assessed in women with PCOS? As you can imagine, from all of the risk factors we just examined, it should be assessed upon diagnosis and routinely thereafter. I think it's important to think about the ways in which we may be asked to calculate this risk. It may be an 18-year-old with a new diagnosis of PCOS, a 25-year-old woman who has a history of PCOS, that's in your office for obesity management. Could be a 33-year-old woman with a history of PCOS, who is in your office for anovulatory infertility. Or a 44-year-old woman with female pattern hair loss who was just diagnosed with PCOS. Or a 50-year-old woman with a history of PCOS in your office for menopausal hot flushes. You're considering whether or not to initiate hormone therapy. It's important to understand that with this PCOS, she has a risk for cardiovascular disease and how are you going to assess them? Or say a 61-year-old woman with a history of PCOS who's in your office for impaired glucose tolerance. She may even ask you, do you think my impaired glucose tolerance is related to my PCOS? Based on the genetics, you can now say yes. What are you going to do when all of these women across their lifespan come into your clinic? Yearly, the recommendation is that you seek history and update history. You're looking for a family history of early cardiovascular disease. That is cardiovascular disease in women under the age of 55, or men under the age of 65. You're looking for whether or not they're cigarette smokers. You're looking for sleep apnea symptoms, and for diet and exercise habits. Then on physical exam, you want to check their blood pressure. You're checking for hypertension. You want to look at obesity. You want to look at not just height and weight, but also waist circumference, which is a key factor in metabolic syndrome assessment. At least every three to five years, sometimes more, you want to assess for impaired glucose tolerance or type 2 diabetes with an oral glucose tolerance test. That's considered the best, but you can also use a hemoglobin A1c. I'm going to tell you that my preference is that for a new patient, I always start with an oral glucose tolerance test. If that oral glucose tolerance test reveals impaired glucose tolerance or prediabetes, I typically follow them yearly, alternating with a hemoglobin A1c or an oral glucose tolerance test. If the initial oral glucose tolerance test is normal, every three to five years, sometimes I'll alternate between the two. That's simply because the oral glucose tolerance test, because it's an observed test in the clinic for two hours, can be harder for a patient to achieve. I do want to continue to monitor the status of their glycemia. For dyslipidemia, you do a fasting lipid panel. I strongly suggest that if anyone has symptoms, you order a sleep study because I found a number of women with PCOS with undiagnosed OSA. You'll notice that although testosterone has been causally linked to type 2 diabetes and we just reviewed that data, there's no current recommendation for ongoing assessment of testosterone for cardiovascular disease risk. What do you do with all of this data? Well, one of the things you do is you determine whether or not the woman has metabolic syndrome. One of them is a waist circumference. For this, it's actually important to know if someone is of East Asian or South Asian ancestry because there's a smaller waist circumference that will qualify them for having metabolic syndrome. Just as a reminder, when you're measuring waist circumference, you want the tape measure just above the hip bones, horizontal all the way, snug, and you actually want to measure it when the patient breathes out. There's a lot of variation in waist circumference measurements. Fasting triglycerides greater than 150, HDL equal to or less than 50, and a blood pressure greater than or equal to 130 or greater than or equal to 80. Many of you may be familiar with seeing 85. I have revised that downward in accordance with some recent guidelines and including in accordance with the recent update in hypertension guidelines that suggest that someone who consistently has either a systolic blood pressure above 130 or a diastolic blood pressure equal to or above 80 has stage 1 hypertension. Finally, elevated glucose. This is not type 2 diabetes. Once they have type 2 diabetes, those individuals already have an equivalent for cardiovascular disease, and they have a very different treatment algorithm that you're going to follow as an endocrinologist. It's not simply elevated glucose, it's simply been an elevated fasting glucose greater than 100 milligrams per deciliter. However, what I've added, I think are an expansion of the criteria that many people consider other evidence for elevated glucose. That would be either impaired glucose tolerance, two hours on an OGTT with a glucose greater than or equal to 140 milligrams per deciliter, or it would be a hemoglobin A1c greater than or equal to 