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HMG-CoA Reductase Inhibitors for Cardiovascular Risk Reduction
Ryan Bradley, ND, MPH
Statin drugs, ie, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have become a cornerstone in the conventional management of dyslipidemia and cardiovascular disease. Enthusiasm for statin prescribing is weaker among integrative providers who prioritize lifestyle change and nonpharmaceutical lipid-lowering measures or who deny a contribution of low-density lipoproteins (LDL) to cardiovascular risk. However, numerous large, well-designed, rigorously scrutinized clinical trials have documented the benefits of statin medications in reducing major cardiovascular events, including myocardial infarction, stroke, and revascularization procedures, as well as cardiovascular and all-cause mortality. These benefits have been documented in both primary and secondary prevention and in both low-risk and high-risk patient populations including patients with and without dia-
betes. Additionally, the benefits of statins remain evident for elderly and female patients despite less robust evidence, while less convincing evidence is available in some disease subgroups including congestive heart failure and kidney disease requiring dialysis. Although LDL lowering appears to be the predominant mechanism of statin protection, statins also reduce vascular inflammation, improve endothelial function, and improve LDL size/density patterns. Although adverse effects of statin medications are possible and can be serious, the overall safety profile of statins remains very good. Patients seeking counsel on evidence-based treatments for lipid lowering and protection against cardiovascular disease events and death deserve honest, unbiased dialogue about whether they are good candidates for medications in this class.
Editor’s Note: In the section IMCJ Retrospective: Fundamentals of Integrative Medicine, we run a “primer” that gives good background for this article. Please see “Are Additional Lipid Measures Useful?” by Ryan D. Bradley, ND; and Erica B. Oberg, ND, MPH, on p 56 of this issue. ardiovascular diseases (CVDs) remain the leading causes of death in the developed world; associated medical costs account for $149 billion annually, or 17% of all medical expenditures in the United States.1 Low-density lipoprotein (LDL) concentration has been validated as a modifiable risk factor for CVD through systematic research. Early observations demonstrated that patients with familial hypercholesterolemia died prematurely from cardiac events, typically by age 50.2 Conversely, patients with genetically low LDL-cholesterol (LDL-C) concentrations do not develop CVD.3 Both clinical trials with statin agents and large observational studies, including the Framingham Heart Study, have shown a surprisingly consistent, nearly linear relationship between LDL concentration and risk of cardiac event—with each 1% elevation of LDL-C level associated with a 1% increase in risk for CVD.4 Criticism regarding the lack of generalizability of Framingham findings led to large, case-controlled studies such as INTERHEART.5 The results of the INTERHEART study showed that elevated LDL concentration, or more precisely an elevated apo B100:apo AI ratio (which highly correlates to LDL:high-density lipoprotein [HDL] ratio), accounted for 49%
of the population-attributable risk for myocardial infarction (MI) in a mixed-ethnicity population from 52 countries.6,7 Additionally, evidence from numerous large, randomized, controlled trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase medications, also known as “statins,” have demonstrated reductions in cardiovascular events and death proportional to reductions in LDL concentrations achieved by use of these medications as discussed below.8-14 Patients and colleagues point out statistics on the moderate percentage of patients experiencing a cardiac event who have elevated total cholesterol levels or traditional risk factors.15 Although well-intentioned, these views have the potential to create misinformation regarding the importance of traditional riskfactor reduction for overall cardiovascular risk reduction. Accepting that LDL concentration is an important risk factor is not the same as saying that LDL is the only, or even the best, biomarker for demonstrating risk of CVD. For example, subsequent analyses in the INTERHEART study demonstrated stronger associations between apo B100:apo AI ratio and risk of MI than for total cholesterol:HDL or LDL:HDL ratios.6, 7 The INTERHEART study also demonstrated clear contributions to risk from psychosocial and lifestyle factors, including increased risk due to depression, anxiety, and reduced locus of control and reduced risk from daily vegetable intake, frequent physical activity, moderate alcohol consumption, and not smoking.5 Although residual risk remains and is unexplained, proven modifiable risk factors are low-hanging fruit for therapeutic interventions. LDL levels are readily modified through dietary
Integrative Medicine • Vol. 10, No. 3 • Jun/Jul 2011
Bradley—HMG-CoA Reductase Inhibitors
I summarize landmark clinical trials of statin medications. this makes LDL an easy target for risk reduction in the short term. and adverse musculoskeletal effects in patients receiving statins? In this article. Atheroma volume was significantly reduced (mean change = -5. 9 clinical trials of simvastatin. HPS also demonstrated that for adults 40 years and older with total cholesterol level >135 mg/ dL. 4S: The Scandinavian Simvastatin Survival Study (4S) was the first clinical trial of simvastatin demonstrating a survival benefit in patients with an established history of CVD.” an annual clinical guideline published in Diabetes Care. several highlights from these trials are discussed below. including concerns about musculoskeletal adverse effects and cancer risk. Further confusion abounds about statin use in older adults and women because less evidence of benefit is available in these populations.com. 3 • Jun/Jul 2011 43 . These inconsistencies in practice versus guidelines lead to confusion for both patients and clinicians. a 42% reduction in risk for coronary death. To subscribe. PROSPER evaluated the effect of 40 mg/d of pravastatin on MCEs and demonstrated a 15% reduction in risk.9] %)3 in patients using atorvastatin but not pravastatin. and briefly describe clinical subpopulations where evidence is mixed regarding the benefits of statins. Review of Landmark Statin Clinical Trials HMG-CoA reductase medications have been studied in well-designed clinical trials in tens of thousands of people over the last decade. These concerns are widely discussed on the internet and are commonly raised by patients with considerable CVD risk who are resistant to medications. or atorvastatin in 16 032 participants with diabetes have demonstrated between 8% and 50% risk reduction for 10-year risk of MCEs. After 5. This effect was independent of baseline LDL cholesterol concentration. or blood glucose control.4 years of median follow-up. Use ISSN#1543-953X. patients receiving atorvastatin had reductions of 47% in LDL concentrations and 36% in highly sensitive C-reactive protein (hsCRP) concentrations.13 Bradley—HMG-CoA Reductase Inhibitors Integrative Medicine • Vol. including allcause death. 