Cholesterol Lowering - A Failed Strategy

1. Cholesterol Lowering
A Failed Strategy

2. Cholesterol is a vital substance -
• “Cholesterol, contrary to its popular image as a potent
enemy of health and longevity, is actually a crucial substance
that performs innumerable vital functions in the body.
Cholesterol is needed for the synthesis of bile acids, which are
essential for the absorption of fats, and of many hormones
such as testosterone, estrogen, dihydroepiandrosterone,
progesterone, and cortisol. Together with sun exposure,
cholesterol is required to produce vitamin D. Cholesterol is an
essential element of cell membranes, where it provides
structural support and may even serve as a protective
antioxidant, especially at the level of the synapse”
Colpo A. LDL cholesterol: ‘‘Bad’’ cholesterol, or bad science? J Am Phys Surg 2005;10:83–
89.

3. Although animal studies are often used as mechanistic evidence against
cholesterol, many also show major changes in atherosclerosis unrelated to
cholesterol levels, undermining a major role for cholesterol per se. For example…

6. Of course, extrapolation to humans may be invalid:
• “Although the predictive value of animal studies may seem high if
they are conducted thoroughly and have included several species,
uncritical reliance on the results of animal tests can be dangerously
misleading and has resulted in damages to human health in several
cases, included those of some drugs developed by large
pharmaceutical companies. What is noxious or ineffective in non-
human species can be innoxious or effective in humans and vice
versa;” (Animal Models, Jann Hau, Handbook of Laboratory Animal Science,
Volume II, Third Edition. Apr 2011)

7. Genetic studies do not necessarily support cholesterol lowering:
• “A new argument for the idea that high LDL is a risk factor for CVD, used by Ebrahim et al. as well, is Mendelian
randomization. Proponents of that argument claim that it has been documented because nine single-nucleotide
polymorphisms are associated with high LDL, and because these polymorphisms are found more often in patients
with cardiovascular disease. But association is not the same as causation. These polymorphisms may instead mark
a causal risk factor without being causal themselves, and this explanation is most likely because many
observations have documented that high LDL lacks causality.” (Ravnskov 2014).
• “Mendelian randomization studies indicate that higher LDL-cholesterol increases the risk of ischaemic heart
disease. However, these studies could also be interpreted as showing that a factor that raises LDL-cholesterol also
causes ischaemic heart disease” (Schooling et al. 2014).
• Extrapolation to the general population may be invalid: “Mendelian randomization studies have shown that
people born with genetically low cholesterol levels are at lower risk of CVD, but it is unclear if this is due to
association or causation (Ference et al., 2012). Nevertheless, we should not extrapolate these results to the
broader population who lack these genetic variations” (DuBroff 2016).
• Such data is also consistent with another mechanism that implicates modified cholesterol. See Dr. Masterjohn for
more details on this hypothesis - http://blog.cholesterol-and-health.com/2011/03/genes-ldl-cholesterol-levels-
and.html
• Mendelian randomization also depends on some assumptions which may or may not be true and thus needs to be
supported by other data.

8. Very few randomized studies in patients with familial hypercholesterolemia and
too few events, but no indication that LDL lowering would be beneficial in these
patients:

9. Observationally, LDL is not the best predictor of CV outcomes, but rather lipoprotein
ratios. Also, for mortality, higher cholesterol levels may be better (especially in
elderly):
• “Overall, an inverse trend is found between all-cause mortality and total (or low
density lipoprotein [LDL]) cholesterol levels: mortality is highest in the lowest
cholesterol group without exception. If limited to elderly people, this trend is universal.
As discussed . . . elderly people with the highest cholesterol levels have the highest
survival rates irrespective of where they live in the world”
• “In this supplementary issue, using data in large part from Japan where the mean life
expectancy has been the longest in the world for decades, we have tried to show that
cholesterol is not an enemy but a friend. The general Japanese population with high
total cholesterol levels—or with high levels of low density lipoprotein (LDL)
cholesterol—have very often been shown in cohort studies to have low all-cause
mortality. This phenomenon cannot be explained by so-called reverse causality (i.e.,
where subjects with an as yet subclinical serious disease and lower cholesterol levels
die earlier in a study because of that disease, so cholesterol levels have nothing to do
with their longevity)”
Towards a Paradigm Shift in Cholesterol Treatment. A Re-examination of the Cholesterol Issue in Japan: Abstracts.
Ann Nutr Metab. 2015;66 Suppl 4:1-116.

