The Failure of Cholesterol Lowering Drugs

The Failure of Cholesterol Lowering Drugs by Jeffrey Dach MD

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Jeffrey Dach MD

 

 

 

References:

1) Krumholz, Harlan M., et al. “Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years.” Jama 272.17 (1994): 1335-1340.

2) Criqui, Michael H., and Beatrice A. Golomb. “Low and lowered cholesterol and total mortality.” Journal of the American College of Cardiology 44.5 (2004): 1009-1010.

3) Petersen, Line Kirkeby, Kaare Christensen, and Jakob Kragstrup. “Lipid-lowering treatment to the end? A review of observational studies and RCTs on cholesterol and mortality in 80+-year olds.” Age and ageing 39.6 (2010): 674-680.

4) He, Guo-dong, et al. “A nonlinear association of total cholesterol with all-cause and cause-specific mortality.” Nutrition & metabolism 18 (2021): 1-11.

5) Wu, Wanqing, et al. “Low and High-Density Lipoprotein Cholesterol and 10-Year Mortality in Community-Dwelling Older Adults: The Shanghai Aging Study.” Frontiers in medicine 9 (2022): 783618.

https://esmed.org/MRA/mra/article/dow...
6) Ravnskov, Uffe, and Kilmer S. McCully. “The importance of LDL-cholesterol and infection in the etiology of cardiovascular disease: a meta-analysis of COVID-19 survivors and non-survivors.” Medical Research Archives 12.5 (2024).

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7) Sloop, Gregory D., et al. “Flawed reasoning allows the persistence of mainstream atherothrombosis theory.” Cureus 10.3 (2018).

Despite 60 years of study and an investment of billions of dollars, the rate of deaths due to coronary artery disease is increasing in the United States and in all other countries except the lowest socio-demographic populations worldwide (Figure ​(Figure1,1, Figure ​Figure2)2) [4].

Deaths due to heart disease increased by 3% in the US between 2014 and 2015, the latest years for which data are available [5]. Clearly, lipid theory is not powerful enough to provide the insight necessary to control atherothrombosis.

Popper also wrote “It is easy to obtain confirmations, or verifications, for nearly every theory—if we look for confirmations” [23]. Thus, in the scientific method as conceptualized by Popper, a theory can only be disproved, not proved. No number of confirmations can ever prove a theory.

Popper’s work sheds light on studies of statin therapy. While statins have been shown to reduce morbidity and mortality from atherothrombosis in some studies, DuBroff’s work shows that they have failed in a substantial number of studies despite significantly decreasing LDL levels. This failure falsifies the theory that elevated LDL or cholesterol is the cause of atherothrombosis.

Clinical trials of antioxidant vitamins and immunohistopathology refute oxidation theory. Immunohistopathology shows that oxidized LDL does not cause monocyte chemotaxis, cytotoxicity, or apoptosis as suggested by in vitro studies [27]. The persistent belief in the role of chronic oxidative stress in atherothrombosis can be attributed to the dominance of lipid theory and non-falsifiable defense of the oxidation hypothesis. After refutation in clinical trials, two prominent proponents of the oxidation hypothesis wrote:

“The hypothesis that oxidative modification of LDL plays a significant role in atherogenesis in humans is not necessarily disproved by the failure of these particular clinical trials any more than a negative trial of an ineffectual antibiotic in Pneumococcal pneumonia would prove that pneumonia is not a bacterial disease. The oxidative modification hypothesis is not that vitamin E will ameliorate the human disease but that oxidative modification of LDL and/or other oxidative events play a significant role in human atherogenesis as it does in animal models of atherogenesis. A corollary of the hypothesis is that some appropriate antioxidant intervention, at some appropriate dosage, in appropriately selected patients over an appropriate time interval has the potential to improve prognosis [28].

This paragraph contains numerous non-falsifiable statements meant to prevent refutation of oxidation theory, which is an ad hoc modification of lipid theory.

Oxidation theory is an ad hoc modification made necessary when it was shown that uptake of cholesterol by the LDL receptor was insufficient to form a macrophage foam cell because of negative feedback. However, chemically-modified LDL can be taken up by the scavenger receptor in sufficient quantities to create a foam cell. Oxidation theory has been refuted as discussed above.

