Impact of atorvastatin plus n-3 PUFA on metabolic, inflammatory and coagulative parameters in metabolic syndrome without and with type 2 diabetes mellitus.
It is known that high LDL-Cholesterol (LDL-C), high triglycerides (TG) and low HDL-Cholesterol (HDL-C) levels (lipid triad (1) or combined dyslipidemia) are associated to elevated incidence of cardiovascular events and to sudden death. (2) In clinical practice, elevated TG levels and low HDL-C levels are most often observed in patients with visceral obesity such as patients with Metabolic Syndrome (MS) and Type 2 Diabetes mellitus (T2DM) which have an increased risk of cardiovascular events. (3)
MS is a cluster of impaired glucose tolerance, hypertension, visceral obesity and dyslipidemia, with pro-thrombotic, inflammatory and fibrinolytic features, that expose patients to coronary heart disease and thromboembolism. (4)
T2DM patients have an increased risk for atherosclerotic disease; coronary heart disease and lower extremity occlusive vascular diseases are common and cause a higher mortality and morbidity as compared to patients without diabetes. (5) Several risk factors such as hyperglycaemia, hypertension, smoking, dyslipidemia, increased fibrinogen and decreased fibrinolytic activity may accelerate the atherosclerotic process in these patients. (6)
Many prospective and case-control studies (PROCAM, PHS, Helsinki Heart Study) (7,8,9) have confirmed the positive association between TG levels and Coronary Heart Disease (CHD) risk, so defining TG as independent risk factors for CHD, and among high LDL-C, low HDL-C and cardiovascular events.
Above all the Framingham Heart Study (11), demonstrated that low HDL-C levels predict high risk for CHD, independently of other prognostic factors; for each 1 mg/dl decrease in HDL-C, the risk for a CHD event increases by 2% in men and 3% in women. (12)
In 2004, the Third Adult Treatment Panel (ATPIII) guidelines of the United States National Cholesterol Education Program (NCEP) have stated that lowering LDLC is the first target of dyslipidemic patients. (13) In addition to guidelines on LDL-C, NCEP ATPIII have recommended a treatment for high TG (>150 mg/dl) and for low HDL-C (<40 mg/dl), and have stated a non-HDL-C levels reduction for these patients with elevated TG levels. Nowadays, the American Diabetic Association (ADA) statement recommends further reductions of LDL-C (< 100 mg/dl), increase of HDL-C (>45 mg/dl) and reduction of TG (<200 mg/dl) in diabetic patients. (14)
Although therapeutic lifestyle modifications including diet, physical activity, and loss of weight are the first-line therapy for patients with combined dyslipidemia, these modifications may be inadequate to achieve ATPIII goals without pharmacological therapy. So in these patients pharmacological therapy is commonly based on statins, fibrates or n-3 PUFA with a good efficacy and safety of use.
Evidence based on medicine confirms that statins (3hydroxy-3-methilglutaryl coenzyme A (HMG-CoA) reductase inhibitors) have been shown to affect many lipidic fractions (15) and to reduce cardiovascular disease (CVD) risk, through many mechanisms and above all lowering LDL-C serum levels, in patients with and without diabetes mellitus. A large prospective trial (16) demonstrated that statin therapy is associated with a reduced incidence of diabetes. Moreover statin therapy reduces inflammatory activity (above all CReactive Protein) and consecutively reduces insulinresistance.
The Atorvastatin Comparative Cholesterol Efficacy and Safety Study (17) compared the efficacy and safety of 5 statins (atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin) and demonstrated that atorvastatin produces a marked reduction in LDL-C and a consistent increase in HDL-C compared to other statins.
Omega-3 long-chain polyunsaturated fatty acids (n-3 PUFA), derived from marine vertebrates and from fish oil have TG-lowering effects (18) in patients with diabetes mellitus (19) and MS (20) and in patients with severe hypertriglyceridaemia; moreover they have a protective role in CHD, in patients with a previous miocardic heart failure and in sudden cardiac death. (21,22)
So the combination therapy with statins and omega-3 fatty acids seems to be the best management in MS, T2DM and in those patients with combined dyslipidemia. The aim of the present study has been to investigate the effects of the combined therapy atorvastatin plus n- 3 PUFA on lipidic pattern, in an open-label, cross-over trial, in two groups of patients, the first with MS and the second with T2DM (23) treated with atorvastatin alone (ATV) versus the association of atorvastatin plus n-3 PUFA (ATV/PUFA).
At the same time we have investigated the combination therapy effects on inflammatory parameters (24), on coagulation pathway, on hemorheology parameters (25), and on microalbuminuria, which has been recently proposed as a marker of endothelial dysfunction and a predictive risk factor for cardiovascular events.
MATERIAL AND METHODS
One hundred and eighty-two participants (182) referred to the Lipid and Thrombosis Centre of Internal Medicine Department of the University of Palermo (Palermo, Italy) were recruited in the study.
The eligibility criteria of the study included men and women between the ages of 45 and 65 years, with MS, diagnosed according to the NCEP ATP III criteria (26) with a slightly impaired glucose tolerance, and MS associated to T2DM. Patients included in the study were outpatients at the first visit, never treated for dyslipidemic disorders. We included in the study a sample of patients representative of the average population with T2DM and MS.
The exclusion criteria of the study were: history of cardiovascular disease or myocardial infarction, cerebrovascular events, blood hypercoagulative familial disorders, severe hepatic steatosis, impaired renal and hepatic function, cancer disease, treatments with insulin, oral contraceptives and antithrombotic drugs, nephrotic syndrome, heavy alcohol use. In total, forty seven patients (47) were excluded from the study.
The study's protocol was not submitted to the Local Ethics Committee, because it was not necessary as all patients involved in the study were at high risk for cardiovascular events; all participants received a detailed study description and signed an informed written consent before the investigation (according to the Helsinki declaration).
The eligible patients were divided in two groups: a group of 62 patients with MS (31 women and 31 men; mean age 49 [+ or -] 3,5 years); a group of 60 patients with T2DM-MS (30 women and 30 men; mean age 48 [+ or -] 3,2 years). A group of 60 healthy participants (29 women and 31 men; mean age 47,3 [+ or -]3,0 years) was also included as control for the baseline values.
The baseline characteristics of patients (Age, Gender, Body Mass Index (BMI), Waist Circumference measured at umbilicus level, arterial pressure, metabolic, inflammatory and coagulation parameters) are shown in tables 1,2,3. All patients did not take any drugs interfering with lipidic patterns (i.e. statins, fibrates, n-3 PUFA or their combinations) for at least 4 weeks before the enrolment (wash-out period). Patients with T2DM received metformin and other oral hypoglycaemic drugs, and hypertensive patients continued their medications with angiotensin-converting enzyme inhibitors and AT1-receptor blockers (ARBs). During the study patients were monitored for use of their medications by recalling the tablets ingested.
The patients' body weight was stable for at least 4 weeks before admission to the study and during the testing period all subjects were asked to keep for 4 weeks an isocaloric and lipid-lowering diet, which was composed of: 19[+ or -] 1.9 % proteins, 20% fats (monounsaturated 10.5[+ or -] 1.0%, polyunsaturated 4.1[+ or -] 0.5% and saturated 5.4[+ or -] 0.5%, cholesterol intake <300mg/die) and 55 [+ or -] 5.5% carbohydrates whose simple sugars were only 5%, and with prohibition of alcoholic drinks; after the washout period all participants were submitted to a 8 weeks treatment period with ATV (20 mg/die). After the ATV treatment both patients with MS and with T2DM-MS were randomised, with an open-label cross over design, in two groups: patients who received the association of ATV (20 mg/die) and n-3 PUFA (3 g/die) at 1624 weeks, and then ATV alone (20 mg) at 32-40 weeks (GROUP A) and patients who received ATV (20 mg/die) alone at 16-24 weeks and after that the association of ATV and n-3 PUFA(3 g/die) at 32-40 weeks (GROUP B).
The rationale of the present study has been to compare pharmacological effects and tolerability of the association ATV/PUFA in patiens with T2DM-MS and MS.
We chose a cross-over study design to underline that the strong reduction in the lipidic pattern is due to the additive effect of n-3 PUFA and not to the long statin treatment duration.
All authors contributed to the manuscript and can vouch for the accuracy and completness of the data.
