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Common Variants in Lipid Metabolism-Related Genes Associate with Fat Mass Changes in Response to Dietary Monounsaturated Fatty Acids in Adults with Abdominal Obesity.
Hammad, SS, Eck, P, Sihag, J, Chen, X, Connelly, PW, Lamarche, B, Couture, P, Guay, V, Maltais-Giguère, J, West, SG, et al
The Journal of nutrition. 2019;(10):1749-1756
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Abstract
BACKGROUND Different fatty acids (FAs) can vary in their obesogenic effect, and genetic makeup can contribute to fat deposition in response to dietary FA composition. However, the antiobesogenic effects of the interactions between dietary MUFAs and genetics have scarcely been tested in intervention studies. OBJECTIVE We evaluated the overall (primary outcome) and genetically modulated (secondary outcome) response in body weight and fat mass to different levels of MUFA consumption. METHODS In the Canola Oil Multicenter Intervention Trial II, a randomized, crossover, isocaloric, controlled-feeding multicenter trial, 44 men and 71 women with a mean age of 44 y and an increased waist circumference (men ∼108 cm and women ∼102 cm) consumed each of 3 oils for 6 wk, separated by four 12-wk washout periods. Oils included 2 high-MUFA oils-conventional canola and high-oleic canola (<7% SFAs, >65% MUFAs)-and 1 low-MUFA/high-SFA oil blend (40.2% SFAs, 22.0% MUFAs). Body fat was measured using DXA. Five candidate single-nucleotide polymorphisms (SNPs) were genotyped using qualitative PCR. Data were analyzed using a repeated measures mixed model. RESULTS No significant differences were observed in adiposity measures following the consumption of either high-MUFA diet compared with the low-MUFA/high-SFA treatment. However, when stratified by genotype, 3 SNPs within lipoprotein lipase (LPL), adiponectin, and apoE genes influenced, separately, fat mass changes in response to treatment (n = 101). Mainly, the LPL rs13702-CC genotype was associated with lower visceral fat (high-MUFA: -216.2 ± 58.6 g; low-MUFA: 17.2 ± 81.1 g; P = 0.017) and android fat mass (high-MUFA: -267.3 ± 76.4 g; low-MUFA: -21.7 ± 102.2 g; P = 0.037) following average consumption of the 2 high-MUFA diets. CONCLUSIONS Common variants in LPL, adiponectin, and apoE genes modulated body fat mass response to dietary MUFAs in an isocaloric diet in adults with abdominal obesity. These findings might eventually help in developing personalized dietary recommendations for weight control. The trial was registered at clinicaltrials.gov as NCT02029833 (https://www.clinicaltrials.gov/ct2/show/NCT02029833?cond=NCT02029833&rank=1).
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Homoarginine and Clinical Outcomes in Renal Transplant Recipients: Results From the Assessment of Lescol in Renal Transplantation Study.
Drechsler, C, Pihlstrøm, H, Meinitzer, A, Pilz, S, Tomaschitz, A, Abedini, S, Fellstrom, B, Jardine, AG, Wanner, C, März, W, et al
Transplantation. 2015;(7):1470-6
Abstract
BACKGROUND Despite improvements in kidney transplantation, complications, including cardiovascular morbidity and graft loss, contribute to reduced graft and patient survival. The amino acid homoarginine exerts a variety of beneficial effects that may be relevant for cardiovascular and graft outcomes, which is investigated in the present study. METHODS Homoarginine was measured in 829 renal transplant recipients participating in the placebo group of the Assessment of Lescol in Renal Transplantation study. Mean follow-up was 6.7 years. By Cox regression analyses, we determined hazard ratios (HRs) to reach prespecified, adjudicated endpoints according to baseline homoarginine levels: major adverse cardiovascular events (n = 103), cerebrovascular events (n = 53), graft failure or doubling of serum creatinine (n = 140), noncardiovascular mortality (n = 51), and all-cause mortality (n = 107). RESULTS Patients mean age was 50 ± 11 years, homoarginine concentration was 1.96 ± 0.76 μmol/L, and 65% were men. Patients in the lowest homoarginine quartile (<1.40 μmol/L) had an adjusted 2.6-fold higher risk of cerebrovascular events compared to those in the highest quartile (>2.34 μmol/L) (HR, 2.56; 95% confidence interval [95% CI], 1.13-5.82). Similarly, the renal endpoint occurred at a significantly increased rate in the lowest homoarginine quartile (HR, 2.34; 95% CI, 1.36-4.02). For noncardiovascular and all-cause mortality, there was also increased risk associated with the lowest levels of homoarginine, with HRs of 4.34 (95% CI, 1.63-10.69) and 2.50 (95% CI, 1.38-4.55), respectively. CONCLUSIONS Low homoarginine is strongly associated with cerebrovascular events, graft loss and progression of kidney failure and mortality in renal transplant recipients. Whether interventions with homoarginine supplementation improve clinical outcomes requires further evaluation.
