25 Jun, 14 | by EBM
probably the most exciting new drug for lipids are the PCSK9 inhibitors. i have appended below a blog from march 2012 which discusses proposed mechanism of action of these inhibitors as well as an epidemiologic study showing that those with naturally occurring PCSK9 function loss had much lower LDL levels and many fewer coronary events. this new multicenter, multi-country study is the longest RCT to look at evolocumab, a monoclonal antibody that inhibits PCSK9, to assess its safety and efficacy (see DOI: 10.1056/NEJMoa131622). 901 hyperlipidemic patients per ATPIII were put on several different meds/combos for 4-12 weeks, then randomization of those with CAD and LDL<100, or those without CAD but high risk if LDL<130 to either 420mg of evolocumab (subq injection) or placebo every 4 weeks.
–baseline characteristics: mean age 56, 47% male, 80% white, mean LDL 95-120,
results after 52 weeks, as compared to placebo group:
–baseline diet, evolocumab assoc with 55.7% reduction in LDL
–baseline atorvastatin 10mg, evolocumab assoc with 61.6% reduction in LDL
–baseline atorvastatin 80mg, evolocumab assoc with 56.8% reduction in LDL
–baseline atorvastatin 80mg + ezetimibe, evolocumab assoc with 48.5% reduction in LDL
–overall level of LDL was <70mg/dl in 82.3% of those on the evolocumab
–also significant reductions in apolipoprotein B (40%), non-HDL cholesterol (50%), lipoprotein (a) (25%), chol/HDL ratio (35%) and triglycerides (10%)
–and significant increases in HDL (5.4%), apo A-1 (3.0%). no change in CRP
–adverse effects: pretty minimal. without signif difference from placebo
so, really impressive numbers. all in the right direction. BUT, a few little details.
–how does this translate into clinical events?? we know that ezetimibe lowers LDL a lot (20%), but to no avail. we know that CETP inhibitors (torcetrapib, dalcetrapib) dramatically increase HDL (50-100%) also to no avail. even with our relatively primitive (though improving) understanding of lipids, there are differences in LDLs (the big fluffy ones have 1/3 the coronary risk of the small dense ones — meaning for example that lowering LDL 20% but converting big ones to little ones may worsen the risk!) and HDLs (not just size, but those with apo c-III are pro-inflammatory and assoc with MORE cad. i myself have been led down the primrose path way too many times, thinking that homocysteine, vitamin E, hormone replacement, ezetimibe, CETP inhibitors, etc etc all played an important role….. so, i really bring this new article up to show the impressive initial data but to warn about drawing any conclusions prior to real clinical data (eg ezetimibe was approved based on lipid changes, not clinical events).
–and, then there’s that pesky detail of cost
here is the prior blog from march 2012
2 interesting basic-science type articles on proprotein convertases: to my not-so-sophistocated understanding, these are proteins which, when cleaved and activated, affect cellular function and are often part of cellular homeostasis (like pro-insulin). In any event, there is one (PCSK9, which is paraprotein covertase subtilisin/kexin 9, in case you were wondering), which degrades the hepatic LDL receptor and leads to increased levels of LDL (single point mutations which increase their activity are associated with very high LDLs as in familial autosomal dominant hyperlipidemia). (see N Engl J Med 2011;365:2507-18). Loss of function leads to significantly decreased LDLs, with one study showing 2.6% of black pts have this loss of function naturally, assoc with 88% dec in coronary risk, indep of other risk factors (see N Engl J Med 2006;354:1264-72). Some animal studies with meds to decrease function assoc with >60% dec in LDL. So, may be important in the future.