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.

Cholesterol is carried around the body by lipoproteins. Lipoproteins are like little shuttle buses that carry many things including cholesterol, triglycerides, phospholipids and proteins called apolipoproteins. 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? 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 “6 Country Study” which looked at the dietary patterns of individuals in 22 countries. The study came to the conclusion that eating high levels of saturated fats were associated with heart disease. 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 22 countries. He only chose the six 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 where one had a diet of saturated fat and one of polyunsaturated fat, and it was polyunsaturated fat that showed a risk for cardiovascular disease (CVD), likely secondary to inflammation.

Keys was very influential and made much of his 6 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 Regulation

If saturated fats do not raise cholesterol, what controls how cholesterol is regulated in the body? 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. Even the brain makes its own cholesterol. 50% of the dry weight of brain tissue is fat and of that 20% is cholesterol. It is essential for proper brain functioning.

Cholesterol and Cardiovascular Disease

Does cholesterol lead to CVD? What is known is that CVD starts with coronary artery endothelial cell damage - damage to the cell walls lining the arteries of the heart. This causes an immune response. LDL, a lipoprotein, carries cholesterol to the site of damage to help repair the cell walls. 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.

LDL - Low Density Lipoproteins

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. So, a high LDL could be entirely good LDL. See the studies below:

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

Side Effects of Statins

Taking a statin involves a risk/benefit ratio. As is discussed above, the benefits are few. The risks are many. Many expericnce muscle aches and pains. Statins interfere with mitochondrial function. They have been known to cause intereference in cognition, especially those that are lipophilic (fat loving) and can cross the blood brain barrier. They have been tied to an increased risk of ALS (Lou Gherig’s disease) and Parkinson’s disease. And now it has been shown that statins reduce GLP-1 levels in the body up to 50%. These are the hormones that help with satiety and are mimicked by the new class of GLP-1 agonists like Semaglutide (Wegovy/Ozempic) and Tirzepatide (Mounjaro/Zepbound). Statins have also been shown to CAUSE severe coronary artery calcification. Statins increase the risk of diabetes (which is the highest risk factor for heart disease). And statins have been shown to worsen congestive heart failure (CHF).

Common Side Effects

• Muscle pain and weakness (myalgia): This is the most common side effect, affecting about 1-10% of statin users

• 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

• Increased blood sugar levels or risk of type 2 diabetes: This risk appears to be higher with higher doses of statins

• Memory loss or confusion: While reported by some patients, studies have not consistently found a connection

• 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

• 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

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

Statins Lower GLP-1 Hormones in the Body

There is a new class of drugs that are all the rage in weight loss. These are th GLP-1 agonists such as sumaglutide (Wegovy, Ozempic) and Tirzepatide (Mounjaro, Zepbound) and others. These work by increasing insulin secretion, reducing hunger cravings in the brain and reduces how fast the stomach empties. It remains to be seen what the long term implications on health will be from these drugs. But it has been shown that statins LOWER the amount of GLP-1 in the body by about 50%! Statins depress the feeling of satiation (feeling full).

Proposed mechanisms

• HMG‑CoA reductase inhibition caused by statins and reduced intracellular LDL‑derived cholesterol in L‑cells appear to acutely suppress GLP‑1 secretion; similar suppression was seen when LDL was lowered via a PCSK9 inhibitor, suggesting a cholesterol‑dependent mechanism.​

• Gut microbiota and bile acid shifts under statin therapy can reduce GLP‑1 secretion, with studies noting concurrent declines in GLP‑1 and specific bile acids such as UDCA, along with worsening insulin resistance.​

J. She, G. Tuerhongjiang, M. Guo, J. Liu, X. Hao, L. Guo, N. Liu, W. Xi, T. Zheng, B. Du, B. Lou, X. Gao, X. Yuan, Y. Yu, Y. Zhang, F. Gao, X. Zhuo, Y. Xiong, X. Zhang, J. Yu, Z. Yuan, Y. Wu, Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner, Cell Metab. 36 (2024) 408-421.e5. https://doi.org/10.1016/j.cmet.2023.12.027.

Statins in the Secondary Prevention of CVD

This means taking statins AFTER one has had a MACE event (Major Adverse Coronary Event) or is at high risk such as diabetes, renal disease, peripheral vascular disease, etc. Studies on these show an absolute risk reduction of 2-8% with most falling betwen 3-5% over a five year period in either all cause mortality or CV events. This needs to be addressed relative to side effects of which some are higher.

