Prevention of Cardiovascular Events with Pitavastatin is Associated with Increased Serum Lipoprotein Lipase Mass Level: Subgroup Analysis of the TOHO-LIP.

AIM: To clarify the mechanism by which pitavastatin reduced cardiovascular (CV) events more effectively than atorvastatin in the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP), the changes in (Δ) non-heparinized serum level of lipoprotein lipase mass (LPL mass) during administration of the respective statins were investigated. METHODS: From TOHO-LIP data, 223 hypercholesterolemic patients with any CV risks followed at Toho University Sakura Medical Center were analyzed. The patients were randomized to pitavastatin (2 mg/day) group (n=107) or atorvastatin (10 mg/day) group (n=116), and followed for 240 weeks. In this subgroup study, the primary and secondary end points were the same as those in TOHO-LIP, and 3-point major adverse cardiovascular events (3P-MACE) was added. The relationship between ΔLPL mass during the first year and the incidences of each end point was analyzed. RESULTS: The lipid-lowering effect was not different between the two statins. Cumulative 240-week incidence of each end point was significantly lower in pitavastatin group (primary: 1.9% vs. 10.3%, secondary: 4.7% vs. 18.1%, 3P-MACE: 0.9% vs. 6.9%). Mean LPL mass (64.9 to 69.0 ng/mL) and eGFR (70.1 to 73.6 ml/min/1.73m 2) increased in pitavastatin group, but not in atorvastatin group during the first year. Cox proportional-hazards model revealed that ΔLPL mass (1 ng/mL or 1SD) contributed to almost all end points. CONCLUSIONS: Pitavastatin administration reduced CV events more efficaciously than atorvastatin despite similar LDL cholesterol-lowering effect of the two statins. Increased LPL mass during the first year by pitavastatin treatment may be associated with this efficacy.

CAVI-Lowering Effect of Pitavastatin May Be Involved in the Prevention of Cardiovascular Disease: Subgroup Analysis of the TOHO-LIP.

AIM: In the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP), a multicenter randomized controlled trial, pitavastatin significantly reduced cardiovascular (CV) events compared to atorvastatin in patients with hypercholesterolemia. To investigate the mechanism by which pitavastatin preferentially prevents CV events, we investigated the relationship between CV events and cardio-ankle vascular index (CAVI) using the TOHO-LIP database. METHODS: For the subgroup analysis, we selected patients from a single center, Toho University Sakura Medical Center. After excluding those who had CV events at baseline or during the first year, 254 patients were enrolled. The primary end point was the same as that of TOHO-LIP, and three-point major cardiac adverse events (3P-MACE) was added as secondary end point. RESULTS: The cumulative 5-year incidence of 3P-MACE (pitavastatin 1.6%, atorvastatin 6.1%, P=0.038) was significantly lower in pitavastatin group (2 mg/day) than in atorvastatin group (10 mg/day). CAVI significantly decreased only in pitavastatin group during the first year (9.50-9.34, P=0.042), while the change in low-density lipoprotein cholesterol (LDL-C) did not differ between the two groups. The change in CAVI during the first year positively correlated with 3P-MACE and tended to be an independent predictor of 3P-MACE in Cox proportional hazards model (hazard ratio, 1.736; P=0.079). The annual change in CAVI throughout the observation period was significantly higher in subjects with CV events compared to those without. CONCLUSIONS: In this subgroup analysis, the reduction in CV events tended to be associated with the CAVI-lowering effect of pitavastatin, which was independent of the LDL-C-lowering effect.

Validation of homogeneous assays for HDL-cholesterol using fresh samples from healthy and diseased subjects.

