and a clinical lipid specialist. And we are going to discuss lipid assessment and management. And we're going to try to answer the question of, why is lipid management so important? So first, we're going to discuss lipoproteins and atherosclerosis. Atherosclerosis is responsible for approximately 50% of all deaths in the Western eye society. And ischemic heart disease remains the number one cause of death. And this is despite our best efforts to manage cardiovascular risk factors. Atherosclerosis is an inflammatory disease. And lipoproteins, including low-density lipoprotein cholesterol, or more commonly known as LDL-C, have been associated with the development of atherosclerotic cardiovascular disease and ASCVD events. So understanding lipid targets and treatment strategies, as well as identifying additional cardiovascular risk factors, is extremely critical to reduce the incidence of cardiovascular disease and ASCVD events. So this quote is really important. And I want us to sort of pause for a moment and think about this. It's that atherosclerosis represents a clinical paradox. It is potentially the most preventable or treatable chronic disease, yet it remains the greatest cause of disability and death throughout the world. And this does not have to be the case. Prevention is truly key when it comes to cardiovascular disease and atherosclerosis. So this is a bit of a busy slide, but we're just going to really highlight when we look at atherosclerosis and lipoproteins and atherosclerotic plaque formation. So first, we have lipoprotein retention to the vascular wall. And that disturbed flow can activate the expression of adhesion molecules on the endothelium. And there's subsequent monocyte retention and recruitment into the vessel wall. So these monocytes then differentiate into macrophages, and they take up oxidized low-density lipoprotein particles. So the monocytes differentiate into macrophages and take up the oxidized low-density lipoprotein particles, which then form foam cells. And it sort of activates this pro-inflammatory type of state. Vascular modifications result in smooth muscle cell migration to the endothelial space. And what we have there is formation of a stable plaque, where you see there's this lipid core. We then have accumulation of necrotic cells as foam cells undergo cell death, essentially apoptosis and necrosis. And what happens is that you have the formation of this fibrous cap. Now, plaques that have a more thicker fibrous cap are considered to be more stable plaques. Plaques that have this thin fibrous cap are considered to be vulnerable plaques, and those are at risk of plaque rupture, which can then lead to complications such as thrombosis, and that leads to myocardial infarction. So it is our goal here not only to reduce the incidence of atherosclerosis by reducing the number of atherogenic particles, but also to try to impact plaque composition to create a more stable type plaque. And when we look a little bit closer, what we recognize is that it's not just an LDL problem. And so here we have sort of a cartoon depiction of all of our ApoB particles. And what happens is chylomicrons transport triglycerides to adipose tissue and skeletal muscle. Generally, these particles are considered to be too large to enter the arterial wall, so there's a little bit of uncertainty in terms of how atherogenic they really are. Cholesterol circulates in our plasma within lipoprotein particles. And the cholesterol is deposited, as we saw previously, into the arterial wall, and trapping of the ApoB particles is what drives the process of atherosclerosis. As we see here in the VLDL, it's the chief carrier of triglycerides, but this ApoB particle is also atherogenic. If we take a look at this being not just an LDL particle, but all of the potential ApoB particles that can be atherogenic, we can recognize that ApoB is a stronger indicator of atherogenicity versus just LDL cholesterol alone. So while we've determined that LDL cholesterol is considered a modifiable risk factor associated with atherosclerosis, we really need to consider other major risk factors when assessing cardiovascular risk. And we'll see here that some of these are modifiable, such as cigarette smoking, hypertension, and dysglycemia. Age is also considered to be probably the biggest risk factor or the greatest risk factor for cardiovascular disease. And as we note here, this is a risk factor that is not modifiable. Now, we also need to consider additional risk factors when we're trying to establish cardiovascular risk. And these are considered risk-enhancing markers. And there are several to consider, but it's important for us to have an idea of just which ones really play a role in the development of ASCVD. And when we're doing a risk assessment of our patients, we need to consider these. So first, we look at a family history of premature ASCVD. And we're often asked what defines premature ASCVD. And that is a male with evidence of ASCVD less than the age of 55, or a female less than the age of 60, primary hypercholesterolemia, metabolic syndrome. We need to consider the five components of metabolic syndrome, increased waist circumference, elevated triglycerides, elevated blood pressure, elevated glucose, low HDL. And you need to have at least three or five of those to be able to give you that diagnosis of metabolic syndrome. Chronic kidney disease. We also have to consider chronic inflammatory conditions, such as rheumatoid arthritis or psoriasis. History of premature menopause. And it's considered premature in females that undergo menopause under the age of 40. History of pregnancy-associated conditions and increased later ASCVD risk. And this includes preeclampsia, high-risk race or ethnicity, such as South Asian ancestry, and other lipid biomarkers. And we're going to go into this one a little bit further because it is important to be aware of these other biomarkers that have ASCVD risk associated with them. One being persistently elevated primary hypertriglyceridemia, which includes triglycerides over 175 milligrams per deciliter, elevated HSCRP, elevated LP little a. And it's considered a risk-enhancing marker if the LP little a is greater than or equal to 50 milligrams per deciliter or 125 nanomoles per liter. Elevated APOB, and it's considered a risk-enhancing marker when it's greater than 130, which