The role of metformin and thiazolidinediones in the regulation of hepatic glucose metabolism and its clinical impact

Fasting hyperglycemia in type 2 diabetes mellitus (T2DM) results from elevated endogenous glucose production (EGP), which is mostly due to augmented hepatic gluconeogenesis. Insulin-resistant humans exhibit impaired insulin-dependent suppression of EGP and excessive hepatic lipid storage (steatosis), which relates to abnormal supply of free fatty acids (FFA) and energy metabolism. Only two glucose-lowering drug classes, the biguanide metformin and the thiazolidendiones (TZDs), exert insulin- and glucagon-independent hepatic effects. Preclinical studies suggest that metformin inhibits mitochondrial complex I. TZDs, as peroxisome proliferator-activated receptor (PPAR) γ-agonists, predominantly reduce the flux of FFA and cytokines from adipose tissue to the liver, but could also directly inhibit mitochondrial complex I. Although both metformin and TZDs improve fasting hyperglycemia and EGP in clinical trials, only TZDs decrease steatosis and peripheral insulin resistance. More studies are required to address their effects on hepatocellular energy metabolism with a view to identifying novel targets for the treatment of T2DM.     

The protective effect of silk fibroin on high glucose induced insulin resistance in HepG2 cells

The therapeutic use of silk-derived materials such as fibroin in biomedicine is well-established in Southeast Asian countries. Studies indicated that silk fibroin (SF) peptide enhances insulin sensitivity and glucose metabolism phenomena associated with type 2 diabetes mellitus (T2DM) suggesting this peptide may be beneficial to treat this disease. However, the mechanisms underlying protective effect of SF in insulin-mediated hepatic metabolic dysfunction remains unclear. The aim of this study was to investigate the influence of SF on insulin resistant HepG2 cells which were used a model of T2DM. Treatment of cells with 30 mmol/L of glucose and 10⁻⁶ mol/L insulin for 48 h significantly reduced glucose consumptions and intracellular glycogen levels but increased triglyceride (TG) levels. SF or metformin alone elevated glucose consumptions and glycogen accumulation accompanied by lower TG content. Greater effects in these metabolic parameters were found when SF and metformin were combined. Treatment of insulin resistant cells with SF or metformin alone decreased levels of reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor (TNF-α) and interleukin-6 (IL-6); whereas antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) activity, as well as total antioxidant capacity (T-AOC) ability increased. The combination of SF and metformin produced greater changes in these parameters compared to metformin alone. Data indicated that the protective effect of SF or metformin in insulin resistant HepG2 cells involves inhibition of oxidant processes and that the combination of agents may prove more effective therapeutically.     

Rationale and design of a prospective clinical trial program to evaluate the glucose-lowering effects of colesevelam HCl in patients with type 2 diabetes mellitus

ABSTRACT

Background: Dyslipidemia and type 2 diabetes mellitus (T2DM) increase atherosclerotic coronary heart disease (CHD) risk. In patients with T2DM, improving lipid parameters reduces CHD risk, while optimizing glucose levels reduces microvascular complications and, possibly, macrovascular disease such as CHD. Unfortunately, many patients with T2DM do not achieve either lipid or glucose treatment targets.

Objective: Colesevelam HCl is a specifically engineered bile-acid sequestrant (BAS) indicated to reduce elevated low-density lipoprotein cholesterol concentrations. Earlier studies have demonstrated that BAS not only reduce cholesterol levels, but also lower glucose levels in patients with T2DM. These findings have prompted a robust, prospective phase 3 clinical trial program to further evaluate the safety and tolerability of colesevelam HCl when added to T2DM patients previously treated with metformin, insulin or a sulfonylurea. A limitation of these clinical trials is that none of them assessed colesevelam HCI monotherapy, nor directly compared the glucose-lowering effects of colesevelam HCI to established oral antidiabetes drugs. Nonetheless, this clinical trial program will better determine whether a single agent added to existing diabetes therapy can improve both lipid and glucose parameters in T2DM, which may allow more patients to achieve lipid and glucose treatment targets.

