is the new PCSK9 pill ready for prime time??

 this past July, The FDA approved enclicitide, a new oral proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor that goes by trade name Lipfendra, based on the CORALreef Lipids study; it has a price of $315 for a 30-day supply by Merck: see lipid PCSK9 oral NEJM2026 in dropbox or DOI: 10.1056/NEJMoa2511002

Details:

-- the CORALreef Lipids study was a multinational, double-blind, randomized, placebo-controlled drug company-sponsored trial that enrolled 2909 adult participants in the intention-to-treat population, where 1935 received enlicitide and 969 received placebo

-- this study involved 168 sites in 14 countries (including the US, UK, Italy, South Africa, Colombia, Japan, Argentina, Spain, and China)

-- the participants had a history of a major atherosclerotic cardiovascular disease event (which included acute coronary syndrome, coronary revascularization, MI, ischemic stroke, cerebrovascular arterial revascularization, and peripheral arterial disease with a history of acute limb ischemia, revascularization, or major amputation) and an LDL cholesterol level of 55 mg/dL or higher, and also included individuals who were at intermediate-to-high risk for a first atherosclerotic cardiovascular disease event with an LDL cholesterol level of 70 mg/dL or higher.

    -- this increased risk in the latter group was defined as: "the presence of any of the following conditions: heterozygous familial hypercholesterolemia, diabetes mellitus, stable angina, previous transient ischemic attack, symptomatic peripheral arterial disease, age of at least 40 years with a predicted 10-year risk of an atherosclerotic cardiovascular disease event of at least 7.5% as determined by the American Heart Association and the American College of Cardiology Pooled Cohort Equation risk calculator or equivalent, or a coronary-artery calcium score of at least 100 Agatston units, an indicator of increased cardiovascular risk" [this seems to include pretty much all of my patients. but, after all, it is a drug-company sponsored study that would like to enroll as many people as possible...]

-- participants received enlicitide 20 mg (which includes sodium caprate to improve this oral med absorption, more on this below) or placebo daily for 52 weeks.

-- mean age: 63 years, 39% were women

-- 54% white/26% Asian/9% Black/28% Latino

-- history of major ASCVD event 58%

-- statin use: none 3%/low intensity 1%/moderate intensity 41%/high-intensity 54%

-- bempedoic acid 1%, 26% on ezetimibe or hybutimibe (the latter being a cholesterol-absorption inhibitor, not available in US but does augment LDL lowering when prescribed with statins)

-- baseline lipid levels:

    -- LDL: 96 mg/dL

    -- non-HDL: 123 mg/dL

    -- apolipoprotein B: 91 mg/dL (normal is <100)

    -- median lipoprotein(a) (hereinafter Lp(a)): 59 nmol/L with interquartile range from 14-148 (normal <75 nmol/L)

-- primary end point: the mean percent change in LDL cholesterol level from baseline to week 24

-- key secondary end points:

    -- the mean percent change in LDL cholesterol level at week 52

    -- the mean percent change in levels of non–high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B

    -- the percent change in Lp(a) level at week 24.

Results:

-- 1831 participants (94.6%) assigned to the enlicitide group and 918 participants (94.7%) assigned to the placebo group completed the trial, including 1711 participants (88.4%) in the enlicitide group and 861 participants (88.9%) in the placebo group who received enlicitide or placebo through the end of the trial.

-- adherence to the trial regimen was high in both the enlicitide and placebo groups at a mean of 97.2%.

-- mean percent change in LDL cholesterol levels at week 24 (primary outcome), adjusted for baseline LDL, renal function, and geographical region:

    -- enlicitide: −57.1% (−61.8% to −52.5%), with mean LDL of 38.7 ±35.6 mg/dL

    -- placebo: 3.0% (0.9% to 5.1%), with mean LDL of 98.6 ±42.5 mg/dL

        -- an adjusted between-group difference: −55.8 percentage points (−60.9 to −50.7),  P<0.001

-- mean percent change in LDL cholesterol level at week 52, adjusted for baseline LDL, renal function, and geographical region:

   -- adjusted between-group difference in the mean percent change in the LDL cholesterol level from baseline to week 52 with enlicitide as compared with placebo: −47.6 percentage points (−52.7 to −42.5), P<0.001.

