Rationale for treatment options for mealtime glucose control in patients with type 2 diabetes

While glycemic control is routinely assessed using HbA1c and fasting glucose measures, postprandial glucose (PPG) is also an important contributor of overall glycemia. Furthermore, PPG excursions have been linked to complications of diabetes. This review examines the effects of glucose-lowering therapies (including treatments administered at mealtime) on postprandial hyperglycemia in patients with type 2 diabetes. A PubMed search was conducted to identify clinical studies of treatments for mealtime glucose control in type 2 diabetes. Different treatments may have comparable effects on HbA1c but varying effects on PPG control and glucose fluctuations. Older classes of oral glucose-lowering treatments administered at mealtime to lower PPG include meglitinides and α-glucosidase inhibitors. Injectable therapies, including prandial insulin analogs, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and the amylin analog pramlintide, all effectively target postprandial hyperglycemia. Compared with longer-acting GLP-1RAs, short-acting GLP-1RAs, such as exenatide twice daily and lixisenatide once daily, have a greater effect on PPG control, which is primarily mediated by a more pronounced effect on delayed gastric emptying. Dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors also reduce postprandial hyperglycemia. To achieve more physiologically normal glycemic control, choice of therapy should ideally aim to address daily glucose fluctuations, including hyperglycemic peaks and hypoglycemic troughs, and long-term glycemic control.     

Albiglutide: a unique GLP-1 receptor agonist

ABSTRACT

Introduction: Albiglutide is a long acting GLP-1 receptor agonist (GLP-1 RA) administered by weekly injection.

Area covered: The pharmacokinetic and pharmacodynamic properties of albiglutide and its clinical effects are discussed. The review encompassed a search of PubMed and a thorough analysis of the European Union and US Food and Drug Administration approval documents.

Expert opinion: Albiglutide has a chemical structure quite distinct from that of other marketed GLP-1 RAs. The agent has less gastrointestinal side effects than other comparable GLP-1 RAs and is safe in patients with renal failure. As a sole treatment for diabetes and used with other hypoglycemic agents, it achieves a lowering of HbA1c of up to 1%, less than several competitor GLP-1 RAs. The benefit on weight reduction is minimal compared to other GLP-1 RAs. There exists concern about an imbalance of pancreatitis cases in the approval program as well as injection site reactions which led to discontinuance of therapy in up to 2% of participants. A large long term study now underway will determine if albiglutide, with its lower level of GI intolerance, has a place in the treatment of patients with increased risk of cardiovascular events.     

Differential effects of prandial and non-prandial GLP-1 receptor agonists in type 2 diabetes therapy

In type 2 diabetes mellitus (T2DM), decreased pancreatic beta-cell function and increased insulin resistance contribute to a steady decline in glucose homeostasis. Maintaining levels of glycated hemoglobin ≤7.0% is thought to reduce the microvascular and possibly macrovascular complications that result if T2DM is not properly managed. Recent guidelines have recognized the importance of postprandial glucose (PPG) control in reducing cardiovascular risks, and have recommended a more patient-centered approach. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) mimic the action of the endogenous gastrointestinal hormone GLP-1 to activate the insulin response in pancreatic beta cells in a glucose-dependent manner. Prandial GLP-1 RAs have a short plasma half-life and are particularly effective at targeting PPG elevations, whereas long-acting non-prandial GLP-1 RAs are more effective at reducing fasting plasma glucose. These differences highlight the potential for treatment with these agents to be tailored to the need of individual patients and their glycemic imbalance. All GLP-1 RAs are being evaluated in long-term cardiovascular outcome trials. To date, the only cardiovascular trial that has been completed is the ELIXA trial for lixisenatide, which was found to meet the pre-specified criterion of non-inferiority versus placebo in terms of cardiovascular outcomes.     