5.7, but less than 6.5, indicating elevated glucose is on average suggestive of prediabetes. I'd like to start with a case to figure out how we can dissect these different components, all of which are related, and all of which predispose our women with PCOS to cardiovascular disease. I'm going to start with Monica. She's a 33-year-old female with PCOS. We're going to ask her all of the questions that we discussed. She has no family history of early coronary disease. She's not a cigarette smoker. She has no symptoms of sleep apnea. Diet and exercise she acknowledges could use some work. She mostly eats takeout. She has limited fruits and vegetables and no routine exercise. What you might expect with this, her blood pressure is 130 over 85, so elevated. She is obese with a BMI of 35.7, and her waist circumference is 37 inches. She meets that first criteria for metabolic syndrome. On oral glucose tolerance test, what you can see is that although her fasting glucose is normal, her two-hour glucose is elevated at 145. That is consistent with a hemoglobin A1C of 5.9 percent that suggests prediabetes. Her limits, I would say, are pretty classic for a PCOS patient. Very mildly elevated total cholesterol at 206. Just the limit of being low, an HDL of 50, an LDL of 120, which would be considered elevated but not high by today's standards, and an elevated triglycerides at 180 milligrams per deciliter. We break down each of the components that we can learn. These are the new hypertension guidelines. When we look at these, if we were to confirm on more than one occasion and average, we would put her in the stage 1 hypertension category. If we were to look at the hyperlipidemia, and here I've coded hyperlipidemia, whether or not it's a risk factor for coronary vascular disease, or whether it's a risk-enhancing factor. In this case, she has elevated triglycerides, which are greater than 175 milligrams per deciliter. That's considered a risk-enhancing factor. Furthermore, we can evaluate her for metabolic syndrome. When you're evaluating for a metabolic syndrome, it's important to take into account race and ethnicity. In this case, she is non-Asian origin, and she has an elevated waist circumference. She has elevated fasting triglycerides. She has an HDL that is equal to 50. She has an elevated diastolic blood pressure. So you don't need an elevated systolic blood pressure to get into this category. And she has an abnormal impaired glucose tolerance, as well as a hemoglobin A1c that's suggestive of prediabetes. So she has metabolic syndrome. So what can we say so far? We can say she has stage one hypertension, elevated triglycerides, metabolic syndrome, prediabetes, impaired glucose tolerance, obesity. But how do we integrate this? She's less than 40 years old. Classically, our risk calculators are used for women above 40. Well, so you can use the ASCVD risk estimator. The link is on the bottom of the screen. And what this provides is a lifetime risk estimate. It won't give you a 10-year risk estimate because she's not over age 40 or older. It's based on the ACC AHH pool cohort equations that have been validated for ages 40 to 79. So it's not necessarily considered as validated for this age group. You can set the default age to 40. When you do that, the tool will give you some tools and recommendations for the patient as to next steps. And the classic risk factors for cardiovascular disease are here and are inputs to it. There is another option. And the other option is to do the heart disease risk calculator. I've happened to give you the link for the one in Mayo because I find it particularly easy to use. Most academic hospitals have some version of this heart disease risk calculator. The difference is that it's not just based on the ACC AHH pool cohorts, but it's actually based on the Framingham Heart Study, their 30-year estimates that are age and BMI based. So there's a little bit of additional information that goes into this risk estimator. It includes height, weight, family and personal history of cardiovascular disease, physical activity and diet, such as are you on a high fat diet or do you eat very few fruits and vegetables, in addition to sort of the traditional risk factors. So if we were to integrate this, or Monica, what would this look like? So the first thing we would see is that if we used the ASCVD plus risk estimator, would be that they tell us her lifetime risk is 39%. Well, what does that mean? How do we think about that? Well, if you look at the NHANES data, an estimated lifetime risk of greater than or equal to 39% is considered high, but actually more than 50% of US women between the ages of 20 and 79 have a 10-year risk estimate that's less than 10% and a lifetime risk estimate that's greater than or equal to 39%. What this means is that they have risk factors that over the course of their lifetime will build to predispose them to cardiovascular disease, but that when you look simply