CETP (cholesteryl ester transfer protein) plays an important role in lipid metabolism, facilitating the exchange of esterified cholesterol for triglycerides between lipoproteins. Genetic and cohort studies have demonstrated the presence of low CETP associates with lower rates of cardiovascular disease, diabetes, and neurodegeneration. However, early development programs of pharmacological CETP inhibitors proved disappointing with evidence of off-target toxicity, clinical futility, or marginal cardiovascular benefit with adipose tissue accumulation. Subsequent investigation of these programs and genomic studies has identified a pathway for drug development, in which promoting the ability of CETP inhibitors to lower levels of atherogenic lipids and lipoproteins and exerting a favorable impact on glycemic control may translate to reductions in cardiovascular risk, as opposed to the original motivation to raise HDL (high-density lipoprotein) cholesterol levels. Obicetrapib is a highly selective CETP inhibitor with evidence of favorable effects on atherogenic lipids and lipoproteins, glycemic control, and biomarkers of beta-amyloid pathology in preclinical Alzheimer disease. The ongoing potential for CETP inhibition as an effective tool in the prevention clinic and other emerging applications will be reviewed.

AIMS:Elevated lipoprotein(a) [Lp(a)] is a common risk factor for cardiovascular disease (CVD) affecting ∼1.4 billion people globally, with novel treatments under development. Guidelines recommend one-lifetime measurement, yet <1% are tested. Population-wide screening faces cost and implementation challenges. We developed a machine learning (ML) model to help prioritise patients for Lp(a) testing. METHODS:Ethnicity-calibrated ML models were developed to identify individuals with elevated Lp(a) in UK Biobank. Participants ≥37 years old (N=438,579) were split into feature importance/selection(20%), derivation(60%), and validation(20%) datasets. Performances across risk-enhancing Lp(a) thresholds recommended by clinical guidelines (90, 125, 430 nmol/L) or entry criteria for ongoing Lp(a)-lowering trials (150, 175, 200 nmol/L) were evaluated. External validation was conducted in NHANES III. RESULTS:Screening one million people using a universal approach would identify 222,717 cases above 90 nmol/L and 1950 above 430 nmol/L. In contrast, applying ML-targeted testing using the same number of tests would identify 280,899 (+26%; 95%CI:20-28%) and 6881 (+253%; 95%CI:192-310%) cases, respectively. At the thresholds of 125, 150, 175, and 200 nmol/L, yield increases were 38% (95%CI:35-40%), 51% (95%CI:47-54%), 59% (95%CI:55-63%), and 66% (95%CI:61-71%). Across thresholds 90-430 nmol/L, ML-targeted testing (Number Needed to Screen [NNS] 3.6-145, AUC 0.61-0.84) required 21%-72% fewer tests to identify one million cases. NHANES III validation demonstrated similar performance. Top 4 predictors included age, height (proxy for sex), total cholesterol and statin use. CONCLUSION:A ML-guided approach to prioritise testing for elevated Lp(a) would require fewer tests to identify those above risk-enhancing thresholds or potentially eligible for emerging therapies, offering a scalable interim compromise between the low current testing rates and universal screening aspirations.

