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Polygenic scores can identify individuals at risk of an increase in LDL-C over time

Genetic risk based on polygenic scores (PGS) for low-density lipoprotein cholesterol (LDL-C) can identify individuals who may benefit from more intensive monitoring and therapeutic management, according to an analysis by Dr So Mi Jemma Cho (Massachusetts General Hospital, MA, USA) [1].

The study used data from patients included in the Massachusetts General Hospital Brigham Biobank, with and without atherosclerotic cardiovascular disease. Data were analysed for 2,065 patients in the primary prevention cohort (index date: initiation of first lipid-lowering medication) and 1,331 patients in the secondary prevention cohort (index date: first atherosclerotic cardiovascular disease event). Both cohorts had index events between 2014 (following the 2013 ACC/AHA cholesterol guidelines) and 2021, with a 3-year follow-up to assess longitudinal LDL-C control. Analyses were adjusted for demographic characteristics (age, sex, race and ethnicity, body mass index) and clinical variables (smoking status, lipid levels, blood pressure, eGFR, diabetes, antihypertensive use, and use of antihypertensive and lipid-lowering medications).

Mean (standard deviation [SD]) LDL-C at baseline was 127.1 (42.1) mg/dL in the primary prevention cohort, and 113.0 (36.0) mg/dL in the secondary prevention cohort. Association analyses were conducted between the cumulative fraction of LDL-C above guideline-recommended targets (based on ACC/AHA guidelines) and PGS. For each SD increase in PGS, patients in the primary prevention cohort had a 4.26 mg/dL (95% CI 3.12–5.40) higher cumulative LDL-C above target, while those in the secondary prevention cohort had a 5.00 mg/dL (95% CI 3.37–6.63) higher cumulative LDL-C above target. Overall, LDL-C PGS was independently associated with long-term LDL-C control in both prevention cohorts, irrespective of demographic, lifestyle, and clinical risks, or medication use.

In summary, LDL-C PGS identified individuals with earlier and higher increases in LDL-C who may not achieve optimal management. “Awareness of elevated genetic risk for LDL-C may improve identification of individuals requiring intensive management and those who may benefit from novel lipid-lowering strategies,” concluded Dr Cho.

  1. Cho SMJ, et al. Low-density lipoprotein cholesterol polygenic score predicts cumulative cholesterol burden above target. ACC 2026, 28–30 March, New Orleans, LA, USA.

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Polygenic risk scores improve coronary artery disease risk prediction alongside LDL

Polygenic risk scores (PRS), calculated based on genetic susceptibility variants, have been used to predict the risk of developing coronary artery disease (CAD). Medical student Colin Harper (Broad Institute of MIT and Harvard, MA, USA) presented an analysis evaluating how low-density lipoprotein cholesterol (LDL-C) concentrations can be combined with PRS to refine CAD risk prediction [1].

The study included 257,158 participants from the UK Biobank without prior CAD, stroke, diabetes, or lipid-lowering therapy at baseline, with a median follow-up of 13.5 years. Findings were replicated in 67,668 participants from the All of Us Research Program. In both cohorts, susceptibility to CAD was assessed using LDL-C levels and a CAD-specific PRS.

Overall, a higher PRS combined with lower LDL-C concentrations was associated with a CAD risk comparable to that conferred by severe hypercholesterolaemia (LDL-C ≥190 mg/dL) in both cohorts. CAD risk exceeded that associated with severe hypercholesterolaemia in individuals with PRS ≥2.6 and LDL-C 130–160 mg/dL, and PRS ≥2.8 with LDL-C 160–190 mg/dL. Furthermore, CAD risk was similar between severe hypercholesterolaemia and the following combinations: PRS ≥1.3 with LDL-C 160–190 mg/dL, PRS ≥1.4 with LDL-C 130–160 mg/dL, and PRS ≥1.9 with LDL-C 100–130 mg/dL.

Overall, the analysis showed that PRS can refine risk stratification beyond LDL-C levels alone, identifying individuals at high risk of CAD. “Participants with moderate LDL-C elevations and higher PRS may carry risk comparable to those with severe hypercholesterolaemia,” concluded medical student Colin Harper. “Incorporating PRS may identify high-risk individuals not captured by LDL-C thresholds alone.” However, the analysis did not assess therapy patterns; therefore, it remains unclear whether CAD risk is reduced with therapy to the same extent as in patients with severe hypercholesterolaemia.

