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Brief Report
November 13, 2020

Association of Baseline Low-Density Lipoprotein Cholesterol and Percentage Low-Density Lipoprotein Cholesterol Reduction With Statins, Ezetimibe, and PCSK9 Inhibition

Author Affiliations
  • 1Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 2TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 3Cardiology Division, University of Texas Southwestern Medical Center, Dallas
  • 4Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 5Deputy Editor, JAMA Cardiology
JAMA Cardiol. Published online November 13, 2020. doi:10.1001/jamacardio.2020.6184
Key Points

Question  Is the percentage low-density lipoprotein cholesterol (LDL-C) lowering with different pharmacotherapies attenuated in patients starting with lower baseline LDL-C levels?

Findings  In this study of 39 714 patients from 3 randomized clinical trials, there was a higher percentage reduction in LDL-C with evolocumab in patients with lower baseline LDL-C levels, a more modest difference for simvastatin, and no clinically important difference with ezetimibe.

Meaning  These data are encouraging for the use of intensive LDL-C–lowering therapies even in patients starting with relatively low LDL-C levels.

Abstract

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, 10 680 patients from IMPROVE-IT, and 25 847 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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