Abstract Background Cardiovascular disease (CVD) remains the leading cause of premature death in England, with ethnic minority populations disproportionately affected, largely due to differences in socioeconomic factors, exposure and/or susceptibility to CVD risk factors. Midlife risk assessment does not fully account for observed variation in CVD incidence and mortality. Early and precise quantification of risk factor burden across diverse populations is therefore essential to inform targeted prevention strategies. This study assessed the prevalence of CVD risk factors in apparently healthy individuals residing in London. Methods This cross-sectional study included CVD-free individuals aged 30–90 years residing in London and registered with general practices using the Egton Medical Information Systems (EMIS) electronic health record system. Unadjusted, crude estimates of traditional CVD risk factors were assessed across participants of different ethnicities who underwent a CVD risk assessment between 2009–2020. Results Among 607,327 registered individuals, 83,414 were included (52.0% women, median age 45 [IQR:36–48] years). Ethnic distribution was as follows: White (43.6%), Asian (30.1%), Black (9.7%), Chinese/Other (4.0%), Mixed (2.1%). Overall, 7.8% were current smokers, 31.5% had obesity (universally defined as body mass index (BMI) ≥ 30.0 kg/m2), 48.5% had elevated blood pressure (BP ≥ 140/90 mmHg), 44.9% had hypercholesterolemia (≥ 5.0 mmol/l), 28.2% had elevated triglycerides (TG) ≥ 1.7 mmol/l, and 25.9% had low high-density lipoprotein cholesterol (HDL-C < 1.0/1.3 mmol/l for males/females, respectively). Smoking prevalence was highest among White individuals (9.7%). Obesity prevalence varied across groups, with higher proportions in Black participants (42.3%) and lower in Asian individuals (26.1%). Elevated BP was recorded more frequently in Mixed (54.9%) and Black (53.0%) participants and less frequently in those classified as Chinese/Other (42.7%). Total cholesterol ≥ 5.0 mmol/L was more commonly documented in Mixed (56.8%) and White (49.8%) participants. Higher proportions of Asian individuals had elevated TG (30.9%) and low HDL-C (31.6%), while corresponding proportions were lower among Black participants (14.4% and 19.5%, respectively). Conclusions This large-scale analysis of a diverse population suggests variation in CVD risk factor burden among relatively young individuals without CVD. While not implying causality, these findings reflect inequalities between ethnic groups and support an appraisal of early, tailored, and equitable public health policies to improve CVD risk management across diverse populations.

BackgroundThe SANTORINI study (NCT04271280) was designed to assess lipid management in different European countries and care settings over 1 year of follow-up. Here, we report prospective findings of patient characteristics, low-density lipoprotein cholesterol (LDL-C) goal attainment, and treatment patterns of lipid-lowering therapies (LLTs) in France and the rest of Europe (RoE; without France) at 1-year follow-up.Materials and methodsPatients at high or very high cardiovascular (CV) risk were recruited across 14 European countries from 17 March 2020 to 11 February 2021 and followed for 1 year of prospective follow-up.ResultsAmong 9,559 patients enrolled in the study, 8,802 with available risk classification data and 7,210 with available LDL-C data at baseline and 1-year follow-up were included. Of patients with available LDL-C data, 621 were included in the France cohort and 6,589 were included in the RoE cohort. In the France cohort (full analysis set for risk), investigators classified 20.1% and 79.9% of patients as high and very high CV risk, respectively. When CV risk was recalculated centrally as per the 2019 European Society of Cardiology/European Atherosclerosis Society guidelines, 7.1% and 92.9% of patients in the France cohort were considered high and very high risk, respectively. Total LLT monotherapy and combination therapy use over 1 year increased from 51.2% to 58.5% and 25.3% to 38.2%, respectively. Overall, mean (standard deviation) LDL-C level decreased from 2.6 (1.3) mmol/L to 2.2 (1.2) mmol/L, and LDL-C goal attainment increased from 14.8% to 23.4%. Results in the France cohort were consistent with those observed in the RoE cohort.ConclusionsWhile use of combination LLT and LDL-C goal attainment increased in the France cohort over 1 year of follow-up, the majority of patients remained at an increased risk of CV events.

