Cholesterol, Statins, and a Story of Medical Mistrust

Executive Summary

This is a long post (~25 min read). The summary below covers the key ideas. Use the Table of Contents to jump to sections of most interest.

Trust between patients and their doctors is eroding. People increasingly conduct their own medical research, sometimes placing more weight on social media influencers than on their physicians. This post explores why that mistrust is growing, where it is warranted, where it is being manufactured, and what the science actually says about one of the most contested areas of modern medicine: cholesterol management and the use of statins.

Why the Doctor-Patient Relationship Is Breaking Down

The problem often starts before a patient even sits down with their doctor. Clinic visits that should last 40–60 minutes are compressed into 15–20 minutes, with physicians distracted by mandatory computer documentation requirements that have little to do with actual patient care. Patients may not even see their own physician — they may be seen by a rotating team of nurse practitioners or physician assistants. When a patient can't get an appointment for months, and when the appointment itself feels rushed, they naturally turn elsewhere for answers. This is a system problem, not a doctor problem.

When Doctors (or Their Institutions) Do Fall Short

While the vast majority of physicians put their patients first, there are exceptions. Some practitioners have financial ties to pharmaceutical or device companies that can introduce bias. Professional guidelines and federal dietary recommendations are not always free from corporate influence either. Patients can investigate their doctor's industry payments through public databases like Dollars for Docs and CMS Open Payments. Transparency matters, and patients should feel comfortable asking about these relationships.

Social Media and Medical Contrarians

Some clinicians and online influencers deliberately adopt anti-mainstream positions to build a following, sell products, or generate revenue from advertising. Vaccines are one common target; statins are another. These voices prey on genuine anxieties about health and Big Pharma, sometimes claiming that cholesterol isn't actually a problem and that statins are unnecessary or dangerous. This is a significant departure from the evidence and represents a real risk to patients who avoid treatment based on this messaging.

What the Science Says About Cholesterol

Cholesterol — specifically LDL cholesterol (LDL-C) and the related non-HDL cholesterol — plays a well-established role in the buildup of arterial plaque that leads to heart attacks and strokes. This is not a pharmaceutical industry invention. We see it in patients with genetic mutations that cause extremely high LDL-C (who suffer heart attacks in their teens), and in people with genetic mutations that cause very low LDL-C (who are protected from cardiovascular events without cognitive or reproductive harm). Multiple large trials confirm that lowering LDL-C reduces serious cardiovascular events.

Understanding the Numbers: What "Risk Reduction" Actually Means

Not all statistics are equal. Pharmaceutical marketing often highlights relative risk reduction (RRR), which can sound impressive but may mask a small absolute benefit. What patients should focus on is the absolute risk reduction (ARR) and the number needed to treat (NNT) — how many people need to take a drug for one person to benefit. For statins used after a prior heart attack (secondary prevention), approximately 50 people need to be treated to prevent one serious cardiovascular event. For primary prevention (no prior event), that number rises to around 90. These are comparable to — or better than — other widely accepted treatments like bisphosphonates for hip fracture prevention.

Diet First, Medication When Needed

The Mediterranean diet has hard endpoint data showing it can reduce heart attacks, strokes, and cardiovascular death at rates comparable to statin therapy, making dietary change the essential foundation of cholesterol management. For those who need medication, statins remain the most potent and well-studied option. Muscle pain is the most common side effect but typically resolves when the drug is stopped or the dose adjusted. Statins cause a minor rise in blood sugar, particularly in existing diabetics, but do not convert non-diabetics into diabetics. Other options — ezetimibe, bempedoic acid, and PCSK9 inhibitors — round out the treatment toolkit.

The Bottom Line

Skepticism about medicine is healthy. But there is a difference between informed skepticism and manufactured doubt. The evidence supporting cholesterol management, including the careful use of statins in appropriate patients, is substantial and comes from tens of thousands of patients across multiple independent trials. Doctors are trying to help — and when the system allows them the time and trust to do so, the outcomes are better for everyone.

Table of Contents

1. Why Trust Is Difficult to Build (The broken doctor-patient relationship)

2. When Doctors Fall Short (Industry ties and potential bias)

3. Unwitting Corporate Influence (Conflicts at the guideline and policy level)

4. The Doctors' Role (Evidence-based medicine and healthy skepticism)

5. Social Media and Medical Contrarians (Anti-statin messaging and cholesterol denial)

6. What Is Cholesterol and Why Does It Matter? (LDL-C, non-HDL-C, and vascular biology)

7. How Cholesterol Causes Heart Attacks (The atherosclerosis process)

8. The Genetic Evidence (PCSK9, HMGCR, familial hypercholesterolemia)

9. Medicines That Lower Cholesterol (Statins, ezetimibe, bempedoic acid, PCSK9 inhibitors)

10. Side Effects and Safety of Medicines (Muscle pain, blood sugar, liver)

11. Understanding Risk Reduction: ARR, NNT, and RRR (How to read the numbers)

12. Do Cholesterol Medicines Actually Improve Hard Outcomes? (Primary vs. secondary prevention trials)

13. Eating Patterns as Medicine (PREDIMED, Lyon Diet Heart Study, Mediterranean diet)

14. Core Principles for Cardiovascular Health (Summary takeaways)

Trust Requires a Relationship

For unclear reasons, patients are losing trust in their doctors, often preferring to do their own “deep dive” research and often placing a greater value on the results of their research than guidance from their experienced doctor (Perlis, 2024).  Is the growth of medical mistrust because doctors are intentionally or unintentionally causing harm?  Are patients losing trust in medicine because of ties between medical practitioners and pharmaceutical and device companies?  Are patients simply not able to talk to their doctor in a way that allows them to build a trusting relationship, forcing them to seek answers elsewhere?  Are people being misguided by social media to distrust their doctors?  All may be possible.

