Diagnostic Accuracy of the Aortic Dissection Detection Risk Score Plus D-Dimer for Acute Aortic Syndromes: The ADvISED Prospective Multicenter Study.

BACKGROUND: Acute aortic syndromes (AASs) are rare and severe cardiovascular emergencies with unspecific symptoms. For AASs, both misdiagnosis and overtesting are key concerns, and standardized diagnostic strategies may help physicians to balance these risks. D-dimer (DD) is highly sensitive for AAS but is inadequate as a stand-alone test. Integration of pretest probability assessment with DD testing is feasible, but the safety and efficiency of such a diagnostic strategy are currently unknown. METHODS: In a multicenter prospective observational study involving 6 hospitals in 4 countries from 2014 to 2016, consecutive outpatients were eligible if they had ≥1 of the following: chest/abdominal/back pain, syncope, perfusion deficit, and if AAS was in the differential diagnosis. The tool for pretest probability assessment was the aortic dissection detection risk score (ADD-RS, 0-3) per current guidelines. DD was considered negative (DD-) if <500 ng/mL. Final case adjudication was based on conclusive diagnostic imaging, autopsy, surgery, or 14-day follow-up. Outcomes were the failure rate and efficiency of a diagnostic strategy for ruling out AAS in patients with ADD-RS=0/DD- or ADD-RS ≤1/DD-. RESULTS: A total of 1850 patients were analyzed. Of these, 438 patients (24%) had ADD-RS=0, 1071 patients (58%) had ADD-RS=1, and 341 patients (18%) had ADD-RS >1. Two hundred forty-one patients (13%) had AAS: 125 had type A aortic dissection, 53 had type B aortic dissection, 35 had intramural aortic hematoma, 18 had aortic rupture, and 10 had penetrating aortic ulcer. A positive DD test result had an overall sensitivity of 96.7% (95% confidence interval [CI], 93.6-98.6) and a specificity of 64% (95% CI, 61.6-66.4) for the diagnosis of AAS; 8 patients with AAS had DD-. In 294 patients with ADD-RS=0/DD-, 1 case of AAS was observed. This yielded a failure rate of 0.3% (95% CI, 0.1-1.9) and an efficiency of 15.9% (95% CI, 14.3-17.6) for the ADD-RS=0/DD- strategy. In 924 patients with ADD-RS ≤1/DD-, 3 cases of AAS were observed. This yielded a failure rate of 0.3% (95% CI, 0.1-1) and an efficiency of 49.9% (95% CI, 47.7-52.2) for the ADD-RS ≤1/DD- strategy. CONCLUSIONS: Integration of ADD-RS (either ADD-RS=0 or ADD-RS ≤1) with DD may be considered to standardize diagnostic rule out of AAS. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02086136.

Modification of vascular and inflammation biomarkers after OGTT in overweight healthy and diabetic subjects.

We evaluated the effect of an oral glucose tolerance test (OGTT) on the level of biomarkers of vascular remodelling. We enrolled 256 Caucasian overweight healthy subjects (H) and 274 overweight type 2 diabetic patients (D). All patients underwent basal measurements of blood glucose (BG), nitrites/nitrates, adiponectin (ADP), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) before and after OGTT. Nitrites/nitrates decrease was present after 60, 90, 120, and 180 min in both groups. Nitrite/nitrate levels were decreased at baseline, after 30 and 60 min in D group compared to H group. ADP decrease was present after 90, 120, and 180 min, in both groups. ADP levels were lower in D group than in H group during OGTT. MMP-2 increase was present after 60, 90, and 120 min in H group, while MMP-2 increase was observed after 90, 120, and 180 min in D group. MMP-2 levels were higher in D group than in H group during OGTT. MMP-9 increase was present in H group after 60, 90, 120, and 180 min, while MMP-9 increase was observed after 90, 120, and 180 min in D group. MMP-9 levels were higher in D group than in H group during OGTT. Postprandial glycemia induces an acute increase in biomarkers of vascular remodelling.

Effects of a standardized oral fat load on vascular remodelling markers in healthy subjects.

The most adequate way to experimentally reproduce the post-prandial lipemia condition appears to be the administration of a standardized oral fat load (OFL) to fasting patients. We studied the effects of a standardized OFL on markers of vascular remodelling in healthy subjects. We enrolled 286 Caucasians aged >or= 18 of either sex. The OFL was given after a 12-h fast. Blood samples were drawn before and 3, 6, 9 and 12h after the fat load. The following parameters were evaluated: body mass index (BMI), blood glucose (BG), systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile, nitrites and nitrates, adiponectin (ADP), metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9). High density lipoprotein-cholesterol (HDL-C) decrease was present in subjects after 6h. Triglycerides (Tg) change was observed after 6h. Nitrites/nitrates variation was observed after 6 and 9h during OFL. Adiponectin level was decreased after 6 and 9h during OFL. Both MMP-2 and MMP-9 levels were higher after 6h during OFL. We observed that nitrites/nitrates and ADP significantly decreased and MMP-2 and MMP-9 significantly increased after a standardized OFL. Other studies need to confirm the direct acute effects of post-prandial lipemia on vascular damage.

