Fighting the Ladykiller (and side effects) with Cholesterol Lowering Therapy

Hello. I’m Dr. Margo Minissian, and it’s my absolute pleasure to discuss with you today “Fighting the Ladykiller,” otherwise known as heart disease, “(and side effects) with Cholesterol Lowering Therapy.” I am the Executive Director of the Geri and Richard Brawerman Nursing Institute and the Simms/Mann Family Foundation Endowed Chair in Nursing Education, Innovation and Research at Cedars-Sinai Medical Center in Los Angeles, California. I love all things prevention, and I hope you enjoy today’s discussion around how to improve cholesterol and to help your female patients tolerate their much needed medications. These are my disclosures in regards to honoraria and grant funding. For objectives today are around cholesterol management and heart disease prevention in women. And so when we think about this and we think about all the different types of side effects that women can describe, our primary learning objectives will be to provide two examples of why management of cholesterol can be different in women compared to men. We’re going to list four classifications of patients who qualify for statin therapy, and then we’re going to describe two specific clinical pearls that will help to improve the statin associated muscle symptoms. If you want to play along, there will be some case studies. And so feel free to download. There are two apps in particular that I enjoy. The first one is the new updated ASCVD Risk Calculator Plus from the American College of Cardiology. The American College of Cardiology also has an app in regards to statin intolerance to help walk you through secondary causes of potentials for muscle aches. And so I do find for being able to quantify who is at higher risk with the risk calculator and then how to evaluate for statin intolerance with an app. So I always crack up at this slide. Are there really differences between men and women? I was asked this more often I feel later ... longer times ago, but in this day and age, you know, men and women, the way that we view ourselves, the way that we approach different issues, but also the way that we envision ourselves really does come into play. But physiologically, there are many differences between us as well. And it’s not always psychosocial. So what are those differences? When we start to think about dyslipidemia patterns in women, women typically will have lower HDL, which is good cholesterol. I like to think of H for happy, it’s the good cholesterol and you want it high. In their case, it tends to run lower. They tend to run higher triglycerides, and then we start to see significant potentially cholesterol changes during pregnancy and lactation. This can be a normal variance, but sometimes it is not. In regards to treatment, women tend to describe more types of side effects and statin myalgia as they’re less likely to reach their target goal for a multitude of different reasons that we will be getting into. And they also have less success around secondary prevention, and in particular, they are not screened as much for Familial Hyperlipidemia, which we know is really truly a pandemic here in the United States. And so a lot of this, we feel, is still really stemmed around women. And if you can believe it, in this day and age with social media and all the other different types of electronic platforms, that only half of women really still know that heart disease is their number one killer. And it’s still true today, as it has been for a very long time. But still, when we look at the rate of heart disease and that it kills four times more women than breast cancer. Now, not to compare to breast cancer, we really should envision the breast cancer campaign as a real success. A true example of when predominantly women and scientists and physicians and nurses and all HPs come together, when we start to try and make a difference and we start to talk about increasing awareness. Breast cancer has really done a great job at this. Yet we still lack and and in fact, stroke is the number four cause of death for women in the United States. And so, you know, women are just more likely to die from heart disease and stroke. You know, for men in particular. But the matter of fact is, is that men and women die more of heart disease worldwide than anything else. And lastly, the aged 36 to 54 years of age women, they are actually on the rise, although we are doing a better job in other areas. So why do we think that these numbers still look so staggering? Well, it oftentimes has to do with us not optimizing optimal medical therapy. And undertreatment is a real serious problem. Women receive less statin therapy than men. And this is a paper that describes in 5600 women that qualified for statin therapy, and then as we look across the screen, you’ll see that they were either never offered or they declined or they discontinued their statin. And so, gosh, are women just cranky? They don’t want to take their medications? No, that’s probably not the fact. As a matter of fact, we feel it has a lot to do with pharmacokinetics. And we’re going to get into that. But it’s not even just for statin therapy. Women also receive less therapy than men for hypertension, other treatments of coronary artery disease, and heart failure. And so in 2018, the Multisociety Cholesterol guidelines describe this nocebo effect. So