Enhancing incretin action for the treatment of type 2 diabetes

OBJECTIVE: To examine the mechanisms of action, therapeutic potential, and challenges inherent in the use of incretin peptides and dipeptidyl peptidase-IV (DPP-IV) inhibitors for the treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: The scientific literature describing the biological importance of incretin peptides and DPP-IV inhibitors in the control of glucose homeostasis has been reviewed, with an emphasis on mechanisms of action, experimental diabetes, human physiological experiments, and short-term clinical studies in normal and diabetic human subjects. RESULTS: Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) exert important effects on beta-cells to stimulate glucose-dependent insulin secretion. Both peptides also regulate beta-cell proliferation and cytoprotection. GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. The glucose-lowering actions of GLP-1, but not GIP, are preserved in subjects with type 2 diabetes. However, native GLP-1 is rapidly degraded by DPP-IV after parenteral administration; hence, degradation-resistant, long-acting GLP-1 receptor (GLP-1R) agonists are preferable agents for the chronic treatment of human diabetes. Alternatively, inhibition of DPP-IV-mediated incretin degradation represents a complementary therapeutic approach, as orally available DPP-IV inhibitors have been shown to lower glucose in experimental diabetic models and human subjects with type 2 diabetes. CONCLUSIONS: GLP-1R agonists and DPP-IV inhibitors have shown promising results in clinical trials for the treatment of type 2 diabetes. The need for daily injections of potentially immunogenic GLP-1-derived peptides and the potential for unanticipated side effects with chronic use of DPP-IV inhibitors will require ongoing scrutiny of the risk-benefit ratio for these new therapies as they are evaluated in the clinic.     

Exenatide: a novel approach for treatment of type 2 diabetes

Exenatide (synthetic exendin-4) is the analog of glucagon-like peptide 1 (GLP-1), the major physiologic incretin. The latter is an intestinal hormone that enhances glucose-induced insulin secretion after meals. In addition, GLP-1 stimulates insulin synthesis, inhibits glucagon secretion, delays gastric emptying, and may promote satiety. These glucoregulatory actions help control plasma glucose in the postprandial period. However, in diabetes, the GLP-1 response to nutrient intake is impaired, leading to exacerbation of postprandial hyperglycemia. Exenatide was recently approved as adjunctive therapy in diabetic patients failing sulfonylureas and/or metformin. In clinical trials lasting 30 weeks, exenatide therapy was associated with moderate reduction in mean hemoglobin A1c (HbA1c) levels of approximately 0.8%, and an average weight loss of approximately 2 kg compared with baseline. Hypoglycemia was generally mild and occurred more commonly when exenatide was used in conjunction with sulfonylureas. The requirement of subcutaneous injections twice a day, and the frequent occurrence of nausea and vomiting, represent the main limitations of exenatide. Nevertheless, this agent may be a useful add-on therapy in obese diabetic patients with suboptimal control as a result of continuing weight gain and/or severe postprandial hyperglycemia. The introduction of GLP-1-based antidiabetic drugs is a novel and promising strategy to treat diabetes.     

Exenatide once weekly for the treatment of type 2 diabetes mellitus: clinical results in subgroups of patients using different concomitant medications

Objective: In this pooled analysis, the efficacy and tolerability of exenatide once weekly (EQW) in patients categorized by baseline concomitant glucose-lowering therapy were evaluated. Methods: This post hoc analysis included data from the intent-to-treat populations of 7 randomized controlled trials in which patients with type 2 diabetes mellitus were treated with EQW for 24 to 30 weeks. Patients were classified into subgroups on the basis of their baseline glucose-lowering therapy: diet and exercise only, metformin (MET) only, MET + sulfonylurea (SU), SU ± other (thiazolidinedione [TZD] only or MET + TZD), or TZD ± MET. Changes from baseline in key efficacy endpoints and tolerability were analyzed by baseline concomitant glucose-lowering therapy group. Results: A total of 1719 patients were included. Treatment with EQW was associated with significant improvements from baseline in glycated hemoglobin levels, fasting glucose levels, and body weight in all of the groups. There were significant decreases from baseline for both systolic blood pressure and diastolic blood pressure in the MET and MET + SU groups, and a significant decrease in systolic blood pressure in the diet and exercise group. Lipid profiles generally improved in the diet and exercise, MET only, MET + SU, and TZD ± MET groups. Overall, the most frequent adverse events with EQW treatment, other than hypoglycemia, were nausea (14.7%), diarrhea (10.9%), and nasopharyngitis (7.2%). There was a higher incidence of hypoglycemia when EQW was added to regimens that included an SU. Conclusion: The addition of EQW for 24 to 30 weeks to regimens that included a wide variety of background glucose-lowering therapies was associated with significant improvements in glycemic control and weight loss. The tolerability profile of EQW appeared to be similar regardless of background therapy, except for a higher incidence of minor hypoglycemia when EQW was added to regimens that included an SU.     

