Antioxidant effects of gliclazide, glibenclamide, and metformin in patients with type 2 diabetes mellitus

Background: Hyperglycemia increases oxygen-reactive species generation and reduces the protective capabilities of antioxidant defense systems. In patients with type 1 or 2 diabetes mellitus (DM), the increased production of oxygen free radicals may be linked to the development of chronic complications of diabetes. In vitro studies have demonstrated that oral antidiabetic drugs have antioxidant effects that might be secondary to an inhibiting role in lipid peroxidation.Objective: The purpose of this study was to determine the effects of 3 common oral antidiabetic agents on oxidized anti-low-density lipoprotein antibody (o-LAb) plasma levels and on total antioxidant status (TAS).Methods: We studied in vivo patients with type 2 DM treated with long-term gliclazide, glibenclamide, or metformin therapy along with healthy control subjects. The diabetic patients were randomized to the following treatment groups: group 1, gliclazide 80 to 240 mg/d; group 2, glibenclamide 10 to 15 mg/d; and group 3, metformin 1500 mg/d.Results: Ninety-two patients with type 2 DM (group 1, 18 females, 15 males [mean age, 62.8 ± 9.5 years]; group 2, 19 females, 11 males [mean age, 63.2 ± 8.8 years]; group 3, 16 females, 13 males [mean age, 62.0 ± 5.3 years]) and 28 age- and sex-matched healthy control subjects (18 females, 10 males; mean age, 59.1 ± 5.3 years) were enrolled. In group 1, both the o-LAb level and TAS were similar to those of the control group. The o-LAb level was highest and the total antioxidant plasma level was lowest in group 3, whereas intermediate levels were found in group 2. Multivariate analysis using stepwise regression showed that the type of oral antidiabetic agent was independently associated with o-LAb and total antioxidant levels, as well as with sex, age, and type of antidiabetic agent.Conclusion: In the patients with type 2 DM in this study, gliclazide had a positive effect on the oxidation-reduction system.     

Durable efficacy of metformin/glibenclamide combination tablets (Glucovance) during 52 weeks of open-label treatment in type 2 diabetic patients with hyperglycaemia despite previous sulphonylurea monotherapy

Oral anti-diabetic combinations that address insulin resistance and beta-cell dysfunction (e.g. metformin and glibenclamide) represent a rational therapeutic option for patients uncontrolled on monotherapy. A 52-week, open-label extension to a double-blind study evaluated metformin-glibenclamide combination tablets (Glucovance) in 477 patients with hyperglycaemia despite sulphonylurea therapy. Reductions in HbA1C were maintained, with a mean reduction of -1.7% after 52 weeks, compared with the baseline value for the double-blind trial. Eighty-five patients receiving 4 x 500 mg/2.5 mg tablets daily displayed a marked improvement in HbA1c following up-titration to a regimen of 2 x 500 mg/2.5 mg + 3 x 500 mg/5 mg tablets. Lipid profiles improved significantly. The combination tablets were well tolerated: 11.1% of patients reported hypoglycaemic symptoms (all either mild or moderate severity). No patient withdrew or required pharmacologic intervention for hypoglycaemia. Metformin-glibenclamide combination tablets are an effective and well-tolerated therapeutic option for intensifying oral anti-diabetic therapy.     

Beta-cell response to metformin-glibenclamide combination tablets (Glucovance) in patients with type 2 diabetes

This exploratory double-blind, randomised, 20-week study evaluated the mechanism of action of metformin-glibenclamide combination tablets (Glucovance) vs. metformin and glibenclamide in 50 type 2 diabetes patients inadequately controlled by diet and exercise. A glycaemic target of HbA1C 7.0% was used. Final HbA(1C), fasting glucose and post-oral glucose tolerance test (OGTT) glucose were similar between groups, although average doses of metformin and glibenclamide from combination tablets (708 and 3.5 mg) were lower than monotherapy doses (1500 and 6.6 mg). Second-phase insulin during a hyperglycaemic clamp increased by 93% with combination tablets, 36% with metformin and 46% with glibenclamide. The insulin response post-OGTT was more rapid with the combination tablets vs. glibenclamide. First-phase insulin responses improved modestly in all groups, possibly due to reduced glucotoxicity. Changes in insulin sensitivity were minor. Larger beta-cell responses between combination tablets and glibenclamide may reflect more rapid glibenclamide absorption.     