the 2018 guideline offers guidance for their clinicians and patients who develop these types of symptoms for statin therapy., and it prefers to designate such symptoms as statin associated side effects. This acknowledges that blinded placebo controlled trials of patients recruited with these statin associate muscle symptoms, sometimes you’ll see that called SAMs, saw a clinically significant percentage of symptoms both for participants received only placebo and not statins. So our mind is really a powerful instrument first and foremost. But secondarily, if somebody is feeling symptoms, they’re not going to be compliant to their medications, and so I feel that that’s really the take home point, is that if somebody feels that they’re not tolerating a medication, it’s really important for their providers to listen and to create change. So cantankerous or lack of clinical trial data on medication effects in women. So these are some school aged kids who say if we don’t know which drugs are safest and most effective for pregnant women and children, why don’t they just let us do more clinical trials? And the professor says, well, it’s to protect you from untested drugs, and around and around and around we go. And so really, in my opinion, the perfect definition of what a catch 22 is, because it’s very easy to figure out, for example, if a woman is pregnant. And it really should not limit her from having a particular medication prescribed to her. And we know that this in particular happens a lot for statins. So who would benefit from a statin anyway? If we’re going to help our patients, let’s make sure that we have the right patient and that we’re selecting the right level of medication for dosing for them. So we know that patients who have clinical atherosclerotic cardiovascular disease, they don’t need the ASCVD risk calculator, you can go ahead and just treat them. Same thing for our patients with an LDL, that’s the bad cholesterol if it’s greater than 190 milligrams per deciliter. Most people cannot even eat their way through McDonald’s to those types of levels, and so we’re really likely dealing with a genetic disorder. And so you also don’t need to do a calculation for them. They should be placed on a high intensity statin. So we’re really looking to lower that LDL by more than 50%. And so there’s two main statins that you would choose from Atorvastatin at a 40 to 80 milligrams dose to achieve that greater than 50% reduction or Rosuvastatin 20 to 40 milligrams daily. The other two categories, diabetics aged 40 to 75 years of age and they have LDLs say between 70 and 189. They would also qualify for cholesterol lowering therapy. It may be a moderate dose. And then the magic box where you see the person’s hand, this is the primary prevention patient who has an ASCVD risk calculator that is greater than 7.5%. They would be the fourth group and they traditionally are the grayest area, if you will, for us being able to figure out their statin dose. Now luckily, the ASCVD risk calculator plus has been updated and is very well validated in both African-Americans and Caucasians, in male and female, and it is quite a good predictor at us being able to phenotype out those individuals who will reach a greater than 7.5% risk. And so you would plug in the the numbers that you see here and it will help you decide if somebody is greater than 7.5%. Now, sometimes there are individuals that are in that 5 to 7.5% risk category, and then they have other types of risk factors. And we’re going to talk about them next because they get a little bit tricky. But when we’re starting to think about those ASCVD patients and really, who would you put on the highest dose of cholesterol, essentially? Who would you throw the kitchen sink at when it comes to cholesterol lowering? That would be this very high risk of future CVD event category. So a major ASCVD event is a recent acute coronary syndrome, within the last 12 months, history of MI other than a recent ACS, if they’ve had a history of ischemic stroke or they have symptomatic peripheral artery disease. High risk conditions include being over the age of 65, having heterozygous familial hypercholesterolemia, or having a history of prior coronary artery bypass grafting or PCI intervention. If you have diabetes mellitus, if you are hypertensive, if you have renal dysfunction, if you’re a smoker, or if you have chronically elevated bad cholesterol, which is LDL and you did not tolerate either a statin and or ezetimibe, and then lastly, if you have a history of heart failure. So when we start to think about risk enhancers around this risk score, so we just reviewed over who’s the highest risk patients, and those were those two in the upper two boxes. Now, when we start to look at those moderate risk patients, risk enhancing factors can really be helpful. So these include family history of premature heart disease or persistently elevated LDL that is equal or greater to 160 milligrams per deciliter, chronic kidney disease, metabolic syndrome, or pay attention, here’s conditions specific to women such as adverse pregnancy outcomes. So this is a woman who’s had gestational diabetes, pre-eclampsia or women who had premature menopause, or they’re in a post-menopausal state. In addition to that, also is more common in women are inflammatory disease processes. And then, of course, we need to consider