Today, it is estimated that 50% of the American population have cholesterol levels that fall outside the accepted healthy range, and the prevalence of cardiovascular disease reflects this. However, the idea that cholesterol is a major risk factor for the development of heart attacks and strokes was one that was rejected by the scientific community for decades. Although high cholesterol is now a universally accepted warning sign, some medical professionals are starting to question the current standard of care when it comes to statin therapy, as these cholesterol-lowering medications may not benefit all patient populations equally. Will history repeat itself? Here I will present the story of cholesterol, and how it has – and continues to be - a controversial component of modern medical history.

A cholesterol narrative and the uphill battle linking it to cardiovascular risk

In the early 1900s, a young Russian scientist named Anitschkow serendipitously conducted what would be one of the founding experiments for cardiovascular disease research. Instead of disproving his colleague’s hypothesis on ageing, Anitsckow discovered a link between cholesterol and vascular damage (atherosclerosis) after feeding rabbits purified cholesterol. Yet, despite these findings, cholesterol research in the context of human health was not of interest, mostly because many leading scientists did not consider the rabbit – an herbivore by nature - to be relevant to human disease. Furthermore, atherosclerosis was thought to be a natural and inevitable component of ageing and most scientists didn’t see cholesterol as being causative. Therefore, cholesterol research as it relates to cardiovascular disease remained stagnant for several decades.

Approximately 40 years after Anitschkow published his cholesterol studies in rabbits, Gofman had great interest in the concept of cholesterol as being a determinant of cardiovascular disease. An American scientist with a penchant for biomedical research, Gofman was aware of Anitschkow’s cholesterol feeding experiments and, unlike most other scientists during that era, he took these results quite seriously. He was convinced of a clear link between cholesterol and atherosclerosis, which ultimately lead him to question exactly how cholesterol was transported in the blood stream. Using newly established techniques, he started to examine the different chemical forms of cholesterol found in the blood, and identified the components that make up total cholesterol (such as HDL and LDL, which will be discussed in detail below). Unfortunately, the significance of this research would not be realized until many years later.

As time went on and rogue supporters of the “lipid hypothesis” increased in number, the notion that high levels of cholesterol in the bloodstream, a phenomenon known to physicians as hypercholesterolemia, was a causative factor for heart disease started to catch on. It was becoming clearer that diet had an impact on cholesterol levels, and therefore, the incidence of heart attacks. In 1955, Ancel Keys, a prominent nutritional scientist at the University of Minnesota, suggested that, despite the costs and length of time required, it was important to conduct large-scale clinical studies where diet and health were researched [PDF]:

“There are good reasons for the current great interest in the effects of the diet on the blood lipids. It is now generally agreed that there is an important relationship between the concentration of certain lipid fractions in the blood and the development of atherosclerosis and the coronary heart disease it produces. The outstanding characteristic of atherosclerosis is the presence of lipid deposits, mainly cholesterol, in the walls of the arteries. And both in, man and animals the most obvious factor that affects the blood lipids is the diet.”

As a result, we started to see an increase in clinical studies examining the impact of diet on cardiovascular health, including Keys’ own Seven Countries Study beginning in 1958. This study, which was the first of its kind, examined the connection between lifestyle, diet, and prevalence of cardiovascular disease in men from different world populations. Though the study design is considered to be flawed by today’s standards, the major finding that linked high intake of dietary cholesterol to heart disease, regardless of cultural background, were quite influential.

Alongside the Seven Countries Study, the National Heart Institute (now known as the National Heart, Lung, and Blood Institute – NHLBI) decided in 1948 to begin following people between the ages of 30 and 62 living in the town of Framingham, MA. Perhaps one of the most well-known and cited clinical studies aimed to determine common patterns related to the development of cardiovascular disease, the currently ongoing Framingham Heart Study identified a number of factors related to heart health, including smoking, high blood pressure, and - you guessed it - high blood cholesterol. However, the latter was not a reported cardiovascular disease risk factor until 1961.