in 10-year increments, you can actually miss the magnitude of the risk. Similar to this, if you were to use the heart disease risk calculator, it gives you not a full lifetime, but a 30-year risk of cardiovascular disease. You'll notice this 30-year risk and the lifetime risk don't match. And one of the reasons why is because this patient is 33. So this is estimating the likelihood that she's going to have heart disease between now and when she's actually 63. But what you can see below and what I like about this heart disease risk calculator for patients under 40 is it tells you that she can cut her risk in half by modifying her risk factors. We're going to talk about that a little bit more. So this is sort of a classic 33-year-old woman with PCOS. And what we can now say is in addition to everything else, we can tell her that her lifetime risk to develop cardiovascular disease is actually up. And that there are some things that we should do to help mitigate this risk. So let's take a look at another case. This patient is significantly older. This is Cynthia. She's a 61-year-old female with PCOS. Now, what's her history? Again, no significant family history of early cardiovascular disease, not a cigarette smoker, no symptoms of sleep apnea, the same poor diet and exercise habits. Now, her blood pressure is a little bit higher. It's 150 over 95. She's the same BMI in waist circumference. Now on testing, again, she still has a normal fasting glucose, but her two-hour glucose is a little bit higher. Her A1c is in the prediabetes range, but a little bit higher. And her lipids have risen. And this is kind of classic for what you might see as your PCOS women age. And here she still has elevated triglycerides, but now she also has an elevated LDL cholesterol so that her total cholesterol is now significantly elevated at 275 milligrams per deciliter. So if we were to follow the same type of estimates that we did for Monica with Cynthia, we would find that she actually has stage two untreated hypertension. We would find that in addition to having elevated triglycerides, she now also has high LDL, which is another risk-enhancing factor for cardiovascular disease. And if we looked at her for metabolic syndrome, she would check all the same boxes. But what you will see now is she meets the blood pressure by both criteria, and she has a slightly worse elevated glucose. But where it looks different is when we take all of these pieces of information and we put them into a risk assessment calculator because she's now 61. So the ASCVD risk estimator will now give us a 10-year risk estimate. The heart disease risk calculator will give us two different options. It will give you that 30-year risk estimate between 40 and 59, and for 60 and older, it too will give you a 10-year risk estimate. So now when we actually plug in the data, the data really starts to match. And this has to do with Cynthia is in the age for which these risk calculators were created and for which the underlying data is valid. So what you're finding right here is that her 10-year risk for cardiovascular disease is 6.6% for both calculators. And both calculators say she could significantly lower her risk, potentially cut it by 60 to 70% if she were to modify certain risk factors. But 6.6% isn't particularly high in a 10-year risk calculator estimate. It's considered a borderline risk. It's not intermediate, it's not high. So what does that mean? How do we take this data? So we've now characterized our women with PCOS. We've assessed them for all of the risk factors for cardiovascular disease that we know come with PCOS. How do we turn this into treatment options? So how and when should women with PCOS be treated for primary prevention of cardiovascular disease? So I'd like to put Monica and Cynthia side by side. And one of the things I've done is, this is exactly how we've characterized both patients, but you're now gonna see constrictions. That constrictions are around things that while they don't formally go into some of their risk calculators, they're felt to be risk-enhancing factors. What does that mean? That means that if you get kind of a lower risk for cardiovascular disease, a borderline risk, maybe a mildly elevated, but not a high risk. If someone has multiple risk-enhancing factors, you should probably treat them more aggressively. So the classic risk-enhancing factors are elevated triglycerides, a high LDL that's not greater than 190, something like metabolic syndrome. However, there is both ACE and the Endocrine Society speak about the concept that PCOS itself, because the genetic basis of PCOS also predisposes to cardiovascular disease, that PCOS itself could be considered a risk-enhancing factor. So given that, how do we lower both Monica and Cynthia's risk of developing cardiovascular disease? So the first thing to think about is to return to our hypertension guidelines that have been revised. And first to recognize that