Exenatide (Byetta) for type 2 diabetes

An injected hypoglycemic drug that does not cause weight gain.     

Colesevelam hydrochloride for the treatment of type 2 diabetes mellitus

Background: Colesevelam hydrochloride is a bile acid sequestrant approved in January 2008 by the US Food and Drug Administration (FDA) for the treatment of adult patients with type 2 diabetes mellitus (DM) in combination with a sulfonylurea, metformin, and/or insulin therapy.Objective: The purpose of this article was to review the pharmacology, pharmacokinetics, efficacy, adverse effects and tolerability, drug-drug interactions, contraindications/precautions, dosage and administration, pharmacoeconomics, and the overall role of colesevelam in the management of adult patients with type 2 DM.Methods: A literature search using MEDLINE (1966–October 27, 2008), PubMed (1950–October 27, 2008), Science Direct (1994–October 27, 2008), Web of Science (1980–October 27, 2008), American Diabetes Association Scientific Abstracts (2004–2008), and International Pharmaceutical Abstracts (1970–October 27, 2008) was performed using the term colesevelam. English-language, original research and review articles were examined, and citations from these articles were assessed. Manufacturer prescribing information and the FDA review of the new drug application for colesevelam were also examined.Results: Colesevelam is a hydrophilic, water-insoluble polymer, with negligible absorption and systemic distribution, that is excreted primarily in the feces. Through a mechanism still under investigation, colesevelam effectively lowers glycosylated hemoglobin (HbA_1c) when used in combination with a sulfonylurea, metformin, and/or insulin therapy. Three completed, published Phase III clinical trials investigating colesevelam for the treatment of type 2 DM were evaluated for information, data, and conclusions. At dosing of 1.875 g BID or 3.75 g once daily in combination with one of the aforementioned agents versus placebo, reductions in HbA_1c in all 3 Phase III clinical trials of colesevelam ranged from 0.5% to 0.7% (P < 0.02). In clinical trials, colesevelam was well tolerated, with hypoglycemia occurring in ~3% of studied patients.Conclusions: When used in combination with a sulfonylurea, metformin, and/or insulin therapy, colesevelam has been reported to significantly reduce HbA_1c in adult patients with type 2 DM. Colesevelam's role in the management of type 2 DM remains undefined, however; further investigation into its mechanism of action and long-term efficacy and safety should be performed.     

Exenatide once weekly for the treatment of type 2 diabetes: effectiveness and tolerability in patient subpopulations

Objective: Patient numbers in individual diabetes trials are often too limited to assess the effect of a treatment by different patient characteristics, and meta‐analyses often do not include patient‐level data. The purpose of this pooled analysis was to evaluate the efficacy and tolerability of exenatide once weekly (EQW) in patients with type 2 diabetes grouped into subpopulations by key demographic characteristics. Methods: This post hoc analysis included data from patients who received EQW in seven randomised, controlled phase 3 trials that were 24–30 weeks in duration. Patients were classified into subpopulations on the basis of their baseline age (< 65 or ≥ 65 years), gender (male or female), race (White, Black, Asian, Hispanic), duration of diabetes (< 10 years, ≥ 10 years) and body mass index (BMI; < 25, ≥ 25 to < 30, ≥ 30 to < 35, ≥ 35 to < 40 or ≥ 40 kg/m²). Results: A total of 1719 patients were included in this analysis of patient subpopulations. All subpopulations experienced significant improvements from baseline in haemoglobin A1C, fasting glucose and body weight. Most subpopulations experienced significant improvements in blood pressure and lipid parameters. Overall, the most common AEs were hypoglycaemia (16.4% overall; 2.3% in patients not on concomitant sulfonylurea), nausea (14.7%), diarrhoea (10.9%) and nasopharyngitis (7.2%). Conclusion: These results show that the treatment of type 2 diabetes with EQW for 24–30 weeks was associated with significant improvements in glycaemic control and body weight, irrespective of age, gender, race, duration of diabetes or BMI. The most common adverse events were gastrointestinal in nature.     

