The Cholesterol Paradox: A Critical Examination of Contradictory Findings and Flawed Evidence

Can High Cholesterol Actually Be Good for You?....NO!

I woke up this morning and became enraged after I saw some prominent medical influencers make false claims that “high cholesterol causing atherosclerosis” is a myth. As a heart surgeon who made my career doing coronary artery bypass grafting and then refocused on the medical management of lipid (cholesterol) disorders, I can assure you with certitude that this garbage is false, It would be inappropriate for me to tell you how I truly feel about these people who intentionally disseminate dangerous misinformation. From medical influencers, to naturopaths who practice functional medicine, to medical doctors who have zero experience in cardiovascular disease, to our new HHS Secretary, RFK Jr., all of these people can be described in one word, charlatans. As I state in every article I write about cardiovascular disease, it is the #1 killer of men and women in the United States. The “lipid hypothesis” was first demonstrated in 1913 by Nikolay Anichkov who demonstrated that feeding rabbits a cholesterol-rich diet led to cholesterol deposits in their artery walls. This pivotal experiment established a link between dietary cholesterol and atherosclerosis. Fast forward to today, where anybody can say absolutely anything on the internet with impunity while making a profit at the same time. This is where we will begin our story.

Imagine being told that having high cholesterol might help you live longer. The so-called "cholesterol paradox" has emerged as a controversial concept in cardiovascular medicine, suggesting that higher cholesterol levels might be associated with reduced mortality—a finding that appears to contradict decades of established research. This article provides a comprehensive analysis of this phenomenon, focusing on the recent study by Rozanski et al. in 2022 that reported these counterintuitive results, while critically examining its methodological limitations and the broader context of cholesterol research.

Understanding the Cholesterol Paradox

The cholesterol paradox refers to observational findings where hypercholesterolemia appears associated with “reduced” mortality risk, particularly in certain patient populations. This contrasts sharply with conventional medical wisdom that consistently links elevated cholesterol, especially low-density lipoprotein cholesterol (LDL-C), with increased cardiovascular risk and mortality.

Several studies have noted this apparent paradox in specific contexts:

1. Among older adults where low cholesterol correlated with higher mortality.

2. In hospitalized patients where lower cholesterol levels predicted worse outcomes.

3. In cardiac imaging cohorts where hypercholesterolemia was associated with survival benefits.

However, this seems to contradict everything we know—hence the "paradox." But as physician and researcher, Peter Attia MD, points out: "Upsetting conventional wisdom takes more than an appealing idea, particularly when convention is backed by reams of research ranging from countless human randomized clinical trials to Mendelian randomizations to (literally) millions of patient-years of epidemiology." In other words, one controversial study doesn’t outweigh mountains of evidence to the contrary.

The Rozanski Study: What Did It Find?

What did this study say that seems to be the source for most of the internet misinformation? Rozanski’s team retrospectively analyzed over 100,000 patients who had heart imaging tests. The study analyzed four cardiac imaging cohorts totaling over 100,000 patients referred for various cardiac tests:

• CAC scanning cohort: 64,357 patients

• CCTA cohort: 10,814 patients

• SPECT-MPI (diagnostic): 31,411 patients without known CAD

• SPECT-MPI (known CAD): 5,051 patients with established coronary artery disease

Their key results:

• High cholesterol was linked to lower death risk.

• Lower LDL cholesterol was linked to “higher death risk” in some groups.

At first glance, this seems shocking—but the study had “major flaws” that explain these weird results. Unfortunately, most people, including physicians, either don’t know how to or don’t want to critically examine this study. So I will do it for all of them.

Five Big Problems with the Rozanski Study

1. They relied on self-reports of cholesterol testing results…NOT Blood Tests. To most academicians, researchers, and clinical medical doctors, this alone would be disqualifying…..93% of patients just “said” they had high cholesterol or took meds, NO actual lab tests were checked. Furthermore, people misremember or misreport their health details all the time. I forgot what I had for dinner last night.

   As Attia notes, this is "a notoriously unreliable means of gathering information" that severely limits the study's validity.

