Please wait a minute...
Reviews in Cardiovascular Medicine  2019, Vol. 20 Issue (1): 1-8     DOI: 10.31083/j.rcm.2019.01.31812
Review | Next articles
A short review of proprotein convertase subtilisin/kexin type 9 inhibitors
Rudaynah A. Alali1, *()
1Department of Internal Medicine, King Fahd Hospital of the University, Alkhobar, College of Medicine, Imam Abdulrahman bin Faisal University 31441, Dammam, Saudi Arabia
Download:  PDF(1063KB)  ( 565 ) Full text   ( 70 )
Export:  BibTeX | EndNote (RIS)      
Abstract:

Cardiovascular disease is the leading cause of morbidity and mortality globally, as estimated by the World Health Organization, where in 2016, 15.2 million deaths were attributed to ischemic heart disease and stroke. It is therefore essential to try to reduce the incidence of Cardiovascular disease by controlling modifiable risk factors. One such major modifiable risk factor is cholesterol, which influences the pathogenesis and progression of atherosclerosis. Statins are often prescribed to lower blood levels of low density lipoprotein cholesterol, thereby reducing the risk of Cardiovascular disease by approximately 25-35%. However, there is an increasing number of patients (in particular those with intolerance to statin therapy and those with familial hypercholesterolemia) for whom statin therapy alone is not enough to control low density lipoprotein cholesterol. In this review, the regulation of cholesterol metabolism will be discussed with an emphasis on novel cholesterol lowering drugs used in clinical trials. These second-generation drugs, monoclonal antibodies against the low density lipoprotein receptor gene known as proprotein convertase subtilisin/kexin type 9 inhibitors, are expected to be prescribed to patients who are intolerant to statins, as well as in conjunction with statins. Future perspectives of the clinical use of these drugs is also discussed.

Key words:  Cardiovascular disease      statin      hypercholesterolemia      proprotein convertase subtilisin/kexin type 9 inhibitors     
Published:  30 March 2019     
*Corresponding Author(s):  Rudaynah A. Alali     E-mail:  rudaynahalali@hotmail.com

Cite this article: 

Rudaynah A. Alali. A short review of proprotein convertase subtilisin/kexin type 9 inhibitors. Reviews in Cardiovascular Medicine, 2019, 20(1): 1-8.

URL: 

https://rcm.imrpress.com/EN/10.31083/j.rcm.2019.01.31812     OR     https://rcm.imrpress.com/EN/Y2019/V20/I1/1

Figure 1.  Mortality as a result of various diseases worldwide, led byischemic heart disease and stroke(Source: Global health estimates 2016: deaths by cause, age, sex, by country and by region, 2000-2016. Geneva, World Health Organization; 2018)

Table 1  Comparison of the three clinical trials of the PCSK9 inhibitors
FOURIER ODYSSEY OUTCOMES SPIRE-1/SPIRE-2
Type of PCSK9 inhibitor Evolocumab (Fully human monoclonal Ab) Alirocumab (Fully human monoclonal Ab) Bococizumab (Murine-derived Ab)
Timelines Start: Jan. 2013; End: Feb. 2018 Start: Oct. 2012; End: March 2018 Start: Oct. 2013; End: Aug. 2017
Study design Randomized, parallel, double-blind placebo -
Patient type History of clinically evident CVD at high risk for recurrent event ACS within the last 4-52 weeks. History of clinically evident CVD at high risk for recurrent event Subjects at high risk of a CVD event receiving background lipid lowering therapy
Follow up Median 2.2 years Median 2.8 years -
Total patients 22,500 (including 9,000 ≥ 65 years) 18,000 SPIRE-1: 12,000; SPIRE-2: 6,300
LDL-C (mg/dl) on background therapy LDL-C ≥ 70 or Non-HDL-C ≥ 100 LDL-C ≥ 70; Non-HDL-C ≥ 100 or
Apo B ≥ 80
SPIRE-1: LDL-C ≥ 70 & < 100 or
Non-HDL-C > 100 & < 130
SPIRE-2: LDL-C ≥ 100 or
Non-HDL-C ≥ 130
