JTT-130, a microsomal triglyceride transfer protein (MTP) inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs

BACKGROUND: Microsomal transfer protein inhibitors (MTPi) have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG). However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver. METHODS: Male guinea pigs (n = 10 per group) were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control), 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7(th )week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism. RESULTS: Plasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P < 0.05). Atorvastatin had the most pronounced hypolipidemic effects with a 35% reduction in LDL cholesterol and 40% reduction in TG. JTT-130 did not induce hepatic lipid accumulation compared to controls. Cholesteryl ester transfer protein (CETP) activity was reduced in a dose dependent manner by increasing doses of MTPi and guinea pigs treated with atorvastatin had the lowest CETP activity (P < 0.01). In addition the number of molecules of cholesteryl ester in LDL and LDL diameter were lower in guinea pigs treated with atorvastatin. In contrast, hepatic enzymes involved in maintaining cholesterol homeostasis were not affected by drug treatment. CONCLUSION: These results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations

Increased prevalence of risk factors for cardiovascular disease in long-term survivors of acute lymphoblastic leukemia and Wilms tumor treated with radiotherapy

BACKGROUND: Only a few studies have assessed cardiovascular risk factors (CRFs) in childhood cancer survivors. We determined the prevalence of CRFs in long-term survivors of acute lymphoblastic leukemia (ALL) and Wilms tumor. PROCEDURE: Adult survivors of ALL and Wilms tumor treated with radiotherapy and chemotherapy (RT + CT) or treated with chemotherapy alone (CT) were compared with sibling controls. CRFs (hypertension, diabetes mellitus, hypercholesterolemia, obesity, renal insufficiency) and hormonal deficiencies were assessed in each participant. Multivariate logistic regression analysis was used to evaluate the association between CRFs and treatment. RESULTS: Seventy-nine ALL, 62 Wilms tumor survivors, and 69 control subjects (mean ages 24.5, 25.9, and 26 years, respectively) were enrolled. Mean follow-up time since cancer treatment was 20.8 years. In the Wilms RT + CT group significantly more survivors had hypertension (21.6% vs. 1.4%, P < 0.001) and renal insufficiency (8.1% vs. 0%, P = 0.016) compared to controls. There were also more patients with multiple CRFs in the Wilms RT + CT group (16.2% vs. 2.9% in controls, P = 0.019). Almost 15% of ALL RT + CT survivors had growth hormone deficiency. Hypogonadism was seen in 18.9% of survivors in the Wilms RT + CT group. We observed no significant differences between CT-treated survivors of both malignancies and controls. The adjusted odds ratio for the occurrence of at least one CRF was 2.6 increased for survivors following abdominal radiotherapy. Treatment with CT alone was not associated with the occurrence of multiple CRFs. CONCLUSIONS: Long-term survivors of ALL and Wilms tumor have unfavorable CRFs due to previous RT not CT. Pediatr Blood Cancer. (c) 2010 Wiley-Liss, In

Independent Association of HbA(1c) and Incident Cardiovascular Disease in People Without Diabetes

Recent studies have reported no association between elevated glycated hemoglobin (HbA(1c)) and incident cardiovascular disease (CVD) among women without diabetes. This study describes associations between HbA(1c) and new onset CVD in a representative adult population cohort. Assessment of participants in The North West Adelaide Health Study (NWAHS), a population study of randomly selected adults (age > or =18 years, n = 4,060), included measurement of height, weight, blood pressure, fasting lipids, glucose, and HbA(1c). A self-completed questionnaire assessed doctor-diagnosed diabetes, CVD and stroke, smoking status, and demographics. The cohort was followed for an average 3.5 years. Of the 2,913 adults free of diabetes at baseline and follow-up, 94 (3.5%) reported new onset coronary heart disease (CHD) and/or stroke. Compared with those with an HbA(1c) or =5.7% (OR 1.9, 95% CI 1.1, 3.4), after adjustment for other risk factors. The association was stronger in women than men (P = 0.03), and attenuated to only a small degree by addition of impaired fasting glucose (IFG), hypertension, hypercholesterolemia, BMI, waist circumference, or smoking to the model. Elevated HbA(1c) is related to new onset CVD over a relatively short follow-up period in both men and women without diabetes and who do not develop diabetes, after adjustment for other major risk factors. Unlike previous studies, this relationship was not substantially attenuated by other traditional risk factors.Robert J. Adams, Sarah L. Appleton, Catherine L. Hill, David H. Wilson, Anne W. Taylor, Catherine R. Chittleborough, Tiffany K. Gill and Richard E. Ruffi