User’s guide to mechanism of action and clinical use of GLP-1 receptor agonists

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are injectable glucose-lowering medications approved for the treatment of adult patients with type 2 diabetes mellitus (T2DM). This article provides practical information to guide primary care physicians on the use of GLP-1RAs in patients with T2DM. Two short-acting (once- or twice-daily administration; exenatide and liraglutide) and three long-acting (weekly administration; albiglutide, dulaglutide and exenatide) GLP-1RAs are currently approved in the US. These drugs provide levels of GLP-1 receptor agonism many times that of endogenous GLP-1. The GLP-1RAs have been shown to significantly improve glycemic parameters and reduce body weight. These agents work by activating GLP-1 receptors in the pancreas, which leads to enhanced insulin release and reduced glucagon release—responses that are both glucose-dependent—with a consequent low risk for hypoglycemia. Effects on GLP-1 receptors in the CNS and the gastrointestinal tract cause reduced appetite and delayed glucose absorption due to slower gastric emptying. The most common adverse effects are gastrointestinal, which are transient and less common with the long-acting drugs. GLP-1RAs are recommended as second-line therapy in combination with metformin, sulfonylureas, thiazolidinediones or basal insulin, providing a means of enhancing glucose control while offsetting the weight gain associated with insulin and some oral agents. GLP-1RAs represent a useful tool that the primary care physician can use to help patients with T2DM achieve their therapeutic goals.     

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.     

The Role of the Pharmacist in Managing Type 2 Diabetes with Glucagon-Like Peptide-1 Receptor Agonists as Add-On Therapy

The prevalence and associated clinical burden of type 2 diabetes (T2D) is increasing in the USA and other countries. As a consequence, the role of the pharmacist in managing T2D is expanding, and it is becoming increasingly important for pharmacists to have a complete understanding of the disease course and treatment options. Pharmacists have a key role in the use of injectable therapies, including incretin-based treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This article discusses the role of the pharmacist in the management of patients with T2D, particularly with respect to the use of GLP-1RAs to achieve glycemic control. GLP-1RAs are a class of injectable agents used as an adjunct to diet and exercise to improve glycemic control in adults with T2D. GLP-1RAs have been shown to lower glucose levels, slow gastric emptying, enhance satiety, and reduce body weight without increasing the risk of hypoglycemia. GLP-1RAs currently approved in the USA include exenatide twice daily, liraglutide once daily, and albiglutide, dulaglutide, and exenatide once weekly. Pharmacists can work with physicians to help identify patients for whom GLP-1RA therapy is appropriate. In addition, pharmacists can educate patients regarding medication storage, preparation, and injection techniques, glycated hemoglobin (HbA_1c) targets, pre- and post-meal blood glucose goals, adverse events and management strategies, and the long-term benefits of reducing HbA_1c. As members of the diabetes care team, pharmacists play an important role in improving patient outcomes. Funding: AstraZeneca.     

Combination therapy with SGLT-2 inhibitors and GLP-1 receptor agonists as complementary agents that address multi-organ defects in type 2 diabetes

ABSTRACT

Type 2 diabetes (T2D) has a complex pathophysiology composed of multiple underlying defects that lead to impaired glucose homeostasis and the development of macrovascular and microvascular complications. Of the currently available glucose-lowering therapies, sodium–glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) both provide effective glycemic control and have been shown to reduce cardiovascular (CV) events in patients with T2D and a high CV risk or established CV disease. Because these agents have complementary mechanisms of action, they are able to act on multiple defects of T2D when used in combination. This review discusses the rationale for and potential benefits of SGLT-2i plus GLP-1RA combination therapy in patients with T2D. A search of the PubMed database was conducted for studies and reviews describing the combined use of SGLT-2is and GLP-1RAs, with a specific focus on identifying clinical studies of combination therapy in patients with T2D. In clinical studies, glycated hemoglobin (A1c) was significantly reduced over 28–52 weeks with SGLT-2i plus GLP-1RA therapy versus the individual agents or baseline. Several CV risk factors, including body weight, blood pressure, and lipid parameters, were also improved. SGLT-2i plus GLP-1RA therapy was generally well tolerated, with a low risk of hypoglycemia and no unexpected findings. Taken together with results from large CV outcomes trials of SGLT-2is and GLP-1RAs, combination therapy with these agents potentially provides effective durable glycemic control and CV benefits due to their complementary actions on the defects of T2D.     

