LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature

References

• Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532–2561.
   PubMed Web of Science ®Google Scholar
• Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: systematic review and meta-analysis. JAMA. 2016;316:1289–1297.
   PubMed Web of Science ®Google Scholar
• 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. Eur Heart J. 2017;38:2459–2472.
   PubMed Web of Science ®Google Scholar
• Landé KE, Sperry WM. Human atherosclerosis in relation to the cholesterol content of the blood serum. Arch Pathol. 1936;22:301–312.
   Google Scholar
• Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM. 2002;95:397–403.
   PubMed Web of Science ®Google Scholar
• Solberg LA, Hjermann I, Helgeland A, et al. Association between risk factors and atherosclerotic lesions based on autopsy findings in the Oslo study: a preliminary report. In: Schettler G, Goto Y, Hata Y, et al., editors. Atherosclerosis IV. proc 4. int. symp. Berlin: Springer Verlag; 1977. p. 98–100.
   Google Scholar
• Anderson KM, Castelli WP, Levy D. Cholesterol and mortality. 30 years of follow-up from the framingham study. JAMA. 1987;257:2176–2180.
   PubMed Web of Science ®Google Scholar
• LaRosa JC, Hunninghake D, Bush D, et al. The cholesterol facts. A summary of the evidence relating dietary fats, serum cholesterol, and coronary heart disease. A joint statement by the American heart association and the national heart, lung, and blood institute. Circulation. 1990;81:1721–1733.
   PubMed Web of Science ®Google Scholar
• Kannel WB, Doyle JT, Ostfeld AM, et al. Optimal resources for primary prevention of atherosclerotic diseases. Atherosclerosis study group. Circulation. 1984;70:157A–205A.
   Web of Science ®Google Scholar
• National Research Council Diet and Health. Implications for reducing chronic disease risk. Washington, DC: National Academy Press; 1989.
   Google Scholar
• Ravnskov U. Quotation bias in reviews of the diet-heart idea. J Clin Epidemiol. 1995;48:713–719.
   PubMed Web of Science ®Google Scholar
• Ravnskov U. High cholesterol may protect against infections and atherosclerosis. QJM. 2003;96:927–934.
   PubMed Web of Science ®Google Scholar
• Ulmer H, Kelleher C, Diem G, et al. Why Eve is not adam: prospective follow-up in 149650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality. J Womens Health. 2004;13:41–53.
   PubMed Web of Science ®Google Scholar
• Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet. 2007;370:1829–1839.
   PubMed Web of Science ®Google Scholar
• Okuyama H, Hamazaki T, Ogushi Y. New cholesterol guidelines for longevity (2010). World Rev Nutr Diet. 2011;102:124–136.
   PubMedGoogle Scholar
• Hecht HS, Superko HR. Electron beam tomography and national cholesterol education program guidelines in asymptomatic women. J Am Coll Cardiol. 2001;37:1506–1511.
   PubMed Web of Science ®Google Scholar
• Fernández-Friera L, Fuster V, López-Melgar B, et al. Normal LDL-cholesterol levels are associated with subclinical atherosclerosis in the absence of risk factors. JACC. 2017;70:2979–2991.
   Google Scholar
• Dimsdale JE, Herd A. Variability of plasma lipids in response to emotional arousal. Psychosom Med. 1982;44:413–430.
   PubMed Web of Science ®Google Scholar
• Rosenman RH. Relationships of neurogenic and psychological factors to the regulation and variability of serum lipids. Stress Med. 1993;9:133–140.
   Google Scholar
• Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in get with the guidelines. Am Heart J. 2009;157:111–117.
   PubMed Web of Science ®Google Scholar
• Al-Mallah MH, Hatahet H, Cavalcante JL, et al. Low admission LDL-cholesterol is associated with increased 3-year all-cause mortality in patients with non-ST segment elevation myocardial infarction. Cardiol J. 2009;16:227–233.
   PubMed Web of Science ®Google Scholar
• Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci. 2009;39:3–16.
   PubMed Web of Science ®Google Scholar
• Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Am J Med Sci. 2012;344:391–394.
   PubMed Web of Science ®Google Scholar
• Ravnskov U, Rosch PJ, McCully KS. The statin-low cholesterol-cancer conundrum. QJM. 2012;105:383–388.
   PubMed Web of Science ®Google Scholar
• Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:3030–3044.
   PubMed Web of Science ®Google Scholar
• Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016;6:e010401.