The “weight-of-evidence fallacy” refers to the belief that the majority of evidence determines truth. This fallacy is widely used to support lipid theory, even appearing in the title of lipidologist Daniel Steinberg’s defense of lipid theory, The Cholesterol Wars: Cholesterol Skeptics vs. the Bulk of Evidence. This fallacy is also seen in the following quotation:

“The suggestion that the ‘limited success of cholesterol-lowering therapy in numerous prospective randomized controlled studies, some of which show significant decreases in serum LDL cholesterol but no improvement in outcome’ refutes the causal effect of LDL on the risk of ASCVD [atherosclerotic cardiovascular disease] is not a quantitatively literate argument. Instead, a synthesis of the totality of the evidence … provides overwhelming quantitative evidence that LDL causes ASCVD… [32].”

Regarding the weight of evidence fallacy, Skrabanek and McCormick wrote:

“Such an approach to establishing truth is nonscience: not only is it nonscience; it is also dangerous, because reasoning of this sort may lead to action that (particularly in the field of preventive medicine) can touch many people’s lives [31].” The danger of accepting lipid theory is that it makes the search for a better theory unnecessary.

Conclusions
In spite of extensive investigation into the role of lipids in atherothrombosis, the disease is not controlled and death rates are increasing around the globe. This failure is due to shortcomings of lipid theory. Lipid theory is incomplete because it does not explain the majority of cases of atherothrombosis. The theory that hypercholesterolemia is the cause of atherothrombosis and the theory that atherothrombosis is an inflammatory disease are examples of inappropriate extrapolation. These theories are special cases of the general theory that increased viscosity accelerates atherothrombosis by fostering mural thrombosis. Control of atherothrombosis will require that lipid theory is superseded by a superior theory.

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8) Sloop, Gregory D., et al. “Apolipoprotein (a) is the Product of a Pseudogene: Implications for the Pathophysiology of Lipoprotein (a).” Cureus 10.5 (2018).

Lipoprotein(a) [Lp(a)] is a particle composed of a core which is indistinguishable from that of low density lipoprotein (LDL) and a single molecule of apolipoprotein(a) [apo(a)]. Lp(a) is clinically significant because it is a risk factor for accelerated atherothrombosis as well as arterial and venous thrombosis.

Rather, Lp(a) (and LDL) accelerate atherothrombosis by increasing blood viscosity. The most effective intervention for elevated levels of Lp(a), therapeutic apheresis, works by decreasing blood viscosity. In areas where this intervention is not available, therapeutic phlebotomy or blood donation are alternatives.

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New Non-statin cholesterol drugs

Click to access f3d1aae01e08d46caf5f91f7b2ab83019a46.pdf

Rabaeus, Mikael, and Michel de Lorgeril. “A Systematic Review of Clinical Trials Testing CETP and PCSK9 Inhibitors: The Cholesterol-Heart Theory—Time for a Requiem?.” Journal of Controversies in Biomedical Research 5.1 (2019): 4-11.

despite a very significant effect on cholesterol levels, the CETP and PCSK9 inhibitors have not been shown to diminish the frequency of clinical events in high-risk patients, especially not the important ones represented by total and cardiovascular deaths.

Another consequence of these findings is that they speak strongly against the cholesterol-heart theory, confirming the doubts that have already been raised by a large group of scientists all over the world. As this theory leads to millions of people taking statin drugs, it appears highly necessary that access to raw data of all statin trials be allowed so as to reappreciate them. This is an important aspect considering the very strong conflicts of interest that the majority of scientists present, all the more concerning as many of these scientists exercise official activities in Association boards and guidelines committees and in medical journals. Therefore, we continue to maintain that the cholesterol-heart theory should be seriously challenged.
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44 randomised controlled trials (RCTs) of drug or dietary interventions to lower LDL-C in the primary and secondary prevention literature, which show no benefit on mortality [8]

Demasi, Maryanne, Robert H. Lustig, and Aseem Malhotra. “The cholesterol and calorie hypotheses are both dead—it is time to focus on the real culprit: insulin resistance.” Pharmaceutical Journal (2017).

