TY - JOUR
T1 - A meta-analysis of medications directed against PCSK9 in familial hypercholesterolemia
AU - Brandts, Julia
AU - Dharmayat, Kanika I.
AU - Vallejo-Vaz, Antonio J.
AU - Azar Sharabiani, Mansour Taghavi
AU - Jones, Rebecca
AU - Kastelein, John J. P.
AU - Raal, Frederick J.
AU - Ray, Kausik K.
N1 - Funding Information: This report is independent research supported by the National Institute for Health Research Applied Research Collaboration Northwest London (KD, KKR ). The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. Funding Information: KKR reports personal fees for consultancy from AbbVie, Amgen, AstraZeneca, Sanofi, Regeneron, Merck Sharp & Dohme, Pfizer, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda, Kowa, Algorithm, Cipla, Cerenis, Dr. Reddys, Lilly, Zuellig Pharma, Bayer, Daiichi Sankyo, The Medicines Company, and Esperion, as well as research grant support from Pfizer, Amgen, Sanofi, Regeneron, and Merck Sharp & Dohme. JB reports participation in research grants from AstraZeneca. AJVV reports honoraria for lectures from Amgen, Mylan, and Akcea; personal fees for consultancy from Bayer; and participation in research grants from Amgen, Sanofi, MSD, Pfizer, Regeneron and Daiichi Sankyo to Imperial College London/European Atherosclerosis Society; all outside the submitted work. JK reports personal fees for consultancy from AstraZeneca, CSL Behring, Daiichi-Sankyo, Esperion, Genentech, Menarini, Novartis, Novo-Nordisk, Pfizer, and Regeneron. FJR has received research grants, honoraria, or consulting fees for professional input and/or delivered lectures from Sanofi, Regeneron, Amgen, Novartis and The Medicines Company. The other authors report no conflicts.This report is independent research supported by the National Institute for Health Research Applied Research Collaboration Northwest London (KD, KKR). The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. Funding Information: KKR reports personal fees for consultancy from AbbVie , Amgen , AstraZeneca , Sanofi , Regeneron , Merck Sharp & Dohme , Pfizer , Resverlogix, Akcea, Boehringer Ingelheim , Novo Nordisk , Takeda , Kowa, Algorithm, Cipla, Cerenis, Dr. Reddys, Lilly , Zuellig Pharma, Bayer , Daiichi Sankyo, The Medicines Company , and Esperion, as well as research grant support from Pfizer , Amgen , Sanofi , Regeneron , and Merck Sharp & Dohme . JB reports participation in research grants from AstraZeneca . AJVV reports honoraria for lectures from Amgen , Mylan , and Akcea; personal fees for consultancy from Bayer; and participation in research grants from Amgen , Sanofi , MSD , Pfizer , Regeneron and Daiichi Sankyo to Imperial College London/European Atherosclerosis Society; all outside the submitted work. JK reports personal fees for consultancy from AstraZeneca , CSL Behring , Daiichi-Sankyo , Esperion, Genentech , Menarini, Novartis , Novo-Nordisk, Pfizer , and Regeneron . FJR has received research grants, honoraria, or consulting fees for professional input and/or delivered lectures from Sanofi , Regeneron , Amgen , Novartis and The Medicines Company . The other authors report no conflicts. Publisher Copyright: © 2021 Elsevier B.V.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - Background and aims: Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant. Methods: We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity. Results: Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (QM = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (QM = 8.3, df = 4, p = 0.08). Conclusions: Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants.
AB - Background and aims: Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant. Methods: We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity. Results: Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (QM = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (QM = 8.3, df = 4, p = 0.08). Conclusions: Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants.
KW - Familial hypercholesterolemia
KW - Genotype
KW - LDL-Cholesterol
KW - Meta-analysis
KW - PCSK9 lowering medication
UR - http://www.scopus.com/inward/record.url?scp=85104591068&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.atherosclerosis.2021.03.042
DO - https://doi.org/10.1016/j.atherosclerosis.2021.03.042
M3 - Article
C2 - 33901739
VL - 325
SP - 46
EP - 56
JO - Atherosclerosis
JF - Atherosclerosis
SN - 0021-9150
ER -