Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance.

AIMS: To determine the effects of rosiglitazone on insulin sensitivity, glucose tolerance and ambulatory blood pressure when administered to subjects with persistent impaired glucose tolerance (IGT). METHODS: Eighteen subjects with persistent IGT were randomized to receive rosiglitazone 4 mg twice daily or matching placebo for 12 weeks. Evaluation at baseline and at the end of treatment included measurement of whole body insulin sensitivity during a euglycaemic hyperinsulinaemic clamp and deriving an insulin sensitivity index. Changes in glucose and insulin concentration were determined after oral glucose tolerance test (OGTT) and mixed meal tolerance tests, and 24-h ambulatory blood pressure was monitored. RESULTS: Rosiglitazone significantly improved the insulin sensitivity index by 2.26 micro g/kg per min per pmol/l relative to placebo (P = 0.0003). Four of nine subjects receiving rosiglitazone reverted to normal glucose tolerance and 5/9 remained IGT, although four of these had improved 2-h glucose values. In the placebo group, 1/9 subjects progressed to Type 2 diabetes and 8/9 remained IGT. Following OGTT and meal tolerance test, glucose and insulin area under curve were reduced over 3 and 4 h, respectively. Compared with placebo, ambulatory blood pressure decreased significantly in the rosiglitazone group by 10 mmHg systolic (P = 0.0066) and 8 mmHg diastolic (P = 0.0126). CONCLUSIONS: Consistent with its effects in patients with Type 2 diabetes, rosiglitazone substantially improved whole body insulin sensitivity and the glycaemic and insulinaemic responses to an OGTT and meal tolerance test in subjects with persistent IGT. Furthermore, rosiglitazone reduced systolic and diastolic ambulatory blood pressure in these subjects.     

Effects of rosiglitazone on endothelial function, C-reactive protein, and components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome

Fifty nondiabetic patients who met a modified National Cholesterol Education Program definition for the metabolic syndrome were randomized to receive either rosiglitazone (4 mg/day; n = 25) or placebo (n = 25) for 8 weeks. Compared with those receiving placebo, patients in the rosiglitazone group achieved significant reductions in fasting plasma insulin levels (-40%), homeostasis model assessment indexes (-45%), systolic and diastolic blood pressures, and high-sensitivity C-reactive protein levels (-31%). There were no changes in fasting plasma glucose with either treatment. Although rosiglitazone treatment greatly increased plasma levels of low-density lipoprotein cholesterol (18%) and apolipoprotein B (16%), it significantly improved both endothelium-dependent flow-mediated vasodilation (p <0.001) and endothelium-independent nitroglycerin-induced vasodilation (p = 0.01) of the right brachial artery.     

Simvastatin (40 mg/day), adiponectin levels, and insulin sensitivity in subjects with the metabolic syndrome

The metabolic syndrome (MS) is characterized by low-grade inflammation and confers an increased risk for diabetes mellitus and cardiovascular disease. Statins reduce cardiovascular events in patients with the MS and have pleiotropic effects in addition to lowering low-density lipoprotein cholesterol. Because there is a paucity of data on the effect of statins on adiponectin levels and insulin sensitivity in the MS, this study was conducted to test the effect of simvastatin (40 mg/day) compared with placebo on circulating adiponectin levels and homeostasis model assessment insulin resistance in subjects with the MS in a randomized, double-blind, placebo-controlled study. Simvastatin therapy failed to affect circulating adiponectin levels or insulin sensitivity compared with placebo over 8 weeks. In conclusion, although simvastatin is anti-inflammatory, it failed to affect adiponectin levels or improve insulin sensitivity in subjects with the MS.     

Relation of improvement in endothelium-dependent flow-mediated vasodilation after rosiglitazone to changes in asymmetric dimethylarginine, endothelin-1, and C-reactive protein in nondiabetic patients with the metabolic syndrome