For instance, there are 44 randomised controlled trials (RCTs) of drug or dietary interventions to lower LDL-C in the primary and secondary prevention literature, which show no benefit on mortality [8] . Most of these trials did not reduce CVD events and several reported substantial harm. Yet, these studies have not received much publicity. Furthermore, the ACCELERATE trial, a recent well-conducted double-blind randomised controlled trial, demonstrated no discernible reduction in CVD events or mortality, despite a 130% increase in high-density lipoprotein cholesterol (HDL-C) and a 37% drop in LDL-C. The result dumbfounded many experts, sparking renewed scepticism about the veracity of the cholesterol hypothesis[8] .

[8] DuBroff R. Cholesterol paradox: a correlate does not a surrogate make. Evid Based Med 2017;22(1):15–9.

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.

Rudolf Virchow first described the microscopy of the atherosclerotic plaque, but Nikolay Anichkov is credited with elucidating the central role of cholesterol in atherosclerosis.
Ironically, cholesterol is also essential for life as a key component of cell membranes, steroid hormones and bile acids.

Table 1 lists 44 cholesterol-lowering RCTs that reported no mortality benefit. Most reported no reduction in CV events, and several reported substantial harm (CDP, HERS, Minnesota Coronary Experiment, Sydney Diet Heart Study, WHI, WHO). This lack of benefit was seen even with profound reductions in LDL cholesterol (50% in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial). Although several studies were not pecifically designed to assess mortality, the reported lack of mortality benefit should not be disregarded…While some experts have dismissed or criticised these negative trials, the totality of evidence simply cannot be ignored. Even when researchers demonstrate a statin mortality benefit, the findings are underwhelming. A recent analysis concluded that statins would only postpone death by a median of 3.1 and 4.2 days for primary and secondary prevention, respectively.6

DuBroff, Robert. “A reappraisal of the lipid hypothesis.” The American Journal of Medicine 131.9 (2018): 993-997.

Regrettably, some clinical trials prior to 2004 have been tainted by scandals that led to new clinical trial regulations intended to safeguard patients and lend credibility to subsequent trials.3, 4

The table summarizes 29 major RCTs of cholesterol reduction reported after the publication of these regulations (Table). Notably, only 2 of these 29 studies reported a mortality benefit, while nearly two-thirds reported no cardiovascular benefit at all. These unfavorable outcomes and inconsistent results suggest that the lipid hypothesis has failed the test of time.

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DuBroff, Robert, Aseem Malhotra, and Michel de Lorgeril. “Hit or miss: the new cholesterol targets.” BMJ Evidence-Based Medicine 26.6 (2021): 271-278.

The new guidelines recommend three classes of drugs for cholesterol reduction:
β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins), cholesterol absorption inhibitors (ezetimibe) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9…It is noteworthy that a beneficial reduction in cardiovascular events was seen with LDL-C reductions as little as 11%–15% in Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) and Management of Elevated Cholesterol in the primary prevention Group of Adult Japanese (MEGA), while a lack of cardiovascular benefit was seen with LDL-C reductions as great as 50% or more in Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY FH 1 and 2), Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) and Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE 1 and 2).5–9

Limitations of LDL-C as a treatment target
Because of the putative role of LDL-C in the pathogenesis of ASCVD, it seems intuitive and logical to target LDL-C to prevent cardiovascular disease. Indeed, there is much evidence to support this approach. However, decades of RCTs of LDL-C reduction have failed to demonstrate a consistent benefit.19 Conspicuous by its absence in the AHA/ACC guidelines is any endorsement of niacin or cholesteryl ester transfer protein (CETP) inhibitors, agents with a proven track record of reducing LDL-C but failing to consistently save lives or prevent cardiovascular disease.20 21 To validate the theory that reducing LDL-C reduces the risk of cardiovascular disease (the lipid hypothesis), LDL-C lowering interventions must be efficacious. Considering that dozens of RCTs of LDL-C reduction have failed to demonstrate a consistent benefit, we should question the validity of this theory.22

In this analysis over three-quarters of the cholesterol lowering trials reported
no mortality benefit and nearly half reported no cardiovascular benefit at all.

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

there was no mortality benefit in roughly three-fourths of the trials, and nearly half reported no significant reduction in cardiovascular events. According to his analysis, some of the trials that reported the greatest drop in LDL-C among participants demonstrated no accompanying cardiovascular benefit. But in other trials where LDL-C levels dropped only modestly, there was a robust reduction in cardiovascular risk. “The cause of atherosclerosis is far more complex than we originally thought,” DuBroff says. “But our LDL-centric approach to preventing cardiovascular disease may have distracted us from investigating other mechanisms and treatments.”

