Safety and Effect of Very Low Levels of Low-Density Lipoprotein Cholesterol on Cardiovascular Events

Safety and Effect of Very Low Levels of Low-Density Lipoprotein Cholesterol on Cardiovascular Events John C. LaRosa, MDa,*, Terje R. Pedersen, MD, PhDb, Ransi Somaratne, MDc, and Scott M. Wasserman, MDc Based on the cardiovascular (CV) outcomes data derived predominantly from 3-hydroxy3-methylglutaryl-coenzyme A reductase inhibitor (statin) trials, guidelines have set lowdensity lipoprotein (LDL) cholesterol targets at successively lower levels over time. Recent data have demonstrated that more-intensive statin therapy (and, consequently, lower LDL cholesterol level) is more effective at reducing CV events than less-intensive statin therapy. Although the average LDL cholesterol level for a United States adult is 119 mg/dl, within the “normal” range (90 to 130 mg/dl) per the United States National Cholesterol Education ProgrameAdult Treatment Panel III guidelines, data from fetal studies, diet studies, contemporary hunter-gatherer populations, and other mammals have suggested that the “normal” physiologic range for LDL cholesterol in humans is likely 50 to 70 mg/dl. Low LDL cholesterol levels have been sporadically associated with an increased risk of cancer, hemorrhagic stroke, and other complications in population studies and clinical trials. However, statin clinical trials have generally not demonstrated correlations between ontreatment LDL cholesterol levels and safety. Clinical data have suggested a linear relation between LDL cholesterol lowering and CV risk reduction, supporting a favorable risk/ benefit ratio for attaining very low levels of LDL cholesterol to minimize the risk of CV events. In conclusion, clinical trial evidence demonstrating the efficacy and safety of LDL cholesterol lowering to a very low level is essential to ascertain the benefits and risks in reducing the residual risk of vascular disease. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;-:-e-) Hypercholesterolemia is an established risk factor for atherosclerosis and the development of coronary heart disease (CHD).1 Early pivotal statin trials reported reductions in cardiovascular (CV) events by approximately 25% to 35% with reductions in baseline low-density lipoprotein (LDL) cholesterol levels from approximately 120 to 190 mg/dl to approximately 100 to 140 mg/dl.2e4 Data from recent statin trials have shown that more-aggressive lipidlowering therapy is more effective at reducing CV events than less-aggressive lipid-lowering therapy.5e8 Still, doubt remains regarding the validity of the LDL cholesterol targets,9 with clinical trials of hypercholesterolemia designed to assess the efficacy and safety of different interventions (e.g., statin therapy vs placebo, more- vs lessintensive statin therapy) rather than to assess the merits and safety of achieving one specific LDL cholesterol level versus another. An important question that remains is whether the residual CV risk seen in these trials could be reduced or eliminated by further LDL cholesterol lowering. The present report reviewed the currently available clinical trial evidence that describes the effect of a very low level of a State University of New York Health Science Center, New York, New York; bCenter for Preventative Medicine, Oslo University Hospital, Ullevål and University of Oslo, Oslo, Norway; and cAmgen Inc., Thousand Oaks, California. Manuscript received September 25, 2012; revised manuscript received and accepted December 17, 2012. See page 7 for disclosure information. *Corresponding author: Tel/fax: (718) 270-1000. E-mail address: [email protected] (J.C. LaRosa).

0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.12.052

LDL cholesterol (<50 mg/dl) in subjects at risk of CV events. Human LDL Cholesterol Levels: Normal Versus Optimal Data from the early period in life (from gestation to adolescence) and from populations that consume a nonWestern diet have provided useful insight into what could be considered the “physiologic lipid levels” in humans. Total cholesterol and LDL cholesterol change as humans age (Table 1).10e14 During late gestation in utero, the total cholesterol and LDL cholesterol levels reach approximately 55 and 30 mg/dl, respectively, and these levels increase during breastfeeding.10,11 A similar pattern has been observed in pigs and sheep though after weaning, the total cholesterol levels decrease dramatically in pigs and sheep but not in humans (Figure 1).11 This phenomenon might result from the Western diet11 (as evidenced by comparisons of cholesterol levels across different populations and discussed by Dietschy and Turley,11 with data for nonhuman primates lending additional support to the effect of diet on serum lipids15). The cholesterol content of breast milk is believed to be sixfold greater than that of standard infant formula, and, accordingly, greater total cholesterol and LDL cholesterol levels have been described for breast-fed versus formula-fed infants. This greater cholesterol exposure in infancy has been postulated to downregulate cholesterol synthesis later in life.12 Data on cholesterol levels (LDL cholesterol levels not available) from the National Health and Nutrition Examination Surveys (NHANES III), www.ajconline.org