For most people, gone are the days when you could form a lasting relationship with your doctor.  Trust takes time to build and we simply don’t get the time to form a relationship between the patients and doctors.  Clinic visits that should take 40-60 minutes are compressed into 15-30 minutes and those abbreviated visits include time when the doctor is distracted by required computer tasks (Rotenstein, 2023).  No doctor entered medicine with a deep desire to stare endlessly at a computer screen checking boxes and clicking buttons while a patient begs for meaningful eye contact and attention sitting just five feet away.  We doctors are forced to attend to the computer to satisfy administration and insurance companies, with much of that time wasted on tasks irrelevant to the care of the person in front of them.  I’ll say it again to be clear.  Many, many tasks forced on us at the computer have nothing to do with how well the doctor can care for the patient.  So, if the patient is frustrated that the doctor isn’t paying attention to them, please don’t blame the doctor.  Complain to the administration that their system is forcing the doctor to practice in a way that hurts the doctor-patient relationship.

A Doctor’s “Panel” Explained

What is a doctor's panel? The “panel” is the total group of people considered to be under the care of an individual doctor.  The panel size can be confusing, as there are different definitions.  For instance, some may define a panel based on the number of new patients the doctor sees in 18 or 24 months.  If a doctor is forced to have larger panels, this can be harmful for the existing patients by limiting access.  If a doctor is only able to have 20 patient slots in a day, with new patients typically using two slots, there are a limited number of spaces open for “sick” or “acute” visits.  New patients will often utilize 6-10 slots and planned follow-up visits will be scheduled into the remainder.  If a doctor’s day is fully scheduled, then there is no space for the sick, same-day, or emergency room follow-up visits.  Some administrators will abuse staff and mandate doctors have “double-book” slots where they tell the doctor to put two patients into the same slot, pressuring the doctor to shorten visits or forgo bathroom or lunch breaks.  The doctors are typically forced into the double-book scenario and don’t willingly use that practice routinely.  With increasing panel sizes, the doctor struggles to see routine follow-up visits, much less having any space for the “sick” visits.

 The abbreviated, distracted visits are but one part of why you can’t form a relationship with your doctor.  You may not even get to talk to your doctor.  They may be so busy, with administration forcing them to have larger panels of patients for which they are responsible, that you may have to see a covering nurse practitioner (NP)/physician assistant (PA) instead of your doctor.  You may not have even been told prior to the visit that you weren’t going to see your physician.  Team practice where a doctor and NP/PA work together has some benefits, but it results in a fragmentation because the patient then has to form two relationships.  Some practices make it worse whereby you never get the same NP/PA and you are thrown into a rotating team of physicians and NP/PA’s who are overworked and in “whack-a-mole” mode with days compressed into 15-20 minute visits.  The patient can forget trying to address that issue they’ve been worrying about for six months.  Because it is so hard to get in to see their doctor, they have to bring a list of questions to ensure they don’t forget them.  However, the doctor may only have time for short answers to multiple questions (Freedman, 2021).  That 15-20 minute time slot they have for the visit also includes the time for them to document the visit, to say nothing of possibly using the restroom, catch up after a patient arrives late, or for a phone call to a collaborating doctor.

But what about the patient?  They wake up one day and realize something isn’t right.  They decide their concern is serious enough to contact their doctor, but not enough to go to the emergency department or urgent care.  They call their doctor and learn the next available follow-up is 3-4 months, though they can get on a call list in case of cancellations.  If the symptoms sound urgent enough, the office will likely refer the patient to the emergency department or urgent care for patient safety reasons.  For some things, a wait can be ok, but for other issues waiting can cause the patient to worry the entire time they are waiting.  Perhaps they don’t go to the emergency department or urgent care due to the added costs or the long waits, so the patient is left with few options but to wait and worry.  Then, when the day of the appointment finally arrives, the doctor may be 20-30 minutes late for a variety of reasons, and understandably, the patient is desperate to get their issue addressed.  While waiting months for the appointment, other issues may have come up such that the patient has multiple concerns.  Or, perhaps the patient was so worried about their condition that they started seeking advice from friends, family, and/or social media.  That means the doctor may have to spend time addressing the patient’s concerns as well as addressing the opinions of others and what the patient learned on social media.  The bottom line is the system is not set up for the physician to give the patient all the time they deserve.  Very few doctors have any control over their schedule, which is part of why patients are seeing more interest among doctors in unionizing.

