The Cholesterol Wars: The Skeptics vs the Preponderance of Evidence 1st Edition

Steinberg at the beginning mentions "exaggerated skepticism" and "totality of the evidence". The suggestion is that those who do not believe in the lipid hypothesis were overly cautious and have not looked at the totality of the evidence, which is not true at all. One has to keep high standards, but not so high as to stifle the growth of knowledge. On the other hand, standards cannot be so low such that almost anything goes, which is the case with Steinberg. He is rarely critical of anything that seems to support his case even if it may be of poor quality, but is critical of anything that he does not agree with.

Steinberg starts with the animal evidence where there is the obvious problem of extrapolating the evidence to humans, which he realizes. There have been numerous studies in a variety of animal models using a variety of treatments that show major reductions in atherosclerosis that are independent of cholesterol, and even in the presence of severe hypercholesterolemia (1). What this shows is that the amount of damage caused by increased cholesterol levels in animal models depends strongly on the conditions under which it is placed. It is not as simple as similar cholesterol levels implying similar atherosclerosis, or higher cholesterol levels implying greater atherosclerosis. It should be noted also that hypercholesterolemia induces oxidative stress and other factors in these models (which can be reduced without reducing cholesterol), so it is not a case of simply having high cholesterol levels. This is the most that can be said without drifting into speculation about mechanisms.

Observationally, the total/HDL ratio seems to be the most reliable predictor of cardiovascular outcomes. In the elderly, the relation between total cholesterol, LDL cholesterol, and cardiovascular events is inconsistent and much less clearer (2-6). Of course, it does not mean that these associations are causal. For example, HDL-C is one of the most robust predictors of CV events (admitted by Steinberg), and many researchers naively thought that such relation was probably causal, but today the trial evidence says otherwise and researchers are now claiming that HDL function is important. In other words, let's not forget that correlation does not imply causation.

It is amazing to see how Steinberg dismisses the low cholesterol-high mortality relation as not causal, but readily accepts any high-cholesterol relations as being casual without any criticism. Nevertheless, he cites one study which apparently (it's speculation) supports his claim, while ignoring other studies saying otherwise. For example, he could have cited the later Honolulu Heart Program (7) which referred to the very study Steinberg cites. The authors based on their data explicitly stated that the Iribarren hypothesis was "implausible", and even found an "inverse trend" between cholesterol and CV mortality. This is not by any means an isolated finding, as numerous large studies (8-18) have repeatedly confirmed what is found in reviews (19-21). Dismissing this relation is even more absurd when one considers that there is little benefit to be gained from lowering cholesterol, contrary to what Steinberg will have you believe.

With regard to the trial evidence, Steinberg cites some early dietary trials to support his case, but leaves out some important facts:

To anyone who has read the Oslo Diet Heart Study (22), would realize this involved massive dietary changes. The experimental group increased their EPA/DHA and vitamin D intake through seafood and cod liver oil, reduced their intake of trans fat dramatically, increased their nut, fruit, vegetable intake and restricted their intake of refined grains and sugar. Yet Steinberg ignores all this and claims that it was the drop in cholesterol level that was responsible for the protective effect. With regard to all-cause mortality Steinberg claims that a larger number of subjects would be needed to find a statistically significant decrease in all-cause mortality. A better explanation for the lack of a larger difference in mortality was the excessive intake of omega-6 consumption in the intervention group.

Steinberg to his credit realizes that the primary endpoint of the LA Veterans was not statistically significant (23). The only statistically significant result was a post-hoc pooled endpoint. Despite no significant difference in the primary endpoint including CHD death and total mortality, Steinberg states that it "stands as one of the most important and persuasive studies of the prestatin era". Even if it were successful it would not have provided evidence for cholesterol lowering since there was a combination of confounders in favor of the experimental group such as less heavy smokers, less trans fat, higher n-3 intake, and higher vitamin E status.

Steinberg goes on to cite the Finnish Mental Hospitals Study, and contrary to what he says, it is in fact one of the worst dietary trials ever conducted. In fact, some meta-analyses exclude it because of its inappropriate design (never to be seen again) and large confounding (24, 25). He also attempts to dismiss the Minnesota CS trial (26) because of its short duration which he would have no doubt accepted if the result had went his way. Nevertheless, despite its short duration, the Minnesota CS actually provided a large number of events, and the overall analysis found no reduction whatsoever in CHD or mortality events. In fact, there were non-significantly more CHD events and overall deaths in the lower cholesterol group suggesting that maybe it is a good thing the trial was not longer, since these results are consistent with longer studies employing a similar intervention (omega-6 rich oils) suggesting even larger increases in CHD events and mortality (27, 28). So its likely that if the study was longer it would have ended up in disaster, not benefit as Steinberg seems to believe.

There are other trials cited by Steinberg which don't make much sense. For example, Steinberg cites the non-randomized/non-blinded Anti-Coronary Club (29) which not only employed multiple interventions, but also found a greater number of deaths from all causes and deaths from CHD in the lower cholesterol group. Of course, imbalances between the groups could have played a part in such a non-randomized study, but it is absurd to claim a result as "positive" when there are more deaths in the intervention group. This should not be dismissed, as we are talking about total mortality, which is the most reliable endpoint in any study, especially in a non-blinded trial. Nevertheless, Steinberg rightly acknowledges that the study was "seriously flawed". In the Medical Research Council (30), which Steinberg rightly calls a "negative study" there were non-significant differences between the groups, including strikingly similar rates in the harder endpoints of CHD/CVD/overall death. Steinberg also claims that the St. Vincent's Hospital study was "a case-control study, not a randomized trial", but fails to mention that it did originally have a randomized comparison with five years follow-up. Maybe Steinberg does not mention this better controlled comparison because the results were not in accord with his beliefs (92).