Statin regimen Atorvastatin 20-80 mg or an alternative statin. High dose 69%, Moderate dose 30%, Ezetimibe: 5.1% Atorvastatin 20-80 mg or Rosuvastatin 20-40 mg. High-dose: 89%, Ezetimibe: 3% Not specified
Inhibitor dose 140 mg Q2 weeks or 420 mg Q4 weeks 75 mg or 150 mg Q2 weeks 150 mg Q2 weeks
Mean age 63 years 58 years -
% DM/HTN/Smoking 37% / 80% / 28.2% 29% / 63.3% / 23.9% -
Stroke/PAD history 19.3% / 13.2% 2.9% / 3.7% -
Exclusion criteria ?Myocardial infarction or stroke within 4 weeks
?NYHA class III or IV CHF symptoms or LVEF < 30% or uncontrolled VT
?Planned revascularization within the next 3 months
?Uncontrolled HTN or hemorrhagic stroke
?CKD
?Organ transplant or major active infection
?Recurrent ACS or coronary revascularization within 2 weeks
?NYHA class III or IV CHF; LVEF < 25%
?Uncontrolled HTN or hemorrhagic stroke
?Fasting TG > 400 mg/dl or use of fibrates other than fenofibrate
?Liver transaminases > 3 x ULN; HBV, HCV infection, CK > 3 x ULN
?Estimated GFR < 30 ml/min/1.73 m2
?Positive pregnancy test
-
Primary endpoint 5-point MACE: CVS death, non-fatal MI, unstable angina, ischemic stroke & coronary revascularization 4-point MACE: CVS death, non-fatal MI, unstable angina & ischemic stroke CVS death, non-fatal MI, unstable angina, ischemic stroke & coronary revascularization
Major findings/Outcomes Lowered LDL-C by 59%; significantly reduced MACE by 9.8%, relative risk reduction of 15% over 2.2 years and absolute risk reduction of 1.5% Lowered LDL-C by 63% with notable attenuation in reduction to 55% over the course of follow up due to the down titration of Alirocumab dose at low LDL-C levels; The reduction in MACE is also a challenge to interpret due this reason. Lowers LDL-C by 55-60%; significantly reduced CV event rates in the higher-risk SPIRE-2 trial;
Patients developed anti-drug antibodies
Abifadel, M., Varret, M., Rabès, J.P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derré, A., Villéger, L., Farnier, M., Beucler, I., Bruckert, E., Chambaz, J., Chanu, B., Lecerf, J.M., Luc, G., Moulin, P., Weissenbach, J., Prat, A., Krempf, M., Junien, C., Seidah, N.G. and Boileau, C . ( 2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics 34, 154-156.
doi: 10.1038/ng1161
Androulakis, E., Zacharia, E., Papageorgiou, N., Lioudaki, E., Bertsias, D., Charakida, M., Siasos, G. and Tousoulis, D . ( 2017) High-density Lipoprotein and Low-density Lipoprotein Therapeutic Approaches in Acute Coronary Syndromes. Current Cardiology Reviews 13, 168-182.
Aspelund, T., Gudnason, V., Magnusdottir, B.T., Andersen, K., Sigurdsson, G., Thorsson, B., Steingrimsdottir, L., Critchley, J., Bennett, K., O'Flaherty, M. and Capewell, S . ( 2010) Analysing the large decline in coronary heart disease mortality in the Icelandic population aged 25-74 between the years 1981 and 2006. PLoS One 5, 1-8.
Bays, H., Gaudet, D., Weiss, R., Ruiz, J. L., Watts, G. F., GouniBerthold, I., Robinson, J., Zhao, J., Hanotin, C. and Donahue, S . ( 2015) Alirocumab as add-On to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. The Journal of Clinical Endocrinology & Metabolism 100, 3140-3148.
Bentzon, J. F., Otsuka, F., Virmani, R. and Falk, E . ( 2014) Mechanisms of plaque formation and rupture. Circulation Research 114, 1852-1866.
doi: 10.1161/CIRCRESAHA.114.302721
Blanchard, V., Khantalin, I., Ramin-Mangata, S., Chémello, K., Nativel, B. and Lambert, G . ( 2019) PCSK9: from biology to clinical applications. Pathology 51, 177-183.
doi: 10.1016/j.pathol.2018.10.012
Bohula, E. A., Giugliano, R. P., Leiter, L. A., Verma, S., Park, J. G., Sever, P. S., Lira Pineda, A., Honarpour, N., Wang, H., Murphy, S.A., Keech, A., Pedersen, T.R. and Sabatine, M.S . ( 2018) Inflammatory and cholesterol risk in the FOURIER trial. Circulation 138, 131-140.