10. and a 34% relative reduction in major cardiovascular events (MCEs) compared to placebo.9 In 4S.4] mm3 and mean percent reduction = 1.8 In addition to the positive primary outcome of an 18% reduction in coronary death. REVERSAL: The study titled Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) was a comparative effectiveness trial assessing intensive lipid lowering using atorvastatin with moderate lipid lowering using pravastatin in 654 patients with a 20% minimal luminal narrowing from atherosclerotic disease in at least 1 coronary artery. the simvastatin group experienced a 30% relative reduction in all-cause mortality. In which populations does the evidence support the use of statin medications for risk reduction? Are reductions in LDL levels solely responsible for these effects? What does the current literature show regarding risk of cancer. Although many allopathic standards of care recommend the use of statins to control LDL-related risk in high-risk populations.18 many clinicians have encountered low-risk patients prescribed statins by other providers. review the evidence to date demonstrating the LDL-lowering benefits of statins. HPS: The Heart Protection Study (HPS) was the first land- mark clinical trial of simvastatin in patients with type 2 diabetes. Several of these clinical trials deserve mention either for the specific population the trial was conducted in. pravastatin. however. Landmark clinical trials of statins are summarized in the Table. remains debatable.10 Further summaries of randomized controlled trials are available in the current American Diabetes Association “Standards of Medical Care in Diabetes.19 PROSPER: Because of concerns regarding the lack of generalizability of the conclusions from previous statin trials to older adults. In total. stroke. the magnitude of the results. CARDS demonstrated a 37% reduction in MCEs. In essence. an uncontrolled. greater reductions in atheroma volume occurred in patients receiving atorvastatin who had reductions in both LDL and hsCRP levels. and atheroma reduction occurred only in those who experienced reductions in hsCRP levels.16 The best way to achieve desirable LDL levels.com.1 [31. including fatal and nonfatal MI. Leading to considerable concern and controversy was the observation of a 25% increase in newly reported cancer diagnoses in patients receiving pravastatin. type or duration of diabetes. this creates a clinical challenge for the provider attempting to honor patient preferences while recommending the most effective treatment. the 4S trial set the performance bar for statin trials to come and tipped the evidence scale in favor of the use of statins for secondary prevention of CVD because of the demonstrated reduction in hard clinical events.17 including patients with diabetes. To share or copy this article. change plus available nutraceuticals and pharmaceutical treatments. please visit copyright. no hsCRP data was reported. Participants in the REVERSAL study who had reductions in LDL levels with no change or elevation of hsCRP levels demonstrated progression of disease but to a lesser degree than participants who had increases in both LDL and hsCRP levels.14 In this study. ASTEROID: Regression of atheroma volume (in each of 3 separate measurements) was also demonstrated in A Study to Evaluate the Effect of Rosuvastatin on Ultrasound-Derived Coronary Atheroma Burden (ASTEROID). and subsequently reduce CVD events and CVD-related death.9 [4.11 This observation has led to several meta-analyses examining statin use and cancer risk. this issue is discussed below (see Statin Controversies section). CARDS: The Collaborative Atorvastatin Diabetes Study (CARDS) is one of the first primary prevention trials of statins in patients with diabetes without known CVD. Further confusion occurs for the provider due to controversies surrounding the safety of statins. preexisting disease. No. discuss rates of adverse events associated with statins including cancer. and/or because of findings of possible interest to the integrative clinician. visit imjournal.This article is protected by copyright. more than 4000 patients with previous histories of CVD or a CV event were randomized to receive simvastatin or a placebo. and revascularization procedures. a 30% reduction in total cholesterol level using simvastatin corresponded to a 25% reduction in first MCEs. the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) was conducted in high-risk elderly adults aged 70 to 82 years with history of MI or multiple elevated risk factors for CVD. depression. open-label trial of 40 mg/d of rosuvastatin.
visit imjournal. or revascularization Main Results 30% risk reduction for all-cause death 34% risk reduction for MCEs 1. stroke. stroke. cardiac death. or CVD (n=2838) Mortality. Summary of Landmark Clinical Trials of HMG-CoA Reductase Inhibitors Study Name (Year) 4S (1994)9 Intervention Simvastatin 20-40 mg/d for 5. revascularization.7% CVD complications (eg. elderly adults aged 70-82 y with history of or elevated risk factors for MI and stroke (n=5804: men=2804. and 3) AV change in entire artery Significant regression in all 3 measures of AV LDL level reduction of 53.2% discontinued the trial leading to an evaluable n=349 Musculoskeletal complaints occurred in 3. fatal. 10.2% in PS group ASTEROID (2006)13 Rosuvastatin 40 mg/d for 24 mo Adults at least 18 y of age who underwent angiography for clinical indication and had at least 20% luminal narrowing in any coronary vessel (n=507) Progression of atherosclerosis measured by: 1) % change in total AV.This article is protected by copyright. terminated early due to definitive benefit Pravastatin 40 mg/d or placebo for 2 y Combined fatal and nonfatal vascular events including MI. To share or copy this article.1% ALT level elevation in 1% of both groups 15% reduction in primary endpoint 33% reduction in LDL Atherosclerosis progression measured by change in AV Mean reduction in AV in AS group vs progression in PS group LDL level reductions of 47% in AS group vs 27% in PS group hsCRP level reductions of 36. and death Combined fatal and nonfatal MI and stroke PROSPER (2002)11 High-risk. please visit copyright.01% increase in myopathy No difference in cancer or hospitalizations for other causes No difference between groups No reported cases of rhabdomyolysis Myopathy present in both groups at 0. and nonfatal vascular events Reduced total mortality due to an 18% reduction in coronary death 37% reduction in primary endpoint 0. Use ISSN#1543-953X.7% reduction in MCEs for each 1% reduction in LDL level HPS (2002)8 Simvastatin 20 mg/d or placebo for 6 y High-risk patients aged 40-80 y with coronary and/or peripheral vascular disease and/or diabetes (n=20 536) Adults aged 40-75 with diabetes but without previously diagnosed MI. women=3000) Adults aged 35-75 y with established luminal narrowing of at least 20% in any coronary vessel (n=654) REVERSAL (2004)14 Atorvastatin (AS) 80 mg/d or pravastatin (PS) 40 mg/d for 18 mo 44 Integrative Medicine • Vol. arrhythmia.4 y Population (n) High-risk patients aged 35-70 y with history of acute MI or active angina (n=4444) Outcome Measures Death from any cause MCEs including MI. Table. angina requiring revascularization) led to discharge in 4.3% No differences between groups including musculoskeletal and hepatic abnormalities 25% higher rate of newly reported cancers in pravastatin group No differences between treatments Musculoskeletal AEs reported in ~3% of each group Reported Adverse Effects (AEs) No differences between groups in any musculoskeletal symptoms or any laboratory abnormality including liver function tests A single case of rhabdomyolysis occurred in the simvastatin group CARDS (2004)10 Atorvastatin 10 mg/d or placebo for 3 y.com. CHF.2% HDL level increase of 14. 2) AV change in most-diseased segment at baseline. No.4% in AS group vs 5. 3 • Jun/Jul 2011 Bradley—HMG-CoA Reductase Inhibitors .7% 12. stroke. To subscribe.com.
