Atherosclerotic cardiovascular diseases are a leading global cause of death, driven significantly by elevated low-density lipoprotein cholesterol levels. Despite the emergence of effective lipid-lower Show more
Atherosclerotic cardiovascular diseases are a leading global cause of death, driven significantly by elevated low-density lipoprotein cholesterol levels. Despite the emergence of effective lipid-lowering therapies such as statins and other agents, a significant proportion of high-risk patients fail to reach the recommended low-density lipoprotein cholesterol targets. This highlights a critical unmet need for additional lipid-lowering therapies that are not only efficacious and orally administered, but also demonstrate durable safety and cardiovascular benefits. CETP (cholesteryl ester transfer protein) inhibition alters lipid metabolism by preventing the transfer of cholesteryl esters from high-density lipoprotein to apolipoprotein B-containing lipoproteins, thereby reducing atherogenic cholesterol burden. CETP inhibitors have had a challenging development history due to off-target effects observed in early compounds like torcetrapib. However, obicetrapib is a highly selective and hydrophilic CETP inhibitor that heralds a promising new generation of drugs with robust lipid-lowering capabilities and a favorable safety profile. This review presents a comprehensive overview of obicetrapib's mechanism of action, its pharmacokinetic and pharmacodynamic profiles, and a detailed critical assessment of its clinical development through various pivotal trials including TULIP (TA-8995: Its Use in Patients With Mild Dyslipidemia), ROSE (Trial Evaluating Obicetrapib in Combination With Ezetimibe), ROSE2 (Phase 2b ROSE Trial Evaluating Obicetrapib in Combination With Ezetimibe), BROADWAY (Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies), BROOKLYN (Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies, TANDEM (Study of Obicetrapib and Ezetimibe Fixed Dose Combination on Top of Maximum Tolerated Lipid-Modifying Therapies), and the ongoing PREVAIL (Cardiovascular Outcome Study to Evaluate the Effect of Obicetrapib in Patients With Cardiovascular Disease) cardiovascular outcomes trial. We compare the efficacy, safety, and tolerability of obicetrapib against prevailing treatment options, positioning it as a potential oral adjunct to maximally tolerated lipid-lowering regimens in the current lipid management landscape. Show less
Lipoprotein(a) [Lp(a)] and PCSK9 are emerging lipid biomarkers implicated in atherogenesis and residual cardiovascular risk, but their relationship with coronary disease complexity in acute coronary s Show more
Lipoprotein(a) [Lp(a)] and PCSK9 are emerging lipid biomarkers implicated in atherogenesis and residual cardiovascular risk, but their relationship with coronary disease complexity in acute coronary syndrome (ACS) is unclear. This study evaluates their serum levels in first-episode ACS patients versus controls and explores their relationship with SYNTAX score-defined coronary severity. This single-centre observational study enrolled 160 patients presenting with their first episode of ACS (aged 18-75) and 40 age-matched healthy controls. All participants were free from lipid-lowering therapy and major comorbidities. Fasting serum samples were collected to measure the standard lipid profile, Lp(a), and PCSK9 levels. The severity of coronary artery disease was quantified using the SYNTAX score after coronary angiography. The ACS cohort (mean age 55.7 years; 73.1 % male) most frequently presented with STEMI (53.7 %). Traditional risk factors included smoking/tobacco use (48.8 %), diabetes (40.0 %), and hypertension (38.1 %). Median SYNTAX score was 19.4. Compared with controls, ACS patients had significantly lower HDL-C and higher LDL/HDL and cholesterol/HDL ratios. Lp(a) (38.9 vs. 15.9 mg/dL, p < 0.001) and PCSK9 (272.3 vs. 169.6 ng/mL, p < 0.001) were markedly elevated in ACS patients. Neither Lp(a) nor PCSK9 correlated with SYNTAX score. LDL-C showed a modest positive correlation with Lp(a) (r = 0.163, p = 0.040). Higher SYNTAX scores were associated with more extensive multivessel disease. Patients with ACS exhibited significantly higher Lp(a) and PCSK9 levels compared with healthy controls, but these biomarkers did not reflect angiographic disease complexity. Their role may lie more in underlying cardiovascular risk assessment than in predicting anatomical severity. Show less