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A Reappraisal of the Lipid Hypothesis

  • Robert DuBroff
    Correspondence
    Requests for reprints should be addressed to Robert DuBroff, MD, Department of Medicine Cardiology Division, MSC10-5550, Albuquerque, NM 87107.
    Affiliations
    University of New Mexico School of Medicine, Department of Medicine, Division of Cardiology, Albuquerque
    Search for articles by this author
      The lipid hypothesis, which postulates that lowering serum cholesterol saves lives and prevents cardiovascular disease, has been supported by a prodigious volume of evidence over the past 30 years.
      • Ference BA
      • Ginsberg HN
      • Graham I
      • et al.
      Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
      Lowering low-density lipoprotein cholesterol (LDL-C) has become the foundation of cardiovascular disease prevention guidelines, yet not all of the evidence supports this recommendation.
      • DuBroff R
      Cholesterol paradox: a correlate does not a surrogate make.
      A reappraisal of the lipid hypothesis may hold the key to understanding this inconsonance.

      Clinical Trial Results

      The randomized controlled trial (RCT) is the gold standard for validating or rejecting a medical hypothesis. Initial proof of the lipid hypothesis came from some of the earliest RCTs of cholesterol reduction, such as the Coronary Primary Prevention Trial of cholestyramine and the first statin trials (Scandinavian Simvastatin Survival Study [4S], West of Scotland Coronary Prevention Study [WOSCOPS], and Cholesterol and Recurrent Events [CARE]). More widespread trials over the next 20 years produced mixed results, however.
      • DuBroff R
      Cholesterol paradox: a correlate does not a surrogate make.
      Regrettably, some clinical trials prior to 2004 have been tainted by scandals that led to new clinical trial regulations intended to safeguard patients and lend credibility to subsequent trials.
      • Krumholz HM
      • Ross JS
      • Presler AH
      • Egilman DS
      What have we learnt from Vioxx?.
      • Miossec M
      • Miossec P
      New regulatory rules for clinical trials in the United States and the European Union: key points and comparisons.
      The table summarizes 29 major RCTs of cholesterol reduction reported after the publication of these regulations (Table). Notably, only 2 of these 29 studies reported a mortality benefit, while nearly two-thirds reported no cardiovascular benefit at all. These unfavorable outcomes and inconsistent results suggest that the lipid hypothesis has failed the test of time. Alternatively, some have suggested that this lack of benefit could be due to inadequate intensity or duration of treatment, insufficiently powered studies, targeting LDL-C instead of apolipoprotein B, or perhaps these trials are attempting to lower LDL-C too late in the course of the disease.
      TableRandomized Controlled Trials of Cholesterol Reduction Reported After Publication of 2004 Clinical Trial Regulations
      StudyYearPatient Population Size and CharacteristicsInterventionStudy DurationCholesterol ReductionMortality BenefitCV Benefit
      Defined as the primary endpoint of the trial unless specified otherwise.
      St. Francis20051005 CCS > 80th percentileAtorvastatin 20 mg/d4.3 y39%-43% LDLNRNo (P = .08)