ethnicity. Now, when we start to talk about what’s available, when we’re starting to treat our moderate or high risk patient, we start to look at the different intensity types of statins. Not all statins are created equal, and in fact, they can be very, very different. They can behave very differently and they can oftentimes provide us with different levels of result. So for our very high risk ASCVD patients, you’re going to really focus on the left side of our table here with the high intensity statin therapy or our familial hyperlipidemics, they oftentimes require that as well. When we start to think about moderate intensity statins, so this is if you’re looking to achieve an LDL, 30 to 50% reduction, then you can choose 10 to 20 milligrams, 5 to 10 milligrams Atorvastatin, Rosuvastatin, Simvastatin 20 to 40 milligrams. And down the list we go. We also have some more unique statins on here that may not be as familiar to you, such as Fluvastatin. It comes in a extended release and also a short acting and as well as Pitavastatin. Now lower intensity statins are essentially these that are in the moderate intensity, they’re just at lower doses. And when you see the parentheses, those are the less studied doses, but that we typically do. So now that we’ve reviewed over who needs a statin and at what dose, let’s go see a patient together. So Barbara is a 56-year-old female. She has two stents that were placed in 2017 in her left interior descending artery. She’s had prior statin associated side effects with Atorvastatin 80 once daily. And her lipid, oh, sorry. She comes into the lipid clinic and she is now taking rosuvastatin. So the provider has switched her over. And so she’s on rosuvastatin 20 milligrams. She’s taking it Monday, Wednesday and Friday, and then she’s taking 40 milligrams Tuesday, Thursday and Sunday. So in your opinion, is Barbara, on a high intensity statin dose? Yes or no? She’s alternating between the 20 and 40 milligram of the rosuvastatin. And the answer is yes. She’s still on high intensity statin dosing, but we were able to avoid her side effects by being able to adjust different levels of high intensity dosing. So oftentimes we need to do this. And why? Because of these lovely statin side effects that we see. Women, in particular, as we talked about, have poor adherence. And it’s oftentimes because of all these certain darn side effects, such as myalgias, hair loss, malaise, GI upset. Sometimes they’ll just feel flu-like, and this can be secondary to a side effect of their statin. So if these individuals find that they can’t be on the right dose of statins without having these side effects, if they are a primary prevention patient, then you can go ahead and stop and give them a drug holiday for two weeks and then go ahead and re-challenge the same statin. For some reason, interestingly enough, some people can go back and tolerate a dose that they prior could not. And while you’re trying that, you want to ensure that you’ve ruled out secondary causes of statin intolerance. And as I’m going to remind you, we don’t have to just try two statins. There are seven available and they have different levels of intensity and they have different ways of interacting with our bodies. So if you’ve tried two, don’t lose hope. They all work fairly differently and here’s why. So the CYP450, these isoenzymes that are known to bio transform are our drugs and basically everything that we put into our mouth. This is essentially the freeway system into our metabolism and into our system. So the CYP pathway. I live in Los Angeles, so I will describe the CYP450 as essentially the 101 freeway in Los Angeles. It is a busy road. I don’t know if any of you have ever driven on it or the 405, but you basically have the CYP2C9 and CYP3A4 is essentially the 405 freeway and the 101 freeway. And so many of the drugs, in particular the drugs that we use in cardiovascular medicine really go down these primary pathways. And if you see here in red, I have underlined different statins that many of us use, in red. And you can see that essentially they are competing on the same freeway to metabolize. And unfortunately, statins tend to be poorer metabolizers, so if you have a patient on diltiazem or nifedipine or verapamil, sildefanil, warfarin, any of these commonly used medications and they’re having side effects, you may potentially be dealing with a drug-drug interaction. Essentially the calcium channel blocker is the Ferrari and the atorvastatin and the lovastatin are the Yugo. And so it just really, quite frankly, gives off to more by product and that our muscle has to therefore excrete. If you look down below such as Rosuvastatin, Pravastatin, and Pitavastatin, Rosuvastatin and Pravastatin, where sort of use like a side street to metabolize. And so oftentimes we can avoid side effects with these two medications because they’re not in competing contingencies with these other metabolic pathways. Pitavastatin is really fantastic because it really uses a unique substrate. And so therefore, we can we have demonstrated that there are less myalgias as a result of that. So Dr. Toth and colleagues had put together a very comprehensive review article in 2018 that describes the management of statin intolerance. And they they go into a real pragmatic way of being able to treat individuals who have these types of side effects. And then they touch on