Hypercholesterolemia & New Guidelines – Dr. Karol E. Watson, MD | UCLA Primary Care Update 2015

all right without further ado in 2013 the American Heart Association issued new cholesterol guidelines guidelines that placed a lesser emphasis on LDL and non HDL targets and instead introduced the concept of statin benefit groups as well as moderate and high intensive statin therapy to discuss this topic I can think of no one better qualified then our first speaker today dr. Carol Watson dr. Watson is a professor of medicine at UCLA in the division of Cardiology she’s the director of the UCLA preventive cardiology program and and in addition she’s the director of the Barbara Streisand heart health center dr. Watson my pleasure to be here today to discuss these guidelines these are my disclosures so as dr. Kwan said in at the end of 2013 we released the accha guideline on the treatment of blood cholesterol to reduce at the Roddick cardiovascular risk in adults I was a member of this guideline writing committee which was chaired by dr. Neal Stone so I’d like to give you our impression of where it stands now a year and a half later and what we were thinking when we put what we put in the guidelines I can tell you they actually the guidelines started out with a little bit of a tortured history it was initially convened by the NIH the National Heart Lung and Blood Institute and it was in convened to be the update of the ATP three guidelines so we were the ATP for panel we worked under these auspices for about three and a half years when they convened the panel they told us what they wanted they wanted us to scour the literature using randomized control trial data and meta-analyses primarily or only and tell us what works to reduce adverse credit cardiovascular disease events hard events so that’s mi in cardiovascular death it’s a very clear charge but a really small box and pretty different than ATP 3 which use much less stringent definition of what kind of evidence they would use they also didn’t require the hard cardiovascular outcomes so this was a different set of guidelines we worked under the auspices of the NIH for about three and a half years and then at the 11th hour they sort of said we want to get out of the guideline writing business so we’re going to hand it over to the professional organization so they handed our guidelines committee in toto and our guidelines which were pretty much finished at that point to the ACCC Naha we worked under the auspices of ACC NHA for about six months they really did not change the guidelines they did a lot of review and it added more ad hoc reviewers but they really didn’t change the guidelines and so that’s what was published in 2013 okay I want to give you our background thinking about these guidelines and some of the inside points that we wanted to emphasize and I’m going to do it by going through really what we were thinking front and foremost about when we put these guidelines together the first thing you’ll note that the guidelines seem like a drug guideline and they really were under the feeling of this everyone everyone who has any cardiac risk should be treated with lifestyle lifestyle is the basis of all of our treatments so when the NIH put all the panelists together they put together three panels and three working groups the panels were the cholesterol panel the blood pressure panel and the obesity panel the working groups were the risk assessment working group the lifestyle working group and an implementation working group which never got off the ground but anyway what we what they wanted to do was have lifestyle recommendations that span to all three panels so what we did was we endorsed these in our guidelines and we said that in the text very prominently and everything that’s in the accha lifestyle recommendations is pretty much everything we know we should do so it’s a healthy diet regular physical activity things like that so then we did this exhaustive literature search really looked at everything we

could find that was a randomized control trial or a meta-analysis for really the last 40 years when you do that it really becomes evident that the best way to reduce mi stroke and cardiovascular death is what statins so with that we came up with what we call the statin benefit groups so what when we did that it was important to note that not everybody benefits from a statin so we didn’t want to recommend everyone get one what we wanted to do was target statin therapy to those groups most likely to benefit and target people away from treating those who are not for instance heart failure patients really sounds good makes a lot of sense that statin should benefit them but when you look at the randomized control trial data it doesn’t support that so we did not make a recommendation for or against treating heart failure patients the same thing for a chronic renal failure for in stage and renal disease patients we said the clinical trial data does not support or you know refute using so we didn’t make a recommendation for or against but these were the groups that there was clear randomized control trial data that they benefited and again this is why we focused on statins when you look at all of the randomized control trials and meta-analysis danton’s really rise to the top this is data from the cholesterol treatment trial this meta analysis looking at statin there before the reduction of cardiovascular events and there’s a real consistency of all the results really regardless of where your baseline risk is regardless of what your risk is driven by whether it’s smoking blood pressure or something else there’s about a 25% cardiovascular hard cardiovascular risk reduction for every 40 milligram per deciliter LDL lowering you get would stand it’s important to note also that really all of these trials were fixed dose trials so for years we had sort of worked under the theory that we needed to get to a certain target and treat to that target and that would improve