What we have then is a multitude of negative trials: La Veterans (23), Medical Research Council (30), Minnesota CS (26), Rose Corn Oil Trial (32), Sydney Diet-Heart Study (28), DART fat arm (31), WHI (33), St. Vincent's Hospital Study (92), and the Research Committee low-fat trial (34). In fact, if some of the better controlled fat replacement trials ("modified fat intake") are pooled in an analysis (23,26,28,30,32,90), there is a non-significant 5% increase in total mortality for unsaturated diets (91). In others words, the evidence from dietary trials does not support Steinberg, and in reality argues against his position. This is even clearer when one considers that many of these trials may have had confounders that favored the lower cholesterol groups e.g. less trans fat, less processed foods. Steinberg should also take note that the most successful dietary trials ever conducted had little to no reductions in cholesterol levels (in comparison to the control group of course), and achieved benefits in short time, suggesting together with the negative trials, that reductions in cholesterol are irrelevant (31, 35-37).

Speaking of the LRC-CPPT trial (38), Steinberg claims that the use of the one-tailed test was appropriate. However, the issue here is not really a one-tailed test, but the fact that it was never prespecified and used such a low standard (one-tailed at 0.05 rather than 0.025). Using conventional statistics, the primary endpoint of the trial was not statistically significant, and the decrease in CHD death was nowhere near statistical significance including no decrease in the objective endpoint of total mortality. Also, although less studied than other drugs, resins may actually have pleiotropic effects (39-42). Despite all of this Steinberg somehow finds the results convincing as evidence to lower cholesterol. Steinberg also mentions the POSCH trial (43), but nowhere does he mention that the surgery resulted in weight loss (among other effects), already recognized by others (44), and neither does he mention that the results were not statistically significant at the formal end and instead cites an observational follow-up.

Steinberg apparently thinks that fibrates and niacin are effective drugs even though fibrates fail to lower CHD/CV mortality and total mortality (45,46,93), and niacin fails to lower these same endpoints (47-50,93). This is despite the fact that these drugs "improve" numerous lipid markers and also have pleiotropic effects. Claiming that niacin in the Coronary Drug Project (48) was a success is ridiculous, since there was no reduction in its primary endpoint of total mortality including CHD/CV mortality at the end of the formal trial, which is all you really need to know. Instead, Steinberg cherry-picks a few lesser important secondary endpoints, and an observational follow-up, which is problematic as already pointed out by others (51,52). Other drugs that lower cholesterol have also failed miserably such as hormones (53-58), CETP inhibitors (59-61,93), and ezetimibe (99). Note carefully: fibrates, niacin, hormones, resins, CETP (and sPLA2) inhibitors, and ezetimibe, all fail to reduce CHD/CV death and total mortality despite "favorable effects" on cholesterol markers.

What about statins? In the section about statins Steinberg asks: Is the effect of the statins on coronary event rates all due to the extent to which they lower LDL? Or do their so-called pleiotropic effects (i.e. effects independent of cholesterol lowering) also play a significant role? The implication with these questions is that the pleiotopic effects may be responsible for only part (not all) of the benefits. The problem is that Steinberg (or anyone) has never proved that the benefits of statins are due to LDL lowering per se in the first place, and so there is the third possibility that the pleiotropic effects are responsible for all the benefits.

Even though the modest benefits of statins are probably due to its pleiotropic effects, the so called benefits of statins are without doubt, greatly exaggerated. Steinberg states that "The 4S study showed, for the first time in any cholesterol-lowering trial, a significant decrease in all-cause mortality". What Steinberg does not mention is that this is also the last time such a reduction in mortality was seen. The trial has never been replicated, was stopped based on an interim analysis, and had major conflicts of interest (62). The mortality reduction seen in LIPID (63) was not seen in a similar population in CARE (64), the latter being the better designed study, and HPS (65) failed to report results for all groups involved (factorial design), and claimed mortality benefits for numerous subgroups, which was not confirmed in later studies.

There is controversy with regard to statin use in primary prevention, and meta-analyses only show mortality reductions of around 10%, some not statistically significant. Also, without going into detail, most of these studies are of poor quality, resulting in uncertainty as to whether statins should be used this population (66,67).

Statins have also failed to lower mortality in the elderly (68), failed to lower CHD/CV death and total mortality in hypertensive patients (69,70), failed to lower coronary events, CV/cardiac death, and total mortality in heart failure patients (71,72), failed to lower CHD death, CV/cardiac death, and total mortality in kidney patients (73-76), failed to lower CV death and total mortality in aortic stenosis patients (77), failed to lower CV/cardiac death and total mortality in stroke patients (78), failed to lower CV events, CHD/CV mortality and total mortality in diabetic patients (73, 79-82), and have failed to lower CHD death and total mortality in secondary prevention patients using intensive treatment (83,84).

In short, even with all the "favorable effects" of statins, both lipid and non-lipid (pleiotropic), these drugs are next to useless. Of course, corruption and a lack of transparency are major problems in the pharmaceutical industry (94-98), and another reason why one should not place too much weight on such research, especially the earlier statin trials (88,89).

One other thing you would notice from those supporting cholesterol lowering (including Steinberg) is that they often refer to non-randomized analyses e.g. a graph of many studies apparently showing that the greater the reduction in cholesterol the greater the reduction in risk, or analyses claiming that "each 1 mmol/L reduction in LDL...". Do not be fooled by this, as these analyses are non-randomized and inevitably problematic, as already pointed out by researchers before (85,86). What you have to look at is the randomized comparison, which is the whole purpose trials are set up in the first place.

