Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. Heart Disease and Stroke Statistics-2021 update: a report from the American Heart Association. Circulation. 2021;143(8):e254–743. https://doi.org/10.1161/CIR.0000000000000950.

Article  PubMed  Google Scholar 

Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, Nichols M. Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J. 2016;37(42):3232–45. https://doi.org/10.1093/eurheartj/ehw334.

Article  PubMed  Google Scholar 

Shimada YJ, Cannon CP. PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the future. Eur Heart J. 2015;36(36):2415–24. https://doi.org/10.1093/eurheartj/ehv174.

CAS  Article  PubMed  Google Scholar 

Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22. https://doi.org/10.1056/NEJMoa1615664.

CAS  Article  PubMed  Google Scholar 

Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–107. https://doi.org/10.1056/NEJMoa1801174.

CAS  Article  PubMed  Google Scholar 

Kulkarni JA, Witzigmann D, Thomson SB, Chen S, Leavitt BR, Cullis PR, et al. The current landscape of nucleic acid therapeutics. Nat Nanotechnol. 2021;16(6):630–43. https://doi.org/10.1038/s41565-021-00898-0.

CAS  Article  PubMed  Google Scholar 

• Warden BA, Duell PB. Inclisiran: a novel agent for lowering apolipoprotein B-containing lipoproteins. J Cardiovasc Pharmacol. 2021;78(2):e157–74. https://doi.org/10.1097/FJC.0000000000001053. A comprehensive report on inclisiran.

CAS  Article  PubMed  Google Scholar 

Katzmann JL, Packard CJ, Chapman MJ, Katzmann I, Laufs U. Targeting RNA with antisense oligonucleotides and small interfering RNA: JACC state-of-the-art review. J Am Coll Cardiol. 2020;76(5):563–79. https://doi.org/10.1016/j.jacc.2020.05.070.

CAS  Article  PubMed  Google Scholar 

• Landmesser U, Poller W, Tsimikas S, Most P, Paneni F, Luscher TF. From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur Heart J. 2020;41(40):3884–99. https://doi.org/10.1093/eurheartj/ehaa229. A comprehensive review of nucleic acid-based therapies.

CAS  Article  PubMed  Google Scholar 

Arsenault BJ. The promise and challenges of RNA-targeted therapeutics in preventive cardiology. Eur Heart J. 2022;43(7):550–2. https://doi.org/10.1093/eurheartj/ehab462.

Article  PubMed  Google Scholar 

•• Musunuru K, Chadwick AC, Mizoguchi T, Garcia SP, DeNizio JE, Reiss CW, et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature. 2021;593(7859):429–34. https://doi.org/10.1038/s41586-021-03534-y. The study shows the successful application of CRISPR adenine base editors for in vivo PCSK9 editing in non-human primates, showing durable LDL-C and PCSK9 resonses over 8 months after induction of a single-nucleotide LOF mutation.

CAS  Article  PubMed  Google Scholar 

• Rothgangl T, Dennis MK, Lin PJC, Oka R, Witzigmann D, Villiger L, et al. In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels. Nat Biotechnol. 2021;39(8):949–57. https://doi.org/10.1038/s41587-021-00933-4. The study also shows the successful application of CRISPR adenine base editors for in vivo PCSK9 editing in non-human primates after induction of a single-nucleotide LOF mutation.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Banerjee Y, Pantea Stoian A, Cicero AFG, Fogacci F, Nikolic D, Sachinidis A, et al. Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia. Expert Opin Drug Saf. 2022;21(1):9–20. https://doi.org/10.1080/14740338.2022.1988568.

CAS  Article  PubMed  Google Scholar 

Scicchitano P, Milo M, Mallamaci R, De Palo M, Caldarola P, Massari F, et al. Inclisiran in lipid management: a Literature overview and future perspectives. Biomed Pharmacother. 2021;143:112227. https://doi.org/10.1016/j.biopha.2021.112227.