outcomes but when you actually look at the trials do you realize that’s not how they were done they picked a drug and they picked a dose and they just treat it and that’s really what we saw so I for one was like most of the panel when we came we thought you know I bet we’re gonna lower the goals to lower and lower but when you look at how the trials are done they’re just not done that way they pick a drug they pick a dose and they just treat okay so we came up with these four statin benefit groups and that’s some figure number one from our guidelines listing the four statin benefit groups the top three groups are sort of the very high risk patients that there really was very little controversy or discussion about the bottom square is the primary prevention group which I’ll spend a lot of time talking about because it was that’s where all the controversy was okay Stanton benefit group one individuals who have clinical cardiovascular disease acute coronary syndrome myocardial infarction and Jenna already revascularize everybody agreed they deserve treatment so what we said is if they’re under the age of 75 we recommend high intensity statin if they’re above the age of 75 we recommended moderate intensity statin therapy and that was actually only because there’s pretty good evidence that most statin side effects are increased in individuals of under over the age of 75 statin side effects are dose related so we said in this high-risk group but higher risk for adverse events also we recommend a moderate dose the next statin benefit group awful that very little controversy these were individuals with LDL cholesterol above 190 those are individuals who we recommended high intensity statin therapy because that’s what you’re going to need to get their LDL down to a level which we believe they’re not as no longer at risk the reason we put this in there if you do their risk calculator with these individuals they will calculate low because most of them are young because they don’t live when they’re really old but most of these individuals will not calculate to be a high risk but most of them will have a genetic dislocate emia it’s almost impossible just to eat yourself up to an LDL of 190 without having some genetic defect we recommend families screening in these patients as well statin benefit group number three people with diabetes both type 1 and type 2 now this group the type 2 evidence was clear for type 1 diabetes we actually made it an expert opinion because there’s much less evidence in that group we say in the document ages 40 to 75 only because that’s where the clinical trial data was but we also say it’s really reasonable

to treat someone under the age of 40 or over the age of 75 if they have diabetes because it’s likely they’re going to achieve the same benefits very little discussion or controversy about this recommendation either now statin benefit group for these are individuals who are primary prevention they’d have no clinical cardiovascular disease they don’t have really high LDL they don’t have diabetes but they have an estimated a thorough scored a vascular disease risk of greater than or equal to 7.5 percent over the next 10 years and for them we recommend moderate to high intensity statin therapy this is the most controversial part of the guidelines we also said 7.5 is the threshold which we really want you to recommend it but it’s reasonable we said to recommend it down to a risk of 5.5% over the next 10 years and I’ll show you how we came up with those numbers as I said most controversial part of the guidelines because of the risk calculator to a large part and also because of the lower thresholds of treatment but I’ll explain to you why we got there where we got to let’s talk about statins for primary prevention well we were fortunate to have two very well done men to base our recommendations on about the same time the guidelines were being completed the most recent one was the Cochrane meta-analysis which was done by Fiona Taylor and this meta-analysis she looked at all of the primary prevention statin studies that she could find and then looked at all the important outcomes all cause mortality cardiovascular mortality coronary heart disease stroke non cardiovascular etc what they found was that if you look at the statin treatment those individuals had a significantly lower risk of all the major outcomes the only one that didn’t go the right way was type 2 diabetes where there was an increased risk which actually just met the limit of statistical significance we’ll talk about that the cholesterol treatment trials had performed a primary prevention ban analysis about a year before and so we had access to that as well and what they found was that if you look at the x-axis going across that’s the LDL cholesterol reduction so the more LDL reduction is over to the right if you look at the y-axis that’s the number of vascular events avoided vascular deaths avoided and if you look across the z axis there’s the baseline risk of the patient so if you start off as a low-risk patient and you give a statin the more statin you give the more vascular events are avoided but as you increase the risk of the primary prevention patient the more satiny give more LDL reduction the more events are avoided so this was pretty clear evidence to us that the higher risk primary prevention patients should excuse me should be treated with a statin okay but there was a lot of controversy a lot of people had a lot of things to say I’m going to talk a bit about the risk estimator and also about how we got our treatment threshold where we decided we should recommend treatment okay here’s the @a s CVD risk estimator it is available for Apple products for Android products it’s a free download and I highly recommend that you all do that these are the variables that are put into it gender age race total cholesterol HDL cholesterol systolic blood pressure whether or not you’re on treatment for high pull up rescher diabetes