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DHA-enriched high-oleic acid canola oil improves lipid profile and lowers predicted cardiovascular disease risk in the canola oil multicenter randomized controlled trial.
Jones, PJ, Senanayake, VK, Pu, S, Jenkins, DJ, Connelly, PW, Lamarche, B, Couture, P, Charest, A, Baril-Gravel, L, West, SG, et al
The American journal of clinical nutrition. 2014;(1):88-97
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Abstract
BACKGROUND It is well recognized that amounts of trans and saturated fats should be minimized in Western diets; however, considerable debate remains regarding optimal amounts of dietary n-9, n-6, and n-3 fatty acids. OBJECTIVE The objective was to examine the effects of varying n-9, n-6, and longer-chain n-3 fatty acid composition on markers of coronary heart disease (CHD) risk. DESIGN A randomized, double-blind, 5-period, crossover design was used. Each 4-wk treatment period was separated by 4-wk washout intervals. Volunteers with abdominal obesity consumed each of 5 identical weight-maintaining, fixed-composition diets with one of the following treatment oils (60 g/3000 kcal) in beverages: 1) conventional canola oil (Canola; n-9 rich), 2) high-oleic acid canola oil with docosahexaenoic acid (CanolaDHA; n-9 and n-3 rich), 3) a blend of corn and safflower oil (25:75) (CornSaff; n-6 rich), 4) a blend of flax and safflower oils (60:40) (FlaxSaff; n-6 and short-chain n-3 rich), or 5) high-oleic acid canola oil (CanolaOleic; highest in n-9). RESULTS One hundred thirty individuals completed the trial. At endpoint, total cholesterol (TC) was lowest after the FlaxSaff phase (P < 0.05 compared with Canola and CanolaDHA) and highest after the CanolaDHA phase (P < 0.05 compared with CornSaff, FlaxSaff, and CanolaOleic). Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were highest, and triglycerides were lowest, after CanolaDHA (P < 0.05 compared with the other diets). All diets decreased TC and LDL cholesterol from baseline to treatment endpoint (P < 0.05). CanolaDHA was the only diet that increased HDL cholesterol from baseline (3.5 ± 1.8%; P < 0.05) and produced the greatest reduction in triglycerides (-20.7 ± 3.8%; P < 0.001) and in systolic blood pressure (-3.3 ± 0.8%; P < 0.001) compared with the other diets (P < 0.05). Percentage reductions in Framingham 10-y CHD risk scores (FRS) from baseline were greatest after CanolaDHA (-19.0 ± 3.1%; P < 0.001) than after other treatments (P < 0.05). CONCLUSION Consumption of CanolaDHA, a novel DHA-rich canola oil, improves HDL cholesterol, triglycerides, and blood pressure, thereby reducing FRS compared with other oils varying in unsaturated fatty acid composition. This trial was registered at www.clinicaltrials.gov as NCT01351012.
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A randomized clinical trial with two doses of an enteral diabetes-specific suplements in elderly patients with diabetes mellitus type 2.
de Luis, DA, Izaola, O, de la Fuente, B, Terroba, MC, Cuellar, L, Cabezas, G
European review for medical and pharmacological sciences. 2013;(12):1626-30
Abstract
OBJECTIVES The aim of our study was to investigate whether two different daily doses of a high monounsaturated fatty acid (MUFA) specific diabetes enteral formula could improve nutritional variables as well as metabolic parameters. PATIENTS AND METHODS We conducted a randomized, open-label, multicenter, parallel group study. 27 patients with diabetes mellitus type 2 with recent weight loss were randomized to one of two study groups: group 1 (two cans per day) and group 2 (three cans per day) for a ten week period. RESULTS A significative decrease of HbA1c was detected in both groups. The decrease 0.98% (confidence interval 95% 0.19-1.88) was higher in group 2 than group 1 0.60% (confidence interval 95% 0.14-1.04). A significant increase of weight, body mass index, fat mass, albumin, prealbumin and transferrin was observed in both groups without statistical differences in this improvement between both groups. The increase of weight 4.59kg (confidence interval 95% 1.71-9.49) was higher in group 2 than group 1 1.46% (confidence interval 95% 0.39-2.54). Gastrointestinal tolerance (diarrhea episodes) with both formulas was good, without statistical differences (7.60% vs 7.14%: ns). CONCLUSIONS A high monounsaturated fatty acid diabetes-specific supplement improved HbA1c and nutritional status. These improvements were higher with three supplements than with two per day.
