Review Article
Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes: Differences and similarities

https://doi.org/10.1016/j.ejim.2014.03.005Get rights and content

Highlights

  • GLP-1R agonists address several of the pathophysiological features of T2D

  • GLP-1R agonists are different based on their structure, pharmacokinetics and size

  • Differences between the GLP-1R agonists lead to different clinical effects

  • Long-term effects of and potential differences between GLP-1R agonists are awaited

Abstract

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, secreted in response to ingestion of nutrients, and has important effects on several of the pathophysiological features of type 2 diabetes (T2D). The effects include potentiation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and suppression of appetite. In circulation, GLP-1 has a half-life of approximately 2 min due to rapid degradation by the enzyme dipeptidyl peptidase 4 (DPP-4). Because of this short half-life GLP-1 receptor (GLP-1R) agonists, resistant to degradation by DPP-4 have been developed. At the moment four different compounds are available for the treatment of T2D and many more are in clinical development. These compounds, although all based on the effects of native GLP-1, differ with regards to structure, pharmacokinetics and size, which ultimately leads to different clinical effects. This review gives an overview of the clinical data on GLP-1R agonists that have been compared in head-to-head studies and focuses on relevant differences between the compounds. Highlighting these similarities and differences could be beneficial for physicians in choosing the best treatment strategy for their patients.

Introduction

Worldwide the number of patients with type 2 diabetes (T2D) increases as economic development and urbanization lead to lifestyle changes encompassing reduced physical activity and increased food intake resulting in obesity. In 2013 the International Diabetes Federation (IDF) estimated the number of people with diabetes worldwide, to be 382 million, a number expected to approach 590 million in 2035, with T2D accounting for up to 95% [1], [2]. T2D is progressive and characterised by insulin resistance, a steady decline in glucose-induced insulin secretion, and inappropriately high glucagon levels, which in combination leads to high blood glucose concentrations [3]. Over time T2D results in complications that broadly can be classified as microvascular (neuropathy, nephropathy and retinopathy) or macrovascular (atherosclerotic manifestations such as myocardial infarction and stroke). In 2012 it was estimated that almost 5 million deaths worldwide were attributable to diabetes, obesity and its complications [1], [4], [5]. The ultimate goal of glucose lowering drugs is to control glucose homeostasis as tight as possible to prevent the development of micro- and macrovascular complications and early death [6], [7]. In order to reach this, a treatment regimen combining several glucose-lowering drugs is often needed. However, several treatment modalities are associated with a number of shortcomings: hypoglycaemia (sulphonylureas (SUs) and insulin); weight gain (SUs, insulin and thiazolidiones (TZD)); gastrointestinal side effects (metformin, bile acid sequestrants and α-glucosidase inhibitors); increased risk of genital and urinary tract infections (sodium-glucose co-transporter 2 inhibitors); and increased risk of bone fractures and heart disease (TZD) [8], [9], [10], [11]. In addition to side effects none of these glucose-lowering drugs target the multifaceted pathophysiology of T2D.

In 2005, the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists were introduced into clinical practise, and since 2009 they have been part of the joint position statements on treatment of T2D by the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) [12], [13]. The GLP-1R agonists target a broad spectrum of the multifaceted pathophysiology of T2D. Thus, they improve glucose homeostasis without risk of hypoglycaemia, facilitate body weight loss, and exert effects on cardiovascular parameters of potential benefit. Naturally, the introduction of the GLP-1R agonists has generated substantial clinical interest. However, many physicians and other healthcare providers have limited experience with this novel therapy, and as several GLP-1R agonists are emerging, it has become apparent that there are clinical relevant differences between them, which make the therapeutic field challenging to navigate within. This review provides an overview of the current clinical data on GLP-1R agonists that have been compared in head-to-head studies and focuses on relevant differences between the compounds.