  1. Harper C, et al. Coronary artery disease polygenic risk scores refine low-density lipoprotein cholesterol-based risk stratification. ACC 2026, 28–30 March, New Orleans, LA, USA.

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The efficacy of bempedoic acid on cardiovascular outcomes is not impacted by autoimmune or inflammatory disease

Bempedoic acid, compared with placebo, reduced the risk of major adverse cardiovascular events among patients with statin intolerance, regardless of the presence of autoimmune or inflammatory disease.

Dr Bernardo Frison Spiazzi (Cleveland Clinic, OH, USA) presented a subanalysis of CLEAR Outcomes (NCT02993406), a randomised, double-blind, placebo-controlled trial that assigned patients intolerant of statins and at high risk for cardiovascular disease to bempedoic acid or placebo [1]. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularisation. In total, 13,970 patients were enrolled, including 1,044 with a history of autoimmune or inflammatory disease at baseline.

Bempedoic acid versus placebo led to similar improvements in the primary endpoint among patients with a history of autoimmune or inflammatory disease (HR 0.89; 95% CI 0.65–1.21) and those without such a history (HR 0.87; 95% CI 0.79–0.96). Comparable effects were observed across secondary endpoints, including the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, as well as individual endpoints such as fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, and coronary revascularisation.

In addition, bempedoic acid significantly reduced low-density lipoprotein cholesterol (LDL-C) from baseline to month 6 in both patients with autoimmune or inflammatory disease (-23.8% vs -0.5% with placebo) and those without such conditions (-21.5% vs -0.6% with placebo).

Overall, Dr Spiazzi concluded that, in the CLEAR Outcomes trial, “bempedoic acid demonstrates a consistent efficacy profile in lowering LDL-C and major adverse cardiovascular events in participants with and without autoimmune inflammatory disease.”

  1. Spiazzi BF, et al. Bempedoic acid and cardiovascular outcomes in patients with autoimmune or inflammatory diseases: An analysis of the CLEAR Outcomes trial. ACC 2026, 28–30 March, New Orleans, LA, USA.

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Evolocumab improves cardiovascular outcomes in patients with high-risk diabetes without significant atherosclerosis

Evolocumab versus placebo significantly improved outcomes for coronary heart disease death, myocardial infarction, and ischaemic stroke in patients with high-risk diabetes and no significant atherosclerosis.

Prof. Nicholas Marston (Harvard Medical School, MA, USA) presented data from VESALIUS-CV (NCT03872401), a phase 3, randomised 1:1, controlled trial evaluating evolocumab versus placebo on background of statin therapy in stable patients at high risk of cardiovascular events but without prior myocardial infarction or stroke. Patients were eligible if they had qualifying atherosclerotic risk factors and/or high-risk diabetes. The dual primary endpoints were 3-point major adverse cardiovascular events (MACE; time to coronary heart disease death, myocardial infarction, or ischaemic stroke) and 4-point MACE (3-point MACE plus ischaemia-driven arterial revascularisation). The presented analysis focused on patients with no significant atherosclerosis (n=3,655) and high-risk diabetes [1].

In this subgroup, evolocumab significantly prolonged the time to 3-point MACE compared with placebo, corresponding to a 31% relative risk reduction and a 2.1% absolute reduction. Evolocumab also significantly reduced 4-point MACE (absolute risk reduction, 2.9%; HR 0.69; 95% CI 0.55-0.86; P=0.001). The benefit of evolocumab was maintained for cardiovascular death (cumulative incidence 2.6% vs 4.0% at 5 years) and all-cause mortality (cumulative incidence 7.8% vs 10.1% at 5 years) [1]. The incidence of adverse events was similar between treatment groups [2].

In summary, VESALIUS-CV demonstrated significant reductions in MACE among high-risk primary-prevention patients with diabetes who had no known significant atherosclerosis. “The benefits observed in this subgroup support earlier intensification of lipid-lowering therapy beyond statins in the atherosclerotic cardiovascular disease continuum,” concluded Prof. Marston. “These data further suggest that, even in lower-risk patients, LDL-C targets typically reserved for very high-risk secondary prevention populations may be appropriate” [1].

