An informative overview of statin mechanisms was recently published (Medicine Weekly 26 Sept.2006) in which the authors promote the safety of statins, their efficacy in stroke reduction and their benefits to patients with Acute Coronary Syndrome (ACS). (Drs. Vaughan and O’Sullivan).
Their review of current literature serves to establish HMG CoA reductase inhibitors as powerful lipid lowering agents in patients with elevated, average and below average cholesterol levels.
The authors outline the mechanisms of statin activity in reducing hepatocyte cholesterol content by exploring the metabolic pathways of the P(Cyt)450 and its related systems, and illustrate, with reference to various trials, the benefits of HMG CoA reductase inhibition, while alluding also to possible toxicity and potential side effects, particularly through competition with other drugs metabolised via the CYP 3A4 system.
There is also a passing reference to genetic variations of CYP 450 producing the inevitable and undesirable side-effects of statin therapy.
The authors attribute the benefits of statins to the pharmacological lowering of elevated LDL- C, but fail to provide conclusive evidence that LDL-C lowering, in itself, causes atheroma reduction and thereby improves cardiovascular mortality.
Despite the identifiable association between elevated LDL-C and coronary atherosclerosis, a causal relationship has not been demonstrated and the authors acknowledge this.
These factors call into question the relevance, and thus the wisdom, of LDL-C lowering strategies, and challenges the rationale for guidelines which encourage LDL-C lowering without taking account of lifestyle factors and individual risk status of the patient concerned.
As early as the 1980s some researchers reported that LDL-C was not a reliable independent risk factor for coronary heart disease (CHD) since half of those who suffer with CHD have been shown to have LDL-C levels within normal limits.
In the Women’s Health Study, 28,000 participants had their LDL-C levels measured and cardiovascular status evaluated, and 46% of the first cardiovascular events were noted in women who had LDL-C levels lower than the recommended targets of 3.3 mmol/L.
However, the practice of aggressive statin therapy, aimed at maximal reduction of LDL-C, is widely promoted and continues to be encouraged by some researchers, while others question the lack of clinical evidence for such practices, and emphasize that the mortality benefits of statins have only been evident in a select group of patients, namely middle-aged males with established cardiovascular disease.
The observed benefits of statins, as in these cases, has not been conclusively shown to result from LDL-C reductions , but derive from several mechanisms other than cholesterol synthesis inhibition.
In addition to the lowering of LDL-C through HMG CoA reductase inhibition, statins also inhibit nuclear factor Kappa Beta (NF-kB), by about 50%, a vital factor in inflammation response which is linked to endothelial dysfunction and atherosclerosis.
Inhibition of NF-kB also alters the effectiveness of the immuno-defence system generating additional risks for immuno compromised patients. It follows then, that statin-induced NF-kB inhibition increases the risks of infection and malignancy by suppressing inflammation. (Thereby also providing a useful therapeutic tool in treating organ transplant recipients, a likely area of future use.)
It is likely that these and other anti-inflammatory mechanisms, unrelated to LDL-C lowering are implicated in the scenario of stroke and myocardial ischaemia reduction. (Natural Medicine 6: 1399-1402, 2000).
But these mechanisms may also underlie some of the many unwanted consequences of statin therapy.
The PROSPER trial reported an increase in the incidence of cancer death in participants using statins, thereby off-setting the slight decrease in death from cardiovascular disease.
Dr. Paul Rosch warns of this potential danger and predicts the emergence of more cases of statin-induced cancer. (Proceedings of the Western Price Foundation Meeting, 2003) The Japan Lipid Intervention (J-LIT) trial reported 12 cancer deaths in a group whose cholesterol was reduced by excessive HMG CoA reductase inhibition.
The observed benefits attributed to the anti-inflammatory effects of statins, do not, however, relate to levels of cholesterol reduction, since numerous studies show that minimal LDL-C reductions provide sufficient reductions in coronary risk reduction.
In the large West of Scotland Coronary Prevention Study (WOSCOPS) the researchers expressed surprise that larger decreases of LDL-C were not associated with greater benefit, and in the widely publicised CARE trial (Cholesterol and Recurring Events) moderate reductions of LDL-C equated with coronary risk reduction which was not improved with further LDL-C reductions.
The researchers stated that “no further decline (in coronary problems) was seen in the LDL-C ranges below 3.2 mmol/L”
Since the majority of patients given statin drugs are not at high risk, despite having mild to moderate elevations of cholesterol, the rationale for widespread policy of aggressive cholesterol lowering needs to be reviewed, and physicians should be appropriately cautioned about the attendant risks involved in so doing.
Lowering cholesterol in otherwise healthy subjects confers no benefits and increases the possibilities of serious adverse events. In an independent, evidence based analysis funded by the Ministry of Health of British Columbia, Canada, the researchers state “statins have not been shown to to provide an overall health benefit in primary prevention trials”
Lowering LDL-C in subjects who do have Coronary Heart Disease (CHD), and who may thus be at greater risk, has been associated with clinical benefit, but, as stated above, these benefits have never been causally related to LDL-C reduction.
It is therefore possible, that the favourable mechanisms that produced these benefits could be equally provided by anti-inflammatory interventions other than statin therapy.
Many non-statin forms of anti-inflammatory remedies are available, which have been widely used with marked benefit and proven safety.
