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A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality

Open AccessPublished:November 20, 2015DOI:https://doi.org/10.1016/j.jacl.2015.11.010

      Highlights

      • Hypercholesterolemia represents the highest population attributable risk factor for CHD.
      • LDL-C remains the primary treatment target for reduction of ischemic events.
      • Intensive statins and statin/ezetimibe are proven for secondary prevention.
      • Treatment of LDL-C to <50 mg/dL is being tested with novel therapies.
      • Public policies are needed to shift-down the whole population LDL-C distribution.

      Abstract

      Cardiovascular (CV) disease is a leading cause of death worldwide, accounting for approximately 31.4% of deaths globally in 2012. It is estimated that, from 1980 to 2000, reduction in total cholesterol accounted for a 33% decrease in coronary heart disease (CHD) deaths in the United States. In other developed countries, similar decreases in CHD deaths (ranging from 19%–46%) have been attributed to reduction in total cholesterol. Low-density lipoprotein cholesterol (LDL-C) has now largely replaced total cholesterol as a risk marker and the primary treatment target for hyperlipidemia. Reduction in LDL-C levels by statin-based therapies has been demonstrated to result in a reduction in the risk of nonfatal CV events and mortality in a continuous and graded manner over a wide range of baseline risk and LDL-C levels. This article provides a review of (1) the relationship between LDL-C and CV risk from a biologic, epidemiologic, and genetic standpoint; (2) evidence-based strategies for LDL-C lowering; (3) lipid-management guidelines; (4) new strategies to further reduce CV risk through LDL-C lowering; and (5) population-level and health-system initiatives aimed at identifying, treating, and lowering lifetime LDL-C exposure.

      Keywords

      Introduction

      Cardiovascular (CV) disease is the leading cause of mortality worldwide, accounting for 31.4% of deaths in 2012.

      World Health Organization: Health statistics and information systems. Cause-specific mortality. Glob Summ estimates for 2000-2012. Available at: http://www.who.int/healthinfo/global_burden_disease/estimates/en/index1.html. Accessed January 2, 2015.

      In developed countries, age-adjusted CV mortality rates are declining, but CV disease remains the leading cause of mortality due to rapid aging of the population. In low-income to middle-income countries, both age-adjusted CV mortality rates and aging of these populations are contributing to a rapid increase in CV mortality.
      Epidemiology of Cardiovascular Disease
      Institute of Medicine (US) Committee on Preventing the Global Epidemic of Cardiovascular Disease: Meeting the Challenges in Developing Countries.
      Data from 2010 demonstrate that CV disease accounted for 31.9% of US deaths, with ischemic heart disease and stroke accounting for the vast majority (total 27.6%; 21.1%, and 6.5%, respectively). In the United States, the resultant direct and indirect annual costs were estimated to be $240.9 billion.
      • Go A.S.
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      Heart disease and stroke statistics–2014 update: a report from the American Heart Association.
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      • Lopez A.D.
      Measuring the global burden of disease.
      The global cost of CV disease was estimated to be $863 billion in 2010, with a 22% increase expected by 2030.
      • Bloom D.E.
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      • et al.
      The Global Economic Burden of Noncommunicable Disease.
      A large, worldwide study found that among all modifiable risk factors, abnormal lipid levels were associated with the highest population attributable risk (approximately 50%) for the occurrence of myocardial infarction (MI; Table 1).
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      • Hawken S.
      • Ounpuu S.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      Table 1Population attributable risk for the incidence of acute MI for modifiable risk factors
      Based on the INTERHEART study by Yusuf et al., 2004.6
      Risk factorPopulation attributable risk (%)
      Population attributable risk percentages do not add up to 100% for a combination of risk factors, because an MI can be simultaneously attributed to >1 risk factor and thus be counted twice.
      Abnormal lipids
      Estimated by apoB/apoA1 ratio (fifth quintile compared to first).
      49.2
      Tobacco consumption (current smoker)35.7
      Psychosocial32.5
      Abdominal obesity20.1
      Hypertension17.9
      Diet (lack of daily vegetable and fruits)13.7
      Physical activity12.2
      Diabetes9.9
      Alcohol intake6.7
      Apo, apolipoprotein.
      Based on the INTERHEART study by Yusuf et al., 2004.
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      Estimated by apoB/apoA1 ratio (fifth quintile compared to first).
      Population attributable risk percentages do not add up to 100% for a combination of risk factors, because an MI can be simultaneously attributed to >1 risk factor and thus be counted twice.
      This is due to their prevalence and strong, independent association with the risk of MI. In western countries, lifestyle interventions and evidence-based therapies, including those focused on hypercholesterolemia, have led to a reduction in CV risk on a population level. In a series of studies covering the 1980 to 2010 time period in the United States, Canada, and Europe (Table 2), it was estimated that 19%–46% of the total reduction in the rate of coronary heart disease (CHD) mortality was explained by a reduction in total cholesterol levels attributed to lifestyle changes and pharmacologic treatment.
      • Bjorck L.
      • Rosengren A.
      • Bennett K.
      • et al.
      Modelling the decreasing coronary heart disease mortality in Sweden between 1986 and 2002.
      • Bandosz P.
      • O'Flaherty M.
      • Drygas W.
      • et al.
      Decline in mortality from coronary heart disease in Poland after socioeconomic transformation: modelling study.
      • Wijeysundera H.C.
      • Machado M.
      • Farahati F.
      • et al.
      Association of temporal trends in risk factors and treatment uptake with coronary heart disease mortality, 1994-2005.
      • Flores-Mateo G.
      • Grau M.
      • O'Flaherty M.
      • et al.
      [Analyzing the coronary heart disease mortality decline in a Mediterranean population: Spain 1988-2005].
      • Hughes J.
      • Kee F.
      • O'Flaherty M.
      • et al.
      Modelling coronary heart disease mortality in Northern Ireland between 1987 and 2007: broader lessons for prevention.
      • Ford E.S.
      • Ajani U.A.
      • Croft J.B.
      • et al.
      Explaining the decrease in U.S. deaths from coronary disease, 1980-2000.
      • Aspelund T.
      • Gudnason V.
      • Magnusdottir B.T.
      • et al.
      Analysing the large decline in coronary heart disease mortality in the Icelandic population aged 25-74 between the years 1981 and 2006.
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      • Bennett K.
      • Giampaoli S.
      • et al.
      Explaining the decrease in coronary heart disease mortality in Italy between 1980 and 2000.
      • Hotchkiss J.W.
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      • Dundas R.
      • et al.
      Explaining trends in Scottish coronary heart disease mortality between 2000 and 2010 using IMPACTSEC model: retrospective analysis using routine data.
      • Bajekal M.
      • Scholes S.
      • Love H.
      • et al.
      Analysing recent socioeconomic trends in coronary heart disease mortality in England, 2000-2007: a population modelling study.
      Table 2Studies assessing the attributable risk reduction in CHD mortality driven by statins and other changes affecting total cholesterol levels
      StudyCountryTime periodAttributable risk reduction
      Represents the attributable reduction in CHD mortality risk from changes in total cholesterol via statin treatment and other (e.g., diet related) causes.
      (%)
      Statin treatmentOther causesTotal
      Bjorck et al., 2009
      • Bjorck L.
      • Rosengren A.
      • Bennett K.
      • et al.
      Modelling the decreasing coronary heart disease mortality in Sweden between 1986 and 2002.
      Sweden1986–20026.239.545.7
      Bandosz et al., 2012
      • Bandosz P.
      • O'Flaherty M.
      • Drygas W.
      • et al.
      Decline in mortality from coronary heart disease in Poland after socioeconomic transformation: modelling study.
      Poland1991–20053.439.042.4
      Wijeysundera et al., 2010
      • Wijeysundera H.C.
      • Machado M.
      • Farahati F.
      • et al.
      Association of temporal trends in risk factors and treatment uptake with coronary heart disease mortality, 1994-2005.
      Canada1994–200515.422.838.2
      Flores-Mateo et al., 2011
      • Flores-Mateo G.
      • Grau M.
      • O'Flaherty M.
      • et al.
      [Analyzing the coronary heart disease mortality decline in a Mediterranean population: Spain 1988-2005].
      Spain1988–20055.631.136.7
      Hughes et al., 2013
      • Hughes J.
      • Kee F.
      • O'Flaherty M.
      • et al.
      Modelling coronary heart disease mortality in Northern Ireland between 1987 and 2007: broader lessons for prevention.
      Northern Ireland1987–20078.725.834.5
      Ford et al., 2007
      • Ford E.S.
      • Ajani U.A.
      • Croft J.B.
      • et al.
      Explaining the decrease in U.S. deaths from coronary disease, 1980-2000.
      USA1980–20008.524.232.7
      Aspelund et al., 2010
      • Aspelund T.
      • Gudnason V.
      • Magnusdottir B.T.
      • et al.
      Analysing the large decline in coronary heart disease mortality in the Icelandic population aged 25-74 between the years 1981 and 2006.
      Iceland1981–20060.532.032.5
      Palmieri et al., 2010
      • Palmieri L.
      • Bennett K.
      • Giampaoli S.
      • et al.
      Explaining the decrease in coronary heart disease mortality in Italy between 1980 and 2000.
      Italy1980–20006.423.429.8
      Hotchkiss et al., 2014
      • Hotchkiss J.W.
      • Davies C.A.
      • Dundas R.
      • et al.
      Explaining trends in Scottish coronary heart disease mortality between 2000 and 2010 using IMPACTSEC model: retrospective analysis using routine data.
      Scotland2000–201013.38.922.2
      Bajekal et al., 2012
      • Bajekal M.
      • Scholes S.
      • Love H.
      • et al.
      Analysing recent socioeconomic trends in coronary heart disease mortality in England, 2000-2007: a population modelling study.
      England2000–200713.95.519.4
      CHD, coronary heart disease.
      Represents the attributable reduction in CHD mortality risk from changes in total cholesterol via statin treatment and other (e.g., diet related) causes.
      Low-density lipoprotein cholesterol (LDL-C) has now largely replaced total cholesterol as the primary lipid measurement for evaluation of risk due to atherogenic lipoproteins. LDL-C is a measure of the total cholesterol content of LDL particles, reflecting both the number of LDL particles and their individual cholesterol content. Most current guidelines include LDL-C as a primary target for initiating and adjusting lipid-lowering interventions.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • et al.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Catapano A.L.
      • Reiner Z.
      • De Backer G.
      • et al.
      Task Force for the management of dyslipidaemias of the European Society of Cardiology, European Atherosclerosis Society
      ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
      • Jacobson T.A.
      • Ito M.K.
      • Maki K.C.
      • et al.
      National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1-executive summary.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel Members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia–full report.
      In addition, more effective and/or scalable LDL-C reduction strategies are under investigation for risk reduction in both primary and secondary prevention. This article provides a review of (1) the relationship between LDL-C and CV risk from a biologic, epidemiologic, and genetic standpoint; (2) evidence-based strategies for LDL-C lowering; (3) lipid-management guidelines; (4) new strategies to further reduce CV risk through LDL-C lowering; and (5) population level and health-system initiatives aimed at identifying, treating, and lowering lifetime LDL-C exposure.

