another PCSK9 study: clinical benefit for high Lp(a)

 This is an addition to the last blog on PCSK9 inhibitors and lipoprotein (a): I should have included this impressive study on PCSK9 inhibitors and their clinical benefit in Lp(a) reduction, a benefit independent of LDL reduction, in the Fourier study mentioned in the last blog (see Lp(a) Fourier study PCSK9 dec events Circ2019 in dropbox, or DOI: 10.1161/CIRCULATIONAHA.118.037184)

--Lp(a) was measured in 25,096 patients randomized to the injectable PCSK9 inhibitor evolocumab vs placebo with a prespecified endpoint analysis to assess the relationship between Lp(a) levels, PCSK9 inhibition with evolocumab, and cardiovascular risk reduction, finding:
    -- patients with higher Lp(a) levels were at increased risk of a cardiovascular event independent of their LDL levels
    -- evolocumab reduced Lp(a) levels by 26.9%
    -- there was a moderately positive correlation between the percent change in Lp(a) and LDL levels (evolocumab decreased both)
    -- there was a 23% decrease in coronary heart disease deaths, myocardial infarction, or urgent revascularization
    -- in patients with Lp(a) levels greater than the median, there was a 23% decreased cardiovascular risk
    -- in patients with Lp(a) levels lower than the median, there was a 7% cardiovascular decreased risk (this was a 4 year study, so lower risk patients with lower Lp(a) levels will take longer to show benefit)
    -- patients who achieved lower LDL and Lp(a) levels derived the greatest benefit from PCSK9 inhibition (as would be expected)
    -- this reduction in cardiovascular events with evolocumab was independent of the baseline or achieved LDL levels (ie, lowering Lp(a) levels with this PCSK9 inhibitor seemed to confer cardiovascular benefit)
    -- but it should be noted that a prespecified endpoint analysis does not have the statistical rigor of a true randomized controlled trial, since patients in the study were not randomized based on their Lp(a) level


so, this reinforces the conclusions in the last blog:
-- it shows for the manyth time that PCSK9 inhibitors lower Lp(a) levels, pretty consistently by 20-30% 
-- the dramatic decrease in cardiovascular events from the current injectable (and quite expensive) injectable PCSK9 inhibitors is extremely likely to be from lowering this highly atherogenic Lp(a) levels along with the major lowering of LDL levels
-- we are on track to having a clear treatment for high Lp(a) levels, either with the hopefully upcoming  oral PCSK9 inhibitor per the last blog (which hopefully will be affordable and broadly prescribable), or with one or more of the clinical trials directly targeting Lp(a) mentioned in the last blog, one of which interferes with RNA PCSK9  (though none of these are ready for prime time until there is documentation of clinical cardiovascular benefit)
-- and hopefully we will be able to have several options. for example, my patients with Lp(a) levels in the 500+ range may really need one of the meds being studied that reduces Lp(a) levels by more than the PCSK9 does (20-30%), such as lepodisiran (decreases Lp(a) by 93.9%), olpasoram (decreases it by 76.2%), or pelacarsen (decreases it by 80%)
-- more to come, hopefully soon......

geoff

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