neither Monica nor Cynthia have any cardiovascular disease, and their 10-year ASCVD risk is less than 10% for Cynthia. And for Monica, we can't even calculate that because she's too young. So where does that put us? Well, Cynthia has a blood pressure of 150 over 95. So very clearly she meets the criteria for treatment. She argued though, with her PCOS and her borderline risk, she has multiple risk-enhancing factors. So even if Cynthia's blood pressure was 130 over 95, or if Cynthia's blood pressure was 135 over 85, I might seriously consider starting treatment with her. And that's how you would use those risk-enhancing factors to try to interpret when to treat and what goal to set. Monica, however, with her blood pressure of 130 over 85, really falls into the category of stage one hypertension that should be managed with lifestyle. And I wanna take a moment to talk about the current lifestyle recommendations. Because one of the things that I wanna emphasize throughout the talk is that our chance to intervene with these young women with a high lifetime risk really is in modifying behavior, which is a really, really challenging thing to do. So I wanna talk about what might improve Monica's blood pressure. Well, the first thing is weight loss. She is obese. She actually has stage two obesity. And for every one kilogram reduction in body weight, you would expect about a one millimeter of mercury decrease in blood pressure. But beyond weight loss, you can offer some standard dietary advice. That is a healthy diet. We said she eats mostly fast food, sort of relatively high in fat, not a lot of fruits and vegetables. One of the first things you can do is suggest that she add more fruits and vegetables into her diet. We can talk about some of the studies that have explicitly looked at women with PCOS and obesity to see whether or not there's a particular diet that you might recommend. You can suggest reduced sodium and enhanced dietary potassium. You'll notice that if she did all of these changes, she really would no longer have stage one hypertension, which I think is really important to recognize. Moderate alcohol consumption is also recommended. I know certainly as we're living through this pandemic, I certainly have seen alcohol consumption take off in my patients. Asking about this is important when you're trying to modify risk factors. And finally, physical activity. So I think it's often very hard for people to get to the aerobic and dynamic resistance recommendations of 90 to 150 minutes a week. I often recommend that my patients start slow. So if they can even just take a 15 minute walk during lunchtime and get themselves moving, that's better than sort of the limited exercise that they currently. So Monica, 33 with PCOS, we've emphasized what she needs to do from a lifestyle standpoint. Cynthia with PCOS and with her prediabetes, we choose maybe to start her on an ACE inhibitor for her hypertension and also encourage lifestyle. What do we do with the rest of these risk factors? So the next piece that we need to consider is the revised guidelines on the primary prevention of cardiovascular disease and how to treat dyslipidemia. So from this standpoint, if someone has a fasting LDL cholesterol that's greater or equal to 190 milligrams per deciliter, really no matter what their age, I would argue they should be on a statin. It's important to recognize that we're talking about women with PCOS. And because we're talking about women, that means we need to consider fertility. So statins are absolutely contraindicated during pregnancy. So you need to consider whether or not your patient is interested in conceiving or whether or not they are on a form of birth control that would allow you to safely start a statin. I'm not gonna talk about the recommendations for diabetes, because like I said, those are separate. And instead, what I'm going to consider is someone between the ages of 20 to 39. So this is exactly like Monica. We've estimated her lifetime risk. We've established that her lifetime risk is high. If her lifetime risk is high and her LDL was greater than or equal to 160, we would be starting a statin, but it's not, it's 120. So although she has two risk enhancers, metabolic syndrome and elevated triglycerides, my first push for her would be on lifestyle. Now, in contrast, Cynthia is 61. So she reaches between the ages of 40 and 75. Her LDL is technically less than 190, although I think we can all agree it's pretty darn close. She doesn't have diabetes and she has a borderline risk. So the recommendation is that you have a risk discussion about moderate intensity statin therapy. I would argue that with her persistently elevated LDL greater than or equal to 160, metabolic syndrome and her persistently elevated triglycerides in this woman with PCOS, I actually think that she would benefit from moderate intensity statin therapy. So I would bump her up into the 7.5 to 20% category and would