Pramlintide and the treatment of diabetes: a review of the data since its introduction

INTRODUCTION: Postprandial glucose excursions negatively affect glycemic control and markers of cardiovascular health. Pramlintide, an amylinomimetic, is approved for treatment of elevated postprandial glucose levels in type 1 and type 2 diabetes mellitus. AREAS COVERED: A literature search of PubMed was conducted to locate articles (up to January 2011) pertaining to original preclinical and clinical research and reviews of amylin and pramlintide. Additional sources were selected from reference lists within articles obtained through the original literature search and from the internet. This article describes the known effects of endogenous amylin and the pharmacodynamics, pharmacokinetics and clinical efficacy of pramlintide. Drug-drug interactions and safety and tolerability are also reviewed. EXPERT OPINION: Pramlintide significantly reduces hemoglobin A(1c) and body weight in patients with type 1 and type 2 diabetes mellitus. Newer research is focusing on weight loss effects of pramlintide and pramlintide plus metreleptin in nondiabetic obese individuals. Preliminary results of these studies are discussed.     

Pramlintide for the treatment of insulin-requiring diabetes mellitus: rationale and review of clinical data

Despite a number of incremental, beneficial improvements in diabetes mellitus therapy over the past few decades, the fundamental challenge of replicating the physiological entry into, and uptake of glucose from, the circulation remains unresolved. Pramlintide is an analogue of the beta-cell hormone amylin that simulates its important glucoregulatory actions. In humans, pramlintide slows gastric emptying and suppresses glucagon secretion during the prandial/postprandial period to slow and reduce the entry of glucose into the circulation. These actions, in conjunction with the glucose cellular uptake function of insulin, help normalise fluctuations in circulating glucose levels to a greater degree than is possible with insulin treatment alone. In clinical studies, pramlintide treatment as an adjunct to insulin decreased glycosylated haemoglobin levels (0.39-0.62%) with a concomitant weight loss (0.5-1.4kg) and no significant increase in severe hypoglycaemia.Pramlintide treatment as a potential adjunct to insulin therapy is in late-stage development for patients with type 1 diabetes and insulin-using patients with type 2 diabetes.     

Pramlintide acetate.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of pramlintide are reviewed. SUMMARY: Pramlintide, a synthetic analogue of the human hormone amylin, is the first of a new class of amylinomimetic compounds. It was approved in March 2005 as a subcutaneous injection for the adjunctive treatment of patients who have type 1 or 2 diabetes mellitus and have failed to achieve glycemic control despite optimal therapy with insulin. Pramlintide complements the effects of insulin in postprandial glucose regulation by decreasing glucagon secretion. Pramlintide exhibits linear pharmacokinetics, and peak serum levels are reached within 30 minutes of administration. The drug is predominantly renally eliminated, with a mean elimination half-life of 30-50 minutes. Clinical trials have shown that pramlintide suppresses postmeal glucagon secretion, slows gastric emptying, reduces postprandial glucose levels, and improves glycemic control while managing weight loss. Pramlintide has also been shown to decrease hemoglobin A(1c), serum fructosamine, and total cholesterol levels. Pramlintide has been associated with an increased risk of insulin-induced severe hypoglycemia; other adverse events include nausea, anorexia, fatigue, and vomiting. The dosage varies with the type of diabetes. Because of the cost associated with the complications of uncontrolled diabetes, pramlintide may have a beneficial effect on total costs associated with this chronic disease. CONCLUSION: Pramlintide in combination with insulin is a potential therapeutic option for improving glycemic control in patients with diabetes, but the increased risk of hypoglycemia must be aggressively monitored.     

