Models for describing relations among the various statin drugs, low-density lipoprotein cholesterol lowering, pleiotropic effects, and cardiovascular risk

Five models are proposed to describe the relations among statins, pleiotropic effects, low-density lipoprotein (LDL) cholesterol lowering, and cardiovascular risk reduction. On the basis of the evidence available, the pleiotropic effects of statins do not appear to reduce cardiovascular risk more than would be predicted from LDL cholesterol lowering alone, which suggests that model 1 is not a valid model. Although most attention has focused on models 2 through 4, most data to date support model 3 for describing the relation between statins, inflammation, and cardiovascular risk. Stronger consideration should also be given to model 5, in which pleiotropic effects are the result of cardiovascular risk reduction in and of itself. It may be that other models are operative for nonatherosclerotic inflammatory disorders. However, beneficial effects of statins on rheumatologic or other noncardiovascular may still be due to effects of cholesterol reduction on the immune system, as in model 3. More high-quality research is needed to determine the role of statin pleiotropic effects in cardiovascular risk reduction. Well-designed animal studies can help elucidate potential mechanisms, which will then require confirmation in human studies with cardiovascular event outcomes. Substudies of cardiovascular end point trials and mechanistic studies should be methodologically sound and designed to test specific models. To sort out the independence of pleiotropic effects from LDL cholesterol lowering, studies will need to achieve similar LDL cholesterol reductions in each treatment group. It may be that the biologic impact of a specific pleiotropic effect is mediated by >1 model. Ultimately, once a predominant model has been identified for a given pleiotropic effect, long-term studies would be needed to evaluate the relative contributions of various pleiotropic effects to cardiovascular risk reduction. These findings may reveal new targets for the development of new agents that will prove effective for reducing cardiovascular events when added to LDL cholesterol lowering. To date, little evidence supports consideration of statin pleiotropic effects in clinical decision making. In conclusion, LDL cholesterol is currently the only reliable marker for statin effects on cardiovascular risk reduction. The focus should remain on closing the treatment gap and improving adherence to therapies directed at lowering LDL cholesterol and non-high-density lipoprotein cholesterol to reduce the burden of cardiovascular disease.     

Hypercholesterinämie – Wo stehen wir heute? Wo wollen wir hin?

Hypercholesterolemia is one of the major modifiable risk factors for the development of atherosclerosis. Increasing LDL cholesterol is associated with an increased risk of developing cardiovascular diseases as well as cardiovascular ischemic complications. Studies with statins and ultimately with ezetimibe have been able to impressively demonstrate that lowering LDL cholesterol contributes to a significant reduction of cardiovascular ischemic complications.Based on the results of randomized trials for lipid lowering, the practice guidelines developed by the professional societies have defined LDL cholesterol goals. High-risk patients, such as patients with clinically manifest cardiovascular disease, type 2 diabetes, type 1 diabetes with organ damage, moderate or severe chronic kidney disease or a risk of SCORE ≥10?%, should reach LDL cholesterol values <70 mg/dl. Data from observational trials demonstrated that in daily practice only about 20?% of treated high-risk patients reached this recommended LDL cholesterol goal. The therapeutic options are not yet exhausted; patients are treated mainly with low or at most average statin dosages. There should be more potent and high-dose statins used as well as the combination therapy of statin and ezetimibe to achieve the recommended LDL cholesterol goals. Specific cardiac rehabilitation and prevention programs with regular benchmarking could support improved goal-achievement. The new therapeutic option of PCSK9 inhibitors, which significantly and safely lower LDL cholesterol on top of statins and ezetimibe, is currently investigated in large randomized outcome trials.     

The evolving role of statins in the management of atherosclerosis

Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.     

