Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin

AIM: To assess the efficacy and safety of a 24-week treatment with sitagliptin, a highly selective once-daily oral dipeptidyl peptidase-4 (DPP-4) inhibitor, in patients with type 2 diabetes who had inadequate glycaemic control [glycosylated haemoglobin (HbA(1c)) >or=7.5% and metformin. METHODS: After a screening, diet/exercise run-in and drug wash-off period, a glimepiride +/- metformin dose titration/stabilization period and a 2-week, single-blind placebo run-in, 441 patients (of ages 18-75 years) were randomized to receive the addition of sitagliptin 100 mg once daily or placebo in a 1 : 1 ratio for 24 weeks. Of these patients, 212 were on glimepiride (>or=4 mg/day) monotherapy and 229 were on glimepiride (>or=4 mg/day) plus metformin (>or=1,500 mg/day) combination therapy. Patients exceeding pre-specified glycaemic thresholds during the double-blind treatment period were provided open-label rescue therapy (pioglitazone) until study end. The primary efficacy analysis evaluated the change in HbA(1c) from baseline to Week 24. Secondary efficacy endpoints included fasting plasma glucose (FPG), 2-h post-meal glucose and lipid measurements. RESULTS: Mean baseline HbA(1c) was 8.34% in the sitagliptin and placebo groups. After 24 weeks, sitagliptin reduced HbA(1c) by 0.74% (p < 0.001) relative to placebo. In the subset of patients on glimepiride plus metformin, sitagliptin reduced HbA(1c) by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride alone. The addition of sitagliptin reduced FPG by 20.1 mg/dl (p < 0.001) and increased homeostasis model assessment-beta, a marker of beta-cell function, by 12% (p < 0.05) relative to placebo. In patients who underwent a meal tolerance test (n = 134), sitagliptin decreased 2-h post-prandial glucose (PPG) by 36.1 mg/dl (p < 0.001) relative to placebo. The addition of sitagliptin was generally well tolerated, although there was a higher incidence of overall (60 vs. 47%) and drug-related adverse experiences (AEs) (15 vs. 7%) in the sitagliptin group than in the placebo group. This was largely because of a higher incidence of hypoglycaemia AEs (12 vs. 2%, respectively) in the sitagliptin group compared with the placebo group. Body weight modestly increased with sitagliptin relative to placebo (+0.8 vs. -0.4 kg; p < 0.001). CONCLUSIONS: Sitagliptin 100 mg once daily significantly improved glycaemic control and beta-cell function in patients with type 2 diabetes who had inadequate glycaemic control with glimepiride or glimepiride plus metformin therapy. The addition of sitagliptin was generally well tolerated, with a modest increase in hypoglycaemia and body weight, consistent with glimepiride therapy and the observed degree of glycaemic improvement.     

A randomized placebo-controlled trial of metformin for the treatment of HIV lipodystrophy

OBJECTIVE: We conducted a randomized placebo-controlled trial to examine the effects of metformin on visceral adipose tissue (VAT), appendicular fat, lipid profile and insulin sensitivity in HIV-infected persons with central adiposity and mild insulin resistance. METHODS: Forty-eight HIV-infected men and women with a self-reported increase in abdominal girth and an abnormal waist-to-hip ratio were randomly assigned in double-blind fashion to receive metformin 1500 mg or placebo daily for 24 weeks. Persons with diabetes were excluded. The following measures were obtained at baseline and 24 weeks: single-slice computed tomography (CT) scan, dual-energy X-ray absorptiometry (DEXA), lipid profile and oral glucose tolerance test. RESULTS: The median fasting insulin concentration of all participants was 12.3 microU/mL. The percentage change in VAT was not significantly different between the metformin and placebo groups in univariate analysis and linear regression analysis adjusting for age, height, baseline VAT and insulin area under the curve (10.1% vs 3.2%; P=0.58). Metformin was associated with a significant decrease in appendicular fat mass compared with placebo (-686.0 vs 161.0 g; P=0.03). There was no significant change in lipid profile or insulin sensitivity between the two groups at 24 weeks. CONCLUSION: Metformin should be used with caution in the treatment of HIV lipodystrophy, and, if used, should be reserved for persons with adequate peripheral fat and marked insulin resistance.     

