Practical Approaches to Navigating Statin-Associated Side Effects and Intolerance

go ahead hi everyone Welcome to our Monty heart lecture series it's a great pleasure to have today Dr Dave Dixon who

will be giving a lecture to us on practical approaches to navigating stating Associated side effects and

intolerance I believe this is a very very important topic and so I'm sure everyone would enjoy it so Dave Dixon is

the Nan Ronald McFarland professor of Pharmacy and chair of the Department of pharmacotherapy and outcomes science at

Virginia Commonwealth University School of Pharmacy his primary clinical and research interests include the

management of lipid disorders resistant hypertension and guidance adherance and implementation Dr Dixon is an associate

editor for the Journal of the American pharmacist Association and the journal of clinical lipidology he is a fellow of

the American Heart Association National lipid Association American College of clinical Pharmacy and American College

of Cardiology he has published over 140 peer review Publications and co-author multiple practice guidelines and

scientific statements for those of us that work in the prevention lipid Arena we know him very well and he's you know

someone that we admire for his knowledge about H pharmacotherapy in general and statins in particular so thank you so

much for joining us and and spending time with us no thank you uh it's really a pleasure to be with you all I know

that there are some competing things going on like a basketball tournament I think the today's games are starting

here in the next few minutes uh so I appreciate you taking your time uh to learn more about Staten uh in tolerance

instead of uh basketball but feel free to keep tab on the scores and feel free to update me if you want um so we'll

just jump right in and uh uh do have some disclosure so I have received Grand funding from boinger engelheim uh they

do not make any lipid Ling agents so I will not be uh that should not be an issue and then the second item is that I

do serve as coach chair uh of the scientific statements committee for the national lipid Association uh and that

is relevant uh because uh a good bit of what I'll be sharing today uh comes from uh two documents that the national lipid

Association has published over the past couple of years uh one of which uh really kind of redefining or updating

our definition uh for Statin intolerance and then another paper that uh is really aimed at clinicians uh in terms of

helping clinicians uh assess and manage Statin Associated muscle symptoms so we're going to talk about

Statin Associated side effects and Statin intolerance uh the assessment and management of Statin Associated muscle

symptoms or what I will refer to as Sams and then I think most importantly apply evidence-based strategies for managing

these patients that uh I know we all see and you know uh we deal with this issue on a on a very regular basis in clinical

practice so uh want to start off with a patient case uh and then we'll kind of come back to this at the end uh so this

is a 64 year-old uh referred to you for suspected Statin intolerance uh they had a PCI in November they have a history of

hypertension and diabetes uh this individual was started on a torva tvat and 80 milligrams per day which is not

uncommon uh for these high-risk patients but discontinued it four weeks later due to muscle aches uh in his legs that did

improve after after discontinuation his primary care provider then started him on pravastatin

10 milligrams per day which he did okay on for a couple of weeks before these same symptoms came back again uh and

then finally those resolved uh after drug discontinuation this is a story that again I'm sure is very familiar to

all of you uh you can see the list of current medications uh and his lipid profile uh without any treatment uh

shows an elevated LDL cholesterol of 158 milligrams per deciliter so I want you to think about whether or not you think

this patient has Staten intolerance or not and we will come back to this uh toward the end of the

talk so I'm a big history guy uh and so it's always fascinating to me to kind of go back especially in the medical or or

Pharmacy history uh for some of these topics and I think it's really relevant here because if you go back and you

think okay uh where did this idea of satin Associated muscle symptoms really come from and you really have to go all

the way back to 1988 uh to a correspondents a couple of them that were published in the New

England Journal of Medicine uh and these were related to cases of patients that developed uh

rabdomiolisis uh these were patients that had received uh a heart transplant and were on Lois Statin which of course

uh had been approved uh in the year prior and was the first Statin that was approved by the

FDA and these are really the first reports that we have uh in the literature of the potential for at least

uh you know severe uh muscle related side effects uh from statins and uh it's really interesting

in that there's sort of this correspondence that happens in the New England Journal uh and these letters

were essentially referred to T Merc uh and which of course was the company that developed uh

Lovastatin uh and their response was that yeah we are aware uh of some a small number of patients uh with

myopathy uh consisting of skeletal muscle pain weakness uh associated with highly elevated serum

uh cring kinas levels and uh also saying that you know they conclude that Lo Lovastatin May rarely be associated with

a myopathy uh but that the incidence appears to be greatly increased by concominant therapy with gy fibril uh

and also in these transplant patients of course patients were on anti- rejection or immunosuppressive medications such as

cyclosporin which we now know know uh both of those medications have significant drug drug interactions uh

particularly with Lovastatin uh because it is metabolized through sit 384 at this time that was not common knowledge

uh and so it's really from this point forward that we start to see uh you know more in the literature uh about Statin

Associated muscle symptoms and if you go and look at some of the early the first you know large outcomes trial trials

that were published with stat therapy uh you will not you will find in a lot of the adverse effect tables that muscle

related symptoms uh aren't even listed uh there might be mentioned in the text you know the one or two patients that

developed rabdom myisis uh but it was something that sort of over time snowballed as to where now you know if

you go and uh you Google statins and muscle injury uh you will find a lot of reasons not to take your stattin right

uh and this is sort of uh what we struggle with in practice on a basis uh as patients come in uh you know citing

some of this information uh and have concerns about the potential for muscle injury so that's what we're going to

dive into um another factor that or incident that occurred that I think also uh put this idea that statins are are

you know potentially problematic from a muscle injury perspective was with civa Statin or ball uh which based on this

analysis here of of available cases for rabdo fatal rabdo myisis you can see that uh the reporting rate with civa

