Comparison of effects of azelnidipine and trichlormethiazide in combination with olmesartan on blood pressure and metabolic parameters in hypertensive type 2 diabetic patients.

UNLABELLED: Aims/Introduction: Angiotensin II type 1 receptor blockers (ARB) are regarded as first-line treatment for type 2 diabetes with hypertension. However, lowering blood pressure to the target level often requires more than one antihypertensive agent as recommended by the guideline. In this open-label, prospective, crossover clinical trial, we compared the effects of combination treatment of ARB with a calcium channel blocker (CCB) or with a low-dose thiazide diuretic on blood pressure (BP) and various metabolic parameters in hypertensive patients with type 2 diabetes. MATERIALS AND METHODS: A total of 39 Japanese type 2 diabetics with hypertension treated with olmesartan (20 mg/day) for at least 8 weeks were recruited to this study. At study entry, treatment was switched to either olmesartan (20 mg/day)/azelnidipine (16 mg/day) or olmesartan (20 mg/day)/trichlormethiazide (1 mg/day) and continued for 12 weeks. Then, the drugs were switched and treatment was continued for another 12 weeks. We measured clinical blood pressure and various metabolic parameters before and at the end of each study arm. RESULTS: Compared with the olmesartan/trichlormethiazide treatment, treatment with olmesartan/azelnidipine achieved superior clinical blood pressure and pulse rate control. In contrast, the treatment with olmesartan/trichlormethiazide resulted in increased HbA1c, serum uric acid and worsening of estimated glomerular filtration rate, though there were no differences in other metabolic parameters including urine 8-hydroxy-2'-deoxyguanosine, C-reactive protein and adiponectin between the two treatments. CONCLUSIONS: Our results show that the combination of ARB with azelnidipine is more beneficial with regard to blood pressure control and metabolic outcome than the combination of olmesartan with low dose trichlormethiazide. This trial was registered with UMIN clinical trial registry (no. UMIN000005064). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00135.x, 2011).

Diabetic retinopathy is associated with pulse wave velocity, not with the augmentation index of pulse waveform.

BACKGROUND: To investigate the clinical differences between pulse wave velocity and augmentation index in diabetic retinopathy. METHODS: The subjects were 201 patients with type 2 diabetes. These subjects were measured for both augmentation index (AI) and brachial-ankle pulse wave velocity (baPWV) by a pulse wave analyzer. The relationships between AI, baPWV, and diabetic retinopathy were examined. RESULTS: BaPWV was significantly higher in patients with diabetic retinopathy than in individuals without the disease. (20.13 +/- 3.66 vs.17.14 +/- 3.60 m/s p < 0.001) AI was higher in patients with diabetic retinopathy, but not significantly. (19.5 +/- 15.2 vs. 14.8 +/- 20.5% p = 0.14) The association between baPWV and diabetic retinopathy remained statistically significant after adjustment. (Odds ratio: 1.21 Per m/s, 95% confidence interval: 1.07-1.37) On the other hand, the association between AI and diabetic retinopathy was not statistically significant. (Odds ratio: 1.01 Per %, 95% confidence interval: 0.98-1.03) CONCLUSION: BaPWV is associated with diabetic retinopathy, but AI is not. The clinical significance appears to be different between PWV and AI in patients with diabetes.

Efficacy and adverse effects of nateglinide in early type 2 diabetes. Comparison with voglibose in a cross-over study.

An open-label prospective cross-over trial was performed to compare the efficacy and adverse effects of nateglinide with those of voglibose on Japanese early type 2 diabetes (who were oral hypoglycemic agent naïve and whose HbA(1C) levels were between 7.0 and 7.9% before treatment). Fourteen patients received 270 mg/day of nateglinide and 15 patients received 0.6 mg/day of voglibose. After 12 weeks of either therapy, the drugs were switched and treatment was continued for another 12 weeks. After 3-month treatment with each drug, HbA(1C) value decreased significantly (baseline HbA(1C) 7.24 +/- 0.42%, 6.70 +/- 0.47% with nateglinide: p<0.01, 6.93 +/- 0.62% with voglibose: p<0.05) but the difference in the effect between nateglinide and voglibose was not significant (p = 0.121). Symptoms related to hypoglycemia (e.g., increased appetite, palpitation, sweating, tremor) were scarcely observed with either voglibose or nateglinide treatments. Abdominal fullness/borborygmi was frequently reported, with variable severity, by patients on voglibose but this was absent or mild in those on nateglinide. After completion of both arms of the study, more patients favored nateglinide than voglibose. Our results suggest that nateglinide is an effective and safe drug in the treatment of early type 2 diabetes, similar to voglibose.

Strict glycemic control ameliorates the increase of carotid IMT in patients with type 2 diabetes.

The aim of this study was to investigate the effect of strict glycemic control on the carotid artery intima-media thickness (IMT) in type 2 diabetic patients who initially had good glycemic control (HbA1c between 5.8 and 6.4 %). The subjects were 67 patients showing deterioration of the mean HbA1c over 3 years by more than 0.2% from baseline (D group) and 33 subjects showing improvement of the mean HbA1c by more than 0.2% from baseline (A group). The clinical characteristics and annual change of IMT during the observation period were compared between the two groups in a 3-year retrospective longitudinal study. The baseline characteristics and the mean values of BMI, blood pressure, and serum lipids during the study period did not differ significantly between the two groups. However, the mean HbA1c of A group was significantly lower than that of D group (5.67 +/- 0.10 vs. 6.28 +/- 0.08, mean +/- SE, p<0.001). The adjusted annual increase rate of IMT was significantly less in A group than in D group (-0.035 +/- 0.019 vs. 0.036 +/- 0.015 mm, M +/- SEM, p<0.001). These results indicate that further improvement of glycemic control from a good HbA1c value can prevent an increase of IMT in type 2 diabetic patients.