com. Use ISSN#1543-953X.This article is protected by copyright. ED is considered a common precursor to atherosclerosis. The results were so strikingly protective that the trial was stopped early by the Data Safety and Monitoring Board after just 1. Meals high in advanced glycosylation end products also induce short-term ED.12 Of note. and adding to the validity of hsCRP as an important biomarker for CVD risk. Although the topic remains controversial. and fat.0 mg/L was required for enrollment). hepatic. Resch et al demonstrated reduced oxLDL in an open-label Bradley—HMG-CoA Reductase Inhibitors Integrative Medicine • Vol. congestive heart failure. These additional actions include antiinflammatory action such as potent reduction of hsCRP levels. CARDS=Collaborative Atorvastatin Diabetes Study. Does LDL Lowering Alone Accomplish the CVD Risk Reduction Observed from Statins? Although the established mechanism of statin medications is direct inhibition of HMG-CoA reductase resulting in reduced endogenous production of LDL. which results in increased susceptibility of LDL to oxidative stress. patients with type 2 diabetes have higher baseline levels of oxidative stress markers of ED compared with their nondiabetic counterparts. for example. increase fat content of HDL cholesterol as well as increase its density and reduce its antioxidant capacity. please visit copyright.26 Biomarkers of ED increased in parallel with serum concentrations of triglycerides and glucose. Summary of Landmark Clinical Trials of HMG-CoA Reductase Inhibitors (continued) Study Name (Year) JUPITER (2008)12 Intervention Rosuvastatin 20 mg/d or placebo for 1. HPS= Heart Protection Study.20-25 ED is mediated acutely by increased vascular oxidative stress.26 Longer-term indices of dietary patterns affect the inflammatory processes during ED. 49 mg/dL for HDL.0 mg/L or higher (n=17 802) Outcome Measures MCEs including MI. 94 mg/dL for fasting glucose. CRP=C reactive protein. longer duration of ED resulted from mixed hyperglycemia and hypertriglyceridemia. additional actions have been documented in translational and clinical research of statins. CHF=congestive heart failure. and type 2 diabetic patients. shifting of LDL size and density related to triglyceride-lowering and HDL-elevating actions of potent statins. and development of insulin resistance. ALT=alanine aminotransferase. MCE=major cardiovascular event. and regression of established atherosclerotic lesions.16 As one might speculate. and environmental exposures. MI=myocardial infarction. CVD=cardiovascular disease. stroke. GI=gastrointestinal. the population studied in JUPITER would be considered low to moderate risk with the exception of their hsCRP levels (hsCRP of at least 2. cerebrovascular disease.9 y. glucose. PROSPER=Pravastatin in the Elderly at Risk. hypertension. To subscribe. improvement in endothelial flow–mediated dilation and reduction in endothelial dysfunction. hypertensive (with or without hypercholesterolemia). LDL=low-density lipoprotein. 10.26 In fact. chronic kidney disease. this relationship has been previously described. specifically apo B100. ASTEROID=A Study to Evaluate the Effect of Rosuvastatin on Ultrasound-Derived Coronary Atheroma Burden. trial was stopped early due to definitive benefit Population (n) Men aged 50 y or older and women aged 60 y or older with LDL level <130 mg/dL but with hsCRP level 2. chemical. baseline values averaged 108 mg/dL for LDL. To share or copy this article.9 years. 118 mg/dL for triglycerides. simvastatin. JUPITER=Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin. type 2 diabetes may be considered the end result of a cumulative proinflammatory soup resulting in endothelial and beta cell dysfunction from decades of exposure to elevated dietary glycosylation products. No. 134/80 mm Hg for blood pressure (BP). HDL=high-density lipoprotein. the study titled Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) demonstrated a 47% reduction in MCEs and a 20% reduction in all-cause death by achieving a >50% reduction in LDL levels and a 37% reduction in hsCRP levels using rosuvastatin. have all been documented to prevent oxidative stress– mediated ED in hypercholesterolemic.com. Statin medications. Chronically elevated triglyceride levels. or revascularization Main Results 47% reduction in MCEs including 20% reduction in death from all causes LDL level reduction by >50% CRP level reduction by 37% Reported Adverse Effects (AEs) No differences in adverse events between groups 10 cases of myopathy in statin group vs 9 cases in placebo group 1 nonfatal rhabdomyolysis in statin group No differences in cancer. and atorvastatin. 3 • Jun/Jul 2011 45 . visit imjournal. and 28. hsCRP=highly-sensitive C reactive protein. including lovastatin. postprandial ED in both normal and diabetic participants following high-glucose. the pioneering research of Ceriello et al has demonstrated short-term. oxidation of LDL (oxLDL). GI. the JUPITER study showed that lowering hsCRP levels (in this case.27 There is also evidence of a cumulative process of chronic ED.35 for body mass index. Table. or hematologic disorders Key: 4S=Scandinavian Simvastatin Survival Study. including elevations in hsCRP. and combined high-glucose/high-fat challenge meals. Specifically.26-28 For example. REVERSAL=Reversal of Atherosclerosis with Aggressive Lipid Lowering JUPITER: Adding further support to the hsCRP-lowering actions of statins. renal. cardiac death. Protection Against Endothelial Dysfunction Endothelial dysfunction (ED) is the lack of a normal nitric oxide-mediated dilatory response to changes in blood flow or pressure in major arteries. and elevated nitrotyrosine (a biomarker of peroxynitrite-mediated modification of the endothelial wall).29-34 Statins appear to reduce ED by reducing the susceptibility of LDL to oxidation. with use of rosuvastatin) also reduces risk of cardiovascular-related and all-cause death. high-fat. These elevations in oxidative stress have been demonstrated in response to dietary. AV=atheroma volume.
