Rambam health care campus, Haifa, Israel Niacin Administration significantly reduced Oxidative Stress in Patients with Hypercholesterolemia and Low HDL  

Rambam health care campus, Haifa, Israel Shadi Hamoud, Marielle Kaplan, Edna Meilin, Ahmad Hassan, Rafael Torgovicky, Raanan Cohen, Tony Hayek   Internal Medicine E department, The Lipid Research Laboratory, The Clinical biochemistry Laboratory. Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel.   Merck, Sharp and Dohme, Medical Department, Israel The American Journal of the Medical Sciences 345(3) · September 2012 

Background Rambam health care campus, Haifa, Israel Oxidative stress has been implicated in the pathogenesis of cardio-vascular disorders, including atherosclerosis. Mechanism: promoting lipid peroxidation of serum lipoproteins, enhancing their pro-atherogenic properties Serum paraoxonase (PON1), an HDL-associated esterase, was shown to protect lipoproteins and atherosclerotic lesions against lipid peroxidation

Background Rambam health care campus, Haifa, Israel Hypercholesterolemia is associated with increased oxidative stress Hypercholesterolemic patients are prone to accelerated atherosclerosis and resulting cardiovascular complications. Moreover, lower levels of blood HDL-c are also associated with higher rate of atherosclerotic cardiovascular complications

Background Rambam health care campus, Haifa, Israel Protection from oxidative stress may be achieved by: Endogenous antioxidants, such as the enzymes superoxide dismutase, catalase and glutathione reductase Exogenous antioxidants, like nutritional antioxidants including tocopherols, ascorbic acid, carotenoids and polyphenols, extracts from red wine, pomegranate juice and licorice root In pharmacological doses niacin (Vitamin B3) was proved to reduce total cholesterol, triglycerides, VLDL and LDL, and to increase HDL levels.

Background: NIACIN Rambam health care campus, Haifa, Israel vitamin B3 or nicotinic acid A water-soluble vitamin. Organic compound derivative of pyridine 2000-6000 mg daily blocks the breakdown of fats in adipose tissue, more specifically the very-low-density lipoprotein (VLDL). Causes a decrease in free fatty acids in the blood and, as a consequence, decreased secretion of VLDL and cholesterol by the liver. By lowering VLDL levels, niacin also increases the level of high-density lipoprotein cholesterol in blood, and therefore it is sometimes prescribed for patients with low HDL-c, who are also at high risk for myocardial infarcts

AIM Rambam health care campus, Haifa, Israel To study the Effects of Niacin Administration for Patients with Hypercholesterolemia and low HDL-cholesterol (HDL-c) on their serum Oxidative Stress as well as inflammatory status.

PATIENTS & METHODS Rambam health care campus, Haifa, Israel Seventeen patients with hypercholesterolemia and low HDL-c (<40 MG%) Eight healthy matching control subjects were enrolled in the study. Patients treated with niacin for twelve weeks. Lipid profile, oxidative stress parameters (TBARS & Lipid peroxides) and CRP levels were determined at the time of enrollment, two weeks and twelve weeks after initiation of niacin treatment.

STATISTICAL METHODS Rambam health care campus, Haifa, Israel Statistical analyses included the use of the Student’s t-test, when comparing the means of two groups. ANOVA was used when more than two groups were compared. Results are given as mean ± SEM.

RESULTS Rambam health care campus, Haifa, Israel Subjects with lower HDL-c exhibited higher oxidative stress compared to subjects with normal HDL-c.