BACKGROUND: High-density lipoprotein-cholesterol (HDL-C) is a negative risk factor for cardiovascular events. Although several homogeneous HDL-C assays are available, their accuracy has not been validated, particularly in subjects with disease. We aimed to clarify whether HDL-C concentrations measured by homogeneous assays [HDL-C (H)] agree with those determined by the reference measurement procedures [HDL-C (RMP)] using ultracentrifugation and precipitation with heparin-manganese reagent in fresh clinical samples. METHODS: HDL-C concentrations in samples from 48 healthy subjects and 119 subjects with disease were determined using 12 homogeneous assays and RMPs. RESULTS: All reagents showed excellent intra- and inter-assay CVs (<2.23%) for two pooled sera. Furthermore, the mean bias was within ± 1.0% in nine reagents using samples from healthy subjects and in eight reagents using samples from subjects with disease. In a single HDL-C (H) determination, the total error requirement of the National Cholesterol Education Program (95% of results < 13%) was fulfilled in nine reagents using samples from healthy subjects and six reagents in those from subjects with disease. Error component analysis revealed that only one reagent exceeded ± 10% total error in samples from healthy subjects, whereas four reagents exceeded this error in samples from subjects with disease. Correlations between HDL-C (H) and HDL-C (RMP) revealed that the slopes were within 1.00 ± 0.06 in six reagents in healthy subjects, and eight reagents in subjects with disease. CONCLUSIONS: Except for three reagents, HDL-C (H) agrees well with HDL-C (RMP) in subjects with common disease, but not in those with extremely low HDL-C or abnormal HDL composition.

The effects of partial use of formula diet on weight reduction and metabolic variables in obese type 2 diabetic patients--multicenter trial.

AIMS: To clarify the usefulness of protein-sparing modified formula diet in obese type 2 diabetic patients, the effects of partial use of formula diet on weight reduction and changes in related metabolic variables, and the improving rates of risk factors per 1% body weight reduction, were compared with those of conventional subcaloric diet. SUBJECTS AND METHODS: Obese patients [BMI >25 kg/m²] with diabetic mellitus were randomly assigned to a low-caloric diet with partial use of formula diet group (FD, n = 119) and a conventional low-caloric diet group (CD, n = 110). Subjects in FD took one pack of formula diet (MicroDiet®, 240 kcal/pack) in place of one of three daily low-caloric meals for 24 weeks. Total daily calorie prescribed was same. RESULT: Weight reduction was greater in FD than in CD (week 24: -3.5 vs -1.4 kg; all p < 0.001). Systolic blood pressure decreased significantly only in FD. HbA1c reduction was greater in FD than in CD. HDL-cholesterol increased significantly more in FD than in CD (week 24: +2.8 vs. +0.6 mg/dl, p < 0.001). Among several improving rates (%) of risk factors/1% body weight reduction, those of HbA1c at weeks 16 and 24, triglyceride at week 8 and HDL-cholesterol at week 24, were significantly higher in FD than CD. Doses of sulfonylurea and thiazolidinedione were significantly decreased in FD than in CD. CONCLUSION: Partial use of formula diet was much more effective in reducing body weight, and also in improving coronary risk factors than conventional diet in part due to reduced body weight through decreased energy diet intake and due to dietary composition of the formula diet.

Effects of body weight reduction on cardio-ankle vascular index (CAVI).

OBJECTIVE: Obesity is associated with type 2 diabetes, dyslipidemia and hypertension, contributing to atherogenesis. Weight reduction is the fundamental therapy for obesity. Recently, a novel arterial stiffness parameter called cardio-ankle vascular index (CAVI) has been developed. We hypothesized that CAVI may be a candidate marker of increased vascular stiffness in obese patients. The aim of this study is to investigate the effect of weight reduction on CAVI. SUBJECTS AND METHODS: Using CAVI as an indicator, we assessed the changes in arterial stiffness in 47 obese Japanese subjects (aged 46 ± 13 years) who underwent a 12-week weight reduction program consisting of a calorie restriction diet (20-25 kcal/day) and exercise therapy. Visceral fat area (VFA) was evaluated by CT. RESULTS: At baseline, CAVI correlated positively with age (r = 0.70), blood pressure (r = 0.23), VFA (r = 0.26) and HbA1c (r = 0.39). After 12 weeks of weight reduction, mean BMI decreased from 33.3 ± 7.5 to 30.7 ± 6.4 kg/m(2) (p < 0.0001), and mean CAVI decreased from 8.3 to 7.9 (p < 0.01). The change in VFA correlated positively with change in CAVI in subjects with decrease in CAVI (r = 0.47). Furthermore, change in VFA was a significant independent predictor for change in CAVI. No significant correlation was observed between change in CAVI and clinical variables such as BMI, HbA1c and lipids. CONCLUSION: This study demonstrated that CAVI decreased after weight reduction, and was associated with a decrease in VFA. CAVI reduction maybe a marker of improved vascular stiffness after weight reduction in subjects with visceral adiposity.