favor initiating statin therapy based on these risk enhancers. And that's why it's so important that although you're treating a woman with PCOS, you really think about the other risks that PCOS are creating in her metabolic milieu. So for Monica, I'm going to send her to medical nutrition therapy. The nutritionists are your friends when it comes to this. For Cynthia, I'm going to initiate a moderate statin therapy and also send her to medical nutrition. How do you think about the metabolic syndrome and her prediabetes and the impaired glucose tolerance? So I think what's important is that a lot of the data we have on metabolic syndrome and treating metabolic syndrome really is based on treating patients with impaired glucose tolerance and prediabetes. So I'm going to take a moment just to focus on what that data is. So there are multiple studies, many of which you're very familiar with, including the Daking study, the Finnish Diabetes Prevention Study and the Diabetes Prevention Program, or the DPP, which is near and dear to my heart because it's at the institution where I am. And what they have demonstrated is that individuals with impaired glucose tolerance or prediabetes who undergo a lifestyle management intervention have a 30 to 58% decrease in type 2 diabetes at three to six years. There is now data that there is long-term risk reduction in the risk of cardiovascular disease. What's key is that all of these lifestyle therapies are geared towards weight reduction due to a change in diet and increased physical activity. And I'm going to come back to that a little bit later. The CDC actually has resources. So if you're wondering, what is the DPP program? How is it something I could even use? There are instructions in both English and Spanish on the CDC website that can be used, and I would encourage anyone who's interested to take a look. When it comes to what diet is the right diet, the pre-DIND study is a study that I think is actually really important. It was published just several years ago, and it was looking at individuals who had type 2 diabetes or risk factors, exactly the type of risk factors we're looking at in terms of cardiovascular disease. And I want to focus particularly on the hypertension, the elevated cholesterol, overweight, or obesity. These are all the type of things that we see in our women with PCOS. And what they did is they randomized individuals to a control or to a Mediterranean diet, either with extra virgin olive oil or with nuts. And so the primary endpoint was acute MI, stroke, or death from cardiovascular causes. And they followed these individuals for five years. And what I want to point out is that the Mediterranean diet was far superior than the control diet in preventing these types of events. And in fact, when you look more specifically about overall mortality, so not just cardiovascular causes, but overall mortality, nuts was not the preferred. It was the Mediterranean diet with the extra virgin olive oil. So when people ask me what diet I recommend or what I want them to talk to their nutritionist about, I usually start by encouraging a Mediterranean diet with extra virgin olive oil. How durable is this? If I looked at people 15 years out from the Diabetes and Prevention Study, what would it look like? Well, the DPP had three arms. It had a placebo arm, a metformin arm, and a lifestyle arm. And so the first thing I want to point out is both metformin and lifestyle, even at 15 years, outperformed the placebo arm. The other thing is that the lifestyle arm beat the pharmacologic arm, which was metformin, hands down. So how do we think about this in terms of putting it into practice? Oh, lifestyle change is hard. So I'm sure as many of you have, we counsel, we encourage our patients. I sometimes use the DPP resources off the website. I send them to nutrition, particularly for our patients who are obese. If they struggle with knee pain, hip pain, back pain, I'll actually refer them to physical therapy to try to help them get more mobile and more active. But all of these things are actually incredibly hard to do. And if you speak with the team that ran the DPP, they will tell you that they had really wonderful participants who really engaged across the study. And so I typically give my patients three to six months to make a lifestyle change. I will continue to encourage lifestyle change, but at that point, we don't delay in initiating pharmacologic therapy. And I think that's actually really important for particularly for our women with PCOS. So if the purpose behind initiating this therapy is to reduce cardiovascular disease risk, delay the diagnosis of diabetes. And if all of these prevention studies have focused on weight loss, is metformin the best option? So I wanna talk a little bit about liraglutide, which is FDA approved for the treatment of obesity and also for individuals who are overweight, who have additional risk factors. And so I will even