Following an average follow-up period of 3.This article is protected by copyright. To subscribe. 14 Notably. depression. Compared with a reference group of LDL reduction that was <10 mg/dL. As mentioned above. moderate (40-70 mg/ dL). respectively. including adherence). 47%. concerns about coenzyme Q10 deficiency. with greater reductions proportional to dose and percentage of LDL reduction. patients aged ≥75. At the end of the 12-month intervention. treatments that have a proven impact on reducing progression of. 46 Integrative Medicine • Vol. the consistency of the results in both observational and experimental analyses demonstrates that there is nothing fundamentally different about the protection granted from LDL reduction in high-risk older patients compared with younger patients.33. and 62%. in vivo animal data supports lycopene having similar. No. Statin use was commonplace in every age quartile ranging from 69.39 Although the importance of LDL pattern on cardiovascular outcomes is debatable because all LDLs appear to be positively correlated with progressive disease. please visit copyright.com. including a vegetarian diet with 10% fat content. respectively.1 years. can reverse coronary heart disease42.36 Of note. statins also clearly shift lipoprotein subtypes from pattern B (smaller. if not greater.3-75. including the PROSPER and Pravastatin Antiatherosclerosis Trial in the Elderly (PATE) studies and the Study Assessing Goals in the Elderly (SAGE).40 Although statins are not known or approved for their effects on triglycerides. or causing regression of. 0. approximately 80% of patients had demonstrable regression after only 1 year of intensive lifestyle modification. improved antioxidant capacity of HDL.35 This reduction in oxLDL may result from an increase in antioxidant capacity of LDL cholesterol. Statin Controversies Clinical recommendations for lipid lowering are not popular amongst patients. 69. Lipoprotein Pattern Modification In addition to reduced ED and improved resistance of oxidative stress. The SAGE trial compared atorvastatin 80 mg/d versus pravastatin 40 mg/d in 893 patients (30% women) aged 65 to 85 years with ischemic heart disease. many concerns are largely unsupported by available evidence.3 years. Vasankari et al demonstrated increased LDL antioxidant capacity per LDL particle following 1 year of either simvastatin or atorvastatin treatment. and reasons for avoiding lipid-lowering treatment abound.com. and large (≥70 mg/dL) LDL reductions had an adjusted relative risk reduction for MI and revascularization surgery of 36%. 95% CI. 38 The interactions of statin medications and antioxidants deserve more research attention. then returned to the research facility once or twice per week for 4-hour sessions over the duration of the study.11.37. trial of rosuvastatin (10-40 mg/d).43 For less adherent patients and/or patients with financial or temporal limitations. which results from an increased clearance of VLDL. the atorvastatin group had a significant reduction in all-cause death (HR=0. and regular stress reduction and yoga.1-69.3 years who had small (10-40 mg/dL). To share or copy this article. Regression of Atherosclerosis The landmark clinical trial by Dean Ornish published in 1998 clearly demonstrated that intensive lifestyle modification. Reasons for avoiding statin therapy include concerns in the elderly population. reduced lipid storage in HDL. respectively).41 Because change in HDL is an important variable in risk determination. 61. more buoyant LDLs). Participants in the Ornish trials were immersed in an intensive lifestyle modification retreat for up to 6 weeks. Although questions remain about the safety and effectiveness of statins for select groups and for durations longer than currently reported in clinical trials. therapies that preserve HDL cholesterol from clearance have important therapeutic potential. Although established cardiovascular-protective lifestyle modifications should always be recommended and reinforced. 3 • Jun/Jul 2011 Bradley—HMG-CoA Reductase Inhibitors .83) and greater LDL reductions compared with the pravastatin group. these clinical trials were of relatively short duration (18 months and 24 months. actions on the prevention of oxLDL formation than fluvastatin. established CVD deserve discussion. Statin Use in Women Despite lower representation of women in some clinical trials of statins for primary and secondary prevention of CVD.13.7% to 81.13-0. daily physical activity. potent statins including atorvastatin and rosuvastatin can have a pronounced lowering effect on triglycerides. male veterans who were at least 60 years of age.2% of the sample. the potential clinical efficacy (ie. especially to optimize the practice of the integrative clinician. visit imjournal.46 Although the findings summarized above are largely limited to high-risk elderly patients. Use ISSN#1543-953X. 50% to 55% for moderate reductions. and ≥75.9 years. and concerns about cancer risk. These findings are consistent with clinical trials of statins in elderly patients. everyone does everything you say and it works) does not equal the achieved clinical effectiveness (ie. participants receiving standard-dose pravastatin had a 36% risk reduction for MCEs. 10. whether it works the way it happens in practice.3 years.3 years. Lipid-lowering Therapy and Statin Use in Elderly Patients The benefits of lipid-lowering therapy in elderly patients have been recently evaluated in a cohort of 20 132 high-risk. whereas concomitant use of lovastatin (60 mg/d) partially attenuated the antioxidant effects of supplemental alpha-tocopherol (450 IU/d) on oxLDL formation in humans. the REVERSAL and ASTEROID clinical trials have demonstrated reductions in atheroma volume using 80 mg/d of atorvastatin and 40 mg/d of rosuvastatin. These risk reductions were relatively consistent across all age quartiles with ranges of 27% to 36% for small reductions.45. more dense LDLs) to pattern A (larger. this shift in LDL subtype is predictably accompanied by reductions in very low-density lipoprotein (VLDL) concentrations.44 Age quartiles were <61. and increases in HDL concentrations. and 63% to 74% for large reductions.45 The protective benefits appeared greatest in nondiabetic patients with mild cholesterolemia and patients with established coronary disease.46 The PATE study randomized more than 600 patients with a mean age of 73 years to low-dose (5 mg/d) versus standard-dose (10-20 mg/d) pravastatin. and musculoskeletal adverse effects.
