Hi, I'm Lisa Davis and here we're going to discuss advanced lipid management and we're going to start by looking at hypercholesterolemia classification. So as referenced in the previous lecture, there's primary, secondary, and multifactorial. For the purpose of this presentation, what we're going to primarily focus on is primary causes, which includes genetic and idiopathic. And again, we looked at this algorithm previously and I'm not going to go through each step, but again, I just want to point out here that when we first see an LDL cholesterol that's elevated greater than 130 or non-HDL greater than or equal to 160, always look for secondary causes. Can't stress that enough. If there's no underlying secondary cause, then what we look for is sort of that middle algorithm here. Or if there's a strong family history of significantly higher LDL or non-HDL cholesterol, we consider, is there a monogenic criteria? If the candidate has those genes, then it's considered a monogenic hypercholesterolemia. If not, we can look at LP little a, and if that is found to be elevated, it could be a hyper lipoproteinemia a. So let's look at a definition of primary hypercholesterolemia, and I know it gets a little bit complex, so we'll try to go through this to make it understandable. It's hypercholesterolemia that occurs in the absence of a secondary cause and meeting one of the following criteria. Genetic hypercholesterolemia in patients who have an LDL cholesterol greater than or equal to 130 or non-HDL greater than or equal to 160. In patients with those cholesterol levels, you also need to have a definitive diagnostic genetic study. So individuals who do genetic testing, who have pathological or likely pathogenic variant in a gene for monogenic hypercholesterolemia, or those with high polygenic score for LDL cholesterol. And once you get to doing genetic testing, I know this can sound a little bit confusing, but when you start doing genetic testing and you get the results back, it's all pretty much explained. Also looking at primary hypercholesterolemia with evidence of Mendelian inheritance in multigenerational families and LDL cholesterol greater than or equal to 190 or non-HDL greater than or equal to 220. And again, that non-HDL becomes important, particularly in patients who have hypertriglyceridemia, as discussed in the previous lecture. Or primary hypercholesterolemia with lipoprotein A greater than 100 milligrams per deciliter and LDL cholesterol greater than 190 milligrams per deciliter, or again, the non-HDL that's greater than 220. So meeting one of those criteria can give you that diagnosis of a primary hypercholesterolemia. So let's look at certain highlighted primary genetic hypercholesterolemia. So again, what we're looking at here for the purpose of this lecture is more of the genetic causes of hypercholesterolemia. There's heterozygous familial hypercholesterolemia. We see FH for short. And homozygous FH, dysbeta lipoproteinemia, cytosterolemia, lysosomal acid lipase deficiency or LAL deficiency, and hyperlipoproteinemia A. So first, we're going to spend a decent amount of time talking about familial hypercholesterolemia. And as this lecture progresses, hopefully, you'll have an understanding of why it's important to spend some time talking about this and recognizing how important it is to screen for it and manage it. So when we look at FH, so that's familial hypercholesterolemia and cardiovascular risk, what happens is that lifelong elevation of LDL cholesterol, if left untreated, significantly increases cardiovascular risk. Men and women with FH have a 30% to 50% risk of cardiac event by the age of 50 and 60 respectively. And this is something that I often convey to my patients. I'll tell them, patients that I'm suspicious of FH, I'll say if left untreated, a man by the time they're 50, female by the time they're 60, can have up to a 50% chance of having a cardiac event. And that sort of puts things in perspective for them and I think allows them to appreciate how important it is to manage this. It's been identified that as many as 20% of myocardial infarctions in men under the age of 45 are attributed to FH. Now we should note that persons with an LDL cholesterol greater than or equal to 90 without an identified FH mutation still have up to a six-fold higher risk of CAD. Persons with an LDL cholesterol greater than that 190 with pathogenic FH mutations have up to a 22-fold higher risk of CAD. So if we think about the previous lecture where they've identified that one of the four statin benefit groups are patients with an LDL cholesterol baseline greater than or equal to 190, I think here we can appreciate why it's so important to treat those patients because even without an FH mutation, they can have up to a six-fold higher risk. And again, we see up to a 22-fold higher risk in our FH patients with a pathogenic mutation. Now obviously, it's important for us to consider other additional risk factors. Who falls into that 22-fold higher risk versus six-fold higher risk? And that's where, again, we look at the more risk factors that are compounded, the higher the cardiovascular risk. And here we're going to consider several additional cardiovascular risk factors that have been noted to increase the risk of ASCVD in patients with FH. And that includes age, male gender, hypertension, smoking, elevated LP little a, and family history of coronary artery disease. One thing I want to point out here is several of these risk factors are non-modifiable. We can't change our family history, can't necessarily change if we have a