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Table 1 Changes in total cholesterol and low-density lipoprotein (LDL) cholesterol with aging Age

In utero (weeks)10,11 33e34 41e42 Infancy (age 4e5 months*)12 Breast fed Formula fed Children and adolescents (age 4e19 yrs, National Health and Nutrition Examination Survey 1988e1994)13 (yrs) 4e5 6e8 9e11 12e15 16e19 12e19 Adults (age 20e74 years, National Health and Nutrition Examination Survey 1999e2006)14 (yrs) 20e39 40e59 60e74

Mean Total Mean LDL Cholesterol Cholesterol (mg/dl) (mg/dl) 73 53

49 28

183 112 165

83 48 —

162 166 171 161 165 163 200

— — — — — — 119

189 209 209

113 124 123

* Based on a small series of breast-fed (n ¼ 6) or formula-fed (n ¼ 12) infants.

focusing on children and adolescents aged 4 to 19 years (1988 to 1994), demonstrated a mean total cholesterol level of 165 mg/dl, with a peak level at ages 9 to 11 years (mean 171 mg/dl), a reduction at ages 12 to 15 years (mean 161 mg/dl), and a subsequent postpubertal increase at ages 16 to 19 years (mean 165 mg/dl).13 Similarly, the NHANES III data for children and adolescents (1999 to 2004) showed a mean total cholesterol concentration of 163.0 mg/dl among children and adolescents aged 6 to 17 years that peaked at around 8 to 10 years of age and then showed a postpubertal increase starting at 17 years of age.16 The contemporary Western diet appears to be a major contributor to the greater LDL cholesterol levels and atherosclerotic disease observed in Western populations. Subjects who consume a typical Western diet have an average total cholesterol level of about 200 mg/dl.17 This level, however, should not be considered normal, given the high rate of atherosclerosis in Western populations.17,18 According to the NHANES III data, the average serum LDL cholesterol and total cholesterol concentration among United States adults age 20 to 74 years (1999 to 2006) is 119 and 200 mg/dl, respectively.14 These levels are lower than previous NHANES-derived averages14 yet remain much greater than those documented in adult “wildforaging” nonhuman primates (approximately 30 to 50 and 70 to 110 mg/dl, respectively).15 Westernized humans are the only adult mammals known to have a mean LDL cholesterol and total cholesterol level >80 and >160 mg/dl, respectively.19 The human transition from a hunter-gatherer to an agricultural society is believed to underlie the observed change from a low-carbohydrate/high-protein diet, which included

Figure 1. Plasma total cholesterol concentrations in sheep (A), pigs (B), and humans (C) during the fetal, suckling, and adult stages. Reproduced from Dietschy and Turley11 with permission from the publisher.

lean meat from game (with a high polyunsaturated fat content), to a greater consumption of grains and farm animal meat, which is higher in saturated fat.20 Today, the total cholesterol and LDL cholesterol levels of subjects from developed countries who do not consume red meat are lower than those of subjects who do consume red meat. A crosssectional study performed in Brazil showed a mean LDL cholesterol level of 69, 88 to 101, and 123 mg/dl among subjects consuming vegan, vegetarian, and omnivorous diets, respectively (p <0.001 for omnivorous vs vegan diets).21 Similarly, many of the remaining hunter-gatherer societies have a LDL cholesterol and total cholesterol level of 70 and <135 mg/dl, respectively.22 McMurry et al23 showed that when Tarahumara Indians, whose traditional diet is low in fat and cholesterol and high in complex carbohydrates (e.g., corn, beans, and other vegetables, fruits, and small quantities of game, fish, and eggs), adopted a Western diet