Although serious musculoskeletal reactions can occur and symptoms should be critically evaluated. available trials do not support routine Co-Q10 supplementation for primary prevention of myopathic symptoms. Recently. benefits. and associated costs to the patient regarding routine Co-Q10 supplementation. cell membrane structure and signaling).This article is protected by copyright.48 JUPITER demonstrated nearly equivalent reductions in the prespecified outcome measure of composite CVD. pulsing statin therapy.001) for men and 0.74-1. No. controlled trial to answer the important clinical question of whether routine Co-Q10 supplementation in addition to statins improves outcomes.com. CVD. The trial design would require approximately 4000 very high-risk participants. Additionally. patients are aware of reports that these symptoms occur and frequently raise these concerns to clinicians. the reduction in event rates for fatal and nonfatal MI.47 Specifically evaluating the question of statin use for primary prevention in women.54 (0.37-0. statin dose reductions. including reduced building blocks for cellular needs (eg.002) for women. a clinical trial of red yeast rice for statin-intolerant patients (due to musculoskeletal symptoms) demonstrated significant reductions of LDL levels and improved tolerance of red yeast rice compared with statins. Myalgia. Although ideally this trial would be of high priority to research sponsors. including cardiac and all-cause death. and a budget greater than $25 million to detect a 20% difference in MCEs. better representation of women in more recent trials. other causes for myalgia should not be overlooked.50 a negative impact on outcomes from statin-induced Co-Q10 deficiency is not currently supported by the available literature. balancing potential risks. For example. and switching to red yeast rice.7%.87. Although representation of women in statin trials has been historically limited. 10. meta-analyses.53 For patients with congestive heart failure (CHF). shortterm periods without statin use. only reached statistical significance for men. A definitive trial would randomize all participants to statin with or without Co-Q10 at an adequate dose. including vitamin D deficiency.45-0. Specifically. Use ISSN#1543-953X. Bradley—HMG-CoA Reductase Inhibitors Integrative Medicine • Vol.73. Although optimization and preservation of patient health is the philosophical underpinning of these concerns. the high cost and necessary duration of the trial may prevent it from ever being performed. In a worst-case scenario. and at risk for. while clinical trials demonstrate that Co-Q10 supplementation may reduce the frequency and severity of symptoms in statin-treated patients who develop myopathy. both in vitro and in vivo models suggest that all peripheral cholesterol needs would be provided by an LDL concentration of 25 mg/dL. as well as fatal and nonfatal stroke. In their accompanying meta-analysis of 5 primary prevention-oriented clinical trials including observations from more than 13 000 women and nearly 450 events. Stocker et al conducted a 6-year.10. 3 • Jun/Jul 2011 47 . many integrative clinicians employ complex protocols to match androgen levels in older adults to those in younger adults. Co-Q10 deficiency may be responsible for the lack of observed benefit of statins in this subgroup. correction of vitamin D deficiency. etc).13. combined with the protective benefits of LDL lowering down to levels below 75 mg/dL in select populations using statins. yet this orientation does not seem to hold true for LDL-C. at least a 5-year follow-up period.51 Also. clinicians have to use their best judgment. In the absence of a definitive result. in high-risk patients. they would not prevent protection by statins against MCEs. has led the recommendation for an optimal LDL-C level of 50 to 70 mg/dL by some authors. The medical community lacks a definitive randomized. case-control study in 250 cases and 250 matched controls. Although small clinical trials of supplemental Co-Q10 in statin-treated diabetics support further improvements in endothelial function compared with statin treatment alone. However. 0.49 However.55 This study included an integrative approach for LDL reduction in statin-intolerant patients. please visit copyright. Mora et al recently published a meta-analysis of statin primary prevention trials comparing pooled results with those observed in JUPITER. several pieces of evidence indicate requirements are much lower than one may suspect. 95% CI. P<. P=.88. statins appear to reduce risk of MCEs by approximately 37% in women.54 These observations.54 Ironically. reductions in risk from MCEs and cardiovascular mortality appear to be equivalent in both men and women. suggest an equivalent level of protection by statins in men and women with. these reactions are extremely rare (0. electrolyte abnormalities including magnesium deficiency. Myopathy. and this question deserves more research attention. as can be seen in the Table8. Peripheral Cholesterol Requirements and Optimal Levels The most common concern I hear from medical students and patients is a fear that using statin medications will reduce endogenous cholesterol to a level too low for normal function. reductions in revascularization and hospitalization for angina were significant for men and women. well-designed clinical trials do not support a significant increase in musculoskeletal symptoms in statin-treated patients compared with placebo-treated controls.18. To subscribe. the significance of these reductions is unknown.2. Coenzyme Q10 Deficiency Reduction of coenzyme Q10 (Co-Q10) is caused by statin medications. the hazard ratio was 0. including lifestyle modifications. and systemic hormonal needs (eg.14) and should not prevent appropriate prescribing of statins. even if hypothetical impairments in peripheral cholesterol requirements did occur. which is approximately equivalent to the observations in JUPITER. In outcome subgroup analyses.52.49). there was no effect on risk for future cardiac event (OR: 1. See below for further discussion of statins in CHF. Even though the exact circulating cholesterol requirements in adults are definitively established. musculoskeletal injury.01%-3. although Co-Q10 concentrations were lower in the statin-treated group.18 Further support for the adequacy of low LDL comes from observations in newborns demonstrating circulating LDL levels of approximately 50 mg/dL.58 (0. P=. glucocorticoids. and rheumatic disease. the concerns are not validated by the available science. visit imjournal. fibromyalgia. To share or copy this article. prospective. and Rhabdomyolysis As demonstrated in the Table.com. as well as subgroup analyses from past trials. cholecalciferol.
However. however. this technique breaks the randomized nature of these trials and thus cannot prove causation. Risk of Cancer Bonovas et al have investigated the issue of cancer risk from statin therapy in great detail. Yet Morales et al reported conflicting evidence in a small.61 Readers may consider this finding and evidence of increased cancer risk from the PROSPER study concerning enough to avoid statin use. Additionally. including patients with diabetes. readers must be cautious with this interpretation.5 However. congestive heart failure. especially given the availability of effective treatments for depression. and CARDS have clearly demonstrated significant risk reduction in high-risk patient populations. PROSPER. To subscribe. and 22% increase in relative risk for cancer in adults aged 65 to 70. and atrial fibrillation. including noncoronary atherosclerotic disease. For the purposes of lipid-lowering therapy. vascular disease subgroups that lack substantial evidence supporting benefit of statins include chronic kidney disease. clinical trials such as HPS. 3 • Jun/Jul 2011 Bradley—HMG-CoA Reductase Inhibitors . including those with diabetes. reported estimates suggest that for patients with established CVD (including patients with diabetes. or increase. represented by reductions in all-cause death. only 37 patients require treatment to prevent 1 death from all causes.60 Of note.2-0. please visit copyright. Although evidence is mounting. pancreatic. Specifically. the possible contribution to increased risk through mostly unsubstantiated increases in depression secondary to statin use must be balanced by the established >49% of population-attributable risk of MI due to dyslipidemia (also per INTERHEART5) and the risk reductions for CVD events achieved by the use of statins in appropriate patients.66 Although statin medications are costly. this finding must be placed in the context of the need for CVD risk reduction despite this risk. Meta-analyses support this observed increase in cancer risk in elderly patients using pravastatin. controlled trials. Applications of Statins in Vascular Disease Subgroups Although the evidence supporting statin use to reduce CVD events. cardiovascular-related death. and history of psychiatric disorders) in statin-treated patients compared with nonstatin-treated patients. current findings appear mixed. 10. or colorectal cancers. any increase in relative cancer risk must be kept in the context of the absolute risk for cancer versus vascular events and death. pravastatin use was associated with a 6%. number of primary care visits. 