consider it for my patients who are overweight with PCOS. And so what do we know about liraglutide? There have been seven relatively small randomized trials in women with PCOS who are overweight or obese. It's got 172 patients and over a three month period, they decreased their BMI by 1.65 kilograms per meter square. So this is taking someone with a BMI of 31 to a BMI of say 29.4. There also has been a decrease in testosterone levels. And as we had correlated the testosterone levels to increase risk for diabetes, that's important. There's some mixed data on changes in insulin resistance, but like I said, it's only 172 patients over about seven trials. There has been one trial in particular looking at liraglutide and metformin therapy that I wanna speak about briefly. And so what they found is that liraglutide at three milligrams, people lost about six kilos, their BMI dropped by about 2.2 kilograms per meter squared, and very importantly, their waist circumference shrunk by about four centimeters. So if you think it's about two inches, if you think about pulling someone away from having metabolic syndrome, that's one of the things this did. Now, you couldn't treat with the same dose of liraglutide when you had metformin on board. And this really has to do with side effects. So the liraglutide and metformin together had more side effects. And so you could really only get to a liraglutide of about 1.2 milligrams daily. The metformin was up to about 1,000 milligrams twice a day. And what you can see is that although these patients lost weight, although their BMI fell and their waist circumference fell, it fell at about 50% of what liraglutide alone did. So when we think about our PCOS women, many of whom who are overweight and obese, treating the obesity reduces the likelihood that they have metabolic syndrome and reduces the obesity itself, and can even modify some additional PCOS risk factors, all of which can reduce their risk for cardiovascular disease. So I push pretty heavily on weight loss in my patients with PCOS. I typically give them an option of liraglutide, metformin, or liraglutide and metformin. So if we were to look at this, so for Monica, who's 33 with PCOS, when we talk about what she might like to take, she's going to tell you, I'm 33, I'm interested in having kids in the next couple of years. I don't really want to take an injectable. Liraglutide is currently an injectable. And so for her, we go with metformin and lifestyle. For Cynthia, who has slightly worse metabolics in terms of her prediabetes risk, we won't go with liraglutide and lifestyle. But this is sort of an individual patient-based decision. So now what else do we need to do in terms of treating them for their cardiovascular disease? Well, these risk calculators, really what they're telling us is how aggressively should we go after the other aspects of Monica and Cynthia's risk? And so from that standpoint, it's a consideration for therapy. How aggressive should we be? How long should we wait until we start therapy? And it's also a point of counseling, right? Someone who's 33 is really not thinking, I'm going to have heart disease. But we know that a tremendous number of women have heart disease, die from heart disease, and are undertreated for heart disease risk factors. So having this discussion early and often is critical. So what can we say about cardiovascular disease risk and PCOS and what we do about it? We can say that there is a complex genetic relationship between PCOS, cardiovascular risk factors, and cardiovascular disease. And what this means is that women with PCOS are more likely to develop cardiovascular disease, and women with PCOS are more likely to have multiple cardiovascular disease risk factors. As soon as you diagnose someone with PCOS, you should be thinking, how do I comprehensively and routinely assess them for cardiovascular disease? Even when they're 18, this is when it starts. So it's a personal and family history. It's understanding lifetime, lifestyle, BMI, blood pressure, assessments for metabolic syndrome, including waist circumference, measures of glycemia, OGTT, hemoglobin A1C, and fasting lipids. It's using that overall assessment, whether it's a 30-year risk, a lifetime risk, a 10% risk, and putting it in the context not just of that risk, but the risk-enhancing factors they have, and the risk that they could have if they modified their lifestyle. So I think it's incredibly powerful to say to someone who's 33, if you were more active, if you ate more fruits and vegetables, and less fast food, and if we treat you to help you achieve weight loss, you might be able to cut your risk of developing cardiovascular disease by 50%. And I think it's also empowering for patients to let them know, what am I doing? Why am I doing this? Maybe I'm not super happy that I'm overweight, but it's not something that I feel like is affecting my daily life. And I think it's important to recognize