Review/Very Low Levels of LDL Cholesterol

(high in fat, cholesterol, sugar, and calories), their mean LDL cholesterol levels increased 39%, from 72 to 100 mg/dl (p <0.001). Similarly, in a recent cross-sectional study, significantly greater levels of total cholesterol were observed in Intuit women and men, respectively, who were consuming a Western diet (with a high content of glycemic carbohydrates and saturated fat) versus a predominantly traditional Arctic marine diet (240.2 and 240.5 mg/dl vs 192.5 and 196.1 mg/dl; p <0.05 for a Western diet vs a traditional Arctic marine diet).24 In a prospective observational study initiated in Shanghai, China, during the 1970s, both the average baseline serum cholesterol level (4.2 mmol/L; 162.4 mg/dl) and the CHD mortality rate (7%) during the 8to 13-year follow-up period were low; however, the baseline serum cholesterol was identified as a highly significant (p <0.001) predictor of CHD mortality.25 In summary, these reports suggest that “normal” Western levels of total cholesterol and LDL cholesterol are greater than those of our evolutionary ancestors and of those of non-Western human populations and Western vegetarians.

Safety of Very Low LDL Cholesterol Levels Although these observations generally support the safety of lower LDL cholesterol levels than specified in the current treatment guidelines from North America, Europe, and Australia/New Zealand, some epidemiologic and clinical trial data have led to concern that very low levels of LDL cholesterol might increase the risk of cancer,26,27 hemorrhagic stroke,27e29 and non-CV death.7,27 Data from the Framingham Study were used to examine the relation between lipoprotein levels and non-CHD outcomes, noted by the investigators as being limited by the small number of cases during the 6-year follow-up period. Logistic regression analyses showed significant inverse associations between the LDL cholesterol levels and stroke (both hemorrhagic and nonhemorrhagic) in women, cancer deaths in men, and death from non-CHD causes in both genders.27 Although the limited nature of the data precluded any conclusions regarding the risks of attaining low cholesterol levels, it brought to light the need for additional research to elucidate the relation between lipoprotein levels and outcomes beyond CHD and CHD-related mortality. The relation between cholesterol levels and cancer incidence has been extensively investigated. In an early prospective study of approximately 22,000 men aged 35 to 64 years, the cholesterol levels did not differ between men with and men without, a cancer diagnosis during the 5year follow-up period.30 However, a significantly lower cholesterol level was observed among patients diagnosed with cancer relative to the noncancer controls, specifically, within 2 years of cholesterol screening, a finding suggested by the study investigators as being a metabolic consequence of the underlying cancer.30 Two meta-analyses published during the 1990s found no inverse association between cholesterol levels and the overall risk of cancer or cancerrelated mortality.31,32 These results are consistent with the conclusions of other analyses in which an association between cholesterol and cancer was either absent or was attributable to preclinical cancer.33e35

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Reports have been published suggesting that the effects of cholesterol levels on cancer risk are not neutral, including 1 study in which low cholesterol levels were not associated with an increased risk of total cancer or major site cancers, except for liver cancer (even after adjustment for early incident cases).36 That same study found an association between low cholesterol levels and a reduced risk of prostate cancer.36 In contrast, data from the Prostate Cancer Prevention Trial suggested that this relation might be restricted to the development of high-grade disease.37 Although the mechanism by which malignancy might lower cholesterol levels has not been fully elucidated to date, there are several possibilities, including the potential effect of tumor necrosis factor on cholesterol metabolism38 and a propensity for malignant cells to exhibit high levels of LDL receptor activity (and, consequently, enhanced LDL cholesterol clearance).39 An accumulated body of data on the topic of statin use and cancer risk derived from other meta-analyses of clinical trials and observational studies have suggested that statins do not increase the overall risk of cancer,40e43 might potentially be protective against certain malignancies,40,44,45 and might be associated with reduced cancer-related mortality.46 The largest and most inclusive of these meta-analyses, the Cholesterol Treatment Trialists’ (CTT) Collaboration, analyzed data from 170,000 subjects in 26 randomized trials evaluating standard statin therapy versus controls (usual care/ no treatment/placebo) and more-intensive versus less-intensive statin therapy.42 No significant differences were observed in cancer incidence or deaths from cancer between statin or more-intensive therapy versus control or lessintensive therapy. Furthermore, no indication was found that a reduction of LDL cholesterol in patients with a lower baseline LDL cholesterol level increased their cancer risk. Similarly, a recent meta-analysis of 27 large-scale, placebocontrolled statin trials and 5 trials of more-intensive versus less-intensive statin therapy showed no effect of statin therapy versus placebo or more-intensive versus less-intensive statin therapy on newly diagnosed cancer or cancer mortality.43 Overall, the CTT meta-analyses suggested that no evidence exists of an increased cancer incidence among statin users or an excess risk of cancer associated with moreintensive regimens versus standard regimens. Additionally, the most recent cancer site-specific analyses from the CTT group found no evidence of risk reduction for any specific cancer types (including prostate cancer and gastrointestinal malignancies) after a 5-year median follow-up period.42 Concerns that low cholesterol might precipitate hemorrhagic stroke or be associated with an increase in CV-related mortality have stemmed from a small number of clinical trial observations. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, a significant excess of hemorrhagic stroke, accompanied by a significant reduction in ischemic stroke and major vascular events, was observed with atorvastatin (vs placebo) among patients who had a recent history of a stroke or transient ischemic attack.47 On multivariate analysis, the risk of hemorrhagic stroke was significantly increased among patients with hypertension at the study visit preceding the stroke (hazard ratio [HR] 6.19, 95% confidence interval [CI] 1.47 to 26.11; p ¼ 0.01); however, no relation was found

