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Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development. The structural model that best described obicetrapib PK was a 3‐compartment model with 4‐compartment transit absorption and first‐order elimination. Body weight was the only covariate found to significantly explain observed variability and was therefore included using allometric scaling on all disposition parameters. For a typical patient weighing 75 kg, the estimated apparent total body clearance and apparent volume of distribution of the central compartment was 0.81 L/h and 36.1 L, respectively. The final PK model parameters were estimated with good precision and were ultimately leveraged to sequentially inform 2 turnover models that describe obicetrapib's effect on low‐density lipoprotein cholesterol (LDL‐C) and high‐density lipoprotein cholesterol (HDL‐C) concentrations. The maximum stimulatory effect of obicetrapib on LDL‐C loss was estimated to be 1.046, while the maximum inhibitory effect of obicetrapib on HDL‐C loss was 0.691. This corresponds to a predicted typical maximum percent change from baseline LDL‐C and HDL‐C of 51.1% and 224%, respectively. The final sequential model described obicetrapib PKPD well and was ultimately able to both demonstrate evidence of internal consistency and support decision‐making throughout the development lifecycle. [ABSTRACT FROM AUTHOR]

Background Vasa vasorum ( VV) vessels are critical in the genesis of atherosclerosis. Therefore, we assessed measures of carotid VV, intima-media thickness ( CIMT), and patient risk factors in a primary prevention population. Methods We used multivariable linear models to evaluate the relationship between baseline covariates and a measure of carotid VV ( VV ratio) and CIMT among 324 diabetics and 141 nondiabetics. Results Median CIMT (in mm) and VV ratio among nondiabetics were 0.82 ± 0.22 and 0.80 ± 0.19, respectively, and 1.06 ± 0.19 and 1.21 ± 0.26 among diabetics (P < 0.0001). Diabetes was associated with 36% (95% CI: 24.3-48.0, P < 0.001) higher VV ratio whereas a unit change in BMI was associated with ≈1% (95% CI: 0.5-1.4, P < 0.001) change in VV ratio. A 10-year increase in age was associated with 4% (95% CI: 1-7, P = 0.005) higher CIMT. Each 10 mmHg increase in mean systolic blood pressure was associated with 2% (95% CI: 1-4, P = 0.003) higher CIMT whereas diabetes conferred 31% (95% CI: 19.1-42.1, P < 0.001) higher CIMT. Female sex was associated with a 9% (95% CI: −12.9 to −4.1, P < 0.001) lower CIMT. Low density lipoprotein ( LDL) cholesterol, blood pressure, and CIMT were not significantly associated with VV ratio. Conclusion In this cohort of patients with low CIMT, VV ratio, and CIMT were distinctly unrelated, but each independently associated with diabetes. VV ratio and CIMT relationships warrant further investigation in large-scale studies and across a spectrum of atherosclerostic states. [ABSTRACT FROM AUTHOR]

The association between low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and the development of coronary heart disease (CHD) is well established. The management of CHD has traditionally focused on the reduction of LDL cholesterol or on the total lipid profile. Yet, treatment strategies for reducing risk in CHD also requires a focus on increasing low HDL cholesterol, as LDL cholesterol reduction alone is insufficient in preventing CHD events. This article reviews the strategies for targeting HDL cholesterol to optimize outcomes in CHD. [ABSTRACT FROM AUTHOR]

Advancing age is an independent risk factor for the development of coronary heart disease. However, the significance of hypercholesterolemia as a cardiovascular risk factor in the elderly, has been widely debated. While no large-scale, randomized clinical trial has been conducted to evaluate cholesterol lowering solely in the elderly, evidence from older subgroups in several intervention trials supports the efficacy of lowering elevated low-density lipoprotein cholesterol for reducing cardiovascular risk in the elderly. Furthermore, although the relative risk of hypercholesterolemia for coronary heart disease incidence may be attenuated with advancing age, the population-wide impact of treating elevated cholesterol levels in the elderly would be large, due to the high frequency of coronary heart disease in the elderly. This article reviews key issues in the management of hypercholesterolemia with respect to coronary heart disease risk reduction in the elderly. [ABSTRACT FROM AUTHOR]