and smoking you put all those variables into the equation and it spits out both a 10 year after Scarlet cardiovascular disease risk and a lifetime risk we thought the lifetime risk was really important because for young individuals you’re probably not going to get a high enough tune your risk regardless of what the risk factors are but we know that if they have a very adverse risk factor profile their lifetime risk is very high what’s different about this is a couple of things one is races included and by that they only have two fields for race it’s either white or african-american but if you open up the decision support tools that are available on this download they talk about other ethnic groups as well they talk about Asians South Asians Hispanics and tells you like how you should think about those patients the other thing that’s different is diabetes is included if you’ll remember the old Framingham risk estimator diabetes was taken out because diabetes was a risk equivalent we now have a lot more information about diabetes that it’s a very heterogeneous disorder some

patients are very very high-risk and you it’s reasonable to treat them like they have coronary heart disease but some are not and those patients it doesn’t necessarily make sense to now again all of these patients are recommended for statin therapy but if they are a patient with diabetes who’d you do the athos chronic cardiovascular disease risk estimator on and they turn out to have a risk lower than 7.5% we recommend moderate intensity statin therapy if they have a risk estimator that comes out to be above 7.5% we recommend high intensity of statin therapy the other difference about this customer as compared to Framingham Framingham really only predicted cardiac events this risk estimator predicts stroke and coronary heart disease events so that’s we thought was very important here’s how we got the thresholds whenever you treat someone with a therapy you want to base the decision to treat on the risk benefit ratio if the risks exceed the the harms we reckon so if the benefits exceed the risk we recommend that therapy typically so what we wanted to do was to put together all the risks the harms that we could think of and calculate a number needed to harm and what we did that we threw every harm in there that was in int that came out in an indie statin trial even if we didn’t think it was causal so we put in hemorrhagic stroke diabetes my up but the L of T abnormal is everything and when you calculate a number needed to harm it’s constant regardless of the baseline cardiac risk of the patient so when you look at that cardiac risk of a patient done here it doesn’t change going across and the number needs to harmed and for high-intensity satton therapy are shown there in red and for low to moderate intensity of statin therapy are shown there on the right now the number needed to treat for benefit does vary according to the baseline risk of a patient so the higher the baseline risk of the patient the lower the number need needed to treat so you end up getting this curvilinear relationship so what we decided was that if the number needed to treat for benefit was below the number needed to harm that was a reasonable therapy to recommend and at that threshold and if you look at the the 7.5 the 7.5% threshold it’s well below the number needed to harm for a high intensity statin therapy and even the 5% threshold that we say is an optional treatment level is well below if you’re talking about low to moderate intensity statin therapy you actually never exceed that never needed to harm so we actually don’t recommend low intensity of statin therapy for anybody in our groundling but it’s a that’s what the data looks like okay now let’s talk about the risk estimator as I said we worked in parallel with a risk assessment working group and we actually you know there was some talking back and forth but they worked all alone and came up with this and that risk estimator was adopted by all the panels how do you make a risk assessment clinical prediction tool well you have to figure out what population wanna you want to derive it in and it makes sense to derive the risk estimator and at using data that looks just like the population you actually are gonna apply it too that’s the first thing so Framingham only used Framingham but in this prediction calculator we used Framingham original cohort the cardia study which is a younger multi-ethnic cohort the cardiovascular health study which is an older cardiovascular risk cohort and the Eric study which is a middle-aged a thorough Scott ik multimedia risk prediction tool and then you want to validate it to validate it you want to validate it in the same populations in which you will apply it ultimately in so for that we use the multi-ethnic study of atherosclerosis which is a multi-ethnic cohort on the regards study again a more african-american cohort the Eric study multi-ethnic and the Framingham a current cohort study that’s what we did now the final step is where you do impact analysis you say okay this is what we did does it really work and that’s where we are right now one of our external reviewers for the cholesterol guidelines was Paul Ridd ker Paul great care is a cardiology great cardiologist at Harvard and so he had all the data and he had sort of his guns ready so the day the guidelines were released he also released his report he basically said come on you guys this risk estimator over predicts he didn’t mention that to

