Scott Webb (Host): Welcome to Addressing Treatment Disparities to Reduce Risk and Improve Cardiovascular Outcomes Among Women and People from Various Racial and Ethnic Groups, a Spotlight on LDL-C Lowering. I'm Scott Webb and I'm joined today by two esteemed faculty members, Dr. Keith C. Ferdinand, Gerald S. Berenson Endowed Chair in Preventative Cardiology, and Professor of Medicine in the Department of Medicine at Tulane University School of Medicine in New Orleans, Louisiana. And Dr. Erin Michos, Director of Women's Cardiovascular Health Research, Associate Director of Preventative Cardiology at Johns Hopkins University School of Medicine, Co-Director of the IMPACT Center at Johns Hopkins University, and Co-Editor in Chief for the American Journal of Preventative Cardiology.

For full relevant financial disclosure information, please see iridiumce.com/lipidsinwomen. This educational activity is supported by an independent educational grant from Aspirian. We'd like to thank them for their support for this initiative. The learning objective for this program is applying the clinical trial data, guidelines, and new indications for the use of non-statin treatments in appropriate patients.

 Dr. Michos, I'm going to start with you, have you start our conversation today by summarizing what clinicians need to know about the medications that are available to help patients achieve their therapeutic objectives for LDL-C.

Erin D. Michos, MD, MHS, FAHA, FACC, FASE, FASPC: Thank you. Well, there's overwhelming evidence from genetic studies, observational studies, and randomized clinical trials that LDL cholesterol is causally related to atherosclerotic cardiovascular disease pathogenesis. And as such, LDL-C is our primary lipid target for cardiovascular prevention across all major society guidelines.

With the adage that lower LDL is better and getting earlier is better. Now, apoB captures all the atherogenic particles, so not only LDL, but lipoprotein little A and the triglyceride rich lipoproteins, but apoB is not always clinically available. However, a non HDL cholesterol is a reasonably good surrogate for apoB, and this is available just with a standard lipid panel.

It's a simple subtraction of total cholesterol minus HDL cholesterol because there can be discordance when an individual might be at their LDL cholesterol goal, but still have high ApoB or high non HDL cholesterol due to these triglyceride rich lipoproteins or remnant cholesterol. So the AHA ACC has also set non HDL cholesterol thresholds as a second objective after the LDL cholesterol being the primary target.

And the non HDL thresholds are typically 30 milligrams per deciliter higher than the LDL thresholds. So in a little bit, Dr. Ferdinand is going to review what these thresholds are. They're based on the risk of the patient. But first, I will mention that we are in an exciting era. We have more tools than ever before to get to these thresholds.

Of course, lifestyle is the foundation for all prevention. And then statins are the first line therapy for both primary and secondary prevention. But statins are not the only game in town anymore. We have ezetimibe, which has been available since 2002. And then there's a really old therapy, that's still around, bile acid sequestrons, but this isn't used that much because it's not really well tolerated due to GI side effects.

And then we're going to be discussing a really good option, a new oral therapy, bempedoic acid. This gives you about 22 percent LDL lowering when used alone, about 38 percent lowering when used in combination with ezetimide. It can come in a fixed dose combination pill with ezetimide, and bempedoic acid can also be used, with or without a statin.

And then we have the injectable medicines, non statins. So they're the PCSK9 monoclonal antibodies. These are typically dosed by subcutaneous injection twice a month. It can give you about a 60 percent LDL lowering. And then there's inclisiran. This is a small interfering RNA targeting PCSK9. After the loading doses, it's dosed just every six months. And this can lower LDL by about 50%.

So those are our tools. And to achieve these risk based thresholds, you need both adequate control of your LDL cholesterol and your non HDL cholesterol. Many patients will actually need combination therapy to get there. And we should be thinking about combination therapy earlier in our management, just like we commonly use combination therapy for the management of hypertension and diabetes.

So if you're not at goal, we really need to intensify more quickly. But I'm going to have my colleague, Dr. Ferdinand review for us what these risk-based thresholds are that we should be achieving for our patients.

Keith Ferdinand, MD, FACC, FAHA, FASPC, FNLA: Well, thank you, Dr. Michos. As you know, atherosclerotic cardiovascular disease is the number one killer in the United States and indeed most industrialized westernized societies. And if you look at it, LDL cholesterol, along with hypertension, sedentary lifestyle, obesity, diabetes; LDL is perhaps one of the more potent risk factors for ASCVD. Now, what's a normal LDL cholesterol? Well, the average LDL cholesterol in the United States is about 113 mg per deciliter. But that's not normal. Especially if a person has ASCVD. They now should have a target LDL cholesterol less than 70 milligrams per deciliter. Dr. Michos introduced the concept of non HDL cholesterol, where you take the total and subtract the HDL, add 30. That will give you a non HDL cholesterol of less than 100.