      Relationship between LDL and CV risk

      Cholesterol is circulated in the body's aqueous extracellular environment by 5 major types of lipoprotein (chylomicrons, very low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], LDL, and high-density lipoprotein [HDL]). The liver serves as the key organ for cholesterol metabolism and regulation of plasma levels of cholesterol. The process of LDL formation begins when intrahepatic cholesterol, either from gut absorption or de novo synthesis, is repackaged by the liver (along with proteins, triglycerides, and phospholipids) into VLDL. VLDL then enters the circulation and is converted by lipoprotein lipase and cholesteryl ester transfer protein (CETP) into more cholesterol-enriched species, first IDL and then LDL. The liver regulates the concentration of these circulating lipoprotein species primarily by their clearance through LDL receptors on the hepatic surface.

      Feingold KR, Grunfeld C: Introduction to Lipids and Lipoproteins. In: De Groot LJ, Beck-Peccoz P, Chrousos G, et al, eds. Endotext. South Dartmouth (MA), 2000.

      Circulating LDL particles are able to penetrate the endothelium of arterial walls and become oxidized, promote inflammation, and drive injury to the overlying endothelium and surrounding smooth muscle cells.
      • Ross R.
      Atherosclerosis is an inflammatory disease.
      Persistent elevations in circulating LDL-C have been directly linked to progression from early-stage fatty streaks to advanced-stage, lipid-rich plaques. For example, LDL receptor-deficient mice (i.e., unable to clear LDL from the circulation) have elevated LDL-C and consequently develop severe atherosclerosis.
      • Veniant M.M.
      • Sullivan M.A.
      • Kim S.K.
      • et al.
      Defining the atherogenicity of large and small lipoproteins containing apolipoprotein B100.
      Conversely, mice with virtually no LDL-C do not develop atherosclerosis irrespective of diet and other CHD risk factors.
      • Lieu H.D.
      • Withycombe S.K.
      • Walker Q.
      • et al.
      Eliminating atherogenesis in mice by switching off hepatic lipoprotein secretion.
      Epidemiologic investigations have validated LDL-C as an independent predictor of CV risk. The Framingham Heart Study demonstrated that men and women were >1.5 times more likely to develop clinically significant CHD if their LDL-C was >160 mg/dL compared to a reference population with LDL-C <130 mg/dL.
      • Wilson P.W.
      • D'Agostino R.B.
      • Levy D.
      • et al.
      Prediction of coronary heart disease using risk factor categories.
      In the Atherosclerosis Risk in Communities (ARIC) study, the risk of an incident CHD event was elevated by approximately 40% for every 39 mg/dL incremental increase in LDL-C.
      • Sharrett A.R.
      • Ballantyne C.M.
      • Coady S.A.
      • et al.
      Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study.
      Genetic analyses have demonstrated that a number of single-nucleotide polymorphisms (SNPs) are associated with LDL-C and CV risk. A study by Willer et al. demonstrated that SNPs of genes such as PCSK9, APOE, APOB, and LDLR that result in elevated LDL-C are also associated with elevated CV risk.
      • Willer C.J.
      • Sanna S.
      • Jackson A.U.
      • et al.
      Newly identified loci that influence lipid concentrations and risk of coronary artery disease.
      Another study by Kathiresan et al. demonstrated that specific SNPs of genes such as PCSK9, APOE, APOB, HMGCR, and LDLR result in decreased LDL-C and are associated with decreased CV risk.
      • Kathiresan S.
      • Melander O.
      • Anevski D.
      • et al.
      Polymorphisms associated with cholesterol and risk of cardiovascular events.
      These associations have been validated in other investigations.
      • Stitziel N.O.
      • Won H.H.
      • Morrison A.C.
      • et al.
      The Myocardial Infarction Genetics Consortium Investigators
      Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease.
      • Linsel-Nitschke P.
      • Gotz A.
      • Erdmann J.
      • et al.
      Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease–a Mendelian Randomisation study.
      • Stender S.
      • Frikke-Schmidt R.
      • Nordestgaard B.G.
      • et al.
      The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease.
      • Crosby J.
      • Peloso G.M.
      • Auer P.L.
      • et al.
      TG HDL Working Group of the Exome Sequencing Project National Heart Lung and Blood Institute
      Loss-of-function mutations in APOC3, triglycerides, and coronary disease.
      Genetic studies suggest that CV risk is associated not just with the absolute concentration of LDL-C but also with the duration of exposure. Certain genetic mutations resulting in lower LDL-C have demonstrated a greater impact on CV risk reduction (Fig. 1) than similar levels of statin-induced LDL-C reduction, presumably because statin treatment is typically initiated later in life.
      Figure thumbnail gr1
      Figure 1Association between absolute change in LDL-C levels over lifetime due to genetic variation and the change in relative risk for CHD.
      Based on data from Willer et al., 2008,
      • Willer C.J.
      • Sanna S.
      • Jackson A.U.
      • et al.
      Newly identified loci that influence lipid concentrations and risk of coronary artery disease.
      Myocardial Infarction Genetics Consortium et al., 2014,
      • Stitziel N.O.
      • Won H.H.
      • Morrison A.C.
      • et al.
      The Myocardial Infarction Genetics Consortium Investigators
      Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease.
      Linsel-Nitschke et al., 2008,
      • Linsel-Nitschke P.
      • Gotz A.
      • Erdmann J.
      • et al.
      Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease–a Mendelian Randomisation study.
      Cohen et al., 2006,
      • Cohen J.C.
      • Boerwinkle E.
      • Mosley Jr., T.H.
      • et al.
      Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
      Ference et al., 2012,
      • Ference B.A.
      • Yoo W.
      • Alesh I.
      • et al.
      Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis.
      and Stender et al., 2014
      • Stender S.
      • Frikke-Schmidt R.
      • Nordestgaard B.G.
      • et al.
      The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease.
      The figure has been limited to data from these studies regarding mutations with significant associations with both LDL-C levels and coronary outcomes. The studies were reviewed for duplicate reporting of data. Labels in the graph represent genes; repeated observations (e.g. LDLR) represent different SNPs. Where OR or HR were reported, change in relative risk was approximated as OR – 1 or HR – 1. The solid line represents estimated relationship via linear unweighted regression (Y = 0.0259 × X + 0.0173).
      CHD, coronary heart disease; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; OR, odds ratio; SNP, single-nucleotide polymorphism.
      For example, sequence variation in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene was associated with a 15% reduction in LDL-C and a 47% reduction in CHD risk. Nonsense mutations of this gene were associated with a 28% reduction in LDL-C and an 88% reduction in CHD risk.
      • Cohen J.C.
      • Boerwinkle E.
      • Mosley Jr., T.H.
      • et al.
      Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
      Naturally occurring, inactivating mutations of the Niemann-pick C1-like 1 (NPC1L1) gene in humans were associated with LDL-C reductions of 12 mg/dL and a 53% reduction in CHD risk.
      • Stitziel N.O.
      • Won H.H.
      • Morrison A.C.
      • et al.
      The Myocardial Infarction Genetics Consortium Investigators
      Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease.
      A meta-analysis by Ference et al. demonstrated that 9 polymorphisms in 6 different genes were associated with a 54% reduction in CHD risk per 1 mmol/L reduction in LDL-C.
      • Ference B.A.
      • Yoo W.
      • Alesh I.
      • et al.
      Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis.
      In comparison, only a 24% reduction in major coronary events with statin therapy over a median follow-up of 4.8 years has been demonstrated.
      • Mihaylova B.
      • Emberson J.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists Collaborators
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      The significance of the chronicity of LDL-C exposure is also supported by recent epidemiologic analyses, which suggest that strategies for earlier initiation and prolonged LDL-C lowering might yield striking benefits for reducing CV risk.
      • Steinberg D.
      • Witztum J.L.
      Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels.
      • Navar-Boggan A.M.
      • Peterson E.D.
      • D'Agostino Sr., R.B.
      • et al.
      Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease.
      The association of LDL with CV risk is also supported by data from alternative measures of atherogenic lipoproteins. For example, at identical LDL-C levels, measurement of the number of circulating LDL particles has important prognostic value. A higher number of smaller LDL particles is associated with higher CV risk.
      • Otvos J.D.
      • Mora S.
      • Shalaurova I.
      • et al.
      Clinical implications of discordance between low-density lipoprotein cholesterol and particle number.
      In one study of approximately 7000 participants without CV disease at baseline, LDL-attributable atherosclerotic risk was better indicated by LDL particle number when LDL-C and LDL particle number were discordant.
      • Otvos J.D.
      • Mora S.
      • Shalaurova I.
      • et al.
      Clinical implications of discordance between low-density lipoprotein cholesterol and particle number.
      This may be due to the enhanced delivery of cholesterol to an atheroma by greater numbers of smaller LDL particles.
      • Tabas I.
      • Williams K.J.
      • Boren J.
      Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications.
      Furthermore, small dense LDL particles are more susceptible to oxidation and experience-decreased uptake by LDL receptors.
      • Berneis K.K.
      • Krauss R.M.
      Metabolic origins and clinical significance of LDL heterogeneity.
      Other laboratory markers of atherogenic lipoproteins correlate with LDL-C and also demonstrate similar relationships with CV risk. Both apolipoprotein (apo) B and non–high-density lipoprotein cholesterol (non-HDL-C) measure the contribution to atherogenic risk from the total number of atherogenic particles, including LDL, VLDL, IDL, chylomicrons, and lipoprotein(a).
      • Jacobson T.A.
      • Ito M.K.
      • Maki K.C.
      • et al.
      National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1-executive summary.
      The total number of apoB particles represents the total number of atherogenic lipoproteins, whereas non-HDL-C measures the total cholesterol content carried by these particles. These assays may be especially useful for patients with elevated triglycerides, who derive a greater proportion of their CV risk from triglyceride-rich particles than those with lower triglyceride levels. In a meta-analysis of epidemiologic studies of 3 atherogenic biomarkers, apoB was found to be the best CV risk predictor, followed by non-HDL-C and LDL-C.
      • Sniderman A.D.
      • Williams K.
      • Contois J.H.
      • et al.
      A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk.
      In an analysis of statin-treated patients, non-HDL-C was found to be the best predictor of CV risk when compared to apoB and LDL-C.
      • Boekholdt S.M.
      • Arsenault B.J.
      • Mora S.
      • et al.
      Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
      These findings have led to the incorporation of non-HDL-C and apoB as primary or secondary treatment targets in recent guidelines. Although the roles of LDL particle number, apoB, non-HDL-C, or other measures such as the ratio of apoB/apoA1 for CV risk assessment are increasing, LDL-C remains the measure most commonly used for clinical trials and in clinical care.

