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.     

Evaluation of treatment adherence in type 1 diabetes: a novel approach

BACKGROUND: Intensified insulin therapy requires outstanding compliance but no measure of therapy adherence has been agreed upon. The aim of the current study was to test the hypothesis that treatment adherence, as described by a novel multiple regression model, relates to glycosylated haemoglobin and hypoglycaemia frequency in type 1 diabetes. Furthermore, we sought to analyse the complex diurnal patterns of therapy adherence. MATERIALS AND METHODS: Thirty type 1 diabetes patients (20 females and 10 males), treated with intensified insulin therapy, were studied in a retrospective manner. Patients were trained to follow treatment algorithms for adjusting regular insulin dosage which took into account the actual blood glucose, food intake and the time of the day. By means of multiple linear regression analysis, with regular insulin dosage as the dependent variable, blood glucose and food intake as the independent variables, the insulin treatment algorithms actually used by the individual patient were retrieved. The correlation between prescribed and implemented insulin therapy served as a measure of adherence. Metabolic control was assessed by glycosylated haemoglobin and hypoglycaemia frequency. RESULTS: Median glycosylated haemoglobin was 7.7% (range: 6.3-10.8); median monthly hypoglycaemia frequency was 3.8 (range: 0-9.8). Patients with good metabolic control (glycosylated haemoglobin < 7.7 and/or hypoglycaemia frequency < 3.8 per month) adhered to prescribed insulin dosing algorithms more frequently than those with poor metabolic control. CONCLUSIONS: In patients with type 1 diabetes on intensified therapy a positive relationship between adherence to the therapy prescribed and metabolic control exists.     

Gene therapy for type 1 diabetes: a novel approach for targeted treatment of autoimmunity

It has been difficult to develop therapies that target those T cells initiating and mediating the pathogenesis of autoimmune disease. Indeed, most current treatments indiscriminately affect both the autoreactive T cells and the "good" T cells, putting the patient at risk of compromised immune function. A new approach raises the possibility of targeted therapy for autoimmunity. Transplantation of hematopoietic stem cells modified to express a protective form of MHC class II corrects a defect in central tolerance. This method contrasts with other targeted therapies that attempt to modify peripheral tolerance, which is also defective in type 1 diabetes mellitus.     

A practical approach to type 2 diabetes

Diabetes mellitus is among the most serious, costly, and in some cases, preventable health care problem in the United States today. Primary care providers such as nurse practitioners are ideally suited to manage chronic conditions such as diabetes and provide counseling and interventions regarding intensive management (i.e., medications, nutrition, and exercise), prevention of complications, immunizations, laboratory screenings, and physical examinations. This article provides a general overview of type 2 diabetes and the role of the nurse practitioner in the prevention and management of this disorder.     

Differentiating among incretin therapies: a multiple-target approach to type 2 diabetes

What is known and Objective: Incretin-based glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitor therapies provide glycaemic control with reduced risks associated with weight gain or hypoglycaemia. Incretin therapies are compared with their mechanisms of action, effects on haemoglobin A(1C) (HbA(1C) ), fasting plasma glucose (FPG), post-prandial glucose (PPG), body weight, β-cell function, cardiovascular biomarkers and in their safety profiles to aid clinicians in the selection of individualized pharmacotherapy for patients with type 2 diabetes. Methods: Relevant articles for a systematic review were identified through PubMed. Randomized, head-to-head comparison studies among incretin therapies were identified and included in the review. Additionally, randomized, controlled monotherapy and combination therapy studies examining glycaemic and extraglycaemic effects of individual incretin therapies from 2007 to 2011 were reviewed. Results and Discussion: Glucagon-like peptide-1 receptor agonists are generally preferred over DPP-4 inhibitors because of their greater effectiveness in reducing HbA(1C) , FPG and PPG excursions, and greater weight loss potentiation. As a monotherapy option, longer-acting GLP-1 RAs, including liraglutide and exenatide once-weekly, may be preferred at higher HbA(1C) because of their more pronounced effects on FPG. At lower/near normal HbA(1C) , a short-acting GLP-1 RA, such as exenatide twice-daily, may be a better choice as its effects are more pronounced with PPG. Ideal patients or patient situations for DPP-4 inhibitors include patients who need minimal reduction in HbA(1C,) elderly patients, patients who are unwilling or unable to take an injectable agent, when GLP-1 RAs are contraindicated or when the patient will not benefit from weight loss. Treatment benefits common to all incretin-based therapies include minimal hypoglycaemia risk, potential preservation of β-cell function and effective targeting of multiple organs underlying type 2 diabetes and of comorbidities commonly associated with type 2 diabetes, such as obesity and hypertension. What is new and Conclusion: Key differences in mechanisms of action and in glycaemic and extra-glycaemic treatment outcomes exist among incretin therapies, both within the GLP-1 RA class, and between GLP-1 RAs and DPP-4 inhibitors. Clinical judgment acknowledging important differences among incretin therapies and treatment-related patient characteristics will aid in the selection of the appropriate incretin agent for individualized pharmacotherapy.     

Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: a complementary approach to the treatment of type 2 diabetes

Among persons with type 2 diabetes (t2d), the development of glucose intolerance involves dysfunction in several organs and tissues, including the muscle, liver, pancreas, kidney, gastrointestinal tract, adipose tissue, and brain. individuals with t2d typically have a number of comorbidities, including hypertension, hyperlipidemia, and being overweight or obese, and are, consequently, at high cardiovascular risk. guidelines recommend a comprehensive care strategy that includes treatment of diabetes-related complications and comorbidities beyond those related to hyperglycemia. use of glucose-lowering therapies with complementary activities that address multiple facets of the disease may improve long-term outcomes for patients with t2d. two recent drug classes developed for use in t2d, glucagon-like peptide-1 receptor agonists (glp-1ras) and sodium glucose cotransporter 2 (sglt2) inhibitors, have been shown in clinical trials to have beneficial effects on glycemic control, body weight, cardiovascular risk factors, and (for liraglutide, semaglutide, and empagliflozin) cardiovascular outcomes, while having an acceptable safety profile. between them, these drug classes directly or indirectly affect many of the organs and tissues involved in the pathogenesis of t2d, and their beneficial effects on glycemic- and cardiovascular-related parameters are likely to be complementary and potentially additive. in the largest clinical trial of a glp-1ra and an sglt2 inhibitor in combination (duration-8), patients with t2d (n = 685) who received exenatide plus dapagliflozin added to their treatment regimen for 28 weeks had significantly greater reductions from baseline in glycated hemoglobin, body weight, and systolic blood pressure compared with patients who received either drug as monotherapy. this review summarizes the complementary aspects of these drug classes and presents the available data among patients receiving dual therapy with a glp-1ra and an sglt2 inhibitor.     

Acceptability and satisfaction with a telecarer approach to the management of type 2 diabetes

OBJECTIVE: To examine patients' views of the acceptability of and satisfaction with telephone care center support provided to improve blood glucose control in type 2 diabetes. RESEARCH DESIGN AND METHODS: The Pro-Active Call-Center Treatment Support (PACCTS) Trial randomized patients from 47 general practices in a deprived urban area in northwest England to usual care or to proactive call center support in addition to usual care. Satisfaction with care was assessed in all 591 patients at baseline and the end of the study using the Diabetes Satisfaction and Treatment Questionnaire (DTSQ). Acceptability was assessed in 394 intervention patients after at least three proactive calls from the call center and at the end of the trial. A purposive sample of 25 patients took part in in-depth semistructured interviews. RESULTS: The response rates to the questionnaires were 79% (DTSQ) and 65% (acceptability). Persons receiving the intervention continued to report high levels of satisfaction with their treatment (95% CI 32.3-33.2 at 1 year), and >90% strongly agreed or agreed that the telecarer approach was acceptable. Qualitative comments pointed to the importance of a personalized service; increased feelings of well-being, including confidence and self-control; help with problem-solving; and patients developing rapport and a strong bond with the telecarers. CONCLUSIONS: A personalized PACCTS approach is acceptable to patients. A service giving priority to the interpersonal dimension leads to increased commitment from patients to improve long-term glycemic control.     

