Lipid management for cardiovascular disease (CVD) prevention is entering a new phase defined by two converging trends: earlier intervention (“the earlier the better”) and broader targeting of residual risk beyond low-density lipoprotein cholesterol (LDL-C). Recent trial readouts and guideline updates (2025–2026) have reinforced the principle that sustained, deep lowering of atherogenic lipoproteins—especially LDL-C and apolipoprotein B (apoB)—reduces future events, while also elevating triglyceride-rich lipoproteins, lipoprotein(a) [Lp(a)], and metabolic comorbidities as major contributors to persistent risk.1,2 The field’s most visible breakthroughs include (1) expansion of proprotein convertase subtilisin/kexin type 9 (PCSK9) therapy into event reduction for high-risk patients without prior myocardial infarction (MI)/stroke (primary prevention), (2) the emergence of oral PCSK9 inhibition as a potentially adherence-transforming modality, (3) pivotal evidence that targeting apolipoprotein C-III (apoC-III) can meaningfully reduce severe hypertriglyceridemia and pancreatitis events, and (4) an accelerating race to develop Lp(a)-lowering agents with outcomes data anticipated in 2026.3,4,5,6 Meanwhile, guidelines in Europe and North America increasingly emphasize risk-based intensification, earlier combination therapy, and “lower for longer” LDL-C strategies.1 Taken together, these developments suggest a coming era of personalized lipid prevention that is earlier, more aggressive, and mechanistically broader than the statin-only paradigm of prior decades.
For years, clinicians have known that LDL cholesterol contributes causally to atherosclerosis, but recent discussions in preventive cardiology have sharpened the message: waiting to intensify therapy leaves patients accumulating arterial plaque and “lipid burden” that is harder to reverse later. At the 2025 National Lipid Association (NLA) Scientific Sessions, experts underscored a shift away from a slow, stepwise “treat-to-target” mindset toward rapid initiation and early combination therapy, especially for high-risk patients.7
This clinical reframing is echoed in the NLA’s 2025 guidance—explicitly summarized as “Lower for Longer is Better”—which emphasizes that maintaining LDL-C at very low levels long-term is both safe and essential for lowering atherosclerotic cardiovascular disease (ASCVD) risk.8 In parallel, European guidance updates released during ESC Congress 2025 focus on optimizing lipid management across complex populations (e.g., acute coronary syndrome, cancer, human immunodeficiency virus [HIV]), reinforcing the need to reduce cardiovascular risk with individualized approaches and newer LDL-lowering options for those who cannot tolerate statins.1
As a whole, “The earlier the better” is no longer just a slogan; it reflects a prevention strategy built on earlier risk identification, earlier therapy intensification, and longer duration of protection—especially as novel tools broaden what can be treated.
A major headline from American Heart Association (AHA) 2025 came from the VESALIUS-CV trial, which tested evolocumab in high-risk patients with atherosclerosis or diabetes but without prior myocardial infarction or stroke. The trial showed evolocumab reduced the risk of first major cardiovascular events compared with placebo, with a 25% risk reduction reported in a composite of CHD death, MI, or ischemic stroke. A meaningful LDL-C reduction was also observed (median LDL-C 45 mg/dL at 48 weeks in a substudy).3,9 This matters because it strengthens the logic of earlier aggressive LDL-C lowering with potent non-statin therapies in patients who have not yet had an event but are at high risk.
Injectable PCSK9 therapies are effective yet historically underused in some settings. An important development is the progress of enlicitide decanoate (MK-0616), an investigational oral PCSK9 inhibitor.
Positive topline results have been recently announced from the Phase 3 CORALreef (HeFH and AddOn) studies, noting statistically significant, clinically meaningful LDL-C reductions and no clinically meaningful differences in adverse events versus comparators for adults with hyperlipidemia already on lipid-lowering therapies. This Phase 3 program includes trials in heterozygous familial hypercholesterolemia (HeFH), hypercholesterolemia with add-on comparisons, and a large outcomes study targeting time to first major adverse cardiovascular events.10
Importantly, CORALreef HeFH demonstrated an approximately 58% LDL-C reduction at 24 weeks (placebo-adjusted) and sustained efficacy through 52 weeks of treatment, with reductions in non-HDL-C, apoB, and Lp(a) also observed.11
If oral PCSK9 therapy proves scalable and durable in real-world practice, it may reduce barriers linked to injections and could materially improve long-term adherence—a critical determinant of prevention benefits.
While LDL-C remains central, triglyceride-rich lipoproteins and remnants increasingly represent “residual risk.” This is especially dramatic in severe hypertriglyceridemia, where pancreatitis risk is high and standard care is often insufficient. In recent years there is a growing trend of using antisense oligonucleotides (ASO) to treat lipid disorders. ASOs are short, synthetic, single-stranded nucleic acids that bind to specific mRNA, preventing the translation of proteins involved in lipid metabolism (Figure 1).12
Figure 1. The mechanism of action of ASOs.12 ASO, antisense oligonucleotides; mRNA, messenger ribonucleic acid; RNaseH1, Ribonuclease H1.