Continuous glucose monitoring system in free-living healthy subjects: results from a pilot study.

BACKGROUND AND AIM: The Continuous Glucose Monitoring System (CGMS) (Medtronic Minimed, Northridge, CA) provides an opportunity to better understand abnormalities in glucose metabolism in both healthy subjects and those with diabetes. The aims of our study were to assess the reliability of CGMS compared to self-monitoring of blood glucose (BG) and to analyze the graphs obtained in a sample of healthy free-living subjects in order to establish the suitability of CGMS in physiological studies. METHODS: Eighteen healthy adults, 12 women and six men, were enrolled in this study. Each subject performed 24-h CGMS and inserted 24 glycemic values, measured through a glucose meter, during their common daily activities. Three subjects were excluded from the analysis since they did not meet accuracy criteria. None of the participants received any advice as regard diet and physical activity. Means and standard deviations were used to summarize quantitative data. Normal distribution of data was tested with the Shapiro-Wilk W test. Differences over time and association between glucose levels with other variables were evaluated with linear regression models for repeated measures. RESULTS: We did not find statistically significant differences between CGMS measures and meter readings. In the subjects studied the mean glucose levels increase according to age, and we found a mean increase in glucose concentration of 0.50 mg/dL for every year of age. As regards gender, men presented a 4.63% higher mean glucose concentration than women. A 1.16% higher glucose concentration for every unit (kg/m(2)) of body mass index (BMI) was observed in both groups. All subjects presented glucose concentrations within the established range of normal glucose levels for 91% of the total duration of CGMS. CONCLUSIONS: Our results suggest that long-term studies on larger groups of healthy subjects performing CGMS would be useful in order to better understand if BMI, daily stressors due to work or psychological stress, or other factors can influence daily BG variability and if these nonpathological alterations are related to development of glucose metabolism disorders.

Oral fat load effects on inflammation and endothelial stress markers in healthy subjects.

The aim was to study the effect of a standardized oral fat load (OFL) on different inflammatory parameters in a large sample of adult healthy subjects (n = 286) of both sexes. The fat load 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. All patients underwent a measurement of body mass index (BMI), blood glucose (BG), 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), 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). Fasting plasma glucose (FPG) increase was +3.26% at 3 h, +4.35% at 6 h, +1.09% at 9 h while FPG decrease was -1.09% at 12 h. High-density lipoprotein cholesterol increase was +2.08% at 3 h, and at 12 h during OFL study; a significant HDL-C decrease was present in subjects after 6 h (-4.17%; P < 0.05 vs 0). A significant Tg change was observed after 6 h (+70.37%; P < 0.01 vs 0) and 9 h (+58.33%; P < 0.05 vs 0) respectively, and the increase was +22.22% at 3 h and +18.52% at 12 h. Total cholesterol increase was +0.52% after 3 h, +1.04% after 6 h, while after 12 h the decrease was -0.52%. Low-density lipoprotein cholesterol increase was +1.64% after 6 h with a decrease of -0.82% at 9 and 12 h. A significant sICAM-1, hsCRP, and sE-selectin variation was observed after 6 and 9 h, while a significant sVCAM-1 change occurred after 3, 6, and 9 h. Soluble ICAM-1 increase was +20.58% at 3 h, +34.10% at 6 h (P < 0.05 vs 0) +25.94% at 9 h (P < 0.01 vs 0), and +19.14% at 12 h; sVCAM-1 increase was +13.97% (P < 0.05 vs 0) at 3 h, +18.55% at 6 h (P < 0.01 vs 0), +12.02% at 9 h (P < 0.05 vs 0), and +8.70% at 12 h. High-sensitivity CRP increase was +36.36% at 3 h, +90.91% at 6 h (P < 0.01 vs 0), +63.64% at 9 h (P < 0.05 vs 0), and +36.36% at 12 h. Soluble E-selectin increase was +27.11% at 3 h, +51.90% at 6 h (P < 0.05 vs 0), +45.19% at 9 h (P < 0.01 vs 0), and +20.12% at 12 h. Interleukin-6 increase was +61.11% at 3 h (P < 0.05 vs 0), +83.33% at 6 h (P < 0.001 vs 0), +55.56% at 9 h (P < 0.01 vs 0), and +22.22% at 12 h. Tumor necrosis factor-alpha increase was +42.86% at 3 h (P < 0.05 vs 0), +71.43% at 6 h (P < 0.01 vs 0), (+50.00% at 9 h (P < 0.05 vs 0), and +28.57% at 12 h. We observed that the OFL induces a complex and massive systemic inflammatory response that includes IL-6, TNF-alpha, hsCRP, and cell adhesion molecules, even before Tg significantly rises.

Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in combined dyslipidemia.