Statin was significantly higher than the other statins and so as a result uh this was when Staten that was eventually

pulled from the market so do we actually know uh about the effects of statins and their effects

on skeletal muscle function we all know that statins inhibit the rate limiting step in the endogenous cholesterol

process so HMG COA reduct a we also know that the me me late pathway is important for the regulation of proteins uh

skeletal muscle adaption maintenance and there was a really interesting study that was published in Jack basic

translational science in 2019 uh they actually looked a bit deeper into this and it is true that

there are some preclinical data suggesting statins may actually trigger um sarcoplasmic reticulum calcium leak

and may have some triggering of pre pro apoptopic U signaling which could of course lead to some muscle injury but

when they actually um assess the contractile function of the skeletal muscle there was no detrimental effect

found with stat so from a mechanism perspective uh there definitely is that potential uh but we do have some data to

suggest that there may not be a at least a direct effect on the contractile function of skeletal

muscle so Sam's uh what is it what is it not um Sams or stattin Associated muscle symptoms are it's generally described by

patients as a bilateral muscle discomfort uh more often than not they'll describe this ache in the legs

particularly larger muscle groups so thighs or also the calves uh but also in the upper back upper torso uh occurring

usually within the first uh 12 weeks of starting Statin therapy one other key aspect is that these symptoms resolve

within two to four weeks of stopping the stat if these symptoms continue or persist beyond that uh then quite often

it's it's pretty unlikely that we're talking about the stattin and that there's probably some other in uh

underlying issue Sams is rarely unilateral rarely begins after 12 weeks

of being on a Statin and it's almost never joint pain and and this is something that we'll come back to in a

moment but if I have that patient and they you know they've got I'm sure you've heard these complaints their left

elbow started to hurt uh it's very unlik that the Statin is causing the left elbow to hurt they may have some tennis

elbow they may have some other things going on but it's it's probably not the Statin another key aspect here is using

the correct terminology and I think even we as clinicians sometimes can use these terms interchangeably which really uh

you know isn't helpful when we're trying to communicate with patients and by and large what we're talking about is

myalgia myalgia uh you know the the prevalence of myalgias with Staten use if you look at the the clinical iCal

trials and observational data ranges somewhere between 5 to 30% of patients these are typical uh muscle symptoms

described as a soreness and achiness cramping muscle fatigue and or weakness but without an elevation in creatin kise

myopathy on the other hand uh which again not that common so one in 10,000 patients per year used per year myopathy

unexplained muscle pain or weakness accomp need by a CK elevation of uh greater than 10 times a limit of normal

and then rapis which is really what we're you know super concerned about right because of the potential uh fatal

risk for the uh risk of of renal failure and and then of course death um very very rare so one in 100,000 uh patient

use per year and this is when the CK is elevated greater than 40 times upper limit of normal and again they get that

myoglobinuria and renal failure that really gets patients in trouble so make sure we're using the right

terminology is is really key so the elephant in the room right uh our stattin Associated muscle symptoms real

and I'm sure you've all heard um of some of the couple of trials that have been published in the recent years uh

exploring the no sio effect uh when a harmless thing that causes a particular effect you know you believe that it it's

Associated and so uh you know as a result it's easy to to pen whatever you're experiencing on that drug in this

case being statins um on the left this is a figure from uh the Samson trial published in

Jack and in this study where patients were uh receiving Placebo uh some months they were receiving Statin on some

months and so patients didn't really know what they were getting and they were keeping track of their symptoms and

the overall conclusion of the study was that 90% of the symptoms were likely explained by the nobo effect so then one

could conclude well most of this is not real and so you know if it's not real then then why is this such a big deal

and at the end of the day we just have to ask ourselves you know does it matter and my somewhat of a hot take here is

that it it doesn't matter if they're real or not scientifically yes we'd like to know the

answer to this question but let's think about the patient does it matter to the patient like if they think that their

satin can attributed to these muscle symptoms you can in some cases provide education and and maybe there's a way

for them to at least consider the possibility of trying another Statin or you know in some cases maybe they just

completely don't want to take one but whatever they experienced is what they experienced and so at the end of the day

I don't think it matters whether they're real or not um that's a debate that we can have scientifically but when it

comes to clinical care and taking care of patients I don't think it matters because we still have to deal with it um

in in the clinic so what are some common risk factors for Sams uh and you know the caveat here is

that if if 90% of the symptoms are potentially explained by the nobo effect then are these risk factors even real

right um I will say that uh if you reflect back on patients that you've seen with u possible Statin intolerance

I think some of these characteristics you know they almost always show up um they might be an older patient uh they

may be uh you know a a a female patient particularly one of lower body weight if they tell you that they have

family members that have had Statin intolerance that's one that I hear quite frequently um it's very rare that

someone has their genetic data uh about you know stat metabolism but if they have a n variant that could play into it

other comorbid conditions so hypothyroidism uh which can cause kind of muscle aches and weakness vitamin D

deficiency uh and then a host of other you know comorbid conditions that cause muscle symptoms you know independent of

Statin use um and then socially so new exercise routine so right someone has that first uh you know um bioc cardio

infarction uh they go out and they immediately want to change their lifestyle and then they come back and

they're you know uh they can barely walk because they haven't exercised in you know maybe 15 or 20 years or or maybe

not at all um and then medications so you know obviously with my Pharmacy background uh the drug drug interaction

aspect I I think is probably the most legitimate risk factor uh especially when we're thinking about combining the

use of fibrates gem fibers gem fibril in particular uh which is now contraindicated for use with statins uh

and so if we're using a fibrate at all we should really only be using pH fibrate and then there's a host of other

medications that can uh impair the metabolism of Statin therapy primarily affecting loast Statin and sast Statin

uh because they are two statins that heavily rely on the CP 3a4 enzyme atorvastatin is metabolized through CP