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Proto Magazine Cholesterol Deniers by Anita Slomski Mass General Hospital

“I believe there is an association between LDL cholesterol and heart disease, but it’s very weak and it’s certainly not causal,” says Redberg, professor of medicine at University of California, San Francisco. She declines to treat patients with statins to prevent a first heart attack or stroke regardless of LDL-C levels. Although current clinical guidelines call for giving statins to anyone who has LDL-C of at least 190 milligrams per deciliter, Redberg advised her mother, who had high total cholesterol, not to take any statins. Redberg attributes the longevity of her mother, who lived to age 94, to a good diet and exercise. “Mine is a minority opinion among physicians, but it should be mainstream,” says Redberg, who launched a “Less is More” series of articles in JAMA Internal Medicine that focuses on what she considers the overmedicalization of Americans.

Retired cardiologist Robert DuBroff, who taught at the University of New Mexico, says some patients with high LDL-C may benefit from statins. But he thinks it’s time for physicians to acknowledge that randomized controlled trials have at times produced inconsistent and contradictory evidence about the benefits of cholesterol reduction. His analysis of 35 cholesterol-lowering drug trials, published in BMJ Evidence-Based Medicine in 2020, found that there was no mortality benefit in roughly three-fourths of the trials, and nearly half reported no

A 2016 meta-analysis examining 25 statin trials showed that the more you reduce cholesterol, the greater the cardiovascular benefit. And Labos’s own study that analyzed data from recent randomized trials of statins found conclusively that statins’ cardiovascular benefit is directly related to their LDL-C-lowering properties rather than to any other effects.

Redberg has long disputed the majority view of cholesterol and statins. “I believe there is an association between LDL cholesterol and heart disease, but it’s very weak and it’s certainly not causal,” says Redberg, professor of medicine at University of California, San Francisco. She declines to treat patients with statins to prevent a first heart attack or stroke regardless of LDL-C levels. Although current clinical guidelines call for giving statins to anyone who has LDL-C of at least 190 milligrams per deciliter, Redberg advised her mother, who had high total cholesterol, not to take any statins. Redberg attributes the longevity of her mother, who lived to age 94, to a good diet and exercise. “Mine is a minority opinion among physicians, but it should be mainstream,” says Redberg, who launched a “Less is More” series of articles in JAMA Internal Medicine that focuses on what she considers the overmedicalization of Americans.

Redberg says she believes there are minimal benefits in taking a statin to prevent a heart attack or stroke for someone who hasn’t already had one. “If 100 people take statins for primary prevention, only two will avoid a heart attack, which means that 98 won’t get any benefit from the statins, but up to 20% will have adverse effects and none will live longer,” she says.

But Redberg’s advice about statins is different for those who have already had a heart attack or stroke. For so-called secondary prevention, taking a statin may be worthwhile because the cardiovascular risk is so much higher, she says. “Everyone who has had a heart attack gets a statin, regardless of their cholesterol level, because you are much more likely to have a second heart attack after your first one,” Redberg says. “If your risk of having a second heart attack is 20%, a statin may cut that risk by 2%.” In contrast, a healthy person with high cholesterol may have a 1% chance of having a heart attack, and taking a statin reduces that risk by a mere 0.1%, she says. This is accurate, according to Labos. “The higher your risk, the more you benefit from treatment, which is pretty standard in all fields of medicine,” he says.

Data Kept Secret

For instance, the Cholesterol Treatment Trialists’ (CTT) Collaboration, a division at the University of Oxford in the United Kingdom that has received significant financial support from the pharmaceutical industry, keeps patient-level trial data secret. “Virtually everything we and the experts who write clinical guidelines know about statins comes from the CTT Collaboration,” says John Abramson, a lecturer on health care policy at Harvard Medical School and author of Overdosed America. “Individual patient-level data from the trials remains sealed, which means we have no confidence that the published data are a fair and complete representation of the trials’ results.”

Editorials in JAMA and The BMJ have criticized the CTT Collaboration for refusing to make all trial data available to other researchers. The editors of The BMJ say they have made multiple requests over several years to the CTT to release the data, but only a handful of collaboration members who conduct statin trials have complied. Secrecy about statin trial results underscores the “deep flaws in our current system for evaluating medicines and guiding clinical decisions,” The BMJ editors wrote.

