Rethinking Statins: Time for Primordial Prevention?

Few agents in the landscape of medicine have had as dramatic an impact on disease course as statins for prevention of cardiovascular disease. September 1 marked 35 years since approval of lovastatin in 1987 introduced statins to the general population. To say statins have revolutionized the care of dyslipidemia and prevention of atherosclerotic cardiovascular disease since that approval on September 1, 1987, would be an understatement.

In the past 35 years, mountains of data have emerged outlining the efficacy and safety of these agents as LDL-lowering agents, but also for reducing risk of cardiovascular events. In addition to this, unlike many gamechanging agents that are bogarted by steep prices or limited availability, statins are among the most widely prescribed and inexpensive drugs in the US, with insurance coverage and prescription programs reducing costs to under $100 per month for generics.

Given the availability of statins and growing understanding of LDL-C exposure, some have begun to question whether the role of statins should be expanded to include a wider swath of the population. This question of whether the role of statins in primary prevention should be expanded to be more akin to primordial prevention is the subject of this feature: “Rethinking Statins: Time for Primordial Prevention?”.

As part of the feature, Practical Cardiology queried a half dozen of the leading experts in cardiometabolic health on the topic. This group of experts includes Erin Michos, MD, of Johns Hopkins School of Medicine, Peter Toth, MD, PhD, of the CGH Medical Center, Deepak Bhatt, MD, MPH, of Brigham and Women’s Hospital, Jorge Plutzky, MD, of Brigham and Women’s Hospital, Alison Bailey, MD, of Centennial Heart, and Robert Busch, MD, of Albany Medical Center.

Rethinking Statins: Time for Primordial Prevention?

Erin Michos, MD

Erin Michos, MD: Well, it would be great to kind of eradicate atherosclerosis, right? I think this is really important that when we think about LDL years or cholesterol years, we are not only thinking of the magnitude of elevation, but the number of years of exposure. Even with mild to moderately elevated cholesterol for a longer duration of time, these individuals have increased risk for earlier onset of atherosclerotic cardiovascular disease compared to their counterparts that have had lifelong low LDL.

I think we wait too long to treat. The ideal LDL in fetuses and infants is around 30 mg/dL. Compare it to the concept of blood pressure management. So, if you have somebody who is 20-30 years of age that comes in with a systolic blood pressure of 160, you're not going to say, 'Oh, your 10-year risk is low. We're not going to treat your blood pressure'. No, we treat their blood pressure. So, I think that some of the problems of using these 10-year risk scores for cholesterol or for making decisions for initiating statins is that young adults do have a low risk in the next 10 years, but I don't want to just prevent a heart attack in the next 10 years, I want to prevent a heart attack over their lifetime for the next 30 or 40 or 50 years.

So, we wait too long to treat because we focus on these 10-year risk scores and younger adults are never eligible. The whole time their arteries are marinating in these atherogenic lipid particles. The classic example of this is familial hypercholesterolemia. These individuals have genetically very high cholesterol from birth and studies have already shown that if you intervene early and you treat with statins, by adolescence, the offspring don't develop the early onset of ASCVD as their parents. You can change the whole trajectory by starting early. So, that's the classic example with FH.

We should be thinking about this for broader populations and getting LDL lower starting earlier. There is certainly an important role for lifestyle and, particularly, for young adults who are at lower risk. Diet and lifestyle is one of the mainstays of therapy, although the LDL makes that liver makes LDL cholesterol and a lot of cholesterol is genetically determined—up to 3/4ths of this is genetically determined, but 20-30% can still be influenced by diet. So, that does matter, especially in younger adults. If we could be trying to have everybody eating a healthier diet and optimizing lifestyle from utero on through childhood and into young adulthood, that'd be really, really important, but I do think we should have increased consideration for starting statins early.

Peter Toth, MD, PhD

Peter Toth, MD, PhD: That's actually a fabulous question. For a long time in primary prevention, an LDL-C of less than 130 was considered to be normal. The average patient who presents to the ER with an MI has an LDL of 128. So, how could that LDL of 128 be normal? It's simply ludicrous. Yet, the older guidelines said less than 130 was normal. In fact, for the low-risk patient, less than 160 was considered to be okay.

I'll tell you right now, for the average patient, if their LDL is above 100, they're experiencing atherogenesis from an early age. We know that in familial hypercholesterolemia, children can have fatty streaks in their coronary tree. We also know, based on autopsy studies from Korea and Vietnam, when looking at young men killed at time of war, more than 50% had anatomical evidence of established plaquing in their coronary arteries. Atherogenesis begins in childhood and it progresses throughout our lifetimes. People, on average, have events in their 5th, 6th, or 7th decades depending upon how much LDL they've been exposed to and what other risk factors they may harbor.

In this light, I think we're now looking at LDL exposure almost like cigarette smoking. What dose of LDL-C you have been exposed to and over how much time can very nicely predict how long it's going to take for that patient to develop significant disease and have an event.

Do I favor lowering LDL cholesterol in everybody? Given the fact that coronary disease is a scourge globally and gives rise to more suffering and more deaths than any other disease? Yes. Do I find it ludicrous that we typically wait till people have their first event and then start a statin? I think it's ludicrous, because certainly we have enough data that this disease starts early, progresses through life, and gives rise to human suffering. Does it make sense to reduce the LDL burden, the burden of atherogenic lipoprotein in serum at a much younger age? You better believe it does.

Deepak Bhatt, MD, MPH

Deepak Bhatt, MD, MPH: That's a great question. I never overreact to what's going on in social media, because it's typically an echo chamber of people confirming their own beliefs, but I do think statins could and should have a larger role in primary prevention on the basis of LDL cholesterol. That is, I think there are a lot of people walking around with elevated LDL cholesterol, where starting them on a statin earlier in life would probably reduce a substantial number of atherosclerotic events. We already have positive primary prevention data for statins—the JUPITER trial, for example. So, it's not a data-free zone.

