Acute myopathy in a type 2 diabetic patient on combination therapy with metformin, fenofibrate and rosiglitazone

Aims/hypothesis This report describes the case of a 75-year-old male type 2 diabetic Caucasian who was admitted to the clinical ward because of acute pain and cramps in both calf muscles.Materials and methods Neuromuscular function was assessed by electromyography and electroneurography of the right leg. An open biopsy was taken from the left vastus lateralis muscle for histological and histochemical analyses. Southern blotting was performed to detect defects in mitochondrial DNA and tRNA. Cytochrome P450 (CYPP450) polymorphisms were analysed in blood cells.Results Fifteen weeks before admission, the patients lipid-lowering medication was switched from simvastatin to fenofibrate because of predominant hypertriglyceridaemia; this did not affect creatine kinase levels. Three weeks before admission, rosiglitazone was added to his existing metformin therapy because of worsening metabolic control. Upon admission, serum enzymes indicating myopathy were elevated (creatine kinase 6897 U/l, myoglobin 902 ng/ml) and kidney function was impaired (creatinine 0.116 mmol/l, blood urea nitrogen 2.3 mmol/l). Electrophysiology revealed myopathy and sensory polyneuropathy. Histology showed multiple damage of the myofibrillar architecture. There was no evidence of defects in mitochondrial DNA or tRNA. Furthermore, no functional limitations in CYP2C9, CYP2C19 and CYP2D6 were detected. Following withdrawal of the oral medication and intravenous hydration, clinical symptoms and laboratory parameters gradually decreased.Conclusions/interpretation Until more data from controlled trials are available, we recommend that combination therapy with fibrates and thiazolidinediones should be monitored frequently by measurements of serum creatine kinase and creatinine, specifically in patients with pre-existing nephropathy and polyneuropathy.     

罗格列酮联合阿司匹林治疗对糖尿病代谢综合征患者胰岛素抵抗的影响

目的探讨罗格列酮（RGZ）联合阿司匹林（Asp）治疗对糖尿病代谢综合征（MS）患者胰岛素抵抗（IR）的影响。方法126例MS患者按随机区组设计法分为基础治疗组（31例）,Asp组（31例）,RGZ组（32例）,RGZ联合Asp组（32例）,观察各组治疗前后FPG、2hPG、HbA1c、Ins、C-P、C—RP、纤维蛋白原水平及HOMA—IR等的变化。结果RGZ联合Asp组FPG、2hPG、Ins、HOMA—IR、炎症因子水平均较其他三组下降。结论RGZ联合Asp应用可协同改善糖尿病MS患者IR,并具有抗炎作用。     

Insulin resistance and metabolic parameters in type 2 diabetic patients

Background: The importance of insulin resistance in type 2 diabetes mellitus has been generally accepted. Only very few data about the degree of insulin resistance in a representative group of type 2 diabetic patients are available. The aim of this study was to ascertain the degree of insulin resistance and its relation to metabolic parameters in type 2 diabetic patients. Methods: We studied 96 type 2 diabetic patients. The inclusion criteria were type 2 diabetes according to WHO criteria and HbA(1c) between 6.8% and 10.5%. Insulin resistance was estimated in a euglycemic hyperinsulinemic clamp. Blood parameters like lipids, insulin, glucose, fatty acids, and leukocytes were also studied. Results: The insulin sensitivity of 71 of the type 2 diabetic patients was markedly lower than that of the controls. Twenty-five diabetic patients had an M(c) value within the range of the controls. The M(c) values, as a measure of insulin resistance, of the diabetic patients were between 0.3 and 5.2 mg/(kg min insulin), whereas the M(c) range of the controls was from 2.6 to 10.8 mg/(kg min insulin). Conclusions: Approximately 75% of the type 2 diabetic patients were insulin-resistant. Hence, type 2 diabetes mellitus was not equivalent to insulin resistance in every case.     