Novel peptides under development for the treatment of type 1 and type 2 diabetes mellitus

Recent availability of expanded treatment options for both type 1 and type 2 diabetes has not translated into easier and significantly better glycemic and metabolic management. Patients with type 1 diabetes continue to experience increased risk of hypoglycemic episodes and progressive weight gain resulting from intensive insulin treatment, despite the recent availability of a variety of insulin analog. Given the progressive nature of the disease, most patients with type 2 diabetes inevitably proceed from oral agent monotherapy to combination therapy and, ultimately, require exogenous insulin replacement. Insulin therapy in type 2 diabetes is also accompanied by untoward weight gain. Both type 1 and type 2 diabetes continue to be characterized by marked postprandial hyperglycemia. Two hormones still in development are candidates for pharmacologic intervention, have novel modes of action (some centrally mediated), and show great promise in addressing some of the unmet needs of current diabetes management. Pramlintide acetate, an analog of the beta cell hormone amylin and the first non-insulin related therapeutic modality for type 1 and type 2 diabetic patients with severe beta cell failure, may be useful as adjunctive therapy to insulin. The principal anti-diabetic effects of pramlintide arise from interactions via its cognate receptors located in the central nervous system resulting in postprandial glucagon suppression, modulation of nutrient absorption rate, and reduction of food intake. Another polypeptide hormone, exendin-4, exerts at least some of its pharmacologic actions as an agonist at the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 and related compounds exhibit multiple modes of action, the most notable being a glucose-dependent insulinotropic effects and the potential to preserve or improve the beta-cell function. The latter effect could potentially halt or delay the progressive deterioration of the diabetic state associated with type 2 diabetes. Physiologically, both amylin and glucagon-like peptide (GLP)-1, along with insulin, are involved in a coordinated and concerted interplay between hormones acting both centrally and peripherally to provide meticulous control over the rate of appearance of exogenous and endogenous glucose and to match that rate to the rate of glucose disappearance. Both hormones are deficient in diabetes. Therapies directed at restoring this complex physiology have the potential to facilitate glucose control and thus minimize the attendant complications of diabetes.     

Amylin receptor agonists: a novel pharmacological approach in the management of insulin-treated diabetes mellitus

Amylin is a peptide hormone which is co-secreted with insulin from the pancreatic beta-cell. Type 1 diabetic individuals and some Type 2 diabetic individuals are characterised by amylin deficiency. Animal experiments have revealed several actions of amylin on intermediary metabolism, of these some have been demonstrated to be of potential physiological relevance in humans. In particular amylin appears to have important actions in controlling prandial glucose homeostasis. The peptide hormone inhibits postprandial glucagon secretion and delays gastric emptying thereby modifying postprandial hyperglycaemia in diabetic individuals which presumably adds to overall glycaemic control without a concomitant increase in the number of severe hypoglycaemic episodes. Moreover, amylin acts as a satiety agent. Amylin replacement may therefore improve glycaemic control in diabetes mellitus. However, human amylin exhibits physicochemical properties predisposing the peptide hormone to aggregate and form amyloid fibres, which makes it unsuitable for pharmacological use. A stable analogue, pramlintide, with actions and pharmacokinetic and pharmacodynamic properties similar to the native peptide has therefore been developed. The efficacy and safety of pramlintide administration to diabetic individuals have been tested in a large number of clinical trials. It is the aim of this review to describe possible (patho)physiological actions of amylin as demonstrated in animal and human models, to discuss the background for potential amylin (analogue) replacement in diabetes mellitus and to review results from clinical trials with the amylin receptor analogue pramlintide.     

Pramlintide and the treatment of diabetes: a review of the data since its introduction

Introduction: Postprandial glucose excursions negatively affect glycemic control and markers of cardiovascular health. Pramlintide, an amylinomimetic, is approved for treatment of elevated postprandial glucose levels in type 1 and type 2 diabetes mellitus.

Areas covered: A literature search of PubMed was conducted to locate articles (up to January 2011) pertaining to original preclinical and clinical research and reviews of amylin and pramlintide. Additional sources were selected from reference lists within articles obtained through the original literature search and from the internet. This article describes the known effects of endogenous amylin and the pharmacodynamics, pharmacokinetics and clinical efficacy of pramlintide. Drug–drug interactions and safety and tolerability are also reviewed.

Expert opinion: Pramlintide significantly reduces hemoglobin A_1c and body weight in patients with type 1 and type 2 diabetes mellitus. Newer research is focusing on weight loss effects of pramlintide and pramlintide plus metreleptin in nondiabetic obese individuals. Preliminary results of these studies are discussed.     

