BACKGROUND AND AIMS:As survival improves in patients with homozygous familial hypercholesterolemia (HoFH), exposure to traditional cardiovascular risk factors may increasingly influence outcomes. This study aimed to determine the prevalence of traditional coronary artery disease (CAD) risk factors-hypertension, diabetes, smoking, and obesity-and their associations with CAD in HoFH. METHODS:We performed a cross-sectional analysis of patients enrolled in the HoFH International Clinical Collaborators (HICC) registry (NCT04815005) between February 2016 and December 2024. Logistic regression was used to estimate the association between risk factors and CAD in risk factor propensity score-matched subgroups. Analyses were stratified by sex, on-treatment LDL-C tertiles, and country-income status. RESULTS:Among 912 patients with HoFH (53.3% female; median age 33.0 years), the prevalence of hypertension was 16.5%, diabetes 3.8%, smoking 8.2%, overweight 25.4%, and obesity 17.6%. Cardiovascular risk factors were more frequent in older patients (e.g., hypertension: 25.7% ≥ 30 years vs. 4.3% < 30 years; p < 0.001), in those from high-income countries (17.8% vs. 14.9%; p = 0.011), and in those achieving lower LDL-C levels (24.1% in the lowest vs. 14.6% in the highest LDL-C tertile; p = 0.004). After propensity score matching, hypertension was significantly associated with CAD (OR 1.85; 95%CI 1.11-3.08, p = 0.02), while diabetes, smoking, and obesity were not associated. CONCLUSIONS:Despite the dominant role of cumulative LDL-C burden in the development of CAD, our findings indicate an association between hypertension and CAD in HoFH. Although causal inference is limited by the cross-sectional design, these results highlight the importance of proactive identification and management of hypertension in HoFH alongside intensive lipid-lowering therapy.

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder marked by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels from birth and a very high risk of premature atherosclerotic cardiovascular disease (ASCVD). To address the global paucity of observational data, the HoFH International Clinical Collaborators (HICC) registry (NCT04815005) was established. To date, over 950 HoFH individuals from 45 countries have been included. The median age at diagnosis was 12 years (IQR: 5.5-27.0), and untreated LDL-C levels were markedly elevated [median 14.7 mmol/L (11.6-18.4)]. At diagnosis, 9% had ASCVD or (supra)aortic valve disease, and despite the widespread use of lipid-lowering therapy (LLT), only 4% achieved guideline-recommended LDL-C goals. Early initiation of lipoprotein-apheresis was associated with greater LDL-C reductions and delayed ASCVD onset. Cardiovascular burden remains substantial, with a median age at death of 37 years [20-50]. No sex differences were observed in age or clinical characteristics at diagnosis, treatment patterns, or timing of ASCVD, although the usual sex gap in cardiovascular disease onset was absent. Profound global disparities persist, including limited genetic screening, restricted access to LLT, and earlier onset of major adverse cardiovascular events in non-high-income countries. Reproductive care for women remains highly variable and understudied. The HICC aims to guide global stakeholders in improving clinical outcomes for individuals with HoFH through earlier diagnosis, equitable access to advanced therapies, and broader inclusion of underserved regions. By generating evidence from routine clinical care and patient-reported data, identifying gaps in care, and fostering international collaboration, HICC seeks to advance a more equitable and effective global approach to HoFH management.

