This secondary exploratory analysis evaluates the association between baseline low-density lipoprotein cholesterol and the percentage low-density lipoprotein cholesterol reduction with a statin, ezetemibe, and a PCSK9 inhibitor using data from 3 randomized clinical trials
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.
Introduction
Low-density lipoprotein cholesterol (LDL-C) is an important modifiable risk factor for atherosclerotic cardiovascular disease. Statins remain the cornerstone of LDL-C–lowering therapy, with ezetimibe and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors indicated to achieve further cardiovascular risk reduction in selected patients.1,2,3,4 The clinical benefit of LDL-C lowering depends on the magnitude of LDL-C reduction regardless of which agent is used.5,6
With more recent data showing a monotonic relationship between LDL-C and cardiovascular risk reduction that extends to LDL-C values below 38.61 mg/dL (to convert to millimoles per liter, multiply by 0.0259),7 guidelines now call for increasingly lower LDL-C targets.8 As a consequence, further LDL-C–lowering therapy may be added for individuals with relatively lower baseline LDL-C levels. Therefore, we sought to quantify the association between baseline LDL-C levels and the magnitude of LDL-C lowering with a statin, ezetimibe, and a PCSK9 inhibitor.
Methods
Data from 3 randomized, double-blind, placebo-controlled trials of lipid lowering were used. The Aggrastat to Zocor–Thrombolysis in Myocardial Infarction 21 trial (A to Z–TIMI 21; NCT00251576)9 randomized 4497 patients with an acute coronary syndrome 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. Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT; NCT00202878)2 randomized 18 144 patients stabilized after an acute coronary syndrome to ezetimibe, 10 mg, daily plus simvastatin, 40 mg, daily vs placebo plus simvastatin, 40 mg, daily. The Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk trial (FOURIER; NCT01764633)3 randomized 27 564 patients with clinically evident atherosclerotic cardiovascular disease receiving an optimized statin therapy (preferably a high-intensity statin but at least atorvastatin, 20 mg, daily or its equivalent) to evolocumab, 140 mg, every 2 weeks or 420 mg monthly vs matching placebo. All trials were approved by all relevant institutional review boards, and written informed consent was obtained from all participants.
For these analyses of LDL-C lowering, the study populations were restricted to patients with LDL-C values at baseline and at follow-up and who were taking study drug through that period. For A to Z–TIMI 21 and for IMPROVE-IT, the analyses were also restricted to patients who were statin-naive (no long-term statin therapy for the past 4 weeks). The outcome of interest for this investigation was the relative reduction in LDL-C level while receiving therapy, which was measured at 1 month in A to Z–TIMI 21 and IMPROVE-IT and at 3 months in FOURIER. Percentage LDL-C reduction was calculated as follows. First, the achieved LDL-C measurements as a function of baseline LDL-C levels were fitted using a generalized linear regression model to generate least square means for each treatment arm at each baseline LDL-C value. The percentage LDL-C reduction corresponding to each baseline LDL-C value was then estimated. The lower and upper confidence limits were estimated using asymptotic Cauchy distribution of the percentage LDL-C reduction with the variance derived using Taylor series expansion. All analyses were performed using SAS version 9.4 (SAS Institute). Two-sided P values less than .05 were considered significant. Analyses took place from April to October 2020.
Results
There were 3187 patients from A to Z–TIMI 21, 10 680 patients from IMPROVE-IT, and 25 847 patients from FOURIER included in these analyses. The data for the study populations are shown in the Table. In brief, the median (interquartile range) baseline LDL-C level was 112.0 (95.0-131.0) mg/dL in A to Z–TIMI 21, 83.0 (67.0-100.0) mg/dL in IMPROVE-IT, and 91.5 (79.5-108.5) mg/dL in FOURIER. In FOURIER, 17 948 (69.4%) were taking a high-intensity statin, 7844 (30.3%) were taking a moderate-intensity statin, and 1365 (5.3%) were taking ezetimibe.
Table. Study Populations.
| Characteristic | A to Z–TIMI 21 | IMPROVE-IT | FOURIER |
|---|---|---|---|
| No. of participants | 3187 | 10 680 | 25 847 |
| Age, median (IQR), y | 61.0 (52.0-69.0) | 61.7 (55.6-69.5) | 63.0 (56.0-69.0) |
| Female, No. (%) | 752 (23.6) | 2484 (23.3) | 6231 (24.1) |
| White, No. (%) | 2748 (86.3) | 8911 (83.4) | 22 013 (85.2) |
| BMI, median (IQR) | 27.0 (24.6-30.1) | 27.4 (24.7-30.8) | 28.8 (25.9-32.1) |
| Diabetes, No. (%) | 647 (20.3) | 2321 (21.7) | 9400 (36.4) |
| Baseline LDL-C level, median (IQR), mg/dL | 112.0 (95.0-131.0) | 83.0 (67.0-100.0) | 91.5 (79.5-108.5) |
| Triglyceride level, median (IQR), mg/dL | 151.0 (117.0-201.0) | 125.0 (97.0-164.0) | 133.0 (100.0-181.5) |
| Taking statin at baseline, No. (%) | 0 (0) | 7706 (72.2)a | 25 839 (100.0) |
| Taking ezetimibe at baseline, No. (%) | 0 (0) | 103 (1.0) | 1365 (5.3) |
| Achieved LDL-C level in placebo arm, median (IQR), mg/dL | 124.0 (105.0-145.0) | 62.0 (51.0-76.0) | 88.0 (75.0-106.0) |
| Achieved LDL-C level in treatment arm, median (IQR), mg/dL | 67.0 (53.0-82.0) | 45.0 (36.0-57.0) | 28.0 (19.0-43.0) |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol.