PURPOSE: To evaluate the distribution of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and their specific inhibitors in a sample of patients affected by mild dyslipidemia but not yet treated with antihyperlipidemic drugs. METHODS: One hundred and sixty-eight Caucasian patients aged >or=18 yr of either sex with combined dyslipidemia and who had never previously taken lipid-lowering medications were evaluated. As a control population, we enrolled 179 Caucasian healthy subjects, aged >or=18 yr of either sex. We evaluated body mass index (BMI), fasting plasma glucose (FPG), fasting plasma insulin (FPI), 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), lipoprotein(a) Lp(a), plasminogen activator inhibitor-1 (PAI-1), homocysteine (Hct), fibrinogen (Fg), high sensitivity C-reactive protein (Hs-CRP), adiponectin (ADP), MMP-2, MMP-9, tissue inhibitors of metalloproteinase-1 (TIMP-1), and tissue inhibitors of metalloproteinase-2 (TIMP-2). RESULTS: TC, Tg, and LDL-C were higher (P < < 0.05, P < < 0.01 and P < < 0.05, respectively) in the dyslipidemic group, while HDL-C levels were lower (P < < 0.01) compared with the control group. Increases of PAI-1, Hct, Fg, and Hs-CRP (P < < 0.01, P < < 0.05, P < < 0.05, and P < < 0.05, respectively) were present in the dyslipidemic group, while ADP level was lower (P < < 0.01) in the dyslipidemic patients compared with controls. MMP-2, MMP-9, TIMP-1, and TIMP-2 levels were higher (P < < 0.0001) in the dyslipidemic group. CONCLUSIONS: Combined hyperlipidemic patients have increased levels of prothrombotic and microinflammatory parameters and higher levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 than control subjects. The prognostic importance of this observation has to be evaluated in adequately designed prospective studies.

Effects of insulin therapy with continuous subcutaneous insulin infusion (CSII) in diabetic patients: comparison with multi-daily insulin injections therapy (MDI).

We compared the effects of continuous subcutaneous insulin infusion (CSII) and multi-daily insulin injections therapy (MDI) on glicemic control and on lipid profile in type 1 and type 2 diabetic patients. We divided the patients in two groups: in the first one (n=32) CSII was administered, in the second one (n=32) MDI was administered. HbA(1C) value was lower after 3, 6, 9, and 12 months with CSII compared to MDI. Fasting plasma glucose (FPG) value was lower with CSII after 3, 6, and 12 months compared to MDI. Post-prandial glucose (PPG) value was lower in the group with CSII after 3, 6, 9, and 12 months compared to MDI. A significant TC decrease was observed in the group treated with CSII at 9, and 12 months while a significant TC increase was observed with MDI at 6, and 12 months. A significant LDL-C decrease was obtained with CSII after 9, and 12 months while no significant changes were observed with MDI. A significant HDL-C increase was observed with CSII after 12 months. A significant Tg decrease was observed with CSII after 12 months while a significant Tg increase was observed with MDI at 6, and at 12 months. CSII therapy allows a faster and better achievement of the therapeutic target and also gives an improvement of the lipid profile.

Rosiglitazone therapy improves insulin resistance parameters in overweight and obese diabetic patients intolerant to metformin.

BACKGROUND: Few studies have directly compared rosiglitazone and metformin effects on adipocytokines. The aim was to observe the possible effects of rosiglitazone and metformin on glycemic control, insulin sensitivity, plasma leptin (pL), adiponectin (ADN), tumor necrosis factor-alpha (TNF-alpha), and resistin (R) in overweight and obese diabetic patients intolerant to metformin. METHODS: Six hundred and ninety-four consecutive overweight and obese type 2 diabetic patients were evaluated and 56 patients were intolerant to metformin at maximum dosage. We added rosiglitazone to metformin in these intolerant patients (RM) and we compared them with 61 patients treated with metformin (M) in a single-blind placebo-controlled trial. We evaluated body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), fasting plasma insulin (FPI), pL, ADN, TNF-alpha, and R at baseline and after 3 and 6 months. Furthermore, we calculated insulin resistance index (HOMA-index) using FPG and FPI. RESULTS: Glycated hemoglobin, FPG, FPI, and HOMA-index results were lower than baseline values in RM and M groups. Glycated hemoglobin and HOMA-index values were significantly lower in RM group compared to M group at 6 months. Plasma leptin, ADN, TNF-alpha, and R were significantly improved in RM group compared to M group at 6 months. CONCLUSIONS: No BMI change was observed, probably because rosiglitazone was added to metformin, that could mitigate the body increase of rosiglitazone. Rosiglitazone improved glycemic control and insulin resistance-correlated parameters when added to intolerant metformin patients. These data suggest that rosiglitazone may be the drug of choice for the treatment of overweight and obese type 2 diabetic patients.

Blood pressure control and inflammatory markers in type 2 diabetic patients treated with pioglitazone or rosiglitazone and metformin.