  1. Marston N, et al. Evolocumab in patients without significant atherosclerosis: Results from VESALIUS-CV. ACC 2026, 28–30 March, New Orleans, LA, USA.
  2. Bohula EA, et al. N Engl J Med. 2026;394(2):117-127.

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Therapy targeting lower LDL-C levels improves cardiovascular outcomes

Targeting low-density lipoprotein cholesterol (LDL-C) levels <55 mg/dL is associated with improved cardiovascular outcomes compared with a target of <70 mg/dL in patients with atherosclerotic cardiovascular disease, without an increase in adverse events, according to a report by Prof. Byeong-Keuk Kim (Yonsei University College of Medicine, Republic of Korea) [1].

Ez-PAVE (NCT04626973) was a phase 3, randomised, investigator-led trial conducted entirely in Korea. Patients with atherosclerotic cardiovascular disease were assigned to either an intensive LDL-C target (<55 mg/dL) or a conventional target (<70 mg/dL). Within these groups, patients were further randomised to receive either a statin plus ezetimibe combination or a statin monotherapy. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, any revascularisation, or hospitalisation for unstable angina. In total, 3,048 patients were randomised and included.

In Ez-PAVE, intensive LDL-C targeting resulted in significantly lower rates of the primary endpoint compared with conventional targeting, corresponding to a 33% reduction in relative risk. Analyses of individual components showed no significant differences in cardiovascular death or all-cause mortality, but significantly lower rates of non-fatal myocardial infarction, non-fatal stroke, and revascularisation with intensive targeting. Safety analyses demonstrated no significant differences between groups in new-onset diabetes, worsening of glycaemic control, statin-associated muscle symptoms, new cancer diagnoses, or elevations in aminotransferases or creatine kinase. Notably, intensive targeting was associated with significantly lower rates of creatinine elevation to >1.5 times baseline.

“Ez-PAVE is the first randomised trial comparing LDL-C targets of <55 mg/dL versus <70mg/dL in patients with atherosclerotic cardiovascular disease,” concluded Prof. Kim. “Intensive targeting was associated with a significantly lower 3-year risk of the composite endpoint than conventional targeting, without major safety concerns. These findings provide randomised evidence supporting more intensive lipid-lowering strategies for secondary prevention, consistent with guideline recommendations.”

  1. Kim K, et al. Intensive low-density lipoprotein cholesterol targeting in patients with atherosclerotic cardiovascular disease. ACC 2026, 28–30 March, New Orleans, LA, USA.

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Efficacy of evolocumab confirmed in large meta-analysis

Evolocumab demonstrates favourable effects on lipid profiles with an overall acceptable safety profile in adults with cardiovascular disease or major risk factors, according to a meta-analysis.

Dr Musa Khalil (Howard University Hospital, Washington DC, USA) presented results from a systematic review and meta-analysis of randomised clinical trials and cohort studies evaluating evolocumab in adults with cardiovascular disease or major risk factors [1]. The pooled data were analysed for efficacy (effects on lipids and major cardiovascular adverse events) and safety (therapy discontinuation and injection-site reactions). In total, 10 studies comprising 67,727 patients were included.

In the overall meta-analysis, evolocumab versus control resulted in a significant reduction in low-density lipoprotein cholesterol (LDL-C), with a mean difference of -57.7 mg/dL (95% CI, -60.7 to -54.8; P<0.0001). Additionally, evolocumab reduced in total cholesterol (mean difference -52.3 mg/dL; 95% CI -66. to -37.9; P<0.0001) and triglycerides (mean difference -21.2 mg/dL; 95% CI -26.0 to -16.4; P<0.0001), increased high-density lipoprotein cholesterol (HDL-C) (mean difference 3.7 mg/dL; 95% CI 1.7–5.7; P=0.0003), and significantly reduced major adverse cardiovascular events (RR 0.53; 95% CI 0.40–0.71; P<0.0001). These results were consistent in the subgroup of patients aged >60 years.

In terms of safety, there was a non-significant trend toward increased treatment discontinuation with evolocumab in both the overall population and the subgroup aged >60 years. There was also a trend toward increased injection-site reactions, which reached statistical significance in the older age group (RR 1.32; 95% CI 1.13–1.55; P=0.0004).