Outpatient Clinic, Urgent Care, or Emergency Department – Access vs. Cost

There are numerous reasons why it is challenging to see a doctor.  One important one is how the trio of outpatient clinic, urgent care, and emergency department are related.  The health system that owns the clinic, urgent care, and emergency department would likely rather have patients go to the urgent care or emergency department instead of the clinic, because the system may make more money on the visit, even if the care is the same, because there are add-on fees associated with being seen in the acute setting (Poon, 2018; Tong, 2018).  So, the health system will likely prefer to keep the clinics full of new patients (the ones requiring more frequent and more expensive testing) and occasional return visits, but effectively will limit return access by requiring larger panel sizes, which ultimately encourages people to go to the more expensive urgent care and emergency department that they own.

While I’ve certainly been on both sides of the doctor-patient interaction, please understand that very few physicians want the visit with patients to be rushed.  Most aspects of the doctor-patient interaction are out of the control of the doctor.  The day-to-day operations of a clinic are usually controlled by a manager and it is impressive to see how much control doctors have lost over time.  On a positive note, many of us are pushing back, hanging our own shingles again by forming independent practices or forming unions.

Some Bad Pennies

As with any profession, doctor’s, NP’s, and PA’s judgment will occasionally deviate from the norm.  I believe that the number of doctors who truly set out to hurt their patients is tiny, though some may practice in ways that may not put the patient’s interests at the forefront.  Some practitioners may favor ways for them to earn more money or prestige.  Alternatively, some may act in ways to improve their standing with pharmaceutical or device companies to allow them to get more research money – the lifeblood of an academic researcher.  Or, it could be as simple as just wanting that free dinner put on by a company.  Suffice it to say, there are rare people who work in medicine in ways that may tarnish the image of doctors, NP’s, and PA’s to varying degrees.

Drug or Device Company Payments

Has the doctor gotten excess payments?  If so, there may be bias to consider.

Dollars for Docs = https://projects.propublica.org/docdollars/

CMS Open Payments = https://openpaymentsdata.cms.gov/

Word of caution:  Physician names may be added to lists of participants at meals/events to unethically inflate the number of attendees to events to promote the company representative’s efforts.

Thankfully, with the passage of the Sunshine Act as part of the Affordable Care Act in 2010 (also referred to as Open Payments), patients can now get more information about their doctors to see how much money the medical practitioner gets from companies.  Admittedly, not all relationships are bad; there can be some good that comes out of a partnership between clinicians and industry.  However, I have seen examples where it went too far.  For instance, one physician got tens of thousands of dollars from a company to promote a new medicine.  He was relentless in trying to get that company’s drug onto the hospital formulary.  Thankfully, it didn’t work.

If a patient is concerned about ties between their medical practitioner and industry, whether it is a large pharmaceutical company, a small medical device company, or they sell medicines or supplements directly from their office, patients should pay attention to the money.  If the practitioner is endorsing a specific pill or product by name, the patient should be upfront and ask if the practitioner gets money from the company.  If they are open and disclose the relationship, patients should take the time to decide if they are getting a biased opinion.  If, instead, the practitioners are threatened by questions about the relationship, patients should consider obtaining care elsewhere.  If the clinic has enough brand names displayed that it resembles race car advertising, the patient should be skeptical if the treatment they are given matches the advertising in the clinic.

In the end, have doctors been responsible for some of the loss of trust in the doctor-patient relationship?  Yes, but it’s important to understand these are the exceptions and not the rules.  Patients can do their own research to identify doctors that may be tied too closely to industry or behave in ways more concerning for bias.  In all aspects of life, we need to do our own due diligence and evaluate our options, much the way we would evaluate a plumber, electrician, or lawyer.

Why Do Researchers Accept Money From Companies?

Basic truths about research are that it is expensive and often inefficient.  I don’t say research is inefficient to be critical, but to point out that much of research is investigational and may not translate rapidly to a clinical and/or commercial application.  Having spent over a decade in basic science and clinical research myself, I have experienced the challenges of research.

Research is typically funded through a combination of at least a few different sources:  federal funding (e.g., National Institutes of Health), non-profit groups (e.g., American Heart Association or Howard Hughes Medical Institute), and corporate sponsors.  Success rates for receiving federal funding grants, such as the pinnacle NIH R01, may be in the 10-15% realm.  To make matters more challenging, university salaries are often on the lower end compared to similar private work.  This deficit creates pressure for researchers to seek alternative sources of income, particularly given the medical school costs with which many researchers are saddled.

When I asked AI tools such as Perplexity, Gemini, and Copilot about research success, they each suggested the chance of a basic science project leading to clinically significant results is <1% and may take at least 1-2 decades.  For studies that involve taking a medicine from initial testing to getting the medicine to market, perhaps only 10% of those medicines are successful.  While few researchers would complain about the limit research success, given they know the nature of their work, those in political circles may view the disconnect of today’s dollars not producing results close to the same fiscal year as a reason to limit funding, with politicians suggesting a university may be “wasting” money on research.  Politicians may then constrain funding for a variety of reasons.

