New Study Strengthens the Case that LDL Causes Heart Disease

There is little remaining doubt in the scientific/medical community that high levels of LDL, so-called "bad cholesterol", cause heart disease.  Yet in some alternative health circles, the debate continues.  A new study adds substantially to the evidence that LDL plays a causal role in heart disease.

Introduction

Fat and cholesterol are transported through our blood via carriers called lipoprotein particles.  The primary cholesterol-carrying lipoprotein particle in humans is low-density lipoprotein, or LDL.  LDL delivers cholesterol to the body's tissues, where it's used to regulate cell membrane fluidity, synthesize hormones, and play many other important roles in the body [4/27 note: see comment section for information on LDL's role in reverse cholesterol transport].  Yet, we don't need very much LDL to fulfill this function, and most traditionally-living cultures have lower LDL levels than the modern average.

There is a huge mountain of evidence from multiple lines of investigation that high levels of LDL contribute to the thickening and degeneration of arteries called atherosclerosis.  LDL particles get trapped in the blood vessel lining, depositing cholesterol and activating immune cells called macrophages.  Somewhere along the line, the LDL becomes oxidized.  Macrophages accumulate the oxidized LDL, grow into giant "foam cells", and eventually die, releasing their cargo of cholesterol and fat into the artery wall.  Arterial lesions swell, and the tissue inside them becomes fibrous, calcified, and necrotic.  Blood flow through the artery is restricted.  Sometimes, the lesion bursts, causing a clot that stops blood flow to the heart, brain, or other tissues.  This is a heart attack, stroke, or other embolism.

There are certainly contributors to cardiovascular risk besides LDL particles.  HDL particles, for example, are probably protective*.  Also, cigarette smoking greatly increases the risk of having a heart attack, and this increase in risk is largely independent of effects on blood lipids.  Similarly, the protective effects of exercise are partially independent of blood lipids.  Yet nothing changes the fact that, all things being equal, higher lifetime LDL = higher risk.

In some corners of the alternative health community, the idea persists that LDL is unrelated to cardiovascular risk.  I think this is wrong, and frankly, dangerous.

Statin drugs, as we know, reduce LDL cholesterol and also reduce cardiovascular risk in high-risk groups.  Some people have argued that statins have effects besides LDL lowering that could explain their protective action.  It's not an unreasonable idea.  Yet a new class of cholesterol-lowering drug promises to erase any remaining doubt that lowering LDL protects against heart attack risk.

Enter PCSK9

PCSK9 (proprotein convertase subtilisin/kexin type 9) is an enzyme that regulates levels of the LDL receptor.  The less PCSK9 there is in a liver cell, the more LDL receptor that cell will express, and the more LDL cholesterol it will remove from the blood.  In short, lower PCSK9 = lower LDL.  Researchers have known since 2006 that people with naturally occurring mutations that inactivate PCSK9 have a much lower risk of cardiovascular events (1).  Therefore, PCSK9 was considered an extremely valuable drug target.

Well, a decade has passed, and we now have drugs that inhibit PCSK9.  They are antibodies that, once injected, bind and inactivate the enzyme.  Turns out, these drugs can lower LDL by about half, which beats statins.  Yet PCSK9 inhibitors have not gone completely through the drug development pipeline, so all we have are preliminary studies on whether or not they actually protect against heart attacks and stroke.  A new meta-analysis cobbles together all of the preliminary reports, allowing us to get a better idea of whether or not these drugs actually work.

The study

Eliano Navarese and colleagues collected data from 24 phase II and phase III randomized, placebo-controlled trials of PCSK9 inhibitors (2).  These trials included data from over 10,000 patients.  Navarese and colleagues compiled the data on efficacy and safety, and analyzed it statistically.

The results

PCSK9 inhibitors reduced LDL cholesterol by nearly half (49.5%).  They also reduced heart attacks by more than half (51%), and all-cause mortality by more than half (55%).

PCSK9 inhibitors didn't increase the rate of serious adverse events.

Interpretation

We now have two independent drug therapies, statins and PCSK9 inhibitors, that substantially reduce LDL levels by completely different mechanisms.  Both appear to reduce cardiovascular risk, although we'll need additional randomized, controlled trials to be 100% certain about the efficacy and safety of PCSK9 inhibitors (the trials in this meta-analysis were generally short and weren't designed to measure effects on cardiovascular events or mortality).

The mountain of evidence implicating LDL in cardiovascular disease just got larger.  I hope this will be a wake-up call for people who don't think LDL is important.


* Some people have questioned this, based on the results of the CETP inhibitor trials, which increased HDL cholesterol but didn't reduce cardiovascular risk.  This is not a very convincing argument against the importance of HDL, and here's why: there's no reason to expect that pumping HDL particles full of extra cholesterol would reduce cardiovascular risk.  One of HDL's jobs is to take cholesterol out of the artery wall and bring it to the liver for disposal.  Artificially increasing the cholesterol cargo of the particle, as CETP inhibitors do, isn't going to help HDL take more cholesterol out of the artery-- if anything, it should reduce its capacity to do so.  It's essentially "treating a number", with no regard for the biological mechanism of action of the HDL particle.  We don't yet understand how to increase the ability of the HDL particle to transport cholesterol out of the artery, but if we can enhance that process, we will probably have another effective means of protecting against heart disease.