What’s in the web for family physicians - the cholesterol and statin controversy

Sio-pan Chan 陳少斌，Wilbert WB Wong 王維斌，Alfred KY Tang 鄧權恩

The "war" on cholesterol has been going on for over a century. As early as 1913, Nikolai Anitschkow showed that feeding rabbits with cholesterol could induce symptoms similar to atherosclerosis and first laid the foundation of the “lipid hypothesis”. However, similar experiments with dogs and mice failed to reproduce the same results. In 1945, President Franklin Roosevelt died of a sudden heart attack, hence aroused much concern about the cause of myocardial infarction. Three years later, the Framingham Heart Study was initiated by the National Health Institute (NHI) to study the causality of Coronary Heart Disease (CHD). It was demonstrated that cigarette smoking increases risk of heart disease. Increased cholesterol and elevated blood pressure also increase the risk of heart disease. Exercise decreases risk while obesity increases risk of CHD. On the other hand, it is known that people with some form (not all) of familial hypercholesterolaemia had a much higher incidence of CHD. So cholesterol was portrayed as the culprit and pharmaceutical companies were racing to develop a “cure” for atherosclerosis.

Pathogenesis of atherosclerosis

The exact pathogenesis of atherosclerosis has long been a subject of debate. It is a complex multi-factorial process in which blood lipids play an important role. It is postulated that the primary aetiology of atherosclerosis is endothelial damage by various insults, common agents include genetic predisposition, hypertension, smoking, diabetes, stress and other oxidative stressors. Once the smooth endothelium is damaged, very small particle size lipoproteins including very low-density lipoproteins (VLDL-C) and Apolipoprotein B (ApoB), can enter the sub-endothelial layers and are oxidised to low density lipoproteins (Ox-LDL). Ox-LDL attracts monocyte infiltration. Monocytes combine with Ox-LDL and transform into macrophages. The scavenging macrophages take up more Ox-LDL and turn into foam cells, thus initiating and perpetuating a local vascular inflammatory response. This chronic inflammatory state leads to plaque formation and atherosclerosis. LDL-C itself is an antioxidant and its presence in the plaque is likened to firemen trying to contain damages, rather than the "bad" guy to be blamed. If the present atherosclerosis theory is correct, could we be fighting the wrong enemy for over the last few decades?

Interpretation of "lipid profile"

Almost all family doctors are performing cholesterol or lipid profile checks routinely for their patients. If the lipid profile revealed high total and LDL-C (despite lifestyle and diet modification), prescribing statin may not be the appropriate option and further evaluation of the lipid profile is needed. Ideally a lipid profile should include VLDL and ApoB value. The “bad” cholesterol, LDL-C, actually represents a very heterogeneous group of low density lipoproteins of various particle sizes. The smaller the particle size, the higher the chance that the lipoprotein (including ApoB) can enter a damaged endothelial surface and become oxidised and then initiates the atherosclerosis process. For practical and economical reason, it is not always practical to perform VLDL and ApoB test, a simple indication of how much VLDL is present in the serum can be estimated by the level of triglycerides.

If the level of triglycerides is within normal limit, a general guide is VLDL-C = 1/5 x triglycerides. So people with very low triglycerides probably do not need treatment even if their LDL-C is high. Furthermore, simple calculation of the total cholesterol/ HDL-C ratio and the non-HDL (subtracts HDL-C from total cholesterol) are claimed to be more accurate indicators of atherosclerosis risk. ApoB is usually included in the more elaborated lipid profile test. The higher the Apo-B level, the higher the risk of atherosclerosis.

The physiological role of LDL-C

After millions of years of evolution and natural selection, it is hard to comprehend why nature can leave so much "harmful" cholesterol in our body. Cholesterol is there for a reason. It is one of the most important chemical compounds in evolution for the very existence of life form. LDL-C is the fundamental building block of our steroid hormones, bile, vitamin D and many other important chemicals. Pure cholesterol is insoluble in water, it needs different lipoprotein molecules to make it soluble in our blood, such lipoproteins are high density lipoprotein which makes up the HDL-C which carry cholesterol to the liver and low density lipoproteins which makes up the LDL-C to transport it out of the liver. LDL-C is actually an antioxidant which protects us from oxidative stresses. It is also responsible for the repair and maintenance of cell membrane integrity, host defence against bacterial, viral and other infections, cancer surveillance and modulation of inflammation. Cholesterol is so important to our brain that the brain cells manufacture their own cholesterol, independent of the liver.

