The Failure of Cholesterol Lowering Drugs

The Failure of Cholesterol Lowering Drugs by Jeffrey Dach MD

Ellen is a 56 year old assistant county attorney who has been doing well on her post-menopausal bioidentical hormone program. Ellen recently had a routine visit with her primary care doctor at the Mayo Clinic and was prescribed a statin anti-cholesterol drug for a slightly elevated cholesterol.  Ellen runs 3 miles in the morning twice a week. Soon after starting the statin drug, she noticed cramping in her leg muscles with each run. She called me at the office to discuss the new myalgia symptoms. I explained to Ellen that muscle pain, and muscle damage are well known adverse effects of statin drugs, and I suggested she take a break from the drug. Sure enough, off the statin drug the muscle pain promptly resolved. About 6 months later, Ellen was due for another routine visit with her primary care doctor at the Mayo Clinic, who again prescribed a statin drug stating this new statin drug is safer and does not cause muscle pain. Ellen obediently started the new statin drug, and just like clockwork, muscle pain came back again. At Ellen’s next follow up call with me at the office, I explained to Ellen she is statin drug intolerant, and should not be taking them. I explained to Ellen that doing the same thing over and over and expecting a different result is the definition of insanity, a quote misattributed to Albert Einstein. My plea to stop the statin drug went unheeded. Ellen replied no, she is not crazy at all, and she plans to stay on the statin drug as prescribed by the Mayo Clinic. Part of my job as a physician is to “reverse brainwash” my patients of the false propaganda from the drug industry. Unfortunately in Ellen’s case, my reverse brainwashing failed. That is the motivation for this newsletter.

Header image: Jogging in the Park. Upper East Side, Central Park – Jun 2008 Source Flickr: Jogging with our iPhones. Author Ed Yourdon, Courtesy of Wikimedia Commons.

Statin Drugs for Marathon Runners

For statin drugs users, the most common complaint is myalgia, muscle soreness, weakness, cramping, and aching in the legs, all of which resolves after stopping the statin drug. Because of the muscle pain, people on statin drugs usually reduce their physical activity. Statins are mitochondrial toxins which deplete CoEnzyme Q-10 and reduce mitochondrial energy production by 30 percent. At the same time, damaging reactive oxygen species (ROS) is increased. In 2020, Dr. Allyson M. Schweitzer studied the impact of statin drugs on physical activity finding that up to 29% of statin users develop statin-associated muscle symptoms (SAMS) including muscle pain (myalgia), inflammation (myositis), muscle damage (myopathy), and in extreme cases, rhabdomyolysis (necrosis of muscle cells). Statins may also cause neuropathy (nerve pain), and the patient may have a severely painful arm which prevents  sleeping at night. Dr. Allyson M Schweitzer writes:

Statins in particular have been demonstrated to reduce mitochondrial respiration and increase ROS production. Allard et al. (2018) demonstrated that muscle from symptomatic statin users had reductions in complex II and IV activity [of the electron transport chain] and an approximate 28% decrease in ATP [energy] production capacity…compared to muscle from non-statin users. Additionally, Dohlmann et al. (2019) demonstrated reduced complex II respiration in both symptomatic and asymptomatic statin users…Due to its roles within the mitochondria, it was hypothesized that this lack of CoQ10 may be contributing to the reduced respiration and increased ROS production demonstrated in the mitochondria of statin users…Unsurprisingly, CoQ10 supplementation has been proposed as a treatment for SAMS. (11)

Statin induced muscle toxicity is made worse by Vitamin D deficiency, and supplementation with vitamin D may ameliorate symptoms. Statin users have a 40% reduction in the sarcolemma membrane protein, called CLC-1 (chloride channel proteins), thought to be the cause muscle cramping, spasm, and weakness. Dr. Allyson M Schweitzer writes:

reduced vitamin D levels can reduce statin metabolism and clearance, resulting in a greater chance for myotoxicity…statin users with SAMS [Statin Associated Muscle Symptoms] had significantly lower plasma vitamin D levels than asymptomatic statin users…Khayznikov et al. (2015) found previously statin-intolerant patients to be free of SAMS after 24 months of vitamin D supplementation…In addition, statin users with SAMS demonstrate a 40% reduction in CLC-1 chloride channel proteins when compared to non-statin users. This channel is responsible for resting sarcolemma membrane stability, and thus reductions may lead to membrane hyperexcitability, and a decreased threshold for subsequent muscle cramping, spasm, and weakness….It has been suggested that statins alter mPTP [mitochondrial permeability transition pore] permeability and increase mitochondrial calcium uptake. If enough calcium is taken up by the mitochondria, respiration is impeded, swelling may occur, and apoptotic/necrotic pathways may be initiated. This could explain the deficits in mitochondrial respiration demonstrated in statin users as well as the reduction in ATP production capacity. In support of this concept, Busanello et al. (2018) showed that blocking the mPTP, mitochondrial permeability transition pore in statin-treated mice restored normal mitochondrial respiration… Compared to non-users, Parker et al. (2013) and Bouitbir et al. (2016) found statin users to have elevated CK [creatine kinase] levels at rest, indicating a greater baseline level of muscle damage. A recent case study also describes the development of acute rhabdomyolysis in a marathon runner treated with rosuvastatin, characterized by severe pain and elevated CK levels. Note: rhabdomyolysis is a severe form of muscle necrosis. (11)

Statins Impair Muscle Repair and Regeneration

Statin users may have difficulty healing muscle injuries with deficient muscle repair and regeneration. Another downstream product of the MVA (mevalonate pathway) is geranylgeraniol, involved in muscle repair and regeneration. Dr. Allyson M Schweitzer writes:

Geranylgeraniol, downstream of mevalonate in the cholesterol biosynthesis pathway, has been shown to induce myogenic differentiation of murine myoblasts derived from muscle satellite cells…Similarly, statin treatment has been shown to affect satellite cell differentiation and reduce myoblast fusion, attenuating the production of multinucleated entities. These impairments were rescued with mevalonate co-treatment, validating the importance of downstream products of the cholesterol biosynthesis pathway in muscle maturation. As satellite cells are primary mediators of muscle regeneration, these results are indeed concerning for muscle repair and regeneration in the presence of statin therapy…Taken together, the above preclinical studies suggest that statins delay muscle regeneration and impede satellite cell function. (11)

Statin induced muscle pain may be aggravated by physical activity, and statin users have reduced muscle strength and higher CK (creatine kinase) serum levels compared to non-users indicating ongoing muscle damage. Dr. Allyson M Schweitzer writes:

A 2005 study by Bruckert et al. is commonly cited as evidence that SAMS [Statin associated muscle symptoms] are aggravated by physical activity. In  this study, 40% of the population reporting myalgia indicated that certain factors triggered their symptoms. Of this 40%, over half indicated ‘unusual physical exertion’ as a trigger. Bruckert et al. (2005) also report the prevalence of myalgia to be greater in physically active individuals…Thompson et al. (1997) demonstrated serum CK levels to be elevated in statin users compared to non-users following treadmill exercise, indicating a greater presence of  muscle damage. These serum CK levels returned to baseline within 3 days…Established literature has demonstrated that statins reduce muscle strength during strength testing, as well as elevate serum CK both at rest and after exercise, raising the concern that physical exertion may exacerbate muscle damage…The current review demonstrates that statins do alter skeletal muscle metabolism, in particular, mitochondrial metabolism. (11)

Statin Drugs Cause Mitochondrial Dysfunction

In 2023, Lize Kroon from South Africa wrote her PhD thesis on muscle injuries in runners, finding statin drugs cause mitochondrial dysfunction in skeletal muscle, thus producing muscle pain, compromising aerobic exercise capacity and increasing muscle injury, writing:

New evidence suggests that statin use can directly compromise aerobic exercise capacity and increase risk of muscle injuries; however, it is just the beginning of comprehension between the interactions of statins with exercise training. The use of statins may result in mitochondrial dysfunction in skeletal muscle cells, which in turn may interfere with aerobic capacity and training adaptations. (153, 154)…Research has demonstrated that statins induce high levels of myalgia during moderate physical exertion, resulting in a decrease in participation in physical activity, consequently affecting exercise performance. A growing body of evidence in both human and animal models indicates that physical exercise, especially when it involves eccentric contractions, can aggravate statin-induced myopathy, while statin therapy may predispose runners to exercise-induced muscle damage.(152, 155) Therefore, adults on statin therapy avoid moderate physical exertion during everyday life. Research has demonstrated that subjects who discontinued statin use exhibited a significantly smaller decline in leg strength and leg muscle quality over the study period compared with those subjects who maintained the statin regimen.(153, 154)…A cross-sectional survey of amateur runners in the Netherlands found an association between statin use and the prevalence of exercise-related injuries. Research indicated that among statin users, 41% reported an injury in the previous year: tendon- or ligament-related sport injuries 22%, muscle-related injuries 15% and other injuries 13%.(88) The majority (30%) of the statin users reported one injury and 10% reported two injuries. Simvastatin 57% and atorvastatin 25% were the most frequently used statins. (157) Findings indicate that in top sports performers only about 20% tolerate statin treatment, involving atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin, demonstrating no side-effects.(158) Research suggested that older athletes are at increased risk of falling and decreased muscle strength and muscle quality are present in adults receiving statin therapy.(1-10)

Cardiotoxicity of Statin Drugs

In addition to skeletal muscle toxicity, statin drugs are toxic to cardiac muscle cells, a possible etiology for the increasing epidemic of congestive heart failure, related to Co-Enzyme Q10 depletion, an important co-factor in the mitochondrial transport chain.(13-16)

In 2020, Dr.  Hans-Ulrich Kloer advises all patients on statin drugs with depressed cardiac function should be given CoQ-10, writing:

Heart failure (HF) is one of the most common causes of death in Western society. Recent results underscore the utility of coenzyme Q10 (CoQ10) addition to standard medications in order to reduce mortality and to improve quality of life and functional capacity in chronic heart failure (CHF)…Previous reports have shown that CoQ10 concentration is decreased in myocardial tissue in CHF and by statin therapy, and the greater the CoQ10 deficiency the more severe is the cardiocirculatory impairment. In patients with CHF and hypercholesterolaemia being treated with statins, the combination of CoQ10 with a statin may be useful for two reasons: decreasing skeletal muscle injury and improving myocardial function…However, particular caution is advisable with the use of strategies of extreme lowering of cholesterol that may negatively impact on myocardial function. All in all there is a strong case for considering co-administration of ubiquinol [CoQ-10] with statin therapy in patients with depressed or borderline myocardial function. (13-16)

Statins Are Causing an Epidemic of Congestive Heart Failure

In 2015, Dr. Harumi Okuyama reviewed the effects of statin drugs on the MVA pathway inhibition of prenyl intermediates causing vitamin K depletion which increases coronary calcification. Increasing coronary calcification is the definition of progressive coronary artery disease as demonstrated by the coronary calcium score test. Statin inhibition of prenyl intermediates also causes selenoprotein depletion which decreases anti-oxidant protection in mitochondria. Similarly, statins cause CoEnzyme Q10 depletion and Heme A depletion which inhibits mitochondrial energy production causing congestive heart failure. Dr. Okuyama believes the statin induced heart damage is permanent, representing a direct cause of the epidemic of congestive heart failure with more than one million cases annually, writing:

Physicians in general are not aware that statins can cause heart failure and are clearly not recognizing it. Although vast majority of physicians readily recognize and diagnose heart failure in patients taking statins, the heart failure is almost always attributed to other non-statin related factors, such as aging, hypertension and coronary artery disease…The mechanism for the impairment in heart muscle function appears to be related to impaired mitochondrial function, which in turn is related to statin depletion of CoQ10, selenoproteins and ‘heme A’, all required for normal mitochondrial function…Statin-induced impairment in heart muscle function appears to be permanent, and even though patients may clinically benefit from discontinuation of the statin along with supplemental CoQ10, we believe that many years of statin drug therapy result in the gradual accumulation of mitochondrial DNA damage. A prolonged decrease in mitochondrial CoQ10 would diminish the ability to protect mitochondrial DNA from free radical damage. After a critical percentage of mitochondrial DNA is mutated, offspring mitochondria will progressively lose their efficiency to produce ATP and simultaneously can generate more free radicals and result in a self-perpetuating vicious cycle. The negative consequences of statin-induced increase in coronary artery disease, coupled with a direct statin toxicity upon the myocardium, can be expected to be additive with enormous clinical implications…With more than one million heart failure hospitalizations every year in the USA, the rapidly increasing prevalence of congestive heart failure is now described as an epidemic and it is likely that statin drug therapy is a major contributing factor. (40)

Why Are Statin Drugs So Toxic?

Statin drugs were originally derived from fungal toxins, representing a fungal adaptation to drive away predators in the wild. There are many poisonous mushrooms, and statin drugs are another one by virtue of potent inhibition of the mammalian mevalonate (MVA) pathway as demonstrated in the chart below. Notice the chart shows that statins strongly inhibit the HMGR enzyme (hydroxy-methyl-glutaryl-reductase) which converts Acetyl-Co-A into cholesterol and other end-products required for proper functioning of mammalian cell. The below diagram illustrates statin drugs are poisons which throw a monkey wrench into proper functioning of the mammalian cell. In 2019 , Dr. Anna Fracassi writes:

This [mevalonate, MVA] pathway mainly produces cholesterol, but it is also responsible for the generation of other important end-products that play several physiological roles: Coenzyme Q-10 (mitochondrial respiratory chain), farnesyl and geranylgeranyl moieties (protein post-translational modifications), isopentenyl tRNAs (RNA transcription involved in selenoprotein production), and dolichol (protein N-glycosylation) []. (17)

Above Chart Fig.11 The main steps of MVA pathway. MVA pathway, also known as cholesterol/isoprenoid biosynthetic pathway, is a pivotal metabolic pathway expressed in all mammalian cells. It leads to the production of several end-products, required for the proper functioning of cell physiology. HMGR represents the key and rate-limiting enzyme of the whole pathway, and is responsible for the conversion of HMG-CoA into MVA. HMGR is strongly inhibited by statins. Courtesy of Dr. Anna Fracassi, 2019, (15)

Statins Block Hormone Production

As you can see in the above chart, blocking HMG reductase inhibits the production of cholesterol, leading to low cholesterol levels, an intervention thought to prevent atherosclerotic coronary artery disease. Whether or not this is true will be discussed later. For now, remember that cholesterol is the precursor for production of all hormones in the body. See below chart of steroid synthesis in the body. Blocking cholesterol also blocks ALL hormone production. Needless to say, we need our hormones, and doing this makes people sicker, not healthier.

Above Image: Steroid hormone synthesis chart. Notice Cholesterol (Green Ellipse and Arrow) is the precursor for all other hormones (Red Ellipses): progesterone, cortisol, estradiol, and testosterone. Courtesy of wikimedia commons. Author: Endocrine doctor. CC 4.0.

Neurotoxicity of Statin Drugs – Memory Loss

In 2012, the FDA added the warning of possible memory loss to statin drug labels. Although the brain is only 2 percent of the body weight, the brain contains about 25% of the total body cholesterol. Since the blood brain barrier (BBB) prevents cholesterol uptake from the bloodstream, the neurons in the brain must make their own cholesterol (called de novo synthesis). Unfortunately, statin drugs easily cross the blood-brain-barrier and block production of cholesterol in the brain. About 70% of the brain cholesterol is found in myelin sheaths of oligodendrocytes, and 30 percent in cell membranes of neurons and astrocytes (brain cells). Would you take a drug that prevents your brain from making essential cholesterol? Cholesterol depletion in the hippocampus “leads to progressive loss of dendritic spines and synapses”. In 2019, Dr. Anna Fracassi writes:

Synaptic vesicle biogenesis depends on high cholesterol levels. The remarkable need of cholesterol for vesicle membranes seems to be fundamental for maintaining a proper vesicle curvature and for the assembly of vesicle-specific proteins and lipids . For instance, intracellular cholesterol levels are essential … for the release of synaptic vesicles. Experimental evidence has demonstrated that cholesterol is not only crucial in presynaptic terminals, but also for postsynaptic functions. For instance, a number of neurotransmitter receptors and other postsynaptic components are closely associated to cholesterol-rich lipid rafts, suggesting that an optimal cholesterol concentration is imperative for the structural and the functional organization of post-synaptic terminals. Both reduction and enrichment of cholesterol hamper the activity of gamma aminobutyric acid A (GABAA) receptor. Similarly, cholesterol depletion in hippocampal neurons destabilizes surface…(AMPA) receptors and leads to progressive loss of dendritic spines and synapses. (17)

Lipophilic Statin Drugs Accelerate Early Dementia

IN 2023, Dr P. Padmanabham did a prospective study of 299 patients with early cognitive impairment enrolled in the Alzheimer’s Disease Neuroimaging Initiative database. The patients statin use was categorized as: none (nonS), lipophilic (LS) or hydrophilic (HS), along with recorded baseline serum cholesterol values. The rate of conversion to demntia was determined with global cognition (ADAS13 and MoCA), and memory domain testing. Metabolic brain imaging was was also performed. Use of lipophilic statins was associated with triple the risk of being demented within 8 years compared to statin non-users. This decline into dementia was preceded by metabolic brain imaging changes associated with early Alzheimer’s Dementia. Dr P. Padmanabham writes:

Conclusions: Use of lipophilic, but not hydrophilic, statins by subjects with early cognitive impairment and normal cholesterol levels at baseline was associated with nearly double the risk of becoming demented within 4 years, and risk of becoming demented within 8 years was triple that for non-statin users. Moreover, this was preceded during the first 2 years after baseline by metabolism in brain regions associated with early Alzheimer’s demonstrating significantly greater decline, and correlating with magnitudes of clinically measurable loss of cognitive and general function. (41-44)

Note: Lipophilic statins are atorvastatin (lipitor), simvastatin, lovastatin, fluvastatin, cerivastatin and pitavastatin. Hydrophilic statins are rosuvastatin and pravastatin.

Coenzyme Q, Prenylated Proteins and Dolichol

Other than cholesterol, another end-product of the MVA pathway essential for the brain is CoQ-10, responsible for electron transport in the mitochondria. A deficiency in CoQ-10 may result in cerebellar ataxia, encephalomyopathy and brain atrophy. Yet another end-product is involved in protein prenylation, needed for correct localization of proteins in the cell membrane, needed for signalling cascades. In 2019, Dr. Anna Fracassi writes:

For instance, isoprenoids constitute the side chain of coenzyme Q (CoQ), which assures ATP [energy] production in all mammalian cells including neurons. In mitochondria, CoQ is responsible for the electron transport during the oxidative phosphorylation. CoQ also preserves brain cells from central neurotoxic damages, acting as a powerful anti-oxidant and neuroprotective compound. In addition, clinical evidence indicates that CoQ10 deficiency often results in neuropathological conditions, such as cerebellar ataxia, encephalomyopathy and multiple system atrophy….Protein prenylation consists in the covalent binding of farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) moieties to proteins. The attachment of a prenyl group is an essential prerequisite for the regulation of protein localization on cell membranes and, in turn, for key signaling cascades… It was reported that HMGR inhibition by statins significantly decreases cholesterol biosynthesis in rodent brains and, more recently…statins also lead to a significant reduction in protein prenylation in this organ. From these observations, it is not surprising that clinically relevant doses of statins can induce important biological effects in the brain….Several reports indicated that statins may alter synaptic transmission by modulating the function of neurotransmitter receptors.(17-23)

Statins and Neuropathy

Statin drugs are known to cause painful neuropathies. For more about statin induced neuropathy, see The Art of the Curbside Cholesterol Consult. (35-38)(45)

Statins Cause New Onset Diabetes

In 2015, Dr. Lorenzo Arnaboldi studied new onset diabetes in statin users, noting that in 2012, the FDA added a warning label that statins may raise levels of blood sugar and could cause memory loss, writing:

Large meta-analyses, posthoc and genetic studies showed that statins might increase the risk of new-onset diabetes (NOD), particularly in insulin-resistant, obese, old patients. …Based on this evidence, to warn against the possibility of statin-induced NOD or worsening glycemic control in patients with already established diabetes, FDA and EMA changed the labels of all the available statins in the USA and Europe. [In 2012, the FDA added warning  label: statins may raise levels of blood sugar and could cause memory loss]. Recent meta-analyses and retrospective studies demonstrated that statins’ diabetogenicity is a dose-related class effect, but the mechanism(s) is not understood. Among statins, only pravastatin and pitavastatin do not deteriorate glycemic parameters in patients with and without type 2 diabetes mellitus. Interestingly, available data, obtained in smallscale, retrospective or single-center clinical studies, document that pitavastatin, while ameliorating lipid profile, seems protective against NOD. Beyond differences in pharmacokinetics between pitavastatin and the other statins (higher oral bioavailability, lower hepatic uptake), its consistent increases in plasma adiponectin documented in clinical studies may be causally connected with its effect on glucose metabolism. Adiponectin is a protein with antiatherosclerotic, anti-inflammatory and antidiabetogenic properties exerted on liver, skeletal muscle, adipose tissue and pancreatic beta cells. (24)

The Failure of Cholesterol Lowering Drugs

Now that we have reviewed the toxicity and adverse effects of statin drugs which are broad spectrum poisons of the mammalian cell, let us now turn our attention to the question of efficacy of lowering cholesterol with a drug. This is called the cholesterol theory of heart disease, and is the same question asked by Dr. Mikael Rabaeus in 2019 who reviewed all the studies on the new cholesterol lowering drugs called CETP and PCSK9 Inhibitors. Firstly, Dr. Rabaeus tells us we have no access to the raw data of these studies, and we should. Why is the raw data kept secret? In the absence of the raw data, Dr. Mikael Rabaeus suggests we should rely on mortality outcomes as the most reliable data. Dr. Rabaeus was disappointed to find despite a very significant lowering of cholesterol, these new drugs were a complete failure: “neither anti-CETP nor anti-PCSK9 treatment can significantly reduce the risk of cardiovascular death,”. Obviously this leads to overturning the theory that reducing cholesterol prevents heart disease, writing:

In the absence of open access to the raw data for independent scientists, it is clear that the mortality endpoint should be the main criterion to test efficacy…If cholesterol-lowering treatments other than statins reduce the risk of cardiovascular complications, it would confirm that the cholesterol-heart theory is correct. However, if these substances fail to reduce the risk, the cholesterol-heart theory should be rejected…The two groups of medications are (i) the cholesteryl ester transfer protein (CETP) inhibitors, which we will call anti-CETP in the present study, and (ii) the proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors, which we will call anti-PCSK9 in this study…The review did show that neither anti-CETP nor anti-PCSK9 treatment can significantly reduce the risk of cardiovascular death, thereby giving credit to the questioning of the cholesterol-heart theory…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 re-appreciate 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. (25)

In 2023, Dr. J. Grover from Blacktown Hospital, Sydney, Australia did a systematic review and meta-analysis of 10 PCSK9 inhibitor clinical trials. The authors declared no industry funding of their study. Ten randomized controlled trials of PCSK9 inhibitors with 57,890 patients were reviewed. Dr. Grover found: “no statistically significant effect was observed… for all-cause mortality.” In other words, a placebo gave the same mortality benefit as the PCSK9 drug, indicating the failure of cholesterol lowering drugs. Think of it this way. Approximately 500,000 deaths every year in the US are attributed to cardiovascular disease. An effective drug for prevention of cardiovascular disease should reduce this mortality number by 50-90 percent. That is what we are looking for. Why in the world would anyone take a drug to prevent heart disease that has no mortality benefit? Such a drug is a fraud. (47)

CETP Inhibitor Drugs All Abandoned

After disappointing clinical trials, all four CETP inhibitor drugs anacetrapib, dalcetrapib, evacetrapib, and torcetrapib were abandoned by their drug company sponsor. They were never FDA approved, and never brought to the market. This is the definition of a failed drug.

Torcetrapib (Pfizer) was abandoned in 2006.
Evacetrapib (Eli Lilly) failed a clinical trial in 2014 and was abandoned.
Dalcetrapib (Hoffmann–La Roche) drug development abandoned in May 7, 2012 “due to a lack of clinically meaningful efficacy.”
Anacetrapib (Merck) halted drug development in 2017.
Obicetrapib (Amgen, AMG-899) abandoned in 2017. In 2020, Amgen licensed the drug to NewAmsterdam Pharma which is in Phase III trial as of 2023.(48-49)

44 Randomized Controlled Trials (RCTs)

In fact, as pointed out in 2017 by Maryanne Demasi there are 44 randomized controlled trials of drug or dietary interventions which lower LDL cholesterol for primary or secondary prevention of coronary artery disease which show no mortality benefit. (26-33)

Making things even worse, a recent analysis found that taking a statin drug would lengthen a person’s life by 3.1 and 4.2 days for primary and secondary prevention, respectively. (34)

In 2021, Dr Robert Dubroff reviewed the new cholesterol targets and analyzed the prevailing medical studies on cholesterol lowering drugs, finding contradictory evidence of efficacy, writing:

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.(33)

Statin Drugs Increase Coronary Calcium Score

Replacing the old cholesterol panel is the coronary calcium score, a highly accurate and sensitive test for predicting risk for future heart attack. Increasing calcium score over 15 percent annually is highly predictive for active coronary artery disease and impending heart attack, while under 15 percent annual increase indicates dormant disease with low risk for impending heart attack. Interventions which decrease calcium score progression are preventive for coronary artery disease. Unfortunately for the statin drug industry, statin drugs do not decrease calcium score progression. It is now widely accepted by mainstream cardiology that statin drugs tend to increase calcium score, or have an effect indistinguishable from placebo. The current explanation is the statin induced increase in calcium score is a benign stabilization of the atherosclerotic plaque, since “we know how beneficial statin drugs are”. If you believe this, I have a bridge to nowhere to sell you. In a 2004 by Dr. Paolo Raggi, over 15 percent annual progression of calcium score while on a statin drug predicted impending myocardial infarction, not stabilization. See this reference:

Raggi, Paolo, Tracy Q. Callister, and Leslee J. Shaw. “Progression of coronary artery calcium and risk of first myocardial infarction in patients receiving cholesterol-lowering therapy.” Arteriosclerosis, thrombosis, and vascular biology 24.7 (2004): 1272-1277.

Our Calcium Score Protocol

Our calcium score protocol for preventing calcium score progression, and thereby preventing and  reversing coronary artery disease is as follows: Plant based diet, Vitamin C, Tocotrienol vitamin E, Aged Garlic, Magnesium, Vitamin K (MK-7), Berberine, Curcumin, Proteolytic enzymes (lumbrokinase, serrapeptidase, nattokinase), Dental hygiene and dental cleaning, and the control of metabolic syndrome, insulin sensitivity and fasting blood sugar with dietary modification and metformin. For diabetics and others with leaky gut, a probiotic program from Microbiome Labs called Mega-sporebiotic Total Gut Restore is useful. I would suggest this calcium score protocol is more effective and safer than cholesterol lowering drugs. However, we will never see a randomized controlled trial comparing them, and we should.

Conclusion: When prescribing a drug for the prevention or treatment of a disease, one must weigh the benefits against the adverse effects. In view of the fact that statins are mitochondrial and cellular poisons with extensive adverse side effects on muscle and brain, one would expect the drug to be highly effective. Quite to the contrary, we find cholesterol lowering is a complete failure for preventing cardiovascular disease. There is no mortality reduction, and half the RCTs have no cardiovascular benefit. Why in the world would any rational thinking human being take such as drug? This brings us back to my original question: why are there are so many failed randomized drug trials for cholesterol lowering drugs? Why keep repeating the same drug experiment over and over again expecting a different result? This is the definition of insanity.

In 2016, Dr. David Diamond studied the entire statin drug medical literature, finding the small benefit in cholesterol lowering trials is independent of cholesterol lowering. This is exactly what we are seeing with the failed clinical trial for the newer drugs, both anti-CETP and anti-PCSK9 drugs reduce cholesterol levels even lower than statins, yet have no mortality benefit. In my opinion, any benefit from statin drugs is due to anti-inflammatory and antimicrobial properties, which can be easily replicated with our calcium score protocol listed above without statins, avoiding their adverse effects on muscle, heart, and brain. (46)

Heart Book by Jeffrey dach MDMy book is called: Heart Book

If you liked this article, you may like my book, entitled Heart Book on Amazon. See cover image at left.

Click Here for Link to book on Amazon

Articles with Related Interest:

Coronary Artery Disease: Questions and Answers

Calcium Score Determines Who to Treat with Statin Drug

Calcium Score Diabetes and Statin Drugs

Cardiomyopathy Reversible with CoQ10 and Selenium

Plant Based Diet, Health Benefits for Coronary Artery Disease

Diabetes, Arterial Calcification and Statin Drugs

LDL-Cholesterol Does Not Cause Coronary Artery Disease

LDL Particle Size and Number, What Gives?

All Articles on Coronary Artery Disease

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
my blog: www.jeffreydachmd.com 

———————————————— –

Images:

References:

Statins in Marathon Runners

1) Kroon, Lize. The epidemiology and associated risk factors for muscle strain injuries in endurance running athletes. Diss. UNIVERSITY OF PRETORIA, 2023.

New evidence suggests that statin use can directly compromise aerobic exercise capacity and increase risk of muscle injuries; however, it is just the beginning of comprehension between the interactions of statins with exercise training. The use of statins may result in mitochondrial dysfunction in skeletal muscle cells, which in turn may interfere with aerobic capacity and training adaptations.(153, 154)

Research has demonstrated that statins induce high levels of myalgia during moderate physical exertion, resulting in a decrease in participation in physical activity, consequently affecting exercise performance. A growing body of evidence in both human and animal models indicates that physical exercise, especially when it involves eccentric contractions, can aggravate statin-induced myopathy, while statin therapy may predispose runners to exercise-induced muscle damage.(152, 155) Therefore, adults on statin therapy avoid moderate physical exertion during everyday life. Research has demonstrated that subjects who discontinued statin use exhibited a significantly smaller decline in leg strength and leg muscle quality over the study period compared with those subjects who maintained the statin regimen.(153, 154)

A cross-sectional survey of amateur runners in the Netherlands found an association between statin use and the prevalence of exercise-related injuries. Research indicated that among statin users, 41% reported an injury in the previous year: tendon- or ligament-related sport injuries 22%, muscle-related injuries 15% and other injuries 13%.(88) The majority (30%) of the statin users reported one injury and 10% reported two injuries. Simvastatin 57% and atorvastatin 25% were the most frequently used statins. (157) Findings indicate that in top sports performers only about 20% tolerate statin treatment, involving atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin, demonstrating no side-effects.(158) Research suggested that older athletes are at increased risk of falling and decreased muscle strength and muscle quality are present in adults receiving statin therapy.(159)

2) 152. Murlasits Z, Radak Z. The effects of statin medications on aerobic exercise capacity and training adaptations. Sports Medicine. 2014;44(11):1519-30.

3) 153. Charlton-Menys V, Durrington PN. Human cholesterol metabolism and therapeutic molecules. Experimental Physiology. 2008;93(1):27-42.

4) 154. Bouitbir J, Charles AL, Rasseneur L, Dufour S, Piquard F, Geny B, et al. Atorvastatin treatment reduces exercise capacities in rats: involvement of mitochondrial impairments and oxidative stress. Journal of Applied Physiology. 2011;111(5):1477-83.

5) 155. Mikus CR, Boyle LJ, Borengasser SJ, Oberlin DJ, Naples SP, Fletcher J, et al. Simvastatin impairs exercise training adaptations. Journal of the American College of Cardiology. 2013;62(8):709-14.

6) 156. Schwellnus MP, Swanevelder S, Jordaan E, Derman W, Van Rensburg DCJ. Underlying chronic disease, medication use, history of running injuries and being a more experienced runner are independent factors associated with exercise-associated muscle cramping: a cross-sectional study in 15778 distance runners. Clinical Journal of Sport Medicine. 2018;28(3):289-98.

7) 157. Murlasits Z, Radák Z. The effects of statin medications on aerobic exercise capacity and training adaptations. Sports Medicine. 2014;44(11):1519-30.

8) 158. Sinzinger H, O’grady J. Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems. British Journal of Clinical Pharmacology. 2004;57(4):525-8.

9) 159. Scott D, Blizzard L, Fell J, Jones G. Statin therapy, muscle function and falls risk in community-dwelling older adults. QJM: An International Journal of Medicine. 2009;102(9):625-33.

10) 160. Muraki A, Miyashita K, Mitsuishi M, Tamaki M, Tanaka K, Itoh H. Coenzyme Q10 reverses mitochondrial dysfunction in atorvastatin-treated mice and increases exercise endurance. Journal of Applied Physiology. 2012;113(3):479-86.