The aim of the study was to assess the effects of the combination of metformin plus pioglitazone or rosiglitazone on glucose and blood pressure in type 2 diabetic patients with metabolic syndrome, as well as its tolerability in those patients. In this 12-month, multicentric, double-blind, randomized, controlled, parallel-group trial, all patients began with metformin. Patients were randomized for self-administration of either pioglitazone or rosiglitazone for 12 months. We assessed body mass index (BMI), glycemic control (glycosylated hemoglobin [HbA(1c)], fasting and postprandial plasma glucose and insulin levels [FPG, PPG, FPI and PPI, respectively] and homeostasis model assessment [HOMA] index) and systolic and diastolic blood pressure (SBP and DBP, respectively), at baseline and at 3, 6, 9 and 12 months of treatment, as well as high-sensitivity C-reactive protein (hs-CRP), nitrites/nitrates and adiponectin (ADN) at baseline and at 12 months of treatment. Significant HbA(1c) decreases were obtained after 9 (p<0.05) and 12 (p<0.01) months in both groups. After 9 and 12 months, mean FPG and PPG levels were decreased in both groups (p<0.05 and p<0.01, respectively). We observed decreases in FPI and PPI at 9 and 12 months (p<0.05 and p<0.01, respectively) compared to the baseline values in both groups. Furthermore, HOMA index improvement over the baseline value was obtained only at 12 months (p<0.05) in both groups. SBP and DBP improved significantly (p<0.05, for each) in both groups after 12 months. hs-CRP decreased significantly (p<0.05) in both groups after 12 months; nitrites/nitrates and ADN increased significantly (p<0.05, for each) in both groups after 12 months. The combination of thiazolinediones and metformin is associated with a slight but significant improvement in the long-term blood pressure control of these patients, and with an improvement in the anti-inflammatory state, both of which are related to a similar reduction in insulin-resistance.

Metabolic and antihypertensive effects of moxonidine and moxonidine plus irbesartan in patients with type 2 diabetes mellitus and mild hypertension: a sequential, randomized, double-blind clinical trial.

BACKGROUND: The autonomic nervous system plays an important part in the homeostasis of blood pressure (BP), and sympathetic overactivity may contribute to metabolic conditions such as glycemic intolerance or insulin resistance. OBJECTIVE: This study evaluated the anti-hypertensive and metabolic effects of moxonidine, a selective imidazoline II-receptor agonist that lowers BP by central inhibition of the sympathetic nervous system, and moxonidine plus the angiotensin II-receptor blocker irbesartan in patients with type 2 diabetes mellitus and mild hypertension. METHODS: This was a study in patients with type 2 diabetes previously untreated with medication and untreated mild hypertension (diastolic blood pressure [DBP] >90 and <105 mm Hg). For the first 3 months of the study, all patients were treated for hypertension with moxonidine 0.2 mg once daily (M0.2) to establish a moxonidine baseline. After this single-arm period, patients were randomized to receive double-blind treatment with moxonidine 0.2 mg BID (M0.4) or moxonidine 0.2 mg plus irbesartan 150 mg (M0.2+1) once daily for 3 months. Changes in DBP, systolic blood pressure (SBP), body mass index (BMI), fasting and postprandial plasma glucose (FPG and PPG), fasting and postprandial plasma insulin (FPI and PPI), glycosylated hemoglobin (HbA(1c)), Homeostasis Model Assessment of insulin sensitivity (HOMA-S), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were evaluated at baseline, 3 months (end of single arm period), and 6 months (end of randomized treatment period). RESULTS: The study enrolled 99 patients (50 men, 49 women; mean [SD] age, 55 [7] years; mean BMI, 26.8 [0.9]). No significant changes in BMI, PPG, PPI, TC, or LDL-C were observed over the entire study period. At 3 months, treatment with M0.2 was associated with significant improvements from baseline in SBP and DBP (P < 0.05), whereas there were no significant changes in HbA(1c), FPG, FPI, HOMA-S, HDL-C, or TG. At 6 months, significant decreases from baseline in HbA(1c), FPG, FPI, HOMA-S, and TG were observed in the M0.4 group (all, P < 0.05), but not in the M0.2+1 group. The M0.4 group also had a significant increase from baseline in HDL-C (P < 0.05) that was not seen in the M0.2+1 group. The changes in FPI and HOMA-S were significantly greater in the M0.4 group compared with the M0.2+1 group (P < 0.05). Significant decreases from baseline in SBP and DBP were observed in both the M0.4 and M0.2+1 groups (P < 0.02 and P < 0.01, respectively). No patient withdrew from the study because of a drug-related adverse event, and there were no clinically significant drug-related changes in laboratory values during the study. CONCLUSION: In these patients with type 2 diabetes and mild hypertension, the M0.4 group had greater improvements in measures of glucose metabolism and the plasma lipid profile compared with those treated with M0.2+1.

Prospects for the development of novel anti-hyperlipidemic drugs.

