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PCSK9 inhibition with evolocumab produced dose-related reductions in lipoprotein(a)
A pooled analysis of data from four phase 2 trials of evolocumab demonstrated significant dose-related reductions in lipoprotein(a).
Evolocumab (Amgen) is a fully human monoclonal antibody to PCSK9.
Researchers performed a pooled analysis of data from four phase 2, randomized, double blind, controlled trials that assessed the effects of evolocumab on lipoprotein(a) — or Lp(a) — the relationship between Lp(a) and lowering of LDL and apolipoprotein B, and the influence of background statin therapy. The analysis included 1,359 participants (mean age, 56 years; 56% women; 60% statin users).
All four studies were of 12-week duration. The researchers evaluated various doses and dose frequencies of evolocumab as compared with ezetimibe (Zetia, Merck) and/or placebo. The primary endpoint in all four trials was percentage change from baseline in LDL. A secondary endpoint, the focus of the pooled analysis, was percentage change in baseline Lp(a) by dose group and for the high-risk group with baseline Lp(a) values >125 nmol/L.
Reductions in Lp(a)
Frederick J. Raal, MBBCh, MMed, PhD, of the University of Witwatersrand in Johannesburg, South Africa, and colleagues reported that evolocumab treatment resulted in dose-related mean reductions in Lp(a) for all treatment groups compared with control treatment (P<.001). For participants assigned 140 mg evolocumab every 2 weeks, the mean Lp(a) reduction was 29.5% (95% CI, 23.3-35.7). For those assigned 420 mg evolocumab every 4 weeks, the mean Lp(a) reduction was 24.5% (95% CI, 20.4-28.7). No plateau effect was observed, the researchers wrote.
All treatment groups also showed reductions from baseline LDL and ApoB compared with controls (P<.001 for all).
The researchers found correlations between percentage reductions in Lp(a) and LDL (Spearman rank correlation, 0.5134) and also with ApoB (Spearman rank correlation, 0.5203; P<.001 for both).
No difference by age or sex
Mean reductions in Lp(a) did not differ by age or sex, but participants who used statins showed greater reductions than those not using statins, Raal and colleagues wrote.
Patients with baseline Lp(a) levels ≤125 nmol/L assigned evolocumab had greater percentage reductions vs. controls compared with those with baseline Lp(a) levels >125 nmol/L assigned evolocumab (140 mg every 2 weeks, –33.2% vs. –20%; 420 mg every 4 weeks, –28.7% vs. –16.1%). However, absolute reductions in Lp(a) vs. controls were greater in those with baseline Lp(a) levels >125 nmol/L assigned evolocumab (140 mg every 2 weeks, 34.1 nmol/L vs. 8.9 nmol/L; 420 mg every 4 weeks, 38.6 nmol/L vs. 9.7 nmol/L), according to the study.
Adverse events were observed in 56.8% of participants assigned evolocumab and 49.2% assigned placebo. Serious adverse events were observed in 2% of the evolocumab group and 1.2% of the placebo group, but no events were considered to be treatment-related, according to the researchers.
“It remains unknown whether lowering lipoprotein(a) will yield clinical benefit and reduce cardiovascular mortality,” Raal and colleagues wrote. “Nevertheless, the strong epidemiologic and genetic evidence suggesting that lipoprotein(a) is an independent causal risk factor for CVD makes it a valid interventional target for therapy when attempting to further reduce CVD risk.”
Disclosure: The study was funded by Amgen. See the full study for a list of the researchers’ relevant financial disclosures.