      Evidence-based strategies for LDL-C lowering

      A number of approaches for LDL-C lowering have been well studied. These include lifestyle interventions, pharmacologic treatment, intestinal bypass surgery, and lipid apheresis. Below, we focus on the evidence for lifestyle interventions and pharmacologic treatment as well as their influence on cholesterol management guidelines.

      Lifestyle interventions

      Societal changes, largely resulting from agricultural and industrial expansion, have led to higher population LDL-C levels. Evidence from hunter-gatherers has demonstrated that these populations have LDL-C levels typically ranging from 50 to 75 mg/dL. These populations are characterized by an absence of atherosclerosis, even in individuals living up to 8 decades. Furthermore, healthy, wild, adult primates have LDL levels of approximately 40 to 80 mg/dL.
      • O'Keefe Jr., J.H.
      • Cordain L.
      Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer.
      • Cordain L.
      • Eaton S.B.
      • Miller J.B.
      • et al.
      The paradoxical nature of hunter-gatherer diets: meat-based, yet non-atherogenic.
      In contrast, the currently accepted “normal” LDL-C range in Westernized societies is 100 to 160 mg/dL. This suggests that LDL-C levels in Western societies are grossly above the true physiologic range.
      • O'Keefe Jr., J.H.
      • Cordain L.
      • Harris W.H.
      • et al.
      Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal.
      Development and promotion of lifestyle recommendations to reduce CHD, initiated in the second half of the 20th century, have played a critical role in the decline of death from CHD.
      • Bjorck L.
      • Rosengren A.
      • Bennett K.
      • et al.
      Modelling the decreasing coronary heart disease mortality in Sweden between 1986 and 2002.
      • Bandosz P.
      • O'Flaherty M.
      • Drygas W.
      • et al.
      Decline in mortality from coronary heart disease in Poland after socioeconomic transformation: modelling study.
      • Wijeysundera H.C.
      • Machado M.
      • Farahati F.
      • et al.
      Association of temporal trends in risk factors and treatment uptake with coronary heart disease mortality, 1994-2005.
      • Flores-Mateo G.
      • Grau M.
      • O'Flaherty M.
      • et al.
      [Analyzing the coronary heart disease mortality decline in a Mediterranean population: Spain 1988-2005].
      • Hughes J.
      • Kee F.
      • O'Flaherty M.
      • et al.
      Modelling coronary heart disease mortality in Northern Ireland between 1987 and 2007: broader lessons for prevention.
      • Ford E.S.
      • Ajani U.A.
      • Croft J.B.
      • et al.
      Explaining the decrease in U.S. deaths from coronary disease, 1980-2000.
      • Aspelund T.
      • Gudnason V.
      • Magnusdottir B.T.
      • et al.
      Analysing the large decline in coronary heart disease mortality in the Icelandic population aged 25-74 between the years 1981 and 2006.
      • Palmieri L.
      • Bennett K.
      • Giampaoli S.
      • et al.
      Explaining the decrease in coronary heart disease mortality in Italy between 1980 and 2000.
      • Hotchkiss J.W.
      • Davies C.A.
      • Dundas R.
      • et al.
      Explaining trends in Scottish coronary heart disease mortality between 2000 and 2010 using IMPACTSEC model: retrospective analysis using routine data.
      • Bajekal M.
      • Scholes S.
      • Love H.
      • et al.
      Analysing recent socioeconomic trends in coronary heart disease mortality in England, 2000-2007: a population modelling study.
      One striking example began with a comprehensive, community pilot project conducted in North Karelia, Finland. In the late 1960s, men from this region had the highest CHD mortality rate in the world predominantly due to consumption of saturated fats and sodium, as well as smoking. Based on the results of the pilot project and implementation of its findings through national policy and health promotion initiatives (e.g., health education, development of a domestic vegetable oil industry) across Finland, a shift in the nationwide population distribution of cholesterol, blood pressure, and smoking was achieved. Reductions in saturated fat consumption led to a 60 mg/dL decline in mean national total cholesterol levels. Over the course of 35 years, in men aged 35 to 64 years, drastic reductions in age-adjusted CHD mortality rates of 85% in North Karelia and 80% across Finland (down to 100 CHD deaths per 100,000 individuals) were achieved. Approximately 75% of this reduction was explained by a decrease in the 3 targeted risk factors. Among these, lowering of cholesterol accounted for most of the observed benefit.
      • Puska P.
      From Framingham to North Karelia: from descriptive epidemiology to public health action.
      • Vartiainen E.
      • Laatikainen T.
      • Peltonen M.
      • et al.
      Thirty-five-year trends in cardiovascular risk factors in Finland.
      Cholesterol reduction can be achieved by a number of other changes in dietary habits. A meta-analysis of 67 controlled studies demonstrated that 2 to 10 g per day of dietary soluble fiber consumption reduces LDL-C by 2.2 mg/dL.
      • Brown L.
      • Rosner B.
      • Willett W.W.
      • et al.
      Cholesterol-lowering effects of dietary fiber: a meta-analysis.
      Phytosterol consumption reduces LDL-C by 13 mg/dL for every 2.15 g consumed daily.
      • Demonty I.
      • Ras R.T.
      • van der Knaap H.C.
      • et al.
      Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake.
      Nut consumption (67 g daily) decreases LDL-C by 10.2 mg/dL and daily soy isoflavone consumption by 5 mg/dL.
      • Sabate J.
      • Oda K.
      • Ros E.
      Nut consumption and blood lipid levels: a pooled analysis of 25 intervention trials.
      • Taku K.
      • Umegaki K.
      • Sato Y.
      • et al.
      Soy isoflavones lower serum total and LDL cholesterol in humans: a meta-analysis of 11 randomized controlled trials.
      Small LDL particle number has also been shown to be inversely correlated with crude-fiber consumption and positively related to dietary cholesterol intake, high-carbohydrate (and particularly high glycemic index) diets, and trans-fatty acid (TFA) consumption.
      • Williams P.T.
      • Krauss R.M.
      • Kindel-Joyce S.
      • et al.
      Relationship of dietary fat, protein, cholesterol, and fiber intake to atherogenic lipoproteins in men.
      • Siri P.W.
      • Krauss R.M.
      Influence of dietary carbohydrate and fat on LDL and HDL particle distributions.
      TFA consumption is associated with significantly higher LDL-C levels but has been decreasing over the past 3 decades due to efforts to eliminate industrial TFA in foods.
      • Mozaffarian D.
      • Aro A.
      • Willett W.C.
      Health effects of trans-fatty acids: experimental and observational evidence.
      Beyond individual foods, comprehensive diets such as the Mediterranean diet, which is comprised of primarily fruits, vegetables, legumes, grains, nuts, and olive oil, have been shown to reduce LDL-C by 10% after 5 weeks.
      • Richard C.
      • Couture P.
      • Desroches S.
      • et al.
      Effect of the Mediterranean diet with and without weight loss on surrogate markers of cholesterol homeostasis in men with the metabolic syndrome.
      A recent study found that adults who followed the Mediterranean diet over 10 years were 47% less likely to develop heart disease compared to similar adults who did not follow this diet.
      • Georgousopoulou E.N.
      • Pitsavos C.
      • Panagiotakos D.
      • et al.
      Adherence to Mediterranean is the most important protector against the development of fatal and non-fatal cardiovascular event: 10-year follow-up (2002-12) of the Attica study.
      The more stringent Ornish diet has been shown to reduce LDL-C by 37%, although adherence is extremely difficult to achieve.
      • Ornish D.
      • Brown S.E.
      • Scherwitz L.W.
      • et al.
      Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial.
      Exercise training, independent of weight loss, does not significantly reduce LDL-C levels.
      • Belardinelli R.
      • Paolini I.
      • Cianci G.
      • et al.
      Exercise training intervention after coronary angioplasty: the ETICA trial.
      • Wosornu D.
      • Bedford D.
      • Ballantyne D.
      A comparison of the effects of strength and aerobic exercise training on exercise capacity and lipids after coronary artery bypass surgery.
      • Yu C.M.
      • Li L.S.
      • Ho H.H.
      • et al.
      Long-term changes in exercise capacity, quality of life, body anthropometry, and lipid profiles after a cardiac rehabilitation program in obese patients with coronary heart disease.
      • Wood P.D.
      • Stefanick M.L.
      • Dreon D.M.
      • et al.
      Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting as compared with exercise.
      However, randomized studies indicate that physical activity results in a decrease in small LDL particle number.
      • Halle M.
      • Berg A.
      • Konig D.
      • et al.
      Differences in the concentration and composition of low-density lipoprotein subfraction particles between sedentary and trained hypercholesterolemic men.
      • Williams P.T.
      • Krauss R.M.
      • Vranizan K.M.
      • et al.
      Effects of exercise-induced weight loss on low density lipoprotein subfractions in healthy men.
      • Kraus W.E.
      • Houmard J.A.
      • Duscha B.D.
      • et al.
      Effects of the amount and intensity of exercise on plasma lipoproteins.
      Thus, a shift from higher numbers of smaller, more atherogenic particles to fewer, larger particles, may partially explain the reduction in CV risk associated with physical activity.
      • Ahmed H.M.
      • Blaha M.J.
      • Nasir K.
      • et al.
      Effects of physical activity on cardiovascular disease.
      Overall, an improved diet and exercise regimen most commonly lowers LDL-C by 10%–15%.
      • Scirica B.M.
      • Cannon C.P.
      Treatment of elevated cholesterol.
      Consistent with genetic data demonstrating large CV risk reductions from chronic small to moderate reductions in LDL-C, improved dietary habits across the population beginning very early in life can yield large reductions in CHD and CHD-related healthcare spending. New research focusing on developing better dietary habits in children will be discussed later in the review.

