Hit or miss: the new cholesterol targets

[Todd Allen]

https://ebm.bmj.com/content/early/2020/07/20/bmjebm-2020-111413.full

Abstract
Drug treatment to reduce cholesterol to new target levels is now recommended in four moderate- to high-risk patient populations: patients who have already sustained a cardiovascular event, adult diabetic patients, individuals with low density lipoprotein cholesterol levels ≥190 mg/dL and individuals with an estimated 10-year cardiovascular risk ≥7.5%. Achieving these cholesterol target levels did not confer any additional benefit in a systematic review of 35 randomised controlled trials. Recommending cholesterol lowering treatment based on estimated cardiovascular risk fails to identify many high-risk patients and may lead to unnecessary treatment of low-risk individuals. The negative results of numerous cholesterol lowering randomised controlled trials call into question the validity of using low density lipoprotein cholesterol as a surrogate target for the prevention of cardiovascular disease.

Discussion
This analysis highlights the discordance between a well-researched clinical guideline written by experts and empirical evidence gleaned from dozens of clinical trials of cholesterol reduction. It further underscores the ongoing debate about lowering cholesterol in general and the use of statins in particular. In this analysis over three-quarters of the cholesterol lowering trials reported no mortality benefit and nearly half reported no cardiovascular benefit at all.

The widely held theory that there is a linear relationship between the degree of LDL-C reduction and the degree of cardiovascular risk reduction is undermined by the fact that some RCTs with very modest reductions of LDL-C reported cardiovascular benefits while others with much greater degrees of LDL-C reduction did not (MEGA, ALLIANCE, SEAS, ODYSSEY FH 1 and 2, SPIRE 1 and 2).5–9 23 This lack of exposure–response relationship is illustrated in figure 3, where the scatter plot and the calculated correlation coefficient (R) suggest there is no correlation between the percent reduction in LDL-C and the absolute risk reduction in cardiovascular events. Moreover, consider that the Minnesota Coronary Experiment, a 4-year long RCT of a low-fat diet involving 9423 subjects, actually reported an increase in mortality and cardiovascular events despite a 13% reduction in total cholesterol.24 What is clear is the lack of clarity of these issues. In most fields of science the existence of contradictory evidence usually leads to a paradigm shift or modification of the theory in question, but in this case the contradictory evidence has been largely ignored simply because it doesn’t fit the prevailing paradigm.25 26

[Mike41]

July 7, 2020

Statins Associated with Mortality Benefit in Older Adults

By Joe Elia

Edited by David G. Fairchild, MD, MPH, and Lorenzo Di Francesco, MD, FACP, FHM

Statin use is associated with lower mortality risk in older adults, according to a retrospective study in JAMA.

Over 300,000 U.S. veterans aged 75 and older were followed for roughly 7 years. At the outset, all were free of atherosclerotic cardiovascular disease. 

Death rates per 1000 person-years were 79 among new statin users and 98 among non-users. After adjustment for propensity scores, the hazard ratio for statin users was 0.75 for all-cause mortality and 0.80 for cardiovascular mortality, compared with non-users.

Editorialists write that the results "provide a compelling argument for use of statins for primary prevention in older patients."

NEJM Journal Watch General Medicine's Dr. Thomas Schwenk has summarized and commented on the study. See his take at the link below.

[TomBAvoider]

Mike, there is no link.

The other thing I’m curious about is what were the adjustments they made. Because a very natural speculation is that those who take statins are under better, or more medical care, or are more conscientious and better follow medical orders, and it’s those factors that account for the mortality differences.

[Todd Allen]

1 hour ago, Mike41 said:

Statins Associated with Mortality Benefit in Older Adults

https://sci-hub.tw/https://jamanetwork.com/journals/jama/article-abstract/2767861

Quote

To create a cohort of older adults that reflects usual clinical practice, those with cancer, dementia, or paralysis were not excluded, in contrast to other studies.10 Those who died within 150 days of entry into the cohort were excluded to avoid selection bias, as statins for primary prevention are estimated to take 2 to 5 years for benefit and are generally not recommended for those with very limited life expectancy.