10. Trials: Two endpoints will be the main focus – cause-specific mortality
(CV/CHD/cardiac) and total mortality. Total mortality should not be
ignored…

11. • Total Mortality is “the most objective and most meaningful of end-points" (Dayton and Pearce 1969), the "most
unassailable and meaningful end point of them all" (Dayton 1972).
• “Total mortality was examined as it is an important outcome, and there is little likelihood of ascertainment or
diagnostic bias which may occur with cause-specific event outcomes” (Hooper et al. 2012).
• “The endpoint that is most encompassing, and least subject to bias, in statin trials is all cause mortality…It is
rarely misdiagnosed and not susceptible to inaccurate determination of cause.” (Abramson et al. 2013).
• “If a particular type of observation or treatment is in fact associated with a lower likelihood of cardiac death,
but is also associated with higher rates of noncardiac death, neither patients nor investigators should be
comforted…clinical investigators should rely on all-cause death as an objective, unbiased end point that is of
primary interest to everyone in the general public and, similarly, should be of primary interest to medical
professionals as well” (Lauer et al. 1999).
• “In clinical trials, all-cause mortality is the hardest endpoint possible, not being subject to clinical judgment or
errors in assessment. In addition, if county departments of public health are not reducing all-cause mortality,
but are merely changing the distribution of what individuals die of, it is hardly a sign of success.” (Brown 2014).
• “It is not whether we could avoid CVDs by changing our diet that people want to know. No, what they want to
know is whether they could avoid those diseases altogether that shorten life expectancy...What was the point
in protecting ourselves (even so slightly) from heart attacks if nothing was gained in terms of life expectancy?"
(De Lorgeril, Michel. Cholesterol and Statins: Sham Science and Bad Medicine. N.p.: Thierry Souccar Publishnig,
2014. Print.).

12. It is important to keep in mind that all drugs appear to have pleiotropic effects. Therefore, if a
treatment produces a reduction in risk, it does not necessarily mean it was due to lipid lowering per
se:

13. Hormones reduce total and LDL cholesterol and increase HDL
cholesterol but have no effect on CHD/CV death and total mortality:
• Bucher HC, Griffith LE, Guyatt GH. Systematic review on the risk and
benefit of different cholesterol-lowering interventions. Arterioscler
Thromb Vasc Biol. 1999;19(2):187-95.
• Boardman HMP, Hartley L, Eisinga A, Main C, Roqué i Figuls M, Bonfill
Cosp X, Gabriel Sanchez R, Knight B. Hormone therapy for preventing
cardiovascular disease in post-menopausal women. Cochrane
Database of Systematic Reviews 2015, Issue 3 . Art. No.: CD002229.
DOI: 10.1002/14651858.CD002229.pub4.

14. Boardman et al. 2015

15. Fibrates, niacin, and CETP inhibitors reduce total and LDL
cholesterol and increase HDL cholesterol but have no effect on
CHD/CV death and total mortality
• Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular
risk of high density lipoprotein targeted drug treatments niacin,
fibrates, and CETP inhibitors: meta-analysis of randomised controlled
trials including 117 411 patients. 2014;349:g4379.

17. Ezetimibe reduces total and LDL cholesterol but has no effect on CV death and total mortality:
Savarese, Gianluigi, et al. "Safety and efficacy of ezetimibe: A meta-analysis." International
journal of cardiology 201 (2015): 247-252.

18. Varespladib decreased LDL without effect on CV mortality and total mortality (with a large
increase in heart attacks):
Nicholls SJ, Kastelein JJ, Schwartz GG, et al. Varespladib and cardiovascular events in patients
with an acute coronary syndrome: the VISTA-16 randomized clinical trial. JAMA.
2014;311(3):252-62.

19. Resins have been the subject of many poor quality trials. The LRC-CPPT trial is an
example:
• Investigators did not prespecify the statistical test and used a lax one-sided
statistical test at the 0.05 level rather than the conventional standard of a
two-sided test or a one-sided test at the 0.025 level. This was described by
one researcher/statistician as “alpha corruption” (Moyé, Lemuel A.
Statistical Reasoning in Medicine - The Intuitive P-Value Primer 2nd ed.
2006, XX, 301 p.)
• Despite this lax statistical standard, and a population with very high
cholesterol levels, neither CHD mortality nor non-fatal MI were significantly
reduced. Furthermore, overall mortality was not reduced.
• A recent 2015 analysis found that studies funded by the NHLBI before the
year 2000 (like the LRC-CPPT) gave more favorable results to drugs than
studies conducted after the year 2000, which they attributed to the stricter
research and reporting standards enforced after the year 2000 (Kaplan et
al. 2015)

20. Regardless, analysis of eight resin trials still showed no mortality benefit:

21. Conversely, some drugs might reduce CV mortality and total mortality despite
increasing LDL, such as Empagliflozin:
Zinman, Bernard, et al. "Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes." New
England Journal of Medicine 373.22 (2015): 2117-2128.