腹腔镜迷你胃转流术治疗2型糖尿病

目的 回顾2010年5月-2012年6月进行的12例腹腔镜迷你胃转流术治疗2型糖尿病的资料并进行疗效分析。方法 患者确诊2型糖尿病，全身麻醉下进行腹腔镜迷你胃转流术12例。其中，男性8例，女性4例；年龄42～59岁，平均（47±10）岁，术中计算手术时间、出血量，分别在术前以及术后15 d、1、3及6个月对检测患者空腹血糖、餐后2 h血糖（2h PBG）、空腹C肽、胰岛素抵抗指数、空腹胰岛素（Fins）、糖化血红蛋白（HbA1c）的水平、营养状况以及并发症进行随访。结果 患者手术顺利，平均手术时间（140±55）min，术中出血平均（90±25）mL；腹腔镜迷你胃转流术后15 d、1、3及6个月与术前相比空腹血糖、2 h PBG、空腹C肽及胰岛素抵抗指数改善显著（P <0.05），HbA1c术后3个月明显改善（P <0.05）；Fins差异无显著性（P >0.05），患者术后恢复较好，没有并发症发生，术后3个月不用任何降糖药物，血糖控制良好，补充相关微量元素的情况下没有发生营养不良和贫血。结论 腹腔镜迷你胃转流术治疗2型糖尿病安全、有效，是术后胰岛细胞功能明显改善的一种术式。     

Exenatide and pramlintide: new glucose-lowering agents for treating diabetes mellitus

Insulin is not the only hormone that regulates plasma glucose levels. Glucagon-like peptide 1 (GLP-1), produced in the small intestine, and amylin, produced by beta cells in the pancreas, also have glucose-lowering effects. Synthetic analogues of these hormones are now available for clinical use.     

The glitazones: a new treatment for type 2 diabetes mellitus.

The glitazones are a new class of anti-diabetic drugs that act by improving sensitivity to insulin and are indicated in the treatment of type 2 diabetes. The glitazones have effects on carbohydrate and lipid metabolism and hold the promise of being able to influence the many components of the insulin resistance syndrome seen in type 2 diabetes. It is possible that the glitazones may be able to prevent or delay the cardiovascular disease which accompanies type 2 diabetes, long-term studies are required to determine if this is the case. In addition to drug treatment patients with type 2 diabetes should be strongly encouraged to make life style changes which will improve glycaemic control such as weight reduction and increase exercise.     

Saxagliptin for the treatment of type 2 diabetes mellitus: focus on recent studies

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycemic control without causing weight gain or increasing hypoglycemic risk in patients with type 2 diabetes (T2DM). The efficacy and tolerability of saxagliptin, a once-daily DPP-4 inhibitor, administered as monotherapy, as add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione, and as initial combination therapy with metformin, was demonstrated in pivotal 24-week clinical trials. Additional information about the clinical profile of saxagliptin was recently obtained from extension studies, head-to-head clinical trials, and post-hoc analyses. In extension studies, the efficacy and tolerability of add-on saxagliptin and initial saxagliptin-plus-metformin therapy were maintained for up to 102 weeks. Saxagliptin plus metformin was shown to be non-inferior to glipizide plus metformin in lowering glycated hemoglobin from base-line, with reduced body-weight and lower hypoglycemic risk. Post-hoc analyses indicate that the clinical benefits of saxagliptin extend across demographic subgroups and special populations. A meta-analysis found no evidence for increased cardiovascular risk in T2DM patients exposed to saxagliptin for > 1 year. On the basis of this clinical profile, saxagliptin is an attractive option for initial and add-on therapy for T2DM patients with inadequate glycemic control.     