Conclusions: This phase 3 clinical trial program will evaluate colesevelam's glucose-lowering effects in patients with T2DM. In addition, based upon a review of the relevant medical literature through an online electronic PubMed search (without restriction to date other than otherwise occurs through PubMed), potential mechanisms as to how BAS may lower glucose levels are discussed.     

Rationale and design of a clinical trial to evaluate metformin and colesevelam HCl as first-line therapy in type 2 diabetes and colesevelam HCl in prediabetes

ABSTRACT

Objective: The complications of type 2 diabetes mellitus (DM) can begin early in the progression from impaired glucose tolerance to type 2 DM. Metformin is recommended as initial drug therapy for managing hyperglycemia in type 2 DM. The bile acid sequestrant colesevelam hydrochloride (HCl) is approved in the United States for glycemic control in adults with type 2 DM. Colesevelam HCl improves glycemic control and reduces low-density lipoprotein-cholesterol in patients inadequately controlled on metformin-, sulfonylurea-, or insulin-based therapy. This trial is designed to evaluate whether initial therapy with metformin?+?colesevelam HCl provides greater glucose control and additional lipid and lipoprotein benefits, as compared to metformin alone in drug-naïve patients with type 2 DM, and whether treatment with colesevelam HCl has a beneficial effect on lipid and glucose levels in drug-naïve patients with impaired glucose tolerance and/or impaired fasting glucose (prediabetes).

Research design and methods: In this multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, drug-naïve patients with type 2 DM will be randomized 1?:?1 to metformin?+?colesevelam HCl or metformin?+?matching placebo, while those with prediabetes will be randomized 1?:?1 to colesevelam HCl or placebo, for 16 weeks of treatment. The primary efficacy endpoint will be change in glycosylated hemoglobin (HbA_1c) in patients with type 2 DM and change in low-density lipoprotein-cholesterol levels in patients with prediabetes.

Conclusion: A potential limitation is that there is no direct comparator for the dual glucose- and lipid-lowering effect of colesevelam HCl in the prediabetes cohort. However, results of this trial will help to define the extent to which colesevelam HCl can help improve cardiometabolic risk factors for complications of type 2 DM in the first-line environment, and will also indicate the extent to which early intervention with colesevelam HCl can help to correct metabolic abnormalities associated with prediabetes.     

Combination therapy of sodium–glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors in type 2 diabetes: rationale and evidences

No single antidiabetic agent can correct all the pathophysiologic defects manifested in type 2 diabetes mellitus (T2DM) and, therefore, multiple agents are often required to achieve optimal glycemic control. Combination therapies, having different mechanisms of action, not only have the potential to complement their action, but may possess the properties to counter the undesired compensatory response. Recent finding suggests that sodium–glucose co-transporter-2 inhibitors (SGLT2i) increase endogenous glucose production (EGP) from liver, due to the increase in glucagon which may offset its glucose-lowering potential. In contrast, dipeptidyl peptidase-4 inhibitors (DPP4i) decrease glucagon and EGP. Especially in the light of this finding, combination therapies with SGLT2i and DPP4i are particularly appealing, and are expected to produce an additive effect. Indeed, studies find no drug–drug interaction between SGLT2i and DPP4i. Moreover, significant reduction in glycated hemoglobin has also been observed. This article aims to review the efficacy and safety of combination therapy of SGLT2i and DPP4i in T2DM.     

