Effect of Alirocumab on Lipoprotein(a) Over ≥1.5 Years (from the Phase 3 ODYSSEY Program)

Abstract

Elevated lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a).

Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials

“…Alirocumab also produced significant reductions in Lp(a), which has been proposed to be an independent cardiovascular risk factor; however, other commonly used lipid‐lowering strategies such as statins or ezetimibe have little or no effect on Lp(a) 39. The percentage reduction in Lp(a) observed in individuals with DM and ASCVD who were treated with alirocumab was similar to that observed in the overall alirocumab‐treated patient populations in the ODYSSEY trials,39 with the exception of the pool without statins. For the DM and ASCVD population, Lp(a) changes from baseline were −36.0% with alirocumab and +10.0% with ezetimibe, compared with −25.9% with alirocumab and −7.3% with ezetimibe in the overall population 25.…”

PCSK9 targets important for lipid metabolism

“…Clinical studies show that use of the two PCSK9 antibodies alirocumab and evolocumab potently lowers Lp(a) [31, 72, 81], the latter also in patients with type 2 diabetes [77]. Interestingly, PSCK9 inhibition reduces Lp(a) in patient with homozygous familial hypercholesterolemia despite their lack or dysfunction of the LDLR.…”

Primary and secondary prevention of cardiovascular disease in patients with hyperlipoproteinemia (a)

“…In contrast to their impressive potential on LDL-cholesterol, the influence on Lp (a) is markedly lower; a lowering of Lp (a) levels by up to 30% has been reported, the reduction rate is below 20% in patients with high levels of Lp (a) [14, 15]. …”