3a4 but it is to a lesser extent uh it doesn't mean that there's no drug drug interactions but it just means that the

significance of those might be a little bit less so Statin intolerance uh what is it

so Statin intolerance is generally defined as one or more adverse effects associated with Statin therapy that

resolves or improves with either reducing the dose or stopping the medic Al together one thing we did was sort of

divide out Statin in toolerance into these two categories so you can have complete intolerance where the patient

is unable to tolerate any Statin dose or regimen period or maybe they're you know they refuse uh to take a Statin and then

you can have partial intolerance where there's an ability to tolerate a lower dose of a Statin but it's less than what

is clinically indicated so you have someone postm who cannot tolerate that high-intensity Statin and so they're

taking a moderate intensity Statin that patient still has partial Statin intolerance so to qualify someone as

Statin intolerant uh a minimum of two statins uh should have been attempted including at least one at the lowest

approved daily dosage why does this matter uh it matters in part because there are payers that require clear

documentation that a patient has stattin intolerance before uh they will approve uh some of the newer non-statin

medications such as the PCS ke9 monoclonal antibodies or encin or bidic acid um so really important to document

this in the note uh it will you know improve your chances of a successful prior authorization review uh if you're

documenting this uh and so again we're looking at patients that have tried at least two statins one of which being at

the lowest approved dose so some strategies for addressing and managing SS uh if you've seen

Indiana Jones Raiders of the law Stark this will look familiar to you uh and it is really about making wise choices and

that's what we're going to talk about here so I want to back up to those patients that you're actually starting

on a Statin you know from the beginning this is the first time they've ever you know taken a Staten maybe they've had an

MI or maybe you've evaluated their cardiovascular risk and there's a strong indication for Statin therapy uh because

I think it's at that point uh that we can do a lot to uh you know help that patient persist with that therapy over

time uh communication and education right uh immensely important in helping patients understand why they're taking

the Statin educating them about the risk and benefit something else that I've been doing for a while now is I actually

take a baseline pain inventory why do I do that I have had some success by documenting upfront a

patient Baseline pain issues whether it's arthritis in the left knee or or whatever they have going on when they

come back in a few months uh and they you know talk to their neighbor or a family member and they say well you know

that that elbow or that knee that's hurting that might be your Statin then they come back in the office and then

they're you know again trying to blame it on the Statin we can go back to the note uh and we can kind of talk about

you know this was something that you were experiencing before now not always but often patients just kind of forget

uh or they don't they there's this like disconnect or this desire to find a reason why they're having pain um and so

it can be very helpful at least to kind of take that Baseline pain inventory to determine you know what's a new symptom

versus something that was pre-existing um Statin selection and dosing so I mentioned Lovastatin and

sast Statin having the highest risk of drug drug interactions I don't really use either of them anymore um a torvis

satin rast Statin uh particularly rast Statin uh fewer drug drug interaction risk um there's a general perception at

least as being you know better tolerated they're all generic now uh so kind of from the get-go being smart uh with

Staten selection if there are modifiable risk factors for Sams uh it's important to address those up front uh

particularly related to drug drug interactions and another option here that I think there is a increasing

interest in is is similar to how we treat patients with Stage 2 hypertension going ahead and starting with

combination lipid lowering therapy and so maybe we can achieve high-intensity Statin potency with using maybe a zmod

plus maybe a moderate intensity Statin or even a low intensity Statin and I'll show you that data in a little bit um

and just starting at kind of that combination therapy from the beginning especially for the very high-risk

patient and that patient that has a severely elevated LDL you know why not why why keep waiting uh you know to

check a a lipid panel before we do that why don't we go ahead and consider combination therapy

earlier so communication education uh just to come back to that for a moment um you know providing that rationale for

satin therapy upfront is important but it's really important to make that individualized you know get granular um

if they've just had the Mi it's a great time to provide that education but to also individualize

their potential benefit from Statin therapy if it's a high-risk primary prevention patient with a strong family

history of heart disease individualize the education of the risk and the benefit we tend to stay very macro but

the more we can personalize the information we're giving to the patient the more meaningful it's going to be to

them and the more likely they might actually adhere to therapy does that patient want the big picture I see some

patients who don't really want to know the details they just want to know big picture am I you know what's the size

effects how am I going to benefit you w run into some that really want detailed information I have some patients that

actually want to want me to forward them the clinical trials for them to read um so figuring that out and tailoring that

education to the level that the patient wants include family members include caregivers um being respectful in your

inquiry especially if the patient reports side effects um using non-judgmental questioning uh again that

goes back to that question of are stattin associated muscle symptoms real or not

you got to throw that out the window like whether you think it's real or not um because you're going to lose that

trust with that patient if you come in in a judgmental way or you try really really hard to convince them that it's

not this impossible um using positive verbal reinforcement and then of course shared

decision making now there's a picture of a a watch here on the right because this

takes a lot of time uh and we're all busy clinicians and I I know particularly uh from a physician

perspective uh you know there there are many demands uh we have an emerging and growing shortage of Physicians and I

think this is where the healthcare team becomes really critical um and it's a big function you know uh in the clinic

for me to to take this extra time with patients um to help them navigate some of these challenges get them on

appropriate therapy monitoring them uh and making sure that they're achieving treatment goals for chronic disease so

just a little plug here for the team uh the healthcare team so Statin dosing uh high intensity

moderate intensity statins are are primarily uh the statins that we kind of start based on risk uh the

high-intensity stattin therapy uh options of course at torvet and Rua uh one thing that I think I've seen at

least anecdotally is more and more initiation of of that 40 of atorva or 20 of Rua uh in hopes of maybe you know

reducing even a perception of um risk of satin Associated side effects uh and I think the other aspect is it's very

reasonable uh to to think about using lower intensities of statins in combination with non-statin such as a