Probucol suppresses initiation of chronic hemodialysis therapy and renal dysfunction-related death in diabetic nephropathy patients: Sakura study.

AIM: Probucol has antioxidant as well as cholesterol-lowering effects. We examined the effect of probucol on the progression of diabetic nephropathy. We named this study 'Sakura Study' after our hospital and city. METHODS: We performed a randomized, open trial on 162 type 2 diabetic patients with clinical albuminuria (urinary albumin excretion >300 mg/g creatinine). Eighty patients were assigned to probucol treatment (500 mg/day) and 82 patients to no probucol treatment. All patients were followed for five years. The primary outcome was the time to renal dysfunction events, defined as the initiation of chronic hemodialysis therapy and renal dysfunction-related death. RESULTS: Probucol decreased total cholesterol, HDL-cholesterol, and LDL-cholesterol compared to the control group. The serum creatinine increase rate was significantly lower (p= 0.015) in the probucol group (0.066 mg/dL/month) than in the non-probucol group (0.116 mg/dL/month). Renal dysfunction events occurred in 72 patients during this study. The 69 patients who were initiated on chronic hemodialysis comprised 42 in the non-probucol group and 27 in the probucol group. Three patients in the non-probucol group, but no patients in the probucol group died of renal dysfunction. The renal dysfunction event-free survival rate was significantly higher (log-rank: p= 0.02) in the probucol group than in the non-probucol group. CONCLUSION: Probucol suppressed the progression of diabetic nephropathy and renal dysfunction events.

A multicenter study on the precision and accuracy of homogeneous assays for LDL-cholesterol: comparison with a beta-quantification method using fresh serum obtained from non-diseased and diseased subjects.

BACKGROUND: Homogeneous assays for low-density lipoprotein-cholesterol (LDL-C) have good precision and are pretreatment-free procedures. However, their accuracies have been questioned, especially in diseased subjects. In this study, we aimed to verify whether LDL-C levels determined by homogeneous assays [LDL-C (H)] agree with those determined by a beta-quantification method [LDL-C (BQ)] in fresh clinical samples. METHODS: We determined LDL-C levels in 49 non-diseased and 124 diseased subjects whose triglyceride (TG) levels were less than 11.29 mmol/L (1000 mg/dL) using 12 homogeneous assays and a BQ method simultaneously. RESULTS: In total, 30.6% of non-diseased subjects and 46.0% of diseased subjects were in the postprandial state. The maximum inter- and intra-assay CVs were 1.8% and 1.5%, and 8 reagents had a CV of 1.0% or less. The mean bias ranged from -0.5% to 1.8% for non-diseased subjects and from -0.7% to 1.6% for diseased subjects. For non-diseased subjects, all but one reagent achieved the National Cholesterol Education Program (NCEP) total error requirement in more than 90% of samples. However, for diseased subjects, the number of reagents that met this requirement was low. With some reagents, LDL-C (H) was higher than LDL-C (BQ), especially in subjects with hypertriglyceridemia. While for other reagents, the difference between the two methods was not associated with hypertriglyceridemia except for type I (n = 2) and type III hyperlipidemia (n = 1). Postprandial sampling was not the main factor for discordant results. CONCLUSIONS: LDL-C (H) agrees with LDL-C (BQ) in non-diseased subjects, but exhibits positive bias for subjects with hypertriglyceridemia in diseased subjects for some reagents.

