Glucose-lowering effect and glycaemic variability of insulin glargine, insulin detemir and insulin lispro protamine in people with type 1 diabetes.

AIM: To compare, using a continuous glucose monitoring (CGM) system, the effect on glycaemic variability of insulin glargine, detemir and lispro protamine. METHODS: A total of 49 white people with type 1 diabetes, not well controlled by three times daily insulin lispro, taken for at least 2 months before study and on a stable dose, were enrolled. The study participants were randomized to add insulin glargine, detemir or lispro protamine, once daily, in the evening. We used a CGM system, the iPro Digital Recorder (Medtronic MiniMed, Northridge, CA, USA) for 1 week. Glycaemic control was assessed according to mean blood glucose values, the area under the glucose curve above 3.9 mmol/l (AUC(>3.9)) or above 10.0 mmol/l (AUC(>10.0)), and the percentage of time spent with glucose values >3.9 or >10.0 mmol/l. Intraday glycaemic variability was assessed using standard deviation (s.d.) values, the mean amplitude of glycaemic excursions and continuous overlapping of net glycaemic action. Day-to-day glycaemic variability was assessed using the mean of daily differences. RESULTS: The s.d. was found to be significantly lower with insulin lispro protamine and glargine compared with insulin detemir. AUC(>3.9) was higher and AUC(>10.0) was lower with insulin lispro protamine and glargine compared with detemir. The mean amplitude of glycaemic excursions and continuous overlapping net glycaemic action values were lower with insulin lispro protamine and glargine compared with detemir. In addition, the mean of daily differences was significantly lower with insulin lispro protamine and glargine compared with detemir. Fewer hypoglycaemic events were recorded during the night-time with insulin lispro protamine compared with glargine and detemir. CONCLUSIONS: The results suggest that insulin lispro protamine and glargine are more effective than detemir in reducing glycaemic variability and improving glycaemic control in people with type 1 diabetes. Insulin lispro protamine seems to lead to fewer hypoglycaemic events than other insulin regimens.

Obliquity-paced Pliocene West Antarctic ice sheet oscillations.

Thirty years after oxygen isotope records from microfossils deposited in ocean sediments confirmed the hypothesis that variations in the Earth's orbital geometry control the ice ages, fundamental questions remain over the response of the Antarctic ice sheets to orbital cycles. Furthermore, an understanding of the behaviour of the marine-based West Antarctic ice sheet (WAIS) during the 'warmer-than-present' early-Pliocene epoch ( approximately 5-3 Myr ago) is needed to better constrain the possible range of ice-sheet behaviour in the context of future global warming. Here we present a marine glacial record from the upper 600 m of the AND-1B sediment core recovered from beneath the northwest part of the Ross ice shelf by the ANDRILL programme and demonstrate well-dated, approximately 40-kyr cyclic variations in ice-sheet extent linked to cycles in insolation influenced by changes in the Earth's axial tilt (obliquity) during the Pliocene. Our data provide direct evidence for orbitally induced oscillations in the WAIS, which periodically collapsed, resulting in a switch from grounded ice, or ice shelves, to open waters in the Ross embayment when planetary temperatures were up to approximately 3 degrees C warmer than today and atmospheric CO(2) concentration was as high as approximately 400 p.p.m.v. (refs 5, 6). The evidence is consistent with a new ice-sheet/ice-shelf model that simulates fluctuations in Antarctic ice volume of up to +7 m in equivalent sea level associated with the loss of the WAIS and up to +3 m in equivalent sea level from the East Antarctic ice sheet, in response to ocean-induced melting paced by obliquity. During interglacial times, diatomaceous sediments indicate high surface-water productivity, minimal summer sea ice and air temperatures above freezing, suggesting an additional influence of surface melt under conditions of elevated CO(2).

Comparison of vildagliptin and glimepiride: effects on glycaemic control, fat tolerance and inflammatory markers in people with type 2 diabetes.