SI conversion factor: To convert LDL-C to millimoles per liter, multiply by 0.0259; triglycerides to millimoles per liter, multiply by 0.0113.
Not long-term therapy, but started in setting of qualifiying acute coronary syndrome.
The percentage LDL-C reductions in the overall study populations were 45.2% (95% CI, 44.2%-45.3%) with simvastatin, 40 mg, daily in A to Z–TIMI 21, 25.8% (95% CI, 22.3%-25.8%) with ezetimibe in IMPROVE-IT, and 62.3% (95% CI, 61.7%-62.9%) with evolocumab in FOURIER. The percentage of LDL-C reduction as a function of baseline LDL-C level is shown for simvastatin, ezetimibe, and evolocumab in Figure 1. There was a higher percentage reduction in LDL-C level 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). Achieved LDL-C level in the individual treatment arms for the 3 studies is shown in Figure 2. The pattern seen with evolocumab was consistent in patients taking high-intensity statin and in patients taking moderate-intensity (eFigure 1 in the Supplement). We observed a similar effect with apolipoprotein B (eFigure 2 in the Supplement).
Figure 1. Percentage of Low-Density Lipoprotein Cholesterol (LDL-C) Lowering as a Function of Baseline LDL-C.
Figure 2. Achieved Low-Density Lipoprotein Cholesterol (LDL-C) as a Function of Baseline LDL-C.
LS indicates least squares.
Discussion
We evaluated the association of baseline LDL-C with the percentage LDL-C lowering with the 3 major classes of LDL-C–lowering therapy: statins, ezetimibe, and PCSK9 inhibition. Rather than observe any attenuation, the percentage LDL-C lowering was greater in patients starting with lower baseline LDL-C, particularly for PCSK9 inhibition.
PCSK9 is a circulating protein produced by the liver that binds LDL receptor (LDLR) at the hepatocyte surface and targets it for lysosomal degradation.10,11 PCSK9 inhibition leads to less degradation of LDLR and hence greater LDL-C clearance from the circulation. Both LDLR and PCSK9 are regulated transcriptionally by sterol regulatory element-binding protein-2. In healthy individuals, sterol regulatory element-binding protein-2 responds to low intracellular cholesterol levels by increasing transcription of LDLR and PCSK9 production. It may be that in such individuals, PCSK9 inhibition is more effective in lowering LDL-C levels.
The clinical benefit of LDL-C lowering has been shown to be proportional to the absolute LDL-C reduction. Although absolute LDL-C lowering will naturally be less in patients starting with lower vs higher baseline LDL-C, these finding illustrate that it will be somewhat greater than anticipated for statins and PCKS9 inhibitors had one assumed a constant percentage reduction. These findings may help explain why the clinical efficacy of the lipid-lowering therapy in these 3 trials was not attenuated in patients starting with lower baseline LDL-C levels.2,3,9 To put the data in perspective, the additional 6.6% greater LDL-C lowering with evolocumab is what one expects for doubling a statin dose. Such data are encouraging for reaching the progressively lower LDL-C targets that are being set,8 particularly for those defined in the guidelines as being at very high risk.1,12
Limitations
There are limitations to this study. First, patients in A to Z–TIMI 219 and IMPROVE-IT2 had recently had an acute coronary syndrome, which can cause small alterations in lipid values.13 However, such alterations should apply equally to both the experimental and control arms in those trials and would not be expected to change the slope of the curve. Second, although the 3 studies are randomized clinical trials of lipid-lowering therapy vs placebo, the comparisons between patients with different baseline LDL-C levels are exploratory and observational in nature and cannot prove causality, and there was heterogeneity among the 3 studies with respect to the timing of follow-up. However, the timing of assessment reflects the time to steady state lipid levels after adding the medications studied in the respective trials. Third, our findings should be replicated in other studies with PCSK9 inhibitors to determine whether this observation represents a class effect. Lastly further biochemical investigation is needed to confirm our postulated mechanism for these findings.
Conclusions
The percentage LDL-C reduction with statins, ezetimibe, and PCSK9 inhibition is not attenuated in patients starting with lower baseline LDL-C levels, and in fact is noticeably greater for PCSK9 inhibition. These data are encouraging for reaching the progressively lower LDL-C targets that are being set.
eFigure 1. Relationship of percentage LDL-C lowering as a function of baseline LDL-C stratified by moderate vs high intensity statin in FOURIER
eFigure 2. Relationship of percentage ApoB lowering as a function of baseline ApoB in FOURIER
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eFigure 1. Relationship of percentage LDL-C lowering as a function of baseline LDL-C stratified by moderate vs high intensity statin in FOURIER
eFigure 2. Relationship of percentage ApoB lowering as a function of baseline ApoB in FOURIER