Treatment of Hyperthyroidism

Abstract

Albiglutide is a glucagon-like peptide-1 analogue composed of tandem copies of modified human glucagon-like peptide-1 (7–36) coupled to recombinant human albumin that is approved in adults for the treatment of type 2 diabetes mellitus. After subcutaneous administration, albiglutide is likely primarily absorbed via the lymphatic circulation, with maximum concentrations being reached in 3 to 5 days; steady-state exposures are achieved following approximately 4 to 5 weeks of once-weekly administration. The elimination half-life of albiglutide is approximately 5 days. Clearance of albiglutide is 67 mL/h with between-subject variability of 34.9%; no covariates have been identified that would require dose adjustment of albiglutide. Albiglutide lowers the fasting plasma glucose and reduces postprandial glucose excursions. In addition, β-cell secretion is enhanced by albiglutide during hyperglycemia, whereas secretion is suppressed during hypoglycemia; α-cell response to hypoglycemia is not impaired by albiglutide. Albiglutide does not prolong the corrected QT interval but has a modest effect on heart rate in patients with type 2 diabetes mellitus. Dose adjustment is not suggested in patients with renal impairment, but experience in patients with severe renal impairment is very limited, and it is recommended that albiglutide be used with care in such patients due to an increased frequency of diarrhea, nausea, and vomiting. No clinically relevant drug interactions have been observed in clinical trials. Trial Registration: NCT00938158, NCT01406262, NCT00537719, NCT01077505, NCT01147731, NCT01147718, NCT01147692, NCT00354536, NCT00394030, NCT00530309, NCT01357889, NCT00518115, NCT01098461, NCT01475734, NCT00849017, NCT00838916, NCT00839527, NCT01098539.     

The once-daily human glucagon-like peptide-1 (GLP-1) analog liraglutide improves postprandial glucose levels in type 2 diabetes patients

Introduction  

Fasting and postprandial plasma glucose (FPG, PPG) control are both necessary to achieve glycosylated hemoglobin (HbA_1c) regulation goals. Liraglutide, based on its glucagon-like peptide 1 (GLP-1)-mediated pharmacology and pharmacokinetics may reduce HbA_1c through both FPG and PPG levels. The objective of the present study was to investigate the effect of once-daily liraglutide (0.6, 1.2, and 1.8 mg) at steady state on FPG, PPG, postprandial insulin, and gastric emptying.     

全面评估，合理决策:基于胰高血糖素样肽1受体激动剂用药风险的最新发现

胰高血糖素样肽1受体激动剂(glucagon-like peptide-1 receptor agonists, GLP-1RAs)作为一种新型降糖药物,被广泛应用于2型糖尿病的治疗。GLP-1RAs能够有效降低血糖且低血糖风险小,此外,GLP-1RAs减重效果显著,兼具一定的心血管及肾脏保护作用; 轻中度胃肠道症状是GLP-1RAs最常见的不良反应,一般随时间延长可逐渐减轻。最新研究显示,GLP-1RAs的使用与胆囊或胆道疾病发生风险相关,尤其在高剂量、长时间使用以及用于减重治疗时,风险显著增加,但胆囊或胆道疾病的绝对风险不高。临床医生需全面权衡GLP-1RAs使用的获益与风险,并与患者共同作出合理决策。     

Mechanisms and Clinical Efficacy of Lixisenatide for the Management of Type 2 Diabetes

Introduction

“Incretin-based” therapies, such as the glucagon-like peptide-1 (GLP-1) receptor agonists, represent a major advance in type 2 diabetes mellitus (T2DM) treatment. GLP-1 receptor agonists differ substantially in their duration of action, frequency of administration and clinical profile.

Methods

This article reviews the mechanisms of action and clinical evidence for GLP-1 receptor targeting and discusses differences between GLP-1 therapies, focusing particularly on clinical data for the GLP-1 receptor agonist, lixisenatide.