All blood analyses were performed only between 08:00 and 09:00 AM, at rest, after overnight fast, and after an 8-hour abstinence from smoking and physical exercise. Blood glucose, serum TG, T-C and HDL-C levels (by selective precipitation with magnesium chloride and dextran sulphate), were determined in fresh serum using conventional enzymatic methods (Boeringer Mannheim, Milano, Italy). LDL-C concentration was estimated using the Friedwald formula and Non-HDL-C with a numerical formula (TC - HDL-C). Apolipoprotein A1 and B (Apo A1 and Apo B), and hs-CRP levels were measured by nephelometric system (Nephelometer BN100 DADEBehring S.p.A. Milan, Italy). Insulin was measured with the use of a radioimmunoassay (Sorin Biomedica).
HOMA/IR was evaluated with a standardized formula (glycaemia (mg/dl) x insulinemia (mU/l)/ 405). Glycated haemoglobin (HbA1c) was measured in whole blood containing fluoride oxalate using a Biorad Diamat High Pressure Liquid Chromatography analyser with standards and controls supplied by the manufacturer.
Blood coagulation parameters were drawn from an antecubital vein using a 1.2 mm siliconized needle with minimal stasis. After discarding the first 2 ml, blood was drawn into one/tenth volume of 3.8 % sodium-citrate in polypropylene tubes, kept on crushed ice until centrifugation (40[degrees]C, 2,500x g, 15 min) and plasma was used within two hours. We determined in all samples: baseline plasminogen activator inhibitor (PAI-1) activity by enzyme- linked immunoadsorbent assay (ELISA-Innogenetics NY, Antewerp, Belgium). Fibrinogen and Factor VII concentrations were determined in plasma by clot system (Multifibren (R) DADE-Berhing, Milan, Italy).
Blood samples for the measurements of the hemorheologic parameters were collected in polypropylene tubes, using for the determination of blood and plasma viscosity and haematocrit, sodium heparin 40 microliters (from a solution containing 5000 IU/ml = 150 IU/mg) for 5 ml of blood to give a final concentration for 0.8 %. All the hemorheologic tests were made within 2 hours after the drawing of the samples. We measured: haematocrit (by Wintobe macromethod), blood and plasma viscosity by cone-on-plate micro-viscosimeter (Wells-Brookfield Viscosimeter - Model DV - II, Stoughton, Massachusetts, U.S.A.) estimated at different shear rates and the results were expressed in centipoise (cP).
24h-Urine were collected on three consecutive days, and the mean urinary albumin excretion was calculated. Diagnosis of microalbuminuria was based on the detection of albumin excretion of 30-300 mg/day in a 24h-urine sample.
Clinic visits were scheduled at week -4 (visit 1; screening), week 0 (visit 2; atorvastatin treatment and measurements of all parameters), week 8 (visit 3; randomization and control of all parameters), week 16 (visit 4; control of all parameters), week 24 (visit 5; control of all parameters and cross-over), week 32 (visit 6; control of all parameters), week 40 (control and efficacy assessment).
Patients were followed for all time of the study and we recorded all parameters at weeks 0, 8,16, 24, 32, 40. Only HbA1c was measured at week 0, 8, 24, 40. We reported only baseline, week 8, week 24 and week 40 results.
Standardized laboratoristic methods were used.
Safety and tolerability
Safety and tolerability were evaluated by reviewing patient-reported adverse events, investigators' observations and various laboratory tests including blood analyses (creatinine, AST, ALT, CPK, gamma glutamiltransepeptidase, RBC count). Investigators determined the severity of adverse events (mild, moderate, severe or life threatening) and the potential relationship to study drug (unexpected and expected). Safety variables were the incidence of clinical and/or laboratoristic adverse events treatment-related (pain, epigastric burning, myophathy, rhabdomyolysis) and discontinuations due to adverse events.
Consecutive elevations in ALT and AST >3 times the upper limit of the normal range (ULN) and single CK elevation of 3 times ULN were considered as reasons of discontinuations. Myopathy was defined as a CK elevations >10 times ULN, with associated muscle symptoms.
All values were expressed as mean [+ or -] SD. The significance of differences between groups was determined using Student's t-test for unpaired data with normal distribution according to the Kolmogorov-Smirnov test. The non parametric Mann-Whitney U-test was used for data not normally distributed. Paired data were analysed using the Wilcoxon signed rank test. All statistical tests were two tailed with a 5% level of significance.
Our study enrolled 182 participants. There were no statistical baseline differences among T2DM-MS, MS and control groups about age, gender and number of smokers (Table 1). BMI, Waist circumference, systolic and diastolic pressures were significantly higher in T2DM-MS and MS patients compared to control patients (p<0.01 for systolic and diastolic pressures; p<0.001 for BMI and waist circumference). All these parameters were not significant between MS and T2DM-MS groups.
Baseline (Table 2) TC, TG, HDL-C, NON-HDL-C, LDLC, Apo-B, glycaemia, plasmatic insulin, HOMA/IR, HbA1c, microalbuminuria values were significantly higher in MS and T2DM-MS patients compared to control group (p<0.001; only for LDL-C and Apo-A1 p<0.01). In diabetic patients glycaemia, plasmatic insulin, HOMA/IR (p<0.001), HbA1c and microalbuminuria (p<0.01) were significantly higher compared to MS patients.
Baseline (Table 3) hs-CRP, fibrinogen, Factor VII, PAI-1, Haematocrit, blood viscosity (230.0-1 and 11,5-1 cps) and plasma viscosity values were statistically significant in T2DM-MS and MS patients compared to control patients (p<0.001; p<0.01). Moreover fibrinogen and factor VII were significant higher in diabetic patients compared to MS patients (p<0.01), while other parameters were not significantly different between MS and T2DM-MS groups.
During the first 8 weeks of ATV, in patients with MS (Table 4) significant (p<0.001) reductions of T-C, non-HDLC, LDL-C and Apo-B levels and significant (p<0.01) increases of HDL-C and Apo-A1 levels were observed. In the cross over phase, during ATV/PUFA, significant (p<0.01) reductions of TG and microalbuminuria levels and significant (p<0.001) increases of HDL-C and Apo-A1 levels were observed in groups A and B, compared to ATV alone. TC, Non-HDL-C, LDL-C and Apo-B levels were not significantly changed, even if, during ATV/ PUFA, these values were slightly decreased, compared to ATV alone. Glycaemia, plasma insulin, HOMA/IR and HbA1c levels were maintained steady during both the treatments (Table 5).
In patients with T2DM-MS (Table 7) significant (p<0.001) T-C, non-HDL-C, LDL-C and Apo-B lowering and significant (p<0.01) increases of HDL-C and Apo-A1 were observed in the first 8 weeks of the study. After that, in the cross over phase, during ATV/PUFA, further, even if not significant, reductions of T-C, non-HDL-C, LDL-C and Apo-B, were observed. TG levels were significantly (p<0.01) decreased during ATV/PUFA, compared to ATV alone. Moreover further significant (p<0.001) increases of HDL-C and Apo-A1 levels were observed during ATV/ PUFA. Glycaemia, Plasmatic insulin, HOMA/IR and HbA1c levels were maintained both during ATV and during ATV/ PUFA ( Table 8).
Modifications of inflammatory, coagulative and haemorheologic profiles, were also observed. In patients with MS (Table 6) hs-CRP levels were significantly reduced (P< 0.001) (lowering by 25%) during the first 8 weeks of ATV alone. In the cross over phase hs-CRP levels were further reduced during ATV, even if the supplementation of n-3 PUFA caused a slightly but not significant lowering. Besides the fibrinogen, Factor VII, blood viscosity (230.0-1 and 11.5-1) and plasma viscosity levels were not significantly modified during the first 8 weeks of ATV alone, while, in the cross over phase, during ATV/ PUFA significant (p<0.01) decreases were observed. PAI-1 levels were significantly (p<0.001) reduced during the combined treatment compared to ATV alone results. Haematocrit hold steady compared to time 0 (beginning of the study).
In patients with T2DM-MS (Table 9) hs-CRP levels were significantly (p<0.005) decreased at week 8.
In the cross over phase, further, but not significant reductions of hs-CRP levels were observed during ATV/PUFA, while fibrinogen, plasma and blood viscosity (230.0-1 and 11.5-1) levels were significantly (p<0.05; p<0.005) reduced, compared to ATV alone. Moreover during ATV/PUFA, PAI-1 levels were significantly (p<0.05; p<0.005) and progressively reduced, compared to ATV alone.
