LDL Cholesterol Particle Size and Number What Gives ?

Posted on February 27, 2018

LDL Particle Size and Particle Number, What Gives?

Ron is a 72 year old retired engineer, and has a total cholesterol of 174 which hasn’t changed over the seven years we have been following him. This is quite low. Yet, Ron is concerned because his LDL particle number and LDL particle size are “outside of the lab range”.  He is very worried about this and is concerned about his risk for future heart attack.  I explained to Ron the lab range doesn’t apply to him.  Ron’s Calcium Score is low, and his total cholesterol is 174, and he does not have metabolic syndrome or diabetes, so he doesn’t need to worry about the LDL particle size or particle number.

What does the mainstream cardiology say about the value of LDL particle size and number?

The Quebec Study – Small Dense LDL Associated with Increased Mortality from Coronary Artery Disease

You might say “wait just a minute here”, the Quebec study followed 2072 males over 13 years and found that small dense LDL was associated with increased mortality from cardiovascular disease above chart).(6)  The above chart is very convincing, and the three lines for small dense LDL are nicely separated. (6) However, as pretty as the above chart looks, Correlation is not necessarily causation.  If increased small dense LDL particle number causes coronary artery disease, then an intervention that reduces small dense LDL particles should be preventive.  However we know that it is not. Above image courtesy of Medscape.

Houston, We Have a Problem,  New Drug Reduces Small LDL,

However, No Benefit in Preventing Heart Disease

Treatment with the new cholesterol lowering drug, Evacetrapib, resulted in significant decreases in “total LDL particle number (LDL-P) (up to -54%), and small LDL particle (sLDL) (up to -95%) concentrations”.(5) Yet, according to Dr Lincoff in NEJM 2017,

“treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease.”(4)

As a matter of fact, Eli Lilly abandoned drug development after this failed study.(4)  So we see that reducing total LDL particle number, or increasing LDL particle size had no benefit for preventing death from heart disease.  The benefit was same as a placebo.

Dr Allaire  agrees that LDL particle size is not very useful.  Dr Allaire writes in 2017 Current Opinion in Lipidology:(1)

“LDL particle size….has not been independently associated with CVD risk after adjustment for other risk factors such as LDL cholesterol, triglycerides, and HDL-C and that routine use of information pertaining to particle size to determine and manage patients’ risk is not yet justified.”(1)

In other words, according to Dr Allaire,  the LDL particle size is not a good predictor of cardiovascular risk.(1)

Predicting Risk: LDL Subfraction Vs. Calcium Score

The next question you might ask: “If LDL cholesterol is not helpful, then what other test is useful for predicting risk of cardiovascular disease?” 

The answer is the Calcium Score which is an inexpensive test which uses a CAT scan to measure the amount of calcium in the coronary arteries.  Studies show that the higher the number the greater the risk, the lower the number the smaller the risk.  None of the cholesterol subfractions can provide this type of information, and in my opinion should be relegated to the medial museum, as a relic from the past.

Conclusion: When it comes down to a contest between LDL Cholesterol Subfractions and Calcium Score, there is no contest.  The Calcium Score wins every time.

Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie Florida 33314
954 792-4663

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Links and References

Header Image LDL particle courtesy of Drs Wolfson

1) Curr Opin Lipidol. 2017 Jun;28(3):261-266. LDL particle number and size and cardiovascular risk: anything new under the sun? Allaire J1, Vors C, Couture P, Lamarche B.

LDL particle size, on the other hand, has not been independently associated with CVD risk after adjustment for other risk factors such as LDL cholesterol, triglycerides, and HDL-C and that routine use of information pertaining to particle size to determine and manage patients’ risk is not yet justified.

We provide here an up-to-date perspective on the potential use of LDL particle number and size as complementary risk factors to predict and manage cardiovascular disease (CVD) risk in the clinical realm.
RECENT FINDINGS:  Studies show that a significant proportion of the population has discordant LDL particle number and cholesterol indices [non-HDL cholesterol (HDL-C)]. Data also show that risk prediction may be improved when using information on LDL particle number in patients with discordant particle number and cholesterol data. Yet, most of the current CVD guidelines conclude that LDL particle number is not superior to cholesterol indices, including non-HDL-C concentrations, in predicting CVD risk. LDL particle size, on the other hand, has not been independently associated with CVD risk after adjustment for other risk factors such as LDL cholesterol, triglycerides, and HDL-C and that routine use of information pertaining to particle size to determine and manage patients’ risk is not yet justified.
SUMMARY:  Additional studies are required to settle the debate on which of cholesterol indices and LDL particle number is the best predictor of CVD risk, and if such measures should be integrated in clinical practice.

Women with discordant high particle concentration were more likely to have metabolic syndrome (MetS) and diabetes

2) Clin Chem. 2017 Apr;63(4):870-879. doi: 10.1373/clinchem.2016.264515. Epub 2017 Feb 7.  Discordance between Circulating Atherogenic Cholesterol Mass and Lipoprotein Particle Concentration in Relation to Future Coronary Events in Women.
Lawler PR1,2,3,4, Akinkuolie AO1,3, Ridker PM2,3, Sniderman AD5, Buring JE3,4, Glynn RJ3,4, Chasman DI3, Mora S6,2,3.
It is uncertain whether measurement of circulating total atherogenic lipoprotein particle cholesterol mass [non-HDL cholesterol (nonHDLc)] or particle concentration [apolipoprotein B (apo B) and LDL particle concentration (LDLp)] more accurately reflects risk of incident coronary heart disease (CHD). We evaluated CHD risk among women in whom these markers where discordant.
METHODS:Among 27533 initially healthy women in the Women’s Health Study (NCT00000479), using residuals from linear regression models, we compared risk among women with higher or lower observed particle concentration relative to nonHDLc (highest and lowest residual quartiles, respectively) to individuals with agreement between markers (middle quartiles) using Cox proportional hazards models.
RESULTS:Although all 3 biomarkers were correlated (r ≥ 0.77), discordance occurred in up to 20.2% of women. Women with discordant high particle concentration were more likely to have metabolic syndrome (MetS) and diabetes (both P < 0.001). Over a median follow-up of 20.4 years, 1246 CHD events occurred (514725 person-years). Women with high particle concentration relative to nonHDLc had increased CHD risk: age-adjusted hazard ratio (95% CI) = 1.77 (1.56-2.00) for apo B and 1.70 (1.50-1.92) for LDLp. After adjustment for clinical risk factors including MetS, these risks attenuated to 1.22 (1.07-1.39) for apo B and 1.13 (0.99-1.29) for LDLp. Discordant low apo B or LDLp relative to nonHDLc was not associated with lower risk.
CONCLUSIONS:Discordance between atherogenic particle cholesterol mass and particle concentration occurs in a sizeable proportion of apparently healthy women and should be suspected clinically among women with cardiometabolic traits. In such women, direct measurement of lipoprotein particle concentration might better inform CHD risk assessment.

