Cardiovascular disease (CVD) is the number one cause of premature death worldwide. The goal to raise high density lipoprotein cholesterol (HDL) or ‘Good Cholesterol’ and harness its beneficial actions in reducing the risk of atherosclerotic CVD has been pursued for almost 4 decades (1). Despite numerous attempts, the goal remains elusive. In contrast, the use of statins to reduce low density lipoprotein cholesterol (LDL) or ‘Bad Cholesterol’ has decreased death and events in CVD patients (2). Although statin therapy has been remarkably successful, we must not forget that its use has not eliminated CVD and only decreases its risk by 1/3. Thus, there remains a significant residual risk that, in part, may be attenuated by the actions and functionality of HDL.
Large population studies have shown an inverse relationship between HDL and CVD risk such that people with low HDL levels have a higher risk of CVD events (3, 4). These findings underlie what has been termed the “HDL hypothesis” which states that raising HDL should lower CVD risk (1). Studies of a similar nature suggested that lowering LDL was beneficial and helped in forging a simple but direct relationship between LDL and CVD risk such that: ‘The lower the LDL, the higher the reduction in CVD risk’. When we turn to HDL, it is tempting to think that the converse would apply. If so, then higher HDL levels should lead to decreased CVD risk. While the large population studies support this idea, there are inconsistencies.
For instance, analysis of one particular population study revealed that some individuals with high levels of HDL were not protected against CVD events (5). Moreover, when people with genetic mutations that raise HDL were studied, it turned out they too were not protected from CVD (6). Another example of ‘a fly in the ointment’ is evident in people who have a particular mutation in apoA-I, the dominant protein in HDL (7). They have HDL levels that are roughly 1/2 of those in the general population yet their risk of CVD is lower compared to the general population. Together these examples go against the powerful population data that points to HDL levels being inversely related to CVD risk.
More recently, evidence that further questions the HDL hypothesis is found in the failed human trials of drugs (8, 9) which inhibit the cholesteryl ester transfer protein (CETP). This enzyme plays an integral role in HDL metabolism and inhibiting CETP activity leads to massive increases in HDL ranging from 30 to >100%. If the HDL hypothesis was correct, then the actions of CETP inhibitors should have decreased CVD risk significantly. Unfortunately, the first candidate in this class actually caused harm in raising CVD deaths by 60% (8) and development of the second compound was halted in the midst of large Phase 3 human trials because of futility in lowering CVD (9). Both CETP inhibitors lead to huge increases in HDL, but the desired beneficial actions of these particles did not materialize.
Despite this conflicting evidence, a generation of healthcare workers and patients were brought up on and now married to the idea that raising HDL should decrease CVD risk. In light of the new observations and other findings, many believe it is time to initiate divorce proceedings or at least a trial separation. However, I believe there is significant evidence suggesting that HDL can play an important role in reducing the risk of CVD. We shouldn’t proceed to divorce but instead try counseling, aimed at altering our view of the relationship between HDL and CVD risk. Some experts believe it’s not that the HDL hypothesis is wrong, it’s that this relationship is more complicated than we originally thought (10-11).
Could it be that simply raising HDL levels is not the right goal? Is it time to abandon the goal to raise HDL? The press has already announced a funeral for the HDL hypothesis (12). In my opinion, and that of many, this may be premature. The hypothesis as it was articulated almost 4 decades ago however likely needs significant modification (1, 10).
Data from the population studies, clinical trials and animal studies have given us a better understanding of HDL biology. Now it is proposed that the goal should be to focus on HDL functionality rather than just its levels (13). Support for this idea comes from knowledge that HDL has many activities believed to be of benefit to those with CVD such as; anti-atherosclerosis, anti-inflammation, anti-thrombosis, anti-oxidation, and many more.
The current search is for therapies that enhance the anti-atherosclerotic function of HDL particles because they mediate a normal physiologic process called ‘reverse cholesterol transport’ (RCT). In this process, HDL particles remove cholesterol that has built up in artery walls and deliver it to the liver for elimination from the body. RCT essentially results in a reversal of the atherosclerotic disease that is the primary culprit in CVD events such as heart attacks.
Recent data from proteomic (14) and lipidomic (15) studies tell us HDL particles are not uniform, that there are many sub-fractions which make up this class of lipoproteins. Each of these varies in size, composition and most importantly, function. This knowledge may be the key to the development of a successful HDL therapeutic and provide insight into why the CETP inhibitors failed. If all types of HDL particles mediated RCT, then raising HDL levels with drugs like CETP inhibitors should reduce CVD risk.
But all the evidence appears to argue against this thought. CETP inhibitors raise HDL by preventing old, cholesterol-filled HDL particles from dumping its contents in the liver (16). These filled HDL particles have already completed its function of scooping up cholesterol from body tissues like the coronary arteries. They are “old” and have passed their prime in collecting cholesterol. Thus, the large increase in HDL seen on blood tests, caused by CETP inhibition, does not reflect functionality. The lesson learned here prompts us to look at therapies that will enhance those sub-fractions of HDL that are “new” and “young”, essentially, focusing on the functionality of HDL.
In development are potential HDL therapies specifically designed to enhance RCT; not by simply increasing the HDL level but by focusing on improving HDL functionality or in other words augment the sub-fractions that are primarily responsible for RCT. These therapies may be broadly divided into injectable or oral treatments. Both groups aim to stimulate RCT by improving the functionality of HDL involving creation of young and empty HDL particles that have ample capacity to take up cholesterol from the walls of arteries and deliver it to the liver for removal.
The first therapeutic group, in which there are several candidates, requires the injection of the apoA-1 protein mixed with lipids. ApoA-I is the key component of HDL. This mixture forms particles that mimic the actions of the very young HDL capable of performing RCT. To date, three small human clinical trials have been conducted and the therapy has proven to be successful in shrinking atherosclerotic lesions in the coronary arteries of patients (17-19). Removing cholesterol and reducing the size of atherosclerotic plaques in the coronary arteries has been shown to reduce the risk of CVD events like heart attacks. However, whether this therapy will ultimately translate into reduced CVD events in large groups of patients is unknown. Additionally, this form of therapy can only be used for a very short time following an acute CVD event and not for chronic treatment.
The second treatment class is an oral small-molecule therapy in the form of a pill that raises apoA-I production at the genetic level (20). In this category, there is only one candidate named RVX-208. This compound works via a novel epigenetic mechanism to increase apoA-1 protein production in the liver which in turn triggers formation of new or young HDL particles, the sub-fraction required to mediate RCT. RVX-208 is currently in Phase 2 human clinical trials (21). But like any drug-development program, whether RVX-208 will ultimately reduce CVD risk, remains to be proven.
Biologically, HDL has the ability to reverse atherosclerotic heart disease and possibly reduce the risk of CVD events like heart attacks. Accordingly, doctors and patients hoped that merely raising HDL levels would reduce CVD risk. But like so many seemingly simple biological systems...it’s just not that simple. Thus in order to make HDL work to reduce CVD risk, we must turn to the more recently elucidated facts of HDL biology. This new knowledge forces us to rethink the “HDL hypothesis” and more than likely modify it. HDL’s ability to reverse atherosclerosis appears to rely heavily on enhancing its functionality rather than just raising its levels. Stay tuned for results from ongoing clinical trials of new therapies designed to enhance HDL functionality.
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