is approximately equivalent to an LDL cholesterol of greater than 160. And an ABI less than 0.9. And here it just gives you a more comprehensive list of what we just previously discussed. Now, it's important for us to know how do we assess lipid results. And I know this is something that comes across our desk several times a day. So we're just going to take a quick look at how a typical lipid panel will be reported. We're going to look at the total cholesterol. We're going to look at the HDL cholesterol. We look at the triglycerides and the LDL cholesterol. It's also important to note what the non-HDL cholesterol level is. And if it's not reported on your lipid panel, it's extremely easy to calculate. All you do is you take your total cholesterol. You subtract your HDL cholesterol. That gives you your non-HDL. So here we would have the total cholesterol of 280. We subtract the HDL cholesterol of 79. And we could see that our non-HDL cholesterol is 201. So how do we define hypercholesterolemia? Hypercholesterolemia, important to note, should be defined based on either the LDL cholesterol and HDL cholesterol. A non-HDL cholesterol is a combination of your very, very low density lipoprotein cholesterol, or your VLDL, and your LDL cholesterol. We should not define hypercholesterolemia based on total cholesterol. The LDL and non-HDL cholesterol are the most abundant aphlogenic lipoprotein fractions. So that's what should be considered. When triglycerides are elevated at least greater than 150 milligrams per deciliter, it should be noted that LDL cholesterol is less reliable, as cholesterol may be increased in VLDL, IDL, and IDL. So if we think back about those ApoB particles and we saw the ratio of triglyceride to cholesterol, we can see how elevated triglycerides can impact your LDL cholesterol. In the setting of hypertriglyceridemia, we can either use non-HDL cholesterol or ApoB. And those have been proven to have much better sensitivity. Now, in terms of HDL cholesterol, it should be noted that it does have value in risk stratification of atherosclerotic cardiovascular disease. However, important to note that there are no large-scale data to show that targeting HDL cholesterol levels is beneficial in the prevention and treatment of ASCBD. So looking at lipid-based definitions, we should really note that it's difficult to define what truly normal cholesterol levels are, as blood cholesterol levels vary by sex, age, and various metabolic states. So there is no definitive definition, but it's important for us to share what we would consider certain definitions to be of hypercholesterolemia. So generally speaking, hypercholesterolemia is with plasma concentrations of LDL cholesterol greater than or equal to 130 and or non-HDL cholesterol greater than or equal to 160. Primary isolated hypercholesterolemia is considered with an LDL cholesterol greater than or equal to 190 milligrams per deciliter with normal triglyceride levels. Combined hyperlipidemia is considered when you have a non-HDL cholesterol greater than 220 and triglycerides greater than 150. So now let's consider hypercholesterolemia classifications. There's primary, secondary, and multifactorial classifications. Primary is defined as hypercholesterolemia that occurs in the absence of a secondary cause, and this includes genetic hypercholesterolemia as well as idiopathic primary hypercholesterolemia. Anybody who you're considering a diagnosis of hypercholesterolemia, it's extremely important to consider hypothyroidism, nephrotic syndrome, and drugs. There have been several examples of patients who have been found to have extremely high levels of LDL cholesterol that would be considered a primary hyperlipidemia, that we found that the TSH levels are high. And once the patient is treated and then your thyroid, the LDL levels come down significantly. So we always need to consider these secondary causes before we make the diagnosis. And then there is multifactorial, and multifactorial hypercholesterolemia is when the LDL cholesterol is greater than 130, or again, non-HDL greater than 160, and it does not meet the criteria for either primary or secondary classification. So we discussed that medications can be associated with hypercholesterolemia, and it's really important that we at least have an awareness of the medications that are more responsible for driving up these cholesterol levels. The medications that are usually responsible include anabolic steroids, protease inhibitors, immunosuppressive agents, and high-dose corticosteroids. Medications that are more promotional Medications that are more promoting are retinoids, low-dose corticosteroids, antipsychotics, progesterones, and estrogen. Now, it's important to note that while we may be able to identify that a patient is on one of these medications and that could be contributing to their hyperlipidemia, that doesn't mean that we automatically suspend that treatment. We always need to consider the risks versus the benefits. It may be determined that is extremely important for the patient to consider on one of these medications, and we just need to then treat the hyperlipidemia with the appropriate medical therapy. If we identify that one of these medications could be contributing to their hypercholesterolemia, if there is a safe alternative that would be equally effective, then we consider making that change. So this is a busy slide, and I don't at all expect that you're making a diagnosis of hypercholesterolemia that you're gonna pull out this algorithm and go through it, but there's a couple of things that I would just wanna point out here. So when you're evaluating a patient and you see that there's an LDL cholesterol of greater than 130 or non-HDL greater than or equal to 160, again, be very mindful of looking for those secondary causes. It's considered secondary hypercholesterolemia and see if there's any way that we can be mitigating those secondary causes to lower their cholesterol levels. If there's a strong family history, we need to be thinking about, is there a genetic component to this? And we will discuss that in more detail later on. And then we need to consider multifactorial causes of hypercholesterolemia if, again, it doesn't meet the criteria of primary or secondary. So now let's look at the numbers and let's consider how big of a problem really is this. And the