      Nonstatin pharmacologic therapies

      In addition to lifestyle changes, LDL-C lowering has been advanced by drug-based therapy. The first pharmacologic treatment for LDL-C lowering, which demonstrated a significant reduction on a primary CV endpoint was cholestyramine, a bile acid sequestrant. In the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), cholestyramine lowered LDL-C levels by 12% (22 mg/dL) compared with placebo, with a relative reduction in the risk of nonfatal MI or CHD death by 19%.
      The Lipid Research Clinics Coronary Primary Prevention Trial results II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering.
      The relative CV risk reduction per mg/dL reduction in LDL-C from this trial is consistent with the subsequent findings from the large meta-analysis of statin trials from the Cholesterol Treatment Trialists Collaboration (CTT).
      • Mihaylova B.
      • Emberson J.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists Collaborators
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      No large, randomized trials have tested whether bile acid sequestrants would reduce CV events on top of statin therapy in a primary or secondary prevention population.
      Before the statin era, niacin, which influences VLDL metabolism and lowers LDL-C, was compared to placebo in the Coronary Drug Project.
      • Canner P.L.
      • Berge K.G.
      • Wenger N.K.
      • et al.
      Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.
      Although niacin did not reduce total mortality (primary endpoint), it did reduce nonfatal MI (secondary endpoint), which may be related to the 26 mg/dL (10.1%) reduction in total cholesterol. A post-trial exploratory analysis conducted 9 years after the completion of the trial found that these effects were associated with reduced mortality.
      The role of niacin in patients well-treated with statins remains unclear. In the HPS2-THRIVE trial, the addition of extended-release niacin to a background of statin therapy reduced LDL-C and raised HDL-C levels by 10 mg/dL (15.6%) and 6 mg/dL (13.6%), respectively, compared to placebo. Niacin did not reduce the risk of major CV events and was accompanied by a range of serious adverse events.
      • Landray M.J.
      • Haynes R.
      • Hopewell J.C.
      • et al.
      HPS2-THRIVE Collaborative Group
      Effects of extended-release niacin with laropiprant in high-risk patients.
      The results of the much smaller AIM-HIGH trial also failed to demonstrate a CV benefit for niacin on top of statins.
      • Boden W.E.
      • Probstfield J.L.
      • Anderson T.
      • et al.
      AIM-HIGH Investigators
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      A plausible explanation for the nonsignificant CV risk reduction findings in these trials is that niacin only resulted in a modest absolute reduction in LDL-C because the baseline LDL-C was well-controlled (e.g., <80 mg/dL). To date, it is unknown whether niacin results in a clinical benefit when added to statin therapy in patients with higher baseline LDL-C levels.
      Ezetimibe inhibits the function of the NPC1L1 protein, which is responsible for transportation of dietary cholesterol from the gut lumen to intestinal enterocytes, thus reducing the absorption of dietary cholesterol.
      • Altmann S.W.
      • Davis Jr., H.R.
      • Zhu L.J.
      • et al.
      Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.
      • Sudhop T.
      • Lutjohann D.
      • Kodal A.
      • et al.
      Inhibition of intestinal cholesterol absorption by ezetimibe in humans.
      Although ezetimibe was approved by the Food and Drug Administration (FDA) to lower LDL-C in 2002, its efficacy in reducing CV outcomes was only recently demonstrated. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) studied ezetimibe in a post-acute coronary syndrome (ACS) population with well-controlled LDL-C on background statin therapy. Ezetimibe resulted in a 15.8 mg/dL (23.9%) reduction in LDL-C levels and a 6.4% relative risk reduction in the primary composite endpoint of CV death, major coronary events, or nonfatal stroke at 7 years, as well as a 13% relative reduction in risk of any MI and 7.2% relative risk reduction in rate of major vascular events (MVE).
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      The findings from IMPROVE-IT suggest that the ezetimibe-induced CV risk reduction per mg/dL LDL-C reduction is similar to statins. Ezetimibe is the first LDL-C-lowering drug to demonstrate a reduction in CV outcomes in patients well-treated with statins.

