I am such a geek sometimes that I forget that other people don’t spend a lot of their free time pouring through the literature and reading articles and abstracts “for fun.” This is why I’m still surprised when I come across “the great debate of cholesterol” over and over again in my readings. Doesn’t everyone know by now that every person is different and “high” cholesterol is a symptom, not the cause of various issues? Nope, guess not. This means, I have to step it up and join the blogosphere on this topic again, my BreakFree friends! It just so happens, the timing is kismet!
This weekend, I was polishing up the editing (again) on one of my chapters of my upcoming book, BreakFree Medicine, and decided to add some more sources to my section regarding cardiovascular health and cholesterol. (Segue…to make sure you stay updated on its releases. Keep an eye on my Facebook and Twitter pages.)
I was getting a little seduced by the hits I got on PubMed regarding the efficacy of statins and their role in cardiovascular disease. However, I knew where to look and reviewed and dug a little deeper into the research. I jotted down some of the not-so-mainstream references that pointed out some biases and other issues on the current evidence of their effectiveness. As with anything in medicine, all things have their place; but when something is reported as a panacea, it will unattractively raise my eyebrows to my hairline.
The final nudges for this week’s blog on cholesterol consisted of (1) a few recent consultations where I had a number of clients ask about diet and as to whether eggs will raise their cholesterol (2) being bombarded by blogs on this very subject from some of my respected colleagues and famous web celebs. Therefore, I thought I’d create a trilogy in my cholesterol series.
The (Not-So-Much) Connection to Cholesterol and Heart Disease Mortality
According to the Centers for Disease Control and Prevention (CDC), 33.5% (71 million American adults) have high low-density lipoprotein (LDL), or “bad cholesterol” and only 1 out of 3 of them has the “condition under control.” The CDC Cholesterol Fact Sheet states:
- Lowering your cholesterol can reduce your risk of having a heart attack, needing heart bypass surgery or angioplasty, and dying of heart disease. (1)
However, when I read the reference for the CDC’s report of LDL having a significant effect on cardiovascular mortality (2), this analysis of 31 randomized trials did report some caveats as to their conclusion. These included inconclusive evidence for support of statins’ effectiveness in long-term trials and a lack of direct evidence linking a decrease in mortality by lowering LDL. Furthermore, the analysis stated that secondary prevention was more supported than primary prevention. (This means that preventing a first cardiovascular event has less evidence than preventing a second event.) The study reads:
There is evidence to suggest that statin therapy is associated with a statistically significant reduction in the risk of primary and secondary cardiovascular events. As the confidence intervals for each outcome in each prevention category overlap, it is not possible to differentiate, in terms of relative risk, between the effectiveness of statins in primary and secondary prevention. However, the absolute risk of CHD death/non-fatal MI is higher, and the number needed to treat to avoid such an event is consequently lower, in secondary than in primary prevention. The generalisability of these results is limited by the exclusion, in some studies, of patients who were hypersensitive to, intolerant of, or known to be unresponsive to, statins, or who were not adequately compliant with study medication during a placebo run-in phase. Consequently, the treatment effect may be reduced when statins are used in an unselected population. The results of the economic modelling show that statin therapy in secondary prevention is likely to be considered cost-effective. In primary prevention, the cost-effectiveness ratios are dependent on the level of CHD risk and age, but the results for the CVD analyses offer support for the more aggressive treatment recommendation issued by recent guidelines in UK. Evidence on clinical endpoints for rosuvastatin is awaited from on-going trials. The potential targeting of statins at low-risk populations is however associated with major uncertainties, particularly the likely uptake and long-term compliance to lifelong medication by asymptomatic younger patients. The targeting, assessment and monitoring of low-risk patients in primary care would be a major resource implication for the NHS. These areas require further research. (3)