二甲双胍格列本脲片中两种成分的离子对HPLC法测定

目的：建立用离子对HPLC法测定二甲双胍格列本脲片（复方盐酸二甲双胍片）中盐酸二甲双胍和格列本脲含量的方法。方法：以地西泮为内标,采用Symmetry C18柱（150mm×4．6mm,5ym）,流动相为甲醇～2mmol／L十二烷基磺酸钠溶液（58：42）,流速1．0mL／min．检测波长分别为232nm（盐酸二甲双胍）和300nm（格列本脲）。结果：盐酸二甲双胍和格列本脲分别在0．500～16．016μg／mL（r=0．9995）和20．040～120．240μg／mL（r=0．9998）范围内线性关系良好。平均方法回收率分别为（100．14±1．79）%（RSD=0．62％,n=3）和（99．95±1．16）％（RSD=0．56％,n=3）。结论：本方法操作简便,结果准确,重现性好,可用于二甲双胍格列本脲片的质量控制。     

玉泉丸对盐酸二甲双胍大鼠肠吸收的影响

目的:研究玉泉丸对盐酸二甲双胍大鼠肠吸收的影响。方法:采用大鼠在体肠单向灌流吸收实验模型,应用重量法校正灌流液体积,考察玉泉丸对盐酸二甲双胍肠吸收的影响。结果:盐酸二甲双胍组、盐酸二甲双胍与玉泉丸联合灌流组、玉泉丸诱导组的吸收速率常数分别为0.38,0.28,0.38min-1,吸收渗透系数分别为0.38,0.29,0.37cm.min-1。结论:玉泉丸可能竞争盐酸二甲双胍大鼠肠吸收途径,对盐酸二甲双胍的吸收有一定的抑制作用。     

Antihyperglycemic activity of Selaginella tamariscina (Beauv.) Spring

Aim of the study

The present study was designed to investigate the effects of the EtOH and H₂O extracts of Selaginella tamariscina (Beauv.) Spring on hyperglycemia in diabetic rats and HepG2 cells, and to confirm the active fractions of EtOH extract in HepG2 cells.

Materials and methods

HepG2 cells and type II diabetic rats induced by low-dose streptozotocin (STZ) and high-fat diet (HFD) were used to evaluate the hypoglycemic effect of EtOH and H₂O extracts of Selaginella tamariscina. HepG2 cells were used to evaluate the promotive effect of different fractions of EtOH extract obtained from a polyamide column on glucose utilization.

Results

The results in HepG2 cells indicated that the EtOH extract had a better hypoglycemic effect than the H₂O extract. The results in diabetic rats indicated that both EtOH extract and H₂O extract were able to ameliorate the fasting blood glucose (FBG) level and improve oral glucose tolerance (OGTT). Total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-c), free fatty acids (FFA), tumor necrosis factor-α (TNF-α), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and malondialdehyde (MDA) levels in serum were lowered. High density lipoprotein (HDL-c), insulin and superoxide dismutase (SOD) levels in serum were elevated as well as the hepatic glycogen content in diabetic rats. Compared with H₂O extract, the effects of EtOH extract were more marked. The 80% ethanol fraction exhibited a stronger hypoglycemic effect than the aqueous and 50% ethanol fractions, but the 95% ethanol fraction did not show any appreciable effects in HepG2 cells.

Conclusions

The results suggested that the EtOH extract had a better hypoglycemic effect than the H₂O extract; the 80% ethanol fraction from polyamide column had a strong hypoglycemic activity in HepG2 cells.     

High HbA1c is a risk factor for complications after hepatectomy and influences for hepatocellular carcinoma without HBV and HCV infection

BackgroundCurrently, the population with type 2 diabetes mellitus (DM) is increasing worldwide. However, the influence of DM or hyperglycemia on the outcome of resected hepatocellular carcinoma (HCC) is unclear.MethodsWe analyzed 756 patients with HCC who underwent hepatectomy. These patients were assigned to an HbA1c ≥7.0% (H-A1c; n=100) or HbA1c <7.0% (L-A1c; n=656) group depending on their HbA1c level at admission. We investigated prognoses, clinicopathological characteristics and surgical outcomes including morbidities of HCC patients with high HbA1c, prognoses according to the treatment for DM were also investigated.ResultsAmong all patients and those with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, overall survival (OS) and relapse-free survival (RFS) did not differ significantly between the H-A1c and L-A1c groups. In contrast, the 5-year OS rate of the H-A1c group was 55% and that of the L-A1c group 71% among patients without HBV and HCV (NBNC patients) (P=0.03). Among NBNC patients, the median RFS of the H-A1c group was 13 months, and that of the L-A1c group was 26 months (P=0.02). In addition, metformin use was an independent favorable factor for both OS and RFS. The H-A1c group had significantly higher rates of hyperbilirubinemia, wound infection, and pneumonia.ConclusionsHCC patients with high HbA1c might have poor prognoses for both survival and recurrence in NBNC-HCC. High HbA1c may also be a risk factor for morbidities after hepatectomy. Metformin use may constitute a good option for NBNC patients with HCC.     