Does excluding those who died within 150 days sufficiently correct for the bias caused by the practice of not prescribing statins to those perceived to be near the end of life? What would the results be if they excluded those who died within a year or two or five? Heart disease develops over decades and statins at best have a modest impact on the rate it progresses. Is it credible that they have a dramatic impact when taken for the last few years of life? Or is this result an artifact of the rules by which this data was produced and processed?

Observational studies of this nature at best find correlation and other methods such as RCTs are better for evidence of causation.  The ALLHAT-LLT Randomized Clinical Trial found the opposite.

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2628971

Quote

Conclusions and Relevance  No benefit was found when pravastatin was given for primary prevention to older adults with moderate hyperlipidemia and hypertension, and a nonsignificant direction toward increased all-cause mortality with pravastatin was observed among adults 75 years and older.

 

Edited August 5, 2020 by Todd Allen

[TomBAvoider]

Yeah, it seems the study finding benefits for those over 75 is quite poor. I wouldn't put too much stock in that one, sadly.

[Ron Put]

The preponderance of the evidence is still on the side of a significant correlation between cholesterol and CVD.

While there are a number of studies challenging the established view, cholesterol values remain a significant predictor.

[Todd Allen]

29 minutes ago, Ron Put said:

The preponderance of the evidence is still on the side of a significant correlation between cholesterol and CVD.

Yes, there is a lot of evidence that low HDL is a serious risk factor but unfortunately trials of drugs which raise it and even niacin failed to show benefit.  Low HDL is probably an indicator of metabolic derangements such as insulin reistance and hyperinsulinemia and artificially fixing it without addressing the underlying issues doesn't seem to help.  

[Ron Put]

7 minutes ago, Todd Allen said:

Yes, there is a lot of evidence that low HDL is a serious risk factor but unfortunately trials of drugs which raise it and even niacin failed to show benefit.  Low HDL is probably an indicator of metabolic derangements such as insulin reistance and hyperinsulinemia and artificially fixing it without addressing the underlying issues doesn't seem to help.

Low LDL due to disease is not a great problem for the general population but maintaining healthy low levels of LDL appears to be. 

Here is the prevailing view among most practitioners:

"Cholesterol is a waxy substance found in your blood. Your body needs cholesterol to build healthy cells, but high levels of cholesterol can increase your risk of heart disease.

With high cholesterol, you can develop fatty deposits in your blood vessels. Eventually, these deposits grow, making it difficult for enough blood to flow through your arteries. Sometimes, those deposits can break suddenly and form a clot that causes a heart attack or stroke.

High cholesterol can be inherited, but it's often the result of unhealthy lifestyle choices, which make it preventable and treatable. A healthy diet, regular exercise and sometimes medication can help reduce high cholesterol."

[Mike41]

On 8/5/2020 at 2:12 PM, Todd Allen said:

https://sci-hub.tw/https://jamanetwork.com/journals/jama/article-abstract/2767861

Does excluding those who died within 150 days sufficiently correct for the bias caused by the practice of not prescribing statins to those perceived to be near the end of life? What would the results be if they excluded those who died within a year or two or five? Heart disease develops over decades and statins at best have a modest impact on the rate it progresses. Is it credible that they have a dramatic impact when taken for the last few years of life? Or is this result an artifact of the rules by which this data was produced and processed?

Observational studies of this nature at best find correlation and other methods such as RCTs are better for evidence of causation.  The ALLHAT-LLT Randomized Clinical Trial found the opposite.

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2628971

 

https://bmjopen.bmj.com/content/5/9/e007118
 

and another study not very encouraging for cholesterol lowering 

I am not going to dig it up. But there is extensive research and data showing people with familial hypercholesteremia  die in their 30s 40s and fifties. My father and his brother, cousin and his father all died in their mid forties from very high cholesterol. 350-400. Now here is my take on all of this and I have dug into it extensively.