Atorvastatin and pitavastatin enhance lipoprotein lipase production in L6 skeletal muscle cells through activation of adenosine monophosphate-activated protein kinase.

Pravastatin and atorvastatin increase the serum level of lipoprotein lipase (LPL) mass in vivo but do not increase LPL activity in 3T3-L1 preadipocytes in vitro. LPL is mainly produced by adipose tissue and skeletal muscle cells. Metformin enhances LPL in skeletal muscle through adenosine monophosphate-activated protein kinase (AMPK) activation but not in adipocytes. This study aimed to examine the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on LPL production and to investigate the mechanism by which statins enhance skeletal muscle cell LPL production. L6 skeletal muscle cells were incubated with pravastatin, simvastatin, atorvastatin or pitavastatin. LPL activity, protein levels and mRNA expression were measured. Atorvastatin and pitavastatin significantly increased LPL activity, protein levels and mRNA expression in L6 skeletal muscle cells at 1 µmol/L, but neither statin had an effect at 10 µmol/L. We measured AMPK to clarify the mechanism by which statins increase LPL production in skeletal muscle cells. At 1 µmol/L, both atorvastatin and pitavastatin enhanced AMPK activity, but this enhancement was abolished when AMPK signaling was blocked by compound C. The increased expressions of LPL protein and mRNA by atorvastatin and pitavastatin were reduced by compound C. In addition, mevalonic acid abolished atorvastatin- and pitavastatin-induced AMPK activation and LPL expression. These results suggest that atorvastatin and pitavastatin increase LPL activity, protein levels and LPL mRNA expression by activating AMPK in skeletal muscle cells.

Formula diet is effective for the reduction and differentiation of visceral adipose tissue in Zucker fatty rats.

AIM: Formula diet (FD), which is used as a tool for calorie restriction, has beneficial effects on metabolic disorders in obese patients; however, the molecular mechanism is not fully understood. METHODS: Sixteen-week-old male Zucker Diabetic Fatty (ZDF) rats were divided into 3 groups (n= 10 each): calorie-controlled low-fat diet [Control; 75 kcal/day, protein : fat : carbohydrate (P:F:C)=25:15: 60], calorie-restricted low-fat diet (CR-LFD; 56 kcal/day, P:F:C=25:15:60), and calorie-restricted FD (CR-FD; 56 kcal/day, P:F:C=50:14:36) group, and fed each diet for 4 weeks. Before the study, baseline data were obtained in 10 rats. After 4 weeks, body weight and epididymal fat weight were measured, and blood samples, mesenteric and subcutaneous adipose tissues were collected for analyses. Messenger RNA expression was evaluated by real-time PCR, and protein expression by Western blotting. RESULTS: The decrease in epididymal fat weight was significantly greater in the CR-FD group than in control and CR-LFD groups, although changes in body weight were not different among groups. The decrease in fasting plasma glucose and increase in plasma adiponectin were greater in the CR-FD group than in the control group, but not in the CR-LFD group. The decrease in triglyceride and increase in HDL-cholesterol were greatest in the CR-FD group. Both mRNA and protein of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α, adiponectin, lipoprotein lipase and PPARγ were overexpressed in the CR-FD group, especially in mesenteric adipose tissue. CONCLUSIONS: FD may have beneficial effects on abdominal obesity and metabolic disorders by reducing visceral fat and improving glucose and lipid profiles, possibly through modulating adipose tissue function.

Cardio-ankle vascular index (CAVI) as a novel indicator of arterial stiffness: theory, evidence and perspectives.