All told, with university salaries often on the lower end, limited funding options, and unstable federal funding, it’s not surprising to see some researchers looking to industry as an alternative source of funding for income and operating costs.  Ultimately, seeing an individual with industry ties may raise concern of undue influence or bias, but corporate sponsorship should not inherently invalidate the results of the work of the researcher.  As with all research, critical appraisal of the data is essential.

Unwitting Corporate Collaborator?

While a patient learning if their doctor has a direct tie to a drug or device company can be important, a different type of connection can be more challenging to tease apart, but no less important.  Even if a physician is trying to be completely removed from bias and shunning corporations, the organizations providing guidance through professional guidelines may have connections to drug and/or device companies, thereby raising concern for inappropriate corporate influence at the medical society level.  Similarly, there can be corporate connections to those individuals setting federal policy, such as dietary guidelines by the U.S. Department of Agriculture.  As such, a doctor who intentionally avoids drug or device representatives to avoid inappropriate relationships must also be wary of conflicts of interest in their reference material and legislative policies (e.g., food safety).

A historic practice related to medical references that raises concern is ghostwriting, where a corporation would write a paper and then an academic person would take over authorship to lend academic weight to the piece, even though it was primarily a piece promoting the company’s interests.  Unfortunately, ghostwriting is not universally banned.  Increasingly, academic centers are banning gifts from corporations to limit influence, though the bans are not universal.  Direct payments from corporations to individuals are not banned, but are routinely tracked by larger companies.  Part of the current pressure to monitor for conflicts of interest came about after Merck was found to have misled the public about the VIGOR study published in the New England Journal of Medicine in 2000, wherein the authors hid cardiovascular events among those taking rofecoxib (Vioxx) (Tanne, 2006).  Merck paid at least $6-7 billion in lawsuits and fines as a result of the Vioxx issue.

Doctors' Roles?

Doctors have a number of important roles when practicing medicine.  First and foremost, the interests of the patient must be put first.  I sincerely believe that the overwhelming majority of doctors do exactly that and very few of us put other interests ahead of those of the patient.  In pursuit of the best care possible for their patients, doctors practice evidence-based medicine, paying close attention to the sources used to build that evidence and utilize continuing education to monitor for important changes to existing practices.  Doctors, like many other professions, are taught to “trust but verify.”  While maintaining our level of education and clinical knowledge base, we must have a healthy skepticism if suggested changes, be they from societal guidelines or federal mandate, represent a marked change from prior practice. We must be mindful of potential influences with ulterior motives than those pertaining to the patient.

In the patient-doctor relationship, we ideally would start from a position of trust and more often of late it feels that trust is fading.  Just as patients are sincere in their desire to get help, doctors want to provide help to the best of their abilities.  There has been a significant loss of inherent trust in the relationship and we need to make inroads to repair the relationship.

Social Media and Medical Contrarians

Unfortunately, some clinicians and social media influencers are seeking vulnerable patients desperate for answers and are adopting anti-consensus positions as a means of building their professional and/or personal brands.  They may have books to sell, they may sell access to their blog posts, they may sell advertising on their blog pages, or they may promote natural or alternative products that provide “the real” solutions to what Big Pharma doesn’t want you to know.  These individuals act as non-mainstream medical voices, at times obscuring their identities for unclear reasons, preying on the fear and worry people feel regarding their health and wellbeing.

While vaccines are one of the most common topics for medical contrarians of late, another common topic is the treatment of high cholesterol with a class of medicines known as statins.  Some of these contrarians may agree that high cholesterol is a problem, while others will go so far afield as to suggest elevated cholesterol levels aren’t actually a problem, which is dramatically different than mainstream medicine.  A variety of reasons may be behind why some people have visceral responses against statins, such as inherently being susceptible to fear tactics brought on by the echo chamber of social media, scientific denial, and possibly even fear of conspiracy by those “pushing” statins.  Regardless of the why, a significant number of patients will come to the clinic afraid of statins, on the defensive against possibly being needed to be treated with a statin, or possibly even denying the importance of treating cholesterol. The avoidance of statins is a prominent example of medical mistrust in today's medicine.

Endpoints:  Soft or Hard?  What Matters?

When discussing treatments in medicine, whether they are a new pharmaceutical medicine, new dietary supplement, or lifestyle changes, it is essential to be aware of how much a given action benefits the individual.  When walking around day-to-day, people likely don’t really care if their systolic blood pressure is 125 or 145 mmHg or whether their total cholesterol is 145 or 175 mg/dL.  What they most likely care about is whether they’ve had a heart attack, stroke, or nearly died.  For cardiovascular medicine, example endpoints are:

• Hard Endpoints = heart attack, stroke, mortality

• Soft Endpoints = blood pressure, cholesterol level, walking distance, hospitalization, chest pain

When making decisions about health, it is essential to think in terms of hard endpoints.  I show here two classic examples of treatments that have lost favor after evaluation of hard endpoints.  First, the AIM-HIGH and HPS2-THRIVE trials raised high-density lipoprotein (HDL; soft endpoint) with extended-release niacin, but the medicine did not affect cardiovascular events (hard endpoints).  Similarly, traditional fish oil with both docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which is what most people buy at their local stores, may lower triglycerides (soft endpoint), but does not have a significant impact on serious cardiovascular events (hard endpoints).  Failing to meet hard endpoints has led us to stop recommending either treatment in cardiology.