二甲双胍对合并代谢综合征的2型糖尿病患者代谢指数的影响

目的观察二甲双胍对合并代谢综合征的2型糖尿病患者代谢指数的影响。方法将45例正使用诺和灵30R治疗的合并代谢综合征的2型糖尿病患者随机分为两组,对照组维持原治疗方案,治疗组加用二甲双胍（0．5g3次／d）观察随访12周。结果治疗组与联合二甲双胍治疗前相比,联合二甲双胍治疗后空腹血糖,糖化血红蛋白（HbA1c）,甘油三酯（TG）,总胆固醇（TC）,体质指数（BMI）,腰围（WC）明显下降（尸〈0．001）。血压无明显改变。对照组的上述指标与治疗前相比差异无统计学意义（P〉0．05）。结论对合并代谢综合征的2型糖尿病患者联合应用二甲双胍可有效控制血糖、血脂,减轻体重。     

Serum sialic acid changes in type 2 diabetic patients on metformin or rosiglitazone treatment

What is known and objective: Serum sialic acid is a recently investigated potential risk‐marker for cardiovascular complications. There is a known association between sialic acid and cardiovascular complications in diabetes mellitus. We aimed to investigate the effect of antidiabetic drugs on the serum concentration of sialic acid. Methods: We investigated the effect of metformin and rosiglitazone on the concentration of sialic acid in 120 type 2 diabetic patients, divided into a group (n = 60) receiving metformin and a group (n = 60) receiving rosiglitazone treatment. Results: Serum sialic acid was significantly higher in patients on rosiglitazone (66·90 ±8·80 mg/dL vs. 57·6 ± 8·46 mg/dL, P <0·01) and metformin (61·95 ± 10·49 mg/dL vs. 57·6 ±8·46mg/dL, P < 0·04) when compared with control subjects. In addition, rosiglitazone‐treated patients showed a significant increase in cardiovascular risk factors, notably total cholesterol (246·45 ± 20·2 mg/dL vs. 170·6 ± 15·1 mg/dL, P =0·01), triglyceride (178 ± 9·20 mg/dL vs. 149·35 ±6·31 mg/dL, P < 0·04) and glycohemoglobin (HbA1‐c) concentration (8·17 ± 1·43% vs. 4·38 ±0·96%, P < 0·02) compared with normal control subjects. The patients on metformin also showed significantly higher levels of serum glucose (133·7 ± 9·63 mg/dL vs. 88·35 ± 6·31 mg/dL, P <0·04) and glycohemoglobin (HbA1‐c) (8·23 ±1·75% vs. 4·38 ± 0·96%, P < 0·02) when compared with control subjects. Comparison of the two groups of patients revealed a significantly higher serum sialic acid (66·90 ± 8·80 mg/dL vs. 61·95 ±10·49 mg/dL, P < 0·05), total cholesterol (246·45 ±20·2 mg/dL vs. 192 ± 14·23 mg/dL, P <0·02) and triglyceride (178 ± 9·20 mg/dL vs. 158 ± 14·51mg/dL, P < 0·05) concentrations in the rosiglitazone‐treated patients. What is new and conclusions: This study suggests significantly higher levels of serum sialic acid and other cardiovascular risk factors in rosiglitazone‐treated patients than in metformin‐treated patients. The lower sialic acid concentration may explain a better metformin antidiabetic effect than with rosiglitazone.     