So called primary prevention, those persons who don't document as of yet, ASCVD; the LDL cholesterol should be less than 100, the non HDL cholesterol less than 130. However, there's a group of patients who have ASCVD, have had two major events, or they have had one major event and have multiple risk factors, and these risk factors are very common.

They include age, hypertension, diabetes, smoking, a positive family history of familial hypercholesterolemia. Those patients are considered very high risk. And in that particular situation, the LDL cholesterol should be less than 55,

and the non HDL cholesterol add another 30, less than 85.

You know, for a long time, we would look at the average LDL cholesterol and say that's good enough and perhaps drop it less than 100.

But what's average is not normal. And especially for those high risk patients, we need more intensive LDL-C reduction. And in my patients, I have a threshold if that LDL-C is greater than 55 and they're very high risk, two or more major atherosclerotic cardiovascular events or just one event and multiple risk factors, which are very common; I targeted LDL cholesterol less than 55 milligrams per deciliter. So we have to really move away from the concept that what is common is normal because it's not. And in fact, cardiovascular mortality in the United States is going the wrong way, and we need to intensify our efforts to control blood pressure, cholesterol, and diabetes.

Host: And Dr. Michos, we've summarized and simplified the therapeutic objectives and treatment strategies from the 2018 AHA ACC Multi Society Guideline for the Management of Blood Cholesterol and the 2022 Expert Consensus Decision Pathway on the role of non statin therapies for LDL cholesterol lowering in the management of ASCVD risk. Can you describe the evidence from key CV outcome trials for therapies that lower LDL-C?

Erin D. Michos, MD, MHS, FAHA, FACC, FASE, FASPC: Yeah. So, you know, the reason why we have these new thresholds is we really now have a lot of amounting evidence, both from genetic studies and these trials, that lower LDL is associated with reduced risk. In fact, both data from statin trials and nonstatin trials have really shown the reduction in major adverse cardiovascular events is proportional to the degree of LDL lowering. So we know that about one millimole per liter, which is 38 milligrams per deciliter lower of LDL cholesterol can confer a reduction in cardiovascular events by about 22 percent. And that's with trial data, but we know individuals who've had longer exposure to lower LDL, such as having low cholesterol, from birth, you know, may experience even a 50 percent reduction with one millimole per liter lower LDL. So we want to get lower, earlier.

So in terms of the cardiovascular outcome trials of nonstatins, so we have ezetimide, which was studied in the IMPROVE IT trial. That was a secondary prevention trial of patients with acute coronary syndrome where ezetimide was added to a moderate intensity statin, and shown a reduction in events.

And then, we have EUTOPIA, which was a randomized open label trial in Japan of primary prevention patients who were over the age of 75, but had elevated LDL. And again, these patients didn't have established coronary disease and also showed the benefit of LDL lowering with ezetimide. Now, the ODYSSEY outcomes and FOURIER trials were the trials evaluating the PCSK9 inhibitors, the monoclonal antibodies in secondary prevention patients.

FOURIER enrolled stable ASCVD patients and ODYSSEY outcomes enrolled patients who've had a prior acute coronary syndrome. And again, all these patients were treated with maximally intensive tolerated statins and showed that adding PCSK9 monoclonal antibodies on top of statins lowering LDL further, conferred further reduction in events.

And those trials were stopped early, there were relatively short term trials. But we saw that the curves were continuing to separate, and with extended follow up, we see that the benefit of more intensive LDL lowering continued to accrue benefit in terms of cardiovascular risk reduction.

Now, we have some really old data from even the pre statin era, with cholestyramine in the Lipid Research Clinic Coronary Primary Prevention Trial. It was published back in 1984, before the first statin became available on the market in 1987. But this showed that bile acid sequestrons, also reduced cardiovascular events by 19%, with LDL lowering.

Now, moving to more recent trials, last year in 2023, the CLEAR Outcomes trial was published. And this demonstrated that bempedoic acid which is a nonstatin inhibitor of cholesterol synthesis, reduced the risk of major adverse cardiovascular events by 13 percent in patients with or at high risk for cardiovascular disease who were unable or unwilling to take guideline recommended doses of statins.