“Evolocumab significantly improves lipid profiles and reduces major adverse cardiovascular events in patients with or at high risk of cardiovascular disease, while demonstrating a generally favourable safety profile,” concluded Dr Khalil. “These results support evolocumab as an effective adjunct to standard lipid-lowering therapies, particularly in patients who are unable to tolerate statins or achieve LDL targets.”

  1. Goel A, et al. Evolocumab decreases low density lipoprotein and reduces major adverse cardiovascular events – A systematic review and meta-analysis. ACC 2026, 28–30 March, New Orleans, LA, USA.

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Obicetrapib shows favourable safety in a pooled analysis of phase 3 trials

Obicetrapib, compared with placebo, was associated with a lower risk of adverse events related to diabetes, kidney function decline, and liver function, according to a pooled phase 3 analysis presented by Dr Adam Nelson (Monash University, Australia) [1].

The pooled safety analysis was based on 2 phase 3 trials evaluating obicetrapib 10 mg/day versus placebo: BROOKLYN (NCT05425745) in patients with heterozygous familial hypercholesterolemia, and BROADWAY (NCT05142722) in patients with heterozygous familial hypercholesterolemia or a history of atherosclerotic cardiovascular disease. In both trials, patients had uncontrolled cholesterol levels despite receiving maximally tolerated lipid-lowering therapies. In total, 2,880 participants were included in the pooled analysis, of whom 1,919 patients received obicetrapib and 961 received placebo.

Rates of treatment-emergent adverse events, discontinuations due to adverse events (AEs), and serious AEs were similar between the obicetrapib and placebo groups. An analysis of AEs of special interest showed a reduced risk with obicetrapib versus placebo for new-onset diabetes mellitus or worsening glycaemic control (32.9% vs 37.6%; RR 0.88; 95% CI 0.79–0.97), decline in eGFR (6.7% vs 8.7%; RR 0.77; 95% CI 0.59–1.00), increases in bilirubin to >2 times upper limit of normal (0.1% vs 0.7%; RR 0.17; 95% CI 0.03–0.83), and increases in serum creatinine of ≥0.3 mg/dL (5.0% vs 7.3%; RR 0.69; 95% CI 0.51–0.93).

In contrast, rates of increase in transaminases and creatine kinase, as well as events indicative of heart failure and changes in heart rhythm and blood pressure, were similar between treatment groups.

Overall, the safety profile in this pooled analysis was consistent with that reported in the individual trials. Dr Nelson concluded that “this analysis supports the safety and tolerability of obicetrapib in patients with high cardiovascular risk. If confirmed in larger and adequately powered trials, the safety profile of obicetrapib with respect to hepatic, renal, muscle, and glycaemic events may favourably differentiate it from other available lipid-lowering therapies.”

  1. Nelson AJ, et al. Safety of obicetrapib: An integrated pooled phase III safety analysis. ACC, 28–30 March 2026, New Orleans, LA, USA.

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Meta-analysis confirms the impact of obicetrapib on atherogenic lipid levels

Obicetrapib, compared with placebo, reduces low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B (ApoB) levels, while increasing HDL-C levels, according to a systematic review and meta-analysis presented by Dr Prutha R. Pathak (North Alabama Medical Center, AL, USA) [1].

The systematic literature review identified 802 records, of which 9 randomised controlled trials were included in the meta-analysis, comprising more than 3,700 patients. Random-effects meta-analyses using mean differences were conducted to assess the treatment effect of obicetrapib versus placebo on LDL-C, non-HDL-C, and ApoB levels. Dose-response analyses were also performed to determine the maximally effective dose of obicetrapib.

Overall, obicetrapib significantly improved all lipid parameters compared with placebo across the included trials. Mean reductions were -38.1% in LDL-C levels (95% CI -43.0 to -33.2; P<0.00001), -32.3% in non-HDL-C levels (95%CI -33.5, -29.0; P<0.00001), and -25.9% in ApoB levels (95% CI -30.3 to -21.4; P<0.00001). In addition, obicetrapib increased HDL-C levels by approximately 150%. Dose-response analyses demonstrated an increase in LDL-C reduction up to 8 mg/day, with a plateau observed at doses up to 10 mg/day.

In terms of safety, obicetrapib was well tolerated, with no off-target toxicity signals identified. There were no significant differences compared with placebo in live or haematologic markers, or in treatment discontinuation rates (RR 1.04; 95% CI 0.7–1.9).