In 2010, a landmark study, the JUPITER trial, which was touted as a main support of using statins for primary prevention in heart mortality, was called into question. (4-5) This randomized, double-blind, placebo-controlled, multicenter trial conducted at 1315 sites in 26 countries concluded that rosuvastatin prevented vascular events in men and women with LDL equal or less than 130 mg/dl with concurrent elevated c-reactive protein (greater than 2.0 mg/liter), a marker of inflammation. The results were so convincing, the trial was stopped after 1.9 years. (4) However, according to Medpage Today:
The reanalysis of the massive JUPITER trial involving almost 18,000 people with low or normal cholesterol but elevated levels of the inflammatory biomarker C-reactive protein (CRP) — turned up no evidence of the “striking decrease in coronary heart disease complications” reported by the trial investigators. Instead, the reanalysis has called into question the involvement of drug companies in such clinical trials, according to an article in the June 28 issue of the Archives of Internal Medicine. (5)
Another systematic review to determine the effects (benefits and harms of statins) for primary prevention of cardiovascular disease (CVD) was recently done. The authors searched databases and assessed 14 randomized control trials with a total of 34,272 subjects from 1994-2006. It compared statins to usual care or placebo. The studies included treatment for a minimum of one year and consisted of a minimum of six months of follow-up. According to the plain-language summary, the results of trials appear confirmatory for statins, but biases exist:
All cause mortality, coronary heart disease and stroke events were reduced with the use of statins as was the need for revascularisations. Statin treatment reduced blood cholesterol. Taking statins did not increase the risk of adverse effects such as cancer and few trials reported on costs or quality of life. (6)
Sounds good right?
Read on, as the authors reported some issues how these conclusions came about:
This current systematic review highlights the shortcomings in the published trials and we recommend that caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk. (6)
What Are Statins REALLY Doing?
Interestingly, as reported above, there is some evidence that for secondary prevention, statins may be helpful. However, it may not be due to their attack on your livers’ production of cholesterol, but on various other effects that are multifactorial (pleiotropic). One such study reported on another factor, statins’ antioxidant effects, as a possible mechanism for efficacy. (My note…this could explain the discrepancy in findings of secondary and primary prevention):
Cardiovascular diseases, which are the leading cause of mortality in the Western World, are closely associated with atherosclerosis development. Atherosclerosis is a chronic multifactorial disease of the arterial wall characterized by endothelial dysfunction, inflammation and oxidative stress. Oxidative stress is an alteration of the balance between pro-oxidant and antioxidant mechanisms which promotes vascular complications and represents a valid therapeutic target to prevent or treat cardiovascular diseases. Statins are enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that have been included in the therapeutic regimen of cardiovascular diseases due to their lipid-lowering activity. Experimental and clinical data demonstrated that the antiatherogenic effects of these drugs are also related to other pleiotropic activities, particularly to their anti-inflammatory, anti-thrombotic and antioxidant effects. This review summarizes experimental and clinical studies demonstrating the impact of statins on atherosclerotic disease with a focus on the antioxidant activity of atorvastatin. Atorvastatin is a synthetic statin characterized by a high efficacy, in part due to its longer half-life compared to other molecules of the same group. It also exerts high antioxidant effects, independent from its hypolipidemic activity, beneficial for the prevention and therapy of atherosclerosis. (7)
Furthermore, a recent sub-study sought to determine the relationship between lipid and non-lipid biomarkers’ levels achieved during statin therapy and the incidence of MCVEs (major cardiovascular events) in patients with stable coronary heart disease (CHD). The study was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin on those with stabilized coronary artery disease. This was done by assessing fasting plasma levels of standard lipids and also included 18 non-lipid biomarkers. The study was an 8-week trial comparison between 157 subjects on atorvastatin 10 mg who experienced major cardiovascular events (MCVEs) and 1,349 controls after 4.9 years follow up. The authors reported, that of all the lipid and non-lipid biomarkers studied, “only Lp(a) showed a modest interaction with the atorvastatin dose in predicting outcomes after 1 year of atorvastatin therapy as all other biomarkers did not interact with statin dose in prediction outcomes after one year.”