And then shortly after the original publication, the Primary Prevention Analysis was also published. In the CLEAR Outcomes trial, there was 4,206 patients who did not have established cardiovascular disease, primary prevention, but they had risk factors, so high risk primary prevention. And it was shown that bempedoic acid conferred an even greater reduction in four point MACE compared to placebo, a 30 percent reduction.

This is a greater reduction than we saw in the main overall trial. Even in this primary prevention group, we saw a reduction in cardiovascular death and all cause mortality. And the Primary Prevention Analysis was a pre specified analysis. So I really think this speaks to treating patients earlier in the disease process when plaque might be more modifiable to regression with intensive LDL lowering.

I think often we wait too long to treat when there's disease. And if you go back to the JUPITER trial, which was a primary prevention trial of rosuvastatin, we also saw significant reductions in cardiovascular events, including reduction in all cause mortality. And so this really highlights the importance of treating earlier and not forgetting about your high risk primary prevention group.

And you know, I think CLEAR Outcomes was really pivotal because as Dr. Ferdinand likely will attest to, statin intolerance is a really vexing problem in clinical practice. And whether it's real or due to the nocebo effect, you know, it's been estimated up to 90 percent of statin intolerance is due to the nocebo effect, and it's always worth trying to do a statin re-challenge.

But we know that statin intolerance remains a barrier to effective lipid management in many patients for cardiovascular prevention, and medications don't work in patients who don't take them, and nonadherence is associated with greater risk. So, it's really good that we have more tools in our toolbox and that tools have actual hard cardiovascular outcome evidence.

But the big challenge now is implementation. We've got great tools and we've got great guidelines. We just need to do better at translating this evidence into clinical practice.

Keith Ferdinand, MD, FACC, FAHA, FASPC, FNLA: Well you know, I agree with you 100%. If you look at all the various pathways that you have discussed for lowering LDL cholesterol; they all seem to give a benefit. And starting earlier,

keeping the patients on their medications longer, and being more persistent in therapy, is what we really need to do. Starting the medicine is probably the easiest part if the person has access and affordability. But nonadherence, not just to LDL lowering medicines, but even antihypertensives, is a real problem.

Another concern is making sure that the medicines work across populations. And many of the studies have under powered with women. And I know that's been one of your charges, Dr. Michos, to have increased diversity based on sex and gender in these trials. CLEAR Outcomes was somewhat unique in that it was fairly robust in the number of women enrolled and did show a benefit in that population.

Here's the general take home, however, from what I've heard.

You have suggested to us that early lowering is better, longer is needed, and lower is essential. So start early, keep the patient on their medication, and achieve lower goals or get below thresholds, which is the language that the 2018 Cholesterol Guideline uses in terms of more intensive therapy.

Host: And Dr. Michos, ACC 24, which is the annual meeting for the American College of Cardiology, of course, was held April 6th through the 8th. Maybe you can share some of the news and updates and late breaking trial results that were presented at the meeting.

Erin D. Michos, MD, MHS, FAHA, FACC, FASE, FASPC: So it was an exciting meeting. At ACC 24 Scientific Sessions, there was actually three secondary analysis from the CLEAR Outcomes Trial that was presented, that evaluated diverse populations, including women, Hispanic and Latino individuals, and persons with obesity.

So first was a sex stratified analysis that was presented by Dr. Leslie Cho, and as you heard from Dr. Ferdinand, in the CLEAR Outcomes trial, there was nearly half, 48 percent of trial participants were women. So this is the largest proportion of female patients of any contemporary cardiovascular outcome trial. We saw that the LDL cholesterol with bempedoic acid was significantly reduced by 24% in women and 19% in men compared to placebo.

And notably, the reduction in cardiovascular events conferred with bempedoic acid was similar between women and men with no interaction by sex. The next analysis was presented by Dr. Fatima Rodriguez, who examined the Hispanic Latinos subgroup. Hispanic patients represented about 17 percent of those enrolled in CLEAR Outcomes.

And this ethnicity is one of the fastest growing populations in the U.S. but has been really historically underrepresented in prior trials. Previously, I published that about only 4 percent of trial participants were Hispanic ethnicity in other cardiovascular trials. But we saw in CLEAR Outcomes that this subgroup had similar reduction in major adverse cardiovascular events among the Hispanic versus the nonHispanic individuals with no interaction by ethnicity. In this population, bempedoic acid did not worsen glucose or weight. And I think this is really important because we know Hispanic and Latino individuals face a disproportionate burden of cardiometabolic risk factors.