-- mean percent changes in non-HDL cholesterol, adjusted for baseline non-HDL, renal function, and geographical region:

    -- adjusted between-group difference for the mean percent change in the non-HDL cholesterol level from baseline to week 24: −53.4 percentage points (−55.5 to −51.2),  P<0.001

-- mean percent change in apolipoprotein B levels at week 24, adjusted for baseline apoB, renal function, and geographical region:

    -- between group difference for the mean percent change in the apolipoprotein B level from baseline to week 24: −50.3 percentage points (−52.1 to −48.5), P<0.001

-- the percent change in lipoprotein(a) levels at week 24, adjusted for baseline Lp(a), renal function, and geographical region:

    -- median between group difference in the percent change in Lp(a) levels from baseline to week 24: −28.2 percentage points (−30.3 to −26.0), P<0.001

        -- this is in the range of the current injectable PCSK9 inhibitors

-- an LDL cholesterol level of less than 70 mg/dL with a reduction of 50% or more from baseline was observed in 70.3% of the participants in the enlicitide group and in 1.5% of those in the placebo group

-- an LDL cholesterol level of less than 55 mg/dL with a reduction of 50% or more from baseline was observed in 67.5% of the participants in the enlicitide group and in 1.2% of those in the placebo group

--The incidence of adverse events did not differ between the groups (none were statistically significant), comparing enlicitide to placebo:

    -- any adverse event: 64.3% vs 62.1%

    -- any serious adverse event: 9.9% vs 12.0%

    -- any moderate or serious adverse event: 33.5% vs 32.4%

    -- discontinuation of trial due to adverse event: 3.1% vs 4.1%

    -- new onset diabetes or worsening of diabetes: 6.1% vs 5.8%

    -- most common adverse events with at least 2.5% prevalence in either group (all events were equal between the groups); diabetes in 4%, the rest less prevalent, including nasopharyngitis, URI, coronavirus disease in 2019, headache, hypertension, diarrhea, back pain, UTI, and bronchitis

Commentary:

-- this study incorporated the LDL goal of <55 mg/dL as per the new 2026 AHA/ACC/ADA/ASN guidelines for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic Syndrome: doi.org/10.1016/j.jacc.2026.03.056 or JACC Vol 87, number 225, 2026

    -- this guideline takes ASCVD out of the cardiac silo and (appropriately) assesses the interaction with other important, involved systems (renal, endocrine, etc)

    -- it proferred an LDL target of <55 g/dL for those at very high risk (eg coronary artery calcium >100 AU, "high-risk diabetes", coronary atherosclerosis, or these but without prior MI or stroke, those with diabetes and stage 4 CKM (cardiovascular-kidney-metabolic syndrome): see the guidelines for more details. this new guideline would increase the numbers of high-risk patients with prior cardiovascular who would qualify for PCSK9s (and now include the majority of my patients)

    -- and, by the way, they do stress the importance of assessing cystatin C as a marker of renal disease, noting "Estimated GFR using both creatinine and cystatin C provides better accuracy than eGFR using either marker alone". in fact, studies have found that cystatin C is the most relevant marker: http://gmodestmedblogs.blogspot.com/2023/12/cystatin-c-better-predictor-of-bad.html

-- the above CORALreef Lipids study did find that Merck's oral PCSK9 was associated with impressive decreases of LDL, nonHDL, apoB and Lp(a) levels, similar to the results of the current injectables (eg evolocumab) at 1 year later (though there was a small trend to fall-off by one year in the above enlicitide

 study, as noted in the graphs), with essentially no adverse effects vs placebo

    -- given the potency of PCSK9s, it is not surprising that the lipid improvement is beyond that of bempedoic acid and ezetimibe alone. the EXPLORER study, however, did find that combining the most potent statin rosuvastatin 40mg with ezetimibe 10mg did lead to a 70% reduction of LDL in very high-risk individuals vs 57% for rosuvastatin 40mg alone: https://pubmed.ncbi.nlm.nih.gov/17317370/