Metformin-pioglitazone and metformin-rosiglitazone effects on non-conventional cardiovascular risk factors plasma level in type 2 diabetic patients with metabolic syndrome

BACKGROUND AND OBJECTIVE: Metformin is considered the gold standard for type 2 diabetes treatment as monotherapy and in combination with sulphonylureas and insulin. The combination of metformin with thiazolidinediones is less well studied. The aim of the present study was to assess the differential effect, and tolerability, of metformin combined with pioglitazone or rosiglitazone on glucose, coagulation and fibrinolysis parameters in patients with type 2 diabetes mellitus and metabolic syndrome. METHODS: This 12-month, multicentre, double-blind, randomized, controlled, parallel-group trial was conducted at three study sites in Italy. We assessed patients with type 2 diabetes mellitus (duration >or=6 months) and with metabolic syndrome. All patients were required to have poor glycaemic control with diet, or experienced adverse effects with diet and metformin, administered up to the maximum tolerated dose. Patients were randomized to receive either pioglitazone or rosiglitazone self-administered for 12 months. We assessed body mass index (BMI), glycaemic control [glycosylated haemoglobin (HbA(1c)), fasting and postprandial plasma glucose and insulin levels (FPG, PPG, FPI, and PPI respectively), 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)], lipoprotein (a) [Lp(a)] and homocysteine (HCT) at baseline and at 3, 6, 9 and 12 months of treatment. RESULTS AND DISCUSSION: No BMI change was observed at 3, 6, 9 and 12 months in either group. Significant HbA(1c) decreases were observed at 9 and 12 months in both groups. After 9 and 12 months, mean FPG and PPG levels decreased in both groups. Decreases in FPI and PPI were observed at 9 and 12 months compared with the baseline in both groups. Furthermore, in both groups, the HOMA index improved but only at 12 months. Significant TC, LDL-C, HDL-C, TG improvement was present in the pioglitazone group at 12 months compared with the baseline values, and these variations were significantly different between groups. No TC, LDL-C, TG improvement was present in the rosiglitazone group after 12 months. Significant Lp(a) and HCT improvement was present in the pioglitazone group at 12 months compared with the baseline values, and Lp(a) change was significant compared with the rosiglitazone group. Significant HCT decrease was observed in the rosiglitazone group at the end of the study. In our type 2 diabetic patients, both drugs were safe and effective for glycaemic control and improving HCT plasma levels. However, long-term treatment with metformin plus pioglitazone significantly reduced Lp(a) plasma levels, whereas metformin + rosiglitazone did not. CONCLUSION: For patients with type 2 diabetes mellitus and metabolic syndrome, combined treatment with metformin and rosiglitazone or pioglitazone is safe and effective, However, the pioglitazone combination also reduced the plasma Lp(a) levels whereas the rosiglitazone combination did not.     

高敏C反应蛋白在双胍类和磺脲类治疗后的糖尿病患者中的变化

目的探讨炎症因子高敏C反应蛋白(hs-CRP)在使用双胍类和磺脲类联合治疗12周后的2型糖尿病患者中的变化。方法采用免疫比浊法定量检测48例2型糖尿病患者治疗前后hs-CRP的水平,酶法检测空腹血糖(FBG)、血脂,高效液相法检测糖化血红蛋白(HbA1c),比较其治疗前后的变化。结果2型糖尿病患者治疗前后体质量指数(25.62±2.92)vs(25.09±2.98),腰围(85.73±8.66)cm vs(84.75±8.72)cm,FBG(7.92±1.43)mmol/L vs(5.96±1.31)mmol/L,总胆固醇(5.63±1.08)mmol/L vs(4.98±0.79)mmol/L,甘油三酯(2.19±2.09)mmol/L vs(1.58±0.96)mmol/L,低密度脂蛋白胆固醇(3.29±1.17)mmol/L vs(2.91±0.59)mmol/L,hs-CRP(1.66±0.93)mg/L vs(1.20±0.86)mg/L,HbA1c(7.29±1.26)%vs(6.79±0.96)%;上述指标治疗后较治疗前明显下降,其差异有统计学意义(均P<0.01)。结论2型糖尿病患者在血糖、体质量和腰围控制的同时hs-CRP水平降低,hs-CRP可作为临床医生治疗2型糖尿病及其血管并发症时疗效观察的监测指标之一。     

Metabolic effects of telmisartan and irbesartan in type 2 diabetic patients with metabolic syndrome treated with rosiglitazone