The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms

Metformin is regarded as an antihyperglycaemic agent because it lowers blood glucose concentrations in type 2 (non-insulin-dependent) diabetes without causing overt hypoglycaemia. Its clinical efficacy requires the presence of insulin and involves several therapeutic effects. Of these effects, some are mediated via increased insulin action, and some are not directly insulin dependent. Metformin acts on the liver to suppress gluconeogenesis mainly by potentiating the effect of insulin, reducing hepatic extraction of certain substrates (e.g. lactate) and opposing the effects of glucagon. In addition, metformin can reduce the overall rate of glycogenolysis and decrease the activity of hepatic glucose-6-phosphatase. Insulin-stimulated glucose uptake into skeletal muscle is enhanced by metformin. This has been attributed in part to increased movement of insulin-sensitive glucose transporters into the cell membrane. Metformin also appears to increase the functional properties of insulin- and glucose-sensitive transporters. The increased cellular uptake of glucose is associated with increased glycogen synthase activity and glycogen storage. Other effects involved in the blood glucose-lowering effect of metformin include an insulin-independent suppression of fatty acid oxidation and a reduction in hypertriglyceridaemia. These effects reduce the energy supply for gluconeogenesis and serve to balance the glucose-fatty acid (Randle) cycle. Increased glucose turnover, particularly in the splanchnic bed, may also contribute to the blood glucose-lowering capability of metformin. Metformin improves insulin sensitivity by increasing insulin-mediated insulin receptor tyrosine kinase activity, which activates post-receptor insulin signalling pathways. Some other effects of metformin may result from changes in membrane fluidity in hyperglycaemic states. Metformin therefore improves hepatic and peripheral sensitivity to insulin, with both direct and indirect effects on liver and muscle. It also exerts effects that are independent of insulin but cannot substitute for this hormone. These effects collectively reduce insulin resistance and glucotoxicity in type 2 diabetes.     

Metformin + saxagliptin for type 2 diabetes

INTRODUCTION: Metformin is considered as the first-line drug therapy for the management of type 2 diabetes. Dipeptidyl peptidase-4 (DPP-4) inhibitors, by promoting insulin secretion and reducing glucagon secretion in a glucose-dependent manner, offer new opportunities for oral therapy after failure of metformin. AREAS COVERED: An updated review of the literature demonstrates that saxagliptin, a DPP-4 inhibitor, and metformin may be administered together, separately or in fixed-dose combination (FDC), either as saxagliptin added to metformin or as initial combination in drug-naive patients. Both compounds exert complementary pharmacodynamic actions leading to better improvement in blood glucose control (fasting plasma glucose, postprandial glucose, HbA1c) than either compound separately. Adding saxagliptin to metformin monthotherapy results in a consistent, sustained and safe reduction in HbA1c levels. Tolerance is excellent without hypoglycemia or weight gain. EXPERT OPINION: The combination saxaglitpin plus metformin may be used as first-line or second-line therapy in the management of type 2 diabetes, especially as a valuable alternative to the classical metformin-sulfonylurea combination.     

Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus

Diabetes mellitus and depressive disorders are both common chronic diseases that increase functional disability and social burden. Cognitive impairment is a potentially debilitating feature of depression. Previous evidence indicates that the antidiabetic drug metformin could be suitable for diabetic patients with cognitive impairment. However, there is no direct evidence from clinical studies that metformin treatment improves cognitive function in diabetic patients suffering from depression. In the present study, 58 participants diagnosed with depression and type 2 diabetes mellitus (T2DM) were recruited and divided into two groups, one treated with metformin and the other treated with placebo for 24 weeks. Cognitive function, depressive behaviour and diabetes improvement were evaluated. Chronic treatment with metformin for 24 weeks improved cognitive performance, as assessed by the Wechsler Memory Scale–Revised, in depressed patients with T2DM. In addition, metformin significantly improved depressive performance and changed the glucose metabolism in depressed patients with diabetes. Depressive symptoms were negatively correlated with cognitive performance in metformin‐treated participants. Furthermore, associations were observed between the parameters of blood glucose metabolism and the depression phenotype. These findings suggest that chronic treatment with metformin has antidepressant behavioural effects and that improved cognitive function is involved in the therapeutic outcome of metformin. The results of the present study also raise the possibility that supplementary administration of antidiabetic medications may enhance the recovery of depression, comorbid with T2DM, through improvements in cognitive performance.     