22. POSCH Trial – A non-blinded surgical trial often cited as strong evidence
for cholesterol lowering:
• 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.

23. Many observational follow-ups usually cited, but the formal trial ended
at 9.7 years without significant results -
• Primary Endpoint of
Total Mortality:
0.78 (0.55–1.11)

24. Furthermore:
Smith GD, Song F, Sheldon TA. Cholesterol lowering and mortality: the importance of
considering initial level of risk. BMJ. 1993;306(6889):1367-73.

25. Indeed, POSCH can be described as the first trial of surgical
weight loss on mortality:

26. Consideration of dietary factors also present problems for the cholesterol
hypothesis:
• Saturated fat increases LDL, yet there is no credible evidence that decreasing its
intake reduces heart attacks, strokes, CV mortality and total mortality, as noted
by many analyses and reviews on the topic (e.g., Mente et al. 2009, Siri-tarino et al.
2010, Hoenselaar 2012, Hooper et al. 2012/2015, Chowdhury et al. 2014, Schwingshackl et al.
2014, Vallurupalli and Mehta 2014, Harcombe et al. 2015, de Souza et al. 2015,
DiNicolantonio et al. 2015, Parodi and Lawrence 2015).
• Omega-6 reduces LDL, yet there is no credible evidence that specifically
increasing its intake reduces heart attacks, strokes, CV mortality and total
mortality (Ramsden et al. 2010/2013). In fact, the only dietary/nutrient trials to
ever find clear mortality benefits were those involving increases in omega-3
without reductions in cholesterol (DART 1989, Lyon 1999, GISSI-Prevenzione 1999).

27. Here are many diet trials with cholesterol reductions that have failed:

28. Statins do not provide evidence that cholesterol/LDL lowering per se is
beneficial -
• Statins possess numerous pleiotropic effects (expected to be dose-dependent):
Anti-inflammatory, antithrombotic, immunomodulatory, antioxidant effects;
inhibits modified LDL/Oxidative stress/Lox-1; enhances NO bioavailability; other
possible effects (e.g. iron metabolism/HO-1 etc.). Therefore, the effect of
cholesterol lowering has not been isolated:
"The claim that LDL reduction is responsible for any statin-induced reduction in
cardiovascular events or mortality rates is unsupported“ (Colpo A. LDL cholesterol:
‘‘Bad’’ cholesterol, or bad science? J Am Phys Surg 2005;10:83–89).

29. Yet, statins are still not very effective. For example:
• In the widely cited HPS study, 14.7% of those not taking statins died,
compared to 12.9% of those taking statins – a 13% risk reduction. This is a
very small difference, and means that the statin failed to prevent 87% of the
expected deaths over the study period. Or, an absolute risk reduction of only
1.8%, needing to treat 56 patients to prevent 1 from dying over the 5-year
period (see Diamond and Ravnskov 2015 or http://www.thennt.com).
• In those who benefit, analyses show that statins might only prolong life by
months at best. (See Kristensen et al. 2015 and
http://endobioticselfexperimentation.blogspot.com.es/2016/01/statins-and-
death-postponement.html).

30. Not to mention the numerous statin trials not finding any
mortality benefit at all:
• “Although a number of statin trials have reported a mortality
benefit, quite a few have not” (Dubroff R, De lorgeril M. Cholesterol
confusion and statin controversy. World J Cardiol. 2015;7(7):404-9.)
• Examples – CARE, AFCAPS, MIRACL, ALLHAT, ALLIANCE, PROSPER,
TNT, IDEAL, SEARCH, ASPEN, SHARP, SEAS, SPARCL, 4D, AURORA,
CORONA, GISSI-HF, HOPE-3, among others without statistically
significant effects.