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Table 2 Primary results of 5 large-scale, randomized studies comparing more-intensive versus less-intensive statin therapy Investigators

Study Population

Cannon ACS within preceding 10 days et al,70 2004 (PROVE IT) LaRosa Stable CHD and LDL cholesterol et al,7 2005 <130 mg/dl (TNT) Pedersen Prior MI (IDEAL) et al,5 2005 Armitage Previous MI, TC 135 mg/dl et al,71 2010 with statin or 174 mg/dl if not (SEARCH) de Lemos NoneST-segment elevation ACS et al,72 2004 or ST-segment elevation MI, TC 250 mg/dl (A to Z)

Treatment Arms

P A A A S A S S

(40 (80 (10 (80 (20 (80 (20 (80

mg) mg) mg) mg) mg) mg) mg) mg)

Primary End Point

Follow-up Baseline LDL Mean (yrs; median Cholesterol On-Treatment or mean) (mg/dl; mean LDL Cholesterol or median) (mg/dl)

Composite*

2

First major CV event†

4.9

Major coronary eventz

4.8

Compositex

6.7

S (20 mg) Compositejj S (80 mg)

0.5e2

106 106 98 97 121 122 97

111 112

Reduction in Primary End Point With More- vs Less-Intensive Statin Therapy

95 16% (p ¼ 0.005) 62 101 22% (p <0.001) 77 104 11% (p ¼ 0.07) 81 14 mg/dl lower 6% (p ¼ 0.10) with S (80 mg) 81 66

11% (p ¼ 0.14)

A ¼ atorvastatin; A to Z ¼ Aggrastat to Zocar; ACS ¼ acute coronary syndrome; IDEAL ¼ Incremental Decrease in End Points Through Aggressive Lipid Lowering; MI ¼ myocardial infarction; P ¼ pravastatin; PROVE IT ¼ Pravastatin or Atorvastatin Evaluation and Infection Therapy; S ¼ simvastatin; SEARCH ¼ Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; TC ¼ total cholesterol; TNT ¼ Treating to New Targets. * Death, MI, unstable angina requiring rehospitalization, revascularization, and stroke. † Death from CHD, nonfatal noneprocedure-related MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke. z Coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation. x Coronary death, MI, stroke, or arterial revascularization. jj CV death, nonfatal MI, readmission for ACS, and stroke.