Background:Obicetrapib is a potent, selective cholesteryl ester transfer protein (CETP) inhibitor that lowers LDL-C and raises HDL-C. Although prior studies have demonstrated efficacy and general tolerability, a comprehensive evaluation of its safety profile across later-stage clinical trials is needed. Methods:Safety outcomes were assessed in a pooled analysis of two phase III trials comparing obicetrapib 10 mg daily with placebo in adults with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD). Participants received treatment for 365 days. Safety endpoints included treatment-emergent adverse events (TEAEs) and prespecified events of special interest including hepatic, muscular, glycemic, renal and ocular parameters as well as overall rates of discontinuation. Results:A total of 2,880 participants were included (mean age 64 years; 36 % female; 82 % with ASCVD; 35.8 % with diabetes). Overall TEAE rates were similar between obicetrapib and placebo (60.2 % vs 62.0 %). AEs leading to treatment discontinuation occurred in 4.1 % of obicetrapib-treated participants and 5.3 % on placebo, Risk Ratio (RR) 0.77 [0.54-1.08]. No clinically significant change in blood pressure was observed between groups and hypertension events were comparable. There was no difference between the groups in liver or muscle-related endpoints. Reduction in eGFR occurred less often with obicetrapib ( compared to placebo (6.7 % vs. 8.7 % RR 0.77 [0.59, 1.00])). Macular degeneration was reported once in the obicetrapib group (n= 1 [0.1 %]). Deaths were similar between treatment groups. No new safety signals were identified. Conclusions:Obicetrapib demonstrated a favorable safety profile over 12 months, with AE rates comparable to placebo. These findings extend our understanding of the safety and tolerability of obicetrapib.

AIMS:Novel therapies are under evaluation for upstream inhibition of inflammatory pathways in atherosclerotic cardiovascular disease (ASCVD). Elevated high-sensitivity C-reactive protein (hsCRP) is a downstream marker of these pathways but is not routinely measured. We aimed to identify potential factors associated with elevated hsCRP. METHODS AND RESULTS:This cross-sectional study included individuals with ASCVD from the UK Biobank (2006-10) and the US National Health and Nutrition Examination Survey (NHANES; 1999-2010 and 2015-18). Factors associated with elevated hsCRP (2-10 mg/L) were evaluated using multivariable logistic regression. Six factors were associated with greater odds of elevated hsCRP in both cohorts (UK Biobank n = 23 045; NHANES n = 3415): obesity {UK Biobank odds ratio [OR] [95% confidence interval (CI)]: 3.48 [3.18-3.80]; NHANES 4.11 [2.66-6.34]}, overweight [1.56 (1.44-1.70); 2.26 (1.51-3.38)], being a current smoker [2.47 (2.27-2.69); 1.96 (1.23-3.10)], female sex [1.69 (1.59-1.80); 1.69 (1.24-2.31)], and increased LDL cholesterol [1.05 (1.04-1.06); 1.00 (1.00-1.00), per 10 mg/dL increase] and triglyceride levels [1.01 (1.01-1.01); 1.00 (1.00-1.00), per 10 mg/dL increase] (all P < 0.05). Receiving statins was associated with lower odds in both cohorts [UK Biobank OR (95% CI) 0.69 (0.64-0.75); NHANES 0.54 (0.39-0.74)]. When these factors, plus chronic kidney disease stage G3-5, were considered in combination, hsCRP levels were higher in individuals with more factors (median hsCRP with seven factors: UK Biobank 5.39 mg/L; NHANES 6.99 mg/L). CONCLUSION:The factors identified may support data-driven targeted testing to identify those most likely to have elevated hsCRP, who could potentially benefit from emerging anti-inflammatory therapies.

BACKGROUND:Despite high cardiovascular risk, many patients with acute coronary syndrome (ACS) do not receive timely intensification of lipid-lowering therapy (LLT). OBJECTIVE:To predict the impact of LLT intensification on cardiovascular events and attainment of low-density lipoprotein cholesterol (LDL-C) goals in this population. METHODS:A Monte Carlo simulation was conducted using data from 54,154 patients with ACS to estimate 5-year rates of a composite endpoint of myocardial infarction, ischemic stroke, or cardiovascular death. Three immediate LLT strategies were modeled: (1) high-intensity statin (HIS) + ezetimibe (EZE), (2) HIS + alirocumab (ALI), and (3) HIS + EZE + ALI (triple LLT). Two delayed strategies were also assessed: (1) HIS + EZE at baseline with ALI added at 6 months if LDL-C goals were unmet, and (2) HIS alone at baseline with sequential addition of EZE at 6 months and ALI at 12 months if goals were unmet. LDL-C goals included <55 mg/dL and <40 mg/dL, each with and without ≥50% reduction. Subgroups included patients with prior ischemic stroke or without revascularization during ACS hospitalization. RESULTS:Triple LLT reduced the predicted 5-year event rate from 22.2% (95% CI: 21.8-22.6) with HIS alone to 14.3% (95% CI: 14.0-14.6), yielding an absolute risk reduction of 8.0% (95% CI: 7.6-8.3) and a relative reduction of 35.8% (95% CI: 34.4-37.2). Predicted benefit was greater in patients with prior ischemic stroke or no revascularization, with LDL-C goals achieved in nearly all patients. CONCLUSIONS:Triple LLT initiated at ACS hospitalization may markedly reduce cardiovascular events through earlier and more complete achievement of LDL-C targets.