Two pivotal Phase 3 trials—CORE-TIMI 72a and CORE2-TIMI 72b—tested olezarsen, an ASO targeting apoC-III mRNA. The NEJM publication reports large placebo-adjusted triglyceride reductions at 6 months, with significant improvements in apoC-III and remnant measures; and importantly, a lower incidence of acute pancreatitis across both trials (mean rate ratio 0.15). The trial summary of the American College of Cardiology (ACC) similarly highlights significant triglyceride reductions and decreased pancreatitis incidence, with detailed baseline and follow-up triglyceride values and a favorable overall adverse-event profile, though with some safety signals (e.g., liver enzyme elevations, thrombocytopenia more frequent at higher dose) consistent with close monitoring.13
These outcomes have been generally considered as a potential paradigm change for severe hypertriglyceridemia, emphasizing the scale of triglyceride lowering and pancreatitis event reduction on top of standard-of-care therapy. From the prevention perspective, even though these trials focus on a very high-risk lipid phenotype, they validate apoC-III as a mechanistic target and push triglyceride-rich particle biology toward the center of CVD prevention discussions.
Another late-breaking 2025 development is DR10624, described as a first-in-class medication activating FGF21, glucagon, and GLP-1 receptors. The AHA reported that, in a small Phase 2 trial, DR10624 lowered triglycerides in most patients by more than 60% and reduced liver fat by about 63%, an important finding given the overlap between severe hypertriglyceridemia and fatty liver disease. The ACC also provided additional details on dosing arms and response rates, noting that nearly 90% of treated patients achieved triglycerides below 500 mg/dL in this short, 12-week trial. The corresponding ClinicalTrials.gov record confirms the Phase 2 design and completion timeline.14,15
These data are preliminary (conference-level evidence), but they illustrate a broader trend: lipid prevention is increasingly intertwined with metabolic therapeutics that influence adiposity, hepatic steatosis, insulin resistance, and lipoprotein flux—not just LDL receptor biology.
Lp(a) is widely recognized as a genetically determined, independent risk factor that is not meaningfully lowered by lifestyle or many standard lipid drugs. A 2026 editorial in the Journal of Clinical Lipidology emphasizes that multiple phase 3 programs are underway using different modalities—ASOs (e.g., pelacarsen), siRNAs (e.g., olpasiran, SLN360/zerlasiran, lepodisiran), and even oral small molecules (e.g., muvalaplin)—with several cardiovascular outcomes trials expected to complete in 2026.16
The pelacarsen outcomes trial Lp(a)HORIZON is registered on ClinicalTrials.gov with an estimated primary completion in early 2026 and enrollment exceeding 8,000 participants. It is expected that the Phase 3 pelacarsen data will be available in the first half of 2026, reflecting event accrual timing in this event-driven trial.17
While not itself an outcomes readout yet, earlier phase data and continuing development for olpasiran have catalyzed broad interest. Industry reporting notes that olpasiran’s mid-stage results showed substantial Lp(a) lowering and that phase 3 programs are designed to test whether this translates into fewer cardiovascular events.18
Of note, if ongoing trials show that Lp(a)-lowering reduces hard outcomes, prevention strategies may soon include routine Lp(a) measurement and targeted therapy in genetically predisposed patients—representing a true expansion beyond LDL-centric models.16
A 2025 review in the European Heart Journal summarizes the “evolving landscape” of lipid lowering, framing LDL-C as primary but highlighting triglycerides, apoB, and Lp(a) as key drivers of residual risk. It also outlines established and emerging targets: PCSK9 (including evolocumab, inclisiran, and newer agents), ezetimibe, bempedoic acid, and emerging therapies such as ANGPTL3 and apoC-III inhibitors, and revisited CETP inhibition.19
This framework helps connect the latest trial headlines: PCSK9 inhibition with stronger evidence across prevention stages (secondary and high-risk primary prevention), ApoC-III inhibition (olezarsen) showing that triglyceride-rich particles and pancreatitis risk can be modified with modern nucleic acid therapeutics, Lp(a) poised to be the next major frontier if outcomes trials confirm benefit, and oral modalities [oral PCSK9, oral Lp(a) approaches] could broaden reach and adherence.
Although therapeutics dominate headlines, recent prevention trial summaries from AHA 2025 remind us that lipid risk is deeply shaped by social and behavioral context. A 2026 review of AHA 2025 prevention trials notes that home-delivered DASH-style groceries combined with brief counseling improved systolic blood pressure and LDL-C in food-insecure urban settings (GoFresh), and that other programs achieved durable improvements in cardiometabolic risk factors.20
For lipid prevention in the real world, implementation details—access, affordability, medication persistence, and supportive environments—often determine whether “trial efficacy” becomes “population impact.” Oral PCSK9 inhibitors and simplified LDL management guidance may be powerful partly because they can reduce friction in long-term treatment pathways.21
With guidelines emphasizing long-term low LDL (“lower for longer”), clinicians may increasingly: identify high-risk individuals earlier using modern risk algorithms and risk enhancers; intensify lipid therapy earlier via combination regimens; and consider potent non-statins sooner in appropriate high-risk groups.
