Early effects of PCSK9 inhibitors: evolocumab versus alirocumab

1. Description of participants

This was a single-center, retrospective study conducted at a tertiary hospital. We reviewed patients who were diagnosed with ACS, including unstable angina, non-ST-segment-elevation myocardial infarction (NSTEMI), and ST-segment-elevation myocardial infarction (STEMI), between January 2021 and December 2023 at Kosin University Gospel Hospital. All eligible patients received percutaneous coronary intervention (PCI) and were administered one of two types of PCSK9 inhibitor (evolocumab or alirocumab) during hospitalization if their baseline LDL-C level was high (>70 mg/dL). In the evolocumab group, patients were administered a fixed dose of 140 mg, while the alirocumab group received a dose of either 75 or 150 mg according to the treating physician's clinical decision.

2. Serial measurement of LDL-C

In all patients administered a PCSK9 inhibitor, venous sampling was performed to measure LDL-C levels at baseline, in the acute phase, and in the subacute phase. The acute phase was defined as the period 5–14 days following PCSK9 inhibitor administration, while the subacute phase was defined as 15–50 days after treatment. If a patient's follow-up LDL-C level decreased to <55 mg/dL even once during the study period, we considered the event a target achievement.

3. Statistical analyses

Statistical analyses were performed using the IBM SPSS ver. 25 (IBM Corp.). The baseline characteristics of the evolocumab and alirocumab groups were compared using the chi-square test. Serial LDL-C levels were compared between the two groups using the Mann-Whitney U test. p<0.05 was considered indicative of statistical significance in all analyses.

1. Lipid-lowering effect of PCSK9 inhibitors

Our study has three major findings. First, PCSK9 inhibitors lower LDL-C rapidly; we recorded reduction rates of 83.44% in the evolocumab group and 75.84% in the alirocumab group during the acute phase (5–14 days after) and 60.41% in the evolocumab group and 58.51% in the alirocumab group during the subacute phase (15–50 days after). Second, there was no statistical difference between the two types of PCSK9 inhibitors in terms of their lipid-lowering effects based on the reduction rate of follow-up LDL-C level. Interestingly, there were statistical differences in follow-up LDL-C level in the acute phase but not in the subacute phase. This statistical difference is likely caused by the difference in dosage of PCSK9 inhibitor, either 75 mg/mL or 150 mg/mL, in the alirocumab group. Third, the study population of each group showed a specific pattern of serial changes in LDL-C level, with a rapid drop during the acute phase followed by a slight rebound in the subacute phase. This slight rebound seems to be caused by the washout of PCSK9 inhibitors and has no significant clinical implications.

2. Acute effect of PCSK9 inhibitors in ACS

Several randomized clinical trials have tried to establish the benefits of early initiation of PCSK9 inhibitor therapy. The EPIC-STEMI (Effects of Acute, Rapid Lowering of Low-Density Lipoprotein Cholesterol with Alirocumab in Patients with ST-Segment Elevation Myocardial Infarction Undergoing Primary PCI) study was a randomized, double-blind, parallel-group clinical trial that investigated the early effects of alirocumab in patients who had undergone PCI due to STEMI. The experimental group was treated with 150 mg of alirocumab both prior to PCI and 2 or 4 weeks after, and the control group was administered a placebo at the same times. At a median of 45 days of follow-up, the alirocumab group experienced a 22.3% greater LDL-C reduction than the placebo group. However, there was no evidence in the alirocumab group concerning short-term outcomes, including infarct size as measured by the creatine kinase-MB area under the receiver operating characteristic curve and long-term outcomes like major cardiovascular events [4].

In 2022, a retrospective, observational study to establish the acute effects of evolocumab was published. Patients were administered 140 mg of evolocumab within 24 hours after PCI, and blood tests including total cholesterol, triglycerides, high-density lipoprotein cholesterol, LDL-C, apolipoprotein(a), apolipoprotein B-100, phospholipid, lipoprotein(a), and high-sensitivity C-reactive protein were conducted before administration of evolocumab and 2 weeks later. Significant decreases in the values of all the biomarkers other than high-density lipoprotein cholesterol, apolipoprotein(a), and highly sensitive C-reactive protein were documented at 2 weeks, with an especially dramatic reduction of approximately 58% in LDL-C level. However, there were some limitations to that study, including lack of information about clinical outcomes of the study population, who were represented only by lipoprotein values [5].

