Prolonged and Pronounced Low-density Lipoprotein Cholesterol Lowering: The Gift That Keeps Giving

Michael D. Shapiro, DO, MCR


Circulation. 2022;146(15):1120-1122. 

The approval and subsequent clinical implementation of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors have transformed our ability to reduce low-density lipoprotein cholesterol (LDL-C) in a safe, robust, and well-tolerated manner. It is most important that their use in patients with stable atherosclerotic cardiovascular disease (ASCVD) and in those with recent acute coronary syndromes, on top of high-intensity statin therapy, was found to improve cardiovascular outcomes.[1,2] Up until now, the median follow-up of clinical trial participants in the 2 dedicated cardiovascular outcomes trials testing PCSK9 inhibition has been relatively short. Treatment with evolocumab for a median of 2.2 years reduced the risk of the primary composite outcome of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization by 15% in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk).[1] Of note, there was an ostensibly greater cardiovascular benefit with longer exposure to the PCSK9 inhibitor. In the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab), the monoclonal PCSK9 antibody, alirocumab, reduced the risk of major adverse cardiovascular events by the same 15% as observed in FOURIER and nominally reduced mortality in patients after an acute coronary syndrome over a median of 2.8 years.[2] Moreover, there was a greater apparent benefit for those participants treated for >3 years.

To address the salient issue regarding the durability of PCSK9 inhibitor–associated benefit, the authors of the present study investigated longer-term outcomes in individuals participating in the FOURIER-OLE study (FOURIER-Open Label Extension).[3] In brief, participants who completed the FOURIER trial were eligible to receive evolocumab in 2 open-label extension studies in the United States and Europe. For the primary analyses, data were pooled across the studies. Lipid values and major adverse cardiovascular events were prospectively collected. A total of 6635 participants were enrolled in FOURIER-OLE (3355 randomly assigned to evolocumab and 3280 to placebo in the parent study). The median follow-up in FOURIER-OLE was 5 years. Maximum exposure to evolocumab in the main FOURIER study plus FOURIER-OLE was 8.4 years (median, 7.1 years). At 12 weeks in FOURIER-OLE, median LDL-C was 30 mg/dL. During the extension study, patients originally randomly assigned in the parent trial to evolocumab versus placebo sustained a 15% lower risk of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization (hazard ratio, 0.85 [95% CI, 0.75–0.96]; P=0.008), a 20% lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80 [0.68–0.93]; P=0.003), and a 23% lower risk of cardiovascular death (hazard ratio, 0.77 [0.60–0.99]; P=0.04). This latter finding concerning the reduction in cardiovascular death, although small in magnitude, is provocative given that this was not observed in the parent FOURIER trial, which was of short duration (median, 2.2 years), but was found in this study with longer follow-up. Given that major adverse cardiovascular event reduction increases with the duration of LDL-C lowering, it is conceivable that more impressive cardiovascular mortality reduction may follow suit. There was no significant difference in the incidence of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events between the 2 arms. As such, a case was made that longer-term LDL-C lowering with evolocumab was safe and well-tolerated for a median of 7.1 years and led to further improvement in cardiovascular outcomes compared with those started on evolocumab in the open-label extension study.

FOURIER-OLE included participants with the longest exposure to PCSK9 inhibitor to date and thus provides critical data that heretofore were unavailable. These results help to establish the (1) intermediate-term safety and tolerability of prolonged and pronounced LDL-C lowering, and (2) improvement in cardiovascular outcomes with longer duration of exposure to PCSK9 inhibition, in this case, evolocumab. The findings are important because they add to the growing literature that suggests that the benefits of LDL-C lowering accrue with time and that starting such therapy earlier is more effective at preventing events.[4] Moreover, the findings from FOURIER-OLE are consistent with the legacy effect noted in several statin mega-trials.[5,6] In particular, just as statins provide some degree of protection against ASCVD even after therapy is discontinued, it appears that earlier initiation of PCSK9 inhibitors provides a degree of risk mitigation that cannot be achieved when therapy is delayed. Taken together, these findings support the notion that it is LDL-C lowering, and not a specific class of lipid-lowering therapy, that drives the cardiovascular benefit. The main findings from this study are certainly biologically plausible and would be anticipated by most. However, this relatively simple and straightforward message has several nuances that are worth considering.