doi: 10.1161/CIRCULATIONAHA.118.034032
Bove, M., Cicero, A. F. G. and Borghi, C. ( 2019) Emerging drugs for the treatment of hypercholesterolemia. Expert Opinion on Emerging Drugs 24, 63-69.
doi: 10.1080/14728214.2019.1591372
Chan, J. C., Piper, D. E., Cao, Q., Liu, D., King, C., Wang, W., Tang, J., Liu, Q., Higbee, J., Xia, Z., Di, Y., Shetterly, S., Arimura, Z., Salomonis, H., Romanow, W. G., Thibault, S. T., Zhang, R., Cao, P., Yang, X. P., Yu, T., Lu, M., Retter, M. W., Kwon, G., Henne, K., Pan, O., Tsai, M. M., Fuchslocher, B., Yang, E., Zhou, L., Lee, K.J., Daris, M., Sheng, J., Wang, Y., Shen, W. D., Yeh, W. C., Emery, M., Walker, N. P., Shan, B., Schwarz, M. and Jackson, S. M . ( 2009) A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proceedings of the National Academy of Sciences of the United States of America 106, 9820-9825.
doi: 10.1073/pnas.0903849106
Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K. and Hobbs, H. H . ( 2005) Low LDL cholesterol in individuals of african descent resulting from frequent nonsense mutations in PCSK9. Nature Genetics 37, 161-165.
doi: 10.1038/ng1509
Cohen, J. C., Boerwinkle, E., Mosley, T. H. and Hobbs, H. H . ( 2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. New England Journal of Medicine 354, 1264-1272.
doi: 10.1056/NEJMoa054013
Collaborators, G.M.a.C.o.D. ( 2016) Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388, 1459-1544.
doi: 10.1016/S0140-6736(16)31012-1
Correia, L.C., Rocha, M.S. and Esteves, J.P. ( 2009) HDL-cholesterol level provides additional prognosis in acute coronary syndromes. International Journal of Cardiology 136, 307-314.
doi: 10.1016/j.ijcard.2008.05.067 pmid: 18706714
Fasano, T., Cefalù, A.B., Di Leo, E., Noto, D., Pollaccia, D., Bocchi, L., Valenti, V., Bonardi, R., Guardamagna, O., Averna, M. and Tarugi, P . ( 2007) A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arteriosclerosis, Thrombosis, and Vascular Biology 27, 677-681.
doi: 10.1161/01.ATV.0000255311.26383.2f
Feigin, V. L., Nguyen, G., Cercy, K., Johnson, C. O., Alam, T., Parmar, P. G., Abajobir, A. A., Abate, K. H., Abd-Allah, F., Abejie, A. N., Abyu, G. Y., Ademi, Z., Agarwal, G., Ahmed, M. B., Akinyemi, R. O., Al-Raddadi, R., Aminde, L. N., AmlieLefond, C., Ansari, H., Asayesh, H., Asgedom, S. W., Atey, T. M., Ayele, H. T., Banach, M., Banerjee, A., Barac, A., Barker-Collo, S. L., Bärnighausen, T., Barregard, L., Basu, S., Bedi, N., Behzadifar, M., Béjot, Y., Bennett, D. A., Bensenor, I. M., Berhe, D. F., Boneya, D. J., Brainin, M., Campos-Nonato, I. R., Caso, V., Castañeda-Orjuela, C. A., Rivas, J. C., Catalá-López, F., Christensen, H., Criqui, M. H., Damasceno, A., Dandona, L., Dandona, R., Davletov, K., de Courten, B., deVeber, G., Dokova, K., Edessa, D., Endres, M., Faraon, E. J. A., Farvid, M. S., Fischer, F., Foreman, K., Forouzanfar, M. H., Gall, S. L., Gebrehiwot, T. T., Geleijnse, J. M., Gillum, R. F., Giroud, M., Goulart, A. C., Gupta, R., Hachinski, V., Hamadeh, R. R., Hankey, G. J., Hareri, H. A., Havmoeller, R., Hay, S. I., Hegazy, M. I., Hibstu, D. T., James, S. L., Jeemon, P., John, D., Jonas, J. B., Jówiak, J., Kalani, R., Kandel, A., Kasaeian, A., Kengne, A.P., Khader, Y. S., Khan, A. R., Khang, Y. H., Khubchandani, J., Kim, D., Kim, Y. J., Kivimaki, M., Kokubo, Y., Kolte, D., Kopec, J. A., Kosen, S., Kravchenko, M., Krishnamurthi, R., Kumar, G. A., Lafranconi, A., Lavados, P. M., Legesse, Y ., et al. ( 2018) Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016. New England Journal of Medicine 379, 2429-2437.