Hyperlipidemia is a well-established risk factor for atherogenesis and cardiovascular disease. Statins have been the cornerstone of treatment for hyperlipidemia in recent years and have significantly contributed to the improvement of cardiovascular disease therapy. However, novel antihyperlipidemic agents that have been developed over the last decade possess the capacity to significantly reduce plasma lipoproteins. This review analyzes the pharmacological profile, effectiveness and safety of some promising drugs that are either already in clinical use (eg, ezetimibe and nicotinic acid) or under study (eg, acyl-CoA cholesterol acyltransferase inhibitors, cholesteryl ester transfer protein inhibitors and apolipoprotein A-IMilano).

Matrix metalloproteinase-2, -9, and tissue inhibitor of metalloproteinase-1 in patients with hypertension.

There are conflicting data in the literature regarding the expression pattern of the vascular matrix metalloproteinase (MMP) system and their inhibitors (TIMPs) in human hypertension. The authors hypothesized that MMP-2, MMP-9, and TIMP-1 would be abnormal in hypertension, reflecting alterations in extracellular matrix (ECM) turnover. The authors measured plasma levels and activities of MMP-2, MMP-9, and TIMP-1 in 44 hypertensive patients and 44 controls. MMP-2 levels and activity were significantly higher in hypertensive group (p < .0001). Significant increase was also observed for MMP-9 level and activity (p < .0001) and for TIMP-1 (p < .0001) in hypertensive patients. Plasma levels and activities of MMP-2, MMP-9, and TIMP-1 are increased in hypertensive patients, which may reflect abnormal ECM metabolism.

Telmisartan and irbesartan therapy in type 2 diabetic patients treated with rosiglitazone: effects on insulin-resistance, leptin and tumor necrosis factor-alpha.

The aim of our study was to investigate the metabolic effect of telmisartan and irbesartan in subjects treated with rosiglitazone, a well-known insulin-sensitizing drug, in order to clarify the direct metabolic effects of the two former drugs. Patients were enrolled, evaluated, and followed at 3 Italian centers. We evaluated 188 type 2 diabetic patients with metabolic syndrome (94 males and 94 females in total; 49 males and 46 females, aged 56+/-5, treated with telmisartan; and 45 males and 48 females, aged 55+/-4, treated with irbesartan). All had been diabetic for at least 6 months, and glycemic control by the maximum tolerated dietary changes and maximum tolerated dose of oral hypoglycemic agents had been attempted and failed in all cases. All patients took a fixed dose of rosiglitazone, 4 mg/day. We administered telmisartan (40 mg/day) or irbesartan (150 mg/day) in a randomized, controlled, double-blind clinical manner. We evaluated body mass index (BMI), glycemic control (HbA1c fasting plasma glucose and insulin levels [FPG, and FPI, respectively], and homeostasis model assessment [HOMA] index), lipid profile (total cholesterol [TC], low density lipoprotein-cholesterol [LDL-C], high density lipoprotein-cholesterol [HDL-C], and triglycerides [TG]), systolic and diastolic blood pressure (SBP and DBP), tumor necrosis factor-alpha (TNF-alpha), and leptin during the 12 months of this treatment. No BMI change was observed after 6 or 12 months in either group. Significant decreases in HbAlc and FPG were observed after 6 months in the telmisartan group, and after 12 months in both groups. The decrease in HbA1c and FPG at 12 months was statistically significant only in the telmisartan group. A significant decrease in FPI was observed at 12 months in both groups, and this decrease was significantly greater in the telmisartan group. Significant decreases in the HOMA index were observed at 6 and 12 months in both groups, and the decrease in the HOMA index after 12 months was significantly greater in the telmisartan group than in the irbesartan group. Significant changes in SBP, DBP, TC, and LDL-C were observed after 6 and 12 months in both groups. Significant decreases in TNF-alpha and leptin levels were observed after 6 months in the telmisartan group, and after 12 months in both groups. In conclusion, in this study of patients with type 2 diabetes mellitus and metabolic syndrome, telmisartan seemed to result in a greater improvement in glycemic and lipid control and metabolic parameters related to metabolic syndrome compared to irbesartan. These observed metabolic effects of different angiotensin type 1 receptor blockers could be relevant when choosing a therapy to correct metabolic derangement of patients affected by metabolic syndrome and diabetes.

Effects of 1 year of treatment with pioglitazone or rosiglitazone added to glimepiride on lipoprotein (a) and homocysteine concentrations in patients with type 2 diabetes mellitus and metabolic syndrome: a multicenter, randomized, double-blind, controlled clinical trial.