3)   Curr Opin Endocrinol Diabetes Obes. 2018 Jan 10. Discordance between lipoprotein particle number and cholesterol content: an update.
Cantey EP1, Wilkins JT2.
The cholesterol content within atherogenic apolipoprotein-B (apoB) containing lipid particles is the center of consensus guidelines and clinicians’ focus whenever evaluating a patient’s risk for atherosclerotic cardiovascular disease. The pathobiology of atherosclerosis requires the retention of lipoprotein particles within the vascular intima over time followed by maladaptive inflammation resulting in plaque formation and rupture in some. The cholesterol content is widely variable within each particle creating either cholesterol-deplete or cholesterol-enriched particles. This variance in particle cholesterol content varies within and between individuals. Discordance analysis exploits this difference in cholesterol content of particles to demonstrate the differential significance of LDL-cholesterol (LDL-C) and non-HDL-C from measures of lipoprotein particle number in terms of assessing atherosclerotic cardiovascular disease risks.
RECENT FINDINGS:Three studies have added to the growing body of literature of discordance analysis. Despite wide variability of discordance cutoffs, baseline risk of atherosclerotic disease, and populations sampled, the conclusion remains the same: risk of atherosclerotic disease follows apoB lipid particle concentration rather than cholesterol content of lipid particles.
SUMMARY:In addition to traditional lipid fractions, assessments of atherogenic particle number should be strongly considered whenever assessing CVD risk in nontreated and treated individuals. There is a need for clinical trials that focus not only on the reduction in LDL-C but apoB, as well.

4)  Lincoff, A. Michael, et al. “Evacetrapib and cardiovascular outcomes in high-risk vascular disease.” New England Journal of Medicine 376.20 (2017): 1933-1942.

Although treatment with evacetrapib has resulted in reductions of 60 to 70% in the levels of small dense LDL particles,29 effects on the total number of LDL particles and on apolipoprotein B levels (reductions of 22% and 20%, respectively) are considerably less pronounced.

CONCLUSIONS:Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease.

5)  Nicholls SJ, Ruotolo G, Brewer HB, et al. Evacetrapib alone or in combination with statins lowers lipoprotein(a) and total and small LDL particle concentrations in mildly hypercholesterolemic patients. J Clin Lipidol 2016;10:519-527.e4

Potent CETP inhibitors reduce plasma concentrations of atherogenic lipoprotein biomarkers of cardiovascular risk.
OBJECTIVES:To evaluate the effects of the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, as monotherapy or with statins, on atherogenic apolipoprotein B (apoB)-containing lipoproteins in mildly hypercholesterolemic patients.
METHODS:VLDL and LDL particle concentrations and sizes (using nuclear magnetic resonance spectroscopy) and lipoprotein(a) concentration (using nephelometry) were measured at baseline and week 12 in a placebo-controlled trial of 393 patients treated with evacetrapib as monotherapy (30 mg/d, 100 mg/d, or 500 mg/d) or in combination with statins (100 mg plus simvastatin 40 mg/d, atorvastatin 20 mg/d, or rosuvastatin 10 mg/d; Clinicaltrials.gov Identifier: NCT01105975).
RESULTS:Evacetrapib monotherapy resulted in significant placebo-adjusted dose-dependent decreases from baseline in Lp(a) (up to -40% with evacetrapib 500 mg), total LDL particle (LDL-P) (up to -54%), and small LDL particle (sLDL) (up to -95%) concentrations. Compared to statin alone, coadministration of evacetrapib and statins also resulted in significant reduction from baseline in Lp(a) (-31%), LDL-P (-22%), and sLDL (-60%) concentrations. The percentage of patients with concentrations above optimal concentrations for LDL-P (>1000 nmol/L) and sLDL (>600 nmol/L) decreased from 88% and 55% at baseline, respectively, to 20% and 12% at week 12, for patients treated with evacetrapib plus statins. Evacetrapib, alone or with statins, significantly increased LDL-P size.

CONCLUSIONS:Evacetrapib, as monotherapy or with statins, significantly reduces the concentrations of atherogenic apoB-containing lipoproteins, including Lp(a), LDL-P, and sLDL.

6) St-Pierre, Annie C., et al. “Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Quebec Cardiovascular Study.” Arteriosclerosis, thrombosis, and vascular biology 25.3 (2005): 553-559.Low density lipoprotein Risk of ischemic heart disease Quebec St Pierre Annie Arterio thrombo vasc bio 2005

The objective of the present study was to investigate the association between large and small low-density lipoprotein (LDL) and long-term ischemic heart disease (IHD) risk in men of the Quebec Cardiovascular Study.
METHODS AND RESULTS:Cholesterol levels in the large and small LDL subfractions (termed LDL-C> or =260A and LDL-C<255a 13="" 2072="" 262="" a="" all="" and="" angina="" at="" baseline="" cardiovascular="" cohort="" coronary="" death="" during="" electrophoresis="" estimated="" events="" examination="" first="" followed-up="" for="" free="" from="" gel="" gradient="" ihd="" in="" infarction="" men="" myocardial="" nbsp="" nonfatal="" of="" pectoris="" period="" plasma="" polyacrylamide="" population-based="" quebec="" recorded.="" respectively="" strong="" study.="" style="border: 0px; font-family: inherit; font-style: inherit; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;" the="" unstable="" were="" which="" whole="" years="">Our study confirmed the strong and independent association between LDL-C<255a a="" and="" as="" dense="" ihd="" in="" ldl="" levels="" men="" of="" phenotype="" proxy="" risk="" small="" strong="" the="">, particularly over the first 7 years of follow-up. However, elevated LDL-C> or =260A levels (third versus first tertile) were not associated with an increased risk of IHD over the 13-year follow-up (RR=0.76; P=0.07).

CONCLUSIONS:These results indicated that estimated cholesterol levels in the large LDL subfraction were not associated with an increased risk of IHD in men and that the cardiovascular risk attributable to variations in the LDL size phenotype was largely related to markers of a preferential accumulation of small dense LDL particles.

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Read the complete article here.

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease - Gibson

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease


C. Michael Gibson MD‏           

 

Proud to be co-author of this New England Journal Med article showing lowering LDL does not always improve outcomes

Background

The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease.

Conclusions

Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease.

 (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998.)


Read the complete article here.

Cholesterol Paradox: A Correlate Does Not a Surrogate Make

Abstract

The global campaign to lower cholesterol by diet and drugs has failed to thwart the developing pandemic of coronary heart disease around the world. Some experts believe this failure is due to the explosive rise in obesity and diabetes, but it is equally plausible that the cholesterol hypothesis, which posits that lowering cholesterol prevents cardiovascular disease, is incorrect. The recently presented ACCELERATE trial dumbfounded many experts by failing to demonstrate any cardiovascular benefit of evacetrapib despite dramatically lowering low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol in high-risk patients with coronary disease. This clinical trial adds to a growing volume of knowledge that challenges the validity of the cholesterol hypothesis and the utility of cholesterol as a surrogate end point. Inadvertently, the cholesterol hypothesis may have even contributed to this pandemic. This perspective critically reviews this evidence and our reluctance to acknowledge contradictory information.


Read the complete article here.