Without a doubt, the ability to profoundly reduce LDL-C is a major advance in the secondary prevention of ASCVD, and most national and international guidelines recommend the use of PCSK9 inhibitors in high-risk patients who have not attained adequate LDL-C reduction.[7] The data from FOURIER-OLE provide reassurance that dramatic LDL-C lowering with statins plus evolocumab is safe and effective, and produces improved cardiovascular outcomes. The data suggest that earlier initiation of evolocumab is more effective and just as safe as deferring the addition of a PCSK9 inhibitor. This begs the important clinical question as to the optimal timing of adding a PCSK9 inhibitor on top of statin therapy. The implications from FOURIER-OLE are certainly consistent with what we already know from both the observational and genetic epidemiology.[8,9] The data from the present study add to the growing evidence that targeting LDL-C to lower levels for a longer time (starting at a younger age) is likely to yield the best results. The key concept is that the long-term risk of a future ASCVD event is largely influenced by LDL-C levels early in life, and, once a significant burden of atherosclerotic plaque takes hold, residual risk is disproportionately determined by the severity and extent of atherosclerosis.

To be sure, the findings from this study represent a major advance if applied to patient care. However, we must also not miss the forest for the trees. Although the participants in this study certainly benefited from the addition of a PCSK9 inhibitor, and earlier initiation was associated with greater benefit, event rates were extraordinarily high, nonetheless. Examination of the Kaplan-Meier curves for the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization indicates that the cumulative incidence of events during the FOURIER (complete parent FOURIER population) and FOURIER-OLE study periods combined were 26.9% in those allocated to placebo-evolocumab versus 24.4% in those who received evolocumab throughout. Even when we only consider the FOURIER-OLE study period, which is essentially comparing 2 groups on the current best lipid-lowering regimen but started 2 years apart, the cumulative incidence of the primary composite end point was 17.5% in those initially randomly assigned to placebo and 15.4% in those initially randomly assigned to evolocumab in the parent trial. Although extrapolation to 10-year event rates is not possible, these individuals clearly remained at very high risk despite functionally eliminating the contribution of LDL-C to the risk factor equation. Although there was a statistically significant reduction in major adverse cardiovascular events, this decline is far from complete and woefully inadequate. Even with a median 7-year exposure to the most potent LDL-C–lowering treatments available, current strategies are only partially effective at mitigating ASCVD risk.

It is not surprising that recurrent cardiovascular event rates remain high in this patient population because residual risk is only partially modifiable once a significant burden of atherosclerosis has taken root.[10] Relatively late interventions to lower LDL-C fail to eliminate much of the risk accumulated during early exposures. So, although the results in FOURIER-OLE suggest that starting a PCSK9 inhibitor in patients with established ASCVD should take place sooner rather than later, the real message is that early interventions (primary prevention) to lower LDL-C are likely to be far more effective than later ones.[11] From this point of view, the results from FOURIER-OLE should be considered within the context of the primary prevention population as well. All patients in secondary prevention now were in primary prevention the day before their first cardiovascular event. As such, the present findings allow us to conceive that starting risk factor interventions, specifically LDL-C lowering, at a younger age would likely be a more effective approach than waiting until middle-to-older age to embark on serious risk factor modification. To that end, the real revolution in the prevention of cardiovascular disease will arrive when risk assessment and implementation of preventive interventions occur in large swaths of young to middle-aged apparently healthy individuals, at a much earlier point than today's standard of care.

Despite the enormous number of clinical trials that support the need for reducing the concentration of circulating LDL, the percentage of high and very high-risk patients who achieve adequate LDL-C lowering is small. Moreover, LDL-C goal attainment has remained low despite highly effective lipid-lowering therapies. We must not forget that much of ASCVD is preventable. The time has come for us to take primary prevention seriously. Despite major improvements in therapy, most individuals at risk for ASCVD are inadequately treated, leaving them susceptible to progression of atherosclerosis and acute cardiovascular events. The data from FOURIER-OLE provide further justification for the intensification of efforts to reduce risk and decrease disease burden.

In sum, the FOURIER-OLE investigators are to be congratulated for providing the critical data that support the notion that longer-term PCSK9 inhibitor use is safe and effective and is associated with better cardiovascular outcomes. Of perhaps greater importance, the results presented in this seminal article remind us that lipid management should begin significantly earlier in life, and certainly before significant atherosclerosis has taken hold. These results serve as an important reminder that prolonged and pronounced LDL-C lowering is truly the gift that keeps giving.