doi: 10.1056/NEJMoa1804492
Go, A. S., Mozaffarian, D., Roger, V. L., Benjamin, E. J., Berry, J. D., Blaha, M. J., Dai, S., Ford, E. S., Fox, C. S., Franco, S., Fullerton, H. J., Gillespie, C., Hailpern, S. M., Heit, J. A., Howard, V. J., Huffman, M. D., Judd, S. E., Kissela, B. M., Kittner, S. J., Lackland, D. T., Lichtman, J. H., Lisabeth, L. D., Mackey, R. H., Magid, D. J., Marcus, G. M., Marelli, A., Matchar, D. B., McGuire, D. K., Mohler, E. R., Moy, C. S., Mussolino, M. E., Neumar, R. W., Nichol, G., Pandey, D. K., Paynter, N. P., Reeves, M. J., Sorlie, P. D., Stein, J., Towfighi, A., Turan, T. N., Virani, S. S., Wong, N. D., Woo, D., Turner, M. B . and Subcommittee American Heart Association Statistics Committee and Stroke Statistics Subcommittee. ( 2014) Executive summary: heart disease and stroke statistics-2014 update: a report from the American Heart Association. Circulation 129, 399-410.
doi: 10.1161/01.cir.0000442015.53336.12
Gordon, T., Castelli, W. P., Hjortland, M. C., Kannel, W. B. and Dawber, T. R . ( 1977) High density lipoprotein as a protective factor against coronary heart disease: the framingham study. American Journal of Medicine 62, 707-714.
doi: 10.1016/0002-9343(77)90874-9
Hermans, M.P., De Bacquer, D., De Block, C., Truyers, C., Vankeirsbilck, A. and De Backer, G . ( 2014) Cardiovascular risk factors: belgian target achievement. Acta Cardiologica 69, 473-481.
doi: 10.2143/AC.69.5.3044873 pmid: 25638834
Jousilahti, P., Laatikainen, T., Peltonen, M., Borodulin, K., Männistö, S., Jula, A., Salomaa, V., Harald, K., Puska, P. and Vartiainen, E . ( 2016) Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population based observational study. British Medical Journal 352, 1-8.
Ko, D. T., Khan, A. M., Kotrri, G., Austin, P. C., Wijeysundera, H. C., Koh, M., Chu, A., Jackevicius, C. A., Lawler, P. R. and Tu, J. V . ( 2018) Eligibility, clinical outcomes, and budget impact of PCSK9 inhibitor adoption: The CANHEART PCSK9 Study. Journal of American Heart Association 7, 1-11.
Koskinas, K. C., Windecker, S., Buhayer, A., Gencer, B., Pedrazzini, G., Mueller, C., Cook, S., Muller, O., Matter, C.M., Räber, L., Heg, D., Mach, F. and Investigators, E . ( 2018) Design of the randomized, placebo-controlled evolocumab for early reduction of LDL-cholesterol levels in patients with acute coronary syndromes (EVOPACS) trial. Clinical Cardiology 41, 1513-1520.
doi: 10.1002/clc.2018.41.issue-12
Kotowski, I. K., Pertsemlidis, A., Luke, A., Cooper, R. S., Vega, G. L., Cohen, J. C., Hobbs, H. H . ( 2006) A Spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. The American Journal of Human Genetics 78, 410-422.
doi: 10.1086/500615
Lorenzatti, A. J., Eliaschewitz, F.G., Chen, Y., Lu, J., Baass, A., Monsalvo, M. L., Wang, N., Hamer, A. W. and Ge, J . ( 2019) Randomised study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: primary results of the BERSON clinical trial. Diabetes. Obesity and Metabolism 21, 1455-1463.