Dr Pathak concluded that “obicetrapib produces robust reductions in LDL-C, non-HDL-C, and ApoB, while dose-response modelling suggests near-maximal benefit at approximately 7–8 mg/day. Safety and discontinuation rates were comparable to controls.”

  1. Gill OA, et al. Efficacy and safety of obicetrapib in reducing atherogenic lipids: A systematic review and dose response meta-analysis with trial sequential analysis. ACC 2026, 28–30 March, New Orleans, LA, USA.

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Meta-analysis of clinical trials confirms the efficacy of recaticimab in lipid reduction

Recaticimab, compared with placebo, leads to significant improvements in low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) across populations at risk of cardiovascular disease, according to a meta-analysis of phase 3 clinical trials.

Dr Sergio Fausto Girón (Francisco Marroquín University, Guatemala) reported results from a systematic literature review and meta-analysis of phase 3 trials evaluating recaticimab versus placebo [1]. Treatment effects were assessed using random-effects models in pooled populations.

Three randomised trials were included: REMAIN-1 (NCT04849000; non-familial hypercholesterolaemia and mixed hyperlipaemia), REMAIN-2 (NCT04885218; add-on therapy to statins for non-familial hypercholesterolaemia), and REMAIN-3 (NCT04844125; heterozygous familial hypercholesterolaemia), comprising a total of 1,535 patients. Across all trials, recaticimab significantly reduced LDL-C (mean difference -54.0%; 95% CI -62.3 to -45.7) and Lp(a) levels (mean difference -35.0%; 95% CI -39.9 to -30.15).

Dr Girón concluded that, in randomised controlled clinical trials, “recaticimab achieved robust and consistent lipid lowering, with approximately 54% reduction in LDL-C and around 35% reduction in Lp(a) with once-monthly dosing, independent of background therapy. These findings were consistent across diverse populations, supporting recaticimab as a promising long-acting PCSK9 inhibitor.”

  1. Girón SF, et al. Efficacy and safety of recaticimab for LDL-C and lipoprotein(A) reduction: A systematic review and meta-analysis. ACC 2026, 28–30 March, New Orleans, LA, USA.

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Lerodalcibep is effective in reducing LDL-C in high-risk patients on statin therapy

Lerodalcibep, compared with placebo, led to greater reductions in low-density lipoprotein cholesterol (LDL-C) in Chinese patients with high or very high risk of atherosclerotic vascular disease who had elevated LDL-C levels despite statin therapy, according to a phase 3 trial.

Prof. Huo Yong (Peking University First Hospital, China) reported results from a phase 3, randomised, double-blind trial (NCT06568471) that assigned patients in China in a 2:1 ratio to receive lerodalcibep or placebo for 12 weeks [1]. Participants were eligible if they were at high or very high risk of atherosclerotic cardiovascular disease and required additional LDL-C lowering despite statin use. The coprimary endpoints were the percentage change in LDL-C from baseline at week 12 and the mean LDL-C at weeks 10 and 12. In total, 213 patients were randomised, of whom 96.7% completed the trial.

The trial met both coprimary endpoints. At week 12, the mean (standard error) reduction in LDL-C with lerodalcibep versus placebo was 65.9% (8.7; P<0.0001), while the placebo-adjusted mean (standard error) reduction between weeks 10 and 12 was 67.0% (8.2; P<0.0001). Additionally, ≥94% of patients receiving lerodalcibep achieved Chinese lipid management guideline targets for LDL-C at any time during the trial, compared with <5% in the placebo group. Apart from injection-site reactions (7% with lerodalcibep), treatment-emergent adverse events occurred at similar rates between groups.

Prof. Yong concluded that “lerodalcibep, a once-monthly PCSK9 inhibitor, achieved mean LDL-C reductions >65%, with >90% of patients reaching guideline targets and a favourable safety profile in Chinese patients with, or at high or very high risk of, atherosclerotic cardiovascular disease on statin therapy requiring additional LDL-C reduction.”

  1. Chen B, et al. Efficacy and safety of lerodalcibep in Chinese patients with hypercholesterolemia: A randomized, double-blind, placebo-controlled phase 3 trial. ACC 2026, 28–30 March, New Orleans, LA, USA.

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