23 trials demonstrated estimates of lower cancer risk. the findings for pravastatin cannot be generalized to all statins. although these meta-analyses were based on completed randomized. body mass index. peripheral artery disease. the PROSPER11 study demonstrated a 25% increase in new cancer incidence in the pravastatin group versus the placebo group. Specifically. they have demonstrated cost-effectiveness in both primary and secondary prevention. the NNT for statin drugs is reasonable. Statins: Numbers Needed to Treat and Cost-effectiveness The numbers needed to treat (NNT) for statin medications vary for primary versus secondary prevention and depend on the outcome in question. for high-risk elderly patients. prostate. in these patients the NNT to prevent 1 nonfatal vascular event is only marginally increased to 53 patients. To share or copy this article. and/or 2+ traditional cardiovascular risk factors with 10-year 48 Integrative Medicine • Vol. Using a standardized depression scale.4 95%.56-59 However. The impact of statin-induced depression on clinical outcomes deserves further study. the majority of these analyses have been performed to evaluate the hypotheses that statin use may protect against cancer through antiinflammatory and other actions. CI 0. Also. statin use does not appear to protect from. However. visit imjournal. respectively. which is equivalent to the risk of CVD). with greater cost savings in high-risk patients. 2 trials were neutral.56-62 Recent meta-analyses of clinical trials of statins evaluating cancer risk in diverse populations do not support the notion that these drugs are associated with greater risk of cancer overall. appear to outweigh the risks of cancer. Of the 35 meta-analyses by Bonovas et al. Yang et al conducted a case-control study in 458 cases and 1830 controls to evaluate possible relationships between statin use and either newly diagnosed depression or attempted suicide. records of stressful events. Risk of Depression Further criticism of statin medications includes possible increased incidence of depression in statin-treated patients.com. No.com. the evidence for the protective benefits of statins in particular subgroups of patients with comorbid vascular disease is less convincing. Use ISSN#1543-953X. risk of hematologic.65 The cost-effectiveness of statin medications for both primary and secondary prevention has been recently evaluated. As discussed above. greater than 35% of population-attributable risk for MI was due to psychosocial indices.This article is protected by copyright.60 Despite these findings. Specifically. investigators demonstrated a reduction in positive mood after 15 weeks in statin-treated patients. and >75 years of age. and only the PROSPER study demonstrated a statistically significant increase in cancer risk. and/or multiple risk factors. established coronary disease. as mentioned above. “high risk” is defined as patients with established coronary arterial disease or CVD-risk equivalent. the benefits of cardiovascular protection. controlled trial of simvastatin use in elderly patients aged 70 years or older. Finally. no significant association was found between statin use and suicidal behavior. randomized. 13%. and definitive clinical trials are not available. 70 to 75. High-risk Patients As discussed above.9. diabetes. As the INTERHEART study demonstrated. 10 trials showed estimates of greater cancer risk.64 The clinical importance of this reported reduction in mood is not known.63 Contrary to popular belief. for both primary and secondary prevention. including but not limited to depression. respiratory. in pooled analyses from 12 individual trials. they measured a 60% reduction in risk for depression (RR=0. and death from all causes is strong in patients at high risk. adjusted for smoking. The NNT increases to 190 treated to prevent 1 death from all causes in patients without established disease.
can be challenging. placebo-controlled trial of atorvastatin in 80 patients with established AF. Three observational studies have demonstrated an inverse relationship between serum cholesterol levels and mortality in patients with chronic CHF. and viscous fibers. Also observed was a 9% reduction in CRP level only in the atorvastatin group. who do not Bradley—HMG-CoA Reductase Inhibitors Integrative Medicine • Vol. current evidence does not support the use of statins in this vascular disease subgroup. statin use targeting further LDL-C reduction by 30% to 40% using statins appears to add further protection. integrative clinician.40 • All patients are encouraged to follow a modified Portfolio/ Mediterranean diet hybrid rich in vegetables. major clinical trials have found no protective effect of statin medications on dialyzed patients. and these results may not apply to all statins. such as MCEs. and all-cause death. Use ISSN#1543-953X.82. including select use of emerging biomarkers. cold-water fish. 2 clinical trials of atorvastatin (20 mg/d.72-74 Two recent clinical trials.79 However. please visit copyright. but their relative effectiveness. for the objective. neither trial demonstrated protection from all-cause death.77 Also demonstrating a beneficial effect of statin use in AF was a recent randomized. and the contribution of emerging risk factors to CVD risk. my typical approach includes: • I give an individualized risk assessment. The exact reason for this lack of benefit is not known. almonds/ tree nuts. The concern is not the safety of LDL-lowering alternatives. cardiac death. Notably. 3 • Jun/Jul 2011 49 . Controlled Rosuvastatin in Multinational Trial in Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardio-Heart Failure trial (GISSIHF). randomized more than 9500 patients with New York Heart Association stage II-IV CHF and left ventricular ejection fraction between 31% and 33% to 10 mg/d of rosuvastatin or placebo for 36 to 48 months. Marin et al followed 234 consecutive CABG patients and demonstrated a 48% reduction in postoperative AF in statin users compared with nonusers.68 The clinical use of statins in chronic kidney disease recently has been the subject of a Cochrane Review. To subscribe. and statins in particular. LDL-C reductions to <100 mg/dL are targeted. and plant proteins including soy as tolerated. CVD risk >20%. vascular events.67 In these populations. 40 Chronic Kidney Disease Chronic kidney disease is hallmarked by chronic endothelial dysfunction25 and is considered an independent risk factor for MCEs. observational study in 625 patients with new AF.80 Protective effects on the development of postoperative AF by statin use prior to coronary artery bypass grafting (CABG) or other cardiac surgery has been demonstrated in observational studies and 2 clinical trials. 7 days pre-surgery) have demonstrated 14% to 22% reductions in postoperative AF. In a prospective. – high-risk patients. controlled trial of atorvastatin versus placebo showing an adjusted 80% risk reduction in AF events requiring cardioversion in the atorvastatin group. with additional benefits demonstrated at LDL-C <70 mg/dL.76 Despite substantial reductions of LDL levels in both trials. Talking With Patients About Statins Clinician conversations with patients about lipid-lowering therapies. including diabetics.com. Use of atorvastatin resulted in substantial reductions of CRP levels. However. fruits. highpolyphenol content foods. To share or copy this article. or hospitalization.71 Congestive Heart Failure Despite potential benefits from the antiinflammatory and endothelial protective actions of statins in CHF. fermented foods. it must be acknowledged that the recommendation for these alternatives is based on small clinical trials that typically do not evaluate clinical endpoints. 10. a recent trial of 234 AF patients failed to detect improvement in achieving stable sinus rhythm following cardioversion from 80 mg/d of atorvastatin started 14 days prior.69 However. improvement in endothelial dysfunction through the antiinflammatory actions of statins resulting in improved flow-mediated dilation and improved cardiac remodeling postoperatively is the likely mechanism responsible for the observed benefits. these conversations can also be rewarding because they offer an opportunity to engage patients about their risks and discuss our unbiased understanding about their therapeutic options. and AF resolved in 65% of the atorvastatin treatment group. and the avoidance of effective therapy in high-risk patients. however. • My discussion of options for LDL-lowering includes statins in the following circumstances: – moderate-risk patients who do not reach lipid goals after 6 months of lifestyle-change counseling.This article is protected by copyright. visit imjournal. As mentioned at the beginning of this article.81 Additionally. 3 days pre-surgery and 40 mg/d. When the needs for LDL reduction and choice of therapy are questioned. risk stratification.85 The carbohydrate content is modified based on diabetes status and physical activity level. see “Are Additional Lipid Measures Useful?” on p 56 of this issue for further discussion of traditional risk factors. but not in other subgroups. there was no increase in risk of death or events. including adherence to lifestyle changes. Atrial Fibrillation Evidence is mixed but mounting regarding the effects of statins in prevention of atrial fibrillation (AF) episodes requiring cardioversion in patients with chronic AF and in the prevention of AF following cardiac surgery.75.83 Although further research is warranted in patients with AF but without other indications for statin therapy. plant sterols. despite documented reductions in cholesterol and hsCRP levels. The use of statin medications in patients with chronic kidney disease that does not require dialysis is associated with reductions in cardiovascular events.16. lean poultry. Considerations for alternative LDL-lowering and hsCRP-lowering therapies have been reported previously16. neither study demonstrated harm from rosuvastatin. For patients with untreated LDL-C <100 mg/ dL.16. that is. and increases in serum albumin70 levels.78 Further evidence supporting statin use in AF was reported by Dernellis and Panaretou in a 6-month randomized. specifically hsCRP. any statin use was associated with a 74% reduction in recurrent AF in patients on beta-blockers. No.com.84.