   PubMed Web of Science ®Google Scholar
• Bathum L, Depont Christensen R, Engers Pedersen L, et al. Association of lipoprotein levels with mortality in subjects aged 50+ without previous diabetes or cardiovascular disease: a population-based register study. Scand J Prim Health Care. 2013;31:172–180.
   PubMed Web of Science ®Google Scholar
• Hamazaki T, Okuyama H, Ogushi Y, et al. Towards a paradigm shift in cholesterol treatment. A re-examination of the cholesterol issue in Japan. Ann Nutr Metab. 2015;66(suppl 4):1–116.
   PubMedGoogle Scholar
• Burgess S, Timpson NJ, Ebrahim S, et al. Mendelian randomization: where are we now and where are we going? Int J Epidemiol. 2015;44:379–388.
   PubMed Web of Science ®Google Scholar
• West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998;97:1440–1445.
   PubMed Web of Science ®Google Scholar
• Sacks FM, Moyé LA, Davis BR, et al. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the cholesterol and recurrent events trial. Circulation. 1998;97:1446–1452.
   PubMed Web of Science ®Google Scholar
• Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711–1718.
   PubMed Web of Science ®Google Scholar
• Cordoba G, Schwartz L, Woloshin S, et al. Definition, reporting and interpretation of composite outcomes in clinical trials: systematic review. BMJ. 2010;341:c3920.
   PubMed Web of Science ®Google Scholar
• Diamond DM, Ravnskov U. How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease. Expert Rev Clin Pharmacol. 2015;8:201–210.
   PubMed Web of Science ®Google Scholar
• Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland coronary prevention study group. N Engl J Med. 1995;333:1301–1307.
   PubMed Web of Science ®Google Scholar
• Downs JR, 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. JAMA. 1998;279:1615–1622.
   PubMed Web of Science ®Google Scholar
• Sever PS, Dahlof B, Poulter NR, 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. Lancet. 2003;361:1149–1158.
   PubMed Web of Science ®Google Scholar
• Colhoun HM, Betteridge DJ, Durrington PN, 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. Lancet. 2004;364:685–696.
   PubMed Web of Science ®Google Scholar
• Nakamura H, Arakawa K, Itakura H, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA study): a prospective randomised controlled trial. Lancet. 2006;368:1155–1163.
   PubMed Web of Science ®Google Scholar
• Knopp RH, d’Emden M, Smilde JG, 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). Diabetes Care. 2006;29:1478–1485.
   PubMed Web of Science ®Google Scholar
• Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207.
   PubMed Web of Science ®Google Scholar
• Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374:2021–2031.
   PubMed Web of Science ®Google Scholar
• Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in. 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet. 1994;344:1383–1389.
   PubMed Web of Science ®Google Scholar
• Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. cholesterol and recurrent events trial investigators. N Engl J Med. 1996;335:1001–1009.
   PubMed Web of Science ®Google Scholar
• The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med. 1997;336:153–162.
   PubMed Web of Science ®Google Scholar
• Tonkin A, Alyward P, Colquhoun D, et al. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–1357.
   PubMed Web of Science ®Google Scholar
• GISSI Prevenzione Investigators. Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico). Ital Heart J. 2000;1:810–820.
   PubMedGoogle Scholar
• Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;287:3215–3222.
   PubMed Web of Science ®Google Scholar
• 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. Lancet. 2002;360:7–22.
   PubMedGoogle Scholar
• Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with atorvastatin to the national cholesterol educational program goal versus ‘usual’ care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;18:220–228.
   PubMed Web of Science ®Google Scholar
• Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–1630.
   PubMed Web of Science ®Google Scholar
• The Allhat Officers and. Coordinators for the ALLHAT collaborative research group. 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). JAMA. 2002;288:2998–3007.
   PubMed Web of Science ®Google Scholar
• Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–1504.
   PubMed Web of Science ®Google Scholar
• de Lemos JA, Blazing MA, Wiviott SD et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292:1307–1316.
   PubMed Web of Science ®Google Scholar
• Koren MJ, Hunninghake DB. ALLIANCE investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the ALLIANCE study. J Am Coll Cardiol. 2004;44:1772–1779.
   PubMed Web of Science ®Google Scholar
• LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–1435.
   PubMed Web of Science ®Google Scholar
• Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437–2445.
   PubMed Web of Science ®Google Scholar
• Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549–559.
   PubMed Web of Science ®Google Scholar
• Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) 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. Lancet. 2010;376:1658–1669.
   PubMed Web of Science ®Google Scholar
• Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med. 1991;151:43–49.