The cardio-ankle vascular index (CAVI) is a new index of the overall stiffness of the artery from the origin of the aorta to the ankle. The most conspicuous feature of CAVI is its independence of blood pressure at the time of measurement.CAVI increases with age and in many arteriosclerotic diseases, such as coronary artery disease, carotid arteriosclerosis, chronic kidney disease and cerebrovascular disease, and is related to many coronary risk factors, such as hypertension, diabetes mellitus, dyslipidemia and smoking. Furthermore, CAVI decreases by controlling diabetes mellitus and hypertension, and also by abstaining from smoking. This suggests that CAVI is a physiological surrogate marker of athero- or arteriosclerosis, and also might be an indicator of lifestyle modification.Recently, it has been reported that CAVI and several left ventricular functions are co-related, suggesting a connection between the heart muscle and vascular function.This review covers the principles of CAVI and our current knowledge about CAVI, focusing on its roles and future outlook.

Contradictory effects of ß1- and α1- aderenergic receptor blockers on cardio-ankle vascular stiffness index (CAVI)--CAVI independent of blood pressure.

AIM: The cardio-ankle vascular stiffness index (CAVI) is a new parameter that reflects the stiffness of the aorta, femoral artery and tibial artery as a whole. One of its conspicuous features is that CAVI is independent of blood pressure at measuring time, theoretically. But, it has not been experimentally proved yet. For confirmation, pharmacological studies were performed comparing with brachial-ankle pulse wave velocity (baPWV). METHODS: Used drugs were a ß1-adrenoceptor blocker, metoprorol and an α1- adrenoceptor blocker doxazosin. Both were administered to 12 healthy volunteer men. CAVI and baPWV were measured every one hour for 6 hours using VaSera. RESULTS: When metoprolol (80 mg) was administered to 12 healthy volunteer men, systolic blood pressure decreased from 131.4 ± 4.5 to 118.3 ± 4.1 mmHg (mean ± SE) (p < 0.05) at the 3rd hour, and diastolic blood pressure decreased from 85.3 ± 4.0 to 75.3 ± 3.0 mm Hg (p < 0.05). baP-WV decreased from 13.93 ± 0.46 to 12.46 ± 0.49 m/sec (p < 0.05), significantly, but CAVI did not change (8.16 ± 0.29 to 8.24 ± 0.27) (p = 0.449). ΔbaPWV at each time was significantly correlated with both Δsystolic and Δdiastolic blood pressures, but ΔCAVI was not correlated with either Δblood pressure. When doxazosin (4 mg) was administered to the same men, systolic blood pressure decreased from 130.2 ± 4.6 to 117.2 ± 4.8 mmHg (p < 0.05) at the 3rd hour. Diastolic blood pressure also decreased from 85.1 ± 4.1 to 74.2 ± 3.9 mmHg (p < 0.05). baPWV decreased from 13.98 ± 0.68 to 12.25 ± 0.53 m/sec (p < 0.05), significantly. CAVI also decreased from 8.15 ± 0.28 to 7.18 ± 0.37 (p < 0.05), significantly. CONCLUSION: These results suggested that CAVI was not affected by blood pressure at the measuring time directly, but affected by the changes of contractility of smooth muscle cells.

Improvement of postprandial hyperglycemia and arterial stiffness upon switching from premixed human insulin 30/70 to biphasic insulin aspart 30/70.

Postprandial hyperglycemia is known to be associated with increasing cardiovascular mortality in type 2 diabetes mellitus patients. Cardio-ankle vascular index (CAVI) reflects arterial stiffness and is more useful for predicting coronary atherosclerosis than intima-media thickness. Premixed human insulin 30/70 (BHI30) containing rapid-acting insulin has been used conventionally as a biphasic insulin. Recently, a biphasic insulin analogue preparation, biphasic insulin aspart 30/70 (BIAsp30), containing ultrarapid-acting insulin has been approved and expected to improve postprandial hyperglycemia. The aim of this study was to clarify the effects of switching the biphasic insulin from BHI30 to BIAsp30 on arterial stiffness in type 2 diabetes mellitus patients. Twenty-six type 2 diabetes mellitus patients (glycosylated hemoglobin >6.5%) who were already receiving biphasic insulin therapy with BHI30 twice daily were observed for 3 months. Afterward, BHI30 was switched to BIAsp30. At 3 months after switching, relative mobility of the peak of LDL fraction decreased significantly (from 0.3462 ± 0.041 to 0.3356 ± 0.035, P < .01); and CAVI also decreased significantly (from 9.77 ± 1.11 to 9.35 ± 1.17 m/s, P < .005). A significant negative correlation was observed between the change in CAVI and change in 1,5-anhydroglucitol (1,5-AG) (r = -0.3929, P < .05). A stronger correlation between change in CAVI and change in 1,5-AG was observed in the subgroup of patients whose 1,5-AG levels were elevated after switching (r = -0.6261, P < .05) compared with all subjects. These results suggest that switching biphasic insulin from BHI30 to BIAsp30 improves arterial stiffness, and the improvement of arterial stiffness may be associated with improvement of postprandial hyperglycemia.