BACKGROUND AND OBJECTIVE: Angiotensin II receptor blockers represent a class of effective and well-tolerated orally active antihypertensive drugs in the general hypertensive population and in diabetic patients. The aim of our study was to investigate the metabolic effects of telmisartan and irbesartan in diabetic subjects treated with rosiglitazone. METHODS: We evaluated 188 type 2 diabetic patients with metabolic syndrome. All patients took a fixed dose of 4 mg rosiglitazone/day. We administered 40 mg telmisartan/day or 150 mg irbesartan/day and evaluated their body mass index, glycosylated haemoglobin (HbA(1c)), fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment-index (Homa-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, adiponectin and resistin during 12 months of this treatment. RESULTS AND DISCUSSION: In addition to a comparable antihypertensive effect for telmisartan and irbesartan after 6 and 12 months, both treatments were associated with a significant reduction in TC and LDL-C plasma levels compared with baseline. After 6 months of treatment, only the telmisartan group experienced a significant improvement in (HbA(1c)), FPG, Homa-IR, adiponectin and resistin compared with the baseline values, whereas both drug regimens were associated with a significant improvement in these parameters after 12 months. However, the improvements observed in the telmisartan group were significantly larger than that noted in the irbesartan group after 12 months of treatment. FPI significantly decreased only after 12 months of treatment in both groups, but again, the reduction was significantly larger in the telmisartan-treated subjects. CONCLUSIONS: Telmisartan seemed to improve glycaemic and lipid control and metabolic parameters of the metabolic syndrome better than irbesartan. These differences could be relevant in the choice of therapy for this condition and diabetes.     

Acarbose improves glycemic control in overweight type 2 diabetic patients insufficiently treated with metformin

OBJECTIVE: To investigate the efficacy and safety of acarbose as add-on therapy in overweight type 2 patients with diabetes inadequately controlled by metformin. RESEARCH DESIGN AND METHODS: This study adopted a multicenter, randomized, double-blind, placebo-controlled, parallel group design. After a 4-week placebo run-in period, subjects were randomized to either acarbose (titrated up to 100 mg b.i.d.) or placebo. The primary efficacy variable was the change in HbA(1c) from baseline to the end of the 24-week treatment period. Change in fasting blood glucose was assessed as a secondary efficacy parameter. RESULTS: The intention-to-treat analysis from baseline to week 24 (81 patients for HbA(1c) and 82 for fasting blood glucose) showed statistically significant differences between acarbose and placebo treatment in HbA(1c) (1.02%; 95% CI 0.543-1.497; P = 0.0001) and fasting blood glucose (1.132 mmol/l; 95% CI 0.056-2.208; P = 0.0395) (adjusted least square means). In all, 18 patients (47%) in the acarbose group were classified as responders with a > or =5% reduction in HbA(1c) (relative to baseline) at the end point compared to 6 (14%) in the placebo group (P = 0.001). The safety profiles were similar for both treatment groups except for the higher incidence of gastrointestinal side effects during acarbose therapy. CONCLUSIONS: The addition of acarbose to metformin monotherapy provides an efficacious and safe alternative for glycemic improvement in overweight type 2 patients inadequately controlled by metformin alone.     

Efficacy of low-dose metformin in Japanese patients with type 2 diabetes mellitus

The goal of this study was to examine the antihyperglycemic effect of low-dose metformin in nonobese and obese Japanese patients with type 2 diabetes mellitus. After 3 months of reeducation and stabilization of diet therapy (25 kcal/kg of ideal body weight), metformin treatment was initiated. We administered metformin (500 to 750 mg daily) as monotherapy (n = 11) or in combination with a sulfonylurea (n = 14). After 6 months of treatment, the fasting plasma glucose level (mean ± SD) decreased from 190 ± 42 mg/dL to 155 ± 37 mg/dL and the glycated hemoglobin A_1c level (mean ± SD) from 8.8 ± 1.2% to 7.4 ± 1.0% in the monotherapy group. These same variables decreased from 218 ± 60 mg/dL to 162 ± 30 mg/dL and from 9.5 ± 1.2% to 8.4 ± 1.2% in the combination therapy group. All of these changes were statistically significant. Our results demonstrate that even low doses of metformin can improve hyperglycemia in Japanese patients with type 2 diabetes mellitus.     