   PubMed Web of Science ®Google Scholar
• Dujovne CA, Chremos AN, Pool JL, et al. Expanded clinical evaluation of lovastatin (EXCEL) study results: IV. Additional perspectives on the tolerability of lovastatin. Am J Med. 1991;91:25S–30S.
   PubMed Web of Science ®Google Scholar
• Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238–248. Erratum in: N Engl J Med 2005;353:1640
   PubMed Web of Science ®Google Scholar
• Strandberg TE, Pitkala KH, Berglind S, et al. Multifactorial intervention to prevent recurrent cardiovascular events in patients 75 years or older: the Drugs and Evidence-Based Medicine in the Elderly (DEBATE) study: a randomized, controlled trial. Am Heart J. 2006;152:585–592.
   PubMed Web of Science ®Google Scholar
• Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248–2261.
   PubMed Web of Science ®Google Scholar
• Deedwania P, Stone PH, Bairey Merz CN, et al. Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE). Circulation. 2007;115:700–707.
   PubMed Web of Science ®Google Scholar
• Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–1356.
   PubMed Web of Science ®Google Scholar
• Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1231–1239.
   PubMed Web of Science ®Google Scholar
• Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395–1407. Erratum in: N Engl J Med. 2010;362:1450.
   PubMed Web of Science ®Google Scholar
• Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–2397.
   PubMed Web of Science ®Google Scholar
• Cholesterol Treatment Trialists’ (CTT) 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. Lancet. 2015;385:1397–1405.
   Google Scholar
• Kristensen ML, Christensen PM, Hallas J. The effect of statins on average survival in randomised trials, an analysis of end point postponement. BMJ Open. 2015;5:e007118.
   PubMed Web of Science ®Google Scholar
• de Lorgeril M, Rabaeus M. Beyond confusion and controversy, can we evaluate the real efficacy and safety of cholesterol-lowering with statins? J Controvers Biomed Res. 2015;1:67–92.
   Google Scholar
• Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:581–585.
   PubMed Web of Science ®Google Scholar
• Sinzinger H, O’Grady J. Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems. Br J Clin Pharmacol. 2004;57:525–528.
   PubMed Web of Science ®Google Scholar
• Okuyama H, Langsjoen PH, Hamazaki T, et al. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert Rev Clin Pharmacol. 2015;8:189–199.
   PubMed Web of Science ®Google Scholar
• Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ. 2010;340:c2197.
   PubMed Web of Science ®Google Scholar
• Chung SD, Chen CH, Hung SH, et al. A population-based study on the association between statin use and sudden sensorineural hearing loss. Otolaryngol Head Neck Surg. 2015;152:319–325.
   PubMed Web of Science ®Google Scholar
• Davison KM, Kaplan BJ. Lipophilic statin use and suicidal ideation in a sample of adults with mood disorders. Crisis. 2014;35:278–282.
   PubMedGoogle Scholar
• Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy: a case-control study. Neurology. 2002;58:1333–1337.
   PubMed Web of Science ®Google Scholar
• Kang JH, Kao LT, Lin HC, et al. Statin use increases the risk of depressive disorder in stroke patients: a population-based study. J Neurol Sci. 2015;348:89–93.
   PubMed Web of Science ®Google Scholar
• Huang X, Alonso A, Guo X, et al. Statins, plasma cholesterol, and risk of Parkinson’s disease: a prospective study. Mov Disord. 2015;30:552–559.
   PubMed Web of Science ®Google Scholar
• Huang CY, Chung SD, Kao LT, et al. Statin use Is associated with bladder pain syndrome/interstitial cystitis: a population-based case-control study. Urol Int. 2015;95:227–232.
   PubMed Web of Science ®Google Scholar
• Antoniou T, Zheng H, Singh S, et al. Statins and the risk of herpes zoster: a population-based cohort study. Clin Infect Dis. 2014;58:350–356.
   PubMed Web of Science ®Google Scholar
• Solomon H, Samarasinghe YP, Feher MD, et al. Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int J Clin Pract. 2006;60:141–145.
   PubMed Web of Science ®Google Scholar
• Evans MA, Golomb BA. Statin-associated adverse cognitive effects: survey results from 171 patients. Pharmacotherapy. 2009;29:800–811.
   PubMed Web of Science ®Google Scholar
• Padala KP, Padala PR, McNeilly DP, et al. The effect of HMG-CoA reductase inhibitors on cognition in patients with Alzheimer’s dementia: a prospective withdrawal and rechallenge pilot study. Am J Geriatr Pharmacother. 2012;10:296–302.
   PubMedGoogle Scholar
• Muldoon MF, Barger SD, Ryan CM, et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med. 2000;108:538–546.
