What are statins?
Statins are medications that lower cholesterol by inhibiting an enzyme called HMG-CoA reductase. Essentially it blocks cholesterol production. But what is cholesterol? The term is used widely to mean different things. Specifically, cholesterol is a molecule made in the liver but can be acquired from animal based foods.
Cholesterol is needed to make hormones, vitamin D, and substances that help digest foods. It is an essential component of cell membranes and contributes to their structure and fluidity. It is essential for your body to function properly. It is often mislabeled in lab tests. When “total cholesterol” (TC) is measured in a lab panel, it is not the molecule cholesterol that is being measured. It is LIPOPROTEINS.
Lipoproteins carry many things including cholesterol, triglycerides, phospholipids and proteins called apolipoproteins. Lipoproteins are like little cargo vans that carry lipohilic substances around the body. These substances cannot dissolve readily in the blood as they are fatty and the blood is mostly water. There are classes of lipoproteins based upon their size.
Total cholesterol represents the sum of all these types. Individual types include very low density lipoproteins (VLDL), Intermediate density lipoproteins (IDL), low density lipoproteins (LDL) and high density lipoproteins (HDL).
So why is cholesterol (the molecule) bad for you? Maybe it’s not. Let’s progress through the history. Back in the 1950’s a physiologist named Ansel Keys had a theory that eating saturated fats raised cholesterol and caused cardiovascular disease. He did an epidemiological study called the “7 Country Study” which looked at the dietary patterns of individuals in 23 countries. The study came to the conclusion that eating high levels of saturated fats were associated with CVD. However, the study was conducted using food questionnaires which relied on the memory of what one ate, which is pretty unreliable. And Keys actually studied 23 countries. He only chose the seven countries that agreed with his hypothesis. His study was never reproducible. He tried to show that saturated fat raised cholesterol, but failed. In fact, two studies were performed that had a diet of saturated fat and one of polyunsaturated fat, and it was polyunsaturated fat that showed more of a risk for CVD, likely secondary to inflammation. Further, epidemiological studies can not prove causation, they only provide associations.
Keys was very influential and made much of his 7 Country Study, even managing to make the cover of time magazine.
Keys also managed to to get on the McGovern Senate committee that was setting up US dietary guidelines in 1978. Keys was known as quite the bully and pushed his Diet Heart Hypothesis theory very strongly. The committee adopted his findings and used them to set guidelines and make the food pyramid, which is utilized to this day in the US.
Cholesterol Homeostasis
If saturated fats do not raise cholesterol, what controls cholesterol homeostasis? Almost everything in our body is regulated by a feed back mechanism. Cholesterol has one as well, as was found out in this study:
Amadi PU, Zhang D-W. Cholesin, a new hormone bridges intestinal cholesterol absorption and hepatic synthesis. Life Metab. 2024;3(4):loae024.
If you eat cholesterol, your gut makes a hormone called cholesin which down-regulates the production of cholesterol in the liver. If you do not eat much cholesterol, then your liver makes more. Our bodies are fine tuned to regulate the amount of cholesterol we need.
Cholesterol and Cardiovascular Disease
Does cholesterol lead to CVD? What is known is that CVD starts with coronary artery endothelial cell damage. This causes an immune response. LDL, a lipoprotein, carries cholesterol to the site of damage to help repair the cell wall. That is why it is present in great quantities. The body also mounts an inflammatory response. It is this response that causes damage. The true cause of CVD has shifted to inflammation, clot formation after endothelial cell damage and oxidized LDL.
Lipoproteins
The paradigm of CVD has changed from cholesterol the molecule to lipoproteins, which are now called cholesterol, which is absolutely misleading. Total cholesterol, HDL and LDL are not cholesterol molecules, they are lipoproteins that carry cholesterol and other hydrophobic/lipophilic molecules. So how does lowering cholesterol, the molecule, affect the number and kinds of lipoproteins? When cholesterol levels increase, the liver responds by producing more very-low-density lipoproteins (VLDL). As VLDLs circulate and lose triglycerides, they become intermediate-density lipoproteins (IDL) and eventually low-density lipoproteins (LDL). Therefore, an increase in cholesterol often leads to a higher number of LDL particles, which are rich in cholesterol. When cholesterol molecules are not made in huge quantities, the number of lipoproteins, and subsequently LDL particles, decrease. This lowering of LDL is supposed to help prevent CVD. But, numerous studies have said that LDL does not cause CVD.