罗格列酮干预对糖尿病大鼠肾病的影响

目的探讨PPAR7激动剂罗格列酮（RGZ）对糖尿病（DM）大鼠肾病有否保护作用及其机制。方法正常饮食，高脂高糖＋链脲佐菌素制备DM模型，将其随机分为RGZ大剂量干预组灌胃RGZ小剂量干预组和糖尿病非干预组。12周处死大鼠，取血、尿、肾标本，检测血糖、肾功能、肾脏指数（KD及UAlb、尿α-MG、β-MG。电镜观察肾脏超微结构。通过图像分析软件检测PPARγ、α-SMA及Ⅰ型胶原在肾脏的表达水平。结果与糖尿病非干预组比较，大剂量RGZ干预组的血糖、KI、UAlb、α-MG、β-MG及α-SMA、I型胶原的表达显著降低（P〈O．05），PPAR7的表达显著增多（P〈O．05）。结论RGZ大剂量干预可能对DM大鼠的肾病有保护作用。     

罗格列酮对2型糖尿病患者尿白蛋白的影响

目的应用罗格列酮（RGZ）治疗2型糖尿病（T2DM）早期肾病患者,观察尿白蛋白及纤维蛋白原（Fib）、C反应蛋白（C—RP）的变化。方法T2DM早期肾病患者[尿白蛋白排泄率（UAER）20～200／μg／min]60例,随机分为RGZ治疗组及非RGZ治疗组,各30例,测定血糖、血脂、UAER、C-RP、Fib、Fins及HOMA—IR等。另选30名健康者和30例单纯T2DM患者作对照。结果RGZ治疗组和非RGZ治疗组治疗后,血糖、TG、Fins、HOMA-IR、C—RP、Fib、UAER均较治疗前下降,治疗后两组间比较差异有统计学意义（P〈0．01）。HDL—C治疗后逐渐升高,与非RGZ治疗组比较差异有统计学意义（P〈0．05）。结论RGZ可缓解胰岛素抵抗,在有效降低血糖、TG、C-RP、Fib水平的同时,降低UAER水平,使用罗格列酮进行干预可有效减轻糖尿病肾病患者白蛋白尿。     

不同剂量罗格列酮对2型糖尿病大鼠的体重增加效应

目的探讨不同剂量罗格列酮(ROS)对2型糖尿病(T2DM)大鼠体重增加效应的影响。方法 SD大鼠高脂喂养4 w,腹腔注射链脲佐菌素(STZ,35 mg/kg)建立T2DM大鼠模型。造模成功后随机分为模型对照(T2DM)组、ROS治疗的低剂量组(LD)、中剂量组(MD)和高剂量组(HD);另将同批次普食大鼠腹腔注射枸橼酸钠缓冲液作为正常对照组(NC组)。各组分别接受8 w干预处理。检测各组大鼠体重、摄食、血糖(BG)、胰岛素(INS)、甘油三酯(TG)及胆固醇(TC)水平。结果与T2DM组比较,各剂量组ROS治疗8 w后,空腹BG和血清INS水平较T2DM组明显降低,但体重和体重指数(BMI)均显著增加。MD、HD组的TG和TC水平均高于T2DM组,其中MD组TG和TC水平升高最显著。结论 ROS三个剂量都具有降糖效应,但长期使用均可诱导T2DM大鼠体重增加,甚至肥胖,但该体重增加效应不存在剂量依赖性,以中剂量组的效应最显著。     

罗格列酮对2型糖尿病大鼠抵抗素基因表达的调节作用

高脂饮食和STZ联合制备的糖尿病大鼠，用罗格列酮治疗者空腹血糖、胰岛素和胆固醇比不治疗者降低，而胰岛素敏感指数升高，抵抗素基因表达明显下降。     

罗格列酮对冠心病合并2型糖尿病患者MMP的影响

目的:研究罗格列酮治疗冠心病合并2型糖尿病患者时血清基质金属蛋白酶(MMP)-2、9的变化,以探讨罗格列酮减少动脉粥样硬化(AS)炎症反应、稳定斑块的作用机制。方法:选取冠状动脉造影证实的冠心病患者62例,其中单纯冠心病者34例,合并2型糖尿病者28例,两组均给予血管紧张素转化酶抑制剂、硝酸脂类、抗血小板等常规治疗,合并2型糖尿病者给予口服罗格列酮4mg,2次/d,共12周;比较两组间及治疗前、后MMP-2及9含量变化。结果:与单纯冠心病患者比,冠心病合并2型糖尿病患者血浆中MMP-2及MMP-9水平明显升高(P<0.01);经罗格列酮治疗12周后血清MMP-2、9水平较治疗前明显降低(P<0.01)。结论:罗格列酮可降低冠心病合并糖尿病患者血清MMP-2及9水平,从而可减少冠状动脉粥样斑块基质成分的降解和炎症反应,起到稳定动脉粥样硬化斑块的作用。     