The mechanisms by which thiazolidinediones exert beneficial effects on the endothelium are still not clear. We examined the effects of rosiglitazone on the plasma markers of metabolic control (glucose, insulin, adiponectin, resistin, and lipid profiles), markers of inflammation (high-sensitivity C-reactive protein [CRP], interleukin-6, soluble CD40 ligand, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1), and markers of vasoreactivity (asymmetric dimethylarginine [ADMA] and endothelin-1) and analyzed the relations between changes in endothelium-dependent flow-mediated dilation of the brachial artery and changes in these markers to elucidate their roles in mediating the vascular protective effects of rosiglitazone. Of 70 nondiabetic patients who met a modified National Cholesterol Education Program definition of the metabolic syndrome, 35 were randomized to receive rosiglitazone (4 mg/day) and 35 to receive placebo for 8 weeks. At study end, treatment with rosiglitazone had significantly reduced plasma insulin (-25%, p = 0.004) and resistin (-16%, p <0.001), increased adiponectin (164%, p <0.001), low-density lipoprotein cholesterol (16%, p = 0.005), and apolipoprotein-B (14%, p = 0.003), and decreased CRP (-30%, p = 0.005), soluble CD40 ligand (-20%, p = 0.014), ADMA (-16%, p <0.001), and endothelin-1 (-11%, p <0.001) concentrations and systolic and diastolic blood pressures. Rosiglitazone treatment significantly improved flow-mediated dilation (p <0.001) and nitroglycerin-induced vasodilation (p = 0.001) of the right brachial artery. On multivariate analysis, changes in ADMA, endothelin-1, and CRP were independent predictors of improved endothelial reactivity with rosiglitazone. In conclusion, we have, for the first time, demonstrated the independent associations between the improvement in flow-mediated dilation and reductions in ADMA, endothelin-1, and CRP after 8 weeks of treatment with rosiglitazone in nondiabetic patients with the metabolic syndrome. These findings suggest that decreases in ADMA, endothelin-1, and CRP may serve as possible mechanisms for the improvement in endothelial function conferred by rosiglitazone treatment.     

Vascular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes

Mechanisms underlying biological effects of statin and angiotensin-converting enzyme inhibitor therapies differ. Therefore, we compared vascular and metabolic responses to these therapies either alone or in combination in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled crossover trial with 3 treatment arms (each 2 months) and 2 washout periods (each 2 months). Fifty patients with type 2 diabetes were given simvastatin 20 mg and placebo, simvastatin 20 mg and ramipril 10 mg, or ramipril 10 mg and placebo daily during each 2-month treatment period. Ramipril alone or combined therapy significantly reduced blood pressure when compared with simvastatin alone. When compared with ramipril alone, simvastatin alone or combined therapy significantly improved the lipoprotein profile. All 3 treatment arms significantly improved flow-mediated dilator response to hyperemia and reduced plasma levels of malondialdehyde relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy when compared with simvastatin or ramipril alone (P<0.001 by ANOVA). When compared with simvastatin or ramipril alone, combined therapy significantly reduced high-sensitivity C-reactive protein levels (P=0.004 by ANOVA). Interestingly, combined therapy or ramipril alone significantly increased plasma adiponectin levels and insulin sensitivity relative to baseline measurements. These changes were significantly greater than in the group treated with simvastatin alone (P<0.015 by ANOVA). Ramipril combined with simvastatin had beneficial vascular and metabolic effects when compared with monotherapy in patients with type 2 diabetes.     

Comparison of fixed-dose rosiglitazone/metformin combination therapy with sulphonylurea plus metformin in overweight individuals with Type 2 diabetes inadequately controlled on metformin alone.

AIM: This 52-week, randomized, double-blind, parallel-group study was designed to compare rosiglitazone/metformin fixed-dose combination therapy with combination sulphonylurea plus metformin therapy in overweight individuals with inadequately controlled type 2 diabetes mellitus. METHOD: Individuals with inadequate glycaemic control (HbA (1c)> or =7%) while on metformin monotherapy (> or =0.85 g/day) entered a 4-week run-in period during which they received metformin 2 g/day. At the end of the run-in, individuals with fasting plasma glucose > or =7.0 mmol/l were randomized to treatment with metformin (2 g/day) and either rosiglitazone (4 mg/day; RSG+MET [N=294]) or a sulphonylurea (glibenclamide 5 mg/day or gliclazide 80 mg/day; SU+MET [N=302]). Medications were up-titrated to maximum tolerated doses (rosiglitazone 8 mg, glibenclamide 15 mg or gliclazide 320 mg plus metformin 2 g/day) during the first 12 weeks of double-blind treatment. The primary efficacy end point was the change in HbA (1c) from baseline after 52 weeks of treatment. RESULTS: RSG+MET was non-inferior to SU+MET with respect to changes in HbA (1c) after one year of treatment (DeltaHbA (1c)= -0.78% and -0.86%, respectively; treatment difference =0.09%, 95% CI=-0.08, 0.25). The HbA (1c) reductions with RSG+MET, but not SU+MET, were accompanied by significant improvements in measures of beta-cell function including proinsulin:insulin ratio. The degree of beta-cell failure was significantly greater with SU+MET compared to RSG+MET as measured by the coefficient of failure (0.543 vs. 0.055 HbA (1c)%/year, respectively, p=0.0002). The proportion of individuals who experienced hypoglycaemic events was significantly (p<0.0001) lower with RSG+MET (6%) than with SU+MET (30%). Diastolic ambulatory blood pressure and cardiovascular biomarkers (high-sensitivity C-reactive protein and plasminogen activator inhibitor-1) were also reduced following one year of treatment with RSG+MET but not SU+MET. Both treatments were generally well tolerated. CONCLUSION: Fixed-dose combination therapy with rosiglitazone/metformin is non-inferior to sulphonylurea plus metformin combination therapy in reducing HbA (1c) over one year of treatment. Improvements in measures of beta-cell function suggest that the improvements in glycaemic control may be better maintained in long-term therapy with the rosiglitazone/metformin combination.     

