Combination therapy in the guidelines: from high-intensity statins to high-intensity lipid-lowering therapies

Combination therapy in the guideline

Luis Masana
Unitat de Medicina Vascular i Metabolisme, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, IISPV, CIBERDEM, Reus, Spain
Daiana Ibarretxe
Unitat de Medicina Vascular i Metabolisme, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, IISPV, CIBERDEM, Reus, Spain
Natalia Andreychuk
Unitat de Medicina Vascular i Metabolisme, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, IISPV, CIBERDEM, Reus, Spain
Meritxell Royuela
Unitat de Medicina Vascular i Metabolisme, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, IISPV, CIBERDEM, Reus, Spain and Unitat de Lípids i Risc Vascular. ALTHAIA. Xarxa assistencial universitària de Manresa, Manresa (Barcelona), Spain
Celia Rodríguez-Borjabad
Unitat de Medicina Vascular i Metabolisme, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, IISPV, CIBERDEM, Reus, Spain
Nuria Plana
Unitat de Medicina Vascular i Metabolisme, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, IISPV, CIBERDEM, Reus, Spain

Abstract

The causal role of cholesterol in atherosclerosis was established more than 100 years ago. Along with the fact that the higher the cholesterol, the greater the risk of atherosclerotic cardiovascular diseases (ASCVD), many randomized controlled trials (RCT) have shown that lowering LDL cholesterol (LDL-C) is associated with a lower incidence of ASCVD. This impact of lipid-lowering therapies on cardiovascular risk is independent of the drug used, as shown by several meta-analyses and Mendelian randomization studies. Therefore, the concept of using “high-intensity statins” should be changed to “high-intensity lipid-lowering therapies” that go beyond the use of statins.
Recent RCTs using non-statin lipid-lowering therapies has provided scientific evidence that the lower the LDL-C, the better in terms of cardiovascular events. Based on these observations, current guidelines recommend achieving very low LDL-C levels in patients with high and very-high cardiovascular risk.
To achieve these demanding goals, the physician must use the full spectrum of lipid-lowering therapies, beyond high-intensity, high-dose statins. Oral combination therapies and, when necessary, subcutaneous treatments become the new standard of care for hypercholesterolemia.
However, the number of patients achieving LDL-C goals is unacceptably low. This is due in part to insufficient prescription and insufficient treatment. To improve the efficacy of therapy, several strategies have been proposed, step by step, planning therapy and maximizing treatment, based on the needs of the patient.
A wider use of lipid-lowering therapies focused on the circumstances of the patient is a step towards personalized and precision medicine.

References

  1. Steinberg D. In celebration of the 100th anniversary of the lipid hypothesis of atherosclerosis. J Lipid Res 2013; 54:2946-9. https://doi.org/10.1194/jlr.R043414
  2. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333:1301-7. https://doi.org/10.1056/NEJM199511163332001
  3. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-9. https://doi.org/10.1016/S0140-6736(94)90566-5
  4. Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:7-22. https://doi.org/10.1016/S0140-6736(02)09327-3
  5. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495-504. https://doi.org/10.1056/NEJMoa040583
  6. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352:1425-35. https://doi.org/10.1056/NEJMoa050461
  7. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129:S1-45. https://doi.org/10.1161/01.cir.0000437738.63853.7a
  8. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372:2387-97. https://doi.org/10.1056/NEJMoa1410489
  9. 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. https://doi.org/10.1056/NEJMoa1615664
  10. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379:2097-107. https://doi.org/10.1056/NEJMoa1801174
  11. Boren J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020; 41:2313-30. https://doi.org/10.1093/eurheartj/ehz962
  12. 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. https://doi.org/10.1016/S0140-6736(10)61350-5
  13. Silverman MG, Ference BA, Im K, et al. Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis. JAMA 2016; 316:1289-97. https://doi.org/10.1001/jama.2016.13985
  14. Ference BA, Cannon CP, Landmesser U, et al. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J 2018; 39:2540-5. https://doi.org/10.1093/eurheartj/ehx450
  15. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41:111-88. https://doi.org/10.1093/eurheartj/ehz455
  16. Masana L, Ibarretxe D, Plana N. Maximum Low-density Lipoprotein Cholesterol Lowering Capacity Achievable With Drug Combinations. When 50 Plus 20 Equals 60. Rev Esp Cardiol (Engl Ed) 2016; 69:342-3. https://doi.org/10.1016/j.rec.2015.11.014
  17. Ray KK, Molemans B, Schoonen WM, et al. EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care: the DA VINCI study. Eur J Prev Cardiol 2021; 28:1279-89. https://doi.org/10.1093/eurjpc/zwaa047
  18. Schubert J, Lindahl B, Melhus H, et al. Low-density lipoprotein cholesterol reduction and statin intensity in myocardial infarction patients and major adverse outcomes: a Swedish nationwide cohort study. Eur Heart J 2021; 42:243-52. https://doi.org/10.1093/eurheartj/ehaa1011
  19. Ray KK, Reeskamp LF, Laufs U, et al. Combination lipid-lowering therapy as first-line strategy in very high-risk patients. Eur Heart J 2021. https://doi.org/10.1093/eurheartj/ehab718
  20. Averna M, Banach M, Bruckert E, et al. Practical guidance for combination lipid-modifying therapy in high- and very-high-risk patients: A statement from a European Atherosclerosis Society Task Force. Atherosclerosis 2021; 325:99-109. https://doi.org/10.1016/j.atherosclerosis.2021.03.039
  21. Packard C, Chapman MJ, Sibartie M, et al. Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges. Heart 2021; 107:1369-75. https://doi.org/10.1136/heartjnl-2020-318760
  22. Amarenco P, Kim JS, Labreuche J, et al. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. N Engl J Med 2020; 382:9. https://doi.org/10.1056/NEJMoa1910355

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