between hemorrhagic stroke and baseline LDL cholesterol or the most recent on-treatment LDL cholesterol.47 The Treating to New Targets (TNT) study revealed a nonsignificant (p ¼ 0.06) excess of non-CV deaths in the patients receiving atorvastatin 80 mg versus atorvastatin 10 mg, but no significant increase was seen in adverse events of any type in patients with an on-treatment LDL cholesterol level of 70 mg/dl versus those with higher LDL cholesterol levels.7 In the recent CTT meta-analysis, no indication was found that a reduction in the LDL cholesterol level in patients with lower baseline LDL cholesterol levels increased nonvascular mortality. An excess of hemorrhagic stroke in patients receiving statin therapy (vs placebo) or moreintensive statin therapy (vs less-intensive statin therapy) was not statistically significant (257 vs 220 events; p ¼ 0.2).42 Also of note, the rate of physician-reported diabetes was more frequent with rosuvastatin than with placebo (p ¼ 0.01) in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study. However, because the rates of reported diabetes were not significantly different among the rosuvastatin-allocated participants with and without an LDL cholesterol level <50 mg/dl, the observed increase in new-onset diabetes appeared to be a noneLDL-related issue.48 Accordingly, data from a recent meta-analysis of large statin trials have suggested a slightly increased risk of incident diabetes in patients receiving statin therapy (9% increased risk, 95% CI 2% to 17%), and a change in LDL cholesterol levels did not account for the observed variation in the risk of diabetes.49 Results from another recent meta-analysis indicated that the risk of diabetes was greater with more-intensive statin therapy than with less-intensive statin therapy (12%

increased risk, 95% CI 4% to 22%).50 A post hoc analysis of the data from the JUPITER trial suggested that the risk of developing diabetes appears to be limited to those patients already at high risk of developing diabetes (i.e., patients with impaired fasting glucose, the metabolic syndrome, severe obesity, or elevated hemoglobin A1c levels).51 Thus, the increased incidence of some adverse events observed in statin-treated patients did not correlate with the on-treatment LDL cholesterol levels and might not result from, per se, the achieved LDL cholesterol levels. Subjects with genetic variations such as familial hypobetalipoproteinemia (FHBL) should also be considered when evaluating the safety of very low LDL cholesterol levels. FHBL is most commonly caused by APOB truncating mutations,52e54 with the heterozygous form (more common and extensively studied than the homozygous form) occurring at an estimated frequency of 1/500 to 1/ 1,000 in Western populations.55 Those with heterozygous FHBL are recognized as having a less severe lipoprotein deficiency (LDL cholesterol w30 to 50 mg/dl and total cholesterol w90 to 140 mg/dl) relative to those who are homozygous (or compound heterozygous) for FHBLcausing APOB mutations, associated with extremely low to undetectable levels of apolipoprotein B (apoB) and very low levels of LDL cholesterol (w0 to 20 mg/dl) and total cholesterol (25 to 75 mg/dl).55 Although most heterozygotes are clinically asymptomatic, the clinical phenotype of FHBL homozygotes is highly variable, with null-allele homozygotes producing no detectable apoB and often having prominent clinical features, and “normotriglyceridemic” homozygotes possibly producing small amounts of apoB and could be asymptomatic.55 Because apoB is critical for

4.9 yrs (median) Statin vs placebo (2 trials) or more- vs less-intensive statin (5 trials)

2 yrs (median) R (80 mg) vs placebo

24 mo (mean) P (40 mg) vs A (80 mg)

4.9 yrs (median) A (10 mg) vs A (80 mg)

None

Cholesterol Treatment Trialists’ Collaboration,42 2010

Hsia et al,48 2011

Wiviott et al,75 2005

LaRosa et al,74 2007

LDL cholesterol level available 6e8 mo after receiving drug-eluting stent CHD and LDL cholesterol <130 mg/dl after run-in on atorvastatin 10 mg (TNT) ACS within preceding 10 days (PROVE IT) Healthy with LDL cholesterol <130 mg/dl and hs-CRP 2.0 mg/L (JUPITER) Patients from statin trials (1,000 patients and 2-yr duration (CTT) Kim et al,73 2010

A ¼ atorvastatin; ACR ¼ acute coronary syndrome; CTT ¼ Cholesterol Treatment Trialists; hs-CRP ¼ high-sensitivity C-reactive protein; MACCE ¼ major adverse cardiac and cerebrovascular events; P ¼ pravastatin; PROVE IT ¼ Pravastatin or Atorvastatin Evaluation and Infection Therapy; R ¼ rosuvastatin; TNT ¼ Treating to New Targets; TVR ¼ target vessel revascularization.

