Cholesterol LoweringA Failed Strategy

Animal studies show significant reductions in atherosclerosis unrelated to cholesterol levels. Few examples:

Therefore, animal models suggest that:

• Other factors are critical in the development of atherosclerosis, perhaps more so than cholesterol levels per se, since major reductions in atherosclerosis can take place independently of cholesterol levels and in the presence of high cholesterol levels.• Increased cholesterol levels do not necessarily translate into

increased atherosclerosis, or decreased cholesterol levels into decreased atherosclerosis. • Oxidative events are not necessarily associated with cholesterol

levels.• The quality of cholesterol or cholesterol particles is more

important than quantity.

Modified cholesterol/particles may be the major issue (which is not necessarily associated with cholesterol levels):

• Kummerow FA. Interaction between sphingomyelin and oxysterols contributes to atherosclerosis and sudden death. Am. J. Cardiovasc. Dis. 3(1), 17–26 (2013).• Yoshimoto R, Fujita Y, Kakino A, Iwamoto S, Takaya T, Sawamura T. The

discovery of LOX-1, its ligands and clinical significance. Cardiovasc Drugs Ther 2011; 25:379–91.• Silverstein RL. Teaching an old dog new tricks: potential

antiatherothrombotic use for statins. J Clin Invest. 2012;122(2):478-81.

Observationally, the total/HDL ratio is one of strongest predictors of CV outcomes. However, for mortality, higher cholesterol levels may be better (especially in elderly). Few examples:

Hormones reduce total and LDL cholesterol and increase HDL cholesterol but have no effect on events

• 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.• 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.• 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.• 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.

Fibrates, niacin, and CETP inhibitors reduce total and LDL cholesterol and increase HDL cholesterol but have no effect on CHD 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.

Resins have never been properly tested. Only the LRC-CPPT trial is methodologically acceptable and had enough hard events. However:

• 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.

POSCH Trial

• 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.• Buchwald, H.; Boen, J. R.; Williams, S. E.; Nguyen, P. A.; Matts, J. P., 2003:

Blood pressure, weight, and cholesterol: a report of the Program on the Surgical Control of the Hyperlipidemias POSCH. Journal of Applied Research 3(2): 112-117• Smith GD, Song F, Sheldon TA. Cholesterol lowering and mortality: the

importance of considering initial level of risk. BMJ. 1993;306(6889):1367-73.

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)

Furthermore

Many diet trials with cholesterol reductions have failed

Whereas other diet trials with similar or no reductions in cholesterol (in comparison to control group) have looked far more promising, suggesting that cholesterol is irrelevant to risk.

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 Effects• Antioxidant• Inhibits modified LDL/Oxidative stress/Lox-1, enhances NO

bioavailability• Other possible effects (iron metabolism/HO-1 etc.)

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.

Researchers have already shown these types of analyses to be flawed, in addition to pointing out the lack of evidence for cholesterol treatment targets or “the lower the better”:

• 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;145:520–530.• Hayward RA, Krumholz HM. Three reasons to abandon low-density

lipoprotein targets: an open letter to the Adult Treatment Panel IV of the National Institutes of Health. Circ Cardiovasc Qual Outcomes. 2012;5(1):2-5.• Hayward RA. Moneyball, gambling, and the new cholesterol

guidelines. Circ Cardiovasc Qual Outcomes. 2014;7(2):311-4.

In short, the most reliable and unbiased result of any trial is the randomized comparison – a straightforward comparison, and the whole reason randomized trials are set up in the first place.

Benefits of statins in secondary prevention not as strong as claimed and benefits are probably overestimated

• 4S was never replicated• GREACE very poorly designed (unclear randomization procedure and

allocation concealment, two different non-blinded committees, and employed two different standards of care).• LIPID not supported by CARE where there were no significant

reductions in CHD death and total mortality and was the better designed trial (allocation concealment and not stopped early based on an interim analysis).• Should also be taken into consideration that most statin trials are

either fully or partially funded by pharmaceutical companies.

Benefits of statins in primary prevention uncertain

• The small 10% reduction in mortality (sometimes non-significant) seen in meta-analyses may be due to bias since the vast majority of the individual trials were of poor quality, contributing to the uncertainty in this population. Also, transparency is needed.• Do statins have a role in primary prevention? An update. Therapeutics

Letter 2010;77:1–2 Available: www.ti.ubc.ca/letter77• Prasad V. Statins, primary prevention, and overall mortality. Ann

Intern Med. 2014;160(12):867-9.• Statins and The BMJ. BMJ. 2014;349:g5038.

The JUPITER trial is not reliable evidenceDe 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.

No credible evidence that statins benefit diabetics

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.

De lorgeril M, Hamazaki T, Kostucki W, et al. Is the use of cholesterol-lowering drugs for the prevention of cardiovascular complications in type 2 diabetics evidence-based? A systematic review. Rev Recent Clin Trials. 2012;7(2):150-7.

• This review does not support the use of cholesterol-lowering drugs (such as statin and fibrate) to reduce mortality and cardiovascular complications in type 2 diabetics. Official guidelines should be re-examined and reformulated by experts independent from the pharmaceutical industry.

• In conclusion, statins seems to be protective in lowering CVD risk. However, our results suggest that more informative, double blind, randomized, controlled trials are necessary to confirm the role for statins in cardiovascular protection in diabetic patients.

High dose statin in secondary prevention does not reduce CHD death and total mortalityHigh dose versus standard dose statins in stable coronary heart disease. Therapeutics Letter Issue 87 / Jul - Aug 2012 - http://www.ti.ubc.ca/letter87

Spector R, Snapinn SM. Statins for secondary prevention of cardiovascular disease: the right dose. Pharmacology. 2011;87(1-2):63-9.

Statins have also failed in many other populations

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.

Total mortality is the most objective and unbiased endpoint, and also very important to patients. Therefore, it should always be taken into consideration when interpreting the data. Despite all the lipid and non-lipid effects of all these treatments, the vast majority of trials ever conducted have failed:

Conclusion:

The strategy of cholesterol lowering has failed, and the poor results of trials are likely due to targeting a non-causal factor. Where small mortality benefits are seen in some cases, there is zero credible evidence that this is due to cholesterol lowering, since if not due to bias, may well be due to the pleiotropic effects of treatments.