Remnant Cholesterol and Cardiovascular Risk: What the Latest Genetic Research Tells Us
- Alastair Hunt
- Oct 5, 2023
- 7 min read
Updated: Mar 25
In recent years, remnant cholesterol (RC) has emerged from the shadow of its more famous lipid relatives, such as LDL (“bad” cholesterol), as a potentially important contributor to cardiovascular disease. But does remnant cholesterol truly cause heart problems, or is it just along for the ride? Two new Mendelian randomisation studies - large genetic analyses that simulate clinical trials—now offer stronger answers to that question.
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 the bottom of the page.
Remnant cholesterol refers to the cholesterol content found in triglyceride-rich lipoproteins- mainly very low-density lipoproteins, intermediate-density lipoproteins and remnants of chylomicrons. These are the particles that remain in your blood after triglycerides have been delivered to your cells. RC is considered highly atherogenic, meaning it plays a key role in the build-up of plaques in artery walls, which can eventually lead to heart attacks or strokes.
Mendelian randomisation studies are a modern way of investigating whether a risk factor actually causes a disease, rather than just being associated with it. By using genetic variants that people are randomly born with - similar to a natural lottery - these studies mimic randomised controlled trials. This approach helps minimise the usual confounding factors that can affect observational research, giving us stronger evidence about causality. Read more about Mendelian randomisation here.
A Clear Causal Link: What the Studies Show
Both studies - one published in Scientific Reports and another in Arteriosclerosis, Thrombosis and Vascular Biology - used genetic data to test whether people born with a tendency for higher RC are more likely to suffer from cardiovascular diseases. And both studies arrived at the same fundamental conclusion:
Higher remnant cholesterol levels cause a higher risk of atherosclerotic cardiovascular disease.
Study 1: Broad Risk Across Multiple Conditions
The first study by Lei Zhong and colleagues analysed data from over 115,000 people of European descent, looking at genetic predisposition to higher RC and its link to a wide range of cardiovascular conditions. It found that for every standard deviation increase in RC:
Risk of unstable angina rose by 62%
Risk of myocardial infarction (heart attack) rose by 53%
Risk of cardiac arrest rose by 60%
Risk of major coronary heart disease events rose by 52%
Even hypertension and heart failure showed modest increases in risk (about 9% and 8.6% respectively)
Interestingly, RC was not linked to cardiomyopathy (a disease of the heart muscle) or pericarditis (inflammation of the heart’s outer lining), suggesting it mainly affects conditions caused by artery blockages, like heart attacks and angina.
This study also found possible reverse causality - in other words, developing heart disease could influence RC levels. Still, their main conclusion remained firm: remnant cholesterol contributes causally to many cardiovascular conditions, independent of other lipid factors.
Study 2: Independent of LDL Cholesterol
The second study, led by Eliano P. Navarese and team, zoomed in on the link between remnant cholesterol and three major outcomes: coronary artery disease (CAD), heart attack (MI) and stroke. Using data from nearly a million participants, they found that for every standard deviation increase in RC:
CAD risk increased by 51%
MI risk increased by 57%
Stroke risk increased by 23%
What’s most striking is that these effects were largely independent of LDL cholesterol, as confirmed by mediation analysis. That means even if LDL-C levels are well-controlled, high remnant cholesterol still poses a risk.
Why This Matters: Beyond LDL
The traditional focus of cholesterol management has been LDL-C. Statins and other LDL lowering treatments have saved countless lives. But some people continue to experience cardiovascular events despite good LDL control - a phenomenon known as 'residual risk'.
These studies suggest that remnant cholesterol is a major part of that residual risk. Unlike LDL, remnant cholesterol particles are rich in triglycerides and penetrate artery walls easily, where they can trigger inflammation and contribute to plaque build-up. They may even turn into foam cells - early culprits in the development of atherosclerosis.
A Future of Targeted RC Reduction?
Both studies call for a rethinking of clinical guidelines. If remnant cholesterol is an independent cause of heart disease, it deserves attention in cardiovascular screening and management. Proposed interventions include:
Lifestyle changes: Weight loss, reduced saturated fat intake, regular exercise and quitting smoking can all help lower RC.
Emerging drugs: Therapies targeting apolipoprotein C-III or angiopoietin-like protein 3 are in development and may offer new ways to lower RC specifically.
Final Thoughts
Taken together, these two large Mendelian randomisation studies provide strong evidence that remnant cholesterol is not just a bystander - it is a driver of heart disease, even when LDL levels are under control. They show that addressing remnant cholesterol could be key to preventing coronary events, particularly in people already taking steps to lower their LDL cholesterol.
The good news is that knowledge is power. These studies don’t just highlight a risk - they point us toward new ways to take control of our heart health. If you're already managing your cholesterol, blood pressure or weight, you're on the right path. And if you're just getting started, small steps like moving more, eating well and checking in with your healthcare provider can make a meaningful difference.
As research progresses, remnant cholesterol may become a more routine part of cardiovascular screening. That means more personalised care, better prevention, and fewer surprises. Whether through lifestyle changes or future therapies, reducing remnant cholesterol could be one more way to protect your heart for the long haul. Your heart health journey is just that - a journey. And every step counts.
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Stay Healthy,
Alastair
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Related Studies
The studies reviewed in the article...
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.
Other
Wadström BN, Pedersen KM, Wulff AB, Nordestgaard BG. Remnant Cholesterol, Not LDL Cholesterol, Explains Peripheral Artery Disease Risk Conferred by apoB: A Cohort Study. Arterioscler Thromb Vasc Biol. 2024 May;44(5):1144-1155. doi: 10.1161/ATVBAHA.123.320175. Epub 2024 Mar 21. PMID: 38511326.
Johnasen, M. Ø., Vedel-Krogh, S., Nielsen, S. F., Afzal, S., Davey Smith, G., & Nordestgaard, B. G. (2025). Association of remnant cholesterol with unhealthy lifestyle and risk of coronary heart disease: a population-based cohort study. The Lancet Regional Health - Europe, Article 101223. Advance online publication. https://doi.org/10.1016/j.lanepe.2025.101223
Simonen P, Öörni K, Sinisalo J, Strandberg TE, Wester I, Gylling H. High cholesterol absorption: A risk factor of atherosclerotic cardiovascular diseases? Atherosclerosis. 2023 Jul;376:53-62. doi: 10.1016/j.atherosclerosis.2023.06.003. Epub 2023 Jun 2. PMID: 37290267.
Nguyen XT, Ho YL, Li Y, Song RJ, Leung KH, Rahman SU, Orkaby AR, Vassy JL, Gagnon DR, Cho K, Gaziano JM, Wilson PWF. Serum Cholesterol and Impact of Age on Coronary Heart Disease Death in More Than 4 Million Veterans. J Am Heart Assoc. 2023 Nov 7;12(21):e030496. doi: 10.1161/JAHA.123.030496. Epub 2023 Oct 27. PMID: 37889207; PMCID: PMC10727410.
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Quispe R, Martin SS, Michos ED, Lamba I, Blumenthal RS, Saeed A, Lima J, Puri R, Nomura S, Tsai M, Wilkins J, Ballantyne CM, Nicholls S, Jones SR, Elshazly MB. Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study. Eur Heart J. 2021 Nov 7;42(42):4324-4332. doi: 10.1093/eurheartj/ehab432. PMID: 34293083; PMCID: PMC8572557.
Hooper L, Martin N, Jimoh OF, Kirk C, Foster E, Abdelhamid AS. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2020 Aug 21;8(8):CD011737. doi: 10.1002/14651858.CD011737.pub3. PMID: 32827219; PMCID: PMC8092457.
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.
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