      TNT200510,001 CHD, LDL < 130 mg/dLAtorvastatin 10 mg/d or 80 mg/d4.9 y24% LDLNo (HR 1.01; 95% CI, 0.85-1.19)Yes (HR 0.78; 95% CI, 0.69-0.89)
      IDEAL20058888 s/p MIAtorvastatin 80 mg/d or simvastatin 20 mg/d4.8 y20% LDLNo (HR 0.98; 95% CI, 0.85-1.13)No (HR 0.89; 95% CI, 0.78-1.01)
      FIELD20059795 T2DMFenofibrate 200 mg/d6 y12% LDLNo (HR 1.11; 95% CI, 0.95-1.29)No (HR 0.89; 95% CI, 0.75-1.05)
      4D20051255 T2DM, hemodialysisAtorvastatin 20 mg/d4 y42% LDLNo (RR 0.93; 95% CI, 0.79-1.08)No (RR 0.92; 95% CI, 0.77-1.10)
      ASPEN20062410 T2DMAtorvastatin 10 mg/d4 y29% LDLNoNo (HR 0.9; 95% CI, 0.73-1.12)
      SPARCL20064731 s/p stroke or TIAAtorvastatin 80 mg/d4.9 y43% LDLNo (HR 1.0; 95% CI, 0.82-1.21)Yes (HR 0.84; 95% CI, 0.71-0.99)
      WHI200648,835 postmenopausal womenLow-fat diet8.1 y7% LDLNo (HR 1.01, 95% CI, 0.81-1.27)
      CHD death.
      No (HR 0.97; 95% CI, 0.9-1.06)
      MEGA20067932 hypercholesterolemiaPravastatin 10-20 mg/d5.3 y15% LDLNo (HR 0.72; 95% CI, 0.51-1.01)Yes (HR 0.67; 95% CI, 0.49-0.91)
      ILLUMINATE200715,067 high riskTorcetrapib2.2 y25% LDLNo (HR 1.58; 95% CI, 1.14-2.19)No (HR 1.25; 95% CI, 1.09-1.44)
      CORONA20075011 > 60 years, ischemic systolic HFRosuvastatin 10 mg/d33 mo45% LDLNo (HR 0.95; 95% CI, 0.86-1.05)No (HR 0.92; 95% CI, 0.83-1.02)
      SEAS20081873 mild-moderate aortic stenosisSimvastatin 40 mg + ezetimibe 10 mg/d4.4 y50% LDLNo (HR 1.04; 95% CI, 0.79-1.36)No (HR 0.96; 95% CI, 0.83-1.12)
      GISSI-HF20084271 chronic HFRosuvastatin 10 mg/d3.9 y27%-32% LDLNo (RR 1.00; 95% CI, 0.90-1.22)No (HR 1.01; 95% CI, 0.91-1.11)
      Admitted to hospital for cardiovascular reasons.
      JUPITER200817,800 LDL < 130 mg/dL, hsCRP > 2 mg/LRosuvastatin 20 mg/d1.9 y49% LDLNo (HR 0.81; 95% CI, 0.63-1.04)
      Reported among white subjects.
      Yes (HR 0.55; 95% CI, 0.43-0.69)
      Reported among white subjects.
      AURORA20092776 hemodialysisRosuvastatin 10 mg/d3.8 y43% LDLNo (HR 0.96; 95% CI, 0.86-1.07)No (HR 0.96; 95% CI, 0.84-1.11)
      SEARCH201012,064 s/p MISimvastatin 80 or 20 mg/d6.7 y0.35 mmol/L LDLNo (RR 0.99; 95% CI, 0.91-1.09)No (RR 0.94; 95% CI, 0.88-1.01)
      AIM-HIGH20113414 CVD, low HDL, on simvastatin ± ezetimibeNiacin ER 1.5-2.0 g/d3 y16% LDLNo (HR 1.16; 95% CI, 0.87-1.56)No (HR 1.02; 95% CI, 0.87-1.21)
      SHARP20119270 CKDSimvastatin 20 mg/d + ezetimibe 10 mg/d4.9 y31% LDLNo (RR 1.01; 95% CI, 0.75-1.35) CHD deathYes (RR 0.83; 95% CI, 0.74-0.94)
      SDHS2013458 men s/p recent coronary eventPUFA or SFA diet39 mo7.8% TCNo (HR 1.62; 95% CI, 1.00-2.64)No (HR 1.70; 95% CI, 1.03-2.80)
      HPS2-THRIVE201425,673 vascular disease on statinsNiacin ER 2 g/d + laropiprant 40 mg/d3.9 y16% LDLNo (RtR 1.09; 95% CI, 0.99-1.21)No (RtR 0.96; 95% CI, 0.90-1.03)
      IMPROVE-IT201518,144 s/p ACS on simvastatin 40 mg/dEzetimibe 10 mg/d7 y24% LDLNo (HR 0.99; 95% CI, 0.91-1.07)Yes (HR 0.94; 95% CI, 0.89-0.99)
      MCE20169423 institutionalizedPUFA or SFA diet41-56 mo13% TCNo (HR 1.22; 95% CI, 1.14-1.32)NR
      HOPE-3201612,705 HBP, intermediate riskRosuvastatin 10 mg/d5.6 y26% LDLNo (HR 0.93; 95% CI, 0.80-1.08)Yes (HR 0.76; 95% CI, 0.64-0.91)
      ACCELERATE201712,092 high riskEvacetrapib 130 mg/d26 mo37% LDLYes (HR 0.84;95% CI, 0.70-1.00)No (HR 1.01; 95% CI, 0.91-1.11)
      HIJ-PROPER20171734 with ACS on pitavastatinEzetimibe 10 mg/d3.9 y15% LDLNo (HR 0.70; 95% CI, 0.47-1.04)No (HR 0.89; 95% CI, 0.76-1.04)
