oral PCSK9 improves all bad lipids

 A recent study found that the oral PCSK9 inhibitor Enlicitide decreased an array of adverse lipid markers including lipoprotein(a) (referred to as Lp(a)) in the phase-3 CORALreef HeFH study: see lipid oral PCSK9 lipid effect JAMA2025 in dropbox, or doi:10.1001/jama.2025.20620

 

Details:

-- 303 participants with genetically-confirmed heterozygous familial hypercholesterolemia (HeFH) who were at least 18 years old and were on statin therapy as well as many being on ezetimibe were randomized to the oral PCSK9 inhibitor enlicitide decanoate 20 mg once daily for 52 weeks versus placebo. Patients were instructed to take this medication on an empty stomach 30 minutes prior to eating

    -- these patients had either an LDL level of 55 mg/dL or greater and a history of major atherosclerotic cardiovascular disease (ASCVD), or a level of 70 mg/dL or greater without a history of ASCVD

-- this trial was conducted in 59 sites across 17 countries, screening patients in 2023 with the last follow-up in April 2025

-- study visits occurred at baseline and at weeks 4, 8, 16, 24, 36, and 52

-- all patients did continue to take their background lipid-lowering therapies at their prescribed dose

 

-- mean age 52, 54% female, mean BMI 28

-- geographical region 25% Asia Pacific, 36% Europe and Middle East, 22% Latin and South America, 12% North America; 17% of th patients self-identified as Asian/3% Black or African-American/12% multiple races/69% white/22% Latino

-- high intensity statin in 82%, moderate intensity statin in 18%, ezetimibe in 63% (none on bempedoic acid)

-- variants of heterozygous familial hypercholesterolemia: LDLR in 51%, APOB in 6%, PCSK 9 in 1% (see below for more on this)

 -- major atherosclerotic cardiovascular disease event in 27%, coronary revascularization in 17%, an MI in 15%, acute coronary syndromes 13%, ischemic stroke 3%

-- type II diabetes 12%, eGFR at least 60 in 97% (with the rest between 45 and 60)

-- baseline lipids: LDL 118, non-HDL 142, apolipoprotein B 103, Lp(a) 52, triglycerides <150 in 75%

 

-- primary outcomes: mean percentage change in LDL level at week 24; the proportion of patients with adverse events and the proportion who discontinued the intervention due to these adverse effects

-- secondary outcomes: mean percentage change in LDL at week 52, and the mean percentage change at week 24 in levels in non-high density lipoprotein cholesterol (non-HDL), apolipoprotein B (apoB) levels and median percentage change in lipoprotein (a) (Lp(a))

 

Results:

 -- 97.0% of those in the enlicitide group and 96.0% in the placebo group completed the study

-- adherence to treatment was 97% in the enlicitide group and 98% in placebo; adherence to the fasting instructions prior to taking the med was more than 96% of the participants who took either the med all or most of the time at each point during the 52-week period

 

-- primary efficacy outcome of percentage change in LDL at week 24:

    -- enlicitide group: -58.2% (-62.1% to -54.3%)

    -- placebo group: 2.6% (-2.2% to 7.3%) (not statistically significant)

        -- between group difference: -59.4% (-65.6% to -53.2%), p<0.001

    -- mean absolute change in LDL at week 24: -69.5 mg/dL (-74.7 to -64.3 mg/dL) in the enlicitide group versus 0.3 mg/dL (-5.8 to 6.4 mg/dL) in the placebo group, with between group difference of -67.2 mg/dL (-74.9 to -59.5 mg/dL)

 

-- these reductions in LDL occurred by week 4 and persisted through week 52

    -- mean percentage change in LDL at week 52:

        -- enlicitide group: −55.3% (−59.3% to −51.4%)

        -- placebo group: 8.7% (2.0% to 15.4%)

            --between-group difference, −61.5% (−69.4% to −53.7%), P < 0.001

        -- mean absolute change in LDL at week 52 was −64.3mg/dL (−69.7 to −59.0 mg/dL) in the enlicitide group vs 8.1 mg/dL ( 0.1 to 16.1 mg/dL) in the placebo group; between group difference, −71.2mg/dL (−80.4 to −61.9mg/dL)