11) Schweitzer, Allyson M., et al. “The impact of statins on physical activity and exercise capacity: an overview of the evidence, mechanisms, and recommendations.” European Journal of Applied Physiology 120 (2020): 1205-1225.

Though generally well tolerated, up to 29% of statin users develop statin-associated muscle symptoms (SAMS) (Fernandez et al. 2011; Sathasivam and Lecky 2008),
including muscle pain (myalgia), inflammation (myositis), damage (myopathy), and in extreme cases, rhabdomyolysis (Bruckert et al. 2005; El-Salem et al. 2011; Pasternak et al. 2002; Thompson et al. 2016). Despite reports implicating the ‘nocebo effect’ in many SAMS cases (Finegold et al. 2014; Gupta et al. 2017), the cessation of these symptoms is often only achieved through statin discontinuation (Cohen et al. 2012; Colivicchi et al. 2007). Of the SAMS, myalgia is by far the most common complaint (Ramkumar, Raghunath and Raghunath 2016), presenting as muscle soreness, weakness, cramps, and aches in the upper and/ or lower extremities…In fact, statin prescription is widely associated with a reduction in physical activity levels, with similar conclusions drawn by 3 large observational studies (Lee et al.2014; Loenneke and Loprinzi 2018; Scott et al. 2009)… Statins in particular have been demonstrated to reduce mitochondrial respiration and increase ROS production (Allard et al. 2018; Bouitbir et al. 2016; Busanello et al. 2017; Davies et al.1982; Pryor 1982; Rebalka et al. 2019). Allard et al. (2018) demonstrated that muscle from symptomatic statin users had reductions in complex II and IV activity and
an approximate 28% decrease in ATP production capacity…compared to muscle from non-statin users. Additionally, Dohlmann et al. (2019) demonstrated reduced complex II respiration in both symptomatic and asymptomatic statin users…Due to its roles within the mitochondria, it was hypothesized that this lack of CoQ10 may be contributing to the reduced respiration and increased ROS production demonstrated in the mitochondria of statin users…Unsurprisingly, CoQ10 supplementation has been proposed as a treatment for SAMS. Recent literature, however, demonstrated that while CoQ10 supplementation effectively increased serum CoQ10 levels, SAMS developed at the same rate with and without supplementation (Banach et al. 2015; Bogsrud et al. 2013; Bookstaver et al. 2012; Rott et al. 2016; Taylor et al. 2015; Young et al. 2007). This lack of symptom relief may be explained by the absence of change in intramuscular CoQ10 levels….reduced vitamin D levels can reduce statin metabolism and clearance, resulting in a greater chance for myotoxicity (Ahmed et al. 2009; Glueck et al. 2011a, b; Glueck et al. 2011a, b; Pérez-Castrillón et al. 2010)…statin users with SAMS had significantly lower plasma vitamin D levels than asymptomatic statin users (Michalska-Kasiczak et al. 2015)…Khayznikov et al. (2015) found previously statin-intolerant patients to be free of SAMS after 24 months of vitamin D supplementation. Overall, while statins seem to reduce serum vitamin D levels, the muscle-specific role of vitamin D in SAMS is largely unknown….In addition, statin users with SAMS demonstrate a 40% reduction in CLC-1 chloride channel proteins when compared to non-statin users (Camerino et al. 2017). This channel is responsible for resting sarcolemma membrane stability, and thus reductions may lead to membrane hyperexcitability, and a decreased threshold for subsequent muscle cramping, spasm, and weakness….It has been suggested that statins alter mPTP permeability and increase mitochondrial calcium uptake (Busanello et al. 2018). If enough calcium is taken up
by the mitochondria, respiration is impeded, swelling may occur, and apoptotic/necrotic pathways may be initiated (Busanello et al. 2018; Marchi et al. 2018; Orrenius et al. 2003; Pinton et al. 2008). This could explain the deficits in mitochondrial respiration demonstrated in statin users as well as the reduction in ATP production capacity. In support of this concept, Busanello et al. (2018) showed that blocking the mPTP Mitochondrial permeability transition pore in statin-treated mice restored normal mitochondrial respiration.  Compared to non-users, Parker et al. (2013) and Bouitbir et al. (2016) found statin users to have elevated CK levels at rest, indicating a greater baseline level of muscle damage. A recent case study also describes the development of acute rhabdomyolysis in a marathon runner treated with rosuvastatin, characterized by severe pain and elevated CK
levels (Toussirot et al. 2015).

A study by Trapani et al. (2012) looked later in the time course of muscle repair
in the presence of statin treatment. 21 days following muscle injury, histology revealed completely restored tibialis anterior muscle architecture in the absence of statin treatment. Simvastatin treated mice, however, still displayed central nucleation. Importantly, mevalonate co-therapy negated the effect of statin treatment, abrogating the presence of central nuclei and supporting that the observed regenerative delay was a result of reduced cholesterol biosynthesis pathway entities (Trapani et al. 2012).

Statins Impair Muscle regeneration

Geranylgeraniol, downstream of mevalonate in the cholesterol biosynthesis pathway, has been shown to induce myogenic differentiation of murine myoblasts derived from
muscle satellite cells and reduce statin-induced muscle cell damage (Cao et al. 2009; Matsubara et al. 2018). Similarly, statin treatment has been shown to affect satellite cell differentiation and reduce myoblast fusion, attenuating the production
of multinucleated entities (Baba et al. 2008; Martini et al. 2009; Trapani et al. 2012). These impairments were rescued with mevalonate co-treatment, validating the importance
of downstream products of the cholesterol biosynthesis pathway in muscle maturation (Trapani et al. 2012). As satellite cells are primary mediators of muscle regeneration,
these results are indeed concerning for muscle repair and regeneration in the presence of statin therapy.

Taken together, the above preclinical studies suggest that statins
delay muscle regeneration and impede satellite cell function.

A 2005 study by Bruckert et al. is commonly cited as evidence that SAMS are aggravated by physical activity. In  this study, 40% of the population reporting  myalgia indicated that certain factors triggered their symptoms. Of this 40%, over half indicated ‘unusual physical exertion’ as a trigger. Bruckert et al. (2005) also report the prevalence of myalgia to be greater in physically active individuals.

Thompson et al. (1997) demonstrated serum CK levels to be elevated in statin users compared to non-users following treadmill exercise, indicating a greater presence of  muscle damage. These serum CK levels returned to baseline within 3 days.

physical activity provides many systemic health benefits that statins cannot, including improved muscle health,cognitive function, functional capacity, and quality of life (Baptista et al. 2018; Kubota et al. 2017; McPhee et al. 2016; Molina-sotomayor et al. 2018; Myers et al. 2015).

Discussion and Conclusion

Established literature has demonstrated that statins reduce muscle strength during strength testing, as well as elevate serum CK both at rest and after exercise (Bouitbir et al. 2016; Parker et al. 2013; Parker et al. 2012; Toussirot et al.2015), raising the concern that physical exertion may exacerbate muscle damage…The current review demonstrates that statins do alter skeletal muscle metabolism, in particular, mitochondrial metabolism.

12) Toussirot, Éric, Fabrice Michel, and Nicolas Meneveau. “Rhabdomyolysis occurring under statins after intense physical activity in a marathon runner.” Case Reports in Rheumatology 2015.1 (2015): 721078.

Cardiotoxicity of Statins

13) Chaulin, Aleksey. “Cardiotoxicity as a Possible Side Effect of Statins.” Reviews in Cardiovascular Medicine 24.1 (2023): 22.
In addition, a number of side effects of statins, in particular, myotoxicity, hepatotoxicity, diabetogenic property, etc., may limit the possibility of using statins or even force doctors to cancel these drugs. Also, some concerns are caused by recent studies reporting cardiotoxicity of statins and increased serum concentrations of biomarkers of myocardial damage (highly sensitive cardiac troponins (hs-cTns)) in patients taking statins.

14) Chaulin, Aleksey M. “The Negative Effects of Statin Drugs on Cardiomyocytes: Current Review of Laboratory and Experimental Data (Mini-Review).” Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Cardiovascular & Hematological Agents) 22.1 (2024): 7-16.

Thus, statin drugs can have a number of negative effects on cardiomyocytes, in particular, increased oxidative stress, endoplasmic reticulum stress, damage to mitochondria and intercalated discs, and inhibition of glucose transport into cardiomyocytes.

15) Langsjoen, Peter H., et al. “Statin-associated cardiomyopathy responds to statin withdrawal and administration of coenzyme Q10.” The Permanente Journal 23 (2019).

16) Kloer, Hans-Ulrich, et al. “Combining ubiquinol with a statin may benefit hypercholesterolaemic patients with chronic heart failure.” Heart, Lung and Circulation 29.2 (2020): 188-195.

STATINS and The BRAIN

17) Fracassi, Anna, et al. “Statins and the brain: more than lipid lowering agents?.” Current neuropharmacology 17.1 (2019): 59-83.

Statins consist of a class of drugs at first identified as fungi metabolites, characterized by different lipophilicity and effectiveness []. They are potent inhibitors of mevalonate (MVA) pathway (Fig. 11). This pathway mainly produces cholesterol, but it is also responsible for the generation of other important end-products that play several physiological roles: Coenzyme Q (mitochondrial respiratory chain), farnesyl and geranylgeranyl moieties (protein post-translational modifications), isopentenyl tRNAs (RNA transcription), and dolichol (protein N-glycosylation) [].

Despite the brain constitutes 2% of the body weight, it contains about 25% of the total body cholesterol []…in the CNS, the blood brain barrier (BBB) hinders cholesterol uptake from the bloodstream, thus de novo synthesis represents the only source for practically all cholesterol present in this organ []…Essentially all (>99,5%) cholesterol in the CNS is present in an unesterified free form. This lipid is divided into two major pools: the former retains up to 70% of the brain cholesterol and represents a key constituent of myelin sheaths of oligodendrocytes; the latter is made up by plasma membranes of neurons and astrocytes []. Astrocytes are able to synthesize at least 2- to 3-fold more cholesterol than neurons. Cholesterol demand by neurons is very high, since this compound is required for a variety of neuronal processes, such as neurite formation and synapse activity [].

Cholesterol plays pivotal functions in CNS physiology []. It carries out structural roles in cellular membranes, as it modulates their fluidity and thickness, [] and provides axonal electrical insulation for the conduction of rapid saltatory impulse [] by restricting ion leakage through cholesterol-rich myelin membranes []. Furthermore, cholesterol is crucial for synapse formation, as it increases the number of synapses by enhancing their stability []. Different reports indicated that the biogenesis of organelles and structures belonging to the synaptic terminals requires a high cholesterol content. Indeed, synaptic vesicle membranes possess a relevant amount of cholesterol compared to other intracellular organelles [], supporting the hypothesis that synaptic vesicle biogenesis depends on high cholesterol levels []. The remarkable need of cholesterol for vesicle membranes seems to be fundamental for maintaining a proper vesicle curvature and for the assembly of vesicle-specific proteins and lipids []. For instance, intracellular cholesterol levels are essential for the interaction between synaptobrevin and synaptophysin and, as a consequence, for the release of synaptic vesicles []. Experimental evidence has demonstrated that cholesterol is not only crucial in presynaptic terminals, but also for postsynaptic functions. For instance, a number of neurotransmitter receptors and other postsynaptic components are closely associated to cholesterol-rich lipid rafts, suggesting that an optimal cholesterol concentration is imperative for the structural and the functional organization of post-synaptic terminals []. Both reduction and enrichment of cholesterol hamper the activity of gamma aminobutyric acid A (GABAA) receptor []. Similarly, cholesterol depletion in hippocampal neurons destabilizes surface alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and leads to progressive loss of dendritic spines and synapses [].

