Investigational glucagon-like peptide-1 agonists for the treatment of obesity

Introduction: Obesity is a worldwide problem predisposing to type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease, cancer and other comorbidities. Lifestyle modification is the first line intervention but adjunctive pharmacotherapy is often required. The GLP-1 receptor agonists (GLP-1RAs) were developed primarily for T2DM and they also reduce body weight. Liraglutide was approved for the treatment of obesity and other GLP-1RAs are likely to be suitable for this indication.

Areas covered: This review describes the GLP-1RAs that have been approved for the treatment of T2DM as potential candidates for the treatment of obesity and the new agents currently under development which may have advantages in patient adherence.

Expert opinion: The GLP-1RAs offer a welcome addition to obesity pharmacotherapy. They appear to be free of serious adverse effects although uncertainty remains about possible risks of pancreatitis and neoplasms. However, they have frequent gastrointestinal side effects, particularly nausea, which limits their tolerability. Cardiovascular outcome studies in T2DM support their use and this is likely to increase in both T2DM and obesity. Other GLP-1RAs which can be given by subcutaneous injection once weekly or less frequently or by oral administration would have advantages especially if nausea is less frequent than with liraglutide.     

Spotlight on Canagliflozin 300: review of its efficacy and an indirect comparison to other SGLT-2 inhibitors and long-acting GLP-1 receptor agonists

Introduction: Both sodium-glucose co-transporter-2 inhibitors (SGLT-2Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been consistently found to lower blood glucose, body weight and systolic blood pressure (SBP) in patients with type 2 diabetes mellitus (T2DM). While all the SGLT-2Is inhibit glucose reabsorption by blocking SGLT-2 receptor in kidney, dose-dependently, the highest licensed dose of canagliflozin 300-mg has an additional ability to inhibit SGLT-1 receptor in intestine transiently, that may lead to additional inhibition of prandial glucose absorption, unlike other approved highly selective SGLT-2Is.

Areas covered: An electronic search on studies with highest licensed dose of all approved SGLT-2Is and long-acting GLP-1RAs was made up to December 2016. We systemically reviewed the studies of canagliflozin 300-mg and compared its glucose, body weight and SBP lowering with other approved SGLT-2Is and GLP-1RAs in their highest approved doses.

Expert commentary: From the available evidences, it appears that canagliflozin 300-mg may have the highest potential to improve gluco-metabolic profile in T2DM, amongst the SGLT-2Is class. While the highest approved dosage of GLP-1RAs lowered HbA1c better than canagliflozin 300-mg, weight and SBP lowering could be non-inferior or slightly better with the latter drug. Nonetheless, only head-to-head trial can conclusively answer these questions.     

An overview of new GLP-1 receptor agonists for type 2 diabetes

Introduction: The increasing prevalence of type 2 diabetes mellitus (T2DM) and the eventual need for multiple medications in most patients stimulated the development of new drug classes to reduce plasma glucose levels. The GLP-1 receptor agonists (GLP-1RAs) are established as an option for treatment of T2DM after metformin. They are also effective in reducing body weight but current GLP-1RAs have to be given by subcutaneous injection daily or once weekly.

Areas covered: This review focuses on the new GLP-1RAs currently undergoing development, some of which require less frequent subcutaneous administration and others that are being developed in oral formulations that may favor patient adherence.

Expert opinion: The new GLP-1RAs may have the benefit of requiring less frequent subcutaneous dosing or being active by oral administration. However, cardiovascular outcome trials have shown that DPP4 inhibitors are neutral for cardiovascular events and the first cardiovascular outcome trial with lixisenatide reported similar results, whereas the trial with the SGLT2 inhibitor empagliflozin showed a reduction in cardiovascular events. These findings in patients with high cardiovascular risk may favor the use of SGLT2 inhibitors as a second line treatment after metformin but there should still be an important role for novel GLP-1RAs, especially when weight reduction is required.     

Glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes:real-world evidence from a Mediterranean area

Aims: To assess clinical characteristics and factors associated with glycated hemoglobin (HbA1c) reduction in type 2 diabetes (T2DM) patients initiating glucagon-like peptide-1 receptor agonists (GLP-1RAs).

Methods: Retrospective cohort study in patients with T2DM who initiated GLP-1RAs between 2007 and 2014 in primary health care centers in Catalonia (Spain). We evaluated changes in HbA1c and body weight at 6–12?months, and factors independently associated with achieving ≥1% HbA1c target reduction.

