Association of vascular indices with novel circulating biomarkers as prognostic factors for cardiovascular complications in patients with type 2 diabetes mellitus.

BACKGROUND: The pathophysiology of atherosclerosis in type 2 diabetes mellitus (T2DM) is multifactorial. The association of vascular indices with circulating biomarkers of inflammation and insulin resistance and their role in the long-term cardiovascular prognosis in T2DM patients were currently investigated. PATIENTS AND METHODS: Patients with T2DM and poor glycemic control without known cardiovascular diseases (n=119) at baseline were enrolled and followed for about 9years. The end-point was the occurrence of any cardiovascular event (coronary heart disease, stroke, peripheral artery disease or cardiovascular death). Aortic pulse wave velocity (PWV), augmentation index (AIx), brachial flow-mediated dilation (FMD), hsCRP, Chitinase-3-like protein 1 (YKL-40), Neutrophil Gelatinase-Associated Lipocalin (NGAL), Fatty Acid Binding Protein (FABP-4) were assessed. RESULTS: Higher YKL-40 and NGAL were associated with higher PWV, while higher YKL-40 and FABP-4 were related to higher AIx (p<0.05 for all). In univariate Cox regression analysis, PWV>10m/s, YKL-40>78ng/ml and NGAL>42ng/ml were associated with cardiovascular events (p<0.05 for all). In multivariate analysis, after adjusting for classical risk factors and glycemic control, increased NGAL, YKL-40 and PWV and decreased FMD (i.e. ≤2.2%) (p<0.05 for all) were independently associated with cardiovascular events. CONCLUSION: In T2DM patients without established cardiovascular disease, novel indices of vascular inflammation (NGAL and YKL-40) were associated with subclinical atherosclerosis (arterial stiffness) but also with adverse clinical prognosis. Arterial stiffness and endothelial dysfunction were also independently related to adverse prognosis.

Determinants of vascular function in patients with type 2 diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is independently associated with an increased risk for cardiovascular diseases that is primarily due to the early development of advanced atherosclerotic vascular changes. The aim of our study was to investigate the predictors of vascular dysfunction in T2DM patients. METHODS: We studied 165 T2DM patients without known macrovascular or microvascular disease. Standard demographic (age, gender, cardiovascular risk factors, medications), clinical (body mass index, blood pressure) and laboratory (glucose, glycated hemoglobin, lipids, renal function) parameters were included in analyses. Brachial artery flow-mediated dilation (FMD), nitrate mediated dilation (NMD) and Carotid-Femoral Pulse Wave Velocity (PWV) were measured. RESULTS: Median age was 66 years and duration since T2DM diagnosis was 10 years, 70% were females and 79% hypertensives, while only 10% had a glycated hemoglobin <7%. FMD was positively associated with NMD (r 0.391, P < 0.001), while PWV was inversely associated with FMD (r -0.218, P = 0.014) and NMD (r -0.309, P < 0.001). Time since diagnosis of diabetes was the single independent predictor of FMD (ß -0.40, P = 0.003). Increased age and fasting glucose and the presence of hypertension were independent predictors of decreased NMD (P < 0.001). Increased age and systolic blood pressure were independently associated with increased PWV (P < 0.001). CONCLUSIONS: In T2DM patients, impairment of endothelium-dependent vasodilation was independently associated only with longer diabetes duration while no association with other established risk factors was found. Vascular smooth muscle dysfunction and increased arterial stiffness were more prominent in older T2DM patients with hypertension. Worse glycemic control was associated with impaired vascular smooth muscle function.

Effects of pioglitazone and metformin on vascular endothelial function in patients with type 2 diabetes treated with sulfonylureas.

Pioglitazone and metformin are insulin sensitisers used for the treatment of T2DM. The effects of pioglitazone and metformin on endothelial function, assessed by FMD, in T2DM patients treated with sulfonylureas were compared. Patients were randomised to receive pioglitazone (n = 15) 30 mg once daily or metformin (n = 16) 850 mg twice daily for six months. Pioglitazone significantly decreased fasting insulin, HbA(1C) and HOMA-IR (p < 0.05 for all) and increased FMD (p = 0.002). Metformin induced a significant decrease in HbA(1C) (p = 0.02) and only a trend for increase in FMD (p = 0.08). The greater improvement in FMD with pioglitazone, compared with metformin, did not reach significance (p = 0.11). Treatment-induced changes in FMD were not associated with the effects of the two insulin sensitisers on glycaemic control or insulin resistance. The beneficial effects of pioglitazone and metformin on endothelial function in T2DM patients did not differ greatly. Larger studies are needed to explore whether a potentially greater benefit with pioglitazone may exist.

