Cholesterol Paradox: A Correlate Does Not a Surrogate Make – Robert DuBroff – Evid Based Med. 2017
The global campaign to lower cholesterol by diet and drugs has failed to thwart the developing pandemic of coronary heart disease around the world.
Some experts believe this failure is due to the explosive rise in obesity and diabetes, but it is equally plausible that the cholesterol hypothesis, which posits that lowering cholesterol prevents cardiovascular disease, is incorrect.
The public is certainly not aware that lowering cholesterol to prevent heart disease is just a theory because, as is the case with most things medical, it is presented as a fact.
This is exactly what has happened with opioids, making the public believe that these effective medications are useless for chronic pain and always horrendously addictive for all people under all circumstances.
The recently presented ACCELERATE trial dumbfounded many experts by failing to demonstrate any cardiovascular benefit of evacetrapib despite dramatically lowering low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol in high-risk patients with coronary disease.
This clinical trial adds to a growing volume of knowledge that challenges the validity of the cholesterol hypothesis and the utility of cholesterol as a surrogate end point.
In clinical trials, a surrogate endpoint (or marker) is a measure of effect of a specific treatment that may correlate with a realclinical endpointbut does not necessarily have a guaranteed relationship. The National Institutes of Health (USA) defines surrogate endpoint as “a biomarker intended to substitute for a clinical endpoint”.
Inadvertently, the cholesterol hypothesis may have even contributed to this pandemic. This perspective critically reviews this evidence and our reluctance to acknowledge contradictory information.
The cholesterol hypothesis has been debated for years, but in light of recent clinical trial results, a reappraisal of the evidence is warranted.
Cholesterol is an ostensibly ideal surrogate target: it is present in atherosclerotic plaque; cholesterol is an established risk factor for CHD; Mendelian randomisation studies suggest benefit from lifelong reduced cholesterol levels and cholesterol-lowering drug trials have reduced the risk of cardiovascular (CV) events.
Consequently, it seemed impossible that the gold standard of modern medical research—a large, double-blind, randomized controlled trial (RCT)—could undermine, rather than confirm, this theory.
Yet the ACCELERATE trial reported that evacetrapib, a novel cholesteryl ester transfer protein inhibitor, reduced low-density lipoprotein (LDL) cholesterol by 37%, raised high-density lipoprotein (HDL) cholesterol by 130%, but produced no discernible reduction in CV events or mortality in high-risk patients.
I believe the ACCELERATE trial adds to the chorus that cholesterol is not a valid surrogate end point.
Many experts cite numerous RCTs of statins in support of the cholesterol hypothesis, but we should not ignore the dozens of cholesterol-lowering trials that do not.
Table 1 lists 44 cholesterol-lowering RCTs that reported no mortality benefit. Most reported no reduction in CV events, and several reported substantial harm (CDP, HERS, Minnesota Coronary Experiment, Sydney Diet Heart Study, WHI, WHO).
This lack of benefit was seen even with profound reductions in LDL cholesterol (50% in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial).
A recent analysis concluded that statins would only postpone death by a median of 3.1 and 4.2 days for primary and secondary prevention, respectively
Finally, consider that the cholesterol hypothesis may have inadvertently contributed to the very disease we seek to prevent.
The cholesterol hypothesis risks oversimplifying the complex interaction of cholesterol, diet and coronary disease, leading many statin users to overeat with consequent obesity.
the food industry developed and continues to promote low-cholesterol foods that are nonetheless high in sugar and refined carbohydrates. These dietary changes have likely contributed to the current epidemic of obesity and diabetes that can lead to CV disease.
The empirical record is now clear that lowering cholesterol through diet or with eight different classes of drugs does not significantly prolong life or consistently prevent CHD.
Yet experts continue to proclaim the success of cholesterol-lowering.
Fifty-four years ago, Thomas Kuhn described this reluctance to acknowledge anomalies in a theory
Dr Kuhn wrote that a paradigm shift would only occur when the evidence contradicting a theory is overwhelming. Therefore, we must accept the empirical record even though it contradicts our long-held beliefs.
Other researchers believe this reluctance can be explained by the tendency to “see what you want to see,” and ignore what you do not.
The debate over the cholesterol hypothesis has continued because the results of cholesterol-lowering interventions are inconsistent and contradictory.
Nevertheless, clinical guidelines continue to emphasize the critical importance of cholesterol-lowering to prevent CHD. Unfortunately, I believe this one-dimensional approach may have impeded the advancement of science and our search for other preventive strategies.
Evid Based Med. 2017;22(1):15-19. © 2017 BMJ Publishing Group