Off-label use of exenatide for the management of insulin-resistant type 1 diabetes mellitus in an obese patient with human immunodeficiency virus infection

Exenatide is an incretin mimetic indicated for the treatment of type 2 diabetes mellitus in combination with a sulfonylurea, a thiazolidinedione, metformin, or metformin plus a sulfonylurea or thiazolidinedione. Exenatide lowers postprandial blood glucose levels by stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, slowing gastric emptying, and increasing satiety. Therapy with exenatide often results in weight loss, which further assists in decreasing insulin resistance. This feature makes the drug an attractive therapeutic option for obese patients. We report the successful off-label use of exenatide in an obese, 40-year-old man with type 1 diabetes and human immunodeficiency virus (HIV) infection who had gastrointestinal intolerance to pramlintide. The patient had experienced a dramatic weight gain secondary to his antiretroviral drugs. This weight gain led to insulin resistance and the development of type 2 diabetes; thus he had characteristics of both types 1 and 2 diabetes, or double diabetes. Before the start of exenatide therapy, he weighed 123 kg, had a body mass index of 42.3 kg/m(2), and had a suboptimal hemoglobin A(1c) value of 8.7%. After 11 months of therapy, the patient lost 24 kg (19.5% of his body weight) and achieved a hemoglobin A(1c) value of 7.3%. His basal insulin requirement was reduced by 25%, and his use of short-acting insulin before breakfast and before dinner was discontinued. In addition, the patient's quality of life substantially improved, as he was able to return to work and exercise after being nearly incapacitated by his weight. To our knowledge, this is the first published case report of the use of exenatide in a patient with type 1 diabetes mellitus or human immunodeficiency virus infection. Given this experience, exenatide may prove to be a useful alternative in selected patients with type 1 diabetes.     

Adjunctive therapy with pramlintide in patients with type 1 or type 2 diabetes mellitus

Uncontrolled diabetes mellitus is associated with both microvascular and macrovascular complications. Despite an array of treatment options available, achievement of euglycemia in most patients with diabetes is still lacking. Pramlintide acetate, a synthetic analog of the human hormone amylin and belonging to a new class of agents, was approved in March 2005 as adjunctive treatment in patients with type 1 or 2 diabetes mellitus. To evaluate the data available on the efficacy and safety of pramlintide, we conducted a search of MEDLINE (January 1966-May 2006) and International Pharmaceutical Abstracts (January 1970-May 2006). Bibliographies of clinical trials were reviewed for additional references. The literature reviewed demonstrated that pramlintide is effective in reducing levels of glycosylated hemoglobin and potentially preventing weight gain. The most commonly reported adverse effects associated with pramlintide were nausea, anorexia, and hypoglycemia. These adverse effects occurred more often during the initiation of therapy and were usually mild to moderate in nature. Whether this therapy is a cost-effective option for patients with type 1 or type 2 diabetes mellitus is yet to be determined.     

中效胰岛素联合那格列奈与预混胰岛素治疗2型糖尿病疗效比较

目的:预混胰岛素血糖控制不佳者改用那格列奈联合中效人胰岛素(NPH)在2型糖尿病患者中的有效性及安全性。方法:选择应用预混人胰岛素3月及以上血糖控制不佳的2型糖尿病患者108例,分为2组,一组(42例)维持原方案的基础上调整预混胰岛素用量,另一组(66例)改用那格列奈联合中效人胰岛素治疗,随访3月及6月,比较治疗前后两组空腹血糖(FBG),餐后2 h血糖(2hPBS),糖化血红蛋白(HbA1c)及低血糖发生率,体重变化情况。结果:那格列奈联合中效人胰岛素与预混胰岛素治疗3月和1年时比较,FBG、2hPBS及HbA1c较治疗前均明显下降;同时低血糖发生率减少;体重及体重指数3月后无明显变化但1年后有所降低。结论:2型糖尿病患者应用那格列奈联合中效胰岛素能更好控制血糖;同时减少低血糖的发生率,不增加体重,兼顾了治疗的有效性及安全性,疗效优于预混胰岛素。     