us when he actually reviewed our guidelines but this is what he did the day and the guidelines were released so he said I’m gonna use my own cohurt the Nurses Health Study also called the Women’s Health Study in the physicians health study to see if this risk estimator predicts well and lo and behold it didn’t so if you look at the predicted number of events which are shown in red they’re higher at every risk level than the observed number of the VIS shown in blue this is data for the women’s health study and this is data for the women’s health study here physicians health study here so the predicted events are shown in red the actual events shown in blue and you can see it every level they were higher so he said ha this thing doesn’t work at all but when you think about it as I mentioned you’re supposed to use this risk estimator for a general multi-ethnic multi-religious income average everything American population when you look at these two cohorts US physicians u.s. women health care workers they’re much higher sociodemographics than the average u.s population much healthier than average and many of them were actually taking statins the risk estimator is not meant to be used in a population already taken statins that it’s meant to be used to decide on statin therapy ok so let’s look at other cohorts Rotterdam it’s a observational study in the Netherlands and what they found was if you look at the Ryder damn cohort it also showed showed poor calibration it didn’t predict very well so the number of predicted events was higher in this Rotterdam study as well compared to the actual number of observed events so you think what’s going on here but then you think who cares what’s going on in Rotterdam these are meant to be American guidelines and there it meant for a broad-based US population okay so they did another study epic Norfolk observational study out of of London area outside of London and in this study they actually showed excellent calibration the number of observed events was actually about the same as the number of predicted events but I reiterate you know who cares how predicts in Norfolk what we want is it to predict well in US cohorts and when you look at them it does predict pretty well the regard study as I mentioned is it is a population-based study of black and white patients who are being followed for a Thirsk Roddick cardiovascular disease predominantly stroke and then a validation study they found that the risk estimator performed very well again if you look at the predicted events here shown as the blue bars and the observed events shown as the red bars they’re virtually identical so in this population it performed very well the investigators from the Dallas Heart Study also just recently released a report saying that the risk estimator performed very well in their core whole cohort as well they say our results from a contemporary multi-ethnic younger population suggest that the application of the accha guidelines will have a favorable effect on a s CVD prediction with reasonable efficiency of statin use when compared with the prior ATP 3 recommendations so what we’re starting to see is that when the risk estimator is applied to populations for which it was intended it actually performs pretty well ok let’s go back to the guidelines one of the other things we put in there which was actually new if you look at a lot of treatment guideline recommendations you won’t see this this was noon we thought we’re gonna get a lot of controversy about this well we got almost none we recommend that when you’re using statin therapy for primary prevention patients especially you need to really engage in a patient clinician discussion about this this is a therapy that’s meant to reduce risk and that’s something that’s sort of hard to get your head around and you have to get buy-in from the patient if they’re not willing to do this then there’s no reason to even attempt because it’s not gonna work so we really didn’t emphasize patient shared decision-making this is what we envision sort of a clinician patient decision making discussion might look like first of all review their risk factors and their respect or control because their primary prevention you’re going to estimate their tenure AS CVD risk now in some patients either their estimated risk just doesn’t jive with what you really think their risk is or you think there’s a hidden bris somewhere there are a number of things that we’ve put in the guidelines that you can use sort of to help you up upgrade your risk so if

they have LDL above 160 family history of premature at this car do vascular disease HSC RP above two coronary calcium score above 300 or an ankle brachial index less than point nine there are other things but these are the ones that we put in the guidelines because they have the best evidence behind them so after you do that we say we really want you to discuss the lifestyle with the patient so review the the potential benefit from lifestyle then it’s really important to think about potential benefits from Sandton potential harms from statin and certainly drug drug interactions and then finally and probably most importantly you need to take into account the patient preferences okay then the other thing that was pretty controversial in the guidelines says that we said after we looked at all the data they really said the current evidence is inadequate to support treatment to specific LDL cholesterol and or non HDL cholesterol goals so that meant no more LDL goals and what we instead wanted people to do was to use the intensity of statin therapy that was studied in clinical trials so this is a figure exactly from our guidelines as well where we talked about high intensity statin therapy moderate intensity and low intensity now we defined high intensity statin therapy arbitrarily and I will admit it was very arbitrarily as anything that gives you an LDL reduction of about 50% on average when you look at which can do that there’s only two either atorvastatin or rosuvastatin only at two doses for each of them harvest out in 40 or 80 receive a statin 20 or 40 when we talked about moderate intensity statin therapy we arbitrarily defined that as anything that gave you a 30 to 50 percent LDL production and these are the drugs that end doses that can do that and again we don’t actually recommend low intensity statin therapy for any patient but those are the drugs that do that the drugs that end the doses that have been