high LP little a, can't change our age. But when we look at the modifiable risk factors, these are really important. And it's important to stress to our FH patients, even if we're suspicious of it at a very young age, the importance of abstaining from smoking. Because when you take FH and you put smoking on top of it, that risk is really amplified. So now let's start looking at the prevalence of familial hypercholesterolemia. And FH is an autosomal dominant disorder that results in significant LDL cholesterol levels from birth. And the incidence of heterozygous FH occurs in approximately 1 to 250 to 1 in 500 persons. So we can see what a significant number of patients and how common this really is. Homozygous FH, luckily, is much less common. And it's estimated that occurs anywhere from 1 in 160,000 patients to 1 in a million persons. The diagnosis of FH occurred at a mean age of 50 years old. And by this time, it's been noted that greater than a third of the patients already had an ASCVD event. So greater than 33% of the patients had an event before they were even diagnosed. And I just want to pause here for a moment and really highlight that familial hypercholesterolemia is the most common inherited disease. And we're not just talking about the most common inherited lipid disorder. It is the most common inherited disease. So it's extremely important that we screen for it. It's extremely important that when we identify it, we recognize the importance of cascade screening and have particularly first degree relative screen for it as well. And FH, as we said, is remarkably underdiagnosed and undertreated. So less than 40% of FH patients are on high intensity statin therapy, which is truly the mainstay of treatment. And 2 thirds of those patients failed to reach target goals. So again, only 1 third of patients that we're treating were able to achieve target LDL goals. It's estimated that between 13 and 34 million individuals worldwide have FH. And it's estimated, which is even more shocking, that less than 10% of the persons in the United States with FH have been diagnosed. So we're leaving a lot of residual risk out there. And this actually shows how many opportunities we have to really screen for, identify, and treat this risk factors. Because when FH is diagnosed and treated early, that risk of ASCVD can be reduced by up to 80%. And this is important to note. I like to say there's very few things that we do in medicine or cardiology where by treating with these safe, effective therapies, we've been shown to reduce risk by up to 80%. So in diagnosing FH, first and very important, we need to rule out common secondary causes. And the most common ones that we're going to see in terms of chronic illnesses are hypothyroidism, nephrotic syndrome, and cholestasis. I will tell you the first two, hypothyroidism and nephrotic syndrome. Patients who are not euthyroid, especially have high TSH levels, hypothyroidism, or patients who have nephrotic syndrome, their labs are going to come back pretty much identical to what an FH patient looks like. You treat the underlying cause, and you'll see a significant reduction in their LDL cholesterol. So it's important to screen for those, and also to look out for medications. And the common ones are going to be anabolic steroids, protease inhibitors, immunosuppressive agents, and high-dose corticosteroids. Again, as we said previously, we may not be able to alter this treatment. The benefits of the therapy might outweigh the risk. But we could consider that if there is an alternative, that would be equally effective for the patient, but maybe not have that impact on the lipids that we consider making those changes. Now, further diagnosing FH, there are certain physical exam findings that are really considered pathognomonic for FH. However, they're often not found in children or even adults. Actually, less than 15% of our heterozygous FH patients have these physical exam findings. We've gotten better at treating it, so perhaps that has prevented some of these patients from developing. We treat it before they develop these PE findings. Oftentimes family history of premature CAD and LDL cholesterol levels are the only findings of heterozygous FH. Very important to do a thorough physical exam, and I will tell you that this is something that we definitely do see in clinic. And if you look for it, you will find it. So the xanthelasma, which you will see the sort of yellow discoloration commonly around the eye. Tendon xanthomas, commonly you will see Achilles tendon xanthoma. It's important that you don't just look for it, but you actually feel the Achilles tendon. And oftentimes you feel on the Achilles tendon, it's going to feel the sort of lumpy, bumpy Achilles tendon. It's actually cholesterol deposits on the tendons or corneal arcus. Important to note that corneal arcus, as we get older, may just be a normal finding. So it's only clinically significant in diagnosing FH in persons under the age of 45. So there are some tools that can help you to assist with diagnosing FH. Three formal diagnostic tools are the MedPed, which looks at LDL cholesterol and family history, Simon-Broome LDL cholesterol, family history, tendon xanthomas, and the presence of genetic mutation. What we're going to look at a little bit more closely is the Dutch Lipid Clinic Network. This is a tool that can be used. You can, again, put it on your desktop. And it tells you the probability that the patient has familial hypercholesterolemia looking at specific diagnostic criteria. So what it looks for is family history. And we're not