Cholesterol had become the indisputable villain for heart disease over the last several decades.  After all, it seemed intuitive that cholesterol was the cause of heart disease, since cholesterol made up a large portion of the vascular plaque that characterized atherosclerotic heart disease.  But as the understanding of cholesterol metabolism has become better delineated, the connection between cholesterol and the cause of heart disease has become considerably more tenuous, and the role of statin drugs questionable.

 Data from the landmark Framingham Heart Study revealed that the distribution of cholesterol levels among individuals that had a heart attack and those that did not essentially mirrored each other.  That means at any given cholesterol number, the chance is equally good that you will or will not have a heart attack.  In another very large study looking at the lipid numbers of more than 136,000 people admitted to hospitals across the country with coronary artery disease, more than 70% of those individuals had LDL (“bad”) cholesterol numbers in the “normal” range, and 50% had numbers considered in an “optimal” range.[i]

 Most heart attacks occur in people who have “normal” cholesterol.  So, using cholesterol as the predictor of a future heart attack is not even as good as flipping a coin.   This is borne out by the facts   There has been a concerted and aggressive focus on lowering cholesterol over the last two or three decades, yet heart disease remains the leading killer of people worldwide.  A number of studies have suggested that total cholesterol and LDL levels have been decreasing in the general US population.[ii]  In the United States, heart disease kills more people than the next five causes combined; including all cancers. Cholesterol, it seems, may be found at the scene of the crime but is not necessarily the guilty party.  Many factors go into the development of arterial plaque and heart disease.

 Cholesterol is carried in the blood in a variety of different proteins.  Each of these particles contains cholesterol, triglycerides and lipoproteins.  HDL cholesterol (“good”) has different lipoproteins than LDL cholesterol (“bad”).  Within each class, the particles differ in size and density.  Simply measuring LDL tells nothing about the particle size or number.  The ability of cholesterol to penetrate the arterial lining is dependent on the amount of inflammation present, type of lipoprotein carrying it, the particle size and number rather than on the total level of cholesterol in the blood.  Two of the most important sub-particles are Apolipoprotein (apo) B, a component of LDL and apo A-1, a component of HDL.  Several large prospective studies have clearly shown that Apo B/Apo AI ratio is a superior marker of CHD risk to all conventional markers.[iii]  These measurements can be made using one of several sub-particle tests; the most common being the VAP or LPP tests.

 It has become increasingly clear that chronic silent inflammation plays a critical role in the development of atherosclerotic heart disease.  Markers of inflammation, such as C-reactive protein, homocysteine, interleukin-6 and tumor necrosis factor (TNF alpha) have been associated with an increased risk of heart disease.  According to the American Heart Association, “high-sensitivity C-reactive protein (hs-CRP) levels are an independent marker of cardiovascular disease risk.”[iv]  And, elevated homocysteine levels were associated with increased risk for mortality in patients with coronary artery disease.[v]

 Statin drugs were developed to treat high cholesterol and have been prescribed with alarming frequency to reduce cholesterol to ever lower and lower numbers.  It seems that the process to lower cholesterol has taken on a life of its own, even in the face of scientific reviews questioning the benefit of that approach.  Statin drugs are not without risk.  They frequently cause people taking them to feel fatigued and old.  They deplete coenzyme-Q10, which is central to cellular energy production and heart health.  They can also cause muscle pains and weakness, flu-like symptoms, liver dysfunction, peripheral neuropathy, cognitive impairments, total global amnesia and interfere with neuro-synaptic transmissions in the brain.

 Despite marketing efforts to the contrary, the results of recent cholesterol-lowering drug trials on decreasing morbidity and mortality among persons with or without coronary heart disease (CHD) have been consistently negative.[vi] [vii] [viii] [ix] [x]Although some statin drugs, most notably Lipitor, have been shown to lower heart attack risk and lower cholesterol, it is now believed that those are two independent effects.  The latest scientific information suggests that statins reduce heart attack risk by reducing silent inflammation; the same risk reduction mechanism attributed to fish oil, stress reduction and healthy lifestyles.  All of the latter do not carry the potential risk of statin side effects and are quite a bit less costly to implement.  Several studies comparing omega-3 fish oils to statins demonstrate significant reduction in all cause mortality in heart failure patients taking fish oil, but statins showed no effect on all cause mortality or cardiovascular admissions. 

 One drug, Zetia, illustrates this phenomenon.  It is not absorbed and lowers cholesterol by blocking its absorption in the gut.  It has no effect on blood vessels or systemic inflammation and has failed to demonstrate any effect on the progression of atherosclerosis.  Recent studies have shown participants taking Ezitimibe (active ingredient in Zetia and Vytorin) may actually have an increased risk for cardiovascular events by increasing carotid intima-media thickness.[xi]  So just lowering cholesterol alone has not shown any consistently demonstrated benefit for the prevention of atherosclerotic heart disease.