The attention to apoB, triglyceride-rich remnants, and Lp(a) suggests lipid clinics will increasingly track beyond LDL-C alone. The Journal of Clinical Lipidology editorial notes that many guidelines recommend measuring Lp(a) at least once in a lifetime, and anticipates multiple Lp(a) outcomes trials completing in 2026, which could change practice patterns.16
ipid research in 2025–2026 is redefining CVD prevention around a central message: the earlier the better—earlier identification of risk, earlier intensification of therapy, and longer duration of exposure to protective lipid levels. This shift is reinforced by major guideline and consensus updates emphasizing “lower for longer” LDL-C strategies and simplified treatment pathways.
At the same time, the science has moved decisively beyond LDL-C alone. Pivotal evidence for apoC-III inhibition demonstrates that severe triglyceride-rich lipoprotein disorders can be treated in ways that reduce clinically meaningful events like pancreatitis—validating remnant biology as an actionable pathway and strengthening the case for targeting residual risk. The emergence of oral PCSK9 inhibition points to a future where powerful LDL lowering could become more accessible and adherable for broader populations. Meanwhile, Lp(a) stands as the most anticipated frontier, with multiple outcomes trials expected to read out in 2026—potentially ushering in a new era of genetically targeted prevention.
Taken together, these developments suggest the next decade of lipid prevention will be defined by earlier and more personalized intervention, guided by a wider set of lipoprotein targets and delivered through more varied modalities—from injectables to daily pills and RNA therapeutics—while continuing to rely on scalable lifestyle and community interventions to make prevention real at the population level.
References
1. Mach F, et al. Eur Heart J. 2025;46(42):4359–78. 2. Fukase T, et al. Sci Rep. 2025;16(1):1196. 3. Bohula EA, et al. N Engl J Med. 2026;394(2):117–27. 4. Ho VQT, et al. J Clin Lipidol. 2026;20(1):31–43. 5. de Moura de Souza M, et al. Metabolism. 2025;167:156187. 6. Cho L, et al. Am Heart J. 2025;287:1-9. 7. Pharmacy Times. Highlights From NLA 2025: Early LDL-C Reduction and Emerging Therapies. 9 July 2025. Available from: https://www.pharmacytimes.com/view/highlights-from-nla-2025-early-ldl-c-reduction-and-emerging-therapies. [Accessed 15 January 2026]. 8. Jackson EJ, et al. J Clin Lipidol . 2025;19(5):1200–7. 9. ACC. VESALIUS-CV: Evolocumab vs. Placebo in Patients Without Previous MI or Stroke. 8 November 2025. Available from: https://www.acc.org/Latest-in-Cardiology/Articles/2025/11/03/16/19/sat-1010am-vesalius-aha-2025. [Accessed 15 January 2026]. 10. Pharmaceutical Executive. Phase III Trials Show Merck’s Oral PCSK9 Inhibitor Significantly Reduces LDL-Cholesterol in Hyperlipidemia. 9 June 2025. Available from: https://www.pharmexec.com/view/phase-iii-trials-show-merck-oral-pcsk9-inhibitor-significantly-reduces-ldl-cholesterol-hyperlipidemia. [Accessed 15 January 2026]. 11. Ballantyne CM, et al. JAMA. 2026;335(2):129–39. 12. Ersöz E, et al. Drug Dev Res. 2024;85(4):e22187. 13. Marston NA, et al. N Engl J Med. 2026;394(5):429–41. 14. ACC. Late-Breaking Science Highlights New Treatments For Severe Hypertriglyceridemia. 8 November 2025. Available from: https://www.acc.org/latest-in-cardiology/articles/2025/11/03/16/19/sat-940am-hypertriglyceridemia-aha-2025. [Accessed 15 January 2026]. 15. ClinicalTrials.gov. A Phase II Study to Evaluate the Efficacy and Safety of of DR10624 in Subjects With Severe Hypertriglyceridemia. 13 January 2026. Available from: https://clinicaltrials.gov/study/NCT06555640. [Accessed 23 January 2026]. 16. Maki KC, et al. J Clin Lipidol. 2026;20(1):1–3. 17. ClinicalTrials.gov. Assessing the Impact of Lipoprotein (a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD (Lp(a)HORIZON). 31 December 2025. Available from: https://clinicaltrials.gov/study/NCT04023552. [Accessed 23 January 2026]. 18. ClinicalTrials.gov. OCEAN(a)-PreEvent - Olpasiran Trials of Cardiovascular Events And LipoproteiN(a) Reduction to Prevent First Major Cardiovascular Events. 29 January 2026. [Accessed 30 January 2026]. 19. Ballantyne CM, et al. Eur Heart J. 2025;46(44):4737–50. 20. Juraschek SP, et al. JAMA. 2026;335(1):36–48. 21. Patel S, et al. J Clin Med. 2025;14(17):6034.