Razionale. L’acido bempedoico (AB), un inibitore dell’adenosina trifosfato-citrato liasi, è efficace nel ridurre il colesterolo LDL (C-LDL) e il rischio cardiovascolare (CV), come dimostrato da studi clinici randomizzati. Tuttavia, i dati di “real-world” relativi al suo impiego nella pratica clinica sono ancora limitati.Materiali e metodi. MILOS (NCT04579367) è uno studio osservazionale prospettico europeo volto a valutare efficacia e sicurezza dell’AB, in monoterapia o in associazione a dose fissa con ezetimibe (AB+EZE FDC), in pazienti adulti con ipercolesterolemia primaria o dislipidemia mista. Il presente lavoro riporta i dati ad interim a 8 settimane dei pazienti italiani arruolati tra marzo e dicembre 2023. Risultati. Dei 1310 pazienti arruolati, 855 (AB, n = 445; AB+EZE FDC, n = 410) disponevano di dati di C-LDL sia al basale che al follow-up a 8 settimane. L’età media complessiva era di 66.0 ± 10.7 anni; l’11.1% era affetto da ipercolesterolemia familiare eterozigote e il 15.1% presentava diabete. Il 57.7% dei pazienti era in prevenzione secondaria e l’82.4% presentava un rischio CV elevato o molto elevato. Prima dell’inizio del trattamento con AB o AB+EZE FDC, il 33.1% dei pazienti non assumeva alcuna terapia ipolipemizzante. Dopo una durata media di trattamento di 59.3 ± 19.3 giorni, si è osservata una riduzione media del C-LDL del 22.6 ± 32.3%, con una riduzione mediana del 25.4% (range interquartile 8.1-43.2), da 2.9 ± 1.2 mmol/l (110.7 ± 44.8 mg/dl) a 2.1 ± 0.8 mmol/l (79.2 ± 32.2 mg/dl), in seguito al trattamento con AB/AB+EZE FDC, con o senza terapia ipolipemizzante di background. La percentuale complessiva di pazienti che hanno raggiunto gli obiettivi di C-LDL è aumentata dal 7.1% (61/855) prima del trattamento al 37.2% (318/855) a 8 settimane di follow-up, con un incremento del 29.4% nei soggetti a rischio CV molto elevato. Eventi avversi correlati al farmaco sono stati riportati nel 4.3% dei pazienti, senza nuovi segnali di sicurezza, analogamente a quanto riportato nella letteratura.Conclusioni. Nella coorte italiana dello studio MILOS, l’AB, da solo o in associazione ad ezetimibe, si è dimostrato un’opzione terapeutica efficace e ben tollerata per la gestione dei pazienti ad elevato rischio CV, supportando il raggiungimento degli obiettivi di C-LDL raccomandati dalle linee guida nella pratica clinica reale.

