Review ArticleGlucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes: Differences and similarities
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)
By the numbers: new estimates from the IDF Diabetes Atlas Update for 2012
Diabetes Res Clin Pract
(2012)- et al.
Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences
FEBS Lett
(1995) - et al.
GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2 + channel-dependent exocytosis
Cell Metab
(2010) Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications
Am J Med
(2011)- et al.
Glucagon-like peptide 1 and appetite
Trends Endocrinol Metab
(2013) - et al.
Higher fasting plasma concentrations of glucagon-like peptide 1 are associated with higher resting energy expenditure and fat oxidation rates in humans
Am J Clin Nutr
(2006) - et al.
Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas
J Biol Chem
(1992) - et al.
Effects of lixisenatide once daily on gastric emptying in type 2 diabetes—relationship to postprandial glycemia
Regul Pept
(2013) - et al.
Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)
Lancet
(2009) - et al.
Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial
Lancet
(2009)
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
Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial
Lancet
Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study
Lancet
Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study
Lancet
IDF diabetes atlas sixth edition
Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function
Diabetes
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
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
Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study
BMJ
Cost-effectiveness of intensified versus conventional multifactorial intervention in type 2 diabetes: results and projections from the Steno-2 study
Diabetes Care
Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus
Ann Intern Med
Therapy: what evidence should guide the use of thiazolidinediones?
Nat Rev Endocrinol
Ezetimibe and bile acid sequestrants: impact on lipoprotein metabolism and beyond
Curr Opin Lipidol
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
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
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
On the physiology of GIP and GLP-1
Horm Metab Res
GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting
J Nucl Med
GLP-1 receptor localization in monkey and human tissue; Novel distribution revealed with extensively validated monoclonal antibody
Endocrinology
GLP-1 based therapies: differential effects on fasting and postprandial glucose
Diabetes Obes Metab
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
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
Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans
Am J Physiol
Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans
J Clin Invest
Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I
Diabetes
Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects
J Clin Endocrinol Metab
Effect of renal impairment on the pharmacokinetics of exenatide
Br J Clin Pharmacol
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
Prescribing information Byetta® Amylin Pharmaceuticals
Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes
Diabetes Care
Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes
Diabetes Care
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
Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes
Am J Hypertens
Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis
BMJ Open
Cited by (129)
Exendin-4 increases the firing activity of hippocampal CA1 neurons through TRPC4/5 channels
2024, Neuroscience ResearchAntidiabetic agents as a novel treatment for Alzheimer's and Parkinson's disease
2023, Ageing Research ReviewsLoureirin B promotes insulin secretion through GLP-1R and AKT/PDX1 pathways
2022, European Journal of PharmacologyEngineering of smart nanoconstructs for delivery of glucagon-like peptide-1 analogs
2021, International Journal of Pharmaceutics