Results: Overall, 4242 patients (47.9% male; mean BMI 37.5?kg/m²) initiated a GLP-1RA. At 6–12?months, the mean HbA1c level decreased from the baseline 8.8% to 7.7% (?1.0%; SD?=?1.6). A 1% reduction in HbA1c was observed in 47.2% of patients. Patients lost a mean of 3.6?kg (SD?=?6.2). Sixty percent of patients reduced both HbA1c and body weight, and 17% achieved only one of these targets. Independent determinants of a 1% HbA1c reduction were baseline HbA1c, age, diabetes duration and being on insulin treatment. Reduction in weight or HbA1c and the proportion of patients achieving a HbA1c reduction of ≥1% was significantly larger among subjects prescribed liraglutide than exenatide and lixisenatide.

Conclusions: In this real-world, retrospective study, the magnitude of HbA1c and body weight reductions after addition of a GLP-1RA were similar to those observed in randomized controlled trials. Approximately 60% of patients attained reductions in both HbA1c and body weight, and there were significant differences among different drugs from this therapeutic group.     

The design and discovery of lixisenatide for the treatment of type 2 diabetes mellitus

Introduction: Lixisenatide is a once-daily short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) used in the treatment of type 2 diabetes mellitus (T2DM). It is used in combination with oral antidiabetics and/or basal insulin in patients inadequately controlled on these medications and who are undergoing diet and lifestyle modification. GLP-1RAs glucose-dependently increase insulin secretion, decrease glucagon secretion, and slow gastric emptying, thereby improving glycemic control. GLP-1RAs are associated with body weight benefits and low rates of hypoglycemia which are welcome in patients with T2DM.

Areas covered: The authors describe the identification of GLP-1RAs as suitable targets for modification with structure-inducing probe technology to improve stability and resistance to proteolytic degradation. Clinical studies have assessed lixisenatide across > 5000 patients as a monotherapy or add-on to a variety of commonly used antidiabetic medications. These studies highlighted the effects of lixisenatide on gastric emptying, explaining its particular improvements in postprandial plasma glucose (PPG) excursions and underscoring its efficacy in combination with insulin glargine. Lixisenatide was well tolerated, with nausea and vomiting being the most frequently reported adverse events.

Expert opinion: The once-daily administration of lixisenatide as well as its substantial sustained effect on gastric emptying and, hence, PPG excursions are all important features compared with the other GLP-1RAs. The combination of two injectables, such as basal insulin to lower fasting plasma glucose and a GLP-1RA that curtails PPG excursions, is clinically valuable and could differentiate lixisenatide from other GLP-1RAs, especially from those continuously acting GLP-1RAs with little effect on gastric emptying and PPG excursions.     

An emerging new concept for the management of type 2 diabetes with a paradigm shift from the glucose-centric to beta cell-centric concept of diabetes - an Asian perspective

ABSTRACT

Introduction

Recent advances in anti-diabetic medications and glucose monitoring have led to a paradigm shift in diabetes care. Newer anti-diabetic medications such as DPP-4 inhibitors, GLP-1 receptor agonists (GLP-1RAs), and SGLT2 inhibitors have enabled optimal glycemic control to be achieved without increasing the risk of hypoglycemia and weight gain. Treatment with GLP-1RAs and SGLT2 inhibitors has been demonstrated to improve cardiorenal outcomes, positioning these agents as the mainstay of treatment for patients with type 2 diabetes (T2DM). The development of these newer agents has also prompted a paradigm shift in the concept of T2DM, highlighting the importance of beta cell dysfunction in the pathophysiology of T2DM.     

Do glucagon-like peptide-1 receptor (GLP-1R) agonists have potential as adjuncts in the treatment of type 1 diabetes?

ABSTRACT

Introduction: Glucagon-like peptide-1 (GLP-1) is produced by the gut, stimulates insulin secretion from the pancreatic β-cells, and inhibits glucagon secretion from the α-cells. The GLP-1 receptor (GLP-1R) agonists are used in the treatment of type 2 diabetes (T2DM).

Area covered: This review covers the clinical trials of the GLP-1R agonists (exenatide and liraglutide) and their potential as adjunct treatment in type 1 diabetes mellitus (T1DM).