Section snippets

Methodology

Literature searches were performed by using the MEDLINE database with key words: “glucagon-like peptide-1”, “glucagon-like peptide-1 receptor agonists”, “exenatide”, “lixisenatide”, “liraglutide”, “exenatide once-weekly”, “albiglutide”, “dulaglutide”, “semaglutide”. Additionally published abstracts from the ADA and EASD were searched. Furthermore manual searches including scanning of reference lists in relevant papers and specialist journals have been performed.

The physiology and antidiabetic actions of GLP-1

During a meal, plasma-levels of GLP-1 rise within minutes and return to very low levels in the fasting state [14]. GLP-1 asserts its effects through binding to the GLP-1Rs expressed in the pancreas and a variety of other tissues including: lung, heart, blood vessels, gastrointestinal tract, kidney, breast and central nervous system (CNS) [15], [16], [17]. In the pancreatic beta cell, receptor-binding of GLP-1 in the presence of elevated glucose concentrations leads to stimulation of insulin

GLP-1R agonists

One of the challenges in developing GLP-1R agonists is that native GLP-1 is very rapidly degraded by the enzyme dipeptidyl peptidase 4 (DPP-4) resulting in a half-life of approximately 2 min [28]. To overcome this problem GLP-1R agonists resistant to degradation by DPP-4 have been developed by two different strategies. One strategy exploits the structure of native GLP-1, with a few amino acid alterations that protect the molecule from being degraded by DPP-4 (Fig. 2). The other strategy exploits

Exenatide twice-daily

Exenatide, the first GLP-1R agonists available, was introduced to the market in the United States of America (USA) in 2005 and in Europe in 2007 under the trade name Byetta® (Bristol Myers Squibb–AstraZeneca). Exenatide is a synthetic version of exendin-4 which has a low (53%) amino acid sequence homology with human GLP-1 [31] (Fig. 2). Exenatide is primarily cleared in the kidneys by glomerular filtration [29], and the half-life after subcutaneous (s.c.) injection is approximately 2 to 3 h with

Albiglutide

Albiglutide is a continuous-acting GLP-1R agonist in late clinical development by GlaxoSmithKline. Albiglutide (previously named albugon) is developed by covalently binding of a ‘double’ copy DPP-4 resistant GLP-1 analogue to human albumin (Fig. 2), leaving this relatively large molecule somewhat resistant to filtration by the kidneys. Peak plasma levels of albiglutide are achieved 2 to 5 days after s.c. injection, and half-life is approximately 5 to 8 days, making it suitable for once-weekly

Side effects and safety issues

The most frequent side effects of GLP-1R agonists are dose-dependent, mild to moderate nausea, vomiting and diarrhoea. These side effects are generally mild to moderate and decline over time. Continuous-acting compounds seem to be associated with a higher degree of gastrointestinal tolerability compared to the short-acting compounds; most likely due to reduced fluctuations of plasma peptide concentrations in plasma. Besides the gastrointestinal side effects, debate regarding an association

Summary

GLP-1R agonists share the same basic mechanisms and all utilise the pleiotropic effects of native GLP-1, however, differences in pharmacokinetics, structure and size of the compounds result in different clinical profiles. Most notable are the clinical relevant differences between the short-acting and continuous-acting compounds (Table 1). The continuous-acting compounds have a greater effect on glycaemic control and overall they are better tolerated [54], [67], [74]. On the other hand, the

Conclusion

The introduction of the GLP-1R agonists has provided a valuable new treatment concept for patients with T2D. The GLP-1R agonists target the multifaceted pathophysiology of T2D with positive effects on both alpha and beta cell dysfunction and provide improvements in HbA1c with a relatively low risk of hypoglycaemia and notably accompanied by a weight loss. There are however some clinical relevant differences between the compounds. Thus, the continuous-acting GLP-1R agonists seem to be preferable

Learning points

  • GLP-1R agonists provide clinical relevance and sustained improvements in body weight and glycaemic control without hypoglycaemia.