INTRODUCTION:Atherosclerotic cardiovascular disease (ASCVD) remains the leading global cause of morbidity and mortality, with elevated low-density lipoprotein cholesterol (LDL-C) as a major modifiable risk factor. Despite intensive statin therapy, many high-risk patients do not achieve increasingly stringent LDL-C goals, highlighting the need for additional lipid-lowering strategies. The development of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has significantly advanced lipid management, although currently available agents require subcutaneous administration and may be limited by adherence, accessibility, and cost. AREAS COVERED:This review discusses the pharmacological profile, clinical efficacy, safety, and potential therapeutic positioning of enlicitide decanoate, the first oral PCSK9 inhibitor. Evidence from phase 2 and phase 3 CORALreef program clinical trials evaluating enlicitide in patients with hypercholesterolemia, heterozygous familial hypercholesterolemia, and established or high risk for ASCVD is summarized. Available data on enlicitide are also compared with existing lipid-lowering therapies, including statins, ezetimibe, and approved therapies targeting PCSK9. EXPERT OPINION:Enlicitide decanoate is a promising addition to lipid-lowering therapy, potentially expanding access to PCSK9 inhibition through oral administration. However, its definitive clinical role will depend on cardiovascular outcomes data, long-term safety, adherence in real-world practice, and cost-effectiveness compared with established injectable therapies.

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.

AIM:Current proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (the monoclonal antibodies evolocumab and alirocumab, and the siRNA inclisiran) require parenteral administration, which may limit long-term adherence. Orally active PCSK9 inhibitors could improve convenience and treatment accessibility. This meta-analysis evaluates LDL-C reduction and other lipid changes reported in randomized controlled trials (RCTs) of oral PCSK9 inhibitors. METHODS:RCTs comparing oral PCSK9 inhibitors with placebo and reporting LDL-C changes were identified through PubMed, EMBASE, Web of Science, CENTRAL, and ClinicalTrials.gov up to November 2025. Pooled mean percentage changes in lipid parameters were calculated using random- and fixed-effects models. Serious adverse events (SAEs) were analysed using risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS:Five RCTs on three different molecules (enlicitide, NNC0385-0434, and laroprovstat), including a total of 3,295 participants with hypercholesterolemia receiving stable doses of background lipid-lowering therapy prior to study initiation, met the inclusion criteria. Treatment durations ranged from 8 to 24 weeks. Pooled analysis showed a significant LDL-C reduction of -59.31% (95% CI -62.33 to -56.28) compared with placebo. Additional lipid parameters also improved: apolipoprotein B (-49.53%, 95% CI -54.19 to -44.79), non-HDL cholesterol (-55.41%, 95% CI -57.35 to -53.48), and Lipoprotein(a) (-22.74%, 95% CI -26.67 to -18.81). The pooled RR for SAEs was 0.84 (95% CI 0.68-1.03; p = 0.41), indicating no increased risk versus placebo. CONCLUSIONS:Oral PCSK9 inhibitors demonstrate potent LDL-C-lowering efficacy, comparable to parenteral PCSK9i, with favourable effects on other atherogenic lipids and a reassuring short-term safety profile.

Background: Elevated low-density lipoprotein cholesterol (LDL-C) is a causal driver of atherosclerotic cardiovascular disease (ASCVD). Although current European guidelines recommend intensive LDL-C lowering strategies in high, very high, and extreme cardiovascular risk patients, real-world data consistently show suboptimal goal achievement. Aim and Methods: The TRAP-HC study aims to evaluate real-world treatment patterns, LDL-C goal attainment, and adherence to lipid-lowering therapies (LLTs) in patients with hypercholesterolemia, including familial hypercholesterolemia (FH), at high, very high, and extreme cardiovascular risk over a 1-year follow-up. TRAP-HC is a multicenter, prospective, longitudinal, observational study conducted across up to 15 lipid clinics within the Italian LIPIGEN network. Approximately 2,500 adult patients will be enrolled and followed for one year. The primary endpoint will be the change in LDL-C levels and achievement of guideline-recommended LDL-C goals. Secondary endpoints will include adherence, treatment intensification patterns, and patient-reported attitudes toward therapy. Conclusion: TRAP-HC will provide contemporary real-world evidence on lipid management in high-risk populations and identify gaps between guideline recommendations and clinical practice.

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.