复方醋酸环丙孕酮联合二甲双胍治疗多囊卵巢综合征的疗效及对内分泌代谢的影响

目的探讨复方醋酸环丙孕酮联合二甲双胍治疗多囊卵巢综合征（PCOS）的疗效及其对内分泌与代谢的影响。方法将该院2011年12月至2012年12月收治的72例PCOS患者按照1∶1比例随机分为2组,每组各36例,对照组单纯给予复方醋酸环丙孕酮治疗,观察组在对照组基础上联合二甲双胍治疗,并对2组患者的相关指标进行统计学分析。结果治疗后2组患者多毛评分、痤疮评分、卵巢体积均较治疗前改善（P〈0.05）;但观察组改善程度较对照组显著,差异有统计学意义（P〈0.05）;治疗后观察组患者黄体生成素（LH）、卵泡刺激素（FSH）、黄体生成素/卵泡刺激素比值（LH/FSH）、雌二醇（E2）、总睾酮（T）、硫酸脱氢表雄酮（DHEAS）、性激素结合球蛋白（SHBG）各项指标变化幅度均优于对照组（P〈0.05）;观察组治疗后空腹胰岛素（FINS）、低密度脂蛋白（LDL）显著降低（P〈0.05）,总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白（HDL）显著上升（P〈0.05）;LDL、TC、HDL各指标变化优于对照组,差异均有统计学意义（P〈0.05）。结论复方醋酸环丙孕酮联合二甲双胍在PCOS的治疗上有显著优势,可明显改善患者的内分泌及代谢功能,且临床疗效及安全性均较好。     

Cardiovascular effects of treatment of type 2 diabetes with pioglitazone, metformin and gliclazide

Cardiovascular mortality and morbidity are increased in patients with type 2 diabetes. However, there are few data from clinical trials comparing cardiovascular effects of alternative oral anti-diabetic agents. Major cardiovascular outcomes during four one-year, double-blind trials in over 3700 patients with type 2 diabetes randomised to either a thiazolidinedione, pioglitazone, metformin or a sulphonylurea, gliclazide treatment have been combined. Mean blood pressure was slightly reduced by all treatments, with pioglitazone treatment resulting in the largest falls (approximately 1.5 mmHg). Hospitalisations for cardiac or cerebrovascular events were similar with the different treatments. Overall mortality was seven of 1857 for pioglitazone and 10 of 1856 for non-pioglitazone treatments, of which three and six were cardiac deaths, respectively. The incidence of congestive cardiac failure was similar with pioglitazone (12/1857) and non-pioglitazone (10/1856) treatments. The results show similar cardiovascular outcome for the three different treatments over a one-year period, but demonstrate interesting differences, which will require longer-term formal outcome studies to determine their significance.     

Forearm vascular reactivity is differentially influenced by gliclazide and glibenclamide in chronically treated type 2 diabetic patients

Sulphonylureas (SUs) act by inhibition of beta-cell K(ATP) channels after binding to the sulphonylurea receptor SUR1. K(ATP) channels are also expressed in cardiac and vascular myocytes coupled to SUR2A and SUR2B involved into adaptations of vascular tone and myocardial contractility. Different influence of SUs on vascular function is based on different binding to the SUR family. Few data on the effect of different SUs, used in patients in therapeutic doses, on vascular function are currently available. We investigated possible effects of acute and chronic treatment with glibenclamide and gliclazide on forearm postischaemic reactive hyperaemia (RH) in type 2 diabetic patients. To that purpose a double-blind, randomized, cross-over study with gliclazide (80 mg, b.i.d.) and glibenclamide (5 mg, b.i.d.) was performed in 15 type 2 diabetic patients. Forearm vascular reactivity was measured after 5 min of ischaemia by plethysmography before and after 4 weeks treatment. After acute administration of gliclazide (80 mg) or glibenclamide (5 mg) RH was not influenced. After 4 weeks of treatment, no influence of either drug was seen in the steady state before dosing. After dosing glibenclamide induced a significant (P = 0.004) reduction of RH from 26.4 +/- 6.9 to 21.9 +/- 7.6 ml min(-1)/100 ml after 4 h. Gliclazide, conversely, did not induce a reduction of RH (23.9 +/- 6.0 to 23.3 +/- 6.6 ml min(-1)/100 ml). No influence of HbA1c or actual glycaemia on RH was observed. Our results indicate that in chronically treated patients with type 2 diabetes ingestion of glibenclamide but not gliclazide results in sustained reduction of postischaemic RH. This difference is most probably based on different SUR binding.     