studied in clinical trials are highlighted in yellow in this chart here you can see not all of the drugs and all the doses have been studied in large-scale clinical trials but we believe the consistency of data with statins is such that we think the benefits will be the same in all of the cases okay so here is how the guidelines look you should have an adult over 20 years of age who’s a candidate for sent in therapy yes the first question do they cliff have clinical athos chronic cardiovascular disease and/or less than 75 if the answer is yes then you give them high intensity statin therapy there are over 75 given moderate the answer’s no you ask the next question is their LDL above 190 if the answer is yes they have high intensity statin therapy the answer’s no yes the third question do they have diabetes either type 1 or type 2 the answer is yes they get high intensity if their estimated risk comes out to be about 7.5 they get moderate intensity if it’s below I’m sorry that’s the type of there but if the answer is no then you ask the third the fourth question do they have a 7.5 percent or greater 10% estimated cardiovascular risk and to do that you have to use the rest custom eater if the answer is yes then you give the moderate or high dose high intensity statin therapy the answer’s no what we wrote in the guidelines is you just continually reassess we wrote every four to six years I see my patients up more often than that but just continue to reassess and recalculate their risk the other thing we put in the guidelines let’s follow up so what we recommend is that you do repeat lipids and there’s some misunderstanding out there about that you definitely do repeat your lipids you actually assess them initially at three to twelve weeks following the initiation of therapy and then periodically thereafter I do every six to twelve months depending on my patients risk if they have the expected response and by expected what we said is we said that we don’t have data to either argue for or against LDL goals but we understood that many clinicians would have in their minds and LDL they felt their patient should be a below so if you have the expected response then great you’ve Pat them on the back you you congratulate them on their adherence and you continue routinely following them if the answer is no then you have to ask why is it statin intolerance if the answer is yes then you have to figure out how to manage that so we actually put into the guidelines a number of tips for managing staunton intolerance and that includes things like I’m switching statins changing to a

lower dose alternate day dosing even as little as once a week dosing but what’s important is we say max intensity tolerated statin therapy for patients who you recommend high intensity if they can’t tolerate that we don’t say just abandon the Stenton get them on some dose of a statin as long as it’s tolerable if they don’t have stand intolerance to ask them if they’re being adherent and reinforced medication adherence and then hopefully get them to get the expected response and if that happens and you go ahead and reinforce compliance and adherence if not then you have to figure out what else you want to do again if you believe your patient should be at an LDL level that’s lower than what they currently are you can either increase the dose reinforce adherence or considering adding a non statin drug to your stand okay what do we say about adding a non statin drug well we say again use the maximal and tolerated intensity statin therapy so don’t ditch the statin and switch to an on stand we’d like you to get the patient understanding for the optimal risk reduction but then you can consider addition of non staunton cholesterol-lowering drugs if there’s a less than anticipated therapeutic response but really only if you really believe that the benefit will outweigh the risk and for the higher risk patients that’s the ones that it’s most likely to be true for we then recommend that non-stem cluster along drugs shown to it is athos product cardiovascular disease events in randomized control trials upper 4/3 now recently we had a new trial called the improvement trial and it was very important because it was the very first trial that had ever shown incremental cardiovascular risk reduction when you add a non-stem to a stem so this trial was a pick up ended up being over 20,000 patients who had a recent acute coronary syndrome they were randomized either to ezetimibe plus some of the statin 40 or simvastatin alone then they look for the primary endpoint of cardiovascular death MI unstable angina revascularisation stroke or bleeding and they found there was a benefit so with the group that got the seven statin plus is that am I they had a reduction in clinical events so again the very first trial that showed additional benefit of adding an on statin drug to a statin and when you look at the meta regression line of cholesterol reduction which shows where a trial ends up on this line the amount of LDL reduction they get going across and the cardiovascular event production they actually achieve it falls right on that line for heart major cardiovascular events and hard cardiovascular events so we were actually quite pleased to see this trial it’s only been presented at the American Heart Association last year since its published we’re gonna incorporate it into the guidelines how will we incorporate it well it won’t have the same loss of recommendation as statins there’s so many different statin trials have gone into making that a class one recommendation level of evidence a at most it will be a 2a or 2b level of evidence B but we will incorporate it into the guidelines once it’s published if the results are the same as what we’ve been presented okay some common misses misconceptions about the guidelines some people think that all patients with the 10-year cardiovascular disease risk of greater than 7.5% need to be treated it’s not true we actually really do