The Use of Fibric Acid Derivatives in Cardiovascular Prevention

Clinical trials have demonstrated the benefit of reduction of low-density lipoprotein (LDL) cholesterol levels in the prevention of atherosclerotic cardiovascular disease. Evidence is less robust for the effect of reduction of triglyceride levels and increase of high-density lipoprotein (HDL) cholesterol levels. In spite of the decrease of cardiovascular events in trials of LDL cholesterol–lowering medications, considerable residual risk remains, even with the use of high-dose statins. The fibric acid derivatives or fibrates reduce triglyceride and increase HDL cholesterol levels, effects that would be expected to affect cardiovascular events. However, clinical outcomes trials with fibrates have shown mixed results. Post-hoc analyses of fibrate trials as well as several meta-analyses suggest an overall decrease in primarily non-fatal coronary events without decrease in total mortality. The effects are most apparent in patients with elevated triglycerides and low HDL cholesterol levels. Statin therapy is the treatment of choice for most patients with dyslipidemia. The addition of a fibrate appears to be most beneficial in high-risk patients who continue to have significant dyslipidemia on statin therapy, most notably patients with diabetes mellitus or the metabolic syndrome. Thus, fibrates are not first-line drugs, but they do have a place in the management of the atherogenic lipid profile.     

Current questions regarding the use of statins in patients with coronary heart disease

The discovery of statins caused a revolution in the field of lipid intervention. Statins are drugs with a good safety profile. Their clinical benefit has been extensively documented in primary and secondary prevention of coronary heart disease. There is substantial evidence that the clinical outcome can be improved with aggressive statin treatment both in patients with unstable as well as with stable coronary heart disease. Also, early administration of statins in acute coronary syndromes is accompanied by rapid clinical benefits, mainly through their "pleiotropic" action (anti-inflammatory, anti-thrombotic, improvement of endothelial function, etc) which is probably a lipid-independent effect. Moreover, emerging data indicate that statins can achieve additional benefit when low density lipoprotein (LDL) cholesterol reduction is coupled with C-reactive protein reduction (<2 mg/L). The prevailing message from the recent statin trials is that intensive LDL cholesterol lowering treatment with statins achieves further clinical benefit beyond that achieved with standard statin therapy. This should encourage the medical community to consider prescribing statins in every coronary patient, aiming at LDL cholesterol levels <100 mg/dL, preferably in the range of 70-80 mg/dL in stable coronary patients, while in coronary patients at very high risk, the optional target for LDL cholesterol levels should be in the range of 50-70 mg/dL.     

Nonlipid-lowering effects of statins

Optional statement Statins have been shown to effectively reduce cardiovascular events in patients with hypercholesterolemia, diabetes, and coronary disease, and after an acute coronary syndrome in several large-scale clinical trials. Interestingly, numerous studies have suggested that statins exert potentially important effects independent of lipid lowering (ie, improve endothelial function, reduce oxidant stress), and have direct antiinflammatory, antithrombotic, and plaque-stabilizing effects. These beneficial effects may contribute to cardiovascular protection by statin therapy beyond low-density lipoprotein (LDL) cholesterol lowering. Therefore, it remains unclear at present to what extent the beneficial cardiovascular effects of statin treatment are dependent on LDL cholesterol lowering (ie, whether the same effect would be achieved by other modes of lipid lowering). Consequently, statins should be used as a first-line therapy for lipid lowering. Importantly, the observation of LDL cholesterol-independent effects of statins has stimulated clinical studies testing a wider use of statin treatment for diseases that are not thought to be related to increased LDL cholesterol levels, such as in patients with chronic heart failure (in particular dilated cardiomyopathy) and even in inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.     

Optimization of cholesterol reduction principles and clinical results of dual inhibition

Ezetimibe is a recently developed compound, which inhibits intestinal cholesterol absorption. Because there are hints for an increase of cholesterol absorption during statin therapy, the combination of Ezetimibe with a statin seems to be appropriate. This dual approach -- inhibition of intestinal cholesterol absorption and hepatic cholesterol synthesis -- offers a very potent reduction of cholesterol. The combination of statins with Ezetimibe leads to a further reduction of LDL-cholesterol up to 12-21%. The dual inhibition causes a more effective reduction of LDL-cholesterol than a statin monotherapy. LDL treatment goals can be reached more easily, and possible side effects of otherwise necessary high doses of statins can be avoided. Clinical endpoint studies with Ezetimibe are underway.     

