FOURTH-GENERATION STATINS: ADVANCES IN LIPID-LOWERING THERAPY AND REDUCTION OF CARDIOVASCULAR RISK
Abstract
Over the past four decades, statins have remained the cornerstone of cardiovascular disease prevention, evolving from natural compounds to highly effective third-generation drugs. However, the persistence of residual cardiovascular risk, statin intolerance, and the need for deeper lipid reduction have led to the emergence of fourth-generation agents. This paper examines the modern pharmacological landscape, including both improved statins and new classes of lipid-lowering drugs with different mechanisms of action.
Pitavastatin occupies an intermediate position, characterized by a favorable pharmacokinetic profile, minimal drug interactions, and a neutral effect on carbohydrate metabolism. Bempedoic acid represents an innovative drug that inhibits ATP citrate lyase, providing effective LDL cholesterol reduction without myotoxicity and demonstrating a reduction in cardiovascular events in patients with statin intolerance.
PCSK9 inhibitors, including monoclonal antibodies (evolocumab, alirocumab) and RNA interference agents (inclisiran), provide significant reductions in LDL cholesterol levels and the incidence of major cardiovascular complications. Inclisiran is particularly notable for its convenience of use due to its twice-yearly administration.
Promising agents such as obicetrapib and RNA-based therapies targeting lipoprotein(a) open new possibilities for reducing residual risk not directly related to LDL cholesterol levels. These advances reflect a shift from traditional statin monotherapy to a personalized approach in lipid metabolism management, taking into account individual risk, genetic factors, and therapy tolerability.
Fourth-generation agents not only enhance the effectiveness of lipid-lowering therapy but also form a new paradigm for long-term cardiovascular disease prevention based on a comprehensive and individualized approach.
Keywords
fourth-generation statins; lipid-lowering therapy; cardiovascular risk; pitavastatin; bempedoic acid; PCSK9 inhibitors; inclisiran; low-density lipoproteins; lipoprotein(a); personalized medicine; statin intolerance; atherosclerosis; combination therapy; innovative drugs.How to Cite
References
Baigent C., Blackwell L., Emberson J., 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 // The Lancet. – 2010. – Vol. 376. – No. 9753. – P. 1670–1681.
Mihaylova B., Emberson J., Blackwell L., et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease // The Lancet. – 2012. – Vol. 380. – No. 9841. – P. 581–590.
Libby P., Ridker P. M. Inflammation and atherosclerosis: role of C-reactive protein in risk assessment // The American Journal of Medicine. – 2019. – Vol. 132. – No. 1. – P. 10–15.
Banach M., Rizzo M., Toth P. P., et al. Statin intolerance – an attempt at a unified definition // Position paper from an International Lipid Expert Panel. – 2015. – Vol. 72. – P. 1–23.
Cannon C. P., Blazing M. A., Giugliano R. P., et al. Ezetimibe added to statin therapy after acute coronary syndromes // The New England Journal of Medicine. – 2015. – Vol. 372. – No. 25. – P. 2387–2397.
Sabatine M. S., Giugliano R. P., Keech A. C., et al. Evolocumab and clinical outcomes in patients with cardiovascular disease // The New England Journal of Medicine. – 2017. – Vol. 376. – No. 18. – P. 1713–1722.
Schwartz G. G., Steg P. G., Szarek M., et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome // The New England Journal of Medicine. – 2018. – Vol. 379. – No. 22. – P. 2097–2107.
Ray K. K., Wright R. S., Kallend D., et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol // The New England Journal of Medicine. – 2020. – Vol. 382. – No. 16. – P. 1507–1519.
Nissen S. E., Lincoff A. M., Brennan D., et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients // The New England Journal of Medicine. – 2023. – Vol. 388. – No. 14. – P. 1353–1364.
Kathiresan S., et al. Lipoprotein(a) and cardiovascular disease: insights from genetic studies // Journal of the American College of Cardiology. – 2016. – Vol. 68. – No. 25. – P. 2764–2772.
Tall A. R., Rader D. J. The trials and tribulations of CETP inhibitors // Circulation Research. – 2022. – Vol. 130. – No. 1. – P. 106–120.
Mach F., Baigent C., Catapano A. L., et al. 2023 ESC/EAS Guidelines for the management of dyslipidaemias // European Heart Journal. – 2023. – Vol. 44. – No. 39. – P. 3899–3981.
Ference B. A., Ginsberg H. N., Graham I., et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease // European Heart Journal. – 2017. – Vol. 38. – No. 32. – P. 2459–2472.
Арутюнов Г. П., Драпкина О. М. Дислипидемия и сердечно-сосудистый риск: современные подходы к терапии // Кардиология. – 2020. – Т. 60. – № 3. – С. 4–12.
Шляхто Е. В., Конради А. О., Бойцов С. А. и др. Клинические рекомендации по лечению дислипидемий // Российский кардиологический журнал. – 2021. – Т. 26. – № 5. – С. 4298.
Чазов Е. И., Бойцов С. А. Атеросклероз и профилактика сердечно-сосудистых заболеваний // Терапевтический архив. – 2019. – Т. 91. – № 9. – С. 5–12.
Конради А. О., Недогода С. В., Шляхто Е. В. Современные подходы к снижению липидов в клинической практике // Артериальная гипертензия. – 2020. – Т. 26. – № 2. – С. 123–131.
Драпкина О. М., Самородская И. В. Первичная и вторичная профилактика сердечно-сосудистых заболеваний // Профилактическая медицина. – 2021. – Т. 24. – № 4. – С. 7–15.
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