Is LDL Cholesterol Trying to Save Your Life? High LDL Does Not Matter!? A Closer Look at the Evidence

There is plenty of conflicting information online about cholesterol, particularly LDL cholesterol and its role in cardiovascular disease (CVD). Some voices argue that LDL is misunderstood or even beneficial - an often-heard quote is that 'blaming cholesterol for heart disease is like blaming the firemen attending a burning house for starting it'. However, the scientific consensus – particularly from large-scale studies – clearly suggests otherwise. So what is going on?

As ever, please talk to your doctor or medical practitioner most familiar with your medical history before implementing any changes in diet, exercise or lifestyle, especially if you are under treatment. Links to all studies at bottom of page.

Studies and Research

Views on LDL cholesterol have shifted over time. In the past, healthcare professionals and researchers often focused on the ratio of HDL ("good" cholesterol) to LDL ("bad" cholesterol) as a key indicator of heart disease risk. A higher ratio - more HDL relative to LDL- was thought to offer protection, even if LDL levels were moderately high. However, current research suggests that this ratio is of little consequence. What matters more is the absolute level of atherogenic particles, particularly LDL cholesterol and apolipoprotein B (ApoB)

ApoB is the protein component of all atherogenic lipoproteins, including LDL, VLDL, IDL and remnant cholesterol particles. Each of these particles carries a single ApoB molecule, meaning ApoB levels provide a direct count of the number of cholesterol-rich particles capable of penetrating the arterial wall. This makes ApoB a more accurate predictor of cardiovascular risk than LDL cholesterol concentration alone, particularly in individuals with metabolic syndrome or elevated triglycerides. So rather than relying on a ratio, clinicians now place greater emphasis on directly measuring ApoB to assess cardiovascular risk more accurately. (PMID 28444290 and 38839200)

One of the most compelling areas of evidence comes from Mendelian randomisation studies. These studies leverage natural genetic variations – randomly distributed in populations – to mimic the design of randomised controlled trials. Several of these studies, involving millions of participants, demonstrate a clear linear relationship between lifelong exposure to higher levels of LDL and increased risk of cardiovascular events (PMID 23083789).

The mechanistic data further support this view. We now understand that LDL cholesterol – regardless of whether it's oxidised or in its small dense form – can cross the endothelium (PMID 35722128 and 40013359).

Once in the intima (the innermost layer of a blood vessel wall), the ApoB component of LDL can be enzymatically modified, leading to its retention in the arterial wall. This retention initiates an inflammatory response, recruiting macrophages and leading to the formation of foam cells, which eventually narrow the arteries (PMID 35310965).

Importantly, this process has been shown to occur even in the absence of systemic inflammation (PMID 29146277). In other words, LDL can actively initiate inflammation at the site of arterial damage – it doesn’t just respond to it.

Remnant cholesterol refers to the cholesterol content found in triglyceride-rich lipoproteins, after triglycerides have been removed. It is considered a strong independent risk factor for cardiovascular disease, particularly because these remnants can penetrate arterial walls and contribute to plaque buildup similarly to LDL cholesterol (PMID 39511362 and 37439258).

Final Thoughts

When it comes to challenging prevailing narratives, it's essential to rely on robust data. Anecdotes and analogies don’t carry the same weight as peer-reviewed evidence, especially when there are studies involving millions of participants available for analysis. Any counter-arguments should ideally be supported by comparable high-quality evidence.

Supporting your body through balanced nutrition, physical activity, stress reduction, quality sleep and meaningful social connection (these are known as the Pillars of Health) are some of the most powerful longevity tools we have. As always, it's about progress, not perfection, and even small changes can make a meaningful difference over time.

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Related Studies and Resources

Lipidologists to follow:

Studies

Bolanle IO, de Liedekerke Beaufort GC, Weinberg PD. Transcytosis of LDL Across Arterial Endothelium: Mechanisms and Therapeutic Targets. Arterioscler Thromb Vasc Biol. 2025 Apr;45(4):468-480. doi: 10.1161/ATVBAHA.124.321549. Epub 2025 Feb 27. PMID: 40013359; PMCID: PMC11936472.

Johannesen CDL, Langsted A, Nordestgaard BG, Mortensen MB. Excess Apolipoprotein B and Cardiovascular Risk in Women and Men. J Am Coll Cardiol. 2024 Jun 11;83(23):2262-2273. doi: 10.1016/j.jacc.2024.03.423. PMID: 38839200.

Zhong L, Xie B, Wang HL, Ji XW. Causal association between remnant cholesterol level and risk of cardiovascular diseases: a bidirectional two sample mendelian randomization study. Sci Rep. 2024 Nov 7;14(1):27038. doi: 10.1038/s41598-024-78610-0. PMID: 39511362; PMCID: PMC11544147.

Navarese EP, Vine D, Proctor S, Grzelakowska K, Berti S, Kubica J, Raggi P. Independent Causal Effect of Remnant Cholesterol on Atherosclerotic Cardiovascular Outcomes: A Mendelian Randomization Study. Arterioscler Thromb Vasc Biol. 2023 Sep;43(9):e373-e380. doi: 10.1161/ATVBAHA.123.319297. Epub 2023 Jul 13. PMID: 37439258.

Jiang H, Zhou Y, Nabavi SM, Sahebkar A, Little PJ, Xu S, Weng J, Ge J. Mechanisms of Oxidized LDL-Mediated Endothelial Dysfunction and Its Consequences for the Development of Atherosclerosis. Front Cardiovasc Med. 2022 Jun 1;9:925923. doi: 10.3389/fcvm.2022.925923. PMID: 35722128; PMCID: PMC9199460.

Storey BC, Staplin N, Haynes R, Reith C, Emberson J, Herrington WG, Wheeler DC, Walker R, Fellström B, Wanner C, Landray MJ, Baigent C; SHARP Collaborative Group. Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation. Kidney Int. 2018 Apr;93(4):1000-1007. doi: 10.1016/j.kint.2017.09.011. Epub 2017 Nov 14. PMID: 29146277; PMCID: PMC5978933.

Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR, Tokgözoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017 Aug 21;38(32):2459-2472. doi: 10.1093/eurheartj/ehx144. PMID: 28444290; PMCID: PMC5837225.

Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, Mewada A, Kahn J, Afonso L, Williams KA Sr, Flack JM. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012 Dec 25;60(25):2631-9. doi: 10.1016/j.jacc.2012.09.017. Epub 2012 Oct 17. PMID: 23083789.