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Statins in Elderly AAA3

A prototype of the Jarvik-7 artificial heart at the National Museum of Amercian History
Date 6 November 2023, 17:13:46
Source Own work
Author Votpuske

Lipitor and The Dracula of Modern Technology

Lipitor and The Dracula of Modern Technology

Jarvik is best known from the media circus surrounding the 1982 implantation of his Jarvik-7 into the Seattle dentist, Barney Clark. Although the artificial heart continued to beat, Barney died of multi-organ failure 112 days after the operation, tethered to a dishwasher sized air compressor. The heart device acted as a blender which chewed up the blood cells. Recipients of the Jarvik-7 suffered horribly for months, finally succumbing to infections, strokes, convulsions, and immune system failure with decline in T cells, thus making the Jarvik-7 another cause of HIV negative AIDS.
During the ensuing media coverage, the New York Times dubbed the Jarvik Heart the “Dracula of Medical Technology” .(3,4) Jarvik-7 patients had the Kevorkian option of assisted suicide, a small “kill” switch to turn off the mechanical heart when it becomes unbearable. About 90 people received the Jarvik heart before it was banned by the FDA.
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Pro-Statins

https://www.scirp.org/journal/paperin...

Schade, David S., Lynda Shey, and R. Philip Eaton. “In Defense of the LDL Hypothesis.” World Journal of Cardiovascular Diseases 9.3 (2019): 245-252.

 

https://openheart.bmj.com/content/9/1...

Bots, Sophie H., et al. “Statins are associated with a large reduction in all-cause mortality in women from a cardiac outpatient population.” Open Heart 9.1 (2022): e001900.

Electronic health record data from 47 801 patients (17 008 statin users and 30 793 non-users) without prior cardiovascular disease were extracted from thirteen Dutch outpatient cardiology clinics. Patients prescribed statins at baseline were propensity-score matched to those eligible for statin therapy (low-density lipoprotein >2.5 mmol/L) without a statin prescription. Statins were divided into low-intensity and high-intensity according to Dutch guidelines.

Results
Propensity score matching created a cohort of 8631 statin users and 8631 non-users. 35% of women and 28% of men received a low-intensity statin. The beneficial effect of statins on both all-cause and cardiovascular mortality was stronger in women (HR 0.66, 95% CI 0.58 to 0.74 and HR 0.55, 95% CI 0.39 to 0.71, respectively) than in men (HR 0.89, 95% CI 0.81 to 0.95 and HR 0.93, 95% CI 0.77 to 1.08, respectively). High-intensity statins conferred modest protection against all-cause mortality (HR 0.94, 95% CI 0.88 to 1.00) and cardiovascular mortality (HR 0.86, 95% CI 0.74 to 0.98) in both sexes
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ANti Statins

 

Rabaeus, Mikael, and Michel de Lorgeril. “A Systematic Review of Clinical Trials Testing CETP and PCSK9 Inhibitors: The Cholesterol-Heart Theory—Time for a Requiem?.” Journal of Controversies in Biomedical Research 5.1 (2019): 4-11.

https://newswithviews.com/Ellison/sha...
THE HIDDEN ORIGIN OF STATIN DRUGS. Shane Ellison M. Sc.
April 10, 2005 NewsWithViews.com

Statins are poisons derived from fungus… statins are nothing more than an isolated poison derived from the fungus known as red yeast rice (Monascus purpurus).[1]
As a toxic agent, the consumption of lovastatin via red yeast rice by its predators leads to sickness and in some cases, death… Nowhere in the history of man has an acknowledged poison been touted as a daily vitamin for every man, woman and child.

https://pubmed.ncbi.nlm.nih.gov/15673...
Schupf, Nicole, et al. “Relationship between plasma lipids and all‐cause mortality in nondemented elderly.” Journal of the American Geriatrics Society 53.2 (2005): 219-226.

Nondemented elderly with levels of total cholesterol, non-HDL-C, and LDL-C in the lowest quartile were approximately twice as likely to die as those in the highest quartile (rate ratio (RR)=1.8, 95% confidence interval (CI)=1.3-2.4).

Low cholesterol level is a robust predictor of mortality in the nondemented elderly and may be a surrogate of frailty or subclinical disease.