What about MACE (Major Adverse Cardiovascular Events)?

Early trials focused on traditional hard endpoints, though studies began to expand MACE to include more components (e.g., hospitalization and revascularization).  There is no unified definition of what should be included in MACE, so it may not be clear between studies what endpoints are included without thoroughly reading the study.  A criticism of using broader endpoints is that the use of broad composites of endpoints may allow a study to suggest a treatment was significant, though in fact it may have been driven by less important, softer endpoints.  Bottom line?  Focus on trials with solid results with 3-point MACE of heart attack, stroke, and cardiovascular death.  The trials with 5- or 6-point MACE may be important, though they may drift closer to being hypothesis-generating than evidence for definitive treatment success.

Cholesterol and Why it Matters

Because some medical contrarians argue against the importance of cholesterol in vascular biology, I will delve into the weeds a bit about cholesterol.  One type of cholesterol that has been studied is called low-density lipoprotein cholesterol (LDL-C) and it has been associated with cardiovascular disease and hard endpoints.  For years, LDL-C was the main marker of clinical trials associated with hard endpoints.  LDL-C can be technically challenging to measure and is most often derived through calculations related to total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides.  The specific formulae used have changed over time to try to improve their accuracy.  Direct measure of LDL-C is possible, though there is significant variation in measurement between different laboratories, so obtaining a direct LDL-C is not routinely used in practice.  Instead, research has shifted to simply using a measure called non-HDL cholesterol (non-HDL-C), which is determined simply by subtracting HDL-C from total cholesterol.  With this simple measure, the non-HDL-C has been shown to encompass more of the atherogenic particles than LDL alone.  The use of non-HDL-C has gained traction as a better predictor of those at risk of hard cardiovascular endpoints than LDL-C.  Nonetheless, LDL-C remains an important number in discussions of cholesterol due to historical reference of many, many trials.  Other related particles are also important, such as apoB and Lp(a), though these can be saved for discussion elsewhere.  Suffice it to say, our most prominent targets in managing cholesterol are LDL-C and the closely-related, but more important, non-HDL-C.

Vascular Health and Cholesterol

There is a complex process where an artery transitions from being normal to being blocked, such as with a heart attack.  The established process of atherosclerosis is below:

1. 

   Endothelial dysfunction – Inner lining of healthy vessel is damaged by processes including high blood pressure, diabetes, and oxidative stress, becoming more permeable and less flexible.

2. LDL-C accumulation – The dysfunctional endothelium allows LDL-C to enter the intima, where it becomes oxidized and modified, triggering an inflammatory process.

3. Inflammatory cell recruitment – Endothelial damage and modified LDL recruits monocytes from the blood, drawing them into the intima.

4. Monocyte differentiation – Once in the intima, monocytes differentiate into macrophages, which are especially suited to consume oxidized LDL, with the process lacking feedback inhibition.  As the macrophages swell, they become enlarged foam cells, forming the lesions known as fatty streaks, with the foam cells further stimulating the inflammatory process.

5. Immune activation – T-lymphocytes are recruited to the lesion and activated, leading to continued macrophage activation and progressive inflammation.

6. Smooth muscle cell migration – Vascular smooth muscle cells are drawn from the media into the intima, wherein they increase in number and produce extracellular matrix proteins, especially collagen, which forms the fibrous cap.

7. Necrotic core formation – Foam cells and vascular smooth muscle cells die and their debris gathers, forming a lipid-rich necrotic core.  Local macrophages are impaired and unable to consume the debris, leading to an expanding core containing cholesterol crystals, lipids, and debris that can all promote platelet adherence.

8. Calcium deposition – Early microcalcifications develop through localized mineralization and by vascular smooth muscle cells being driven by inflammation to form cells capable of producing calcium.  Microcalcifications progress to spotty calcification to fragmented calcium to sheet-like calcium, with the earlier forms being associated with unstable plaque, while sheet forms are more often found in stable plaque.

9. Vulnerable plaque – Over time, inflammation may create an ominous thin-cap fibroatheroma consisting of a large, lipid-rich core, a thin fibrous cap, plentiful inflammatory cells, and immature calcium formation.

10. Weakened fibrous cap – Ultimately, inflammation both impairs collagen formation and also accelerates collagen cap degradation, leading to a weakened cap.

11. Plaque rupture/erosion – In nearly two-thirds of heart attacks, plaque ruptures when the thin cap breaks.  In one-quarter of heart attacks, particularly in women, a more gradual plaque erosion occurs.

12. Thrombosis and platelet accumulation – Once the necrotic core is exposed, this leads to both activation of the coagulation cascade and platelet activation, leading to clot formation and either partially or completely blocking the artery, and ultimately the heart attack.

(Jinnouchi, 2020; Libby, 2013; Moore, 2018; Ross, 1999)

The Genetic Evidence of LDL-C and Heart Attacks

We have ample evidence that both LDL-C and non-HDL-C are closely linked with cardiovascular disease.

