Updated Cholesterol Management Guidelines Reflect Evolution of Evidence-Based Care

Parag Joshi, MD, is a preventative cardiologist at UT Southwestern Medical Center in Dallas. He explains the relevance of the new guidelines on cholesterol management that were presented in November of 2018 at the AHA Scientific Sessions.

Can you discuss some of the highlights of the updated cholesterol management guidelines announces at the AHA Scientific Sessions?

The guidelines have several major updates from the most recent, previous guidelines in 2013. One of the big shifts in recommendations in 2013 was that we moved away from an LBL cholesterol target. Prior to 2013, there was a focus on estimating a patient’s risk for a heart attack, which has remained in the guidelines and, based on that risk, targeting a certain LDL cholesterol level. For example, if you were at high risk in the previous guidelines, you would be targeted for more aggressive cholesterol levels; your LDL target may be as low as 70 mg/dl or 100 mg/dl. If you were estimated to have lower risk for heart attacks and strokes, then your target may be more lenient, for example, an LDL cholesterol target of 130 mg/dl. In 2013, that approach was reevaluated because we found that we didn’t have the highest quality evidence to support that approach. Instead, it became clear that the high intensity statin medications were outperforming any of our other cholesterol lowering medications at that time. The 2013 guidelines shifted away from a cholesterol target and, instead, focused on intensity of therapy with statin medications. The goals of the guideline writers in 2013 was to maximize the use of statins when appropriate for high-risk patients. There was a lot of uncertainty about how that would be implemented into practice, but I think over the last 5 years, statins are being prioritized as our primary way to address cholesterol related risk for heart attacks and strokes.

In 2018, though, we did see a re-entrance of an LDL cholesterol target, in this case, for very high-risk patients. Those are patients who have had multiple heart attacks or strokes, or have had a heart attack or stroke, or needed bypass surgery, and also have other high-risk factors. In that group, it would be reasonable to target an LDL cholesterol less than 70 with proven medications. The reason that the guideline writers have now changed back to a target, or at least incorporated that target, is that since 2013 we’ve had two big classes of medications that have had positive outcomes on events. Prior to 2013, other than statins, there were no other therapies that had been proven to reduce heart attacks and strokes when added to statin therapy. Since 2013, there were three big trials that have been positive in terms of lowering cholesterol and lowering heart attacks and strokes when added to statins. One is the IMPROVE IT study of ezetimibe, which showed that a reduction in LDL cholesterol from about 70 mg/dl to 50 mg/dl led to an improvement in heart attacks, strokes, and revascularization procedures. In 2015, we started to learn more about the PCSK9 inhibitors. This is a totally different and very effective way of lowering LDL cholesterol, with reductions as high as 50% or 60% on top of statin therapy. In 2017 and this year, we had reports in the outcomes trials of two of the PCSK9 inhibitors, evolocumab and alirocumab. Both of those studies showed dramatic reductions in LDL cholesterol on top of statin therapy. Accompanying that, they showed dramatic reductions in risk for heart attacks and strokes. With that new data, there was now enough evidence to say that with these other drugs on top of statins in a really high-risk population (people who have already had heart attacks or strokes), you can target an LDL less than 70 mg/dl. That is what we call secondary prevention, and that was the major change that came up in the guidelines.

The other large population at risk are the people who have not had a heart attack or stroke but are at risk for a first event. We call this primary prevention. One of the big changes in our approach to primary prevention over the last 5 years is to better understand risk of a first event and what tests may help estimate that risk. In 2013, we had a new calculator to estimate a given patient’s risk for a heart attack or stroke in the next 10 years. Since then, we’ve seen multiple studies that show areas where it may not be as accurate as we would hope. In addition to that, we’ve seen studies showing how other tests can help with that estimate of risk and help our patients decide for themselves how aggressive they want to be with their treatment. Above all of these other tests that you can add onto the risk estimator is one called a coronary artery calcium score, which is a CAT scan of the chest that looks for evidence of plaque buildup in the arteries. That test was prioritized over all others for two really important reasons. One, the presence of coronary artery calcium varies across risk categories and, importantly, when it is normal, it can reclassify risk downwards. Two, it helps our patients decide for themselves whether they want to take a statin or be more aggressive with their therapies, or it can reassure them when they don’t have any coronary artery calcium. If a patient comes in and has an intermediate risk, we know that if they don’t have coronary artery calcium on this test that their risk is really much lower than that. It can be cut nearly in half. If they have high burdens of coronary calcium, a score greater than 100, then it suggests that their risk is accurate or even higher than we’re estimating, and they really want to be aggressive with prevention. The upgrade in the recommendation for that coronary artery calcium test is as a tiebreaker when our patients are uncertain or when we, as physicians, are uncertain. This was a big change in the guidelines from 2013.

One of the big questions that has arisen over the last 5 years with newer drugs is how do these fit in with prescribing statins?

