Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial

Abstract

Aims Lipoprotein(a) concentration is associated with first cardiovascular events in clinical trials. It is unknown if this relationship holds for total (first and subsequent) events. In the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab reduced lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), and cardiovascular events compared with placebo. This post hoc analysis determined whether baseline levels and alirocumab-induced changes in lipoprotein(a) and LDL-C [corrected for lipoprotein(a) cholesterol] independently predicted total cardiovascular events. Methods and results Cardiovascular events included cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina or heart failure, ischaemia-driven coronary revascularization, peripheral artery disease events, and venous thromboembolism. Proportional hazards models estimated relationships between baseline lipoprotein(a) and total cardiovascular events in the placebo group, effects of alirocumab treatment on total cardiovascular events by baseline lipoprotein(a), and relationships between lipoprotein(a) reduction with alirocumab and subsequent risk of total cardiovascular events. Baseline lipoprotein(a) predicted total cardiovascular events with placebo, while higher baseline lipoprotein(a) levels were associated with greater reduction in total cardiovascular events with alirocumab (hazard ratio Ptrend = 0.045). Alirocumab-induced reductions in lipoprotein(a) (median −5.0 [−13.6, 0] mg/dL) and corrected LDL-C (median −51.3 [−67.1, −34.0] mg/dL) independently predicted lower risk of total cardiovascular events. Each 5-mg/dL reduction in lipoprotein(a) predicted a 2.5% relative reduction in cardiovascular events. Conclusion Baseline lipoprotein(a) predicted the risk of total cardiovascular events and risk reduction by alirocumab. Lipoprotein(a) lowering contributed independently to cardiovascular event reduction, supporting the concept of lipoprotein(a) as a treatment target after ACS.

Effectiveness of proprotein convertase subtilisin/kexin‐9 monoclonal antibody treatment on plasma lipoprotein(a) concentrations in patients with elevated lipoprotein(a) attending a clinic

“…This is generally in agreement with a population study showing that a reduction of Lp(a) concentration by 50 mg/dl lowered ASCVD risk by 20% in a secondary prevention setting 43 . The effect of Lp(a) on the risk of ASCVD events appears to be proportional to the absolute reduction in Lp(a), not the percent reduction 28 . The mean reduction in Lp(a) of 0.29 g/L with a PCSK9mAb could be approximately translated into 12%–15% reduction of ASCVD 28,43 .…”

“…Several large clinical trials of PCSK9mAb treatment have consistently demonstrated a significant reduction in Lp(a) concentration. [15][16][17][18] In the ODYSSEY OUTCOMES trial, 18,28 alirocumab reduced Lp(a) by −0.20 g/L (−22%) in a subset of patients with elevated Lp(a). In an observational study of four high-risk patients with elevated Lp(a), 6 month PCSK9mAb treatment lowered plasma Lp(a) levels by 12%.…”

“…Recent randomized controlled trials (RCTs) and meta-analyses have favorable safety and good tolerability profile of PCSK9mAbs. 13,[16][17][18][19]28,30,34,35 These findings may not be fully applicable to clinical practice which encompasses patients with diverse comorbidities and multiple therapies. There are also limited data on the safety of PCSK9mAb in real-world settings.…”

Recent Updates of Lipoprotein(a) and Cardiovascular Disease

“…In the ODYSSEY OUTCOMES trial, it was shown that the Lp(a) reduction caused by alirocumab was related to the reduction of cardiovascular event risk and was not directly related to the simultaneous reduction of LDL. 75 In addition, after the use of alirocumab, for every 5 mg/L reduction of Lp(a), the total number of cardiovascular events was relatively reduced by 2.5%. 76 Although PCSK9 inhibitors can reduce plasma Lp(a) levels, the mechanism of action and clinical correlation remains to be explored.…”

Lipid Lowering Drugs: Present Status and Future Developments

“…Available lipid-lowering therapies have little value for Lp(a) reduction. Aside from statins that could raise Lp(a) blood concentrations [68,69], PCSK9 inhibitors reduce Lp(a) levels by 25-30% [70] and there is evidence that reduction of Lp(a) elicited by these drugs might contribute to an improved prognosis in coronary disease patients [71]. Finally, for patients with progressive ASCVD and high plasma Lp(a), a possible approach sometimes used is lipoprotein apheresis [72].…”