going to go through the whole thing. There are definitely many points to this. But when we look at family history, we look at the incidence of premature CAD, LDL cholesterol that's greater than the 95th percentile, just to name a few. We look at personal history, which is primarily looking at the incidence of premature CAD in that patient. Clinical examination, if patients have tendon xanthomas or the corneal arcus, again, significant less than 45 years of age for the arcus cornealis. And LDL cholesterol. Now, something I just want to point out here is that even with an LDL cholesterol less than, what, 90 threshold, so LDL cholesterol of 155 to 189, we still should consider screening for familial hypercholesterolemia. And finally, the presence of functional LDL receptor mutation. And that's really in the genetic testing. So you add up the score, and it tells you the probability of the patient having FH. I just want to point out here that it's not necessary for patients to have positive genetic mutations in order to have probable or even definite FH. And so that's something to be mindful of when using this scoring system. We're going to talk about genetic testing for familial hypercholesterolemia. The most common causes of FH, including pathogenic variants of an LDL receptor gene, apolipoprotein B gene, or gain a function of PCSK9. Now, we should really note that a large percentage of patients with definitive clinical diagnosis, as we spoke about on the previous slide, may not have an identifiable mutation. So even if you do genetic testing, some of the results can come back of a variant of unknown significant or no identified variant at all, and the patient may still have familial hypercholesterolemia. So if we look at sort of a cartoon depiction of the most common pathogenic variants causing FH, I think it just helps to look at what normal LDL cholesterol metabolism is, and then what the variants look like. So normal LDL clearing is you have an LDL cholesterol particle that attaches to an LDL receptor. It is internalized in the hepatocyte, the LDL cholesterol particle is degraded, and then that LDL receptor should be able to recirculate up to 150 times to keep clearing more LDL cholesterol particles. So if we have an LDL receptor variant, we have no binding of the LDL particle to a defective LDL receptor. If we have the ApoB variant, we have limited binding of the LDL cholesterol to the LDL receptor due to dysfunctional ApoB. And if we have gain of function of PCSK9, what we have is that that PCSK9 attaches to the LDL cholesterol particle and the LDL receptor. So when that complex is brought down into the hepatocyte and degraded, it also kills off the LDL receptor. So that PCSK9 inhibits that LDL receptor from recirculating and clearing more cholesterol. So if we make too much PCSK9, we're limiting our ability to be able to clear LDL cholesterol particles. All of these mechanisms, all of these variants lead to increased circulating LDL cholesterol levels. So now let's look at a treatment algorithm for adults without ASCVD. So these are just patients who have a baseline LDL cholesterol greater than or equal to 190 milligrams per deciliter without established ASCVD. So first treatment of choice is high intensity statin or maximum tolerated statin. But ideally, you try to get patients on high intensity statin. If there is less than a 50% LDL reduction or the LDL cholesterol remains greater than 100, then we consider additional non-statin lipid lowering therapies. And at this point, we consider ezetimibe and or PCSK9 inhibitor monoclonal antibodies. And it's noted that all of these medications, statins, ezetimibe, and PCSK9 inhibitor monoclonal antibodies can be used together. And when we consider the addition of a Zetamib or PCSK9 inhibitor monoclonal antibody, ideally, it is used on top of maximum tolerated statin. Now, the next step would be to consider the use of, or the addition of, bempedoic acid or Incliseron. Now, we go a step further, and there are other therapies that we need to consider, which would be evanocumab or lomidipide. Additionally, LDL apheresis, which we're going to talk about further. But if you get to that point where you're needing to consider one of those treatments, we should really recommend referral to a lipid specialist. And as also noted, any of our FH patients should be referred to a dietitian as well as per the guideline recommendations. So now let's talk about homozygous familial hypercholesterolemia a bit. This is due to a mutation in two alleles, if untreated, fatal cardiovascular complications could occur in as early as the first decade of life. So very poor prognosis in these patients if left untreated, often do not live beyond 30 years of age. Luckily, as we said, this is much, much less common. But again, something to be aware of. The cause of death is often due to myocardial infarction or aortic stenosis. Aggressive LDL cholesterol lowering is recommended as early as possible. Genetic testing and cascade screening is recommended for any suspected homozygous FH patient. I just want to highlight the importance of cascade screening, again, not just for homozygous FH patients, but for heterozygous FH patients as well. And these patients absolutely should be referred to a lipid specialist for management. And when we consider that triad of clinical features in our homozygous FH patients, it includes significantly elevated LDL cholesterol levels, cutaneous and tendinous anthomas, and premature ASCBD. And some pictures of what you might expect to see in our homozygous FH patient, you'll see that