TY - JOUR
T1 - Association of Baseline Low-Density Lipoprotein Cholesterol and Percentage Low-Density Lipoprotein Cholesterol Reduction with Statins, Ezetimibe, and PCSK9 Inhibition
AU - Marcusa, Daniel P.
AU - Giugliano, Robert P.
AU - Park, Jeong Gun
AU - De Lemos, James A.
AU - Cannon, Christopher P.
AU - Sabatine, Marc S.
N1 - Funding Information:
reports grants from Amgen Research and Anthos Therapeutics to the Brigham And Women’s Hospital during the conduct of the study; personal fees from Amgen, Daiichi Sankyo, Merck, Pfizer, and Servier for continuing medical education lectures and consulting outside the submitted work; and personal fees from American College of Cardiology, Amgen, Amaarin, AstraZeneca, Bristol Myers Squibb, CryoLife, CVS Caremark, Daiichi Sankyo, Esperion, Gilead, GlaxoSmithKline, SAJA Pharmaceuticals, Samsung, and Servier outside the submitted work. Dr Park reports grants from GlaxoSmithKline, Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, Machines Company, and Zora Biosciences during the conduct of the study. Dr de Lemos reports personal fees from Amgen during the conduct of the study and from Regeneron Pharmaceuticals and Esperion outside the submitted work. Dr Cannon reports grants from Merck, Amgen, Sanofi, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Merck, and Pfizer during the conduct of the study; personal fees from Merck, Amgen, Sanofi, Bristol Myers Squibb, Aegerion, Innovent, Pfizer, and Alnylam during the conduct of the study; grants from Boehringer Ingelheim and Janssen outside the submitted work; and personal fees from Boehringer Ingelheim, Janssen, Amarin, Applied Therapeutics, Ascendia, Corvidia, HLS Therapeutics, Kowa, Eli Lilly and Company, and Rhoshan outside the submitted work. Dr Sabatine reports research grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, and Takeda and consulting for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol Myers Squibb, CVS Caremark, DalCor, Dr. Reddy’s Laboratories, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, and Novartis. Drs Giugliano, Park, and Sabatine are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Roche, The Medicines Company, and Zora Biosciences. No other disclosures were reported.
Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - Importance: Low-density lipoprotein cholesterol (LDL-C) is an important modifiable risk factor for atherosclerotic cardiovascular disease. It is unclear whether the percentage LDL-C lowering with pharmacotherapies differs on the basis of baseline LDL-C levels. Objective: To evaluate the association between baseline LDL-C levels and the percentage LDL-C reduction with a statin, ezetimibe, and a PCSK9 inhibitor. Design, Setting, and Participants: This secondary exploratory study analyzed data from 3 randomized placebo-controlled clinical trials (Aggrastat to Zocor-Thrombolysis in Myocardial Infarction 21 [A to Z-TIMI 21], Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT], and Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]) of lipid-lowering therapies (statin, ezetimibe, and a PCSK9 inhibitor) and included participants with atherosclerotic cardiovascular disease. Analyses took place form April to October 2020. Interventions: In A to Z-TIMI 21, 1:1 randomization to simvastatin, 40 mg, daily for 30 days followed by 80 mg daily thereafter vs placebo for 4 months followed by simvastatin, 20 mg, daily thereafter. In IMPROVE-IT, 1:1 randomization to ezetimibe, 10 mg, daily plus simvastatin, 40 mg, daily vs placebo plus simvastatin, 40 mg, daily. In FOURIER, 1:1 randomization to evolocumab, 140 mg, every 2 weeks or 420 mg monthly vs matching placebo. Main Outcomes and Measures: The percentage LDL-C reduction at either 1 month (A to Z-TIMI 21, IMPROVE-IT) or 3 months (FOURIER) as a function of baseline LDL-C level. Data were modeled using a generalized linear regression model. Results: A total of 3187 patients from A to Z-TIMI 21, 10680 patients from IMPROVE-IT, and 25847 patients from FOURIER were analyzed. There was a higher percentage reduction in LDL-C levels with evolocumab in patients with lower baseline LDL-C levels, ranging from 59.4% (95% CI, 59.1%-59.8%) in patients with a baseline LDL-C level of 130 mg/dL to 66.1% (95% CI, 65.6%-66.6%) in patients with a baseline LDL-C level of 70 mg/dL (P <.001). In contrast, across the same range of baseline LDL-C level, there was a more modest difference for simvastatin (44.6% [95% CI, 43.9%-45.2%] vs 47.8% [95% CI, 46.4%-49.2%]; P <.001) and minimal difference with ezetimibe (25.0% [95% CI, 23.3%-26.6%] vs 26.2% [95% CI, 24.2%-28.1%]; P =.007). Conclusions and Relevance: The percentage LDL-C reduction with statins, ezetimibe, and PCSK9 inhibition is not attenuated in patients starting with lower baseline LDL-C levels and is 6.6% greater for PCSK9 inhibition. These data are encouraging for the use of intensive LDL-C-lowering therapy even for patients with lower LDL-C levels..