In the end, there is no "preponderance of evidence", and to support Steinberg's view you have to selectively cite the evidence, selectively interpret the evidence, and create a bunch of unproven ad hoc hypotheses to explain away a massive amount of the data. You get the impression that in Steinberg's mind, cholesterol was already guilty before he reviewed the evidence, and he interprets the evidence based on this belief rather than looking at the evidence objectively. Given the utter failure of cholesterol lowering treatments to lower CHD/CV mortiality and total mortality in almost every study, maybe it is really time for a reappraisal of the idea that cholesterol is to blame (87-89).

As another reviewer stated, most of the information in this book is already available in Steinberg's Thematic review series available on the net for free. If you decide to get this book be sure to pick up other books for balance: my recommendations would be "The Great Cholesterol Con" by Anthony Colpo, "Cholesterol is Not the Culprit: A Guide to Preventing Heart Disease" by Fred Kummerow, and "Cholesterol and statins: Sham science and bad medicine" by Michel de Lorgeril.

References

1) https://drive.google.com/file/d/0B-PNpZO95GCUYjVQZTJTOU9IbkE/view?usp=sharing
2) Lewington S, Whitlock G, Clarke R, et al. 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(9602):1829-39.
3) Petersen LK, Christensen K, Kragstrup J. Lipid-lowering treatment to the end? A review of observational studies and RCTs on cholesterol and mortality in 80+-year olds. Age Ageing. 2010;39(6):674-80.
4) Anum EA, Adera T. Hypercholesterolemia and coronary heart disease in the elderly: a meta-analysis. Ann Epidemiol. 2004;14 (9):705-21.
5) Nagasawa SY, Okamura T, Iso H, et al. Relation between serum total cholesterol level and cardiovascular disease stratified by sex and age group: a pooled analysis of 65 594 individuals from 10 cohort studies in Japan. J Am Heart Assoc. 2012;1 (5):e001974.
6) Manolio TA, Pearson TA, Wenger NK, Barrett-connor E, Payne GH, Harlan WR. Cholesterol and heart disease in older persons and women. Review of an NHLBI workshop. Ann Epidemiol. 1992;2(1-2):161-76.
7) Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet. 2001;358(9279):351-5.
8) Bae JM, Yang YJ, Li ZM, Ahn YO. Low cholesterol is associated with mortality from cardiovascular diseases: a dynamic cohort study in Korean adults. J Korean Med Sci. 2012;27(1):58-63.
9) Nago N, Ishikawa S, Goto T, Kayaba K. Low cholesterol is associated with mortality from stroke, heart disease, and cancer: the Jichi Medical School Cohort Study. J Epidemiol. 2011;21(1):67-74.
10) Iso H, Naito Y, Kitamura A, et al. Serum total cholesterol and mortality in a Japanese population. J Clin Epidemiol. 1994;47(9):961-9.
11) Petursson H, Sigurdsson JA, Bengtsson C, Nilsen TI, Getz L. Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the Norwegian HUNT 2 study. J Eval Clin Pract. 2012;18(1):159-68.
12) Bathum L, Depont christensen R, Engers pedersen L, Lyngsie pedersen P, Larsen J, Nexøe J. 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(3):172-80.
13) Ulmer H, Kelleher C, Diem G, Concin H. 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 (Larchmt). 2004;13(1):41-53.
14) Noda H, Iso H, Irie F, Sairenchi T, Ohtaka E, Ohta H. Gender difference of association between LDL cholesterol concentrations and mortality from coronary heart disease amongst Japanese: the Ibaraki Prefectural Health Study. J Intern Med. 2010;267(6):576-87.
15) Song YM, Sung J, Kim JS. Which cholesterol level is related to the lowest mortality in a population with low mean cholesterol level: a 6.4-year follow-up study of 482,472 Korean men. Am J Epidemiol. 2000;151(8):739-47.
16) Matsuzaki M, Kita T, Mabuchi H, et al. Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia. Circ J. 2002;66(12):1087-95.
17) Casiglia E, Mazza A, Tikhonoff V, Scarpa R, Schiavon L, Pessina AC. Total cholesterol and mortality in the elderly. J Intern Med. 2003;254(4):353-62.
18) Newson RS, Felix JF, Heeringa J, Hofman A, Witteman JC, Tiemeier H. Association between serum cholesterol and noncardiovascular mortality in older age. J Am Geriatr Soc. 2011;59(10):1779-85.
19) Jacobs D, Blackburn H, Higgins M, et al. Report of the Conference on Low Blood Cholesterol: Mortality Associations. Circulation. 1992;86(3):1046-60.
20) Kirihara Y, et al. The Relationship between Total Blood Cholesterol Levels and All-cause Mortality in Fukui City, and Meta-analysis of This Relationship in Japan. Journal of Lipid Nutrition, 2008; 17 (1): 67-78.
21) Simes RJ. Low cholesterol and risk of non-coronary mortality. Aust N Z J Med. 1994;24(1):113-9.
22) Leren P. The effect of plasma-cholesterol-lowering diet in male survivors of myocardial infarction. A controlled clinical trial. Bull N Y Acad Med. 1968;44(8):1012-20.
23) Dayton S, Pearce ML, Hashimoto S, Dixon WJ, Tomiyasu U. A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation. 1969;40(suppl II):1-63.
24) Ramsden CE, Hibbeln JR, Majchrzak SF, Davis JM. n-6 fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials. Br J Nutr. 2010;104(11):1586-600.
25) Hooper L, Summerbell CD, Thompson R, et al. Reduced or modified dietary fat for preventing cardiovascular disease. Cochrane Database Syst Rev. 2012;5:CD002137.
26) Frantz ID, Dawson EA, Ashman PL, et al. Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey. Arteriosclerosis. 1989;9(1):129-35.
27) Ramsden CE, Hibbeln JR, Majchrzak SF, Davis JM. n-6 fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials. Br J Nutr. 2010;104(11):1586-600.
28) Ramsden CE, Zamora D, Leelarthaepin B, et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ. 2013;346:e8707.
29) Christakis G, Rinzler SH, Archer M, Kraus A. Effect of the Anti-Coronary Club program on coronary heart disease. Risk- factor status. JAMA. 1966;198(6):597-604.
30) Medical Research Council (1968) Controlled trial of soya-bean
oil in myocardial infarction. Lancet ii, 693-699.
31) Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2(8666):757-61.
32) Rose GA, Thomson WB, Williams RT. CORN OIL IN TREATMENT OF ISCHAEMIC HEART DISEASE. Br Med J. 1965;1(5449):1531-3.
33) Howard BV, Van horn L, Hsia J, et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295(6):655-66.
34) Low-fat diet in myocardial infarction: A controlled trial. Lancet. 1965;2 (7411):501-4.
35) De lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994;343(8911):1454-9.
36) De lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99(6):779-85.