Troglitazone prevents and reverses dexamethasone induced insulin resistance on glycogen synthesis in 3T3 adipocytes

Troglitazone lowers blood glucose levels in Type II diabetic patients. To evaluate the insulin sensitizing action of troglitazone on glycogen synthesis we have used dexamethasone-treated 3T3 adipocytes as an in vitro model. Differentiated 3T3 adipocytes were incubated with 100 nM dexamethasone for 6 days. Troglitazone (1.0 microM) or metformin (1.0 mM) with or without 200 nM insulin was added during the last 4 days. At the end, insulin (100 nM) stimulated glycogen synthesis was determined using (14)C-glucose. Dexamethasone caused a 50% reduction in glycogen synthesis. Troglitazone caused an approximately 3 fold increase in glycogen synthesis from 43.9+/-3.4 to 120+/-16.2 nmols h(-1). Under identical conditions metformin had no significant effect. When cells were incubated with troglitazone and dexamethasone simultaneously for 6 days, troglitazone but not metformin completely prevented dexamethasone-induced insulin resistance. RU 486 (1.0 microM) also completely prevented the insulin resistance. Chronic incubation with dexamethasone and insulin resulted in a 73% reduction in glycogen synthesis. In these adipocytes, troglitazone was partially active with glycogen synthesis rising from 23.1+/-3.0 to 44.4+/-4.5 nmol h(-1), P<0.01 while metformin was inactive. Troglitazone stimulated 2-deoxyglucose uptake by 2 - 3 fold in dexamethasone-treated adipocytes. Metformin also increased glucose uptake significantly. Troglitazone did not affect insulin binding while a 2 fold increase was observed in normal adipocytes where it exhibited a modest effect. Since the effect of troglitazone was greater in dexamethasone-treated adipocytes, troglitazone is likely to act by preventing dexamethasone-induced alterations which may include (i) binding to glucocorticoid receptor and (ii) effect on glucose uptake. These data demonstrate the direct insulin sensitizing action of troglitazone on glycogen synthesis and suggest a pharmacological profile different from metformin.     

甘精胰岛素联合口服降糖药治疗糖尿病的疗效

目的：探讨首次诊断2型糖尿病患者应用甘精胰岛素联合口服降糖药物治疗的疗效。方法：45例初发的2型糖尿病患者分别应用甘精胰岛素联合二甲双胍或阿卡波糖治疗3个月，比较两组治疗前后空腹血糖、餐后血糖、糖化血红蛋白（HbA1c）、低血糖发生率。结果：两组治疗后血糖和HbA1c均下降，与治疗前比较有统计学差异；治疗后血糖、HbA1c和低血糖发生率，两组间比较无统计学差异。结论：对于初发2型糖尿病患者，应用甘精胰岛素联合二甲双胍或阿卡波糖均可良好控制血糖，且低血糖发生率较低。     

Tofogliflozin: the road goes ever on

Several drugs are available for the treatment of type 2 diabetes mellitus (T2DM), but few patients achieve and maintain glycaemic control without weight gain and hypoglycaemias. Sodium glucose co-transporter 2 (SGLT-2) inhibitors are an emerging class of drugs with an original mechanism of action involving inhibition of renal glucose reabsorption. Two agents of this class, dapagliflozin and canagliflozin, have already been approved, although we need more data on cardiovascular outcomes along with bladder and breast cancer. Tofogliflozin is a further SGLT-2 inhibitor, which exhibits the highest selectivity for SGLT-2, the most potent antidiabetic action and a reduced risk of hypoglycaemia. Recently, a 52-week, multicentre, open-label, randomised controlled trial in Japanese T2DM patients has shown that tofogliflozin exhibits adequate safety and efficacy as monotherapy or as add-on treatment in patients suboptimally controlled with oral agents. Despite the very promising characteristics of this new drug, important questions remain to be answered, mainly additional data on safety outcomes and potential beneficial effects of tofogliflozin, for instance in prediabetes and diabetic nephropathy. Moreover, it would be welcome to examine the utility of its therapeutic use in combination with insulin and metformin.     