BACKGROUND: Although the metabolic effects of the thiazolidinediones have been well studied, there is a lack of comparative data on their effects on certain cardiovascular risk factors, such as elevated plasma levels of lipoprotein (a) (Lp[a]) and homocysteine (Hcy). OBJECTIVE: This study compared the effects of pioglitazone or rosiglitazone added to glimepiride on a range of lipid parameters, focusing on Lp(a) and Hcy, in patients with type 2 diabetes mellitus and the metabolic syndrome. METHODS: This was a multicenter, randomized, controlled, double-blind study in patients with type 2 diabetes and the metabolic syndrome (hypertension [>or=130/85 mm Hg]) and triglyceridemia (>or=150 mg/dL). In addition to glimepiride 4 mg/d, patients received pioglitazone 15 mg QD or rosiglitazone 4 mg QD for 1 year. The primary efficacy variables were change from baseline in body mass index (BMI), glycosylated hemoglobin (HbA(1c)), Lp(a), and Hey. Secondary efficacy measures were changes in fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) concentrations, fasting and postprandial insulin concentrations (FPI and PPI, respectively), the Homeostasis Model Assessment index, and the lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides). All these parameters were measured after a 12-hour fast every 3 months for 1 year. Tolerability was assessed based on reported adverse events and laboratory abnormalities at each study visit. RESULTS: Ninety-one white patients with type 2 diabetes and the metabolic syndrome were enrolled, and 87 completed the study (43 men, 44 women; mean [SD] age, 53 [6] years; mean weight, 68.4 [3.3] kg). Mean baseline values for BMI and HbA(1c) were 24.3 (0.8) kg/m(2) and 8.1 % (0.8 %), respectively. At the end of 1 year, both treatment groups had significant increases from baseline in BMI (4.9% glimepiride + pio glitazone, 6.2% glimepiride + rosiglitazone; P < 0.05). Glimepiride + pioglitazone was associated with the following percent improvements from baseline in measures of glycemic control: -17.1% in HbA(1c), -19.3% in FPG, -17.8% in PPG, -40.1% in FPI, and -22.6% in PPI (all, P < 0.01). The corresponding percent improvements from baseline with glimepiride + rosiglitazone were -16.3%, -19.9%, -15.0%, -44.8%, and -22.1% (all, P < 0.01). There were no significant differences between treatment groups in any of these parameters. The pioglitazone group had significant improvements from baseline in TC (-11.1%), LDL-C (-12.0%), HDL-C (15.0%), and triglycerides (-22.4%) [corrected] (all, P < 0.05), whereas the rosiglitazone group had significant increases in TC (14.9%), LDL-C (16.5%), and triglycerides (17.9%) (all, P < 0.05); the difference between pioglitazone and rosiglitazone was statistically significant (P < 0.05). The change from baseline in Lp(a) was significant in the pioglitazone group, both relative to baseline and compared with the rosiglitazone group (-19.7% vs 0.5%, respectively; P < 0.05 vs baseline and vs rosiglitazone). Changes from baseline in Hey were significant in both the pioglitazone and rosiglitazone groups (-20.2% and -25.0%, respectively; P < 0.05), with no significant difference between groups. Both treatments were well tolerated, and no patients had significant changes in transaminases. CONCLUSIONS: In these patients with type 2 diabetes and the metabolic syndrome, the combinations of glimepiride with pioglitazone and glimepiride with rosiglitazone produced significant improvements in measures of glycemic control, plasma lipids, and homocysteinemia. One year of treatment with the pioglitazone combination was associated with significantly reduced plasma Lp(a) levels compared with the rosiglitazone combination.

Synergistic effect of doxazosin and acarbose in improving metabolic control in patients with impaired glucose tolerance.

OBJECTIVE: The aim of this study was to evaluate if the expected improvement in glucose and lipid metabolism obtainable with doxazosin is or is not synergistic with standard antihyperglycaemic treatment using the alpha-glucosidase inhibitor acarbose. METHODS: Patients in this randomised, controlled, double-blind clinical trial were enrolled, evaluated and followed up at three Italian centres. We evaluated 107 patients (53 males and 54 females) with impaired glucose tolerance (IGT) as determined by oral glucose tolerance tests (OGTTs). All patients took a fixed dose of acarbose 150 mg/day for 3 months, after which they were titrated up to 300 mg/day for the next 3 months. In addition, patients were randomised to either placebo (53 patients: 27 males and 26 females, aged 50 +/- 4 [mean +/- SD] years) or doxazosin 4 mg/day (54 patients: 26 males and 28 females, aged 51 +/- 5 years) for the entire 6-month treatment period. Parameters evaluated during the 6-month treatment period included body mass index (BMI), glycaemic control (glycosylated haemoglobin [HbA(1c)], fasting plasma [FPG] and post-prandial plasma [PPG] glucose, fasting plasma [FPI] and post-prandial plasma [PPI] insulin levels, homeostasis model assessment [HOMA]-index [insulin resistance]), lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides [TG]), and systolic (SBP) and diastolic (DBP) blood pressure. RESULTS: Significant reductions in BMI, HbA(1c), FPG and PPG compared with baseline were observed after 6 months in both groups (p < 0.05). A significant decrease in FPI was obtained after 6 months (p < 0.05) in the doxazosin group compared with baseline, and this difference was also significant (p < 0.05) compared with the placebo group. Similarly, a significant decrease in HOMA-index was observed at 6 months (p < 0.05) compared with baseline in the doxazosin group, and this difference was also significant (p < 0.05) compared with the placebo group. Significant decreases in TC, LDL-C, HDL-C and TG (p < 0.05) were observed in the doxazosin group after 6 months compared with baseline values. Significant decreases in SBP and DBP were also observed at 3 months in the doxazosin group compared with baseline (p < 0.05), and these differences were significant (p < 0.05) compared with placebo. Furthermore, significant decreases in SBP and DBP were observed at 6 months (p < 0.01) in the doxazosin group compared with baseline, and these differences were also significant (p < 0.01) compared with placebo. All patients who completed an OGTT at 6 months (96 patients) were restored to normal glucose tolerance status. CONCLUSION: In patients with IGT, doxazosin given in combination with acarbose seemed to improve glycaemic and lipid control compared with placebo, with the benefits observed appearing to extend beyond those expected from improvements in blood pressure. Patients in this study also benefited from acarbose therapy, which restored all patients from IGT to normal glucose tolerance status.