利拉鲁肽治疗腹型肥胖2型糖尿病患者的临床观察

目的：观察腹型肥胖的2型糖尿病患者应用利拉鲁肽治疗的疗效及其安全性。方法筛选20例符合入选标准的腹型肥胖2型糖尿病患者,在原有降糖药物基础上,加用利拉鲁肽0.6~1.8 mg皮下注射,1次/d。治疗随访观察12周,比较治疗前后空腹血糖（FPG）、餐后2 h血糖（2 hPG）、空腹及餐后2 h胰岛素及C肽、糖化血红蛋白（HbA1c）、体重指数（BMI）、腰围、血压、血脂的变化情况。观察并记录其不良反应。结果对采用利拉鲁肽治疗患者前后的空腹血糖、餐后2h血糖、糖化血红蛋白、体重、BMI、腰围、HOMA-β及HOMA-IR指数相互比较,其差异有统计学意义（ P〈0.05）。观察到有少数患者出现不良反应,但均能耐受治疗。结论在原有口服降糖药物基础上加用利拉鲁肽能有效降低血糖,显著降低患者体重,并能改善胰岛β细胞功能,降低血脂、血压,且发生低血糖的风险低,是2型糖尿病患者治疗的新选择。     

胰岛素及其类似物治疗糖尿病进展

目的了解胰岛素及其类似物在治疗糖尿病中的应用进展。方法汇总文献资料,对胰岛素及其类似物在药代动力学、药理作用、疗效、不良反应等方面的研究进行总结。结果速效胰岛素、长效胰岛素和吸入胰岛素有独特的药代动力学;艾塞那肽和普兰林肽可以降低餐后高血糖,还可以延缓胃排空,减少能量摄入,使体质量降低。结论仍需要努力开发出更好的胰岛素制剂以便于糖尿病患者使用。     

Defining the role of insulin lispro in the management of postprandial hyperglycaemia in patients with type 2 diabetes mellitus

The role of postprandial hyperglycaemia in contributing to the risk of both micro- and macrovascular complications in patients with diabetes mellitus is being increasingly recognized. In type 2 diabetes, there is a progressive shift in the relative contributions of postprandial and fasting hyperglycaemia to the overall glycaemic control as the disease progresses. For patients with fairly good glycaemic control (glycosylated haemoglobin [HbA(1c)] <8.5%), postprandial hyperglycaemia makes a relatively greater contribution to the overall glycaemic load than fasting hyperglycaemia, but in patients with poorer control, the relative contribution of the two states to the overall glycaemic load is reversed. This finding, coupled with epidemiological evidence that elevated postprandial glucose concentration is an independent risk factor for cardiovascular disease (CVD), and is associated with a greater CVD risk than elevated fasting glucose, points to the need to monitor and target postprandial glucose, as well as fasting glucose and HbA(1c) levels, when optimizing insulin therapy for patients with type 2 diabetes. When insulin therapy becomes necessary in patients with type 2 diabetes who can no longer be controlled with oral antihyperglycaemic therapy, use of short-acting insulin analogues with a rapid onset of action and capable of controlling postprandial glycaemic excursions when injected immediately before a meal, has advantages over regular human insulin in that they provide a more favourable time-action profile that mimics normal physiological insulin secretion. Among the available rapid-acting insulin analogues, insulin lispro has been shown to reduce postprandial glucose concentrations to a significantly greater degree than regular human insulin in patients with type 2 diabetes. Moreover, premixed combinations of insulin lispro with the longer acting analogue neutral insulin lispro protamine suspension in 25% : 75% or 50% : 50% combinations are significantly more effective in lowering postprandial blood glucose concentrations than premixed regular human insulin plus neutral protamine Hagedorn (NPH) 30% : 70%. The premixed insulin lispro combinations offer the advantage of fewer daily injections than intensive insulin therapy, and the convenience of not having to mix insulin preparations manually. Although it has yet to be conclusively established that targeting postprandial hyperglycaemia reduces CVD risk, the potential benefits of improved postprandial and interprandial hyperglycaemia favour the use of newer insulin analogues, such as insulin lispro and insulin lispro mixes, over conventional insulin therapy, whenever insulin therapy becomes necessary in patients with type 2 diabetes.     