And then the third CLEAR Outcomes analysis that was presented was the obesity analysis, presented by Dr. Harold Bays. And it should be noted that nearly 45 percent of patients in CLEAR Outcomes had obesity defined as a BMI greater than 30 at the start of the study. And in this analysis, patients with obesity treated with bempedoic acid were 23 percent less likely to experience a major adverse cardiovascular event compared to placebo.

And as I mentioned, the overall trial results showed a 13 percent reduction. So when you look at this subgroup with obesity, it seems like they even experienced even a greater benefit with bempedoic acid than the overall trial group. So I think these results in aggregate continue to reinforce the importance of early and aggressive LDL lowering to reduce cardiovascular events.

Again, underscoring what you heard from Dr. Ferdinand about even lower, even earlier is better and bempedoic acid is a good oral option for LDL lowering. I should mention that after CLEAR Outcomes, the FDA recently expanded the label indication for bempedoic acid. So in addition to its label indication for the management of hyperlipidemia, including primary hyperlipidemia, it's now also indicated to reduce the risk of myocardial infarction and coronary vascularization in adults who are unable to take recommended statin therapy, including even those not taking a statin, who either have established cardiovascular disease or is a high risk of a cardiovascular event.

Now also at ACC-24, one of the other trials I thought was really important was the Victorian Initiate randomized clinical trial that was presented by Professor Michael Koren. This was a pragmatic open label trial. You know, again, it was small, only 450 patients who had established cardiovascular disease, but remained with an LDL above 70 milligrams per deciliter on a maximally tolerated statin. In fact, the average LDL of these ASCVD patients was 97. So they're randomized to an inclisiran upfront approach on top of their statin as soon as their LDL was above 70.

Or, the usual care arm where their lipid lowering management was left up to the discretion of their treating clinician. So we saw at follow up that the LDL was 53 percent lower in the inclisiran upfront arm compared to usual care, and significantly more patients in the inclisiran arm reached their target LDL goals of less than 70 in more than 80 percent of patients and, even less than 55 milligrams per deciliter in greater than 70 percent of the population, where it was suboptimal in the usual care arm, really highlighting how poor we are in clinical practice at intensifying therapy.

So I thought this trial was important because it's just a reminder that clinicians, especially in these very high risk patients, should think about combination therapy upfront and earlier. Like, as I mentioned, we do for blood pressure. And then, you know, also at ACC 24, there was also some exciting phase one and phase two data from some investigational therapies in the pipeline.

We heard about a new potential novel PCSK9 inhibitor. There's also, you know, an oral CTEP inhibitor that can confer potent LDL lowering, and also had significant reduction on LDL particles. And we also saw phase one data for a small interfering RNA that would inhibit ANGPTL3. And this is an interesting pathway because ANGPTL3 inhibitors can confer reduction in LDL, triglycerides, independent of the LDL receptor.

These therapies are not available yet, but it just shows us that we even might have new tools for lipid lowering therapy coming down the pipeline, in the near future.

Keith Ferdinand, MD, FACC, FAHA, FASPC, FNLA: Boy, that was a lot. And I think when you look at the data that you described, it is somewhat heartening to hear that there was some diversity related to ethnicity, although the Black population in CLEAR Outcomes was clearly underrepresented. We would expect, however, that if you intensively lower LDL cholesterol in patients, you're going to get similar results.

Now, Jupiter which had an average LDL remember that's not normal. That's average, with the CRP greater than 2, did show a benefit across all of the various diverse populations. So hopefully as we get some of the new medicines and some of the new trials come to fruition, we apply these data equally across populations.

You also mentioned statin intolerance, and I listened very carefully. You said it may sometimes just be what they call a nocebal effect, where the patient feels that he or she can't take the medication. We know, however, that it may be as much as 10 or even 15 percent of practicing clinician patients will say they can't take a statin.

So I'm very heartened that we now have alternatives with shared decision making, where we, the clinician, whether we be a physician, nurse practitioner, advanced practice nurse, clinical pharmacist, sits down, eye level, culturally competent, clinically appropriate discussions on what we can do to lower their risk.

So, we have a wide range of options, and I'm very heartened to hear that we now have other options other than simply giving the patients high intensity statins to lower LDL, get it down quicker, longer, and persistently.

Host: Dr. Ferdinand, I'm going to stay with you, wondering if you could summarize the key points of the Clinician Patient Risk Discussion that should occur as outlined by the 2018 AHA ACC Multi Society Guideline on the Management of Blood Cholesterol.