doi: 10.1111/dom.2019.21.issue-6
Lorenzatti, A. J., Eliaschewitz, F. G., Chen, Y., Fialkow, J., Lu, J., Baass, A., Monsalvo, M. L., Hsu, H. C., Somaratne, R. and Ge, J . ( 2018) Rationale and design of a randomized study to assess the efficacy and safety of evolocumab in patients with diabetes and dyslipidemia: The BERSON clinical trial. Clinical Cardiology 41, 1117-1122.
doi: 10.1002/clc.2018.41.issue-9
Lüscher, T. F . ( 2018) Lipids and lipid lowering: current management with statins and PCSK9 inhibitors. European Heart Journal 39, 1117-1120.
doi: 10.1093/eurheartj/ehy187
Mancini, G. B., Tashakkor, A.Y., Baker, S., Bergeron, J., Fitchett, D., Frohlich, J., Genest, J., Gupta, M., Hegele, R. A., Ng, D. S., Pearson, G. J. and Pope, J . ( 2013) Diagnosis, prevention, and management of statin adverse effects and intolerance: canadian working group consensus update. Canadian Journal of Cardiology 29, 1553-1568.
doi: 10.1016/j.cjca.2013.09.023
McKenney, J. M., Koren, M. J., Kereiakes, D. J., Hanotin, C., Ferrand, A. C. and Stein, E. A . ( 2012) Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. Journal of the American College of Cardiology 59, 2344-2353.
doi: 10.1016/j.jacc.2012.03.007
McKinney, J. S. and Kostis, W. J . ( 2012) Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials. Stroke 43, 2149-2156.
doi: 10.1161/STROKEAHA.112.655894
Melendez, Q. M., Krishnaji, S. T., Wooten, C. J. and Lopez, D . ( 2017) Hypercholesterolemia: the role of PCSK9. Archives of Biochemistry and Biophysics 625- 626, 39-53.
doi: 10.1016/j.abb.2017.06.001 pmid: 28587771
Nasir, K. ( 2018) Just price for PCSK9 inhibitors: no less, no more. Journal of American Heart Association 7, 1-3.
Olson, R. E . ( 1998) Discovery of the lipoproteins, their role in fat transport and their significance as risk factors. Journal of Nutrition 128, 439S-443S.
doi: 10.1093/jn/128.2.439S
Ott, B. R., Daiello, L. A., Dahabreh, I. J., Springate, B. A., Bixby, K., Murali, M. and Trikalinos, T. A . ( 2015) Do statins impair cognition? a systematic review and meta-analysis of randomized controlled trials. Journal of General Internal Medicine 30, 348358.
Packard, C. J . ( 2018) LDL cholesterol: how low to go? Trends in Cardiovascular Medicine 28, 348-354.
doi: 10.1016/j.tcm.2017.12.011
Pitts, R. N. and Eckel, R. H . ( 2014) The emerging role of PCSK9 inhibitors in preventive cardiology. European Cardiology 9, 65-70.
doi: 10.15420/ecr.2014.9.2.65
Ridker, P. M., Amarenco, P., Brunell, R., Glynn, R. J., Jukema, J .W., Kastelein, J. J., Koenig, W., Nissen, S., Revkin, J., Santos, R. D., Schwartz, P. F., Yunis, C., Tardif, J. C . and Investigators, Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Investigators. ( 2016) Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: rationale and design of the studies of PCSK9 inhibition and the reduction of vascular events (SPIRE) lipid lowering and SPIRE cardiovascular outcomes trials. American Heart Journal 178, 135-144.
doi: 10.1016/j.ahj.2016.05.010
Ridker, P. M., Revkin, J., Amarenco, P., Brunell, R., Curto, M., Civeira, F., Flather, M., Glynn, R. J., Gregoire, J., Jukema, J. W., Karpov, Y., Kastelein, J. J. P., Koenig, W., Lorenzatti, A., Manga, P., Masiukiewicz, U., Miller, M., Mosterd, A., Murin, J., Nicolau, J. C., Nissen, S., Ponikowski, P., Santos, R. D., Schwartz, P. F., Soran, H., White, H., Wright, R. S., Vrablik, M., Yunis, C., Shear, C. L., Tardif, J. C. and Investigators, S.C.O . ( 2017) Cardiovascular efficacy and safety of bococizumab in high-risk patients. New England Journal of Medicine 376, 1527-1539.