Despite the rejection of the lipid hypothesis by several “old-schoolers,” many scientists and physicians began to see the link between blood cholesterol and human health. But, even more brazen was the idea that negative health effects stemming from high cholesterol could be treated and reversed. In the early 1950s, research from the laboratories of Laurance Kinsell (Institute for Metabolic Research, Highland General Hospital) and Edward H. Ahrens (The Rockefeller University) concluded that eliminating dietary saturated fats and replacing them with unsaturated fats has a profound effect on reducing blood cholesterol. This finding was strengthened by the results of three pre-1970s clinical studies: The Paul Leren Oslo Study (1966); The Wadsworth Veterans Administration Hospital Study (1969); and The Finnish Mental Hospitals Study (1968).

Yet, the reaction of medical professionals was still mixed. Some embraced these new data and organizations such as the American Heart Association went on record with a (carefully worded) message urging a reduction in saturated fat consumption. However, others were more pessimistic of these findings, perhaps because they did not feel that the American population would be willing to dramatically change their current lifestyle and dietary habits. Or, perhaps the non-universal acceptance of the lipid hypothesis was because there wasn’t enough information regarding the biochemistry surrounding how cholesterol wreaks havoc in our bodies. And then the work of Gofman became more relevant.

Enter Donald S. Fredrickson. Fredrickson realized the potential of Gofman’s findings regarding how cholesterol was carried in the blood and became convinced that the pattern of cholesterol carriers – known as lipoproteins - was a valuable approach to determining cardiovascular disease risk. Building on Gofman’s research, Frederickson and his colleagues brought lipoprotein science into the clinical setting, busting open the field of lipoprotein metabolism as it relates to atherosclerosis. Still, there were many questions regarding the regulation of lipoprotein level in the blood, especially that which surrounded the matter of nature versus nurture.

Whether there was a genetic component to high cholesterol and cardiovascular risk was a question that fueled a young postdoctoral scientist working in the laboratory of Arno G. Motulsky at the University of Washington. In 1973, Joe Goldstein, now considered to be one of the founders of modern cholesterol research, was one of the first to genetically classify the types of cholesterol-carrying lipoproteins in the blood. However, it was when Goldstein teamed up with Michael Brown – a collaboration that would lead to the 1985 Nobel Prize in Physiology or Medicine – that the genetic regulation of cholesterol metabolism was realized. In a series of research papers published in the 1970s and 1980s, Brown and Goldstein not only how a critical enzyme involved in the generation of cholesterol was regulated, but also elegantly showed that there is a genetic basis behind the inability to remove a pro-heart disease form of cholesterol called low density lipoprotein (LDL) from the blood.

Thanks to Brown and Goldstein, a target for cholesterol therapy was finally identified; however, there was yet to be an actual drug on the market. Proof was still needed that lowering LDL cholesterol will lower ones risk of heart attacks and strokes, and this had to be accompanied by proof of efficacy. The clinical trial that sealed the deal, ending cholesterol’s long road to being taken seriously as a primary cardiovascular disease risk factor, was the Coronary Primary Prevention Trial (CPPT), launched in 1973 by the NHLBI Lipid Research Clinics. This randomized, double blind study showed that lowering blood cholesterol (in this case using cholestryamine – a compound that prevents the intestinal reabsorption of cholesterol and promotes its removal via excretion in the feces) leads to a reduction in heart attacks.

When these data were published in the early 1980s1, there was a consensus among many in the medical community that the lipid hypothesis was correct. Furthermore, the evidence linking cholesterol to cardiovascular disease resulted in many programs and policies aimed at both educating the public about dietary management of blood cholesterol levels and exploring new methods for treatment. This opened up a new area for research and, of course, a new area for cholesterol controversy.

Deconstructing Cholesterol: “Bad” is still bad, but is “good” still good?

Now that a “lipid panel” has become a standard part of the medical check-up, we are easily provided with an extremely valuable, personalized metabolic snapshot. But, the information can also be overwhelming. In the lipid panel, we will see cholesterol broken down into basic components: HDL, which stands for high density lipoprotein; and LDL, an acronym for low density lipoprotein. Added together, they make up most of our total cholesterol.