Effect of PPAR-gamma agonist on adiponectin levels in the metabolic syndrome: lessons from the high fructose fed rat model

BACKGROUND: The health hazard of the metabolic syndrome (MS) is increasing, yet there is no effective pharmacologic treatment to this entity as a whole. Recently, hypoadiponectinemia was found to play an important role in the development of MS. We studied the effect of the PPAR-gamma agonist rosiglitazone on adiponectin and the metabolic profile in the fructose-induced hypertensive, hyperinsulinemic, hypertriglyceridemic rat model. METHODS: Thirty male Sprague-Dawley rats were divided into three groups. Ten were fed standard rat chow for 5 weeks, 10, a fructose-enriched diet for 5 weeks, and 10, a fructose-enriched diet for 5 weeks, with rosiglitazone 10 mg/kg/d added during the last 2 weeks. Blood pressure (BP), oral glucose tolerance test (OGTT), plasma insulin, triglycerides, and adiponectin were recorded, as well as mRNA levels of the adiponectin gene in visceral adipose tissue. RESULTS: Fructose-fed rats developed MS as manifested by the increase in systolic BP (from 139 +/- 3 to 158 +/- 4 mm Hg, P < .05), insulin (from 26 +/- 1.6 to 40 +/- 2.5 muU/mL, P < .05), triglycerides (from 91 +/- 9 to 304 +/- 24 mg/dL, P < .05), and impaired OGTT (area under the curve from 13,894 +/- 246 to 17,725 +/- 700 mg/dL/min). Treatment with rosiglitazone reversed these effects and reduced BP to 133 +/- 7 mm Hg, insulin levels to 30 +/- 2.8 muU/mL, triglycerides to 116 +/- 9 mg/dL, and the OGTT to 15,415 +/- 372 mg/dL/min (P < .05 for all variables). In addition, rosiglitazone increased plasma levels of adiponectin fourfold from 4.3 +/- 0.1 to 18.4 +/- 0.6 mug/mL (P < .05). This increase was coupled with 3.8-fold increase in adiponectin mRNA in visceral adipose tissue. CONCLUSIONS: This study shows for the first time that in an animal model of MS, the insulin sensitizer, rosiglitazone, improves the metabolic profile and increases plasma levels of adiponectin and its gene expression. It is possible therefore that rosiglitazone exerts its beneficial effects by increasing the levels of adiponectin.     

Olmesartan/amlodipine vs olmesartan/hydrochlorothiazide in hypertensive patients with metabolic syndrome: the OLAS study

We studied the effects of treatment with olmesartan/amlodipine and olmesartan/hydrochlorothiazide on inflammatory and metabolic parameters (including new-onset diabetes as a secondary endpoint) in non-diabetic hypertensive patients with metabolic syndrome (MetS). A total of 120 patients with MetS and stage I and II hypertension were randomized to olmesartan 20?mg/amlodipine 5?mg or olmesartan 20?mg/hydrochlorothiazide 12.5?mg. If target systolic blood pressure (<140?mm?Hg) was not reached, doses were doubled after 13 weeks; doxazosin 4?mg was added after 26 weeks, and doubled after 39 weeks; follow-up ended at 78 weeks. At each visit, blood pressure (BP), fasting plasma glucose, insulin, adiponectin, tumour necrosis factor-α, C-reactive protein (CRP), intercellular adhesion molecule-1, vascular cell adhesion molecule-1, interleukins-1β, -6 and -8, and albuminuria were measured; BP was similarly reduced in both groups; 80% of patients reached target BP. Reductions in albuminuria were also similar (50%). Only olmesartan/amlodipine reduced the insulin resistance index (24%, P<0.01), increased plasma adiponectin (16%, P<0.05) and significantly reduced all of the inflammation markers studied, except CRP, which showed a similar reduction in each group. The risk of new-onset diabetes was significantly lower with olmesartan/amlodipine (P=0.02). Both olmesartan-based combinations were effective, but the amlodipine combination resulted in metabolic and anti-inflammatory effects that may have advantages over the hydrochlorothiazide combination.     