CAS  Article  PubMed  Google Scholar 

• Wright RS, Ray KK, Raal FJ, Kallend DG, Jaros M, Koenig W, et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol. 2021;77(9):1182–93. https://doi.org/10.1016/j.jacc.2020.12.058. Pooled analysis of 3 phase 3 trials, ORION-9, -10 and -11, providing confirmatory evidence that inclisiran reduces LDL-C by ~50% and is well tolerated over 540 days of treatment.

CAS  Article  PubMed  Google Scholar 

Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(16):1507–19. https://doi.org/10.1056/NEJMoa1912387.

CAS  Article  PubMed  Google Scholar 

Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382(16):1520–30. https://doi.org/10.1056/NEJMoa1913805.

CAS  Article  PubMed  Google Scholar 

Clinicaltrials.gov: A randomized trial assessing the effects of inclisiran on clinical outcomes among people with cardiovascular disease (ORION-4). https://www.clinicaltrials.gov/ct2/show/NCT03705234. Accessed 21 May 2022.

•• Gennemark P, Walter K, Clemmensen N, Rekic D, Nilsson CAM, Knochel J, et al. An oral antisense oligonucleotide for PCSK9 inhibition. Sci Transl Med. 2021;13(593). https://doi.org/10.1126/scitranslmed.abe9117. The first report on a potential oral ASO inhibiting PCSK9.

•• Katzmann JL, Cupido AJ, Laufs U. Gene therapy targeting PCSK9. Metabolites. 2022;12(1). https://doi.org/10.3390/metabo12010070. A comprehensive review on gene therapies targeting PCSK9.

Wang L, Smith J, Breton C, Clark P, Zhang J, Ying L, et al. Meganuclease targeting of PCSK9 in macaque liver leads to stable reduction in serum cholesterol. Nat Biotechnol. 2018;36(8):717–25. https://doi.org/10.1038/nbt.4182.

CAS  Article  PubMed  Google Scholar 

•• Wang L, Breton C, Warzecha CC, Bell P, Yan H, He Z, et al. Long-term stable reduction of low-density lipoprotein in nonhuman primates following in vivo genome editing of PCSK9. Mol Ther. 2021;29(6):2019–29. https://doi.org/10.1016/j.ymthe.2021.02.020. Sustained knockdown of PCSK9 in non-human primates for up to 3 years using AAV delivery of a meganuclease.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Breton C, Furmanak T, Avitto AN, Smith MK, Latshaw C, Yan H, et al. Increasing the specificity of AAV-based gene editing through self-targeting and short-promoter strategies. Mol Ther. 2021;29(3):1047–56. https://doi.org/10.1016/j.ymthe.2020.12.028.

CAS  Article  PubMed  Google Scholar 

Nishiga M, Liu C, Qi LS, Wu JC. The use of new CRISPR tools in cardiovascular research and medicine. Nat Rev Cardiol. 2022. https://doi.org/10.1038/s41569-021-00669-3.

Article  PubMed  Google Scholar 

Akinc A, Querbes W, De S, Qin J, Frank-Kamenetsky M, Jayaprakash KN, et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther. 2010;18(7):1357–64. https://doi.org/10.1038/mt.2010.85.

CAS  Article  PubMed  PubMed Central  Google Scholar 

van Kampen SJ, van Rooij E. CRISPR base editing lowers cholesterol in monkeys. Nat Biotechnol. 2021;39(8):920–1. https://doi.org/10.1038/s41587-021-00975-8.

CAS  Article  PubMed  Google Scholar 

• Guedeney P, Giustino G, Sorrentino S, Claessen BE, Camaj A, Kalkman DN, et al. Efficacy and safety of alirocumab and evolocumab: a systematic review and meta-analysis of randomized controlled trials. Eur Heart J. 2019. https://doi.org/10.1093/eurheartj/ehz430. Large meta-analysis using data from 39 phase 2 or phase 3 randomized controlled trials and totalling 66,478 patients showing the efficacy and safety of evolocumab and alirocumab.

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383–9.

Long-Term Intervention with Pravastatin in Ischaemic Disease Study G. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339(19):1349–57. https://doi.org/10.1056/NEJM199811053391902.

Sabatine MS. PCSK9 inhibitors: what we know, what we should have understood, and what is to come. Eur Heart J. 2019. https://doi.org/10.1093/eurheartj/ehz514.