Thiazolidinedione effects on blood pressure in diabetic patients with metabolic syndrome treated with glimepiride.

The aim of our study was to compare the long-term effect of pioglitazone and rosiglitazone on blood pressure control of diabetic patients with metabolic syndrome treated with glimepiride. We evaluated 91 type 2 diabetic patients with metabolic syndrome. All were required to have been diagnosed as diabetic for at least 6 months, and to have failed to achieve glycemic control by dietary changes and the maximum tolerated dose of the oral hypoglycemic agents sulfonylureas or metformin. All patients took a fixed dose of 4 mg/day glimepiride. We administered pioglitazone (15 mg/day) or rosiglitazone (4 mg/day) for 12 months in a randomized, double-blind fashion, and evaluated body mass index (BMI), glycemic control, blood pressure and heart rate (HR) throughout the treatment period. A total of 87 patients completed the study and were randomized to receive double-blind treatment with pioglitazone or rosiglitazone. An increase in BMI was observed after 12 months (p < 0.05) in both groups. After 9 and 12 months, there were significant decreases in glycated hemoglobin (HbA(1c)), mean fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), and postprandial plasma insulin (PPI) in both treatment groups (p < 0.05 at 9 months and p < 0.01 at 12 months for all parameters). Furthermore, homeostasis model assessment index (HOMA index) improvement was obtained at 9 and 12 months (p < 0.05 and p < 0.01, respectively) in both groups. Significant systolic blood pressure (SBP) and diastolic blood pressure (DBP) improvement (p < 0.05, respectively) was observed in both groups after 12 months. There were no significant changes in transaminases at any point during the study. We can conclude that the association of a thiazolinedione to the glimepiride treatment of type 2 diabetic subjects with metabolic syndrome is associated to a significant improvement in the long-term blood pressure control, related to a reduction in insulin-resistance.

Long-term effects of glimepiride or rosiglitazone in combination with metformin on blood pressure control in type 2 diabetic patients affected by the metabolic syndrome: a 12-month, double-blind, randomized clinical trial.

BACKGROUND: Some evidence suggests that antihyperglycemic drugs might have a small but clinically significant beneficial effect on blood pressure in patients with diabetes mellitus. Based on a literature search, few direct comparisons of different antihyperglycemic treatments on blood pressure have been reported. OBJECTIVES: The primary aim of the present study was to compare the effect of long-term (12-month) combination treatment with glimepiride or rosiglitazone plus metformin on blood pressure in patients with type 2 diabetes mellitus (DM-2) and the metabolic syndrome. Secondary end points were glycemic control and improvement in insulin sensitivity. METHODS: This randomized, double-blind study was conducted at 2 centers in Italy. Patients aged > or =18 years with DM-2 and the metabolic syndrome and poor glycemic control (insulin resistance) with monotherapy with the maximum tolerated dose of an antihyperglycemic agent (eg, a sulfonylurea, metformin) were enrolled. All patients received 12 months of oral treatment with metformin 500 mg TID plus glimepiride 2 mg QD (G + M) or rosiglitazone 4 mg QD (R + M). Blood pressure, heart rate (HR), and body mass index (BMI); plasma levels of fasting and postprandial glucose and insulin (FPG, PPG, FPI, and PPI, respectively) and glycosylated hemoglobin (HbA(1c)); and homeostasis model assessment (HOMA) index were determined at 0 (baseline), 3, 6, 9, and 12 months of treatment. Adverse effects (AEs) were assessed using spontaneous reporting, patient interview, and laboratory analysis. RESULTS: Ninety-nine patients were enrolled in the study; 95 completed it (48 men, 47 women; mean age, 54 years [range, 47-58 years]; G + M, 47 patients; R + M, 48 patients). Four patients did not complete the study due to noncompliance (2 patients in the R + M group), protocol violation (1 patient in the G + M group), and loss to follow-up (1 patient in the G + M group). Mean blood pressure values were not significantly improved in the G + M group at any time point, whereas these values were significantly improved at 12 months in the R + M group. Mean BMI, HbA(1c), FPG, and PPG were significantly decreased from baseline in both groups at 12 months (all, P < or = 0.05). Mean FPI, PPI, and HOMA index were significantly improved at 12 months only in the R + M group (all, P < or = 0.05 vs baseline); these changes were not found in the G + M group. No significant changes in HR were found. Headache and flatulence were reported in both groups (G + M, 2 patients each; R + M, 1 and 2 patients, respectively), but these AEs were mild and transient. In the R + M group, liver enzyme levels were increased to 1.5-fold the upper limit of normal in 3 patients, but were normalized by study end. CONCLUSIONS: In this study in patients with DM-2 and the metabolic syndrome, long-term (12-month) combination treatment with R + M, but not G + M, was associated with a significant improvement in blood pressure control. Improvements in glycemic control and insulin resistance-related parameters were found at 9 months with R + M, compared with 12 months with G + M. Both treatments were well tolerated.

