Table 1
Effect of various therapies on lipoprotein(a) levels. apo(a): apolipoprotein(a); apoB: apolipoprotein B; ASCVD: atherosclerotic cardiovascular disease; ASPREE: ASPirin in Reducing Events in the Elderly; BROOKLYN: Bempedoic Acid and Ezetimibe for LDL-C Lowering in Patients with Established ASCVD; CAD: coronary artery disease; CETP: cholesteryl ester transfer protein; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; FDA: Food and Drug Administration (United States); FH: familial hypercholesterolemia; FOURIER: Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; HPS2-THRIVE: Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events; IL-6: interleukin-6; LDL: low-density lipoprotein; LDL-C: low-density lipoprotein cholesterol; Lp(a): lipoprotein(a); LPA: ipoprotein(a) gene; mRNA: messenger ribonucleic acid; N/A: Not applicable; ODYSSEY Outcomes: Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia; ORION: Inclisiran for subjects with ASCVD or ASCVD-risk equivalents and elevated LDL-C; PAD: peripheral artery disease; PCSK9i: proprotein convertase subtilisin/kexin type 9 inhibitors
| DRUG | ASSOCIATION WITH Lp(a) | CLINICAL SIGNIFICANCE | MECHANISM |
|---|---|---|---|
| Aspirin | No effect | Post hoc analyses of primary prevention trials (ASPREE and Women’s Health Study) suggest net benefit in those with high Lp(a) | Related to its antiplatelet effect mitigating the prothrombotic and antifibrinolytic properties of Lp(a) |
| Statins | No effect or modest increase | Cardiovascular benefits from LDL-C reduction outweigh modest Lp(a) increase | Upregulation of hepatic LPA gene expression; compensatory increase in hepatic lipoprotein production |
| PCSK9i | Decrease by ~20–25% | Post hoc analysis of FOURIER and ODYSSEY Outcomes suggests cardiovascular benefit may be partly from Lp(a) lowering | Enhanced hepatic clearance of Lp(a) particles; possible reduction in hepatic Lp(a) production |
| Inclisiran | Decrease by ~15–25% | Sustained Lp(a) reduction with twice-yearly dosing; ORION-1 demonstrated consistent effect | Silencing of PCSK9 mRNA leading to increased LDL and Lp(a) receptor expression |
| Ezetimibe | No effect or minimal reduction | Minimal to no effect on Lp(a) | N/A |
| Fibrates (fenofibrate, gemfibrozil) | No effect | Inconsistent: some studies show increases, others show modest decreases; meta-analyses show no effect | N/A |
| Niacin (nicotinic acid) | Decrease | Despite Lp(a) lowering, HPS2-THRIVE showed no cardiovascular benefit and increased adverse effects; not recommended solely for Lp(a) lowering | Downregulation of LPA gene transcription at promoter level; reduced hepatic apo(a) synthesis |
| Omega-3 fatty acids (icosapent ethyl, EPA/DHA) | No effect | No clinically meaningful effect on Lp(a); cardiovascular benefit is independent of Lp(a) | N/A |
| Bempedoic acid | No effect | Meta-analyses show no effect | N/A |
| CETP inhibitors (eg, obicetrapib) | Decrease | Phase 3 BROOKLYN showed 51% Lp(a) reduction at 52 weeks with 10 mg daily | Likely decreased apo(a) production |
| Estrogen | Decrease | Not recommended solely for Lp(a) lowering due to other cardiovascular and thrombotic risks | Downregulation of hepatic LPA gene expression via estrogen response elements |
| Testosterone | Decrease | Not recommended for Lp(a) lowering alone | Androgen-mediated reduction in hepatic apo(a) synthesis |
| Levothyroxine (in hypothyroidism) | Decrease | Normalization of thyroid function can lower Lp(a); hypothyroidism associated with elevated Lp(a) | Correction of hypothyroid state normalizes hepatic lipoprotein metabolism |
| IL-6 inhibitor (eg, ziltivekimab) | Decrease by 16–25% (dose-dependent) | IL-6 inhibition shows dose-dependent Lp(a) reduction; supports Lp(a)–inflammation–atherogenesis axis; under investigation | Inhibition of IL-6 signaling reduces LPA gene transcription; IL-6 response elements present in LPA promoter |
| Lipoprotein apheresis | Decrease | FDA-approved for Lp(a) > 60 mg/dL with FH and progressive CAD/PAD; observational data suggest cardiovascular benefit | Physical removal of apoB-containing lipoproteins including Lp(a) from circulation |
Table 2
Ongoing phase 3 randomized controlled trials on the effect of lipoprotein(a) lowering therapy on cardiovascular outcomes. ASCVD: atherosclerotic cardiovascular disease; CHD: coronary heart disease; CV: cardiovascular; CVD: cardiovascular disease; LDL-C: low-density lipoprotein cholesterol; Lp(a): lipoprotein(a); MACE: major adverse cardiovascular events; MI: myocardial infarction; NCT: National Clinical Trial (ClinicalTrials.gov identifier); PCI: percutaneous coronary intervention; SC: subcutaneous
| DRUG | STUDY | DESIGN | PRIMARY OUTCOME AND STATUS |
|---|---|---|---|
| Antisense Oligonucleotides | |||
| Pelacarsen | Lp(a) HORIZON (NCT04023552) | Double-blind, placebo-controlled; 8,323 patients with established ASCVD, Lp(a) ≥ 70 mg/dL, on LDL-C–lowering therapy; 80 mg SC monthly vs placebo; started December 2019 | MACE (CV death, nonfatal MI, nonfatal stroke, urgent coronary revascularization); enrollment complete; estimated trial completion in June 2026 |
| Small Interfering RNA | |||
| Olpasiran | OCEAN(a)-Outcomes (NCT05581303) | Double-blind, placebo-controlled; ~7,300 patients with ASCVD (MI or PCI + CVD risk factor) and Lp(a) ≥ 200 nmol/L; SC injection vs placebo every 12 weeks; started December 2022 | CHD death, MI, or urgent coronary revascularization. Enrollment complete; estimated trial completion in March 2028 |
| Olpasiran | OCEAN(a)-PreEVENT (NCT07136012) | Double-blind, placebo-controlled; estimated to enroll 11,000 patients at risk of first ASCVD and Lp(a) ≥ 200 nmol/L; SC injection vs placebo every 12 weeks; started August 2025 | CHD death, MI, or urgent coronary revascularization. Recruiting; estimated trial completion in October 2031 |
| Lepodisiran | ACCLAIM-Lp(a) (NCT06292013) | Double-blind, placebo-controlled; 17,300 patients with Lp(a) ≥ 175 nmol/L at risk of CV events or with established ASCVD; SC injection vs placebo; started March 2024 | Cardiovascular death, nonfatal MI, nonfatal ischemic stroke, and urgent coronary revascularization. Enrollment complete; estimated trial completion in March 2029 |
| Small Molecules | |||
| Muvalaplin | MOVE-Lp(a) (NCT07157774) | Double-blind, placebo-controlled trial; estimated to enroll 11,450 patients with established or at risk of ASCVD and Lp(a) ≥ 175 nmol/L; oral drug vs placebo; started September 2025 | Cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, and urgent coronary revascularization. Trial estimated to be completed in March 2031 |