Statins

Dyslipidemia, particularly elevated levels of Low Density Lipoprotein (LDL) cholesterol, plays a crucial role in atherogenesis and cardiovascular risk. Thus, the cholesterol-lowering agents known as statins, or 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, are one of the cornerstones of cardiovascular risk management in diabetes patients. These agents block a crucial step in the synthesis of cholesterol in the liver. As a result, the expression of receptors for LDL by the hepatocytes increases, leading to an increased uptake of LDL from the plasma and thus a lower plasma LDL-cholesterol. This lower LDL-cholesterol translates into a reduced risk for cardiovascular mortality and morbidity. The effects of the statins are dose dependent, and besides first generation agents such as simvastatin and pravastatin, next generation statins with somewhat higher potencies are now available. The statins are generally well tolerated although small differences in risk-benefit ratio's exist; principal side-effects are myalgia, which may occur in up to 30% of patients and (in rare cases) rhabdomyolysis. Curiously enough, statins are associated with a mildly elevated risk of developing diabetes.

History of statins

The detrimental role of lipids in atherosclerosis was already suggested more than a century ago, and confirmed in the second half of the 20th century by epidemiological studies such as the Framingham study. In the late 1960s the cholesterol metabolic pathway was elucidated, and Goldstein and Brown (who were to receive a Nobel prize in 1985) identified the LDL-receptor in 1972. The actual discovery of the first HMG-CoA reductase inhibitor was a serendipitous finding by the Japanese microbiologist Akira Endo, who was actually looking for new antimicrobials. Building on this work, the Merck laboratories developed the first commercial statin, lovastatin by 1978. Clinical trials in the 1980s showed the statins to be highly efficacious and they have been a cornerstone of treatment ever since.

Mechanism of Action

Statins are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate limiting enzyme in cholesterol synthesis. By blocking cholesterol synthesis in the liver, the liver secretes less Very Low Density Lipoprotein (VLDL) cholesterol into the circulation, and the low intracellular cholesterol leads to an increased expression of LDL receptors on the hepatocyte and thus increased clearance of LDL cholesterol from the circulation. This, in turn, leads to a small rise in plasma High Density Lipoprotein (HDL) cholesterol levels. The end result is a decrease of plasma LDL by 30-40%, a decrease of plasma triglycerides of about 15% and an increase of plasma HDL of about 10%

Clinical Efficacy

The statins were among the first drugs systematically studied for hard endpoints on a large scale. Thus, a wealth of data about their efficacy exists, which have been summarized in a very good meta-analysis[1] In patients with diabetes, a 1 mmol/l lowering of LDL-cholesterol results in a 9% proportional reduction in all-cause mortality. This is fully attributable to a 13% reduction in cardiovascular mortality; statins have no effects on non-vascular mortality. Apart from mortality, statins reduce major vascular events by 21%, with similar effects for myocardial infarction, coronary death, coronary revascularisation and stroke. The Number-Needed-to-Treat (NNT) for one year to avoid one macrovascular event was about 125 patients. In this meta-analysis, the proportional effects of statin therapy were similar irrespective of whether there was a prior history of vascular disease and irrespective of other baseline characteristics. It should however be noted that only one of all the statin studies included elderly patients. Based on this study [2] and on the results of a meta-analysis of vascular risk factors across age groups [3] (see table) it would seem that starting statin treatment becomes less efficacious in the elderly, particularly with regards to stroke prevention. A possible explanation is that atherosclerosis is a life-long process with irreversible damage accumulating as one grows old.

Table: Hazard ratio's for vascular outcomes associated with 1 mmol/l lowering of LDL cholesterol* *Adapted from reference 3.

Age Group Ischaemic Heart Disease Stroke Other Vascular
40-49 0.45 0.87 0.62
50-59 0.57 0.91 0.75
60-69 0.68 0.93 0.83
70-79 0.79 1.02 0.89
80-89 0.85 1.05 1.02

Side-effects

Statins are generally well tolerated and less than 5% of patients stop taking medication because of side effects. However, the most common side effect, myalgia, may affect up to 30% of patients and can vary from annoying to disabling, particularly in elderly patients. More serious myopathy, with raised plasma CPK levels, or even rhabdomyolysis, is relatively rare but necessitates direct discontinuation of statin therapy and appropriate treatment of rhabdomyolysis. Since many of the statins are metabolized by the cytochrome P450 system, inhibitors of this system such as cyclosporin, erythromycin, antimycotic agents, nicotinic acid and fibrates, increase the risk of serious side effects such as rhabdomyolysis. Statins are associated with a small increase in the risk of type 2 diabetes, which is described in our page on Statin-induced diabetes.

References

  1. ^ Cholesterol Treatment Trialist's Collaborators. Efficacy of cholesterol-lowering therapy in 18 686 people with diabetes in 14 randomised trials of statins: a meta-analysis.Lancet 2008;371:117–25

  2. ^ Shepherd J et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623–30.

  3. ^ Prospective studies collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007:1829-1839

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