      Statin therapy

      Statins inhibit the rate-limiting enzyme, HMG-CoA reductase, in the synthesis pathway of cholesterol. This results in lower intrahepatic cholesterol and an up-regulation of hepatic cell surface LDL receptors, resulting in enhanced receptor-mediated uptake of LDL and other apoB-containing lipoproteins from the circulation. Evidence supports their effectiveness in lowering coronary, cerebrovascular, and peripheral vascular events.
      Primary prevention trials with statins have demonstrated a CV outcomes benefit in patients with hypercholesterolemia, diabetes mellitus, chronic kidney disease, and normal LDL-C (100 to 160 mg/dL) in the setting of other risk factors (Table 3).
      • Shepherd J.
      • Cobbe S.M.
      • Ford I.
      • et al.
      Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.
      • Downs J.R.
      • Clearfield M.
      • Weis S.
      • et al.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • et al.
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      ALLHAT Officers and Coordinators for the Allhat Collaborative Research Group, The Antihypertensive Lipid-Lowering Treatment to Prevent Heart Attack Trial
      Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).
      • Sever P.S.
      • Dahlof B.
      • Poulter N.R.
      • et al.
      Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.
      • Colhoun H.M.
      • Betteridge D.J.
      • Durrington P.N.
      • et al.
      Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
      • Knopp R.H.
      • d'Emden M.
      • Smilde J.G.
      • et al.
      Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN).
      • Nakamura H.
      • Arakawa K.
      • Itakura H.
      • et al.
      Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial.
      • Ridker P.M.
      • Danielson E.
      • Fonseca F.A.
      • et al.
      Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
      A meta-analysis of the lowest risk subjects from statin trials found that 1 mmol/L (∼39 mg/dL) of LDL-C reduction was associated with 38% and 31% decreases in the relative risk of MVE (nonfatal MI, coronary death, coronary revascularization, or stroke) in subgroups of 5-year predicted risk <5% and ≥5% to <10%, respectively. When these 2 subgroups were pooled, the absolute reduction in MVE was 11 per 1000 over 5 years.
      • Mihaylova B.
      • Emberson J.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists Collaborators
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      Table 3Summary of trials assessing the impact of statin therapy on LDL-C and cardiovascular outcomes
      StudyPopulationDrug (mg)PEP
      In the ALLHAT-LLT, 4S, and HPS studies the primary endpoint (PEP) was defined as all-cause mortality. Only CV-related endpoints are summarized for these studies.
      Mean follow-up (y)Baseline mean LDL (mg/dL)
      Baseline LDL-C is intended to denote achieved LDL-C without statin therapy. In some cases, baseline LDL-C was back-estimated from available data.
      Change relative to comparator arm
      LDL-C reduction (%)LDL-C reduction (mg/dL)Absolute CV risk reductionRelative CV risk reduction5-Year NNT
      5-year NNT estimated from available data on absolute risk reduction, relative risk reduction, and duration of follow-up.
      Primary prevention trials (statin vs placebo/usual care)
       WOSCOPS
      • Shepherd J.
      • Cobbe S.M.
      • Ford I.
      • et al.
      Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.
      6595 men aged 45–64 y with high cholesterol and no history of MI in West of ScotlandPravastatin 40Nonfatal MI, CHD death4.919226%49.92.4% (P < .001)31% with pravastatin (P < .001)41
       AFCAPS/TexCAPS
      • Downs J.R.
      • Clearfield M.
      • Weis S.
      • et al.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
      6605 patients without CHD and average LDL-CLovastatin 20–40MI, UA, sudden cardiac death5.215025%37.54.1% (P < .001)37% with lovastatin (P < .001)25
       PROSPER
      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • et al.
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      5804 patients aged 70–82 y with preexisting vascular disease or risk factorsPravastatin 40Nonfatal MI, stroke, coronary death3.214634%49.62.1% (P = .014)15% with pravastatin (P = .014)33
       ALLHAT-LLT
      ALLHAT Officers and Coordinators for the Allhat Collaborative Research Group, The Antihypertensive Lipid-Lowering Treatment to Prevent Heart Attack Trial
      Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).
      10,355 patients aged ≥55 y with high cholesterol, HTN, and ≥1 other CHD risk factorsPravastatin 40Nonfatal MI, CHD death4.814617%24.81.1% (P = .16)9% with pravastatin (P = .16)88
       ASCOT-LLA
      • Sever P.S.
      • Dahlof B.
      • Poulter N.R.
      • et al.
      Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.
      10,305 patients with HTN, ≥3 risk factors, and lower than average cholesterolAtorvastatin 10Nonfatal MI, CHD death3.3 (median)13335%46.43.4% (P = .0005)36% with atorvastatin (P = .0005)20
       CARDS
      • Colhoun H.M.
      • Betteridge D.J.
      • Durrington P.N.
      • et al.
      Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
      2838 patients with type 2 diabetes and without CV disease or high LDL-CAtorvastatin 10MI, UA with hospitalization, coronary revascularization, stroke, resuscitated cardiac arrest, CHD death3.9 (median)11740%46.83.2% (P = .001)37% with atorvastatin (P = .001)25
       ASPEN
      • Knopp R.H.
      • d'Emden M.
      • Smilde J.G.
      • et al.
      Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN).
      2410 patients with type 2 diabetes and LDL-C below guideline targetsAtorvastatin 10Nonfatal MI, UA with hospitalization, CABG, nonfatal stroke, resuscitated cardiac arrest, CV death4.0 (median)11329%32.81.3% (P = .34)10% with atorvastatin (P = .34)64
       MEGA
      • Nakamura H.
      • Arakawa K.
      • Itakura H.
      • et al.
      Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial.
      7832 patients with high cholesterol and without CV disease in JapanPravastatin 10–20MI, angina, coronary revascularization, cardiac death5.315715%23.21.7% (P = .01)33% with pravastatin (P = .01)62
       JUPITER
      • Ridker P.M.
      • Danielson E.
      • Fonseca F.A.
      • et al.
      Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
      17,802 patients without CV disease, LDL-C <130 mg/dL and hsCRP >2 mg/LRosuvastatin 20MI, UA with hospitalization, arterial revascularization, stroke, CV death1.9 (median)108 (median)50%54.00.59% (P < .00001)44% with rosuvastatin (P < .00001)66
      Secondary prevention trials (statin vs placebo/usual care)
       4S
      • Pedersen T.R.
      • Olsson A.G.
      • Faergeman O.
      • et al.
      Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S).
      4444 patients with CHDSimvastatin 20–40MI, resuscitated cardiac arrest, cardiac death5.4 (median)18738%71.19.0% (P < .00001)34% with simvastatin (P < .00001)12
       CARE
      • Sacks F.M.
      • Pfeffer M.A.
      • Moye L.A.
      • et al.
      The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
      4159 patients with average LDL-C and history of MIPravastatin 40Nonfatal MI, CHD death5.0 (median)13932%44.53.0% (P = .003)24% with pravastatin (P = .003)33
       LIPID
      The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group
      Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
      9014 patients with recent history of MI or hospitalization for UAPravastatin 40CHD death6.1150 (median)25%37.51.9% (P < .001)24% with pravastatin (P < .001)63
       LIPS
      • Serruys P.W.
      • de Feyter P.
      • Macaya C.
      • et al.
      Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
      1677 patients after first PCI with stable angina, UA, or silent ischemiaFluvastatin 80Nonfatal MI, coronary reintervention, cardiac death3.9 (median)13127%35.45.3% (P = .01)22% with fluvastatin (P = .01)16
       HPS
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      20,536 patients with CV disease, diabetes, or HTN in UKSimvastatin 40Nonfatal MI, coronary or non-coronary revascularization, stroke, CHD death5.013130%38.75.4% (P < .001)24% with simvastatin (P < .0001)19
       ALLIANCE
      • Koren M.J.
      • Hunninghake D.B.
      ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study.
      2442 patients with CHD and hyperlipidemiaAtorvastatin 10–80Nonfatal MI, UA with hospitalization, cardiac revascularization, resuscitated cardiac arrest, cardiac death4.314711%16.23.5% (P = .02)17% with atorvastatin (P = .02)25
      Secondary prevention trials (intensive vs less-intensive statin)
       PROVE-IT
      • Cannon C.P.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      4162 patients recently hospitalized for ACSAtorvastatin 80 vs pravastatin 40MI, UA with hospitalization, coronary revascularization, stroke, all-cause death2.012429%36.03.9% (P = .005)16% with atorvastatin (P = .005)15
       A to Z
      • de Lemos J.A.
      • Blazing M.A.
      • Wiviott S.D.
      • et al.
      Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.
      4497 patients after ACSSimvastatin 40 for 1 month then simvastatin 80 vs placebo for 1 month then simvastatin 20Nonfatal MI, readmission for ACS, stroke, CV death2.0 (median)12211%13.42.3% (P = .14)11% with simvastatin only (P = .14)24
       TNT
      • LaRosa J.C.
      • Grundy S.M.
      • Waters D.D.
      • et al.
      Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
      10,001 patients with stable CHDAtorvastatin 80 vs atorvastatin 10Nonfatal MI, resuscitated cardiac arrest, stroke, CHD death4.9 (median)15215%22.82.2% (P < .001)22% with atorvastatin 80 mg (P < .001)45
       IDEAL
      • Pedersen T.R.
      • Faergeman O.
      • Kastelein J.J.
      • et al.
      High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.
      8888 patients with a history of MIAtorvastatin 40–80 vs simvastatin 20–40Nonfatal MI, resuscitated cardiac arrest, coronary death4.8 (median)15716%25.11.1% (P = .07)11% with atorvastatin (P = .07)88
       SEARCH
      • Armitage J.
      • Bowman L.
      • Wallendszus K.
      • et al.
      Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine Collaborative Group
      Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial.
      12,064 patients with history of MISimvastatin 80 vs simvastatin 20MI, arterial revascularisation, stroke, coronary death6.713.51.2% (P = .10)6% with simvastatin 80 mg (P = .10)106
      ACS, acute coronary syndrome; CABG, coronary artery bypass graft; CHD, coronary heart disease; CV, cardiovascular; hsCRP, high-sensitivity C-reactive protein; HTN, hypertension; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PCI, percutaneous coronary intervention; PEP, primary endpoint; UA, unstable angina.
      In the ALLHAT-LLT, 4S, and HPS studies the primary endpoint (PEP) was defined as all-cause mortality. Only CV-related endpoints are summarized for these studies.
      Baseline LDL-C is intended to denote achieved LDL-C without statin therapy. In some cases, baseline LDL-C was back-estimated from available data.
      5-year NNT estimated from available data on absolute risk reduction, relative risk reduction, and duration of follow-up.
      The benefit of statin therapy in reducing CV events in patients with known atherosclerotic CV disease has been well-established (Table 3).
      • Pedersen T.R.
      • Olsson A.G.
      • Faergeman O.
      • et al.
      Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S).
      • Sacks F.M.
      • Pfeffer M.A.
      • Moye L.A.
      • et al.
      The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
      The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group
      Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
      • Serruys P.W.
      • de Feyter P.
      • Macaya C.
      • et al.
      Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      • Koren M.J.
      • Hunninghake D.B.
      ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study.
      • Cannon C.P.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      • de Lemos J.A.
      • Blazing M.A.
      • Wiviott S.D.
      • et al.
      Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.
      • LaRosa J.C.
      • Grundy S.M.
      • Waters D.D.
      • et al.
      Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
      • Pedersen T.R.
      • Faergeman O.
      • Kastelein J.J.
      • et al.
      High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.
      • Armitage J.
      • Bowman L.
      • Wallendszus K.
      • et al.
      Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine Collaborative Group
      Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial.
      In addition, more intensive (i.e., potent) statin regimens have been found to have greater efficacy compared to less-intensive regimens. The CTT meta-analysis demonstrated that 1 mmol/L (∼39 mg/dL) reduction in LDL-C resulted in a 10% relative reduction in all-cause mortality and a 21% relative reduction in MVE for statins vs placebo. Decreases in the rate of individual endpoints per 1 mmol/L LDL-C reductions were major coronary events (24%), coronary revascularization (24%), ischemic stroke (20%), and any stroke (15%). Intensive statin (≥50% LDL-C lowering) vs less intensive (<50%) regimens further reduced LDL-C by 0.51 mmol/L (20 mg/dL) and led to another 15% relative risk reduction in MVE. These relationships were found to be consistent for all patient subtypes studied and indicated no threshold beyond which LDL-C lowering would not provide benefit (including <2 mmol/L [∼80 mg/dL]), findings consistent with other large-scale studies.
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Cholesterol Treatment Trialists Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      The efficacy of statins on CV outcomes also appears to be consistent in both primary and secondary prevention populations across racial, ethnic, and regional practice differences.
      • Mihaylova B.
      • Emberson J.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists Collaborators
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Cholesterol Treatment Trialists Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      In another CTT meta-analysis, statins were found to reduce LDL-C similarly in both men and women, with similar proportional reductions in MVEs. However, in the subgroup with no prior CV disease, the relative risk reduction in women was found to be lower compared with men (15% and 28%, respectively per 1 mmol/L LDL-C reduction).
      • Fulcher J.
      • O'Connell R.
      • Voysey M.
      • et al.
      Cholesterol Treatment Trialists Collaboration
      Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials.

      Statin adverse effects

      Statins have also been evaluated for potential long-term adverse effects. Estimates of statin-related adverse events differ between randomized trials and observational studies, likely due to differences in patient selection. In randomized trials, elderly individuals, subjects with multiple comorbidities or on multiple medications, and women are generally excluded or under-enrolled despite being prescribed statins in clinical practice. Although observational trials have limitations, they provide useful data regarding adverse events in clinical practice.
      • Maningat P.
      • Breslow J.L.
      Needed: pragmatic clinical trials for statin-intolerant patients.
      Statins have been reported to increase the incidence of nonserious musculoskeletal side effects (e.g., myalgia without elevation in creatine kinase) in uncontrolled observational studies (up to 20%), although this has not been detected in randomized, double-blinded, clinical trials.
      • Maningat P.
      • Breslow J.L.
      Needed: pragmatic clinical trials for statin-intolerant patients.
      Rhabdomyolysis occurs in an excess of 4 cases per 10,000 participants in intensive vs less-intensive statin trials, and only 1 case per 10,000 participants in less-intensive vs placebo trials.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Cholesterol Treatment Trialists Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      Statin-induced transaminase elevation occurs at an excess rate of only 4.2 per 1000 patients and is reversible with dose reduction or discontinuation.
      • Kashani A.
      • Phillips C.O.
      • Foody J.M.
      • et al.
      Risks associated with statin therapy: a systematic overview of randomized clinical trials.
      Past statin-related safety concerns including malignancy and cognitive dysfunction have been directly assessed using randomized trial data without any suggestion of a causal relationship.
      • Emberson J.R.
      • Kearney P.M.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists Collaboration
      Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy.
      Statin therapy is associated with a slight increase in risk of new onset diabetes. This relationship is dose-dependent, and in 1 meta-analysis, the risk of incident diabetes in participants receiving intensive statin treatment was 12% (P > .05) higher compared to moderate statin treatment.
      • Preiss D.
      • Seshasai S.R.
      • Welsh P.
      • et al.
      Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
      However, the risk is low in absolute terms, and the CV benefits of statin therapy likely outweigh risk even in low-risk patients.
      • Sattar N.
      • Preiss D.
      • Murray H.M.
      • et al.
      Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.
      • Ridker P.M.
      • Pradhan A.
      • MacFadyen J.G.
      • et al.
      Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial.

      Lipid-management guidelines

      Guidelines offer practical recommendations for achieving consistent, evidence-based care. Guidelines for cholesterol management are available from the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS), American College of Cardiology (ACC)/American Heart Association (AHA), National Lipid Association (NLA), and International Atherosclerosis Society (IAS) among other committees.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • et al.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Catapano A.L.
      • Reiner Z.
      • De Backer G.
      • et al.
      Task Force for the management of dyslipidaemias of the European Society of Cardiology, European Atherosclerosis Society
      ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
      • Jacobson T.A.
      • Ito M.K.
      • Maki K.C.
      • et al.
      National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1-executive summary.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel Members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia–full report.
      These documents identify similar patient groups that benefit from LDL-C lowering. Below, we focus on the recommendations from the ESC/EAS and ACC/AHA, as this discussion illustrates the major differences between available guidelines.