The fact that very high is very bad leads to over treatment possibly. For instance my mom is 91 and totally without any chronic illness nor signs of dementia. Her lifetime cholesterol levels have been mid 200s. Doctor wanted her to take statins years ago and she refused. This is not at all uncommon in the general population. cholesterol is manufactured for good reason. It’s not a silly mistake of nature. OTOH we have an epidemic of obesity, diabetes, terrible junk food addictions, smoking, lack of exercise etc. it’s complex iows. If the system is overwhelmed with cholesterol and cannot handle it then it’s bad news. But how far do we go to lower it. Very low ldl levels are definitely associated with less heart disease, but there tends to be higher cancer rates and again if the levels were higher and all the lifestyle conditions were favorable we just might see a disadvantage to very low levels. But that’s a guess. So it appears from Todd’s post and the one posted above and many more that we still just do not know if lowering cholesterol beyond very high levels has any benefit especially in those with relatively decent lifestyle like my Mom.

Edited August 11, 2020 by Mike41

[TomBAvoider]

Doesn't it all come down to - yet again - individual effects? Perhaps statins are helpful for individual X, but not Y, and the criteria by which we group people are too broad to show the effects of individual variation. After all, even something as profound in its effects as tobacco smoking has variable outcomes - there are those who have smoked all their lives and go on to live to be centenarians - although of course, those will be rare exceptions. 

The criteria provided above for statin use:

patients who have already sustained a cardiovascular event, adult diabetic patients, individuals with low density lipoprotein cholesterol levels ≥190 mg/dL and individuals with an estimated 10-year cardiovascular risk ≥7.5%. 

I don't fit a single of those criteria. And yet, I am on a statin (10mg atorvastatin daily). This was something my PC suggested, because of my consistently elevated LDL (never below 128 mg/dL or so, and frequently going as high as 148). My HDL has been all over the place - the very lowest 60 (one occasion) the highest 101 (one occasion) and usually in the 70's (the latest 79). My triglicerides have always been reasonable (latest: 57), though not spectacular like some on here where their trigs are in the 30's. Not high BP. I exercise and have a heart-friendly diet. And yet, those pesky LDL numbers worried my PC for years, until finally he suggested a statin, which I'm now taking. The statin has not affected my HDL or triglicerides, but my LDL is now down to 73 mg/dL.

Now, does the statin do nothing for my healthspan or lifespan, does it harm it, does it benefit? No way to tell. It's a total gamble. 

But the statin may have a different effect depending on your age group. There is conflicting info - some studies suggest that it's a negative or neutral at best in the over 75, the subpar study recently discussed saw a benefit. But there is nothing definitive.

Yet, there can be profound differences in different age groups. Same as aspirin. There's been a lot of noise about aspirin being a cancer suppresant and if not that, at least preventing/slowing down metastasis. Well. Al Pater has just posted a study that turns those results on its head when it comes to the elderly. It transpires that a daily low dose aspirin not only does not prevent cancer, it may increase it, and it very strongly suggests that it accellerates metastasis - the exact opposite of what was suggested previously - thank you, Al Pater! - :

Effect of aspirin on cancer incidence and mortality in older adults.
McNeil JJ, Gibbs P, Orchard SG, Lockery JE, Bernstein WB, Cao Y, Ford L, Haydon A, Kirpach B, Macrae F, McLean C, Millar J, Murray AM, Nelson MR, Polekhina G, Reid CM, Richmond E, Rodríguez LM, Shah RC, Tie J, Umar A, van Londen GJ, Ronaldson K, Wolfe R, Woods RL, Zalcberg J, Chan AT; ASPREE Investigator Group.
J Natl Cancer Inst. 2020 Aug 11:djaa114. doi: 10.1093/jnci/djaa114. Online ahead of print.
PMID: 32778876
Abstract
Background: ASPirin in Reducing Events in the Elderly (ASPREE), a randomized double-blind placebo-controlled trial (RCT) of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast prior RCTs, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality.
Methods: 19,114 Australian and U.S. community-dwelling participants aged 70+ years (U.S. minorities 65+ years) without cardiovascular disease, dementia or physical disability were randomized and followed for a median of 4.7 years. Fatal and non-fatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records.
Results: 981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (HR = 1.04, 95% CI = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64).
Conclusions: In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and thus, suggest caution with its use in this age group.[my bold TA]

So the bottom line is, pay extreme attention to the age group - what may be beneficial in younger cohorts may be deadly for the elderly. This surely applies not only to medication, but to supplements, diet, exercise and other lifestyle factors. So often we tout various supplements and interventions, but we don't look to see if it's good for us specifically, given our individual physiology and situation including age.  