Zeta uh going back to that idea of combination therapy so uh it'll be interesting to see how this kind of

unfolds and obviously we need more data you know with that kind of an approach uh could we get by with a lower

intensity Statin plus a ZM is that going to be as effective as say starting that postm patient on a torva 80 because we

don't have that data yet um but I think that these are certainly good clinical questions to to

explore so what about achieving uh high intensity satin potency so a torbist Statin 80 milligrams per day can give us

about a 55 60% reduction in LDL cholesterol but if you actually um look at the LDL reduction with Statin therapy

the bulk of that reduction of that 55 or 60% actually comes at the lowest dose so a torbit 10 gives you about a 40%

reduction in LDL as you double the dose of the Statin you only get about an additional six to maybe 8% depending on

the reference you look at additional reduction in LDL cholesterol and the reason for that is because statins

upregulate the expression of pcsk9 because we get this that's why we get this flattening of the dose response

curve and it's also why when we combine a Statin with um a pcsk9 therapy anti- pcsk9 therapy we get such a profound

additional reduction in LDL so if you take a torvis satin 10

milligrams per day and you also give that patient a zetto 10 milligrams per day you're going to achieve about a 58%

reduction which looks very much similar to what you would get with a torist Statin 80 milligrams per day uh and so

this is kind of the basis for the rationale of you know do we need to kind of rethink this you know is it really

just about achieving similar ldr L effcacy that a high-intensity Statin would achieve um do we have to use that

high-intensity Statin because it is true uh and if you look at the literature that it's very consistent uh that the

adverse effects associated with statins uh we see more of them at the highest doses um so some food for thought here

um you know there there was a combination products uh and I think that that would really be great to see the

combination um high intensity stattin a zamite products uh come back uh because I think that that would be a great

option to have in practice um I've touched on the Staten pharmokinetics a little bit um I

mentioned kind of the major sip uh enzymes for atorva Loa and semi Statin uh renal excretion you know for statins

it's not a huge deal you know you can see that most statins uh really don't rely that much on renal excretion

atorvastatin you know is is probably the most favorable and so in those patients have more moderate to severe kidney

disease uh you know torbist stattin especially our nefrology colleagues tend to to lean toward that one um the

elimination halflife comes into play as well so a tvist stattin and ruist Statin have very long half- lives and uh you

can achieve about a 30% reduction in LDL with every other day dosing uh with the torva and Rua uh because of that long

halflife there are also two statins that can be taken at any time of day uh I still run into patients who uh have

trouble adhering to their atorvastatin because they were told uh by someone that they must take it at bedtime and

they don't take anything else at bedtime and so they forget to take it uh so this is a plug to say that no it it doesn't

really matter now if we're talking about Lovastatin seatin pravastatin there is some logic

to taking it uh at nighttime because of that overlap uh with uh kind of lipid synthesis that occurs during those

evening hours pitavastatin has a half life of 12 hours and so it's another kind of emerging option for that

alternative daily dosing we just don't have as many uh trials looking at that um but I think that that's another one

and then last Point here is that all statins use various drug Transporters uh to get around in the

body and um it's another reason that you also see variability in the response to a given dose of a stat because there are

uh genetic variants in these different um drug Transporters uh and another plug here to say that we do need to monitor

the lipid profile we do need to monitor for the LDL cholesterol uh because uh just because the Statin dosing chart

says you should get a 40% reduction doesn't mean you actually will the role of genetic testing um you

know I there's a lot of optimism that this was really going to be helpful um it's just

not uh usually it's just not indicated because there's a lack of clinical utility and the reason for that is some

patients with Sams may have no identifiable causitive variance other patients that have known

causitive variants will never have Sams and again this goes back to our conversation of um is this real or not

you know scientifically there's data suggesting that for most patients maybe it's not real and that's where this gets

complicated to then tie the genetic variant to the outcome with that said documenting a family history of

intolerance I have found to be helpful uh anecdotally uh there sometimes there are common statins that within a a

family you know there's this consistency of not tolerating them well and so I will still steer clear of those Statin

uh but again by and large uh the the the the hope that this was going to be really helpful it just hasn't panned out

what about other Laboratory Testing so creatine kinase or ck comes up quite frequently uh the issue with that is

it's a non-specific marker of muscle injury inflammation damage Etc and so um most patients with Sams however they

don't have an elevated CK uh I have you know we've periodically checked cks or if we suspect maybe their symptoms are

more severe and we're thinking maybe myopathy you know could be going on uh quite often the CK is completely normal

you can also have an elevated CK and be completely asymptomatic uh there are individuals that have elevated CK for

other reasons you can have idiopathic hyperemia uh that's really just you know unexplainable and so the basic

recommendation is that if you suspect that and the symptoms are severe enough that there's a possibility of myopathy

or rabdomiolisis uh then obtaining a CK might be clinically indicated not so

much uh outside of that uh dsh just a screen for hypothyroidism it is an important secondary cause of not just