37) Hjermann I, Velve byre K, Holme I, Leren P. Effect of diet and smoking intervention on the incidence of coronary heart disease. Report from the Oslo Study Group of a randomised trial in healthy men. Lancet. 1981;2(8259):1303-10.
38) The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251(3):351-64.
39) Hussein O, Frydman G, Frim H, Aviram M. Reduced susceptibility of low density lipoprotein to lipid peroxidation after cholestyramine treatment in heterozygous familial hypercholesterolemic children. Pathophysiology. 2001;8(1):21-28.
40) Hoffman R, Brook GJ, Aviram M. Hypolipidemic drugs reduce lipoprotein susceptibility to undergo lipid peroxidation: in vitro and ex vivo studies. Atherosclerosis. 1992;93(1-2):105-13.
41) Sullivan JL. Lipid Research Clinics Program. JAMA 1984;252:2547.
42) Yamaoka-tojo M, Tojo T, Izumi T. Beyond cholesterol lowering: pleiotropic effects of bile acid binding resins against cardiovascular disease risk factors in patients with metabolic syndrome. Curr Vasc Pharmacol. 2008;6(4):271-81.
43) Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med. 1990;323(14):946-55.
44) Smith GD, Song F, Sheldon TA. Cholesterol lowering and mortality: the importance of considering initial level of risk. BMJ. 1993;306(6889):1367-73.
45) Saha SA, Kizhakepunnur LG, Bahekar A, Arora RR. The role of fibrates in the prevention of cardiovascular disease--a pooled meta-analysis of long-term randomized placebo-controlled clinical trials. Am Heart J. 2007;154(5):943-53.
46) Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375(9729):1875-84.
47) Schoch HK. The US Veterans Administration cardiology drug-lipid study: an interim report. Adv Exp Med Biol. 1996;4:405- 420.
48) Clofibrate and niacin in coronary heart disease. JAMA. 1975;231(4):360-81.
49) Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255-67.
50) Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203-12.
51) Friedman, Lawrence M., Furberg, Curt D., DeMets, David L. Fundamentals of Clinical Trials 4th ed. 2010, XVIII, 445 p.
52) Jackevicius CA, Krumholz HM. Role of nicotinic Acid in atherosclerosis prevention-reply. JAMA Intern Med. 2014;174 (4):649.
53) Godsland IF, Wynn V, Crook D, Miller NE. Sex, plasma lipoproteins, and atherosclerosis: prevailing assumptions and outstanding questions. Am Heart J. 1987;114(6):1467-503.
54) http://link.springer.com/chapter/10.1007/978-94-011-6264-7_10
55) Schoch HK. The US Veterans Administration cardiology drug-lipid study: an interim report. Adv Exp Med Biol. 1996;4:405- 420.
56) Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280(7):605 -13.
57) Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33.
58) Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative. Arch Intern Med. 2006;166(3):357-65.
59) Kaur N, Pandey A, Negi H, Shafiq N, Reddy S, et al. (2014) Effect of HDL-Raising Drugs on Cardiovascular Outcomes: A Systematic Review and Meta-Regression. PLoS ONE 9(4): e94585. doi:10.1371/journal.pone.0094585
60) Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089-99
61) Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109-22.
62) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383-9.
63) Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339(19):1349-57.
64) 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 (14):1001-9.
65) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22.
66) Do statins have a role in primary prevention? An update. Therapeutics Letter 2010;77:1-2 Available: www.ti.ubc.ca/letter77
67) Prasad V. Statins, primary prevention, and overall mortality. Ann Intern Med. 2014;160(12):867-9.
68) 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(9346):1623-30.
69) 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(23):2998-3007.
70) Sever PS, Dahlöf 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(9364):1149-58.
71) Kjekshus J, Apatrei E, Barrios V, et al, for the CORONA group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; 357: 2248-61.
72) GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1231-39.
73) Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353(3):238-48.
74) Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360(14):1395-407.
75) Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181-92.
76) Asselbergs FW, Diercks GF, Hillege HL, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation. 2004;110(18):2809-16.
77) Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359(13):1343-56.
78) Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549-59.
79) 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(9435):685-96.
80) 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). Diabetes Care. 2006;29(7):1478-85.
81) De Lorgeril, Michel, et al. "Is the use of cholesterol-lowering drugs for the prevention of cardiovascular complications in type 2 diabetics evidence-based? A systematic review." Reviews on recent clinical trials 7.2 (2012): 150-157
82) Chang YH, Hsieh MC, Wang CY, Lin KC, Lee YJ. Reassessing the benefits of statins in the prevention of cardiovascular disease in diabetic patients--a systematic review and meta-analysis. Rev Diabet Stud. 2013;10(2-3):157-70.
83) High dose versus standard dose statins in stable coronary heart disease. Therapeutics Letter Issue 87 / Jul - Aug 2012 - [...]
84) Spector R, Snapinn SM. Statins for secondary prevention of cardiovascular disease: the right dose. Pharmacology. 2011;87 (1-2):63-9.
85) Hayward RA, Hofer TP, Vijan S. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med. 2006;145(7):520-30.
86) Newman DH, Saini V, Brody H, Brownlee S, Hoffman JR et al. (2012) Statins for people at low risk of cardiovascular disease. Lancet. 380: 1814. doi:10.1016/S0140-6736(12)62020-0.
87) De lorgeril M, Salen P, Abramson J, et al. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal. Arch Intern Med. 2010;170(12):1032-6.
88) de Lorgeril M: Disappointing recent cholesterol-lowering drug trials: is it not time for a full reappraisal of the cholesterol theory? World Rev Nutr Diet 2009, 100:80-89.
89) De lorgeril M, Salen P, Defaye P, Rabaeus M. Recent findings on the health effects of omega-3 fatty acids and statins, and their interactions: do statins inhibit omega-3?. BMC Med. 2013;11:5.
90) The national diet-heart study final report. Circulation 1968;37(II):1-428.
91) Hooper L, Summerbell CD, Thompson R, et al. Reduced or modified dietary fat for preventing cardiovascular disease. Cochrane Database Syst Rev. 2012;5:CD002137.
92) Bierenbaum ML, Fleischman AI, Green DP, et al. The 5-year experience of modified fat diets on younger men with coronary heart disease. Circulation. 1970;42(5):943-52.
93) Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular

This book contains a history of the research relating serum cholesterol to heart disease, from Anitschkow's rabbits to statin trials that reduced heart attacks and all-cause mortality. It exposes the error of those who claim that there is no evidence that saturated fat in the diet or LDL in the blood are related to heart disease. Whether you are convinced or not it's easy to see how reasonable people can hold Dr. Steinberg's position. Anyone who reads books by cholesterol skeptic also needs to read this book to hear the other side, presented by a real scientist. The following contains some evidence referenced in the book as well as additional evidence.

OBSERVATIONAL EVIDENCE
1. Atherosclerotic plaque contains a lot of cholesterol. In 1856 a German pathologist named Rudolf Virchow proposed that lipid accumulation in the artery wall caused atherosclerosis. In 1914 Nikolai Anitschkow also observed cholesterol crystals in advanced plaque in the aorta of cholesterol fed rabbits.
2. Michael Brown and Joseph Goldstein discovered that the number of functional LDL receptors on the surface of cells, especially liver cells determines the level of LDL in the blood. If the receptors are defective or too few in number, LDL builds up in the blood instead of being taken into the cells. Familial hypercholesterolemia (FH) is caused by the mutation of a single gene that does one thing; make LDL receptors. People with two copies of the mutation for FH have LDL levels 6 to 10 fold above normal and can have a heart attack as early as 18 months of age. People with one copy of the mutation have LDL levels 2 to 4 times above normal and develop clinical symptoms between the ages of 30 and 60. There is an obvious dose response relationship. (1) In the era before the statins, FH patients aged 20 to 39 years old were 100 times more likely die of heart disease and 10 times more likely to die from all causes than someone in the general population. (2) In a later study, FH patients treated with statins lived just as long as people without FH. (3)
3. People with very low LDL tend to be protected from CHD, with the exception of alcoholics. (Alcohol lowers LDL and damages the endothelium at the same time.) The normal LDL cholesterol range is 50 to 70 mg/dl for modern hunter-gatherers, healthy human newborns, free-living primates, and other wild mammals (all of whom do not develop atherosclerosis). (4) And during the 80s, rural Chinese had an average serum cholesterol level of 127 mg/dl. And the men in rural China had a rate of CHD that was only 1/17th that of American men. This was in spite of the fact that close to 80% of them smoked. (5) According to the third report of the National Cholesterol Education Program (NCEP), "Only in populations that maintain very low levels of serum cholesterol, e.g., total cholesterol <150 mg/dL (or LDL cholesterol <100 mg/dL) throughout life do we find a near-absence of clinical CHD." (6)
4. People with an intermediate level of LDL have intermediate levels of heart disease. Virtually 100% of observational studies comparing people within the same country show an association between serum cholesterol and heart disease. (7,8,9)
5. The fact that HDL is protective and does the opposite of LDL is further proof of the harmfulness of elevated LDL. The INTERHEART study looked at 52 different countries and found that the ratio of apo-B (mostly LDL) to apo-A1 (HDL) could account for 50% of the risk of CHD mortality. (10)