Expert opinion: GLP-1R agonists are unable to increase insulin secretion, in subjects with T1DM, who are C-peptide negative. Also, the GLP-1R agonists either have no effect or cause a small inhibition of glucagon secretion in subjects with T1DM. There is no evidence that the GLP-1R agonists cause a major reduction in HbA1c, or have a major effect on hypo- or hyperglycemia in subjects with TD1M. The main beneficial effect of the GLP-1R agonists is probably the modest weight loss, which may underlie the reduction in dose of insulin used. Given that the GLP-1R agonists cause gastrointestinal adverse effects, and with reduced insulin doses, increase the risk of ketosis, it seems to me that the risk with these agents may outweigh any benefit in T1DM, and that they have little potential as adjuncts in the treatment of T1DM.     

Lixisenatide as add-on to insulin glargine for the treatment of type 2 diabetes mellitus

Introduction: As type 2 diabetes mellitus (T2DM) advances, patients receiving basal insulin will eventually require another agent on top of their current regimen in order to achieve glycemic control. One such agent that can be administered in combination with basal insulin is the glucagon-like peptide-1 receptor agonist (GLP-1 RA) lixisenatide. GLP-1 RAs, such as lixisenatide, and basal insulin offer complementary mechanisms of action in their ability to provide glycemic control, thus providing a strong rationale for using them in combination with each other for the treatment of T2DM.

Areas covered: The current data available on the use of lixisenatide added to basal insulin for the management of T2DM is reviewed.

Expert opinion: Lixisenatide as add-on to basal insulin provides overall glycemic control as well as offering a number of other treatment benefits, such as a reduction in both body weight and the risk of hypoglycemia. Therefore, when basal insulin becomes inadequate in managing T2DM, lixisenatide should be considered as an add-on agent to help patients achieve glycemic targets with a low risk of hypoglycemic events.     

Cardiovascular safety and benefits of GLP-1 receptor agonists

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP-1RAs have other beneficial effects such as weight loss and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients with established and/or high risk of CVD. The CV safety of the remaining GLP-1RAs in type 2 diabetes patients with established and/or high risk of CVD remains uncertain, but ongoing CV outcome trials (CVOTs) will elucidate this within a few years.

Areas covered: The aim of this review is to provide an overview of the existing GLP-1RAs with a particular focus on their clinical effects on CV risk factors and their CV safety and benefits.

Expert opinion: Data on the CV risks and benefits associated with GLP-1RA treatment in patients with type 2 diabetes and high risk of CVD are emerging – and look promising (especially for liraglutide and semaglutide). Data from ongoing CVOTs will be crucial for the positioning of the individual GLP-1RAs in the treatment of patients with type 2 diabetes and high risk of CVD. However, the long-term CV safety and the potential of GLP-1RAs to prevent CVD in type 2 diabetes patients with less risk of CVD (e.g. newly diagnosed patients) remain uncertain.     

Individualized,patient-centered use of lixisenatide for the treatment of type 2 diabetes mellitus

Introduction: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease associated with hyperglycemia, which can lead to serious vascular complications. Current treatment guidelines place particular emphasis on personalization of therapy. Within this guidance, the use of various second-line therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), is recommended under certain circumstances.

Areas covered: Factors influencing glucose homeostasis, including gastric emptying and the associated cardiovascular (CV) risk when homeostasis is not maintained, are reviewed. Physiology relating to the mechanism of action of GLP-1 RAs is summarized, with a particular focus on lixisenatide. In addition, an overview of efficacy and safety data for lixisenatide is presented and the CV effects of GLP-1 RAs are examined. Finally, the rationale and clinical data supporting the combination of lixisenatide and basal insulin are explored.

Expert opinion: GLP-1 analogs meet a need for better glycemic control, with the added benefits of reduced hypoglycemic risk and body weight. The combination of a short-acting GLP-1 RA, such as lixisenatide, with a basal insulin, exploits the complementary effects of both of these therapies and seems well suited for the treatment of T2DM. However, further studies are needed to establish the associated CV risks and/or benefits of GLP-1 RAs.     

Cardiovascular safety of liraglutide for the treatment of type 2 diabetes

Introduction: Liraglutide is a GLP-1 RA that is an option for treatment of T2DM. Typical of all new glucose-lowering agents, its CV safety profile is of great interest.