Because high levels of LDL cholesterol in the blood have been shown to promote atherosclerosis, this form of cholesterol has been appropriately nicknamed “bad cholesterol.” However, whether or not HDL – known to many as “good cholesterol” - can save the day is up for debate. When studying cholesterol characteristics in the population, there is some indication of an inverse relationship between HDL levels and cardiovascular risk. In other words, it seems like high HDL is correlated with low heart attack numbers.

From a mechanistic standpoint, this makes sense. In the body, HDL acts to remove cholesterol from specialized cells called macrophages, which helps to prevent the build-up of cholesterol in our blood vessels. Furthermore, it has been proposed that HDL has antioxidant and anti-inflammatory properties, which are beneficial when it comes to heart disease. But, it isn’t always that simple. In some contexts, HDL can become damaged, transforming into something that actually promotes damage to our blood vessels. Thus, HDL levels may not be an informative parameter at the individual level.

The idea that raising HDL might be beneficial came from clinical studies, including the coronary Drug Trial (1965-1974), where the effects of niacin were examined. To date, niacin is the most effective FDA approved means of raising HDL-cholesterol. Interestingly, niacin also lowers LDL-cholesterol, as well as another type of blood lipid called triglycerides. Because of this, it is hard to tease out whether the protective effects of niacin are actually related to raising HDL levels. Fibrates, such as TriCor or Lopid, are another class of compounds that can significantly raise HDL levels, but, like niacin, these drugs also affect LDL and triglycerides.

Despite some of the uncertainties, several pharmaceutical companies were driven to explore potential cardio-protective effects of specifically raising HDL levels in the blood stream. Based largely on the work of Alan Tall at the Columbia University Medical Center, many pharmaceutical labs are working on targeting a molecule in our body called cholesteryl ester transfer protein, more easily referred to as CETP. Studies have shown that blocking the action of CETP leads to an increase in HDL levels in the blood, and, based on the notion that increased HDL is beneficial, it is thought that these drugs would be a great option to what we already have on the market. However, the first drug trial investigating a CETP-inhibitor had disastrous consequences.

When administered alone, torcetrapib – a CETP inhibitor drug produced by Pfizer – was shown to increase HDL levels without significantly affecting LDL levels. The hope was that this biochemical data would translate into a heart-protective effect in humans. However, a clinical trial showed that when provided in combination with another cholesterol-lowering medication called a statin (we will get to these later), torcetrapib treatment was associated with a 50% increase in deaths from cardiovascular disease compared to placebo. These results occurred because torcetrapib was reported to increase blood pressure.

Some of the criticisms regarding torcetrapib surrounded the idea that this was not a “pure” medication, especially considering that the blood pressure effect does not seem to be associated with the mechanism of torcetrapib action. And it is this reasoning that the idea of CETP inhibition has not been totally abandoned.

Many have high hopes for Merck’s CETP inhibitor anacetrapib. In a Phase III study, it was reported that anacetrapib had significant HDL-raising effects when administered to patients already taking a statin, and this was without any of the off-target effects seen with torcetrapib.

However, do HDL levels really matter if LDL levels are in check? In other words, is their any benefit to raising HDL levels if LDL levels are adequately treated? Conclusions from the AIM-HIGH study suggest that the answer is no. In May of this year, the NHLBI announced that they would be prematurely halting this clinical study, which was investigating the effects of taking niacin on top of a statin, citing futility. This decision was made after taking into consideration the negative results from the ACCORD lipid study, which showed that taking a fibrate in combination with a statin provided no extra benefit for diabetic patients.

This certainly creates a fair amount of confusion when it comes to the current “HDL is good” dogma, and many doctors are reconsidering how they treat patients with low HDL levels if LDL is low or normal. Given the currently available data, LDL appears to be the major risk factor when it comes to cardiovascular disease susceptibility. Should we re-interpret the early studies showing an association between high HDL and a lower incidence of heart attacks?

As the investigation into the efficacy of anacetrapib moves forward, perhaps we will become more informed. But what is the point if it is only being tested on top of a statin? To truly know the benefits of raising HDL, pwe need to find a way to only study the effects of altering HDL levels. However, there are always ethical considerations to take into account. It is not good practice to prevent a patient from taking a medication that is known to be beneficial to their condition, just so we can make a point in the name of science.