BACKGROUND:Enlicitide decanoate, an oral proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, was shown to reduce low-density lipoprotein (LDL) cholesterol levels in a phase 2 trial; longer-term data are needed. METHODS:In this multinational, double-blind, randomized, placebo-controlled trial, we enrolled adults with a history of a major atherosclerotic cardiovascular disease event with an LDL cholesterol level of 55 mg per deciliter or higher and those who were at risk for a first atherosclerotic cardiovascular disease event with an LDL cholesterol level of 70 mg per deciliter or higher. Participants were assigned in a 2:1 ratio to receive enlicitide at a dose of 20 mg or placebo daily for 52 weeks. The primary end point was the mean percent change in LDL cholesterol level from baseline to week 24. Key secondary end points were the mean percent change in LDL cholesterol level at week 52 and the mean percent change in levels of non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B and the percent change in lipoprotein(a) level at week 24. RESULTS:Of the 2909 participants in the intention-to-treat population, 1935 received enlicitide and 969 received placebo (5 did not receive enlicitide or placebo). The mean age of the participants was 63 years, and 39.3% were women. The mean (±SD) LDL cholesterol level at baseline was 96.1±38.9 mg per deciliter. The mean percent change in LDL cholesterol levels at week 24 was -57.1% (95% confidence interval [CI], -61.8 to -52.5) with enlicitide and 3.0% (95% CI, 0.9 to 5.1) with placebo, representing an adjusted between-group difference of -55.8 percentage points (95% CI, -60.9 to -50.7; P<0.001). The mean percent change in LDL cholesterol level at week 52, the mean percent changes in non-HDL cholesterol and apolipoprotein B levels at week 24, and the percent change in lipoprotein(a) levels at week 24 were significantly greater with enlicitide than with placebo (P<0.001 for all comparisons). The incidence of adverse events did not appear to differ between the groups. CONCLUSIONS:Among participants who had a history of or were at risk for a first atherosclerotic cardiovascular disease event, treatment with the oral PCSK9 inhibitor enlicitide resulted in significantly lower LDL cholesterol levels than placebo at 24 weeks. (Funded by MSD [Rahway, NJ]; CORALreef Lipids ClinicalTrials.gov number, NCT05952856.).

BACKGROUND:Many adults fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals on statin monotherapy, requiring additional nonstatin lipid-lowering medication. Enlicitide, an oral proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor, lowered LDL-C by 60% compared with placebo; its efficacy compared with other oral nonstatin therapies has yet to be examined. OBJECTIVES:This study assessed the efficacy of enlicitide, a novel oral PCSK9 inhibitor, vs other oral nonstatin therapies. METHODS:In this phase 3, randomized, double-blind, active-comparator trial, statin-treated adults aged ≥18 years with LDL-C ≥55 mg/dL and a previous major atherosclerotic cardiovascular disease (ASCVD) event, or LDL-C ≥70 mg/dL if at intermediate to high risk for a first event, were randomized in 2:1:1:2 fashion to 20 mg enlicitide (n = 101), 180 mg bempedoic acid (n = 50), 10 mg ezetimibe (n = 50), or 180 mg bempedoic acid plus 10 mg ezetimibe (n = 100) once daily for 56 days. The primary endpoint was mean percentage change in LDL-C from baseline to day 56; secondary endpoints included mean percentage changes in apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (nonHDL-C). Safety endpoints included overall adverse events (AEs) and discontinuations due to AEs. RESULTS:Among 301 randomized participants (mean age 64.4 years, 37% female, 98% receiving moderate- to high-intensity statin), 298 (99.0%) completed the trial. The mean percentage change in LDL-C from baseline to day 56 was -64.6% (95% CI: -68.3% to -60.9%) with enlicitide, -6.3% (95% CI: -13.5% to 0.8%) with bempedoic acid, -27.8% (95% CI: -32.3% to -23.4%) with ezetimibe, and -36.5% (95% CI: -40.8% to -32.2%) with bempedoic acid plus ezetimibe; enlicitide was superior to each comparator (all P < 0.001). Reductions in ApoB and nonHDL-C were also greater with enlicitide (all P < 0.001). Proportions of participants with AEs and discontinuations due to AEs were similar across treatment arms. CONCLUSIONS:In statin-treated adults with a history of a major ASCVD event or at increased risk for a first event, enlicitide achieved greater reductions in LDL-C, ApoB, and nonHDL-C than other oral nonstatin therapies, demonstrating its potential role as an important add-on option when LDL-C goals are not met with the use of statins alone. (A Study to Evaluate the Efficacy and Safety of Enlicitide Decanoate [MK-0616, Oral PCSK9 Inhibitor] Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia [MK-0616-018] [CORALreef AddOn; NCT06450366).