AIMS: To compare the effects of vildagliptin with those of glimepiride on glycaemic control, fat tolerance and inflammatory markers in people with Type 2 diabetes mellitus receiving metformin treatment. METHODS: A total of 167 participants were randomized to vildagliptin 50 mg twice a day or glimepiride 2 mg three times a day, for 6 months. We evaluated the following variables: BMI; glycaemic control; fasting plasma insulin; homeostatic model assessment of insulin resistance index; fasting plasma proinsulin; glucagon; lipid profile; adiponectin; high-sensitivity C-reactive protein; interleukin-6; and tumour necrosis factor-α. A euglycaemic-hyperinsulinaemic clamp procedure and an oral fat load test were also performed. RESULTS: Despite a similar decrease in HbA1c levels (P = 0.009, and P = 0.008, respectively), body weight increased with glimepiride (P = 0.048 vs baseline) and decreased with vildagliptin (P = 0.041 vs baseline and vs glimepiride). Fasting plasma insulin and homeostatic model assessment of insulin resistance index were significantly lower with vildagliptin compared with glimepiride (P = 0.035 and 0.047). M value, an index of insulin sensitivity, increased with vildagliptin, both compared with baseline and with glimepiride (P = 0.028 and 0.039, respectively). Vildagliptin improved all post-oral fat load peaks of lipid profile compared with glimepiride. Adiponectin levels were higher (P = 0.035) and high-sensitivity C-reactive protein levels were lower (P = 0.038) with vildagliptin vs glimepiride. During the oral fat load test, interleukin-6, high-sensitivity C-reactive protein and tumour necrosis factor-α peaks were lower and adiponectin peak was higher in the vildagliptin group than in the glimepiride group. There was a higher dropout rate as a result of hypoglycaemia in the glimepiride group than in the vildagliptin group. CONCLUSIONS: Vildagliptin was more effective than glimepiride in reducing post-oral fat load peaks of lipid-trafficking adipocytokines and inflammatory markers.

A randomized, placebo-controlled study on the effects of a nutraceutical combination of red yeast rice, silybum marianum and octasonol on lipid profile, endothelial and inflammatory parameters.

The aim of this study was to evaluate the effects of a combination of red yeast rice, Silybum marianum and octasonol compared to placebo on lipid profile, endothelial, and inflammatory parameters in low risk dislipidemic patients. One hundred and thirty-four dislipidemic patients were randomised to take placebo or a patented nutraceutical association in tablet form (Zeta ColestRT), 1 tablet /day (immediately after the dinner), for three months in a double-blind, placebo-controlled trial. At baseline and after 3 months the following were evaluated: body weight, body mass index (BMI), fasting plasma glucose (FPG), lipid profile, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), metalloprotineases-2 and -9 (MMP-2 and MMP-9), high sensitivity C-reactive protein (Hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). The nutraceutical combination decreased total cholesterol and low density lipoprotein cholesterol compared to baseline (p = 0.042, and p = 0.041, respectively) and to placebo (p = 0.039, and p = 0.037, respectively). Triglycerides were reduced by the active treatment (p = 0.039), but not by placebo, even if, in group to group comparison, no differences were recorded (p = 0.061). All adipocytokines were reduced by the nutraceutical combination, in particular p = 0.044 for sICAM-1, p = 0.045 for sVCAM-1, p = 0.040 for sE-selectin, p = 0.035 for MMP-2, p = 0.039 for MMP-9, p = 0.038 for Hs-CRP, p = 0.036 for TNF-α, and p = 0.036 for IL-6 compared to baseline, and p = 0.042 for sICAM-1, p = 0.043 for sVCAM-1, p = 0.042 for sE-selectin, p = 0.031 for MMP-2, p = 0.038 for MMP-9, p =0.038 for Hs-CRP, and p = 0.043 for TNF-alpha, espectively, compared to placebo. We can conclude that a combination of red yeast rice, Silybum marianum and octasonol was effective in improving lipid profile, endothelial, and inflammatory parameters in low risk dislipidemic patients.

Effects of enalapril/lercanidipine combination on some emerging biomarkers in cardiovascular risk stratification in hypertensive patients.

