GLP-1 (Glucagon like Peptide-1) receptor agonists have been shown to be effective in the treatment of type 2 diabetes mellitus (T2DM). Although the first GLP-1 receptor agonist, Exenatide, was approved in the year 2000, other agents with a longer duration of action that do not require twice-daily dosing are now being developed. Indeed, Liraglutide, a once-daily GLP-1 receptor agonist, was approved in 2010, a once-weekly extended-release formulation of Exenatide (Exenatide ER) was approved in 2011 and now more recently Semaglutide, an oral GLP 1 receptor agonist was approved for medical use in the United States in September 2019 and in the European Union in April 2020. The importance of GLP-1 itself and the use of GLP-1 receptor agonists in T2DM are discussed. An overview of the clinical development of the GLP-1 receptor agonists (Exenatide ER, Liraglutide, Lixisenatide, Albiglutide, Taspoglutide and Semaglutide) is provided and their mechanism of action, efficacy in terms of glycaemic control, weight loss and tolerability are reviewed.
Diabetes mellitus is one of the most challenging health problems worldwide with an alarming increase in its prevalence and associated conditions such as hypertension, dyslipidaemia and cardiovascular disease. It is one of the main threats to human health and a chronic metabolic disorder that results from defects in either insulin secretion and/or insulin action or both.
The total number of people with diabetes worldwide was estimated between 151 million and 171 million in 2000 and is projected to increase to 221 million in 2010 and to 366 million in 2030
The biochemical and physiological processes that underlie T2DM are still unclear, although most certainly involve impairment in insulin secretion and insulin action at the periphery. Chronic hyperglycaemia results from these defects due to which the patients with diabetes experience significant morbidity and mortality from microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (heart attacks, stroke and peripheral vascular disease) complications.
Given that type 2 diabetes accounts for more than 90% of cases of diabetes worldwide, it is important that we understand the pathogenesis of this condition and develop new approaches to its prevention and treatment. Despite a broad range of effective blood glucose-lowering therapies, almost half of T2DM patients are not reaching recommended glycaemic targets. Conventional T2DM therapies are effective at lowering blood glucose but they do not impact upon the progressive decline of β-cell function, so glycaemic control continues to deteriorate unless treatment is intensified. In addition, most conventional T2DM therapies are associated with weight gain and/or hypoglycaemia, which pose significant barriers to treatment intensification.
There is evidence that nutrient-induced secretion of the glucose regulating incretin hormone i.e. glucagon-like peptide-1 (GLP-1) is impaired in diabetes mellitus.
Incretins are a group of hormones that includes Glucagon like peptide-1 (GLP-1) and Glucose dependent insulinotropic polypeptide (GIP) that are released after meals from the upper and lower bowel. These incretins augment glucose dependent insulin secretion, during the phase of nutrient absorption from the GIT. Among them, GLP-1 is the prominent insulinotropic incretin, which has a very short half-life (1-2 min) due to its quick metabolism by DPP-IV enzyme.
Glucagon like peptide-1 (GLP-1) is an incretin hormone released from intestinal L-cells into the circulation in response to dietary nutrient intake. It increases β cell insulin secretion and reduces alpha cell glucagon secretion in a glucose dependent manner. In recent years, considerable interest has focused on the potential of GLP-1 as a novel treatment strategy for type 2 diabetes.
The most important action of GLP-1 occurs in the pancreas. Its receptors have been located in β, α and δ- cells.
Many of the pathophysiologic disturbances that are present in T2DM can be corrected by incretin replacement with GLP-1. In response to the physiologic loss of incretin activity associated with T2DM, administration of exogenous GLP-1 has been shown to lower both fasting and postprandial plasma glucose significantly.
It had been demonstrated that glucagon secretion in T2DM is not suppressed after a carbohydrate-rich meal
This considerable clinical interest derived from GLP-1 having a rather large spectrum of effects, all working in favour of efficacious lowering of blood glucose and simultaneous lowering of body weight with a low risk of hypoglycaemia.
Liraglutide, Exenatide ER, Lixisenatide, Albiglutide, Taspoglutide, Semaglutide, Efpeglenatide, Dulaglutide.