The Functional Medicine Approach to High Cholesterol

"The message that “cholesterol is bad and if you have high cholesterol you should take a statin to lower it” is out of date and not in sync with the most recent scientific evidence. Unfortunately, the latest findings have not trickled down to the average primary care doctor—or even the average cardiologist. Today I discuss the six underlying causes of high cholesterol and how addressing those issues can often alleviate the need to take statins."

The Functional Medicine Approach to High Cholesterol

Study says there's no link between cholesterol and heart disease

Mon, 13 Jun 2016 12:33:00 EST

"Controversial report claims there's no link between 'bad cholesterol' and heart disease," the Daily Mail reports, while The Times states: "Bad cholesterol 'helps you live longer',".
The headlines are based on a new review which aimed to gather evidence from previous observational studies on whether LDL cholesterol (so-called "bad cholesterol") was linked with mortality in older adults aged over 60. The conventional view is that having high LDL cholesterol levels increases your risk of dying of cardiovascular diseases, such as heart disease.
Researchers chose 30 studies in total to analyse. 28 studies looked at the link with death from any cause. Twelve found no link between LDL and mortality, but 16 actually found that lower LDL was linked with higher mortality risk – the opposite to what was expected.
Only nine studies looked at cardiovascular mortality link specifically – seven found no link and two found the opposite link to what was expected.
However, there are many important limitations to this review. This includes the possibility that the search methods may have missed relevant studies, not looking at levels of other blood fats (e.g. total and HDL cholesterol), and the possibility that other health and lifestyle factors are influencing the link.
Most importantly, as the researchers acknowledge, these findings do not take account of statin use, which lowers cholesterol. People found to have high LDL cholesterol at the study's start may have subsequently been started on statins, which could have prevented deaths. 

Where did the story come from?

The study was carried out by researchers from the University of South Florida, the Japan Institute of Pharmacovigilance and various other international institutions in Japan, Sweden, UK, Ireland, US and Italy.
Funding was provided by the Western Vascular Institute. The study was published in the peer-reviewed BMJ Open and, as the journal name suggests, the article is open-access, so can be read for free.
Four of the study authors have previously written book(s) criticising "the cholesterol hypothesis". It should also be noted that nine of the authors are members of THINCS – The International Network of Cholesterol Skeptics. This is described as a group of scientists who "oppose…that animal fat and high cholesterol play a role [in heart disease]".
If you were playing Devil's Advocate, you could argue that this represents a preconceived view of the authors regarding the role of cholesterol, rather than the open, unbiased mind you would hope for in the spirit of scientific enquiry. That said, many important scientific breakthroughs happened due to the efforts of individuals who challenged a prevailing orthodoxy of thinking.
In general, the UK media provided fairly balanced reporting, presenting both sides of the argument – supporting the findings, but with critical views from other experts.

Read the complete article here.

Science News

from research organizations

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Sugar consumption plays greater role in heart disease than saturated fat

Date:

January 13, 2016

Source:

Elsevier

Summary:

Atherosclerotic Coronary Heart Disease (CHD) is responsible for one in every six deaths in the United States as well as being the leading cause of death throughout the developed world. Healthcare professionals have for many years sought to limit and control CHD by focusing on prevention and, from a dietary perspective, on limiting saturated fats.

 

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Atherosclerotic Coronary Heart Disease (CHD) is responsible for one in every six deaths in the United States as well as being the leading cause of death throughout the developed world. Healthcare professionals have for many years sought to limit and control CHD by focusing on prevention and, from a dietary perspective, on limiting saturated fats.

 

In an article published in the journal Progress in Cardiovascular Diseases, Saint Luke's Mid America Heart Institute cardiovascular research scientist and James J.. DiNicolantonio, PharmD, and James H. O'Keefe, MD, examined the question of whether that focus may be misplaced and ask does sugar have a greater impact on coronary heart disease than saturated fat?

The theory of dietary saturated fats as the principal promoter of elevated serum cholesterol and heart disease stems from research beginning in the 1950's by an American scientist Ancel Keys. It was this theory which was embraced by the American Heart Association and the US federal government in the 1960s and 70s. However, at the same time of Keys research, a British physiologist John Yudkin argued that sugar intake was more closely related to incidence of and mortality from CHD.

Both Yudkin and Keys were able to support their theories through observational studies in large part because people eat foods, not isolated food constituents. Dietary sources of saturated fat are also often dietary sources of sugar and people who eat lots of sugar often also eat lots of saturated fat.
Along with co-author, Sean C. Lucan, MD, MPH, MS, from the Albert Einstein College of Medicine, DiNicolantonio and O'Keefe evaluated the evidence to date linking saturated fats and sugars to CHD, considering basic science, epidemiology, and clinical trial data related to CHD risk, CHD events, and CHD mortality. The authors concluded that sugar consumption, particularly in the form of refined added sugars, are a greater contributor to CHD than saturated fats.

"While the original studies upon which the longstanding guidelines were based were largely observational," said DiNicolantonio, "We now have more than a half century of data as well as increased understanding of how nutrition impacts the body and specifically coronary heart disease."
The metabolic aspects of saturated fatty acids (SFAs) are complex but existing research suggests that certain SFAs may actually confer measurable benefits for lipid profiles and CHD risk. For instance, some SFAs increase high-density lipoprotein cholesterol (HDL), which is often referred to as the "good cholesterol" as this lipoprotein is associated with a reduced risk of CHD
Replacing saturated fats, or any other component, from one's diet almost inevitably means replacing it with something else. When carbohydrates, particularly refined carbohydrates like sugar, replace saturated fats, which can have a negative impact on lipid profiles (HDL tends to fall and triglycerides tend to rise).

As stated earlier, people don't eat isolated fatty acids -- they eat foods that are a mix of various fatty acids and other food constituents. While high intakes from processed meats may increase risk of CHD, higher intakes from dairy sources of saturated fat may not only pose no risk but actually decrease risk.

Consuming a diet high in sugar for just a few weeks has been shown to cause numerous abnormalities found in patients with CHD, such as high total cholesterol, triglycerides, LDL, oxidized LDL, uric acid, insulin resistance and abnormal glucose tolerance, low HDL, and altered platelet function. The overall effect of consuming a diet high in sugar on these numerous health markers is likely more detrimental to overall health compared to increased consumption of saturated fat, which can increase LDL but at the same time raise HDL.

Added fructose -- generally in the form of sucrose (table sugar) or high fructose corn syrup (HFCS) in processed foods and beverages seems especially potent for producing harm. Consuming these sugars can lead to resistance in leptin, which is a key hormone in the maintenance of normal body weight. The overconsumption of added fructose undoubtedly increases the risk for obesity, which is also a risk factor for CHD.

Excess fructose also markedly increases the risk for non-alcoholic fatty liver disease (NAFLD) -- the most common liver disease in the US and a strong independent risk factor for CHD. The association between NAFLD and CHD is stronger than the link between CHD and smoking, hypertension, diabetes, male gender, high cholesterol or metabolic syndrome.