Keith Ferdinand, MD, FACC, FAHA, FASPC, FNLA: Well, in general, there's a pneumonic called SHARE, where you talk to the patients about their preferences. You talk to them about the means by which they're going to lower their risk. And remember, non pharmacological lifestyle modifications remains the bedrock of care. So having that patient referred to a dietician or nutritionist, or giving helpful hints on how better to embrace therapeutic lifestyle, has to be part of that discussion.

And then in that SHARE model, you want to reach for a medication that's available and affordable. You know, there are barriers to access in the United States based on not having insurance or having a form of insurance which you cannot get prior authorization in order to use some of the newer medicines. And we need to overcome that. The other part of the SHARE, S-H-A-R-E, is to educate the patients. Here's my idea. If the patient is educated, if he or she understands the risk of having elevated LDL cholesterol, and specifically in those patients who already have ASCVD or are very high risk, have two types of ASCVD or have had one ASCVD event and other major risk factors; you need to educate that patient that there is a reason why we're adding combination therapy.

You know, I spent a lot of time in the blood pressure world, and we know that for most patients, middle aged and older, one antihypertensive agent just won't get it. It's two or more, it's a cocktail, what we call in New Orleans a gumbo, a mixture of medicines that may be needed to lower blood pressure. Well, hearing the data that Dr. Michos has described, it appears now it will be a mixture of medications that will be needed, especially in these patients with very high risk, to get the threshold less than 55 or the non HDL threshold less than 85.

SHARE. Educate. Empower the patients so that they can push us, the clinicians, to do the right thing.

Host: Dr. Michos, in a previous episode of the program, we discussed the factors that may contribute to the risk of ASCVD in women and people from various racial and ethnic groups, including lower rates of treatment for hypercholesterolemia. Based on your previous discussions and the points Dr. Ferdinand just shared, what are some shared decision making strategies clinicians can utilize with their female patients when addressing their ASCVD risk and hypercholesterolemia management?

Erin D. Michos, MD, MHS, FAHA, FACC, FASE, FASPC: So just as a reminder, what we talked about in our prior program is that, you know, cardiovascular disease remains the leading cause of death in women. There's still this perception that women are lower risk, but that's not true, and actually, myocardial infarction rates are on the rise in women under the age of 50, so women are at risk.

And particularly, you know, there's this undertreatment of women of reproductive age. There's often this concern that they might possibly become pregnant, but we can manage around pregnancy. You know, women can be of reproductive potential for four decades, so not treating high risk patients, female patients, you know, we doom them to early onset morbidity and mortality.

So lipids matter just as much in women. If we look at Mendelian randomization studies, we see that for every genetically determined 1 millimole per liter increase in LDL cholesterol, that their risk is the same or even greater in women as it is in men. So we do need to treat lipids in women, particularly when you think about something like familial hypocholesterolemia,

heterozygous FH, there is no female advantage of delayed onset of ASCVD. Women who have FH, they have the same early onset of an event, if untreated as their male counterparts. In fact, 30 percent of women with FH will have an MI before the age of 60 if they're not treated. So we need to know FH, look for FH, and treat for FH.

But beyond that, you know, when you're thinking about patients in primeary prevention who are not this severe primary hyperlipidemia group with LDLs above 190, people who don't have already have diabetes, and of course, people who have already have established cardiovascular disease, that's your secondary prevention group.

So when you look at this other bucket of primary prevention, you know, you apply those risk scores that Dr. Ferdinand outlined, and in fact, we have a new risk score that from the American Heart Association called PREVENT, which I like because, not only does it give you a 10 year risk, but it gives you a 30 year risk of cardiovascular disease, both ASCVD and heart failure.

And so particularly, I think for women, you know, when you think about younger individuals, longer risks. So, this 30 year risk is really important, and this new PREVENT score also includes some social determinants and factors about kidney function, so I really think it was an advantage over prior risk estimators.

But one thing our guidelines previously had said is that after you calculate this 10 year risk, that you need to be thinking about risk enhancers. And I was really pleased that the guidelines included some female specific risk enhancers, including adverse pregnancy outcomes such as preeclampsia, which is they specified in the guidelines, but we also know that other adverse pregnancy outcomes include gestatial diabetes and preterm delivery, pregnancy losses.

They also highlighted in the guidelines early menopause as a risk enhancing factor. So this just really emphasizes that as part of cardiovascular risk assessment, we need to take a comprehensive, reproductive history of our female patients to identify these red flags of risk. Other risk enhancers include these autoimmune diseases like lupus and rheumatoid arthritis that are more prevalent in women.