Liraglutide is a modified form of human glucagon like peptide 1(GLP-1) analogue, was FDA approved and licensed for treating adults with type 2 diabetes mellitus.
It is a modified form of human GLP-1 (γ-Lglutamyl [N-α-hexadenoyl]-Lys 26, Arg34-GLP-1).
The drug increase insulin secretion from β-cells thereby decreasing the elevated blood glucose levels. Its effects on β-cells are mediated by a G-protein-linked receptor that involves cAMP formation and protein kinase A (PKA) activation to bring about the closure of ATP-sensitive K+ channels in a synergistic interaction with glucose, a phenomenon called glucose competence.
Pharmacokinetic studies show that liraglutide after a subcutaneous injection has a time to maximum plasma concentration (Tmax) of 9–13 hours and a half-life of13 hours.
Clearance of native GLP-1 and its metabolites is largely mediated via the kidneys.
In the liraglutide clinical trial program, there were seven cases of pancreatitis among liraglutide treated patients and one case among comparator treated patients (2.2 vs. 0.6 cases/1000 patient years).
In preclinical studies, C-cell carcinoma was observed in rats treated with Liraglutide and mice treated with very high doses of Liraglutide.
More data are required to provide reassurance about current safety concerns surrounding this class of therapies including the risk of pancreatitis, C-cell carcinoma and cardiovascular safety. Liraglutide and exenatide are now being investigated as potential weight loss therapies. While liraglutide is undergoing Phase III trials as a general obesity therapy. Exenatide is now being studied in a number of defined phenotypes of obesity such as Prader Willi syndrome, hypothalamic obesity, pediatric obesity, olanzapine induced obesity and polycystic ovary syndrome.
Liraglutide provided additional glycaemic control when added to intensive insulin therapy in T1DM patients.
The effect of the injection site (abdomen, upper arm and thigh) on the pharmacokinetic profile of liraglutide was investigated.
Available preclinical and clinical data clearly demonstrate the utility of liraglutide in reducing weight, thus making it a drug of choice for obese patients with diabetes.
Furthermore, Liraglutide has been shown to reduce triglyceride levels without affecting the concentration of other lipids. This makes it an attractive choice for patients with diabetic dyslipidaemia, which is characterized by high levels of triglycerides. While no long-term data of cardiovascular outcomes is available however other studies show a cardioprotective effect of liraglutide.
A detailed analysis of its pleiotropic or extra glycaemic effects however reveals a multifaceted character of the molecule. Liraglutide is effective in reducing body weight, decreasing visceral fat, lowering systolic blood pressure and improving lipid profile as well as other cardiovascular risk markers while reducing insulin resistance.
Exenatide is a synthetic form of exendin-4 which shares 53% homology with human GLP-1.
Approval of once-weekly exenatide in the EU was granted on the basis of four Phase III clinical trials (the DURATION trials). In these trials, the safety and efficacy of once-weekly exenatide were determined in comparison with exenatideb.i.d. (DURATION-1 and DURATION-5),
Phase III trial results demonstrate that liraglutide, exenatide BID and exenatide ER are effective at lowering blood glucose.
Conversely, liraglutide is degraded completely within the body by DPP-4 and neutral endopeptidase. A recent study showed that mild renal impairment had no effect on the safety and efficacy of liraglutide.
Lixisenatide is a GLP-1 receptor agonist structurally based on exenatide with a modified C terminus of six Lysine residues that can withstand physiological degradation by DPP-4 and therefore, prolong the physiological effects of GLP-1 itself. In a Phase III trial,
As in the Phase II studies, significant reductions in body weight were reported with lixisenatide 20 and 30 μg once daily and 30 μg twice daily doses compared with the placebo (p < 0.01). The most frequent adverse event reported was nausea. Lixisenatide is undergoing further evaluation in combination with other antidiabetic agents and as monotherapy in the Phase III Get Goal clinical trial program. Of particular note, further to successful outcomes from the GETGOAL-L-ASIA study,
Albiglutide is a GLP-1 dimer albumin fusion peptide, which has a prolonged half-life as a result of its fusion with albumin and associated resistance to DPP-4, leading to prolonged physiological effects of GLP-1 itself. Due to this long half-life, albiglutide can be administered once weekly via s.c. injection.
