Dov Gavish

Flushing Profile of Extended-Release Niacin/Laropiprant Versus Gradually Titrated Niacin Extended-Release in Patients With Dyslipidemia With and Without Ischemic Cardiovascular Disease

Niacin has beneficial effects on a patients lipid and lipoprotein profiles and cardiovascular risk, particularly at doses >2 g/day, but is underused due to flushing. Laropiprant (LRPT), a selective prostaglandin D(2) receptor-1 antagonist, decreases flushing associated with extended-release niacin (ERN). We compared flushing with ERN/LRPT dosed by a simplified 1-g --> 2-g regimen versus gradually titrated niacin extended-release (N-ER; given as NIASPAN, trademark of Kos Life Sciences LLC). Patients with dyslipidemia (n = 1,455) were randomized 1:1 to ERN/LRPT (1 g for 4 weeks advanced to 2 g for 12 weeks) or N-ER (0.5 g for 4 weeks titrated in 0.5-g increments every 4 weeks to 2 g for the final 4 weeks). Aspirin/nonsteroidal anti-inflammatory drugs were allowed to mitigate flushing. Flushing severity was assessed using the validated Global Flushing Severity Score (GFSS; none 0, mild 1 to 3, moderate 4 to 6, severe 7 to 9, extreme 10). Patients on ERN/LRPT, despite more rapid niacin titration, had less flushing than those on N-ER, as measured by number of days per week with moderate or greater GFSS across the treatment period (p <0.001). More than 2 times as many patients had no episodes of moderate, severe, or extreme flushing (GFSS > or =4) with ERN/LRPT than with N-ER (47.0% vs 22.0%, respectively) across the treatment period. Fewer patients on ERN/LRPT discontinued due to flushing than those on N-ER (7.4% vs 12.4%, p = 0.002). Other than the decrease in flushing, the safety and tolerability profile of ERN/LRPT was similar to that of N-ER. In conclusion, improvement in flushing with ERN/LRPT versus gradually titrated N-ER supports a rapidly advanced 1-g --> 2-g dosing regimen, allowing patients to start at 1 g and quickly reach and tolerate the optimal 2 g dose of ERN.

Treatment with atorvastatin improves small artery compliance in patients with severe hypercholesterolemia.

BACKGROUND We studied the effect of atorvastatin on arterial compliance in patients with severe hypercholesterolemia. METHODS Seventeen patients with low-density lipoprotein cholesterol levels above 170 mg/dL, were included in the study, none of whomever received hypolipidemic medication or had other risk factors. Patients were followed for five visits, every 4 weeks. RESULTS After 20 weeks of treatment, lipid profile improved significantly. Large artery elasticity index did not change significantly, but small artery elasticity index increased by 21% (4.6+/-0.5 to 5.6+/-0.9, P < .01). Although none of our patients suffered from hypertension, both systolic and diastolic blood pressure (BP) decreased significantly (6 mm Hg and 3 mm Hg, respectively). CONCLUSIONS We conclude that atorvastatin improves the elasticity of small arteries and reduces systolic and diastolic BP in patients with severe hypercholesterolemia.

Treatment with amlodipine andatorvastatin have additive effect in improvement of arterial compliance in hypertensive hyperlipidemic patients

BACKGROUND This study investigates the effect of amlodipine on arterial compliance (AC), and the effect of atorvastatin on AC when given in combination with amlodipine. METHODS Twenty-one consecutive hypertensive hyperlipidemic patients were included in this study. Patients were followed every month for 6 months (3 months of amlodipine therapy and 3 months of amlodipine and atorvastatin combination). RESULTS During the 3 months of amlodipine monotherapy, large and small AC were improved by 26% and 38%, respectively, and the systemic vascular resistance was reduced by 10%. The addition of atorvastatin during the next 3 months improved small AC by an additional 42% and decreased the systemic vascular resistance by another 5%, but large AC and blood pressure did not change. CONCLUSIONS Amlodipine improves large and small AC, and the beneficial effect of atorvastatin on small AC is additive to the effect achieved by amlodipine.