All patients completed the study, both study medications were well tolerated, none had adverse events during the study and there were no significant changes in body weight (reduction by 2%) or in laboratory routine parameters, such as liver enzymes, creatinine, RBC count, creatine kinase or glycaemic patterns (Results not shown).
Our results suggest that the association ATV (20 mg/die) and n-3 PUFA (3g/die) improves lipidic, hemorheology and haemostasis parameters in patients with MS and T2DM-MS than ATV alone treatment.
The lipid-lowering effect of statins has been consistently supported by many epidemiological and clinical studies. A large trial of lipid lowering drug therapy " The Collaborative Atorvastatin Diabetes Study (CARDS)" (27) has focused on the role of atorvastatin in type 2 diabetic patients random-ised to either 10 mg atorvastatin daily or placebo. According to this study atorvastatin 10 mg reduced LDL-C by 40%, and TG by 13-27% (depending on initial levels), compared to placebo. (28,29) At four years atorvastatin 10 mg gave evidence of a 37% relative risk reduction in the primary end-point (acute coronary heart disease death, fatal or not fatal myocardial infarction, coronary revascularisation procedures and stroke), while in the secondary endpoints reduced total mortality by 27%, acute coronary events by 36%, coronary revascularisation by 31% and stroke by 48%.
Another large trial, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) (30) enrolled 19,000 hypertensive patients. Of these patients 10,305 with a serum TC level of about 250 mg/dl were randomised to either atorvastatin (10 mg/day) or placebo in the ASCOT lipid-lowering arm (LLA). Patients receiving atorvastatin experienced a significant reduction in LDL-C by 35% and TC, compared to those who received placebo, and a highly significant reduction in the primary end point of non fatal MI and fatal CHD by 36% and in both fatal and non fatal stroke by 27%.
Recently the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) (31) has focused whether intensive LDL-cholesterol lowering to a level of approximately 70 mg/dl with atorvastatin 80 mg/day was more efficacious than standard LDL-C lowering to 100 mg/dl with pravastatin 40 mg/day, in reducing the incidence of cardiovascular events in patients with acute coronary syndrome. Treatment with pravastatin 40 mg/day resulted in a LDL-C reduction by 22% compared to a 51% reduction with atorvastatin 80 mg/day. (32)
At the same time also the role of n-3 PUFA in the management and treatment of plasmatic disorders and cardiovascular disease has received much attention in the literature.
The effects of n-3 PUFA on TG, TC, HDL-C, LDL-C, have been reviewed systematically in meta- analyses in patients with (33) and without (34) diabetes. An Italian study (35) demonstrated that six months therapy with 2 to 3 g/day n-3 PUFA in 935 patients with hypertriglyceridemia, with and without type 2 diabetes, significantly reduced TG levels by 25.2% and increased HDL-C by 7.4% on average.
Although several prospective cohort studies have found an inverse association between fish consumption and risk of CHD or sudden cardiac death in the general population. (36) Among diabetic patients two prospective cohort studies (37,38), showed that the risk of coronary heart disease is lower in diabetic women who consume n-3 PUFA, compared to those who do not.
In contrast few studies on the effects of the combination of statins and n-3 PUFA in T2DM-MS and MS patients have been published.
In a recent double-blind, parallel study (39) of 42 patients with combined hyperlipidemia, the supplementation with 1.68 g/die of eicosapentaenoic acid and docosahexaenoic acid, associated to atorvastatin 10 mg/die, significantly increased HDL-C (additional 6.5% compared to atorvastatin alone), reduced LDL-C, as well as postprandial hypertriglyceridemia, compared to baseline levels.
The dyslipidemia in patients with T2DM-MS and MS is typically characterized by hypertriglyceridaemia, low HDL-C and high LDL-C, which particles are smaller and denser compared to those observed in the general population. (40) This characteristic feature is believed to be an important CVD risk factor.
A recent update from the NCEP ATP III (16) recommends a target for LDL-C, which should be < 100mg/dl for patients at high risk of CVD or CVD equivalents (other atherosclerotic diseases or T2DM) with a secondary therapeutic target non-HDL-C that should be <130 mg/dl; in individuals with = 2 risk factors (cigarette smoking, hypertension, low HDL-C < 40 mg/dl, family history of CVD) LDL-C should be < 130 mg/dl and non-HDL-C<160 mg/dl; in individuals with 0-1 risk factors LDL-C should be <160 mg/dl and non-HDL-C<190 mg/dl.
An aggressive lipid lowering therapy is a priority in patients with T2DM-MS and MS which are at high risk for cardiovascular events.
The present study examined the lipid-lowering, hemorheologic and inflammatory-modifying effects of the supplementation of n-3 PUFA to ATV in patients with T2DM-MS and MS, compared to ATV alone, with a crossover design.
Both ATV alone and ATV/ PUFA has been significantly effective at modifying the lipidic profile in both the groups treated, compared with baseline values.
Stronger LDL-C and TG lowering effects and HDL-C increasing effect were observed during ATV/ PUFA than during ATV alone, as supported by results observed in patients who discontinued ATV alone treatment at 24-week vs ATV/ PUFA, while patients who discontinued ATV/PUFA vs ATV alone had slight LDL-C and TG increasing effects, whit a slight HDL-C lowering.
In the present study the supplementation of n-3 PUFA to ATV has reduced consistently TG levels by 20-25% and slightly non-HDL-C by 10% and has increased strongly HDL-C by 10%, than ATV alone, at the end -point. (41) At the same time those patients who discontinued ATV/ PUFA at 24 week, vs ATV alone had, at the end-point, slight LDL-C increase by 5% and consistent TG increase by 20% and HDL-decrease 15%, compared to results obtained during ATV/ PUFA treatment.
Thus the supplementation of n-3 PUFA seems to have an additional TG and LDL-C lowering effect and a HDL-C increasing effect.
Many comparative trials have moreover suggested that non-HDL-C lowering could provide clinical benefits, in patients with a combined dyslipidemic profile, as also underlined by the NCEP ATP III guidelines.
In the present study the supplementation of n-3 PUFA to ATV had also an additional lowering effect on non-HDL-C levels, compared to ATV alone results.
A good control of blood glucose and insulin activity both in patients with MS (43) and T2DM-MS was maintained, ATV and n-3 PUFA have not evident effects on glucose homeostasis.
Several clinical studies in 1980s and early 1990s have reported adverse effects on blood glucose and insulin activity in subjects with T2DM who consumed a large amount of fish oil. (44) It is now known that these deleterious effects were largely related to the high doses used, 10 g/day of fish oil. Recent studies using low doses of n-3 PUFA, ranging from 1 to 5 g/day, have reported no deterioration in glucose control. (45)
The vascular endothelium is actively involved in maintaining blood circulation, fluidity and various haemostatic processes. (46) It is involved in the development of Atherosclerosis and is associated with impaired function in Cardiovascular Disease and T2DM. (47) Many studies have demonstrated that n-3 PUFA decrease markers of endothelial cell activation and reduce soluble adhesion molecules. (48,49)
In atherosclerosis the supplementation of n-3 PUFA to ATV improves endothelial function with oxide nitric release (50), reduces the plaques progression, interacting with adhesion molecules and inflammatory mediators, has got an antiarrhythmic action reducing the incidence of sudden cardiac death (Gissi and Gissi-HF studies). (52,53) Furthermore, in thrombogenesis n-3 PUFA reduce the platelets aggregation (54,55), and improve the fibrinolysis pathway. (56)
In the present study, ATV/PUFA effects on haemostatic and hemorheologic parameters, were also evaluated. During ATV/PUFA both groups of patients (with MS and T2DMMS) have shown a significant reduction on plasma and blood viscosity (230.0-1 and 11.5-1 cps) levels, than ATV alone.
The supplementation of n-3 PUFA to ATV had got favourable effects on fibrinogen, Factor VII and PAI-1-lowering, compared to ATV alone, with an improvement of fibrinolytic and coagulative profiles, as already emphasized in some studies such as the CARDIA (Coronary Artery Risk Development in Young Adults)57 and the ARIC58 studies.
The inflammatory marker, CRP which is believed to predict CVD-related mortality and morbidity, independently of traditional risk factors (59,60) has been significantly reduced during ATV treatment, while the addition of n-3 PUFA had got not further favourable effects.
The definition of global risk for Cardiovascular events, above all in patients with T2DM and MS, includes the screening for kidney disease (evaluation of microalbuminuria).