CDC estimates that greater than 30% of adults have LDL cholesterol levels above the recommended threshold. It's difficult, however, to really assess the exact prevalence of this because many are unaware of their LDL cholesterol levels and the criteria to define hyperlipidemia as we've discussed are variable. Now, what are the screening recommendations for hypercholesterolemia? Well, the American Academy of Pediatrics recommends universal screening with a lipid profile initially between the ages of nine and 11 years of age, and then again, between the ages of 17 and 21. However, it should be noted that if there is suspected or confirmed familial hypercholesterolemia in a parent, we could consider screening starting at the age of two. Now, when we look at screening for adults, the American College of Cardiology and the American Heart Association have guidelines for adult screening. And baseline screening is recommended for all patients starting at the age of 20. And what do we do in terms of repeat screening? So if a patient has normal cholesterol levels, we can recheck those every four to six years. If a patient does have additional risk factors, smoking, diabetes, hypertension, family history, premature cardiovascular disease, then more frequent checks are indicated. Who do we treat? So the 2018 AHA, ACC, and multi-society guidelines have identified four statin benefit groups. And so if we identify patients that fit into any one of these four groups, it's been determined that their cardiovascular risk is high enough that that warrants treatment and the initiation of a statin therapy. And that includes patients with clinical ASCVD, patients with untreated baseline LDL cholesterol greater than or equal to 190 milligrams per deciliter, patients between the ages of 40 and 75 with diabetes, without clinical ASCVD, and patients aged between 40 and 75 years with a 10-year ASCVD risk score of greater than 7.5%. Again, any patients that meet any of these four buckets, appropriate to have a conversation with them about initiation of a statin. However, we can look that there are further ways that we can stratify cardiovascular risk for those patients who fall into more of those borderline categories. So how do we determine what their 10-year ASCVD risk is? And there are these calculators, these tools that we can download to our phones. We can put it on our desktop and they're really easy to use. And here's an example of an ASCVD risk estimator plus tool. And what you do is you plug in certain demographics such as age, sex, race, data, including blood pressure, cholesterol levels, and other comorbidities. And it gives you a 10-year ASCVD risk score. So we can look at this patient was calculated as having a 5% 10-year ASCVD risk. We can also look at their lifetime risk. So here, I wanted to plug in. If we look at that lipid panel that we saw in our previous slide, I wanted to give an example of how that calculator would work. So here we plugged in. And if you remember that that patient had fairly elevated cholesterol levels with a total cholesterol of 280, 49-year-old Caucasian female, doesn't have other comorbidities such as diabetes, smoking or hypertension. And what we could see here is even with that very high cholesterol levels, 10-year risk is calculated to be 0.8%. And what is the biggest driver of this risk calculator is age. So if we consider that we take the same exact levels and plug them into somebody 10 or 20 years older, we're gonna see a much different 10-year risk score. Now, if we look at lifetime risk, we can see that that lifetime risk is elevated because the patient is young with these high levels. So this is a risk assessment algorithm for patient's primary prevention. And very important to point that this is for primary prevention only. And what we do is we assess ASCVD risk in each age group. All of this is always we're supposed to emphasize to our patient healthy lifestyle. If we note here that patients between the ages of zero and 19 years of age, we really focus on lifestyle modifications, the time that we would consider statin therapy, these are for patients that we suspect familial hypercholesterolemia. Patients between the ages of 20 and 39 years of age, again, we estimate their lifetime risk to encourage lifestyle modifications to reduce ASCVD risk. And again, we consider stat therapy for patients who have family history of premature disease, or again, that LDL cholesterol that's elevated. Here we consider greater than 160 milligrams per deciliter. Now for our patients between the ages of 40 and 75, that's where we utilize that ASCVD risk calculator. And we can see that a 10-year risk less than 5% is considered low risk. And this is where we, again, want to emphasize lifestyle modifications. That 5% to 7.5% borderline risk, we consider having a conversation with our patients regarding moderate intensity stat, and that's where shared decision-making with a patient becomes extremely important. That intermediate risk is that 7.5 to less than 20%. And this is where it's been determined that it's appropriate to have that conversation about initiating a stat and to reduce LDL cholesterol by up to 50%. Patients with a 10-year risk score greater than 20%, these have been determined to be very high risk patients. We should truly be treating these patients aggressively, initiating statin and aiming to achieve greater than a 50% reduction. Now, the guidelines included other tools to further stratify risk, and particularly for those patients who fall into that borderline to intermediate risk. And for those patients, we consider the use of a coronary calcium score, again, to further stratify cardiovascular risk. And what we've determined in those borderline or intermediate risk groups is that a coronary calcium score of zero, again, helps to re-stratify the risk. And we've determined that could be appropriate to first initiating a statin therapy in those patients. And with the intention of then repeating the coronary calcium score at a later date. It should be noted that's really the one time that you consider repeating a coronary calcium score as if the score is zero. Now, there's a couple little asterisks to that that we need to consider. We've determined that even patients who have a coronary calcium score of zero, if they are current smokers, have diabetes, or strong family history