Gene Therapy for Lipid Management: Dawn of a New Era

NOVEL DIRECTIONS IN LIPID-LOWERING THERAPY FOR THE PREVENTION OF CARDIOVASCULAR DISEASES

Cardiovascular diseases remain the leading cause of mortality worldwide despite significant advances in preventive cardiology. Dyslipidemia is one of the most important modifiable risk factors contributing to the development and progression of atherosclerotic cardiovascular disease. While statins continue to represent the cornerstone of lipid-lowering therapy, a substantial proportion of high-risk patients fail to achieve recommended low-density lipoprotein cholesterol targets or experience recurrent cardiovascular events despite optimal treatment. Recent years have witnessed remarkable progress in the development of novel lipid-lowering agents that target different pathways of lipoprotein metabolism, offering improved efficacy and longterm cardiovascular protection. Emerging therapeutic strategies include proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, small interfering RNA (siRNA)-based therapies such as inclisiran, adenosine triphosphate citrate lyase inhibitors represented by bempedoic acid, and innovative approaches targeting lipoprotein(a), angiopoietinlike protein 3, and apolipoprotein C-III. These therapies not only achieve profound reductions in LDL-C but also address residual cardiovascular risk that persists despite intensive statin therapy. Furthermore, advances in precision medicine, genetic profiling, and artificial intelligence have facilitated individualized lipid management strategies, improving patient adherence and optimizing clinical outcomes. This review summarizes current evidence regarding novel lipid-lowering therapies, their mechanisms of action, clinical efficacy, safety profiles, and future perspectives in the prevention of cardiovascular diseases.

Current Trends in Lipid-Lowering Target Therapy

Approach to the Patient with Elevated Lipoprotein(a).

Lipoprotein(a) [Lp(a)] is a common, genetically determined lipoprotein that is independently associated with myocardial infarction, stroke, peripheral artery disease, and calcific aortic stenosis. Because Lp(a) levels are stable over time and minimally influenced by lifestyle, the 2026 ACC/AHA/Multisociety Dyslipidemia Guideline now recommends one-time measurement in all adults and cascade screening in high-risk families; as a result, endocrinologists can expect to encounter and manage elevated Lp(a) frequently in routine clinical practice. Despite its clinical importance, no approved drug therapies specifically targeting Lp(a) yet exist, therefore management should currently focus on aggressive optimization of traditional risk factors, particularly LDL-C lowering with statins and selective use of adjunctive therapies such as PCSK9 inhibitors and lipid apheresis. Emerging evidence suggests potential benefit of selective aspirin use, while novel therapeutics - anti-sense oligonucleotides and small interfering RNAs - which robustly lower Lp(a) are currently being tested in phase 3 clinical trials. We present case-based examples to highlight practical approaches to risk assessment and management of elevated Lp(a).

Novel Lipoprotein (a) Therapies: A Comprehensive Review

Lipoprotein(a) [Lp(a)] is a genetically determined, independent risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Plasma Lp(a) levels are 70–90% heritable, largely unresponsive to lifestyle changes, and poorly controlled with typical lipid-lowering drugs such as statins and PCSK9 inhibitors. The development of powerful RNA-based therapies offers a new chance to specifically target and significantly lower Lp(a). We examined available phase 1–3 trial data, regulatory updates, and trial registries up to mid-2026 to provide an overview of the current pipeline, ongoing cardiovascular outcomes trials (CVOTs), and new mechanistic and genomic methods. Five agents across three mechanisms have reached late-stage development. Pelacarsen, a GalNAc-conjugated antisense oligonucleotide (ASO), reduces Lp(a) by about 80% via hepatic apo(a) mRNA reduction and is the subject of the phase 3 Lp(a) HORIZON trial, with results due in late 2026. Three small interfering RNA (siRNA) drugs, olpasiran (> 95% reduction, OCEAN(a)-Outcomes), lepodisiran (93.9% reduction lasting over 12 months after one dose, ACCLAIM-Lp(a)), and zerlasiran (96.4% reduction), allow quarterly or possibly yearly dosing. Muvalaplin, the first oral small-molecule Lp(a) inhibitor, interferes with apo(a)-ApoB particle formation and reduces intact Lp(a) by up to 85.8% in phase 2 KRAKEN trials; its phase 3 CVOT (MOVE-Lp(a)) is underway. Additionally, CRISPR/Cas9-based liver gene editing targeting the LPA gene (CTX320) has entered phase 1 studies. All agents have shown good safety so far. The Lp(a) treatment landscape has moved from basic science to an active late-stage clinical pipeline. Positive outcomes from these CVOTs could lead to regulatory approvals and guideline updates affecting hundreds of millions of high-risk patients globally. Recent guidelines now recommend universal Lp(a) measurement, in anticipation of more effective therapies becoming available within the next 1 to 2 years. Created in BioRender. https://biorender.com/y1mu0lh Created in BioRender. https://biorender.com/y1mu0lh

Contemporary non-statin therapies for dyslipidemia management: achieving current lipid targets

The current treatment of dyslipidemia in patients with cardiovascular risk (CR) is based on three well-defined principles: First, given the extensive evidence demonstrating the association between elevated low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular risk, the primary therapeutic target is LDL-C. Second, as current guidelines recommend LDL-C targets below 55 mg/dL for high-risk patients, therapeutic goals according to risk level should be achieved as early as possible, and combination therapy is increasingly necessary. Third evidence indicates that non-statin therapies—including ezetimibe, bempedoic acid, PCSK9 inhibitors (evolocumab and alirocumab), and inclisiran—provide substantial LDL-C reductions and reduce cardiovascular events. These agents are particularly effective in very high-risk and statin-intolerant populations, with bempedoic acid addressing both lipid and inflammatory pathways. Additionally, the fixed-dose combination of bempedoic acid and ezetimibe produces an approximately 36.2% reduction in LDL-C in high-risk patients. Risk-stratified guidelines recommend ezetimibe as first-line add-on therapy, followed by PCSK9 inhibitors or bempedoic acid based on residual LDL-C levels and tolerability. Alirocumab has demonstrated a significant reduction in the primary composite endpoint of major adverse cardiovascular events (MACE), with a favorable trend in all-cause mortality. Furthermore, inflammation (measured by hsCRP) provides complementary prognostic information beyond LDL-C. This expert position paper proposes practical algorithms for a precision medicine approach in Latin America, matching treatment intensity to individual risk profiles for the primary and secondary prevention of atherosclerotic cardiovascular disease.

Beyond therapeutic maximalism: Prioritization and personalization in preventive therapies.

The landscape of lipid management has transitioned from a statin-monotherapy and statin-intensification paradigm to a sophisticated, multi-axis intervention model targeting low-density lipoprotein cholesterol, triglyceride-rich lipoproteins, lipoprotein(a), and vascular inflammation. The emergence of PCSK9-targeted small interfering RNA therapies, CETP inhibitors, and Lp(a)-directed antisense and RNA based agents has enabled complementary modulation of diverse lipid pathways through distinct molecular targets. However, this increasingly multidrug approach may also increase treatment complexity, healthcare burden, and adherence challenges, particularly among high-risk patients already receiving multidrug cardiometabolic therapy. Although intensive and sustained LDL-C lowering remains foundational to preventive cardiology, the real-world effectiveness of increasingly complex treatment strategies may ultimately depend on long-term adherence, affordability, patient capacity, and implementation feasibility. We propose a Clinical Prioritization and Personalization Framework centered on individualized risk-based intensification, comprehensive residual risk management, and optimization of treatment delivery to achieve sustainable, patient-centered cardiovascular protection.