Chemotactic cytokine receptor 5 (CCR5) gene promoter polymorphism (59029A/G) is associated with diabetic nephropathy in Japanese patients with type 2 diabetes: a 10-year longitudinal study.

We previously showed that polymorphisms of the promoter area of chemokine receptor 5 (CCR5) gene (59029G/A) and its agonist, regulated upon activation, normal T-cell expressed and secreted (RANTES) gene (-28C/G) were new candidates for susceptibility to diabetic nephropathy. The aim of this study was to confirm the effect of these polymorphisms on the development and progression of diabetic nephropathy. We performed a 10-year retrospective study of 191 Japanese type 2 diabetic patients with normoalbuminuria at baseline. The subjects were classified into two groups: (1) those with persistent normoalbuminuria (group N) and (2) those with progression from normoalbuminuria to microalbuminuria or overt proteinuria (group P). Then, their association with CCR5 59029G/A and RANTES -28C/G polymorphisms was assessed. The frequency of the RANTES -28G(+) genotype did nor differ between the two groups, but the CCR5 59029A(+) genotype had a significantly higher frequency in group P than in group N (83% versus 71%, p=0.04). By discriminant analysis, only the CCR5 59029A(+) genotype showed an independent positive correlation with the onset or progression of nephropathy (p=0.03, odds ratio=2.41, 95% CI=1.09-5.33). Therefore, the CCR5 59029A(+) genotype seems to be related the etiology of diabetic nephropathy in Japanese type 2 diabetics.

Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients.

Insulin resistance is associated with the circulating free fatty acid (FFA) level and intracellular lipid content in muscle and liver. We investigated the effect of 2-wk diet and exercise therapy on total adiposity, circulating FFA, intracellular lipid content in muscle and liver, and peripheral insulin sensitivity. Type 2 diabetic patients were divided into a diet group (n = 7) and a diet plus exercise group (n = 7). We performed a hyperinsulinemic-euglycemic clamp study before and after treatment. Intramyocellular lipid (IMCL) in the tibialis anterior muscle and intrahepatic lipid (IHL) were evaluated by (1)H-magnetic resonance spectroscopy. Fasting FFA were not altered, and total body fat showed a slight, but significant, decrease in both groups after treatment. IMCL was decreased by 19%, and the glucose infusion rate was increased by 57% in the diet plus exercise group, whereas neither IMCL nor glucose infusion rate was significantly altered in the diet group. However, IHL showed a significant decrease in both groups. In summary, we found that 2 wk of diet and exercise decreased IMCL and increased muscle insulin-mediated glucose uptake, whereas diet with or without exercise decreased IHL. These effects were evident despite a small decrease in body fat and were observed independently of fasting FFA levels.

Effect of cilostazol, a phosphodiesterase inhibitor, on carotid IMT in Japanese type 2 diabetic patients.

The aim of this study was to investigate the effect of cilostazol, a cAMP phosphodiesterase inhibitor, on carotid artery intima-media thickness (IMT) and on the incidence of cardiovascular events in Japanese subjects with type 2 diabetes. A total of 62 type 2 diabetic subjects were allocated equally to the cilostazol treatment group (n = 31) and the control group (n = 31). Carotid IMT was evaluated before and after treatment using B-mode ultrasonography. After the study period (mean +/- SD: 2.6 +/- 0.17 years), carotid IMT showed a significantly greater increase in the control group than in the cilostazol group (0.12 +/- 0.14 mm vs. 0.04 +/- 0.02 mm, p < 0.05). In the control group, 1 out of 31 patients suffered from symptomatic cerebral infarction and 1 had angina pectoris during the observation period. On the other hand, no subject in the cilostazol group developed cardiovascular events during the study period. At baseline, the diabetic patients given cilostazol had a significantly lower HbA1c level than the control subjects, but the other atherosclerotic risk factors (BMI, blood pressure, and serum lipids) and the duration of diabetes did not differ between the two groups. These results indicate that cilostazol therapy can attenuate the increase of carotid artery IMT in Japanese subjects with type 2 diabetes.

A new En face method is useful to quantitate endothelial damage in vivo.

Endothelial damage is considered to be an initial change in the atherosclerotic process. However, it has been difficult to detect this initial change in vivo. We established a modified En face immunostaining method that enabled us to obtain clear images of the entire endothelial surface, including at arterial bifurcations, and to quantitate the number of cells of interest in the endothelium. Using this method, we found that treatment with an atherogenic factor, albumin-derived advanced glycosylation end products, for only 2 weeks caused a significant increase in the number of proliferating cell nuclear antigen-positive endothelial cells and the number of macrophages adhering to the endothelium, suggesting that these changes might be relevant to the early events of endothelial dysfunction. In conclusion, the present modified En face immunostaining method may be a promising tool for understanding the pathophysiology of atherosclerosis.