December 17, 2025
More than half of American adults have elevated cholesterol levels, yet statins, first approved decades ago, remain the foundation of lipid management. While effective for many patients, statins do not always achieve target lipid reductions or are poorly tolerated. In response, a growing pipeline of non-statin therapies is expanding treatment options across injectables, oral medicines, RNA-based approaches, and gene editing technologies.
Clinical guidelines now increasingly incorporate add-on therapies when LDL cholesterol targets are not met, particularly in high-risk populations. What distinguishes the current wave of innovation is not only potency, but also durability of effect, dosing convenience, and the potential for long-term or even one-time interventions.
Cholesterol-Lowering Therapies Beyond Statins
The table below summarizes approved and emerging cholesterol-lowering medicines, including modality, target or mechanism of action, development status, and reported lipid effects, based on US regulatory
| Company | Medicine | Modality | Target or Mechanism | Phase or Status | Reported LDL or TG Effect |
| Amgen | Repatha (evolocumab) | Monoclonal antibody, injectable | PCSK9 inhibition | Approved 2015; label expanded 2025 | Approximately 60 percent LDL reduction |
| Regeneron and Sanofi | Praluent (alirocumab) | Monoclonal antibody, injectable | PCSK9 inhibition | Approved 2015 | Approximately 55 percent LDL reduction |
| Novartis | Leqvio (inclisiran) | siRNA, injectable | PCSK9 mRNA silencing | Approved 2020; monotherapy label 2025 | Approximately 50 percent LDL reduction |
| Esperion Therapeutics | Nexletol (bempedoic acid) | Oral small molecule | ACL inhibition | Approved 2020; label expanded 2024 | Approximately 15 to 20 percent LDL reduction |
| Regeneron | Evkeeza (evinacumab) | Monoclonal antibody, injectable | ANGPTL3 inhibition | Approved 2021 for HoFH; label expanded 2023 | LDL and triglyceride reduction |
| Merck | Enlicitide (MK-0616) | Oral peptide | PCSK9 to LDLR interaction blocker | Phase 3 positive 2025 | Up to 61 percent LDL reduction |
| AstraZeneca | AZD0780 | Oral small molecule | PCSK9 inhibition | Phase 3 | Approximately 50 percent LDL reduction |
| Arrowhead Pharmaceuticals | Zodasiran | siRNA, injectable | ANGPTL3 silencing | Phase 3 for HoFH | Approximately 20 percent LDL reduction; up to 63 percent triglyceride reduction |
| Arrowhead Pharmaceuticals | Plozasiran (ARO-APOC3) | siRNA, injectable | APOC3 silencing | Phase 3 | Approximately 45 to 62 percent triglyceride reduction; modest LDL effect |
| Novartis and Ionis | Pelacarsen (TQJ230) | Antisense oligonucleotide | Lipoprotein(a) silencing | Phase 3 | Approximately 35 to 80 percent Lp(a) reduction |
| Amgen | Olpasiran | siRNA, injectable | Lipoprotein(a) silencing | Phase 3 | Approximately 70 to 100 percent Lp(a) reduction |
| Eli Lilly | Lepodisiran (LY3819469) | siRNA, injectable | Lipoprotein(a) silencing | Phase 3 | Greater than 90 percent Lp(a) reduction; modest LDL effect |
| NewAmsterdam Pharma | Obicetrapib | Oral small molecule | CETP inhibition | Phase 3 | Approximately 35 percent LDL reduction |
| Verve Therapeutics | VERVE-102 | Base editing gene therapy | PCSK9 gene inactivation | Phase 1 | Up to 69 percent LDL reduction in early data |
| Verve Therapeutics | VERVE-201 | Base editing gene therapy | ANGPTL3 gene inactivation | Phase 1b | LDL reduction observed |
| Verve Therapeutics | VERVE-301 | Gene editing | Lipoprotein(a) gene inactivation | Preclinical | Lp(a) reduction in preclinical studies |
Note: Phase and approval status reflect the US market and FDA actions and may differ in other regions.
PCSK9 Inhibition: From Injectables to Oral Agents
Monoclonal antibodies such as Repatha and Praluent established PCSK9 inhibition as a highly effective strategy for LDL reduction, particularly in patients at very high cardiovascular risk. Despite strong efficacy and outcomes data, uptake was initially constrained by cost and injection burden.
siRNA-based approaches, led by inclisiran, addressed some of these barriers by offering sustained LDL reduction with twice-yearly dosing. The 2025 label expansion enabling earlier use in high-risk patients reflects growing confidence in durable RNA-based therapies.
The emergence of oral PCSK9 inhibitors represents a potential inflection point. Merck’s enlicitide decanoate has reported positive Phase 3 results across the CORALreef program, with LDL reductions comparable to injectable agents. AstraZeneca’s AZD0780 has also demonstrated substantial LDL lowering in mid- and late-stage trials. If approved, these oral options could significantly expand access and adherence.
Beyond PCSK9: New Targets and Broader Lipid Effects
Other lipid pathways are gaining prominence. ANGPTL3 inhibition, through antibodies or siRNA, offers benefits across LDL cholesterol, triglycerides, and non-HDL cholesterol, particularly in severe dyslipidemias. CETP inhibition, exemplified by obicetrapib, provides moderate LDL reduction alongside favorable effects on HDL cholesterol, ApoB, and lipoprotein(a).
Targeting lipoprotein(a) has emerged as a major focus, with multiple siRNA and antisense programs achieving profound reductions in this genetically driven risk factor. These therapies address a gap not adequately managed by statins or PCSK9 inhibitors.
Gene Editing: Toward One-Time Therapies
Gene editing approaches represent the most forward-looking segment of the lipid pipeline. Early clinical data from PCSK9 and ANGPTL3 base-editing programs suggest the possibility of long-lasting LDL reductions following a single treatment. While still early in development, these results point to a future where durable cholesterol control may be achieved without chronic therapy.
Takeaway
The cholesterol-lowering landscape is undergoing a structural shift. While statins remain foundational, a diverse set of add-on and alternative therapies is expanding treatment flexibility. Twice-yearly siRNA injections, oral PCSK9 inhibitors, and early gene editing programs each address different barriers that previously limited adoption of non-statin therapies. Together, these advances suggest that access, adherence, and overall market penetration are likely to improve as the next generation of lipid-lowering medicines reaches clinical practice.