And, of course, there's a number of other risk enhancers, including kidney disease, metabolic syndrome, and race ethnicities, like South Asian ancestry, and also certain biomarkers if measured, such as having an elevated C reactive protein, an elevated, apoB level, and also an elevated lipoprotein little a above 125 nanomoles per liter.

And I'll just mention, I was part of a recent National Lipid Association scientific statement that just came out where we do endorse universal screening of lipoprotein little a in all adults, at least once in their lifetime. Going back to what you started with, with risk assessment. So we need to factor all these things into the counseling for our primary prevention patients to estimate their 10 year risk, their 30 year risk, consider some of these risk enhancing factors, including these female specific ones that may not be captured in the calculator. And then, have a shared decision making conversation with the patient, just as Dr. Ferdinand outlined.

Keith Ferdinand, MD, FACC, FAHA, FASPC, FNLA: I know there's a case that we may want to discuss, but before we do that, can I make a few comments based on what you just said, Dr. Michos? One of the things that we should be aware of, although breast cancer is an important condition that needs a lot of attention and care, 10 times more women die from ASCVD than die from breast cancer.

The other thing that we should be aware of is that Type 2 diabetes, which is very common, found in as much as 29.2 percent of persons who are 65 years and older, and more common in patients who are self-identified as Black or Hispanic Latina; those patients have an increased risk. And in fact, having diabetes removes any protective effect of being female.

So, clinicians need to get away from the idea that this is a man's disease and recognize, especially in women, who have some of the characteristics that Dr. Michos just described, they also need to be intensively treated, lower is better, longer is necessary, and starting earlier. In terms of the NLA statement, I also was an author, and I think we did the right thing suggesting that lipoprotein a be checked at least once in everyone's lifetime.

It should be noted that lipoprotein little a is not just elevated in persons of South Asian descent, but also in those persons who have West African descent. So African Americans tend to have higher levels of LP a. This was demonstrated in the MESA trial where it was two and a half times more common than those that were identified as white, Asian, or Hispanic.

So we now know there's a wide range of things that we need to look at when we assess that patient. And simply saying, how you feel today, Ms. Mary? Oh, you're not having any chest pain. See you in three months. It's not going to get it. We have thresholds. We have new therapies. We have combination of those therapies that suggest we can do much better in lowering LDL cholesterol.

Host: Dr. Ferdinand, are there specific strategies you would add for shared decision making, strategies clinicians can utilize with their patients from various racial and ethnic groups when addressing their ASCVD risk and hypercholesterolemia management?

Keith Ferdinand, MD, FACC, FAHA, FASPC, FNLA: Absolutely. Patients like to see themselves in patient information. You're not going to have concordance where the female patient gets a female doctor, although many times that's a request. Or where the Black patient gets a Black doctor, although that may be a request. But all of us can be sensitive, that when we have patient information, that it is literacy appropriate, and language appropriate, and has pictures, colorful pictures, big font, easy to read and understand, but evidence-based, that allow a patient to have some sense of comfort,

that the information that's being given to them is information that is relevant to them. You know, older persons have smartphones, but they usually use them to call the grandkids. And simply telling an older person, go to this website or go to this link, they'll nod and look at you and smile because they don't want to be perceived as being uninformed.

But I like the idea of giving a handout, that doctor patient relationship, that clinic patient relationship, where you hand something to the patient and you say, this is important. This describes your condition and what we're going to do to help you live a better, more healthy life.

Host: Just wondering if you have any additional thoughts about communication strategies for patients to increase their understanding of treatment options, a clinician may discuss with them.

Keith Ferdinand, MD, FACC, FAHA, FASPC, FNLA: Sure, I use the technical terms and I also inscribe what the technical terms mean. I also have a bag of models that I bring around. It's a, picture, but it's also a model. A model is actually physical. And I'll show plaque. I may show thrombus superimposed on plaque to get the person to understand why it's necessary to more intensively lower their LDL cholesterol, control their blood pressure, and lower their glucose.

It's not enough to just talk about these big words that we use in medicine because patients often don't really understand the impact of their disease process or our therapeutic interventions. So, I use a combination of handouts, but also models, physical tools, to help describe to the patient their condition and why it's necessary to take multiple medications to control those risk factors.

Host: Well, I want to thank you both for sharing your insight about strategies for clinician patient communication, shared decision making. Dr. Michos, let's now explore a patient case.