Sugars occurring naturally in fruits and vegetables pose no increased risk for CHD. The problem is refined sugars -- with ultraprocessed foods being of greatest concern. Products with added sugars represent 75% of all packaged foods and beverages in the US and most commonly contain sucrose or HFCS, which seem to raise CHD risk even more than other sugars such as glucose.

A diet high in sugar has also been found to promote prediabetes and diabetes. And patients with both of these conditions have a much greater risk for CHD compared to normal healthy patients, particularly a severe narrowing of the left main coronary artery.

Ultra-processed foods also tend to be sources of saturated fats but the harms associated with eating these products may have nothing to do with the fat and everything to do with processed foods themselves. Therefore, best advice is to avoid processed foods rather than to simply avoid SFAs as avoiding SFAs might direct people away from foods that are not only completely benign but actually beneficial (such as dairy foods) but also steer people towards foods that may be harmful -- i.e. low-fat, ultra-processed, with huge amounts of hidden added sugars.

"After a thorough analysis of the evidence it seems appropriate to recommend dietary guidelines shift focus away from recommendations to reduce saturated fat and towards recommendations to avoid added sugars," said Dr DiNicolantonio. "Most importantly recommendations should support the eating of whole foods whenever possible and the avoidance of ultra-processed food."

 

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Journal Reference:

1. James J. DiNicolantonio, Sean C. Lucan, James H. O’Keefe. The Evidence for Saturated Fat and for Sugar Related to Coronary Heart Disease. Progress in Cardiovascular Diseases, 2015; DOI: 10.1016/j.pcad.2015.11.006

Read the complete article here.

WEIGHING UP THE EVIDENCE ON STATINS - Dr Verner Wheelock

WEIGHING UP THE EVIDENCE ON STATINS

Statins are certainly in the news these days. NICE has put forward proposals that all those with a 10% risk of developing heart disease should be treated with statins. Effectively this means that everyone over the age of 50 years, including those who are fit and healthy, would be expected to have the treatment. On the other hand this strategy is being questioned by many within the medical profession. In this blog I will try to tease out the information which individuals need in order to make a sound judgment on whether or not to go on statins.

 

Essentially people need to know if they will derive any benefit from the statins which will have to be balanced against the type, frequency and severity of any side-effects.

 

According to Professor Sir Rory Collins, from Oxford University, GPs and the public are being made unjustifiably suspicious of the drug, creating a situation that has echoes of the MMR vaccine controversy(1). Collins is the leader of the Cholesterol Treatment Trialists’ (CTT) Collaboration which has been analysing data on the effects of statins which has been supplied to them by the drug companies. In their latest report it was claimed that statins significantly reduced major cardiovascular events and all-cause mortality in people at low risk (2). The results of this trial were a critical factor influencing the position taken by NICE.

 

This is somewhat surprising because other studies have concluded that statins are not beneficial to people at low risk. It is also highly relevant that the CTT study has been subject to severe criticisms.

In an exercise of this kind one would expect the investigators to compare the results of those who had been treated with statins with those of a control, consisting of a similar group of people who had not been treated. When this approach has been used, others have not been able to find that there were any appreciable benefits in the statin group. For example, Ray and co-workers analysed the results of 11 clinical trials involving 65,229 participants with approximately 244,000 person-years of follow-up and 2793 deaths (3). All of these individuals were high risk but without previous cardiovascular disease. Over an average treatment period of 3.7 years the use of statin therapy did not result in any reduction in all-cause mortality.

 

By contrast the CTT group has adopted a totally different approach which has been explained by Dr David Newman in an article on his blog (4). Instead of comparing those who were treated with statins with the controls, they selected those individuals in which the statin treatment reduced the LDL Cholesterol 1 mmol/L or 40 points in US terms. As Dr Newman describes it:

 

“…they shifted the data so that their numbers corresponded precisely to patients whose cholesterol responded perfectly.”

 

He goes on:

“Patients whose cholesterol drops 40 points are different than others, and not just because their body had an ideal response to the drug. They may also be taking the drug more regularly, and more motivated. Or they may be exercising more, or eating right, and more health conscious than other patients. So it should be no surprise that this analysis comes up with different numbers than a simple comparison of statins versus placebo pills. Ultimately, then, this new information tells us little or nothing about the benefits someone might expect if they take a statin. Instead it tells us the average benefits among those who had a 40-point drop in LDL.”

 

Furthermore the LDL Cholesterol drop cannot be predicted because the effect of the statins is unknown. This means that the conclusions of this analysis have absolutely no relevance to patients and doctors who have to decide if statins should be prescribed.

Here is a final quote from Dr Newman:

 

“Perhaps never has a statistical deception been so cleverly buried, in plain sight. The study answers this question: how much did the people who responded well to the drug benefit? This is, by definition, a circular and retrospective question: revisiting old data and re-tailoring the question to arrive at a conclusion. And to be fair they may have answered an interesting, and in some ways contributory, question. However the authors’ conclusions imply that they answered a different, much bigger question. And that is not a true story.”

 

But it does not stop here because the CTT also argued that the side-effects of the statin treatments are relatively small. Rhabdomolysis, which is the catastrophic breakdown of muscle tissue, has an excess incidence of about 0.1 per 1000 over 5 years according to CTT calculations. However Dr Malcolm Kendrick, author of “The Great Cholesterol Con” refers to a study conducted in the USA, which analysed data on statin side-effects recorded on the FDA’s Medwatch. Between July 2005 and March 2011 there were 186,796 case reports of which 8,111 were due to rhabdomolysis. This equates to 811 deaths over this period. As it is accepted that reporting rates are extremely low, this figure can be multiplied by a factor of 10 or even 100 to obtain the true value (5). If precedents were followed up this evidence should be more than enough to have the drugs withdrawn.

 

The CTT authors reported a 10% increase in the relative risk of developing diabetes while on statins. This equates to 5 new cases per 1000 people treated for 5 years. However other studies have reported values of up to 50% more (6).

 

Uffe Ravnskov is an independent researcher in Sweden who has suggested that if you are a healthy person who is being advised to go on statins then this is what you should be told before going ahead (7):

 

“Your chance not to get a non-fatal heart event during the next five years ……is 97.1 per cent. You can increase your chance to 98.1 per cent if you take a statin every day. But then your risk of suffering muscle problems is about 25 per cent unless you never exercise (1); your risk of becoming sexually impotent is about 20 per cent (2); your risk of suffering from diabetes is about 4 per cent (3), and you also run a risk of memory loss, liver damage, peripheral neuropathy, cataract, and cancer, but we do not yet know how large these risks are. And don´t forget that many non-fatal heart events may heal with minor health consequences or none at all.”

 

The picture now becomes very clear. The positive results which have been claimed for the CTT study have only been obtained by manipulating the data. Unfortunately this is typical of how the modern pharmaceutical industry functions. It hypes up the benefits and plays down the undesirable side-effects. This is a particularly bad example because the leader of the CTT is a knighted professor from the prestigious University of Oxford. Nevertheless the case which they present should be subject to rigorous examination. It is extremely regrettable that NICE has allowed itself to be taken in by what can only be described as rubbish!