    -- of note, the Fourier study found cardiovascular benefit when achieving an LDL <20 mg/dL using the currently available injectable PCSK9 evolocumab: cad high risk LDL less than 20 fourier studyCirc2023 in dropbox, or DOI: 10.1161/CIRCULATIONAHA.122.063399. Another analysis of this well-conducted Fourier study (see Lp(a) Fourier study PCSK9 dec events Circ2019 in dropbox, or doi: 10.1161/CIRCULATIONASA.118.037184) found:

       -- higher levels of Lp(a) were associated with increased cardiovascular events in patient with established cardiovascular disease

        -- this benefit was independent of LDL levels

        -- the higher the baseline Lp(a) level, the greater the reduction in Lp(a) and the greater the coronary benefit

            -- the study thereby reinforced the importance of Lp(a) as an important cardiovascular risk factor, and one that is associated with fewer cardiovascular events when it is lowered

 -- and a systematic review/meta-analysis of several studies that predominantly employed PSCK9-based therapy (only one study was on statins) found that the lower the LDL, the better with increasing benefit without harm (this analysis included the early results of the Fourier study finding benefit with LDL <40mg/dL): https://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html

-- there was a companion article to the above one by the same authors called the phase-3 CORALreef HeFH study (for full analysis, see https://gmodestmedblogs.blogspot.com/2025/11/oral-pcsk9-improves-all-bad-lipids.html, or for the original articles see lipid PCSK9 enlicitide efficacy JAMA2026 in dropbox, or doi:10.1001/jama.2025.20620

-- the following is a quick and dirty brief summary:

    -- 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 10mg 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

-- 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)

-- mean percentage change at week 24:

     -- non–HDL:−52.3% in the enlicitide group vs +2.1% in the placebo group; between-group difference of −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

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

        -- ie, this PCSK9 med worked well in those hard-to-treat individuals with genetically-confirmed HeFH

-- this blog also contained the lipid benefits of the several other new PCSK9 drugs in the pipeline. all of the studies assessed just the lipid markers and not clinical events. those clinical analyses are in progress

the issue of using surrogate markers (LDL or Lp(a)) instead of actual clinical cardiovascular events is pretty fraught, questioning the FDA approval of the PCSK9 inhibitor enlicitide to prevent cardiovascular disease without data on this endpoint, with the following relevant past mistakes:

    -- there was impressive evidence that individuals who had low CETP (cholesteryl ester transfer protein) levels have high HDL and apolipoprotein A-1 levels as well as fewer cardiovascular events (https://pubmed.ncbi.nlm.nih.gov/34613338/). so, the development of CETP inhibiters was greeted with great enthusiasm since it raised HDL levels dramatically (which are not raised much by statins) and lowered the LDL levels even in those already on statins. The initial study confirmed that 19 subjects taking the CETP inhibitor torcetrapib with HDL <40 mg/dL (9 were on atorvastatin 20mg), found that the HDL increased 61% (p<0.001) and 46% (p=0.001) respectively in those on and not on the atorvastatin; the LDL decreased 17% further in those on the statin (N Engl J Med 2004;350:1505-1515, DOI: 10.1056/NEJMoa031766)

        -- but, but, but it turned out that in the subsequent RADIANCE study carotid artery intima-media thickening was increased in those on torcetrapib: Circulation Volume 118, Issue 24, 9 December 2008; Pages 2515-2522 (24):  doi.org/10.1161/CIRCULATIONAHA.108.772665 

        -- and further studies found that major cardiovascular events (composite of CHD death, nonfatal MI, stroke, hospitalization for unstable angina) was increased 25%, HR 1.25 (1.09–1.44), p = 0.001), 6.2% VS 5.0%; and all-cause mortality increased 58%, HR 1.58 (1.14–2.19; p = 0.006); 93 vs 59 deaths

        -- ultimately this unexpected increase was attributed in part to mineralocorticoid-mediated toxicity from the torcetrapid

    -- and another and more current example was a new drug to decrease inflammation:

        -- we do know that cardiac inflammation is associated with atherosclerotic heart disease, and the early atherosclerotic lesions have a lipid core replete with inflammation and susceptible to rupture and acute coronary syndromes