      ESC/EAS guidelines, 2011

      The ESC/EAS joint guidelines recommend lifestyle modification as a component of all lipid-lowering treatment strategies. They also recommend consideration of an add-on pharmacologic treatment, with the intensity of therapy adjusted to achieve specific LDL-C goals.
      • Catapano A.L.
      • Reiner Z.
      • De Backer G.
      • et al.
      Task Force for the management of dyslipidaemias of the European Society of Cardiology, European Atherosclerosis Society
      ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
      Statin use is principally recommended, although the addition of bile acid sequestrants, cholesterol absorption inhibitors, or niacin is suggested in patients unable to achieve the desired LDL-C goal despite statin monotherapy or in patients with statin intolerance. Use of the Systematic Coronary Risk Estimation (SCORE) model, validated in European populations, is recommended for the estimation of 10-year CV risk in populations without established atherosclerotic CV disease (ASCVD).
      • Conroy R.M.
      • Pyorala K.
      • Fitzgerald A.P.
      • et al.
      Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project.
      Established ASCVD (ACS, history of MI, stable angina, coronary or other arterial revascularization, stroke, transient ischemic attack or peripheral arterial disease presumed to be of atherosclerotic origin), diabetes, moderate/severe chronic kidney disease or a 10-year SCORE ≥10% establishes “very high risk” with an LDL-C goal of <70 mg/dL. “High risk” is established by marked elevation of a single risk factor (e.g., familial dyslipidemia or hypertension) or a 10-year SCORE ≥5 to <10% with an LDL-C goal of <100 mg/dL. Guidance on secondary targets (non-HDL-C or apoB) is also provided.

      ACC/AHA guidelines, 2013

      Like the ESC/EAS guidelines, the ACC/AHA guidelines recommend lifestyle modification as a component of all lipid-lowering treatment strategies. The ACC/AHA guidelines, however, recommend an alternative drug treatment approach and the new Pooled Cohort Equation for 10-year risk estimation in primary prevention cohorts. High-intensity statin therapy is recommended in (1) individuals 21 to 75 years of age with ASCVD; (2) individuals ≥21 years of age with LDL-C >190 mg/dL; and (3) individuals 40 to 75 years of age with no ASCVD but diabetes and LDL-C 70 to 189 mg/dL with ≥ 7.5% 10-year ASCVD risk. Moderate-intensity statin therapy is recommended in (1) individuals >75 years of age with ASCVD; (2) individuals 40 to 75 years of age with no ASCVD but diabetes and LDL-C 70 to 189 mg/dL with <7.5% 10-year ASCVD risk; and (3) individuals 40 to 75 years of age with no ASCVD or diabetes and LDL-C 70 to 189 mg/dL with ≥7.5% 10-year ASCVD risk.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • et al.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      These guidelines also suggest that when randomized control trial evidence demonstrates that nonstatin therapy further reduces adverse CV events when added to statin therapy, nonstatin therapy should be considered. A lipid profile is recommended after initiation of statin therapy, primarily to ensure adherence, but routine monitoring (e.g., every 6–12 months) is not recommended.

      Comparison of ESC/EAS and ACC/AHA guidelines

      The ACC/AHA's emphasis on a strategy of fixed-dose statin therapy based on risk without titration to pre-defined LDL-C goals is distinct from the ESC/EAS guidelines. The authors of the ACC/AHA guidelines decided on this approach to be consistent with the design of statin trials, which tested fixed dose (e.g., simvastatin 40 mg), rather than “titrate-to-goal” strategies. Simplification of the appropriate drug choice may result in greater treatment with potent statins, avoiding the well-documented problems of suboptimal statin dose initiation and limited uptitration.
      • Abdallah M.S.
      • Kosiborod M.
      • Tang F.
      • et al.
      Patterns and predictors of intensive statin therapy among patients with diabetes mellitus after acute myocardial infarction.
      • Arnold S.V.
      • Kosiborod M.
      • Tang F.
      • et al.
      Patterns of statin initiation, intensification, and maximization among patients hospitalized with an acute myocardial infarction.
      • Javed U.
      • Deedwania P.C.
      • Bhatt D.L.
      • et al.
      Use of intensive lipid-lowering therapy in patients hospitalized with acute coronary syndrome: An analysis of 65,396 hospitalizations from 344 hospita participating in Get With The Guidelines (GWTG).
      A fixed dose strategy eliminates the need for routine lipid monitoring but raises the importance for thorough lifestyle and statin adherence evaluations and discussions at each clinical encounter. Rates of nonadherence are high, thus it is possible that without lipid monitoring, nonadherence may be less frequently identified.
      • McGinnis B.
      • Olson K.L.
      • Magid D.
      • et al.
      Factors related to adherence to statin therapy.
      De-emphasis of achievement of specific LDL-C levels leaves it unclear whether physicians should consider the addition of other lipid-lowering treatments in patients with recalcitrantly high LDL-C despite high-intensity statin therapy. As discussed in previous sections, the body of evidence across genetic studies, epidemiologic studies, animal models, and post-hoc/meta-analyses of trial data indicate that residual CV risk is associated with achieved LDL-C. Reported after the publication of both guidelines, the IMPROVE-IT trial results demonstrated the effectiveness and outstanding tolerability of ezetimibe. These findings may shift the focus of future guidelines toward achievement of specific LDL-C goals (e.g., <50 mg/dL not just by statins but also ezetimibe).
      A greater number of US patients are expected to qualify for statin therapy under the 2013 AHA/ACC guidelines (approximately 12.8 million more between the ages of 40 to 75 years) compared to the National Cholesterol Education Program Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults Adult Treatment Panel III (NCEP ATP III) guidelines.
      • Pencina M.J.
      • Navar-Boggan A.M.
      • D'Agostino Sr., R.B.
      • et al.
      Application of new cholesterol guidelines to a population-based sample.
      National Cholesterol Education Program Expert (NCEP) Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
      The vast majority of this expansion in statin treatment would be based on a 10-year ASCVD risk ≥7.5%.
      • Pencina M.J.
      • Navar-Boggan A.M.
      • D'Agostino Sr., R.B.
      • et al.
      Application of new cholesterol guidelines to a population-based sample.
      • Ray K.K.
      • Kastelein J.J.
      • Boekholdt S.M.
      • et al.
      The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011.
      A recent analysis supports this expansion and suggests that treatment beyond this threshold (even down to ≥3.0% 10-year ASCVD risk) would be cost effective.
      • Pandya A.
      • Sy S.
      • Cho S.
      • et al.
      Cost-effectiveness of 10-year risk thresholds for initiation of statin therapy for primary prevention of cardiovascular disease.

      Next steps in LDL-C-lowering therapeutics

      Results from the IMPROVE-IT trial, taken together with the CTT meta-analysis of statin trials, demonstrate a continuous relationship between LDL-C lowering and CV risk reduction down to about 50 mg/dL.
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      Whether a beneficial net efficacy/safety profile can be achieved when targeting even lower LDL-C levels is unknown, but evidence suggests this may be a promising strategy for new drug development. In addition, there is a need for new LDL-C-lowering therapies for those on maximal statin therapy and/or ezetimibe who are unable to achieve current LDL-C goals (e.g., <70 mg/dL). These therapies may also be beneficial for patients not able or unwilling to take statins or other LDL-C-lowering drugs.

      Targeting very low LDL-C

      Post-hoc analyses of randomized trials consistently suggest a potential benefit from treatment to LDL-C levels beyond those currently recommended by guidelines. A recent meta-analysis of statin trials indicated that individuals achieving LDL-C levels <50 mg/dL with statin therapy had a lower risk of major CV events, but possibly slightly higher risk of hemorrhagic stroke (although absolute event rate was low), compared to those achieving levels between 75 and <100 mg/dL.
      • Boekholdt S.M.
      • Hovingh G.K.
      • Mora S.
      • et al.
      Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
      One trial included in the meta-analysis (JUPITER), reported no systemic increase in adverse events in those achieving LDL-C <50 mg/dL (median follow-up of 2 years).
      • Hsia J.
      • MacFadyen J.G.
      • Monyak J.
      • et al.
      Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin).
      In the PROVE IT-TIMI 22 trial, achieving LDL-C ≤40 mg/dL on atorvastatin 80 mg was associated with a lower risk of major CV events without any increase in adverse events (mean follow-up of 2 years).
      • Wiviott S.D.
      • Cannon C.P.
      • Morrow D.A.
      • et al.
      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.
      Another analysis of JUPITER demonstrated that achieving LDL-C <30 mg/dL was also not associated with a higher total adverse event rate; it was, however, associated with more physician-reported diabetes, hematuria, hepatobiliary disorders, and insomnia.
      • Everett B.M.
      • Mora S.
      • Glynn R.J.
      • et al.
      Safety Profile of Subjects Treated to Very Low Low-Density Lipoprotein Cholesterol Levels (<30 mg/dl) With Rosuvastatin 20 mg Daily (from JUPITER).
      Naturally occurring examples in humans suggest that good health may coexist with prolonged exposure to very low LDL-C levels. Umbilical-cord measurements suggest that fetal growth and development occurs in the setting of LDL-C <40 mg/dL.
      • Nagasaka H.
      • Chiba H.
      • Kikuta H.
      • et al.
      Unique character and metabolism of high density lipoprotein (HDL) in fetus.
      • Averna M.R.
      • Barbagallo C.M.
      • Di Paola G.
      • et al.
      Lipids, lipoproteins and apolipoproteins AI, AII, B, CII, CIII and E in newborns.
      In individuals with hypobetalipoproteinemia, lifelong very low levels of LDL-C (<15 mg/dL) has not been associated with adverse effects.
      • Steinberg D.
      • Glass C.K.
      • Witztum J.L.
      Evidence mandating earlier and more aggressive treatment of hypercholesterolemia.
      In a report of 2 individuals, both women with homozygous loss-of-function PCSK9 mutations resulting in LDL-C ≤15 mg/dL, subjects appeared to be asymptomatic with normal development, intelligence, and ability to bear healthy children.
      • Hooper A.J.
      • Marais A.D.
      • Tanyanyiwa D.M.
      • Burnett J.R.
      The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population.
      • Zhao Z.
      • Tuakli-Wosornu Y.
      • Lagace T.A.
      • et al.
      Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.
      Thus, it is possible that the physiologic range for LDL-C extends to these extremely low levels. These data provide reassurance for an acceptable safety profile to pursue research in novel LDL-C lowering mechanisms to be used in conjunction with potent statins or potent statins plus ezetimibe.