Patient treated group (n=14) Rambam health care campus, Haifa, Israel RESULTS   Patient treated group (n=14) Control group (n=8) p-value Age (years) 48.5 49.5 N.S. Gender (%) Males (9) 64% Females (5) 36% Males (4) 50% Females (4/8) 50% Mean statin dose (equivalent to simvastatin (mg)) 45.8 ______ HDL (mg/dl) 37.3 52.2 0.0012 LDL (mg/dl) 115.1 143.7 0.015 Triglycerides (mg/dl) 202 98 0.039 hs C-Reactive protein (mg/L) 3.734 1.94 0.097 Baseline characteristics of the Patient treated group and the control groups

RESULTS Rambam health care campus, Haifa, Israel Niacin treatment to hypercholesterolemic patients caused a significant increase ( by 10.5%) in HDL-c levels, and in Apolipoprotein A1 levels (by 8%) A decrease by 24% in triglyceride levels. Niacin also significantly reduced oxidative stress, as measured by a significant decrease in serum content of TBARS, lipid peroxides and paraoxonase activity by up to12%, 40% and 12% respectively, compared to levels before treatment. Although CRP serum levels were not affected by Niacin treatment, a correlation between CRP levels and HDL levels was obtained when computing all the results. SAFETY MEASURES: No elevation of liver enzymes was observed One patient exhibited adverse side effects (intractable flushing with pruritus that started after doubling the niacin dose)

+10.1%, p=0.04 +10.4%, p=0.002

-23%, p=0.042 -24.2%, p=0.013 Triglycerides (mg/dl)

-10% P=0.012 -12% P=0.011

-33% P=0.04 -40% P=0.003 Basal PD (nmol/ml)

Correlation between HDL & CRP Levels

CONCLUSION Rambam health care campus, Haifa, Israel Niacin treatment to hypercholesterolemic patients with low HDL levels caused a significant decrease in their oxidative stress status. These results indicate an additional beneficial effect of Niacin beyond its ability to affect lipid profile

DISCUSSION Rambam health care campus, Haifa, Israel Our study demonstrates that administration of niacin to patients with hypercholesterolemia and low HDL-c (<40 mg%) had favorable effects, both on the serum lipid profile, mainly on the HDL-c and triglyceride levels, and on the patients serum oxidative stress. Previous studies have demonstrated that treatment with niacin for 19 weeks caused a 24% increment in the HDL-C levels (by increasing the level of Apolipoprotein A I – ApoAI). It should be noticed that despite being the patients treated with statin medications and having significantly lower values of LDL than the subjects in the control group, the patients' group had significantly higher rates of oxidative stress before treatment . In our study, Niacin treatment significantly reduced the treated patients’ oxidative stress, including paraoxonase activity. There are no published studies examining the direct effect of niacin to hypercholesterolemic patients on their oxidative stress. Ganji et al (26) showed in vitro that niacin inhibits vascular inflammation by decreasing LDL-c oxidation and inflammatory cytokines production using cultured human aortic endothelial cells.

DISCUSSION Niacin, by increasing the level of HDL-c in blood, induces HDL activities, resulting in the anti-atherogenic activity through the observed favorable effect on the lipid profile on the one hand, and on the decrement of the oxidative stress on the other hand. Moreover the effect of Niacin on paraoxonase activity could have beneficial effect since PON1 protects HDL as well as LDL from oxidation. Although Niacin did not significantly affected CRP levels in the hypercholesterolemic patients, an inverse linear correlation between CRP serum levels and HDL-C levels was detected, illustrating the higher inflammatory status in low HDL patients as well as an associated reduction in inflammation following Niacin increasing effect on HDL. Our study is the first study that examined the direct effect of niacin administration to humans on the oxidative stress, in vivo. Our results are comparable to the known data in the literature in regard to the effect of niacin on the lipid profile. It is the first study that proves in humans the favorable anti-atherogenic properties of niacin, carried out by the anti-atherogenic effects of higher HDL-c levels. Thus, niacin could be effective in patients with hypercholesterolemia, especially those with low HDL-c, because this is the only effective drug that increases HDL-c on one hand and decreases the oxidative stress on the other hand. This effect would be more dramatic in patients with coronary heart disease or diabetes mellitus, or in patients with multiple risk factors for atherosclerosis.

CONCLUSION Rambam health care campus, Haifa, Israel Niacin treatment to hypercholesterolemic patients with low HDL levels caused a significant decrease in their oxidative stress status. These results indicate an additional beneficial effect of Niacin beyond its ability to affect lipid profile

Thank you !