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Potential benefit of statin therapy for dyslipidemia with chronic kidney disease: Fluvastatin Renal Evaluation Trial (FRET).
Inoue, T, Ikeda, H, Nakamura, T, Abe, S, Taguchi, I, Kikuchi, M, Toyoda, S, Miyazono, M, Kishi, T, Sanai, T, et al
Internal medicine (Tokyo, Japan). 2011;(12):1273-8
Abstract
BACKGROUND Dyslipidemia is a common complication of chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality of CKD patients. AIM: The aim of the present study was to determine whether fluvastatin, which is mostly characterized by its pleiotropic anti-oxidant effects, has renoprotective effects in dyslipidemic patients with CKD. METHODS In 43 dyslipidemic patients with CKD taking fluvastatin 10 mg/day, 20 mg/day or 30 mg/day, renal functions as well as lipid profiles were assessed. RESULTS After 3 months of treatment with fluvastatin, LDL-cholesterol level significantly decreased. Serum creatinine level, estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), urinary liver-type fatty acid binding protein (L-FABP) level and urinary 8-hydroxydeoxyguanosine (8-OHdG) level did not change in overall patients. However, in patients with microalbuminuria (baseline UAE ≥ 30 mg/g·creatinine; n = 23), the UAE significantly decreased [2.43 ± 0.67 to 1.98 ± 0.80 log(mg/g·creatinine), p = 0.01]. In patients with high L-FABP group (baseline L-FABP ≥ 11 µg/g·creatinine; n = 18), the urinary L-FABP level was significantly decreased (1.52 ± 0.45 to 1.26 ± 0.43 µg/g·creatinine, p < 0.01). In the limited 23 patients with microalbuminuria, the L-FABP level was significantly decreased [1.20 ± 0.62 to 1.03 ± 0.49 log(µg/g·creatinine), p = 0.042], although the LDL-cholesterol level (139 ± 28 to 129 ± 23 mg/dL, p = 0.08) only showed a tendency to decrease. The 8-OHdG level also was significantly decreased (13.6 ± 9.6 to 9.8 ± 3.8 ng/g·creatinine, p = 0.043). In the overall patients, changes in the values for UAE and urinary L-FABP were not correlated with the changes in LDL-levels. CONCLUSION Fluvastatin reduces both UAE and the urinary L-FABP level, and thus, has renoprotective effects, independent of its lipid lowering effects in dyslipidemic patients with CKD.
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Applicability of non-cholesterol sterols in predicting response in cholesterol metabolism to simvastatin and fluvastatin treatment among hypercholesterolemic men.
Nissinen, MJ, Miettinen, TE, Gylling, H, Miettinen, TA
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2010;(5):308-16
Abstract
BACKGROUND AND AIMS We hypothesized that (I) certain features in cholesterol metabolism at baseline could predict a response to statins, (II) good and poor responders to statins have a differential profile of serum and fecal sterols and (III) serum non-cholesterol sterols reflect cholesterol metabolism on statins. METHODS AND RESULTS We examined serum lipids, serum and fecal cholesterol, cholesterol precursors, cholestanol and phytosterols and cholesterol metabolism among 20 hypercholesterolemic men at baseline and on 16-wk simvastatin/fluvastatin treatment. At baseline, the mean of serum cholestanol/cholesterol was 11% lower but those of lathosterol/cholesterol, lathosterol/cholestanol, desmosterol/cholesterol, desmosterol/cholestanol were 36-65% higher among good than poor responders (p<0.05 for each). On statins, reductions in ratios of serum precursor sterols and increases of absorption sterols were 1.8-2.9 times higher among good than poor responders (p<0.05 for each). In the whole study group, changes from baseline values of lathosterol/cholestanol were related to those of cholesterol and LDL-C in serum (r=+0.513 and +0.451, p=0.021 and 0.046, respectively). Serum lathosterol ratios to cholesterol, cholestanol and sitosterol consistently reflected a ratio of cholesterol synthesis (mg/d/kg)/fractional cholesterol absorption (%) (r-range +0.456 to +0.727, p<0.05 for each). CONCLUSIONS Low serum baseline ratios to cholesterol of lathosterol, cholestenol and desmosterol, but a high ratio of cholestanol predicted a poor response to statins. Good responders were characterized by more profound reductions of serum and fecal (lathosterol) precursor sterols and increases of serum absorption marker sterol ratios on statins. Serum surrogate sterol markers of cholesterol metabolism were applicable in evaluating cholesterol absorption and synthesis also on statins.