Significantly lower TVR and MACCE rates with LDL cholesterol <70 vs 70 mg/dl Quintiles: <64, 64e<77, 77e<90, Highly significant reduction in rate of major CV 90e<106, and 106 events with descending on-treatment LDL cholesterol levels <40, >40e60, >60e80, >80e100 Lowest rates of major cardiac events in patients with LDL cholesterol <40 mg/dl <50 vs 50 Significant reductions in major CV events and all-cause mortality with LDL cholesterol <50 mg/dl Statin/more intensive vs placebo/less Major CV events and all-cause mortality reduced intensive by 22% and 10%, respectively, for each 1 mmol/L of LDL cholesterol reduction

<70 vs 70; <100 vs 100 30 mo (mean)

Lowest Achieved LDL Cholesterol (mg/dl) on Treatment Follow-up Duration Study Treatment Study Population Investigators

Table 3 Summary of reports supporting the clinical benefits of lowering low-density lipoprotein (LDL) cholesterol to levels <70 mg/dl

Key Results

Review/Very Low Levels of LDL Cholesterol

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the absorption of fat and fat-soluble vitamins in the intestine, the most severe cases have clinically evident fat and fatsoluble vitamin malabsorption and related disorders.52,56 Those with FHBL (predominantly heterozygotes for APOB mutations) might be at an increased risk of fatty liver disease (for which the underlying mechanism appears to be related to impaired hepatic secretion of low-density lipoproteins57); however, the long-term sequelae are not known.54,57,58 FHBL might provide protection against the development of coronary artery disease and, possibly, a longer than average life expectancy.55,59 FHBL can also be caused by loss-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene. PCSK9 is a circulating protein that inhibits clearance of LDL cholesterol by binding to hepatic LDL receptors and facilitating their degradation.60,61 In the Atherosclerosis Risk In Communities (ARIC) prospective cohort study, PCSK9 nonsense mutations were identified in 2.6% of black participants and a PCSK9 sequence variation was identified in 3.2% of white participants.62 During the 15-year followup period, PCSK9 nonsense mutation carriers were associated with significant reductions in mean LDL cholesterol at baseline (28%; p <0.001) and in the risk of CHD (HR 0.11, 95% CI 0.02 to 0.81; p ¼ 0.03) relative to noncarriers.62 Similarly, PCSK9 sequence variation mutation carriers were associated with significant reductions in mean LDL cholesterol at baseline (15%; p <0.001) and in the risk of CHD (HR 0.50, 95% CI 0.32 to 0.79; p ¼ 0.003) relative to noncarriers.62 These 15-year observations suggest that the “residual” risk observed in 5-year clinical trials might be dramatically lowered with longer treatment periods. Patients with PCSK9 loss-of-function mutations are apparently healthy (1 patient was a 32-year-old black woman63 who was heterozygous for loss-of-function mutations in PCSK9 and the other was a 49-year-old white man64 who was heterozygous for 2 PCSK9 missense mutations; both patients were fully deficient in PCSK9) and have extremely low levels of LDL cholesterol (typically <20 mg/dl), without an increased risk of fatty liver disease.65 Those who are compound heterozygotes for loss-of-function mutations in PCSK9, despite having no immunodetectable circulating PCSK9 and strikingly low LDL cholesterol levels, have shown no apparent adverse health issues.63 A separate, and less common, genetic entity than FHBL, abetalipoproteinemia, occurs at a frequency of <1/1,000,000 humans and is linked to mutations in the gene encoding microsomal transfer protein, which is required for assembly and secretion of apoB-containing lipoproteins in the liver and intestine.53,56 Consequently, these subjects have near or complete absence of apoB-containing lipoproteins (chylomicrons, very-low-density lipoprotein, and LDL), with associated severe symptoms from the malabsorption of dietary fat and fat-soluble vitamins.56,66 No currently available cholesterol-lowering regimen is capable of achieving levels of LDL cholesterol this low, believed to reflect the severity of abetalipoproteinemia-associated malabsorption. Effects of Very Low LDL Cholesterol Levels on CV Risk The potential of LDL cholesterol reduction to reduce the risk of CV events has been clearly established in secondary

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Figure 2. Results of the Cholesterol Treatment Trialists’ Collaboration meta-analysis of major vascular event rates relative to baseline LDL cholesterol in studies comparing more- versus less-intensive statin therapy and statin versus control (usual care/no treatment/placebo). Reproduced from Cholesterol Treatment Trialists’ (CTT) Collaboration et al42 with permission from the publisher.