[Todd Allen]

On 8/11/2020 at 12:48 PM, Mike41 said:

For instance my mom is 91 and totally without any chronic illness nor signs of dementia. Her lifetime cholesterol levels have been mid 200s. Doctor wanted her to take statins years ago and she refused.

She probably read this paper:

Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC31037/

Quote

People in the first generations of our pedigree reached old age. Such higher survival of ancestors with familial hypercholesterolaemia has been reported previously in Utah pedigrees,3 and hypercholesterolaemia may have conferred a survival advantage when infectious disease was prevalent. This hypothesis is supported by the observation that genetically modified mice with high cholesterol concentrations were protected against severe Gram negative infections.17

Harlan et al described normal survival in a large pedigree with familial hypercholesterolaemia in 1966. They suggested that “the precocious onset of cardiovascular disease and the bad prognosis of familial hypercholesterolemia have been overemphasized because many of the early studies were of the relatives of patients who had sought medical attention.”18 These findings were largely ignored, and since then many studies have been done in probands (and relatives) who presented with symptoms of cardiovascular disease in lipid clinics. We found many affected people who had normal lifespans. Nevertheless, increased mortality does exist in some affected families. These families are probably characterised by clustering of risk factors. Lifestyle factors such as high fat diet, cigarette smoking, and physical activity3,8,19,20 and factors that influence lipid metabolism8,21 have been associated with a higher prevalence of cardiovascular disease in patients with familial hypercholesterolaemia. Because of the large time span of our study, we do not have information on specific environmental factors.

Future research should be directed at determining which patients with familial hypercholesterolaemia are at particularly high risk of premature cardiovascular disease and which environmental factors are effective in modulating this risk.

 

[AlPater]

Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group.
[No authors listed]
BMJ. 1991 Oct 12;303(6807):893-6. doi: 10.1136/bmj.303.6807.893.
PMID: 1933004 Free PMC article.
https://www.bmj.com/content/bmj/303/6807/893.full.pdf
Abstract
Objectives: (a) To determine the excess mortality from all causes and from coronary heart disease in patients with familial hypercholesterolaemia; (b) to examine how useful various criteria for selective measurement of cholesterol concentration in cardiovascular screening programmes are in identifying these patients.
Design: Prospective cohort study.
Setting: Eleven hospital outpatient lipid clinics in the United Kingdom.
Patients: 282 men and 244 women aged 20-74 with heterozygous familial hypercholesterolaemia.
Main outcome measure: Standardised mortality ratio, all adults in England and Wales being taken as standard (standardised mortality ratio = 100 for standard population).
Results: The cohort was followed up for 2234 person years during 1980-9. Fifteen of the 24 deaths were due to coronary heart disease, giving a standardised mortality ratio of 386 (95% confidence interval 210 to 639). The excess mortality from this cause was highest at age 20-39 (standardised mortality ratio 9686; 3670 to 21,800) and decreased significantly with age. The standardised mortality ratio for all causes was 183 (117 to 273) and also was highest at age 20-39 (standardised mortality ratio 902; 329 to 1950). There was no significant difference between men and women. Criteria for measurement of cholesterol concentration in cardiovascular screening programmes (family history, presence of myocardial infarction, angina, stroke, corneal arcus, xanthelasma, obesity, hypertension, diabetes, or any of these) were present in 78% of patients.
Conclusions: Familial hypercholesterolaemia is associated with a substantial excess mortality from coronary heart disease in young adults but may not be associated with a substantial excess mortality in older patients. Criteria for selective measurement of cholesterol concentration in cardiovascular screening programmes identify about three quarters of patients with the clinically overt condition.

[TomBAvoider]

hypercholesterolaemia may have conferred a survival advantage when infectious disease was prevalent. 

And yet wasn't it found that statins might helpful wrt. COVID-19 mortality, whereas high cholesterol was detrimental?