Microalbuminuria is defined by the excretion of more than 30 mg/day, it is associated to an increased cardiovascular risk and it is a strong predictor of mortality. It reflects an abnormal loss of albumin from the vascular system and early functional and/or organic changes in endothelium, vascular system, haemostasis and fibrinolytic activity. (61) The hyperlipidemia may play an active role in the progression of renal disease as shown in many reports. (62,63)
Many study had demonstrated the benefits of ATV alone and n-3 PUFA alone (64) on renal damage (65,66), in the present study a progressive and significant reduction of the microalbuminuria was observed during ATV/PUFA treatment.
The microalbuminuria loss-lowering effect involves a progressive restore of renal efficiency, avoiding an evolution towards the Chronic Renal Insufficiency. This benefit may be due to the lipid-lowering effect and seems to be enhanced by the addition of n-3 PUFA to ATV.
In conclusion, the supplementation of n-3PUFA to ATV is significantly more efficacious, than ATV alone, not only in lowering TG and other lipid parameters, but also in reducing blood pressure, insulin resistance and in the improvement of inflammation markers, both in patients with T2DM-MS and in patients with MS.
With appropriate pharmacotherapy to control blood glucose, hypertension, n-3 PUFA associated to ATV may have the potential to stem the rising tide of MS and T2DM and their own cardiovascular sequelae (67), reducing disease progression and risk of mortality for sudden death.
The prospect of our results is that double-blind studies on larger numbers of patients, enrolling patients for a long period of time, may lead to a definitive use of atorvastatin and n-3 PUFA treatment in terms of a leading CVD prevention policy.
The study was supported in part by a grant from the University of Palermo for Scientific Research (2005-06). We are indebted to De Simone Rosa and Raneli Gilia for their excellent technical support.
(1.) Austin MA, King MC, Vranizam KM, Krauss RM: Atherogenic lipoprotein phenotype: A proposed genetic marker for coronary heart disease risk. Circulation 1990; 82: 495-506.
(2.) Lacoste L, Lam JYT, Hung J, Letchacovski G, Solymoss CB, Waters D. Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction. Circulation 1995; 92: 3172-3177.
(3.) Bays HE. Atherogenic dyslipidemia in type 2 diabetes and metabolic syndrome: current and future treatment options. British Journal of Diabetes and Vascular Disease 2003;3:356-360.
(4.) Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. American Heart Association, National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004; Jan 27; 109 (3):433-8.
(5.) Kannel WB, MacGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framing-han Study. Diabetes Care 1979; 2:120-126.
(6.) Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007 Aug. 262 (2): 157-72.
(7.) Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atheroscle-rotic coronary artery disease (the PROCAM experience). Am J Cardiol 1992;70:733-737.
(8.) Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Sacks FM, Hennekens CH. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA 1996;276:882- 888.
(9.) Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: Implications for treatment. Circulation 1992;85:37-45.
(10.) Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996;3:213-219.
(11.) Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA 1986;256:2835-2838.
(12.) Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR Jr, Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation 1989; 79:8-15.
(13.) Grundy S, Cleeman J, Merz N, Brewer B et al. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110:227-239.
(14.) American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2002;25(suppl 1):S74-S77.
(15.) Avellone G., Di Garbo V, Abruzzese G, Campisi D, De Simone R, Raneli G, Licata G. One-year atorvastatin treatment in hypercholesterolemic patients with or without carotid artrey disease. Int Angiol 2006 Mar; 25(1): 26-34.
(16.) Freeman DJ, Norie J et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West Scotland Coronary Prvention Study. Circulation 2001; 103:357-362.
(17.) Andrews TC, Ballantyne CM, Hsia JA, Kramer JH. Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins. Am J Med 2001;111:185-191.
(18.) Weber P, Raederstorff D. Triglyceride-lowering effect of omega-3 LC polyunsaturated fatty acids-a review. Nutr Metab Cardiovasc Dis 2000;10:28-37.
(19.) Farmer A, Montori V, Dineen S, Clar C. Fish oil in people with type 2 diabetes mellitus. Cochrane Database Syst Rev 2001; (3): CD0032205.
(20.) Cottrell DA, Marshall BJ, Falko JM. Therapeutic approaches to dyslipidemia in diabetes mellitus and metabolic syndrome. Curr. Opin. Cardiol. 2003; 28:301-308.
(21.) Albert Cm, Campos H, Stampfer MJ et al. Blood levels of long-chain n-3 fatty acids and risk of sudden death. N Engl J Med 2002; 346: 1113-18.
(22.) Yokoama M. Effects of eicosapenataenoic acid on major coronary events in hypercholesterolaemic patients (Jelis); a randomised open-label, blinded endpoint analysis. Lancet 2007; 369: 1090-1098.
(23.) Avellone G, Di Garbo V, Guarnotta V, Prestipino E,Campisi D, Abruzzese G, De Simone R, Raneli G, Licata G. Relationship between body fat distribution and blood disorders in patients with visceral obesity with and without Diabetes mellitus. Archives The Inter Journal Med 2008;1:17-22.
(24.) Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836-843.
(25.) Sola E, Vaya A, Sims M, Hernandez-Mijares A, Morillas C, Espana F, Estelles A, Corella D. Fibrinogen, plasma viscosity and blood viscosity in obesity. Relationship with insulin-resistance. Clin Hemorheol and Microcirc 2007; 37: 309-318.
(26.) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP). JAMA 2001;285:2486-97.
(27.) H. M. Colhoun, M. J. Thomason, M. I. Mackness, et al and the CARDS Investigators. Design of the Collaborative Atorvastatin Diabetes Study (CARDS) in patients with Type 2 diabetes. Diabetic Medicine 2002; Vol 19 N 3: 201-211.
(28.) Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998; 81: 582-587.
(29.) Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn JL, Weiss SR et al. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA 1996; 275 : 128-133.
(30.) Sever PS. Lipid-lowering therapy and the patient with multiple risk factors: what have we learned from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)? Am J Med 2005;118:Suppl: 12-19.
(31.) Rouleau J. Improved outcome after acute coronary syndromes with an intensive versus standard lipid-lowering regimen: results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. Am J Med 2005; 118 Suppl: 12A: 28-35.
(32.) Ray KK, Cannon CP, Cairns R, Morrow DA, Rifai N, Kirtane AJ, McCabe CH, Skene AM, Gibson GM, Ridker PM, Bramwald E; PROVE IT TIMI 22 Investigators. Relationship between uncontrolled risk factors and C-reactive protein levels in patients receiving standard or intensive statin therapy for acute coronary syndromes in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005; 46(8): 1417-24.
(33.) Farmer A, Montori V, Dinneen S, Clar C Fish oil in people with type 2 diabetes mellitus. Cochrane Database Syst Rev 2001:CD003205.
(34.) Lewis A, Lookinland S, Beckstrand RL, Tiedeman ME. Treatment of hypertriglyceridemia with omega-3 fatty acids: a systematic review. J Am Acad Nurse Pract 2004;16:384-395.
(35.) Sirtori CR, Crepaldi G, Manzato E, Mancini M, Rivellese A, Paoliett R, Pazzucconi F, Pamparana F, Stragliotto E. One-year treatment with ethyl esters of n-3 fatty acids in patients with hypertriglyceridemia and glucose intolerance: Reduced triglyceridemia, total cholesterol and increased HDL-C without glycemic alteration. Atherosclerosis. 1998;137:419-427.
(36.) Bucher HC, Hengstler P, Schindler C, Meier G. n-3 polyunsaturated fatty acids in coronary heart disease: a metaanalysis of randomized controlled trials. Am J Med 2002; 112:298-304.
(37.) Hu FB, Cho E, Rexrode KM, Albert CM, Manson JE. Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women. Circulation 2003; 107:1852-1857.
(38.) Erkkila AT, Lichtenstein AH, Mozaffarian D, Herrington DM. Fish intake is associated with a reduced progression of coronary artery atherosclerosis in postmenopausal women with coronary artery disease. Am J Clin Nutr 2004;80:626-632.
(39.) Nordoy A, Hansen JB, Brox J, Sveenson B. Effects of atorvastatin and w-3 fatty acids on LDL subfractions and postprandial hyperlipemia in patients with combined hyperlipemia. Nutr Metab Cardiovasc Dis 2001; 11: 7-16.