emphasize that patient provider discussion and we want the patient preference to take really supreme importance in that discussion some people think there’s no longer a role for we checking lipids and I hope I’ve convinced you that we do say that you should recheck lipids about 3 to 12 weeks after initiation of your statin and then periodically every 4 to 12 months some people think there’s no role for non-standard peein I think I’ve just shown you that there really does remain a role depending on what the clinician believes the LDL level should be and finally other people believe that the noob risk estimator abandons Framingham it doesn’t it at all it includes frating Framingham along with three other well validated cohorts to try to add power and diversity okay finally the last thing I want to try to UM I hope I’ve convinced you of the efficacy of statins I want to talk to you about the safety statins are remarkably safe drugs but just like indie drugs they have side effects some side effects that have been touted and that patients worry about really are probably nothing to worry about others really are something to worry about so I want to go through each of these liver muscle side effects cognitive effects

cancer and diabetes what about the liver well for years what we’ve done is chucked lfts before initiation every six months anytime you change does and we’re really vigilant about checking lfts because we worried that statins might be hip had a toxic what the FDA two years ago though came out saying is that huh you know we don’t see about a toxicity like we thought we were going to so you need to check your lfts before you initiate them but you don’t have to routinely check and that was a really really rare move by the FDA without encouragement or any kind of lobbying from any drug company they actually took away a prescription that they had done for years what they said was in early clinical trials lft elevations were seen so healthcare providers were advised to regularly follow lfts however the FDA found that statin liver damage is rare and Alvis tees are not effective at predicting or preventing this rare side effect so FDA is now recommending that lfts be performed before statin treatment begins and then is needed if there are symptoms of liver damage so that’s the liver let’s talk about the muscle now the muscle size fix are showing the one side effect I really do worry about that’s because we do sometimes see deaths from that statin adverse effects are of various types there’s what I call the achy pain a feeling which is just myalgias and that’s actually pretty common I ran a lipid clinic and I see a lot of patients like that it’s common but it’s not dangerous it’s never been shown to lead to muscle damage or any adverse event myopathy however is when you have the the achy pain feeling plus an elevation in your CPK that means you are actually getting them some muscle damage again it’s pretty rare about six cases per 100,000 patients about spasibo but it’s you know it’s it’s concerning to the patient and the increased CPK makes us worry about muscle damage so if the CPK is more than ten times the upper limit of normal that is the definition of myopathy now no deaths occur because of myalgias or myopathy what can cause deaths are true rhabdomyolysis that’s a frank idiopathic muscle breakdown it’s not just statins that can cause it a lot of drugs and a lot of other things can cause it but when it happens it can be life-threatening and that is what I worry about so the incidence is low only about 1.6 patients per 100,000 but when did happens it can be life-threatening so every patient every last one whenever they get their statin they get this morning any unexplained tenderness muscle pain weakness stop the dirt and call me every sale patient gets it if you get a patient with rhabdo stop the drug give them hydration they’ll be fine but you don’t want to let that patient continue to take their statin or going otherwise unmonitored okay how can we know that Stanton muscle effects happen in randomized controlled trials it’s a really low reported rate but when you think about how the trials are done almost all of them have an active running phase that means they have P before they even randomized them to either the statin or the not the placebo group to give everybody a statin and see who can tolerate it if they can’t tolerate it they get you know kicked out of the system they never even get randomized so the incidence rates are very low in randomized control trials but in real life it’s probably much higher it’s probably much closer to 10% myopathy and rhabdomyolysis are associated with statin therapy as a class affect every single statin can do this the risk increases with increase statin dose and with drug drug interactions so but prior to initiating statins patients need to know to promptly report in the unexplained muscle pain Anderton weakness everybody gets that warning there are some patient characteristics that increase the risk of statin myopathy and some statin characteristics that are shown here the ones I want you to focus on in the randomized control clinical trials if you look at who gets rammed up rhabdomyolysis is overwhelmingly the little old ladies so then low muscle mass get massive dose of statin they’re the ones that are most at risk okay cognitive effects if you look at observational studies and look the patients that get a stem actually looked like they have a lower incidence a cognitive impairment and there’s another analysis done sort of a post hoc analysis of about 60,000 individuals over the age of 65 no history of