            -- the anti-inflammatory drug colchicine, which has been around for about 3500 years, decreases CRP levels, lowers the risk of recurrent pericarditis, and studies have found that low-dose colchicine (0.5mg/day) decreases the risk of major adverse cardiovascular events by more than 30%: https://pmc.ncbi.nlm.nih.gov/articles/PMC11047118/, and https://gmodestmedblogs.blogspot.com/2024/03/colchicine-decreases-cardiovasc-events.html

            -- the monoclonal antibody canakinumab that targets interleukin-1b was evaluated in patients with a history of a myocardial infarction and high CRP level and was found to have a 14% decrease in the combination of nonfatal MI, nonfatal stroke, or cardiovascular death, as well as hospitalization for unstable angina: https://www.nejm.org/doi/full/10.1056/NEJMoa1707914

            -- BUT, but the new drug ziltivekimab, an IL-6 inhibitor, was tested in the phase 3 ZEUS trial, a double blind, event-driven study assessing cardiovascular outcome:

                -- ZEUS enrolled more than 6300 people with ASCVD, CKD, and cardiovascular inflammation that was defined by hsCRP levels of 2 mg/L or higher. Participants received once-monthly subcutaneous ziltivekimab 15 mg or placebo on top of standard care. This phase 3 trial followed the phase 2 RESCUE study, in which ziltivekimab produced dose-dependent reductions in hsCRP of up to 92% versus 4% with placebo in patients with moderate to severe chronic kidney disease and elevated hsCRP, thereby providing the biomarker rationale for testing cardiovascular outcomes in ZEUS.

                --The primary endpoint was time to first occurrence of 3-point MACE

                -- Ziltivekimab showed no reduction in major adverse cardiovascular event (MACE) risk compared with placebo: HR 0.99 (0.88-1.11).

                      -- the result held despite ziltivekimab producing the anticipated pharmacodynamic effect on the IL-6 pathway, with the expected reductions in free IL-6 and hsCRP consistent with target engagement

                      -- the lack of separation on the primary endpoint indicates inflammation reduction via IL-6 inhibition did not translate into a measurable cardiovascular benefit in this population.

                      -- why did this happen?? unclear, but there are many different cytokines associated with inflammation and many of these work together. so, was isolating IL-6 instead of targeting a broader inflammatory cytokine range the problem?

                          -- an interesting study finding that both stress from racial discrimination and increased systemic inflammation led to decreased longevity, and the combination of both was even worse (https://gmodestmedblogs.blogspot.com/2026/02/racial-disparities-stress-and-mortality.html); this study assessed systemic inflammation by the combination of CRP and IL-6

    -- bottom line here is that we really need to assess actual clinical outcomes before we start using new meds in our patients. we do not know if there are off-target effects of this medication that may well be harmful....

  -- for a review of the pitfalls of relying on several of the surrogate markers approved by the FDA (eg hemoglobin A1c for diabetes, creatinine-based eGFR, LDL for ASCVD risk, etc): see https://gmodestmedblogs.blogspot.com/2024/06/using-surrogate-markers-for-disease-are.html

-- it is projected that the CORALreef Outcomes trial will evaluate clinical outcomes, but that data will not be completed until December 2029

-- another cause for pause:

    -- this new oral medication contains sodium caprate in it to improve the small intestinal absorption of the oral enlicitide by opening the tight junctions in the intestines (https://pubmed.ncbi.nlm.nih.gov/23069717/ ) in a "rapid and reversible way"; sodium caprate is also a mild surfactant that alters membrane fluidity (https://pmc.ncbi.nlm.nih.gov/articles/PMC8728740/)

    -- there have been no reported adverse effects on short term use of sodium caprate (https://www.sciencedirect.com/science/article/pii/S0169409X0900297X?via%3Dihub), and it has been approved in the US as a direct food additive and emulsifier for several years

        -- many foods and medications already include sodium caprate or its cousin salcaprozate sodium (SNAC), with the latter being involved in oral wegovy (semaglutide)

    -- as noted in https://pubmed.ncbi.nlm.nih.gov/30781867/, there are no assessments of long-term effects of sodium caprate on the microbiome

-- so, the questions comes up: 

    -- food emulsifiers are known as microbiome disruptors by allowing bacteria (including the harmful ones) to have easier access to the blood stream by destroying the protective mucus layer in the intestine (https://www.mdpi.com/2304-8158/11/15/2205)

    -- though sodium caprate has short effects that rapidly revert to normal, what is the effect of taking sodium caprate daily for the rest of one's life to decrease LDL and Lp(a)?