some of the research in this field and where we’re really going to be able to find some different solutions. So this slide, you’ll see a bunch of words in the background in regards to definitions around statin intolerance. And this is just to give you a feel that basically worldwide that there are four major organizations that are all considered the experts and go-to resources for cardiovascular national guidelines, international guidelines, and they all use lots and lots of words to describe different ways of describing a statin myalgia and so, basically, here’s what you need to know when you start to look through all of these different definitions for statin intolerance. Basically, if you’ve tried two statins at a low daily dose and then you’ve tried a second statin at any dose, so remember, Barbara, we had her on like a Monday, Wednesday, Friday of a different kind of a dose. That’s a great strategy to try. So they recommend that and then see if the patient is still describing symptoms. And as I have alluded before, whether they are real or perceived, the end result will be that they won’t be on their medication, and that’s not what our goal is here. So we really want to listen to the symptoms that they describe and acknowledge that. We also look at laboratory values, but oftentimes these abnormalities that we see in labs are few and far between. And so the best thing to do in particular for primary prevention is to stop the statin, and see if the symptoms improve and then re-challenge. But if the symptoms continue, then we start going down a different type of a workup. So when we start to look at the role of those biomarkers, some still look at CK, I personally in my clinic don’t as much and oftentimes CK is affected by exercise and workouts and we’re really looking for something that would be ten times a considerations of significant. We also will look for liver abnormalities. So we are okay watching ALT numbers, so one and a half times normal and oftentimes we will see this, in particular, in patients who have fatty liver or other types of situations that are quite common actually for individuals who have dyslipidemias, so they have a one in a million chance literally of having a serious liver disease and 10 to 30% of patients who don’t receive statins, unfortunately, because of the fear of this liver disease. So we’re really unfortunately not using data really to its highest potential. Now, the good news is that there are emerging markers that will hopefully paint a more clear picture as to the potential behind having any type of an issue. But if we think about that, the use of statins prevent 33% of all major cardiovascular events compared to placebo compared to a one in a million chance of a serious liver disease, we as providers really need to get serious about helping our patients get on something, and that is also a very unique characteristic to statins, is that you can take a little bit of it. A little bit is even better than not taking it at all, unlike other medications such as antihypertensive and anticoagulants, for example. So when we start to think about statin intolerance management, what’s most important is that we need to continue the statin therapy for the highest risk patients. You can help them work through their side effects while still continuing to have them on the highest tolerated dose of statin. And then we want to start to think about the different types of statins and the characters around them. So for example, if they have not yet tried a hydrophilic statin such as Pravastatin or if they’re a high risk patient, Rosuvastatin, you can switch directly and you don’t need to give them time to wash out. You can just literally swap it over. And these medications are driven to be better tolerated in the elderly, which is definitely important when we’re thinking about polypharmacy. Now, in my clinic, we’ve described this alternate day statin dosing in women who’ve had previous statin intolerance and it’s been really working quite well as a really tried and true staple to our program, in helping, in particular, our women with ischemic heart disease get the important medications that they need. So here are some of my clinical pearls and tricks of the trade. So we want to make sure that we pay attention to drug-drug interactions, and I do like using eproperties to be able if someone is on some medication and that are raising an eyebrow to me, that they may be having a competing CYP pathway interaction, I will look them up and make sure. Alternate statin dosing monday-thursday dosing for a month and then adding one day per week as tolerated. I have some women that will take a high dose, such as rosuvastatin 40 on a Monday, Thursday, and they will see a 30% reduction throughout the entire week and they can tolerate that without having side effects. I have some women that can progress up and take it six days a week, not seven, five days a week, not six, four days a week, not five. So every week I have them add a dose of statin and then if their symptoms reproduce, I have them go back to the last dose that they tolerated. And it’s been quite successful at this point. Also, consider supplementing their LDL lowering with plant sterols and soluble fiber is a wonderful strategy that’s good for us in particular, and also can really help lower cholesterol. Mediterranean style eating, polyunsaturated fatty