BACKGROUND AND AIMS:The 2021 ESC guidelines on cardiovascular (CV) disease prevention recommend the SMART-REACH lifetime risk model to guide treatment decisions in patients with established atherosclerotic CV disease. The aim was to develop the SMART-REACH2 model for estimating lifetime risk of recurrent CV events and treatment benefits in patients with established atherosclerotic CV disease, with systematic recalibration to the four European and other global risk regions. METHODS:SMART-REACH2 was derived in 8708 individuals aged 40-90 years with coronary, cerebrovascular, peripheral artery disease and/or abdominal aortic aneurysm from the UCC-SMART cohort. Sex-stratified, cause-specific Cox models for recurrent CV events and non-CV death were fitted using age as timescale and routinely available predictors. Recurrent CV events were defined as a composite of myocardial infarction, stroke, or CV death. Recalibration was based on representative cohorts per risk region. External validation was performed in 2 085 780 patients from 54 countries; model performance was assessed by calibration plots and Harrell's C-statistic. RESULTS:In the derivation cohort, 2057 recurrent CV events occurred over a median follow-up of 8.5 years (25th-75th: 4.3-13.0). In external validation, 307 706 events occurred. The pooled C-statistic was 0.68 (95% confidence interval 0.66-0.69) and ranged from 0.66 (0.64-0.69) for European low-risk region up to 0.72 (0.66-0.78) for Latin America, with adequate calibration across risk regions. Performance was consistent across sexes and CV disease subtypes. Using SMART-REACH2, estimated potential gains in CV disease-free life expectancy for a 50-year-old example patient receiving intensified preventive treatment (15 mmHg systolic blood pressure and 1.0 mmol/L low-density lipoprotein cholesterol reduction) ranged from 2 years in the low-risk region to 4.4 years in the very-high-risk region. CONCLUSIONS:The updated SMART-REACH2 model accounts for geographical and sex-specific variations and allows estimation of short-term and lifetime risk of recurrent CV events and treatment benefits, facilitating shared decision-making as recommended by guidelines.

Key Points Inclisiran for LDL cholesterol reduction was analyzed post hoc in patients with CKD. Mean percentage LDL cholesterol reduction from baseline was around 50% regardless of eGFR in phase 3 trials. Inclisiran showed sustained and effective LDL cholesterol–lowering in patients across various levels of eGFR values, without new safety findings. Background Lowering LDL cholesterol reduces the risk of atherosclerotic cardiovascular disease in patients with CKD. The efficacy and safety of inclisiran versus placebo in patients without and with CKD were investigated in a post hoc pooled analysis of three phase 3 trials (ORION-9, ORION-10, and ORION-11). Methods Patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease or its risk equivalent, and elevated LDL cholesterol were randomized 1:1 to subcutaneous inclisiran or placebo on days 1 and 90 and every 6 months thereafter for 540 days. Patients were stratified based on baseline eGFR (by CKD Epidemiology Collaboration equation): ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m 2 . Coprimary end points were percentage change in LDL cholesterol at day 510 and time-adjusted percentage change after day 90 and through day 540. Safety was also evaluated. Results Of 3660 patients, 1610 (44%) had eGFR ≥90, 1608 (44%) 60 to <90, 300 (8%) 45 to <60, and 142 (4%) 15 to <45 ml/min per 1.73 m 2 . The mean (95% confidence interval) placebo-corrected percentage changes in LDL cholesterol from baseline at day 510 in patients with eGFR ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m 2 were −49.9% (−53.2 to −46.6), −51.2% (−54.4 to −48.0), −54.7% (−62.5 to −47.0), and −44.7% (−57.6 to −31.8), respectively ( P < 0.001); the corresponding mean (95% confidence interval) time-adjusted placebo-corrected percentage changes in LDL cholesterol from baseline after day 90 through day 540 were −48.4% (−50.8 to −46.1), −51.8% (−54.2 to −49.4), −55.6% (−61.0 to −50.2), and −50.4% (−59.3 to −41.5; each P < 0.001). Significant decreases in total cholesterol, apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) occurred in all eGFR groups. Inclisiran was well tolerated without new safety findings. Conclusions Inclisiran demonstrated sustained and effective LDL cholesterol reduction in patients with or at risk of atherosclerotic cardiovascular disease, regardless of baseline eGFR as low as 15 ml/min per 1.73 m 2 , without new safety findings. Clinical Trial registry name and registration number: ClinicalTrials.gov, ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800).

