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Purpose of Review To discuss the history of cardiovascular outcomes trials of cholesteryl ester transfer protein (CETP) inhibitors and to describe obicetrapib, a next-generation, oral, once-daily, low-dose CETP inhibitor in late-stage development for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD). Recent Findings Phase 1 and 2 trials have evaluated the safety and lipid/lipoprotein effects of obicetrapib as monotherapy, in conjunction with statins, on top of high-intensity statins (HIS), and with ezetimibe on top of HIS. In ROSE2, 10 mg obicetrapib monotherapy and combined with 10 mg ezetimibe, each on top of HIS, significantly reduced low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total LDL particles, small LDL particles, small, dense LDL-C, and lipoprotein (a), and increased HDL-C. Phase 3 pivotal registration trials including a cardiovascular outcomes trial are underway. Summary Obicetrapib has an excellent safety and tolerability profile and robustly lowers atherogenic lipoproteins and raises HDL-C. As such, obicetrapib may be a promising agent for the treatment of ASCVD.

Purpose of Review To provide perspective on the current development status, and potential future role, of obicetrapib, a third-generation cholesterylester transfer protein (CETP) inhibitor. Obicetrapib has received recent attention following positive Phase II clinical trial data and initiation of Phase III trials for the treatment of dyslipidemia and atherosclerotic cardiovascular disease (ASCVD). Recent Findings The ROSE and ROSE2 trials are Phase II studies that examined the lipid lowering effects of obicetrapib in patients on pre-existing high-intensity statin therapy. Obicetrapib significantly reduced key dyslipidemia biomarkers including low density lipoprotein cholesterol (LDL-C), Apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) while increasing high-density lipoprotein cholesterol (HDL-C). Four phase III clinical trials, including a cardiovascular outcomes trial, are ongoing. Summary Preliminary data for obicetrapib shows favorable effects on dyslipidemia, which could theoretically lead to a decrease in ASCVD clinical events. Short-term safety data in preliminary studies shows no significant safety signals.

Background Hyperlipidemia, a key risk factor for cardiovascular disease, is characterized by elevated low‐density lipoprotein cholesterol (LDL‐C), triglycerides, and reduced high‐density lipoprotein cholesterol (HDL‐C). Cholesteryl ester transfer protein (CETP) inhibitors, such as anacetrapib, obicetrapib, evacetrapib, dalcetrapib, and torcetrapib, aim to improve lipid profiles by increasing HDL‐C and reducing LDL‐C, but their comparative efficacy remains unclear. Methods This systematic review and frequentist network meta‐analysis, conducted per PRISMA‐NMA guidelines, included 33 randomized controlled trials (RCTs) involving 120,292 adults with hyperlipidemia. We compared CETP inhibitors, alone or with statins, against placebo or other lipid‐lowering therapies. Primary outcome was LDL‐C reduction; secondary outcomes included HDL‐C, triglycerides, and total cholesterol changes. Random‐effects models calculated mean differences (MD) with 95% confidence intervals (CI), and P‐scores ranked interventions. Results Atorvastatin + obicetrapib showed the largest reduction in LDL‐C levels (MD: −69.00, 95% CI: −95.96 to −42.04, p < 0.0001), followed by rosuvastatin + obicetrapib (MD: −60.70, 95% CI: −99.28 to −22.12, p = 0.0020). Atorvastatin + obicetrapib yielded highly significant increase in HDL‐C levels (MD: 149.90, 95% CI: 121.70 to 178.10, p < 0.0001), but rosuvastatin + obicetrapib showed the greatest increase (MD: 158.90, 95% CI: 118.59 to 199.21, p < 0.0001) and obicetrapib monotherapy (MD: 139.00, 95% CI: 129.05 to 148.96, p < 0.0001), while rosuvastatin + evacetrapib led triglyceride reductions (MD: −31.70 mg/dL). Rosuvastatin was most effective for total cholesterol (MD: −31.60 mg/dL). Conclusion CETP inhibitors, particularly anacetrapib and obicetrapib combined with statins, significantly improve lipid profiles, offering potential therapeutic benefits for hyperlipidemia management and cardiovascular risk reduction. Trial Registration: The study was registered with PROSPERO to ensure transparency and adherence to methodological rigor (Registration ID: CRD420250652666). Summary Network meta‐analysis compares CETP inhibitors’ effects on lipid profile. Atorvastatin + obicetrapib tops LDL‐C reduction in hyperlipidemia. Rosuvastatin + obicetrapib markedly boosts HDL‐C levels. Rosuvastatin + evacetrapib leads in triglyceride reduction. Rosuvastatin excels in lowering total cholesterol.

Background: Atherosclerosis is a multi-factorial disease, and low-density lipoprotein cholesterol (LDL-C) is a critical risk factor in developing atherosclerotic cardiovascular disease (ASCVD). Cholesteryl-ester transfer-protein (CETP), synthesized by the liver, regulates LDL-C and high-density lipoprotein cholesterol (HDL-C) through the bidirectional transfer of lipids. The novelty of CETP inhibitors (CETPis) has granted new focus towards increasing HDL-C, besides lowering LDL-C strategies. To date, five CETPis that are projected to improve lipid profiles, torcetrapib, dalcetrapib, evacetrapib, anacetrapib, and obicetrapib, have reached late-stage clinical development for ASCVD risk reduction. Early trials failed to reduce atherosclerotic cardiovascular occurrences. Given the advent of some recent large-scale clinical trials (ACCELERATE, HPS3/TIMI55-REVEAL Collaborative Group), conducting a meta-analysis is essential to investigate CETPis’ efficacy. Methods: We conducted a thorough search of randomized controlled trials (RCTs) that commenced between 2003 and 2023; CETPi versus placebo studies with a ≥6-month follow-up and defined outcomes were eligible. Primary outcomes: major adverse cardiovascular events (MACEs), cardiovascular disease (CVD)-related mortality, all-cause mortality. Secondary outcomes: stroke, revascularization, hospitalization due to acute coronary syndrome, myocardial infarction (MI). Results: Nine RCTs revealed that the use of a CETPi significantly reduced CVD-related mortality (RR = 0.89; 95% CI: 0.81–0.98; p = 0.02; I2 = 0%); the same studies also reduced the risk of MI (RR = 0.92; 95% CI: 0.86–0.98; p = 0.01; I2 = 0%), which was primarily attributed to anacetrapib. The use of a CETPi did not reduce the likelihood any other outcomes. Conclusions: Our meta-analysis shows, for the first time, that CETPis are associated with reduced CVD-related mortality and MI.

Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half‐life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted in pre‐clinical and Phase I and II clinical studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months of dosing up to 50 mg/kg/day in cynomolgus monkeys, obicetrapib was completely eliminated from systemic circulation and not detected in adipose tissue after a 13‐week recovery period. In healthy humans receiving 1–25 mg of obicetrapib, the mean terminal half‐life of obicetrapib was 148, 131, and 121 h at 5, 10, and 25 mg, respectively, and food increased plasma levels by ~1.6‐fold with a 10 mg dose. At the end of treatment in Phase II trials, mean plasma levels of obicetrapib ranged from 194.5 ng/mL with 2.5 mg to 506.3 ng/mL with 10 mg. Plasma levels of obicetrapib decreased by 92.2% and 98.5% at four and 15 weeks post‐treatment, respectively. Obicetrapib shows no clinically relevant accumulation, is minimally affected by food, and has a mean terminal half‐life of 131 h for the 10 mg dose. These data support once daily, chronic dosing of obicetrapib in Phase III trials for dyslipidemia management.