Lipoprotein(a): An Emerging Risk Factor in Cardiovascular Diseases – Current Management and Therapeutic Horizons (as of December 2025) Integrative Functional Medicine IA, IL, MO, GA FL, TX

IntroductionLipoprotein(a) [Lp(a)] is a genetically determined lipoprotein that has emerged as one of the most important independent causal risk factors for atherosclerotic cardiovascular disease (ASCVD), ischemic stroke, and calcific aortic valve stenosis. Approximately 20–25% of the global population has elevated Lp(a) levels, which confer a lifelong increase in cardiovascular risk (Reyes-Soffer et al., 2022; Nordestgaard & Langsted, 2023).

Biology and PathophysiologyLp(a) consists of an LDL-like particle in which apolipoprotein B-100 is covalently bound to apolipoprotein(a), a glycoprotein with high homology to plasminogen. Inter-individual variation in Lp(a) concentration is almost entirely explained by copy-number variation in the LPA gene, resulting in >90% heritability and remarkable stability of levels throughout life (Nordestgaard & Langsted, 2023).

Epidemiology and RiskMendelian randomization studies and large prospective cohorts consistently demonstrate a log-linear, continuous association between Lp(a) concentration and ASCVD risk, independent of LDL-C and other traditional risk factors (Kamstrup, 2024). Individuals with Lp(a) ≥125 nmol/L (≈50 mg/dL) have a 2–3-fold higher lifetime risk of myocardial infarction and aortic valve stenosis compared with those with levels <50 nmol/L (Reyes-Soffer et al., 2022).

Risk AssessmentMajor North American and European guidelines now recommend at least one lifetime measurement of Lp(a) in:

• Patients with premature ASCVD or strong family history

• Familial hypercholesterolemia

• Recurrent ASCVD despite optimal LDL-C lowering

• Intermediate or high calculated risk in whom further risk stratification is desired (Grundy et al., 2019; Mach et al., 2020; Pearson et al., 2021; Reyes-Soffer et al., 2022).

Assays should report results in nmol/L (particle number) rather than mg/dL (total mass) for better standardization.

Current Management (2025)No drug is yet approved specifically for lowering Lp(a). Management therefore focuses on aggressive modification of all other risk factors:

1. LDL-C lowering: High-intensity statins ± ezetimibe ± bempedoic acid ± PCSK9 inhibitors to reach guideline-directed goals. Note: statins may slightly raise Lp(a) (≈10%), whereas PCSK9 inhibitors lower it modestly (23–30%) (Waldmann & Parhofer, 2024).

2. Lipoprotein apheresis: The only currently approved Lp(a)-specific therapy in many jurisdictions; indicated in very high-risk patients with Lp(a) >100–200 nmol/L and progressive ASCVD despite maximal medical therapy (Duell et al., 2023).

3. Other traditional therapies: Niacin is no longer recommended because of lack of outcome benefit and side effects.

Lifestyle MedicineLp(a) concentrations are largely unaffected by diet, exercise, weight loss, or alcohol moderation (Enkhmaa & Berglund, 2025; Cronin & Steiner, 2024). Lifestyle interventions remain essential, however, for controlling co-existing risk factors (blood pressure, diabetes, smoking, obesity, inflammation) and should follow standard AHA/ESC recommendations.

Emerging Lp(a)-Specific Therapies (Phase 3 and beyond, December 2025)

Agent	Company	Mechanism	Phase / Status (Dec 2025)	Mean Lp(a) Reduction	Key Trials / Expected Primary Completion
Pelacarsen	Novartis / Ionis	Antisense oligonucleotide	Phase 3 ongoing	70–80%	Lp(a)HORIZON (CV outcomes) – 2026
Olpasiran	Amgen	siRNA	Phase 3 ongoing	>95%	OCEAN(a)-Outcomes – 2027–2028
Lepodisiran	Eli Lilly	siRNA (single-dose durability)	Phase 3 ongoing	>90% at 1 year	ACCLAIM-Lp(a) – 2029
Zerlasiran	Silence Therapeutics	siRNA	Phase 2 completed → Phase 3 planned	>80–90%	–
Muvalaplin	Eli Lilly	Oral small molecule (apo(a)–apoB disruptor)	Phase 2 completed	63–75%	Phase 3 planning
Obicetrapib (± ezetimibe)	NewAmsterdam Pharma	Oral CETP inhibitor	Phase 3 (LDL-C primary endpoint)	30–50%	PREVAIL (CV outcomes)

(Khera & Hegele, 2025; Tsimikas et al., 2023 and subsequent updates)

These agents represent the first realistic prospect of directly attenuating the causal risk conferred by genetically elevated Lp(a). Cardiovascular outcome data are expected starting in 2026–2029.

ConclusionLp(a) is a potent, prevalent, and currently under-recognized causal risk factor for ASCVD. Until specific therapies are approved, clinicians must screen appropriately, aggressively treat all modifiable risk factors, and consider lipoprotein apheresis in extreme cases. The rapid development of potent LPA gene-silencing drugs and oral small molecules promises to transform the management of this previously untreatable risk factor within the next 3–5 years.

Dr. Kim practices virtual integrative & functional medicine serving IA, IL, MO, GA, FL, TX. www.directintegrativecare.com

Yoon Hang Kim MD Integrative & Functional Medicine Expert Serving IA, IL, MO, FL, GA, TX

References (APA Style)

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