The Discovery of statin

Ever since cholesterol was targeted to be the culprit in CHD, the pharmaceutical industry had come up with various agents for lowering cholesterol. After unsatisfactory results with nicotinic acid, clofibrates, cholestyramine and compactin, they eventually came up with the ultimate weapon, the statins.

Lovastatin, a HMG-CoA reductase inhibitor, was the first FDA approved statin for commercial use in 1987. Since then statins had become the cornerstone in the treatment of hypercholesterolaemia and CHD. Lipitor is the single most lucrative medicine in history. Statins are proven to be very effective and safe in lowering cholesterol, but does the widespread use of statins actually lower the incidence of CHD and stroke? Many recent large scale meta-analysis studies have cast doubts on the present cholesterol paradox, i.e. that cardiovascular disease (CVD) deaths continue to be the leading cause of deaths in places where statins are used most liberally.

The role of statin in CVD primary prevention

There is little argument in the role of statins in secondary CVD prevention, i.e. those who already had a cardiovascular event. Its role in primary prevention is much more controversial. Lay people and even some medical professionals may have a misconception that taking a statin will protect one from having a heart attack. Popular press often quotes a 30% reduction rate of heart attack if someone is taking a statin. In fact that cannot be more far from the truth. People are often confused with regard to a relative risk reduction from an absolute risk reduction, equally important is the number of need-to-treat in order to reduce a single incidence of cardiovascular diseases. According to many metaanalysis studies, the absolute risk reduction is about 1% and 80 persons have to take statin for five years in order to reduce a single myocardial infarction (MI). One big question remains, if statins are very effective in preventing CVD, why CVD still remains the number one killer after 30 plus years of using statin? In fact, it was demonstrated that 70% of patients with MI have normal levels of cholesterol. One school of thought suggests that it is because we are not treating cholesterol aggressively enough and advocates high intensity and maximally tolerated statin. The present trend for primary prevention of CVD inclines to allow the patients at risk to make their own informed choice on whether to start on statin treatment. After all, cholesterol is but one of the many factors, in addition of life-style changes, weight reduction and diet, etc to prevent CVD.

Safety issues on aggressive cholesterol treatment

Although statins are generally considered to be very safe, just like any other useful medication, statins are not without side effects, and many of them are dose related. At present the ACC/AHA guidelines recommend that "In patients with clinical ASCVD, reduce low-density lipoprotein cholesterol (LDL-C) with high-intensity statin therapy or maximally tolerated statin therapy", typical dose of such are atorvastatin 80mg or rosuvastatin 20 to 40mg. One must consider the potential risk to benefit ratio. Well known side effects of high dose statin include myalgia, myopathy, rhabdomyolysis, diabetes and possibly memory loss and cognitive impairment. In fact, the Mayo Clinic website listed five possible side effects with very low cholesterol, namely, cancer, haemorrhagic stroke, depression, anxiety and preterm birth and low birth weight.

It is difficult to find independent research papers that are not heavily sponsored, e.g. the IMPROVE-IT Trial or the JUPITER Trial. So we prefer to choose an independent paper whose authors have no conflict of interest to declare. Most studies focused on secondary prevention and the consensus is “the earlier, the lower, the longer, the better” with regard to LDL-C treatment. Most other studies claimed that the side effects from very low LDL-C were almost negligible. This paper has more or less the same conclusion that a lower LDL-C does reduce overall cardiovascular events with no apparent increase in risk of side effects from treatment. However, at the conclusion of the paper, the authors mentioned, “Nevertheless, we have to wait for the result of ongoing trials to have a conclusive answer on the long-term effect of lowering the current LDL goal.”