(40.) Manzato E, Zambon A, Lapolla A et al. Lipoprotein abnormalities in well-treated type II diabetic patients. Diabetes Care 1993; 16: 469-475.
(41.) Chan DC, Watts GF, Mori TA, Barrett PH, Redgrave TG, Beilin LJ: Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity. Am J Clin Nutr 2003;77:300 -307.
(42.) Bitter V. Non-high-density lipoprotein cholesterol: an alternate target for lipid lowering therapy. Prev Cardiol 2004; 7(3):122-126.
(43.) Sirtori C.R., Paoletti R, Mancini M, Crepaldi G, Manzato E, Rivellese A, Pamparana F, Stragliotto E, on behalf of The Italian Fish Oil Multicenter Study. Universita di Palermo U.O. G. Avellone, V. Di Garbo. n-3 Fatty acids do not lead to an increased diabetic risk in patients with hyperlipidemia and abnormal glucose tolerance. Am J Clin Nutr 1997; 65: 1874-81.
(44.) Sirtori CR, Crepaldi G, Manzato E, Mancini M, Rivellese A, Paoliett R, Pazzucconi F, Pamparana F, Stragliotto E. One-year treatment with ethyl esters of n-3 fatty acids in patients with hypertriglyceridemia and glucose intolerance: Reduced triglyceridemia, total cholesterol and increased HDL-C without glycemic alteration. Atherosclerosis. 1998;137:419-427.
(45.) Luo J, Rizkalla SW, Vidal H, Oppert JM, Colas C, Boussairi A, Guerre-Millo M, Chapuis AS, Chevalier A, Durand G, Slama G. Moderate intake of n-3 fatty acids for 2 months has no detrimental effect on glucose metabolism and could ameliorate the lipid profile in type 2 diabetic men. Results of a controlled study. Diabetes Care. 1998;21:717-724.
(46.) Brown AA, Hu FB. Dietary modulation of endothelial function: Implications for cardiovascular disease. Am J Clin Nutr 2001; 73: 673-786.
(47.) Hogikyan RV, Galecki At, Pitt B, Alter JB, Green DA, Supiano MA. Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity. J Clin Endocrinol Metab. 1998;83:1946-1952.
(48.) Thies F, Miles EA, Nebe-von-Caron G, Powell JR, Hurst TL, Newsholme EA, Calder PC. Influence of dietary supplementation with long-chain n-3 or n-6 polyunsaturated fatty acids on blood inflammatory cell populations and functions and on plasma soluble adhesion molecules in healthy adults. Lipids 2001; 36: 1183-1193.
(49.) Okumura T, Fujioka Y, Morimoto S, Tsuboi S, Masai M, Tsujino T, Ohyanagi M, Iwasaki T. Eicosapentaenoic acid improves endothelial function in hypertriglyceridemic subjects despite increased lipid oxidability. Am J Med Sci 2002;324: 247-253.
(50.) De Caterina R, Liao Jk, Libby P. Fatty acid modulation of endothelial activation. Am J Clin Nutr 2000; 71 (Suppl 1): 213-235.
(51.) De Caterina R, Libby B. Control of endothelial leukocyte adhesion molecules by fatty acids. Lipids 1996; 31 :S57-63.
(52.) GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico). Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI- Prevenzione Trial. Lancet 1999;354 (9177) : 447-455.
(53.) Gissi-HF Investigators, Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 4;372(9645):1223-30.
(54.) Mori TA, Beilin LJ, Burke V. Interactions between dietary fat, fish and fish oils and their effects on platelets function in men at risk of cardiovascular disease. Arterioscler Thromb Vasc Biol 1997; 17: 279-86.
(55.) Lagarde M, Croset M, Vericel E, Calzada C: Effects of small concentrations of eicosapentaenoic acid on platelets. J Intern Med 1989;Suppl 731:177-179.
(56.) Barcelli U, Glas-Greenwalt P, Pollak VE. Enhancing effect of dietary supplementation with omega-3 fatty acids on plasma fibrinolysis normal subjects. Thromb Res 1985; 39: 307-12.
(57.) Sujata L. Archer; David Green; Maryann Chamberlain; Alan R. Dyer,Kiang Liu. Association of Dietary Fish and n-3 Fatty Acid Intake With Hemostatic Factors in the Coronary Artery Risk Development in Young Adults (CARDIA) Study . Arterioscler Thromeb Vasc Biol. 1998;18:1119-23.
(58.) Shahar E, Folsom AR, Wu KK, Dennis BH, Shimakawa T, Conlan MG, Davis CE, Williams OD. Association of fish intake and dietary n-3 polyunsaturated fatty acids with a hypocoagulable profile: the Atherosclerosis Risk in Communities (ARIC) study. Arterioscler Thromb. 1993;13:1205-1212.
(59.) Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347: 1557-1565.
(60.) Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet 1997; 349:426-462.
(61.) Ross R. The pathogenesis of Atherosclerosis- an update.N Engl J Med 1986; 314: 488-500.
(62.) Oda H, Keane F. Lipids in progression of renal disease. Kidney Internat 1997; 52: 36-8.
(63.) Mantari M, Tiula E, Alikoski T, Manninen V. Effects of hypertension and dyslipidemia on the decline in renal function. Hypertension 1995; 26: 670-5.
(64.) Lungershausen YK, Howe PR, Clifton PM, Hughes CR, Phillips P, Graham JJ, Thomas DW. Evaluation of an omega-3 fatty acid supplement in diabetics with microalbuminuria. Ann N Y Acad Sci 1997 Sep 20; 827: 369-81.
(65.) Sinziger H, Kritz H, Furberg C. Atorvastatin reduces microalbuminuria in patients with familial hypercholesterolemia and normal glucose tolerance. Med Sci Monit 2003; 9(7): P188-92.
(66.) Bianchi S, Bigazza R, Chiazza A, Campese VM. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 2003; 41(3): 565-70.
(67.) Albert CM, Hennekens CH, O'Donnell CJ, Ajani UA, Carey VJ, Willett WC, Ruskin JN, Manson JE. Fish consumption and risk of sudden cardiac death. JAMA 279:23-28, 1998.