Coenzyme Q, Prenylated Proteins and Dolichol

Besides cholesterol, other MVA end-products play essential roles in the brain. For instance, isoprenoids constitute the side chain of coenzyme Q (CoQ) [], which assures ATP production in all mammalian cells including neurons. In mitochondria, CoQ is responsible for the electron transport during the oxidative phosphorylation. CoQ also preserves brain cells from central neurotoxic damages, acting as a powerful anti-oxidant and neuroprotective compound []. In addition, clinical evidence indicates that CoQ10 deficiency often results in neuropathological conditions, such as cerebellar ataxia, encephalomyopathy and multiple system atrophy []….Protein prenylation consists in the covalent binding of farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) moieties to proteins. The attachment of a prenyl group is an essential prerequisite for the regulation of protein localization on cell membranes and, in turn, for key signaling cascades [].

After a single dose administration, statins can be detected at significant levels in the brain [], thus producing inhibitory effects on MVA production. It was reported that HMGR inhibition by statins significantly decreases cholesterol biosynthesis in rodent brains [, ] and, more recently, two-dimensional gel electrophoresis approaches provided evidence that statins also lead to a significant reduction in protein prenylation in this organ []. From these observations, it is not surprising that clinically relevant doses of statins can induce important biological effects in the brain….Several reports indicated that statins may alter synaptic transmission by modulating the function of neurotransmitter receptors.

18) Segatto, Marco, et al. “Cholesterol homeostasis failure in the brain: implications for synaptic dysfunction and cognitive decline.” Current medicinal chemistry 21.24 (2014): 2788-2802.

ZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZZ

19) Mailman, Tiffany, Manoj Hariharan, and Barbara Karten. “Inhibition of neuronal cholesterol biosynthesis with lovastatin leads to impaired synaptic vesicle release even in the presence of lipoproteins or geranylgeraniol.” Journal of neurochemistry 119.5 (2011): 1002-1015.

Cholesterol is highly enriched in the brain, and plays a key role in synapse formation and function. The brain does not derive cholesterol from the circulation; instead, the majority of cholesterol is made in glia and secreted in form of lipoproteins. Neurons can synthesize cholesterol, but the extent of neuronal cholesterol biosynthesis in the adult brain is unknown. Cholesterol biosynthesis inhibitors of the statin family are widely used to lower circulating cholesterol and cardiovascular risk. Lipophilic statins can cross the blood brain barrier and inhibit brain cholesterol biosynthesis with possible consequences for synaptic cholesterol homeostasis. We have investigated the effects of lovastatin on synapse maturation and synaptic vesicle release. Treatment of primary hippocampal neurons with low levels of lovastatin for one week reduced synapse density and impaired synaptic vesicle release. Neither lipoproteins nor geranylgeraniol fully counteracted the lovastatin-induced decrease of synaptic vesicle exocytosis, even when cholesterol depletion was prevented. In contrast, restoration of neuronal cholesterol synthesis with mevalonate prevented defects in vesicle exocytosis without fully normalizing neuronal cholesterol content. These results raise the possibility that chronic exposure of neurons to lipophilic statins may affect synaptic transmission, and indicate that hippocampal neurons need a certain level of endogenous cholesterol biosynthesis.

20) Miron, Veronique E., et al. “Statin therapy inhibits remyelination in the central nervous system.” The American journal of pathology 174.5 (2009): 1880-1890.

21) Klopfleisch, Steve, et al. “Negative impact of statins on oligodendrocytes and myelin formation in vitro and in vivo.” Journal of Neuroscience 28.50 (2008): 13609-13614.

22) Xiang, Zhongmin, and Steven A. Reeves. “Simvastatin induces cell death in a mouse cerebellar slice culture (CSC) model of developmental myelination.” Experimental neurology 215.1 (2009): 41-47.

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

We show that both protein isoprenylation and cholesterol synthesis are required for the normal differentiation of OLGs. It is further demonstrated that the expression of 2′,3′-cyclic-nucleotide-3′ phosphodiesterase (CNP) and tubulin is lowered, concomitant with a reduction of membrane-bound CNP as well as tubulin. Therefore, we propose that lack of isoprenylation of CNP could help to explain the altered morphological and biochemical differentiation state of treated OLGs. Moreover, expression of specific myelin markers, such as myelin basic protein, myelin-associated glycoprotein, and myelin oligodendrocyte glycoprotein, was compromised after treatment. We conclude that simvastatin treatment has detrimental effects on OLG process outgrowth, the prior step in (re)myelination, thereby mortgaging long-term healing of MS lesions

23) Goldstein, Mark R., and Luca Mascitelli. “Regarding long-term statin therapy: Are we trading stronger hearts for weaker brains?.” Medical hypotheses 83.3 (2014): 346-351.

Ideally, the benefits of long-term statin therapy should outweigh the risks in all populations. However, some data suggest that long-term statin therapy might promote cerebral small vessel disease and impair myelination, perhaps resulting from cholesterol depletion and pleiotropic effects on amyloid-β metabolism and oligodendrocyte function. The clinical ramifications can be problematic and have a negative impact on the quality of life. Questions are proposed and the answers should be found by analysis of randomized prospective trials specifically investigating the effects of statin therapy on brain structure and function. Those trials should not be funded by drug companies and the investigators should not have financial ties to the pharmaceutical industry. The relevance of the aforementioned is amplified in light of the new cardiovascular guidelines that might culminate in more than a billion people receiving statin therapy worldwide.

24) Arnaboldi, Lorenzo, and Alberto Corsini. “Could changes in adiponectin drive the effect of statins on the risk of new-onset diabetes? The case of pitavastatin.” Atherosclerosis Supplements 16 (2015): 1-27.

Statins represent the elective lipid-lowering strategy in hyperlipidemic and high cardiovascular-risk patients. Despite excellent safety and tolerability, reversible muscle-related and dose-dependent adverse events may decrease a patient’s compliance. Large meta-analyses, posthoc and genetic studies showed that statins might increase the risk of new-onset diabetes (NOD), particularly in insulin-resistant, obese, old
patients. Race, gender, concomitant medication, dose and treatment duration may also contribute to this effect. Based on this evidence, to warn against the possibility of statin-induced NOD or worsening glycemic control in patients with already established diabetes, FDA and EMA changed the labels of all the available statins in the USA and Europe. Recent meta-analyses and retrospective studies demonstrated that statins’ diabetogenicity is a dose-related class effect, but the mechanism(s) is not understood. Among statins, only pravastatin and pitavastatin do not deteriorate glycemic parameters in patients with and without type 2 diabetes mellitus. Interestingly, available data, obtained in smallscale, retrospective or single-center clinical studies, document that pitavastatin, while ameliorating lipid profile, seems protective against NOD. Beyond differences in pharmacokinetics between pitavastatin and the other statins (higher oral bioavailability, lower hepatic uptake),
its consistent increases in plasma adiponectin documented in clinical studies may be causally connected with its effect on glucose metabolism. Adiponectin is a protein with antiatherosclerotic, anti-inflammatory and antidiabetogenic properties exerted on liver, skeletal muscle, adipose tissue and pancreatic beta cells. Further studies are required to confirm this unique property of pitavastatin and to understand the mechanism(s)
leading to this effect.

=========================

*********************************************************
!!!!!!!!!!!!!!!!!!!!!!!!!!!!! BEST !!!!!!!!!!!!!!!!!!!
**********************************************************

New Non-statin cholesterol drugs are a failure !!!

Click to access f3d1aae01e08d46caf5f91f7b2ab83019a46.pdf

25) 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.

In the absence of open access to the raw data for independent scientists, it is clear that the mortality endpoint should be the main criterion to test efficacy.

If cholesterol-lowering treatments other than statins reduce the risk of cardiovascular complications, it would confirm that the cholesterol-heart theory is correct. However, if these substances fail to reduce the risk, the cholesterol-heart theory should be rejected.

(CETP) inhibitors and (PCSK9) inhibitors

The two groups of medications are (i) the cholesteryl ester transfer protein (CETP) inhibitors, which we will call anti-CETP in the present study, and (ii) the proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors, which we will call anti-PCSK9 in this study

The review did show that neither anti-CETP nor anti-PCSK9 treatment can significantly reduce the risk of cardiovascular death, thereby giving credit to the questioning of the cholesterol-heart theory.

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.
==========================

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]

26) 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

—————————— –

duplicate : see (8) above

27) DuBroff, Robert. “Cholesterol paradox: a correlate does not a surrogate make.” BMJ Evidence-Based Medicine 22.1 (2017): 15-19.

Ironically, cholesterol is also essential for life as a key component of cell membranes, steroid hormones and bile acids.

Figure 1 illustrates this concept and the original Framingham cholesterol data. The cholesterol levels of Framingham participants who did and did not develop CHD are remarkably similar except when the cholesterol level was extremely low (<150 mg/ dL) or extremely high (>380 mg/dL). For the vast majority of patients, cholesterol levels do not help us differentiate those who will and will not develop CHD.

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 specifically designed to assess mortality, the reported lack of mortality benefit should not be disregarded.

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

some refer to meta-analysis as ‘statistical alchemy for the twenty-first century’.

Thomas Kuhn: reluctance to acknowledge anomalies in a theory

The empirical record is now clear that lowering cholesterol through diet or with eight different classes of drugs does not significantly prolong life or consistently prevent CHD (table 1). Yet experts continue to proclaim the success of cholesterol lowering. Fifty-four years ago, Thomas Kuhn described this reluctance to acknowledge anomalies in a theory.18

Kuhn TS. The structure of scientific revolutions. Chicago: University of Chicago Press, 1962

Dr Kuhn wrote that a paradigm shift would only occur when the evidence contradicting a theory is overwhelming. Therefore, we must accept the empirical record even though it contradicts our long-held beliefs.

Other researchers believe this reluctance can be explained by the tendency to “see what you want to see,” and ignore what you do not.19

28) McCormack J, Greenhalgh T. Seeing what you want to see in randomised controlled trials: versions and perversions of UKPDS data. United Kingdom prospective diabetes study. BMJ 2000;320:1720–3

For example, a recent editorial in the New England Journal of Medicine proclaimed, “Proof That Lower Is Better—LDL Cholesterol and IMPROVE-IT.”20 IMPROVE-IT, a RCT of ezetimibe added to simvastatin in patients with a recent acute coronary syndrome, reported a 24% reduction in LDL cholesterol, but an absolute risk reduction in combined CV events of only 2% after 6 years. Furthermore, the results barely achieved statistical significance (HR 0.936, 95% CI 0.89 to 0.99) and there was no mortality benefit The debate over the cholesterol hypothesis has continued because the results of cholesterol lowering interventions are inconsistent and contradictory.

