GLP-1 Receptor Agonists in Type 2 Diabetes and Beyond – New Insights 2015

Abstract Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were introduced for type 2 diabetes therapy nearly 10 years ago, among them short-acting compounds on the basis of the GLP-1-like peptide exendin-4 (exenatide and lixisenatide) and a long-acting GLP-1 RA based on the human GLP-1 sequence (liraglutide). Recently, two novel long-acting GLP-1 RAs on the basis of human GLP-1 sequence, for once-weekly application, have been approved for therapy of type 2 diabetes. Additionally, liraglutide has been approved for treatment of obesity at a higher dose than that used for diabetes therapy. This mini-review gives a short overview of the novel long-acting GLP-1 RAs albiglutide and dulaglutide and also reviews the studies of liraglutide in treatment of obesity leading to its approval for this use. These studies were largely presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in fall 2014.

for the therapy of type 2 diabetes about 10 years ago, with exenatide the first drug in the class. Natural GLP-1 is secreted post-prandially by the L-cells of the intestine. It stimulates insulin secretion and inhibits glucagon secretion in a glucose-dependent manner. In addition to having direct effects on glucose metabolism, GLP-1 also slows gastric emptying, acts as a neurotransmitter in hypothalamic nuclei stimulating satiety, lowers blood pressure and has a positive influence on beta cell mass in animal models with high beta cell turn-over. Because GLP-1 itself has a very short half-life, long-acting GLP-1 RAs have been designed to use GLP-1 action for type 2 diabetes therapy. 1,2 Recently, two GLP-1 RAs for once-weekly injection were approved for the treatment of type 2 diabetes. Albiglutide (Eperzan ® , GlaxoSmithKline Pharmaceuticals) and dulaglutide (Trulicity ® , Lilly Pharmaceuticals) are based on the human GLP-1 peptide sequence, whereas exenatide for onceweekly use (Bydureon ® , AstraZeneca Pharmaceuticals), introduced in 2012, is based on the sequence of exendin-4, a peptide with >50 % sequence homology to human GLP-1. [3][4][5] Apart from this difference, exenatide for once-weekly use has a long pharmacological action thanks to galenic preparation, with a retarded and slow continuous release of exenatide from a suspension of soluble microspheres loaded with the compound. 6 This review aims to give an overview of the recently published clinical study data on the novel long-acting GLP-1 RAs albiglutide and dulaglutide with a human GLP-1 ligand. In addition, recent data on the long-acting GLP-1 receptor agonist liraglutide, which also has a human GLP-1 sequence and is for treating obesity, are presented. Most of the clinical study data dealt with in this article were presented at the recent annual meeting of the European Association for the Study of Diabetes (EASD) 2014. These data were also prerequisites for the approval of albiglutide and dulaglutide for the treatment of type 2 diabetes with once-weekly injections. The indication for liraglutide was widened to additionally include the treatment of morbid obesity without type 2 diabetes.

Albiglutide
Albiglutide is a molecule consisting of two copies of a 30-amino acid sequence of a human GLP-1 dimer genetically fused to human albumin.
Degradation is inhibited by a single amino acid substitution within the GLP-1 fragment. Additionally, the fusion to albumin results in a longer halflife. Maximum concentrations of albiglutide are reached 3 to 5 days after a subcutaneous dose, and steady-state concentrations are achieved after 4 to 5 weeks of once-weekly administration. 7 Albiglutide has been studied in a set of prospective randomized clinical studies at various stages of type 2 diabetes and in different combination therapies. An overview of the comparative clinical study programme with albiglutide is given in Table 1. In summary, the programme consisted of eight independent studies (HARMONY 1 to HARMONY 8) with the usual primary endpoint of glycated haemoglobin (HbA 1c ) reduction at 26, 32, 52 or 104 weeks. Overall, the trials involved more than 5,000 patients, including more than 2,000 patients on albiglutide, representing more than Diabetes EuropEan Endocrinology 7,500 patient-years of treatment. The mean baseline HbA 1c for the study population ranged from 8.0 % to 8.5 %, and the mean baseline body weight was 83-95 kg. [8][9][10][11][12][13][14][15][16] An HbA 1c reduction of -0.55 % to -0.9 % was observed in these studies, and albiglutide was found superior to treatment using a sulphonylurea, pioglitazone or dipeptidyl peptidase-4 (DPP4) inhibitor. Non-inferiority was demonstrated versus insulin therapy. 3 The mean body weight change was lower in comparison to other GLP-1 RAs, amounting to 0.3 to -1.2 kg, and was less when albiglutide was combined with oral anti-diabetics known to cause weight gain (pioglitazone, sulphonylurea). [8][9][10][11][12][13][14][15][16] The overall hypoglycaemia rates were low, similar to those of other GLP-1 RAs, when albiglutide was used as monotherapy or in combination  with metformin or pioglitazone. Higher rates were observed only in combination with a sulphonylurea or insulin. As expected when using a GLP-1 RA, the most commonly reported adverse events were gastrointestinal and occurred at a higher rate than with placebo, pioglitazone, sulphonylurea, a DPP-4 inhibitor or insulin, but less frequently than with liraglutide. [8][9][10][11][12][13][14][15][16] The advantages of albiglutide include once-weekly dosing and fewer gastrointestinal side effects than the GLP-1 RA liraglutide, but it is less effective at reducing HbA 1c and body weight than liraglutide is. On the other hand, it is effective, safe and approved for patients who have renal impairment. 16,17 Dulaglutide Dulaglutide has two human GLP-1 analogues fused to an immunoglobulin (Ig)-G fragment via two short peptide linkers. The half-life after injection amounts to ~90 hours. It is a clear solution, injected with a pen device.
The AWARD studies 7-9 are still ongoing, with results expected soon (AWARD 7: a study in patients with renal insufficiency dulaglutide vs.