A big emphasis that is really important to make is that the primary way to reduce risk related to cholesterol is with statins. These other drugs should only be used either on top of statin therapy when risk is really high or in the small percentage of patients who cannot tolerate statins. I would say, in my practice, 90% of my patients can tolerate statins, whether it is the first one we try or if we switch to a different one. There is a small percentage, somewhere around 3-5% percent, that we cannot get on enough statin medication to lower their risk. In that group, that is where these other medications may play a role. Ezetimibe lowers cholesterol by about 20% and lowers risk over seven years by about 15%. The PCSK9 inhibitors lower cholesterol by about 50% and lower risk over just 2-3 years by 25%. You can imagine, over time, that risk reduction will be even greater.

There are several groups of risk that are right for these medications. One are the patients who have had a heart attack or stroke and still have a lot of high-risk factors or have had multiple heart attacks and strokes whose LDL cholesterol is still above 70 mg/dl despite being on as much statin as they can tolerate, preferably the highest dose of statin that they can take. Those are the patients that we would recommend starting with adding ezetimibe, mostly because it’s cheaper and well tolerated and well studied. If you are still not able to get below 70 mg/dl, that is when we would add the PSK9 inhibitors. We really are talking about a tiered approach in that statins should be prioritized and then, if you need to get more aggressive targets, that’s when you start adding these other medications. There is one other group that is really important here, and that is the patients with what we think of as genetically high cholesterol, the familial hypercholesterolemia patient population, people whose LDL cholesterol is above 190 mg/dl. The risk for heart disease, in general, is made up of multiple risk pathways, a combination of cholesterol, smoking, lifestyle, diet, exercise, and blood pressure. People who have really high cholesterol have high risk regardless of any of their other risk factors. In that group, you really want to get the cholesterol related risk way down. PCSK9 inhibitors or ezetimibe on top of statins definitely have a big role to play here.

Another question that comes up in my patients is, if you have a lot of coronary calcium, how aggressive should you be with non-statin medications? That’s more of a provider-patient discussion. If we feel like there is still residual cholesterol-related risk, that would be an area to target use of those medications in patients who have not already had a heart attack or stroke but are at high risk for a future one. The coronary calcium score ranges from zero to several thousand. When it’s above 100, we know that the risk is high for a heart attack or stroke. When it’s really high, above 400 or above 1000, those might be patients that you get more aggressive with more than just a statin medication to try and get their cholesterol as low as you can get it. That is where the coronary calcium score makes a difference. With that in mind, the guideline writers were prioritizing the calcium score to help encourage payers to look at that as something that they would cover because it can have big implications in these decisions for lifelong medications.

How have the recommendations changed for patients with diabetes?

In general, for patients with diabetes, we already have known over the last 5 to 10 years or even longer that their risk for heart disease is higher than we generally would think. The recommendations for that group has not changed dramatically. If you are aged 40 to 75 and you have diabetes, the recommendation is that you should be on at least a moderate intensity statin if you have an LDL cholesterol above 70. There is some risk estimation involved there. If you have really high risk based on a risk estimate where your 10 year risk is greater than 20 percent, you may want to be even more aggressive with your statin therapy in those patients where you want to be on a high intensity statin.

Generally, for diabetes, we want to be aggressive with your risk reduction. That’s a group where the recommendations have not changed dramatically. There have been small adjustments, but I’d say, for the broad population of diabetic patients, we want to be very aggressive with their cholesterol related risk and getting them on statins.

How do you approach the question of cost-effectiveness when it comes to PCSK9 inhibitors?

Certainly, we recently have seen the cost dropped by the two major companies that have a PCSK9 product on market. The question about cost-effectiveness from a guideline perspective becomes more of a public health approach. Does it make sense for a small benefit on a per dollar basis? One way to think of this is that there is a relatively smaller benefit if you were to end up prescribing this to everybody vs targeting the people that are going to benefit the most from it. From a public health standpoint of how we spend our health care dollars, that makes sense. From a patient-provider standpoint, it becomes a little more murky. If I tell a patient that there is a therapy that might help lower their risk, they don’t necessarily care about the overall health care cost of that medication. They care about their co-pay and how much it will cost them out of pocket. If it is not very much, then they are going to want that medication.

There is a challenge right now of how we target these medications best and make sure that people that benefit the most from it can get it. I think the guideline writers recognized that in identifying that the highest risk group will be the ones that benefit the most from PCSK9 inhibitors. That would be the group that we target the most. That is the group with familial hypercholesterolemia, who are genetically at risk for high cholesterol or they have LDL levels at that level. However, I don’t know that you necessarily have to have the genetically proven familial hypercholesterolemia to warrant being treated aggressively with LDL reduction. I think my patients who have an LDL above 190 mg/dl are going to have high risk for heart disease going forward, whether it is through a proven genetic mechanism or not. Based on that, I think those patients should be on as much LDL lowering that they can tolerate and safely take, which would include PCSK9 inhibitors.

Certainly, patients who have other high-risk factors and whose LDL cholesterols are not getting as low as we would like are another group that we think would benefit from PCSK9 inhibitor. Identifying that group is what we’re still working on. I think that’s another role for calcium scoring. If you do have a high coronary artery calcium score and a residual LDL cholesterol elevation despite a statin, that might be a group where you would say these are high risk folks. They would benefit from PCSK9 inhibition. If we can figure out the cost-effectiveness of that approach, that would be ideal.