Effect of exercise performed at anaerobic threshold on serum growth hormone and body fat distribution in obese patients with type 2 diabetes.

SUMMARY: The mechanism by which exercise reduces visceral fat is not fully understood. We have reported that increase in serum growth hormone (GH) level by mild exercise is associated with increase in lipolysis in type 2 diabetes (T2D), and that GH stimulates lipolysis in rat visceral adipose tissue. The aim of this study was to investigate the effect of GH secretion in response to exercise on visceral fat in obese subjects with T2D. Subjects were divided into exercise (n = 11) and non-exercise (n = 8) groups. Exercise was performed at anaerobic threshold (AT). Blood samples were obtained at weeks 0 and 4. To evaluate the secretion of GH and catecholamines in response to exercise, serum GH and catecholamines levels were measured before and after a bout of exercise on day 1. Visceral fat area (VFA) reduction tended to be greater in exercise group compared to non-exercise group (p = 0.067), whereas subcutaneous fat area (SFA) reduction was not different between two groups. In exercise group, serum GH level tended to increase during exercise, while catecholamines showed no significant changes. The change in serum GH level correlated negatively with the change in VFA during this study, but did not correlate with SFA. The increase in serum insulin-like growth factor-I level in exercise group was 10-fold higher than that in non-exercise group. These results suggest that in obese patients with T2D, exercise performed at AT may reduce visceral fat and the reduction appears to be associated with GH secretion but not with catecholamine in response to exercise.:

Effect of ezetimibe monotherapy on lipid metabolism and arterial stiffness assessed by cardio-ankle vascular index in type 2 diabetic patients.

AIM: High cholesterol absorption in the small intestine has been proposed to be a risk factor of atherosclerosis. In this study, we evaluated the effect of ezetimibe monotherapy on arterial stiffness in type 2 diabetic patients. METHODS: Forty type 2 diabetes mellitus patients with high serum low-density lipoprotein cholesterol (LDL-C) were enrolled and treated with ezetimibe 10 mg/day for 6 months. HbA1c, serum lipids, remnant-like particle-cholesterol (RLP-C), serum lipoprotein lipase mass (LPL mass) and the cardio-ankle vascular index (CAVI) were measured before and after ezetimibe treatment. RESULTS: After 6 months of ezetimibe treatment, significant decreases in LDL-C, RLP-C and CAVI were observed. In the group that achieved the LDL-C goal of <120 mg/dL after 6 months of ezetimibe treatment, the pretreatment CAVI was markedly high, and CAVI decreased significantly after ezetimibe treatment. CONCLUSIONS: In type 2 diabetic patients, ezetimibe monotherapy may have the potential to ameliorate arterial stiffness in addition to lowering LDL-C and RLP-C.

Pioglitazone decreases plasma angiotensin II concentration in type 2 diabetes.