胰高糖素样多肽 1———老年 2 型糖尿病治疗的新靶点

由肠道内分泌L细胞所产生胰高糖素样多肽1（GLP-1）,其数量和功能的减少和／或损害参与了糖尿病的发生和发展,围绕提升GLP-1的水平如二肽基肽酶抑制剂及其受体激动剂的药物已经在临床应用,在2型糖尿病治疗中除了能够发挥降低血糖的作用外,还具有降低体重、有效避免严重低血糖发作、心血管保护等独特优势,对老年2型糖尿病患者也很安全,为2型糖尿病患者的治疗提供了新选择,其在阻止和／或延缓2型糖尿病进展中的作用优势将会给临床医生和患者带来新的治疗希望。     

Matching treatment to pathophysiology in type 2 diabetes

BACKGROUND: Because type 2 diabetes is a progressive condition, >50% of all patients whose disease is initially controlled with diet and exercise will eventually need single or multiple pharmacologic agents to maintain adequate glycemic control. Although current treatment standards require that combination therapy be instituted only after the failure of monotherapy, the results of the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study suggest that aggressive initial treatment is crucial to slowing the evolution of long-term complications associated with this disease. OBJECTIVES: This article reviews the diagnosis and classification of type 2 diabetes, describes the multiple defects in glucose metabolism associated with the disease, and discusses the various pharmacologic options for achieving glycemic control in these patients. METHODS: The information in this review was compiled through a search of MEDLINE. Search terms included but were not limited to type 2 diabetes and antihyperglycemic agents. In addition, abstracts were identified using the Web sites of diabetes-related professional organizations. RESULTS: Two pathophysiologic mechanisms, insulin resistance and impaired insulin secretion, are usually present at diagnosis in type 2 diabetes. Several studies have shown that combination therapy with antihyperglycemic agents having different mechanisms of action provides greater efficacy than treatment with single agents. CONCLUSIONS: Current research suggests that early aggressive treatment with combination therapy achieves glycemic control at lower doses and with fewer side effects than monotherapy with either component.     

Current therapeutic options in type 2 diabetes mellitus: a practical approach

The incidence of type 2 diabetes mellitus (DM) in the United States continues to grow rapidly, paralleling the overweight and obesity epidemic. For many years the only therapeutic options for type 2 DM were sulfonylureas and insulin. However, over the last 9 years there has been an explosion of new and exciting agents approved for the treatment of type 2 DM. Some of the treatments target insulin deficiency and others insulin resistance, the hallmarks of the disease. Other drugs delay the intestinal absorption of carbohydrate. Recently several combination agents have been released. With these new drugs has come an overwhelming mountain of information, making it difficult for the busy clinician to know how best to manage the ever-increasing portion of patients with type 2 DM.New questions have arisen: Which agent to start as first line? How much of this drug to use before adding something else? How long for this drug to reach full effect? Which agent to add second? Should a patient uncontrolled on dual therapy begin insulin or start a third oral agent? If insulin therapy is started, what should become of the patient''s oral agents? How best to explain the patient''s weight gain on therapy? These are not easy questions and no review can fully detail all the therapeutic combinations possible. Instead, the practical approach of reviewing the agents in terms of their mechanism of action and critically comparing their dosing, effect and cost, is undertaken herein. Also addressed is the possible niche some newer classes of agents and combination drugs may or may not hold in the management of type 2 DM. The decision of using insulin versus a third oral agent will be looked at from the standpoint of where the patient is on dual therapy in relation to the hemoglobin A_1c goal. In this way it is hoped that some clarity will be brought to the dizzying array of information that both the physician and patient have to deal with in regard to the management of this prevalent and serious disease.     

Thiazolidinedione derivatives as novel GPR120 agonists for the treatment of type 2 diabetes

GPR120, also called FFAR4, is preferentially expressed in the intestines, and can be stimulated by long-chain free fatty acids to increase the secretion of glucagon-like peptide-1 (GLP-1) from intestinal endocrine cells. It is known that GLP-1, as an incretin, can promote the insulin secretion from pancreatic cells in a glucose-dependent manner. Therefore, GPR120 is a potential drug target to treat type 2 diabetes. In this study, thiazolidinedione derivatives were found to be novel potent GPR120 agonists. Compound 5g, with excellent agonistic activity, selectivity, and metabolic stability, improved oral glucose tolerance in normal C57BL/6 mice in a dose-dependent manner. Moreover, compound 5g exhibited anti-diabetic activity by promoting insulin secretion in diet-induced obese mice. In summary, compound 5g might be a promising drug candidate for the treatment of type 2 diabetes.

GPR120 has emerged as an attractive target for the treatment of type 2 diabetes and obesity. Thiazolidinedione derivatives were found to be novel potent GPR120 agonists.