A statin and PCSK9 alternative is on the horizon—here's what we know so far

By Alpana Mohta, MD, DNB, FEADV, FIADVL, IFAAD | Fact-checked by Barbara Bekiesz

Published March 31, 2025

Key Takeaways

Industry Buzz

“CETP inhibitors increase HDL-C, decrease LDL-C, and reduce ApoB and non-HDL-C—key factors in cardiovascular protection.” — Marschall S. Runge, MD, Dean of the Medical School at the University of Michigan

Low-density lipoprotein cholesterol (LDL-C) is the key driver of atherosclerosis and major adverse cardiovascular events (MACE). Despite the widespread use of statins and the emergence of biological drugs like PCSK9 inhibitors, many patients still struggle to achieve optimal LDL-C levels due to factors such as statin intolerance, residual cardiovascular risk, and the high cost of biological treatments.

Now, obicetrapib, a next-generation CETP inhibitor, has shown potential in clinical trials as a safe and effective oral alternative to statins and PCSK9 inhibitors.

Why CETP inhibitors are back in focus

In the mid-1980s, researchers first identified a genetic CETP deficiency in Japanese individuals, noting its association with lower LDL-C, higher HDL-C, and a reduced risk of early atherosclerosis. This finding sparked interest in developing CETP inhibitors as a potential therapeutic approach for improving lipid profiles and cardiovascular health.^[]

Marschall S. Runge, MD, Dean of the Medical School at the University of Michigan, explains, “CETP inhibitors increase HDL-C, decrease LDL-C, and reduce ApoB and non-HDL-C—key factors in cardiovascular protection.”

Board-certified physician Alok Mohta, MD, adds, “Earlier CETP inhibitors, torcetrapib, dalcetrapib, and evacetrapib, were unsuccessful in delivering clinical benefit despite favorable lipid profile changes.” Torcetrapib, in particular, was associated with increased cardiovascular mortality, leading to its discontinuation in 2006.^[] While safer, dalcetrapib and evacetrapib failed to significantly reduce cardiovascular events in large clinical trials.^[]^[]

Obicetrapib, however, is distinct in its selective CETP inhibition, avoiding the off-target effects that plagued its predecessors.^[]

What sets obicetrapib apart?

Compared to other lipid-lowering agents, obicetrapib offers some advantages:^[]^[]

Oral administration, unlike PCSK9 inhibitors, which require subcutaneous injection
Potential for monotherapy or combination use with statins
Significant LDL-C reduction without the adverse cardiovascular effects seen with earlier CETP inhibitors
Favorable safety profile based on current clinical data

Clinical evidence supporting obicetrapib

Phase 2 ROSE trial evaluated obicetrapib 5 mg or 10 mg as an adjunct to high-intensity statin therapy in patients with hypercholesterolemia.^[]

The trial found that obicetrapib reduced LDL-C by approximately 50%, with a favorable safety profile and no significant increase in blood pressure, an issue that contributed to the failure of torcetrapib.

Phase 3 BROOKLYN trial assessed obicetrapib in patients with heterozygous familial hypercholesterolemia (HeFH) who were already on maximally tolerated lipid-lowering therapy.^[] Key findings included:

36.3% reduction in LDL-C at day 84
Sustained LDL-C reduction over 1 year
Over 50% of participants achieved LDL-C levels <70 mg/dL
No significant differences in adverse events compared to the placebo

Phase 3 PREVAIL trial is a large-scale study evaluating obicetrapib’s ability to reduce MACE in over 9,500 patients with ASCVD who have suboptimal LDL-C levels despite maximally tolerated standard therapy. The trial will be completed by 2026 and will provide definitive evidence on whether CETP inhibition can effectively reduce cardiovascular risk.^[]

According to Dr. Runge, if obicetrapib demonstrates a reduction in cardiovascular events in the PREVAIL trial, it could become a widely used oral alternative to PCSK9 inhibitors for patients who do not tolerate statins, require additional LDL-C reduction, or remain inadequately treated with existing therapies.

The drug is also being investigated for its potential cognitive benefits via lipid regulation, as well as for age related-macular degeneration, type 2 diabetes, sepsis, and renal dysfunction.^[]