1.
MEDI6012: Recombinant Human Lecithin Cholesterol Acyltransferase, High-Density Lipoprotein, and Low-Density Lipoprotein Receptor-Mediated Reverse Cholesterol Transport.
George, RT, Abuhatzira, L, Stoughton, SM, Karathanasis, SK, She, D, Jin, C, Buss, NAPS, Bakker-Arkema, R, Ongstad, EL, Koren, M, et al
Journal of the American Heart Association. 2021;(13):e014572
Abstract
Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate-limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double-blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment-emergent adverse events that were similar to those of placebo. Dose-dependent increases in high-density lipoprotein cholesterol were observed with area under the concentration-time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high-density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non-ATP-binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low-density lipoprotein particles by 41%, 88%, and 79% at the 80-, 240-, and 800-mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high-density lipoprotein cholesterol, endogenous apoA1, and non-ATP-binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low-density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high-density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601560.
2.
Adverse risk factor trends limit gains in coronary heart disease mortality in Barbados: 1990-2012.
Sobers, NP, Unwin, N, Samuels, TA, Capewell, S, O'Flaherty, M, Critchley, JA
PloS one. 2019;(4):e0215392
Abstract
BACKGROUND Although most countries face increasing population levels of obesity and diabetes their effect on coronary heart disease (CHD) mortality has not been often studied in small island developing states (SIDs) where obesity rates are among the highest in the world. We estimated the relative contributions of treatments and cardiovascular risk factors to the decline in CHD mortality from 1990 to 2012 in the Caribbean island, Barbados. METHODS We used the IMPACT CHD mortality model to estimate the effect of increased coverage of effective medical/surgical treatments and changes in major CHD risk factors on mortality trends in 2012 compared with 1990. We calculated deaths prevented or postponed (DPPs) for each model risk factor and treatment group. We obtained data from WHO Mortality database, population denominators from the Barbados Statistical Service stratified by 10-year age group (ages 25-34 up to 85 plus), population-based risk factor surveys, Global Burden of Disease and Barbados' national myocardial infarction registry. Monte Carlo probabilistic sensitivity analysis was performed. RESULTS In 1990 the age-standardized CHD mortality rate was 109.5 per 100,000 falling to 55.3 in 2012. Implementation of effective treatment accounted for 56% DPPs (95% (Uncertainty Interval (UI) 46%, 68%), mostly due to the introduction of treatments immediately after acute myocardial infarction (AMI) (14%) and unstable angina (14%). Overall, risk factors contributed 19% DPPs (95% UI 6% to 34%) mostly attributed to decline in cholesterol (18% DPPs, 95% UI 12%, 26%). Adverse trends in diabetes: 14% additional deaths(ADs) 95% UI 8% to 21% ADs) and BMI (2% ADs 95%UI 0 to 5% ADs) limited potential for risk factor gains. CONCLUSIONS Given the significant negative impact of obesity/diabetes on mortality in this analysis, research that explores factors affecting implementation of evidenced-based preventive strategies is needed. The fact that most of the decline in CHD mortality in Barbados was due to treatment provides an example for SIDs about the advantages of universal access to care and treatment.
3.
Cholesterol efflux capacity, HDL cholesterol, and risk of coronary heart disease: a nested case-control study in men.
Cahill, LE, Sacks, FM, Rimm, EB, Jensen, MK
Journal of lipid research. 2019;(8):1457-1464
Abstract
The capacity of HDLs to accept cholesterol effluxing from macrophages has been proposed as a new biomarker of HDLs' anti-atherogenic function. Whether cholesterol efflux capacity (CEC) is independent of HDL cholesterol (HDL-C) as a biomarker for coronary heart disease (CHD) risk in a generally healthy primary-prevention population remains unanswered. Therefore, in this nested case-control study, we simultaneously assessed CEC (using J774 cells) and plasma HDL-C levels as predictors of CHD in healthy middle-aged and older men not receiving treatment affecting blood lipid concentrations. We used risk-set sampling of participants free of disease at baseline from the Health Professionals Follow-Up Study, and matched cases (n = 701) to controls 1:1 for age, smoking, and blood sampling date. We applied conditional logistic regression models to calculate the multivariable relative risk and 95% CIs of CHD over 16 years of follow-up. CEC and HDL-C were correlated (r = 0.50, P < 0.0001). The risk (95% CI) of CHD per one SD higher CEC was 0.82 (0.71-0.96), but completely attenuated to 1.08 (0.85-1.37) with HDL-C in the model. The association per one SD between HDL-C and CHD (0.66; 0.58-0.76) was essentially unchanged (0.68; 0.53-0.88) after adjustment for CEC. These findings indicate that CEC's ability to predict CHD may not be independent of HDL-C in a cohort of generally healthy men.