first picture on the left is looking at cutaneous anthomas. The presence of cutaneous anthomas in childhood is strongly suggestive of homozygous FH. And tendinous anthomas, which you see on the right on this patient's hands, are generally prominent in adults with homozygous FH. So again, a bit of a busy slide here, but just let's consider the clinical and genetic testing criteria for diagnosing familial hypercholesterolemia. So clinical criteria. Patient has an LDL cholesterol greater than or equal to 400. Again, this is LDL, not total cholesterol. And one or both parents has clinically diagnosed FH with positive genetic testing for known LDL cholesterol raising defect. So patients greater than 400 who meet that criteria, that can make a diagnosis of homozygous FH. If there's the presence of two identical or non-identical LDL raising gene defects, including the rare autosomal recessive type. Now, for patients who have LDL cholesterol greater than 560 or greater than 400 with aortic valve disease or xanthomata at less than 20 years of age, that's enough of a clinical criteria to give you a diagnosis of homozygous FH. Occasionally, patients will have LDL cholesterols less than 400. But again, in that case, you need the genetic testing or confirmation. Now, some of their treatment challenges, especially with our homozygous FH patients, you can see some of these challenges in our heterozygous FH patients as well, is that usually they require high doses of combination lipid lowering therapy. Many of these therapies may not have been adequately studied in the pediatric population, but we've recognized the importance of starting treatment early. So that creates a bit of a challenge. Also, what we need to consider is that many of these usual therapies are dependent on patients having functional LDL receptors. And as we discussed, many of these treatments that we use to lower LDL cholesterol are dependent on patients having functional LDL receptors. So that can lead to patients having a blunted response to these therapies, and again, creating definite treatment challenges. So treatment of familial hypercholesterolemia, adults with FH, as we said before, high-intensity statin is first-line therapy. The two high-intensity statins are atorvastatin or resuvastatin in the highest doses. That's 80 or 40 milligrams with atorvastatin and 40 or 20 milligrams of resuvastatin. If the LDL cholesterol is still greater than or equal to 100, again, this is without ASCVD because we're going to be more aggressive in our patients who have established ASCVD on maximum-tolerated statin, then additional lipid lowering therapy is indicated. Children with FH. And this is something that, again, even if you're not seeing pediatric patients, you can highlight this to the patients that you're seeing who perhaps have children and grandchildren because it's important for them to then have that discussion with their pediatrician. The recommendation for children with diagnosed FH is to start a low-dose statin as early as 8 to 10 years of age. And this is for patients who have persistently elevated LDL cholesterol levels greater than or equal to 160 milligrams per deciliter after 3 to 6 months of lifestyle management. Pravastatin and metavastatin are FDA-approved for patients greater than or equal to 8 years of age, and the other statins are approved for patients at least 10 years old. Now, a couple little caveats of treatment for children with FH. The target is considered to be an LDL cholesterol of less than 130, although some have suggested that we use a more aggressive target of less than 100, or at least a 50% LDL reduction from baseline. Ezenomibe is approved for heterozygous FH, but not reviewed in children less than the age of 10 or premenarcheal girls. Colicevalem is approved for boys and postmenarcheal girls greater than or equal to 10 years of age. And evolocumab, which again is a PCSK9 inhibitor monoclonal antibody, is actually approved for heterozygous and homozygous FH greater than or equal to 10 years of age. Now, as we said earlier, low-density lipoprotein receptor-dependent mechanisms are the most common targets for several of our lipid lowering therapies, and this includes statins, ezenomibe, bioacid sequestrants, PCSK9 inhibitor monoclonal antibodies, Inclisiron, which is the PCSK9 inhibitor silencing RNA and bempedoic acid. Though it should be noted that we don't have any data yet for bempedoic acid in our homozygous FH patients. So again, this is important to note because if patients have an LDL receptor defect, their LDL cholesterol is gonna have a blunted response to these medications. So here we look at LDL receptor-independent mechanisms, and this is really for our homozygous FH. So again, if we're getting to the point that we need to consider these therapies, referral to a lipid specialist is recommended, but it's important to know that there are therapies that still can be used. The first therapy that we're gonna talk about is lomidipide, and this reduces LDL cholesterol by inhibiting the microsomal triglyceride protein to reduce production of VLDL and LDL. And again, independent of LDL receptor activity. This needs to be prescribed through a REMS program. There's a black box warning due to hepatotoxicity risk. Fat-soluble vitamin supplementation is recommended. I'm highlighting all of these things because again, unless you're really in a lipid-type clinic, you don't wanna necessarily be starting patients on these therapies. The other therapy is evanocumab. It's an ANG-PTL3 inhibitor, and it really promotes clearance of remnant LDL and