Intensive Lipid Intervention in the Post-ENHANCE Era

Abstract

In this issue of Mayo Clinic Proceedings, Shepherd et al1Shepherd J Kastelein JJP Bittner VA Treating to New Targets Steering Committee and Investigators et al.Intensive lipid lowering with atorvastatin in patients with coronary heart disease, diabetes, and chronic kidney disease.Mayo Clin Proc. 2008; 83: 870-879PubMed Scopus (65) Google Scholar report that high-dose statin therapy improved cardiovascular (CV) outcomes particularly well for diabetic patients with mild to moderate chronic kidney disease (CKD). These authors focused, in a post hoc analysis of the Treating to New Targets (TNT) study, on the effects of high-dose atorvastatin (80 mg/d) vs low-dose atorvastatin (10 mg/d) in diabetic patients with coronary artery disease (CAD) with and without CKD. Interestingly, high-dose atorvastatin reduced the relative risk of major CV events by 35% in diabetic patients with CKD but by only 10% in those with diabetes and normal kidney function. Although the results of this subgroup analysis of the TNT trial are novel, they are not unexpected. Any beneficial therapy typically provides greatest therapeutic benefits in patients at highest risk for the measured outcome. Underlying CAD inherently places patients at risk for subsequent ischemic CV events. Additionally, diabetes and renal insufficiency are now considered CAD risk equivalents in those without known CAD.2Harper C Jacobson T Managing dyslipidemia in chronic kidney disease.J Am Coll Cardiol. 2008; 51: 2375-2384Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Therefore, patients with known CAD and concomitant diabetes or renal insufficiency are at particularly high risk for ischemic CV events and would be expected to derive more benefit from a proven therapy, such as high-dose atorvastatin, than patients at lower risk. High-dose atorvastatin therapy has produced similar marked benefits in 2 acute coronary syndrome trials,3Wiviott SD Cannon CP Morrow DA Ray KK Pfeffer MA Braunwald E PROVE IT-TIMI 22 Investigators Can low-density lipoprotein be too low? the safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy.J Am Coll Cardiol. 2005; 46: 1411-1416Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 4Schwartz GG Olsson AG Ezekowitz MD Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) Study Investigators et al.Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.JAMA. 2001; 285: 1711-1718Crossref PubMed Google Scholar in a recent stroke trial,5Amarenco P Bogousslavsky J Callahan III, A Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators et al.High-dose atorvastatin after stroke or transient ischemic attack.N Engl J Med. 2006; 355: 549-559Crossref PubMed Scopus (2323) Google Scholar and in other high-risk patient cohorts, such as the elderly6Maroo BP Lavie CJ Milani RV Efficacy and safety of intensive statin therapy in the elderly.Am J Geriatr Cardiol. 2008; 17: 92-100PubMed Google Scholar or patients with heart failure.7Khush KK Waters DD Bittner V et al.Effect of high-dose atorvastatin on hospitalizations for heart failure: subgroup analysis of the Treating to New Targets (TNT) study.Circulation. 2007 Feb 6; 115 (Epub 2007 Jan 29.): 576-583Crossref PubMed Scopus (156) Google Scholar, 8Bybee KA Lee JH O'Keefe JH Cumulative clinical trial data on atorvastatin for reducing cardiovascular events: the clinical impact of atorvastatin.Curr Med Res Opin. 2008 Apr; 24 (Epub 2008 Mar 20.): 1217-1229Crossref PubMed Scopus (29) Google Scholar Results of the current analysis are important, particularly because they clarify the extent to which atorvastatin can reduce CV events in patients with renal dysfunction.1Shepherd J Kastelein JJP Bittner VA Treating to New Targets Steering Committee and Investigators et al.Intensive lipid lowering with atorvastatin in patients with coronary heart disease, diabetes, and chronic kidney disease.Mayo Clin Proc. 2008; 83: 870-879PubMed Scopus (65) Google Scholar, 2Harper C Jacobson T Managing dyslipidemia in chronic kidney disease.J Am Coll Cardiol. 2008; 51: 2375-2384Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar High-dose statin therapy, especially with rosuvastatin, in rare instances has been associated with low-grade proteinuria that appears to be benign.2Harper C Jacobson T Managing dyslipidemia in chronic kidney disease.J Am Coll Cardiol. 2008; 51: 2375-2384Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar However, previous studies have shown that statins typically do not exacerbate renal disease but in fact do the opposite: they slow the gradual deterioration of kidney function as measured by glomerular filtration rate.2Harper C Jacobson T Managing dyslipidemia in chronic kidney disease.J Am Coll Cardiol. 2008; 51: 2375-2384Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 9Shepherd J Kastelein JJ Bittner V Treating to New Targets Investigators et al.Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study.Clin J Am Soc Nephrol. 2007 Nov; 2 (Epub 2007 Oct 17.): 1131-1139Crossref PubMed Scopus (278) Google Scholar A separate analysis of the TNT trial reported elsewhere showed that atorvastatin therapy at both the 10-mg and 80-mg doses reversed (as measured by estimated glomerular filtration rate) the expected decline in renal function, which is normally seen over time in patients with stable CAD.9Shepherd J Kastelein JJ Bittner V Treating to New Targets Investigators et al.Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study.Clin J Am Soc Nephrol. 2007 Nov; 2 (Epub 2007 Oct 17.): 1131-1139Crossref PubMed Scopus (278) Google Scholar Recently published trials have raised new questions about the optimal treatment of hyperlipidemia, and highly publicized articles in the lay press10Carey J Do cholesterol drugs do any good?.BusinessWeek. January 17, 2008; Google Scholar, 11Carey J Heart disease: not about cholesterol?.BusinessWeek. 2008; Google Scholar have questioned whether cholesterol drugs are effective. Much of this heightened skepticism over treatment of cholesterol stems from negative publicity generated by the Effect of Combination Ezetimibe and High-Dose Simvastatin versus Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) study.12Kastelein JJ Akdim F Stroes ES ENHANCE Investigators et al.Simvastatin with or without ezetimibe in familial hypercholesterolemia [published correction appears in N Engl J Med. 2008;358 (18):1977].N Engl J Med. 2008 Apr 3; 358 (Epub 2008 Mar 30.): 1431-1443Crossref PubMed Scopus (1124) Google Scholar This trial examined changes in carotid intimal-medial thickness (CIMT) over 2 years of follow-up in 720 patients with familial hypercholesterolemia who were randomized to receive either 80 mg/d of simvastatin or 80 mg/d of simvastatin with 10 mg/d of ezetimibe. Although ezetimibe with simvastatin reduced low-density lipoprotein cholesterol (LDL-C) by 16.5% and C-reactive protein (CRP) by 25.7% beyond the changes induced by simvastatin alone, the CIMT progression was similar in the 2 groups. The ENHANCE study was flawed in several ways, but perhaps most worrisome was the presence of completely normal CIMT (about 685 μm) at baseline in both groups. The CIMT progression was minimal and statistically similar in the 2 groups during the course of the study (5.8 μm in the simvastatin group and 11 μm in the simvastatin with ezetimibe group; P=.29). In comparison, the expected 2-year CIMT progression in an untreated group with familial hypercholesterolemia would be about 50 μm.13Bots ML Evans GW Riley WA Grobbee DE Carotid intima-media thickness measurements in intervention studies: design options, progression rates, and sample size considerations: a point of view.Stroke. 2003 Dec; 34 (Epub 2003 Nov 13.): 2985-2994Crossref PubMed Scopus (297) Google Scholar Thus, both treatment regimens, simvastatin alone and simvastatin with ezetimibe, could have slowed CIMT progression, albeit with no statistically significant difference between the treatments. Neither clinical event reduction nor added toxicity was seen with the combination simvastatin with ezetimibe vs simvastatin alone; however, the ENHANCE study was not designed to address these issues. The backlash in the lay and medical media to the results and delayed publication of the ENHANCE study was severe and overblown, inappropriately casting doubt on the importance of LDL-C in the minds of many patients and physicians. In some reports the entire body of evidence was misrepresented as the “LDL conspiracy.” BusinessWeek published articles entitled: “Do cholesterol drugs do any good?”10Carey J Do cholesterol drugs do any good?.BusinessWeek. January 17, 2008; Google Scholar and “Heart disease: Not about cholesterol?”11Carey J Heart disease: not about cholesterol?.BusinessWeek. 2008; Google Scholar wherein one physician was quoted as declaring, “Current evidence supports ignoring LDL cholesterol altogether.” Clearly, we need more clinical data on the effects of ezetimibe on CV outcomes and atherosclerosis progression. Well-designed outcome studies are now under way, but the one most likely to provide definitive results (Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]) will not be completed until 2012. Meanwhile, it is important to understand that statin therapy, as confirmed by large randomized trials, is among the most effective and safest strategies for improving arterial health and CV prognosis. High-dose statin therapy with either atorvastatin or rosuvastatin has repeatedly been shown to slow atherosclerotic progression or induce regression of atherosclerotic changes in both the coronary arteries and the carotid arteries.14Crouse III, JR Raichlen JS Riley WA METEOR Study Group et al.Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial.JAMA. 2007 Mar 28; 297 (Epub 2007 Mar 25.): 1344-1353Crossref PubMed Scopus (634) Google Scholar, 15Nissen SE Tuzcu EM Schoenhagen P REVERSAL Investigators et al.Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.JAMA. 2004; 291: 1071-1080Crossref PubMed Scopus (2079) Google Scholar, 16Nissen SE Nicholls SJ Sipahi I ASTEROID Investigators et al.Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial.JAMA. 2006 Apr 5; 295 (Epub 2006 Mar 13.): 1556-1565Crossref PubMed Scopus (1741) Google Scholar However, the recently reported Carotid Atorvastatin Study in Hyperlipidemic Post-menopausal Women: a Randomized Evaluation (CASHMERE) was similar in design to the ENHANCE study and showed that atorvastatin (+13 μm) was no better than a placebo (+11 μm) for slowing CIMT progression during the 1-year study.17Pfizer Carotid Atorvastatin Study in Hyperlipidemic Post-Menopausal Women: a Randomized Evaluation of atorvastatin, versus placebo (CASHMERE).http://www.clinicaltrials.gov/ct2/show/record/NCT00163163Google Scholar Importantly, the CIMT was normal at baseline in the CASHMERE, as it was in the ENHANCE study, suggesting that the surprisingly neutral results for both trials were likely due to a flawed surrogate marker (CIMT in the setting of normal arteries at baseline) than to flawed clinical efficacy of either atorvastatin or simvastatin with ezetimibe. Yet statin therapy has been shown to improve endothelial function and reduce platelet aggregation more than combination therapy with low-dose statin with ezetimibe.18Lavie CJ Milani RV O'Keefe JH Statin wars: emphasis on potency vs event reduction and safety [editorial]?.Mayo Clin Proc. 2007; 82: 539-542Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 19Menuet R Lavie CJ Milani RV Importance and management of dyslipidemia in the metabolic syndrome.Am J Med Sci. 2005; 330: 295-302Crossref PubMed Scopus (29) Google Scholar, 20Lavie CJ Milani RV Lipid therapy in the elderly—emphasis on clinical event reduction and safety.Am J Geriatr Cardiol. 2006; 15: 245-247Crossref PubMed Scopus (3) Google Scholar, 21Piorkowski M Fischer S Stellbaum C et al.Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets?.J Am Coll Cardiol. 2007 Mar 13; 49 (Epub 2007 Feb 23.): 1035-1042Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar Therefore, statin therapy should remain the cornerstone for pharmacologic therapy aimed at lowering risk of CAD and should be titrated up to full doses as needed to achieve the aggressive LDL-C goals.22O'Keefe Jr, JH Cordain L Harris WH Moe RM Vogel R Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal.J Am Coll Cardiol. 2004; 43: 2142-2146Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 23Smith Jr, SC Allen J Blair SN et al.AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update.Circulation. 2006; 113: 2363-2372Crossref PubMed Scopus (1541) Google Scholar For the past 2 decades, statins have been subjected to scores of large randomized controlled trials, which have consistently and conclusively shown that statin therapy lowers risk of myocardial infarction, CV death, stroke, and need for coronary revascularization procedures.6Maroo BP Lavie CJ Milani RV Efficacy and safety of intensive statin therapy in the elderly.Am J Geriatr Cardiol. 2008; 17: 92-100PubMed Google Scholar, 18Lavie CJ Milani RV O'Keefe JH Statin wars: emphasis on potency vs event reduction and safety [editorial]?.Mayo Clin Proc. 2007; 82: 539-542Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar These trials, now comprising more than 130,000 randomized patients, clearly indicate that statins reduce risk of adverse CV events in proportion to the extent of LDL-C reduction (approximately a 20% reduction in CV events for each 40-mg/dL decrease in LDL-C level), with no threshold yet demonstrated in which further reductions in LDL-C do not result in further reduction in CV events.24Cholesterol Treatment Trialists' (CTT) Collaborators Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins [published correction appears in Lancet. 2005;366 (9494):1358].Lancet. 2005 Oct 8; 366 (Epub 2005 Sep 27.): 1267-1278Abstract Full Text Full Text PDF PubMed Scopus (5760) Google Scholar For every 10,000 individuals with or at high risk of CAD being treated with a statin, each year approximately 100 myocardial infarctions or strokes will be prevented, and approximately 1 patient will experience rhabdomyolysis (the most serious adverse event noted with statins).25Davidson MH Robinson JG Safety of aggressive lipid management.J Am Coll Cardiol. 2007 May 1; 49 (Epub 2007 Apr 16.): 1753-1762Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar Contrary to popular opinion among the general American public, the main problem with statins is not the frequent occurrence of serious adverse effects, but rather the tendency for many at-risk individuals to be nonadherent with or discontinue their statin therapy because of misperceptions about the risk-benefit ratio of this safe and effective class of drugs. Fresh and powerful evidence bolstering and expanding the LDL-C hypothesis will be provided by the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study.26Ridker PM JUPITER Study Group Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial.Circulation. 