 

-- mean percentage change at week 24:

     -- non–HDL:−52.3% in the enlicitide group vs 2.1% in the placebo group; between-group difference, −53.0% (−58.5% to −47.4%), P < 0.001

     -- apolipoprotein B: −48.2% vs 1.8%, respectively; between-group difference, −49.1% (−54.0% to −44.3%), P < 0.001

     -- lipoprotein(a) [Lp(a)] level was −24.7% vs −1.6%, respectively; between-group difference, −27.5% (−34.3% to −20.6%), P < 0.001

 

-- overall, there was at least a 50% reduction in LDL and an LDL < 70 mg/dL in 70.8% in the enlicitide group vs 1.0% in the placebo group; between-group difference 69.8% (62.6% to 75.9%); P < 0.001

-- at least a 50% reduction in LDL and an LDL < 55mg/dL in 67.3% in the enlicitide group vs 1.0% in the placebo group; between-group difference 66.3% (59.1% to 72.6%); P < 0.001

-- subgroup analyses of the primary efficacy outcome showed consistent magnitude of LDL reduction across prespecified subgroups for demographics and baseline characteristics including sex, race, ethnicity, background statin therapy, and history of major ASCVD event

 

-- safety:

    -- overall, similar percent of adverse events between the enlicitide group (77.7%) and the placebo group (76.2%)

        -- the maximum intensity per participant was mild for the majority of specific adeverse events (AEs)

        -- the number of participants who discontinued treatment due to AEs was low and similar between treatment groups: 2.0% of participants in the enlicitide group vs 3.0% in the placebo group

    -- the most commonly occurring AEs were nasopharyngitis, similar between the enlicitide group and the placebo group (77.7% and 76.2%, respectively) and of mild intensity, as well as influenza, headache, and nausea

    -- the number of participants who discontinued treatment due to AEs was low and similar between treatment groups  (2.0%of participants in the enlicitide group vs 3.0% in the placebo group), as were the proportions of participants with serious AEs (4.5% vs 4.0%,respectively). None of the serious AEs were deemed by the investigator as being related to the intervention.

    -- there was 1 death in the enlicitide group in a participant who experienced an ischemic stroke and cardiovascular death; neither the stroke nor death was considered to be from the med

    -- there were no clinically meaningful between-group differences for changes in the laboratory parameters (including the chemistry and hematologic parameters), kidney and liver function or injury test results, electrocardiographic measurements, and hemoglobin A1C level. The incidence of new or worsening diabetes was low and similar among participants receiving enlicitide (2.0%) vs those receiving placebo (3.0%)

 

Commentary:

-- this study was performed in patients with heterogeneous familial hypercholesterolemia, a high-risk condition for atherosclerotic disease leading to a higher incidence of cardiovascular disease in men <55yo and women <60yo. But of note, this condition is not so uncommon and affects approximately one in 100 and 250 individuals and is associated with elevated LDL levels since birth. one study found that the incidence of ASCVD was 7 years younger in those with HeFH

    -- these individuals  have very high LDL levels and are also more likely to have corneal arcus, xanthelasma, tendon xanthoma, or periosteal xanthoma, as well as the cardiovascular effects

    -- these individuals typically have functional genetic mutations of one of 3 genes that impair LDL receptor-mediated catabolism of LDL particles: LDLR (low-density lipoprotein receptor gene, also called the apo B/E receptor), gain-of-function mutations of PCSK9 gene, and mutations of the apolipoprotein B gene (mostly APOB3500)

    -- an early study found that the risk of fatal or nonfatal CAD by age 60 was 52% for male and 32% for women, vs 13% for males and 9% for women lacking this condition (per Austin MA, et al. Am J Epidemiol. 2004;160(5):421)

    -- i believe that this is the reason that the American Association Pediatrics recommends lipid testing all patients age 9 to 11, as well as at age 2 in those more likely to have a familial hypercholesterolemia (if family history of heart disease or diabetes, hypertension, smoke exposure, high BMI, parent with total cholesterol of >240 mg/dL or known dyslipidemia)

    -- these HeFH patients are also at high risk of not being able to achieve guideline recommended LDL levels through conventional therapy with statins with or without ezetimibe