Results

GLP-1 therapies target islet cell “defects” of insufficient insulin and excessive glucagon secretion in T2DM, in a glucose-dependent manner, with minimal risk of hypoglycemia. Different GLP-1 therapies exert differential effects on fasting and postprandial glycemia (both being major determinants of glycemic control). They also slow gastric emptying to different extents, probably accounting for different effects to reduce postprandial glycemia. The GetGoal phase 3 studies in T2DM have confirmed the efficacy of once-daily lixisenatide in reducing plasma glucose and glycated hemoglobin (HbA_1c), with a pronounced lowering of postprandial plasma glucose (PPG), as monotherapy and as add-on to oral antidiabetic drugs and to basal insulin. Lixisenatide’s ability to diminish PPG is probably partly mediated by its marked ability to delay gastric emptying. Lixisenatide is generally well tolerated, with possibly better gastrointestinal tolerability and lower risk of hypoglycemia than exenatide immediate release. Lixisenatide is associated with a beneficial effect on weight, with either no change or a decrease in body weight when administered as add-on therapy to basal insulin in overweight patients with T2DM.

Conclusions

Lixisenatide improves glycemic control, by primarily affecting PPG, while preventing weight gain or reducing body weight with a low risk of hypoglycemia in T2DM. Lixisenatide is likely to represent a significant advance in the management of T2DM, perhaps particularly in those patients with relatively faster gastric emptying and lower levels of HbA_1c, including those receiving basal insulin.     

Current treatments and strategies for type 2 diabetes: can we do better with GLP-1 receptor agonists?

Abstract Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, -0.8 to -1.1%; liraglutide, -0.8 to -1.6%), as has weight loss (exenatide, -1.6 to -3.1 kg; liraglutide, -1.6 to -3.2 kg). GLP-1 RAs also stimulate β-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM.     

Current treatments and strategies for type 2 diabetes: Can we do better with GLP-1 receptor agonists?

Abstract

Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, ?0.8 to ?1.1%; liraglutide, ?0.8 to ?1.6%), as has weight loss (exenatide, ?1.6 to ?3.1 kg; liraglutide, ?1.6 to ?3.2 kg). GLP-1 RAs also stimulate β-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM.     

Postprandial peaks as a risk factor for cardiovascular disease: epidemiological perspectives

A key issue in diabetes care is selecting glucose parameters to monitor and control. The recommendations of the American Diabetes Association for glycaemic control do not address postprandial glucose (PPG), but patients with type 2 diabetes experience wide variations in glucose levels after meals. We have observed a remarkable increase in plasma glucose two hours after breakfast and/or lunch in most non-insulin-treated patients; for up to 40% of them the increase is >40 mg/dl (2.2 mmol/l). As many as 70% of patients with an HbA1c <7% have PPG values >160 mg/dl (8.9 mmol/l) after meals. Fasting plasma glucose (FPG) is a poor indicator of plasma glucose at other times. The coefficient of correlation of FPG with plasma glucose at other times ranges from 0.50-0.70. Nor is the correlation of FPG with HbA1c very strong: in hundreds of determinations of HbA1c and FPG in our patients, the coefficient of correlation was not greater than 0.73. For the same FPG value, HbA1c varied markedly, and vice versa; further, the correlation between PPG and HbA1c was no higher than that between FPG and HbA1c (r = 0.65). Thus, monitoring in type 2 diabetes should include PPG along with FPG and HbA1c. Recent data provide direct and indirect evidence suggesting that PPG is independently related to cardiovascular disease (CVD), and supporting the idea that PPG should be assessed and glucose excursions with meals should be controlled: 1. Studies conducted by other investigators and ourselves in patients with type 2 diabetes have shown that the incidence of CVD is independently related to postprandial or post-OGTT (oral glucose tolerance test) blood glucose at baseline. In addition, data collected in the general population show an association between 2-hour OGTT plasma glucose (a surrogate of PPG) and cardiovascular morbidity and mortality that is independent of FPG. Also, subjects with impaired glucose tolerance (IGT) and isolated post-challenge hyperglycaemia have an increased cardiovascular risk over subjects with normal glucose tolerance (NGT). We found that IGT subjects had a risk of carotid stenosis 3-fold higher than subjects with NGT, even after adjustment for several confounders. Thus, a modest increase in post-OGTT plasma glucose and, by extrapolation, PPG seems to have a major detrimental effect on the arteries. 2. When FPG and/or HbA1c were the targets of glucose control in studies of patients with type 2 diabetes (the UGDP, VACSDM, and UKPDS) the effects on CVD were minimal. However, when the targets of glucose control included PPG (the Kumamoto Study and DIGAMI Study) favorable effects on CVD were observed. 3. There is experimental data suggesting that acute hyperglycaemia can exert deleterious effects on the arterial wall through mechanisms including oxidative stress, endothelial dysfunction, and activation of the coagulation cascade. This evidence prompted the European Diabetes Policy Group to set postprandial targets for blood glucose control: postprandial peaks should not exceed 135 mg/dl (7.5 mmol/ml) to reduce arterial risk and should not exceed 160 mg/dl (8.9 mmol/l) to reduce microvascular risk. Thus, glucose care in diabetes is not only "fasting glucose care" or "HbA1c care" but is also "postprandial glucose care."     