WHAT IS KNOWN AND OBJECTIVE: There is considerable interest in pharmacogenetic and molecular biomarkers. Our aim was to evaluate the effects of enalapril/lercanidipine combination on some emerging biomarkers for cardiovascular risk stratification of hypertensive patients, such as lipoprotein(a) [Lp(a)], soluble advanced glycation end products (sRAGE), soluble CD40 ligand (sCD40L) and serum myeloperoxidase (MPO). RESEARCH DESIGN AND METHODS: Three hundred and forty-five patients were enrolled in this randomized, double-blind, clinical trial: 120 hypertensive patients were randomized to enalapril 20 mg, 110 to lercanidipine 10 mg and 115 to enalapril/lercanidipine 20/10 mg fixed combination. We measures the following markers at baseline and after 6, 12, 18 and 24 months: blood pressure, fasting plasma glucose (FPG), lipid profile, Lp(a), sRAGE, sCD40L and MPO. RESULTS: There was a decrease in blood pressure in all groups compared with baseline, even if, as expected, enalapril/lercanidipine combination was more effective in reducing blood pressure compared with the monotherapies. No variations in lipid profile or FPG were recorded in any of the groups. Lercanidipine, but not enalapril, improved Lp(a) levels compared with baseline. The combination enalapril/lercanidipine improved it more than the single therapies. All treatments increased sRAGE levels, and decreased sCD40L and MPO, with a better effect seen with the enalapril/lercanidipine combination compared with single monotherapies. WHAT IS NEW AND CONCLUSION: The combination enalapril/lercanidipine seems to be better than the single monotherapies in reducing not only blood pressure, but also the levels of some emerging biomarkers, potentially useful for cardiovascular risk stratification of hypertensive patients.

A comparison between sitagliptin or glibenclamide in addition to metformin + pioglitazone on glycaemic control and ß-cell function: the triple oral therapy.

AIMS: To evaluate which triple oral therapy between metformin + pioglitazone + sitagliptin and metformin + pioglitazone + glibenclamide can be more useful in improving glycaemic control and should be preferred in clinical practice. METHODS: During the 2-year run-in period, patients were instructed to take metformin monotherapy for the first year, then a combination of metformin and pioglitazone for the second year, then patients were randomized to add glibenclamide or sitagliptin to the dual combination of metformin and pioglitazone for another year. RESULTS: Body weight reached with sitagliptin at 36 months was lower than that reached with glibenclamide. Fasting plasma insulin and homeostasis model assessment of insulin resistance were significantly increased by triple therapy with glibenclamide and decreased by that with sitagliptin. While sitagliptin did not change homeostasis model assessment of ß-cell function, this value was significantly increased by glibenclamide. Fasting plasma proinsulin was not influenced by triple oral therapy including glibenclamide, while it was decreased by the therapy including sitagliptin compared to glibenclamide. Triple oral therapy with sitagliptin better improved ß-cell function measures compared with the glibenclamide therapy. CONCLUSIONS: Sitagliptin should be preferred to glibenclamide as an addition to the metformin + pioglitazone combination for its better protection of ß-cell secretion and its neutral effect on body weight.

Effects of Berberis aristata/Silybum marianum association on metabolic parameters and adipocytokines in overweight dyslipidemic patients.

Nutraceuticals and functional foods have attracted considerable interest as potential alternative therapies for treatment of different cardiovascular disorders and insulin resistance. We evaluated the efficacy of a combination of Berberis Aristata/Silybum Marianum extract (Berberol®) in a sample of overweight, dyslipidemic patients at low cardiovascular risk. We enrolled 105 Caucasian, euglycemic, overweight, dyslipidemic patients, of either sex. At baseline all patients underwent a 6 months run-in period during which they followed an adequate diet and practiced physical activity. At the end of the run-in period, patients were randomised to take placebo or a combination of Berberis aristata/Silybum marianum, 1 tablet during the lunch and 1 tablet during the dinner, for three months, in a double-blind, placebo-controlled design. Berberis aristata/Silybum marianum and placebo were then interrupted for 2 months (wash-out period), and all patients continued with only diet and physical activity. At the end of the wash-out period, patients re-started Berberis aristata/Silybum marianum or placebo twice a day for further 3 months. We evaluated during the run-in period, at randomisation, before and after the wash-out period these parameters: body weight and BMI, fasting plasma glucose, lipid profile, insulin resistance, retinol binding protein-4 (RBP-4), adiponectin (ADN), resistin. Total cholesterol, LDL-C, and Tg decreased, and HDL-C increase after 3 months of Berberis aristata/Silybum marianum, both compared to baseline and placebo. Berberis aristata/Silybum marianum decreased fasting plasma insulin, and HOMA-IR, both compared to baseline and to placebo. Moreover, there was a decrease of RBP-4, and resistin, and an increase of ADN after 3 months of Berberis aristata/Silybum marianum. All these positive effects disappeared after the wash-out period, and re-appeared after the re-introduction of the drug. We observed a significant correlation between HOMA-index decrease and resistin, and RBP-4 decrease, and between HOMA-index decrease and ADN increase in Berberis aristata/Silybum marianum group, but not in placebo group. Berberis aristata/Silybum marianum fixed combination seems to be safe and effective in improving lipid profile, but also in improving insulin resistance and adipocytokines levels.