acids, these are all great nutritional strategies that are good for our cardiovascular system and great for our cholesterol. And in regards to vitamin D and Co Q 10, there’s lots and lots of old data, but there’s less data showing outcomes that if you treat with these two things, that it actually makes a resulting difference in heart outcomes such as heart attacks, strokes and death. And so essentially how I use these two vitamins is that if a patient feels compelled that taking some over-the-counter Co Q 10 helps them stay on their high intensity statin dose, I absolutely do not discourage that because I want them to stay on the national guidelines recommendation, right, which is the statin. So, but I don’t usually recommend it, but I don’t really necessarily go against it either. And before you consider alternate statin therapies, make sure that you verify that they’re really are truly adhering to their medication practices, that they really are trying to take it daily, and it’s not something more to do with keeping their prescriptions in the glovebox of the car and forgetting to take it. We definitely want to reiterate adherence to lifestyle, exercise, nutrition. This is all very important. And then are they completely statin intolerant? If they’re completely statin intolerant, and you’ve gone through a fairly exhaustive list of statins and they just really haven’t been able to tolerate anything, then we want to consider the addition of a non-statin therapy. Also consider coronary calcium scoring in our primary prevention patients, how badly do we need to push? And then of course, you’re going to want to listen to your patient and their preferences. So which non-statin therapies are there to choose from? And from that, was supported by the data? So here’s a little joke for you. As it turns out, I was in the group that received nothing but a placebo the whole time. And there there they go walking into heaven. So we don’t want to do that. We want to follow where the data lies. And before we get into non-statins therapies, nutrition, lifestyle recommendations, they make significant differences for both lipids and blood pressure. And so really emphasizing DASH and Mediterranean style eating plans, which has got a good assortment of fruits, vegetables and whole grains, low saturated fats, no trans fats. And we want to avoid any type of tropical oils, cut down on processed foods and really think about how we think of ourselves eating over a lifetime. DASH has new fantastic handouts that are available through the National Heart, Lung and Blood Institute that you can download that really help describe both scientifically as well as pragmatically why DASH is so good for cholesterol and blood pressure, and also provides some eating plans that I find very helpful for patients. Now let’s talk about some of these non-statin therapies. So Ezetimibe is our next go-to according to national guidelines, and it reduces blood cholesterol by inhibiting the absorption of cholesterol in the small intestine. It has meta-analyses of randomized controlled trials that lowers that they see Ezetimibe lowering and improving CV outcomes. You’ll see about a 24% reduction when added to a statin therapy and a 19% reduction when it’s added by itself. The improve-IT Trial showed over a course of seven years, we started to see this hazard curve start to separate. Since we’re talking about women and we’re talking about statins and myalgias, I will note that they were an older population ASC and they were, they were more men. So not exactly falling within our purview, but it is what is currently suggested within guidelines and typically a an affordable treatment as well. Niacin. Many people used to ask a lot about niacin. We don’t really use niacin at all and that’s because of have a lot of really good data, and then we saw then we started to see some increases in diabetes and we started to see some harm. So really not using that niacin anymore, but it is a B3 vitamin, and it’s important to know that your patients might ask for it. Bile acid sequestrants, they promote elimination of cholesterol through the bowel. They are daily doses of colesevelam, or 4.5 grams LDL cholesterol can be reduced 18 to 25%. But with that being said, it’s a hard drugs to take, a lot of stomach upset, and a fair amount of drug-drug interactions and down below here on your slide, you’ll see that the 2013 guidelines had suggested not using it if fasting triglycerides over 300 or the patient was diagnosed with type III hyperlipoproteinemia, and that we want to check fasting lipids at baseline, at three months, and every 6 to 12 months thereafter. And that we want to really use caution if we start to see triglycerides climbing. Fibrates are not used for LDL lowering and I do have it here just to let you know that people do use them, take them for lowering triglycerides and potentially raising HDL. And it’s important if you’re going to prescribe a fibrate along with a statin for that, you know, low HDL, high triglyceride, to monitor urine creatinine for elevations. And I have seen a couple of those in my practice, although infrequent. And a newer player to the game, are PCSK9 inhibitors, which are a monoclonal antibody. We’ve had them now for more than a few years and have demonstrated that they are very safe and effective. They are expressed in the liver and in the intestine, and