 

There is no doubt that there is growing awareness that the case in support of statins is full of holes. To-day in The Daily Telegraph there is an article by Haroun Gajraj, a vascular surgeon, no less, who decided to stop his treatment with statins. After looking more closely at the research, he concluded that statins were not going to prevent a heart attack and that his cholesterol levels were all but irrelevant. He also draws attention to a recent survey by Pulse magazine, which found that six out of 10 GPs opposed the draft proposal to lower the risk level at which patients are prescribed statins. As many as  55% said they would not take statins themselves or recommend them to a relative, based on the proposed new guidelines(8).

 

REFERENCES

1. http://www.theguardian.com/society/2014/mar/21/-sp-doctors-fears-over-statins-may-cost-lives-says-top-medical-researcher
2. CTT (2012) Lancet 380 pp 581-590.
3. http://archinte.jamanetwork.com/article.aspx?articleid=416105
4. http://cardiobrief.org/2012/05/27/guest-post-data-drugs-and-deception-a-true-story/
5. http://drmalcolmkendrick.org/tag/rhabdomyolysis/
6. http://www.abc.net.au/catalyst/heartofthematter/download/StatinsshouldNOTbebroadedtowiderpopulation.pdf
7. http://www.bmj.com/content/348/bmj.g280?tab=responses
8. http://www.telegraph.co.uk/health/10717431/Why-Ive-ditched-statins-for-good.html

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Read the complete article here.

The games played to protect the cholesterol hypothesis are, literally, endless. - Malcolm Kendrick

The planet Vulcan

  

I love reading about the history of science. In part, because I think you can learn so much about the process of thinking itself. Especially when it goes wrong. More especially when you are looking at the process of immunisation.

Immunisation is something that Karl Popper was particularly interested in. Popper was a scientific philosopher who is a bit of a hero of mine (when I can actually understand what he is saying). Amongst many other things, he was interested in the techniques used by scientists to protect favoured scientific hypotheses, which he called ‘immunisations’.

An immunisation is essentially a way of explaining why a fact, which appears to contradict a favoured hypothesis, does not actually contradict it at all. For example, when it was found that the orbit of the planet mercury could not be explained by classical Newtonian physics, a mathematician called Le Verrier postulated that there must be another, smaller, planet inside the orbit of Mercury that was affecting Mercury’s orbit. The planet Vulcan.

Vulcan was invisible – primarily because it did not exist. But for many years the invisible and non-existent planet served its purpose. It protected classical Newtonian physics from a potential contradiction, or refutation. Or, to be more blunt, of being simply wrong. In this case, scientists were quite happy to believe in invisible non-existent things, if the alternative was to cast aside a hallowed hypothesis.

Of course, this is just one of thousands of examples whereby unwelcome facts have been simply swatted aside, or immunised against. It is not just the Catholic Church that refuses to look through telescopes.

Vulcan, although just one example, does provide a good case study of a widely used form of immunisation tactic, the ‘ad-hoc’ hypothesis. An ad-hoc hypothesis is a secondary hypothesis that is bolted on to the side of the main hypothesis in order to defend it, or protect it. A more recent example of this can be seen in the Global warming debate.

It has been noted that global temperatures have not increased by much, if at all, in the last 15 years. This, however, is not viewed as a contradiction to the hypothesis of man-made global warming. Why not? Because it is argued that the oceans are taking in the excess heat, and trapping it. This process has held back the degree of global warming that had been predicted by the experts.

I am not going to debate whether or not this is true. I am just using it as a more recent example of an ‘ad-hoc’ hypothesis which came into existence to protect the central hypothesis. I would further add that ad-hoc hypothesis are not always wrong. They can very often be right. Le Verrier, prior to inventing the planet Vulcan, had predicted the presence of the plant Neptune due to irregularities in the orbit of Uranus.

However, if you read his works, you will know that Popper was not a fan of ad-hoc hypotheses. He felt that a good hypothesis should be fully predictive of future ‘events’ without the need for additional explanations, adaptations, or suchlike.

He did not state how many ad-hoc hypotheses it took before you had to admit defeat. One, ten, a hundred, a thousand? No-one can give you a clear cut figure, but the more of them there are, the less likely it is your central hypothesis was correct in the first place. The phenomenon of adaptation/immunisation had been recognised many years before Popper.

‘A nice adaptation of conditions will make almost any hypothesis agree with the phenomenon. This will please the imagination, but does not advance our knowledge.’ J Black 1803
I have recently been pondering the ad-hoc hypothesis once more in relation to heart disease. For I suspect that never in the history of science has a central hypothesis had so many ad-hoc hypotheses bolted on to it. Indeed, we have now reached the point where ad-hoc hypotheses have had ad-hoc hypotheses bolted onto them, to protect the ad-hoc hypotheses themselves from being refuted.
Just to look at one example. There are a number of drugs that have been developed to raise High Density Lipoproteins (HDL), the supposed ‘good’ cholesterol. A few of them also lower LDL ‘bad’ cholesterol at the same time. Billions have been spend on this class of drugs known as ‘trapibs’ . The first of these was Torcetrapib.

At this point I should probably remind you that the ‘good’ cholesterol hypothesis was only created as an ad-hoc hypothesis to explain why some/many people with high total cholesterol levels do not suffer from heart disease. ‘It’s because they have a high HDL level.’

The logic here was obvious, if horribly facile. Raise the HDL and reduce the risk of heart disease. Anyway, ignore the chasms of logic, along came the ‘trapibs’, which were going to take over from statins:

‘Hailed as a potential blockbuster that could take Lipitor’s place, torcetrapib was a cholesteryl-ester transfer protein inhibitor (CEP-T inhibitor) designed to increase good cholesterol and lower bad cholesterol. Development of the drug began in 1990 with clinical trials starting nine years later. But it wasn’t until 2006 that Pfizer got close to submitting the drug to the FDA. The company touted torcetrapib as the answer to its near-term pipeline woes, predicting the potential blockbuster could make up for billions of dollars in lost Lipitor sales when that drug went off patent in 2011.’
Well, torcetrapib certain raised HDL by about 50%, and lowered LDL by about 10%. So, what could possibly go wrong?

‘What went wrong: In late 2006, the walls came crashing down around the company. Pfizer announced in December that it was halting development of it’s prized Phase III asset. The decision came after an independent Data Safety Monitoring Board recommended terminating the study because of an imbalance of mortality and cardiovascular events. Results from a 15,000-person trial showed that patients taking torcetrapib with Lipitor experienced excess deaths than those taking Lipitor alone. Not long after torcetrapib demise, Pfizer announced that it was cutting 10,000 jobs. The company spent $800 million developing the drug.’ http://www.fiercepharma.com/special-reports/pharmas-biggest-flops/torcetrapib-pharmas-biggest-flops

What went wrong was the Torcetrapib increased cardiovascular deaths about around 50% (relative increase in risk). Several other ‘trapibs’ have since come, failed, and slunk from the playing field, taking many billions down the drain with them. Yes, I know, you have never heard of them. At the risk of sounding rather big-headed, I predicted their total and abject failure long before the results of the clinical trials came out.