SCH 48461, an inhibitor of gastrointestinal absorption of cholesterol, was evaluated for its effects on lipid parameters in patients with primary hypercholesterolemia in a multicenter, double-blind, randomized, parallel-group study. Following the baseline phase, which consisted of a 2-to 10-week drug washout and dietary stabilization phase and a 4-week placebo lead-in (placebo baseline phase), 190 patients were randomized to an 8-week double-blind active drug (SCH 48461 1, 6.25, 25, 100, 200, or 400 mg) or 40 mg lovastatin once daily each morning or placebo treatment phase. By week 2, patients who received SCH 48461 6.25 to 400 mg or lovastatin demonstrated greater reduction from baseline in directly measured low-density lipoprotein cholesterol (LDL-C) levels than patients in the placebo group (p 0.03). Overall, the percent reductions in LDL-C from baseline increased as the dose of SCH 48461 increased, with 0.6% to 15.5% reductions from the minimum dose of 1 mg to the maximum dose of 400 mg. Lovastatin 40 mg/day reduced LDL-C by 30.7% (p < 0.01). Statistically significant decreases were also seen for total cholesterol and apolipoprotein B (apo B) with doses of 25 mg to 400 mg of SCH 48461 and lovastatin. SCH 48461 was well tolerated. There was a similar incidence of adverse events in each SCH 48461-or lovastatin-treated group compared to placebo. This study demonstrated a clinically and statistically significant cholesterol-lowering effect of SCH 48461 in patients with primary hypercholesterolemia. [ABSTRACT FROM PUBLISHER]

Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Previous research has demonstrated similar pharmacokinetic (PK) responses to single doses of obicetrapib between Japanese and White males, but the PK responses have not been established in Chinese individuals. The purpose of this randomized, parallel, open‐label trial was to characterize the PK and pharmacodynamic (PD; CETP activity and plasma lipids) responses and safety of single doses (5, 10, or 25 mg; N = 36) and multiple doses (10 mg for 14 days; N = 12) of obicetrapib in healthy Chinese individuals. The maximum concentration and area under the drug concentration‐time curve of obicetrapib from 0 h to infinity increased with dose after all single doses of obicetrapib. After 7 consecutive days of dosing, low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol reached their minimum and maximum changes of 42% reduction and 108% increase, respectively. Primary PK and PD parameters after single‐ and multiple‐dose administration of obicetrapib were similar to those in healthy white participants in previous studies. One participant in the 5 mg dose group experienced a treatment‐emergent adverse event of decreased white blood cell and neutrophil counts, which resolved without intervention. In conclusion, these findings support the inclusion of Chinese individuals in the ongoing phase 3 clinical development program of obicetrapib. [ABSTRACT FROM AUTHOR]

Small, dense LDL are more atherogenic than larger LDL particles. It has been hypothesized that individuals shift from a predominance of larger (pattern A) to smaller LDL particles (pattern B) when the fasting triglyceride (TG) concentration exceeds a threshold, typically in the range of 100-250 mg/dL. The present investigation assessed the influence of TG-lowering with prescription omega-3-acid ethyl esters on LDL size in men and women with TG 200 to 499 mg/dL while on statin therapy. After 8 weeks on simvastatin 40 mg/d, 254 subjects were randomly assigned to 4 g/d of Omacor® (3.4 g/d EPA + DHA) or placebo for an additional 8 weeks. Median LDL particle size increased in the omega-3 treated group (19.90 to 20.20 nm, p=0.007 vs. placebo). Median changes from baseline were 0.60, 0.40, 0.15 and -0.20 nm, when the on-treatment TG concentrations were <150, 150-199, 200-249 and >250 mg/dL, respectively (p<0.001). In these on-treatment TG subsets, pattern B was present in 36, 50, 82 and 84% of subjects (p<0.001), compared to 68, 79, 93, and 73%, respectively, at baseline. The association of on-treatment TG category with the change in LDL particle size remained highly significant (p<0.001) after adjusting for the degree of TG-lowering. These results support the concept of a TG threshold for conversion from LDL subclass pattern B to A. [ABSTRACT FROM AUTHOR]