of premature ASCVD, we should still consider initiating statin therapy because their lifetime risk is still increased, which has been shown that they benefit from initiating statins earlier on. Coronary calcium score between one and 99 favors initiation of a statin, especially for patients who are over the age of 55, a calcium score of 100 or greater, and or greater than 75th percentile, statin therapy should be initiated. So again, let's dive a little bit deeper into hyperlipidemia treatment guidelines. And now we're gonna focus more on treatment algorithms and strategies for patients who have clinical ASCVD. So patients who have clinical ASCVD, as mentioned previously, always recommend lifestyle modifications. ASCVD not at very high risk, and we're defining a little bit later on in this lecture what really defines very high risk patients. So patients not at very high risk, but who have clinical ASCVD, less than 75 years of age, high intensity statin is recommended, greater than 75. These patients have been shown to still benefit from statin therapy, and we use either moderate to high intensity statin. If a patient is already on a high intensity statin, we don't just deescalate therapy just based on age. Now for a very high risk ASCVD patients, high intensity statin again is recommended. And if LDL cholesterol is still greater than or equal to that threshold of 70, it is appropriate to add an additional non-statin lipid lowering therapies, as NMIB is reasonable to add next. If patient still is not at goal, then we consider PCSK9 inhibitor monoclonal antibodies. Now, I just wanna point out a little nuance here with the guidelines. They don't say that the LDL goal is less than 70 milligrams per deciliter. What they say is that an LDL cholesterol of greater than or equal to 70 is the threshold of when we consider adding on additional lipid lowering therapies. And this is an important nuance because it recognizes that the guidelines have really aligned with the idea that the lower LDL cholesterol, the better, and there truly is a linear relationship as the LDL cholesterol goes down, the number of ASCVB events goes down as well. Now, where it gets a little bit complicated is that there's more than one guideline to consider. The European Society of Cardiology and the European Atherosclerosis Society guidelines came out in less than one year after the 2018 HACC lipid management guidelines were published, the European lipid guidelines were updated. And similar and sort of aligning more with the American Association of Clinical Endocrinology guidelines, they recommend targeting an LDL cholesterol of less than 55 for certain groups, especially those very high risk ASCVB patients. It's also important to note that the European guidelines tend to focus less on cost when compared to our American guidelines and are really more focused on clinical impact. Now, something else that was included in the guidelines is that they've established these ApoB goals. And this is important because when we look at ApoB in certain populations as being a more sensitive target, we actually have goals. And this is gonna be extremely useful for those patients that we determined that ApoB is a more effective target. We actually have predetermined goals of where we wanna try to target our patients getting to. So for our very high risk patients, they recommend an ApoB of less than 65 milligrams per deciliter. We can see low risk, there's really no recommendation. We should note that again, an ApoB of 130 is approximately equivalent to an LDL cholesterol of 160. So finally, we're very excited that in about the summer of 2022, there was an expert consensus pathway that was developed essentially to address gaps in care of LDL cholesterol management to reduce ASCVD risk. And it was really built on evidence that was established by the 2013-2018 AHA-ACC multi-society guidelines. And this was helpful because this consensus pathway aligns better with the European guidelines and the endocrine guidelines. And just looking at a few things that were highlighted, particularly on the role of non-stanton therapies for LDL lowering, it recognizes and supports the idea that for LDL cholesterol, lower is better. And it says for adults with ASCVD who are considered very high risk if a patient does not achieve greater than or equal to 50% LDL reduction or LDL non-HDL cholesterol are not less than 55 or less than 85 respectively on maximum tolerated statin. First line treatment can be either azetamide or PCSK9 inhibitor monoclonal antibody. Second line of treatment after that, we consider bampidoic acid or Inclisiron. I just want to point out here that all of these recommendations for additional non-statin lipid lowering therapies are always on top of maximum tolerated statin therapy. So all of these medications that we're going to discuss, their true indications are for use on statin therapy. So it's not expected that if you're going to be starting any of these additional non-statin therapies that we then discontinue the statin. Now for some patients, we may find that maximum tolerated statin therapy is no statin. So in that case, we could use these other therapies in combination or as monotherapy, but statin shouldn't be discontinued when we start any of these additional medications. So we keep talking about these very high risk patients. Let's go into a little bit further detail about what really defines a very high risk patient, what patients meet that criteria. So we define these very high risk ASCBD patients as patients who have had more than one major ASCBD event and that includes a recent acute coronary syndrome within the past year, history of MI other than the recent event as noted above, history of ischemic stroke, symptomatic PAD, which we always need to look out for our PAD patients. Oftentimes these patients are not considered and when we're doing our risk assessment, it's important that we recognize that our PAD patients are also considered very high risk or patients who have had at least one of these major ASCBD events and at least two of these multiple high risk conditions. So let's look at what those high risk conditions are, age greater than or equal to 65, previous coronary revascularization outside of their event, diabetes, heterozygous FH, smokers, CKD, hypertension, history of congestive heart failure or persistently