BACKGROUND AND AIMS:Familial hypercholesterolemia (FH), primarily caused by pathogenic LDLR, APOB, or PCSK9 variants, results in elevated LDL-C and increased cardiovascular risk. Genetic testing offers the definitive diagnosis, yet global approaches to FH genetic testing remain unstandardized. We investigate current testing practices worldwide and provide relevant recommendations. METHODS:A survey was distributed to national lead-investigators (NLIs) of 68 countries in the FH-Studies Collaboration, assessing referral criteria, assay methodologies, target genes, and pathogenicity interpretation methods. RESULTS:NLIs from centres in 55/68 countries (81%) responded, spanning Africa (N=2), Americas (N=6), Asia (N=20), Europe (N=26), and Oceania (N=1). DLCN scores were the most common reason for referral to genetic testing (adults:72%; children:57%). Simon Broome and MEDPED criteria were reported only by centres from high-income countries (adults: 7% and 2%; children: 12% and 2%). Methods for testing in index versus non-index cases were significantly different (p <0.001). Next-generation sequencing (NGS) was the predominant assay method for index cases (62%), while Sanger sequencing was favoured for non-index (71%). However, these testing techniques did not differ between centres from high- and non-high-income countries for index cases (p=0.74) and non-index cases (p=0.49). Copy-number variants (CNVs) were assessed by 65% of centres, with most integrating CNV analysis into NGS platforms (86%) and others (14%) using multiplex ligation-dependent probe-amplification (MLPA) or microarrays. Screening encompassed LDLR (100%), APOB (97%), PCSK9 (95%), and other genes. Most centres (96%) incorporated pathogenicity interpretation into their reports, adhering largely to American College of Medical Genetics and Genomics guidelines. CONCLUSIONS:FH genetic testing practices vary widely across countries surveyed, emphasizing the need for global standardization to enhance accuracy and comparability of FH diagnoses worldwide. We suggest that genetic testing should include the three FH-causing genes and ideally the five associated/phenocopy genes.

This review examines the emerging role of cholesteryl ester transfer protein (CETP) inhibition, with a focus on obicetrapib, in lipid management and its potential implications beyond atherosclerotic cardiovascular disease (ASCVD), including neurodegeneration, glycaemic control, age-related macular degeneration (AMD), sepsis, and kidney function. Obicetrapib is a potent, selective CETP inhibitor that overcomes the limitations of earlier agents, demonstrating substantial reductions in LDL-C, apolipoprotein B, non-HDL-C, and lipoprotein(a), alongside marked increases in HDL-C. Phase 2 and 3 trials confirm robust lipid-modifying efficacy and favourable safety. Emerging data suggest broader biological effects. Genetic and mechanistic studies link reduced CETP activity to improved brain structure and lower dementia risk, with biomarker analyses showing attenuation of Alzheimer’s disease-related markers, particularly in APOE ε4 carriers. Evidence further indicates potential metabolic benefits, including reduced risk of type 2 diabetes and improved glycaemic control. While genetic studies raise concerns about increased AMD risk, clinical trial data have not confirmed this association. Preclinical and human data suggest a protective role in sepsis via HDL-mediated endotoxin clearance, and early analyses indicate possible renal benefits through slower decline in kidney function. Obicetrapib represents a promising advancement in CETP inhibition, combining potent lipid-lowering effects with a good safety profile. Beyond cardiovascular risk reduction, emerging evidence supports potential roles in neurodegenerative disease, metabolic regulation, infection outcomes, and renal function. Ongoing outcome trials will determine its clinical impact and broader therapeutic relevance.