Gino Avellone, Valentina Guarnotta, Vincenzo Di Garbo, Giovanni Abruzzese, Domenico Campisi, Antonio Pinto, Giuseppina Pizzo Giuseppe Licata
Department of Clinical Medicine, Lipid and Thrombosis Research Centre, University of Palermo, Palermo, Italy
Corresponding author: Prof. G. Avellone, Via De Gasperi 203, 0146 Palermo, Tel: 0039-091-6552135- Fax: 0039-0916552248, E-mail: firstname.lastname@example.org
Table 1. Anthropometric and life-style baseline data in recruited groups Control Group (n=60) Age (years) 47.3 [+ or -] 3.0 Genders (males/females) 31/29 BMI (kg/[m.sup.2]) 22 [+ or -] 1.2 Waist Circumference (cm) 76 [+ or -] 4.5 Systolic pressure (mmHg) 131 [+ or -] 4.0 Diastolic pressure (mmHg) 80 [+ or -] 3.0 Smokers/ Non smokers 29/31 Metabolic Syndrome Group (n=62) Age (years) 49 [+ or -] 3.5 Genders (males/females) 31/31 BMI (kg/[m.sup.2]) 35.2 [+ or -] 2.5 ** Waist Circumference (cm) 115 [+ or -] 2.5 ** Systolic pressure (mmHg) 136 [+ or -] 5.5 * Diastolic pressure (mmHg) 86 [+ or -] 2.8 * Smokers/ Non smokers 31/31 Type II Diabetes Mellitus--MS Group (n=60) Age (years) 48 [+ or -] 3.2 Genders (males/females) 30/30 BMI (kg/[m.sup.2]) 33.5 [+ or -] 3.0 ** Waist Circumference (cm) 118 [+ or -] 3.3 ** Systolic pressure (mmHg) 140 [+ or -] 5.5 * Diastolic pressure (mmHg) 88 [+ or -] 3.0 * Smokers/ Non smokers 28/32 * p < 0.01 vs control group ** p < 0.001 vs control group Table 2. Metabolic baseline parameters in recruited groups Control Group (n=60) Total Cholesterol (mg/dl) 178.4 [+ or -] 19.7 Triglycerides (mg/dl) 118.3 [+ or -] 20.3 HDL-Cholesterol (mg/dl) 44.6 [+ or -] 2.3 Non-HDL-Cholesterol (mg/dl) 133.8 [+ or -] 14.5 LDL-Cholesterol (mg/dl) 110.2 [+ or -] 13.0 Apo A1 (mg/dl) 139.6 [+ or -] 12 Apo-B (mg/dl) 106.7 [+ or -] 13.9 Glycaemia (mg/dl) 87 [+ or -] 3.2 Plasmatic Insulin (mU/l) 4.9 [+ or -] 1.0 HOMA/IR 1.91 [+ or -] 2.0 Microalbuminuria (mcg/24 h) <10 [HbA.sub.1]C(%) 4.2 [+ or -] 0.5 Metabolic Syndrome Group (n=62) Total Cholesterol (mg/dl) 220.8 [+ or -] 16.5 * Triglycerides (mg/dl) 198 [+ or -] 11 * HDL-Cholesterol (mg/dl) 31.6 [+ or -] 4.0 ** Non-HDL-Cholesterol (mg/dl) 189.2 [+ or -] 13.5 ** LDL-Cholesterol (mg/dl) 149.7 [+ or -] 13.8 * Apo A1 (mg/dl) 112 [+ or -] 10.4 * Apo-B (mg/dl) 162.3 [+ or -] 22.5 ** Glycaemia (mg/dl) 100.2 [+ or -] 4.4 ** Plasmatic Insulin (mU/l) 13.6 [+ or -] 2.6 ** HOMA/IR 3.36 [+ or -] 0.3 * Microalbuminuria (mcg/24 h) 44 [+ or -] 13 ** [HbA.sub.1]C(%) 5.6 [+ or -] 0.5 ** Type II Diabetes Mellitus--MS Group (n=60) Total Cholesterol (mg/dl) 230 [+ or -] 20 * Triglycerides (mg/dl) 242 [+ or -] 25.2 ** HDL-Cholesterol (mg/dl) 30 [+ or -] 6 ** Non-HDL-Cholesterol (mg/dl) 200 [+ or -] 13 ** LDL-Cholesterol (mg/dl) 151.6 [+ or -] 12.0 * Apo A1 (mg/dl) 110.2 [+ or -] 12.4 * Apo-B (mg/dl) 175 [+ or -] 25 ** Glycaemia (mg/dl) 155.8 [+ or -] 8.2 ** ## Plasmatic Insulin (mU/l) 28.0 [+ or -] 3.5 ** ## HOMA/IR 10.77 [+ or -] 0.7 ** ## Microalbuminuria (mcg/24 h) 85 [+ or -] 20 ** # [HbA.sub.1]C(%) 7.2 [+ or -] 1.2 ** * p < 0.01 vs control group ** p < 0.001 vs control group # p < 0.01 vs metabolic syndrome group ## p <0.001 vs metabolic syndrome group Table 3. Hemorrheologic, inflammatory and coagulation baseline parameters in recruited groups Control Group (n=60) Hs-CRP (mg/dl) 1.38 [+ or -] 0.32 Fibrinogen (mg/dl) 326.5 [+ or -] 58.3 Factor VII (%) 81.1 [+ or -] 12.1 PAI-1 (UI/ml) 1.4 [+ or -] 0.4 Haematocrit (%) 42.5 [+ or -] 1.8 Blood viscosity ([230.0.sup.-1])(cps) 4.37 [+ or -] 0.35 Blood viscosity ([11.5.sup.-1])(cps) 9.85 [+ or -] 0.5 Plasma viscosity (cps) 1.52 [+ or -] 0.1 Metabolic Syndrome Group (n=62) Hs-CRP (mg/dl) 2.39 [+ or -] 0.44 ** Fibrinogen (mg/dl) 480.2 [+ or -] 66.8 ** Factor VII (%) 118.1 [+ or -] 21.8 * PAI-1 (UI/ml) 8.8 [+ or -] 2.4 ** Haematocrit (%) 47.2 [+ or -] 1.5 ** Blood viscosity ([230.0.sup.-1])(cps) 5.23 [+ or -] 0.38 ** Blood viscosity ([11.5.sup.-1])(cps) 12.72 [+ or -] 0.4 ** Plasma viscosity (cps) 1.96 [+ or -] 0.12 ** Type II Diabetes Mellitus--MS Group (n=60) Hs-CRP (mg/dl) 2.42 [+ or -] 0.53 ** Fibrinogen (mg/dl) 580 [+ or -] 96.3 ** # Factor VII (%) 135.7 [+ or -] 24.9 ** # PAI-1 (UI/ml) 9.5 [+ or -] 2.2 ** Haematocrit (%) 49.5 [+ or -] 2.3 ** Blood viscosity ([230.0.sup.-1])(cps) 5.75 [+ or -] 0.4 ** Blood viscosity ([11.5.sup.-1])(cps) 12.82 [+ or -] 0.4 ** Plasma viscosity (cps) t1.98 [+ or -] 0.12 ** * p < 0.01 vs control group ** p < 0.001 vs control group # p < 0.01 vs metabolic syndrome group Table 4. Metabolic parameters in patients with Metabolic Syndrome: Groups A and B Parameters Baseline Week 8 Total 220.8 [+ or -] 16.5 157.8 [+ or -] 18 ** Cholesterol (mg/dl) Triglycerides 198 [+ or -] 11 174 [+ or -] 12.2 (mg/dl) HDL-C (mg/dl) 31.6 [+ or -] 4.0 33 [+ or -] 4.5 * Non-HDL-C 189.2 [+ or -] 13.5 124.8 [+ or -] 14.2 ** (mg/dl) LDL-C (mg/dl) 149.7 [+ or -] 13.8 90.2 [+ or -] 13.8 ** Apo-A1 (mg/dl) 112 [+ or -] 10.4 120.5 [+ or -] 12.2 * Apo-B (mg/dl) 162.3 [+ or -] 22.5 108.5 [+ or -] 21 ** Parameters Randomization in Week 24 two groups Total A 158 [+ or -] 17.5 ** A 156 [+ or -] 15.5 ** Cholesterol B 160.4 [+ or -] 19 ** B 158.2 [+ or -] 18 ** (mg/dl) Triglycerides A 174.5 [+ or -] 12.5 ** A 130 [+ or -] 8.8 * (mg/dl) B 178.2 [+ or -] 12 ** B 178 [+ or -] 11.5 HDL-C (mg/dl) A 30.5 [+ or -] 4.5 ** A 40 [+ or -] 3.9 ** B 34.5 [+ or -] 4.2 ** B 35.0 [+ or -] 