Lipid lowering with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or ‘statins’ has dramatically reduced morbidity and mortality in patients with established cardiovascular disease. Recently, there have been multiple studies investigating the role of high-dose potent statin therapy with more aggressive lipid lowering in this setting.
There is increasing evidence implicating a role of inflammation in the pathogenesis of atherosclerosis. These high-dose potent statin trials and other studies have also provided a wealth of data suggesting that statins have anti-inflammatory and anti-oxidant properties that go beyond their lipid-lowering effects.
The role of inflammation in the pathogenesis of atherosclerotic coronary disease has been extensively investigated over my lifetime. There is considerable evidence to implicate inflammation in each step of the atherosclerotic process, from the initial fatty streak formation to plaque progression and rupture (Figure 2).
Among the numerous circulating inflammatory biomarkers that have been found to be predictive of cardiovascular events, the most extensively studied has been the acute-phase reactant “high-sensitivity or ultra-sensitive C-reactive protein” (us-CRP). Multiple studies, including several meta-analyses, have demonstrated us-CRP to be an independent predictor of cardiovascular risk. Further, recent laboratory studies of intravenous C-reactive protein infusion in animal models and human volunteers demonstrated increased inflammation and atherosclerosis and activation of coagulation, providing evidence for a direct role of C-reactive protein in the pathogenesis of coronary artery disease.
Statins have been recognized to have anti-inflammatory and antioxidant properties, and it has been suggested that these so-called “pleiotropic” effects may account for some of the benefits of statins beyond LDL-C lowering alone. Recent studies have shown that statins reduce inflammatory macrophage cell growth within atherosclerotic plaques, decrease superoxide (oxidative free radicals) production from NAD(P)H oxidase (nox1) in vascular smooth muscle cells, and increase endothelial nitric oxide production. In addition, they promote potent systemic anti-inflammatory effects by inhibiting the isoprenylation and translocation of “Rac”, a key subunit of the NAD(P)H oxidase complex that catalyses the production of superoxide.
Are there any safety concerns of high-dose statin therapy?
Safety concerns surrounding high-dose statin therapy centre on the traditional liver or skeletal muscle-related disturbances seen at low rates with moderate-dose statin therapy, in addition to potential new risks related to ultra-low cholesterol and LDL-C levels. Major clinical trials, along with previously published data and ongoing trials, have addressed these safety concerns.
Atorvastatin (Lipitor) has been the most extensively studied at high doses (up to 80 mg/d) and so possesses the most data regarding safety and adverse effects. The incidence of hepatic enzyme elevation (defined as ALT or AST > 3 x the upper limit of normal) in patients treated with high-dose atorvastatin, simvastatin, or fluvastatin in major trials is 0.5–3.0% only. Discontinuation or dose reduction of the offending statin usually results in prompt resolution of the enzyme elevations.
The incidence of myopathy (defined as creatine kinase elevation of > 10 x upper limit of normal with muscle related myalgia symptoms) and frank rhabdomyolysis in controlled clinical trials employing the use of high-dose statin therapy is rare. In nearly 12 000 patients encompassing over 40 trials of high-dose atorvastatin, there were only two cases of myopathy, whereas no cases of myopathy have been reported in controlled trials of high-dose fluvastatin. In contrast, high-dose simvastatin therapy seems to be associated with a perceptible increase, although small, in the risk of myopathy (0.4%).
Epidemiological and animal studies have suggested a link between low total cholesterol levels and risk for retinal and optic nerve damage, haemorrhagic stroke, and mortality. As a substantial proportion of patients treated with high-dose statin therapy will reach LDL-C levels far below 1.8 mmol/l, these potential hazards have come to the forefront. The large trials has demonstrated no increase in the risk of these adverse events associated with ultra-low LDL-C levels.
So in summary:
There is substantial support for the institution of high-dose potent statin therapy in various clinical settings in the secondary prevention of coronary events. Two recent meta-analyses of high-dose statin trials have been able to quantify the benefit at an additional 16% reduction in coronary death or myocardial infarction with high dose compared with moderate-dose statin therapy.
High-dose statin therapy in the setting of “acute coronary syndromes” (ACS), demonstrate a 22% reduction in all-cause mortality, as well as a 25% reduction in cardiovascular mortality.
This data provides further insight into the contributions of atherogenic lipoproteins (LDL; IDL and VLDL) and inflammation to atherosclerotic plaque burden through analysis of statin-mediated effects on these parameters. The data linking inflammation and oxidative damage with coronary artery disease and ACS are now mounting. Currently, C-reactive protein remains the most extensively studied marker of inflammation in coronary disease and adds incremental predictive power to traditional risk factors in predicting adverse cardiac events.
Additionally, after weight loss, exercise, and smoking cessation, statins remain the best therapeutic option to mitigate inflammation in coronary artery disease.
I hope this information adds to a growing data bank of safety and efficacy in the the rationale of using high dose potent Statins in reducing the devastating effects of progression of atherosclerotic vascular disease.