myalgia but also hyper lipidemia vitamin D uh the insufficiency of vitamin D stores is associated with muscle

symptoms uh the problem with that is that the trials that have been done looking at Vitamin D supplementation

have not been shown to actually help prevent Sams or reduce Statin continu discontinuation so um you know this is

yet another um uh area with vitamin D that that you know just hasn't panned out uh and then lastly uh you know

anti-hmgcr antibodies incredibly rare um it can come up uh electrography muscle strength testing

biopsy not routinely recommended if you have a patient that continues to have issues certainly if they're referred to

neurology you know they might consider then doing this additional workup uh but it's not something that we're going to

routinely do so in terms of kind of an algorithm for managing uh Sam's uh you know I'm

not going to repeat a lot of this because I think we've discussed it uh in the talk I do want to have a plug here

for the ACC Statin intolerance Tool uh which is an app and there's a website you can kind of go through plug in a

patient's information and it kind of gives you an estimate of the likelihood of Sams uh but again at the end of the

day if the patient thinks they have Sams that's probably all that matters uh but it can be a useful

tool so the question I ask is uh you know do they have impaired quality of life or functional status and if the

answer to that is no uh then we will have a conversation about their interest in continuing therapy um maybe kind of

reemphasizing the benefits are there any education gaps that can be addressed uh to kind of get that patient to maybe

continue with therapy obviously we're going to explore other potential causes uh if the quality of life or

functional status is impaired uh then I think yeah you have some options so de-escalating Statin therapy even

stopping the Statin for two to four weeks and seeing if the symptoms improve uh would be

recommended if the symptoms do not improve uh then we're going to probably select a different STA and dosing

strategy and we're going to use nonstatin as appropriate uh to achieve the LDL

goal if the symptoms improve again going back to kind of this idea of encouraging the continuation of treatment

reemphasizing benefits maybe they're on a lower dose of EST Statin but they're tolerating that well

and their LDL is not where we want it to be and then that's again another opportunity to use uh select non-statin

to achieve treatment goals now if someone has severe impairment uh they can't get out of the

bed uh I had one patient that came into one of the few rabdo cases i' I've seen this was during my training um had a

neighbor um that had to physically pick him up and get him out of the bed and carry him and get him in the car to come

into the clinic we immediately send him to the emergency room um so in those patients with severe

impairment definitely get a CK um and really in all these situations really great opportunity to continue to

optimize lifestyle and supportive care uh therapies as well so stattin dosing strategies to

address Sams uh a really key Point here and I have it highlighted 60 to 80 % of patients are eventually able to tolerate

a Statin regimen it might not be the one that's clinically indicated but they can tolerate some type of a stattin regimen

uh which still is providing us a foundation at which to uh achieve some LDL reduction and then of course we can

kind of use non-statin to get where we want to go um these are all options uh I don't think we've got clear data to show

that one is better than the other uh these really are uh kind of tools in the toolbox I will say that the the um using

the naturally derived uh Statin which is lo Statin which is uh formed directly from yeast whereas the other ones are uh

you know uh synthesized uh I don't use that option a lot but occasionally I have someone that

wants a natural option and if they don't have any other drugs that would interact with their list Statin you know we might

go that route if it gets them mon a Statin the other thing I've done is having periodic uh wash out periods or

drug Hol day uh I definitely see some younger um you know high-risk preventive patients uh that you know they run

marathons they do other activities uh so we may actually have some drug holidays around the time of those strenuous

physical events so a lot of different strategies to use here that I think um can at least get a patient on some kind

of a regimen so non-stat and therapies um just want to highlight a few notes um on

a positive note uh we have options um when I first started practice uh we had a lot fewer options so that's the good

news um basses sequestrant you know Fallen largely out of favor U modest reduction on LDL high risk for GI

intolerability uh risk for drug interactions we do have very excellent long-term safety data they've been

around a long time uh they're not incredibly expensive but we do have other options

uh aetam of course uh you know modest reduction in LDL cholesterol but we do know that there is some modest

Improvement in cardiovascular event rates when we combine it with a Statin from the improve it trial very well

tolerated you know occasionally someone might report GI side effects or muscle issues a zmi b large really is it does

not cause muscle symptoms um but some patients will report that excellent long-term safety data some of the newer

options so bidic acid uh which is an ACL inhibitor we'll talk about that one in just a moment uh as an oral tablet once

a day uh again modest reduction in LDL cholesterol hyperemia was one of the big concerns uh there's actually a few more

and we'll we'll touch on that in a moment um long-term safety is questionable just because it's a newer

option and so we have limited data there um it is branded and so from a a cost perspective it can be prohibitive uh and

we do have positive cardiovascular outcomes trial data the pcsk9 maab so alarab and

evolocumab are of course subq injections self- injected by the patient uh we get quite a significant reduction in LDL

cholesterol uh I'd say very good long-term safety data I mean these drugs have been on the market almost a decade

which you can easily think that they came out two or three years ago but it's been a decade and we do have uh some

long-term uh followup with some of the clinical trials you know over well over five years uh showing good uh safety

outcomes uh and of course both from forier and the Odyssey trial uh combining these with with Staten therapy

improv improves event rates I put two dollar signs there for costs because by and large um the the the monocon

antibodies have become more cost favorable um I run into a lot fewer prior authorization rejects than I did

certainly when they first came out and so I think the affordability there is at least is is improving um and then in

close which is a newer anti- pcsk9 agent uh that's an sna therapy that uh prevents

the synthesis of pcsk9 it is also a subq injection but must be given by a healthc care professional in the clinic about a

