Statin Drugs Have Benefits Beyond Cholesterol Lowering

For most of the last 25 years I have told patients when I recommend  a statin drug to them that they should take it in order to lower their bad cholesterol (and raise the good cholesterol) thereby lowering their risk of future heart attacks.

I based this statement on my understanding of large statin trials which demonstrated reduction in heart attacks seemingly closely tied to drops in the bad cholesterol level.

Although I was aware of the so-called “pleiotropic” (meaning effecting multiple pathways leading to atherosclerosis) of statins it was easier to point to the cholesterol lowering effects and unify that message with the recommendation to reduce fat and cholesterol in the diet , thereby lowering cholesterol in the blood and arteries and cut heart attack risks.

Thus emerged a very simple (and likely false) paradigm: Fat in the diet causes fat in the blood which causes fat in the arteries which causes fatty plaques in the coronary arteries which causes heart attacks when they get too big and block off the blood flow.

I, like most cardiologists and lay people  mistakenly assumed that since lower bad cholesterol levels associated with taking a statin drug were associated with lower heart attack risks then dietary changes aimed at lowering bad cholesterol levels would also lower heart attack risk.

It turns out that we don’t really know how the statins reduce heart attacks . As a recent review points out:

 some of the cholesterol-independent or “pleiotropic” effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins.

Supporting the non cholesterol lowering effects of statins on reducing CVD are the following observations

-Most heart attack victims don’t have elevated bad cholesterol levels and dietary reduction of bad cholesterol doesn’t seem very effective at preventing heart attacks.

-Drugs, like Zetia or ezetimibe which lower cholesterol level by other mechanisms don’t seem to prevent atherosclerosis even though they substantially lower bad cholesterol levels.

-Statin drugs reduce heart attacks in patients who have normal or low bad cholesterol levels

What Causes Atherosclerosis?

An article (Innate and adaptive inflammation as a Therapeutic Target in Vascular Disease) published in JACC recently by Tousoulis,et al. summarizes the current understanding of how atherosclerosis develops and the multiple ways that statins may affect that process. They write

Atherosclerosis, once thought to be a lipid storage disease, is now considered a chronic low-grade inflammatory condition that affects the vascular wall. It is characterized by the deposition of cholesterol and lipids followed by infiltration of T cells and macrophages, all as a result of an endothelial injury response.

I’m including this figure from the article to give you some idea of how incredibly complicated the process is.

atherosclerosis
Overview of Mechanisms Involved in Atherosclerosis Low-density lipoprotein (LDL) is oxidized in the presence of reactive oxygen species (ROS) and binds to proteoglycans (heparin sulfate) while simultaneously stimulating the endothelium, leading to adhesion molecule overexpression and increasing its permeability. Apart from this action, oxidized low-density lipoprotein (ox-LDL) inhibits nitric oxide (NO) production, prohibiting vasodilation. Furthermore, cytokines and other chemoattractant molecules, such as MCP-1, are secreted, favoring leukocyte adhesion. Leukocytes come into random contact with the activated endothelium and, due to interactions with adhesion molecules, roll and tether and are subsequently firmly arrested. In addition, leukocytes transmigrate into the subendothelial space, where they differentiate into macrophages, which in turn take up ox-LDL, forming foam cells. Ox-LDL antigens are presented by macrophage major histocompatibility complex class II (MHC-II) proteins and are recognized by CD4+ T cells. These preferentially differentiate into Th-1 cells, pro-inflammatory cytokine production. Finally, smooth muscle cell (SMC) proliferation and migration are induced as a result of cytokine and growth factor secretion.

Can you imagine trying to explain this to the average patient?

My eyes glazed over once I reached MCP-1.

Thus, doctors end up giving the simple, accepted conventional wisdom that we are “treating” high cholesterol by giving statin drugs. What we are really treating is atherosclerosis. And statins are the only effective drug treatment we have identified for this ubiqitous  and complex process.

It is entirely possible that the lower LDL cholesterol caused by statin drugs is totally unrelated to their ability to forestall atherosclerosis. The new cholesterol guidelines reflect this concept as they don’t recommend treating to an LDL target level.

I end with the closing comments from the article by Tousoulis, et al.

Given the fact that atherosclerosis is a multivariable disease, with several molecules involved in each stage, it is vey difficult to find an effective treatment. However, statins prove to be the most effective treatment so far because they interfere with most of the critical components of the atherosclerotic process and have been proven to have beneficial effects. Further to their well-established impact on nonspecific low-grade inflammation, statins also appear to have significant effects on innate and adaptive immunity that have been underestimated so far.

5 thoughts on “Statin Drugs Have Benefits Beyond Cholesterol Lowering”

  1. Have any studies been done to determine what dosage of a given statin is needed to achieve these non-cholesterol lowering benefits? Perhaps these benefits could be achieved at lower dosage levels, therefore negating the numerous negative side effects that many people currently are suffering at the current statin doses they are taking.

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