• Some patients with mutations, typically loss-of-function or reduced-function of the LDL receptor, can develop familial hypercholesterolemia with LDL-C 190-500+ mg/dL.  Rarely, the mutation can be homozygous and can be associated with heart attacks and strokes prior to 20 years of age.

• Other patients may have loss-of-function mut

  ations of PCSK9 leading to markedly reduced LDL-C's of 20-30 mg/dL and substantially reduced rates of heart attacks.  The identification of individuals with these mutations played an essential role in demonstrating that a very low LDL-C may not be dangerous, as individuals with LDL-C of 20-30 mg/dL don’t inherently have cognitive impairment and they are able to reproduce, which were two areas of concern (i.e., reproductive fitness and cognitive function) when discussing how low is too low in terms of cholesterol.

• The FOURIER ’17 trial with nearly 28,000 patients and the ODYSSEY ’18 trial with nearly 19,000 patients each showed a 15% reduction of major adverse cardiovascular events, with the trials being based on different PCSK9 inhibitors, not statins, yet having similar results.

• An interesting study by Ference et al. (2016) looked at over 110,000 individuals and evaluated their genetic variation in the genes encoding PCSK9 and HMG CoA Reductase (HMGCR), with HMGCR being the target of statins.  In this study, the subjects’ LDL-C level and number of cardiovascular events were evaluated.  They demonstrated that genetic variants of the two genes that were associated with lower LDL-C levels were associated with fewer cardiovascular events.  Interestingly, HMGCR variants associated with lower LDL-C levels were also associated with an increased risk of diabetes, an effect not seen with the PCSK9 variants, raising a question about the role of statins in patients developing diabetes, as perhaps the central issue is actually the inhibition of HMGCR activity and not actually the statin itself.

Medicines to Lower LDL-C and non-HDL-C

Taken together, noting the role of LDL (and related particles) in plaque formation, the worsening cardiovascular events with elevated LDL-C, and the improvement in cardiovascular events with lower LDL-C, the next step is to discuss how we actually lower LDL-C.  I have a feature-rich post talking about lowering LDL-C here, so I won’t rehash the entire post here.  Cholesterol management requires both a healthy diet (e.g., Mediterranean diet pattern) and adequate exercise.  For some people, medications may be needed if diet and exercise are insufficient.  National organizations including the American College of Cardiology, American Heart Association, and National Lipid Association just released updates to the guidelines in managing cholesterol March 13, 2026, emphasizing the importance of aggressively lowering cholesterol in appropriate populations.

A stressful point of clinic visits for some patients is the idea they may need to take a medicine for cholesterol, as people may have heard bad things about statins on social media.  Importantly, statins are one of at least eight unique medicines used to lower cholesterol.  Without going into too much detail, it may be useful to learn a bit about the cholesterol cycles in the body.  There are two main ways to get new cholesterol.  The majority of cholesterol is made in the liver and is vital for our health for numerous tasks including our body making its own hormones and ensuring our cell walls are flexible.  A small portion of cholesterol comes from our diet.  There are extensive regulatory controls in the body to modulate the levels of cholesterol we have, though some of those controls may fail, such as in those with diabetes or obesity.

A simplified listing of the most common medicines to treat LDL-C and their effects is shown in Table 1.

Medicine / Medicine Class	Effect	LDL-C Lowering (%)	Side Effects
Bempedoic acid	Inhibit cholesterol synthesis in liver	17-24%	May worsen gout, gallstones, renal function, and rare tendon rupture
Ezetimibe	Inhibit cholesterol absorption in intestine	15-25%	Well-tolerated; avoid with moderate/severe liver disease
Statin (HMG CoA Reductase Inhibitor)	Inhibit cholesterol synthesis, primarily in liver	30-50%	Muscle pain; avoid with acute liver failure and decompensated cirrhosis
PCSK9 Inhibitor	Decreased LDL receptor breakdown leads to enhanced receptor-mediated LDL clearance	~60%	Injection site reactions

Table 1. Common Medicines to Lower LDL-C

Cholesterol Medicines and Side Effects

Statins have been the work-horse in LDL-C management for years due to their potency and reasonable safety and tolerability profile.  Muscle pain is the main issue limiting its use and may be seen in at least 5% of patients, though for nearly all people the pain goes away after stopping the medicine.  The typical muscle pain can typically be managed with lower doses or creativity such as alternate-day dosing.  A review of statins and their safety was recently published by the Cholesterol Treatment Trialists’ Collaboration in Lancet in 2026 and described the overall favorable safety profile, though liver injury is infrequently noted and muscle pains were also noted.  Lastly, statins are associated with a slight rise in blood sugar, with a larger rise seen in existing diabetics.  For non-diabetics, moderate intensity statin doses lead to a rise in blood sugar of 0.7 mg/dL (with 100 mg/dL being upper-normal) and HbA1c 0.06% (with 5.5% being upper-normal) and high intensity statin to a rise in blood sugar of 0.7 mg/dL and HbA1c of 0.08%.  For diabetics, moderate intensity statins are associated with a blood sugar rise of 2.2 mg/dL and HbA1c of 0.09%, while high intensity statins are associated with a blood sugar rise of 4.0 mg/dL and HbA1c of 0.24%.  All told, statins won’t convert a person with normal blood sugar into a diabetic, though those with pre-diabetes may be pushed into the diabetic blood sugar range and diabetics will see a slight rise in their blood sugar and A1c numbers.  As for other medicines commonly used to treat elevated LDL-C, ezetimibe is generic, though not nearly as potent as statins and lacks some of the hard endpoint data seen with statins.  Bempedoic acid is brand-name only, so remains quite costly, though does have hard endpoint data favoring its use.  Lastly, PCSK9 inhibitors are well-tolerated, though require injections twice per month and are quite expensive.

