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Macrovascular Residual Risk Studies

26 September 2023
More evidence linking remnant cholesterol and cardiovascular outcomes
This Mendelian randomization study including more than 900,000 subjects showed a robust genetic causal association between remnant cholesterol and cardiovascular outcomes.
Navarese EP, Vine D, Proctor S, et al. Independent causal effect of remnant cholesterol on atherosclerotic cardiovascular outcomes: a Mendelian Randomization Study. Arterioscler Thromb Vasc Biol 2023; doi: 10.1161/ATVBAHA.123.319297.
Objective: To investigate the causal role of remnant cholesterol to predict coronary artery disease (CAD), myocardial infarction (MI), and stroke risk.
Study design: Mendelian randomization study
Study population: Data from a combined sample of 958 434 subjects in the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics), the Metastroke consortium, and the GLGC (Global Lipids Genetics Consortium).
Primary variable: • Cardiovascular outcomes, defined as CAD, MI and stroke
Methods: This study used single-nucleotide polymorphisms for remnant cholesterol and low-density lipoprotein cholesterol (LDL-C) as genetic instruments to evaluate the association between these lipids and cardiovascular outcomes.
Main results:

There was a significant causal effect of remnant cholesterol on the risk of CAD, MI and stroke with no evidence of pleiotropy. For each 1 standard deviation (SD) increase in remnant cholesterol, there was a more than 50% increase in the risk for CAD or MI, and this effect was independent of the effect of LDL-C.


Additionally, the study showed that lifelong low remnant cholesterol levels associated with genetic inhibition of remnant cholesterol led to a 40% relative reduction in MI risk.


Table 1. Effect on cardiovascular outcomes per 1 SD increase in remnant cholesterol


Odds ratio (95% CI)

1.51 (1.42-1.60)

1.57 (1.21-2.05)

1.23 (1.12-1.35)









Authors’ conclusion: This large-scale Mendelian randomization study showed a robust genetic causal association between remnant cholesterol and cardiovascular outcomes. The effect on CAD and MI is independent of LDL cholesterol. Early screening for remnant cholesterol along with long-term inhibition of remnant cholesterol should be the focus of future therapeutic interventions.


This study adds to accumulating evidence for a causal association between elevated remnant cholesterol, the cholesterol contained within triglyceride-rich remnant lipoprotein particles, and cardiovascular outcomes. Previous observational and genetic data from the Copenhagen General Population Study and the Copenhagen Ischemic Heart Disease Study showed that per 1 mmol/L increase, non-fasting remnant cholesterol was associated with a greater increase in risk for atherosclerotic cardiovascular disease (ASCVD) outcomes compared with LDL-C (1,2). Additionally, elevated remnant cholesterol associated with elevated mortality risk (3). These data are supported by mechanistic studies which indicated that remnant cholesterol plays an important role in atherosclerosis. The current study adds robust evidence for a genetic causal association between remnant cholesterol and cardiovascular outcomes, with the association for risk of MI or CAD independent of LDL-C.

While the evidence supports remnant cholesterol as a likely causal risk factor for ASCVD, uncertainties persist regarding its measurement and therapeutic approaches (4). For example, calculated remnant cholesterol is dependent on the accuracy of LDL-C measurement (5), and assays for direct measurement of remnant cholesterol require further evaluation (4). Additionally, conflicting results from recent trials have engendered confusion as to how best to target remnant cholesterol therapeutically (6-8). More studies are needed to validate remnant cholesterol measurement and define the most appropriate treatments in high-risk patients.

References 1. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
2. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013; 61:427–36.
3. Jepsen AM, Langsted A, Varbo A, Bang LE, Kamstrup PR, Nordestgaard BG. Increased remnant cholesterol explains part of residual risk of all-cause mortality in 5414 patients with ischemic heart disease. Clin Chem 2016; 62:593–604.
4. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021; 42:4791–806.
5. Lütjohann D, Klör HU, Stellaard F. Measurement of serum low density lipoprotein cholesterol and triglyceride-rich remnant cholesterol as independent predictors of atherosclerotic cardiovascular disease: possibilities and limitations. Nutrients 2023;15:2202.
6. Das Pradhan A, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022; 387: 1923–34.
7. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019; 380: 11–22.
8. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 2020; 324: 2268–80.
Key words : remnant cholesterol; Mendelian randomization; atherosclerotic cardiovascular disease