      Novel therapeutic agents

      Studies of genetic mutations associated with potentially beneficial lipid profiles, including lower LDL-C, have led to the identification of targets for the development of novel therapeutic agents.
      • Cohen J.C.
      Emerging LDL therapies: Using human genetics to discover new therapeutic targets for plasma lipids.
      An example is the PCSK9 inhibitors, alirocumab, evolocumab, and bococizumab. Circulating PCSK9 increases endosomal and lysosomal degradation of hepatic LDL receptors resulting in the decreased ability to clear LDL particles from the circulation.
      • Urban D.
      • Poss J.
      • Bohm M.
      • et al.
      Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis.
      PCSK9 inhibitor-based therapies are fully human monoclonal antibodies that bind to circulating PCSK9 resulting in greater numbers of hepatic LDL receptors.
      Alirocumab has been assessed recently in phase III trials with 75 mg and 150 mg Q2W dosing.
      • Joseph L.
      • Robinson J.G.
      Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition and the Future of Lipid Lowering Therapy.
      The recent ODYSSEY LONG TERM study investigated alirocumab's efficacy and safety in 2341 patients. In high CV risk patients on statins, alirocumab compared with placebo resulted in a 62% reduction in LDL-C and the incidence of major CV events by 48% (P = .02) in a post-hoc analysis with 78-week follow-up.
      • Robinson J.G.
      • Farnier M.
      • Krempf M.
      • et al.
      Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
      The ongoing ODYSSEY OUTCOMES study in approximately 18,000 post-ACS patients is assessing the impact of adding alirocumab to statin therapy on major CV events.
      • Schwartz G.G.
      • Bessac L.
      • Berdan L.G.
      • et al.
      Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial.
      Evolocumab has also recently been evaluated in phase III trials with 140 mg every 2 weeks (Q2W) and 420 mg every 4 weeks dosing.
      • Joseph L.
      • Robinson J.G.
      Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition and the Future of Lipid Lowering Therapy.
      The recent OSLER I and II studies assessing efficacy and safety in 4465 patients demonstrated that evolocumab plus standard therapy reduced LDL-C by 61% and the incidence of major CV events by 53% (P = .003) compared to standard therapy alone in a prespecified but exploratory analysis with 1 year follow-up.
      • Sabatine M.S.
      • Giugliano R.P.
      • Wiviott S.D.
      • et al.
      Efficacy and safety of evolocumab in reducing lipids and cardiovascular events.
      The ongoing FOURIER study in approximately 27,500 patients with established CV disease on statin therapy is assessing as its primary endpoint whether addition of evolocumab reduces the incidence of major CV events.
      • Desai N.R.
      • Sabatine M.S.
      PCSK9 inhibition in patients with hypercholesterolemia.
      In the OSLER and ODYSSEY LONG TERM studies, the rate of any adverse events and/or serious adverse events was similar in patients receiving PCSK9 inhibitors compared to placebo. The rate of neurocognitive events was higher in PCSK9 inhibitor groups, although the total number of events was low.
      • Robinson J.G.
      • Farnier M.
      • Krempf M.
      • et al.
      Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
      • Sabatine M.S.
      • Giugliano R.P.
      • Wiviott S.D.
      • et al.
      Efficacy and safety of evolocumab in reducing lipids and cardiovascular events.
      Rates of newly diagnosed diabetes and worsening of preexisting diabetes were similar.
      • Robinson J.G.
      • Farnier M.
      • Krempf M.
      • et al.
      Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
      A meta-analysis of 24 randomized control trials demonstrated similar rates of serious adverse events between patients receiving PCSK9 inhibitors compared to those who did not (9.26% vs 7.73%, P = .88).
      • Navarese E.P.
      • Kolodziejczak M.
      • Schulze V.
      • et al.
      Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis.
      Data from the ODYSSEY LONG TERM study revealed that driving LDL-C levels to <25 mg/dL did not increase adverse events compared to placebo.
      • Robinson J.G.
      • Farnier M.
      • Krempf M.
      • et al.
      Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
      In light of their efficacy and favorable safety profile, both alirocumab and evolocumab have been approved by the FDA for use in patients with clinical ASCVD who require additional LDL-C lowering, and in adult patients with heterozygous familial hypercholesterolemia already on maximally tolerated statin therapy.
      Another novel pharmacologic approach for LDL-C lowering is CETP inhibition. CETP shuttles triglycerides and cholesteryl esters between apoB-containing lipoproteins and HDL, causing remodeling of circulating lipoproteins. Potent inhibition of this enzyme dramatically increases HDL-C and can reduce LDL-C and lipoprotein(a). The failure of the early CETP inhibitors, torcetrapib (due to an increased risk of CV death presumably secondary to off-target effects), dalcetrapib (presumably due to minimal reductions in LDL-C), and most recently evacetrapib (Phase III trial stopped early due to low probability of achieving the primary endpoint) have not fully closed the door on CETP as a drug target.
      • Barter P.J.
      • Caulfield M.
      • Eriksson M.
      • et al.
      Effects of torcetrapib in patients at high risk for coronary events.
      • Mohammadpour A.H.
      • Akhlaghi F.
      Future of cholesteryl ester transfer protein (CETP) inhibitors: a pharmacological perspective.
      • Schwartz G.G.
      • Olsson A.G.
      • Abt M.
      • et al.
      Effects of dalcetrapib in patients with a recent acute coronary syndrome.

      Lilly to Discontinue Development of Evacetrapib for High-Risk Atherosclerotic Cardiovascular Disease, 2015. Available at: https://investor.lilly.com/releasedetail.cfm?ReleaseID=936130.

      The CETP inhibitor, anacetrapib, has been shown to increase HDL-C by 140% and decrease LDL-C by approximately 40% on top of statin therapy, and is currently undergoing evaluation in the REVEAL HPS3-TIMI 55 trial.
      • Cannon C.P.
      • Shah S.
      • Dansky H.M.
      • et al.
      Safety of anacetrapib in patients with or at high risk for coronary heart disease.
      Although anacetrapib reduces LDL-C, it does increase small (and potentially more atherogenic) LDL particles.
      • Krauss R.M.
      • Pinto C.A.
      • Liu Y.
      • et al.
      Changes in LDL particle concentrations after treatment with the cholesteryl ester transfer protein inhibitor anacetrapib alone or in combination with atorvastatin.
      LDL-C lowering through these therapeutic agents offers a novel strategy to reduce residual risk of atherosclerotic CV events, especially after recent failures of treatments aimed at other targets, including HDL-C and lipoprotein-associated phospholipase A2.
      • O'Donoghue M.L.
      • Braunwald E.
      • White H.D.
      • et al.
      Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial.
      Data from CV outcomes trials of novel, potent LDL-C lowering drugs will provide insight into the net balance of benefits, and risks associated with even greater LDL-C reduction and lower levels of achieved LDL-C (Table 4).
      Table 4Novel LDL-C lowering therapies and their respective CV outcomes trials
      Drug typeTrial nameStudy populationPlanned enrollmentEstimated completion
      PCSK9 inhibitors
       EvolocumabFOURIEREstablished CV disease27,500February, 2018
       AlirocumabODYSSEY OUTCOMESRecent ACS18,600February, 2018
       BococizumabSPIRE IHigh risk for CV events17,000June, 2018
       BococizumabSPIRE IIHigh risk for CV events9,000March, 2018
      CETP inhibitor
       AnacetrapibREVEALEstablished CV disease30,600January, 2017
      ACS, acute coronary syndromes; CETP, cholesterol ester transfer protein; CV, cardiovascular; PCSK9, proprotein convertase subtilisin/kexin type 9.

      Population-level and health-system initiatives

      Population-level and health-system changes could have an immense influence on improving lifestyle behaviors, cholesterol screening, and access to providers and evidence-based therapies. As previously discussed, the Finnish experience is just one example of an effective population intervention guiding public health policy but illustrates the profound population effect (i.e., mean total cholesterol reduction 60 mg/dL) local and national policies can achieve.

      Lifestyle initiatives

      Long-term improvements in diet and exercise through behavioral interventions may significantly reduce LDL-C, which, when initiated in children and adolescents, might result in dramatic reductions in the incidence of CV events later in life. In Bogota, Colombia, a preschool-based intervention targeting 1200 children improved knowledge, attitudes, and habits related to healthy eating and physical activity at 1 year. Three years later, further improvements were seen in the same endpoints in this cohort.
      • Cespedes J.
      • Briceno G.
      • Farkouh M.E.
      • et al.
      Targeting preschool children to promote cardiovascular health: cluster randomized trial.
      This suggests that interventions targeting periods of behavioral malleability (e.g., ages 3 to 5 years) can have beneficial, sustained impacts on lifestyle habits.

      Disease awareness

      Lack of awareness is a significant barrier to the appropriate treatment of hypercholesterolemia. The Minnesota Heart Survey demonstrated that from 2000–2002 over half of men and women at or above moderate risk of CHD were unaware of their elevated cholesterol.
      • Arnett D.K.
      • Jacobs Jr., D.R.
      • Luepker R.V.
      • et al.
      Twenty-year trends in serum cholesterol, hypercholesterolemia, and cholesterol medication use: the Minnesota Heart Survey, 1980-1982 to 2000-2002.
      Data from National Health and Nutrition Examination Survey during 1999–2002 revealed that only 63% of US adults had their cholesterol screened within 5 years (as recommended by the NCEP guidelines).
      Centers for Disease Control and Prevention
      Disparities in screening for and awareness of high blood cholesterol–United States, 1999-2002.
      Furthermore, data from both studies demonstrated that a high proportion of individuals who were aware of their elevated cholesterol levels were not receiving treatment. Policy efforts must focus on better screening with appropriate triage to medical providers for at risk patients. The Affordable Care Act not only expands health insurance coverage, but also promotes preventative screening, including for lipid disorders.