中药仙灵脾对2型糖尿病大鼠炎症因子的影响

目的:评价中药仙灵脾对2型糖尿病大鼠炎症因子的影响。方法:雄性Wistar大鼠70只,从中随机选取10只为正常对照组,其余应用高糖高脂饲料喂养及链脲佐菌素腹腔注射造模,成模2型糖尿病大鼠共44只按血糖值随机分组:糖尿病(DM)模型对照组(16只)、仙灵脾组(16只)、二甲双胍组(12只),各组共相应给药8周,治疗前后取血测量血糖(FBG)、C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)、白细胞介素6(IL-6)。结果:成模2型糖尿病各组大鼠FBG,CRP,TNF-α,IL-6水平均较正常对照组大鼠明显增高(P<0.01)。应用仙灵脾及二甲双胍治疗的两组大鼠的FBG,CRP,TNF-α,IL-6水平均较DM模型对照组显著下降(P<0.05),但两治疗组比较差别无统计学意义(P>0.05)。结论:中药仙灵脾治疗2型糖尿病大鼠可降低炎症因子水平,抑制体内炎症反应。     

胰岛素联合二甲双胍或优降糖治疗2型糖尿病的疗效比较

目的探讨胰岛素联合二甲双胍或优降糖对单一磺酰脲类药物治疗失效的2型糖尿病的临床疗效。方法80例患者随机分为2组，均采用胰岛素治疗，一组加服二甲双胍，一组加服优降糖，观察治疗12周前后空腹血糖（FPG）、餐后2小时血糖（2hPG）、糖化血红蛋白（HbA1C）、体重指数（BMI）、血甘油三酯（TG）、总胆固醇（TC）、低密度脂蛋白（LDL-C）及高密度脂蛋白（HDL-C）的变化。结果两组FPG、2hPG、HbA1C均较治疗前明显下降，优降糖组BMI增高明显，二甲双胍组TG、TC、LDL-C降低有统计学差异。结论2组均能很好控制血糖，但联合二甲双胍在纠正血脂紊乱，避免体重增加等不良反应方面较联合优降糖更佳。     

二甲双胍对骨代谢的影响

二甲双胍（metformin）是2型糖尿病患者的一线用药,在50余年的临床应用中,已显示出安全、有效、全面控制血糖的效果。近年越来越多的研究发现,二甲双胍促进体外成骨细胞的增殖、分化及细胞外基质矿化,逆转高浓度葡萄糖对成骨细胞功能的损伤,抑制破骨细胞的形成;动物研究进一步证实二甲双胍增加鼠的骨矿含量以及松质骨容量,促进新骨形成,促进正常血糖大鼠及糖尿病大鼠的骨损伤修复;临床研究也发现二甲双胍影响糖尿病患者骨密度,但其对骨代谢的影响以及机制尚未完全阐明。本文综述了二甲双胍对骨代谢的影响,并探讨其可能的作用机制。     

Defining the Role of Repaglinide in the Management of Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia due to a combination of insulin resistance and impaired insulin secretion. The hyperglycemia is associated with an increased risk for micro- and macrovascular complications, and lowering fasting and postprandial hyperglycemia may be protective against these complications. Repaglinide is an insulin secretagogue that lowers blood glucose levels in patients with T2DM. We review the effects of repaglinide in patients with T2DM, its impact on glycemia and its non-glycemic effects, and its effects when used in special situations or patient populations. Results from randomized controlled trials, observational studies, and safety reports involving humans and published in the English-language through 1 May 2007 identified by a search in PubMed/MEDLINE were evaluated. Present knowledge indicates that repaglinide reduces fasting and postprandial hyperglycemia and the level of glycosylated hemoglobin (HbA1c) in patients with T2DM. It is at least as effective in reducing HbA1c and fasting plasma glucose as sulphonylureas, metformin, or the glitazones and in combination therapy with other drugs, repaglinide is as effective as any other combination. Some studies show a better effect of repaglinide on postprandial glycemia than the comparators. Its propensity to induce hypoglycemia is similar to or a little less than that of sulphonylureas. Repaglinide is associated with less weight gain than sulphonylureas and the glitazones. Repaglinide has primarily a role in the treatment of T2DM when metformin cannot be used due to adverse effects, when metformin fails to adequately control blood glucose levels, when there is a need for flexible dosing (i.e. the elderly or during Ramadan fasting), or when there is a specific wish to lower postprandial glucose. Repaglinide may also have an advantage when an oral agent is needed in diabetic patients with renal impairment. Because of its short duration of action, repaglinide should be taken before each meal, usually at least three times a day. Although no study has investigated whether repaglinide lowers total mortality or cardiovascular endpoints, several studies indicate beneficial effects on cardiovascular surrogate endpoints, such as carotid intima-media thickening, markers of inflammation, platelet activation, lipid parameters, endothelial function, adiponectin, and oxidative stress. In conclusion, repaglinide is a compound that can be used in both mono- and combination therapy for the treatment of both fasting and postprandial hyperglycemia in patients with T2DM. It can be used in patients at different stages of the disease, from uncomplicated to severe renal impairment. Although the drug has been tested in a large number of clinical trials and observational studies, its world-wide use is far less than, for example, sulphonylureas. Repaglinide may offer an additional potential for lowering blood glucose levels in T2DM that until now has not been fully realized by many clinicians.     