罗格列酮对2型糖尿病患者血清脂肪细胞因子的影响

目的观察罗格列酮（RSG）对2型糖尿病（T2DM）患者血清脂肪细胞因子的影响，探讨血清脂肪细胞因子和胰岛素抵抗（IR）的关系及其在T2DM发病机制中的作用。方法38例新诊断T2DM患者（DM组），以RSG每日4mg口服治疗12周；24例年龄和性别匹配的糖耐量正常者为正常对照（NC）组。检测NC组及DM组患者治疗前后的身高、体重、血压、FPG、2hPG、免疫反应胰岛素（IRI）、真胰岛素（TI）、胰岛素原（PI）、血清脂肪细胞因子瘦素（LEP）、抵抗素（RST）、脂联素（APN）、视黄醇结合蛋白4（RBP-4）、尿白蛋白（UAlb）和血脂谱。计算BMI、胰岛素敏感性指数（QUICKI）、胰岛素抵抗指数（HOMA-IR）和FPI／FTI。结果DM组RSG治疗前PG、IRI、FPI、LEP、RST、RBP-4、HOMA-IR和FPI／FTI均较NC组升高，而APN和QUICK下降（P〈0．05）；DM组RSG治疗后，BMI、UAlb、血脂谱和RBP-4无显著变化，其余指标均向正常转化，APN则升高达2倍多（P〈0．01）。LEP与性别、BMI、FIRI、FTI、FPI、HOMA-IR和QUICKI相关；RST与FPI／FTI和TI相关；APN与年龄、BMI、RBP-4、FPI、2hPI、FTI、HOMA-IR和QuICKI相关；RBP-4与BMI、APN、HOMA-IR相关。多元逐步回归分析提示，LEP和APN与IR独立相关。结论新诊断T2DM患者存在IR和血清LEP、RST、RBP-4升高；APN下降；RSG可能通过改善血清脂肪细胞因子谱而发挥降血糖、改善IR和口细胞功能的疗效。     

非诺贝特对2型糖尿病大鼠肾皮质纤溶酶原激活物抑制物1表达的影响

小剂量链脲佐菌素加高脂饮食诱导的糖尿病大鼠给予非诺贝特灌胃8周，检测显示糖尿病大鼠肾皮质纤溶酶原激活物抑制物1（PAI-1）mRNA表达明显下降，同时肾小球肥大部分改善，提示非诺贝特对糖尿病肾脏的保护作用可能与其下调肾皮质PAI-1基因表达有关。     

Initial treatment with fixed-dose combination rosiglitazone/glimepiride in patients with previously untreated type 2 diabetes

Aim: This study assessed the efficacy and safety of two different dosing regimens of fixed‐dose combination (FDC) rosiglitazone (RSG) plus glimepiride (GLIM) compared with RSG or GLIM monotherapy in drug‐naive subjects with type 2 diabetes mellitus (T2DM). Methods: Drug‐naive subjects (n = 901) were enrolled into this 28‐week, double‐blind, parallel‐group study if their glycosylated haemoglobin A_1c (HbA_1c) was >7.5% but ≤12%. Subjects were randomized to receive either GLIM [4 mg once daily (OD) maximal], RSG (8 mg OD maximal) or RSG/GLIM FDC regimen A (4 mg/4 mg OD maximal) or RSG/GLIM FDC regimen B (8 mg/4 mg OD maximal). Patients were assessed for efficacy and safety every 4 weeks for the first 12 weeks of the study, and at weeks 20 and 28. The primary efficacy endpoint was change in HbA_1c from baseline. Key secondary endpoints included the proportion of patients achieving recommended HbA_1c and fasting plasma glucose (FPG) targets; change from baseline in FPG, insulin, C‐reactive protein (CRP), adiponectin, free fatty acids and lipids; and percentage change in homeostasis model assessment‐estimated insulin sensitivity and β‐cell function. Safety evaluations included adverse‐event (AE) monitoring and clinical laboratory evaluations. Results: At week 28, both RSG/GLIM FDC regimens significantly reduced HbA_1c (mean ± s.d.: ?2.4 ± 1.4% FDC regimen A; ?2.5 ± 1.4% FDC regimen B) to a greater extent than RSG (?1.8 ± 1.5%) or GLIM (?1.7 ± 1.4%) monotherapy (model‐adjusted mean treatment difference, p < 0.0001 vs. both RSG and GLIM). Significantly more subjects achieved HbA_1c target levels of ≤6.5 and <7% with either RSG/GLIM FDC regimen compared with RSG or GLIM alone (model‐adjusted odds ratio, p < 0.0001 for both comparisons). Similarly, a significantly greater reduction in FPG levels was observed in subjects treated with the RSG/GLIM FDC [mean ± s.d. (mg/dl): ?69.5 ± 57.5 FDC regimen A; ?79.9 ± 56.8 FDC regimen B) compared with RSG (?56.6 ± 58.1) or GLIM (?42.2 ± 66.1) monotherapy (model‐adjusted mean treatment difference, p < 0.0001 for both comparisons). Improvement in CRP was also observed in subjects who were treated with a RSG/GLIM FDC or RSG monotherapy compared with GLIM monotherapy. RSG/GLIM FDC was generally well tolerated, with no new safety or tolerability issues identified from its monotherapy components, and a similar AE profile was observed across FDC regimens. The most commonly reported AE was hypoglycaemia, and the incidence of confirmed symptomatic hypoglycaemia (3.6–5.5%) was comparable among subjects treated with an RSG/GLIM FDC and GLIM monotherapy. Conclusions: Compared with RSG or GLIM monotherapy, the RSG/GLIM FDC improved glycaemic control with no significant increased risk of hypoglycaemia. RSG/GLIM FDC provides an effective and well‐tolerated treatment option for drug‐naive individuals with T2DM.     

Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus

This study evaluated the effects of rosiglitazone therapy on lipids and the efficacy and safety of rosiglitazone in combination with atorvastatin in patients with type 2 diabetes mellitus. Three-hundred thirty-two patients entered an 8-week, open-label, run-in treatment phase with rosiglitazone 8 mg/day, and 243 were randomized to a 16-week, double-blinded period of continued rosiglitazone plus placebo, atorvastatin 10 mg/day, or atorvastatin 20 mg/day. With rosiglitazone alone, a modest increase in low-density lipoprotein (LDL) cholesterol (9%), a shift in LDL phenotype from dense to large buoyant subfractions (52% of patients), and an increase in total high-density lipoprotein (HDL) cholesterol levels (6%), predominantly in HDL(2) levels (13%), occurred from week 0 to week 8. When atorvastatin was added, there was a further increase in HDL(3) (5%) and expected significant reductions (p <0.0001) in LDL cholesterol (-39%), apolipoprotein B (-35%), and triglyceride levels (-27%). Glycemic control achieved with rosiglitazone alone was not adversely affected by add-on atorvastatin. The combination was well tolerated compared with placebo. To conclude, in addition to the beneficial effects of rosiglitazone on glycemic control, rosiglitazone and atorvastatin in combination achieved 2 goals: the reduction of LDL cholesterol to <100 mg/dl and the removal of small dense LDL in patients with type 2 diabetes mellitus.     

罗格列酮对2型糖尿病患者血糖及血压的影响

目的比较酒石酸罗格列酮和马来酸罗格列酮在2型糖尿病(T2DM)患者中的降糖作用,及罗格列酮对T2DM合并高血压患者血压的影响。方法222例糖尿病患者随机分为马来酸罗格列酮组和酒石酸罗格列酮组,剂量4～8mg/d,疗程12周。治疗前后测血糖、Ins和HbA1c以及高血压和血压正常者血压的变化。结果(1)两种罗格列酮均能显著降低血糖、HbA1c[(0·67±0·98)%]及胰岛素水平,两组疗效差异无统计学意义。(2)高血压组的血压随着治疗时间的延长逐步降低。治疗12周,高血压组收缩压平均降低了10·6mmHg,舒张压平均降低了6·4mmHg;而血压正常组基本无变化,两组比较差异有统计学意义(P<0·01)。(3)血压的降低与胰岛素水平的改善呈正相关。结论罗格列酮在降低血糖,改善胰岛素抵抗的同时,具有一定程度降低血压的作用。     