AIMS:Despite causal inference from genetically higher triglyceride levels and cardiovascular risk, therapeutic triglyceride lowering has yet to demonstrate cardiovascular benefits. Providing insights into the magnitude of treatment effect needed and the type of patients who might benefit, we assessed the relationship between triglyceride levels and cardiovascular events following myocardial infarction (MI). METHODS AND RESULTS:Between 2005 and 2022, 51,719 MI patients in the Swedish MI registry SWEDEHEART were studied. Triglyceride change from admission to 1-year and 1-year levels was evaluated in adjusted Cox models. Outcomes were MACE (all-cause mortality, non-fatal MI, and non-fatal ischaemic stroke), all-cause mortality, and non-fatal MI. Over 5.6 years, 9008 patients experienced an MACE, and 5148 died. Median triglycerides were 1.4 mmol/L (interquartile range IQR 1.0-2.0) at MI admission and 1.2 mmol/L (0.9-1.6) at 1 year. Patients in the top quartile of triglyceride reduction (≥0.6 mmol/L, median 1.0 mmol/L) had the highest baseline triglycerides of 2.2 mmol/L (1.8-2.9). Compared to patients with minimal change, this quartile had the lowest risk of MACE (HR 0.85 95% CI 0.79-0.92), all-cause mortality (HR 0.90, 0.81-0.99), and non-fatal MI (HR 0.83, 0.74-0.94). Patients in the lowest quartile at 1-year (<0.9 mmol/L) had the lowest cardiovascular risk. CONCLUSION:Among MI patients, triglyceride reductions of ∼1.0 mmol/L were associated with the lowest cardiovascular risk. Only 27% of patients achieved this reduction with baseline triglycerides ∼2.2 mmol/L. These findings may explain neutral results in prior triglyceride-lowering trials and suggest future trials should enrol patients with baseline triglycerides ≥2.2 mmol/L and target reductions ≥1.0 mmol/L.

BACKGROUND AND AIMS:There is interest in developing lipoprotein(a) [Lp(a)] lowering therapies. Cholesteryl ester transfer protein inhibitors lower Lp(a), however the effects of the selective inhibitor obicetrapib on Lp(a) levels in high cardiovascular risk patients have not been fully elucidated. This analysis investigated the effect of obicetrapib on Lp(a). METHODS:A pooled analysis of trials evaluating the 12-week lipid effects of daily obicetrapib 10 mg compared with placebo in patients with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD) investigated the effect of obicetrapib on Lp(a) levels. RESULTS:In 2356 patients, the pooled cohort had a median age of 66 years, 36% were female with a history of ASCVD in 82%, HeFH in 27% and statin use in 91%. Median baseline lipid levels included low-density lipoprotein cholesterol (LDL-C) of 92 mg/dL, apolipoprotein B (apoB) of 87 mg/dL and Lp(a) of 42.9 nmol/L. Obicetrapib produced placebo-adjusted reductions in LDL-C of 37.0% and 35 mg/dL, in apoB of 21.3% and 20 mg/dL, and in Lp(a) of 37.3% and 14.9 nmol/L. In patients with baseline Lp(a) levels ≥50-<150 nmol/L, obicetrapib produced placebo-adjusted reductions in Lp(a) of 43.3% and 36.3 nmol/L. While patients with baseline Lp(a) ≥150 nmol/L demonstrated a lower percentage reduction in Lp(a) with obicetrapib than those with baseline levels ≥50-<150 nmol/L, the absolute reduction in Lp(a) was similar in both groups (-32.3 vs -36.3 nmol/L). CONCLUSIONS:Obicetrapib lowered LDL-C, apoB and Lp(a). The absolute reduction in Lp(a) with obicetrapib was similar in patients with mildly elevated Lp(a) levels, who are unlikely to qualify for administration of RNA-targeted Lp(a) lowering agents.