ARR, NNT, and RRR – Oh My!

(generated with assistance from Claude.ai)

It’s important to understand the percentage improvements often listed in marketing material, as they are frequently misleading of overall value.

ARR (absolute risk reduction) is the raw difference in outcomes between two groups. If 40% of placebo patients had pain and 20% of drug patients did, the ARR is 20 percentage points. It tells you the actual, real-world size of the benefit.  This is the statistic to look for when reviewing data.

NNT (number needed to treat) is 1 ÷ ARR. An NNT of 5 means you'd need to treat 5 people for one person to benefit compared to a placebo. An NNT of 100 means 1 in 100 people gets any added benefit. A smaller NNT is better.

RRR (relative risk reduction) is the percent improvement relative to the baseline risk. This is where things get slippery. If your baseline risk is 40% and a drug cuts it to 20%, the RRR is 50%. But if baseline risk is just 2% and a drug cuts it to 1%, the RRR is also 50% — while the NNT is 100, not 5.  Same headline number, very different real-world value.

Pharmaceutical marketing often leads with RRR because it produces the largest, most impressive-sounding number. A drug that reduces a rare side effect from 2% to 1% can claim "50% risk reduction!" — which sounds transformative but may translate to treating 100 people to help one. Always pair a stated RRR with its ARR and NNT to get the full picture.  Unfortunately, many studies only report the RRR as a means of obscuring the ARR and potentially risk exaggerating the benefit of treatment.

But Do Cholesterol Treatment Medicines Truly Help?

By this point, I have written about vascular biology and blockage development in arteries with the involvement of certain cholesterol-containing particles and the fact that medicines can change the amount of cholesterol-containing particles in our bodies.  I've also touched on the importance of ARR, NNT, and RRR.  The next step is to look at how effectively our current cholesterol medicines are for improving hard endpoints.  But first, it is important to discuss a distinction in hard endpoint data among people who have never had an event, known as primary prevention, and among people who have had an event, known as secondary prevention.  Knowing the distinction between primary and secondary prevention helps people know if a study applies to them.  A medicine may be effective if a person known to have disease (e.g., they had a heart attack), but may not be as useful if they don’t have any evidence of disease yet.  If a person is a blond-haired elf and the study was done on brunette dwarves, then the study may be interesting but not as relevant to them.

Looking at a sampling of trials (Table 2), it is interesting to ask how many people need to be treated with cholesterol-lowering medications to prevent hard outcome events.  When looking at large tables of cholesterol treatment options, NNT can range from ten’s of patients up to hundreds of patients.  If fifty people took atorvastatin after already having had a heart attack or stroke (i.e., secondary prevention treatment), one person would be prevented from having a subsequent event.  This may seem like a small benefit until someone considers that that one event could be a fatal heart attack or stroke.  In truth, the level of complexity in looking at the multitude of studies is impressive, particularly when given the inconsistency between studies (e.g., some with 3-point MACE, while others have 5-point MACE).  One has to wonder how many studies would remain significant if a 3-point MACE were mandated as the primary outcome, as subset analyses are less useful if the primary outcome is not significant. 

Medication	Study	Prevention Type	RRR	ARR	NNT
Atorvastatin	ASCOT-LLA	Primary Prevention	36%	1.1%	91
Rosuvastatin	HOPE-3	Primary Prevention	24%	1.1%	91
Alirocumab	Odyssey	Secondary Prevention	15%	1.6%	63
Atorvastatin	TNT	Secondary Prevention	21%	2.0%	50
Ezetimibe + Statin	IMPROVE-IT	Secondary Prevention	6.4%	2.0%	50

Table 2. Primary and Secondary Prevention Trial Data

For a point of comparison of other common treatments to understand if these cholesterol medicines are useful, patients may be familiar with the use of bisphosphonate medications (e.g., alendronate [Fosamax]) to manage hip fractures in postmenopausal women with osteoporosis.  From an American College of Physicians paper including hip fracture prevention, bisphosphonates are associated with a RRR 26-42%, an ARR 0.6-0.9%, and NNT of 90-111.  This means approximately 100 people have to take alendronate to prevent one hip fracture, which is similar to the primary prevention data for ASCOTT-LLA where 91 people have to take atorvastatin to prevent one heart attack, stroke, or cardiovascular death.  An alternative comparison in the Cochrane database is that of using high-dose probiotics to prevent antibiotic-associated diarrhea in children, with a RRR 63%, an ARR 15%, and NNT 6, which means if six children use the probiotics, one child will not get antibiotic-associated diarrhea.