Adiponectin and vascular properties in obese patients: is it a novel biomarker of early atherosclerosis?

Objectives:Adiponectin is an adipocyte-derived collagen-like protein, highly specific to adipose tissue and may represent an important link between obesity and atherosclerosis. The present study was designed to investigate a possible association between serum adiponectin levels and early vascular changes in obese patients as determined by intima media thickness (IMT) and arterial pulse-wave contour analysis.Design:Obese subjects (n=47) were evaluated for arterial structure and function, metabolic parameters and serum adiponectin levels.Measurements:IMT was measured by ultrasound. Arterial elasticity was evaluated using pulse-wave contour analysis. Insulin resistance was assessed by homeostasis model assessment (HOMA-IR).Results:Adiponectin was significantly, inversely associated with mean IMT (r=−0.369, P=0.011) and significantly positively associated with large artery elasticity index (LAEI) (r=0.467, P=0.001) as well as small artery elasticity index (SAEI) (r=0.462, P=0.001). In separate multivariate models, adiponectin remained significantly associated with mean IMT, LAEI and SAEI even after adjustment for cardiovascular confounders. Among metabolic parameters, adiponectin was significantly positively associated with HDL cholesterol and inversely associated with triglycerides. Adiponectin was significantly inversely associated with fasting insulin and HOMA-IR. In addition, a marginally inverse association between adiponectin and ALT was observed.Conclusions:In this study, serum adiponectin levels were significantly associated with indices of subclinical atherosclerosis, such as IMT and arterial compliance in obese patients. This association was independent of traditional cardiovascular risk factors.

The effect of a rapid weight loss induced by laparoscopic adjustable gastric banding on arterial stiffness, metabolic and inflammatory parameters in patients with morbid obesity.

Objective:To determine the effect of drastic weight loss on arterial compliance, inflammatory and metabolic parameters in patients with morbid obesity with and without cardiovascular risk factors who underwent laparoscopic adjustable gastric banding (LAGB).Design:Open prospective study, morbidly obese subjects divided into low- and high-risk group were evaluated before and 4 months after LAGB.Subjects:Forty-one Caucasian subjects aged between 16 and 55 years, with morbid (grade 3) obesity (20 low- risk and 21 high-risk subjects) who underwent LAGB and completed a 16-week follow-up.Measurments:Patients were evaluated at baseline and 4 months after LAGB for body mass index (BMI), arterial blood pressure (BP), metabolic factors including lipid profile, HbA1C, insulin, C-peptide, fibrinogen, hs-C reactive protein (CRP) and Homeostasis model assessment-insulin resistance (HOMA-IR). Arterial elasticity of large and small arteries was evaluated using pulse-wave contour analysis method (HDI CR 2000, Eagan, Minnesota) at baseline and after 4 months.Results:Body mass index reduction induced by LABG, from 43.55±5.11 to 35.10±4.87 in low-risk patients and from 42.90±3.22 to 35.00±3.24 in high-risk patients, significantly improved small artery elasticity (SAE) from 6.30±2.74 to 7.25±1.85, in morbidly obese patients with multiple cardiovascular risk factors (high-risk group). Improvement in SAE was accompanied by improvement of arterial BP, glucose and lipid metabolism, and reduction of CRP values.Conclusion:Although dramatic weight reduction induced by surgical intervention was associated with similar changes in body weight and significant improvement of metabolic and inflammatory parameters in two groups of obese patients, SAE improved only in high-risk patients.