   PubMed Web of Science ®Google Scholar
• Muldoon MF, Ryan CM, Sereika SM, et al. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med. 2004;117:823–829.
   PubMed Web of Science ®Google Scholar
• Cederberg H, Stančáková A, Yaluri N, et al. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia. 2015;58:1109–1117.
   PubMed Web of Science ®Google Scholar
• Mansi I, Frei CR, Wang CP, et al. Statins and new-onset diabetes mellitus and diabetic complications: a retrospective cohort study of US healthy adults. J Gen Intern Med. 2015;30:1599–1610.
   PubMed Web of Science ®Google Scholar
• Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA. 1996;275:55–60.
   PubMed Web of Science ®Google Scholar
• Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722.
   PubMed Web of Science ®Google Scholar
• Scientific steering committee on behalf of the simon broome register group. Risk of fatal coronary heart disease in familial hypercholesterolaemia. BMJ. 1991;303:893–896.
   PubMed Web of Science ®Google Scholar
• Mundal L, Sarancic M, Ose L, et al. Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 1992–2010. JAMA. 2014;3:e001236.
   Google Scholar
• Seed M, Hoppichler F, Reaveley D, et al. Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med. 1990;322:1494–1499.
   PubMed Web of Science ®Google Scholar
• Wiklund O, Angelin B, Olofsson SO, et al. Apolipoprotein(a) and ischaemic heart disease in familial hypercholesterolaemia. Lancet. 1990;335:1360–1363.
   PubMed Web of Science ®Google Scholar
• Vuorio AF, Turtola H, Piilahti KM, et al. Familial hypercholesterolemia in the finnish north Karelia. A molecular, clinical, and genealogical study. Arterioscler Thromb Vasc Biol. 1997;17:3127–3138.
   PubMed Web of Science ®Google Scholar
• Wittekoek ME, de Groot E, Prins MH, et al. Differences in intima-media thicknessin the carotid and femoral arteries in familial hypercholesterolemic heterozygotes with and without clinical manifestations of cardiovascular disease. Atherosclerosis. 1999;146:271–279.
   PubMed Web of Science ®Google Scholar
• Smilde TJ, Trip MD, Wollersheim H, et al. Rationale, design and baseline characteristics of a clinical trial comparing the effects of robust vs conventional cholesterol lowering and intima media thickness in patients with familial hypercholesterolaemia: the atorvastatin versus simvastatin on atherosclerosis progression (ASAP) study. Clin Drug Investig. 2000;20:67–79.
   PubMed Web of Science ®Google Scholar
• Cenarro A, Artieda M, Castillo S, et al. A common variant in the ABCA1 gene is associated with a lower risk for premature coronary heart disease in familial hypercholesterolaemia. J Med Genet. 2003;40:163–168.
   PubMed Web of Science ®Google Scholar
• Harlan WR, Graham JB, Estes EH. Familial hypercholesterolemia: a genetic and metabolic study. Medicine. 1966;45:77–110.
   Web of Science ®Google Scholar
• Nilsson S, Mölstad S, Karlberg C, et al. No connection between the level of exposition to statins in the population and the incidence/mortality of acute myocardial infarction: an ecological study based on Sweden’s municipalities. J Negat Results Biomed. 2011;10:6.
   PubMedGoogle Scholar
• Kuklina EV, Yoon PW, Keenan NL. Trends in high levels of low-density lipoprotein cholesterol in the United States, 1999–2006. JAMA. 2009;302:2104–2110.
   PubMed Web of Science ®Google Scholar
• Vancheri F, Backlund L, Strender LE, et al. Time trends in statin utilisation and coronary mortality in Western European countries. BMJ Open. 2016;6:e010500.
   PubMed Web of Science ®Google Scholar
• Okuyama H, Hamazaki T, Hama R, et al. A critical review of the consensus statement from the European atherosclerosis society consensus panel 2017. Pharmacology. 2018;101:184–218.
   PubMed Web of Science ®Google Scholar
• Vallejo-Vaz AJ, Robertson M, Catapano AL, et al. LDL-cholesterol lowering for the primary prevention of cardiovascular disease among men with primary elevations of LDL-cholesterol levels of 190 mg/dL or above: analyses from the WOSCOPS 5-year randomised trial and 20-year observational follow-up. Circulation. 2017;136:1878–1891.
   PubMed Web of Science ®Google Scholar
• Ravnskov U, Okuyama H, Sultan S. Serious bias in 20 year follow-up study of statin trial. BMJ. 2017;359:j4906.
   PubMedGoogle Scholar