BACKGROUND:Acute coronary syndrome (ACS) exhibits greater risks of recurrent atherosclerotic cardiovascular disease compared to chronic coronary syndrome (CCS), suggesting the need for more intensified preventive management, including low-density lipoprotein cholesterol (LDL-C) control. However, current guidelines advocate the "same" LDL-C goals in both ACS and CCS. OBJECTIVES:The authors aimed to compare cardiovascular outcomes following attainment of guideline-recommended LDL-C control between ACS and CCS. METHODS:This multicenter retrospective observational study (ACTION-LDLC; jRCT 1050260064) analyzed 2,560 Japanese patients with coronary artery disease (ACS/CCS = 1,682/878). Risk of major adverse cardiovascular events (MACE; cardiac-caused death + nonfatal MI + coronary revascularization in nonculprit segments) was compared according to achieved LDL-C levels 8 weeks after percutaneous coronary intervention (<55, 55-69 and ≥70 mg/dL) in ACS and CCS, respectively. RESULTS:LDL-C <55 mg/dL was achieved in 29.4% and 32.5% of patients with ACS and CCS, respectively (P = 0.124). During the 3.7- and 3.8-year observation, achieving lower LDL-C levels was associated with reduced MACE risks in ACS (P < 0.001) and CCS (P = 0.040). Notably, lower standardized 3-year MACE rates (ACS = 4.4%, CCS = 9.9%, P < 0.001) and greater absolute risk differences (from ≥70 to <55 mg/dL: ACS = -26.5%, CCS = -5.3%, P < 0.001; from 55-69 to <55 mg/dL: ACS = -11.5%, CCS = -1.1%, P < 0.001) following achieved LDL-C <55 mg/dL were observed in ACS compared to CCS. Furthermore, in patients with achieved LDL-C <55 mg/dL (n = 780), an even lower risk of standardized 3-year MACE existed in ACS patients achieving LDL-C <40 mg/dL (log-rank P = 0.017). In contrast, in those who did not achieve LDL-C <70 mg/dL, risks of standardized 3-year MACE substantially increased in ACS compared to CCS (30.9% vs 15.2%, P < 0.001). CONCLUSIONS:Distinct cardiovascular risks with LDL-C control exist in ACS compared to CCS, suggesting the potential importance of achieving stricter LDL-C goals in ACS patients.

Background LDL-C lowering is often delayed in lower-risk primary-prevention settings as absolute benefits appear modest. Trial evidence for greater relative benefits from pharmacologic LDL-C lowering in lower-risk individuals, supporting genetic studies, could strengthen the rationale for initiating LDL-C-lowering therapies at lower-risk levels. Objectives To quantify i) how RRR for 3P-MACE per 1mmol/L LDL-C-lowering varies by baseline risk, ii) the absolute LDL-C reduction required to achieve 25 % RRR at varying risk thresholds. Methods Systematic review and meta-analysis using EMBASE, MEDLINE, and CENTRAL searches for randomized, placebo-controlled lipid-lowering trials in populations with no or low (<20 %) prior atherosclerotic cardiovascular disease prevalence, reporting 3P-MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke). Effect modification of placebo event rate on RRR/1mmol/L was assessed using mixed-effects meta-regression. A second meta-regression plotted the absolute LDL-C reduction associated with 25 % RRR across event-rates. Results 17 trials (105,879 participants) reporting 6076 3P-MACE were included (12 statins only, 5 non-statins); mean age 63.0y, median follow-up 4.4y. LDL-C reduction ranged from 0.38–1.95 mmol/L and placebo event-rate ranged from 0.52 %/year-3.78 %/year. RRR per 1mmol/L LDL-C reduction attenuated from 36 % at 1 %/year event-rate to 13 % at 3 %/year (p < 0.0001). Absolute LDL-C reductions required to achieve 25 % RRR increased with baseline-risk, ranging from 0.36 mmol/L at 1 %/year-risk to 3.09 mmol/L at 3 %/year-risk (p = 0.0001). Conclusion Lower-risk primary prevention populations derive significantly greater relative benefits per 1mmol/L LDL-C lowering. Conversely, higher-risk populations derive less benefit per 1mmol/L LDL-C lowering and hence require greater absolute LDL-C reductions to achieve comparable relative treatment benefits. PROSPERO (CRD420251155320)