盐酸二甲双胍在正常大鼠与糖尿病大鼠体内的药动学比较

目的比较盐酸二甲双胍在正常大鼠与糖尿病大鼠体内的药动学差异。方法正常大鼠与糖尿病模型大鼠,分别灌胃给予盐酸二甲双胍后,于不同时间点采集血样,用HPLC测定血药浓度并绘制药-时曲线,用DAS1.0统计软件计算药动学参数。结果盐酸二甲双胍在正常大鼠与糖尿病大鼠体内的主要药动学参数分别为：Cmax=9.41μg·mL^-1、t1/2=161.8min、Cl/F=0.079L·min^-1·kg^-1;Cmax=20.09μg·mL^-1、t1/2=1718.93min、Cl/F=0.012L·min^-1·kg^-1。结论盐酸二甲双胍在正常大鼠与糖尿病模型大鼠体内的药动学参数有明显差异（P〈0.05）。     

高效液相色谱法研究人体内盐酸二甲双胍药动学和生物等效性

目的：研究健康人口服盐酸二甲双胍片后的药动学和生物等效性。方法：20个健康受试者采用随机分组自身交叉对照试验设计,口服盐酸二甲双胍片0.5 g后用HPLC法测定血浆中盐酸二甲双胍浓度,以DAS软件计算其药动学参数和评价生物等效性。结果：在选定的色谱条件下盐酸二甲双胍与内标及血浆杂质分离良好,在24～2 000 ng&#8226;mL-1范围内线性良好。相对回收率大于91.31％,日内和日间RSD小于9.29%。盐酸二甲双胍片受试制剂和参比制剂的主要药动学参数：Tmax分别为(2.25±0.53)和(2.30±0.44)h,Cmax分别为(1 498.9±207.9)和(1 540.1±209.3)ng&#8226;mL-1;t1/2分别为(3.82±1.40)和(3.90±1.16)h;AUC0~t分别为（8 202±1 624）和（7 979±1 650）ng&#8226;h&#8226;mL-1;用面积法(AUC0~t)估算的盐酸二甲双胍片相对生物利用度为(103.2±9.7)%。结论：用HPLC法测定血浆中盐酸二甲双胍浓度,杂质无干扰,定量限低,重复性好,准确度高。2制剂生物等效。     

反相离子对HPLC法测定盐酸二甲双胍中双氰胺的含量

目的建立反相离子对HPLC法测定盐酸二甲双胍中双氰胺含量的方法。方法采用Agilent HC-C18(2)色谱柱(250 mm×4.6 mm,5μm),以甲醇-10 mmol/L庚烷磺酸钠溶液(含0.8%三乙胺,用H3PO4调pH 3.0)(15∶85)为流动相;流速:1.0 mL/min;检测波长:218 nm;柱温:30℃。结果反相离子对HPLC法测定盐酸二甲双胍中双氰胺含量的线性范围为0.01~26.12μg/mL;相关系数r=0.999 9;重复性的RSD为1.8%;精密度RSD为1.6%;高、中、低3种浓度的加样回收率分别为98.8%,102.1%,103.6%;RSD分别为0.8%,1.2%,0.9%。结论此法简便、快速、准确、专属性好。     

达英-35联合二甲双胍治疗多囊卵巢综合征120例

目的观察达英-35联合二甲双胍治疗多囊卵巢综合征（PCOS）的疗效。方法选择2005年6月～2008年12月在我院就诊PCOS患者120例,口服达英-35联合二甲双胍治疗3个周期,测定患者血清黄体生成素LH、黄体生成素/卵泡刺激素LH/FSH和睾酮T,测量腰臀比值WHR、测量体重指数BMI,并将治疗前后进行比较。结果治疗后LH、LH/FSH、T、WHR、BMI均较治疗前明显下降P〈0.05或P〈0.01,治疗后月经均来潮且规则,痤疮、多毛症状也减轻。结论达英-35联合二甲双胍是治疗多囊卵巢综合征的理想选择。