These include Omega-3 essential fatty acids, nicotinic acid (Niacin), Inositol Hexaniacinate, Policosonal and Plant Sterols, the latter being recommended by the American Heart Association (AHA) –(AM. J. Managed Care 2002).
Dietary interventions have also been shown to provide cardiovascular benefits by reducing atherosclerotic plaque.
In 1998 the Journal of American Medical Association (JAMA) reported the marked clinical benefits of intensive lifestyle changes (Lifestyle Heart Trial) and concluded, “more regression of coronary atherosclerosis occurred in the experimental group. In contrast, in the control group, coronary atherosclerosis continued to progress and more than twice as many cardiac events occurred”.
In the Lyon Diet Heart Study, a mediterranean diet after a heart attack markedly reduced the rate of recurrent heart attack and significantly prolonged life with no change in blood cholesterol levels. LDL-C levels were unchanged.
Despite the beneficial anti-inflammatory effects of statins in select groups of patients, there exists the potential for long term undesirable effects through their unavoidable inhibition of ubiquinol (coenzyme-Q10) production by the liver.
Ubiquinol is a fat-soluble antioxidant and key mitochondrial nutrient in adenosine triphosphate (ATP) production, and widely distributed throughout the body. The benefits of CoQ10 have been widely published by cardiologists Karl Folkers and Peter Langsjoen who document many cases of statin induced cardiomyopathy and several related muscle disorders, such as myositis and rhabdomyolosis through CoQ10 inhibition.
Polyneuropathies (more common) resulting from similar mechanisms causing cellular membrane damage are reported by Gaist and others. (Neurology 58, 2002, p 13333-37).
In Canada the packaged Lipitor warning labels include alerts about Co. Q10 depletion, exposing physicians to risks of litigation for statin induced damage to patients in the absence of supplemental Co Q10 .
Despite the frequent assurances of safety from proponents of statin therapy, there remains legitimate concerns about harmful effects which appear to be underestimated and underreported. Serious adverse effects have been documented in the past (BMJ 2006;332:1330-1332) which include heart failure, myalgia, rhabdomyolysis, neurological desturbances, and cancer, and with the current promotion of aggressive statin therapy there are growing concerns about the unpredictability of long term statin safety.
Baycol was withdrawn in 2001 after several reported deaths from its use, and many currently used statins have been implicated in harmful and potentially fatal reactions. The short term studies from which we derive our limited information are not adequate to predict long term effects and prescribing doctors need to be vigilant about these potential hazards for unsuspecting patients.
An increasing number of cases of Transient Global Amnesia (TGA) are being reported with statin use.
TGA has long been an enigma, and more recently defined by Perigee and Golomb as a statin associated cognitive manifestation. Dr. L.R. Wogstaff reports 60 cases confirming similar findings. (Pharmacotherapy 23, 871-880, 2003).
The potential of statins for violating cellular membrane integrity presents an additional threat to diabetic patients, many of whom are on statins for lipid control, and are already at risk of peripheral neuropathy.
The possibility of this “side” effect calls for careful and responsible approaches to therapy by physicians treating diabetic patients who many be using statin drugs.
Recent evidence also points to strong associations between excessive lipid lowering and behavioural problems, a consequence of dolichol inhibition, another unavoidable action of statins, reportedly thereby causing impaired neuropeptide formation.
Symptoms of aggressiveness, hostility, depression, drug addiction, and suicidal thoughts have been implicated in excessive lowering of cholesterol by high dose statin therapy through this mechanism (Golomb, University of California, and Kaplan, Yale University.)
When the vital role of cholesterol as a synaptogenic factor in the human brain is considered it is not surprising that interference with life maintaining hormone synthesis can result in such gross patterns of abnormal behaviour.
These potential effects have prompted some researchers to call for judicious use of high dose statins, maintaining that the required anti-inflammatory effects are adequate even at low doses.
Matsukazi et al reported in J-LIT decreased cardiovascular risk with fixed low dose statin use.
Current studies such as TNT and SEARCH are in the process of assessing the effectiveness of low dose statins.
Considering the observed benefits of anti-inflammatory mechanisms, markers of cardiovascular inflammation have received much attention in recent literature, noteworthy amongst these being CRP, Homocysteine, fibrinogen, insulin, and iron.
These, amongst others, are currently receiving attention as independent risk factors for cardiovascular disease, and are regarded by many researchers as being more significant than LDL-C in this regard. (New England Journal of Medicine, 2005, Jan 6; 352).
Low levels of HDL-C are, likewise, shown to be independent risk factors which are not effectively improved by statins, whereas nicotinic acid (Niaspan ) has been shown to raise low HDL-C levels by up to 35%.
Statins have a recognised role to play in the secondary prevention of cardiovascular disease acting through a variety of molecular mechanisms, but their beneficial role in primary prevention has not been convincingly demonstrated.
Furthermore, their potential for serious adverse consequences has been underestimated and deserves greater recognition and vigilance from prescribing doctors.
Low dose therapy should be encouraged where and when they are indicated, with a high index of awareness for potential toxicity in long term usage.
Safe, inexpensive and effective alternative strategies are readily available to clinicians when statins are perceived to be inappropriate, and patients should be encouraged to consider these options.
It is assumed that serious efforts at patient life-style modification, stress reduction, and nutritional support have been attempted prior to resorting to pharmacological strategies.