Albiglutide: a new GLP-1 analog for the treatment of type 2 diabetes

Importance of the field: Despite the wide array of treatments available, a significant number of patients with type 2 diabetes continue to remain uncontrolled. The discovery of the incretin hormones and their role in glucose homeostasis has brought about a new class of medications called the glucagon-like peptide-1 (GLP-1) analogs. This new class of medications provides the benefits of weight loss as well as a lack of hypoglycemia. However, the currently available agents require once or twice daily injections.

Areas covered in this review: Relevant literature will be discussed on albiglutide, a new GLP-1 analog in Phase III clinical trials. Several clinical trials examining the use of albiglutide as combination therapy are currently ongoing.

What the reader will gain: To date, results of clinical trials suggest that albiglutide may provide a more attractive dosing profile compared with the currently available GLP-1 analogs.

Take home message: The results of ongoing trials will help define the role of albiglutide in treating patients with type 2 diabetes.     

Effects of LX4211, a Dual Sodium-Dependent Glucose Cotransporters 1 and 2 Inhibitor,on Postprandial Glucose,Insulin, Glucagon-like Peptide 1, and Peptide Tyrosine Tyrosine in a Dose-Timing Study in Healthy Subjects

Background

LX4211 is a first-in-class dual inhibitor of sodium-dependent glucose cotransporters 1 and 2 (SGLT1 and SGLT2). SGLT1 is the primary transporter for glucose absorption from the gastrointestinal tract, and SGLT2 is the primary transporter for glucose reabsorption in the kidney. SGLT1 inhibition reduces postprandial glucose (PPG) levels and increases the release of gastrointestinal peptides such as glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY), whereas SGLT2 inhibition results in increased urinary glucose excretion (UGE).

Objectives

This study evaluated how timing of dose relative to meals changes the pharmacodynamic (PD) effects of LX4211 treatment, including effects on UGE, fasting plasma glucose, PPG, insulin, total and active GLP-1, and PYY. The safety and tolerability of LX4211 in healthy subjects were also assessed.

Methods

This was a randomized, double-blind, placebo-controlled, multiple-dose study to determine the PD effects of LX4211 dose timing relative to meals in 12 healthy subjects. Blood and urine were collected for the analysis of PD variables.