二甲双胍联合西格列汀或吡格列酮对肥胖型2型糖尿病的疗效比较

目的：比较西格列汀与吡格列酮分别联用二甲双胍治疗二甲双胍单药控制不佳的肥胖型2型糖尿病的疗效。方法：60例2型糖尿病肥胖患者在服用二甲双胍片的前提下,随机分为西格列汀组（n=30）和吡格列酮组（n=30）,分别给予西格列汀片与吡格列酮片口服,检测入组时和治疗12周后两组糖化血红蛋白、空腹及餐后血糖水平、低血糖例数、体重指数等数据。结果：治疗12周后,西格列汀组患者的糖化血红蛋白、空腹及餐后血糖、体重指数均比吡格列酮组改善明显,两组均无低血糖发生。结论：西格列汀联用二甲双胍片治疗肥胖型2型糖尿病的疗效优于吡格列酮片联用二甲双胍片。     

Rosiglitazone maleate/metformin hydrochloride: a new formulation therapy for type 2 diabetes

Many patients with type 2 diabetes require treatment with more than one antihyperglycemic drug to achieve optimal glycemic control. The thiazolidinediones are a novel class of oral antihyperglycemic drugs that improve glycemic control primarily by increasing peripheral insulin resistance and sensitizing the skeletal muscle, liver and adipose tissue to the actions of insulin, in addition to improving beta-cell function. One of the many features of the thiazolidinedione class of drugs is their synergism with other antihyperglycemic drugs that have a different mechanism of action. The combination of metformin hydrochloride, a biguanide that enhances glucose uptake in peripheral tissues and reduces hepatic gluconeogenesis, with rosiglitazone maleate, one of the newly available members of the thiazolidinedione family, offers a rational therapeutic approach to the treatment of type 2 diabetes. In patients whose type 2 diabetes is inadequately controlled with metformin monotherapy, the addition of rosiglitazone significantly improves glycemic control, insulin sensitivity and beta-cell function, compared with either drug alone. In addition, this combination therapy has beneficial effects on other cardiovascular risk factors. Rosiglitazone maleate/metformin hydrochloride combination therapy is well tolerated in patients with type 2 diabetes and has a favorable safety profile. This review summarizes the available evidence on the clinical efficacy and safety of rosiglitazone maleate and metformin hydrochloride combination therapy in patients with type 2 diabetes.     

Antihyperglycemic Medications and Impact on Cardiovascular Outcomes: A Review of Current Evidence

Patients with type 2 diabetes mellitus (DM) are known to be at an increased risk for macrovascular complications, and cardiovascular disease (CVD) is one of the greatest drivers of morbidity and mortality in this patient population. Over the past decade, the number of treatment options for type 2 DM has increased. In 2008, the United States Food and Drug Administration mandated an evaluation of cardiovascular (CV) outcomes associated with antihyperglycemic agents. Since that time, the CV risk‐benefit profile of many antihyperglycemic treatment modalities have been evaluated; however, results have remained inconsistent. This article will review the literature on the use of pharmacologic therapies in patients with type 2 DM and associated CVD risk, as well as provide recommendations for appropriate treatment selection in this population. Current evidence has demonstrated CV benefits with metformin, select glucagon‐like peptide‐1 receptor agonists (liraglutide), and sodium‐glucose co‐transporter 2 inhibitors (canagliflozin and empagliflozin).     