elevated LDL cholesterols greater than or equal to 100 despite being on maximum tolerated statin and ezetimibe. So when it comes to treatment strategies for management of hyperlipidemia, always important anytime we're gonna be initiating any type of prescription medication for our PAD patients, we always focus on shared decision-making and this includes discussing both lifestyle modification strategies as well as initiation of pharmacotherapy. And I like to say that I like to use this quote in the 2018 AHA ACC guidelines and it's in all individuals, we emphasize a heart healthy lifestyle across the life course. A healthy lifestyle reduces atherosclerotic cardiovascular disease risk at all ages and in younger individuals particularly, healthy lifestyle can reduce development of risk factors and is the foundation of ASCVD risk reduction. Now, when we really look at the impact of diet on LDL cholesterol lowering, it should be noted that we generally expect to see that diet only impacts LDL cholesterol maybe 10 to 15% but it can have a really big impact on other modifiable risk factors and the more risk factors we have, obviously that compounds cardiovascular risk. So even if we're not gonna see that, for example, adhering to a low cholesterol diet is gonna significantly lower LDL cholesterol in the majority of our patients, that doesn't mean that healthy lifestyle and a heart healthy lifestyle isn't gonna have a significant impact on lowering ASCVD risk. So when we look at lifestyle modifications as the initial management, I wanna say that I know that this can be a sensitive topic here and for the sake of this lecture, I wanna sort of stress that I am not a dietician and I know that in terms of dietary recommendations, it's not a one size fits all and we're really just gonna look at the recommendations as based on the guidelines. So they're gonna recommend consuming a diet that emphasizes vegetables, fruits, whole grains, fish, seafood, nuts and non-tropical vegetable oils. I think it's pretty safe to say that we all would agree that it's important to limit the intake of sweets and sugar sweetened beverages. Exercise is important and a good target is at least 150 minutes of what they consider moderate to vigorous intensity physical activity per week. Again, I don't think there's any debate about the importance of avoiding tobacco products, maintaining a healthy weight. We could also consider dietary adjuncts to lowering cholesterol such as phytosterols and soluble dietary fibers. So I just wanna touch really briefly on the importance of involving patients in goal setting and we can use these SMART goals and truthfully, this doesn't just apply to lifestyle modifications or setting goals to lowering cholesterol. I mean, this is something that I think we could take note of when we're trying to set any goals and really setting successful and really looking at successful goal setting. So we wanna be specific, goals should be clear and focused on a particular behavior and measurable. We wanna be able to really quantify that goal so that we can recognize when that goal is met or not met. Achievable and I think this is really important. It's important that we set realistic goals. We can't expect that a patient who has not exercised in 20 years, we're gonna suggest that they suddenly start doing a high intensity exercise 30 minutes a day. We set a goal of, hey, take five minutes, go for a walk. And slowly increase the amount of activity you can do. And that's going to avoid patients from becoming discouraged by setting these unrealistic goals. Rewarding and relevant, goals should be rewarding, worthwhile and flexible and timely. Again, we should have a timeline for the goals and they should be tracked. So as we discussed earlier, unfortunately lifestyle modifications in Americans usually have low success rates or do not adequately control risk. So medications are important adjuncts. And so now we're gonna do a little deeper dive into exploring pharmacologic management. Now this slide here I know is a little busy, but I like it because it looks at the different mechanism of action of how the major lipid lowering therapy medications work. And we can see where statins and bempedoic acid liver primarily initially to inhibit biosynthesis of cholesterol. Incliseron and PCSK9 inhibitor monoclonal antibodies are really working on PCSK9. PCSK9 is a protein that we make. And when PCSK9 attaches to the LDL receptor, LDL particle complex, which is how normally cholesterol is cleared, it kills off that LDL receptor. So essentially Incliseron and PCSK9 inhibitors monoclonal antibody work by inhibiting PCSK9 from destroying the LDL receptor, essentially allowing your LDL to be cleared more efficiently. Acetamide works in the area of a gut decreasing reabsorption of cholesterol. So we're gonna definitely spend some time talking about statins. It's important to note that as we said earlier, statins are first line therapy across all guidelines. Non-statin therapy, again, only considered or further LDL reduction is needed on top of maximum tolerated statin. The first clinical use statin was Lovastatin that was approved in 1987. There have been many, many multiple randomized controlled trials over the years. We have greater than 30 to 35 years of established safety and efficacy of statins, which is something we should absolutely highlight to our patients. Randomized controlled trials have shown that statins prevent ASCVD in both primary and secondary prevention. And that is important to note that they have been found to be beneficial in primary prevention patients as well. And it's estimated that there's an approximate 22% risk reduction at five years for almost 40 milligrams per deciliter of LDL cholesterol lowering. Meta-analysis of 27 randomized trials have showed that statins prevent vascular events, again, even in individuals who are at lower risk. So the mechanism of action of statins. So it's not just about inhibiting the rate limiting step of cholesterol biosynthesis, which statins work on HMG-CoA reductase, but there is also up-regulation of LDL receptor expression. And again, LDL receptors are what clear the LDL cholesterol. So it decreases the production of cholesterol, up-regulates the LDL cholesterol receptors. And equally important is statins have been shown to have these pleotropic effects. And that results