Nevertheless, clinical guidelines continue to emphasize the critical importance of cholesterol lowering to prevent CHD. Unfortunately, I believe this one dimensional approach may have impeded the advancement of science and our search for other preventive strategies. The ACCELERATE trial may well herald our tipping point and a sea change in our approach to CHD prevention.

ACCELERATE trial dumbfounded many experts by failing to demonstrate any cardiovascular benefit of evacetrapib despite dramatically lowering low-density lipoprotein cholesterol and raising highdensity lipoprotein cholesterol in high-risk patients with coronary disease.

Yet the ACCELERATE trial reported that evacetrapib, a novel cholesteryl ester transfer protein inhibitor, reduced low-density lipoprotein (LDL) cholesterol by 37%, raised high-density lipoprotein (HDL) cholesterol by 130%, but produced no discernible reduction in CV events or mortality in high-risk patients. I believe the ACCELERATE trial adds to the chorus that cholesterol is not a valid surrogate end point.

————————————————————-

29) Nicholls SJ, Lincoff A, Barter P, et al. Late-Breaking Clinical Trials II. The ACCELERATE trial: impact of the cholesteryl ester transfer protein inhibitor evacetrapib on cardiovascular outcome. Presented at the 65th Annual Scientific Session and Expo of the American College of Cardiology; April 2–4, Chicago, IL. 2016.

30) Nozue, Tsuyoshi. “Low-Density Lipoprotein Cholesterol Level and Statin Therapy in Patients With Acute Myocardial Infarction (Cholesterol Paradox).” Circulation Journal 80.2 (2016): 323-324.

31) Kristensen ML, Christensen PM, Hallas J. The effect of statins on average survival in randomised trials, an analysis of end point postponement. BMJ Open 2015;5:e007118.

————————————– –

!!!!!!!!!!!!!!!!!!!!!!!!!!   GOOD !!!!!!!!!!!!!!!!!!!!!!!!

32) 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.

———————- –

33) 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.”

=======================================
34) Hansen, Morten Rix, et al. “Postponement of death by statin use: a systematic review and meta-analysis of randomized clinical trials.” Journal of General Internal Medicine 34 (2019): 1607-1614.

35) Wannarong, Thapat, et al. “Statins and the risk of polyneuropathy: A systematic review and two meta‐analyses.” Muscle & Nerve 65.1 (2022): 120-125.

36) Gurha, Neha, et al. “Association of statin induced reduction in serum coenzyme Q10 level and conduction deficits in motor and sensory nerves: An observational cross-sectional study.” Clinical Neurology and Neurosurgery 196 (2020): 106046.

37) Daliri, Mahla, Thomas P. Johnston, and Amirhossein Sahebkar. “Statins and peripheral neuropathy in diabetic and non-diabetic cases: a systematic review.” Journal of Pharmacy and Pharmacology 75.5 (2023): 593-611.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365998/
38) Jones, Mark R., et al. “Drug-induced peripheral neuropathy: a narrative review.” Current clinical pharmacology 15.1 (2020): 38-48.

————————————— –

39) 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 significant reduction in cardiovascular events.

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.

Arguing FOR Pleiotropic Effects of Statins:

Labos, Christopher, et al. “Evaluation of the pleiotropic effects of statins: a reanalysis of the randomized trial evidence using Egger regression—brief report.” Arteriosclerosis, Thrombosis, and Vascular Biology 38.1 (2018): 262-265.

Arguing Against any pleiotropic effects of statins

Labos, Christopher, et al. “Evaluation of the pleiotropic effects of statins: a reanalysis of the randomized trial evidence using Egger regression—brief report.” Arteriosclerosis, Thrombosis, and Vascular Biology 38.1 (2018): 262-265.

Silverman, Michael G., et al. “Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis.” Jama 316.12 (2016): 1289-1297.

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.

==========================================

40) Okuyama, Harumi, et al. “Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms.” Expert review of clinical pharmacology 8.2 (2015): 189-199.

===============Statins Accelerate Dementia ===============

41) Padmanabham, Prasanna, Stephen Liu, and Daniel Silverman. “Cognitively Impaired Subjects with Normal Total Cholesterol Using Lipophilic Statins Undergo Accelerated Decline to Dementia and Loss of Cognition and General Function Correlating with Loss of Regional Brain Metabolism in a Multi-Center Longitudinal Study.” (2023): P1445-P1445.

42) Padmanabham, Prasanna, Stephen Liu, and Daniel Silverman. “Lipophilic Statin Users without Dementia Undergo Accelerated Decline in Regions Associated with Dementia and Those Regions are Predictive of Further Decline over Subsequent Two-Year Period in a Multi-Center Longitudinal Study.” (2024): 242555-242555.

43) Sahebzamani, Frances M., et al. “Examination of the FDA warning for statins and cognitive dysfunction.” J. Pharmacovigil 2.4 (2014): 1000141-100015.

Methods: De-identified publicly-available data were analyzed from the FDA Adverse Event Reporting System (AERS) in relation to reports of cognitive dysfunction (primary outcome), and by type of statin (lipophilic, hydrophilic) versus “control” drugs used in the general population. Results: Significantly higher proportional reporting ratios (PRRs) were observed for lipophilic statins, which more readily cross the blood-brain barrier, (range: 1.47-3.51) compared to hydrophilic statins (range: 0.69-1.64). However, fluvastatin, lovastatin, and pitavastatin (lipophilic) had relatively few adverse reports. The signal of higher risk of
cognitive dysfunction was observed for the lipophilic statin ato rvastatin (PRR = 2.59, 95% confidence interval:
2.44-2.75) followed by simvastatin (PRR = 2.22, 95% confidence interval: 2.04-2.31). Hydrophilic statins (rosuvastatin, pravastatin) showed essentially no evidence suggestive of heightened risk of cognitive dysfunction. Fluvastatin, lovastatin, and pitavastatin had relatively few adverse reports, and no evidence of a higher proportion of cognitive dysfunction reports compared to the control drugs in aggregate (PRR range: 0.22 to 1.48).
Conclusions: Inconsistent with the FDA class warning, highly lipophilic statins with specific pharmacokinetic properties (atorvastatin, simvastatin) appear to confer a significantly greater risk of adverse cognitive effects compared to other lipophilic statins and those with hydrophilic solubility properties.

44) Padala KP, Padala PR, McNeilly DP, et al.The effect of HMG-CoA reductase inhibitors on cognition in patients with Alzheimer’s dementia: a prospective withdrawal and rechallenge pilot study. Am J Geriatr Pharmacother 2012;10:296-302

Conclusions: This pilot study found an improvement in cognition with discontinuation of statins and worsening with rechallenge. Statins may adversely affect cognition in patients with dementia.

PolyNeuropathy

45) Gaist, D., et al. “Statins and risk of polyneuropathy: a case-control study.” Neurology 58.9 (2002): 1333-1337.

Results: The authors verified a diagnosis of idiopathic polyneuropathy in 166 cases. The cases were classified as definite (35), probable (54), or possible (77). The odds ratio linking idiopathic polyneuropathy with statin use was 3.7 (95% CI 1.8 to 7.6) for all cases and 14.2 (5.3 to 38.0) for definite cases. The corresponding odds ratios in current users were 4.6 (2.1 to 10.0) for all cases and 16.1 (5.7 to 45.4) for definite cases. For patients treated with statins for 2 or more years the odds ratio of definite idiopathic polyneuropathy was 26.4 (7.8 to 45.4). Conclusions: Long-term exposure to statins may substantially increase the risk of polyneuropathy.

46) Diamond, David M., and Uffe Ravnskov. “How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease.” Expert review of clinical pharmacology 8.2 (2015): 201-210.

The almost exclusive presentation of data in the relative risk format by statin advocates has intentionally misled the public to exaggerate the miniscule benefits of statins. Primary-preventive cholesterol-lowering trials have not succeeded in reducing the rate of mortality.
The absolute risk reduction of CVD mortality in secondary-preventive cholesterol-lowering trials is quite small, rarely exceeding two percentage points, and no primary-preventive trial has ever succeeded in prolonging the life of the participants. The rate of serious adverse effects of statin treatment is highly underestimated. Adverse effects of statins are extensive, including diabetes, cognitive impairments, cancer, cataracts and musculoskeletal disorders.. The small benefit seen in the cholesterol-lowering trials is independent of the degree of cholesterol lowering. Approaches to improving cardiovascular outcomes that should be emphasized are the cessation of smoking, avoidance of obesity and to consume foods low in sugar and partially hydrogenated fats and high in saturated fats, such as coconut, butter, eggs and full fat cheese.

47) Grover, J., et al. “Longer-term impact of PCSK9 inhibitors on major adverse cardiovascular events and all-cause mortality: a systematic review and meta-analysis of randomised controlled trials.” European Heart Journal 44.Supplement_2 (2023): ehad655-2808.

The incidence of myocardial infarction and coronary revascularisation was reported in ten studies (encompassing 57,890 participants) out of the eleven RCTs [randomixed controlled trials] that met our inclusion criteria….No statistically significant effect was observed for other MACE or all-cause mortality.

48) Hey, Spencer Phillips, et al. “Success, failure, and transparency in biomarker-based drug development: a case study of cholesteryl ester transfer protein inhibitors.” Circulation: Cardiovascular Quality and Outcomes 10.6 (2017): e003121.

We searched PubMed and Clinicaltrials.gov for clinical studies of 5 known cholesterol ester transfer protein inhibitors: anacetrapib, dalcetrapib, evacetrapib, TA-8995, and torcetrapib.

For the 3 discontinued cholesterol ester transfer protein inhibitors, we found a pattern of consistently positive results on lipidmodification end points followed by negative results using clinical end points.

49) Merc will not seek FDA approval for  anacetrapib in 2017.

=======================================

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

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.

 

=============================
Pro-Statins

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.

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
========================

ANTI-Statins

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.

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.

-========================

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.

2012:

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.

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]

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.

=———————————————————-=

!!!!!!!!!!!! BEST !!!!!!!!!!!!!!

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

Unfortunately, and contrary to expectation, the Framingham Heart Study, has refuted the lipid hypothesis of atherosclerosis. “After age 50 years there is no increased overall mortality with either high or low serum cholesterol levels. There is a direct association between falling cholesterol levels over the first 14 years and mortality over the following 18 years (11% overall and 14% CVD death rate increase per 1 mg/dL per year drop in cholesterol levels).”

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.

==========================
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

STATIN ADVERSE EFFECTS
=========================

 

Toxicity

NICE Images of Flow Chart

Ward, Natalie C., Gerald F. Watts, and Robert H. Eckel. “Statin toxicity: mechanistic insights and clinical implications.” Circulation research 124.2 (2019): 328-350.