Statin-Mediated Low-Density Lipoprotein Lowering in Chronic Congestive Heart Failure

Many theories and clinical trials have attempted to address the effect of low-density lipoprotein (LDL) lowering in chronic congestive heart failure (CHF). The current evidence suggests that there is no convincing reason for administering statins to patients with nonischemic heart failure. Although they do not reduce the mortality rate, statins reduce LDL cholesterol and may provide some benefit to patients with ischemic heart failure. in contrast, some authors believe that statin therapy may actually worsen outcomes in patients with CHF, especially if there is excessive reduction in LDL cholesterol. This review discusses the theories attempting to link the adverse effects of statin-mediated LDL lowering in CHF to increased levels of endotoxin or reduced levels of coenzyme Q10. In addition, the 2 largest randomized, double-blind, placebo-controlled clinical trials (CoRoNA and Gissi-HF) were discussed. it is clear that more trials are needed to definitely ascertain the effect of statins on CHF.     

Optimierte Cholesterinsenkung

Ezetimibe is a recently developed compound, which inhibits intestinal cholesterol absorption. Because there are hints for an increase of cholesterol absorption during statin therapy, the combination of Ezetimibe with a statin seems to be appropriate. This dual approach — inhibition of intestinal cholesterol absorption and hepatic cholesterol synthesis — offers a very potent reduction of cholesterol. The combination of statins with Ezetimibe leads to a further reduction of LDL-cholesterol up to 12–21%. The dual inhibition causes a more effective reduction of LDL-cholesterol than a statin monotherapy. LDL treatment goals can be reached more easily, and possible side effects of otherwise necessary high doses of statins can be avoided. Clinical endpoint studies with Ezetimibe are underway.     

Suggested clinical approach for the diagnosis and management of ‘statin intolerance’ with an emphasis on muscle‐related side‐effects

Hyperlipidaemia is a major risk factor for cardiovascular morbidity and mortality. 3‐hydroxy‐3‐methylglutaryl coenzyme‐A reductase inhibitors (‘statins’) are first‐line therapies for hyperlipidaemia. For each 1.0 mmoL/L reduction in low‐density lipoprotein (LDL)‐cholesterol, statins reduce the risk of major vascular events by 21% and all‐cause mortality by 9%. Owing to their clinical effectiveness and excellent safety profile, many Australians are prescribed statins. There has been widespread reporting of possible side‐effects, particularly muscle pains. Conversely, statin cessation relating to possible side‐effects exposes patients to increased risk of vascular events and death. Although there is clinical consensus for diagnosing rare side‐effects (e.g. myopathy or rhabdomyolysis), confirming that statins cause other less common side‐effects (e.g. memory impairment) is difficult as strong randomised trial evidence related to statins and non‐muscle‐related side‐effects is lacking. A stepwise approach to possible statin intolerance, consistent definitions and a simple flowchart may improve diagnosis and management. An increasing array of potential treatments is emerging, including intermittent statin dosing, new LDL‐lowering drugs, LDL apheresis and supplements. Optimal statin use and management of statin intolerance should improve cardiovascular care and clinical outcomes.     

Isoprenoid metabolism and the pleiotropic effects of statins

Convincing evidence from basic research and animal studies shows that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) exert cardiovascular protective effects beyond cholesterol lowering. Because of the central role of low-density lipoprotein (LDL) cholesterol in mediating vascular pathology and the efficacy of statins for lowering LDL cholesterol, the clinical importance of these additional nonlipid effects remains to be determined. Nevertheless, there is growing evidence from recent clinical trials that suggests that some of the beneficial effects of statins may be unrelated to changes in LDL cholesterol. Indeed, in animal studies many of the cholesterol-independent or pleiotropic effects of statins are due predominantly to inhibition of isoprenoid, but not cholesterol, synthesis. Thus, with the recent findings of the Heart Protection Study and Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm, the potential cholesterol-independent effects of statins have shifted the treatment strategy from numerical lipid parameters to the global assessment of cardiovascular risks.     