There are certainly patients right now that should be getting statins in the primary prevention universe. So, just how low should the LDL be allowed to be before starting a statin? I think that might be a bit controversial. We should normally have LDL at around 30 if we were newborns again. That's sort of the range of LDL that we have seen historically in more rural parts of the world that hadn't been industrialized and urbanized. That was sort of a"normal LDL".

So, most of us in the US are walking around with an abnormal LDL. You could make a theoretical argument just to treat everyone that's got an LDL above that range, but in the absence of actual data supporting statins for primary prevention in the range I'm talking about, I wouldn't just do it. There is, of course, the occasional real side effect that does occur with statins, then there's the more minor side effects, and then there's the nocebo effects where people are really convinced they're having side effects, but if they were on a placebo they would have the same side effects.

So, it makes life tough. I think advocating too strongly for that, where there isn't data, will just sort of fuel the anti-statin folks and then keep statins from being used where they absolutely should be used, including secondary prevention and high-risk primary prevention. So, for now, I'd say to stick where the data are and not go beyond that, but, if one really thinks that type of primordial prevention is the way to go, perhaps then it's not even a statin, but a PCSK9 inhibitor—where it takes adherence out of the question. I'm not advocating for that, by the way, there would need to be data supporting that. If there were data that ultimately support that approach, there you take adherence out of the question, and you get really large reductions in LDL.

I think we really need more research on what to do. Primary prevention is tough. Secondary prevention, I think is a lot easier because, after someone's had an MI, they ought to be on a statin. The only reason not to be are intolerances, perceived intolerances, or side effects, but otherwise they really ought to do it. But, in primary prevention, it gets trickier because the absolute risk reductions are smaller and adherence is really tough. If somebody's feeling great, and they've never had an ischemic event, it can be tough to take a pill a day the rest of your life. So, I think there are a lot of important interesting questions here, but I suspect future research in lower risk primary prevention populations will help define the right thing to do.

Jorge Plutzky, MD

Jorge Plutzky, MD: Well, there is considerable evidence that patients are getting undertreated for primary prevention of cardiovascular risk. The idea that you're going to wait for a patient to have an event before you start treating them is really outdated and dangerous, because we know that those events can be very complicated. So, certainly, earlier intervention and use of statins prior to an event is important, but it has to be placed in the context of the risk for that individual. We know that risk is present and we know that risk involves many different factors. So, fully considering that can have you intervening earlier in someone who's considerably younger, who, for example, is smoking, hypertensive, has an elevated number, strong family history, or has an elevated LPa are all things that we actively engaging. At the same time, we want to balance that and not treat people unnecessarily and expose them to all the various issues that can come up with drug therapy.

So, I think it's a question of balance—of recognizing the risk, recognizing we have an intervention, and supporting that. Sometimes in the younger patient, when you're starting to think about risk, that also becomes a great opportunity to implement lifestyle and to really focus on that because you might be seeing a patient who is really years away from when they might have a first event. Using that time to get them off cigarettes, a little bit more active, and eating a little bit better, I think is really important. We should not just be relying on drug therapy.

Alison Bailey, MD

Alison Bailey, MD: So, we know that your LDL over your lifespan contributes to your burden of atherosclerosis, not just from heart disease, but also from stroke, kidney disease, and all the other sort of chronic illnesses that we deal with in the United States and increasingly around the world. So, I think low LDL over your lifespan is important. How we get there is also important.

I think the first thing we should focus on is lifestyle for everybody. You know, when I meet people who are overweight, not exercising, and eating poorly, I think they can make pretty substantial changes in their lipid profile by changing their lifestyle. So, I like to have that discussion first. Let's change our lifestyle and then let's reassess.

However, I wouldn't want to walk around with an LDL-C of 130 for the remainder of my life, because I know my risk for cardiovascular disease is going to go up. So, I think statin should be offered to patients earlier, but after a patient-centered discussion about the risks, the benefits, and where the data sits today.

We have lots of tools that we never had before, such as CAC scores. We're learning that using those in younger patients than we ever did before, these lower risk cohorts, may give us additional data. So, I think statins should be expanded after having informed discussions. Obviously, there are groups that are at risk, specifically women who are of childbearing age. To me, that one's the trickiest one. I see a lot of women in my practice and we have very extended discussions about using contraceptive and just knowing what the risks are with statins if they were to get pregnant.

Robert Busch, MD

Robert Busch, MD: So, the risk with a statin is so minimal and the benefit is so great, I personally feel statins should be in the drinking water, unless your woman is going to get pregnant or are pregnant. The harm of a statin is so minimal and the benefit of statin is so great. Practicing in an era before statins in the 1980s, compared to after that, I'm not seeing the number of strokes and heart attacks that we saw before. That's the game changer.

As an endocrinologist treating someone with diabetes, that's the easiest drug to initiate. It's very well tolerated, it's inexpensive, and we can use it to get to their LDL target goal. That's why the American College of Endocrinology says to everyone with diabetes 'Where is your statin?', based on outcome studies in people with diabetes. But I agree with the notion that we could take it before that. A person with prediabetes is a person with diabetes waiting to happen. Why not treat that patient? What about the obese patient who didn't yet get prediabetes, but they're going to have diabetes in the future?

So, I agree. Statins are imperative for primary prevention and I know a lot of our colleagues calculate a Framingham risk and all that other stuff, and maybe wait for a cardiac calcium score to push the patient, but the fatty streaks are already there. It's unusual to have a zero cardiac calcium score. So, I do think statins are one of the key primary prevention drugs that we have.

Editor's note: These transcripts have been edited for length and clarity.