        -- will it allow toxins to gain access to the blood stream that would otherwise have been excreted?

        -- some of the toxins in food are associated with cancer (alfatoxins, nitrates and nitrites, high-heat cooking chemicals). and there are toxins from environmental exposures (water, air, soil pollution)

        -- will there be enough of these toxins that sneak through the altered small intestinal absorption by sodium caprate or other absorption enhancers to lead to cancer over time??

       -- and there is evidence that food additives are associated with increased cardiovascular disease, the disease we are trying to prevent with the new PCSK-9 pill!!: https://pmc.ncbi.nlm.nih.gov/articles/PMC11405437/

    -- unfortunately, it will be hard to even construct human studies that will be inclusive enough (eg, assessing all of the many components of potential toxins in the many foods we eat and exposures we have that include emulsifiers and other microbiome disrupters): but we can't do a long randomized controlled trial, with some people randomized to avoid a long list of foods, drugs, environmental exposures and do that for many years to assess outcome vs a control group. that would be impossible

    -- so, one could argue that we should try to avoid adding new potentially dangerous med additives as much as we can (and there are a slew of injectable PCSK9 inhibitors in the pipeline that do not rely on intestinal absorption changes, some with remarkably impressive lipid decreases (eg, pelacarsen, an injectable antisense oligonucleotide that targets the Lp(a) gene found up to an 80% reduction in Lp(a)):  https://www.sciencedirect.com/science/article/pii/S1933287425003228 )

Limitations:

-- for such a group of high risk ASCVD patients in this study, their baseline treatment with high intensity statins was only 54%, which was quite low given the lipid guidelines at the start of the study; perhaps this made the placebo group have even worse relative outcomes than if they had been treated more aggressively 

    -- the baseline LDL was quite high at 96 mg/dL, and the statin usage was really below what it should have been: none 3%/low intensity 1%/moderate intensity 41%/high-intensity 54%, resulting in this really high mean LDL level

-- as noted above in somewhat excruciating detail, we really need to know the clinical effects of the use of this oral PCSK9 before prescribing it, and we should also be concerned about the effects of the sodium caprate as a medication absorber on the gut microbiome; the microbiome has diffuse important systemic associations with the gut-brain axis, the gut-lung axis, the gut-kidney axis, and the gut-liver axis (and likely more)

-- it would be helpful to understand the long-term effects of this PCSK9 med, since we have only a 52-week window in this study (and that was with a prespecified secondary outcome, not a primary one, and is therefore not as statistically robust or reliable). and there seemed to be a decreasing effect of the med on the array of measured outcomes moving from the 24-week to 52-week results

so,

-- i do think we are emerging into a new realm of cardiovascular health with the upcoming, likely very effective new medications targeting inhibition to PCSK9.  this is so important given that cardiovascular disease continues to be the number one cause of death and is a huge cause of major disability in those who survive

-- unfortunately, we are in a society that does not focus well on the non-pharmacological approaches to decreasing the prevalence of cardiovascular disease (or the array of other diseases), which would require uniform enforceable public health initiatives, as done in several other countries to a significant effect, to limit air pollution (worse, of course, with our current push for coal-fired and other fossil fuels based energy), water/soil pollution which clearly affect our food supply and health outcomes, reliance on plastics that break down to microplastics with their array of harmful effects, the lack of healthy food availability to all people requiring decreases in food deserts and food insecurity, and getting rid of the bully pulpit used by the head of health and human services who is promoting red meat and beef tallow as one of the best things to eat...

    -- it is notable that black lung disease in coal miners has reached the levels that existed 50+ years ago....

-- in the absence of an effective public health system, we are left with workarounds: relying on meds that combat disease (though, as we all know, these are often very helpful but are associated with adverse effects)

-- hence the welcoming of newer and better PCSK9 inhibitors...

-- but this oral enlicitide in this current study needs to have more long-term studies assessing cardiovascular outcomes

geoff

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