An evaluation of liraglutide including its efficacy and safety for the treatment of obesity

ABSTRACT

Introduction: The prevalence of obesity is increasing worldwide and associated conditions, particularly type 2 diabetes mellitus (T2DM), also show increasing prevalence. Lifestyle intervention should be the first line of management for obesity but additional pharmacotherapy is often required and bariatric surgery is appropriate in more severe cases. Drugs acting as glucagon-like peptide-1 receptor agonists (GLP-1RAs) developed for the management of T2DM reduce body weight and liraglutide is the first GLP-1RA to be approved for the treatment of obesity in patients with and without T2DM.

Areas covered: In this review of relevant published material, the authors summarize the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of liraglutide for the treatment of obesity.

Expert opinion: Liraglutide effectively reduces body weight and body fat through mechanisms involving reduced appetite and lowered energy intake, independent of its glucose-lowering effects. Like most of the other medications currently available for obesity, liraglutide has some common adverse effects, although generally not serious ones. Liraglutide has additional benefits in reducing cardiovascular events in patients with T2DM but the cost and the need for daily injections may limit its use in obesity. Newer GLP-1RAs, such as semaglutide, or other drugs in development for obesity may have advantages over liraglutide.     

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.     

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.     

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.     

Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review

Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP-1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA.     

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.     

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.     

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.     

Exenatide: pharmacokinetics,clinical use,and future directions

Introduction: The first-in-class glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide, which was initially approved in 2005, is available in twice-daily (BID) and once-weekly (QW) formulations. Clinical trial data suggest both formulations are effective and safe for patients with type 2 diabetes (T2D), both as monotherapy and as part of combination therapy. Since exenatide was approved, several other GLP-1RAs have become available for clinical use.

Areas covered: Many ongoing clinical trials involving exenatide BID and exenatide QW are investigating new indications (exenatide BID) and new end points and combination therapies (exenatide QW). This review provides an overview of the delivery and pharmacokinetics of both formulations of exenatide, reviews existing data in T2D, and summarizes ongoing investigations.

Expert opinion: Exenatide BID and QW have substantial clinical benefits. Comparisons with other GLP-1RAs demonstrate some differences in efficacy and safety profiles that make assessment of benefit:risk ratios complex. Head-to-head comparisons of QW GLP-1RA formulations may assist in the ranking of GLP-1RAs according to efficacy and safety. Results on the impact of exenatide QW on cardiovascular outcomes are eagerly awaited. The potential clinical utility of exenatide BID in other indications will clarify whether exenatide holds clinical promise in diagnoses other than T2D.     

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.     

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.     

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).     

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.     

Targeting amyloid-beta by glucagon-like peptide -1 (GLP-1) in Alzheimer's disease and diabetes

Introduction: Epidemiological evidence suggests an association between type 2 diabetes (T2DM) and Alzheimer's disease (AD), in that one disease increases the risk of the other. T2DM and AD share several molecular processes which underlie the tissue degeneration in either disease. Disturbances in insulin signaling may be the link between the two conditions. Drugs originally developed for T2DM are currently being considered as possible novel agents in the treatment of AD.

Areas covered: This review discusses the potential role of glucagon-like peptide -1 (GLP-1) treatment in AD. GLP-1 receptors are expressed in areas of the brain important to memory and learning, and GLP-1 has growth-factor-like properties similar to insulin. A key neuropathological feature of AD is the accumulation of amyloid-beta (Aβ). In preclinical studies, GLP-1 and longer lasting analogues have been shown to have both neuroprotective and neurotrophic effects, and to protect synaptic activity in the brain from Aβ toxicity.

Expert opinion: A convincing amount of evidence has shown a beneficial effect of GLP-1 agonist treatment on cognitive function, memory and learning in experimental models of AD. GLP-1 analogues may therefore be the new therapeutic agent of choice for intervention in AD.     

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’.     

Pharmacological management of diabetes in severe mental illness: a comprehensive clinical review of efficacy,safety and tolerability

Introduction: The increased prevalence of Type 2 diabetes mellitus (T2DM) in severe mental illness (SMI) contributes to increased cardiovascular morbidity and reduced life expectancy for people with SMI.

Areas covered: In the present clinical review, we summarize the efficacy, safety and tolerability of selected diabetic pharmacotherapy options in SMI and discuss the quality and strength of evidence.

Expert commentary: General principles for treating T2DM in SMI involve identifying treatments which promote weight loss and which have low or no risk of hypoglycemia. Patient engagement in decision making about treatment choices is an important factor to ensure adherence and successful use of the chosen therapy. The first line therapeutic option for T2DM in SMI for which there is most evidence is metformin. Based on general population data, second line treatment options in combination with metformin to achieve glycated haemoglobin treatment goals include GLP-1R agonists, DPP-4 inhibitors, sulphonylureas, SGLT2 inhibitors, pioglitazone and insulin, with most evidence for the use of GLP-1R agonists in SMI. Alongside efficacy and tolerability, treatment for T2DM in SMI should be considered on a patient-tailored basis.     

Preventing and treating kidney disease in patients with type 2 diabetes

Introduction: Chronic kidney disease (CKD) represents a huge burden in patients with type 2 diabetes (T2DM). This review therefore has the aim of assessing the add-on value of new glucose-lowering agents compared or combined with inhibitors of the renin angiotensin aldosterone system (RAAS) on renal outcomes in T2DM patients.

Areas covered: This article first summarizes the results reported with RAAS inhibitors, mainstay of nephroprotection in T2DM with albuminuria. Second, it describes the positive results with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and, even more impressive, sodium-glucose cotransporter type 2 inhibitors (SGLT2is). Third, besides the potential of combined therapies, it briefly considers some new approaches currently in development.

Expert opinion: RAAS inhibitors exert renoprotective effects beyond their blood pressure lowering effects while SGLT2is, and possibly GLP-1RAs, exert nephroprotection independently of their glucose-lowering activity. These effects were demonstrated not only on surrogate endpoints such as albuminuria and estimated glomerular filtration rate decline, but also on hard endpoints, including progression to end-stage renal disease requiring replacement therapy. The underlying mechanisms are different and potentially complementary on glomerular hemodynamics, arguing for combined therapies. Nevertheless, there is still room for new emerging drugs to tackle CKD in T2DM.     

已上市胰高血糖素样肽-1受体激动剂的研究进展

胰高血糖素样肽-1受体激动剂（GLP-1RAs）治疗2型糖尿病受到广泛关注,其不仅具有优异的降糖优势,还有控制体质量,调节血脂,改善胰岛β细胞功能等特点,同时低血糖或体质量增加的不良反应发生率较低。自2005年至今,已经有7个GLP-1RAs经美国食品药品监督管理局批准上市,即艾塞那肽、利拉鲁肽、艾塞那肽长效制剂、阿必鲁肽、度拉糖肽、利西拉来和索马鲁肽;在中国上市的有贝那鲁肽和洛塞那肽。对已经上市的9个GLP-1Ras治疗2型糖尿病的临床研究进展进行综述。