doi: 10.1056/NEJMoa1701488
Roth, G. A., Johnson, C. O., Abate, K. H., Abd-Allah, F., Ahmed, M., Alam, K., Alam, T., Alvis-Guzman, N., Ansari, H., Ärnlöv, J., Atey, T. M., Awasthi, A., Awoke, T., Barac, A., Bärnighausen, T., Bedi, N., Bennett, D., Bensenor, I., Biadgilign, S., CastañedaOrjuela, C., Catalá-López, F., Davletov, K., Dharmaratne, S., Ding, E. L., Dubey, M., Faraon, E. J. A., Farid, T., Farvid, M. S., Feigin, V., Fernandes, J., Frostad, J., Gebru, A., Geleijnse, J. M., Gona, P. N., Griswold, M., Hailu, G. B., Hankey, G. J., Hassen, H. Y., Havmoeller, R., Hay, S., Heckbert, S. R., Irvine, C. M. S., James, S. L., Jara, D., Kasaeian, A., Khan, A. R., Khera, S., Khoja, A. T., Khubchandani, J., Kim, D., Kolte, D., Lal, D., Larsson, A., Linn, S., Lotufo, P. A., Magdy Abd El Razek,, H., Mazidi, M., Meier, T., Mendoza, W., Mensah, G. A., Meretoja, A., Mezgebe, H. B., Mirrakhimov, E., Mohammed, S., Moran, A. E., Nguyen, G., Nguyen, M., Ong, K. L., Owolabi, M., Pletcher, M., Pourmalek, F., Purcell, C. A., Qorbani, M., Rahman, M., Rai, R.K., Ram, U., Reitsma, M.B., Renzaho, A.M.N., RiosBlancas, M.J., Safiri, S., Salomon, J.A., Sartorius, B., Sepanlou, S.G., Shaikh, M.A., Silva, D., Stranges, S., Tabarés-Seisdedos, R., Tadele Atnafu, N., Thakur, J. S., Topor-Madry, R., Truelsen, T., Tuzcu, E. M., Tyrovolas, S., Ukwaja, K. N., Vasankari, T., Vlassov, V., Vollset, S. E., Wakayo, T., Weintraub, R., Wolfe, C ., et al. ( 2018) The burden of cardiovascular diseases among US states, 1990-2016. Journal of the American Medical Association Cardiology 3, 375-389.
Sabatine, M. S., Leiter, L. A., Wiviott, S. D., Giugliano, R. P., Deedwania, P., De Ferrari, G. M., Murphy, S. A., Kuder, J. F., Gouni-Berthold, I., Lewis, B. S., Handelsman, Y., Pineda, A. L., Honarpour, N., Keech, A. C., Sever, P. S. and Pedersen, T. R . ( 2017) Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. The Lancet Diabetes & Endocrinology 5, 941-950.
doi: 10.1016/S2213-8587(17)30313-3 pmid: 28927706
Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Quintero, K., Roe, M. T., Sasiela, W. J., Tamby, J. F., Tricoci, P., White, H. D., Zeiher, A. M . and ODYSSEY OUTCOMES Committees and Investigators. ( 2018) Alirocumab and cardiovascular outcomes after acute coronary syndrome. New England Journal of Medicine 379, 2097-2107.
doi: 10.1056/NEJMoa1801174
Stein, E. A., Gipe, D., Bergeron, J., Gaudet, D., Weiss, R., Dufour, R., Wu, R. and Pordy, R . ( 2012a) Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 380, 29-36.
doi: 10.1016/S0140-6736(12)60771-5
Stein, E. A., Mellis, S., Yancopoulos, G. D., Stahl, N., Logan, D., Smith, W. B., Lisbon, E., Gutierrez, M., Webb, C., Wu, R., Du, Y., Kranz, T., Gasparino, E. and Swergold, G. D . ( 2012b) Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. New England Journal of Medicine 366, 1108-1118.
doi: 10.1056/NEJMoa1105803
Unal, B., Critchley, J. A. and Capewell, S. ( 2004) Explaining the decline in coronary heart disease mortality in England and Wales between 1981 and 2000. Circulation 109, 1101-1107.
doi: 10.1161/01.CIR.0000118498.35499.B2
Waters, D. D., Hsue, P. Y. and Bangalore, S. ( 2016) PCSK9 Inhibitors for Statin Intolerance? Journal of the American Medical Association 315, 1571-1572.
doi: 10.1001/jama.2016.3670
[1] Michele Provenzano, Giuseppe Coppolino, Teresa Faga, Carlo Garofalo, Raffaele Serra, Michele Andreucci. Epidemiology of cardiovascular risk in chronic kidney disease patients: the real silent killer[J]. Reviews in Cardiovascular Medicine, 2019, 20(4): 209-220.