Now, there are those of us i.e. me who would suggest that this blows a hole in the entire good, bad, cholesterol hypothesis. But no. Why not? Because it was found that torcetrapib raised the blood pressure, and lowered potassium levels. This, it seems, was enough to explain the massive rise in CV mortality. Well, quite reasonable, you might say. Yes, but the rise in BP was minute, and the drop in potassium was equally minute. This could explain, perhaps, a 5% rise (at most) in CV mortality. Which should have been overwhelmed by the massive rise in HDL, and drop in LDL.

But no-one was going to look too closely into the figures themselves. An ad-hoc hypothesis had been found. The ‘experts’, rather than questioning the central good/bad cholesterol hypothesis simply bolted on the ‘BP rise, potassium falls’ ad-hoc immunisation device and moved on.

So, here we have an ad-hoc hypothesis, bolted onto an ad-hoc hypothesis, bolted onto the central hypothesis. We have another planet inside the invisible planet Vulcan, to explain why it is so difficult to find the planet Vulcan.

As you can see, the games played to protect the cholesterol hypothesis are, literally, endless. I am not sure when the games end? Perhaps they never do. Very clever people, given enough time and money can, it seems, twist reality round and round, inside out and upside down forever. I would call the process vulcanisation, but I think that has something to do with rubber.
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Early atherogenesis and visceral fat in obese adolescents

 

Early atherogenesis and visceral fat in obese adolescents

A H Slyper, H Rosenberg, A Kabra, M J Weiss, B Blech, S Gensler and M Matsumura

Abstract

Background/Objectives:

 

Little information is available as to the cause of increased thickening of the intima-media of the carotid artery (cIMT) in the pediatric population. Therefore, cIMT was compared in obese adolescents and normal-weight controls, and associations between cIMT and lipid and non-lipid cardiovascular risk factors were assessed.

Subjects/Methods:

 

Subjects included 61 obese non-diabetic male and female volunteers aged 12–18 years inclusive with a body mass index (BMI) >95th percentile for age and 2-h blood glucose <200 class="mb" span=""> 

mg dl⁻¹ matched to 25 normal-weight control volunteers with normal glucose levels. Each subject underwent a 2-h glucose tolerance test and measurement of hemoglobin A1c, ultrasensitive C-reactive protein, fasting insulin, blood lipids, visceral, subcutaneous abdominal and hepatic fat, and cIMT.

Results:

 

Maximum cIMT was 0.647±0.075 mm in the obese subjects versus 0.579±0.027 mm in normal-weight controls (P<0 .001="" 2-h="" and="" assessment="" between="" bmi="" cholesterol="" cimt="" correlations="" difference="" fasting="" female="" glucose="" hdl="" high-density="" homeostasis="" in="" insulin="" ldl="" lipoprotein="" low-density="" male="" maximum="" model="" no="" significant="" sub="" subjects.="" there="" total="" very="" was="" were="" z-score="">2

cholesterol, HDL₃ cholesterol, triglycerides, remnant lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, lipoprotein(a), apoprotein B100, abdominal subcutaneous fat volume, visceral fat volume and hepatic phase difference. On multiple regression analysis, visceral fat was the most significant predictor of maximum cIMT. Two-hour blood glucose, HOMA and systolic blood pressure were also significant predictors of maximum cIMT.

Conclusions:

 

cIMT was increased in the obese adolescents compared with the normal-weight-matched controls. Visceral fat was a key predictor of arterial wall thickening in these subjects. The results suggest that the focus of cardiovascular disease prevention in the adolescent obese should be visceral obesity, and not blood lipids or lipid subclasses.

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International Journal of Obesity (23 January 2014) | doi:10.1038/ijo.2014.11

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Low Cholesterol’s Cancer Link Illustrates Innate Intelligence - Campos

Low Cholesterol’s Cancer Link Illustrates Innate Intelligence

Dr. Nick Campos

 

Oh boy, here we go…so you know that I’m not shy about discussing my health. I’ve got nothing to hide, and I approach my health from a very proactive position. I also have a belief system that is integral to how I care for my health—I know that one day I am going to die, could be tomorrow, but for me to experience my life to the fullest today, I am quite certain that it requires me to care for my body as one of my most valuable assets. So I don’t obsess about “never getting sick,” I just treat my body like I love it, and I trust that it knows—through its innate intelligence–how to run my body, provided I treat it in the right ways. Simple.

So long-time readers of this blog will recall that I have high cholesterol. Have I ever been worried about it? No, never. Not even a little. In fact, I just had my annual physical in February. Once again, stellar health, thank you, thank you…athlete’s numbers…’cept I have high cholesterol.

If you’ve been following my story, you’ll recall that my doc (love him, bless his heart…and I mean that sincerely; he is the greatest) has, of course, recommended I go on statins. Now I’ve got my inner theories about it, regarding liability and stuff like that, but whatever…he knows I’m not going to take them. It’s simple: my HDL levels (“good” cholesterol) are above and beyond excellent. My total cholesterol to HDL ratio is at the “optimum” level. Ha ha ha…I’m in the absolute lowest risk category for heart disease: I’m not taking statins!

And my doctor knows this. I saw the perplexed look on his face when I pointed out those values to him (I guess that’s not the typical presentation of his high cholesterol patients). Shrugging it off, he still recommended the statins (and has every year for the last four). Sigh…

Okay, here’s the point of this piece: A recent study has shown that low levels of LDL (“bad”) cholesterol, in the absence of cholesterol lowering medications, has a strong link to cancer. What?! That’s right, and although we’ve known of this link for a long time (30+ years), this study was the first ever look at the low LDL-cancer link over an extended period of time (~19 years), and only in patients with no history of taking cholesterol-lowering drugs.

The results showed a couple things. One, the link cannot be due to taking statins since all subjects were statin-free throughout the study, and two, low cholesterol cannot be a byproduct of the cancer itself, since low LDL levels were observed well before any preclinical signs of cancer were present. In other words, statins don’t cause cancer, and cancer doesn’t cause low cholesterol. That we know.

What we don’t know is what the connection is. Hmmm…. Well let me give it a try: I believe that the body has an internal wisdom, an Innate Intelligence, that directs its operation. I believe this system is flawless. The body knows what to do at all times, and provided with the right fuel (whole, natural foods), necessary movement, proper bodywork and tension relief, adequate rest, adequate hydration, full, deep abdominal breath and minimal toxins, it will continue to operate flawlessly until it expires (which it will also do flawlessly).

However, too many people do not observe the natural laws of health—they eat poorly, fail to exercise regularly, ignore bodywork until they are in so much pain they can’t stand it, get little rest, drink too many sodas and not enough water, breathe shallowly from their chest, and take multiple drugs and other toxins, and so, yeah…their Innate Intelligence get severely challenged and fatigued; or it can only do the minimum with the resources it is given and becomes overloaded.

Further, we have a medical science that believes its own limited observations are the whole to the puzzle, and it make erroneous conclusions based on this small, piece-wise information, and yet it still believes it knows how to run the body better than Mother Nature does. And then we find out later that there is, in fact, more to the puzzle. You don’t say…?