LDL cholesterol from the circulation. It is an IV infusion that is every four weeks, and this actually has a favorable safety profile, but should be noted that both of these medications are gonna be very expensive, so it's really indicated in a select number of patients. So now we're gonna look at non-pharmacologic treatment, and there's lipoprotein apheresis, LDL apheresis, and this is something that, truthfully with the addition of the PCSK9 inhibitors, and the other novel therapies that we have, it's allowed us to significantly reduce the incidence of needing to use LDL apheresis, but it still can be considered for patients who after six months do not have adequate response to maximum tolerated therapy. Lipoproteins are removed by precipitation, adsorption, or filtration, often still necessary unfortunately for homozygous FH patients. It does result in a 50 to 70% acute LDL cholesterol reduction, so it is quite effective. There is an additional benefit of Lp-a lowering, which has been interesting. Treatments are often weekly or biweekly at a specialized center. The NLA actually, which is the National Lipid Association, has indications for lipoprotein apheresis, and again, not gonna go through each one here, but you can see patients primarily of functional homozygous or heterozygous FH with persistently elevated LDL cholesterol levels. That's who we should consider use of this. Now, in rare cases, in terms of non-pharmacologic treatment of homozygous FH, liver transplant is considered to be a definitive treatment. Now, this is just a little bit of a cartoon schematic of how an LDL apheresis system works, so we're just gonna kind of go through and highlight a few things. Blood is withdrawn from the patient's arm via venous axis. The blood is then combined with heparin, and plasma separator is used to separate the plasma from the cellular components of the blood. Plasma then exits, exits, and the remaining blood, which includes red, white blood cells and platelets are exited. The cell-free plasma is then pumped into one of the adsorption columns where this is how the apolipoprotein B containing lipoproteins are adsorbed and essentially removed from the plasma. Essentially, it is then filtered and then recombined with the cellular elements that originally exited, and the recombined blood and plasma ultimately flow back into the patient via second venous axis. So you can see how this could be a cumbersome process for patients to have to do every couple of weeks, but it is necessary, unfortunately, in some of our patients who have these significantly persistently elevated LDL cholesterol levels, despite our best efforts with medical therapy. Now we're going to talk about other genetic hypercholesterolemias beyond FH. And first, we're going to talk about dysbeta lipoproteinemia. And this is a severe combined hyperlipidemia, and it's caused by the accumulation of triglyceride-rich remnant particles. So it's rare. It's about one in 10,000 to 20,000 individuals, but you can see this. And this is a combination of a familial combined hyperlipidemia and an APOE22 genotype. Physical exam findings that you might see are primarily going to be a Palmer's anthoma or an orange Palmer crease. These patients do carry a high risk of premature coronary artery disease. And when you might be suspicious of these patients, if you get a lipid profile that looks like a total cholesterol with a triglyceride ratio of about one to one. So that's patients who have a total cholesterol of 300 with a triglyceride level of approximately 300 as well. The next disorder we're going to talk about is lysosomal acid lipase deficiency. This is a rare autosomal recessive disorder. And what happens here is you have accumulation of cholesterol esters and triglycerides in the hepatocytes and the macrophages. And especially this occurs in the liver. So I just like to highlight this because this is something we want to be suspicious of making a diagnosis in our young patients who present with combined hyperlipidemia, elevated transaminases and hepatomegaly or hepatic steatosis. So pediatric patients, young patients who have that combined hyperlipidemia with hepatic involvement. So now we're going to look at familial combined hyperlipidemia. And this is an overproduction of apolipoprotein B particles. And patients can have an increase in VLDL, LDL cholesterol and small dense LDL particles. And this presents as a persistent combined hypercholesterolemia and moderate to severe hypertriglyceridemia. So an example of what you might see on a lipid profile in these patients is an elevated LDL cholesterol at approximately 170 milligrams per deciliter and triglycerides over 500. Now, if we see a patient who has that LDL greater than 200, that's usually more consistent with an FH patient. And it's different than the dysbeta lipoproteinemia where the picture was more of a one-to-one in terms of total cholesterol and triglyceride ratio. And this additionally is associated with increased risk of ASCBD. While it could be helpful and you're gonna sound really smart if you put this diagnosis in the chart, the bottom line is that all of these patients that we've discussed so far really have an increased risk of ASCBD. And essentially they're all managed the same way. So with these patients, statins are gonna be first-line mainstay therapy. And then we look to additional lipid lowering therapies or even non-medical therapy if needed. But again, it can help you to sort of be able to make that diagnosis really getting into what their lipid profile looks like. But essentially the treatment