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GPR109A (HM74A), a G‐protein‐coupled receptor, is hypothesized to mediate lipid and lipoprotein changes and dermal flushing associated with niacin administration. GSK256073 (8‐chloro‐3‐pentyl‐1H‐purine‐2,6[3H,7H]‐dione) is a selective GPR109A agonist shown to suppress fatty acid levels and produce mild flushing in short‐term clinical studies. This study evaluated the effects of GSK256073 on lipids in subjects with low high‐density lipoprotein cholesterol (HDLc). Subjects (n = 80) were randomized (1:1:1:1) to receive GSK256073 5, 50, or 150 mg/day or matching placebo for 8 weeks. The primary end point was determining the GSK256073 exposure‐response relationship for change from baseline in HDLc. No significant exposure response was observed between GSK256073 and HDLc levels. GSK256073 did not significantly alter HDLc levels versus placebo, but rather revealed a trend at the 150‐mg dose for a nonsignificant decrease in HDLc (‐6.31%; P = .12) and an increase in triglycerides (median, 24.4%; 95% confidence interval, 7.3%‐41.6%). Flushing was reported in 21%, 25%, and 60% of subjects (5, 50, and 150 mg, respectively) versus 24% for placebo. Results indicated that selective activation of the GPR109A receptor with GSK256073 did not produce niacin‐like lipid effects. These findings add to the increasing evidence that niacin‐mediated lipoprotein changes occur predominantly via GPR109A‐independent pathways. [ABSTRACT FROM AUTHOR]

Abnormalities in HDL-cholesterol and triglyceride values in adults increase the risk for cardiovascular disease, and the prevalence in children has advanced over the last two decades. These values track into adulthood, and already predict sub-clinical disease in adolescents. Pediatric screening and lifestyle changes such as nutrition and exercise are important considerations. HDL and triglyceride values are excellent markers of cardiovascular health and potential targets. [Copyright &y& Elsevier]

Objective: Hypertriglyceridemia is commonly observed in association with diabetes. Despite cross-sectional studies and isolated longitudinal analyses in patients without coronary artery disease, the suggestion that triglyceride levels are relevant to subsequent cardiovascular events in the setting of diabetes remains controversial. This study evaluates the predictive value of serum triglyceride levels on mortality in post-coronary artery bypass graft (CABG) diabetic patients with subsequent analysis by sex.Research Design and Methods: This longitudinal observational study involving a large metropolitan hospital consists of 1,172 diabetic post-CABG patients (792 men and 380 women) with lipid data collected between the years 1982 and 1992. Cox proportional hazards regression models were used to estimate the risk of mortality and cardiac events associated with triglyceride levels in the highest quartile (> 2.90 mmol/l for men and > 3.12 mmol/l for women).Results: Elevated preoperative serum triglyceride values in post-CABG subjects with diabetes were correlated with increased overall mortality (hazard ratio [HR] 1.26, 95% CI 1.00-1.59). The greatest influence of triglyceride levels was observed on overall (1.89, 1.30-2.73) and event-free survival (1.49, 1.06-2.08) in women. High triglyceride values were also modestly related to risk of cardiac events in diabetic men (1.28, 0.99-1.66).Conclusions: These data suggest that increased preoperative triglyceride levels predict increased late mortality and cardiac event risk in diabetic post-CABG patients, more strongly in women than in men. [ABSTRACT FROM AUTHOR]