EXPERIMENTAL EVIDENCE
6. Atherosclerosis can be induced in a great variety of animal species including vegetarian and carnivore species (e.g. insects, birds, cats, dogs, non-human primates etc.) by raising serum cholesterol high enough and maintaining it long enough. Atherosclerosis can also be reversed by lowering TC enough and maintaining it long enough. The lipid deposits and foam cells disappeared but some fibrous tissue remained. Some species, such as the dog and rat, do not get elevated TC from a diet high in saturated fat and cholesterol. But when a way was found to elevate their TC they also developed atherosclerosis. This is so consistent no matter which species is tested that it appears to be a scientific law that elevated LDL can cause atherosclerosis. (11) This can't be explained away by stress, inflammation or some infectious agent. In clinical trials, Dr. Esselstyn's group did better than Dr. Ornish's group even though Dr. Ornish used stress reduction and Dr. Esselstyn didn't. However Dr. Esselstyn's patients had lower LDL. And although inflammatory factors like infection can speed up atherosclerosis, oxidized LDL, foam cells and cholesterol crystals inside the artery wall provide their own inflammation. See point eleven.
7. A meta-analysis of 395 metabolic ward experiments concluded that in typical British diets replacing 60% of saturated fats by other fats and avoiding 60% of dietary cholesterol would reduce blood total cholesterol by about 0.8 mmol/l (that is, by 10-15%), with four fifths of this reduction being in low density lipoprotein cholesterol. (12) According to Dr. Ornish on average a 10% fat, high fiber diet can lower LDL by 40%. (13)
8. In a meta-analysis of 35 randomized trials using diet and/or medication for every 10 percentage points of cholesterol lowering, CHD mortality was reduced by 13% and total mortality by 10% (14). And a meta-analysis of 9 randomized trials shows that when statins are used for secondary prevention in elderly patients they can reduce all-cause mortality by 22% and heart disease mortality by 30%. (15)
9. Lowering LDL can halt and even reverse heart disease in humans. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, coronary atherosclerosis was virtually stopped in its tracks when LDL was maintained at 79 mg/dL. (16) And Dr. Esselstyn was able to reverse atherosclerosis by maintaining LDL at 81 mg/dL using a 10% fat, high fiber diet and a low dose statin. (17)
10. According to a meta-analysis of 19 studies (81,859 participants in all) that lowered LDL and measured clinical disease or death, including 5 diet trials, 3 bile sequestrant trials, 1 surgery trial and 10 statin trials concluded that: "The pleiotropic effects [effects apparently unrelated to lowering LDL] of statins do not seem to contribute an additional cardiovascular risk reduction benefit beyond that expected from the degree of LDL-C lowering observed in other trials that primarily lowered LDL-C." (18)

THE MECHANISM OF ATHEROSCLEROSIS
11. Last but not least elevated LDL is essential to the mechanism of atherosclerosis. Apo B lipoproteins (mostly LDL) diffuse into the artery wall that has been damaged by hypertension (coronary arteries have the highest blood pressure) , smoking or alcohol. They become oxidized and cause inflammation which attracts macrophages. Macrophages devour oxidized LDL and become foam cells which form plaque and produce more inflammatory chemicals. They grow and eventually rupture depositing cholesterol crystals in the plaque. The crystals penetrate the artery wall causing even more inflammation. Elevated LDL also impairs endothelial function, reduces nitric oxide production and promotes platelet aggregation which promotes clotting. There are other factors besides elevated LDL that contribute to heart disease like smoking, hypertension, diabetes, abdominal obesity, stress, inflammation, homocysteine, sedentary lifestyle and excess sucrose but according to the INTERHEART study the ratio of apo-B (mostly LDL) to apo-A1 (HDL) can account for 50% of the risk. (11,19,20,21)

STATIN SIDE EFFECTS
12. Ten milligram simvastatin is so safe it is sold over the counter in the UK. High dose statins on the other hand should probably only be prescribed with caution to patients who have tried a low first and been screened for elevated liver enzymes etc. And statins deplete CoQ10 so anyone taking a statin should also take CoQ10. Should we believe every side effect is caused by low LDL? There are millions of people with LDL levels lower than the levels of people on high dose statins who are not known for muscle weakness or poor memory or liver problems. And wild mammals with 50 to 70 mg/dL LDL are known for their excellent health. Almost all prescription drugs are dangerous if taken by the wrong person. But they can be life saving when taken by the right person. For people who don't want to take statins there are several alternative ways to lower LDL that are not likely to cause side effects.

MORE EVIDENCE THAT REDUCING LDL IN HEART PATIENTS REDUCES ALL-CAUSE MORTALITY
13. In the 1950s, Dr. Morrison put 50 heart attack survivors on a 15% fat, high protein diet and another 50 survivors were told to eat as usual. Total cholesterol fell from 312 mg/dl to 220 mg/dl in the experimental group. That's a reduction of 29%. And over a period of 8 years, 38 patients eating as usual died while only 22 in the experimental group died. (22)
14. In the 80's Dr. Esselstyn used a 10% fat, high fiber diet plus low dose statins to arrest or reverse heart disease in 18 severely ill heart patients. Some had been given less than a year to live by their referring cardiologist. Yet after 12 years "Adherent patients have experienced no extension of clinical disease, no coronary events, and no interventions. This finding is all the more compelling when we consider that the original compliant 18 participants experienced 49 coronary events in the 8 years before the study." Although the sample was small, the results were statistically significant. (23)

TWO NEW STUDIES, ONE CONCERNING LIFELONG LDL LEVELS AND THE OTHER CONCERNING RED MEAT AND HIGH SATURATED FAT DIETS
15. A new study shows that lifelong reductions in LDL are linked to consistent reduction in CHD risk. Scientists studied nine single nucleotide polymorphisms which influence LDL levels. From homozygous familial hypercholesterolemia (FH) at the high extreme (over 600 mg/dL LDL cholesterol) to hypobeta-lipoproteinemia at the low extreme (less than 15mg/dL LDL cholesterol). Since these SNP's are present from birth, this allowed them to see the effect of low LDL levels maintained over a lifetime. The results show a three times greater benefit for these life long low LDL levels compared taking statins later in life. The lead scientist stated, "the effect of each of the included SNPs on risk of CHD is mediated largely or entirely through effect on circulating levels of LDL, rather than through some other pleiotropic effect." "The researchers also conducted a meta-analysis of the "natural" randomized trials by combining non-overlapping data from multiple SNPs involving 326,443 participants. Results of this study indicated that lifetime exposure to lower LDL was associated with a 54% (95% CI, 48-59) relative reduction of CVD for each 38.7 mg/dL (1 mmol/L) lower LDL." There is a clear dose response relationship. (24)
16. In a study co-authored by Ronald Krauss, during weight maintenance two low-carb diets (one high and one low in saturated fat) were compared to a high-carb diet that was also high in saturated fat. The values for small dense LDL were 222 nmol/l in the low-carb, high saturated fat diet ; 207 nmol/l in the high-carb diet, high saturated fat diet; and 187 nmol/l in the low-carb, low saturated fat diet. (25) Here's what Dr. Krauss said about this study: "This is one of the surprises that keep life interesting for us for us as researchers and also for the world out there who happens to be looking over our shoulder. In this case, the surprise was that the combination of the high beef diet and the high saturated fat diet caused very serious increases in all of the cholesterol related risk factors we had been measuring, including total particle numbers, small LDL, total LDL cholesterol, inflammation, whatever we looked at, we saw an adverse effect."