Study Reanalysis Using a Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Pramlintide in Subjects with Type 1 Diabetes

This report describes a pharmacokinetic/pharmacodynamic model for pramlintide, an amylinomimetic, in type 1 diabetes mellitus (T1DM). Plasma glucose and drug concentrations were obtained following bolus and 2-h intravenous infusions of pramlintide at three dose levels or placebo in 25 T1DM subjects during the postprandial period in a crossover study. The original clinical data were reanalyzed by mechanism-based population modeling. Pramlintide pharmacokinetics followed a two-compartment model with zero-order infusion and first-order elimination. Pramlintide lowered overall postprandial plasma glucose AUC (AUC_net) and delayed the time to peak plasma glucose after a meal (T _max). The delay in glucose T _max and reduction of AUC_net indicate that overall plasma glucose concentrations might be affected by differing mechanisms of action of pramlintide. The observed increase in glucose T _max following pramlintide treatment was independent of dose within the studied dose range and was adequately described by a dose-independent, maximum pramlintide effect on gastric emptying of glucose in the model. The inhibition of endogenous glucose production by pramlintide was described using a sigmoidal function with capacity and sensitivity parameter estimates of 0.995 for I _max and 23.8 pmol/L for IC₅₀. The parameter estimates are in good agreement with literature values and the IC₅₀ is well within the range of postprandial plasma amylin concentrations in healthy humans, indicating physiological relevance of the pramlintide effect on glucagon secretion in the postprandial state. This model may prove to be useful in future clinical studies of other amylinomimetics or antidiabetic drugs with similar mechanisms of action.     

甘精胰岛素与西格列汀联用治疗老年2型糖尿病临床观察

目的探讨甘精胰岛素联用西格列汀治疗高龄2型糖尿病的疗效及安全性。方法将78例60岁以上的2型糖尿病患者随机分成甘精胰岛素联用西格列汀组(G组)40例和生物合成预混30/70人胰岛素组(N组)38例,根据血糖情况调整用药剂量,治疗12周后比较两组的空腹血糖、餐后2 h血糖、糖化血红蛋白(HbA1c)、低血糖发生率及体重指数(BMI)。结果 G组在空腹2 h血糖和低血糖发生率方面均低于N组,两组比较差异有统计学意义(P<0.05);在餐后血糖、HbA1c和BMI方面两组比较差异无统计学意义(P>0.05)。结论甘精胰岛素与西格列汀联用对老年2型糖尿病患者是一种安全、有效且方便的治疗方案,低血糖发生率低,尤其是对认知力较差、活动不方便、视力差或合并多种慢性病的高龄2型糖尿病患者尤为适用。     

Preclinical pharmacology of pramlintide in the rat: Comparisons with human and rat amylin

The pancreatic β-cell hormone, amylin, is absent or reduced in individuals with type I diabetes mellitus and in many insulin-treated patients with type II diabetes. Amylin replacement therapy may be beneficial in these individuals, but the pharmaceutically inconvenient physicochemical properties of native human amylin led to the development instead of the amylin agonist, [Pro^25,28,29]human amylin, or pramlintide (formerly designated AC137). Here we compare for rat amylin, human amylin and pramlintide, receptor binding and biological actions in rats in vivo and in rat soleus muscle. In the rat, the spectrum of actions and pharmacokinetic and pharmacodynamic properties of pramlintide are either very similar to, or indistinguishable from, those of rat or human amylin. © 1996 Wiley-Liss, Inc.     

Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus.