prevention, placebo-controlled, statin trials.2,4,67,68 Furthermore, data from more recent trials have favored moreintensive statin therapy instead of less-intensive therapy with respect to a reduction in CV events.7,69 These findings demonstrate that lowering LDL cholesterol beyond current guidelines imparts incremental clinical benefit in high-risk patients. Studies of more- versus less-intensive statin therapy supporting these findings are summarized in Table 2.5,7,70e72 Several reports have suggested that even more-aggressive LDL cholesterol lowering (i.e., target 50 to 70 mg/dl) might further reduce the CV risk (Table 3).42,48,73e75 A post hoc analysis of the TNT trial, which divided patients into quintiles according to the on-treatment LDL cholesterol levels, revealed the lowest rate of major CV events in patients with on-treatment LDL cholesterol levels <64 mg/dl (mean 53; p <0.0001 for trend across LDL cholesterol).74 Analysis of the individual subcomponents of major CV events (i.e., CHD death, nonfatal myocardial infarction, and stroke) similarly showed significant risk reductions with decreasing LDL cholesterol levels.74 The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) study randomized patients hospitalized for acute coronary syndromes within 10 days to pravastatin 40 mg (standard therapy) or atorvastatin 80 mg (intensive therapy).70 A post hoc analysis showed a trend toward fewer major cardiac events (i.e., death, myocardial infarction, stroke, unstable angina requiring rehospitalization, and revascularization) in patients with LDL cholesterol levels 60 mg/dl versus those with higher LDL cholesterol levels.75 A multivariant analysis adjusting for baseline differences showed that the rate of major cardiac events was significantly lower in the groups achieving the lowest LDL cholesterol levels (40 mg/dl,

HR 0.61, 95% CI 0.40 to 0.91; and >40 to 60 mg/dl, HR 0.67, 95% CI 0.50 to 0.92) compared to the referent >80- to 100-mg/dl group.75 In the primary prevention JUPITER study, >17,000 healthy men and women, free of symptomatic vascular disease, with LDL cholesterol levels <130 mg/dl and highsensitivity C-reactive protein levels 2.0 mg/L were randomized to rosuvastatin 20 mg/day or placebo.6 Overall, rosuvastatin reduced the rates of all-cause mortality and major CV events by 20% and 44%, respectively, versus placebo. However, in patients attaining LDL cholesterol levels <50 mg/dl, all-cause mortality and major CV events were reduced by 46% and 65%, respectively (HR 0.54, 95% CI 0.37 to 0.78, and HR 0.35, 95% CI 0.25 to 0.49, respectively).48 Finally, the CTT meta-analysis of data from 170,000 subjects in 26 randomized trials compared standard statin therapy and control (usual care/no treatment/placebo) in 21 trials and more- versus less-intensive statin therapy in 5 trials, with the predetermined outcomes including allcause mortality, major coronary events (coronary death or nonfatal myocardial infarction), coronary revascularization (balloon angioplasty or coronary artery bypass grafting), stroke by subtype (ischemic or hemorrhagic), and sitespecific cancer.42 The weighted median follow-up was 4.9 years. Across all 26 trials, all-cause mortality was reduced by 10% per mmol/L (39 mg/dl) LDL cholesterol reduction (rate ratio [RR] 0.90, 95% CI 0.87 to 0.93; p <0.0001), a reflection of significant reductions in CHD deaths (RR 0.80, 99% CI 0.74 to 0.87; p <0.0001) and deaths from other cardiac causes (RR 0.89, 99% CI 0.81 to 0.98; p ¼ 0.002).42 Although a significant reduction was seen in incident stroke (16% reduction, 95% CI 11% to 21%; p <0.0001), no significant effect was found on deaths from