is gonna be pretty similar, especially when you look at the initial therapies. So I know we talked about this in the previous lecture, but I just wanna touch on this again briefly. And this is looking at the apolipoprotein B particles. And chylomicrons transport triglycerides to the adipose tissue and skeletal muscle, but they're generally considered too large to enter their arterial wall. So atherogenicity is less certain. For the focus of the next few slides, we're really gonna be focusing on hypertriglyceridemia. So what I want you to pay attention to in this slide is really looking at that ratio of the different particles and the ratio of the cholesterol versus the triglyceride in each of the particles. So hypertriglyceridemia, triglycerides have poor solubility in blood. So that's why they require lipoproteins to circulate. Important to note that there are several environmental factors that affect triglyceride levels. And these include diet, alcohol, physical activity, liver fat, insulin resistance, hormonal status, adipose function, and medications. So when we see a patient who has hypertriglyceridemia, important to look at these as components that could be contributing or impacting triglyceride levels. Pregnancy, it should be noted that triglyceride levels in healthy women can be up to three times higher than baseline by the third trimester. So we generally don't monitor triglyceride levels in pregnant patients because we know they're gonna be higher. However, in patients who have underlying triglyceride disorders, hypertriglyceridemia, that should be important to note that throughout their pregnancy, triglyceride levels are increased. So we may need to look at management of that. There's some question about contributing to atherosclerosis, but we know that hypertriglyceridemia definitely increases risk of acute pancreatitis. And that pancreatitis risk does increase and is proportional to triglyceride levels. So that's why the guidelines have really defined severe hypertriglyceridemia levels. And so just like we looked at the LDL cholesterol and the challenges with making a diagnosis of hypercholesterolemia, there's different classifications for the diagnosis of hypertriglyceridemia. And the various cardiovascular societies have categorized hypertriglyceridemia by different serum triglyceride concentrations. And again, we're not gonna go through each one, but just a couple of things to highlight that HAACC guidelines, really looking at normal triglyceride levels less than 175. Severe is considered when it's greater than 500 milligrams per deciliter. The European society is a more aggressive target for normal, less than 150 with severe hypertriglyceridemia being greater than 880. So we see that there's a higher threshold for the severe range, as well as a different category label. The endocrine society actually has even more categories. And if we see here, they're defining severe hypertriglyceridemia greater than 1000 and very severe greater than 2000. I can tell you that definitely when we start seeing the triglyceride levels greater than 1000 is we definitely see that increased risk of acute pancreatitis. So we need to consider common medications that can raise triglyceride levels. And again, important to note that patients may need to continue on these medications, but always weigh risk versus the benefits. And in patients who have severe hypertriglyceridemia, especially with pancreatitis, we may need to consider if there is any other alternative effective option. The common medications include diazide diuretics, beta blockers, especially the non-beta one selective beta blockers, bile acid resins, protease inhibitors, retinoids, atypical antipsychotics, glucocorticoids and estrogens. And you could see that some of these medications are very commonly used. So we need to look out for that and screen for that. Now we're gonna look at some examples of genetic hypertriglyceridemia. And some of these were already covered previously because there is that sort of combined hypertriglyceridemia with hypercholesterolemia such as familial dysbeta lipoproteinemia. But we also have familial chylomicronemia syndrome, familial hypertriglyceridemia. And again, we previously covered familial combined hyperlipidemia. So let's look at familial hypertriglyceridemia a little bit more closely. And this is persistent hypertriglyceridemia due to VLDL excess without chylomicronemia. So generally we're gonna see patients who have a moderate to severe hypertriglyceridemia. Triglycerides in the range between 200 and 500. And what you'll see is that you'll see a triglyceride to total cholesterol ratio of about five to one. The ASCVD risk is only slightly increased and the acute pancreatitis risk is only slightly increased. But where this becomes really important is that patients with familial hypertriglyceridemia are at risk for chylomicronemia syndrome with secondary factors such as uncontrolled diabetes and excess alcohol intake. So when we see these patients who have this moderate to severe hypertriglyceridemia, it's really important to focus on other modifiable risk factors, being more aggressive, making sure that we're keeping diabetes well-controlled and that we're really discouraging excess alcohol intake. So now we're gonna touch on familial chylomicronemia syndrome. And luckily this is a diagnosis that is rare. It occurs in about one in one million individuals, but it's something we should be mindful of because these patients are at risk of particularly recurrent acute pancreatitis and they need to be treated very aggressively. And it