Statins may help older coronavirus patients avoid symptoms; COVID-19 more than respiratory illness

Patients with high blood sugar and cholesterol levels are often at a particularly high risk to develop COVID-19

Edited August 15, 2020 by TomBAvoider

[Mike41]

16 hours ago, TomBAvoider said:

hypercholesterolaemia may have conferred a survival advantage when infectious disease was prevalent. 

And yet wasn't it found that statins might helpful wrt. COVID-19 mortality, whereas high cholesterol was detrimental?

Statins may help older coronavirus patients avoid symptoms; COVID-19 more than respiratory illness

Patients with high blood sugar and cholesterol levels are often at a particularly high risk to develop COVID-19

Tom, Covid appears to be a outlier infectious disease wise. That may partly explain the disconnect. I also doubt the cholesterol lowering effect of statins has anything to do with the Results you posted. Statins have clinically significant effects on inflammation and based on what we know wrt covid this would be the more likely explanation of their possible effects in reducing symptoms. 

Edited August 15, 2020 by Mike41

[Saul]

16 hours ago, TomBAvoider said:

hypercholesterolaemia may have conferred a survival advantage when infectious disease was prevalent. 

And yet wasn't it found that statins might helpful wrt. COVID-19 mortality, whereas high cholesterol was detrimental? 

Statins may help older coronavirus patients avoid symptoms; COVID-19 more than respiratory illness

Patients with high blood sugar and cholesterol levels are often at a particularly high risk to develop COVID-19

COVID-19 isn't a gram negative bacerium.  In fact, it isn't a bacterium.

  --  Saul

[Todd Allen]

17 hours ago, TomBAvoider said:

And yet wasn't it found that statins might helpful wrt. COVID-19 mortality, whereas high cholesterol was detrimental?

...

Patients with high blood sugar and cholesterol levels are often at a particularly high risk to develop COVID-19

From that link:

Quote

 

Their major finding? This virus prevents the routine burning of carbohydrates. As a result, large amounts of fat accumulate inside lung cells, a condition the virus needs in order to reproduce.

This new understanding of SARS CoV-2 may help explain why patients with high blood sugar and cholesterol levels are often at a particularly high risk to develop COVID-19.

...

In lab studies, the cholesterol-lowering drug Fenofibrate (Tricor) showed extremely promising results. By allowing lung cells to burn more fat, fenofibrate breaks the virus' grip on these cells, and prevents SARS CoV-2's ability to reproduce.

 

Sounds like high blood sugar may be the bigger issue here.  No mechanism mentioned for high cholesterol being problematic rather it looks like it is the triglyceride lowering aspect of Fenofibrate which is relevant.

[Ron Put]

On 8/14/2020 at 7:59 PM, TomBAvoider said:

And yet wasn't it found that statins might helpful wrt. COVID-19 mortality, whereas high cholesterol was detrimental?

It's likely that statins are helpful with Covd-19, as they are with most other infections I can think of, because they have anti-inflammatory effects.

Here is something in support:

Association between use of statins and mortality among patients hospitalized with laboratory-confirmed influenza virus infections: a multistate study

Background: Statins may have anti-inflammatory and immunomodulatory effects that could reduce the risk of mortality from influenza virus infections.

Methods: The Centers for Disease Control and Prevention's Emerging Infections Program conducts active surveillance for persons hospitalized with laboratory-confirmed influenza in 59 counties in 10 states. We analyzed data for hospitalized adults during the 2007-2008 influenza season to evaluate the association between receiving statins and influenza-related death.

Results: We identified 3043 patients hospitalized with laboratory-confirmed influenza, of whom 1013 (33.3%) received statins and 151 (5.0%) died within 30 days of their influenza test. Patients who received statins were more likely to be older, male, and white; to suffer from cardiovascular, metabolic, renal, and chronic lung disease; and to have been vaccinated against influenza that season. In a multivariable logistic regression model, administration of statins prior to or during hospitalization was associated with a protective odds of death (adjusted odds ratio, 0.59 [95% confidence interval, .38-.92]) when adjusting for age; race; cardiovascular, lung, and renal disease; influenza vaccination; and antiviral administration.

Conclusions: Statin use may be associated with reduced mortality in patients hospitalized with influenza.