 

-- Lipoprotein (a) has been known for decades to be a potent cause of atherosclerotic events, it being the combination of an LDL-like particle (atherogenic) plus a variable number of “krinkles” (thrombogenic, since they effectively block plasminogen): https://gmodestmedblogs.blogspot.com/2025/06/high-lpa-increases-risk-of-recurrent.html

    -- this Lp(a) blog brings us a few issues:

        -- high Lp(a) levels are genetically determined, PCSK9 inhibitors lower them, and though not a pre-specified outcome, lowering LDL using PCSK9 inhibitors led to many fewer adverse cardiovascular events than similar levels of LDL lowering by statins with or without ezetimibe (ie, PCSK9s were more effective than statins/ezetimibe after controlling for the achieved LDL level, which is likely from their Lp(a) lowering effects)

        -- I have been checking Lp(a) levels regularly in my patients. And, the spread of results from these patients is quite a bit more dramatic than in the chart in this blog, where it was unusual to have an Lp(a) >300 and essentially nonexistent to be >400.  In my first 50 patients, there were many with Lp(a) >200 and several >500, even in healthy young women

        -- there is no clear evidence that PCSK9 inhibitors decrease cardiovascular events by lowering Lp(a) (though the first point above is pretty highly suggestive), so the US and European guidelines suggest that those with high Lp(a) levels just get more aggressive LDL lowering

 

-- PCSK9, proprotein convertase subtilisin/kexin type 9, is associated with increased atherosclerotic events and the two injectable PCSK9 inhibitors significantly decrease cardiovascular events

        -- both alirocumab and evolocumab produce dramatic decreases in cardiovascular events. these are the available injectable PCSK9 inhibitors: finding up to a 27% reduction in Lp(a) as well as marked LDL reductions: https://www.sciencedirect.com/science/article/pii/S1933287425003228

 

-- one review study found that dramatically lowering LDL-cholesterol levels had increasing benefits without significant adverse effects, down to LDLs of 21 mg/dL: https://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html

    -- only one of the studies involved statin therapy, which found that in patients with an initial LDL of 66 mg/dL, there was a 22% relative risk reduction of major vascular events per a 38.7 mg/dL (1 mmol) LDL decrease by more intensive statin therapy

    -- all of the other studies involved PCSK9 inhibitors. one of the best PCSK9 studies was the FOURIER study which initially found a decrease in cardiovascular events down to an LDL <40 mg/dL (see https://gmodestmedblogs.blogspot.com/2021/12/ldl-less-than-40-in-high-risk-patients.html). A subsequent analysis of this study 2 years later found that the benefits extended to an LDL< 20 mg/dL (see cad high risk LDL less than 40 FOURIER circ2021 in dropbox, or DOI: 10.1161/CIRCULATIONAHA.121.056536)

    -- this brings up the question of how much of the benefit of PCSK9 inhibitors is mediated by their relative effects on LDL versus those on Lp(a) levels; i have not found any studies that disaggregate the effects of both of these atherogenic moieties on cardiovascular outcomes by the use of PCSK9 inhibitors

 

-- there are several new medications on the horizon that are direct inhibitors of Lp(a), though all of these studies have assessed the effects on Lp(a) levels but lack data on actual cardiovascular benefit (this is a concern given that the CETP inhibitor torcetrapib was associated with dramatic increases in HDL levels, presumed to be very cardioprotective. yet subsequent testing found increased cardiovascular events, perhaps attributable to small increases in blood pressure but also to the fact that there was an associated atherogenic apolipoprotein C3 instead of the protective apolipoprotein A on the HDL membrane. this emphasize the importance of assessing the effect of medications on actual clinical events). As per above, it does seem to be quite likely that PCSK9 inhibitors do have cardiovascular benefit from lowering Lp(a) levels. The following studies are mostly going to continue to see if there is clinical benefit to lowering Lp(a) levels.