Rosiglitazone improves endothelial function in patients with type 2 diabetes treated with insulin.

An increased incidence of myocardial infarction with rosiglitazone in patients with type 2 diabetes mellitus (T2DM) has been reported. This study aimed to assess the effect of rosiglitazone on endothelial function, assessed by flow-mediated dilation (FMD), in 34 patients with advanced T2DM treated with insulin without known cardiovascular disease. Patients were randomised into two groups: no additional treatment was given in 17 patients, while 17 patients were given rosiglitazone for 6 months. Addition of rosiglitazone significantly reduced glycosylated haemoglobin (HbA(1c)) (p < 0.0005) and fasting glucose (p < 0.05) and improved FMD (p < 0.005). No significant changes were observed in the insulin-only group. The single independent predictor of FMD improvement was rosiglitazone treatment (p = 0.048). These results show that, in patients with advanced T2DM treated with insulin, addition of rosiglitazone may have a beneficial effect on endothelial function. Further research is needed to investigate why this beneficial effect does not translate into improved cardiovascular prognosis in these patients.

Lack of effects of pioglitazone on cardiac function in patients with type 2 diabetes and evidence of left ventricular diastolic dysfunction: a tissue doppler imaging study.

BACKGROUND: Thiazolidinediones, used for the treatment of patients with type 2 diabetes mellitus (DM2), are associated with an increased incidence of heart failure. We sought to investigate the effects of pioglitazone on novel echocardiographic indices of left ventricular (LV) diastolic function in DM2 patients with LV diastolic dysfunction (LVDD). METHODS: Eighty-eight asymptomatic DM2 patients on metformin and/or sulfonylureas, aged 64.5 ± 7.7 years, without known cardiovascular disease, with normal LV systolic function and evidence of LVDD were randomly assigned to pioglitazone 30 mg/day (n = 42) or an increase in dose of other oral agents (n = 39) for 6 months. All patients underwent transthoracic conventional and Tissue Doppler Imaging echocardiography at baseline and follow-up. The primary end-point was change in early diastolic velocity of the mitral annulus (E'). RESULTS: Improvement of glycaemic control was similar in the 2 groups. A significant difference (p < 0.05) between the 2 groups was found in the treatment-induced changes in fasting insulin, the insulin resistance index HOMA, HDL cholesterol, triglycerides, diastolic blood pressure (all in favor of pioglitazone) and in body weight (increase with pioglitazone). No significant changes were observed in any echocardiographic parameter in either group and did not differ between groups (p = NS for all). E' increased non-significantly and to a similar extent in both groups (p = NS). CONCLUSIONS: In asymptomatic DM2 patients with LVDD, the addition of pioglitazone to oral conventional treatment for 6 months does not induce any adverse or favorable changes in LV diastolic or systolic function despite improvements in glycaemic control, insulin sensitivity, lipid profile, and blood pressure.

Pioglitazone vs glimepiride: Differential effects on vascular endothelial function in patients with type 2 diabetes.

OBJECTIVE: The aim of this study was to compare the effect of glimepiride and pioglitazone on endothelial function in patients with type 2 diabetes already on metformin. METHODS: Twenty-eight patients with type 2 diabetes already on metformin, without known cardiovascular disease, were randomized in 2 groups; glimepiride (4 mg od) was added in group A (n=14) and pioglitazone (30 mg od) in group B (n=14) for 6 months. Flow-mediated dilation (FMD) in the brachial artery was assessed in all patients, at baseline and at follow-up. RESULTS: The 2 groups did not differ in age (mean+/-S.D., 63.6+/-7.3 years vs 62.8+/-7.2 years respectively), or any measured variable at baseline. Fasting glucose and glycated haemoglobin improved similarly in both groups. There were significant differences between the 2 groups in the absolute changes observed at follow-up in waist circumference, +1.86+/-3.11 cm vs -1.86+/-1.88 cm in groups A and B respectively; fasting insulin levels, +14.79+/-12.56 pmol/L vs -25.84+/-28.09 pmol/L; homeostasis model assessment (HOMA), +0.66+/-1.01 vs -1.83+/-1.38; HDL cholesterol levels, -0.07+/-0.22 mmol/L vs +0.14+/-0.20 mmol/L and FMD, +0.14+/-1.09% vs +2.02+/-2.05% (p<0.05 for all). The only independent predictor factor of the FMD improvement was treatment-induced changes in HOMA (R(2): 0.488, slope: -0.782, [95% CI: -1.128, -0.436], p=0.0001). CONCLUSIONS: In patients with type 2 diabetes already on metformin, addition of pioglitazone as compared to glimepiride, improved endothelial function despite similar glycemic control. The improvement in endothelial function was mainly due to a reduction in insulin resistance.