The role of statins in reversing atherosclerosis: what the latest regression studies show

Recent clinical trials confirm that aggressive lipid-lowering therapy with statins decreases low density lipoprotein (LDL) cholesterol to well below 100 mg/dL in high risk patients, and prevents cardiovascular events. Similarly, aggressive lipid lowering is being explored as a possible means of promoting regression of atherosclerosis and of affording greater protection from atherosclerotic events. A growing body of evidence indicates that intensive statin therapy, particularly in high risk patients, slows the rate of progression of atherosclerosis compared with moderate therapy, and that reductions of > or =40% in LDL cholesterol are necessary to achieve atherosclerosis regression. Questions remain regarding the extent of regression achieved with statin therapy and whether to dose statins to achieve a specific LDL-cholesterol level or a certain percent reduction; however, ongoing clinical trials may provide insight and guidance.     

Low-density lipoprotein cholesterol reduction: the end is more important than the means

Many epidemiologic studies and clinical trials have demonstrated the linear relation between elevated serum levels of low-density lipoprotein (LDL) cholesterol and the risk for coronary heart disease. Conversely, for each 1% reduction in LDL cholesterol in clinical trials, there is a corresponding 1% reduction in coronary heart disease risk. Although the degree of reduction is more important in affecting risk than the means used to lower LDL, statins are considered the most consistently effective means of lowering LDL. The National Cholesterol Education Program now recommends an optional goal of <70 mg/dl for patients at very high risk for coronary heart disease. In conclusion, on the basis of completed clinical trials, there is no evidence that achieving and maintaining such low levels of LDL cholesterol result in adverse effects. The most potent statins, rosuvastatin and atorvastatin, are capable of getting most patients to their LDL cholesterol goals, but combinations of statins with other drugs may be necessary for patients who require additional lipid lowering.     

Vascular and metabolic effects of treatment of combined hyperlipidemia: focus on statins and fibrates

Combined hyperlipidemia results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins in association with reduced lipoprotein lipase activity. Thus, this condition is typically characterized by concurrent elevations in total cholesterol and triglycerides with decreased high-density lipoprotein cholesterol. High levels of apolipoprotein B-containing lipoproteins, most prominently carried by low-density lipoprotein (LDL) particles, are an important risk factor for coronary heart disease. Statin therapy is highly effective at lowering LDL cholesterol. Despite the benefits of statin treatment for lowering total and LDL cholesterol, many statin-treated patients still have initial or recurrent coronary heart disease events. In this regard, combined therapy with statins and fibrates is more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than either drug alone. Furthermore, statins and fibrates activate PPARalpha in a synergistic manner providing a molecular rationale for combination treatment in coronary heart disease. Endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance so that there may also be additional beneficial metabolic effects of combined statin/fibrates therapy. However, there has been little published evidence that combined therapy is synergistic or even better than monotherapy alone in clinical studies. Therefore, there is a great need to study the effects of combination therapy in patients. When statins are combined with gemfibrozil therapy, this is more likely to be accompanied by myopathy. However, this limitation is not observed when fenofibrate, bezafibrate, or ciprofibrate are used in combination therapy.     

Imaging of Vulnerable Plaques Using Near-Infrared Spectroscopy for Risk Stratification of Atherosclerosis

Large randomized trials have shown that lowering the concentration of LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, with further benefit emerging during each year of treatment allocation. But, limited evidence is available about the long-term efficacy and safety of statin treatment. Long-term follow-up of surviving trial participants allows direct assessment of the benefits (and any hazards) of a sustained reduction in LDL cholesterol concentration during the post-trial period. Post-trial follow-up of several large statin trials (of which the Heart Protection Study was the largest) confirms that the substantial absolute benefits and cost-effectiveness of statin therapy were, in fact, underestimated in previous analyses restricted to the “in-trial” periods of randomized studies. Reassuringly, no adverse effects on cancer incidence or non-vascular mortality emerged during the extended follow-up of the Heart Protection Study. These findings support the prompt initiation and long-term continuation of statin therapy in individuals at increased vascular risk.     