AIM: Adipocytes express all components of the renin-angiotensin system (RAS), and adipocyte RAS regulates adipocyte differentiation and metabolism. Plasma angiotensin II (AII) is a putative marker of adipocyte RAS production. The aim of this study was to investigate the effect of pioglitazone on plasma AII in type 2 diabetes (T2D). METHODS: Fifty Japanese subjects with T2D were randomly allocated to two groups. One group was administered pioglitazone 30 mg/day (pioglitazone group) and the other group was not given pioglitazone (control group) for 16 weeks. Lipoprotein lipase mass in preheparin serum (LPL mass) was measured as an adipocyte-derived factor and a marker of insulin sensitivity. RESULTS: In the pioglitazone group, the mean HbA1c decreased (p<0.0001), LPL mass increased (p<0.0001), and plasma AII decreased (p=0.0007), whereas these parameters were unchanged in the control group. The change in plasma AII correlated negatively with the change in LPL mass (r=-0.312) in the pioglitazone group. In the pioglitazone group, the decrease in plasma AII was higher (p=0.0002) and the increase in LPL mass tended to be higher (p=0.0941) in the subgroup with higher baseline plasma AII than that with lower plasma AII. CONCLUSIONS: The present study indicates that pioglitazone decreases plasma AII associated with an increase in LPL mass in T2D. The insulin-sensitizing effect of pioglitazone may be involved in suppressing adipocyte RAS.

Effects of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on cardio-ankle vascular index in type 2 diabetic patients.

AIM: A novel device has been developed for measuring the cardio-ankle vascular index (CAVI) as an indicator of arterial stiffness. In this study, we evaluated the effect of pitavastatin on CAVI in type 2 diabetic patients. METHODS: Forty-five type 2 diabetes mellitus patients with low-density lipoprotein cholesterolemia were enrolled and treated with pitavastatin 2 mg/day for 12 months. Before and after pitavastatin administration, HbA1c, serum lipids, serum malondialdehyde-LDL (MDA-LDL), urinary 8-hydroxy- 2'-deoxyguanosine (8-OHdG) and CAVI were measured. RESULTS: After pitavastatin treatment for 12 months, significant decreases in 8-OHdG, MDA-LDL and CAVI were observed. DeltaCAVI significantly correlated with DeltaMDA-LDL. CONCLUSIONS: In type 2 diabetic patients, pitavastatin may have an oxidative stress-reducing effect, especially in a state of enhanced oxidative stress, and CAVI may be useful as a routine test for the diagnosis and therapeutic monitoring of atherosclerosis.

Effects of olmesartan, an angiotensin II receptor blocker, and amlodipine, a calcium channel blocker, on Cardio-Ankle Vascular Index (CAVI) in type 2 diabetic patients with hypertension.

AIM: Recently, a novel device for measuring the cardio-ankle vascular index (CAVI) as an arterial stiffness parameter has been developed. In this study, we evaluated the effect of angiotensin II receptor blocker (ARB) and calcium channel (Ca) blocker on CAVI in type 2 diabetic patients with hypertension. METHODS: Seventy type 2 diabetes mellitus patients with hypertension were enrolled and randomly divided into two groups. One group was administered olmesartan medoxomil 20 mg/day [DOSAGE ERROR CORRECTED] for 12 months (ARB group), and the other group was administered amlodipine besilate 5 mg/day for 12 months (Ca blocker group). RESULTS: In the ARB group, a significant decrease in CAVI was observed after 12 months; however, no significant change in CAVI was observed in the Ca blocker group although changes in blood pressure were almost the same. By simple regression analyses, CAVI changes correlated positively with 8-OHdG changes. CONCLUSIONS: Olmesartan, an ARB, improved arterial stiffness more than amlodipine, and this effect might be due to not only the blood pressure-lowering effect but also to reducing the potential of oxidative stress recognized in olmesartan.

Protective effects of efonidipine, a T- and L-type calcium channel blocker, on renal function and arterial stiffness in type 2 diabetic patients with hypertension and nephropathy.