dementia who were taking statins they divided them up into turtles according to the statin dose they were taking and then looked at who got cognitive impairment turns out that those individuals who are taking the highest dose of the statin had the lowest incidence of cognitive impairment there’s sort of a stepwise increases you go from moderate to low so these look pretty good right well there’s a reason we do randomized controlled trials because a lot of confound errs can be seen both in the observational studies and then this type of analysis when you look at randomized control trials where they look specifically for cognitive disorders you actually don’t see anything no harm but no benefit either this is from the heart protection study 20,000 individuals – given seven statin or placebo no real change a more important study was the prosperous study because this was the study that was done all in elderly patients so all of these five doesn’t almost 6,000 patients were over the age of 70 they got 40 milligrams with promised and/or placebo and they actually did formal neurocognitive testing no benefit no harm at all okay so what the FDA said in 2020 twelve of their advisory they said there have been rare post-marketing reports of cognitive impairment in other words memory loss forgetfulness amnesia memory impairment confusion associated with statin use the times I hear of it is cause like this foggy brain feeling patients talk about these reports symptoms are generally not serious and reversible upon statin discontinuation with variable time – septa onset one day two years and center resolution median of three weeks so they that was another weird step by the FDA they looked at all their database and found no cognitive impairment signal at all but they said we’re getting all these reports we need to pass it along we don’t know what it means but is what we see cancer nothing no harm no benefit whether you slice it by statin dose years of use baseline risk baseline risk factors there’s just nothing there no increased risk of cancer but it doesn’t appear that there’s any significant reduction either and the final thing is diabetes there is a diabetes signal so if you know it took we’re using statins at pretty good frequency for about 20 years before we saw the first signal of diabetes that occurred in the Jupiter trial that was a trial of primary prevention patients most of which who had the metabolic syndrome they had high intensity receive a statin or placebo they had a significant cardiovascular risk reduction but out of that trial they saw for the first time there was a statistically significant increase in diabetes development in the statin users turns out then we went back and looked at a bunch of different statins and it looks like most statins can cause it as well so it’s probably a class effect when you look at that same Jupiter trial which is the first trial that showed us the signal in the first place a really interesting thing comes out if you look at if you split so like I said many of those patients actually most of them had the metabolic syndrome but those that didn’t and didn’t have any major risk factors for diabetes they had a significant risk reduction with the receive a statin and they had no excess cases of diabetes so these patients had the benefits but didn’t have this risk from the receive a sin if you did have major risk factors for diabetes metabolic syndrome obesity etc those are the patients who still had a significant benefit 134 deaths or vascular events prevented but all of the excess cases of diabetes happened in that group so what it looks like this type statins tend to raise blood sugar levels about two to three milligrams per deciliter in most of us that’s not going to make a difference but if you’re teetering right on the edge of developing diabetes you might tip you over the investigators estimated that it accelerated the diagnosis of diabetes they said about three weeks I thought it was probably closer to a year but we both made up those numbers so I don’t know being honest what the FDA said was such a small increased risk of elevated blood sugar levels and the development of type 2 diabetes have been reported with the use of statins clearly we think the heart benefits of statins outweighed the small increased risk but blood sugar levels may need to be assessed after instituting statin therapy okay so stats most efficacious LDL lowering agents and had the greatest cardiovascular risk reduction liver damage very rare and probably there’s actually never been a case of documented liver failure with statins statins can’t produce muscle pain and weakness but the

risk of true rhabdomyolysis is small but you still have to give them that warning unexplained muscle tenderness pain weakness stop the drug and calming statins come in clinic shows have found no evidence of cancer or cognitive impairment statins can increase blood glucose levels minimally leading to increased reports of diabetes but in patients at high cardiovascular risks the benefits of statins far outweigh the risks thank you very much for your attention we have time for a few questions if you have a question raise your hand we’ll get your microphone and you can pose your question to dr. Watson and the question is when I say if they obtain the expected response by that women LDL reduction and again we don’t put LDL levels in our islands but we assume that many clinicians will have an LDL level that they really do believe their patients should be loved ya know and I kind of wish we hadn’t put that stat into the guidelines because we don’t recommend you book at the percent LDL reduction because again that’s not how the clinical trials were done and I admit we arbitrarily defined high intensity statin therapy as a 50% but it’s not that we want you to aim for a 50% it’s just that these are the drugs at the doses that in clinical trials caused about a 50% reduction yeah so it’s not that’s not one of the interactions that you have to stop most of them are the really really potent set three a-four inhibitors like drugs like antibiotics and some protease inhibitors where you do really have to be careful it looks like it was included in the risk estimator the HDL cholesterol but I always look at that if my patient has a high HDL that that’s very protective we didn’t comment on