The link between elevated circulating cholesterol and cardiovascular disease including heart attack and stroke is quite clear, as is the benefit keeping circulating cholesterol low for maintenance of cardiovascular health. Drugs called statins work by inhibiting an enzyme called HMG-CoA reductase that is used by the liver to synthesize cholesterol. Statins therefore result in lowered cholesterol levels in the blood. The reduction of new synthesis causes an increased removal of injested cholesterol from the blood by the liver for normal cell health and excretion in the bile. Statins have proven to be extremely effective aids in reduction of circulating cholesterol levels. On average, statins can lower LDL cholesterol (so-called "bad cholesterol") by 1.8 mmol/l (70 mg/dl), which translates to a 60% decrease in the number of cardiac events (heart attack, sudden cardiac death) and a 17% reduced risk of stroke after long-term treatment.
Statins are beneficial in ways other than simply lowering cholesterol. There is substantial scientific evidence that statins prevent cardiovascular disease by decreasing inflammation in the blood vessels which prevent existing fatty plaque formation from becoming loose and causing strokes, and preventing new formation of plaques.
Statins may even benefit those without high cholesterol. In 2008 the JUPITER study showed fewer strokes and heart attacks for patients who had no history of high cholesterol or heart disease, but only elevated C-reactive protein levels, an indicator of systemic inflammation which may be in the blood vessels and could precipitate coronary artery disease and heart attacks. It is notable that although there were fewer cardiovascular “events”, deaths from cardiovascular causes were not reduced (1).
The best known statin is atorvastatin, marketed as Lipitor and manufactured by Pfizer. By 2003 it had become the best-selling pharmaceutical in history, with Pfizer reporting sales of $12.4 billion in 2008. As of 2010, statins on the market include: atorvastatin (Lipitor and Torvast), fluvastatin (Lescol), lovastatin (Mevacor, Altocor, Altoprev), pitavastatin (Livalo, Pitava), pravastatin (Pravachol, Selektine, Lipostat), rosuvastatin (Crestor) and simvastatin (Zocor, Lipex). Several combination preparations of a statin and another agent—such as ezetimibe/simvastatin, sold as Vytorin—are also available.
Initially, statins were approved to prevent second cardiovascular events, then the label was expanded to enable treatment of individuals with high cholesterol and a second cardiovascular risk factor who have been unsuccessful at lifestyle modification to reduce cholesterol. But, the indication for statins has broadened over the years, and the JUPITER study mentioned above enabled approval of Crestor for apparently healthy men over 50 and women over 60 years old if they have elevated inflammation indicated by increased C-reative protein (CRP) plus one additional risk factor including smoking or high blood pressure. Under those criteria, an estimated 6.5 million people in this country who have normal cholesterol levels and no sign of heart problems will be deemed candidates for statins. That is in addition to the 80 million who already meet the current cholesterol-based guidelines — about half of whom now take statins.
Eventually, will everyone pop a statin every day as a preventative measure? Surely, there are risks to inhibiting HMG CoA Reductase chronically.
The most common labeled side effect are muscle aches, which occurs in about 5% of people taking statins. The mechanism is unknown, and the muscle pain is quickly reversible when the drug is withdrawn. Because muscle aches are so common in the general population, to definitively pin the cause on the statin, the physician should recommend stopping treatment. If the muscle pain goes away, switching statins often is successful at enabling continued treatment without any further side effects.
A second rare, but recognized side effect is liver damage. The most common liver-related problem is mild elevations in blood levels of liver enzymes (ALT and AST) without symptoms in 0.5% to 3% of patients who take statins. These abnormalities improve or completely resolve upon stopping the statin or reducing the dose without any permanent liver damage. Very rarely, severe liver damage has been reported in patients on statins. The frequency of severe liver disease caused by satins is likely in the range of 1-2 per million users. As a precaution, the FDA labeling information advises that liver enzyme blood tests should be performed before and 12 weeks following the initiation of statin treatment or increase in dose, and once or twice a year thereafter.
Recently there was a report in Lancet (2) which linked a slightly higher level of diabetes to patients on statins. The researchers examined 13 statin clinical trials with 91,140 patients and concluded that there was a 9% increased risk of developing diabetes in the patients taking statins. To put the findings into context, treatment of 255 patients with statins for 4 years would give one extra case of diabetes—but, for 1 mmol/L reduction in LDL (bad) cholesterol concentrations that statins would cause, the same 255 patients could expect to experience five less major coronary events (ie coronary heart disease, death or non-fatal heart attack). Although the authors conclude that the risk benefit ratio tells one that, “the small absolute risk for development of diabetes is outweighed by cardiovascular benefit…” and “clinical practice for statin therapy does not need to change for patients with moderate or high cardiovascular risk of existing cardiovascular disease. However the potentially raised diabetes risk should be taken into account if statin therapy is considered for patients at low cardiovascular risk…”. Without question, blood glucose should be added to the list of monitored blood levels in patients on chronic statin therapy.
Over the years, there have been a variety of reports linking statins with elevated (and sometimes decreased) incidence of cancer. None of the reports have been adequately randomized or large enough to enable definitive conclusions. Just last week, Dr Jonathan Emberson from the University of Oxford presented a study at the European Society of Cardiology meeting in Stockholm which clearly demonstrated no link between statins and cancer (3). An international team of investigators performed 25 studies to examine cholesterol levels during 5 years of statin or placebo therapy. They also recorded information on incidence of cancer in the 166,365 patients. They concluded that there was no evidence of any effect of statin therapy on cancer incidence or mortality at any anatomic site, with increasing years of treatment, or in any particular subgroup of patients. The size of the study coupled with the study design quite reassuringly demonstrates that there is no link between cancer and statin therapy over the length of time studied. Of course, longer studies still need to be performed, and these are ongoing.
So, with the ever widening indication for use of statins to prevent heart attack and stroke, one must still weigh the risks to the potential benefits of these drugs. But, the evidence as a whole in the huge number of patients taking statins over the 23 years since their first FDA approval seems to indicate that statins are generally quite safe, and the benefit greatly outweighs any safety concerns in patients with a history of cardiovascular disease or at moderate to severe risk. Patients at low risk must make an informed decision and understand that more information will continue to be available during the coming decades as generic availability of statins decreases cost and increases use even more.
1. Ridker P.M., Danielson E., Fonseca F.A.H., et al. Rosuvastin to prevent vascular events in men and women with elevated C-reactive protein. N Eng J Med. 359: 2195–207. 2008.
2. Preiss, S.N., Murray, H.M., Welsh, P., et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet. 375: 735-742. 2010.
3. Emberson J, et al "Safety of statin therapy: meta-analysis of data on cancer from 166,000 participants in 25 randomised trials" ESC 2010; Abstract 5035.
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