The majority of patients with type 2 diabetes mellitus are overweight or obese at the time of diagnosis, and obesity is a recognised risk factor for type 2 diabetes and coronary heart disease (CHD). Conversely, weight loss has been shown to improve glycaemic control in patients with type 2 diabetes, as well as to lower the risk of CHD. The traditional pharmacotherapies for type 2 diabetes can further increase weight and this may undermine the benefits of improved glycaemic control. Furthermore, patients' desire to avoid weight gain may jeopardise compliance with treatment, thereby limiting treatment success and indirectly increasing the risk of long-term complications. This review evaluates the influences of established and emerging therapies on bodyweight in type 2 diabetes.Improvement in glycaemic control with insulin secretagogues has been associated with weight gain. On the other hand, biguanides such as metformin have been consistently shown to have a beneficial effect on weight; metformin appears to modestly reduce weight when used as a monotherapy. alpha-Glucosidase inhibitors are considered weight neutral; in fact, the results of some studies show that they cause reductions in weight.Thiazolidinediones (TZDs) are typically associated with weight gain and increased risk of oedema, while the impact of some TZDs, such as pioglitazone, on lipid homeostasis could be beneficial. Insulin, the most effective therapy when oral agents are ineffective, has always been linked to significant weight gain. Newly developed insulin analogues can lower the risk of hypoglycaemia compared with human insulin, but most have no advantage in terms of weight gain. The basal analogue insulin detemir, however, has been demonstrated to cause weight gain to a lesser extent than human insulin. The emerging treatments, such as glucagon-like peptide-1 agonists and the amylin analogue, pramlintide, seem able to decrease weight in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 inhibitors seem to be weight neutral.In summary, while reduction of hyperglycaemia remains the foremost goal in the treatment of patients with type 2 diabetes, the avoidance of weight gain may be a clinically important secondary goal. This is already possible with careful selection of available therapies, while several emerging therapies promise to further extend the options available.     

2型糖尿病患者合并脂肪肝的临床分析

目的探讨2型糖尿病患者脂肪肝和胰岛素抵抗、体重指数、血糖、血脂、血压的关系。方法采用病例对照研究,分两组,①2型糖尿病合并脂肪肝组;②2型糖尿病不伴脂肪肝组做对照。进行体重指数(BMI)、血脂、空腹和餐后2小时血糖(2hPBG)、胰岛素抵抗指数(HOMA-IR)的比较。结果2型糖尿病合并脂肪肝组的体重、BMI,舒张压、餐后2小时血糖、总胆固醇、甘油三酯、HOMA-IR明显高于2型糖尿病对照组(P<0.05)。结论TC,TG,HOMA-IR,BMI,LDL和糖尿病脂肪肝的形成有关。脂肪肝形成危险因素的Logistic回归分析,体重、2hPBG是2型糖尿病脂脂肝形成的最主要的危险因素。     

Dipeptidyl peptidase IV inhibitors: the next generation of new promising therapies for the management of type 2 diabetes

Type 2 diabetes is a chronic metabolic disease characterized by the presence of both fasting and postprandial hyperglycemia which is a result of pancreas beta-cell dysfunction, deficiency in insulin secretion, insulin resistance and/or increased hepatic glucose production. More recently, the role of other glucoregulatory hormones, including glucagon, amylin, and the gut peptide glucagon-like peptide (GLP)-1, and an increase in the rate of postmeal carbohydrate absorption have also been included as important pathophysiologic defects. Existing anti-diabetes medications are often unefficient at achieving sustained glycemic control because they predominantly address only a single underlying defect. A number of alternative therapies for type 2 diabetes are currently under development that take advantage of the actions of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide on the pancreatic beta-cell. One such approach is based on the inhibition of dipeptidyl peptidase IV (DPP-IV), the major enzyme responsible for degrading the incretins in vivo. DPP-IV exhibits characteristics that have allowed the development of specific inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes and type 2 diabetic patients. While enhancement of insulin secretion, resulting from blockade of incretin degradation, has been proposed to be the major mode of inhibitor action, there is also evidence that inhibition of gastric emptying, reduction in glucagon secretion, peripheral insulin sensitization and important effects on beta-cell differentiation and survival can potentially preserve beta-cell mass, and improve insulin secretory function and glucose handling in diabetic patients. The present article focuses on the preclinical and clinical data of DPP-IV inhibitors that make it unique therapeutic agents representing the next generation of antidiabetes drugs.     