Review/Very Low Levels of LDL Cholesterol

stroke (RR 0.96, 95% CI 0.84 to 1.09; p ¼ 0.5) or other vascular causes (RR 0.98, 99% CI 0.81 to 1.18; p ¼ 0.8).42 Overall, each 39-mg/dl reduction in LDL cholesterol reduced the 1-year rate of major CV events by 22% (p <0.0001), with no evidence of a threshold observed over the LDL cholesterol range studied. Furthermore, the benefits of LDL cholesterol lowering were maintained across age, gender, and risk factor (e.g., hypertension, smoking, diabetes) groups.42 Given a maintained linear relation between LDL cholesterol lowering and risk reduction, a reduction of LDL cholesterol by 2 to 3 mmol/L (77 to 116 mg/dl) would be expected to reduce major CV events by 40% to 50%. Although these reports have clearly established the clinical benefit of attaining very low levels of LDL cholesterol (<50 mg/dl), mainly in the secondary prevention setting, it is still unclear from these studies whether pharmacotherapy to reduce LDL cholesterol should be initiated in at-risk patients with low baseline LDL cholesterol levels. In an observational study of nonstatin-treated patients with acute coronary syndromes and LDL cholesterol levels of 80 mg/dl at hospital admission, those discharged with statin therapy had a lower 6-month incidence of death, reinfarction, or stroke than those not taking statins (9.5% vs 29%).76 However, the on-treatment LDL cholesterol values were not reported. In an analysis of 6,107 consecutive patients with LDL cholesterol <60 mg/dl identified in a community setting and followed up for a mean of 2 years, statin therapy initiated during the 150 days after the low LDL cholesterol value was obtained was associated with improved survival (HR 0.65, 95% CI 0.53 to 0.80) after controlling for propensity to receive statin.77 Reduced mortality was confirmed in the 623 patients with LDL cholesterol levels <40 mg/dl (HR 0.51, 95% CI 0.33 to 0.79).77 Furthermore, the CTT meta-analysis showed that patients whose baseline LDL cholesterol levels were in the lowest tier (<2 mmol/L; 77 mg/dl) benefited from statin therapy to a similar degree as the entire cohort (Figure 2).42 In contrast, in a retrospective study of 1,054 Korean patients who survived acute myocardial infarction and had LDL cholesterol <70 mg/dl, statin therapy initiated at hospital discharge significantly reduced the 1-year risk of cardiac death, coronary revascularization, and major adverse cardiac events versus a nonstatin group, but did not affect the composite of all-cause death, recurrent myocardial infarction, or percutaneous coronary intervention.78 When the baseline LDL cholesterol level was analyzed as a continuous variable in a PROVE IT substudy, the additional benefit of intensive statin treatment compared to standard treatment was no longer observed in patients with baseline LDL cholesterol levels <66 mg/dl.8 Conclusion Humans with very low levels of LDL cholesterol (e.g., those with certain forms of FHBL) are generally healthy and have a low risk of CV events. Although the risk of cancer death was greater among those who did not develop atherosclerosis compared to those who did, this was probably because those protected from atherosclerotic death will succumb to other diseases. Cancer risk was not increased in statin-treated subjects attaining a very low level of LDL

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cholesterol. Furthermore, on the basis of an admittedly sparse database, very low levels of LDL cholesterol (<50 mg/dl) do not appear to be inherently unsafe unless LDL cholesterol is essentially absent, such as in abetalipoproteinemia. Additional studies are needed to more completely characterize the populations that will benefit from LDL cholesterol lowering beyond the levels specified in current guidelines and the risks, if any, associated with such LDL cholesterol lowering. The question of what should be done about the residual risk seen in 5-year clinical trials might find an answer in longer and more aggressive lowering of LDL cholesterol levels. Finally, additional data are required to determine which primary prevention patients might benefit from LDL cholesterol lowering beyond current guidelines. Acknowledgment: We thank Rick Davis, MS, RPh, Complete Healthcare Communications, Chadds Ford, Pennsylvania (whose work was funded by Amgen, Inc.), and Meera Kodukulla, PhD, Amgen, Inc. (Thousand Oaks, California), for assistance with the writing of our report. Disclosures John C. LaRosa, MD, has served as a consultant for Amgen, Inc., and Pfizer. Terje R. Pedersen, MD, PhD, has received speaker honoraria from Merck, Pfizer, AstraZeneca, and Roche, has received research grants from Merck, and has served on advisory boards for Amgen, AstraZeneca and Merck. Ransi Somaratne, MD, and Scott M. Wasserman, MD, are employees of Amgen Inc. and have received Amgen stock/stock options. 1. Anderson KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years of follow-up from the Framingham study. JAMA 1987;257: 2176e2180. 2. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators. N Engl J Med 1996;335: 1001e1009. 3. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333: 1301e1307. 4. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383e1389. 5. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294: 2437e2445. 6. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, Group JS. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195e2207. 7. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK. Treating to new targets: I. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425e1435.

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