50% reduction in LDL cholesterol don't have a lot of long-term safety data and of course the clinical outcomes trial is

still pending um and of course there may be some questions about that that maybe we'll address in the

Q&A um bidic acid uh does inhibit hepatic ATP citrate lias and basically Works Upstream from

HMG COA reductase the key thing about bidic acid and why it is not associated with muscle

complaints is that BPA cannot be activated to its active form which is Bido COA in the skeletal muscle because

the activator acsd1 is absent in that tissue it's only found in the

hepatite bidic acid also Upp regulates uh amp activated protein kinas uh which results in a reduction kind of in

inflammation which we also see with statins and that's why bidic acid also provides us that modest reduction in

height sensitivity CRP we have favorable outcomes data here from the clear outcomes trial showing

that bidic acid in patients that um they actually had to sign a form uh kind of confirming uh that they were indeed

Statin intolerant uh we did see a significant reduction in mace uh 133% relative risk reduction um one thing

that is is honestly it's still bugging me uh if you look at the pre-specified subgroup analysis you can see so this

trial uh enrolled primarily secondary prevention patients but also enrolled high-risk primary prevention patients

and if you look at the force plots here you can see that um the primary prevention group you know benefited you

know significantly there's a separate um I think jamama Cardiology paper if I remembering correctly

um of just the primary prevention cohort the secondary prevention cohort however you can see the uh the force plot the

the whiskers here kind of cross one um and the interaction P value is .003 not sure why that is it could be a play

statistical chance um there's a lot that could be a whole talk by itself um but it is something that's a little bit

bothersome the other aspect is from Adverse Events um overall bidic acid Placebo the

adverse event rate overall was was similar uh there were some newer things that were that kind of popped up in

clear outcomes that weren't quite so obvious in earlier trials so elevated hepatic enzymes were more common which

you know that doesn't mean that there's hepatic injury but um uh renal impairment uh and also um chasis or

gallblader issues the hyperemia and gout we kind of expected to see that uh so I think this again just reinforces the

need for more long-term safety data what about dietary supplements I know patients come in you know wanting to

take these kinds of things um this is the sport trial published in Jack um last year I love this study U maybe it's

just the pharmacist in me but it's really great to see uh you know kind of a very practical study that is really

helpful and I've actually shown this illustration to patients uh Crestor 5 milligram or rubat in 5 milligrams per

day uh produced on average a 35% decrease in LDL which is exactly what we would expect to see

um if you look at the the wave plot here on the right the different colors representing Placebo fish oil everyone's

favorite cinnamon garlic turmeric plant sterols and red yeast rice you can see that there's large variability um

overall none of the dietary supplements showed a significant decrease in LDL cholesterol generally the dietary

supplements were well tolerated although Adverse Events were higher with plant sterols and red yeast rice but there

there's no statistically significant difference so maybe you could say that there's no risk of harm they certainly

don't offer any benefit um touch briefly on other Statin Associated side effects so liver and

hepatic injury incredibly rare um it's also unpredictable uh routine liver function monit liver function test

monitoring has not been shown to really help us uh prevent or circumvent um liver injury from Statin therapy uh that

might OCC it's very reasonable to check the liver function test at Baseline just to make

sure that there's no underlying um liver disease in someone with chronic stable liver disease Statin are absolutely safe

to use new on set type 2 diabetes uh we it's been pretty much confirmed you know higher intensity stattin have a higher

risk of uh you know leading to an increased risk of type 2 diabetes uh the consensus is that the benefit of Statin

therapy far out the risk of developing diabetes cognitive impairment and memory loss um unfortunately this is still in

the Staten uh prescribing information uh and I really think it's something that needs to be Revisited by the FDA there

are post marketing reports but there's no consistency to these uh if we look at a lot of the trials even the pcs9 trials

that drove LDL you know to below 25 and follow these patients perspectively I did not identify any

relationship between very low LDL and cognitive impairment this is extremely uncommon staten's not shown in rcts to

contribute to cognitive decline and if you haven't read this I would highly highly recommend you read

it I I really think this is a really important scientific statement from aha uh looking at aggressive LDL lowering in

the brain and really the consensus is that the data do not support that satins and LDL lowering are associated with

cognitive impairment or dementia might actually be beneficial U so stay tuned on that uh but again certainly encourage

you to check this L all right so let's wrap up here and come back to our patient case so does

this patient have Statin intolerance yes so this patient has tried two statins uh the symptoms

improved after discontinuation we have tried to Statin at the lowest dose and so we can say

this patient has Statin intolerance so what are our options and these have to be individualized and this is where you

want to go through the options with the patient um just because they're Statin intolerant doesn't mean you can't try

another Statin right there's seven of them on the market I have some patients that will tell me I've tried to I'm not

trying anymore let's move on okay uh or you'll have patients that say yeah I don't know

what's going on maybe it's the drug I don't know like I'll try another one okay you know if that door's open and

maybe that's where we reach for in this case maybe something like a ruist Statin maybe we try a low do maybe we try every

other day or on Monday Wednesdays and Fridays and we kind of up TCH rate from there but what I would say is we don't

want to wait forever uh to get this patient's LDL to goal this is a very high-risk patient so what can happen in

practice is that we keep kind of playing along here maybe we get a little reduction in LDL we see them in six

months we see them in another few months and next thing we know it's been two or three years and the LDL has been you

know well above 100 this entire time so go ahead and you know while you're experimenting with getting a Statin of

some type on board go ahead and utilize non-statin therapy don't DeLay So some combination of the above would probably