2003; 108: 2292-2297Crossref PubMed Scopus (390) Google Scholar This large event-driven study was stopped early because rosuvastatin reduced CV morbidity and mortality, despite the fact that patients with high cholesterol were excluded.27AstraZeneca International Web site Crestor outcomes study JUPITER closes early due to unequivocal evidence of benefit.http://astrazeneca.com/pressrelease/5385.aspxGoogle Scholar Instead, patients were considered for study inclusion if they had evidence of systemic inflammation as shown by elevated CRP levels. The JUPITER study randomized 15,000 apparently healthy persons without atherosclerotic disease who had elevated CRP levels (≥2.0 mg/L) and LDL-C levels below 130 mg/dL (mean, 108 mg/dL) to 20 mg/d of rosuvastatin or placebo. After only 2 years into the planned 4-year study, JUPITER was halted because rosuvastatin significantly reduced the primary end point of the trial: major adverse CV events (CV death, stroke, myocardial infarction, hospitalization for unstable angina, or arterial revascularization).27AstraZeneca International Web site Crestor outcomes study JUPITER closes early due to unequivocal evidence of benefit.http://astrazeneca.com/pressrelease/5385.aspxGoogle Scholar With treatment, LDL-C in the rosuvastatin arm will likely be less than 60 mg/dL, which is lower than the mean with LDL-C treatment in any prior large randomized controlled statin trial. JUPITER, when eventually published, will probably confirm that inflammation, as measured by elevated CRP, is an important CV risk factor. Additionally, lowering CRP by intensive statin therapy or exercise training28Milani RV Lavie CJ Mehra MR Reduction in C-reactive protein through cardiac rehabilitation and exercise training.J Am Coll Cardiol. 2004; 43: 1056-1061Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar appears to improve CV prognosis. Naysayers might claim that the JUPITER study punches further holes in the LDL-C hypothesis, given the fact that half of all cases of CAD arise in people with LDL-C levels that are average to low when compared with the general population mean (LDL-C approximately 130 mg/dL). However, truly normal LDL-C levels range between 30 and 70 mg/dL.22O'Keefe Jr, JH Cordain L Harris WH Moe RM Vogel R Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal.J Am Coll Cardiol. 2004; 43: 2142-2146Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar JUPITER provides further evidence that people at high risk, such as those with documented atherosclerotic arterial disease, diabetes, or an elevated CRP level, show marked improvement in CV prognosis when treated with intensive statin therapy to achieve these physiological LDL-C levels. The secondary prevention guidelines from the American College of Cardiology and American Heart Association promote a target LDL-C below 100 mg/dL, with an optional goal of less than 70 mg/dL, as a Class 1A indication (ie, universal consensus between experts exists on the basis of prospective, randomized, blinded trials).23Smith Jr, SC Allen J Blair SN et al.AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update.Circulation. 2006; 113: 2363-2372Crossref PubMed Scopus (1541) Google Scholar Thus, clinicians have the strongest mandate possible from national guidelines to treat LDL-C levels aggressively. Still, nearly all patients are not at LDL-C goals, and the recent negative publicity from the ENHANCE study is likely to worsen physician aggressiveness and patient adherence with LDL-C treatment. The take-home message from the current analysis by Shepherd et al is that patients with CAD, diabetes, and CKD should be treated with high-dose statin therapy to optimally reduce the risk of subsequent CV events. Further studies are needed to determine whether adding ezetimibe (or therapies that reduce triglyceride levels and possibly increase high-density lipoprotein cholesterol levels, such as niacin, fibrates, and high doses of omega-3 fatty acids) to intensive statin therapy will produce additional benefits in primary and secondary CV prevention. Intensive Lipid Lowering With Atorvastatin in Patients With Coronary Artery Disease, Diabetes, and Chronic Kidney DiseaseMayo Clinic ProceedingsVol. 83Issue 8PreviewTo investigate the effect of intensive lipid lowering with high-dose atorvastatin on the incidence of major cardiovascular events compared with low-dose atorvastatin in patients with coronary artery disease and type 2 diabetes, with and without chronic kidney disease (CKD). 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