Short-term treatment with ezetimibe, simvastatin or their combination does not alter circulating adiponectin, resistin or leptin levels in healthy men

Objective Statin therapy decreases cardiovascular morbidity and mortality, and ezetimibe, a novel cholesterol absorption inhibitor has both lipid‐lowering and anti‐atherosclerotic effects in animal models. As several adipokines, that is, adiponectin, high molecular weight (HMW) adiponectin, leptin and/or possibly resistin are involved in the pathogenesis of insulin resistance (IR), dyslipidaemia and atherosclerosis, we investigated whether ezetimibe and/or statin treatment may modulate serum concentrations of these four major adipokines. Research design and methods One‐centre, randomized, parallel three‐group study in 72 healthy men [mean age 32 ± 9 years, mean body mass index (BMI) 25·7 ± 3·2 kg/m²]. Patients Seventy‐two healthy men. Each group of 24 subjects received a 14‐day treatment with either ezetimibe (10 mg/day), simvastatin (40 mg/day) or their combination. Blood was drawn before and after the 14‐day treatment period. Measurements Lipid levels, IR indices, serum leptin, adiponectin, HMW adiponectin and resistin concentrations. Results Neither ezetimibe nor simvastatin or their combination had any effect on serum leptin, adiponectin, HMW adiponectin and resistin concentrations. Baseline leptin levels correlated positively, while adiponectin and HMW adiponectin negatively, with BMI. Leptin concentrations correlated negatively while adiponectin and HMW adiponectin positively with plasma high‐density lipoprotein‐cholesterol concentrations. Resistin concentrations were not associated with BMI, lipid levels or indicators of IR. Conclusions Treatment with ezetimibe, simvastatin or their combination does not alter circulating levels of adiponectin, leptin or resistin in adult healthy men.     

Effect of co-administering ezetimibe with on-going simvastatin treatment on LDL-C goal attainment in hypercholesterolemic patients with coronary heart disease

OBJECTIVE: To determine whether co-administering ezetimibe with on-going simvastatin treatment was more effective than placebo plus on-going simvastatin in achieving an LDL-C treatment target of < or = 2.60 mmol/l (100 mg/dl) in hypercholesterolemic patients with coronary heart disease (CHD). METHODS: Men and women (age > or = 18 years) with documented CHD and on a stable dose of simvastatin 10 mg or 20 mg for at least 6 weeks were recruited for this study. After a 4-week simvastatin 10 or 20 mg plus placebo and diet run-in period, patients were eligible for randomization if LDL-C > 2.60 and < or = 4.20 mmol/l and triglycerides (TG) < or = 4.00 mmol/l. Eligible patients were randomized to a double-blind comparative study with ezetimibe 10 mg co-administered with on-going simvastatin 10 mg or 20 mg (n=181) versus placebo to match ezetimibe co-administered with simvastatin 10 mg or 20 mg (n=191) for 6 weeks. RESULTS: At baseline, mean LDL-C was comparable between the ezetimibe (3.14 mmol/l) and placebo (3.19 mmol/l) groups. With the addition of ezetimibe or placebo to on-going simvastatin therapy, the percentage of patients achieving the LDL-C goal of < or = 2.60 mmol/l after 6 weeks of treatment was significantly (p < or = 0.001) greater in the ezetimibe group (74.3%) than in the placebo group (16.7%). The addition of ezetimibe to on-going simvastatin treatment also resulted in a significantly (p < or = 0.001) larger mean percent reduction in LDL-C from baseline (25.2%) compared with placebo (0.9%). Ezetimibe was generally well tolerated compared to placebo when added to on-going simvastatin treatment. CONCLUSIONS: Co-administering ezetimibe with on-going simvastatin 10 or 20 mg treatment allowed more hypercholesterolemic patients with CHD to reach the LDL-C treatment target of < or = 2.60 mmol/l.     