in anti-inflammatory, antioxidant and anti-proliferative effects. So the first two lower plasma LDL cholesterol and the pleotropic effects promote plaque stability and prevent platelet aggregation. And that's essentially why they've been shown to be so effective at lowering the incidence of ASCBD as well as ASCBD events. So statin intensity and expected LDL cholesterol reduction. We're not gonna go through each one, but what I primarily wanna point out here is that you recognize what are considered to be the high-intensity statins. And there are only two high-intensity statins. That's atorvastatin in the two highest doses of 40 and 80 milligrams, and resuvastatin 20 to 40 milligrams. High-intensity statin therapy, we should expect to achieve greater than a 50% LDL reduction. We can see what qualifies as being our moderate intensity statins. And we expect to see about a 30 to 50% LDL reduction with moderate intensity statins. We really don't use low-intensity statin therapies much, but it would be around that 30% LDL reduction. So statin monitoring, and this is really important. What is recommended is that we get baseline fasting lipids and LFTs, and then repeat fasting lipids and LFTs four to 12 weeks after either initiation or dose adjustment. After that, it's recommended that you recheck lipids every three to 12 months to assess adherence and safety. And it's important to point out, it's not just about safety, but it's also about adherence. And if we're monitoring their lipids at least one to two times a year, we can see if patients are being adherent with their statin therapy. Continued monitoring of hepatic panel is only indicated in patients with symptoms suggestive of hepatotoxicity. And creatinine kinase levels is recommended only in patients with severe SAMs or statin-associated muscle symptoms or objective muscle weakness. So that's a really important point, and I just want to reiterate that again, that the 2018 AHA-ACC Multi-Society Guidelines state that in patients treated with statins, routine measurement of creatinine kinase and transaminase levels are not useful. So let's look at some of the more common statin-associated side effects and statin-associated muscle symptoms or SAMs for short. Let's kind of look at the various definitions. Myalgias are muscle aches with a normal CK level. It's infrequent in randomized controlled trials, estimated to be just about 1% to 5%. If we look at observational studies, it is noted to be slightly higher at 5% to 10%. There is also evidence of possibly having a placebo effect. When we look at myositis or myopathy, that is defined as CK levels at the upper limits of normal with concerning symptoms or objective weakness. This is rare. Rhabdomyolysis is defined as CK levels greater than 10 times upper limits of normal plus renal injury. This is even more rare. And then there's statin-associated autoimmune myopathy, again, very rare. So the most common that we're going to see, which still even in observational trials, is myalgias, normal CK levels, and that's about 5% to 10% of the patients. Now, there is a very useful tool here that we can use to determine the likelihood that someone is having statin-associated muscle symptoms secondary to a statin. And again, this is an app that you can put on your phone or you can just put it on your desktop. And there's a few clinical symptoms that we look for. We look for regional distribution. And what we found is that it's more likely to be secondary to the statin if it's the proximal larger muscles, particularly in the legs. We look at the temporal pattern. If there's onset of muscle symptoms in less than four weeks after statin was initiated, again, that scored higher and more likely to be from the statin, greater than 12 weeks, less likely to be secondary to the statin. So these patients coming in that have been on statin for years suddenly are developing muscle symptoms, much less likely to be secondary to the statin. And then we look at the challenging. We have a patient coming in presenting with those symptoms. We hold the statin. And if the symptoms improve within two weeks, more likely to be from the statin. If it takes greater than four weeks, then less likely. We should always try to re-challenge. Now, you consider re-challenging with a different statin. You consider re-challenging on a lower dose. If the same symptoms occur within four weeks, again, more likely to be secondary to the statin. Greater than 4 to 12 weeks, less likely to be secondary to the statin. And you see you're going to end up coming up with a score. And you can determine the probability of the patient's symptoms being secondary to the statin therapy. Important to note that we always treat the person sitting in front of us. So even if the patient has a SAM score that's low, if you re-challenge, they have the symptoms again, you stop it, they go away. Chances are they're not going to be adherent with their medication. So we still need to look for alternative treatments. So other statin-associated side effects. And we hear about new onset diabetes quite a bit. We should note that this is more frequently seen in patients who have underlying diabetes risk factors, including metabolic syndrome. And it's more frequently seen on high-intensity statin. Clear recommendations that the benefits in patients with diabetes far outweigh the risk. And statin therapy should be continued. In terms of liver, if the transaminase levels are greater than three times upper limits of normal, then we consider holding the statin. But again, it's three times upper limits of normal. Mild elevation beyond that should not be a reason to discontinue statin therapy. Significant elevation in LFTs is rare. And we see that hepatic failure is very rare. So statin-associated side effects continued. Looking at SAMs, again, we re-challenge with, consider re-challenging with a hydrophilic statin. So what does that mean? Hydrophilic statins are water soluble. There are two that we can choose from. That's rosuvastatin and pravastatin. And those are less likely to cause the muscle aches. So if a patient is on one of the lipophilic statins, such as atorvastatin, consider stopping the therapy and then re-challenging with a hydrophilic statin. We also have been successful with statin desensitization. And that's starting on a lower intensity of statin and pulse dosing. So