53(3):244-253. 21. et al. Mehta JL. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Ceriello A. The National Cholesterol Education Program Adult Treatment Panel III guidelines. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. In practice. Wang X. 2009. Gao X. Ounpuu S. 2007.79(6):1842-1851. Taddei S. Integrative Treatments to Reduce Risk for Cardiovascular Disease. 18. Larose E.372(9634):224-233.360(9326):7-22.536 high-risk individuals: a randomised placebo-controlled trial. Zhao XQ. rigorously designed.295(13):1556-1565. Heart Protection Study Collaborative Group. Ryan D. 17. His area of research expertise is the evaluation of biomarkers and treatments for chronic. Karthikeyan G.17(6):631-636. Li Y. Simultaneous low-density lipoprotein-C lowering and high-density lipoprotein-C elevation for optimum cardiovascular disease prevention with various drug classes. Use ISSN#1543-953X. 24. 30. Clearing Up the Cholesterol Confusion. Song J.8(3):234-242. 2009. 398-403. Fang L. et al. et al. Daghini E. et al. Dubois BW. and a second associated with low plasma concentrations of apolipoprotein B-100. Am J Physiol Heart Circ Physiol. 2002. Lipid profile. Islam S. Murphy MB. Rask-Madsen C. 2008.364(9435):685-696. Karagiannis A. Orenstein D. and substantiated risk. Sinha AK. lipoproteins.18 – patients with elevated hsCRP levels who do not respond to dietary and/or supplement trials due to exposures (eg. JAMA. 2004. Schmidt AM. 28. Bortolotto LA. Persistent endothelial dysfunction in humans after diesel exhaust inhalation. 2002. The economic burden of chronic cardiovascular disease for major insurers. have CHF or chronic kidney disease requiring dialysis.13 vascular endothelial protectants. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.This article is protected by copyright. To subscribe. 26.3(1):46-56. 2010. pathogenesis and management. 2004.39 intra-LDL antioxidants. 20. JAMA. Taboga C. evidence. King GL. Gonzalez M. 10. Effect of atorvastatin and irbesartan. 2007. I recommend statins for those diabetic patients with multiple risk factor elevations who may benefit from reaching more intensive targets for LDL (<75 mg/dL). Wei H. et al.14 statins are effective and safe medications when recommended to the right populations. 31. Lancet. Townsend Letter: The Examiner of Alternative Medicine. oxidative stress. 2008. Costa-Hong V.com. Ceriello A. Danielson E. and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Zhang C. To share or copy this article. although clinical review of systems for possible adverse effects and periodic laboratory evaluations are recommended. Endothelial dysfunction in insulin resistance and type 2 diabetes. rumors about adverse effects of statins should be dispelled. et al.29-34 lipid subtype modifiers. 2005. A receptor-mediated pathway for cholesterol homeostasis. on postprandial endothelial dysfunction. The burden of CVDs and diabetes on the health of the public cannot be overstated. Colhoun HM. Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short.178(2):399-401. Lima JJ. et al. including red yeast rice. 2002.360(9346):1623-1630. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. Brown MS. Genetic analysis of a kin- 19. Conclusions 4. 2003. 9. 6. Assaloni R. Teo KK. Nat Clin Pract Endocrinol Metab. Oxidative stress and endothelial dysfunction in chronic kidney disease. Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. Zhang P. It is possible that LDL remains a surrogate clinical endpoint.and long-term simvastatin treatment. et al. 14. American Diabetes Association. Durrington PN. known modifiable risk factors are estimated to account for 90% to 94% of population-attributable risk for acute events. Tuzcu EM. Lancet. 2004. Ridker PM. and inflammation in type 2 diabetic patients. Schoenhagen P. at the Bastyr Center for Natural Health in Seattle. Curtiss LK. cumulative oxidation and inflammation in cardiometabolic risk conditions. J Manag Care Pharm. J Intern Med.344(8934):1383-1389. Evidence for two separate gene defects: one associated with an abnormal apolipoprotein B species. Fonseca FA.20(2):140-146. Am J Respir Crit Care Med.11. 2009. 22. No authors listed. 2006. and their combinations: a meta-analysis of 23 randomized lipid trials.295(2):H491-H498. please visit copyright. Nutr Metab Cardiovasc Dis. Endothelium-dependent contractions and endothelial dysfunction in human hypertension. an integrative specialty clinic for diabetes and heart disease. 23. References 1. dred with familial hypobetalipoproteinemia.8(1):26-32. 2007. Curr Opin Lipidol. Diabetes Care. whether as LDL-lowering agents. the current state of the evidence suggests that. Brown BG.364(9438):937-952. N Engl J Med. randomized trials with independent oversight and monitoring. NADPH oxidase contributes to coronary endothelial dysfunction in the failing heart. Bertics SJ. Statin drugs have demonstrated impressive reductions in MCEs and all-cause death in numerous. Although effective alternatives for lowering LDL levels exist.com. 13. et al. 2009.9. McQueen MJ. Ghiadoni L. Science. 2009. and risk of a first myocardial infarction among Asians: an analysis from the INTERHEART Study. Mills NL. Circulation. Stukovsky KH. 25. alone and in combination. Goldstein JL. This discussion should include relative costs of treatment. Mikhailidis DP. Bradley R. Da Ros R.4(4):333-346.36 or anti-inflammatory agents. Risk reduction of these events correlates greatly to observed reductions in LDL levels and hsCRP levels by statin drugs. Lipsy RJ. Krieger EM. However. is both a clinical scholar and practicing physician. Brunzell JD. Davidson M. IMCJ. 7.8. Blauw GJ. Jorgetti V. 3 • Jun/Jul 2011 Bradley—HMG-CoA Reductase Inhibitors . et al. 27. Standards of medical care in diabetes--2009. 