艾塞那肽联合二甲双胍治疗口服降糖药控制不佳的2型糖尿病疗效观察

目的观察艾塞那肽联合二甲双胍治疗对口服降糖药(OAD)控制不佳的2型糖尿病(T2DM)患者的临床疗效。方法 31例既往使用OAD控制不佳的T2DM患者,改用艾塞那肽联合二甲双胍治疗3个月,观察治疗前后空腹血糖(FPG)、餐后2h血糖(2hPG)、糖化血红蛋白(HbA1c)、体重、体质指数(BMI)、C-肽(空腹及餐后2h)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)的变化。结果治疗后FPG、2hPG、HbA1c、体重、BMI、TC、TG、LDL-C均有明显下降(P均<0.01)。C-肽(空腹及餐后2h)未发现明显变化(P>0.05)。低血糖发生率为3.23%。结论艾塞那肽联合二甲双胍能有效地控制T2DM患者的血糖,减轻体重,且发生低血糖的风险低。     

甘精胰岛素联合二甲双胍治疗2型糖尿病患者的疗效评价

目的探讨甘精胰岛素联合二甲双胍治疗2型糖尿病的临床疗效。方法选择本院收治的2型糖尿病患者100例,其中观察组50例患者采用甘精胰岛素联合二甲双胍进行治疗,对照组50例患者仅口服二甲双胍,比较2组患者的治疗效果。结果治疗后,观察组患者的血糖达标时间、平均空腹血糖、夜间低血糖发生率等指标均明显优于对照组患者,差异有统计学意义(P<0.05);观察组患者的空腹血糖(FBG)、空腹2 h血糖(2hPG)、糖化血红蛋白(HbAlc)等指标的改善情况也明显优于对照组,差异有统计学意义(P<0.05)。结论采用甘精胰岛素联合二甲双胍治疗2型糖尿病疗效显著。     

阿格列汀对经二甲双胍治疗的肥胖2型糖尿病患者外周血氧化相关物质活性的影响

目的探讨阿格列汀对经二甲双胍治疗的肥胖2型糖尿病患者外周血清氧化相关物质活性的影响,并评估该方案的有效性与安全性。方法选取肥胖的2型糖尿病患者200例(均为二甲双胍单药控制不佳),随机分为观察组(100例)和对照组(100例)。对照组患者采用二甲双胍(1 000mg bid,po)治疗,观察组使用二甲双胍(500mg bid,po)联合阿格列汀(25mg qd,po)治疗。2组患者规范治疗24周,比较2组治疗前后外周血超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、活性氧类物质(ROS)活性以及丙二醛(MDA)浓度、体质量指数(BMI)、腰围、糖化血红蛋白(HbA1c)、空腹血糖(FBG)、餐后2h血糖(2hPBG)的变化情况。结果治疗后,2组患者ROS、MDA、FBG、2hPBG、HbA1c、BMI、腰围均较治疗前降低,差异有统计学意义(P0.05)。治疗后观察组患者各指标明显低于对照组,差异有统计学意义(P0.05);2组治疗后SOD、GSH-Px活性较治疗前升高,差异有统计学意义(P0.05),治疗后观察组患者各指标明显高于对照组,差异有统计学意义(P0.05)。结论阿格列汀联合二甲双胍可有效纠正肥胖2型糖尿病患者的外周血氧化与抗氧化物质的失衡,同时能降低患者BMI、腰围等指标,且不增加低血糖风险,具有临床价值。     

A randomized trial of sibutramine in the management of obese type 2 diabetic patients treated with metformin