      Medication adherence

      Medication nonadherence compromises the effectiveness of proven therapies. Registry data of post-MI patients from a large panel of US hospitals from 2003–2009 indicate that approximately only one-third of patients were discharged with an intensive statin.
      • Arnold S.V.
      • Spertus J.A.
      • Masoudi F.A.
      • et al.
      Beyond medication prescription as performance measures: optimal secondary prevention medication dosing after acute myocardial infarction.
      Recent data of those insured under a large commercial plan showed that just 49% of post-MI patients were adherent to statins at 1-year follow-up.
      • Choudhry N.K.
      • Glynn R.J.
      • Avorn J.
      • et al.
      Untangling the relationship between medication adherence and post-myocardial infarction outcomes: medication adherence and clinical outcomes.
      In England in 2007, the rate at which statin prescriptions were filled for patients with established CV disease was somewhat higher at 66%–85%.
      • Bajekal M.
      • Scholes S.
      • Love H.
      • et al.
      Analysing recent socioeconomic trends in coronary heart disease mortality in England, 2000-2007: a population modelling study.
      Causes of statin underutilization are likely multifactorial. A number of patient factors have been associated with statin adherence.
      • McGinnis B.
      • Olson K.L.
      • Magid D.
      • et al.
      Factors related to adherence to statin therapy.
      Age predicts nonadherence in a bimodal fashion, with the oldest (>70) and youngest (<50) being the poorest adherers.
      • Benner J.S.
      • Glynn R.J.
      • Mogun H.
      • et al.
      Long-term persistence in use of statin therapy in elderly patients.
      • Mann D.M.
      • Woodward M.
      • Muntner P.
      • et al.
      Predictors of nonadherence to statins: a systematic review and meta-analysis.
      Patients that are non-Caucasian, low-income, female, or smoke are less likely to be compliant with lipid-lowering drugs, although these demographics are not always reliable predictors.
      • Kiortsis D.N.
      • Giral P.
      • Bruckert E.
      • et al.
      Factors associated with low compliance with lipid-lowering drugs in hyperlipidemic patients.
      • Kopjar B.
      • Sales A.E.
      • Pineros S.L.
      • et al.
      Adherence with statin therapy in secondary prevention of coronary heart disease in veterans administration male population.
      Patients with a history of CHD are up to 3 times more likely to be adherent than those without a history of CHD.
      • Insull W.
      The problem of compliance to cholesterol altering therapy.
      • Jackevicius C.A.
      • Mamdani M.
      • Tu J.V.
      Adherence with statin therapy in elderly patients with and without acute coronary syndromes.
      Limited income, polypharmacy, dementia, and depression and/or anxiety have all been shown to increase nonadherence.
      • Col N.
      • Fanale J.E.
      • Kronholm P.
      The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly.
      • Stilley C.S.
      • Sereika S.
      • Muldoon M.F.
      • et al.
      Psychological and cognitive function: predictors of adherence with cholesterol lowering treatment.
      Health system–related issues also influence adherence. Medicaid patients are approximately 43% less likely to have high statin persistence, supporting that individuals or families with low incomes and limited resources may be prone to nonadherence.
      • Avorn J.
      • Monette J.
      • Lacour A.
      • et al.
      Persistence of use of lipid-lowering medications: a cross-national study.
      High insurance copayments also diminish statin adherence.
      • Gibson T.B.
      • Mark T.L.
      • McGuigan K.A.
      • et al.
      The effects of prescription drug copayments on statin adherence.
      Medication expense is also an important factor. In the USAGE study, cost prompted nearly half of patients to switch statins.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • et al.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      Patient adherence can be improved by interventions that focus on extended care with nonphysician providers, better follow-up, and increased contact with physicians.
      • Maningat P.
      • Gordon B.R.
      • Breslow J.L.
      How do we improve patient compliance and adherence to long-term statin therapy?.
      Enhancing the physician-patient communication axis and providing counseling can improve statin adherence.
      • Yilmaz M.B.
      • Pinar M.
      • Naharci I.
      • et al.
      Being well-informed about statin is associated with continuous adherence and reaching targets.
      Practical interventions such as medication reminders and improved patient education are also effective.
      • Schedlbauer A.
      • Davies P.
      • Fahey T.
      Interventions to improve adherence to lipid lowering medication.
      The use of combination “polypills” may also help simplify complex medication regimens.
      • Muntner P.
      • Mann D.
      • Wildman R.P.
      • et al.
      Projected impact of polypill use among US adults: Medication use, cardiovascular risk reduction, and side effects.
      Provider behavior also contributes to suboptimal statin use. Evidence suggests that providers often fail to start and uptitrate statins appropriately.
      • Abdallah M.S.
      • Kosiborod M.
      • Tang F.
      • et al.
      Patterns and predictors of intensive statin therapy among patients with diabetes mellitus after acute myocardial infarction.
      • Arnold S.V.
      • Kosiborod M.
      • Tang F.
      • et al.
      Patterns of statin initiation, intensification, and maximization among patients hospitalized with an acute myocardial infarction.
      • Javed U.
      • Deedwania P.C.
      • Bhatt D.L.
      • et al.
      Use of intensive lipid-lowering therapy in patients hospitalized with acute coronary syndrome: An analysis of 65,396 hospitalizations from 344 hospita participating in Get With The Guidelines (GWTG).
      • Arnold S.V.
      • Spertus J.A.
      • Masoudi F.A.
      • et al.
      Beyond medication prescription as performance measures: optimal secondary prevention medication dosing after acute myocardial infarction.
      This may be secondary to reluctance to re-evaluate long-standing treatments, mislabeling patients as “statin intolerant” or “allergic”, and busy workflows that interfere with the required time and attention necessary to review and optimize medication regimens. As previously suggested, providers may not provide effective education on statin indications, proper dosing, tolerability, and safety.
      • Abdallah M.S.
      • Kosiborod M.
      • Tang F.
      • et al.
      Patterns and predictors of intensive statin therapy among patients with diabetes mellitus after acute myocardial infarction.
      • Javed U.
      • Deedwania P.C.
      • Bhatt D.L.
      • et al.
      Use of intensive lipid-lowering therapy in patients hospitalized with acute coronary syndrome: An analysis of 65,396 hospitalizations from 344 hospita participating in Get With The Guidelines (GWTG).
      • Arnold S.V.
      • Spertus J.A.
      • Masoudi F.A.
      • et al.
      Beyond medication prescription as performance measures: optimal secondary prevention medication dosing after acute myocardial infarction.
      In addition, providers may underestimate the success rate of statin rechallenges. In an observational study of clinical practices from a single academic institution over 9 years, 17% of 107,835 patients discontinued statin use due to events labeled as “statin related”. Of patients who discontinued statins and were rechallenged over the subsequent 12 months, greater than 90% eventually tolerated statin use.
      • Zhang H.
      • Plutzky J.
      • Skentzos S.
      • et al.
      Discontinuation of statins in routine care settings: a cohort study.

      Technological solutions

      Health system barriers can propagate gaps in chronic disease care. New payment models that reward coordination and quality are being used by the Center for Medicare and Medicaid Services. These models depend on electronic health records (EHRs) to provide the tools necessary to track and improve quality of care. EHR adoption and use for a broader array of tasks is incentivized by the meaningful use criteria established by the HITECH Act. Studies already have demonstrated the impact of EHR-based performance feedback coupled with a quality improvement tool for LDL-C reduction. For example, use of EHRs at Kaiser Permanente was associated with statistically significant improvements in treatment intensification as well as downstream LDL-C reductions.
      • Reed M.
      • Huang J.
      • Graetz I.
      • et al.
      Outpatient electronic health records and the clinical care and outcomes of patients with diabetes mellitus.
      This was attributed to greater alignment with quality measures and clinical guidelines as well as increased availability of information and decision support through the EHR. Other technological interventions such as telemedicine have been shown to improve outcomes in chronic conditions (i.e., diabetes) and are currently undergoing evaluation for dyslipidemia.
      • Levin K.
      • Madsen J.R.
      • Petersen I.
      • et al.
      Telemedicine diabetes consultations are cost-effective, and effects on essential diabetes treatment parameters are similar to conventional treatment: 7-year results from the Svendborg Telemedicine Diabetes Project.
      EHRs and other technological initiatives have the potential to support provider decision-making, patient self-management, and quality improvement.
      • Aspry K.E.
      • Furman R.
      • Karalis D.G.
      • et al.
      Effect of health information technology interventions on lipid management in clinical practice: a systematic review of randomized controlled trials.
      Overall, hypercholesterolemia is best treated through a multi-faceted strategy similar to other public health issues, such as tobacco use. LDL-C reduction will be best achieved not only by continued drug development, but by comprehensive public health initiatives (e.g., nutritional content reporting in restaurants, food product labeling), cholesterol screening, promotion of healthy lifestyles, and technological and health system advances that facilitate and promote value-based care.

      Conclusion

      CV disease causes significant worldwide morbidity and mortality and contributes to substantial health care spending. The treatment of hypercholesterolemia, and specifically elevated LDL-C, represents an established strategy to diminish incident CV events and mortality. Numerous studies have established the continuous, graded, benefit conferred by LDL-C reduction on CV event risk and mortality. Future studies should focus on the impact and safety of targeting “very-low” LDL-C, earlier initiation of LDL-C–lowering interventions, the development and impact of novel therapeutic agents, as well as the use of evidence-based policy and regulatory initiatives to reduce environmental causes of elevated LDL-C on a population level.

      Acknowledgments

      Author contributions: Drs Wadhera, Steen, Khan, and Foody were responsible for conception and design of this work. Drs Wadhera and Steen drafted the manuscript. Drs Foody, Khan, and Guigliano provided critical revisions. All authors provided final approval of the manuscript. The authors would also like to thank Drs Wael Salem and Prakriti Gaba for their contributions in reading and reviewing the manuscript drafts.

      Financial disclosure

      Rishi Wadhera receives modest honoraria for consulting from Sanofi and Regeneron. Dylan Steen reports consulting fees from Sanofi and Regeneron. Irfan Khan is a stockholder and employee of Sanofi. Robert Giugliano reports grants and consultancy fees from Amgen, Daiichi-Sankyo, and Merck and consultancy fees from Briston-Myers-Squibb, CVS Caremark, Lexicon, Sanofi, and Pfizer. JoAnne Foody is an employee at Merck and previously consulted for Sanofi, Pfizer, and AstraZeneca.
      This review article was funded by Sanofi and Regeneron Pharmaceuticals, Inc. The lead author drafted the article, which was critically reviewed and revised by all authors thereafter, who all approved the final manuscript. Editorial assistance was provided by Neil Venn, Prime Medica Ltd, funded by Sanofi and Regeneron Pharmaceuticals, Inc. Responsibility for all opinions, conclusions, and data interpretation lies with the authors.

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