be the approach that I would use here take home points statins are well tolerated by most patients um if you

when I have Learners in my clinic I tell them look you're going to see a lot of satin intolerance but just know that

there are a whole lot more folks out there that are taking their Statin and doing just fine you're just getting you

know the small group that really has issues complete Statin intolerance is rare um the estimates are less than 5%

choose the best Statin for your patient to increase the likelihood of success don't hesitate to use non-statin therapy

and be patient prevention is a marathon not a Sprint and with that I will happily take your

questions thank you very much amazing lecture I enjoyed a lot I'm a little bit biased because I'm very passionate about

this but I think it was amazing for every everyone so please put your questions in the in the Q&A and and

we'll go through them and we'll put now the the CME code for you H I think I want to start with a a question or a

couple of questions that I get a lot from other people so just to make sure that we cover on that uh one question we

get a lot is stating and and hormones bringing the LDL very low if we aim for that what are your thoughts on on

hormones okay so the stat the effect of statins uh and low LDL on

hormones um yeah I you know I have not seen any concrete data from a a clinical perspective to really show that there's

some any significant harm there I mean I think if you look at both um those that have genetic variants so you know hypo

APO lipoproteinemia where you I've seen a couple of these patients that have ldls in their in the single digits their

entire life um and those patients that have been enrolled in the pcsk9 mab trials that

have been maintained on LDL levels below 15 um I haven't seen anything really you know suggesting that there's just

adverse effects on on hormones and uh you know we have to remember that we're not depleting all the cholesterol stores

in the body right um cholesterol is in every cell uh the brain kind of has its its

own pool of cholesterol these drugs are not getting into the brain um so you know by and large uh the concern there

is is quite low yeah I agree and we also have HDL to carry cholesterol as well right so yeah

that shouldn't be a reason and and the other one I want to cover before we move to the questions are with the lfts you

know we get a lot people that stop statins because increases in alt a we see sometimes increases in Billy Rubin

so when should we and if you said we shouldn't check routinely but sometimes people check and so when should we stop

the stating what are they concerning numbers yeah great question so uh statins and lfts so you know three times

the uper limit of normal is is absolutely kind of the hard hard stop um you know you've got to figure out what's

going on and and if I have a patient at Baseline and and you know I see that they've got uh a baseline elevation that

you know two times up limit of normal you know they're slightly elevated uh you know quite often often we will make

sure that that gets worked up um when possible before starting a Statin because um more often than not right

you're probably dealing with um naff Nash right um mled uh you know whatever the updating our yeah keep updating our

acronyms but non-alcoholic fatty liver disease uh especially in patients that have risk factors for that uh making

sure that that gets identified uh so that that can get treated but that shouldn't delay Statin initiation and

that's what I see a lot is you know this this fear for for starting the Statin because of that mild elty elevation and

satins are you know you could argue were somewhat helpful in patients with non-alcoholic fatty liver disease and

that's a risk factor for cardiovascular disease um but three times the upper limit of normal that's that's like the

hard stop there that's that's where you kind of have to you know bail on the Staten and and and certainly figure out

what's going on at that point yeah for sure and even you mentioned in curosis right as long as is compensated you can

also use them great so we have a question from Rob ELD he has he says that's an outstanding talk thank you for

it ER he says I frequently get asked regarding Statin induced diabetes and I even saw a few questions here coming on

that yeah and he's mentioning that there has been the lar study stating a difference between Crestor and and

Lipitor so what are your thoughts uh do you take into account diabetes new diabetes and do you prefer one stating

versus the other in these cases yeah so great question so in terms of the mechanism um there was a a a really well

done uh trial with it was TV a Statin uh and essentially it appears that statins May interfere with insulin cell

signaling and and there is some contribution there to the development uh of insulin resistance you know the way I

like to think about it um is is that these patients are sitting on the edge of a cliff that Cliff being new onset

type 2 diabetes they're already at the edge of the cliff Statin maybe give them that slight nudge maybe this is a bad

analogy um but it it kind of pushes them over the cliff into that you know development of then getting type two

diabetes and the other reason for that thought is from the Jupiter trial with rubat in 20 milligrams per day when they

looked at the patient population uh those that had risk factors for developing diabetes got diabetes if you

looked at the patients that did not get diabetes they didn't have risk factors and so when I talk to patience about

this I kind of talk about you're you're on a train that has a destination statins may just speed up the train a

little bit um that means that we need to work on these other things like lifestyle change or maybe going ahead

and starting met Foreman or you know glp1 receptor Agonist to kind of curvet tail that uh and and provide that

support to the patient so they understand that the Statin is going to still help reduce their risk of

cardiovascular disease and that we can address this potential risk of diabetes now when it comes to the load star trial

our study um that was really intriguing and thought-provoking uh I think there are some limitations of that trial that

would you know make me pause a little bit to to jump to any firm conclusions uh I will say that I I think that I see

a lot more ruist stattin in practice uh is it uh you know the penultimate stat and is it is it truly Superior I think

that's I don't know that I would buy into that uh but I do think that now it is you know generically available such

as a torvest Statin a lot of patients get put on a torvis Statin and have tolerability issues so then they end up

going to ruist stattin and so we have this perception that it's more or better tolerated so I would say ruist Statin is

probably you know used more frequently for for a good reason yeah and you also don't have a risk that is at dichos

right that you have zero risk when your A1C is below 6.5 and it jumps to a high risk so like you mentioned

cardiometabolic risk is already increased so correct great thank you very much so we

have a question here about vering so about natural you know things that we can use to lower the the cholesterol you