Osteoprotegerin as an independent marker of subclinical atherosclerosis in osteoporotic postmenopausal women

Osteoprotegerin (OPG) appears to represent the molecular link between bone resorption and vascular calcification, and may help to explain the high prevalence of atherosclerosis and osteoporosis in postmenopausal women. We investigated a possible association between serum OPG levels and arterial stiffness in postmenopausal women with osteoporosis. 70 postmenopausal women with osteoporosis and cardiovascular risk factors but without coronary artery disease were evaluated for metabolic, inflammatory parameters and serum OPG levels. Pulse wave velocity (PWV) and augmentation index (AIx) were performed as a simple noninvasive recording of the two artery sites pressure waveform using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia). Serum OPG levels were significantly, positively associated with AIx (r=0.39, p=0.003) and with PWV (r=0.81, p<0.0001). No association between OPG levels and hemodynamic variables or measures of glucose metabolism was observed. Among inflammatory markers, OPG was significantly, positively associated with fibrinogen (r=0.323, p=0.015). In a multiple linear regression analysis, OPG was independent predictor of PWV (standardized beta=0.75, p<0.0001) and AIx (standardized beta=0.41, p=0.01). Serum OPG is potentially an independent predictor of early vascular adverse changes in osteoporotic postmenopausal women.

Prolonged treatment with the at1 receptor blocker, valsartan, increases small and large artery compliance in uncomplicated essential hypertension

BACKGROUND Decreased arterial compliance (AC) is considered an early marker of vascular wall damage. Hypertension gradually decreases arterial compliance. We studied whether treatment with the angiotensin type 1 (AT(1)) antagonist valsartan will affect AC in patients with essential hypertension (EH). METHODS Twenty-two patients with EH, 6 men and 16 women, mean age 58.7 +/- 4.1 years, without overt target organ damage were included. Antihypertensive medications were withdrawn for 3 weeks, Valsartan was given at 80- and 160-mg doses. The AC, blood pressure (BP), blood, and urine were measured monthly. Large (C1) and small (C2) AC were derived from radial artery waveforms, obtained using a calibrated tonometer (model CR-2000, HDI Inc., Eagan, MN). RESULTS After 3 months, systolic BP decreased from 172 +/- 17 to 142 +/- 13 mm Hg (P <.0001) and diastolic BP from 95 +/- 9 to 82 +/- 8 mm Hg (P <.0001). The decrease in BP was significant within 1 month and improved further on. The C1 increased by 22%, from 8.0 +/- 3.1 to 9.7 +/- 2.3 mL/mm Hg x 10 (P <.01). The C2 increased by 35%, from 2.9 +/- 1.3 to 3.9 +/- 1.9 mL/mm Hg x 100 (P <.01). Both C1 and C2 reached statistical significance only after 3 months. Systemic vascular resistance (SVR) decreased by 15% from 2,140 +/- 376 to 1,817 +/- 262 dynes/sec/cm(-5) (P <.0001). CONCLUSIONS Treatment with valsartan in patients with EH improves small and large AC. The improvement in AC was significant only after 3 months of treatment, whereas systolic BP, diastolic BP, and SVR decreased earlier. The AT(1) receptor blockade with valsartan seems to be an effective means of not only lowering BP but of reversal of vascular wall damage, which predisposes to cardiovascular events.

Vascular Elasticity of Systemic Lupus Erythematosus Patients Is Associated with Steroids and Hydroxychloroquine Treatment