Areas covered: This article outlines the efficacy of the GLP-1 RA liraglutide from RCTs, moving through the pivotal phase 3 LEAD trials, and subsequent meta-analyses to assess CV safety. This review describes evolution of regulatory requirements to obtain safety information through dedicated CVOTs.

Expert opinion: Since the FDA mandated that CV outcomes for new diabetes therapies should be assessed via a dedicated CVOT, opinion of their utility in T2DM evolved from cynicism through to enthusiasm. In LEADER, liraglutide became the second modern glucose-lowering agent to demonstrate significant CV benefit. CVOTs are now providing important answers, highlighting the CV benefits of modern glucose-lowering agents, but also raising several questions, notably whether the effects seen with liraglutide and empagliflozin are class-effects or are unique to these molecules. Furthermore it is unknown if these results in patients with high CV risk are applicable to all patients with T2DM, and should be incorporated into new treatment guidelines. In our view it’s prudent to suggest that CVOT findings cannot currently be extrapolated to the whole T2DM population.     

GLP-1 receptor agonists in the treatment of polycystic ovary syndrome

Introduction: Polycystic ovarian syndrome (PCOS) affects many women of child-bearing age and is characterized by hyperandrogenism, ovulatory and metabolic dysfunction. A primary treatment goal is weight reduction. The weight loss effects of glucagon-like peptide-1 receptor agonists (GLP-1RA), previously demonstrated in diabetic and obese non-diabetic patients, offer a unique opportunity to expand the medical options available to PCOS patients.

Areas covered: Available clinical trials of glucagon-like peptide-1 receptor agonist therapy in PCOS were reviewed. Literature was searched from PubMed using appropriate search terms up to November 2016.

Expert commentary: The available studies of GLP-1 RA therapy in the treatment of excess body weight in women with PCOS demonstrate that exenatide and liraglutide are effective in weight reduction either as monotherapy or in combination with metformin. A few studies showed that androgens may be modestly decreased and menstrual frequency may be increased. Eating behavior may be improved with liraglutide therapy. Glucose parameters are generally improved. GLP-1RAs were well-tolerated, with nausea being the most significant adverse side effect. Barriers to utilization may be the short duration studies, lack of familiarity of the medication, the route of administration (injection) and the variable outcomes on ovulation and hyperandrogenism.     

Fixed-ratio combination therapy with GLP-1 receptor agonist liraglutide and insulin degludec in people with type 2 diabetes

Introduction: A fixed combination of basal insulin degludec and glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide (IDegLira; 50 units degludec/1.8 mg liraglutide) has been developed as a once daily injection for the treatment of type 2 diabetes (T2D). In the phase 3a trial programme ‘Dual action of liraglutide and insulin degludec in type 2 diabetes’ (DUAL?), five trials of 26 weeks duration and one trial of 32 weeks duration have evaluated the efficacy and safety of IDegLira compared with administration of insulin degludec, insulin glargine, liraglutide alone or placebo.

Areas covered: Combination therapy with IDegLira reduces HbA1c more than monotherapy with a GLP-1RA (liraglutide) or insulin (degludec or glargine). Combination therapy leads also to weight loss, or a stable body weight, with no increase in hypoglycaemia. Rates of adverse events did not differ between treatment groups; however, gastrointestinal side effects were fewer with IDegLira compared with liraglutide treatment alone. A limitation of the DUAL? development programme is that patients receiving basal insulin doses in excess of 50 units were excluded from the studies.

Expert commentary: In conclusion, IDegLira combines the clinical advantages of basal insulin and GLP-1RA treatment, and is a treatment strategy that could improve the management of patients with T2D.     

Adding prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy

Background: Diabetes mellitus is a serious and increasingly prevalent condition in Canada and around the world. Treatment strategies have become increasingly complex, with a widening array of pharmacological agents available for glycemic management in type 2 diabetes mellitus (T2DM). New therapies that act in concert with available basal insulins may represent alternatives to basal insulin intensification with prandial or pre-mixed insulin. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently shown promise as useful additions to basal insulin, with significant reductions in glycated hemoglobin and potentially beneficial effects on body weight. This review will focus on pivotal clinical trials to assess the potential benefits of adding prandial GLP-1 RAs to basal insulin in patients with T2DM.

Methods: Clinical studies combining prandial GLP-1 RAs and basal insulin (published between 2011 and July 2017) were identified and reviewed in PubMed, the Cochrane Central Register of Clinical Trials (Issue 6, June 2017), and clinicaltrials.gov.