The anti-inflammatory effects of exercise training in patients with type 2 diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) and chronic inflammation are strongly related to increased cardiovascular risk. The purpose of this study was to evaluate whether an aerobic training programme would ameliorate inflammatory and anti-inflammatory markers in patients with type 2 DM. DESIGN: Interventional study. METHODS: A total of 60 overweight individuals with type 2 DM, but without vascular complications, were randomly assigned to either a 6-month aerobic exercise training programme (four times/week, 45-60 min/session), designated as exercise group, or to the control group. All participants were on an oral antidiabetic regimen and none was receiving lipid-lowering medications. Anthropometric parameters, cardiorespiratory fitness, glycaemic and lipid profiles, high sensitivity C-reactive protein (hs CRP), adiponectin, interleukin (IL)-10, IL-18, tumour necrosis factor (TNF)-alpha, insulin, reciprocal index of homoeostasis model assessment (HOMA-IR), body fat and blood pressure (BP) were measured at baseline and at the end of the study. RESULTS: In comparison with baseline and control group, exercise-treated patients improved glucose control, lipid profile, exercise capacity (VO2 peak) and exhibited decreased insulin resistance and systolic BP considerably (P<0.05). Plasma adiponectin, TNF-alpha and body weight changed slightly across treatment (P>0.05), whereas diastolic BP and fat mass tended to decrease (P=0.071 and 0.061, respectively). Exercise training reduced hs CRP (from 0.48+/-0.16 to 0.29+/-0.2 mg/dl; P=0.04) and IL-18 (from 315.19+/-122.76 to 203.77+/-96.02 pg/ml; P=0.02). Moreover, exercise provided anti-inflammatory protection through IL-10 increment (P=0.039) and IL-18/IL-10 ratio downregulation (P=0.014). In multiple regression analysis, alteration in IL-18 was independently correlated with hs CRP and VO2 peak changes (P<0.05). CONCLUSION: Aerobic exercise training without significant weight loss improves metabolic profile and exerts anti-inflammatory effects in patients with type 2 DM.     

Improved metabolic control by Ipomoea batatas (Caiapo) is associated with increased adiponectin and decreased fibrinogen levels in type 2 diabetic subjects

Aim: The extract of the white‐skinned sweet potato Ipomoea batatas (Caiapo) has been shown to ameliorate glucose control by improving insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). The present study was designed to further evaluate its mode of action on insulin sensitivity over an extended period of time as well as the effects on fibrinogen and other markers of low‐grade inflammation. Methods: In this randomized trial, 27 patients with T2DM on diet only received 4 g of Caiapo daily for 5 months; 34 patients placebo. Before and after therapy, insulin sensitivity [oral glucose insulin sensitivity (OGIS), as glucose clearance from oral glucose tolerance test], parameters of diabetes control, lipids, plasma adiponectin, high‐sensitivity C‐reactive protein (hs‐CRP) and fibrinogen were measured. Results: Following Caiapo, we observed an increase in OGIS (293 ± 15 vs. 321 ± 12 ml/m²/min, p = 0.0072) and adiponectin (5.97 ± 0.65 to 6.63 ± 0.70 μg/ml, p = 0.013), while fibrinogen decreased from 3.83 ± 0.16 to 3.64 ± 0.18 mg/ml (p = 0.02). This was associated with an improvement in glycated haemoglobin (HbA1c: 6.46 ± 0.12 vs. 6.25 ± 0.11%, p = 0.008), fasting glucose (138 ± 4 vs. 128 ± 5 mg/dl, p = 0.039) and triglycerides (2.36 ± 0.22 vs. 2.07 ± 0.25 mmol/l, p = 0.032). Body weight, lipid levels and hs‐CRP were not altered. No changes were observed in the placebo group except for HbA1c, which significantly increased from 6.25 ± 0.10 to 6.50 ± 0.12% (p = 0.0001). Conclusions: This study confirms the beneficial effects of Caiapo on glucose and HbA1c control in patients with T2DM after 5 months follow‐up. Improvement of insulin sensitivity was accompanied by increased levels of adiponectin and a decrease in fibrinogen. Thus, Caiapo can be considered as natural insulin sensitizer with potential antiatherogenic properties.     

Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study.

OBJECTIVES: The purpose of this study was to test the safety and efficacy of pioglitazone and simvastatin in combination versus each drug individually in non-diabetic subjects with cardiovascular disease (CVD) and elevated high-sensitivity C-reactive protein (hs-CRP) levels. BACKGROUND: Low-grade inflammation is a pathogenic factor for atherosclerosis. High-sensitivity CRP, matrix metalloproteinase (MMP)-9, and plasminogen activator inhibitor (PAI)-1 are markers of inflammation. Statins and peroxisome proliferator-activated receptor (PPAR)-gamma agonists lower inflammatory markers and reduce CVD in type 2 diabetes. METHODS: In a 12-week, prospective, double-blind trial, 125 subjects were randomized to simvastatin or pioglitazone plus placebo or a simvastatin/pioglitazone combination. We tested changes in hs-CRP by analysis of covariance. A subgroup analysis was performed in patients with and without the metabolic syndrome (MetS). The correlation between changes in hs-CRP and homeostasis model assessment (HOMA; a measure of insulin resistance) was calculated with the Spearman's rank test. RESULTS: At baseline, there were no significant between-group differences. At 12 weeks, pioglitazone and simvastatin monotherapies significantly reduced hs-CRP (3.64 +/- 2.42 mg/l to 2.48 +/- 1.77 mg/l and 3.26 +/- 2.02 mg/l to 2.81 +/- 2.11 mg/l) and the combination regimen had an additive effect (from 3.49 +/- 1.97 mg/l to 2.06 +/- 1.42 mg/l, p < 0.001). For subgroups, the difference between monotherapy and combination therapy was only significant for simvastatin versus simvastatin plus pioglitazone in patients without MetS. Homeostasis model assessment decreased in those receiving pioglitazone, and the correlation between changes in HOMA and hs-CRP was significant (r = 0.43; p < 0.05). The PAI-1 decreased significantly in the pioglitazone groups only, and MMP-9 was also significantly lowered in the pioglitazone groups. No treatment-related serious adverse events occurred in any group. CONCLUSIONS: Pioglitazone, probably by reducing insulin resistance, has additive anti-inflammatory effects to simvastatin in non-diabetic subjects with CVD and high hs-CRP.     

