diabetes add PCSK9 decreases heart probs primary prevention

 A very recent study, the VESALIUS-CV (Effect of Evolocumab in Patients at High Cardiovascular Risk without Prior Myocardial Infarction or Stroke) trial found that adding the PCSK9 inhibitor evolocumab to patients with diabetes with no prior history of ASCVD (atherosclerotic cardiovascular disease) prevented the first major cardiovascular event (see diabetes primary ASCVD prevention with PCSK9 JAMA2026 in dropbox, or doi:10.1001/jama.2026.3277)

 

Details:

-- VESALIUS-CV was a randomized, double-blind, placebo-controlled trial of evolocumab conducted across 774 sites in 33 countries, enrolling 12,257 patients with diabetes but no prior myocardial infarction or stroke, LDL-C level 90mg/dL or greater, and qualifying atherosclerosis or high-risk diabetes. This current study was a prespecified subgroup

analysis to examine outcomes in patients without known significant atherosclerosis

    --none of the patients had prior arterial revascularization, arterial stenosis >= 50%, or coronary artery calcium score >=100 Agatston units

    -- enrollment started in 2019 and the last patient visit was July 2025

-- patients were randomized to subcutaneous administration of either evolocumab (140mg every 2 weeks) or matching placebo, added to optimally tolerated statin therapy.

-- of 3655 patients in the substudy, 1849 were randomized to evolocumab and 1806 to placebo

-- median age 65, 57% female, 93% white/3% Black/23% Hispanic

-- weight median 88 kg, BMI median 31

-- 62% from Europe/21% from Central or South America/16% North America/2% Asia-Pacific

-- diabetes 100%, hypertension 89%, current smoking 28%, eGFR (creatinine-based) 79

-- lipid lowering therapy: 89% total with statin in 84% (high intensity 64%, moderate or low intensity in 20%), ezetimibe in 14%, high intensity regimen (regimen to achieve at least 50% lowering of LDL) in 68%, also on aspirin in 32%

-- achieved lipid levels: LDL 132 mg/dL; HDL 48; non-HDL 162; triglycerides 172; apolipoprotein B 110

 

-- dual primary end points: 3-P MACE, a composite of coronary heart disease death, myocardial infarction, or ischemic stroke;  and 4-P MACE, 3-P MACE plus ischemia-driven arterial revascularization, IDR

    --Ischemia-driven arterial revascularization was defined as any arterial revascularization in the presence of ischemia affecting the relevant end organ; this could involve coronary, cerebrovascular, or peripheral arteries.

-- Secondary efficacy end points included 4 composites ([1] myocardial infarction, ischemic stroke, or IDR; [2] CHD death, myocardial infarction, or IDR; [3] cardiovascular death, myocardial infarction, or ischemic stroke; [4] CHD death or myocardial infarction) as well as the individual end points of myocardial infarction, ischemia-driven arterial revascularization, CHD death, cardiovascular death, all-cause mortality, and ischemic stroke

 

-- median follow-up of 4.8 years.

 

Results:

-- median achieved LDL at week 48:

    -- evolocumab group: 121 to 52mg/dL

    -- placebo group: 121 to 111mg/dL 

        -- adjusted decrease of 51.1% with evolocumab

-- change in Apolipoprotein B:

    -- evolocumab group: 105 to 57 mg/dL

    -- placebo group:108 to 101 mg/dL

        -- adjusted decrease of 40.3% with evolocumab

--change in Lipoprotein(a):

    -- evolocumab group: 31 to 18 mg/dL

    -- placebo group: 32 to 31 mg/dL

        -- adjusted decrease of 25.4% with evolocumab

-- 3-P MACE event:

    -- evolocumab group: 83 patients (5-year Kaplan-Meier estimate, 5.0%)

    -- placebo group: 117 patients (5-year Kaplan-Meier estimate, 7.1%)

        -- 31% better in the evolocumab group, hazard ratio [HR] 0.69 [0.52-0.91]; P = .009

        -- between-group difference 2.1% [0.4%-3.8%])

 

-- 4-P MACE event:

    -- evolocumab group: 127 patients (5-year Kaplan-Meier estimate, 7.6%)

    -- placebo group: 178 patients (5-year Kaplan-Meier estimate, 10.5%)

        --  31% better in the evolocumab group, HR 0.69 [0.55-0.86]; P = .001

        -- between-group difference, 2.9% [0.9%-4.9%]

 

-- The effect of evolocumab was more apparent after the first year of treatment, with:

    -- 3-P MACE: 41% decrease, HR 0.59 [0.43-0.81]

    -- 4-P MACE: 39% decrease, HR 0.61 [0.48-0.79]