4.5 * Non-HDL-C A 127.5 [+ or -] 14.5 ** A 116 [+ or -] 13.5 ** (mg/dl) B 125.9 [+ or -] 14.2 ** B 124.2 [+ or -] 13.5 ** LDL-C (mg/dl) A 92.6 [+ or -] 13.6 ** A 84.7 [+ or -] 13 ** B 90.3 [+ or -] 13 ** B 86.7 [+ or -] 13.5 ** Apo-A1 (mg/dl) A 118.6 [+ or -] 11.5 ** A 125.5 [+ or -] 10.8 ** B 122.4 [+ or -] 12 ** B 121 [+ or -] 12 * Apo-B (mg/dl) A 104.5 [+ or -] 19.8 ** A 106 [+ or -] 18 ** B 113.2 [+ or -] 19 ** B 107.5 [+ or -] 19.5 ** Parameters Week 40 Total A 162 [+ or -] 18 ** Cholesterol B 156 [+ or -] 17.5 ** (mg/dl) Triglycerides A 176.5 [+ or -] 11.5 (mg/dl) B 136.5 [+ or -] 12 * HDL-C (mg/dl) A 34 [+ or -] 3.8 * B 41 [+ or -] 3.5 ** Non-HDL-C A 128 [+ or -] 13 ** (mg/dl) B 115 [+ or -] 13.5 ** LDL-C (mg/dl) A 90.4 [+ or -] 13 ** B 85.2 [+ or -] 15 ** Apo-A1 (mg/dl) A 119.5 [+ or -] 13 ** B 126 [+ or -] 12.5 ** Apo-B (mg/dl) A 107 [+ or -] 21 ** B 105 [+ or -] 20 ** * p < 0.01 vs time 0 ** p < 0.001 vs time 0 GROUP A (N=31) atorvastatin plus n-3 PUFA (week-24) vs atorvastatin alone (week 40) GROUP B (N=31) atorvastatin alone (week 24) vs atorvastatin plus n-3 PUFA (week 40) Table 5. Glycaemic and urinary pattern in Metabolic Syndrome: Groups A and B Parameters Baseline Week 8 Glycaemia 100.2 [+ or -] 5.4 99.5 [+ or -] 5.0 (mg/dl) Plasmatic 13.6 [+ or -] 2.6 13.5 [+ or -] 2.5 insulin (mU/l) HOMA/IR 3.36 [+ or -] 0.3 3.31 [+ or -] 0.25 [HbA.sub.1]C 5.6 [+ or -] 0.5 5.6 [+ or -] 0.5 (%) LDL-C 44 [+ or -] 13 42 [+ or -] 12 (mg/dl) Parameters Randomization in Week 24 two groups Glycaemia A 96.5 [+ or -] 5.2 A 102 [+ or -] 5.4 (mg/dl) B 100 [+ or -] 5.2 B 100 [+ or -] 5.5 Plasmatic A 14.3 [+ or -] 2.4 A 13.6 [+ or -] 2.6 insulin B 11.6 [+ or -] 2.5 B 13.7 [+ or -] 3.0 (mU/l) HOMA/IR A 3.20 [+ or -] 0.4 A 3.42 [+ or -] 0.3 B 3.39 [+ or -] 0.5 B 3.38 [+ or -] 0.25 [HbA.sub.1]C A 5.46 [+ or -] 0.4 A 5.7 [+ or -] 0.4 (%) B 5.8 [+ or -] 5.5 B 5.7 [+ or -] 0.5 LDL-C A 46 [+ or -] 12.4 A 28 [+ or -] 9 * (mg/dl) B 39 [+ or -] 11.8 B 38 [+ or -] 12 Parameters Week 40 Glycaemia A 100 [+ or -] 5.5 (mg/dl) B 101 [+ or -] 5.5 Plasmatic A 13.8 [+ or -] 2.5 insulin B 13.6 [+ or -] 2.5 (mU/l) HOMA/IR A 3.41 [+ or -] 0.3 B 3.39 [+ or -] 0.2 [HbA.sub.1]C A 5.65 [+ or -] 0.5 (%) B 5.65 [+ or -] 0.4 LDL-C A 40 [+ or -] 14 (mg/dl) B 28 [+ or -]12 * * p < 0.01 vs time 0 ** p < 0.001 vs time 0 GROUP A (N=31) atorvastatin plus n-3 PUFA (week-24) vs atorvastatin alone (week 40) GROUP B (N=31) atorvastatin alone (week 24) vs atorvastatin plus n-3 PUFA (week 40) Table 6. Inflammatory, coagulation and hemorrheologic parameters in patients with MS: Groups A and B Parameters Baseline Week 8 Hs-CRP 2.39 [+ or -] 0.44 1.70 [+ or -] 0.35 ** (mg/dl) Fibrinogen 480.2 [+ or -] 66.8 470 [+ or -] 57.2 (mg/dl) Factor VII 118.1 [+ or -] 21.8 115.2 [+ or -] 20.9 % PAI-1 8.8 [+ or -] 2.4 8.6 [+ or -] 2.3 (UI/ml) Haematocrit 47.2 [+ or -] 1.5 47.5 [+ or -] 1.8 % Blood viscosity 5.23 [+ or -] 0.38 5.27 [+ or -] 0.40 (230.0-1)(cps) Blood viscosity 12.72 [+ or -] 0.4 12.66 [+ or -] 0.5 (11.5-1)(cps) Plasma viscosity 1.96 [+ or -] 0.12 1.93 [+ or -] 0.15 (cps) Parameters Randomization in Week 24 two groups Hs-CRP A 1.86 [+ or -] 0.38 ** A 1.59 [+ or -] 0.30 ** (mg/dl) B 1.69 [+ or -] 0.36 ** B 1.62 [+ or -] 0.33 ** Fibrinogen A 466 [+ or -] 56.5 ** A 428 [+ or -] 44.6 * (mg/dl) B 492 [+ or -] 59.5 ** B 456 [+ or -] 61 Factor VII A 114.5 [+ or -] 20.2 ** A 104.3 [+ or -] 17.6 * % B 118.2 [+ or -] 22.3 ** B 114.0 [+ or -] 18 PAI-1 A 8.79 [+ or -] 2.6 ** A 5.9 [+ or -] 2.0 ** (UI/ml) B 8.32 [+ or -] 2.1 ** B 8.2 [+ or -] 2.0 Haematocrit A 46.9 [+ or -] 1.6 ** A 47.3 [+ or -] 1.6 % B 48.1 [+ or -] 1.9 ** B 47.6 [+ or -] 1.5 Blood viscosity A 5.24 [+ or -] 0.36 ** A 4.8 [+ or -] 0.36 * (230.0-1)(cps) B 5.29 [+ or -] 0.42 ** B 5.32 [+ or -] 0.5 Blood viscosity A 12.6 [+ or -] 0.45 ** A 11.11 [+ or -] 0.7 * (11.5-1)(cps) B 12.68 [+ or -] 0.5 ** B 12.6 [+ or -] 0.6 Plasma viscosity A 1.96 [+ or -] 0.2 ** A 1.77 [+ or -] 0.19 * (cps) B 1.90 [+ or -] 0.1 ** B 1.86 [+ or -] 0.14 Parameters Week 40 Hs-CRP A 1.66 [+ or -] 0.30 ** (mg/dl) B 1.48 [+ or -]0.3 ** Fibrinogen A 456 [+ or -] 55 (mg/dl) B 426 [+ or -]50 * Factor VII A 114 [+ or -] 20.5 % B 106.5 [+ or -]19.5 * PAI-1 A 8.4 [+ or -] 2.5 (UI/ml) B 5.8 [+ or -] 2.3 ** Haematocrit A 47.5 [+ or -] 1.7 % B 47.3 [+ or -] 1.5 Blood viscosity A 5.2 [+ or -] 0.4 (230.0-1)(cps) B 4.85 [+ or -] 0.4 * Blood viscosity A 12.3 [+ or -] 0.6 (11.5-1)(cps) B 11.05 [+ or -] 0.4 * Plasma viscosity A 1.88 [+ or -] 0.18 (cps) B 1.78 [+ or -] 0.18 * * p < 0.01 vs time 0 ** p < 0.001 vs time 0 GROUP A (N=31) atorvastatin plus n-3 PUFA (week-24) vs atorvastatin alone (week 40) GROUP B (N=31) atorvastatin alone (week 24) vs atorvastatin plus n-3 PUFA (week 40) Table 7. Metabolic parameters in patients with Type 2 Diabetes Mellitus: Groups A and B Parameters Baseline Week 8 Total 230 [+ or -] 20 162.5 [+ or -] 21 ** Cholesterol (mg/dl) Triglycerides 242 [+ or -] 25.2 208 [+ or -] 22.5 (mg/dl) HDL- C 30 [+ or -] 6 32.5 [+ or -] 5 * (mg/dl) Non-HDL-C 200 [+ or -] 13 130 [+ or -] 12.8 ** (mg/dl) LDL-C 151.6 [+ or -] 12 88.4 [+ or -] 10.1 ** (mg/dl) Apo-A1 110.2 [+ or -] 12.4 118 [+ or -] 13.5 * (mg/dl) Apo-B 175 [+ or -] 25 112 [+ or -] 24 ** (mg/dl) Parameters Randomization in Week 24 two groups Total A 161.3 [+ or -] 20.8 ** A 160 [+ or -] 20.5 ** Cholesterol B 164.5 [+ or -] 21.6 ** B 161.5 [+ or -] 22 ** (mg/dl) Triglycerides A 204.3 [+ or -] 20.7 ** A 150 [+ or -] 15.3 * (mg/dl) B 210 [+ or -] 22.9 ** B 198.5 [+ or -] 20.8 HDL- C A 34.3 [+ or -] 5.5 ** A 39.2 [+ or -] 4.0 ** (mg/dl) B 31.5 [+ or -] 4.6 ** B 33.5 [+ or -] 4.0 * Non-HDL-C A 127 [+ or -] 12.3 ** A 120.8 [+ or -] 13 ** (mg/dl) B 133 [+ or -] 13.1 ** B 128 [+ or -] 13 ** LDL-C A 86.2 [+ or -] 9.8 ** A 90.8 [+ or -] 10.8 ** (mg/dl) B 91 [+ or -] 11.9 ** B 90.9 [+ or -] 11.8 ** Apo-A1 A 116 [+ or -] 12.8 ** A 123.8 [+ or -] 10.6 ** (mg/dl) B 120.5 [+ or -] 13.6 ** B 119.5 [+ or -] 13.0 * Apo-B A 114.4 [+ or -] 24.5 ** A 113 [+ or -] 22 ** (mg/dl) B 110.5 [+ or -] 22.2 ** B 108 [+ or -] 23 ** Parameters Week 40 Total A 162 [+ or -] 20 ** Cholesterol B 159.5 [+ or -] 21 ** (mg/dl) Triglycerides A 188 [+ or -] 20.5 (mg/dl) B 141 [+ or -]1 8 * HDL- C A 32 [+ or -] 4.0 * (mg/dl) B 39 [+ or -]5.0 ** Non-HDL-C A 130 [+ or -] 13.5 ** (mg/dl) B 122 [+ or -] 13 ** LDL-C A 92.4 [+ or -] 12.5 ** (mg/dl) B 90.3 [+ or -] 11.2 ** Apo-A1 A 119 [+ or -] 13.0 * (mg/dl) B 125.5 [+ or -] 13.8 ** Apo-B A 112 [+ or -] 24 ** (mg/dl) B 111.5 [+ or -] 24 ** * p < 0.01 vs time 0 ** p < 0.001 vs time 0 GROUP A (N=31) atorvastatin plus n-3 PUFA (week-24) vs atorvastatin alone (week 40) GROUP B (N=31) atorvastatin alone (week 24) vs atorvastatin plus n-3 PUFA (week 40) Table 8. Glycaemic pattern in T2DM-MS: Groups A and B Parameters Baseline Week 8 Glycaemia 155.8 [+ or -] 8.2 154.6 [+ or -] 8.0 (mg/dl) Plasmatic 28.0 [+ or -] 3.5 27.9 [+ or -] 3.0 insulin (mU/l) HOMA/IR 10.77 [+ or -] 0.7 10.65 [+ or -] 0.8 [HbA.sub.1]C(%) 7.2 [+ or -] 1.2 7.3 [+ or -] 1.1 Microalbuminuria 85 [+ or -] 20 68 [+ or -] 16 (mcg/die) Parameters Randomization in Week 24 two groups Glycaemia A 150.5 [+ or -] 7.8 A 155.5 [+ or -] 8.5 (mg/dl) B 158 [+ or -] 8.9 B 154.5 [+ or -] 7.0 Plasmatic A 28.1 [+ or -] 3.2 A 28.7 [+ or -] 3.0 insulin (mU/l) B 27.9 [+ or -] 3.0 B 28.8 [+ or -] 3.2 HOMA/IR A 10.8 [+ or -] 0.9 A 11.01 [+ or -] 0.9 B 10.4 [+ or -] 0.6 B 10.98 [+ or -] 0.8 [HbA.sub.1]C(%) A 7.0 [+ or -] 1.0 A 7.3 [+ or -] 1.0 B 8.0 [+ or -] 1.3 B 7.3 [+ or -] 1.1 Microalbuminuria A 66.5 [+ or -] 15.5 A 39 [+ or -] 10 * (mcg/die) B 70 [+ or -] 16.5 B 64 [+ or -] 16 Parameters Week 40 Glycaemia A 155 [+ or -] 7.5 (mg/dl) B 154.5 8.0 Plasmatic A 28.9 [+ or -] 3.5 insulin (mU/l) B 28.8 [+ or -] 3.5 HOMA/IR A 11.06 [+ or -] 0.9 B 10.98 [+ or -] 0.8 [HbA.sub.1]C(%) A 7.3 [+ or -] 1.2 B 7.3 [+ or -] 1.0 Microalbuminuria A 51 [+ or -] 15 (mcg/die) B 38 [+ or -] 14 * * p < 0.01 vs time 0 ** p < 0.001 vs time 0 GROUP A (N=31) atorvastatin plus n-3 PUFA (week-24) vs atorvastatin alone (week 40) GROUP B (N=31) atorvastatin alone (week 24) vs atorvastatin plus n-3 PUFA (week 40) Table 9. Inflammatory, coagulation and haemorrheologic parameters in patients with T2DM-MS: Groups A and B Parameters Baseline Week 8 Hs-CRP 2.42 [+ or -] 0.53 1.76 [+ or -] 0.42 ** (mg/dl) Fibrinogen 580 [+ or -] 96.3 565 [+ or -] 99.5 (mg/dl) Factor VII 135.7 [+ or -] 24.9 134.6 [+ or -] 25.1 % PAI-1 9.5 [+ or -] 2.2 9.4 [+ or -] 2.2 (UI/ml) Haematocrit 49.5 [+ or -] 2.3 49.4 [+ or -] 2.4 % Blood viscosity 5.75 [+ or -] 0.4 5.72 [+ or -] 0.5 (230.0-1)(cps) Blood viscosity 12.82 [+ or -] 0.4 12.75 [+ or -] 0.5 (11.5-1)(cps) Plasma viscosity 1.98 [+ or -] 0.12 1.94 [+ or -] 0.14 (cps) Parameters Randomization in Week 24 two groups Hs-CRP A 1.78 [+ or -] 0.45 ** A 1.65 [+ or -] 0.35 ** (mg/dl) B 1.70 [+ or -] 0.40 ** B 1.69 [+ or -] 0.38 ** Fibrinogen A 540 [+ or -] 98.6 ** A 480 [+ or -] 69.9 * (mg/dl) B 582.5 [+ or -] 97.6 ** B 542 [+ or -] 80 Factor VII A 138.3 [+ or -] 25.6 ** A 124.6 [+ or -] 25.1 * % B 132.4 [+ or -] 24.8 ** B 132 [+ or -] 25 PAI-1 A 9.2 [+ or -] 2.15 ** A 5.4 [+ or -] 2.2 ** (UI/ml) B 9.6 [+ or -] 2.3 ** B 9.1 [+ or -] 2.2 Haematocrit A 49.6 [+ or -] 2.35 ** A 49.4 [+ or -] 2.4 % B 49.8 [+ or -] 2.4 ** B 49.45 [+ or -] 2.5 Blood viscosity A 5.71 [+ or -] 0.45 ** A 5.10 [+ or -] 0.4 ** (230.0-1)(cps) B 5.76 [+ or -] 0.6 ** B 5.60 [+ or -]0.4 Blood viscosity A 12.78[+ or -] 0.5 ** A 11.30 [+ or -] 0.7 * (11.5-1)(cps) B 12.7 [+ or -] 0.4 ** B 12.3 [+ or -] 0.3 Plasma viscosity A 1.94 [+ or -] 0.15 ** A 1.75 [+ or -] 0.13 * (cps) B 1.94 [+ or -] 0.14 ** B 1.92 [+ or -] 0.15 Parameters Week 40 Hs-CRP A 1.69 [+ or -] 0.42 ** (mg/dl) B 1.65 [+ or -] 0.45 ** Fibrinogen A 525[+ or -] 75 (mg/dl) B 490 [+ or -] 70 * Factor VII A 133 [+ or -] 25.2 % B 121 [+ or -] 24.5 * PAI-1 A 9.1 [+ or -] 2.5 (UI/ml) B 5.3 [+ or -] 2.0 ** Haematocrit A 49.35 [+ or -] 2.5 % B 49.3 [+ or -] 2.3 Blood viscosity A 5.6 [+ or -] 0.6 (230.0-1)(cps) B 5.05 [+ or -] 0.4 ** Blood viscosity A 12.2 [+ or -] 0.6 (11.5-1)(cps) B 11.2 [+ or -] 0.7 ** Plasma viscosity A 1.9 [+ or -] 0.16 (cps) B 1.72 [+ or -] 0.15 * * p < 0.01 vs time 0 ** p < 0.001 vs time 0 GROUP A (N=31) atorvastatin plus n-3 PUFA (week-24) vs atorvastatin alone (week 40) GROUP B (N=31) atorvastatin alone (week 24) vs atorvastatin plus n-3 PUFA (week 40)
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|Title Annotation:||ORIGINAL ARTICLE|
|Author:||Avellone, Gino; Guarnotta, Valentina; Di Garbo, Vincenzo; Abruzzese, Giovanni; Campisi, Domenico; Pi|
|Publication:||Archives: The International Journal of Medicine|
|Date:||Jan 1, 2009|
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