Lipid-lowering therapy does not affect the postprandial drop in high density lipoprotein-cholesterol (HDL-c) plasma levels in obese men with metabolic syndrome: a randomized double blind crossover trial

Introduction The postprandial lipid metabolism in metabolic syndrome patients is disturbed and may add to the increased cardiovascular risk in these patients. It is not known whether postprandial high density lipoprotein‐cholesterol (HDL‐c) metabolism is also affected and whether this can be influenced by statin and/or ezetimibe treatment. Methods Prospective, randomized, double blind, crossover trial comparing simvastatin 80 mg with simvastatin/ezetimibe 10 mg/10 mg treatment for 6 weeks on postprandial HDL‐c metabolism in 15, nonsmoking, male, obese metabolic syndrome patients (Adult Treatment Panel III, ATPIII). Only study medication was allowed. HDL‐c concentrations, cholesteryl ester transfer (CET), CET protein (CETP) mass and adiponectin were measured before and after oral fat loading. ClinicalTrials.gov NCT00189085. Results Plasma HDL‐c levels remained stable during continuous fasting following an overnight fast. Pre‐fat load HDL‐c concentrations without treatment, after simvastatin and simvastatin/ezetimibe treatment were 1·15 ± 0·04, 1·16 ± 0·05 and 1·11 ± 0·04 mmol/l. Fat load induced a 11% drop in HDL‐c plasma levels; 1·02 ± 0·05 mmol/l (P < 0·001) which was not affected by either therapy. Triglyceride levels during fat load were similar after both treatments. Total CET increased from 9·73 ± 0·70 to 12·20 ± 0·67 nmol/ml/h (P = 0·004). Four hours after fat loading CETP mass was increased while adiponectin levels were decreased, irrespective of treatment. Discussion HDL‐c levels decrease as CET increases after fat loading in obese metabolic syndrome patients. This is not influenced by either simvastatin or simvastatin/ezetimibe treatment. After fat loading, CETP mass and CET increased, and adiponectin decreased pointing towards a potential role for intra‐abdominal fat. Decreased postprandial HDL‐c levels may contribute to the increased cardiovascular risk in metabolic syndrome patients on top of already low HDL‐c levels.     

Dutogliptin,a selective DPP4 inhibitor,improves glycaemic control in patients with type 2 diabetes: a 12‐week,double‐blind,randomized, placebo‐controlled,multicentre trial

Aim: To determine efficacy and tolerability of dutogliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, in patients with type 2 diabetes mellitus. Methods: This was a 12‐week, multicentre, randomized, double‐blind, placebo‐controlled trial in 423 patients with type 2 diabetes with suboptimal metabolic control. Following a 2‐week single‐blind placebo run‐in, patients aged 18–75 years with a body mass index of 25–48 kg/m² and baseline HbA1c of 7.3–11.0% were randomized 2:2:1 to receive once‐daily oral therapy with either dutogliptin (400 or 200 mg) or placebo on a background medication of either metformin alone, a thiazolidinedione (TZD) alone or a combination of metformin plus a TZD. Results: Average HbA1c at baseline was 8.4%. Administration of dutogliptin 400 and 200 mg for 12 weeks decreased HbA1c by ?0.52% (p < 0.001) and ?0.35% (p = 0.006), respectively (placebo‐corrected values), with absolute changes in HbA1c for the 400 mg, 200 mg and placebo groups of ?0.82, ?0.64 and ?0.3%, respectively. The proportion of patients achieving an HbA1c < 7% was 27, 21 and 12% at dutogliptin doses of 400 and 200 mg or placebo, respectively (p = 0.008 for comparison of 400 mg vs. placebo). Fasting plasma glucose (FPG) levels were significantly reduced in both active treatment groups compared to placebo: the placebo‐corrected difference was ?1.00 mmol/l (p < 0.001) for the 400 mg group and ?0.88 mmol/l (p = 0.003) for the 200 mg group. Dutogliptin caused significantly greater reductions in postprandial glucose AUC _0–2h in both the 400 and 200 mg groups (placebo corrected values ?2.58 mmol/l/h, p < 0.001 and ?1.63 mmol/l/h, p = 0.032, respectively). In general, patients tolerated the study drug well. There were minor, not clinically meaningful differences in adverse events (AEs) between dutogliptin‐treated patients and placebo controls, and 60% of all reported AEs were mild. Vital signs and body weight were stable, and routine safety laboratory parameters did not change compared with placebo. Trough ex vivo DPP4 inhibition at the end of the 12‐week treatment period was 80 and 70%, at the 400 and 200 mg doses of dutogliptin, respectively. Conclusions: Dutogliptin treatment for 12 weeks improved glycaemic control in patients with type 2 diabetes who were on a background medication of metformin, a TZD or metformin plus a TZD. Tolerability was favourable for both doses tested. The 400 mg dose of dutogliptin resulted in larger changes of HbA1c and FPG and more subjects reached an HbA1c target of < 7% than the 200 mg dose.     