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

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

Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidaemia

The aim of this study was to evaluate the effects of rosuvastatin and fenofibrate alone and in combination in type 2 diabetes associated with combined hyperlipidaemia. A total of 216 patients with total cholesterol >/=200 mg/dl (>/=5.17 mmol/l) and triglycerides >/=200 and <800 mg/dl (>/=2.26 and <9.03 mmol/l) were randomised to one of two placebo groups, rosuvastatin 5 mg or rosuvastatin 10 mg for 6 weeks (fixed-dose phase). During the subsequent 18-week dose-titration phase, one placebo group received titrated rosuvastatin 10, 20 and 40 mg (placebo/rosuvastatin); one placebo group received titrated fenofibrate 67 mg once, twice and three times daily (placebo/fenofibrate); and patients receiving 5 or 10 mg rosuvastatin received titrated fenofibrate as above (rosuvastatin 5mg/fenofibrate and rosuvastatin 10 mg/fenofibrate groups). Doses were increased at 6-week intervals if low-density lipoprotein (LDL) cholesterol remained >50 mg/dl (>1.3 mmol/l). At 24 weeks, the placebo/rosuvastatin group and placebo per fenofibrate group had triglyceride reductions of 30.3% versus 33.6%, respectively (P = NS), and LDL cholesterol was reduced by 46.7% in the rosuvastatin group and increased by 0.7% in the fenofibrate group (P < 0.001). The triglyceride reduction in the rosuvastatin 10 mg/fenofibrate group (47.1%) was significantly greater than in the placebo/rosuvastatin group (P = 0.001), with no significant differences in other lipid measures found between these two groups. No significant differences in effect on high-density lipoprotein (HDL) were observed among treatment groups. In the fixed-dose phase, rosuvastatin 5 and 10 mg reduced triglycerides by 24.5 and 29.5%, respectively, and decreased LDL cholesterol by 40.7 and 45.8%, respectively. All treatments were well tolerated. These results indicated that rosuvastatin produces marked reductions in triglycerides and LDL cholesterol when used alone or in combination with fenofibrate in type 2 diabetes patients with elevated cholesterol and triglyceride levels and may constitute a valuable treatment option in the diabetic population.     

The effect of carvedilol on metabolic parameters in patients with metabolic syndrome

The objective of the present study was to explore the effect of carvedilol treatment on metabolic parameters in patients with metabolic syndrome. A total of 77 patients > or = 20 years of age (59 females, 18 males, mean age, 52.3 +/- 10.3) with stage 1 hypertension who fulfilled at least 3 of the metabolic syndrome criteria proposed by NCEP-ATP III were included in this prospective, randomized, controlled study. Patients were randomly assigned to receive daily treatment with carvedilol (n = 27, 12.5 mg/day orally for the first 2 days and 25 mg/day thereafter), atenolol (n = 26, 50 mg/day orally), or doxazosin (n = 24, 2 mg/day orally) for 90 days. Doses were doubled at the end of the 3rd week in patients whose blood pressure was inadequately controlled and amlodipine 10 mg was added to the treatment if the target blood pressure was still not reached at the end of week 6. The biochemical parameters and insulin sensitivity based on the HOMA-IR model were evaluated at baseline and at the end of treatment. Similar reductions in systolic and diastolic blood pressure were observed in all groups (P > 0.05). A significant decrease in HDL cholesterol levels occurred in the doxazosin and atenolol groups compared to the carvedilol group (percent change: -5.6 +/- 13.5 and -8 +/- 9.8 versus -0.1 +/- 12.2, respectively; P < 0.05) and a significant increase in apolipoprotein A1 level was observed in the carvedilol group compared to the doxazosin and atenolol groups (percent change: + 4.3 +/- 9.6 versus - 0.5 +/- 10.6 and -2.3 +/- 6.6, respectively; P < 0.05). There were no significant differences among the groups with respect to other parameters. It is concluded antihypertensive treatment with carvedilol in patients with metabolic syndrome effectively reduces blood pressure without adversely affecting metabolic parameters.     

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.     