is very challenging to treat these patients. And it's characterized by low or no LPL activity, which results in persistent severe hypertriglyceridemia due to chylomicronemia. Children can present with failure to thrive, steatorrhea and eruptive xanthomas. Triglycerides can be as high as greater than 10,000 and often persist greater than 900. The triglyceride to total cholesterol ratio in this case is 10 to one versus five to one with familial hypertriglyceridemia. The most common complication is recurrent pancreatitis. And again, these patients, it's extremely challenging to treat. Interestingly, premature ASCBD is not necessarily expected. Treatment considerations, these patients require a very, very low fat diet. Patients should absolutely be referred to a dietician because they're gonna need really strict guidance in terms of their diet. I mean, we're talking less than 20 grams of fat per day. They can use an MCT oil to supplement. And important to note that many may not tolerate fish oils. So while we might use omega-3s to treat hypertriglyceridemia, these patients might not be able to tolerate it. And again, due to the challenges in managing these patients and this possibility of serious adverse outcomes, these patients should be referred to a lipid specialist as well. So now again, let's look at treatment of hypertriglyceridemia. And as we said earlier, it's important to address possible secondary factors, which includes obesity, metabolic syndrome, chronic kidney or liver disease, nephrotic syndrome, hypothyroidism, and medications. So what are we doing to treat these patients? In adults between 40 and 75 with moderate to severe hypertriglyceridemia and their ASCVD risk greater than or equal to 7.5%, this still favors the initiation or intensification of statin therapy. So patients wanna reiterate this, mild to moderately elevated triglycerides, target LDL cholesterol and non-HDL cholesterol first. Adults 40 to 75 with severe hypertriglyceridemia. And again, that ASCVD risk are greater than 7.5%, initiate statin therapy. Now, once we get to these patients who have triglycerides over 500, and as I said earlier, especially over 1000, that's when it becomes more important to us to initially focus on triglyceride reduction, ultimately to prevent acute pancreatitis. So patients are gonna need to focus on stricter diet, especially avoidance of refined carbs and alcohol. And these patients, we need to consider omega-3 fatty acids and fibrate therapy. Now, pharmacotherapy for hypertriglyceridemia, let's look at this a little bit more closely. As we talked about in the previous lecture, icosapent ethyl is a highly purified EPA, ethyl ester. And it has a couple of indications. It's indicated for triglycerides greater than or equal to 500. And it also has a separate cardiovascular risk reduction indication. So our patients with severe hypertriglyceridemia, we should consider this therapy. Our patients who also have type 2 diabetes or ASCBD and other risk factors, we should consider this even for patients who have triglyceride levels less than 500. It's gonna help to lower the triglycerides, but there's also a separate cardiovascular risk reduction indicated with this medication. Fibrates are indicated for patients with persistently elevated triglycerides, primarily for patients with triglycerides over 500 and especially over 1000, with the primary goal being to prevent acute pancreatitis. Again, we need to be very cautious in use of fibrates in combination with statins. And we want to avoid using gemfibrozil in combination with statin therapy, secondary to the increased risk of severe myopathy. And it's safer to use phenofibrate with statin therapy. Now, we should note that while the fibrates in clinical trials didn't necessarily show significant ASCBD reduction, and there is no ASCBD risk reduction indication for fibrates, when we looked at subgroup analysis, what we found is that a subset of patients possibly did have risk reduction with fibrates. It was really more patients with metabolic type syndrome picture. It's still not an indicated use for cardiovascular risk reduction, but it's still, I think, interesting to note that perhaps a subgroup of patients did achieve some risk reduction with those therapies. Now, we're just gonna spend a few minutes talking about lipoprotein A. It's getting a lot of attention, and I think for a good reason. It is considered a risk-enhancing marker, and we're gonna talk about how it's likely impacting cardiovascular risk. And if we look at this, again, it's sort of a cartoon depiction where we compare what an LDL cholesterol particle looks like versus an LP little a particle. It has an LDL-like portion with this APOA tail that's sort of attached to it. And if we consider why LP little a, the impact that it has in increasing cardiovascular risk, the APOA component seems to promote thrombosis indirectly through fibrinolysis inhibition at plaque rupture and at turbulent blood flow, which thereby increasing the risk of myocardial infarction and ischemic stroke. It's also involved in atherosclerosis. And it also has this LDL-like particle, which also promotes atherosclerosis through intimal cholesterol deposition, inflammation, and oxidation leading to atherosclerotic stenosis, and aortic valve stenosis. So if we look at LP little a and a little bit more clearly, let's kind of focus on some of the key points. LP little a is genetically transmitted. Why is this important? Because as of now, we screen for it. It is not something that we continue to monitor. There is no recommendation for universal