Differential effect of glimepiride and rosiglitazone on metabolic control of type 2 diabetic patients treated with metformin: a randomized, double-blind, clinical trial

AIM: Accumulating evidence suggests that combination therapy using oral antidiabetic agents with different mechanisms of action may be highly effective in achieving and maintaining target blood glucose levels. The aim of our study is to evaluate the differential effect on glucose and lipid parameters of the association between glimepiride plus metformin and rosiglitazone plus metformin in patients affected by type 2 diabetes and metabolic syndrome. METHODS: Patients were enroled, evaluated and followed at two Italian centres. We evaluated 99 type 2 diabetic patients with metabolic syndrome (48 males and 47 females; 23 males and 24 females, aged 52 +/- 5 with glimepiride; 25 males and 23 females, aged 54 +/- 4 with cglitazone). All were required to have been diagnosed as being diabetic for at least 6 months and did not have glycaemic control with diet and oral hypoglycaemic agents such as sulphonylureas or metformin, both to the maximum tolerated dose. All patients took a fixed dose of metformin, 1500 mg/day. We administered glimepiride (2 mg/day) or rosiglitazone (4 mg/day) in a randomized, controlled, double-blind clinical study. We evaluated body mass index (BMI), glycaemic control, lipid profile [total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol and triglycerides] and lipoprotein parameters [apolipoprotein A-I and apolipoprotein B (Apo B)] during 12 months of this treatment. RESULTS: A total of 95 patients completed the study. Significant BMI decrease was observed at 12 months in glimepiride and rosiglitazone group (p < 0.05 and p < 0.01 respectively) as well as of glycated haemoglobin decrease (p < 0.05 and p < 0.01 respectively), mean fasting plasma glucose and postprandial plasma glucose levels (p < 0.05 and p < 0.01 respectively). A decrease in fasting plasma insulin and postprandial plasma insulin at 12 months (p < 0.05 and p < 0.01 respectively) compared with the baseline value in rosiglitazone group was observed. Furthermore, homeostasis model assessment index improvement was obtained only at 9 and 12 months (p < 0.05 and p < 0.01 respectively) compared with the baseline value in rosiglitazone group. Significant TC, LDL-C and Apo B improvement (p < 0.05 respectively) was present in glimepiride group after 12 months compared with the baseline values, and these variations were significant (p < 0.05) between groups. Of the 95 patients who completed the study, 8.5% of patients in glimepiride group and 12.5% of patients in rosiglitazone group had side-effects (p = not significant). Four patients had transient side-effects in glimepiride group and six patients in rosiglitazone group. Altogether, we did not have statistically significant changes in transaminases. CONCLUSIONS: The rosiglitazone-metformin association significantly improve the long-term control of all insulin-resistance-related parameters in comparison with the glimepiride-metformin-treated group. On the other side, glimepiride treatment is associated to a slight improvement in cholesterolaemia, not observed in the rosiglitazone-treated patients.     

