Residual Risk beyond LDL: What is relevant?

Monday News from EAS Helsinki 2021: 

Low-density lipoprotein cholesterol (LDL-C) is indisputably causal for atherosclerotic cardiovascular disease (ASCVD) (1). However, despite intensive LDL-C lowering, as demonstrated in the PCSK9 inhibitor trials (2,3), ASCVD patients experience recurrent events, underlining the need to target other factors.  This joint European Society of Cardiology (ESC)/EAS session discussed critical contributors and therapeutic approaches to this persistent residual cardiovascular risk.

Professor Brian Ference (University of Cambridge, UK) focused on the key predictors of persistent residual risk. Beyond LDL, other contenders for consideration are lipoprotein(a) and triglyceride-rich lipoproteins. Lipoprotein(a) is clearly a causal risk factor (4), although to date there is no definitive evidence that lowering lipoprotein(a) reduces cardiovascular events against a background of low LDL-C levels. Clinical trials of novel therapies in patients with elevated lipoprotein(a) levels have shown lowering of lipoprotein(a) by more than 80% (5). For outcomes studies, the critical question is how much lipoprotein(a) needs to be lowered for a clinically meaningful reduction in cardiovascular events, against a background of well controlled LDL-C levels. Predictive studies suggest that an absolute reduction by 80-100 mg/dL is needed (6), implying that lipoprotein(a) is only an important contributor to residual risk in those patients with high lipoprotein(a) levels

Similarly, whether lowering triglyceride-rich lipoproteins reduces residual risk is unresolved. The association between triglyceride-rich lipoproteins and cardiovascular risk is complex and conflicting: epidemiologic and genetic studies are supportive whereas clinical trials are not definitive (7). Based on genetic analyses, Professor Ference commented that apolipoprotein (apo)B, common to all atherogenic lipoproteins, may provide an appropriate metric for assessing the clinical benefit of any lipid lowering therapy (8). While this approach is supported by trials of LDL-lowering therapy, it is less clear whether it is applicable to triglyceride-lowering therapies. Additionally, and as for lipoprotein(a), the benefit may be only in patients with very high triglyceride burden.

For patients with severe hypertriglyceridaemia, including those with familial chylomicronaemia, the overall goal of therapy is to reduce the risk of acute pancreatitis, as discussed by Professor Marcello Arca (Sapienza University of Rome, Italy). New insights into the regulation of triglyceride-rich lipoprotein metabolism have led to the development of novel therapeutic approaches, notably those targeting apoCIII (volanesorsen) and angiopoietin like protein 3 (ANGPTL3, i.e., evinacumab and vupanorsen). These have demonstrated substantial triglyceride-lowering efficacy in clinical trials and therefore represent new options for the management of these patients (9,10).

Professor Ulf Landmesser (Charitie University Medicine Berlin, Germany) discussed the role of inflammation as a contributor to residual risk, supported by mechanistic evidence and Mendelian randomisation studies which indicated a causal role of the immune response in the progression of atherosclerosis.  Beyond this, there is also recent evidence suggesting therapeutic potential for targeting healing mechanisms involved in the resolution of inflammation in the arteries, such as those related to CD47 (11).

The CANTOS study (12) provided pivotal proof-of-concept support that targeting residual inflammatory risk with canakinumab reduced cardiovascular events in patients with a history of myocardial infarction, and this was further supported by findings from COLCOT study with low-dose colchicine (13). The lack of benefit in CIRT (14), however, implied that intervention should be targeted to patients with a sufficiently high inflammatory burden to ensure clinically meaningful reductions in cardiovascular events. For both canakinumab and colchicine, the likely biologic mechanism is thought to be mediated via the inhibition of the NLRP3 inflammasome pathway.

Non-adherence is one of the major barriers in cardiovascular disease prevention. The polypill, first mooted in 2003 (15), is a pragmatic approach to targeting multiple risk factors. As discussed by Professor Isabella Sugano (University Hospital Zurich, Switzerland), studies have demonstrated clinical benefit with a polypill based on aspirin and generic agents that lower blood pressure and cholesterol levels (16).  The combination of these inexpensive generic components would have application in lower-income regions where the affordability and accessibility to treatment are major obstacles to cardiovascular disease prevention. Such an approach is also highly relevant in the context of achieving the United Nations Sustainable Development Goals 2030 (17).

Finally, Professor Ference suggested that preventive approaches should be directed to lowering lifetime risk. For example, the benefit from LDL-C lowering is not only related to the magnitude of absolute reduction, but also the duration of exposure (1). Targeting intervention earlier, possibly with siRNA approaches that provide durable and sustained LDL-C lowering with infrequent dosing, offers the opportunity to change the trajectory of disease and, ultimately eliminate residual cardiovascular risk.

Find more at the meeting- view the session on-demand

  • Sessions archive: Monday May 31,  2021: ESC/EAS Joint Session: Decreasing risk beyond LDL-C


  1. Ference BA, Ginsberg HN, Graham I, et 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;38:2459-72.
  2. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
  3. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-107.
  4. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.
  5. Tsimikas S, Karwatowska-Prokopczuk E, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 2020;382:244-55
  6. Burgess S, Ference BA, Staley JR, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian Randomization analysis. JAMA Cardiol 2018;3(7):619-27.
  7. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
  8. Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019;321:364-73.
  9. Gouni-Berthold I, Alexander VJ, Yang Q, et al. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2021;9:264-75.
  10. Gaudet D, Karwatowska-Prokopczuk E, et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur Heart J 2020;41:3936-45.
  11. Jarr KU, Nakamoto R, Doan BH, et al. Effect of CD47 blockade on vascular inflammation. N Engl J Med 2021;384:382-3.
  12. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.
  13. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383:1838-47.
  14. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2019;380:752-62.
  15. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419.
  16. Yusuf S, Joseph P, Dans A, et al. Polypill with or without aspirin in persons without cardiovascular disease. N Engl J Med 2021;384:216-28.
  17. The Sustainable Development Agenda. Available at


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