we may start a hydrophilic statin, a lower intensity, start two to three days a week, and slowly titrate as tolerated or needed. Now, if the liver enzymes or the LFTs are greater than three times upper limits of normal, the recommendation is that you hold the statin. And when the LFTs normalize, it's acceptable to re-challenge. Now, we should note that, again, pravastatin and rosuvastatin have minimal hepatic metabolism. Those are the preferred statins in individuals with chronic liver disease. We're gonna see a lot of patients who have non-alcoholic fatty liver disease. And we should note that these patients have increased cardiovascular risk and non-alcoholic fatty liver disease is considered a risk factor for CVD. So statins have been shown to benefit patients with non-alcoholic fatty liver disease and are not contraindicated in this case. So a few special populations that we need to consider, renal impairment, again, busy slide, and I'm not gonna go through each one, but I just wanna point out particularly atorvastatin as we see on top. Atorvastatin is the one statin that does not require any dose adjustment based on GFR. So it's just easy to remember if we have a patient who has CKD, atorvastatin is a safe statin to use. Rosuvastatin, which is the next statin that is most commonly used, we do need to be mindful of for patients with a GFR less than 30, the maximum dose of rosuvastatin is 10 milligrams and we should start at a dose of five milligrams per day. Now, other special populations we need to consider. When we're considering starting a statin in women, we need to consider that statin should be discontinued about one to two months before contemplating pregnancy. This is a conversation I have with all females that I put on statins. Now, it should be noted that they have stated that statin therapy could be considered to be continued in very high risk patients. These are really patients with homozygous familial hypercholesterolemia and patients with established cardiovascular disease, but it's really best to refer these patients to a lipid specialist. Statin therapy is contraindicated while breastfeeding, important to counsel all your female patients about the importance of using contraception on a statin and that they have a discussion with their healthcare provider before considering pregnancy for guidance. Now, patients with heart failure with reduced ejection fraction, we still consider moderate intensity statin if reasonable life expectancy is three to five years and we see that's a class 2B recommendation. Patients greater than or equal to 75 years of age, when do we consider stopping a statin? And really, if we're seeing significant functional decline, multiple morbidity, frailty, or reduced life expectancy, that's when we consider having that conversation about the need to continue statin therapy. Patients with CKD, stage three to five. Patients taking LDL cholesterol lowering therapy that are initiating dialysis, continue the statin now. If a patient is on dialysis, there is a question about, do we start a statin in that population? But if they're on a statin stable and they start and they're getting ready to initiate that dialysis, class 2B recommendation for the statin to be continued. Now, really important to look for a potential drug interactions with statin therapy. A lot of times we think that fibrates are contraindicated for use with statins, but it should be noted that co-administration of statins and fibrates may be needed to treat complex dyslipidemia and hypertriglyceridemia. But if we're gonna be combining a statin with a fibrate, we want to avoid use of gemfibrazole with statins. Phenofibrate is preferred due to the reduced incidence of drug interactions. The combination of gemfibrazole with statins has an associated rhabdomyolysis risk 10 times greater than that with phenofibrate. So again, if we need to use a fibrate, phenofibrate is preferred. Avoid gemfibrazole with statin therapy. We always need to look for potential drug interactions or need to adjust the dose of statin therapy. And this is really when you're gonna be starting any medication. And we know that there's these great apps available that we can use to assess for drug-to-drug interactions and also can help guide you in terms of maximum recommended statin. We should note that atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3-4A, while rosuvastatin and fluvastatin primarily metabolized by CYP2C9. So there's been a sort of evolving landscape of non-statin therapies. And I know we spent quite a bit of time looking at statin therapies, because again, those are first-line therapy, but for add-on non-statin therapies, we're gonna sort of look at the evolution of that. And the initial therapies that we had were bile acid sequestrants. They bind bile acids in the intestine and really were eliminated by poor tolerance GI side effects. They're also a bit cumbersome to take. It was either a powder or multiple pills per day. Niacin or high-dose niacin primarily was used to raise HDL cholesterol levels. Should be noted that this was not proven effective in reducing cardiovascular events. It was really poorly tolerated due to side effects. And so it's really not recommended for use in any of the guidelines anymore. Fibrates. A variety of randomized control trials have actually failed to demonstrate ASCVD benefit, but it's interesting to note that subgroup analysis has shown possible ASCVD risk reduction in patients with metabolic syndrome. Again, it doesn't have an indication to be used for cardiovascular risk reduction, but perhaps a subgroup of patients are able to achieve this with the fibrates. So now more common and emerging non-statin lipid-lowering therapies. And here again, we're looking at the different targets for LDL reduction. We know that we've already discussed statins and the mechanism of action. So now we're gonna look at the other therapies such as bempedoic acid, ezetimibe, and the BCSK9 inhibitors and gene silencing. So what's next? Patients not at goal on maximum tolerated statin, we can consider adding ezetimibe. This reduces intestinal absorption of cholesterol through targeting the Niemann-Pixie 1, like 1. Combined with the statin, it's expected to achieve about an additional 20% LDL reduction. It should be noted that we do have these outliers of patients who are found to be