Effects of etanercept in patients with the metabolic syndrome

BACKGROUND: Adipose-derived cytokines, including tumor necrosis factor alpha, may contribute to the inflammation that occurs in the metabolic syndrome. We investigated the effects of inhibition of tumor necrosis factor alpha with etanercept in patients with the metabolic syndrome. METHODS: Fifty-six subjects with the metabolic syndrome were randomized to administration of either etanercept or identical placebo, 50 mg subcutaneously once a week for 4 weeks. The C-reactive protein level was the primary end point. Effects on other inflammatory markers (including fibrinogen, interleukin 6, and adiponectin), insulin sensitivity, lipid levels, and body composition were also determined. RESULTS: Baseline characteristics were similar between the groups. Two subjects dropped out of each group, and etanercept was well tolerated throughout the study. The C-reactive protein levels decreased significantly in the treated compared with the placebo group (-2.4 +/- 0.4 vs 0.5 +/- 0.7 mg/L; P<.001). Adiponectin levels rose significantly in the etanercept group compared with the placebo group (0.8 +/- 0.4 vs -0.3 +/- 0.3 microg/mL; P = .03). Fibrinogen levels decreased (-68 +/- 16 vs -2 +/- 31 mg/dL [-2.0 +/- 0.47 vs -0.06 +/- 0.91 micromol/L]; P = .04) and interleukin 6 levels tended to decrease (-1.2 +/- 0.8 vs 0.5 +/- 0.5 ng/L; P = .07) in the etanercept-treated subjects compared with placebo, respectively. No changes occurred in body composition parameters or insulin sensitivity, but high-density lipoprotein levels tended to decrease in the etanercept group (-1 +/- 1 vs 2 +/- 1 mg/dL [-0.03 +/- 0.03 vs 0.05 +/- 0.03 mmol/L]; P = .06) compared with the placebo group. CONCLUSIONS: Etanercept reduces C-reactive protein levels and tends to improve other inflammatory cardiovascular risk indexes in patients with the metabolic syndrome. Etanercept may interrupt the inflammatory cascade that occurs with abdominal obesity. Further, longer-term studies are needed to determine the effects of tumor necrosis factor alpha inhibition on cardiovascular disease in patients with the metabolic syndrome.     

Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with metformin

Background: Metformin is considered the gold standard for type 2 diabetes treatment as monotherapy and in combination with sulphonylureas and insulin, whereas the combination of metformin with thiazolidinediones is relatively less studied. The aim of the present study was to assess the differential effect on glycaemic metabolism and lipid variables of the combination of metformin plus pioglitazone or metformin plus rosiglitazone in diabetic patients with metabolic syndrome. Methods: All patients began metformin and were randomized to receive pioglitazone or rosiglitazone for 12 months. We assessed body mass index, glycated haemoglobin, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin, homeostasis model assessment index, total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, apolipoprotein A‐I, and apolipoprotein B. Results: Significant decreases in glycated haemoglobin, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, and postprandial plasma insulin were seen after 9 and 12 months in both groups. Homeostasis model assessment index improved at 12 months in both groups. Significant total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, apolipoprotein A‐I, and apolipoprotein B improvement was observed in pioglitazone group after 12 months, but not in the rosiglitazone group. These variations were significant between groups. Conclusion: The combination of metformin plus thiazolidinediones was able to improve glycaemic control compared with previous therapy. Pioglitazone was associated with a significant improvement in lipid and lipoprotein variables.     

Effects of metformin and rosiglitazone in HIV-infected patients with hyperinsulinemia and elevated waist/hip ratio

OBJECTIVE: To evaluate the effects of metformin and rosiglitazone, alone or in combination, on fat distribution, insulin sensitivity, and lipids in HIV-infected patients with insulin resistance and changes in fat distribution. METHODS: A total of 105 subjects were randomly assigned to receive metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks) with rosiglitazone placebo (Met/P, N = 26); rosiglitazone (4 mg/day) with metformin placebo (Rosi/P, N = 27); rosiglitazone (4 mg/day) plus metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks; Met/Rosi, N = 25); or dual placebo (P/P, N = 27) for 16 weeks. Efficacy assessments included oral glucose tolerance testing, abdominal computed tomography, whole-body dual-energy X-ray absorptiometry, and the measurement of fasting lipids and other biochemical indices. Safety was monitored throughout. Intent-to-treat analyses were performed using non-parametric methods. RESULTS: The median insulin area under the curve (AUC) decreased significantly compared with baseline in both groups randomly assigned to rosiglitazone (Rosi/P -25.7 microIU/ml, P = 0.012; Met/Rosi -17.7 microIU/ml, P = 0.002); and tended to decrease in the Met/P group (-11.1 microIU/ml, P = 0.058). The change in AUC with combination therapy was significant compared with placebo (P = 0.032). No treatment was associated with significant changes in visceral or subcutaneous abdominal fat. Leg fat increased in subjects on Rosi/P compared with placebo (+4.8 versus -8.3%, P = 0.034). Rosiglitazone, but not metformin, increased adiponectin but also increased LDL-cholesterol and decreased HDL-cholesterol. Gastrointestinal effects occurred frequently in subjects on metformin. CONCLUSION: Both treatments improved insulin sensitivity, but neither reduced visceral fat. Rosiglitazone may increase subcutaneous fat in some individuals.