Effects of an olmesartan/amlodipine fixed dose on blood pressure control, some adipocytokines and interleukins levels compared with olmesartan or amlodipine monotherapies.

WHAT IS KNOWN AND OBJECTIVE: To evaluate the effects of an olmesartan/amlodipine single pill combination compared with olmesartan or amlodipine monotherapies on blood pressure control, lipid profile, insulin sensitivity and some adipocytokines levels. METHODS: Two hundred and seventy-six patients were enroled in the study and were randomly assigned to take olmesartan 20 mg, amlodipine 10 mg, or a single pill containing an olmesartan/amlodipine combination 20 mg/5 mg for 12 months. We evaluated at the baseline, and after 6 and 12 months: body weight, body mass index, systolic and diastolic blood pressure (SBP and DBP), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, adiponectin (ADN), resistin (r), interleukin-1ß (IL-1ß) and interleukin-5 (IL-5). At the baseline, and after 6 and 12 months, patients underwent an euglycemic, hyperinsulinemic clamp to assess insulin sensitivity (M value). RESULTS AND DISCUSSION: There was a similar decrease in SBP and DBP after 6 and 12 months in all groups, even if olmesartan/amlodipine combination gave a major decrease in SBP and DPB compared with amlodipine and olmesartan monotherapies. Olmesartan/amlodipine combination decreased FPG after 12 months compared with amlodipine monotherapy. Olmesartan/amlodipine combination decreased FPI and HOMA index and increased M value both compared with baseline and compared with olmesartan and amlodipine monotherapies. Both olmesartan and olmesartan/amlodipine increased ADN and reduced r, without significant differences between the two groups. Regarding interleukins, no differences emerged in group to group comparison. WHAT IS NEW AND CONCLUSION: Olmesartan/amlodipine combination resulted more effective than olmesartan and amlodipine monotherapies in reducing blood pressure, and in increasing insulin sensitivity parameters, but not resulted more effective in improving adipocytokines and interleukins levels analysed, compared with amlodipine or olmesartan monotherapy in hypertensive patients in this double-blind, randomized clinical trial.

Exenatide plus metformin compared with metformin alone on ß-cell function in patients with Type 2 diabetes.

AIM: To quantify how much exenatide added to metformin improves ß-cell function, and to evaluate the impact on glycaemic control, insulin resistance and inflammation compared with metformin alone. METHODS: A total of 174 patients with Type 2 diabetes with poor glycaemic control were instructed to take metformin for 8 ± 2 months, then they were randomly assigned to exenatide (5 µg twice a day for the first 4 weeks and forced titration to 10 µg twice a day thereafter) or placebo for 12 months. At 12 months we evaluated anthropometric measurements, glycaemic control, insulin resistance and ß-cell function variables, glucagon, adiponectin, high sensitivity-C reactive protein and tumour necrosis factor-α. Before and after 12 months, patients underwent a combined euglycaemic hyperinsulinaemic and hyperglycaemic clamp, with subsequent arginine stimulation. RESULTS: Exenatide + metformin gave a greater decrease in body weight, glycaemic control, fasting plasma proinsulin and insulin and their ratio, homeostasis model assessment for insulin resistance (HOMA-IR), and glucagon values and a greater increase in C-peptide levels, homeostasis model assessment ß-cell function index (HOMA-ß) and adiponectin compared with placebo + metformin. Exenatide + metformin decreased waist and hip circumference, and reduced concentrations of high sensitivity-C reactive protein and tumour necrosis factor-α. Exenatide + metformin gave a greater increase in M value (+34%), and disposition index (+55%) compared with placebo + metformin; first (+21%) and second phase (+34%) C-peptide response to glucose and C-peptide response to arginine (+25%) were also improved by exenatide + metformin treatment, but not by placebo + metformin. CONCLUSION: Exenatide is effective not only on glycaemic control, but also in protecting ß-cells and in reducing inflammation.

Effects of aliskiren on QT duration and dispersion in hypertensive patients with type 2 diabetes mellitus.