that it is going to affect their life 30 years from now in terms of their risk for cardiovascular disease. And so what I think of is dissecting out the different components of cardiovascular disease risk and treating all of them based on best practices. So thinking about blood pressure and lipids, thinking about metabolic syndrome and prediabetes. Now you can have metabolic syndrome without having prediabetes. I'm going to tell you, I have very few patients that are like that. Although they don't have the abnormal glycemia, because it's a risk enhancing factor, and because central adiposity in particular has been related to developing diabetes, as well as being inflammatory and having a negative impact on cardiovascular disease, I do treat them the same way. I treat them as if they had a prediabetes. Obesity, there are a lot more options for obesity treatment and management nowadays. I spoke of just one that I would say is common to use, liraglutide, and that I find it's very easy to get insurance to cover nowadays. So it's an easy go-to thing. For individuals who are hesitant about starting something like liraglutide, which is an injection, what I tell them is we're really only going to do it for three months, because if they don't lose weight after three months, you're going to stop it. But if they do lose weight, they're often motivated to continue going. Finally, counseling based on risk. You know, letting someone know that they have a high lifetime risk, even if they're young. And don't be afraid to use the team around you. I use our nutrition services a lot. Like I said, when there's a thing that's impeding my patients from being active, I'll use physical therapy. And ongoing evaluation. If I implement a therapy that's meant to result in weight loss, or that's meant to improve a metabolic parameter, I will follow up in six months to see if I've actually succeeded. And if not, I will up titrate the therapy. And that's really because I'm trying to aggressively reduce risk in these women with PCOS. A lot of the risk calculators, because women in general are protected for cardiovascular disease before the age of menopause, they often tell you that the patient has a very low risk, but in reality, after the age of menopause, all of this multiple decades of risk factors catch up with women, and then you suddenly see an explosion of cardiovascular disease. And the purpose behind this is to recognize it, screen it, and aggressively treat it. So I want to thank you so much for your time with me today, and I'd be happy to take any questions. Thank you so much. Thank you, Dr. Lippincott, for a very comprehensive presentation on the subject. We will now go ahead and open the session to Q&A, so please go ahead and type your questions in the Cadmium stream. And I'm going to start with a couple that have been answered because I think they're interesting for the whole group. One is, what are the side effects with combined liraglutide and metformin? And if I might add, how do you start? If somebody is not on either, do you start one and then titrate up, or which one would you start first? So which one I would start first really depends upon patient preference. So right now, the liraglutide is an injectable. I am very much looking forward to and hoping that shortly we will have more that are approved GLP-104 obesity management rather than just diabetes that are oral as options, and I think that probably will change my preference. But in someone who the main concern is metabolic parameters, I might start with metformin first. If I think that the main thing that I need to do is help them lose weight and they are amenable to using an injectable, I'll start with liraglutide first. Many of my patients are already on metformin and now are considering liraglutide because often it takes a little while to get to the idea of doing an injectable. And so in that case, I typically have them on about 1,500 milligrams of metformin. I'll drop them down to 1,000 and then start low dose on liraglutide and increase it. If they find the symptoms are intolerable and we've decided that weight loss is the primary driver that will help improve their overall risk, I'll drop the metformin further and have them continue with the liraglutide. Great, that's very helpful, thank you. What about bypass surgery, one person asks? So I think bypass surgery is absolutely a consideration. I think it is major surgery in terms of the ones that have some of the most durable effects. But one of the most biggest challenges is patients, when they go to the weight center and walk through for bypass surgery, need to be able to follow a diet post bypass surgery in order to maintain the impact of the surgery itself. The other thing to realize is think about the BMI of your patient. So if you look at people, patients who have gone through bypass surgery, they lose a tremendous amount of weight, but they typically settle around a BMI of about 