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https://www.ncbi.nlm.nih.gov/pmc/arti...
Golomb, Beatrice A., et al. “Statin Effects on Aggression: Results from the UCSD Statin Study, a Randomized Control Trial.” PLoS ONE 10.7 (2015).

Statin effects on aggression differed by sex and age: Statins generally decreased aggression in men; and generally increased aggression in women. Both findings were selectively prominent in participants with low baseline aggression – bearing lower change-variance, rendering an effect more readily evident.

Newson, Rachel S., et al. “Association between serum cholesterol and noncardiovascular mortality in older age.” Journal of the American Geriatrics Society 59.10 (2011): 1779-1785.

Akerblom, Jennifer L., et al. “Relation of plasma lipids to all-cause mortality in Caucasian, African-American and Hispanic elders.” Age and ageing 37.2 (2008): 207-213.

https://www.ncbi.nlm.nih.gov/pmc/arti...
Cabrera, Marcos Aparecido Sarria, Selma Maffei de Andrade, and Renata Maciulis Dip. “Lipids and all‐cause mortality among older adults: a 12‐year follow‐up study.” The Scientific World Journal 2012.1 (2012): 930139.
This is a 12-year follow-up cohort study with 800 people (60–85 years old)

The mortality showed a positive association with low TC and a negative association with high TC and high LDL-c. After the exclusion of underweight and premature mortality, there was a positive association only with TC <170 mg/dl (HR = 1.36, CI95%: 1.02–1.82). The data did not show a higher risk with high levels of TC, LDL-c, and TG. However, they showed higher mortality among older adults with low TC.

Discussion
The results indicate higher mortality among older people with lower levels of total cholesterol. Furthermore, they show no association between all-cause mortality and hypercholesterolemia, high LDL-c, low HDL-c, hypertriglyceridemia, and high non-HDL-c in this group of older adults.

Our results did not show a positive association between hyperlipidemias and all-cause mortality.

Nguyen, Xuan‐Mai T., et al. “Serum Cholesterol and Impact of Age on Coronary Heart Disease Death in More Than 4 Million Veterans.” Journal of the American Heart Association 12.21 (2023): e030496.

Lv, Yue-Bin, et al. “Low-density lipoprotein cholesterol was inversely associated with 3-year all-cause mortality among Chinese oldest old: data from the Chinese Longitudinal Healthy Longevity Survey.” Atherosclerosis 239.1 (2015): 137-142.
The goal of this study was to assess the relationship between LDL-C and all-cause mortality among Chinese oldest old (aged 80 and older) in a prospective cohort study.

Among the Chinese oldest old, higher LDL-C level was associated with lower risk of all-cause mortality. Our findings suggested the necessity of re-evaluating the optimal level of LDL-C among the oldest old.

 

https://www.ncbi.nlm.nih.gov/pmc/arti...
Wang, Mu-Cyun, et al. “Plasma lipid concentrations and survival in geriatric population: A retrospective cohort study.” Medicine 98.49 (2019).

We concluded that TC, mostly attributed to LDL cholesterol, was inversely related to all-cause mortality. HDL remained to be protective against both cardiovascular and stroke mortality in older females. The target levels of plasma lipids in people older than 65 years should be different from that in younger adults.

It is well known that higher total cholesterol (TC) in mid-life is associated with higher overall and cardiovascular mortality.[1,2]
However, this positive relation attenuates with increasing age.[3,4]

Studies have shown hypercholesterolemia is no longer a risk factor for cardiovascular mortality in people older than 70 years.[5,6]

On the other hand, low TC may increase all-cause mortality in the oldest old.[7–12]

https://jamanetwork.com/journals/jama...
Krumholz, Harlan M., et al. “Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years.” Jama 272.17 (1994): 1335-1340.

Turusheva, Anna, et al. “Low cholesterol levels are associated with a high mortality risk in older adults without statins therapy: An externally validated cohort study.” Archives of gerontology and geriatrics 90 (2020): 104180.

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https://www.researchgate.net/profile/... ved/links/5f3d25a0458515b7292c9c75/Statins-and-death-due-to-any-cause-all-doubts-removed.pdf

Barukčić, Ilija. “Statins and death due to any cause–all doubts removed.” Int J Curr Sci Res 5.12 (2019): 1884-1911.