Pramlintide acetate injection for the treatment of type 1 and type 2 diabetes mellitus

BACKGROUND: Amylin is a hormone cosecreted with insulin by the beta cells of the pancreas. It suppresses postprandial glucagon secretion and slows gastric emptying. Pramlintide acetate is an amylin analogue that was approved by the US Food and Drug Administration in March 2005. OBJECTIVE: This article reviews the current primary literature on the clinical efficacy and tolerability of pramlintide injection in the treatment of type 1 and type 2 diabetes mellitus (DM). Among other topics covered are the pharmacokinetics, pharmacodynamics, and dosing and administration of pramlintide. METHODS: Pertinent English-language articles were identified through a search of MEDLINE (1966-January 2007), International Pharmaceutical Abstracts (1970-present), Database of Abstracts of Reviews of Effectiveness (1995-January 2007), Cochrane Database of Systematic Reviews (1995-January 2007), and EMBASE Drugs & Pharmacology (1991-1st quarter 2007). The search terms included pramlintide, amylin, gastric emptying, pharmacokinetic, pharmacoeconomic, postprandial hyperglycemia, and glucagon. Articles were selected for review if they described studies having a randomized, double-blind, controlled design and included glycosylated hemoglobin (HbA(1c)) as an end point. RESULTS: Pramlintide is administered subcutaneously in the abdominal area or thigh immediately before each main meal to achieve maximal reductions in post-prandial glucose excursions. Its C(max) is reached within 20 minutes, and its t(1/2) is 48 minutes. Metabolism is primarily via the kidneys. Pramlintide therapy was associated with inhibition of postprandial glucagon secretion in 24 patients with type 2 DM; prolonged gastric emptying in 11 patients with type 1 DM; a 23% reduction in total energy intake in 11 patients with type 2 DM; and a reduction in markers of oxidative stress in 18 patients with type 1 DM (all, P <- 0.05 vs placebo). In two 52-week studies in patients with type 1 DM, the groups that received pramlintide 30 to 60 microg QID (n = 243), 60 microg TID (n = 164), and 60 microg QID (n = 161) had respective 0.39%, 0.29%, and 0.34% reductions in HbA(1c) and 0.5-, 0.3-, and 0.6-kg reductions in body weight, respectively (all, P < 0.05 vs placebo). In two 52-week studies in patients with type 2 DM, the groups that received pramlintide 120 microg BID (n = 166) and 150 microg TID (n = 144) had respective 0.62% and 0.6% reductions in HbA(1c) and 1.4- and 1.3-kg reductions in body weight (all, P < 0.05 vs placebo). Hypoglycemia, nausea, vomiting, and anorexia were the most frequently reported (>/=10% occurrence) adverse events in patients receiving pramlintide compared with placebo. These events were mild to moderate and occurred more frequently during the first month of therapy. CONCLUSIONS: Pramlintide therapy was associated with reductions in HbA(1c) and body weight in four 52-week studies in patients with type 1 DM and type 2 DM. Hypoglycemia, nausea, vomiting, and anorexia were the most frequently occurring adverse events, particularly during the first month of therapy. Pramlintide was associated with reductions in measures of oxidative stress, but studies are needed to evaluate the effects of this agent on DM-related complications.     

Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data

The therapeutic options for treating type 2 diabetes have been widened by the introduction of exenatide as the first incretin mimetic. Incretins are gut hormones that contribute to the stimulation of insulin secretion after a carbohydrate rich meal. The incretin hormone glucagon-like peptide-1 (GLP-1) not only stimulates insulin secretion under hyperglycaemic conditions, but also suppresses glucagon secretion, slows gastric emptying, induces satiety and improves beta cell function in type 2 diabetes. These beneficial effects have awakened the interest to use GLP-1 for the treatment of type 2 diabetes. Because of its short biological half-life, GLP-1 itself is not practical for type 2 diabetes therapy. Exenatide is a peptide found in the lizard Heloderma suspectum and has a high similarity to GLP-1. Exenatide belongs to the novel class of incretin mimetics because of its incretin-like action. It has a much longer biological half life than GLP-1 and is a GLP-1 receptor agonist that can be used for therapeutic purposes by twice daily injection. Clinical studies and clinical experience with exenatide have shown a significant reduction in HbA1c, fasting- and postprandial glucose and a marked reduction in body weight in type 2 diabetic patients. Animal studies reveal an improvement of beta cell function and an increase in beta cell mass after exenatide treatment. This review gives an overview on exenatide, its pharmacological profile and its role and potential in the therapeutic setting of type 2 diabetes. Furthermore, future developments concerning exenatide application are highlighted.     