OBJECTIVE: To evaluate the effects of sibutramine (15 and 20 mg/day) on weight, metabolic control, and blood pressure in metformin-treated obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: A 12-month randomized prospective placebo-controlled double-blind study was performed. It included 21 primary and secondary care centers in England, Canada, France, and Belgium. A total of 195 subjects (44% male) with type 2 diabetes and a BMI >27 kg/m(2) were studied. Changes were assessed in weight, blood pressure and resting heart rate, HbA(1c), fasting glucose, and lipids. RESULTS: Sibutramine induced significant weight loss (P < 0.001) with both 15 mg/day (5.5 +/- 0.6 kg at 12 months) and 20 mg/day (8.0 +/- 0.9 kg), whereas placebo did not (0.2 +/- 0.5 kg). Weight loss > or = 10% was achieved by 14 and 27% of subjects receiving 15 and 20 mg, respectively, but by none given placebo. Glycemic control improved in parallel with weight loss, and subjects who lost > or = 10% weight showed significant decreases in both HbA(1c) (1.2 +/- 0.4%, P < 0.0001) and fasting plasma glucose (1.8 mmol/l, P < 0.001). HDL cholesterol increased slightly with the higher dose, whereas plasma triglycerides fell with both doses, especially in subjects with weight loss of > or = 10% (a 29% decrease, P < 0.01). Treatment was generally well tolerated. Sibutramine treatment raised sitting diastolic blood pressure by > or = 5 mmHg in a higher proportion of patients than did placebo (43% with 15 mg/day vs. 25% with placebo, P < 0.05), but this effect was less evident in subjects who had a weight loss of > or = 10% weight. Pulse rate increased significantly more with sibutramine, being > or = 10 bpm higher in 42% of treated patients versus 17% with placebo (P < 0.01). CONCLUSIONS: Sibutramine can be an effective adjunct to metformin treatment in selected obese type 2 diabetic subjects and improves metabolic control in individuals who lose weight.     

Linagliptin plus metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycemia

Objectives: Few studies of oral glucose-lowering drugs exist in newly diagnosed type 2 diabetes (T2D) patients with marked hyperglycemia, and insulin is often proposed as initial treatment. We evaluated the oral initial combination of metformin and linagliptin, a dipeptidyl peptidase-4 inhibitor, in this population.

Methods: We performed a pre-specified subgroup analysis of a randomized study in which newly diagnosed T2D patients with glycated hemoglobin A1c (HbA1c) 8.5%–12.0% received linagliptin/metformin or linagliptin monotherapy. Subgroups of baseline HbA1c, age, body-mass index (BMI), renal function, race, and ethnicity were evaluated, with efficacy measured by HbA1c change from baseline after 24 weeks.

Results: HbA1c reductions from baseline (mean 9.7%) at week 24 in the overall population were an adjusted mean ?2.81% ± 0.12% with linagliptin/metformin (n = 132) and ?2.02% ± 0.13% with linagliptin (n = 113); treatment difference ?0.79% (95% CI ?1.13 to ?0.46, P < 0.0001). In patients with baseline HbA1c ≥9.5%, HbA1c reduction was ?3.37% with linagliptin/metformin (n = 76) and ?2.53% with linagliptin (n = 61); difference ?0.84% (95% CI ?1.32 to ?0.35). In those with baseline HbA1c <9.5%, HbA1c reduction was ?2.08% with linagliptin/metformin (n = 56) and ?1.39% with linagliptin (n = 52); difference ?0.69% (95% CI ?1.23 to ?0.15). Changes in HbA1c and treatment differences between the linagliptin/metformin and linagliptin groups were of similar magnitudes to the overall population across patient subgroups based on age, BMI, renal function, and race. Drug-related adverse events occurred in 8.8% and 5.7% of linagliptin/metformin and linagliptin patients, respectively; no severe hypoglycemia occurred.

Conclusion: Linagliptin/metformin combination in newly diagnosed T2D patients with marked hyperglycemia was well tolerated and elicited substantial improvements in glycemic control regardless of baseline HbA1c, age, BMI, renal function, or race. Thus, newly diagnosed, markedly hyperglycemic patients may be effectively treated by combinations of oral agents.

Clinical trial registration: www.clinicaltrials.gov identifier is NCT01512979