Managed care perspective on three new agents for type 2 diabetes

BACKGROUND: Despite effective monotherapy for diabetes, approximately 50% of patients require additional medications after 3 years to achieve target glycosylated hemoglobin (A1C) < 7%. Three new agents, each the first in its therapeutic class with a unique mechanism of action, have been approved for the treatment of type 2 diabetes by the U.S. Food and Drug Administration: pramlintide in March 2005, exenatide in April 2005, and sitagliptin in October 2006. OBJECTIVE: To review the efficacy and safety of 3 new agents for type 2 diabetes (exenatide and pramlintide by subcutaneous injection and sitagliptin by oral administration) and to define their place in therapy given their relatively high cost and unknown long-term safety and efficacy. METHODS: A MEDLINE search (1950 to June 2007) for English-language articles of studies in human subjects was conducted using these search terms: type 2 diabetes, exenatide, pramlintide, and sitagliptin. This database was supplemented by systematic reviews and meta-analyses through December 2007 and reference citations from the articles identified in the MEDLINE search. RESULTS: Exenatide, pramlintide, and sitagliptin have all been shown to have a modest effect on reducing A1C. In several relatively short-term trials (generally 15-30 weeks in duration), exenatide injection has been shown to be safe and effective for patients with type 2 diabetes who are either at the maximum doses of or cannot tolerate metformin, sulfonylurea, and/or thiazolidinedione therapy and need to further decrease A1C by at least 0.5% to 1%. While weight loss of 1.5 kg to 2.5 kg associated with exenatide is modest, this effect is of obvious value in many patients with type 2 diabetes. Nausea is the most notable side effect with exenatide, occurring in up to 50% of patients within the first 8 weeks of therapy but decreasing to 5% to 10% by week 24. In addition, the risk for hypoglycemia increases 4- to 5-fold when used in combination with sulfonylureas. Like exenatide, pramlintide injection reduces A1C by approximately 0.5% to 1%, carries the advantage of modest weight loss (1.5 kg over 1 year), and has a high incidence of nausea. Pramlintide can also result in severe hypoglycemia because of its ability to enhance the effects of insulin, a concern given that it is only indicated for use in combination with insulin. Sitagliptin is an oral agent that can be used alone or in combination with other oral hypoglycemic agents and has been shown to reduce A1C by 0.5% to 0.7%. It has only been studied in short-term studies, to date, so the long-term safety and efficacy are unknown. There is potential for severe allergic and dermatologic reactions with sitagliptin. CONCLUSIONS: The 3 new agents for the management of type 2 diabetes have been shown to reduce A1C by no more than 1.0%, modest by comparison with insulin and the older oral agents. The 3 newer agents have either modest positive effects on body weight or are weight neutral. The longterm safety and efficacy of the 3 newer agents are unknown, and their cost is considerably higher than the first-line agents, metformin and sufonylureas, which are available by generic name. The newer agents offer treatment options in select patients, although their use should be reserved for patients who are not adequately managed by agents with known longterm efficacy and safety, which are often available at a lower cost.     

格列美脲联合胰岛素治疗2型糖尿病的临床观察

目的评价格列美脲联合胰岛素对2型糖尿病（T2DM）的临床疗效。方法 T2DM患者64例,均为单用胰岛素血糖控制欠佳者,随机分为观察组和对照组,观察组加用格列美脲2~4 mg/d,根据血糖调整胰岛素用量;对照组继续应用胰岛素治疗,并根据血糖加大剂量。12周后观察治疗前后空腹血糖（FBG）、餐后2 h血糖（2 hBG）、糖化血红蛋白（HbA1c）、体重指数（BMI）、每日胰岛素用量变化以及药物不良反应。结果治疗后观察组FBG、2 hBG、HbA1c较对照组明显降低,胰岛素用量减少（P〈0.05）;所有入选者共发生低血糖6例,其中观察组2例,对照组4例。结论 T2DM单用胰岛素血糖控制不佳者,加用格列美脲可显著改善血糖控制,低血糖发生率低,并可减少胰岛素用量。