  • GLP-1R agonists differ with respect to:

    • -

      Structure (exendin-4 based vs. GLP-1-based) responsible for differences in immunogenicity

    • -

      Pharmacokinetics (short-acting vs. continuous-acting); affecting efficacy and side effects differentially

    • -

      Size (small vs. large) possibly affecting signalling to the CNS

  • Prospective trials are underway to assess cardiovascular safety profiles

Conflicts of interest

A. Lund has no conflicts of interests to declare related to this manuscript. F. K. Knop has received lecture fees from AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Gilead Sciences, Merck Sharp & Dohme, Novo Nordisk, Ono Pharmaceuticals, Sanofi, and Zealand Pharma, is a member of the Advisory Boards of Eli Lilly, Bristol-Myers Squibb/AstraZeneca and Zealand Pharma, and has consulted for AstraZeneca, Gilead Sciences, Novo Nordisk, Ono

References (89)

  • R.M. Bergenstal et al.

    Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial

    Lancet

    (2010)
  • M. Diamant et al.

    Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial

    Lancet

    (2010)
  • J.B. Buse et al.

    Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study

    Lancet

    (2013)
  • D.J. Drucker et al.

    Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study

    Lancet

    (2008)
  • International Diabetes Federation

    IDF diabetes atlas sixth edition

  • S.E. Kahn et al.

    Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function

    Diabetes

    (1993)
  • Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group

    Lancet

    (1998)
  • Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group

    Lancet

    (1998)
  • I.M. Stratton et al.

    Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study

    BMJ

    (2000)
  • P. Gaede et al.

    Cost-effectiveness of intensified versus conventional multifactorial intervention in type 2 diabetes: results and projections from the Steno-2 study

    Diabetes Care

    (2008)
  • S. Bolen et al.

    Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus

    Ann Intern Med

    (2007)
  • M.C. Riddle

    Therapy: what evidence should guide the use of thiazolidinediones?

    Nat Rev Endocrinol

    (2010)
  • P. Couture et al.

    Ezetimibe and bile acid sequestrants: impact on lipoprotein metabolism and beyond

    Curr Opin Lipidol

    (2013)
  • A. Berhan et al.

    Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus: a meta-analysis of randomized double-blind controlled trials

    BMC Endocr Disord

    (2013)
  • D.M. Nathan et al.

    Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes

    Diabetes Care

    (2009)
  • S.E. Inzucchi et al.

    Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

    Diabetes Care

    (2012)
  • J.J. Holst

    On the physiology of GIP and GLP-1

    Horm Metab Res

    (2004)
  • M. Körner et al.

    GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting

    J Nucl Med

    (2007)
  • C. Pyke et al.

    GLP-1 receptor localization in monkey and human tissue; Novel distribution revealed with extensively validated monoclonal antibody

    Endocrinology

    (2014)
  • M.S. Fineman et al.

    GLP-1 based therapies: differential effects on fasting and postprandial glucose

    Diabetes Obes Metab

    (2012)
  • T.J. Little et al.

    Effects of intravenous glucagon-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects: relationships with postprandial glycemic and insulinemic responses

    J Clin Endocrinol Metab

    (2006)
  • J.J. Meier et al.

    Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes

    J Clin Endocrinol Metab

    (2003)
  • M.A. Nauck et al.

    Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans

    Am J Physiol

    (1997)
  • A. Flint et al.

    Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans

    J Clin Invest

    (1998)
  • C. Ørskov et al.

    Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I

    Diabetes

    (1996)
  • T. Vilsbøll et al.

    Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects

    J Clin Endocrinol Metab

    (2003)
  • H. Linnebjerg et al.

    Effect of renal impairment on the pharmacokinetics of exenatide

    Br J Clin Pharmacol

    (2007)
  • R.E. Ratner et al.

    Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial

    Diabet Med

    (2010)
  • Prescribing information Byetta® Amylin Pharmaceuticals

  • J.B. Buse et al.

    Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes

    Diabetes Care

    (2004)
  • R.A. DeFronzo et al.

    Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes

    Diabetes Care

    (2005)
  • D.M. Kendall et al.

    Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea

    Diabetes Care

    (2005)
  • T. Okerson et al.

    Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes

    Am J Hypertens

    (2010)
  • L.E. Robinson et al.

    Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis

    BMJ Open

    (2013)
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