-- as a summary of what I have found of several of these Lp(a) inhibitors:

    -- muvalapin (oral small-molecule): 63-65% reduction in Lp(a), with benefit within 4 weeks: https://jamanetwork.com/journals/jama/fullarticle/2808864 

    -- pelacarsen (antisense oligonucleotide that targets the Lp(a) gene): up to 80% reduction in Lp(a):  https://www.sciencedirect.com/science/article/pii/S1933287425003228

    -- evinacumab (anti-ANGPTL3 mAb): 16.5% reduction in Lp(a): https://www.sciencedirect.com/science/article/pii/S1933287425003228

    -- lomitapide (microsomal triglyceride transfer protein inhibitor): 17% reduction in Lp(a), though the studies have mixed results, one suggesting no effect of Lp(a): https://pubmed.ncbi.nlm.nih.gov/18506153/

    -- inclisiran (small interfering RNA PCSK9 inhibitor): 21.9% reduction in Lp(a), though this was likely related to lowering PCSK9 levels: https://www.nejm.org/doi/full/10.1056/NEJMoa1912387

    -- olpasoram (small interfering RNA targeting LPA gene): 76.2% decrease in Lp(a): https://www.jacc.org/doi/10.1016/j.jacc.2024.05.058

    -- lepodisiran (small interfering RNA targeting LPA gene): up to a 93.9 percentage point decrease in Lp(a) in the highest dose group: https://www.nejm.org/doi/abs/10.1056/NEJMoa2415818

    -- zerlasiran (RNA-based to lower Lp(a): more than 80% decrease in Lp(a) levels: https://jamanetwork.com/journals/jama/fullarticle/2826608

 

-- this current study used enlicitide, an oral, small molecule macrocyclic peptide inhibitor of PCSK9 that lowers LDL levels through a mechanism similar to that of the injectable monoclonal antibodies noted above by protecting the LDL receptors from lysosomal degradation and increasing LDL receptors on the hepatocyte surface

   -- prior studies with enlicitide have found a 60.9% reduction in LDL versus placebo

 

Limitations:

-- since the study was done in patients with heterozygous familial hypercholesterolemia, there is the unlikely possibility that the results may not be generalizable to the general population

-- clinical outcomes were not assessed in this study, raising the question of whether this intervention was in fact clinically beneficial. there will be more clinical data in the future

-- there is concern about the accuracy of creatinine-based eGFR assessments (adding cystatin-c more accurately reflects the measured eGFR: https://gmodestmedblogs.blogspot.com/2024/03/cystatin-c-more-evidence-of-its-benefit.html 

-- this study, though including many diverse populations may not apply directly to the US, for example. the Lp(a) levels are clearly genetically-determined, so having only 3% Black or African-American participants may not truly reflect the lipid changes in the US

so, you might ask, why am i doing a blog on a medication that does not have clear clinical benefit??? there are ongoing studies assessing clinical benefits but they will take a while. but there are a few reasons to bring this up now:

-- we do not have a totally acceptable direct intervention for high Lp(a) that clearly shows lower cardiovascular events (though the likelihood of PCSK9s inhibitors working is quite likely), so there seems to be a consensus in the US and Europe that we should at this time really push for lower LDL levels in those with high Lp(a) levels

-- we have pretty remarkable meds for hyperlipidemia, which can be ramped up to giving all 3 of the non-PCSK9 meds (statins, ezetimibe, plus bempedoic acid, and these can all be given together with increasing LDL lowering: https://pmc.ncbi.nlm.nih.gov/articles/PMC11432672/ )

-- atherosclerotic disease is still the major cause of death and is second to musculoskeletal disorders for disability, despite the pretty widespread use of statins

-- my guess is that the likelihood of some or all of the Lp(a) meds noted above will be a major advance in lipid control and decreased cardiovascular events in the relatively near future

-- there were comments from Merck (the drug company making enlicitide) that it is cheaper to manufacture the pills than the injections that we already have, and that their goal was to try to lower the price to the level of statins so that it would be prescribed very broadly (and, of course, generating a potential windfall in profits). And (my guess again) is that would be a hugely important addition to our ability to treat hyperlipidemia more effectively and dramatically improve our clinical cardiovascular outcomes

-- so, this study is pretty exciting in terms of the very likely near-term availability of these Lp(a) lowering agents; and they may be a huge addition to our pharmacologic potential to really decrease the morbidity and mortality of cardiovascular disease

geoff

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