ANSWERS TO SOME OF THE OBJECTIONS OF THE CHOLESTEROL SKEPTICS
17. Before statins or the link between saturated fat and heart disease was discovered, people with chest pain or survivors of heart attacks did not take medication or reduce saturated fat to lower cholesterol. When their LDL was measured it was likely to represent their lifetime average. Now LDL is routinely measured every time someone gets a complete physical, and dietary changes or prescription medication is recommended to high risk individuals long before they have a heart attack. Atherosclerosis is slowed and the heart attack is delayed for several years and occurs with lower saturated fat consumption and/or a lower LDL level. Today the LDL level of a heart patient admitted to the hospital is very unlikely to represent their lifetime average.
18. The age-adjusted mortality rate for cardiovascular disease peaked in 1963 and has been falling ever since. This is a well established fact. According to the CDC: "Age-adjusted death rates per 100,000 persons (standardized to the 1940 U.S. population) for diseases of the heart (i.e., coronary heart disease, hypertensive heart disease, and rheumatic heart disease) have decreased from a peak of 307.4 in 1950 to 134.6 in 1996, an overall decline of 56% (Figure 1). Age-adjusted death rates for coronary heart disease (the major form of CVD contributing to mortality) continued to increase into the 1960s, then declined. In 1996, 621,000 fewer deaths occurred from coronary heart disease than would have been expected had the rate remained at its 1963 peak." A greater than 50% decline in cardiovascular disease is further confirmed by the Framingham Heart Study. (26) And a study by Ergin et al. in 2004 shows that both the incidence and mortality of cardiovascular disease fell in the United states from 1971 through 1992. (27) And according to the Atherosclerosis Risk in Communities (ARIC) Study: "Scientists now have information indicating that reductions in the risk factors for coronary heart disease are contributing to the decline in coronary heart disease rates, such as lowering blood cholesterol, blood pressure, and smoking rates (24%, 20%, and 12% reduction in coronary heart disease mortality from each)." The remaining 44% reduction is due to improved care during an acute heart attack.
19. It is claimed by Dr. Ravnskov that Ancel Keys misled us in his Six Countries Study. In 1957 Yerushalmy and Hilleboe took another look at the FAO data that Keys had used. Their primary criticism was that there were other variables more strongly associated with heart disease mortality than TOTAL FAT which had a correlation of .659. (BTW, even though a graph of all 22 countries didn't make a straight line the correlation for 22 coutries together was strong and significant even for total fat.) It's ironic that Uffe Ravnskov chose to cite this study, since the two variables that Yerushalmy and Hilleboe found most strongly associated with heart disease mortality in the 22 countries were ANIMAL PROTEIN first (correlation of .756) and ANIMAL FAT second (.684). (28) It's Dr. Ravnskov, who is not even a scientist, who misled us.
20. Cholesterol skepics like to point to hunter gatherers as an example of low rates of heart disease on a high animal fat diet. But the the HGs also have very low LDL levels. And these low levels have not been duplicated in clinical trials of Paleo diets. However various parasitic infections which are common among HGs can lower LDL. In fact the parasitic infection, schistosomiasis, has been shown to reverse atherosclerosis in mice. (29)
21. In the US, from 1909 until the peak of the heart disease epidemic around 1965, while butter and lard consumption did fall, meat consumption rose from 141 to 148 pounds per capita and dairy products excluding butter rose from 177 to 237. Wheat flour fell from 291 to 147 and potatoes fell from 182 to 94. Percent fat increased from 32.1 to 41.1 percent and carbohydrates fell from 56.2 to 47.0 percent. During this time period meat transitioned from mostly grass-fed with less saturated fat to factory-farmed which contains several times as much saturated fat. This fact was not considered by the study and would make a large increase in animal fat. (30) So as fat climbed and carbohydrates fell the heart disease epidemic gained momentum.
22. Scientists studying atherosclerosis know more about the subject than anyone else and according to a poll the vast majority think that cholesterol is connected to heart disease. And based on the number of statin prescriptions the vast majority of doctors also believe cholesterol lowing medication is worth prescribing to high risk individuals.