Saxagliptin for the treatment of type 2 diabetes mellitus: Focus on recent studies

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycemic control without causing weight gain or increasing hypoglycemic risk in patients with type 2 diabetes (T2DM). The efficacy and tolerability of saxagliptin, a once-daily DPP-4 inhibitor, administered as monotherapy, as add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione, and as initial combination therapy with metformin, was demonstrated in pivotal 24-week clinical trials. Additional information about the clinical profile of saxagliptin was recently obtained from extension studies, head-to-head clinical trials, and post-hoc analyses. In extension studies, the efficacy and tolerability of add-on saxagliptin and initial saxagliptin-plus-metformin therapy were maintained for up to 102 weeks. Saxagliptin plus metformin was shown to be non-inferior to glipizide plus metformin in lowering glycated hemoglobin from base-line, with reduced body-weight and lower hypoglycemic risk. Post-hoc analyses indicate that the clinical benefits of saxagliptin extend across demographic subgroups and special populations. A meta-analysis found no evidence for increased cardiovascular risk in T2DM patients exposed to saxagliptin for > 1 year. On the basis of this clinical profile, saxagliptin is an attractive option for initial and add-on therapy for T2DM patients with inadequate glycemic control.     

腹腔镜Roux-en-Y胃肠旁路术治疗2型糖尿病

目的 回顾该院第1例腹腔镜Roux-en-Y胃肠旁路术治疗2型糖尿病的资料并进行疗效分析.方法 术前确定2型糖尿病的诊断,完善各项检查,排除手术禁忌证,全身麻醉下进行腹腔镜Roux-en-Y胃肠旁路术,术后对患者恢复情况、血糖、胰岛素抵抗、糖耐量、营养状况以及并发症进行随访.结果 患者术后恢复较好,没有并发症发生,术后不用任何降糖药物,血糖控制良好,糖耐量试验结果转为正常,没有发生营养不良和贫血.结论 该例患者经腹腔镜Roux-en-Y胃肠旁路术治疗后2型糖尿病获得治愈.     

Update on type 2 diabetes mellitus: understanding changes in the diabetes treatment paradigm

Type 2 diabetes mellitus, which is increasingly prevalent in the United States and responsible for the bulk of diabetes-related healthcare costs, has not been adequately managed over the long term with the most commonly prescribed oral hypoglycaemic medications. Although there is evidence that successful management of type 2 diabetes must address both beta-cell deficiency and insulin resistance, most oral agents now prescribed do not prevent the progressive loss of beta-cell function that has traditionally continued during treatment. Increasingly aggressive management guidelines have led to the recommendation that metformin therapy be initiated along with lifestyle modification at the time of diagnosis. It seems unlikely, however, that this strategy will impede the progression of beta-cell dysfunction. Treatment paradigms are emerging that combine routinely used drug categories with newer agents based on the incretin pathway to achieve long-term glycaemic control. The current review discusses the clinical implications of these newer therapeutic alternatives, which enhance insulin secretion through glucose-dependent and physiologic mechanisms.     

Liraglutide for type 2 diabetes mellitus

Introduction: Prevalence of type 2 diabetes mellitus (T2DM) is increasing. Management of this condition and minimizing the cardiovascular risks associated with it poses a significant burden on healthcare resources across the world. Currently available therapeutic agents are effective in glycemic management; however, the majority of these are associated with undesirable effects such as hypoglycemia and weight gain. Incretin-based therapies have been introduced over the last few years and are associated with less risk of hypoglycemia and weight gain.

Areas covered: This review includes current challenges in the management of T2DM, and an overview of glucagon-like peptide-1 (GLP-1)-based therapies, in particular the results of Phase III clinical studies of recently approved liraglutide. Apart from glycemic control, multifactorial interventions are needed to minimize the cardiovascular risks associated with T2DM. Liraglutide is effective in improving glycemic control measured by HbA1c and it is also shown to improve weight. Recently, the National Institute of Health and Clinical Excellence in the UK has approved liraglutide 1.2 mg dose in dual and triple therapy for T2DM.

Expert opinion: Liraglutide, a once-daily GLP-1 analog, has a definite role in selected patients with T2DM and the long-term cardiovascular safety is currently being ascertained in ongoing trials.