They also concluded that Lp(a), neopterin, NT-proBNP and sRAGE related to MCVE remained statistically significant after adjustments and stated, “ In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs.”
Finally, they discussed another factor in predicting outcomes when they reported on findings of other studies linking “genetic variations at the LPA locus as the second most important loci influencing LDL cholesterol reductions (after APOE) upon atorvastatin therapy.” (8)
All these factors combined suggest that the link between heart disease and cholesterol is more complex than a low LDL and total cholesterol level on labs.
Several other analyses have supported this finding by shining light on the biases in studies reporting statin benefits in heart disease outcomes. Specifically, there are issues with conclusions that have linked the role of lower cholesterol to lowered mortality and evidence that benefits-to-harms ratios were ignored.(9-10)
The Age Factor
Interestingly, an observational study actually found increased mortality in a cohort of 80+ year olds with low cholesterol. The study included a total of 12 articles corresponding to 13,622 participants: 3,789 aged 80 and above from eight studies and 9,833 aged 71–103 (mean age 78 years) from four studies. The authors concluded:
Low TC (<5.5 mmol/l) is associated with increased mortality among 80+-year olds. There was no clear optimal level of cholesterol in 80+-year-old people. Some studies found the intermediate level of the cholesterol (around 6 mmol/l) to be associated with the lowest mortality, but this was not consistent (Figure 2). Few data on TC and mortality are available on 80+-year olds.
No conflicts of interest reported. (11)
Furthermore, a population-based study of interviewees in a nationally representative sample of elderly Costa Ricans occurred around 2005. Mortality follow-ups were done in December 2010, and the authors concluded the following:
This study adds to the growing evidence that blood markers for CRP, HbA1c, and DHEAS, along with organ-specific functional reserve indicators (handgrip, walking speed, and pulmonary peak flow), are valuable tools for identifying vulnerable elderly. The results also highlight the need to better understand an anomaly noted previously in other settings: despite the continued medical focus on drugs for BP and cholesterol, high levels of BP and cholesterol have little predictive value of mortality in this elderly population. (12)
This may mean that blood pressure and cholesterol may be the result of an underlying cause that isn’t being addressed.
The Gender Factor
Although a recent analysis of LDL-lowering among men and women reported similar benefits (13), what the authors may have overlooked is the fact that another analysis in 2012 of eleven trials representing 43,193 patients reported that, overall, statin therapy was associated with a reduced risk of cardiovascular events in men and women but they didn’t reduce all-cause mortality in either sexes. Furthermore, statins weren’t effective in preventing stroke in women. The authors concluded that:
Statin therapy is an effective intervention in the secondary prevention of cardiovascular events in both sexes, but there is no benefit on stroke and all-cause mortality in women. (14)
A recent study examined the presence and absence of 5 major traditional coronary heart disease risk factors (hypertension, smoking, dyslipidemia, diabetes, and family history of coronary heart disease) and hospital mortality among 542,008 patients with first myocardial infarction and without prior cardiovascular disease. The authors admitted that the study being observational, could have selection bias and other confounders, but still concluded that all of these components together are factors in determining cardiovascular mortality:
We confirm the high likelihood of risk factor prevalence in patients with first MI, which is consistent with results of previous literature. We found that hospital mortality increased consistently as the number of risk factors declined, which may be due to residual confounding from older age and other unmeasured factors, although this finding persisted even after extensive adjustment for clinical factors and in subgroups stratified by age and severity. Future studies should seek to gain insight into the possible explanations of such an association. (15)
Despite the facts listed above, today more people are being offered statins due to new guidelines issued by the American Heart Association and American College of Cardiology. (16)
What To Do If the Cholesterol Boogie Man Got You?
So, what do you do if you have high cholesterol? Watch Dr. Mercola discuss the 7 factors to consider if you’re told you have high cholesterol. (17-18)
What About Eggs?
No worries, I address this here.