31. Note: The JUPITER trial is questionable
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.
López A, Wright JM. Rosuvastatin and the JUPITER trial:
critical appraisal of a lifeless planet in the galaxy of primary
prevention. Int J Occup Environ Health. 2012;18(1):70-8.
See also -
http://michel.delorgeril.info/conferences/diapositives-
congres-de-l-aha-a-los-angeles.

32. Beware of misleading observational analyses passed off as evidence for cholesterol
lowering, or any analyses claiming reductions per 1 mmol/L decrease. These are not
randomized comparisons. Examples:
Steinberg D. The pathogenesis of
atherosclerosis. An interpretive history of the
cholesterol controversy, part IV: the 1984
coronary primary prevention trial ends it—
almost. J Lipid Res 2006;47:1-14.
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;46:1855-62.

33. Moreover, some analyses come to different conclusions. For example:
• "There was no correlation with all-cause mortality or CV events and baseline lipid values such
as LDL cholesterol, ApoB, or total cholesterol on meta-regression analysis. We further sought to
assess whether there was a study-level correlation between the impact of PCSK9 therapy on
all-cause mortality, CV death, or CV events and between baseline LDL, percent decrease in LDL
for the PCSK9 group, absolute decrease in LDL for the PCSK9 group, or the post-therapy LDL. As
seen in Table 5, there was no significant study-level association between the LDL parameters
and outcomes“ (Lipinski MJ, Benedetto U, Escarcega RO, et al. The impact of proprotein convertase subtilisin-kexin
type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a
network meta-analysis. Eur Heart J. 2015).
• “The lack of relationship of LDL-C reductions by ezetimibe/simvastatin with the logarithm of
the outcome RRs suggests that progressively greater LDL-C reductions do not result in
progressively lower increments of risk reduction. Thus, based on the cross-sectional nature of
our meta-regression data, we could only hypothesize that the reduction of major CV events
following ezetimibe/simvastatin treatment might be independent of the LDL-C–lowering
extent” – (Thomopoulos, Costas, et al. "Effect of Low‐Density Lipoprotein Cholesterol Lowering by
Ezetimibe/Simvastatin on Outcome Incidence: Overview, Meta‐Analyses, and Meta‐Regression Analyses of Randomized
Trials." Clinical cardiology 38.12 (2015): 763-769.)

34. • “Fibrates seemed to exert modest beneficial effects on coronary outcomes. This is
supported by a previous meta-analysis that proposed that the protective effect is
mainly related to the prevention of coronary disease. However, our analysis does
not show clearly the role of lipid modification in this positive outcome. Fibrates
like statins have pleiotropic effects that might explain this discordance” (Hourcade-
Potelleret, F., et al. "Clinical benefit from pharmacological elevation of high-density lipoprotein
cholesterol: meta-regression analysis." Heart (2015): heartjnl-2014)
• “Contrary to the LDL log-linear hypothesis (which would suggest that those who
have a larger LDL cholesterol response from a given statin dose would receive
greater benefit), those with the worst prerandomization LDL response (<38%
reduction in LDL cholesterol level) received the same benefit as those with the
best LDL response (>48% reduction in LDL cholesterol level)” [Hayward, Rodney A.,
Timothy P. Hofer, and Sandeep Vijan. "Narrative review: lack of evidence for recommended low-
density lipoprotein treatment targets: a solvable problem." Annals of internal medicine 145.7
(2006): 520-530]

35. Of course, it would be naïve not to take into consideration conflicts of interest and
lack of transparency -- a major problem:
Statins and The BMJ. BMJ. 2014;349:g5038.
Smith R, Gøtzsche PC, Groves T. Should journals stop publishing
research funded by the drug industry?. BMJ. 2014;348:g171.

36. Older statin trials should probably be viewed more cautiously: 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.

37. • Since around 2005, both statin and non-statin cholesterol lowering
drugs have failed to reduce CV/CHD/cardiac death and total mortality
in numerous populations: ACS patients, stable CHD/CVD patients,
primary prevention, heart failure patients, stroke patients, kidney
patients, aortic stenosis patients, diabetic patients…

39. Conclusions:
The burden of proof lies on those claiming that cholesterol is harmful. This burden
has not been met, since much of the evidence actually argues against it.
Especially staggering is the consistent lack of effect of lowering cholesterol on
survival and even cardiovascular mortality. There is no excuse for such failures. If
lowering cholesterol is beneficial and safe, then there should be clear and
consistent reductions in mortality – period. Thus, one has to wonder whether
lowering cholesterol is actually counterproductive.
The strategy of lowering cholesterol has failed.