But taking all the above points into consideration: Somehow when LDL cholesterol is disrupted from one of its many functions—that is, when it’s in too low of concentration—leads to cell overgrowth or cancer. Thus, not that statins, by lowering cholesterol, will cause cancer, but instead, perhaps this medical campaign to reduce cholesterol at all costs is an erroneous one. Perhaps the body produces what it needs (cholesterol can be both endogenous [created within] and exogenous [recieved from without]), and putting everybody on statins, particularly those with stellar numbers in all other health measurements, is just plain foolish.

No medical doctor or pharmaceutical researcher will ever know human physiology better than the human body does. Why the arrogant medical scientific (?) machine believes that it understands what cholesterol levels should be better than the body does is completely perplexing to me. If we were simply talking about a few hundred thousand people on statins because they have super-dangerously high levels that puts them at severe risk of heart disease, then…okay, I would understand. But to have tens of millions of Americans on these useless and dangerous cholesterol lowering drugs is purely idiotic.

So once again I have to believe it all comes down to three things–money (pharmaceuticals), liability (doctors protecting their asses) and job protection (medical professionals making sure they do not become obsolete). That’s the reality behind the cholesterol-statin push in the western world. I’m sure that’s why my doctor recommends statins to me despite my excellent health, I’m sure it’s why statins are called “the best selling drugs of all time,” and I’m sure it will continue until the next blockbuster drug addressing normal physiology comes along to take it’s place. Shouldn’t be too far off—stay tuned.
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Don’t Give More Patients Statins - ABRAMSON & REDBERG

Don’t Give More Patients Statins

By JOHN D. ABRAMSON and RITA F. REDBERG

November 13, 2013

ON Tuesday, the American Heart Association and the American College of Cardiology issued new cholesterol guidelines that essentially declared, in one fell swoop, that millions of healthy Americans should immediately start taking pills — namely statins — for undefined health “benefits.”
This announcement is not a result of a sudden epidemic of heart disease, nor is it based on new data showing the benefits of lower cholesterol. Instead, it is a consequence of simply expanding the definition of who should take the drugs — a decision that will benefit the pharmaceutical industry more than anyone else.

The new guidelines, among other things, now recommend statins for people with a lower risk of heart disease (a 7.5 percent risk over the next 10 years, compared with the previous guidelines’ 10 to 20 percent risk), and for people with a risk of stroke. In addition, they eliminate the earlier criteria that a patient’s “bad cholesterol,” or LDL, be at or above a certain level. Although statins are no longer recommended for the small group of patients who were on the drugs only to lower their bad cholesterol, eliminating the LDL criteria will mean a vast increase in prescriptions over all. According to our calculations, it will increase the number of healthy people for whom statins are recommended by nearly 70 percent.

This may sound like good news for patients, and it would be — if statins actually offered meaningful protection from our No. 1 killer, heart disease; if they helped people live longer or better; and if they had minimal adverse side effects. However, none of these are the case.

Statins are effective for people with known heart disease. But for people who have less than a 20 percent risk of getting heart disease in the next 10 years, statins not only fail to reduce the risk of death, but also fail even to reduce the risk of serious illness — as shown in a recent BMJ article co-written by one of us. That article shows that, based on the same data the new guidelines rely on, 140 people in this risk group would need to be treated with statins in order to prevent a single heart attack or stroke, without any overall reduction in death or serious illness.

At the same time, 18 percent or more of this group would experience side effects, including muscle pain or weakness, decreased cognitive function, increased risk of diabetes (especially for women), cataracts or sexual dysfunction.

Perhaps more dangerous, statins provide false reassurances that may discourage patients from taking the steps that actually reduce cardiovascular disease. According to the World Health Organization, 80 percent of cardiovascular disease is caused by smoking, lack of exercise, an unhealthy diet, and other lifestyle factors. Statins give the illusion of protection to many people, who would be much better served, for example, by simply walking an extra 10 minutes per day.

Aside from these concerns, we have more reasons to be wary about the data behind this expansion of drug therapy.

When the last guidelines were issued by the National Heart, Lung, and Blood Institute in 2001, they nearly tripled the number of Americans for whom cholesterol-lowering drug therapy was recommended — from 13 million to 36 million. These guidelines were reportedly based strictly on results from clinical trials. But this was contradicted by the data described in the document itself.
For example, even though the guidelines recommended that women between the ages of 45 and 75 at increased risk of heart disease and with relatively high LDL levels take statins, the fine print in the 284-page document admitted, “Clinical trials of LDL lowering generally are lacking for this risk category.” The general lack of evidence for LDL level targets is why they have been dropped from the current guidelines. In fact, committee members noted that cholesterol lowered by drugs may not have the same effect as cholesterol lowered by nondrug methods, such as diet, exercise and being lucky enough to have good genes.

The process by which these latest guidelines were developed gives rise to further skepticism. The group that wrote the recommendations was not sufficiently free of conflicts of interest; several of the experts on the panel have recent or current financial ties to drug makers. In addition, both the American Heart Association and the American College of Cardiology, while nonprofit entities, are heavily supported by drug companies.

The American people deserve to have important medical guidelines developed by doctors and scientists on whom they can confidently rely to make judgments free from influence, conscious or unconscious, by the industries that stand to gain or lose.

We believe that the new guidelines are not adequately supported by objective data, and that statins should not be recommended for this vastly expanded class of healthy Americans. Instead of converting millions of people into statin customers, we should be focusing on the real factors that undeniably reduce the risk of heart disease: healthy diets, exercise and avoiding smoking. Patients should be skeptical about the guidelines, and have a meaningful dialogue with their doctors about statins, including what the evidence does and does not show, before deciding what is best for them.

John D. Abramson, a lecturer at Harvard Medical School and the author of “Overdosed America: The Broken Promise of American Medicine,” serves as an expert in litigation involving the pharmaceutical industry. Rita F. Redberg is a cardiologist at the University of California, San Francisco Medical Center and the editor of JAMA Internal Medicine.
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Do statins have a role in primary prevention? An update.

Do statins have a role in primary prevention? An update.

Therapeutics Letter Issue 77 / Mar - Apr 2010

 

Therapeutics Letter #48 (April-June 2003)¹ concluded that “statins have not been shown to provide an overall health benefit in primary prevention trials” based on the 5 RCTs^8-12 available at that time. More RCTs are now available and 5 systematic reviews^2-6 designed to answer this question have been published since 2003. Unfortunately, these reviews do not answer the question “Do the benefits of statins outweigh the harms in people without proven occlusive vascular disease?” This question is critically important to patients, physicians and health care resource utilization.

The Cochrane Collaboration is regarded as the gold standard of systematic reviews. One of its guiding principles is avoiding unnecessary duplication: any independent reviewer following the proper methodology would include the same trials, extract the same data and come to the same interpretation and conclusions. The review is then updated as new trials are published.

 

The 5 published systematic reviews^2-6 (none of which are Cochrane reviews) vary in the RCTs included, summary effect estimates, conclusions and declared conflicts of interest of the authors (Table 1).