AB - Importance: Low-density lipoprotein cholesterol (LDL-C) is an important modifiable risk factor for atherosclerotic cardiovascular disease. It is unclear whether the percentage LDL-C lowering with pharmacotherapies differs on the basis of baseline LDL-C levels. Objective: To evaluate the association between baseline LDL-C levels and the percentage LDL-C reduction with a statin, ezetimibe, and a PCSK9 inhibitor. Design, Setting, and Participants: This secondary exploratory study analyzed data from 3 randomized placebo-controlled clinical trials (Aggrastat to Zocor-Thrombolysis in Myocardial Infarction 21 [A to Z-TIMI 21], Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT], and Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]) of lipid-lowering therapies (statin, ezetimibe, and a PCSK9 inhibitor) and included participants with atherosclerotic cardiovascular disease. Analyses took place form April to October 2020. Interventions: In A to Z-TIMI 21, 1:1 randomization to simvastatin, 40 mg, daily for 30 days followed by 80 mg daily thereafter vs placebo for 4 months followed by simvastatin, 20 mg, daily thereafter. In IMPROVE-IT, 1:1 randomization to ezetimibe, 10 mg, daily plus simvastatin, 40 mg, daily vs placebo plus simvastatin, 40 mg, daily. In FOURIER, 1:1 randomization to evolocumab, 140 mg, every 2 weeks or 420 mg monthly vs matching placebo. Main Outcomes and Measures: The percentage LDL-C reduction at either 1 month (A to Z-TIMI 21, IMPROVE-IT) or 3 months (FOURIER) as a function of baseline LDL-C level. Data were modeled using a generalized linear regression model. Results: A total of 3187 patients from A to Z-TIMI 21, 10680 patients from IMPROVE-IT, and 25847 patients from FOURIER were analyzed. There was a higher percentage reduction in LDL-C levels with evolocumab in patients with lower baseline LDL-C levels, ranging from 59.4% (95% CI, 59.1%-59.8%) in patients with a baseline LDL-C level of 130 mg/dL to 66.1% (95% CI, 65.6%-66.6%) in patients with a baseline LDL-C level of 70 mg/dL (P <.001). In contrast, across the same range of baseline LDL-C level, there was a more modest difference for simvastatin (44.6% [95% CI, 43.9%-45.2%] vs 47.8% [95% CI, 46.4%-49.2%]; P <.001) and minimal difference with ezetimibe (25.0% [95% CI, 23.3%-26.6%] vs 26.2% [95% CI, 24.2%-28.1%]; P =.007). Conclusions and Relevance: The percentage LDL-C reduction with statins, ezetimibe, and PCSK9 inhibition is not attenuated in patients starting with lower baseline LDL-C levels and is 6.6% greater for PCSK9 inhibition. These data are encouraging for the use of intensive LDL-C-lowering therapy even for patients with lower LDL-C levels..
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U2 - 10.1001/jamacardio.2020.6184
DO - 10.1001/jamacardio.2020.6184
M3 - Article
C2 - 33185670
AN - SCOPUS:85096191296
VL - 6
SP - 582
EP - 586
JO - JAMA Cardiology
JF - JAMA Cardiology
SN - 2380-6583
IS - 5
ER -