mentioned some you mentioned that there was no real effect have you used or have you encountered this from

bin uh I have not used it uh I will say I've encountered a couple of patients that have been taking it kind of on

their own uh you know I think that the challenge there again is is the the quality of the product that you're

getting I remind patients all the time and fellow clinicians that dietary supplements are not regulated by the FDA

uh what is in that bottle and what is on the label it might be accurate but if you

look at a lot lot of the studies that have been done where they take a product they independently evaluate it more

often than not right they find huge variations and that's really the big issue with red yeast rice as well and

there are reports of toxicities in patients having rabdomiolisis because they're getting either um you know the

product says the dose is this much but if you take an independent uh evaluation of that dose it's actually you know

tenfold higher so they're taking in this massive amount of what is it essentially low aat

um so that's really my biggest concern is just the quality and the ability to say that what's in the bottle is really

what's in the bottle that's where I have hesitancy about using dietary supplements for for lipid lowering

especially yeah 100% so I mean instead of showing that it's safe to get it out there you you need to show that it's

unsafe so you take it out of the market right so I agree I tell my patients the same you think it's because it's natural

call Natural it's better but but who knows so the next question about CoQ10 so supplements I'll just weep that in

here and I could have sworn I had a slide on CoQ10 but apparently I did not so um the the lowdown on CoQ10 is that

uh you know it is true that stattin you know depletes the available coenzyme Q10 which does play a role in mitochondrial

function and is at least theorized to be a contributing factor in in the development of Sams um the data if you

look at the randomized trials and we did assist a atic review on this a few years back it's just incredibly mixed and I

think part of the reason for that is the no sibo effect uh because again the outcome that you're looking at

Sam's um a small percentage of that is is going to be true Sams and so it's difficult in a study with coenzyme Q10

to draw firm conclusions and I think that's why you see the variability there's some smaller rcts that show that

co-enzyme Q10 you know works and then there are other studies that show the opposite um the bottom line is that it's

not routinely recommended uh the potential efficacy I think it's very modest uh if anything with that said it

has not been shown to be harmful uh and so if someone comes in already on it or they ask me about taking it I explained

to them what I just told you all and if they want to take it go for it if it helps you you know if there's a placebo

effect there and it gets you to take your Statin I don't have to be concerned about harm now again it is a dietary

supplement so I still have that disclaimer there um but by and large there do not seem to be any major uh

safety or major tolerability issues it is an additional cost it's another pill to take so I kind of have that

conversation but do I proactively use it no some potential effects on on blood pressure right from

CoQ10 yeah yeah again small small small sample size of studies there so I I you know yeah so you have so many tools to

use so you can change to different medications I think that's the big home point from what you said there's a very

good question here in Karen Gand she says they have a question about single dose high do stating versus combination

therapy um how do you decide how do you take into account the multiple medications you know use and what are

your thoughts on that yeah great question so it goes back to where it would be great to have those combination

uh you know formulations available um I'm I'm hopeful that maybe a generic manufacturer will kind of revisit that

because if we had an atorva or Rua combination pill with a ZM uh I mean that would just be you know terrific

right and we used you know sast Statin and aetam in the combination that was branded by Torin uh we used extensively

uh years ago um and so I think that the the adherence piece is important um it all goes back to uh the education

helping them understand uh you know their medication regimen looking for indications do they

need all the medications they're prescribed um helping them develop a schedule and making it habitual that is

to me kind of the biggest thing that you can do to help uh improve adherence is to just make it habitual and I always

have this conversation with patients you know do you brush your teeth twice a day and they'll say of course okay um I need

you to take this medication twice a day or take this one pill in the morning and this other pill at night just like you

brush your teeth and make it just as habitual um but I completely agree with you that that that is a a limitation of

that approach um if we had combination options you know that were R rarily available that would be one way to

minimize that uh the injectable therapies you know that's where they come into play as well I have found

adherence to those to be quite good uh and so maybe it's it's Statin plus an anti- pcsk9 therapy instead of a zmi the

every twoe injection for example uh seems to you know the adherence rates that I've seen uh inexperienced

anecdotally have been been quite good uh but no you bring up a great point it is a limitation of that approach and

there's even some clinical trials going on right now on on initiation of PCS from the GetGo right after an ACF so

we'll have more data on these combinations I think as a last question as we're running out of time from more

fellows they asked do you have a prefer stating in patients with concomitant elevation in triglycerides so do you

look into triglycerides to the side and and and pick the stating so higher dose statins uh higher

intensity statins actually have a pretty significant effect on reducing triglycerides it's it's about up to 30%

and so if I have someone that has elevated triglycerides and obviously we we've rolled out secondary causes you

know we've gone through all of that uh I'm certainly going to think about probably a higher intensity Statin to

try to help address that but at the end of the day we're not treating triglycerides uh we are treating an

abundance of apop B containing Viper proteins LDL is kind of the primary surrogate we use for that you could also

use non-hdl cholesterol uh you could also be in the camp of where you know we should be measuring the apob

lipoproteins and just measuring that and following that um so you know I I don't the triglycerides are are just not um a

target of therapy if they're over 500 they're over a thousand then we need to address that to reduce the risk of

pancreatitis um but you know we're not trying to micromanage the triglycerides if they're just mildly elevated we're

just taking that into account of that patient's overall cardiometabolic risk and then we need to use the right tools

to address that risk not just lower the triglycerides thank you very much well this was a wonderful lecture I enjoyed

it a lot and thank you thank you for for spending our lunch and probably your lunch too lunch time us