Abstract:  We studied the large and small artery elasticity (AE) and systemic vascular resistance (SVR) of systemic lupus erythematosus (SLE) patients according to treatment profile. Forty‐one SLE patients (90% female, mean age 48.7 ± 2.4 years) were compared to 96 healthy controls. The large and small AE and the SVR were derived from radial artery waveforms (model CR‐2000, HDI Inc.). Patients were categorized into groups according to treatment: steroid (12), hydroxychloroquine (HCQ) (9), steroid+HCQ (16), and no‐steroids‐no‐HCQ (4). The steroid group had reduced large AE and increased SVR as compared to the HCQ group (8.3 mmHg·mL·10 and 18.4 dyne·sec·10−3 versus 13.7 and 14.4, respectively). Mean large AE and the SVR of the HCQ group was similar to that of the controls (11.8 mmHg·mL·10 and 14.5 dyne·sec·10−3, respectively). Mean large AE and SVR of the steroid+HCQ group were better than the steroid group (10.4 mmHg·mL·10 and 16.0 dyne·sec·10−3). Patients that received steroids had higher rates of hypertension (36%) and diabetes (11%) compared to rest of the patients (15% and 0%, respectively). Small AE, blood pressure, CRP, and SLEDAI were similar between the groups. Among SLE patients, steroid treatment was associated with the highest degree of vascular damage, and HCQ was associated with the lowest degree of vascular damage. It is possible that the steroids are responsible in part to the increased large‐vessel manifestations observed in these patients, and that HCQ might have a protective effect on the vessel wall.

Relation between augmentation index and adiponectin during one-year metformin treatment for nonalcoholic steatohepatosis: effects beyond glucose lowering?

BackgroundInsulin resistance (IR) is the major driving force behind development and progression of atherosclerosis in patients with nonalcoholic fatty liver disease (NAFLD). Therefore, correction of IR is a relevant therapeutic target.We performed the current trial to evaluate whether 12- month metformin therapy improves vascular stiffness in patients with NAFLD and to assess if this improvement is associated with change in glucose control, insulin resistance or circulating adiponectin.MethodsIn randomized, placebo controlled study, 63 patients with NAFLD were assigned to one of two groups: Group 1 received daily metformin; Group 2 received placebo. Central aortic augmentation index (AI) was performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia) at baseline, at 4-and 12-month treatment period. Metabolic parameters, insulin resistance markers and serum adiponectin levels were determined.ResultsIn placebo group: AI did not improve during the treatment period. Liver function and adiponectin levels did not change during the study.In multiple linear regression analysis, the independent predictors of arterial stiffness improvement were metformin treatment and increase in circulating adiponectin levels.Among metformin treated patients: AI decreased significantly during the study. ALP and ALT decreased during initial 4-month treatment period, however raised to the pretreatment levels after 12 months. Serum adiponectin level tended to increase during treatment period with metformin.ConclusionsMetformin treatment was associated with significant decrease in AI during one year treatment in NAFLD patients. These beneficial vascular effects was associated with exposure to metformin per se as well as change in adiponectin levels suggesting that metformin may mediate its vascular effects via glicemic control-independent mechanisms.Trial registryno: NCT01084486

Diurnal variations of plasma lipids, tissue and plasma lipoprotein lipase, and VLDL secretion rates in the rat. A model for studies of VLDL metabolism

Circadian rhythms of plasma lipids and lipoproteins, lipoprotein lipase activities and VLDL secretion rates were studied in fed and food-deprived (12 h) male rats after a light/dark synchronization of 14 days. In ad libitum fed rats, a circadian rhythm of plasma triacylglycerol, blood glucose and liver glycogen was clearly identified. A rhythm was also identified for plasma cholesterol, but not phospholipids. The peak of plasma triacylglycerol occurred 2 h after the beginning of the light period (7.00 a.m.), and the nadir, 2 h after the beginning of the dark period (7.00 p.m.). The differences of plasma triacylglycerol at these two circadian stages were even more pronounced in food-deprived rats and were confined to the very-low-density lipoprotein (VLDL) fraction. Plasma post-heparin and heart and muscle lipoprotein lipase activities were 50-100% higher at 7.00 p.m., the time when plasma triacylglycerol were lowest, as compared to 7.00 a.m. Plasma post-heparin hepatic lipase and adipose tissue lipoprotein lipase activities, in contrast, did not change. VLDL secretion rates were somewhat higher at 7.00 a.m. compared to 7.00 p.m., but this difference was not significant. It is concluded that physiological variation of heart and muscle lipoprotein lipase together with small differences of VLDL secretion rates are responsible for normal range oscillations of plasma VLDL triacylglycerol levels.