There are ongoing clinical trials investigating the early effects of evolocumab. The EVOLVE-MI (EVOLocumab Administered Very Early to Reduce the Risk of Cardiovascular Events in Patients Hospitalized with Acute Myocardial Infarction) is an open-label, randomized clinical trial aiming to establish the early- and long-term outcomes of PCSK9 inhibitor therapy (evolocumab). The participants consist of about 4,000 patients with NSTEMI or STEMI from three countries administered 140 mg of evolocumab within 10 days of index myocardial infarction (MI) and every 2 weeks thereafter. The primary endpoints were MI, ischemic stroke, any revascularization event, and death. Many physicians are eagerly awaiting the research results of this trial.

Similar to other studies, our study also reported an improved acute effect of PCSK9 inhibitors in ACS, with a rapid drop in LDL-C 5–15 days after administration. There are some differences compared to prior studies. First, there were no comparisons with placebo in our study. Second, we only administered a single dose of PCSK9 inhibitor. With a single dose administration, we were able to access the actual LDL lowering effect of PCSK9 inhibitors, compare the LDL reduction effects of the two drugs, and determine how long the effect of the PCSK9 inhibitor lasts after a single dose.

3. Comparison between evolocumab and alirocumab

In 2021, a systemic review and network meta-analysis was published indirectly comparing the efficacy and safety of two types of PCSK9 inhibitors, evolocumab and alirocumab. Thirty studies and 59,026 patients—of whom 13,607 received alirocumab and 17,931 received evolocumab—were included in the systematic review. Alirocumab and evolocumab demonstrated similar lipid-lowering effects, and there was no significant difference in clinical endpoints, including cardiovascular death, MI, stroke, and coronary revascularization. There was also no significant difference in safety endpoints, including systemic allergic reaction, ophthalmologic events, and new-onset diabetes mellitus. However, there are no available data that directly compare these two different types of PCSK9 inhibitors; most existing clinical trials have focused on the lipid-lowering effect and long-term cardiovascular risk reduction rather than the immediate effects of PCSK9 inhibitors [6].

As for the lipid-lowering effect represented by LDL-C level, the results of our study showed no difference compared to those of the systemic review mentioned above. Specifically, there were no differences in the rate and trend of the decline in LDL-C, which rapidly decreased in the acute phase and slightly rebounded in the subacute phase, between the evolocumab and alirocumab groups. There was also no attempt to compare the side effects of the drugs, as such effects were rarely recorded.

4. Is earlier better?

One of the main mechanisms of plaque generation is accumulation of LDL-C. Retention of LDL particles over time causes them to accumulate in arterial walls, supporting atherosclerotic plaque progression. Both the concentration of LDL-C and the total duration of exposure contribute to the atherosclerotic plaque burden. As the cumulative exposure to LDL-C continues, these atherosclerotic plaques grow larger, and their disruption can lead to an acute obstruction of blood flow by a large thrombus. An average of 5,000 mg-years or 125 mmol-years of cumulative exposure is necessary to develop an atherosclerotic plaque burden large enough to increase the risk of MI. When the cumulative LDL exposure exceeds the threshold, the incidence of MI doubles with every decade of exposure to the same LDL-C level. This can also explain the low risk of a cardiovascular event during young adulthood and middle age [7]. We hypothesized that maintaining a lower LDL-C level after experiencing ACS can be an effective means to reduce future cardiovascular event rates. Based on this, early administration of a PCSK9 inhibitor was performed in patients with high baseline LDL-C levels who were diagnosed with ACS. This retrospective study was designed to elucidate the exact lipid-lowering effect of PCSK9 inhibitors over time and identified a significant decrease in LDL-C level in the early phase followed by a slight rebound in the delayed phase.

5. Limitations

There are a few limitations in this study. First, it concentrated on LDL-C levels and not on clinical outcomes like cardiovascular death, ischemic stroke, MI, or target vessel failure. Additional long-term follow-up of the study population with close observation and a focus on clinical outcomes is warranted. Second, considering the relationship between inflammation and atherosclerotic plaque, serial follow-up of other biomarkers like C-reactive protein that can be surrogates for both inflammation and plaque burden could also help reveal the effects of PCSK9 inhibitors, but no routine follow-up of C-reactive protein was completed in this study [8]. Third, the dosage of PCSK9 inhibitor in the alirocumab group was totally dependent on the treating physician’s clinical decision, meaning it was subjective and could have influenced the results of the study. Finally, because this was a single-center retrospective study and early administration of PCSK9 inhibitors has been performed only since 2021, we enrolled a small study population.

6. Conclusions

Treatment with a PCSK9 inhibitor rapidly lowers LDL-C levels in the early phase after administration. We found no significant differences between two types of PCSK9 inhibitors (evolocumab and alirocumab), and patient LDL-C levels showed a similar pattern of a rapid drop in the acute phase and a slight rebound in the subacute phase. Further studies that demonstrate the correlation between improved clinical outcomes of ACS patients and earlier initiation of PCSK9 inhibitor therapy would help improve the long-term prognosis of these individuals.