      FOURIER201727,564 ASCVD LDL > 70 mg/dL on statinEvolocumab 140 mg q 2 wk or 420 mg/mo2.2 y59% LDLNo (HR 1.04; 95% CI, 0.91-1.19)Yes (HR 0.85; 95% CI, 0.79-0.92)
      REVEAL201730,449 ASCVD on atorvastatinAnacetrapib 100 mg/d4.1 y41% LDLNo (P = .46)Yes (RR 0.91; 95% CI, 0.85-0.97)
      EMPATHY20185042 diabetic retinopathyIntensive vs standard dose statin60 mo26% LDLNo (HR 1.21; 95% CI, 0.77-1.91)No (HR 0.84; 95% CI, 0.67-1.07)
      ODYSSEY201818,924 ACSAlirocumab 75-150 mg q 2 wk2.8 y55% LDLYes (HR 0.85, 95% CI, 0.73-0.98)Yes (HR 0.85; 95% CI, 0.78-0.93)
      ACCELERATE = Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes; ACS = acute coronary syndrome; AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes; ASCVD = atherosclerotic cardiovascular disease; ASPEN = Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus; AURORA = A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis—An Assessment of Survival and Cardiovascular Events; CCS = coronary calcium score; CHD = coronary heart disease; CI = confidence interval; CKD = chronic kidney disease; CORONA = Controlled Rosuvastatin in Multinational Trial in Heart Failure; CV = cardiovascular; CVD = cardiovascular disease; EMPATHY = Standard Versus Intensive Statin Therapy for Hypercholesterolemic Patients with Diabetic Retinopathy; ER = extended release; FIELD = Fenofibrate Intervention and Event Lowering in Diabetes; FOURIER = Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; GISSI-HF = Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca Heart Failure; HBP = high blood pressure; HDL = high-density lipoprotein; HF = heart failure; HIJ-PROPER = Heart Institute of Japan–Proper Level of Lipid Lowering with Pitavastatin and Ezetimibe in Acute Coronary Syndrome; HOPE-3 = Heart Outcomes Prevention Evaluation–3; HR = hazard ratio; HPS2-THRIVE = Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events; hsCRP = highly sensitive C-reactive protein; IDEAL = Incremental Decrease in End Points Through Aggressive Lipid Lowering; ILLUMINATE = Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events; IMPROVE-IT = Improved Reduction in Outcomes: Vytorin Efficacy International Trial; JUPITER = Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; LDL = low-density lipoprotein cholesterol; MCE = Minnesota Coronary Experiment; MEGA = Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; MI = myocardial infarction; NR = not reported; ODYSSEY = Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy; PUFA = polyunsaturated fatty acid; REVEAL = Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification; RinR = reduction in risk; RtR = rate ratio; RR = risk ratio; SDHS = Sydney Diet Heart Study; SEARCH = Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; SEAS = Simvastatin and Ezetimibe in Aortic Stenosis; SFA = saturated fatty acid; SHARP = Study of Heart and Renal Protection; SPARCL = Stroke Prevention by Aggressive Reduction in Cholesterol Levels; TC = total cholesterol; TNT = Treating to New Targets; T2DM = type 2 diabetes mellitus; WHI = Women's Health Initiative; 4D = Die Deutsche Diabetes Studie.
      low asterisk Defined as the primary endpoint of the trial unless specified otherwise.
      low asterisklow asterisk Admitted to hospital for cardiovascular reasons.
      # Reported among white subjects.
      § CHD death.