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/

[5] https://pubmed.ncbi.nlm.nih.gov/29353811/

Does Lowering LDL have any correlation with reductions in Cardiovasular Disease?

Statins do lower LDL cholesterol, but is there a benefit from doing this? Does lowering LDL lower all-cause mortality, myocardial infarction (MI) and Stroke? The two following studies essentially said No. In one study:

P. Byrne, M. Demasi, M. Jones, S.M. Smith, K.K. O’Brien, R. DuBroff, Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment, JAMA Intern. Med. 182 (2022) 474–481. https://doi.org/10.1001/jamainternmed.2022.0134.

there were only reductions in the absolute risk of 0.8% for all-cause mortality, 1.3% for myocardial infarction, and 0.4% for stroke in those randomized to treatment with statins compared with control. A meta-regression was inconclusive regarding the association between the magnitude of statin-induced LDL-C reduction and all-cause mortality, myocardial infarction, or stroke.

In another study:

L. Liaigre, A. Guigui, M. Manceau, J.-L. Cracowski, C. Khouri, M. Roustit, Trial-level surrogacy of non-high-density and low-density lipoprotein cholesterol reduction on the clinical efficacy of statins, Eur. Hear. J. - Cardiovasc. Pharmacother. 11 (2025) 387–392. https://doi.org/10.1093/ehjcvp/pvaf016.

the association between treatment effects on LDL - c or non-HDL-c reduction and clinical outcomes was weak. “Neither LDL - c nor non-HDL-c demonstrated trial-level surrogacy for predicting treatment effects on mortality and cardiovascular events in statin trials. Although they are relevant biomarkers for the follow-up of patients treated with statins, their reduction does not reliably predict a similar reduction in cardiovascular risk. As such, they should not be used as pivotal evidence in drug trials.”

What does this mean? The predictive value of lowering LDL-C on all-cause mortality, MI and Stroke is extremely weak and that lowering LDL-C does not contribute to any benefit that statins have. The true benefits that statins may have is that they are anti-inflammatory and increase Nitric Oxide levels in the vasculature which help dilate them. But one could argue that these can be achieved through other means. Statins have many side effects. If one has already had a major cardiovascular event, that person may already be on a blood lowing medication such as an Ace Inhibitor/Angiotension Receptor Blocker (ACE/ARB) or a Beta Blocker in the same class as Nebivolol which increase NO (nitric oxide). Diet is the best way to reduce inflammation and oxidation/glycation).

Where’s the Beef or AKA Where are the Studies and Negative Research?

There is an organization called the Cholesterol Treatment Trialists Collaberation (CTT) where much of the data from pharmaceurical and non-pharma trials is held centrally by the CTT Secretariat at the University of Oxford’s Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), with coordination shared with the NHMRC Clinical Trials Centre in Sydney. Access to individual-patient data held by the CTT is effectively closed to external researchers; the data are only to be used for CTT meta-analyses, and anyone wanting underlying trial data must approach each original trial’s data custodian or sponsor directly. In other words, no private researchers wanting to fact check data on their own get access to the data.

What information must be shared to the FDA for drug approval? For an FDA new drug application, sponsors are legally required to submit reports and analyses for every controlled clinical study pertinent to the proposed use, including those with negative or inconclusive results; in practice, however, negative studies can be downplayed, summarized in abbreviated form, or never brought into the public domain, which creates room for selective reporting outside the regulator’s files. In other words, the pharmaceutical companies can bias the results presented to the FDA and many are never shared in the public domain for other researchers to verify. Under 21 CFR 314.50, an NDA must include a description and analysis of each controlled clinical study relevant to the proposed indication, including discontinued or incomplete studies, plus a description of uncontrolled studies and any other data relevant to safety and effectiveness from any source. However, how is the public to know if only regulators have access to the data?

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

[2] https://www.heart.org/-/media/Annual-Report/2022-2023-Annual-Report-Files/FY_2022_2023_AHA_Pharma_Disclosure.pdf

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. The primary prevention means those who have never had a MACE or major adverse cardiac event. Looking at the following meta-analysis research article:

Chou R, Cantor A, Dana T, et al. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults. JAMA. 2022;328(8):754–771.

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