Erin D. Michos, MD, MHS, FAHA, FACC, FASE, FASPC: So, I was asked to share a case. So, today we have a 56 year old Hispanic female. She has class 1 obesity with a BMI of 31. She has hypertension and on treatment her blood pressure is still 136 over 82. In addition to her other history, she also has Type 2 diabetes and dyslipidemia.

In terms of her reproductive history, she did have menopause at 51, so that was not premature, but she had gestational diabetes in prior pregnancy. Now, her family history, notable for that her mother who had hypertension actually had a fatal myocardial infarction at age 55. It was unknown what her mother's cholesterol was.

 Social history, the patient did smoke at one time in the past, but she's been a non smoker for more than five years and rarely drinks alcohol. And she's currently taking olmesartan 40 milligrams daily and amlodipine 10 milligrams daily for her blood pressure and metformin 500 milligrams twice a day for her diabetes.

So, let's look at her labs. So, her total cholesterol is 243 mg per deciliter with an LDL cholesterol of 167 mg per deciliter, triglycerides of 172 mg per deciliter, and this translates to a non HDL cholesterol of 201 mg per deciliter. Or, I'm sorry, I should have mentioned her HDL was only 42 mg per deciliter for that calculation.

 She did have a lipoprotein a measured. This, was not elevated. It was 55 nanomoles per liter. Her A1C on treatment was 6.9. Her EGFR was 72. At this point I didn't have a urine albumin creatinine ratio available, but that certainly needs to be measured since she has diabetes. So that's where we are when we first meet the patient.

And I'll turn to Dr. Ferdinand for his initial thoughts on this case.

Keith Ferdinand, MD, FACC, FAHA, FASPC, FNLA: Well, my thoughts on this case is that patient has multiple risk factors that need attention. I put a lot of emphasis on blood pressure. We know that there's a direct linear relationship to lowering blood pressure and decreasing cardiovascular events. She's on two drugs. As I previously noted, most middle aged and older persons will need at least two medications to control their blood pressure. However, in her particular case, it's not adequate. The previous goal of 140 over 90 millimeters of mercury has been superseded by 130 over 80. And that's going to be for most adults, especially someone like this, who has at least intermediate to high risk. I would suggest perhaps adding an additional medicine.

It could be a low dose thiazide type diuretic. I preferally like chlorothalidone, there's another one called indapamide, which can be used at a low dose and add to the combination that she already has. In terms of her lipids, it's clearly suboptimal. We can do a risk calculation and get an idea of what her threshold is or how low we want to go in terms of the LDL cholesterol. The new risk calculation called PREVENT is interesting. It now includes not just the conventional risk factors, but also urine albumin creatinine ratio, which she should have. In fact, all adults who are high risk and especially in view of her diabetes should have gotten that done already. It also includes A1C, which in her case is less than seven.

So there's been some substantial improvement in her diabetes, but also the social determinants of health. It's a term of art that's related to where a person works, she lives, plays, and prays. And in the PREVENT model, they use zip code analysis for social deprivation index. The zip code is a powerful predictor of risk because it tells you the environment in which the patient resides.

In her particular case, I don't know what those data show, but it's something that we should all consider as clinicians, not just looking at the traditional risk factors, but also those social determinants of health. If you calculate her risk based on PREVENT, I'm not sure what the number is, but it will help guide us to more intensive therapy, I'm sure.

Erin D. Michos, MD, MHS, FAHA, FACC, FASE, FASPC: Yeah so I plugged in those numbers for you. And again, I couldn't use the calculation that had the UACR, but she did have an A1C, so you can use the risk estimators with a model that includes A1C. So, she has a 10 year risk of cardiovascular disease of 13%, and a 30 year risk of cardiovascular disease of 46%.

So, at least intermediate risk, short term, and high lifetime risk. Now, in the guidelines, she has diabetes, so all patients with diabetes should be treated with at least a moderate intensity statin. The guidelines say to calculate a 10 year risk estimate and to also consider diabetes specific risk enhancers, such as having albinuria, retinopathy, longer duration of diabetes, a reduced EGFR, a low ABI.

 These would put someone into a higher risk group. Also, if they had evidence of subclinical atherosclerosis, that would put them in the higher risk group where you would want to use a high intensity statin and, aiming for at least a 50 percent reduction in LDL and an LDL less than the 70 milligram per deciliter threshold.

And if you're not there with a high intensity statin, you might consider ezetimide. She is not above 20 percent 10 year risk. She's in the intermediate risk. She has diabetes. So her doctor, after a clinician patient discussion, actually started atorvastatin 20 milligrams a day. And maybe one could argue she should have been put on a high intensity statin. That's a modern intensity statin dose. But unfortunately, even after this dose, she started complaining of muscle aches. So her clinician reduced her dose to 10 milligrams daily and she is tolerating atorva 10 and she had some repeat labs. Those showed a total cholesterol of 192, so there's been some improvement.

