Statins inhibit cholesterol synthesis through competitive inhibition of HMG-CoA reductase activity. The resulting decrease in intracellular cholesterol concentration leads to increased expression of LDL receptors on the cell surface of liver cells.
This results in enhanced uptake of LDL cholesterol (LDL-C) and triglycerides by liver cells, and of triglycerides by hepatocytes, leading to a reduction in blood concentrations of lipoproteins. The extent of this reduction is dose-dependent and varies among different statins.
Table: Equivalent doses of statins
The use of simvastatin 80 mg is not recommended.
The higher the baseline LDL-C level, the greater the absolute reduction in LDL-C. The statin dose should be increased gradually up to the target dose at four-week intervals.
Table modified from: Laufs U. et al. State of the art: Statin therapy. Dtsch Med Wochenschr 2022;147:62–68.
With statins, LDL cholesterol levels can be reduced by 30–40%. The reduction is dose-dependent. Doubling the statin dose does not halve the cholesterol level, but leads only to an additional reduction of about 6% (“rule of six”).
Statins reduce the risk of combined major coronary events, fatal and non-fatal stroke, and revascularization. The greater the reduction in LDL-C, the lower the rate of combined major cardiovascular events. A reduction in LDL-C of 40 mg/dL lowers the risk of coronary events by 21% and of stroke by 17%. The benefits of statin therapy were independent of the subgroups analyzed. As early as the first year of treatment, a significant benefit of statin therapy was observed, which increased in subsequent years. The studies showed no indication that statin therapy increases the risk of other causes of death, particularly cancer.
Risk reduction in primary prevention is approximately the same as in secondary prevention. Naturally, the absolute risk of cardiovascular events is lower in primary prevention. The reduction in cardiovascular risk is completely independent of which statin is used and depends solely on the degree of LDL-C reduction.
Because of the higher incidence of coronary events, statin treatment in diabetic patients with coronary artery disease is, on average, more effective in reducing cardiovascular events than in coronary patients without diabetes. Statins also reduce cardiovascular events in women and men with diabetes who do not have manifest coronary heart disease.
In the meta-analysis, no difference was found between patients with diabetes and those without diabetes.
Unstable plaques with statins
For a long time, aspirin was recommended as a prophylactic therapy based on the assumption that its antithrombotic properties could reduce the risk of vascular occlusion in the event of plaque rupture.
Three large studies with aspirin showed only minor benefits in patients with unstable plaques, while the risk of bleeding remained consistently increased. Therefore, effective modification of the lipid profile with medication is more suitable than prophylactic aspirin use.
A large number of studies have shown that statins reduce plaque volume by approximately 3.6%, decrease non-calcified plaque volume, and increase calcified plaque volume. In contrast, control groups showed a significant increase in both calcified and non-calcified plaque volume. A significant reduction in vulnerable plaques can be achieved with treatment durations of less than six months.
Statins have been carefully investigated for potential increases in the risk of dementia, liver failure, cancer, thrombosis, polycystic ovary (PCO) syndrome, and Alzheimer’s disease. To date, studies have shown no clinically relevant effect on any of these conditions. In particular, a Cochrane analysis found no evidence that statins increase the risk of Alzheimer’s disease.
Statin-associated muscle symptoms (SAMS) are the most clinically significant adverse effect of HMG-CoA reductase inhibitors and often lead to discontinuation of therapy. The frequency of SAMS is difficult to estimate. In randomized clinical trials, the rates of muscle complaints are very similar in placebo and treatment groups; in registry studies, incidence rates of 10–30% of treated patients are reported.
Statin use can cause pre-existing mild myopathies to become symptomatic. A delayed remission of SAMS after discontinuation of the statin may be indicative. Creatine kinase (CK) levels are usually elevated, and patients often had elevated levels even before treatment initiation.
Rhabdomyolysis is particularly feared. Patients develop muscle pain; in advanced stages, muscle breakdown occurs, and CK levels rise to more than ten times the upper limit of normal, potentially leading to life-threatening renal failure. Rhabdomyolysis is rare, with an estimated incidence of one to three cases per 100,000 patient-years. Much more common are myalgias without CK elevation. Approximately 10–15% of patients report muscle complaints.
Simvastatin and atorvastatin are metabolized via the cytochrome P450 isoenzyme 3A4. If myalgias occur, switching to rosuvastatin should be considered. In 0.5–2% of patients, statins cause an increase in glutamate–pyruvate transaminase (GPT). This mild elevation does not impair liver function. Liver failure is extremely rare; therefore, routine GPT monitoring is not required.
Statins slightly increase the risk of developing type 2 diabetes mellitus. Approximately 255 patients must be treated with statins for four years for one additional case of diabetes to occur.
Almost all patients with type 2 diabetes mellitus have metabolic syndrome, characterized by overweight or obesity, hypertension, dyslipidemia, and impaired glucose tolerance. These patients have a markedly increased risk of myocardial infarction and stroke. The risk of stroke and myocardial infarction increases years before the diagnosis of diabetes. One of the most effective measures to reduce this risk is treatment with statins.
In particular, in patients who have already had a myocardial infarction, reduction of LDL cholesterol through statin therapy is essential to prevent another infarction, which may be fatal. The decision to initiate statin therapy should therefore be based on the individual risk profile. In this context, the risk of developing diabetes slightly earlier is negligible.
With the exception of pravastatin and rosuvastatin, most statins are metabolized in the liver via the cytochrome P450 system.
Approximately 10% of rosuvastatin is metabolized by the enzyme CYP2C9, while other CYP enzymes play only a minor role. This reduces the risk of interactions with other medications that affect the cytochrome P450 system.
The majority of rosuvastatin (about 90%) is excreted unchanged via bile and feces, which distinguishes it from other statins that undergo more extensive metabolism. This means that rosuvastatin largely remains in its active form in the body and exerts its effect directly before being eliminated. Other drugs that are metabolized via the same pathway can therefore lead to a marked increase in statin plasma concentrations and cause myalgias and rhabdomyolysis. Such drugs include anti-infective agents such as itraconazole, ketoconazole, erythromycin, clarithromycin, and HIV protease inhibitors. The same metabolic pathway is also used by the calcium channel blockers verapamil, diltiazem, and amlodipine.
Therefore, especially in patients with metabolic syndrome and hypertension, therapy should be initiated with a statin that does not interact with calcium channel blockers. When treating with amlodipine, doses of simvastatin should not exceed 20 mg. Other substances that also interact with statins include ciclosporin, danazol, amiodarone, and grapefruit juice.
LTreatment should be initiated with highly potent statins such as atorvastatin or rosuvastatin. Both can also be taken in the morning. This improves adherence, as doses are less likely to be forgotten. Pravastatin and simvastatin should be taken in the evening; however, this often leads to missed doses. Pravastatin and simvastatin are not more cost-effective than atorvastatin and rosuvastatin, and the latter are substantially more effective.