Results: Most of the studies presented in this review show that the addition of a prandial GLP-1 RA to basal insulin results in equal or slightly superior efficacy compared to the addition of prandial insulin, together with weight loss and less hypoglycemia.

Conclusions: The results of the studies suggest that a prandial GLP-1 RA as an add-on to basal insulin may be a safe and effective treatment intensification option (vs basal-plus or basal-bolus insulin).     

The efficacy and safety of exenatide once weekly in patients with type 2 diabetes

Introduction: Exenatide once weekly (QW) is a glucagon-like peptide 1 receptor agonist (GLP-1RA) that was approved in 2012 in Europe and the U.S.A. for the treatment of type 2 diabetes (T2D).

Areas covered: This review provides an overview of the safety and efficacy of exenatide QW for the treatment of T2D and evaluates the benefit–risk ratio compared to other available long-acting GLP-1RAs. In addition, the authors provide an outline of the novel formulations and delivery methods of exenatide.

Expert opinion: Exenatide QW is an efficacious and safe treatment for T2D. However, head-to-head trials have demonstrated exenatide QW to be inferior to liraglutide and semaglutide with respect to effects on fasting plasma glucose, glycated hemoglobin A1c, and bodyweight. In addition, exenatide QW appears inferior to liraglutide and semaglutide in terms of cardiovascular risk reduction. Currently, the overall risk-benefit profiles for the range of GLP-1RAs point to liraglutide and semaglutide as first-choice for the management of T2D, which has been confirmed by a recently published consensus report on the treatment of T2D from the American Diabetes Association and the European Association for the Study of Diabetes. The pricing of exenatide QW will most likely be a key determinant for its place in the future management of T2D.     

Early use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in Type 2 diabetes

Abstract

Objective:

To evaluate the efficacy and safety of the available glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exenatide and liraglutide (marketed as Byetta and Victoza, respectively) in first- or second-line pharmacotherapy for type 2 diabetes (T2D), described here as ‘early use’.     

Therapies for inter-relating diabetes and obesity – GLP-1 and obesity

Introduction: The dramatic rise in the prevalence of obesity and type 2 diabetes mellitus (T2DM) is associated with increased mortality, morbidity as well as public health care expenses worldwide. The need for effective and long-lasting pharmaceutical treatment is obvious. The record of anti-obesity drugs has been poor so far and the only efficient treatment today is bariatric surgery. Research has indicated that appetite inhibiting hormones from the gut may have a therapeutic potential in obesity. The gut incretin hormone, glucagon-like peptide-1 (GLP-1), appears to be involved in both peripheral and central pathways mediating satiety. Clinical trials have shown that two GLP-1 receptor agonists exenatide and liraglutide have a weight-lowering potential in non-diabetic obese individuals. Furthermore, they may also hold a potential in preventing diabetes as compared to other weight loss agents.

Areas covered: The purpose of this review is to cover the background for the GLP-1-based therapies and their potential in obesity and pre-diabetes. Up-to-date literature on incretin-based therapies will be summarized with a special mention of their weight-lowering properties. The literature updated to August 2014 from PubMed was identified using the combinations: GLP-1, GLP-1 receptor agonists, incretins, obesity and pre-diabetes.

Expert opinion: The incretin impairment, which seems to exist in both obesity and diabetes, may link these two pathologies and underlines the potential of GLP-1-based therapies in the prevention and treatment of these diseases.     

Network meta-analysis of liraglutide versus dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes in Japanese patients

Aims: To determine the comparative efficacy and safety of liraglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors as antidiabetics for Japanese patients with uncontrolled type 2 diabetes (T2DM).

Methods and materials: We searched for randomized controlled trials (RCTs) evaluating outcomes among Japanese adults with uncontrolled T2DM and including liraglutide or DPP-4 inhibitors up to August 2016. We extracted data on trial and patient characteristics, and the following outcomes: HbA1c, weight, patients meeting HbA1c <7%, patients experiencing hypoglycemic events, microalbuminuria, estimated glomerular filtration rate (eGFR) and creatinine. We synthesized data using network meta-analyses (NMA) using a Bayesian framework. Continuous outcomes were modeled using normal likelihoods and an identity link, while dichotomous outcomes were modeled using a binomial likelihood and a logit link.