30. It's actually pretty hard to get them below that, at least from some of the data that I've seen. And so because of that, I often start with diet and exercise, I move to pharmacologics, and then I will discuss bypass as a part of an integrative approach, particularly with patients who have a BMI above 40. Perfect, thank you. The next question is about what's more important for cardiovascular risk assessment. Is it the increased testosterone or solely due to metabolic syndrome or both equal contributors? I don't think we know the answer to that. I think that prior to maybe five years ago, there were just a handful of small studies that would suggest that women with PCOS were at increased risk for cardiovascular disease. And it's not until we really started doing genome-wide association studies of women with PCOS and identifying the genetic risk profile that we were able to understand that that genetic risk profile overlaps with a tremendous number of other risks, for example, hypertriglyceridemia or type 2 diabetes. And so based on that complex relationship, I'm not sure we're ever gonna completely tease it apart. I will say from a practical standpoint, I target the metabolics because even independent of PCOS, we know those metabolics increase your risk for cardiovascular disease. Good point. Okay, a couple of questions have emerged to the top here. What choices do you have for lipid medications for women of childbearing age? Oh, I was hoping to ask that question. Not a lot of great options out there, in all honesty. Statins are contraindicated for women who are pregnant. Now that doesn't mean I won't use statins in women of childbearing age. I will still consider it if I think their risk is high enough. I'm gonna be honest, most of my women though tend to have more of a hypertriglyceridemia profile in PCOS, and that's because the underlying genetics for PCOS really predisposed to the hypertriglyceridemia. So from that standpoint, you do have a couple levers that you can pull in terms of management on the hypertriglyceridemia side. Honestly, I focus the most on diet because I find that these individuals often consume a very high carbohydrate diet that are driving their hypertriglyceridemia. And if I can reduce their carbohydrate content, I can typically get their triglycerides down. So I pull that lever first versus going to the fibrates and the other options we have for hypertriglyceridemia. So there's a lot of questions about the other GLP-1 treatments and why not those and also rubelsis they mentioned. The reason why I chose liraglutide is simply because based on an insurance issue right now, it's FDA approved for obesity. So I can apply it for obesity and my patient does not have to have prediabetes. They don't have to have diabetes. I can just use it for obesity. I think that is changing. There's a whole bunch of FDA approvals that are in the pipeline, and I think it will expand because in reality, liraglutide is not the most powerful GLP-1 receptor agonist when it comes to weight loss. And so I actually think as more approvals come down the pike, we can absolutely use them. I think the related question, I've also found difficulty though with insurance coverage. So I was surprised for you to say that you were having success with liraglutide unless insurance is better in Massachusetts, but you have any comment? So typically what I do is I document their obesity. I document the fact that they have PCOS and write in the note that this puts them at increased risk for cardiovascular disease. I document what they've tried to do in terms of diet and exercise. And then I write liraglutide is indicated in this patient for weight loss. And I find that having that in my note actually gives our prior office what they need to flip the switch on it. Oh, great. Good advice. So there's, I think an important question about NASH, about how you would treat a patient who has elevated LFTs and NASH. So I think NASH is an excellent question because women with PCOS are at an increased risk for NASH. In fact, there's some data that women with PCOS have worse outcomes with NASH when they develop it. I really focus the most on weight loss for these women to try to pull down their BMI. And I refer them to my liver specialist colleagues for a more detailed evaluation, including something like a fibro scan, which can try to determine not just fat content, but fibrosis that could lead to future complications. Great. I'm sorry. I think we're at the end of our time. There's some great discussions and questions. Are you able to still answer those questions that are left? Oh, that'd be wonderful. Well, thank you so much for your excellent presentation and for the participation of the audience. Thank you so much. I so appreciated being able to share with you all today.

PCOS

cardiovascular disease

genetic variants

obesity

hyperlipidemia

type 2 diabetes

coronary artery disease

risk calculations

treatment options