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Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins.
Stein, EA, Ballantyne, CM, Windler, E, Sirnes, PA, Sussekov, A, Yigit, Z, Seper, C, Gimpelewicz, CR
The American journal of cardiology. 2008;(4):490-6
Abstract
Although statin treatment is generally well tolerated, it is estimated that 5% to 10% of patients develop muscle-related side effects (MRSEs), resulting in less effective nonstatin alternatives or cessation of lipid-lowering therapy completely. This study was designed to assess the efficacy and tolerability of extended-release fluvastatin (fluvastatin XL) and ezetimibe alone or in combination in patients with previous MRSEs with other statins. This was a double-blinded, double-dummy trial of 199 mostly moderate- or high-risk dyslipidemic patients randomized to fluvastatin XL 80 mg/day (n = 69), ezetimibe 10 mg/day (n = 66), or fluvastatin XL 80 mg/day plus ezetimibe 10 mg/day (n = 64) for 12 weeks. Fluvastatin XL lowered low-density lipoprotein (LDL) cholesterol by 32.8% compared with 15.6% with ezetimibe (between-group difference -17.1%, 95% confidence interval -23.6 to -10.7, p <0.0001); the fluvastatin XL/ezetimibe combination lowered LDL cholesterol by 46.1% (between-group difference vs ezetimibe -30.4%, 95% confidence interval -37.0 to -23.8, p <0.0001). Proportions of patients achieving their National Cholesterol Education Program Adult Treatment Panel III target LDL cholesterol were 84% with the fluvastatin XL/ezetimibe combination, 59% with fluvastatin XL, and 29% with ezetimibe (p <0.001 for fluvastatin XL monotherapy or combination therapy vs ezetimibe monotherapy). Incidences of MRSEs were 24% in the ezetimibe group, 17% in the fluvastatin XL group, and 14% in the combination group. There were no instances of creatine kinase increases >or=10 times upper limit of normal. In conclusion, in patients with a history of statin-associated MRSEs, fluvastatin XL alone or in combination with ezetimibe offers an effective and well-tolerated lipid-lowering option.
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Efficacy and safety of fluvastatin in children and adolescents with heterozygous familial hypercholesterolaemia.
van der Graaf, A, Nierman, MC, Firth, JC, Wolmarans, KH, Marais, AD, de Groot, E
Acta paediatrica (Oslo, Norway : 1992). 2006;(11):1461-6
Abstract
AIM: To assess whether early initiation of statin therapy for heterozygous familial hypercholesterolaemia favourably affects lipid profiles or vascular morphological changes. METHODS Children and adolescents aged 10-16 y with heterozygous familial hypercholesterolaemia were administered fluvastatin (80 mg/d) for 2 y in a single-arm two-centre study. Carotid B-mode intima-media thickness (IMT) and M-mode arterial wall stiffness (beta) were recorded. Eighty of the 85 enrolled subjects completed the trial. RESULTS The median decrease in low-density lipoprotein (LDL) cholesterol from baseline at last study visit was 33.9%; median decreases in total cholesterol, triglycerides and apolipoprotein B were 27.1%, 5.3% and 24.2%, respectively; the median increase in high-density lipoprotein (HDL) cholesterol was 5.3%. Changes in carotid arterial wall thickness and stiffness versus baseline were fractional and statistically non-significant (delta IMT -0.005 mm, 95% CI -0.018 to +0.007 mm, n=83; and delta beta = 0.017, 95% CI -0.219 to +0.253, n=79). Adverse events, all non-serious, were reported by 58 subjects (68.2%); four were suspected to be drug-related. Change in hormone levels and sexual maturation were appropriate for this age group. CONCLUSION Fluvastatin lowered LDL cholesterol, total cholesterol and apolipoprotein B levels effectively over a prolonged period in children and adolescents with heterozygous familial hypercholesterolaemia. Carotid IMT and wall stiffness remained largely unchanged.