Results: The systematic literature review yielded 39 publications pertaining to 38 trials. A total of 27 trials (5032 patients) reported change in HbA1c at 12 weeks and at 24 weeks 9 trials (2091 patients). All treatments showed statistically significant reductions in HbA1c relative to placebo at 12 and 24 weeks. Liraglutide 0.9?mg was statistically superior to all DPP-4 interventions (vildagliptin, sitagliptin, linagliptin, alogliptin, teneligliptin, trelagliptin and omarigliptin) at 12 weeks and 24 weeks among those reporting. Treatments were not statistically differentiable with respect to weight change and risk of hypoglycemia. Finally, no comparisons of eGFR and microalbuminuria were conducted, as this data was reported in too few trials to conduct analyses.

Limitations: Some important outcomes were limited by poor reporting (eGFR and microalbuminuria) or low event rates (hypoglycemia). The follow-up time was relatively short. Clinically, the 24 week time point is more important as it demonstrates more sustained results.

Conclusions: Our research suggests that liraglutide 0.9?mg offers a more efficacious treatment option for T2DM than the DPP-4 inhibitors among adult Japanese patients and that it is a viable option for this population.     

Is liraglutide or exenatide better in type 2 diabetes?

Background: Subjects with type 2 diabetes have high circulating levels of glucose. Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that has a major role in glucose homeostasis. Exenatide and liraglutide are both agonists at the GLP-1 receptor, and are effective at reducing circulating glucose levels (measured as Hb_A1c levels), but they have not been compared. Objectives/methods: This evaluation is of a clinical trial comparing liraglutide once a day with exenatide twice a day in subjects with type 2 diabetes. Results: In the Liraglutide Effect and Action in Diabetes (LEAD)-6 trial, subcutaneous liraglutide 1.8 mg once a day was compared with exenatide 10 μg twice a day. The primary efficacy outcome was change in Hb_A1c levels, and this was significantly greater with liraglutide (1.12%) than with exenatide (0.79%). Liraglutide and exenatide had similar small abilities to reduce body weight, blood pressure and LDL-cholesterol. Conclusions: Liraglutide was more effective than exenatide for overall glycaemic control in subjects with type 2 diabetes. However, this is only true for the preparations and doses tested, that is liraglutide 1.8 mg once weekly and exenatide 10 μg b.i.d., and may not apply when the comparison is undertaken with the new longer-lasting preparation of exenatide once weekly.     

Adjunctive Role of Glucagon‐Like Peptide‐1 Receptor Agonists in the Management of Type 1 Diabetes Mellitus

Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are commonly used in combination with insulin to manage type 2 diabetes mellitus, and four agents are currently approved for this indication: exenatide, liraglutide, dulaglutide, and albiglutide. The distinctive properties of GLP‐1 RAs—potential hemoglobin A_1c (A1C) reduction, weight loss, potential to reduce insulin doses, and lower hypoglycemia risk—have made these agents potential treatment options for patients with type 1 diabetes mellitus (T1DM) as well. These positive effects are due to glucose‐dependent insulin secretion, reduced glucagon secretion, increased satiety, and delayed gastric emptying. Patients with T1DM are unable to suppress glucagon during meals, which contributes to postprandial hyperglycemia and may be improved with GLP‐1 therapy. In this review, we evaluated the available literature on the clinical efficacy and safety of GLP‐1 RAs in patients with T1DM. We conducted a search of the PubMed (1966–May 2016) and Ovid (1946–May 2016) databases. Abstracts presented at the scientific and clinical sessions of the American Diabetes Association and the American Association of Clinical Endocrinologists were also searched. The references of the published articles were also reviewed to identify additional studies appropriate for inclusion. All identified articles published in English were evaluated. Studies were included if they evaluated the clinical use or safety of GLP‐1 RAs in patients with T1DM. Twelve studies were included, with four evaluating exenatide, one evaluating exenatide extended release, and seven evaluating liraglutide. Both exenatide and liraglutide showed significant reductions in hemoglobin A1C, plasma glucose concentration, body weight, and insulin doses when administered to patients with T1DM already receiving insulin therapy, without increasing the occurrence of hypoglycemia. Adverse effects were mostly gastrointestinal in nature but were mild and transient. Patients who may benefit most are those experiencing adverse effects from insulin, those not at their A1C goal but hypoglycemia prevents insulin titration, and those who may benefit from weight loss.