      Risk-Guided Lipid Therapy

      A corollary to the lipid hypothesis postulates that those individuals at highest cardiovascular risk are most likely to benefit from lipid-lowering therapy. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines advise calculating cardiovascular risk to identify high-risk primary prevention patients for whom lipid-lowering therapy is recommended while seeking to avoid treatment in low-risk individuals. In the YOUNG-MI registry, 51% of myocardial infarction patients would not have been eligible for primary prevention statin therapy based on these 2013 cholesterol guidelines, whereas 71% would not have been statin eligible based on the 2016 U.S. Preventive Services Task Force guidelines.
      • Singh A
      • Collins BL
      • Gupta A
      • et al.
      Cardiovascular risk and statin eligibility of young adults after an MI: partners YOUNG-MI registry.
      Conversely, 44% of subjects in the Multi-Ethnic Study of Atherosclerosis study that were classified as statin eligible based on the 2013 ACC/AHA guidelines had zero coronary calcium scores.
      • Nasir K
      • Bittencourt MS
      • Blaha MJ
      • et al.
      Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines. MESA.
      These studies and others challenge the validity of the risk-guided model.
      • DuBroff R
      Should statin therapy be guided by cardiovascular risk models?.

      Confirmation Bias and Conflict of Interest

      Clinicians often rely upon the opinions of lipid experts in the management of their patients. Unfortunately, some experts selectively cite evidence that validates their own opinion while disregarding or misrepresenting evidence to the contrary. This behavior is called confirmation bias and risks undermining the evidence-based approach to medicine.
      • DuBroff R
      Confirmation bias, conflicts of interest and cholesterol guidance: can we trust expert opinions? [e-pub ahead of print].
      Here are some examples.
      The 2014 AHA/ACC guideline on the management of non-ST-elevation acute coronary syndromes (NSTE-ACS) states, “Therapy with statins in patients with NSTE-ACS reduces the rate of recurrent myocardial infarction, coronary heart disease mortality, need for myocardial revascularization, and stroke.”
      • Amsterdam EA
      • Wenger NK
      • Brindis RG
      • et al.
      2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes.
      Not referenced in this guideline was the Cochrane meta-analysis of 18 RCTs of statins for acute coronary syndrome that reported no benefit in 14,303 patients.
      • Vale N
      • Nordmann AJ
      • Schwartz GG
      • et al.
      Statins for acute coronary syndrome.
      Similarly, the National Lipid Association Statin Diabetes Safety Task Force concluded that the cardiovascular benefits of statin therapy outweigh the modest risk of developing diabetes.
      • Maki KC
      • Ridker PM
      • Brown WV
      • Grundy SM
      • Sattar N
      An assessment by the Statin Diabetes Safety Task Force: 2014 update.
      By reviewing only short-term statin studies, they overlooked the impact of long-term exposure. Omitted from their analysis was a British study reporting a 363% increased risk of diabetes after 15-20 years of statin treatment.
      • Macedo AF
      • Douglas I
      • Smeeth L
      • et al.
      Statins and the risk of type 2 diabetes mellitus: cohort study using the UK clinical practice research datalink.
      The American Diabetes Association recommends statins for most adults with diabetes because “trials in patients with diabetes (41,42) showed significant primary and secondary prevention of atherosclerotic cardiovascular disease events and coronary heart disease death in patients with diabetes.”
      American Diabetes Association
      Cardiovascular disease and risk management.
      Within the quotation, reference 41 is the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus study, an RCT of atorvastatin that actually reported no mortality or cardiovascular benefit.
      • Knopp RH
      • d'Emden M
      • Smilde JG
      • Pocock SJ
      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).
      Financial conflicts of interest also demonstrably influence physician behavior.
      • Orlowski JP
      • Wateska L
      The effects of pharmaceutical firm enticements on physician prescribing patterns.
      In 1 survey, 71% of clinical policy committee chairs and 90.5% of co-chairs had financial conflicts.
      • Kung J
      • Miller RR
      • Mackowiak PA
      Failure of clinical practice guidelines to meet Institute of Medicine standards: two more decades of little, if any, progress.
      In 2009, the Institute of Medicine issued recommendations intended to limit the undue influence of industry on physicians.
      • Steinbrook R
      Controlling conflict of interest—proposals from the Institute of Medicine.
      These proposals include restricting physicians with financial conflicts from participating in guideline panels as well as participating in human research. Years later, little progress has been made, and one can only speculate as to whether financial conflicts may have influenced current lipid recommendations.
      • Lenzer J
      Why we can't trust clinical guidelines.
      • Johnston L
      Scandal of experts who rule on NHS statins but get paid by drug firms.

      Unintended Consequences

      Promoting foods that are low in cholesterol but typically high in refined carbohydrates is supposed to help prevent coronary heart disease. Paradoxically, there is now evidence that these dietary changes have contributed to the epidemic of diabetes that can actually lead to coronary heart disease.
      • Gross LS
      • Li L
      • Ford ES
      • Liu S
      Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment.
      Furthermore, some statin users mistakenly believe they can eat whatever they want, leading to the phenomenon of statin gluttony.
      • Sugiyama T
      • Tsugawa Y
      • Tseng C-H
      • Kobayashi Y
      • Shapiro MF
      Is there gluttony in the time of statins?.
      Consider also that the recent expansion of statin indications may result in millions of healthy individuals being treated because of a risk score even though they may be at extremely low risk of coronary heart disease.
      • Nasir K
      • Bittencourt MS
      • Blaha MJ
      • et al.
      Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines. MESA.

      Final Thoughts

      LDL-C is considered the primary constituent of atherosclerotic plaque. Therefore, it stands to reason that lowering serum LDL-C should prevent cardiovascular disease. Three decades of RCTs, however, have yielded inconsistent and contradictory results. We must acknowledge these anomalies and either modify or reject the lipid hypothesis. Clearly, some individuals do benefit from lipid-modifying therapy. I believe the real question is how to identify them. Our current approach of focusing almost exclusively on lowering LDL-C for everyone does not consistently work, may result in unnecessary treatment of some healthy individuals, and likely reflects the fact that the pathogenesis of atherosclerosis is far more complex than originally thought. Our LDL-C-centric approach to cardiovascular disease prevention may have distracted us from investigating other pathophysiologic mechanisms and treatments. Last, we should not ignore the benefits of a healthy lifestyle. Although changing our patients’ lifestyle is more difficult than prescribing a pill, the benefits are far more robust.
      • Chiuve SE
      • Fung TT
      • Rexrode KM
      • et al.
      Adherence to a low-risk healthy lifestyle and risk of sudden cardiac death among women.

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