Table 1. Published systematic reviews

Two of these reviews report a decrease in total mortality while 3, including the latest, conclude that mortality is not decreased by statins in this setting.

 

What is the explanation for the different relative risk estimates? In part, it is due to the timing of the review and the trials that were available for inclusion. The 2006 review² did not have access to 3 RCTs^17-19.  The 2007 review³ did not have access to 2 RCTs^18,19.  The 2008 review⁴ did not include 2 RCTs^13,19 and included 10 RCTs^20-29 not included in any of the other reviews. The 2009 and 2010 reviews^5,6 had access to the same RCTs and had very small differences in the RCTs included (Table 1). The reason for the variation in the overall mortality estimate between the 2009 and 2010 reviews is that the 2010 review requested and obtained additional details from authors, allowing exclusion of 3659 secondary prevention patients from 4 large RCTs^8,10,11,12.

Why is a new systematic review necessary?

The differences in the interpretation and conclusions of these non-Cochrane reviews are confusing for clinicians. They can be resolved by using Cochrane methodology, including the Cochrane Risk of Bias Tool. Therefore we performed a new systematic review starting with the 22 RCTs included in at least one of these 5 systematic reviews. We excluded 10 of the RCTs^20-29 included in the 2008 review because the population studied was largely or entirely people with occlusive vascular disease at baseline. We included the remaining 12 RCTs^8-19, which provided data for at least one of 3 outcomes that we judged least subject to bias and most meaningful to patients: total all-cause mortality, total people with at least one serious adverse event (SAE) and total people with at least one major coronary heart disease (CHD) serious adverse event. All-cause mortality is an important outcome, for which we used the more accurate data from the 2010 review. Total SAEs capture overall mortality and all serious morbidity. Major CHD (non-fatal MI and death from coronary heart disease) is the outcome specifically reduced by statins, and less subject to bias than other cardiovascular outcomes such as revascularizations and strokes.

 

Results. All 12 RCTs report major CHD data, 11 report mortality data and 6 report SAE data. Our meta-analysis demonstrates that the reduction in mortality and major CHD, both SAE outcomes, is not reflected in a reduction in total SAEs (Table 2). The results are similar if they are limited to the 6 RCTs^{8,9,11,14,16,19} that reported SAEs:  mortality RR 0.90 [0.79-0.98], ARR 0.4%; Major CHD RR 0.70 [0.62-0.79], ARR 1.0%.

 However, getting accurate data entered and analysed is insufficient on its own. Cochrane reviews require assessing the risk of bias for each included RCT using the Risk of Bias Tool. Using this tool we found some risk of bias for each of the 12 included RCTs. Table 2.

 

Table 2. Statins for primary prevention meta-analysis

*Click here to see the forest plots.

 

Loss of blinding to treatment allocation probably occurred in all 12 RCTs, because statins predictably lower LDL cholesterol and the physicians managing the patients knew the lipid parameters. This loss of blinding likely biased clinical decisions regarding revascularization procedures and how outcomes were categorized (e.g. transient ischemic attack or reversible ischemic neurological deficit). Fewer revascularization procedures in the statin group as a result of loss of blinding would result in fewer complications secondary to the procedures, e.g. myocardial infarctions.

 

Other risks of bias affected only some RCTs. Of highest risk are the biases due to stopping RCTs early for benefit, affecting 3 RCTs^12,14,19, and incomplete outcome reporting bias (not an intention to treat analysis), affecting 1 RCT¹⁸. A recent research study demonstrated that the magnitude of the bias effect from stopping RCTs early for benefit is surprisingly large and robust, RR 0.71 [0.66-0.77].⁷ Testing the effect of this bias estimate on the early terminated JUPITER trial changes the RR for major CHD from 0.54 to 0.76 and completely negates the mortality benefit.

 

In order to test the effect of the bias from these 4 RCTs we removed them; analysis of the remaining 7 RCTs (Table 2, second row) shows no reduction in mortality. This suggests that the claimed mortality benefit with statins for primary prevention is more likely due to bias than being a true effect. Removing the 4 potentially biased trials also diminished the magnitude of the major CHD relative risk reduction from 26% to 21%.

How can CHD SAEs decrease, but not total SAEs?

All CHD events are SAEs and are counted in both categories. Therefore a reduction in major CHD SAEs should be reflected in a reduction in total SAEs. The fact that it is not suggests that other SAEs are increased by statins negating the reduction in CHD SAEs in this population. A limitation of our analysis is that we could not get total SAE data from all the included RCTs. However, we are confident that the data from the 6 missing RCTs would not change the results, because they represent only 41.2% of the total population and include ALLHAT-LLT¹⁰, where one would not expect a reduction in total SAEs; in that trial there was no effect on mortality or cardiovascular SAEs. 

Conclusions

• Systematic reviews and meta-analyses are challenging and require much more than locating RCTs and plugging in the numbers.
• The claimed mortality benefit of statins for primary prevention is more likely a measure of bias than a real effect.
• The reduction in major CHD serious adverse events with statins as compared to placebo is not reflected in a reduction in total serious adverse events.
• Statins do not have a proven net health benefit in primary prevention populations and thus when used in that setting do not represent good use of scarce health care resources.

The draft of this Therapeutics Letter was submitted for review to 45 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.

References

1. Therapeutics Initiative. Do statins have a role in primary prevention? Therapeutics Letter. Apr-Jun 2003; 48:1-2. http://ti.ubc.ca/letter48
2. Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166(21):2307-2313.
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4. Mills EJ, Rachlis B, Wu P, et al. Primary prevention of cardiovascular mortality and events with statin treatments. J Am Coll Cardiol. 2008;52(22):1769-1781.
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6. Ray KK, Sreenivasha RKS, Sebhat E, et al. Statins and all-cause mortality in high-risk primary prevention. A meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med. 2010;170(12):1024-1031. 
7. Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA. 2010;303(12):1180-87.
8. Shepherd J. Cobbe SM. Ford I. Isles CG. Lorimer AR. MacFarlane PW. McKillop JH. Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. New England Journal of Medicine. 333(20):1301-7, 1995 Nov 16.
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10. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. 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. 288(23):2998-3007, 2002 Dec 18.
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13. Collins R. Armitage J. Parish S. Sleigh P. Peto R. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 361(9374):2005-16, 2003 Jun 14.
14. 14. Colhoun HM. Betteridge DJ. Durrington PN. Hitman GA. Neil HA. Livingstone SJ. Thomason MJ. Mackness MI. Charlton-Menys V. Fuller JH. CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 364(9435):685-96, 2004 Aug 21-27.
15. Asselbergs FW, Diercks GF, Hillege HL, et al; Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation. 2004;110(18):2809-2816.
16. Anderssen SA, Hjelstuen AK, Hjermann I, Bjerkan K, Holme I. Fluvastatin and lifestyle modification for reduction of carotid intima-media thickness and left ventricular mass progression in drug-treated hypertensives. Atherosclerosis. 2005;178(2):387-397.
17. 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):1478-1485.2007;115(1):114-126.
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