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No detrimental effect on renal function during long-term use of fluvastatin in renal transplant recipients in the Assessment of Lescol in Renal Transplantation (ALERT) study.
Fellström, B, Abedini, S, Holdaas, H, Jardine, AG, Staffler, B, Gimpelewicz, C, ,
Clinical transplantation. 2006;(6):732-9
Abstract
BACKGROUND Concerns have recently been raised regarding a potential harmful effect of statins on renal function. This study investigated the effect of fluvastatin treatment on renal function in renal transplant recipients enrolled in the Assessment of Lescol in Renal Transplantation (ALERT) trial. METHODS ALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40-80 mg daily (n = 1050) or placebo (n = 1052) on cardiac and renal outcomes in renal transplant recipients over a follow-up period of five to six years. The incidence of graft loss, changes in serum creatinine, calculated creatinine clearance and proteinuria, and the incidence of renal adverse events (AEs) were assessed in both treatment groups. RESULTS Fluvastatin treatment in ALERT had no significant effect compared with placebo on renal function, assessed by serum creatinine (overall adjusted mean +/- SEM: fluvastatin, 175.4 +/- 2.20 micromol/L; placebo, 172.7 +/- 2.20 micromol/L; p = 0.39), creatinine clearance (fluvastatin, 55.3 +/- 0.30 mL/min; placebo, 55.8 +/- 0.30 mL/min; p = 0.26) or proteinuria (fluvastatin, 0.58 +/- 0.03 g/24 h; placebo, 0.53 +/- 0.03 g/24 h; p = 0.31). There were no significant differences between treatment groups when the 283 patients suffering graft loss were excluded from the analysis. Fluvastatin also had no detrimental effect on creatinine clearance or proteinuria in the subgroup of 340 diabetic patients without graft loss in ALERT. No notable differences in the rate of renal or musculoskeletal AEs were observed between fluvastatin and placebo groups. CONCLUSIONS Fluvastatin had no detrimental effect on renal function, or the risk of renal AEs, in renal transplant recipients with or without diabetes enrolled in ALERT. Fluvastatin treatment for the prevention of cardiac events may therefore be used without fear of jeopardizing renal function.
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Fluvastatin and lifestyle modification for reduction of carotid intima-media thickness and left ventricular mass progression in drug-treated hypertensives.
Anderssen, SA, Hjelstuen, AK, Hjermann, I, Bjerkan, K, Holme, I
Atherosclerosis. 2005;(2):387-97
Abstract
OBJECTIVES The Hypertension High Risk Management trial (HYRIM) investigated the effect of fluvastatin treatment and lifestyle intervention on development of carotid intima-media thickness (IMT) in drug-treated hypertensive patients. METHODS AND RESULTS HYRIM was a placebo-controlled, 2 x 2 factorial trial in which 568 drug-treated hypertensive men aged 40-74 years with total cholesterol 4.5-8.0 mmol/L, triglycerides <4.5 mmol/L, body mass index 25-35 kg/m2, and a sedentary lifestyle were randomized to receive either fluvastatin, 40 mg daily, or placebo, and either intensive lifestyle intervention (physical activity and diet) or usual care (treatment of hypertension and other disorders by own private physician). Carotid IMT was assessed by B-mode ultrasound vasculography and left ventricular (LV) mass was calculated from ultrasound recordings of the heart. Fluvastatin alone reduced the primary study endpoint of 4-year development of IMT in the common carotid artery (CCA) compared with placebo (p=0.0297). Carotid bulb IMT progression over 4 years was also significantly (p=0.0214) reduced by fluvastatin compared with placebo. Fluvastatin significantly lowered LDL-C levels (mean net difference through 4 years, 0.6 mmol/L; p<0.0001), and reduced the 2-year development of LV mass (p=0.0144) compared with placebo. Lifestyle intervention had no significant effect on LDL-C, carotid IMT or LV mass, and did not increase the effects of fluvastatin. CONCLUSIONS In drug-treated hypertensive patients in a usual care setting, fluvastatin treatment reduces progression of carotid IMT and LV mass.