Results

Twelve healthy subjects 30 to 51 years of age were enrolled and treated. Treatment with LX4211 resulted in significant elevation of total and active GLP-1, and PYY while significantly decreasing PPG levels relative to placebo, likely by reducing SGLT1-mediated intestinal glucose absorption. Comparisons performed among the dosing schedules indicated that dosing immediately before breakfast maximized the PD effects of LX4211 on both SGLT1 and SGLT2 inhibition. The comparative results suggested distinct SGLT1 effects on GLP-1, PYY, glucose, and insulin, which were separate from SGLT2-mediated effects, indicating that SGLT1 inhibition with LX4211 may be clinically meaningful. All treatments were well tolerated with no evidence of diarrhea with LX4211 treatment.

Conclusions

This clinical study indicates that dosing of LX4211 immediately before breakfast maximized the PD effects of both SGLT1 and SGLT 2 inhibition and provided a convenient dosing schedule for future trials. LX4211 was safe and well tolerated and, due to its SGLT1 inhibition, produced strong PPG reductions and low UGE relative to selective SGLT2 inhibitors. LX4211 may provide a promising new therapy for patients with type 2 diabetes mellitus. The potential long-term clinical benefits and safety of LX4211 treatment will need to be confirmed in large clinical trials. ClinicalTrials.gov identifier: NCT01334242.     

Lixisenatide Treatment for Older Patients with Type 2 Diabetes Mellitus Uncontrolled on Oral Antidiabetics: Meta-Analysis of Five Randomized Controlled Trials

Aim

Evaluate the efficacy and safety of lixisenatide, a once-daily prandial glucagon-like peptide-1 receptor agonist, in older patients with type 2 diabetes mellitus (T2DM) insufficiently controlled on oral antidiabetics (OADs).

Methods

A meta-analysis was conducted on data from older patients (≥65 years) from five of the GetGoal trials, in which patients with T2DM were treated with lixisenatide 20 µg once daily or placebo, as an add-on to OADs. The primary endpoint in all trials was change from baseline at week 24 in glycated hemoglobin (HbA_1c). Other endpoints included changes in post-prandial plasma glucose (PPG), fasting plasma glucose (FPG) and weight. Composite and safety endpoints were also analyzed.

Results

A total of 501 patients aged ≥65 years were included in this meta-analysis: 304 received lixisenatide plus OADs and 197 received placebo as add-on to OADs. Lixisenatide as an add-on to OADs significantly reduced HbA_1c, PPG, FPG and weight, with placebo-corrected treatment effects at week 24 of ?0.54% (p < 0.0001), ?126 mg/dL (p < 0.0001), ?13 mg/dL (p = 0.0005) and ?0.90 kg (p = 0.0021), respectively. Patients receiving lixisenatide plus OADs were significantly more likely to achieve composite (HbA_1c levels <7%, HbA_1c levels <7% and no symptomatic hypoglycemia, and HbA_1c levels <7%, no weight gain and no symptomatic hypoglycemia) and safety endpoints than those receiving placebo plus OADs. Symptomatic hypoglycemia was experienced by 8.55% and 3.55% of patients in the lixisenatide plus OADs and placebo plus OADs groups, respectively (p = 0.0276), although no serious hypoglycemic episodes were reported.

Conclusions

Lixisenatide plus OADs improved glycemic control in older patients inadequately controlled on OADs compared with placebo plus OADs. Lixisenatide is well tailored to the pathophysiology of T2DM in older patients.     

Safety and efficacy of a glucagon-like peptide-1 receptor agonist added to basal insulin therapy versus basal insulin with or without a rapid-acting insulin in patients with type 2 diabetes: results of a meta-analysis

Objective: To consolidate the evidence from randomized controlled trials evaluating the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as add-on to basal insulin therapy in type 2 diabetes (T2D) patients.

Research design and methods: We searched the EMBASE® and NCBI PubMed (Medline) databases and relevant congress abstracts for randomized controlled trials evaluating the efficacy and safety of GLP-1 RAs as add-on to basal insulin compared with basal insulin with or without rapid-acting insulin (RAI) through 23 May 2016. The pooled data were analyzed using a random-effects meta-analysis model. A subanalysis was performed for trials investigating basal insulin plus GLP-1 RAs versus basal insulin plus RAI.