[2] Shanna J. Hardin, Mahavir Singh, Wintana Eyob, Jack C. Molnar, Rubens P. Homme, Akash K. George, Suresh C. Tyagi. Diet-induced chronic syndrome, metabolically transformed trimethylamine-N-oxide, and the cardiovascular functions[J]. Reviews in Cardiovascular Medicine, 2019, 20(3): 121-128.
[3] Wenyan Jiang, Mei Wang. New insights into the immunomodulatory role of exosomes in cardiovascular disease[J]. Reviews in Cardiovascular Medicine, 2019, 20(3): 153-160.
[4] Jennifer G. Robinson, Karol E. Watson. Identifying Patients for Nonstatin Therapy[J]. Reviews in Cardiovascular Medicine, 2018, 19(S1): 1-8.
[5] Alan S. Brown, Karol E. Watson. Statin Intolerance[J]. Reviews in Cardiovascular Medicine, 2018, 19(S1): 9-19.
[6] Jennifer G. Robinson, Karol E. Watson. Can We Cure Atherosclerosis?[J]. Reviews in Cardiovascular Medicine, 2018, 19(S1): 20-24.
[7] Seth J. Baum, Alan S. Brown. Familial Hypercholesterolemia: Although Identification Advances, Appreciation and Treatment Lag[J]. Reviews in Cardiovascular Medicine, 2018, 19(S1): 25-30.
[8] Eli M. Roth, Michael H. Davidson. PCSK9 Inhibitors: Mechanism of Action, Efficacy, and Safety[J]. Reviews in Cardiovascular Medicine, 2018, 19(S1): 31-46.
[9] Davide Bolignano, Anna Pisano, Graziella D’Arrigo. Pulmonary hypertension: a neglected risk condition in renal patients?[J]. Reviews in Cardiovascular Medicine, 2018, 19(4): 117-121.
[10] Peter A. McCullough, Aaron Y. Kluger, Kristen M. Tecson, Clay M. Barbin, Andy Y. Lee, Edgar V. Lerma, Zachary P. Rosol, Sivan L. Kluger, Janani Rangaswami. Inhibition of the Sodium–Proton Antiporter (Exchanger) is a Plausible Mechanism of Potential Benefit and Harm for Drugs Designed to Block Sodium Glucose Co-transporter 2[J]. Reviews in Cardiovascular Medicine, 2018, 19(2): 51-63.
[11] Alberto Palazzuoli, Helen Hashemi, Lauren C. Jameson, Peter A. McCullough. Hyperuricemia and Cardiovascular Disease[J]. Reviews in Cardiovascular Medicine, 2017, 18(4): 134-145.
[12] Claudio Ronco, Federico Ronco, Peter A. McCullough. A Call to Action to Develop Integrated Curricula in Cardiorenal Medicine[J]. Reviews in Cardiovascular Medicine, 2017, 18(3): 93-99.
[13] Jane I. Won, Jun Zhang, Kristen M. Tecson , Peter A. McCullough. Balancing Low-density Lipoprotein Cholesterol Reduction and Hepatotoxicity With Lomitapide Mesylate and Mipomersen in Patients With Homozygous Familial Hypercholesterolemia[J]. Reviews in Cardiovascular Medicine, 2017, 18(1): 21-28.
[14] Seth J. Baum, Daniel Soffe, P. Barton Duell. Emerging Treatments for Heterozygous and Homozygous Familial Hypercholesterolemia[J]. Reviews in Cardiovascular Medicine, 2016, 17(1-2): 16-27.
[15] Boback Ziaeian, John Dinkler, Karol Watson. Implementation of the 2013 American College of Cardiology/American Heart Association Blood Cholesterol Guideline Including Data From the Improved Reduction of Outcomes: Vytorin Efficacy International Trial[J]. Reviews in Cardiovascular Medicine, 2015, 16(2): 125-130.
No Suggested Reading articles found!