Statins in stroke prevention: what an internist should know

Historically, the etiological link between hypercholesterolemia and stroke has been less clear than for coronary heart disease. The lack of association between cholesterol levels and stroke in most epidemiological and observational studies has brought about this controversy. Many recent, long-term clinical studies have confirmed that statin therapy results in a reduced risk of strokes, even in so-called "normocholesterolemic" patients. The magnitude of the effect is great. A large-scale analysis of more than 90,000 individuals showed that every 10% reduction in the concentration of LDL-cholesterol reduces the risk of stroke by 15.6%. The positive effect of statins on stroke depends mainly on LDL cholesterol reduction, but other non-lipid mechanisms, so-called "pleiotropic" effects, have been shown to play a role. This review seeks to summarize the role of statins in stroke prevention. Despite the fact that our understanding of the benefits of statins in stroke prevention is still evolving, we find marked room for improvement in stroke risk factor management. Internists must face this challenge and integrate this new knowledge into their daily clinical practice.     

The lower the better? Reviewing the evidence for more aggressive cholesterol reduction and goal attainment

There is considerable evidence that more aggressive lowering of low-density lipoprotein (LDL) cholesterol is associated with increased benefits in reducing atherosclerotic disease burden, supporting the notion of 'the lower, the better.' However, achievement of currently recommended goals has proven difficult with lipid-lowering agents at the commonly used doses. Current options for achieving greater LDL cholesterol reductions include use of high doses of the most effective of the available statins and use of high or moderate statin doses in combination with agents that work in a complementary manner (e.g. bile acid sequestrants or niacin). Near-term options may include statins with increased LDL cholesterol-lowering effectiveness and better-tolerated secondary agents that can be combined with statin therapy. Rosuvastatin (Crestor, AstraZeneca) is a new statin that may prove to be of considerable utility in achieving greater LDL cholesterol reductions than are currently possible with existing statins. Recent phase III clinical trials have shown that this agent produces significantly greater LDL cholesterol reductions than atorvastatin, simvastatin, or pravastatin in patients with primary hypercholesterolemia and significantly greater reductions than the maximal dose of atorvastatin in patients with familial hypercholesterolemia.     

Coronary artery disease prognosis and C-reactive protein levels improve in proportion to percent lowering of low-density lipoprotein

This editorial outlines the data supporting aggressive lipid goals and options for treating low-density lipoprotein (LDL) cholesterol to a range of approximately 30 to 70 mg/dl. The physiologically normal cholesterol range is approximately 30 to 70 mg/dl for native hunter-gatherers, healthy human neonates, free-living primates, and virtually all wild mammals. Randomized statin trials in patients with recent acute coronary syndromes and stable coronary artery disease have demonstrated that cardiovascular events are reduced and cardiovascular survival optimized when LDL cholesterol is reduced to <70 mg/dl. Secondary prevention trials have shown a decrease in all-cause mortality in proportion to the magnitude of LDL cholesterol reduction. An original analysis of available data shows that the ability of a lipid-lowering therapy to reduce the C-reactive protein level is closely correlated with its efficacy in LDL cholesterol reduction. Randomized trial data have shown no relation between either percentage LDL cholesterol decrease or final LDL cholesterol level achieved and the risk for myopathy or hepatic transaminase elevations associated with statins. Therefore, intensive LDL cholesterol reduction to levels of 30 to 70 mg/dl should be pursued in subjects with or at high risk for coronary artery disease.     

Effective use of combination lipid therapy

Despite the benefits of statin therapy, low-density lipoprotein (LDL) cholesterol management remains suboptimal and many patients do not achieve their recommended target goals. The aim of combination lipid drug therapy in high-risk patients is to achieve LDL cholesterol and non-high-density lipoprotein (HDL) cholesterol goals with a minimum of serious adverse effects. Although statins are the drug of first choice, statin monotherapy may be limited by intolerance of dose escalation or failure to attain non-HDL cholesterol goals in those with mixed hyperlipidemia. Statins plus bile acid resins or ezetimibe can achieve greater than 50% reduction in LDL cholesterol, with little or no increase in adverse effects. Fibrates, niacin, and omega-3 fatty acids, when added to statins, can reduce triglycerides, increase HDL cholesterol, and reduce non-HDL cholesterol to a greater extent than statin monotherapy. The safety profile of combination lipid therapy is acceptable if the global coronary heart disease risk of the patient is high, thus producing a favorable risk to benefit ratio. Careful surveillance of hepatic transaminases, avoidance of gemfibrozil in statin-fibrate combinations, and awareness of statin-concomitant drug interactions is key to safe and efficacious use of combination lipid drug therapy.