Antithrombotic effects of rosiglitazone-metformin versus glimepiride-metformin combination therapy in patients with type 2 diabetes mellitus and metabolic syndrome.

STUDY OBJECTIVE: To evaluate the differential effect on coagulation and fibrinolysis parameters of combination therapy with glimepiride-metformin and with rosiglitazone-metformin beyond their effect on glucose metabolism in patients with type 2 diabetes and metabolic syndrome. DESIGN: Multicenter, double-blind, randomized, controlled trial. SETTING: Two university-affiliated medical centers in Italy. PATIENTS: Ninety-five patients with type 2 diabetes for at least 6 months without glycemic control by diet and oral hypoglycemic agents to their maximum tolerated dosage and who also had metabolic syndrome. INTERVENTION: All 95 patients received metformin 1500 mg/day. In a randomized manner, 47 patients received glimepiride 2 mg/day and 48 patients received rosiglitazone 4 mg/day. MEASUREMENTS AND MAIN RESULTS: Body mass index (BMI), glycemic control, and coagulation and fibrinolysis parameters were evaluated at 3, 6, 9, and 12 months of treatment. Compared with baseline values, significant decreases in BMI, fasting plasma glucose, postprandial plasma glucose, and hemoglobin A1c were observed at 12 months in both the glimepiride and rosiglitazone groups (p<0.05 and p<0.01, respectively). Decreases in fasting plasma insulin and postprandial plasma insulin were observed at 12 months (p<0.05 and p<0.01, respectively) compared with baseline values in the rosiglitazone group. Furthermore, improvement in the Homeostasis Model Assessment index was observed only at 9 and 12 months (p<0.05 and p<0.01, respectively) compared with baseline in the rosiglitazone group. Significant improvement in plasminogen activator inhibitor (PAI)-1 was present in the rosiglitazone group after 9 months (p<0.05), and significant PAI-1 improvement was observed in the glimepiride and rosiglitazone groups after 12 months (p<0.05 and p<0.01, respectively). CONCLUSIONS: The rosiglitazone-metformin combination significantly improved the long-term control of all insulin resistance-related parameters compared with the glimepiride-metformin combination. However, both combinations were associated with a slight but statistically significant improvement in PAI-1 value, related to a similar reduction in insulin resistance.

A comparison of the effects of pioglitazone and rosiglitazone combined with glimepiride on prothrombotic state in type 2 diabetic patients with the metabolic syndrome.

OBJECTIVE: To compare the effects of glimepiride plus pioglitazone or plus rosiglitazone in diabetic patients with the metabolic syndrome on coagulation and fibrinolysis parameters. STUDY DESIGN AND METHODS: 91 type 2 diabetic patients with the metabolic syndrome participated. All patients took a fixed dose of glimepiride, 4 mg/day. We administered pioglitazone (15 mg/day) or rosiglitazone (4 mg/day) in a randomized, controlled, double-blind clinical study. We compared body mass index (BMI), glycemic control, coagulation and fibrinolysis parameters, and heart rate (HR) during 12 months of this treatment. RESULTS: A total of 87 completed the study (pioglitazone n=45 or rosiglitazone n=42). Body mass index increased after 12 months compared to baseline (p<0.05) in both groups. A significant decrease in glycated haemoglobin (HbA(1c)) was observed after 9 (p<0.05), and 12 (p<0.01) months in both groups. After 9 and 12 months, mean fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels were lower in both groups (p<0.05 and 0.01, respectively), as were fasting plasma insulin (FPI) and postprandial plasma insulin (PPI) (p<0.05 and p<0.01, respectively). An improvement in the homeostasis model assessment index (HOMA index) was seen at 9 and 12 months (p<0.05 and 0.01, respectively) compared to the baseline value in both groups. Plasminogen activator inhibitor 1 (PAI-1) was significant lower (p<0.05) in both groups after 12 months compared to the baseline values. No changes in tissue-plasminogen activator (t-PA) and fibrinogen (Fg) were seen during the study nor were there any changes in transaminases. CONCLUSIONS: We conclude that the addition of a thiazolinedione to glimepiride treatment in type 2 diabetic subjects with the metabolic syndrome is associated with a slight but significant reduction of PAI-1 value, related to a similar reduction in insulinresistance.