2. The study defined hypercholesterolemia by either diagnosis or lipid-lowering medication use. This creates a "healthy user" effect where:

   - Patients aware of their diagnosis are more health-conscious.

   - Those on medications likely have better healthcare access and adherence.

   - The comparison group may include undiagnosed hypercholesterolemic patients.

   This bias could artificially make the hypercholesterolemia group appear healthier overall.

3. Treatment Bias (The Most Damning Flaw):

   The study didn’t track whether people’s cholesterol actually stayed high. Many likely took statins, lowering their LDL cholesterol over time—so they “started” with high cholesterol but “ended up” with low levels. Bottom line:The study compared “treated” vs. “untreated” people—not truly high vs. low cholesterol.

   As the authors themselves acknowledged, this likely had a "substantial" impact on results.

4. Lack of Duration Data

   The study failed to assess:

   - How long patients had hypercholesterolemia?

   - Cumulative cholesterol exposure

   - Treatment duration before enrollment

   This is crucial because atherosclerotic cardiovascular disease develops over decades of cholesterol exposure-short-term data is misleading.

5. The cohorts consisted of patients referred for cardiac imaging—a specialized population that may not represent the general public. Additionally:

   - Patients over 75 were excluded, limiting generalizability to older adults

   - The study couldn't account for why patients were referred for testing

   - There may have been unmeasured confounding factors affecting both referral patterns and outcomes.

   
   

   MY TAKE: A GARBAGE STUDY THAT ISN’T WORTH THE PAPER IT WAS WRITTEN ON.

Alternative Explanations for the Paradox

When properly controlled for confounding, the cholesterol paradox largely disappears. Several explanations account for the apparent inverse relationship…Here’s what’s really going on:

1. Reverse Causality:

   Low cholesterol can be a sign of illness (cancer, liver disease, malnutrition). It’s not that low cholesterol causes death—it’s that sick people often have low cholesterol.

2. Treatment Works:

   As seen in multiple randomized trials, cholesterol-lowering:

   - Reduces cardiovascular events and mortality

   - The benefits are proportional to LDL-C reduction

   - Even extremely low LDL (<40 mg/dL) has been shown to be safe in all trials. In fact, physiologic LDL-C is 10-30mg/dl.

3. Population-Specific Factors:

   Certain groups show unique cholesterol-mortality relationships:

   - Dialysis patients (where inflammation alters lipid metabolism)

   - Acute illness (where cholesterol drops during metabolic stress)

   - Advanced age (where other co-morbidities dominate risk)

The Weight of Contrary Evidence

The Rozanski findings conflict with an enormous body of evidence supporting LDL cholesterol’s causal role in atherosclerosis:

1. Genetic Studies: Mendelian randomization shows lifelong low LDL-C reduces CVD risk proportionally.

2. Randomized Trials: Statins and other LDL-lowering drugs consistently reduce events.

3. Epidemiology: Across populations, LDL-C strongly predicts atherosclerosis.

4. Pathology: ApoB lipoprotein particles directly contribute to plaque formation in the arterial wall.

The “cholesterol paradox” appears to be little more than a flashy name for a fictitious phenomenon.

Despite the intriguing paradox concept, clinicians should continue following evidence-based guidelines for cholesterol management. They MUST recognize that observational data cannot override randomized trial evidence. Furthermore, an astute physician must view very low cholesterol in ill patients as a potential marker of disease severity rather than a cause. Finally, one must consider the context when interpreting lipid levels.

In conclusion, while the Rozanski study adds to observations of a cholesterol paradox, its methodological limitations—particularly treatment bias and reliance on self-reported data—prevent it from challenging the well-established relationship between LDL-C and cardiovascular risk. The paradox largely reflects study artifacts and confounding rather than a true protective effect of high cholesterol. Yet despite all the evidence showing the false cholesterol paradox, medical “imposters” will continue to infuse the internet with this nonsense for notoriety, fame, and profit. As the preponderance of evidence demonstrates, lowering LDL-C remains a cornerstone of cardiovascular prevention, supported by overwhelming data from diverse research approaches. Future studies examining cholesterol-mortality relationships must rigorously account for treatment effects and longitudinal lipid measurements to avoid similar interpretive pitfalls.