Researchers: here's why cholesterol isn't the sole cause of heart disease

Updated and contextualized version of an article originally published on June 12, 2014
The article retains its original focus by presenting it through a scholarly and accessible perspective, supported by verifiable references.

Authors

• Dr. M. Mondini – Biologist
• Roberto Panzironi –Independent researcher 

Note editoriali

• First publication: June 12, 2014
• Last update: April 18, 2026
• Version: 2026 narrative revision  

Initial note: This article was previously published and has been updated here according to scientific and informative criteria. The text is for informational purposes only and does not replace the advice of your treating physician. For personal clinical decisions, it is recommended to consult a healthcare professional.

IN BRIEF

• Cholesterol (and LDL in particular) is an important factor in cardiovascular risk, but it is not the sole cause of heart disease.
• The transformation of LDL into oxidized forms, local inflammation, and other metabolic factors (e.g., excess sugar) contribute to the formation of atherosclerotic plaque.
• Experimental, genetic, and clinical evidence shows that lowering LDL reduces cardiovascular events, but the effect depends on the context, population, and measure of effect (relative vs. absolute).
• Interventions that reduce inflammation (e.g., selected clinical trials) suggest that inflammation is an independent and relevant pathway.
• Practical recommendations require individual assessment of overall risk (not just cholesterol levels) and discussion with a doctor.

Abstract: what does science say?

Cholesterol is an essential molecule for cellular functions, but an excess of low-density lipoproteins (LDL) increases the risk of atherosclerosis. Integrated evidence — from genetic studies, large meta-analyses of clinical trials, and evidence from new drugs that profoundly lower LDL — supports that reducing exposure to LDL lowers the risk of coronary events. However, cholesterol measurement alone does not explain all ischemic events: lipoprotein oxidation, the presence of small, dense LDL particles, the inflammatory state of the endothelium, and metabolic factors such as excess sugars interact in determining risk. Percentage reductions reported in the media often express relative differences; the absolute impact varies with the baseline risk. Clinical recommendations must therefore take into account the patient's overall profile and the limitations of available studies.

What is cholesterol and when does it become dangerous?

Cholesterol is a lipid substance largely produced by the liver and essential for cell membranes, hormone synthesis, and neurological functions. It circulates in the blood bound to proteins: LDL (transport to tissues) and HDL (return transport to the liver). From an epidemiological and clinical experimental perspective, there is a relationship between prolonged exposure to high LDL and the risk of atherosclerosis: numerous experimental reductions in LDL are associated with a decrease in cardiovascular events in at-risk populations [1].

That said, the numerical level of cholesterol measured in a single blood draw is not the sole determinant of risk. The consistency of the risk depends on the duration of exposure, the composition of the particles (e.g., small, dense particles), local oxidative processes, and the coexistence of other risk factors (hypertension, diabetes, smoking). Furthermore, the percentage contribution of cholesterol varies greatly among individuals and populations; therefore, clinical decisions are based on an assessment of global risk, not on a single laboratory number [1][6].

Biological Mechanisms: LDL, Oxidation, and Inflammation

Atherosclerotic plaque formation is a multifactorial process. LDL can penetrate the arterial intima and undergo chemical modifications, including oxidation; oxidized lipoproteins are more easily recognized and taken up by macrophages, which become foam cells and promote the accumulation of lipid material in the wall [7][8]. In parallel, damaged endothelium generates inflammatory signals: chemokines and cytokines promote the recruitment of immune cells and lesion progression.

LDL Oxidation and 'At-Risk' Particles

Not all LDL behave the same way: small, dense particles (sdLDL) are more susceptible to oxidation and penetrate the arterial wall more easily; for this reason, the concentration of sdLDL or oxidized LDL is associated with a higher coronary risk in observational studies and meta-analyses [8][9]. These data justify attention not only to the total LDL-C value but also to the qualitative characteristics of lipoproteins and the local oxidative/inflammatory state.

Clinical Evidence: What Studies on Statins and Other LDL-Lowering Therapies Show

Evidence for the efficacy of statins comes from numerous randomized trials and meta-analyses. A prospective meta-analysis of over 90,000 participants showed that LDL reduction is associated with significant reductions in coronary events, in a dose-dependent manner and independently of baseline cholesterol levels [1]. Subsequent studies have confirmed that other approaches that reduce LDL (e.g., PCSK9 inhibitors, ezetimibe added to statins) achieve further reductions in events, although the effect size depends on baseline risk and treatment duration [4][5].

Interpreting Relative and Absolute Reductions

When the media reports percentages (e.g., "-36% risk"), this often indicates a relative reduction. The real clinical benefit for a person depends on their baseline absolute risk: a high relative reduction can correspond to a small absolute reduction if the initial risk is low. For example, a study might show that events drop from 3% to 2%: the relative reduction is ~33%, but the absolute reduction is 1 percentage point; the clinical value and risk/benefit assessment must be made on a case-by-case basis [4].

Inflammation as an independent pathway

Inflammation plays a central role in plaque progression. There is clinical experimental evidence that specifically intervening on inflammation (beyond LDL reduction) can reduce cardiovascular events: the CANTOS trial, which tested an anti-interleukin antibody (canakinumab) in patients with persistent inflammation, showed a reduction in cardiovascular events independent of cholesterol modification, suggesting that inflammation is a modifiable risk pathway [3]. In parallel, studies with statins have highlighted that part of the benefit may also derive from their anti-inflammatory action in addition to lipid reduction [2].