AIM: To evaluate the effect of aliskiren compared to amlodipine on QT duration and dispersion in hypertensive patients with type 2 diabetes. METHODS: A total of 170 outpatients aged 50-75 years with mild to moderate hypertension (SBP >130 and <180 mmHg and DBP >80 and <100 mmHg) and type 2 diabetes were randomly treated with aliskiren 300 mg or amlodipine 10 mg, both given once daily for 24 weeks, according to a prospective, open label, blinded-end point, parallel group design. At the end of the placebo run-in, and after 12, and 24 weeks of treatment blood pressure (BP) measurements (by mercury sphygmomanometer, Korotkoff I and V), plasma biochemistry and a standard 12-lead surface ECG were evaluated. RESULTS: Both aliskiren and amlodipine significantly reduced systolic blood pressure (SBP)/diastolic blood pressure (DBP) values (-27.2/-14.3 mmHg, p < 0.001 vs. placebo and -27.8/-14.2 mmHg, p < 0.001 vs. placebo, respectively), with no statistical difference between the two drugs. Aliskiren, but not amlodipine, significantly reduced maximum QT interval (QTmax) (-14 ms at 12 weeks and -17 ms at 24 weeks, both p < 0.05 vs. placebo) and corrected QT max (QTc max) (-26 ms and -31 ms, p < 0.01) as well as the dispersion of both QT (-11 ms and -13 ms, p < 0.01) and QTc (-18 ms and -19 ms, p < 0.01). CONCLUSIONS: Despite similar BP lowering effect, aliskiren, but not amlodipine, reduced QT duration and dispersion, which might be related to the ability of aliskiren to interfere with mechanisms underlying myocardial electrical instability in the heart of diabetic hypertensive patients.

Effects of 1-year orlistat treatment compared to placebo on insulin resistance parameters in patients with type 2 diabetes.

WHAT IS KNOWN AND OBJECTIVE: The behavioural approach is usually slow and not always sufficient to achieve optimal targets in weight and metabolic control in obese diabetic patients, and a pharmacological treatment is often necessary. The aim of this study was to compare the effects of orlistat and placebo on body weight, glycaemic and lipid profile and insulin resistance in patients with type 2 diabetes. METHODS: Two hundred and fifty-four obese, diabetic patients were enrolled in this study and randomized to take orlistat 360mg or placebo for 1year. We evaluated at baseline and after 3, 6, 9 and 12months body weight, waist circumference (WC), body mass index (BMI), glycated haemoglobin (HbA(1c) ), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), lipid profile, retinol-binding protein-4 (RBP-4), resistin, visfatin and high-sensitivity C-reactive protein (Hs-CRP). RESULTS AND DISCUSSION: We observed a significant reduction in body weight, WC, BMI, lipid profile, RBP-4 and visfatin in the orlistat group but not in control group. Faster improvements in HbA(1c) , PPG, FPI, HOMA-IR, resistin and Hs-CRP were recorded with orlistat than with placebo. A similar decrease in FPG was seen in the two groups. Significant predictors of change in insulin resistance (HOMA-IR) were RBP-4 and resistin concentration in the orlistat group (r=-0·53, P<0·05, and r=-0·59, P<0·01, respectively). WHAT IS NEW AND CONCLUSION: To the best of our knowledge, this is the first study investigating the effect of orlistat on insulin resistance and markers of inflammation. Orlistat improved lipid profile and led to faster glycaemic control and insulin resistance parameters than the control, without any serious adverse event. Orlistat also improved RBP-4 and visfatin, effects not observed with placebo.

Pioglitazone compared to glibenclamide on lipid profile and inflammation markers in type 2 diabetic patients during an oral fat load.

The aim of the study was to evaluate the effect of pioglitazone and glibenclamide on lipid profile and inflammatory parameters during an oral fat load (OFL). A total of 201 type 2 diabetic patients on treatment with metformin were enrolled in the study; pioglitazone was titrated till 45 mg/day and glibenclamide till 15 mg/day, in association with metformin, respectively. The patients underwent an OFL at baseline and after 12 months. The OFL was given between 08.00 and 09.00 h after a 12-h fast. Blood samples were drawn before and 3, 6, 9, and 12 h after the OFL. We evaluated glycemic-metabolic parameters [glycated hemoglobin (HbA (1c)), fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment (Homa) index], total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tgs), interleukin-6 (IL-6), high sensitivity C-reactive protein (Hs-CRP), tumor necrosis factor-α (TNF-α), and adiponectin (ADN). Pioglitazone was better than glibenclamide in decreasing HbA (1c), FPG, FPI, lipid profile, and in improving inflammatory parameters such as Hs-CRP, and ADN. Comparing the OFL performed at baseline, and the OFL performed at the end of the study, pioglitazone, but not glibenclamide, improved all post-OFL peaks for all parameters. Comparing the 12 months OFL in the group treated with pioglitazone and in the group treated with glibenclamide, the values recorded with pioglitazone were significantly better than the ones obtained with glibenclamide. We can conclude that pioglitazone was better than glibenclamide in mitigating the variations of lipid components and inflammation parameters in type 2 diabetic patients.