那格列奈或联用二甲双胍对初诊2型糖尿病血糖波动性的作用

目的 观察那格列余或联用二甲双胍对初诊2型糖尿病血糖波动性的作用.方法 60例初诊2型糖尿病患者分为单纯那格列奈治疗组(A组,28例)、那格列奈联合二甲双胍治疗组(B组,32例).人院后检测患者体重指数(BMI)、糖化血红蛋白(HbAlc)等指标;同时采用动态血糖监测系统(CGMS)进行连续72 h血糖监测,以平均血糖标准差(SDBG)、日内平均血糖波动幅度(MAGE)、日间血糖平均绝对差(MODD)反映血糖波动性.治疗3个月后随访复查上述指标.结果 治疗前,B组BMI高于A组(P＜0.05),两组HbA1c、SDBG、MAGE、MODD差异无统计学意义(P＞0.05);治疗后,B组BMI较治疗前降低(P＜0.05),两组HbA1c、SDBG、MAGE、M0DD均分别较治疗前明显改善(P＜0.05).结论 初诊2型糖尿病患者单用那格列奈,或BMI较高患者那格列奈联用二甲双胍治疗,不仅能有效降低血糖,而且能改善血糖波动.     

Efficacy and tolerability of initial combination therapy with nateglinide and metformin in treatment-naïve patients with type 2 diabetes

OBJECTIVE: To assess the efficacy and tolerability of the combination of nateglinide (120 mg, ac) and metformin (500 mg, tid) as initial treatment in drug-na?ve patients with type 2 diabetes mellitus (T2DM). Research design and methods: This study reports data from the treatment-na?ve (TN) subgroup of patients in a previously published, randomized, multicenter, placebo-controlled, 24- week trial that compared nateglinide, metformin, and the combination therapy (CT) in 701 patients with T2DM with baseline HbA(1c) between 6.8% and 11.0%. Of the 401 TN patients, 104, 104, 89, and 104 patients received nateglinide (120 mg, ac), metformin (500 mg, tid), CT, and placebo, respectively. The baseline characteristics of each group were similar, with mean age, BMI, duration of diabetes, HbA(1c), and fasting plasma glucose (FPG) levels of approximately 58 years, 30 kg/m(2), 4 Gastrointestinal side effects occurred in 27% of years, 8.2%, and 10.2 mmol/L, respectively. RESULTS: In patients receiving initial CT, HbA(1c) decreased substantially (Delta = -1.6 +/- 0.1%, p < 0.0001 vs. baseline or placebo) from a mean baseline of 8.2 +/- 0.1%, an effect significantly greater than the 0.8% reduction observed with both monotherapies (p < 0.001); whereas, in placebo-treated patients, HbA(1c) increased modestly (Delta = +0.3 +/- 0.1%, p < 0.05) from an identical baseline value. Seventy percent of CT-treated patients achieved a target HbA(1c) of < 7.0%. Both fasting plasma glucose (FPG) and the 2-hour postprandial glucose excursion (PPGE) after a liquid meal challenge decreased by 2.3 mmol/L in patients receiving CT, while the changes from baseline values in FPG and PPGE were +0.2 +/- 0.3 mmol/L and -0.5 +/- 0.2 mmol/L, respectively, in placebo-treated patients. The incremental 30-minute post-load insulin levels increased by 88 +/- 32 pmol/L (p = 0.006) in patients receiving CT and did not change significantly in placebo-treated patients. patients receiving CT (vs. 27.9% in the metformin monotherapy, and 14.4% in the placebo groups). Confirmed hypoglycemia (glucose 相似文献