Her LDL cholesterol is 117, which is down from 167, but still remains elevated. Triglycerides are 154, non HDL 148, HDL of 44. So what are your thoughts now at this stage, Dr. Ferdinand?

Keith Ferdinand, MD, FACC, FAHA, FASPC, FNLA: Well, I'm going to surprise you. The 2018 Cholesterol Guideline did suggest, in this particular case, that using the PREVENT model or the pooled cohort should be intermediate. But I really like what the American Diabetes Association has done in their standards of care, which is updated each year and supersedes the 2018 ACC AHA Multi Society Guideline.

They suggest that with persons who have diabetes, the LDL should be less than 70. So in this particular case, I still think she has a way to go. I would consider combination therapy. And if she can't get there with increasing intensity of the statin therapy, there are alternatives. You mentioned bempedoic acid.

We know if you add bempedoic acid plus the ezetimide, you may get as much as 40 percent LDL reduction. So I don't think it's good enough. The picture that you have shown us is someone who has increased risk. The PREVENT model suggests intermediate risk, but the ADA standards of care says get that LDL less than 70.

I agree with the ADA. And look at some of those risk enhancing factors, and you can make a powerful, powerful argument for more intensive LDL reduction, combination therapy, and if indeed she can't get there with increasing the statin dose, you can use an alternative, in this particular case, bempedoic acid.

Erin D. Michos, MD, MHS, FAHA, FACC, FASE, FASPC: Yeah, I agree completely. I would target an LDL less than 70 in this patient. She may very well have albuminuria. That would certainly put her in the high risk category. For the National Lipid Association, the definition of statin intolerance is having tried, you know, at least two statins, one at the lowest dose.

 You could try her on a different statin to see if she could get to a higher dose, but I think that already, you know, she's already high risk and we should sort of escalate very quickly. There's a lot of clinical inertia and really we should be checking labs after every change, minimum of four to 12 weeks, so real quickly, and if you're not at goal to keep intensifying.

 Certainly combination therapy, adding ezetimide, adding bempedoic acid would be a good agent. You could also potentially consider one of the injectable medicines. I find that, sometimes it helps getting a coronary calcium score because if it's elevated, and they have coronary artery disease, sometimes that helps with some of the pre authorization paperwork. But we would treat her intensively, sort of regardless of what the calcium score would show. You know, she also has elevated triglycerides, and as a, another consideration, we do know from the REDUCE IT trial that icosapent ethyl in patients who were on a maximally tolerated statin with LDL controlled, but would remain with triglycerides above 150. We did see a 25% reduction in major adverse cardiovascular events and there was both, secondary prevention patients in that trial as well as, primary prevention patients who have diabetes. But I would focus first on her LDL and her non HDL as our first targets and really, work on getting that lower first before considering, um, adding the icosapent ethyl.

Keith Ferdinand, MD, FACC, FAHA, FASPC, FNLA: I agree with you. We have a lot of options to better control her risk. And in this particular case, I think the 2018 cholesterol guideline may underestimate the threshold at which we intensify our therapy. Adding combination therapy of different approaches to LDL lowering surely gives additional benefit.

Another thing we want to make sure that we document, is that she was indeed statin intolerant. Whether we believe it or whether we don't, patients who say they can't take increasing doses of statins or various statins are real, and it may be, as I mentioned, as much as 10 to 15 percent of patients we will see in our practice.

In that particular case, if we document, it may overcome some of the hurdles to prior authorization. Prior authorization often leads to the patient not being able to get access to the medicine because of the financial constraints it will take in order to achieve the medication. So the documentation needs to be done.

We need to use combination therapy and newer approaches to therapy in those patients who can't tolerate increasing intensity of statin therapy. And don't forget the blood pressure. It's simply not enough to say that the blood pressure is a little high. We should lower that blood pressure to a goal of less than 130 over 80, adding a smaller dose of a thiazide type diuretic won't cause any great derangements in her metabolic status, but may go a long way in reducing her cardiovascular risk.

Host: Well, we've reached the end of this episode. I want to thank our esteemed faculty for this engaging discussion. Also want to thank Aspirian for their support of this program. Be sure to claim your CME credit by filling out the evaluation and the post test. And also be sure to follow Iridium on X, Facebook, and LinkedIn to see the corresponding MedEd threads.