Results: The data of the studies reanalyzed provide convincing evidence that statins unfortunately do not exclude death due to any cause. Overwhelming evidence suggests that the risk of harmful effects of statin therapy far outweigh any real or perceived benefit.
Conclusions: An immediate statin therapy discontinuation should be considered.

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https://www.ncbi.nlm.nih.gov/pmc/arti...
Fracassi, Anna, et al. “Statins and the brain: more than lipid lowering agents?.” Current neuropharmacology 17.1 (2019): 59-83.

Zipp, Frauke, et al. “Impact of HMG-CoA reductase inhibition on brain pathology.” Trends in pharmacological sciences 28.7 (2007): 342-349.

Smolders, Inge, et al. “Simvastatin interferes with process outgrowth and branching of oligodendrocytes.” Journal of neuroscience research 88.15 (2010): 3361-3375.

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Ucar, Memduh, Tom Mjörndal, and Rune Dahlqvist. “HMG-CoA reductase inhibitors and myotoxicity.” Drug safety 22 (2000): 441-457.

Omar, Mohamed A., James P. Wilson, and Tamara S. Cox. “Rhabdomyolysis and HMG-CoA reductase inhibitors.” Annals of Pharmacotherapy 35.9 (2001): 1096-1107.

Kajinami, Kouji, Noboru Takekoshi, and Yasushi Saito. “Pitavastatin: efficacy and safety profiles of a novel synthetic HMG‐CoA reductase inhibitor.” Cardiovascular drug reviews 21.3 (2003): 199-215.

Ghirlanda, Giovanni, et al. “Evidence of plasma CoQ10‐lowering effect by HMG‐CoA reductase inhibitors: a double‐blind, placebo‐controlled study.” The Journal of Clinical Pharmacology 33.3 (1993): 226-229.

Golomb, Beatrice A., et al. “Statin effects on aggression: results from the UCSD statin study, a randomized control trial.” PloS one 10.7 (2015): e0124451.

Leppien, Emily, et al. “Effects of statins and cholesterol on patient aggression: is there a connection?.” Innovations in clinical neuroscience 15.3-4 (2018): 24.

Pop, Gabriela, et al. “Post-Marketing surveillance of statins—A descriptive analysis of psychiatric adverse reactions in EudraVigilance.” Pharmaceuticals 15.12 (2022): 1536.

Diamond, David M., Benjamin T. Bikman, and Paul Mason. “Statin therapy is not warranted for a person with high LDL-cholesterol on a low-carbohydrate diet.” Current Opinion in Endocrinology, Diabetes and Obesity 29.5 (2022): 497-511.

Cham, Stephanie, Hayley J. Koslik, and Beatrice A. Golomb. “Mood, personality, and behavior changes during treatment with statins: a case series.” Drug safety-case reports 3 (2016): 1-13.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

https://bmjopen.bmj.com/content/14/3/...
Kip, Kevin E., et al. “Is LDL cholesterol associated with long-term mortality among primary prevention adults? A retrospective cohort study from a large healthcare system.” BMJ open 14.3 (2024): e077949.

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http://drdavidbrownstein.blogspot.com/
From Dr Browntsein

What prompted this post? An article in Clinical Nutrition revealed that compared to elderly patients with cholesterol levels of 200mg/dl, those with cholesterol levels of 183mg/dl had a significantly higher death rate. (1) The authors found that for every 1mg/dl increase in serum cholesterol, the death rate was reduced by 0.4%. You read that correctly—elevated cholesterol levels protect the elderly from death.

The Honolulu Heart Program found that men aged 71-93 years in the lowest total cholesterol group had a 64% increase risk in death as compared to men with the highest cholesterol levels.(2)

The Honolulu study was reported in 2001. It is too bad the media does not trumpet these results.

elderly patients with cholesterol levels of 200mg/dl, those with cholesterol levels of 183mg/dl had a significantly higher death rate

(1) Clinical Nutrition. Nov. 7, 2012. Doi.org/10.1016/j.cinu.2012.11.012

(2) Schatz, I. J. “Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program.” LANCET-LONDON- (2001): 351-355.

Published on July 18th, 2024 by Jeffrey Dach MD

The post The Failure of Cholesterol Lowering Drugs appeared first on Jeffrey Dach MD.