Variation of inflammatory parameters after sibutramine treatment compared to placebo in type 2 diabetic patients.

WHAT IS KNOWN AND OBJECTIVE: The efficacy of sibutramine has been demonstrated in randomized trials in obese/overweight patients including those with type 2 diabetes mellitus (T2DM). Our objective was to evaluate the effects of 1-year treatment with sibutramine compared to placebo on body weight, glycaemic control, lipid profile, and inflammatory parameters in type 2 diabetic patients. METHODS: Two hundred and forty-six patients with uncontrolled T2DM [glycated haemoglobin (HbA(1c) ) > 8·0%] in therapy with different oral hypoglycaemic agents or insulin were randomized to take 10 mg of sibutramine or placebo for 12 months. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), HbA(1c) , fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), leptin, tumour necrosis factor-α (TNF-α), adiponectin (ADN), vaspin, high sensitivity C-reactive protein (Hs-CRP). RESULTS AND DISCUSSION: We observed a decrease of body weight after 9 and 12 months in the group treated with sibutramine, but not in the control group. Regarding glycaemic and lipid profile, although there are differences seen over time within each of the groups, we did not obtain any significant differences between the two groups. Both placebo and sibutramine gave a similar improvement of HOMA-IR, leptin, TNF-α, ADN, and Hs-CRP. No vaspin variations were observed in either group. WHAT IS NEW AND CONCLUSION: Sibutramine resulted in a decrease in body weight at 9 months and at 12 months that was not observed with placebo. Although there were differences seen over time within each of the groups, there were no significant differences between groups for any other parameter that we measured.

Oral glucose tolerance test effects on endothelial inflammation markers in healthy subjects and diabetic patients.

The aim of this study was to evaluate the effect of an oral glucose tolerance test (OGTT) on the level of endothelial dysfunction and vascular inflammation markers in healthy subjects (H) and diabetic overweight patients (D). We enrolled 256 healthy subjects and 274 type 2 diabetic patients. We evaluated blood glucose (BG), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), high-sensitivity C reactive protein (hsCRP), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), and tumor necrosis factor-alpha (TNF-alpha) at baseline and after OGTT. We observed that BG, sICAM-1, IL-6, hs-CRP, sVCAM-1, sE-selectin, and TNF-alpha values were higher in D group than in H group. In a large sample of adult healthy subjects and type 2 diabetics we observed that both answer to an OGTT with a significant increase in biomarkers of systemic low-grade inflammation and endothelial dysfunction such as hsCRP, IL-6, TNF-alpha, sICAM-1, sVCAM-1, and sE-selectin. Type 2 diabetics experienced, however, a more significant increase in TNF-alpha, and sE-selectin.

Effects of one year treatment of vildagliptin added to pioglitazone or glimepiride in poorly controlled type 2 diabetic patients.

The aim of the study was to compare the effects of vildagliptin added to pioglitazone or glimepiride on metabolic and insulin resistance related-indices in poorly controlled type 2 diabetic patients (T2DM). 168 patients with T2DM were randomized to take either pioglitazone 30 mg once a day plus vildagliptin 50 mg twice a day or glimepiride 2 mg 3 times a day plus vildagliptin 50 mg twice a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index (HOMA-beta), fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), adiponectin (ADN), resistin (R), tumor necrosis factor-alpha (TNF-alpha), and high sensitivity C-reactive protein (Hs-CRP) at their baseline values, and after 3, 6, 9, and 12 months of treatment. We observed a similar improvement of HbA1c, FPG, PPG, and Hs-CRP compared to baseline in the 2 groups. Fasting plasma insulin, FPPr, Pr/FPI ratio, R, and TNF-alpha were significantly decreased and ADN was significantly increased with pioglitazone plus vildagliptin, but not with glimepiride plus vildagliptin. HOMA-IR, and HOMA-beta values obtained with pioglitazone plus vildagliptin were significantly better than the values obtained with glimepiride plus vildagliptin. Pioglitazone plus vildagliptin were found to be more effective in preserving beta-cell function, and in reducing insulin resistance, and inflammatory state parameters.