that so we used to think that HDL was this great protect anti atherogenic molecule but there’s many many reports now that not all HDL protects and in fact if you look that’s our big research interest at UCLA and many studies have reported high HDL levels actually causing increased risk rather than being protective so the way it’s still put into the risk score because I mean it it does come out in epidemiologic but we don’t ever ignore a really high LDL just because yet it feels good two questions one any role for vapp studies lipid subfractions myeloperoxidase in risk calculation of making decisions about management and number two when you do have a statin induced myalgia do you ever try just reducing the dose or switching to a different statin so the answer the second question first I always I have my favorite statins and I always just try going down and dose and it typically works that’s question number two question number one there’s most patients don’t need a vapp but there are some instances where I’m sure there’s hidden risk in a patient and I do use some of that data I’ll give you an example at a young young ish woman who has a really bad family history and then her and her Ellie looked pretty good I’m like okay something’s going on I got a bad particle number with like 4,000 it was ridiculous so in her I actually put her on as Downton despite the fact that her alt it looks pretty good but most patients the risk is pretty obvious it’s only in those patients I’m worried about a hidden risk yet so this is so interesting I’m gonna give you all my secrets – you guys still send them to me though so the question was what is the minimum dose of a statin at which you can usually get it benefit and I can tell you I do this a lot and I have gotten benefit in terms of LDL reduction but there are no outcome studies at this dose but she give rasuu statin the lowest dose pill they make is five milligrams tell them to cut it into quarters give as little as one a week and you get some significant benefit I just yesterday called the patient back with his LDL results on that he went from 140 to about 83 no it was once a week I’m sorry how to use the risk calculator if they’ve already been on the statin you can’t so you can’t use the risk calculator is absolutely not meant for someone who’s already on

statins so he is not intend to be used your risk calculator does not take into account family history I have so many patients that have they look great okay but yet they have a horrible family history of premature atherosclerosis and a cardiac events so some of them have chosen to do the cat scan at Harbor and so then how do you decide whether or not the treat because looking at your calculator you think well gosh these young guys that are 50 52 with LDLs of 170 but great lifestyle perfect everything shouldn’t be treated what do you want with that recommendation that’s a great question and remember I showed you in that patient provider risk assessment discussion the things that you can look at in addition to what their estimated risk is if you want to up classify someone is coronary calcium about 300 but I I look at strong family history as well there’s no question and and the reason it’s not in the risk customers is because every time you look up to D me Elijah epidemiologically and then adjust for things like blood pressure or HDL etc family history drops out so then with somebody who has in LDLs 170 with a family history of father dying of a heart attack at age 49 47 what’s your target then does the LDL really not matter no the LDL does matter but my target then is to get them on statin I’d put them on a moderate dose down I don’t use a percent drop or an LDL goal I just use the intensity of statin therapy 170 premature heart disease all bets are off to you in for a 50% reduction as in high intensities no you don’t mean project you should get them only on the intensity of statin therapy that’s what our guidelines does that make sense so you don’t have to say I’m gonna aim for a 50% and then if I you don’t get them there with this dad and I’ll then add zetia or nice and I don’t know just get them on the intensity of statin therapy we recommend okay I’m a little slow maybe okay so if I have 170 to start premature family history I think I want to put them on something so what do I tell the patient moderate or high intensity statin therapy so let me say a word about sorry there’s a real problem of targets a target implies that it just doesn’t matter how you get there and it clearly does statins are by far the best way to get their target also implies that we know where risk tails off we have no clue so we may feel better about a target but again we’re making it up a target further implies that if you’re just above the target you give a tiny dose of a statin then you’ve reduced risk but we clearly know that higher intensity Saten therapy gives you more risk reduction and probably the worst possible thing a target can do tells you that if your patients already below targets you just don’t need to treat them with a stand there by really depriving them of the benefits of these life-saving drugs so there’s a there’s real problems of the target so how long would you actually play see the patient all right okay I’m sorry I’m here how long would you actually a put or place the other patient and therapy for you know at all patients that have more than 7.5 as long as you like them no I’m just you know because you’re gonna take away the benefit if you take away instead you have to recalculate the the risk factor like no you’re no you just put them on indefinitely exactly forever here so I gotta tell you I’ve looked at the data too and there really nothing comes out of the clinical trials but think about this the brain is a big bag of cholesterol there are some people who feel lowering your cholesterol whether it’s by a drug or by LDL apheresis some people just feel it and I don’t doubt that but there’s no systematic evidence of it