screening at this point, although that's something that they are considering in the future, but it is genetically transmitted. That APOA is attached to the APOB segment of the LDL-like particle is a unique protein contained with the LP little a. Again, as we said, it may inhibit fibrinolysis, therefore increasing thrombosis. Inhibiting fibrinolysis at the site of the plaque rupture increases the risk of MI and ischemic stroke. So again, if you have plaque rupture, and then you have promotion of thrombosis, that's gonna increase your risk of having a heart attack or stroke. Thrombosis also at the site of turbulent flow can promote atherosclerosis as well as valvular aortic stenosis. And we need to remember that component of elevated LP little a also increases, increasing the risk of valvular aortic stenosis. And when you're looking at LP little a values, it's important to recognize that it can be reported as either mass concentrations, which is milligrams per deciliter or particle concentrations, which is nanomoles per liter. So values can either be reported as mass concentrations, which is reported as milligrams per deciliter or particle concentrations, which is reported as nanomoles per liter. It is suggested that there is universal use of nanomoles per liter. But as of now, that is not the case. So when you get an LP little a result reported on your lab, it is important for you to look at how it's reported because whether it's elevated or not is gonna be based on how it's reported. So LP little a has been determined to be an independent risk factor for ASCVD and valvular aortic stenosis. And this is where how it's reported is important because it's considered elevated if it's greater than 50 milligrams per deciliter or greater than 100 nanomoles per liter. And that's when they're considered independent risk factors. LP little a could be useful to reclassify cardiovascular risk and aid in pharmacotherapy decision-making. If we're remembering back at our risk enhancing markers, if patients fall into that borderline or intermediate risk, if they've been found to have elevated LP little a levels as well, that might tip the scale towards recommendation to start lipid lowering therapy such as a statin. LP little a as of now is not a target of therapy, but currently there are phase three trials going on that have reported significant LP little a lowering up to 80%. So it may be a target of therapy in the future. So again, as of now, the treatment is more aggressive LDL reduction. We don't specifically put patients on medications to lower LP little a. Statins do not lower LP little a, but the treatment is more aggressive LDL reduction. And because we don't have a target of therapy as of now, repeat measurement of LP little a at this time is not recommended. So who do we consider testing? And again, there's no recommendation for universal screening. So at this time, this could sort of be used as a guide of who we consider testing LP little a in. And again, this is used to further stratify cardiovascular risk. Patients with premature ASCVD. And again, patients with elevated LP little a because it's a genetic marker. We also need to talk about the importance of cascade screening. So patients who have elevated LP little a, premature ASCVD, again, maybe we're already gonna be treating them to a more aggressive guideline, but cascade first degree relatives screen for LP little a is gonna be important as well. Patients with recurrent or progressive ASCVD despite optimal lipid lowering. So these patients that it looks like they're at goal, it looks like they're on all the right guideline directed medical therapy. They go on to have recurrent events or progressive disease. We should check an LP little a in these patients. First degree relatives with premature ASCVD. Again, this is highlighting the importance of cascade screening. Patients who have suspected FH, baseline LDL cholesterols greater than 190. Lower than expected LDL cholesterol lowering with therapy. So again, those patients who have a blunted response to the medications that we start them on. We talked about cascade screening. Also to aid in the clinical decision-making as we discussed previously, and to identify those patients who are at risk for progressive valvular aortic stenosis. So we identify patients who have aortic stenosis. And if they have an LP little a that's elevated, we might want to consider follow-up surveillance tests done a little bit more frequently as they may be at an increased risk of progressive aortic stenosis beyond what we would normally expect to see. So in summary, again, I know we covered a lot of information here, but there's a few things that I really want you to take away from this lecture. And it's first off genetic lipid disorders are responsible for significant morbidity and mortality. And particularly when we look at familial hypercholesterolemia, it is the most common inherited disease worldwide. Screening and identifying patients with these disorders can really help to mitigate ASCBD risk and ASCBD events. Lipid orders discussed are often complex to treat and you should consider a referral to a lipid specialist for further evaluation or treatment recommendations. Here are the references. And any questions that you may have, please feel free to direct those to academy at medxstam.com. Thank you.

advanced lipid management

hypercholesterolemia classification

genetic factors

idiopathic factors

primary hypercholesterolemia diagnosis

familial hypercholesterolemia

cascade screening

genetic lipid disorders

hypertriglyceridemia treatment