        -- there was no statistically significant difference in patients with or without known significant atherosclerosis. BUT, the benefit of evolocumab emerged earlier in those with known atherosclerosis

 

-- results of the primary and secondary endpoints:

This Forest plot displays the benefit of evolocumab in the array of primary and secondary prevention outcomes in the study. As is evident, all of the outcomes found impressive benefits for evolocumab over placebo, with 10 of them being statistically significant. the other 2 had strong trends to evolocumab benefit but too few people experiencing these events, thereby likely decreasing the ability to be statistically significant

Subgroup analyses (buried in the supplementary analysis):

    -- age <65: 21% benefit from evolocumab, vs age >65 37% benefit

    -- female 45% benefit vs male 16% benefit

    -- baseline LDL<132 (the median for the whole group) 27% benefit vs LDL>132 40% benefit

        -- these were for 3-P MACE outcomes, but similar results for 4-P MACE outcomes

        -- and none of them were close to being statistically significant

Safety: no significant difference between groups in any adverse events, adverse events leading to study drug discontinuation or in those who believed their problem was related to the drug study, or in serious adverse events

  

 

Commentary:

-- prior studies of lipid-lowering therapy (LLT) have used statins, with some using non-statin meds (eg ezetimibe), in both primary prevention (no history of ASCVD) and secondary prevention (had history of ASCVD)

-- of note, the percent reduction of ASCVD events is similar in primary and secondary prevention studies (in the 30% range), BUT the absolute benefit in the secondary prevention group is, however,  significantly higher than in the primary prevention group (ie, they remain at a higher absolute risk of an ASCVD event)

-- prior studies on the use of PCSK9 inhibitors were done as secondary prevention to further lower LDL levels; however they also lower the atherogenic lipoprotein(a) levels: for several Lp(a) blogs, see https://gmodestmedblogs.blogspot.com/2024/03/lipoprotein-a-bad-actor.html)

    -- all of the prior studies of PCSK9s were for secondary prevention of ASCVD, until the previous study by the VESALIUS-CV investigators 2 months ago in NEJM. this study assessed patients who had diabetes or had prior known atherosclerosis (though most had either prior revascularization, arterial stenosis of at least 50%, or a CAC score of >100 Agatston units, but were without a prior MI or stroke; ie, they were formally still primary prevention, though a very high risk population) who were then randomized to evolocumab vs placebo, finding that those on evolocumab had a 25% decreased risk of 3-P MACE (see PCSK9 primary prevention dec MACE NEJM2026 in dropbox, or DOI: 10.1056/NEJMoa2514428)

    -- and, this all confirms a former meta-analysis finding that the lower the LDL the better the ASCVD prognosis (see https://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html).

    -- the very well done Fourier study (part of this meta-analysis) after additional followup found that there was benefit to lowering the LDL <20 mg/dL: cad high risk LDL less than 20 fourier studyCirc2023 in dropbox, or DOI: 10.1161/CIRCULATIONAHA.122.063399)

    -- these studies and the meta-analysis overall were for higher risk patients with documented ASCVD (ie secondary prevention). but as per above the prior VESALIUS-CV investigators in NEJM did confirm a real benefit of PCSK9 meds in high risk primary prevention patients

--  it should be noted that for intensification of statin therapy, there was a study finding that adding ezetimibe to a moderate dose statin was more effective clinically than just increasing the statin dose: https://gmodestmedblogs.blogspot.com/2024/12/alternative-ldl-lowering-strategies.html

-- the current study found a few important things:

    -- intensification of LLT by adding evolocumab to mostly background statin therapy (84% were on statins, with 64% on high intensity statins and 14% on ezetimibe), that adding evolocumab led to a 31% decreased in  major adverse cardiovascular events

    -- and this benefit occurred in patients who were primary prevention (though high risk for ASCVD) vs the prior studies for secondary prevention; the results thereby reinforced the meta-analysis above on secondary prevention that aggressive therapy leading to LDL levels <20 had increasing benefit with no clear increased risk (ie, a very low goal LDL helped all)

        -- this study found that the median achieved LDL was 52mg/dL at 48 weeks (44 mg/dL after 96 weeks). it is likely that with a stronger Lp(a) lowering agent than a PCSK9 inhibitor (several are being tested for clinical outcomes) and/or increasing the base statin dose to the max and adding ezetimibe and/or bempedoic acid would improve outcomes much further

    -- for better or worse, in our society, this addition of a PCSK9 would likely apply to lots of people

    -- of course, it would be best to reinforce diet, exercise, maintaining a healthy weight and decreasing the myriad of psychosocial issues associated with chronic inflammation and higher cardiovascular disease and mortality: https://gmodestmedblogs.blogspot.com/2026/02/racial-disparities-stress-and-mortality.html