Role of diet, sugars, and micronutrients

Beyond lipids, other metabolic factors influence cardiovascular risk. Excess sugar (particularly sugary drinks and high fructose intake) is associated with worsening metabolic profiles: increased triglycerides, reduced HDL, and insulin resistance, all conditions correlated with a higher cardiovascular risk observed in large cohorts and meta-analyses [9].

Furthermore, subclinical deficiencies of micronutrients essential for endothelial health and tissue repair can make the arterial wall more vulnerable to mechanical micro-damage and inflammatory processes. These are biological plausibilities supported by experimental data; however, clinical translation (e.g., the effectiveness of targeted supplementation to prevent events) still requires robust confirmation.

What it means in practice

For the average person and for the physician, the key is to assess overall cardiovascular risk, not just a single cholesterol value. Clinical risk tools integrate age, blood pressure, diabetes, smoking, and lipids to estimate 10-year risk and guide the choice of pharmacological or lifestyle interventions.

If the absolute risk is high (for example, due to previous cardiovascular diseases), LDL reduction with statins or other therapies has shown measurable benefits [1][4][5]. In low-risk individuals, the absolute benefit may be small, and the decision to initiate lipid-lowering therapies should consider individual preferences, tolerability, and the presence of additional markers of inflammation or residual risk.

Key points to remember

• LDL is an important causal factor for atherosclerosis but not the only one: oxidation, inflammation, and particle characteristics matter.
• Reducing LDL reduces cardiovascular events in at-risk populations; the extent of the benefit depends on baseline risk and absolute reduction. [1][5]
• Some patients with high inflammation may benefit from inflammation-targeted interventions: clinical data are selective but indicative. [3]
• Diet and lifestyle (reduction of added sugars, physical activity, smoking cessation) significantly influence lipid profile and metabolic risk. [9]
• Therapeutic choice must be individualized and shared with the doctor; absolute and relative percentage numbers should always be interpreted in the context of overall risk.

Limitations of Evidence

It is important to distinguish between observational association and causal proof. Observational studies show correlations between foods or biomarkers and risk, but can be influenced by confounding and imprecise measurements. Randomized trials provide the best evidence of causality for specific interventions (e.g., statins, PCSK9, ezetimibe), but even these have limitations: relatively short duration compared to a lifetime, selected populations, and possible cross-sectional effects not always evaluated.

Mendelian randomization studies offer support for biological causality (for example, for LDL), but do not replace the need for controlled clinical trials to evaluate the benefits and risks of therapeutic interventions in different populations [6]. Finally, much research on diet and micronutrients remains heterogeneous: well-designed trials are needed to establish efficacy and optimal dosages.

Editorial conclusion

The most reliable position in light of current evidence is an intermediate and pragmatic one: LDL cholesterol is a causal factor, and reducing its exposure over time reduces the risk of cardiovascular events in many people; however, atherosclerotic disease is multifactorial. Considering inflammation, qualitative characteristics of lipoproteins, and metabolic factors such as excessive sugar consumption allows for a more complete clinical view. Therapeutic decisions must be personalized, based on overall risk and an informed comparison between expected benefits and possible adverse effects.

Editorial note

The article has been updated to reflect the comparison between genetic, experimental, and clinical evidence. The following bibliography only includes research with verifiable DOI and peer-review. The information is for informational purposes only: it does not constitute individual recommendations.

SCIENTIFIC RESEARCH

1. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of cholesterol‑lowering treatment: prospective meta‑analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005. https://doi.org/10.1016/S0140-6736(05)67394-1.[1]
2. Ridker PM et al. Rosuvastatin to prevent vascular events in men and women with elevated C‑reactive protein (JUPITER). N Engl J Med. 2008. https://doi.org/10.1056/NEJMoa0807646.[2]
3. Ridker PM et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease (CANTOS). N Engl J Med. 2017. https://doi.org/10.1056/NEJMoa1707914.[3]
4. IMPROVE‑IT Investigators. Ezetimibe added to statin therapy after acute coronary syndrome (IMPROVE‑IT). N Engl J Med. 2015. https://doi.org/10.1056/NEJMoa1410489.[4]
5. Sabatine MS et al. Evolocumab and clinical outcomes in patients with cardiovascular disease (FOURIER). N Engl J Med. 2017. https://doi.org/10.1056/NEJMoa1615664.[5]
6. Burgess S, Butterworth A, Thompson SG. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J. 2015. https://doi.org/10.1093/eurheartj/eht571.[6]
7. Alonso‑Palomares L et al. Oxidized LDL and atherosclerosis — review of mechanisms. Lipids Health Dis. 2012. https://doi.org/10.1186/1476-511X-11-85.[7]
8. Liou L, Kaptoge S, et al. Association of small, dense LDL‑cholesterol concentration and lipoprotein particle characteristics with coronary heart disease: systematic review and meta‑analysis. PLoS One. 2020;15(11):e0241993. https://doi.org/10.1371/journal.pone.0241993.[8]
9. Yuan C, Ding EL, et al. Sugar‑sweetened beverage consumption and risk of coronary heart disease: meta‑analysis of prospective studies. Atherosclerosis. 2014. https://doi.org/10.1016/j.atherosclerosis.2014.01.037.[9]

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