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Macrovascular Residual Risk Studies

20 July 2020
High remnant cholesterol levels: an unmet clinical need in secondary prevention
New insights from the Copenhagen General Population Study highlight the importance of targeting high nonfasting remnant cholesterol levels in individuals with atherosclerotic cardiovascular disease.
Langsted A, Madsen CM, Nordestgaard BG. Contribution of remnant cholesterol to cardiovascular risk. J Intern Med 2020; doi: 10.1111/joim.13059. Online ahead of print.
Objective: To test whether an unmet medical need exists in individuals with high nonfasting remnant cholesterol and prior atherosclerotic cardiovascular disease (ASCVD).
Study design: Prospective cohort study of the adult Danish general population (Copenhagen General Population Study)
Study population: 2973 individuals aged 20-80 years with a baseline diagnosis of myocardial infarction (MI) or ischaemic stroke; 1984 had MI only, 1210 had ischaemic stroke only, and 221 had both.
Study outcome: • Recurrent major cardiovascular event (MACE), defined as a composite of cardiovascular mortality, MI, ischaemic stroke, percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG)
• Nonfasting remnant cholesterol
Methods: Recurrent MACE incidence rates per 1000 person-years were estimated for four categories of remnant cholesterol: <0.5mmol/L (<19mg/dL), 0.5-0.99mmol/L (19-38mg/dL), 1-1.49mmol/L (39-57mg/dL), and ≥1.5mmol/L (≥58mg/dL). Hazard ratios with 95% confidence intervals (CI) were estimated using Cox proportional hazards regressions and age was included in the model as underlying timescale. Multivariable adjustment was made for lipid-lowering therapy, smoking, low-density lipoprotein cholesterol, lipoprotein(a), and hypertension. The estimated remnant cholesterol lowering required for a given risk reduction in recurrent MACE was made using multivariable adjusted hazard ratios from the Cox proportional hazard regression.
Results: During 19,831 person-years of follow-up, there were 551 recurrent MACE events including 214 cardiovascular deaths, 218 MI, 236 ischaemic strokes, 152 PCI, and 51 CABG. Individuals with remnant cholesterol levels in the highest quartile (≥1.5mmol/L or ≥58mg/dL) were younger, more likely to be male (75% versus 61% in the lowest quartile), and less likely to be on lipid-lowering medication (68% versus 72%) compared with those with lower remnant cholesterol levels.Analysis of recurrent MACE by nonfasting remnant cholesterol quartiles is summarized in Table 1. For a 20% recurrent MACE risk reduction, estimated remnant cholesterol lowering of 0.83mmol/L (32mg/dL) would be needed, less than the corresponding reduction needed in LDL-C or non-high-density lipoprotein cholesterol, derived from the Cholesterol Treatment Trialists Collaboration (1).

Table 1. Recurrent MACE by nonfasting remnant cholesterol quartile level














MACE/1000 patient-years (95% CI)



All patients

23 (19-27)

27 (24-31)

31 (26-37)

39 (30-50)


<2.5 mmol/L*

24 (19-30)

26 (22-31)

32 (25-42)

42 (29-61)

Hazard ratio (95% CI) for recurrent MACE








* or <97 mg/dL; LDL-C low-density lipoprotein cholesterol
Conclusion: In individuals with a diagnosis of MI/ischaemic stroke, a lower remnant cholesterol of 0.8mmol/L (32mg/dL) was estimated to reduce recurrent MACE by 20% in secondary prevention. Our data indicate an unmet medical need for secondary prevention in individuals with high nonfasting remnant cholesterol levels.


Accumulating evidence shows that higher levels of remnant cholesterol, i.e. the cholesterol that is contained within triglyceride-rich lipoproteins and their remnant particles, are associated with increased risk for ASCVD (2). While there is strong support from mechanistic, observational and genetic studies, evidence from clinical trials is limited (3). The most robust is provided by the REDUCE-IT study (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), in which icosapent ethyl (4 g/day) significantly reduced cardiovascular events and cardiovascular death among patients with high triglycerides and either known ASCVD or at high risk, who were already on statin therapy with relatively well-controlled LDL-C levels (4).  Subsequent analyses, however, have shown that the benefit observed in the trial may be mediated by eicosapentaenoic acid (EPA) levels (5). 

The current study adds important data regarding the association of remnant cholesterol with the risk of recurrent MACE. In a general population with established ASCVD, lowering remnant cholesterol levels by 0.8 mmol/L (32 mg/dL) was estimated to reduce recurrent MACE by 20%. These findings are pertinent for two reasons. First, the results underline the unmet clinical need for treatments targeting elevated remnant cholesterol to reduce the high risk of recurrent cardiovascular events in secondary prevention individuals maintained on best-evidence therapy. Second, the study provides information regarding the magnitude of remnant cholesterol lowering required to reduce recurrent cardiovascular events by 20%. This will undoubtedly aid in the design of trials of novel therapeutic approaches targeting elevated remnant cholesterol in high-risk individuals.   

References 1. Cholesterol Treatment Trialists C, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376:1670-81.
2. Varbo A, Nordestgaard BG. Remnant cholesterol and triglyceride-rich lipoproteins in atherosclerosis progression and cardiovascular disease. Arterioscler Thromb Vasc Biol 2016;36:2133-5.
3. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016; 118:547-63.
4. Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
5. Bhatt DL et al. EPA levels and cardiovascular outcomes in the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial. American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC): Abstract 20-LB-20501-ACC. Presented March 30, 2020.
Key words remnant cholesterol; triglyceride-rich lipoproteins; recurrent cardiovascular events; unmet clinical need