(1) Centers for Disease Control and Prevention (CDC). Cholesterol Fact Sheet. July 22, 2014 (updated). http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_cholesterol.htm
(2) CDC. Vital Signs: Prevalence, Treatment, and Control of High Levels of Low-Density Lipoprotein Cholesterol — United States, 1999–2002 and 2005—2008. Morbidity and Mortality Weekly. February 4, 2011 / 60(04);109-114. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6004a5.htm?s_cid=mm6004a5_w
(3) Ward S, Lloyd Jones M, Pandor A, et al. A systematic review and economic evaluation of statins for the prevention of coronary events. Health Technol Assess. 2007;11:1–160, iii–iv.
(4) Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med. 2008; 359:2195-2207November 20, 2008. DOI: 10.1056/NEJMoa0807646
(5) Bankhead, C. Should Healthy People Take Statins? New Studies Say No. Medpage Today. June 28, 2010. http://www.medpagetoday.com/Cardiology/Prevention/20948. Accessed January 1, 2014.
(6) Taylor F, Ward K, Moore TH, et al. Statins for the primary prevention of cardiovascular disease. The Cochrane database of systematic reviews 2011;(1):CD004816. doi:10.1002/14651858.CD004816.pub4.
(7) Pleiotropic effects of statins in atherosclerotic disease: focus on the antioxidant activity of atorvastatin. Curr Top Med Chem. 2014;14(22):2542-51. http://www.ncbi.nlm.nih.gov/pubmed/25478882
(8) Arsenault BJ, Barter P, DeMicco DA, et al., for the Treating to New Targets (TNT) Investigators, the Treating to New Targets (TNT) Investigators. Prediction of Cardiovascular Events in Statin-Treated Stable Coronary Patients of the Treating to New Targets Randomized Controlled Trial by Lipid and Non-Lipid Biomarkers. Berger JS, ed. PLoS ONE 2014;9(12):e114519. doi:10.1371/journal.pone.0114519.
(9) Newman, D. Statins Given for 5 Years for Heart Disease Prevention (With Known Heart Disease. The NNT. November 2, 2013. http://www.thennt.com/nnt/statins-for-heart-disease-prevention-with-known-heart-disease/. Accessed January 1, 2015.
(10) Thavendiranathan P. Primary prevention of cardiovascular disease with statin therapy. Arch Int Med. 2006; 166: 2307-13. CTT Collaborators. Ef?cacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet. 2005; 366: 1267-1278.
(11) 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 and Ageing. 2010;39(6):674-680. doi:10.1093/ageing/afq129.
(12) Rosero-Bixby L, Dow WH. Predicting mortality with biomarkers: a population-based prospective cohort study for elderly Costa Ricans. Population Health Metrics.2012;10:11. doi:10.1186/1478-7954-10-11.
(13) 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 Jan 8. pii: S0140-6736(14)61368-4. doi: 10.1016/S0140-6736(14)61368-4. [Epub ahead of print]
(14) Gutierrez J, Ramirez G, Rundek T, Sacco RL. Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis. Arch Intern Med. 2012 Jun 25;172(12):909-19. doi: 10.1001/archinternmed.2012.2145.
(15) Number of Coronary Heart Disease Risk Factors and Mortality in Patients With First Myocardial Infarction JAMA. 2011;306(19):2120-2127. doi:10.1001/jama.2011.1654.
(16) Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014 Apr 10;370(15):1422-31. doi: 10.1056/NEJMoa1315665. Epub 2014 Mar 19.
(17) Factors to Consider if You’re Told Your Cholesterol Is Too High. Mercola.com. January 12, 2015. http://articles.mercola.com/sites/articles/archive/2015/01/12/7-factors-cholesterol-levels.aspx
(18) Toothbrushing, inflammation, and risk of cardiovascular disease: results from Scottish Health Survey. BMJ 2010; 340 doi: http://dx.doi.org/10.1136/bmj.c2451
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