What is worth noting is that LDL comes in different forms - large fluffy particles (good LDL) and small dense particles (bad LDL). It is the small dense particles that are damaging. LDL particles become damaged from oxidation and glycation (interacting with glucose in the blood, which is why diabetes leads to CVD). What a normal lipid panel shows is the total LDL count which includes both good and bad LDL. Thus, total LDL does not reflect these “bad” particles. It is a “particle count” that shows what the breakdown is. And even then there is debate on whether or not LDL even causes CVD. See the studies below:
Sources
https://www.ncbi.nlm.nih.gov/books/NBK305896/
https://www.ncbi.nlm.nih.gov/books/NBK351/
Ravnskov U, Lorgeril M de, Diamond DM, et al. LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Expert Rev. Clin. Pharmacol. 2018;11(10):959–970.
Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016;6(6):e010401.
Kip KE, Diamond D, Mulukutla S, 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. 2024;14(3):e077949.
Byrne P, Demasi M, Jones M, et al. Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment. JAMA Intern. Med. 2022;182(5):474–481.
Budoff M, Manubolu VS, Kinninger A, et al. Carbohydrate Restriction-Induced Elevations in LDL-Cholesterol and Atherosclerosis The KETO Trial. JACC: Adv. 2024;3(8):101109.
If LDL contributes to CVD then it is very little, or related to the “Bad” LDL which is the small dense LDL made that way from oxidative or glycation damage.
Side Effects of Statins
Taking a statin involves a risk/benefit ratio. As is discussed above, the benefits are few. The risks are many.
Common Side Effects
Muscle pain and weakness (myalgia): This is the most common side effect, affecting about 1-10% of statin users[1][3].
Fatigue or tiredness
Headache
Difficulty sleeping
Flushing of the skin
Nausea or vomiting
Abdominal pain or cramping
Bloating or gas
Diarrhea or constipation
Rash
Less Common Side Effects
Liver enzyme abnormalities: This affects up to 1% of patients, though the clinical significance is often unclear[3].
Increased blood sugar levels or risk of type 2 diabetes: This risk appears to be higher with higher doses of statins[3].
Memory loss or confusion: While reported by some patients, studies have not consistently found a connection[1].
Sexual problems, such as erectile dysfunction or decreased libido
Rare but Serious Side Effects
Rhabdomyolysis: This is an extreme form of muscle damage that can lead to kidney failure. It occurs in less than 0.1% of statin users[3].
Liver damage: While rare, this can cause symptoms like unusual fatigue, loss of appetite, upper abdominal pain, dark urine, or yellowing of the skin or eyes[2].
Risk Factors for Side Effects
Taking multiple cholesterol-lowering medications
Being female
Having a small body frame
Being 80 years or older
Having kidney or liver disease
Drinking excessive amounts of alcohol
Having certain health conditions like hypothyroidism or neuromuscular disorders[1]
Citations:
[1] https://www.webmd.com/cholesterol-management/side-effects-of-statin-drugs
[3] https://pmc.ncbi.nlm.nih.gov/articles/PMC5126440/
[4] https://www.health.harvard.edu/heart-health/statins-types-uses-side-effects-and-alternatives
[5] https://medlineplus.gov/statins.html
[6] https://my.clevelandclinic.org/health/treatments/22282-statins
Statins in the Overall Prevention of CVD
In this study, lowering total cholesterol (lipoproteins), did not reduce or had an inverse relationship with all-cause mortality. And all-cause mortality is exactly what should be looked at. What good does a drug do if it lowers CVD risk but causes other types of death?
Yi S-W, Yi J-J, Ohrr H. Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults. Sci. Rep. 2019;9(1):1596.
“In conclusion, U-curve relationships between TC and mortality were found, regardless of sex and age. TC ranges associated with the lowest mortality were 210–249 mg/dL in each sex-age subgroup, except for the youngest groups of men, aged 18–34 years (180–219 mg/dL), and women aged 18–34 years (160–199 mg/dL) and 35–44 years (180– 219 mg/dL). Inverse associations in the range <200 mg/dL were more than 3-fold stronger than positive associations for cholesterol levels ≥200 mg/dL, except for the youngest adults. Positive associations in the upper TC range were strongest for youngest adults and weakened with advancing age. TC levels <200 mg/dL may not necessarily be a sign of good health.”