We performed a prospective observational study on 6,602 subjects (94% for 5 years and 34% for 10 to 15 years) who underwent coronary artery bypass graft surgery (CABG) between 1982 and 1992. We examined whether triglyceride concentrations adjusted for other factors (total cholesterol, history of diabetes mellitus, systemic hypertension, left ventricular function, number of coronary arteries significantly narrowed, and use of the internal thoracic arteries) explained total and event-free survival. These analyses were duplicated within gender (1,354 women and 5,248 men). This approach allowed a determination of any gender-related disparities in lipid predictors. Triglycerides in the highest quartile were associated with an increased risk of mortality of 20% (confidence interval [CI] 1.0 to 1.4). Similar risk was seen for event-free survival. Although there was no evidence of gender differences in adjusted survival (p = 0.33), a gender by triglyceride interaction (p = 0.004) indicated that the response to high triglycerides as related to survival did differ by gender. Specifically, women had a dramatically higher risk (hazard ratio [HR] 1.5, CI 1.1 to 2.1) than men (HR 1.1, CI 0.9 to 1. 3). Both men and women did have triglyceride-associated risk with regard to event-free survival (HR in men 1.2, CI 1.1 to 1.4; HR in women 1.4, CI 1.1 to 1.8). Examination of high-density lipoprotein cholesterol in a subcohort did not eliminate the observed triglyceride effects. Thus, triglyceride baseline values are primary determinants (similar to baseline left ventricular function or extent of coronary disease) for long-term total and event-free mortality after CABG in women but not in men. [ABSTRACT FROM AUTHOR]

Background: There is substantial evidence from clinical trials that lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular risk. There is less evidence for the salutatory effects of raising high-density lipoprotein cholesterol (HDL-C). The predictive strength of an initial HDL-C measurement and its change over time for major adverse coronary events is not well understood. Methods: We identified a cohort of all 6928 patients in an urban primary care practice who had two or more lipid measurements between January 1985 and December 1997. We used bivariable and multivariable (Cox proportional hazards) techniques to identify independent predictors of subsequent major adverse coronary events (hospitalization for myocardial infarction or acute coronary syndrome) after the second set of lipid measurements. Results: The time between first and second lipid measurements averaged 2.6 years. During a mean of 5.1 ± 3.2 years of observation after their second lipid measurements, 2167 (31%) patients had an acute coronary event. Patients having events were significantly older, more often white, male, and smokers and more often had antecedent diabetes, hypertension, coronary heart disease, and myocardial infarctions. Adjusting for covariates, a 10-mg/dL higher initial HDL-C was associated with an 11% (95% CI 7%-14%) lower risk of coronary events. A 10-mg/dL increase in HDL-C between lipid measurements was associated with a 7% (95% CI 3%-10%) lower risk of events. Neither initial or change in triglycerides nor LDL-C predicted subsequent coronary events. Conclusion: High-density lipoprotein cholesterol measurements and change in HDL-C predicted major adverse coronary events in this urban practice, which provides support studying interventions targeting HDL-C for cardiovascular risk reduction. [Copyright &y& Elsevier]

ABSTRACT. Patients seen at a pediatric lipid clinic over a 27-month period were reviewed retrospectively to evaluate types of primary lipid disorders and effect of dietary treatment at the first follow-up visit. One hundred eighty-two patients were classified into one of four categories: (1) elevated low-density lipoprotein cholesterol (LDL-C) with LDL-C > 95th percentile (32%); (2) isolated triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) abnormalities, with TG > 95th percentile and/or HDL-C < 5th percentile (30%); (3) borderline LDL-C, TG, or HDL-C (29%); (4) normal (9%). The American Heart Association Step-One Diet was prescribed for all patients older than 2 years, and they received extensive nutritional and risk-management counseling. Of these patients, 59 (32%) returned for at least one follow-up visit and mean changes in lipid values between initial and first follow-up visits were evaluated. Levels of LDL-C decreased by 24 mg/dL in 22 patients with elevated LDL-C levels. Triglyceride levels decreased by a mean of 22 mg/dL and HDL-C increased by a mean of 4 mg/dL in 21 patients with isolated TG/HDL-C abnormalities. Levels of LDL-C tended to rise in this group, but not to a significant degree. A new finding of this report is that screening for total cholesterol results in the identification of many children with TG or HDL-C abnormalities alone and that the Step-One Diet appears to be effective in improving both TG and HDL-C levels in these patients. INSET: REJECTION RATE RISES AT NIH. [ABSTRACT FROM AUTHOR]