Effect of pioglitazone and acarbose on endothelial inflammation biomarkers during oral glucose tolerance test in diabetic patients treated with sulphonylureas and metformin.

WHAT IS KNOWN: The increased risk of cardiovascular events in diabetic patients has been related to numerous metabolic and haemoreological factors. Some of these factors appear to be particularly evident during the post-prandial phases and to be related to peak plasma glucose level. AIM: To compare the effect of addition of pioglitazone and acarbose to sulphonylureas and metformin therapy on metabolic parameters and on markers of endothelial dysfunction and vascular inflammation in type 2 diabetic patients. MATERIALS AND METHODS: We enrolled 473 caucasian type 2 diabetic patients. All patients underwent measurements of height and body weight, body mass index (BMI), glycated haemoglobin (HbA1c) , fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), post-prandial plasma insulin (PPI), homeostasis model assessment (HOMA index), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), sICAM-1, IL-6, high-sensitivity C reactive protein (hsCRP), sVCAM-1, sE-selectin and tumour necrosis factor (TNF-α). Assessments were made at start of titration, after 3 months [before a first oral glucose tolerance test (OGTT)], after 6 months and at the study end (before a second OGTT). RESULTS: Two-hundred and seventy four patients completed the study: 138 were randomized to double-blind treatment with pioglitazone and 136 with acarbose. Significant BMI and weight increase were observed after full treatment in the pioglitazone group relative to the acarbose group. A decrease in glycated haemoglobin was observed after the titration period in the pioglitazone group compared to both baseline value and the acarbose group. A decrease in glycated haemoglobin was also obtained after full treatment in the pioglitazone group when compared to the end of titration period and to the acarbose group. Significant decrease in FPG was obtained in the pioglitazone group after full treatment compared to the end of titration period. Post-prandial plasma glucose decrease was observed in acarbose group compared to the baseline value and to the end of titration period. Fasting plasma insulin decreased in the pioglitazone group after both the titration period and the full treatment period compared to both the baseline value and the acarbose group. The HOMA index decreased significantly after the full treatment in pioglitazone group compared to the end of titration period and to the acarbose group. Interleukin-6 and tumour necrosis factor-α decreased after full treatment in the pioglitazone group relative to the end of titration period. Significant hsCRP decrease was obtained after the titration period when compared to the baseline value in the pioglitazone group. High-sensitivity C reactive protein decreased in the pioglitazone group after full treatment compared to the end of titration period and to the acarbose group. WHAT IS NEW AND CONCLUSION: Pioglitazone reduces the inflammatory response to a glucose challenge more than acarbose in type 2 diabetic patients, already treated with maximal doses of sulphonylureas and metformin.

Effects of pioglitazone and rosiglitazone combined with metformin on body weight in people with diabetes.

Currently, pioglitazone and rosiglitazone are the thiazolidinediones available for clinical use. In the literature, there are different studies concerning the efficacy, safety and tolerability of thiazolidinediones as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin alone. Metformin and thiazolidinediones are both antihyperglycaemic drugs, both lower blood glucose concentrations in type 2 diabetes without causing overt hypoglycaemia and both require the presence of insulin to generate their therapeutic effects, but act without stimulating insulin secretion. Some authors reported that the improved glycaemic control obtained with thiazolidinediones is associated with an increase in body weight with an estimated 2-3 kg weight gain for every 1% decrease in HbA(1c) which could negate some of the benefits of the improved metabolic control. Some other authors, instead, reported that thiazolidinediones give a better improvement in the glycaemic control compared with metformin alone without giving weight gain. The emerging discrepancies from these studies could be because of the study design, the patient selection, the degree of glycaemic control and/or the methods to measure body weight. We have undertaken a thorough literature search on Medline and Embase to evaluate the effects of thiazolidinediones plus metformin combination in people with diabetes on the body weight.

Evaluation of emerging biomarkers in cardiovascular risk stratification of hypertensive patients: a 2-year study.