        -- though i have several patients who have done very well with non-pharmacologic counseling, this is hard in our society in the US, where healthy foods are expensive (and do not have the gustatory pleasure of the cheaper calorie-dense/high salt/high fat/high carbs junk foods), have too busy lives for the time for regular exercise, etc

    -- those patients with known ASCVD did have improvement in their ASCVD risk earlier than those without baseline known ASCVD faster than the 1-year wait for the non-ASCVD group

Limitations:

-- there was very little actionable granular data on subgroups:

    -- it would have been very useful to know the effects of evolocumab stratified by the baseline LDL levels on statins/ezetimibe. would the benefit have been greater if the LDL had been lower at baseline? was there a dose-response to evolocumab such that its benefit for those with an initial LDL of 100 was better than 132mg/dL, LDL of 80 was better than 100, etc down to an LDL of perhaps 40 or 50??? that would suggest that we should be really trying to get the LDL level much lower before the evolocumab was prescribed. perhaps we should first use a higher statin dose if possible, and/or adding ezetimibe, and/or adding bempedoic acid?? then perhaps the benefits of evolocumab would have been faster and better than what was found in the study????

    -- similarly for age at cutpoint of 65. we do know that atherosclerosis is a cumulative process starting at a young age (and is also more aggressive if having diabetes). would the results have been better in someone 50yo? or 40yo? etc.  and if a 40yo or 50yo  had significantly more benefit, perhaps we should begin evolocumab at an earlier age and the PCSK9 benefit might provide faster and more profound benefit???

-- we do not know the degree of atherosclerosis in the enrolled patients for this primary prevention study. did some have minimal atherosclerotic changes and some multi-vessel or left main disease? it would be useful to have had baseline coronary CT angiograms to see the atherosclerotic burden in these high risk patients and subsequent outcomes to stratify our treatment of patients (one could make the argument that really high risk patients with diabetes should have coronary visualization to assess the appropriate intensity of treatment, and coronary CTA is quite good at that and with pretty low ionizing radiation exposure. but this has not bubbled up as a clinical recommendation)

-- the enrolled patients were at pretty high risk, for example with an achieved baseline LDL of 132 mg/dL. i personally have seen oh-so-many patients with diabetes of variable control and many with a trove of cardiac risk factors, but zero patients with an LDL that high unless they were not taking their meds. what was going on in this pretty large study of 3,655 patients? 

-- there was not much diversity in the study. almost all white patients. But there are often significant cultural differences in different groups of patients leading to different diets/exercise/lifestyle issues/stressors/etc that affect clinical outcomes including cardiac ones:https://gmodestmedblogs.blogspot.com/2026/02/racial-disparities-stress-and-mortality.html

-- this whole study was a substudy of the larger one mentioned above, though a prespecified one, and if would best to have a specific prospective patient study

 so,

-- this study adds to the ongoing accumulation of articles and guidelines on lipid management

-- it is abundantly clear that patients at high risk, including the primary prevention patients in this study, should be treated aggressively to lower their LDL levels (and, likely decreasing their apolipoprotein B and lipoprotein(a) levels: https://gmodestmedblogs.blogspot.com/2026/03/2026-acc-cardiology-guidelines-for.html

-- and this study and its recent VESALIUS-CV predecessor add strongly to the argument that PCSK9 meds have an important role in that aggressive lipid management even in primary cardiovascular protection in higher risk individuals. and hopefully the oral PSCK9 med being evaluated will show cardiovascular/all-cause mortality benefit, be affordable, and be covered by insurance

-- i would also like to reinforce that aggressive LDL therapy by the current non-PCSK9 meds do provide great benefit, with the lower the achieved LDL, the better.  the meta-analysis alluded to above of very low LDL levels was largely of patients on PCSK9 meds. but there was one group in this meta-analysis from the CTTC study (Cholesterol Treatment Trialists' Collaboration) that employed only statins and achieved a mean baseline LDL of 66 mg/dL, finding that the relative risk for major vascular events per 1-mmol/L (38.7 mg/dL) further reduction in LDL by intensive statin therapy was 22%, RR 0.78 (0.65-0.94), and this was clear even if the initial LDL was <75 (see lipid CTTC low LDL lancet2010 in dropbox, or Lancet. 2010; 376(9753):1670). 

    -- as we know, there are some patients just on statins (and not necessarily high dose ones) who achieve an LDL <40, but the vast majority need more than statins to achieve really low LDLs

    -- but it is important to emphasize that any lipid lowering therapy should be aligned with the lifestyle changes that improve cardiovascular and pretty much all chronic disease outcomes

geoff

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