Chronic kidney disease (CKD) is a major global health concern driven by hypertension and diabetes, with genetic factors playing a key role in its pathogenesis. CX3CR1, the sole known receptor for the chemokine fractalkine, and its polymorphisms T280M and V249I have been implicated in the progression of several chronic diseases. This prospective observational study investigates the role of the CX3CR1 T280M polymorphism in CKD progression to end-stage disease. We included 121 CKD patients with varying renal insufficiency severity. Patients were stratified by CX3CR1-T280M genotype: Group 1 wild-type (T/T, 71.9%) and Group 2 carriers of the mutated allele (T/M or M/M, 28.1%). The primary outcome was kidney replacement therapy (KRT) initiation over 18 years. Cox proportional hazards univariate analysis was used for survival assessment. The M allele for CX3CR1 is associated with higher baseline serum creatinine levels, consistent with previous cross-sectional studies. During follow-up, KRT was initiated in 26 patients (17.2% in Group 1, 32.3% in Group 2). Survival analysis showed a significant association between the CX3CR1-T280M polymorphism and CKD progression (HR 2.28, 95% CI: 1.04–4.98, p 0.039). This study confirms the role of the CX3CR1-T280M polymorphism in determining prognosis in CKD patients, particularly in predicting the risk of a critical outcome such as initiation of KRT.

Most patients with heterozygous familial hypercholesterolemia fail to achieve adequate low-density lipoprotein (LDL) cholesterol lowering. Here we carried out a randomized trial to test the safety and efficacy of obicetrapib, a highly selective cholesteryl ester transfer protein inhibitor that lowers LDL cholesterol levels in patients with heterozygous familial hypercholesterolemia and an LDL cholesterol level ≥70 mg dl-1 on maximally tolerated lipid-lowering therapy. The trial enrolled 354 patients (190 women, 164 men) with a mean LDL cholesterol level of 122 mg dl-1 (87% on statins) who were randomized (2:1) to receive obicetrapib 10 mg or placebo daily for 365 days. For the primary endpoint, the change in LDL cholesterol from baseline to day 84, obicetrapib treatment resulted in a placebo-adjusted change in LDL cholesterol of -36.3% (95% confidence interval -42.2% to -30.4%, P < 0.0001). In analyses of secondary endpoints at day 84, treatment with obicetrapib resulted in placebo-adjusted reductions in apolipoprotein B of -24.4%, non-HDL cholesterol of -34.5% and lipoprotein(a) of -45.9%, as well as a placebo-adjusted increase in high-density lipoprotein cholesterol of +138.7%. Obicetrapib was well tolerated. These findings suggest that obicetrapib is an effective therapy for additional lipid lowering in patients with heterozygous familial hypercholesterolemia. ClinicalTrials.gov registration: NCT05425745 .

Background and aims Although the safety profile of lipid-lowering therapies (LLTs) is known, there are no comprehensive comparative assessments. We aimed to compare the risk of muscle-related events, diabetes, liver dysfunction, and cognitive disorders among LLTs through a network meta-analysis. Methods and results Databases were searched from inception to May 2025. Eligible studies included adult patients, using statins, ezetimibe, PCSK9 monoclonal antibodies (PCSK9mAbs), inclisiran, bempedoic acid, or their combinations as intervention, reporting the information about any of the selected adverse events, a total sample size of ≥200 subjects, and had ≥1 month of intervention. Pooled estimates were assessed by fixed effects model within a frequentist setting. Pooled relative risks (RR) and their 95% confidence interval were estimated.A total of 303,397 subjects from 153 RCTs were included. Bempedoic acid ranked the lowest risk of myalgia (vs PCSK9mAbs, RR 0.80 [0.69, 0.93]). PCSK9mAbs were associated with lower incidence of creatine kinase (CK) elevation, diabetes, and liver dysfunction comparing to statins (statins vs PCSK9mAbs, RR 1.44 [1.14, 1.81], RR 1.13 [1.05, 1.22], and RR 1.38 [1.17, 1.62], respectively). In terms of muscle-related events and cognitive disorders, no significant risk differences were found among treatments and their combinations. Conclusions PCSK9mAbs appear to have a more favourable safety profile regarding the risk of CK elevation, diabetes, and liver dysfunction. Bempedoic acid seem to be a better choice for subjects with high risk of myalgia. This information can be valuable when selecting therapy for specific patient subgroups at higher risk of certain adverse events.