they basically help to promote intracellular degradation. And so the PCSK9 inhibitor helps to prevent that LDL receptor from being degraded, so then it allows for that receptor to come back up to the cell wall and to help clear the LDL particle. So very, very effective add-on therapy. So how do we apply the new cholesterol guidelines to clinical care? Well, let’s meet Jane. Jane is a 61-year-old female with a history of CABG x 4 in 2003. She has dyslipidemia, hypertension, type 2 diabetes, and obesity. She presented in 2018 with chest pain and abnormal coronary CT angio, and she had a more recent left superficial femoral artery angioplasty and stent placement, and luckily had a good pedal pulse back in 2019. So her family history, unfortunately, her mother had a sudden death event at the age of 52. Her father was obese, had type 2 diabetes, he had coronary artery disease, and he died at the age of 67. She doesn’t smoke and she stopped drinking wine after her bypass surgery. Her vitals in clinic that day, 144 over 77 for heart rate of 86. For total cholesterol 184, her HDL is 50, for LDL is 79, and her triglycerides are 139. Her non-HDL is 124, and her Lp(a) level 118. She’s currently taking Olmesartan/Chlorthalidone 40/25 milligrams daily, Amlodipine ten milligrams at night, Carvedilol CR 40 milligrams daily, and she’s taking Rosuvastatin 40 milligrams daily. She’s on Clopidogrel 75 milligrams daily, Metformin 1000 milligrams twice daily and Canagliflozin 100 milligrams daily. So we’ve properly documented, as many of us know in a very busy clinic, it is important for us to take time to start to document out when somebody is having side effects or that they’re not able to reach the goal of high intensity statins. So we had properly documented that she was actually taking alternating 20 milligram and 40 milligrams statin dosing, she had herself adjusted. And so we also had tried her on Ezetimibe, ten milligrams daily for initial non-statin therapy and her LDL was 76 on the prior when we saw her in clinic, which is not going to meet needs, right? So we really wanted to lower her LDL below 70 and ideally, trends are going that 50 is better than 70 and that lower than 50 is better than that. So we had added evolocumab 140 milligrams every 14 days. And then as you can see here, we were able to achieve an LDL of 26 milligrams per deciliter. What’s nice about this is that she also did achieve a reverse ratio between her HDL and her LDL, and that her Lp(a) also came down. And this is a well-documented phenomena with the PCSK9 inhibitors that you should see around a 30% reduction in Lp(a) as well. So when you’re looking at your highest risk patients and if you see that, the PCSK9 is a really good option for add-on statin therapy. So with an LDL of 26, would you make any further adjustments to Jane’s medication? Would you cut her statins back to 20 milligrams every day of the week? How do you feel about that? So how low is too low? And that’s always been the main discussion and was not really able to be studied in its full extent because we didn’t have the capability of of achieving these really low goals, but now we are able to do so. And so what we’ve learned over the years is that as we continue to achieve lower and lower LDLs that we improve outcomes. And as we look to improve outcomes, we look at safety. Now this slide talks about neonates and LDL levels and how LDL will rise with age, and most of that is oftentimes related to lifestyle and high fat diet. So if you look at different types of animals and you compare them to humans, you can see that we really truly have very high cholesterol. But when we’re born, we’re born with LDLs around 30. So it makes good pragmatic sense that an LDL in the twenties and thirties is a very likely phenomena that our physiology was accustomed to from birth. And then oftentimes I get asked the question about, well, aren’t you starving the brain of cholesterol? And, you know, 20% of the body’s cholesterol actually comes from the brain. But cholesterol does not cross the blood brain barrier, and oftentimes providers think about peripheral cholesterol in our bloodstream and equating that to cholesterol being intracellular and being useful. Cholesterol really has not been proven to be useful in our bloodstream. It is very useful in the cell and they are not created equal, and so we want to help our body be able to utilize, process and then rid of excess cholesterol, and so achieving these low numbers really, truly from many different perspectives around safety, truly lower is better and it is safe to get there. So lower is better. Avoiding drug-drug interactions, select a drug with less utilization of the CYP pathway, alternate statin dosing for a month and then add one day a week as tolerated, daily low dose statins. The use of hydrophilic statins such as Pravastatin, Rosuvastatin and Fluvastatin, enhancing LDL lowering with plant sterols and soluble fiber as well as Mediterranean style eating, polyunsaturated fatty acids and using those vitamins as needed if it helps maintain national guidelines therapy. And with that being said, I want to thank you so much for your time. I would love to hear from you and please feel free to see me on Twitter. I have my email here as well and I wish you all the best in caring for your female patients and hope that they have less side effects. Thank you so much.