 Drilling down to the genetic level, carriers of a specific gene variant, KIF6 have been shown to be at significantly increased risk for cardiovascular events.[xii] [xiii]  That gene variant is present in about 60% of the population studied.  Interestingly, those without the KIF6 variant had no significant CHD event reduction with statin therapy.[xiv] [xv]

 One recent pharmaceutical-industry sponsored trial, the JUPITER trial, concluded that giving rosuvastatin (Crestor) to people with normal cholesterol reduced the risk of cardiovascular events by 50%.[xvi]  This reduction was attributed largely to the reduction of inflammation as measured by C-reactive protein.  This sounds impressive until one scrutinizes the raw data.  The study was flawed.  It turns out that the 50% percent risk reduction occurred in less than 3% of the study population.  In other words, there was no effect in more than 97% of participants.  Furthermore, a recent review concluded that “the results of the JUPITER trial are clinically inconsistent and therefore should not change medical practice or clinical guidelines. The results of the JUPITER trial support concerns that commercially sponsored clinical trials are at risk of poor quality and bias. Documentation of the failure of the JUPITER trial to demonstrate a protective effect of rosuvastatin is all the more important as it occurred in the context of the failure of more than 12 other cholesterol-lowering trials published in recent years and in various clinical settings… the time has come for a critical reappraisal of cholesterol-lowering and statin treatments for the prevention of CHD complications. The emphasis on pharmaceuticals for the prevention of CHD diverts individual and public health attention away from the proven efficacy of adopting a healthy lifestyle, including regular physical activity, not smoking, and a Mediterranean-style diet”[xvii]  I couldn’t have said it better myself.

[i] Sachdeva A, Cannon C, et al. Lipid levels in patients hospitalized with coronary artery disease: An analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J, Jan 2009 111-117

[ii] Carroll MD, Lacher DA, Sorlie PD, et al. Trends in serum lipids and lipoproteins of adults, 1960-2002. JAMA 2005;294:1773-81.

[iii] Kulkarni K, Tlwarl H, et al. A Novel Approach to Measure Apolipoprotein B/A1 Ratio Using the Vertical Auto Profile Method. Diabetes Vasc Dis Res 2007;4:266

[iv] Americna Heart Association Scientific Sessions, 2008

[v] Mager A, Orvid K, et al. Impact of Homocysteine-Lowering Vitamin Therapy on Long-Term Outcome of Patients With Coronary Artery Disease. Am J Card. Vol 104, (6), Pages 745-749 (15 September 2009)

[vi] Kastelein JJ, Akdim F, Stroes ES, et al; ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358 (14):1431-1443.

[vii] Cowell SJ, Newby DE, Prescott RJ, et al; Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) Investigators. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl JMed. 2005; 352(23):2389-2397.

[viii] Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non–Insulin-Dependent Diabetes Mellitus (ASPEN). Diabetes Care. 2006; 29(7):1478-1485.

[ix] Tavazzi L, Maggioni AP, Marchioli R, et al; GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomized, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1231-1239.

[x] Barter PJ, Caulfield M, Eriksson M, et al; ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007; 357(21):2109-2122.

[xi] Tatlor A, Villines C, et al. Extended-release Niacin or Ezitimibe and Carotid Intima-Media Thickness. NEJM Nov 26, 2009 (22) Volume 361:2113-2122

[xii] Bare, L, et. al. Five Common Gene Variants Identify Elevated Genetic Risk for CHD. Genetics in Medicine. 2007: 9(10); 682-689.

[xiii] Shiffman, D, et. al. Association of Gene Variants in Incident MI in the Cardiovascular Health Study. ATVB. 2008;28:173.

[xiv] Iakoubova, O, et al. Polymorphism in KIF6 Gene and Benefit from Statins after ACS. Results from the PROVE IT-TIMI22 Study. JACC. 2008; 51(4): 449-455.

[xv] Iakoubova, O, et al. Association of the Trp719Arg Polymorphism in KIF6 with MI and CHD in 2 Prospective Trials. The CARE and WOSCOPS Trials. JACC. 2008; 51(4): 435-443

[xvi] Ridker P, Danielson C, et al. Rosuvostatin to prevent vascular events in men and Women with Elevated CRP. NEJM Nov 20, 2008. (217) Volume 359:2195-2207

[xvii] Logoril M, Salen P, et al. Cholesterol Lowering, Cardiovascular Diseases, and the Rosuvastatin-JUPITER Controversy.  A Critical Reappraisal. Arch Intern Med. 2010;170(12):1032-1036