The major reason for discontinuation of statin therapy is statin-associated muscle symptoms (SAMSs),2 which are the most well-documented side effect of statins, although there appears to be no unifying mechanism. In addition, other more serious adverse effects of statins may also occur, with the next most established being new-onset type 2 diabetes mellitus for which the mechanisms are far less clear. Other side effects include neurological and neurocognitive effects, hepatotoxicity, renal toxicity, and others (gastrointestinal, urogenital, reproductive)

Statin toxicity or intolerance most commonly presents as SAMSs.17,18 Other side effects of statin therapy, which can be more serious, include new-onset type 2 diabetes mellitus, neurological and neurocognitive effects, hepatotoxicity, renal toxicity, and other conditions.19 Currently, no universally accepted definition of statin toxicity/intolerance exists, with several groups attempting to define the condition (Table 2). The prevalence of statin intolerance is also widely debated, in part because of difficulties in identification and diagnosis, particularly with respect to muscle symptoms.18 Observational studies suggest it occurs in 10% to 15% of patients,21,24 with clinic data putting it as high as 30%.17,22 In randomized controlled trials, the incidence is thought to be 1.5% to 5% of patients, although this is believed to be an underestimation as most studies exclude patients with a history of statin intolerance either before randomization or during the run-in period.18,21,25,26 True diagnosis of the condition requires a systematic approach of dechallenge and rechallenge to assess causation, multiple statin challenges to support diagnosis, and elimination of other underlying causes of the described side effects.25,27 Despite the difficulties in identifying and diagnosing statin toxicity, however, several international organizations have identified statin intolerance to be of major clinical importance that warrants further research and investigation.20,28,29

Figure 1. Potential mechanisms for the development of statin toxicity. FPP indicates farnesyl pyrophosphate; GGPP geranylgeranyl pyrophosphate; GPP, geranyl pyrophosphate; and HMG-CoA reductase, hydroxymethylglutaryl-coenzyme A reductase.

Although the only reliably confirmed adverse events caused by statins are said to be muscle-related, type 2 diabetes mellitus, and possibly hemorrhagic stroke,30,31

Pathological investigation of toxic myopathy reveals necrosis and regenerating muscle fibers, with a negative response to anti–HMG-CoA reductase autoantibodies.34 The precise mechanisms behind toxic myopathy are unknown but have been suggested to be aggravated by conditions that increase statin levels in the blood, such as concomitant medications that interfere with statin metabolism via the CYPP450 enzymes, glucuronidation, or other processes.19 This is particularly relevant as skeletal muscle is 40× more sensitive to HMG-CoA reductase inhibition than hepatocytes.5 A study in skeletal muscle–specific HMG-CoA reductase knockout mice was shown to exhibit postnatal myopathy with elevated CK levels, mitochondrial impairment, and necrosis. This was accompanied by upregulation of LDL receptor and SREBP2 (sterol regulatory element-binding protein 2) mRNA expression, suggestive of adaptations to sterol regulation. Supplementation with mevalonic acid rescued this phenotype, supporting the hypothesis that enzyme inhibition by statins contributes to skeletal muscle toxicity.43

In addition, end products of the mevalonate pathway, which include farnesyl pyrophosphate and geranylgeranyl pyrophosphate, play a role in cell maintenance and growth and reducing apoptosis.19,45 These end products are also involved in activating regulatory GTP-binding proteins and the post-translational modification of GTPases and lamins, both of which play an important role in cell maintenance and chromatin organization. Dysprenylation of small GTPases has been shown to result in apoptosis, whereas dysprenylation of lamin results in fragile nuclear membranes, which induces apoptosis.47 Other compounds also affected by inhibition of the mevalonate pathway include prenylated proteins, electron transport proteins, and heme A, which can result in downstream effects that include impaired cell membrane stability and excitability, impaired signal transduction and intracellular trafficking, and compromised protein structure and function, all of which can lead to dysfunction of or a decrease in membrane receptors, channels and transporters, as well as reduced gene expression.5,47

Inhibition of HMG-CoA reductase can lead to alterations to muscle protein signaling and activity can occur. These include impaired skeletal PI3k (phosphatidylinositol 3-kinase)/Akt (protein kinase B), resulting in inductions in ubiquitin and lysosomal proteolysis through upregulation of the FOXO (Forkhead box protein O) downstream target genes of muscle atrophy, which have been observed in cultured myotubes, zebrafish, and mouse studies.48,49 These include cathepsin-L mRNA, MuRF-1 (muscle RING finger-1) and MAFbx (muscle atrophy F-box), and dephosphorylation of the FOXO1 and FOXO3 transcription factors.50 In vitro studies have demonstrated upregulation of atrogin-1 (MAFbx) in muscle cells exposed to statins. This was prevented by geranylgeranol, although inhibitors of the transfer of geranylgeranol isoprene units caused muscle damage and atrogin-1 induction.51 Others have suggested that suppression of IGF-1 (insulin-like growth factor) signaling with statin treatment contributes as this also leads to FOXO dephosphorylation, nuclear localization, and transcription of the atrogin-1 gene.52 Furthermore, these signaling effects were accompanied by distinct morphological changes to the muscle, including fiber damage, which was prevented by overexpression of PGC-1α (peroxisome proliferator–activated receptor-γ coactivator), a transcriptional coactivator that induces mitochondrial biogenesis.49 This finding was also confirmed in an animal model of statin myopathy, where simvastatin administration impaired PI3K/Akt signaling and upregulated FOXO transcription factors and downstream gene targets known to be implicated in proteasomal- and lysosomal-mediated protein breakdown, muscle carbohydrate oxidation, oxidative stress, and inflammation. Interestingly, the statin-induced signaling effects preceded the evidence of myopathy or change in muscle protein to DNA ratio, implying the direct effect of the statin on this sequence of events.48 The effect on the Akt pathway was also associated with impaired phosphorylation of S6 kinase, ribosomal protein S6, 4E-binding protein 1, and FOXO3a, resulting in reduced protein synthesis, accelerated myofibrillar degradation and atrophy of myotubes, as well as activation of apoptotic caspases and PARP (poly (ADP-ribose) polymerase). In vitro studies suggest differing effects on these signaling cascades in response to different statins, with simvastatin and atorvastatin cytotoxic at lower doses (10 μmol/L) compared with rosuvastatin cytotoxicity at higher doses (50 μmol/L).53

Direct Cellular and Subcellular Effects: Mitochondrial Toxicity and Calcium Signaling
The direct effects on cellular and subcellular structures are predominately responsible for statin-related mitochondrial toxicity and calcium overload. These can result in increased oxidative phosphorylation, which can lead to a decrease in ATP levels, loss of mitochondrial membrane potential, activation of mitochondria permeability transition, decreased mitochondrial density and biogenesis, apoptosis, and calpain-mediated cell death. In addition, these effects can trigger massive calcium release either via the RYR (ryanodine receptor) in the sarcoplasmic reticulum or the permeability transition pore and sodium-calcium exchanger in the mitochondria.5,19 Impaired calcium signaling can then result in mitochondrial depolarization and calcium release, resulting in cytoplasmic calcium waves and subsequent caspase activation and apoptosis. Increased cytosolic calcium can also increase calcium and phospholipid-dependent PKC (protein kinase C) activity, which promotes the closing of the chloride-1 channel, resulting in membrane hyperexcitability.47

Simvastatin-treated patients were also found to have decreased muscle coenzyme Q10 content, which was accompanied by decreased mitochondrial oxidative phosphorylation capacity.57

Neurological conditions that have been associated with statin use include hemorrhagic stroke, cognitive decline, peripheral neuropathy, depression, confusion/memory loss and aggression, and personality changes.19

Observational studies suggest an inverse relationship between cholesterol levels and rates of hemorrhagic stroke, particularly at low concentrations of cholesterol in people with hypertension.30

There is some evidence to show that low cholesterol and statin use have been linked to neuropsychiatric effects including aggression, agitation, irritability, mood changes, violent ideation, sleep problems, and suicidal tendencies.112,113

Animal studies have revealed increased serum and urinary excretion of 1- and 3-methylhistidine in response to cerivastatin-induced mytotoxicity.172 Elevated skeletal muscle phosphodiesters are also related to muscle disorders, and these have been observed to be higher in statin users compared with nonstatin users,173 although further work is required to establish a link between either of these markers and muscle function and myopathy. Other potential biomarkers include lactate/pyruvate ratio, which may reflect a dysfunction in the mitochondrial respiratory chain and myotoxicity. An early study revealed higher lactate/pyruvate ratios in statin-treated hypercholesterolemic patients compared with untreated patients or healthy controls.174

Statin-Associated Muscle Symptoms SAMS

SAMSs are by far the most prevalent and important adverse event, with up to 72% of all statin adverse events being muscle related.33 These can present as myalgia, myopathy, myositis with elevated CK (creatinine kinase), or at its most severe, rhabdomyolysis, with some people reporting additional joint and abdominal pain.17,34 Other skeletal-related side effects include tendinopathies and tendon disorders, as well as arthralgias, although these are rarely evaluated in large randomized controlled trials.35 Since first reported in 2002, several groups have worked to provide a unified definition and diagnostic approach for SAMS.29,36

======================================
Amino Acid Analysis, LC/MS, Urine
Test Code 36183 CPT Code(s) 82139, 82570
=======================================

Muntean, Danina M., et al. “Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms?.” Drug discovery today 22.1 (2017): 85-96.

 

Nice Image below

Pierno, Sabata, and Olimpia Musumeci. “Pharmacotherapy of the lipid-lowering drugs: Update on efficacy and risk.” International Journal of Molecular Sciences 24.2 (2023): 996.

It has been shown that sarcolemma ClC-1 chloride channel protein is reduced in patients with SAMS, and this is often associated with alterations of the electromyographic recordings and myotoxicity occurring as muscle necrosis and manifesting with increased CK levels.

—————————–

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/e077949
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.

—————————————-

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.

================================================

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.

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.

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.

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

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.

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).

QQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ

 

!!!!!!!!!!!!!!!!!!! BEST !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

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

Coronary deaths increasing in US and Outside despite lower cholsterol and higher statin use.

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.

Philosopher of science Sir Karl Popper and the Falsification of 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 [statins] 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.

What About Oxidized Cholesterol?

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].

[27] Sloop, Gregory D., et al. “The distribution of oxidatively-modified lysine in the human vasculature.” Atherosclerosis 148.2 (2000): 255-263.

Sloop, Gregory D., Kenneth B. Fallon, and Arthur W. Zieske. “Atherosclerotic plaque-like lesions in synthetic arteriovenous grafts: implications for atherogenesis.” Atherosclerosis 160.1 (2002): 133-139.

Sloop, Gregory D., Joseph J. Weidman, and John A. St Cyr. “Atherothrombosis is a thrombotic, not inflammatory disease.” Cureus 9.12 (2017).