Influence of nebivolol and enalapril on metabolic parameters and arterial stiffness in hypertensive type 2 diabetic patients

OBJECTIVE: To compare the effects of a cardioselective beta-blocker (nebivolol) with those of an angiotensin-converting enzyme inhibitor (enalapril) on parameters of insulin sensitivity, peripheral blood flow and arterial stiffness during one extended glucose clamp experiment. DESIGN: A randomized, double-blind crossover trial, consisting of two 12-week treatment phases separated by a 4-week wash-out phase. METHODS: Patients with type 2 diabetes and arterial hypertension were randomly assigned to one of two treatment sequences (nebivolol-enalapril, enalapril-nebivolol). Haemodynamic, metabolic and other laboratory measurements were carried out on the first and last day of each treatment period by means of a glucose clamp experiment that also involved the measurement of blood flow and arterial stiffness. RESULTS: Twelve patients were included in this study, of which two dropped out early. Efficacy parameters were therefore available for 10 patients. There was no significant difference in any of the primary efficacy parameters. Moreover, the effects on blood pressure did not significantly differ between both treatments. Six adverse events happened during treatment with nebivolol compared with two during treatment with enalapril, but only one was regarded as possibly related to the treatment. CONCLUSIONS: This pilot study shows that the combined measurement of insulin sensitivity, blood flow and arterial stiffness is feasible. Nebivolol and enalapril did not show different effects with regard to these parameters in hypertensive diabetic patients. If these results are confirmed in larger clinical trials, this would argue against the reservations against beta-blockers as drugs of first choice in patients with diabetes because of potential metabolic side-effects.     

Initial treatment with rosiglitazone/metformin fixed-dose combination therapy compared with monotherapy with either rosiglitazone or metformin in patients with uncontrolled type 2 diabetes

AIM: This study assessed the efficacy and safety of rosiglitazone and metformin (RSG/MET) fixed-dose combination (AVANDAMET) as initial therapy in patients with uncontrolled type 2 diabetes compared with monotherapy with either RSG or MET after 32 weeks of treatment. METHODS: A total of 468 drug-naive patients with uncontrolled type 2 diabetes were recruited for this multicentre, double-blind trial if their glycated haemoglobin (A1c) was greater than 7.5%, but less than or equal to 11%, and their fasting plasma glucose (FPG) was less than or equal to 15 mmol/l. Patients were randomized to 32 weeks of blinded treatment with either RSG/MET fixed-dose combination (n = 155), MET (n = 154) or RSG (n = 159). The groups were comparable at baseline, with mean A1c of 8.8% and FPG of 11 mmol/l. RSG/MET was initiated with a total daily dose of 2 mg/500 mg and could be increased up to 8 mg/2000 mg; MET therapy began with a total daily dose of 500 mg and could be increased up to 2000 mg; and RSG treatment began with a total daily dose of 4 mg and could be increased up to 8 mg. Medication was uptitrated during on-therapy visits based on failure to attain glycaemic target of mean daily glucose less than or equal to 6.1 mmol/l (unless at maximum tolerated dose). Patients were assessed for efficacy and safety at nine visits over a 32-week treatment period. This was a trial designed to show greater efficacy of RSG/MET combination therapy compared with MET or RSG monotherapy. The primary end point was change in A1c from baseline to week 32. Secondary end points included the proportion of patients achieving recommended A1c and FPG targets for glycaemic control and change from baseline in FPG, free fatty acid, lipids, insulin, insulin sensitivity, C-reactive protein and adiponectin. Safety evaluations included adverse-event (AE) monitoring, changes in weight and clinical laboratory evaluations. RESULTS: At week 32, RSG/MET showed significant improvements in A1c from a baseline of 8.9 +/- 1.1% to 6.6 +/- 1.0% at study end, and this 2.3% reduction was significantly greater than the reductions achieved individually with MET (-1.8%; p = 0.0008) and RSG (-1.6%; p < 0.0001). The greatest mean decrease in FPG was seen with RSG/MET (-4.1 mmol/l) and was significant compared with MET (-2.8 mmol/l; p < 0.0001) and RSG (-2.6 mmol/l; p < 0.0001). Target A1c of less than or equal to 6.5% and less than 7% were achieved in more patients in the RSG/MET group (60% and 77%) than with MET (39% and 57%) or RSG (35% and 58%) respectively. Treatment was well tolerated, with nausea, vomiting and diarrhoea as the most commonly reported AEs. Oedema was comparable between RSG/MET (6%) and RSG (7%) and lower in the MET group (3%). No new safety and tolerability issues were observed in the RSG/MET group. CONCLUSIONS: As first-line therapy in patients with uncontrolled type 2 diabetes, RSG/MET fixed-dose combination therapy achieved significant reductions in A1c and FPG compared with either RSG or MET monotherapy. RSG/MET was generally well tolerated as initial therapy, with no new tolerability issues identified with the fixed-dose combination.