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, with elevated low-density lipoprotein cholesterol (LDL-C) recognized as a causal factor and the primary target for the prevention of atherosclerotic cardiovascular disease (ASCVD). Currently available lipid-lowering agents, including statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 inhibitors, can significantly reduce the risk of cardiovascular events across a broad range of patient populations. New oral therapies with novel mechanisms of action and potentially lower costs compared with biologics (including oral proprotein convertase subtilisin/kexin type 9 inhibitors and a new cholesteryl ester transfer protein inhibitor) are under investigation to expand the armamentarium of lipid-lowering drugs and increase the number of patients who can be treated if they prove clinically beneficial. To fully understand the potential health benefits of lipid-lowering therapies, it is essential to consider the concept of cumulative LDL-C exposure and its lifelong impact on ASCVD risk. Genetic studies, Mendelian randomization, and clinical trials consistently demonstrate the cardiovascular benefits of early reduction in LDL-C. However, despite this evidence, treatment gaps, inadequate prescribing, and suboptimal treatment adherence are widespread. The cost-benefit ratio and public health impact emphasize the potential of LDL-C lowering to prevent cardiovascular events and reduce the health care burden. In addition to LDL-C, other risk factors such as lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein B must be considered, whereas nonlipid-based mechanisms of atheroprotection, such as inflammation modulation and thrombogenic risk reduction, are also being explored. The future of lipid-lowering and ASCVD prevention requires a more individualized lipid management strategy to optimize cardiovascular outcomes across the lifespan. SIGNIFICANCE STATEMENT: Early and sustained low-density lipoprotein cholesterol reduction dramatically reduces lifelong cardiovascular risk; however, the adoption of lipid-lowering strategies in clinical practice remains suboptimal. Bridging this gap by understanding the true potential of lipid-lowering therapies could significantly reduce the global burden of atherosclerotic disease.

Low-density lipoprotein cholesterol (LDL-C) reduction is central to the prevention of atherosclerotic cardiovascular disease. This review examines the evolving shift from goal-oriented lipid management toward an approach that prioritises the magnitude and timing of LDL-C reduction, focusing on the comparative roles of stepwise escalation and upfront combination therapy. Evidence from randomised clinical trials confirms that incremental LDL-C reductions lead to proportional reductions in cardiovascular events, supporting the principles that “lower is better” and “earlier is better.” The concept of cumulative LDL-C burden further highlights the importance of early and sustained LDL-C lowering. Upfront combination therapy, typically combining statins with ezetimibe, bempedoic acid, and, when indicated, proprotein convertase subtilisin/kexin type 9 inhibitors, achieves faster and greater LDL-C reductions than statin monotherapy and improves attainment of guideline-recommended goals, particularly in very high-risk patients. Conversely, while guideline-endorsed, the traditional stepwise approach may delay optimal LDL-C reduction due to reassessment intervals and therapeutic inertia, prolonging exposure to atherogenic lipoproteins in high-risk patients. Stepwise escalation remains appropriate for patients at low to moderate cardiovascular risk, those with modest LDL-C elevations, concerns about tolerability, or where cost and access limit early use of non-statin agents. Upfront combination therapy is an effective strategy for rapid LDL-C reduction in patients at high or very high cardiovascular risk, whereas a stepwise approach remains suitable for lower-risk individuals. Optimal lipid management requires an individualised strategy that integrates cardiovascular risk, baseline LDL-C, safety, adherence, and health system considerations, rather than rigid adherence to a single therapeutic goal.