what we call hyperabsorbers that may have a more robust response, but on average, we expect about a 20% reduction. We do have outcome data. So the improvement trial showed an ASCVD risk reduction when added on to a statin. So really where we see the risk reduction is on top of other lipid-lowering therapies, not necessarily as monotherapy. LFT elevation and myopathy may occur when used in combination with statin, but obviously that's ideally how it's used. And this therapy is generally very well tolerated. Now we're gonna look at PCSK9 inhibitor monoclonal antibodies. This includes evolocumab and elirocumab. The mechanism of action is it binds to PCSK9, which ultimately increases the number of LDL receptors that are available to clear circulating LDL cholesterol. So again, works by allowing your body to clear cholesterol more efficiently. The indications for these therapies are decreased LDL cholesterol in adults with primary hyperlipidemia. So this includes our FH, heterozygous FH patients, always on top of diet, or in combination with other lipid-lowering therapies. So small little nuances. Evolocumab decreases risk of MI stroke and coronary revascularization in adults with ASCVD. Also indicated to decrease LDL cholesterol in pediatric patients. So evolocumab has an indication to be used in our FH patients greater than or equal to 10 years of age, as well as in our homozygous FH patients greater than or equal to 10 years of age. Elirocumab is used to, the indications I should say, are to decrease risk of MI stroke and unstable angina requiring hospitalization in adults with ASCVD, and to decrease LDL cholesterol in adults with homozygous FH. So small little nuances in terms of really their indications, but I will tell you in the real world, their use is really interchangeable. These are injectable medications that are primarily dosed every two weeks. There are two big trials looking at these medications. There was a FOURIER trial and the ODYSSEY trial. Both of them led to about a 60% LDL cholesterol reduction when added to maximum tolerated statin. And it is really remarkable how well tolerated these medications have been. And we have no concerning safety signals with either of these therapies. In terms of common adverse effects, we do see a small percentage of patients have nasopharyngitis, injection site reactions, or elevation in their glucose. Both were noted to have statistically significant cardiovascular risk reduction and indications. Now we're gonna take a look at bempedoic acid, and the mechanism of action is it's an ACL inhibitor. So it inhibits cholesterol and synthesis in the liver. It requires coenzyme A activation, which is primarily expressed in the liver. Why is this important? We just think that it's not really becoming an active drug until it sort of hits the liver. So therefore it's been determined to be less likely to cause those statin-associated muscle symptoms. We have outcome data with this medication and the CLEAR outcomes trial, which included statin intolerant patients, high risk for cardiovascular disease. As monotherapy, bempedoic acid was noted to have about a 20% LDL reduction. And trial did show a lower risk of major ASCBD events in these patients. Adverse effects, small number of patients did have a mild increase in their uric acid levels. So monitor for symptoms of gout, URI symptoms, myalgia, back pain, bronchitis, anemia, or elevated LFTs. It should be noted that bempedoic acid also comes in a combination pilled with a xenamide. And when used in combination, we can see a 40 plus percent LDL reduction. So Incliseron, mechanism of action is interesting. It's a long acting synthetic, small interfering RNA that inhibits the production of PCSK9 at the intracellular level. It's a subcutaneous injection and it's administered initially, then again at three months. And after that, it's just a Q6 month administration. We expect to see about a 50% LDL reduction with this therapy. Adverse effects include injection site reaction, arthralgia, UTI, diarrhea, bronchitis, and dyspnea. We don't have any outcome data yet, but there are two outcome trials that are currently in progress. And this is gonna be something interesting going forward, particularly once we have outcome data for those patients who maybe have issues with an adherence. This could end up being a therapy that is extremely effective in those patients. Now, I just wanna talk briefly about icosapent ethyl, which is a highly purified EPA ethyl esters. It's dose two grams BID. It has two indications. So one indication is for severe hypertriglyceridemia greater than or equal to 500 milligrams per deciliter, but it also has a secret cardiovascular risk reduction indication. And these are patients with clinical ASCVD or diabetes and at least one additional risk factor with fasting triglycerides, even in the normal range. So going from 135 up to 499. Patients who have established ASCVD or diabetes and other risk factors, triglycerides in this range, when we add it on to maximum tolerated statin, the reduced trials showed that there was actually a cardiovascular risk reduction. Now we do need to caution about use of this therapy in patients with atrial fibrillation or atrial flutter and at bleeding risk. So I know we covered a lot of information in this lecture, but I really just wanna summarize a couple of really, you know, highlighted points that we discussed. Again, ischemic heart disease, despite our best efforts and novel therapies and being more aggressive with treating risk factors, it remains the number one cause of death. Atherosclerosis is an inflammatory disease and lipoproteins have been associated with the development of ASCVD. So understanding the tools used to assess cardiovascular risk, recognizing really who warrants treatment, promoting lifestyle modifications, initiating lipid lowering therapies when indicated, and setting targeted treatment goals could significantly mitigate the incidence of ASCVD and ASCVD events. Here are the references. References continued. If you have any questions regarding this lecture, please direct any questions to academyatmedaxiom.com. Thank you.

lipid management

cardiovascular disease

atherosclerosis

LDL cholesterol

hypercholesterolemia

statins

non-statin therapies

lifestyle modifications

screening for lipid disorders

reduce cardiovascular disease risk