Results: Of the 2617 retrieved records, 19 randomized controlled trials enrolling 7,053 patients with T2D were included. Compared with basal insulin ± RAI, reduction in glycated hemoglobin (HbA1c) from baseline (difference in means: –0.48% [95% confidence interval (CI), –0.67 to –0.30]; p < 0.0001) and weight loss (–2.60 kg [95% CI, –3.32 to –1.89]; p < 0.0001) were significantly greater with basal insulin plus GLP-1 RA. The subanalysis similarly showed significant results for change in HbA1c from baseline and for weight loss, as well as a significantly lower risk of symptomatic hypoglycemia in patients treated with basal insulin plus GLP-1 RA versus basal insulin plus RAI (odds ratio, 0.52 [95% CI, 0.42 to 0.64]; p < 0.0001).

Conclusions: Addition of GLP-1 RA to basal insulin provided improved glycemic control, led to weight reduction and similar hypoglycemia rates versus an intensified insulin strategy; however, symptomatic hypoglycemia rates were significantly lower when compared with a basal insulin plus RAI.     

Potential of Albiglutide, a Long-Acting GLP-1 Receptor Agonist, in Type 2 Diabetes: A randomized controlled trial exploring weekly, biweekly, and monthly dosing

OBJECTIVE

To evaluate the efficacy, safety, and tolerability of incremental doses of albiglutide, a long-acting glucagon-like peptide-1 receptor agonist, administered with three dosing schedules in patients with type 2 diabetes inadequately controlled with diet and exercise or metformin monotherapy.

RESEARCH DESIGN AND METHODS

In this randomized multicenter double-blind parallel-group study, 356 type 2 diabetic subjects with similar mean baseline characteristics (age 54 years, diabetes duration 4.9 years, BMI 32.1 kg/m², A1C 8.0%) received subcutaneous placebo or albiglutide (weekly [4, 15, or 30 mg], biweekly [15, 30, or 50 mg], or monthly [50 or 100 mg]) or exenatide twice daily as an open-label active reference (per labeling in metformin subjects only) over 16 weeks followed by an 11-week washout period. The main outcome measure was change from baseline A1C of albiglutide groups versus placebo at week 16.

RESULTS

Dose-dependent reductions in A1C were observed within all albiglutide schedules. Mean A1C was similarly reduced from baseline by albiglutide 30 mg weekly, 50 mg biweekly (every 2 weeks), and 100 mg monthly (−0.87, −0.79, and −0.87%, respectively) versus placebo (−0.17%, P < 0.004) and exenatide (−0.54%). Weight loss (−1.1 to −1.7 kg) was observed with these three albiglutide doses with no significant between-group effects. The incidence of gastrointestinal adverse events in subjects receiving albiglutide 30 mg weekly was less than that observed for the highest biweekly and monthly doses of albiglutide or exenatide.

CONCLUSIONS

Weekly albiglutide administration significantly improved glycemic control and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability profile.Early intervention to improve glycemic control reduces microvascular complications in type 2 diabetes (1–4) and may provide long-term macrovascular benefits (5). Despite numerous available therapies, over half of patients with type 2 diabetes are unable to achieve the American Diabetes Association (ADA) target A1C level (<7%) (6–8). Moreover, weight gain and treatment-induced hypoglycemic episodes (9,10) are major barriers to achieving glycemic control (10).Antidiabetic therapies based on glucagon-like peptide-1 (GLP-1) retain the ability of native GLP-1 to stimulate glucose-dependent insulin secretion and suppress inappropriately elevated glucagon secretion (11,12). Native GLP-1 also slows gastric emptying and reduces food intake, which leads to modest weight loss (11). However, native GLP-1 is rapidly inactivated (half-life 1–2 min) by dipeptidyl peptidase-4 (DPP-4), limiting its therapeutic potential (13). Exenatide (half-life 2.4 h) improves glycemic control in combination with metformin, a sulfonylurea, or a thiazolidinedione (14–18). Despite modest weight loss and improved glycemic control, gastrointestinal (GI) intolerability and twice-daily administration may lead to discontinuation (19).Albiglutide (formerly known as albugon) is a GLP-1 receptor agonist developed through the fusion of two repeats of human GLP-1 (7–36) molecules to recombinant human albumin (20). The GLP-1 dimer was used to avoid potential reductions of the interaction of the GLP-1 moiety of the monomer with its receptor in the presence of albumin. A single amino acid substitution (ala8→gly) renders the molecule resistant to DPP-4. The structure of albiglutide provides an extended half-life (∼5 days), which may allow weekly or less frequent dosing. Furthermore, albiglutide is relatively impermeant to the central nervous system (21), which may have implications for GI tolerability. In nonclinical studies, albiglutide stimulated cAMP production through the GLP-1 receptor and induced insulin secretion from INS-1 cells in vitro and in animal models (21–22). It also delayed gastric emptying and reduced food intake in rodents (21–23).This study was designed to explore a wide range of doses (4–100 mg) and schedules (weekly to monthly) to assess glycemic control and adverse event profiles for albiglutide. Exenatide was included as an open-label reference to provide clinical perspective for a GLP-1 receptor agonist.     