Article  PubMed  Google Scholar 

• Oyama K, Giugliano RP, Tang M, Bonaca MP, Saver JL, Murphy SA, et al. Effect of evolocumab on acute arterial events across all vascular territories : results from the FOURIER trial. Eur Heart J. 2021;42(47):4821–9. https://doi.org/10.1093/eurheartj/ehab604. Post-hoc analysis of the FOURIER trial showing the robust reduction of first and total acute arterial events with evolocumab which increased over time but needed at least 9 months to emerge.

CAS  Article  PubMed  Google Scholar 

• Nicholls SJ, Kataoka Y, Nissen SE, Prati F, Windecker S, Puri R, et al. Effect of evolocumab on coronary plaque phenotype and burden in statin-treated patients following myocardial infarction. JACC Cardiovasc Imaging. 2022. https://doi.org/10.1016/j.jcmg.2022.03.002. This study shows that early PCSK9 inhibition with evolocumab after an MI yields plaque stabilization and regression.

Article  PubMed  Google Scholar 

• Raber L, Ueki Y, Otsuka T, Losdat S, Haner JD, Lonborg J, et al. Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI Randomized Clinical Trial. JAMA. 2022;327(18):1771–81. https://doi.org/10.1001/jama.2022.5218. This study shows also that early PCSK9 inhibition with alirocumab after an MI yields plaque stabilization and regression.

CAS  Article  PubMed  Google Scholar 

Prati F, Romagnoli E, Gatto L, La Manna A, Burzotta F, Ozaki Y, et al. Relationship between coronary plaque morphology of the left anterior descending artery and 12 months clinical outcome: the CLIMA study. Eur Heart J. 2020;41(3):383–91. https://doi.org/10.1093/eurheartj/ehz520.

Article  PubMed  Google Scholar 

• Schwartz GG, Szarek M, Bittner VA, Diaz R, Goodman SG, Jukema JW, et al. Lipoprotein(a) and benefit of PCSK9 inhibition in patients with nominally controlled LDL cholesterol. J Am Coll Cardiol. 2021;78(5):421–33. https://doi.org/10.1016/j.jacc.2021.04.102. This post-hoc analysis of ODYSSEY OUTCOMES shows the role even mildly elevated Lp(a) levels play in the remaining cardiovascular risk. Higher Lp(a) levels were associated with a higher event rate, even when LDL-C was <70 mg/dl and interestingly PCSK9 inhibition in patients on optimal statin therapy seems to provide incremental benefit only when Lp(a) levels are even slightly elevated.

CAS  Article  PubMed  PubMed Central  Google Scholar 

• Ying Q, Chan DC, Pang J, Marcovina SM, Barrett PHR, Watts GF. PCSK9 inhibition with alirocumab decreases plasma lipoprotein(a) concentration by a dual mechanism of action in statin-treated patients with very high apolipoprotein(a) concentration. J Intern Med. 2022;291(6):870–6. https://doi.org/10.1111/joim.13457. A small but interesting study which used stable isotopes to examine the kinetic mechanism of the Lp(a) reduction with alirocumab.

CAS  Article  PubMed  Google Scholar 

Kunutsor SK, Seidu S, Khunti K. Statins and secondary prevention of venous thromboembolism: pooled analysis of published observational cohort studies. Eur Heart J. 2017;38(20):1608–12. https://doi.org/10.1093/eurheartj/ehx107.

Article  PubMed  PubMed Central  Google Scholar 

van Schouwenburg IM, Mahmoodi BK, Gansevoort RT, Muntinghe FL, Dullaart RP, Kluin-Nelemans HC, et al. Lipid levels do not influence the risk of venous thromboembolism. Results of a population-based cohort study. Thromb Haemost. 2012;108(5):923–9. https://doi.org/10.1160/TH12-06-0426.

CAS  Article  PubMed  Google Scholar 

Klarin D, Busenkell E, Judy R, Lynch J, Levin M, Haessler J, et al. Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease. Nat Genet. 2019;51(11):1574–9. https://doi.org/10.1038/s41588-019-0519-3.