12. discussions of these alternatives should consider patient risk and set aside biases. 2008. AGE/RAGE produces endothelial dysfunction in coronary arterioles in type 2 diabetic mice. Oberg E. 2006.9(1 Suppl):2-5. Diabetes Care. ND.12. Washington. Endothelial dysfunction in metabolic syndrome: prevalence. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20. 2004. Hou M. Tangka FK. 5. Lovastatin compromises C-reactive protein induced endothelial dysfunction including altered expression of cell adhesion molecules and increased monocyte recruitment. 1986. et al. Lancet. Finkelstein EA. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. et al. Furberg CD. Lipids. Tonutti L. Young SG. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Dr Bradley runs the Diabetes and Cardiovascular Wellness Clinic. Betteridge DJ. Lancet. metabolic disease will be discovered. Jansson PA. plasma apolipoproteins. Hawken S. J Clin Invest. Trogdon JG. 10. 2. 8. He is a clinical research assistant professor at Bastyr University and an affiliate clinical researcher in the Division of Cardiology at the University of Washington Medical Center. et al. Nicholls SJ. Yusuf S.359(21):2195-2207. 11. Nissen SE.296(3):H840-H846.92(5):381-386. Bradley. and better biomarkers for chronic endothelial dysfunction and oxidative. MPH. Circulation. Nwaise IA.35. 3. Chatterjee S. Atherosclerosis. The role of statins in endothelial dysfunction in 50 Integrative Medicine • Vol. 16.232(4746):34-47.291(9):1071-1080. Tornqvist H. Shepherd J. Hawken S. J Am Coll Cardiol. 2005. 413-418. visit imjournal. – patients with diabetes who initially refuse statins but do not reach intermediate LDL goals (<100 mg/dL) after 6 months of dietary change and trials of other supplements. While residual risk remains. Am J Physiol Heart Circ Physiol. No. smoking). Ganz P. Semin Vasc Med. Lancet.111(19):2518-2524. 1987. 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Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE). Sitaras NM. Min WK. 67. Lancet.100(9):1400-1403. O’Keefe JO. 59.28(8):659-676. Jick SS. Varol E. Sitaras NM. Merz CN. Eur Heart J. Comparison of lycopene and fluvastatin effects on atherosclerosis induced by a high-fat diet in rabbits. Gissi-HF Investigators. Clark AL.44(3):720-732. Land JM. 2006. Brown SE.115(6):700-707. Am J Cardiol. 71. et al. Cleeman JI. Heales SJ. Ansell BJ.com. Ozaydin M. May 2009. Malminiemi K. J Card Fail. Jiang CH. 2006.15(4):387-392. Fonarow GC. Karagiannis A.187(1):198-204. Sanchez-Recalde A. Hamilton MA. 73. 35. Matragoon S. Circulation. 37. J Am Coll Cardiol. Dernellis J. 2007. 2010. Effects of lovastatin therapy on susceptibility of LDL to oxidation during alpha-tocopherol supplementation. Sitaras NM. Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients. 2008. Oberg E. et al. visit imjournal. Am J Kidney Dis. Am J Cardiol. when taken at low doses for managing hypercholesterolemia: evidence from a meta-analysis of 12 studies. Song YB. Effect of C-reactive protein reduction on paroxysmal atrial fibrillation.121(9):1069-1077. please visit copyright. 43. Filioussi K.280(23):2001-2007. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Huang YM. JAMA. 42. Lawson WE. Stocker R. 61.150(5):1064. Kim SB. Statins and the risk of colorectal cancer: a meta-analysis of 18 studies involving more than 1. Patti G.32(5):810-812. Sinzinger H.137(2):740. 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Reduction of oxidative stress and modulation of autoantibodies against modified low-density lipoprotein after rosuvastatin therapy.298(7):786-798. 2008. Ridker PM. 2002. 69. The relationship between cholesterol and survival in patients with chronic heart failure. Number-needed-to-treat analysis of the prevention of myocardial infarction and death by antidyslipidemic therapy. Almroth H. Bradley R. Becker DJ. Gastroenterology. 2009. 2009. Filioussi K. 2007. Pollicino C. CMAJ. Am Heart J. Kendall CW. Gordon RY. 2006. Gomez-Rubin MC. Cordain L. Effect of atorvastatin on the recurrence rates of atrial fibrillation after electrical cardioversion. Viikari J. Doring A. Perkovic V. 41. Strippoli GF. The role of statins for the primary and secondary prevention of coronary heart disease in women. et al. Caldwell RW. Gheewala NM. N Engl J Med. Diabetes Care. 76. Lowel H. Sitaras NM.42(11):1933-1940. double-blind. Arch Intern Med. Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia. 62.150(12):830-839. 2008. Humphries KH. Caldwell RB. 50. Lloyd Jones M. Novel risk factors for cardiovascular disease: are additional lipid measures useful? IMCJ.7(3):212-222. Shishehbor MH.123(4):899-904. Sitaras NM. Ahotupa M. Ornish D. 2006. Statins and cancer risk: a confounded association. Florkowski CM. Athyros VG. Neither plasma coenzyme Q10 concentration. inflammation. Pascual DA. et al. et al. Lee SK. O’Keefe JH.336(8708):129-133. Coenzyme Q10 improves endothelial dysfunction in statin-treated type 2 diabetic patients. 75. El-Remessy AB. 2002. Deedwania P. Ouchi Y. 1998. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. et al. Marin F. 57. Use of statins and risk of haematological malignancies: a meta-analysis of six randomized clinical trials and eight observational studies. On YK. Tatzber F. 34. Filioussi K. Arterioscler Thromb Vasc Biol.64(3):255-262. 2009. Am J Cardiol. Direct comparison of a dietary portfolio of cholesterol-lowering foods with a statin in hypercholesterolemic participants. To share or copy this article. Flordellis CS.97(10):1490-1493. Ward S.
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