Atherothrombosis is a thrombotic, not inflammatory disease. On a practical level, a change in the focus of atherothrombosis research from inflammation and lipid metabolism to thrombosis is desirable given that risk factors such as age and hematocrit have no obvious association with either inflammation or dyslipidemia. The origin of atherosclerotic plaques from the organization of mural thrombi explains why varied risk factors all result in the same morphologic lesion, the atherosclerotic plaque. Mainstream atherothrombosis theory sheds no light on how hypertension, male gender, thrombophilias, hypofibrinolysis, etc. accelerate the development of atherosclerotic plaques. Because an elevated LDL concentration is only one of several causes of increased blood viscosity, interventions which decrease LDL levels have limited efficacy in preventing atherothrombosis. DuBroff cataloged 44 randomized controlled trials of cholesterol-lowering therapy which showed no benefit in cardiovascular mortality. Thirty of these trials showed no decrease in nonfatal cardiovascular events [50].

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].

[28] Steinberg, Daniel, and Joseph L. Witztum. “Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis?.” Circulation 105.17 (2002): 2107-2111.

Several large-scale, double-blind, placebo-controlled trials have shown convincingly that neither β-carotene1–3 nor vitamin E, alone3–5 or in combination with other antioxidant vitamins,6 reduces the risk of fatal or nonfatal infarction (or other hard clinical end points) in an unselected population of people with established coronary heart disease (CHD) or at high risk of CHD. Two end point trials, much smaller trials that used vitamin E, have reported positive results,7,8 and one trial, which used ultrasound, showed that a combination of vitamins E and C slowed the progression of carotid artery lesions.9 However, these are far outweighed by the negative results in the other, much larger trials. Certainly there is no basis for recommending vitamin E supplementation to patients with CHD, especially because it may blunt the effectiveness of hypolipidemic therapy with statins and niacin.6 A surprisingly large fraction of cardiologists (≈40%) have been recommending such regimens10 despite warnings that this use was premature.11

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.

Weight of Evidence Fallacy

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].”

32. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Ference BA, Ginsberg HN, Chapman MJ, et al. Eur Heart J. 2017;38:2459–2472

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.

31. Skrabanek P, McCormick J. 1st ed. Buffalo, New York: Prometheus Books; 1990. Follies & Fallacies in Medicine [1st edition]

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.

————

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.

Khan, Tina Z., et al. “Apheresis as novel treatment for refractory angina with raised lipoprotein (a): a randomized controlled cross-over trial.” European heart journal 38.20 (2017): 1561-1569.

Safarova, Maya S., et al. “Effect of specific lipoprotein (a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography.” Atherosclerosis Supplements 14.1 (2013): 93-99.

Zarkovic, Mirjana, and Hau C. Kwaan. “Correction of hyperviscosity by apheresis.” Seminars in thrombosis and hemostasis. Vol. 29. No. 05. Copyright© 2003 by Thieme Medical Publishers, Inc.,

Blum, William, and Pierluigi Porcu. “Therapeutic apheresis in hyperleukocytosis and hyperviscosity syndrome.” Seminars in thrombosis and hemostasis. Vol. 33. No. 04. Copyright© 2007 by Thieme Medical Publishers, Inc.,.

Cyclodextrin and blood viscosity

Toyama, Yoshiharu, et al. “Effects of cyclodextrins on RBC aggregation and blood viscosity.” Clinical hemorheology and microcirculation 36.2 (2007): 173-180.

Cyclic oligomers of glucose, termed cyclodextrins (CDs), can contain 6 (alpha-CD), 7 (beta-CD) or 8 (gamma-CD) glucose units and are able to remove cholesterol from platelet membranes and decrease platelet aggregation. The present study was designed to examine the effects of these CDs on RBC aggregation and blood viscosity. Blood from normal adult volunteers was incubated at 37 degrees C with 3.0 x 10(-4) to 1.5 mM levels of the CDs, then processed to obtain platelet-rich plasma, platelet poor plasma and 40% hematocrit blood; measurements included collagen-induced platelet aggregation, RBC aggregation (Myrenne Aggregometer) and blood viscosity at 1-1000 sec(-1)(Rheolog). Our results indicate the expected dose-dependent inhibition of platelet aggregation by beta-CD, with no significant effects of alpha-CD or gamma-CD. RBC aggregation studies showed no effect of alpha-CD but highly significant (p<0.01) decreases by both beta-CD and gamma-CD; at the concentrations studied (1.5 x 10(-3) to 1.5 mM), beta-CD had somewhat greater effects. Blood viscosity was not affected by alpha-CD, but was significantly decreased in a dose-dependent manner by beta-CD and, at the highest concentration (1.5 mM), by gamma-CD. Interestingly, the effects of beta-CD and gamma-CD were independent of shear, with these effects not explained by the usual mechanisms. These results suggest the potential hemorheological value of CDs, yet also indicate the need for additional studies.

Kritharides, Leonard, et al. “Hydroxypropyl-β-cyclodextrin-mediated efflux of 7-ketocholesterol from macrophage foam cells.” Journal of Biological Chemistry 271.44 (1996): 27450-27455.

Zimmer, Sebastian, et al. “Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming.” Science translational medicine 8.333 (2016): 333ra50-333ra50.

Kim, Heegon, Junhee Han, and Ji-Ho Park. “Cyclodextrin polymer improves atherosclerosis therapy and reduces ototoxicity.” Journal of Controlled Release 319 (2020): 77-86.

==========================================

Olmastroni, Elena, et al. “Statin use and risk of dementia or Alzheimer’s disease: a systematic review and meta-analysis of observational studies.” European journal of preventive cardiology 29.5 (2022): 804-814.

https://citeseerx.ist.psu.edu/document
Sahebzamani, Frances M., et al. “Examination of the FDA warning for statins and cognitive dysfunction.” J. Pharmacovigil 2.4 (2014): 1000141-100015.

Methods: De-identified publicly-available data were analyzed from the FDA Adverse Event Reporting System
(AERS) in relation to reports of cognitive dysfunction (primary outcome), and by type of statin (lipophilic, hydrophilic) versus “control” drugs used in the general population.
Results: Significantly higher proportional reporting ratios (PRRs) were observed for lipophilic statins, which more readily cross the blood-brain barrier, (range: 1.47-3.51) compared to hydrophilic statins (range: 0.69-1.64). However, fluvastatin, lovastatin, and pitavastatin (lipophilic) had relatively few adverse reports. The signal of higher risk of cognitive dysfunction was observed for the lipophilic statin atorvastatin (PRR = 2.59, 95% confidence interval:
2.44-2.75) followed by simvastatin (PRR = 2.22, 95% confidence interval: 2.04-2.31). Hydrophilic statins
(rosuvastatin, pravastatin) showed essentially no evidence suggestive of heightened risk of cognitive dysfunction. Fluvastatin, lovastatin, and pitavastatin had relatively few adverse reports, and no evidence of a higher proportion of cognitive dysfunction reports compared to the control drugs in aggregate (PRR range: 0.22 to 1.48).
Conclusions: Inconsistent with the FDA class warning, highly lipophilic statins with specific pharmacokinetic properties (atorvastatin, simvastatin) appear to confer a significantly greater risk of adverse cognitive effects compared to other lipophilic statins and those with hydrophilic solubility properties.

https://pubmed.ncbi.nlm.nih.gov/22921881/
Padala KP, Padala PR, McNeilly DP, et al.The effect of HMG-CoA reductase inhibitors on cognition in patients with Alzheimer’s dementia: a prospective withdrawal and rechallenge pilot study. Am J Geriatr Pharmacother 2012;10:296-302

Conclusions: This pilot study found an improvement in cognition with discontinuation of statins and worsening with rechallenge. Statins may adversely affect cognition in patients with dementia.

Click to access 2015-How-statistical-deception-created-the-appearance-that-statins-are-safe-an-deffective-in-primary-and-secondary-prevention-of-cardiovascular-disease.pdf

—————————-

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

my blog: www.jeffreydachmd.com 
Natural Thyroid Toolkit by Jeffrey Dach MD
Cracking Cancer Toolkit by Jeffrey Dach MD
Heart Book by Jeffrey Dach MD
www.naturalmedicine101.com
www.bioidenticalhormones101.com
www.truemedmd.com
www.drdach.com

Click Here for: Dr Dach’s Online Store for Pure Encapsulations Supplements
Click Here for: Dr Dach’s Online Store for Nature’s Sunshine Supplements

Web Site and Discussion Board Links:

jdach1.typepad.com/blog/
disc.yourwebapps.com/Indices/244066.html
disc.yourwebapps.com/Indices/244067.html
http://sci.med.narkive.com/covV2Qo2/jeffrey-dach-book-announcment-natural-medicine-101

Disclaimer

The reader is advised to discuss the comments on these pages with his/her personal physicians and to only act upon the advice of his/her personal physician. Also note that concerning an answer which appears as an electronically posted question, I am NOT creating a physician — patient relationship. Although identities will remain confidential as much as possible, as I can not control the media, I can not take responsibility for any breaches of confidentiality that may occur.

Link to this Article

Copyright © 2024 Jeffrey Dach MD All Rights Reserved. This article may be reproduced on the internet without permission, provided there is a link to this page and proper credit is given. See Repost Guidelines.

FAIR USE NOTICE: This site contains copyrighted material the use of which has not always been specifically authorized by the copyright owner. We are making such material available in our efforts to advance understanding of issues of significance. We believe this constitutes a ‘fair use’ of any such copyrighted material as provided for in section 107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section 107, the material on this site is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.

Serving Areas of: Hollywood, Aventura, Miami, Fort Lauderdale, Pembroke Pines, Miramar, Davie, Coral Springs, Cooper City, Sunshine Ranches, Hallandale, Surfside, Miami Beach, Sunny Isles, Normandy Isles, Coral Gables, Hialeah, Golden Beach ,Kendall,sunrise, coral springs, parkland,pompano, boca raton, palm beach, weston, dania beach, tamarac, oakland park, boynton beach, delray,lake worth,wellington,plantation

Last updated on by Jeffrey Dach MD

3 thoughts on “The Failure of Cholesterol Lowering Drugs

  1. Thank you for this excellent blog on Statins.

    I was just at my annual wellness appointment yesterday and got a blistering scolding for declining a statin for my moderately elevated cholesterol.

    I really needed to see this.

    Thank you.

  2. Similar recent experience. My primary care physician initially prescribed statins based on bloodwork but was supportive when I explained my reasons for declining. However the cardiologist I was referred to insisted that my cholesterol must be lowered and statins are my only choice. Despite acknowledging my concerns with loss of muscle strength, cognitive impairment and promoting diabetes. When asked if she actually believed there is a correlation between total cholesterol and heart disease, she said “of course”, “tens of millions of lives have been saved” by statins.

    ….well OK then, first and last appointment with her.

  3. Thank you for the excellent information and research to further endorse negative outcomes and unfounded use of the world s most prevalent drug, statins. Most individuals never question their Dr s insistence to start on the statin treadmill based on big pharma “research” and guided by FDA approval. Keep up the amazing work Dr Dach.

Leave a Reply