Data published in the Journal of the American Heart Association show a high prevalence of discordance in the reduction of low-density lipoprotein cholesterol (LDL-C) and lipoprotein a (Lp[a]) in response to evolocumab treatment.
Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance who were enrolled in 1 of 4 randomized, 12-week, multicenter, phase 3 clinical trials (clinicaltrials.gov identifiers NCT01763827, NCT01763866, NCT01763905, and NCT01763918) evaluating treatment with evolocumab were included in the analysis (n=895).
Treatment regimens consisted of either 140 mg subcutaneous evolocumab every 2 weeks or 420 mg subcutaneous evolocumab every month.
Co-primary end points of each clinical trial included the LCL-C percentage change from baseline to week 12, as well as at the mean of weeks 10 and 12. Primary safety end points included treatment-emergent and serious adverse events, laboratory parameters, and antievolocumab antibodies.
At baseline, the mean level of LDL-C and median level of Lp(a) were 133.6 mg/dL and 46.4 mg/dL, respectively (interquartile range, 18.4-82.4 mg/dL). A total of 165 patients (19.7%) experienced a discordant response.
Nearly 94% of patients achieved an LDL-C reduction of >35% with PCSK9 inhibition; reduction of Lp(a) of >10% was not as prevalent, but was still achieved in the majority of the overall population (78.1%).
Discordance prevalence was higher when patients’ baseline concentrations of Lp(a) were >30 or >50 mg/dL. The average percentage of LDL-C reduction was higher in 23.6% of patients with an Lp(a) reduction of >40% compared with patients with an Lp(a) reduction of <10% (65.8% vs 50.1%, respectively; P <.001).
Limitations of the study include its small sample size and its retrospective nature, as well as the assessment of 2 antibodies vs an analysis and identification of the individual effects of each treatment.
“The results of this analysis suggest that Lp(a) may not always or exclusively utilize LDLR (low-density lipoprotein receptor) as a clearance receptor and, thus, alternative pathways of Lp(a) reduction beyond LDLR-mediated clearance may be affected by PCSK9 blockade,” the researchers concluded.
Shapiro MD, Minnier J, Tavori H, et al. Relationship between low-density lipoprotein cholesterol and lipoprotein(a) lowering in response to PCSK9 inhibition with evolocumab.J Am Heart Assoc. 2019;8(4):e010932.