Eating Patterns as Medicine

As mentioned earlier, the first step in managing cholesterol for most people is ensuring they have a healthy diet, even before considering taking a medicine.  We have data on the impact of dietary patterns on 3-point MACE while following the Mediterranean diet pattern.  Over five years in the PREDIMED primary prevention trial, the RRR was 30%, the ARR was 1.9%, and NNT was 53.  The Lyon Diet Heart Study was a secondary prevention trial, though with some limitations, which showed similar benefit from the Mediterranean diet on fatal cardiovascular disease with RRR 76%, ARR 4%, and NNT 25.  From these data, adoption of the Mediterranean diet pattern was able to favorably influence heart attack, stroke, and cardiovascular death.

A quick aside is to note that NNT is not the only way to convey the use of a treatment, as it may underestimate the total lifetime benefit of a treatment or intervention.  A recent evaluation of time-to-benefit suggested that, in individuals aged 50 to 75, if 100 people were to take statins it would take 2.5 years to avoid one MACE and if 500 people were to take statins, it would only take 0.8 year to benefit (Yourman, 2020).  Consequently, when considering time to benefit, with many people taking statins, benefits will be experienced frequently by a populous.

Core Ideas to Cardiovascular Health

You’ve gotten this far and you remain skeptical of the management by doctors such as me.  You’ve learned enough from your own research that you’re not interested in hearing more.  You may feel I am closed-minded and not willing to learn the “real truth” about information that is only recently coming to light.  I am sincerely curious what I would need to do to help understand the person who is unswayed by discussions of the current standard of care, a standard by which I base my practice.  Will I convince everybody previously uninterested in treating cholesterol to suddenly become interested?  Of course not, but hopefully we can try to get people to reach common ground to try to improve the patient's cardiovascular health.  I hope it’s clear that doctors want the best possible for our patients and we’re doing what we believe is best for them, though we may not always be allowed to do everything we think we should.  Will there continue to be bias in scientific literature?  Of course, just as there is bias in most aspects of our lives.  It’s unrealistic to think medicine would be some magical area spared from bias.  In the end, there are core ideas that are essential in managing cardiovascular health.  My hope is that people will slowly come to trust their doctors again and want to work with them.

Central Principles

1. Healthy food choices are a must.  There is extensive data on the value of a Mediterranean diet, though a pescatarian diet may be a reasonable alternative for some.  Eat real food and avoid alcohol, excess sugar, heavily processed foods, and saturated fat.

2. Get plenty of exercise, which is at least 150 minutes per week of moderate cardiovascular exercise as well as incorporating 2+ days per week of resistance training

3. Maintain a healthy weight through good diet and lifestyle habits.

4. Cholesterol plays a central role in cardiovascular health, so patients benefit from knowing their numbers and should be aware of the impact of their diet and lifestyle on those numbers.

5. For those that need medicines, we are increasingly learning that lower LDL-C and non-HDL-C are associated with a healthier life.  Ideally, patients get their cholesterol checked before reaching 20 years of age and should get it checked at least every five years.

6. Maintain a healthy skepticism about medical information, as there is substantial bias in our literature and social media.  Patients should look for supporting evidence from credible sources (e.g., American Heart Association and European Society of Cardiology) or the local university’s social media.

References:

1. CTT. Assessment of adverse effects attributed to statin therapy in product labels: a meta-analysis of double-blind randomized controlled trials. 2026;407:689

2. Ference, B.A., et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. The New England Journal of Medicine. 2016;375(22):2144

3. Freedman, S., et al. Docs with their eyes on the clock? The effect of time pressures on primary care productivity. J Health Economics. 2021;77:102442

4. Jinnouchi, H., et al. Calcium deposition within coronary atherosclerotic lesion: Implications for plaque stability. Atherosclerosis. 2020;306:85

5. Libby, P. Mechanisms of acute coronary syndromes and their implications for therapy. The New England Journal of Medicine. 2013;368(21):2004

6. Moore, K.J., et al. Macrophage trafficking, inflammatory resolution, and genomics in atherosclerosis: JACC Macrophage in CVD Series (Part 2). Journal of the American College of Cardiology. 2018;72(18):2181

7. Perlis, R.H., et al. Trust in physicians and hospitals during the COVID-19 pandemic in a 50-state survey of US adults. JAMA Network Open. 2024;7(7):e2424984

8. Poon, S.J., et al. Trends in visits to acute care venues for treatment of low-acuity conditions in the United States from 2008 to 2015. JAMA Intern Med. 2018;178(10):1342

9. Ross, R. Atherosclerosis — An inflammatory disease. The New England Journal of Medicine. 1999;340(2):115

10. Rotenstein, L.S., et al., System-level factors and time spent on electronic health records by primary care physicians. JAMA Network Open. 2023;6(11):e2344713

11. Tanne, J.H. NEJM stands by its criticism of Vioxx study. BMJ. 2006;332(7540):505

12. Tong, S., et al. Trends in healthcare utilization and costs associated with acute otitis media in the United States during 2008-2014. BMC Health Serv Res. 2018;18(1):318

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 This post is for educational purposes only and does not constitute medical advice. Please consult a qualified healthcare provider for personalized guidance.

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