REFERENCES
1. Brown MS, Goldstein JL. Human mutations affecting the low density lipoprotein pathway. Am J Clin Nutr. 1977 Jun;30(6):975-8.
2. Risk of fatal coronary heart disease in familial hypercholesterolemia. British Medical Journal, 1991;303:893-896.
3. Neil HA, Hawkins MM, Durrington PN, Betteridge DJ, Capps NE, Humphries SE; Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee. Non-coronary heart disease mortality and risk of fatal cancer in patients with treated heterozygous familial hypercholesterolaemia: a prospective registry study. Atherosclerosis. 2005 Apr;179(2):293-7.
4. O'Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004 Jun 2;43(11):2142-6.
5. Campbell TC, Campbell TM. The China Study. 2005, BenBella Books. Pages 78-79.
6. 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. Circulation 2002;106;3143.
7. Wilson PW, Garrison RJ, Castelli WP, Feinleib M, McNamara PM, Kannel WB. Prevalence of coronary heart disease in the Framingham Offspring Study: role of lipoprotein cholesterols. Am J Cardiol. 1980 Oct;46(4):649-54.
8. Menotti A, Keys A, Kromhout D, Blackburn H, Aravanis C, Bloemberg B, Buzina R, Dontas A, Fidanza F. Giampaoli S, et al. Inter-cohort differences in coronary heart disease mortality in the 25-year follow-up of the seven countries study. Eur J Epidemiol. 1993 Sep;9(5):527-36.
9. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986 Nov 28;256(20):2823-8.
10. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004 Sep 11-17;364(9438):937-52.
11. Malinow MR. Atherosclerosis. Regression in nonhuman primates. Circ Res. 1980 Mar;46(3):311-20.
12. Clarke R, Frost C, Collins R, Appleby P, Peto R. Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies. BMJ. 1997 Jan 11;314(7074):112-7.
13.The Spectrum: A Scientifically Proven Program to Feel Better, Live Longer, Lose Weight, and Gain Health
14. A. Lawrence Gould, PhD; Jacques E. Rossouw, MD; Nancy C. Santanello, MD, MSc; Joseph F. Heyse, PhD; Curt D. Furberg, MD Cholesterol Reduction Yields Clinical Benefit. Circulation. 1995;91:2274-2282.
15. Afilalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ. Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis. J Am Coll Cardiol. 2008 Jan 1;51(1):37-45.
16. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN; REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004 Mar 3;291(9):1071-80.
17. Esselstyn, CB. Prevent and Reverse Heart Disease. 2007, Penguin Group.
18. Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol. 2005 Nov 15;46(10):1855-62.
19. Badimon L, Storey RF, Vilahur G. Update on lipids, inflammation and atherothrombosis. Thromb Haemost. 2011 Apr 11;(Suppl. 1).
20. Abela GS. Cholesterol crystals piercing the arterial plaque and intima trigger local and systemic inflammation. J Clin Lipidol. 2010 May-Jun;4(3):156-64.
21. Miller M, Beach V, Sorkin JD, Mangano C, Dobmeier C, Novacic D, Rhyne J, Vogel RA. Comparative effects of three popular diets on lipids, endothelial function, and C-reactive protein during weight maintenance. J Am Diet Assoc. 2009 Apr;109(4):713-7.
22. Morrison LM. Diet in coronary atherosclerosis. J Am Med Assoc. 1960 Jun 25;173:884-8.
23. Esselstyn CB Jr. Updating a 12-Year Experience With Arrest and Reversal Therapy for Coronary Heart Disease
(An Overdue Requiem for Palliative Cardiology). Am J Cardiol. 1999 Aug 1;84(3):339-41, A8.
24. Ference BA. Late-breaking clinical trials IV. Presented at: the American College of Cardiology 61st Scientific Session & Expo; March 24-27, 2012; Chicago.
25. Mangravite LM, Chiu S, Wojnoonski K, Rawlings RS, Bergeron N, Krauss RM. Changes in atherogenic dyslipidemia induced by carbohydrate restriction in men are dependent on dietary protein source. J Nutr.2011Dec;141(12):2180-5.
26. Sarah Rosner Preis, ScD MPH1,2, Shih-Jen Hwang, PhD1,2, Sean Coady, MA2, Michael J. Pencina, PhD3, Ralph B. D'Agostino Sr, PhD3, Peter J. Savage, MD2, Daniel Levy, MD1,2, and Caroline S. Fox, MD MPH. Trends in All-Cause and Cardiovascular Disease Mortality among Women and Men with and without Diabetes in the Framingham Heart Study, 1950-2005. Circulation. 2009 April 7; 119(13): 1728-1735.
27. Ergin A, Muntner P, Sherwin R, He J. Secular trends in cardiovascular disease mortality, incidence, and case fatality rates in adults in the United States. Am J Med. 2004 Aug 15;117(4):219-27.
28. Yerushalmy J, Hilleboe HE. Fat in the diet and mortality from heart disease; a methodologic note. N Y State J Med. 1957 Jul 15;57(14):2343-54.
29. Doenhoff MJ, Stanley RG, Griffiths K, Jackson CL. An anti-atherogenic effect of Schistosoma mansoni infections in mice associated with a parasite-induced lowering of blood total cholesterol. Parasitology. 2002 Nov;125(Pt 5):415-21.
30. Nutrients in United States Food Supply, A Review of Trends, 1909-1913 to 1965, THE AMERICAN JOURLNAL OF CLINICAL NUTRITION. Vol. 20, No. 8, August, 1967, pp. 907-914.

The most remarkable thing about this book is that it may be the only one of its kind. The number of books attacking the lipid or diet-heart hypothesis (some listed on people who bought the book) is large and growing -- there are two called The Cholesterol Con yet this appears to be the only answer to what are very serious criticisms. Chapter 1 is a shock right off: "...the hypothesis relates to blood lipids, not dietary lipids, as the putative directly causative factor. Although diet, especially dietary lipid, is an important determinant...." What? We haven't been hearing for thirty years that a low fat diet is the key player? Of course, throughout the book, saturated fat is made to appear a major if not overriding factor and the same lack of hard proof that saturated fat causes CVD is missing. The description of the big studies is remarkably different thatn as described by the skeptics. The big save of the diet-heart hypothesis are the statins but the demonstration that there is improvement in risk because of lowered LDL is still not reliable. The book is nonetheless well researched (within the bias) and worth reading but the title tells you that this is, by analogy with a court of law, a civil suit. The cholesterol hypothesis is not established beyond a reasonable doubt.