In a large, randomized, placebo controlled16 week trial in 356 patients, albiglutide was compared in various doses and regimens against exenatide, albiglutide 4, 15 or30 mg weekly or100 mg monthly. Compared with placebo, mean HbA1c was significantly reduced by 0.87 ± 0.65 and 0.87 ± 0.87 from baseline by albiglutide 30 mg weekly and 100 mg monthly respectively (each p < 0.05 vs. placebo). Similarly, fasting plasma glucose levels for the above dosing regimens were significantly lower than placebo (p < 0.05). Weight loss of between 1.1 and1.7 kg was also observed with the above two doses with no significant adverse effects. As of now, Phase III trials with albiglutide are currently ongoing.
Taspoglutide is another long-acting GLP-1 receptor agonist. It has 97% homology with human GLP-1 and is similar in structure to native GLP-1 except that it has two amino acid substitutions in positions 8 and 35 with amino isobutyric acid, which render the molecule resistant to degradation by DPP-4. Taspoglutide is administered once weekly s.c., but has also been shown to be effective when given every 2 weeks.
In an early phase trial,
Ratner and co-workers
Oral semaglutide is the first FDA-approved glucagon-like peptide-1 receptor agonist. Oral semaglutide is an option for type 2 diabetes patients who need glucose control, weight loss and want to avoid injections.
Semaglutide acts like human glucagon-like peptide-1 (GLP-1) so that it increases insulin secretion, thereby increasing sugar metabolism. It is distributed as a metered subcutaneous injection in a prefilled pen. One of its advantages over other anti-diabetic drugs is that it has a long duration of action, thus only once-a-week injection is sufficient.
An injection version (Ozempic) was approved for medical use in the United States in December 2017 and in the European Union, Canada, and Japan in 2018. A version that is taken by mouth (Rybelsus) was approved for medical use in the United States in September 2019 and in the European Union in April 2020. It is the first glucagon-like peptide (GLP-1) receptor protein treatment approved for use in the United States that does not need to be injected. It was developed by Novo Nordisk.
It increases the production of insulin, a hormone that lowers the blood sugar level. It also appears to enhance the growth of β cells in the pancreas, which are the sites of insulin production. On the other hand, it inhibits glucagon, which increases blood sugar. It additionally reduces food intake by lowering appetite and slows down digestion in the stomach. In this way, it works in body fat reduction.
Semaglutide is superior to placebo and sitagliptin, exenatide extended-release, dulaglutide and insulin glargine for reduction of glycated hemoglobin levels and weight. Semaglutide can be considered a preferred first injectable option in the management of type 2 diabetes.
The additional possible benefit of CV risk reduction in patients with established CVD makes it an excellent option for these high-risk patients.
Diabetes mellitus is a serious and growing issue for health care practitioners worldwide and for many patients as the condition is currently insufficiently managed. GLP-1 is an attractive therapeutic target for the treatment of T2DM because of its wide ranging effects such as potentiation of insulin secretion, inhibition of glucagon secretion, suppression of appetite and food intake. These agents can be combined with oral antidiabetic agents or used as monotherapy. Exenatide was the first approved GLP-1 receptor agonist. Although it is effective and used widely, its twice-daily dosing can be inconvenient, which has led to the development of longer-acting GLP-1 receptor agonists. Liraglutide was approved for the treatment of T2DM in 2010 and it has a more convenient once-daily dosing schedule. Other GLP-1 receptor agonists with longer durations of action are in development and have shown promising results in early-phase trial, some of which have once weekly or even less frequent dosing regimens. Semaglutide is a welcome addition to the anti-hyperglycaemic agent armamentarium in type 2 diabetes, offering robust A1C lowering and weight loss across a variety of background therapies, as well as CV safety and convenient once-weekly dosing, and it may have a possible CV benefit in those with established CVD. Furthermore, more and long term studies are required to establish the clinical use of these newer GLP-1 analogues in the management of metabolic syndrome and obesity.