But, science and medicine is not (and should never be) a “one size fits all” philosophy and there are many who would benefit from knowing if raising HDL levels is a true, stand-alone alternative. This is certainly quite relevant when speaking about the percentage of the population who just cannot tolerate statin therapy because of unwanted side effects. There has got to be a way to ensure that everyone has an equal chance at fighting heart disease and perhaps it is time to restructure our current approach.

Cholesterol confusion and why we should rethink our approach to therapy

For many high-risk patients who do not respond to diet and exercise, getting their LDL levels in check is as simple as taking a statin. Statins are drugs that inhibit the natural ability of our body to generate cholesterol and result in the reduction of LDL cholesterol in the blood. These medications have certainly helped many, especially those who are genetically predisposed to high cholesterol levels due to heredity. However, there are some who just cannot tolerate statin therapy and, therefore, we need to be able to provide them with more options.

All statins have been reported to be associated with adverse side effects, especially when administered at high doses2. These side effects include memory problems, sleeping issues, and, most commonly, that which is associated with muscle. For some, these muscle issues might just be minor. For others, however, statin use may come with more serious muscle problems, and this is catching some attention (see this post by Laura Newman). Based on this, as well as results published in November of 2010 in the Lancet, which reported a significant increase in the number of patients experiencing a muscle condition called myopathy as a result of high-dose statins (80mg per day), the FDA has issued the following safety announcement:

[06-08-2011] The U.S. Food and Drug Administration (FDA) is recommending limiting the use of the highest approved dose of the cholesterol-lowering medication, simvastatin (80 mg) because of increased risk of muscle damage. Simvastatin 80 mg should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle injury (myopathy). Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drug. In addition to these new limitations, FDA is requiring changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines.

The reported frequency of adverse side effects relating to statin usage is 5% in randomized clinical trials, but can reach up to 20% in the clinic3,4. It is thought that this discrepancy arises because of patient selection in these randomized clinical trials, which generally tend to exclude groups (such as women or the elderly) who have a higher rate of statin intolerance. Furthermore, patients who are heavy drinkers, those who have a pre-existing condition (such as diabetes), or those taking a cocktail of medications are typically excluded. Yet, these people are prescribed statins in real life.

As of right now, there is no standardized treatment for patients who develop adverse side effects to statin therapy. In a perspective article published in the New England Journal of Medicine (online November 15, 2011)5, Patricia Maningat and Jan Breslow from The Rockefeller University address this issue, citing the need for pragmatic clinical trials for statin-intolerant patients.

As opposed to randomized clinical trials, which usually involved a homogenous patient population, pragmatic clinical trials would be more applicable to a real-world setting, providing detailed information so that caregivers and policy makers can determine more personalized treatment options. These authors also note the fact that most new therapies are tested on top of statins, therefore making it impossible to determine if these drugs are effective as stand-alone treatments for patients who cannot tolerate statins.

There are many who joke that statins should be added to the drinking water, and with the exponentially growing number of those prescribed statins, they might as well be. There is no doubt that the rising number of statin users will be associated with increased reports of negative side effects. The implementation of pragmatic clinical trials may not be the most cost-effective strategy, nor would the study design prove to be easy, but it is important that we effectively meet the needs of every patient who has high cholesterol. The current standard of care is out of date and it is high time that we began a dialogue to correct this.

Additional Reading

References not hyperlinked

[1] The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in incidence of coronary heart disease. JAMA 1984 Jan 20;251(3):351-64.

[1] Bays H. Statin safety: An overview and assessment of the data—2005. AmJ Cardiol 2006;97(8A):6C-26C.

[1] Armitage J. The safety of statins in clinical practice. Lancet 2007; 370(9601):1781-90.

[1] Radcliffe KA, Campbell WW. Statin myopathy. Curr Neurol Neurosci Rep 2008; 8(1):66-72.

[1] Maningat P, Breslow JL. Need: Pragmatic clinical trials for statin-intolerant patients. NEJM 2011