The study found that lowering total cholesterol below 200 mg/dL is detrimental to health unless very young. See below for the results in graphical form based on age and sex. Note, that just like in every lab value, there is a normal range and a high and low value which may be bad for you. The guidelines to lower total cholesterol below 200 mg/dL is false and just a ploy to get more patients on statins.
Statins are big $$$ for Pharma
Without a doubt statins are a cash cow for the pharmaceutical industry.
The global statin market was valued at approximately $15-16 billion in 2023[1][3][4]. Projections for future market size vary.
The U.S. statin market specifically was valued at $4.53 billion in 2023 and is projected to reach $5.10 billion by 2031, growing at a CAGR of 1.5%[1].
Lipitor (atorvastatin): Despite facing generic competition since 2011, Lipitor still generates approximately $2 billion annually for Pfizer, primarily from sales in emerging markets like China[2].
Combined sales of simvastatin, lovastatin, and pravastatin exceed $10 billion globally[4].
Note that while statins remain highly profitable, there is ongoing debate in the medical community about their appropriate use, particularly for primary prevention in low-risk individuals. Some researchers have called for greater transparency regarding clinical trial data to better assess the true benefits and risks of statin therapy[5].
[1] https://www.databridgemarketresearch.com/reports/us-statin-market
[2] https://www.axios.com/2019/10/30/lipitor-pfizer-drug-patent-sales-2019
[3] https://www.databridgemarketresearch.com/reports/global-statin-market
[4] https://www.maximizemarketresearch.com/market-report/global-statin-market/77560/
Big Pharma Influence Using $$$
bviously, the pharmaceutical industry wants to continue to profit from statins and will use their influence to influence doctor’s organizations like the American Heart Association through large donations.
American Heart Association Funding
Fiscal Year 2022-2023
Total cash received: $41,980,787
Future commitments: $26,537,269
This funding represented approximately 4% of AHA's total revenue of $1.2 billion[2].
Major Contributors
Novartis
Bristol Myers Squibb
AstraZeneca
Pfizer
Amgen
Boehringer Ingelheim
Edwards Lifesciences
[1] https://www.pharmexec.com/view/pharma-ties-aha-questioned
Statins cause Severe Coronary Artery Calcification
Here is a new gem. Statin use is associated with severe coronary artery calcification. But haven’t we been using the Coronary Artery Calcification scores to determine the degree of CVD one has. But now, the pharmaceutical industry is saying calcification is good for you, it “stabilizes” the plaques. So, we want more calcification in our arteries? Big Pharma also states that statins use may change the “microarchitexture” of the calcium, thus, making it good calcium. Although I have only seen one study on this point, and it did not come up with this conclusion.
Ngamdu KS, Ghosalkar DS, Chung HE, et al. Long-term statin therapy is associated with severe coronary artery calcification. PLOS ONE. 2023;18(7):e0289111.
Statins in the Primary Prevention of CVD
Statins do very little in the primary prevention of cardiovascular disease. Looking at the following meta-analysis research article:
All cause mortality decreased less than 1% (0.5%). CV Mortality decreased by 0.1%. Stroke decreased by 0.4%. MI (fatal or non-fatal) decreased by 0.8%.
These are all absolute risk reductions. These are very underwhelming. All of these numbers are less than 1%. It means less than 1 in 100 people who receive a statin derive a benefit compared to the control group. Now, Big Pharma will show the relative risk reductions which appear to have a large benefit. It’s mathematical trickery designed to fool. Essentially, statins for the primary prevention of CVD is negligible.
Sandwith L, Forget P. Statins in Healthy Adults: A Meta-Analysis. Medicina. 2021;57(6):585.
“In conclusion, the efficacy of statins in reducing CVD risk in people with no underlying health conditions cannot be directly quantified…Given the evolving research on the relationship between LDL-C and heart disease risk, a review of the current guidelines is highly recommended.”
Statin Statistical Trickery
Relative risk reduction (RR) versus absolute risk reduction (AR)values used in studies is an excellent way to deceive. The pro statin researchers (who are predominately the pharmaceutical companies themselves) tend to use RR as it makes the results seem much better than they truly are. This article details how the pharmaceutical industry misleads through the use of statistics.
Diamond, D. M., & Ravnskov, U. (2015). 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), 201–210. https://doi.org/10.1586/17512433.2015.1012494
Yi S-W, Yi J-J, Ohrr H. Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults. Sci. Rep. 2019;9(1):1596.
