Year: 2025
Type: article
Abstract: In Reply Ms Wu and colleagues raise the concern that use of PCSK9 inhibitors may have resulted in underestimation of the lipid-lowering effect of zerlasiran in our trial.1 We think this is highly unlikely.Although PCSK9 inhibitors slightly reduce lipoprotein(a), the trial protocol (posted with the article), required trial participants receiving lipid-modifying therapy at trial entry (including statins, PCSK9 inhibitors, and ezetimibe) to be taking a stable, maximum-tolerated regimen for a minimum of 8 weeks with no changes to existing regimens, and introduction of new lipid-modifying regimens was not permitted after screening.1 For monoclonal antibody PCSK9 inhibitors, a stable dose was defined as at least 4 doses at a consistent dose level.Given the requirement for stable background lipid-lowering therapies, the effects of zerlasiran on lipoprotein(a) reduction was not likely influenced by use of PCSK9 inhibitors.Wu and colleagues also question the effect of participants' sex on the zerlasiran trial results and point out that there were more male than female participants in the trial, with most female participants likely being postmenopausal.The authors are correct that most female participants in the zerlasiran trial were postmenopausal; only 2 participants were individuals of childbearing age.Increases in lipoprotein(a) concentrations have been reported following menopause in several studies. 2 Because of the moderate size of the current study, we intentionally did not prespecify analysis of subgroups, including differences in response to zerlasiran, by sex or menopausal status.Male and female individuals both have an increased risk of major cardiovascular events associated with elevated lipoprotein(a).3 It is likely that some trial participants were taking hormone therapy, which does reduce lipoprotein(a) concentrations.However, there is no evidence that responses to small-interfering RNA (siRNA) therapies differ by sex and at least 1 other siRNA reported nearly identical lowering of lipoprotein(a) in both male and female participants.4 The increased risk of elevated lipoprotein(a) does not appear to be influenced by hormone therapy.3 Wu and colleagues also suggest that the effect of genetic differences in response to this type of therapy should be explored.In a large study involving more than 500 000 participants in the UK, a genetic risk score strongly predicted lipoprotein(a) concentrations, but the genetic risk score did not provide incremental prognostic information.5 Nonetheless, we
Source: JAMA
Author: Steven E. Nissen
Institution: Cleveland Clinic
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4408890161