General Considerations about Long-acting GLP-1 Receptor Agonists
The two novel long-acting GLP-1 RAs offer patients who have type 2 diabetes the advantage to lower the glycaemic parameters HbA 1c and fasting and postprandial blood glucose while having a low risk of hypoglycaemia as well as the possibility of losing body weight. Generally, the gastrointestinal side effects (fullness and nausea) associated with GLP-1 RAs are less severe and less sustained than those of the short-acting GLP-1 RAs. Head-to-head studies between albiglutide and dulaglutide have not been performed so far. The percentage of patients reaching their glycaemic targets during therapy with GLP-1 RAs has been greater than that achieved with most established therapies for type 2 diabetes mellitus. Figures 1 and 2 show the changes in head-to-head studies with GLP-1 RA for HbA 1c (see Figure 1) and body weight (see Figure 2). 17 The long-acting GLP-1 RAs activate the GLP-1 receptor continuously, in contrast to the short-acting ones. The pharmacokinetic differences between these drugs lead to important differences in their    Data from the ongoing long-term safety studies are needed to judge whether the beneficial effects seen in preclinical and clinical trials will also improve long-term outcomes in the long run. Studies are also ongoing to elucidate the effects of GLP-1 RA in the treatment of type 1 diabetes in conjunction with insulin therapy, in which instance the effects of the GLP-1 RA on gastric emptying and glucagon secretion may have beneficial effects on glycaemic control. 25,26 Liraglutide for the Treatment of Obesity A novel indication for the GLP-1 RA liraglutide is the treatment of obesity.

Figure 2: Body Weight Reductions with GLP-1 RA in Head-to-head Clinical Studies
Previous pivotal studies have already demonstrated a significant and sustained body weight reduction with liraglutide injected once daily at doses greater than the 1.2 mg and 1.8 mg used for diabetes. 27 A large set of prospective clinical studies with more than 3,000 participants has subsequently investigated the effect of 3.0 mg liraglutide daily on the reduction of body weight, cardiovascular effects and safety.
In these studies, liraglutide demonstrated a significantly better body weight reduction with 3.0 mg than with a 1.8 mg dose and with placebo. Indeed, 65 % of patients treated with the high dose of liraglutide lost more than 5 % of their body weight. In participants who had type 2 diabetes, the glycaemic effects of both doses were comparable, whereas in study participants who did not have diabetes but who had prediabetes and obesity, the diabetes progression was retarded with use of the high dose of liraglutide. The reduction of blood pressure and the increase in pulse rate were comparable for both liraglutide doses. An improvement of cardiovascular surrogate risk markers was observed for C-reactive protein (CRP), for the lipid parameters and brain natriuretic peptide (BNP). Non-biochemical risk parameters, symptoms and scores for sleep apnoea also improved.
All effects of liraglutide were reversible, as observed after a 12-week washout phase at the end of the study. [28][29][30] The most common side effect of the 3.0 mg dose of liraglutide was nausea (39 % versus 14 % in the 1.8 mg dose group) and other gastrointestinal side effects characteristic of the GLP-1 RA. Hypoglycaemia was more frequent in the patients who had type 2 diabetes and concomitant sulphonylurea therapy, despite the reduction of the sulphonylurea dose by 50 % (15 % versus 6 %). During the study, seven cases of pancreatitis were observed in the liraglutide group and one case was detected in the placebo group. The incidence of gallstone complications was also higher in the liraglutide group (2.3 % versus 0.9 %). [28][29][30] The US Food and Drug Administration (FDA) has approved the 3. That progression of diabetes is decreased in subjects with prediabetes on treatment with liraglutide is an interesting finding deserving of more attention in further studies of type 2 diabetes prevention. n