AIM: The three types of calcium channel blocker (CCB), L-, T- and N-type, possess heterogeneous actions on endothelial function and renal microvascular function. In the present study, we evaluated the effects of two CCBs, efonidipine and amlodipine, on renal function and arterial stiffness. METHODS: Forty type 2 diabetic patients with hypertension and nephropathy receiving angiotensin receptor II blockers were enrolled and randomly divided into two groups: the efonidipine group was administered efonidipine hydrochloride ethanolate 40 mg/day and the amlodipine group was admin-istered amlodipine besilate 5 mg/day for 12 months. Arterial stiffness was evaluated by the cardio-ankle vascular index (CAVI). RESULTS: Changes in blood pressure during the study were almost the same in the two groups. Sig-nificant increases in serum creatinine and urinary albumin and a significant decrease in the esti-mated glomerular filtration rate were observed in the amlodipine group, but not in the efonidipine group. On the other hand, significant decreases in plasma aldosterone, urinary 8-hydroxy-2'-deoxy-guanosine and CAVI were observed after 12 months in the efonidipine group, but not in the amlo-dipine group. CONCLUSIONS: These results suggest that efonidipine, which is both a T-type and L-type calcium chan-nel blocker, has more favorable effects on renal function, oxidative stress and arterial stiffness than amlodipine, an L-type calcium channel blocker.

Association between cardio-ankle vascular index and serum cystatin C levels in patients with cardiovascular risk factor.

AIM: The aim of this study was to clarify the relationship between CAVI and serum cystatin C levels to understand the role of arterial stiffness in the presence of renal insufficiency. METHODS: We enrolled 206 consecutive patients with cardiovascular risk factors and/or coronary artery disease (CAD) in the study. Serum cystatin C, estimated glomerular filtration rate (eGFR), and plasma levels of von Willebrand factor (vWF) and plasminogen activator inhibitor (PAI-1) were measured. CAVI was determined as an index of arterial stiffness. RESULTS: For all patients, the mean serum cystatin C level was 0.81+/-0.21 mg/L and mean eGFR was 65.8+/-15.5 mL/min per 1.73 m(2). In univariate analysis, CAVI levels significantly correlated with cystatin C levels (r=0.414, p<0.001), eGFR (r=-0.315, p<0.01), PAI-1 (r=0.269, p<0.01), and vWF (r=0.207, p<0.01). Multiple regression analysis showed that age, cystatin C, PAI-1, and a history of CAD were independent variables of CAVI. Age-adjusted CAVI was highest in the presence of both CAD and renal impairment. CONCLUSION: CAVI was closely associated with cystatin C levels. These results suggest a significant role of arterial stiffness in renal insufficiency.

Metformin promotes induction of lipoprotein lipase in skeletal muscle through activation of adenosine monophosphate-activated protein kinase.

Metformin is known to increase lipoprotein lipase (LPL) mass level in serum. Lipoprotein lipase is produced by adipose tissue and skeletal muscles. This study aimed to examine the effect of metformin on LPL production in adipocytes and skeletal muscle cells and to investigate the mechanism by which metformin enhances LPL production. 3T3-L1 preadipocytes and L6 skeletal muscle cells were incubated with metformin or 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Lipoprotein lipase activity, LPL protein expression, and LPL messenger RNA (mRNA) expression were measured. Metformin increased LPL activity only in skeletal muscle cells. To clarify the mechanism of this phenomenon, AICAR, which is well known as an activator of adenosine monophosphate-activated protein kinase (AMPK), was used. Metformin and AICAR enhanced phosphorylated AMPK in skeletal muscle cells by Western blot analysis. Like metformin, AICAR increased LPL activity only in skeletal muscle cells. Both metformin and AICAR also enhanced LPL protein and LPL mRNA expressions in skeletal muscle cells but not in adipocytes. Phosphorylated AMPK protein expression was decreased when AMPK signaling was interfered by AMPKalpha small interfering RNA. Lipoprotein lipase activity and LPL expression, which were enhanced by 1 mumol/L metformin, were reduced by AMPKalpha small interfering RNA. These results suggest that metformin increases LPL activity, LPL protein expression, and LPL mRNA expression through activation of AMPK in skeletal muscle cells but not in adipocytes.