Comparison between repaglinide and glimepiride in patients with type 2 diabetes mellitus: a one-year,randomized, double-blind assessment of metabolic parameters and cardiovascular risk factors

BACKGROUND: Repaglinide and glimepiride are relatively new oral hypoglycemic agents. Few data are available concerning their effects on metabolic parameters other than measures of glycemic control. OBJECTIVES: In addition to assessing the effects of repaglinide and glimepiride on glycemic control in patients with type 2 diabetes mellitus, this study also examined the effects of these agents on 3 metabolic parameters known to be cardiovascular risk factors--lipoprotein(a) (Lp[a]), plasminogen activator inhibitor-1 (PAI-1), and homocysteine (Hcy). METHODS: This randomized, placebo-controlled, double-blind trial was conducted at a single center in Italy. Eligible patients were nonsmokers; had no hypertension or coronary heart disease; were taking no hypolipidemic drugs, diuretics, beta-blockers, or thyroxin; and had normal renal function. After an initial 4-week placebo washout period, patients were randomized to receive repaglinide 1 mg/d or glimepiride 1 mg/d. The dose of study drug was optimized over an 8-week titration period, which was followed by a 12-month treatment period. Measures of glycemic control (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPG], fasting plasma insulin [FPI], postprandial plasma insulin [PPI]) and the other metabolic parameters of interest were assessed after 6 and 12 months of treatment. RESULTS: One hundred twenty-four patients (63 women, 61 men) completed the study, 62 in each treatment group. There were no significant differences in demographic characteristics between groups. After 6 and 12 months of treatment, FPG levels and HbA1c values were significantly reduced from baseline in both groups (6 months, P < 0.05; 12 months, P < 0.01). After 6 months, PPG levels were significantly decreased only in the repaglinide group (P < 0.05 vs baseline); at 12 months, however, PPG levels were significantly reduced from baseline in both groups (P < 0.01 repaglinide, P < 0.05 glimepiride). No significant changes from baseline in FPI or PPI levels were seen in either group at 6 months, although FPI levels were significantly increased in the repaglinide group at 12 months (P < 0.05). Repaglinide significantly lowered levels of Lp(a), PAI-1, and Hcy after 12 months (all, P < 0.05 vs baseline). Glimepiride significantly lowered levels of Lp(a) and Hcy after 6 months (both, P < 0.05 vs baseline) and levels of Lp(a) (P < 0.01 vs baseline), Hcy (P < 0.01 vs baseline), and PAI-1 (P < 0.05 vs baseline) after 12 months. CONCLUSIONS: Repaglinide and glimepiride improved glycemic control and reduced levels of other metabolic parameters of interest in this population of patients with type 2 diabetes. It is possible that the reductions in Lp(a), PAI-1, and Hcy were the result of improved glucose metabolism; however, the possibility that repaglinide and glimepiride may have a direct effect on these parameters should not be excluded.