OBJECTIVE: To evaluate if there is a correlation between some new emerging biomarkers, such as lipoprotein(a) (Lp[a]), apo(a) isoform phenotyping, soluble advanced glycation end products (sRAGE), soluble CD40 ligand (sCD40L), serum myeloperoxidase (MPO), and cardiovascular risk stratification. RESEARCH DESIGN AND METHODS: Three hundred patients were enrolled in this open-label, case-control design trial: 156 hypertensive patients and 144 healthy subjects as control group. Hypertensive patients were treated according to the latest ESH/ESC guidelines, until the desirable goal of systolic blood pressure (SBP)<140 mmHg, and diastolic blood pressure (DBP)<90 mmHg was reached. We evaluated at baseline and after 6, 12, 18, and 24 months: SBP, DBP, lipid profile, Lp(a), apo(a) isoform phenotyping, sRAGE, sCD40L, and MPO. RESULTS: Hypertensive patients presented higher levels of blood pressure, Lp(a), sCD40L, and MPO and lower levels of sRAGE compared with controls. We observed a decrease of blood pressure, Lp(a), sCD40L, and MPO and an increase of sRAGE after anti-hypertensive treatment. Moreover we observed moderate, but statistically significant, correlations between blood pressure decrease and Lp(a), MPO, and sCD40L decrease and between blood pressure decrease and sRAGE increase. There was also a modest, positive correlation between low molecular weight apo(a) isoforms and hypertension. A limitation of this study is that we cannot exclude a role for lifestyle measures. Furthermore the studied markers seem to improve with blood pressure lowering treatment, but we do not have enough statistical power to definitely state which drug used has a specific action on the various variables measured. CONCLUSION: Lp(a), sRAGE, MPO, sCD40L, and low molecular weight apo(a) isoforms are associated with hypertension and may represent an increased cardiovascular risk. Longer studies are needed to see if these parameters can be also used to predict specific complications linked to hypertension.

Thiazolidinediones plus metformin association on body weight in patients with type 2 diabetes.

There are different studies about the efficacy and safety and tolerability of thiazolidinediones added to metformin. The reported improved glycemic control with thiazolidinediones use seems to be associated with an increase in weight with an estimated 2-3 kg weight gain suggesting that maybe thiazolidinediones are not safe for the clinical use. Other authors reported that thiazolidinediones give an improvement in the glycemic without giving weight gain. With our review, we want to evaluate the effects of thiazolidinediones plus metformin combination in diabetic patients on the body weight. From the data emerged from our review we can conclude that even if a small increase in mean body weight was observed in patients treated with thiazolidinediones plus metformin therapy, the weight gain was less than previously reported and it was also considerably less than what might have been expected given the large improvements in glycemic control. For these reasons we can safely say that thiazolidinediones in combination with metformin are effective and well tolerated in patients with type 2 diabetes.

Exenatide versus glibenclamide in patients with diabetes.

BACKGROUND: Incretin-based therapies have provided additional options for the treatment of type 2 diabetes mellitus. The aim of our study was to evaluate the effects of exenatide compared to glibenclamide on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state in patients with diabetes. METHODS: One hundred twenty-eight patients with uncontrolled type 2 diabetes mellitus receiving therapy with metformin were randomized to take exenatide 5 microg twice a day or glibenclamide 2.5 mg three times a day and titrated to exenatide 10 microg twice a day or glibenclamide 5 mg three times a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance (HOMA-IR) index, homeostasis model assessment beta-cell function (HOMA-beta) index, plasma proinsulin (PPr), PPr/FPI ratio, resistin, retinol binding protein-4 (RBP-4), and high-sensitivity C-reactive protein (Hs-CRP) at baseline and after 3, 6, 9, and 12 months. RESULTS: Body weight and BMI decreased with exenatide and increased with glibenclamide. A similar improvement of HbA(1c), FPG, and PPG was obtained in both groups, whereas FPI decreased with exenatide and increased with glibenclamide. The HOMA-IR index decreased and the HOMA-beta index increased with exenatide but not with glibenclamide. A decrease of PPr was reported in both groups, but only glibenclamide decreased the PPr/FPI ratio. Resistin and RBP-4 decreased with exenatide and increased with glibenclamide. A decrease of Hs-CRP was obtained with exenatide, whereas no variations were observed with glibenclamide. CONCLUSIONS: Both exenatide and glibenclamide gave a similar improvement of glycemic control, but only exenatide gave improvements of insulin resistance and beta-cell function, giving also a decrease of body weight and of inflammatory state.