Glucagon-like peptide-1 receptor agonists: Are they all the same?

HbA_1c is the universally accepted marker of average blood glucose levels used to help diagnose type 2 diabetes, and to aid treatment adjustment if required (World Health Organization, 2011). Monnier et al (2003) demonstrated that fasting hyperglycaemia is the major contributor to HbA_1c with poorly controlled diabetes, while postprandial hyperglycaemia is the major contributor in people nearing HbA_1c goals. Therefore, separate measurements of fasting and postprandial glucose levels can provide guidance for which therapies are likely to benefit the individual, depending on need.

To improve glycaemic control to the near-normal range, people with type 2 diabetes are initially treated using oral antidiabetes agents, with lifestyle changes such as diet and exercise being an integral part of managing the condition. When these measures fail to control blood glucose levels adequately, the traditional approach has been to introduce insulin therapy into an individual’s regimen; however, this regimen change may be delayed owing to psychological factors such as fear of hypoglycaemia and weight gain (Gherman et al, 2011). A relatively recent addition to the treatment armamentarium are the glucagon-like peptide-1 (GLP-1) receptor agonists.

GLP-1 receptor agonists: Incretin mimetics
In the 1960s, data suggested that oral glucose elicited a much greater secretion of insulin than when intravenously administered and that this potentiation by the gut of insulin secretion may be responsible for up to 70% of the insulin response to a meal (Elrick et al, 1964). This physiological activity was named the intestinal secretion of insulin, or incretin, effect and is much diminished or even lost in people with type 2 diabetes. Two hormones, gastric inhibitory polypeptide and GLP-1, are responsible for this effect (Drucker and Nauck, 2006).

GLP-1 receptor agonists mimic endogenous GLP-1 by interacting with GLP-1 receptors and stimulating insulin production from pancreatic beta-cells when blood glucose levels are increased. They also inhibit hepatic glucagon release, delay gastric emptying and increase satiety (Drucker and Nauck, 2006). These actions are glucose dependent and so will not be activated in the absence of carbohydrates or when blood glucose is within the normal range (Pratley and Gilbert, 2008).

While the primary effect of GLP-1 receptor agonists is attenuation of postprandial glucose excursions, they can also lower fasting plasma glucose (FPG) levels (Owens et al, 2013). In general, the continuously acting GLP-1 receptor agonists liraglutide and exenatide prolonged release have a greater ability to lower FPG than the shorter-acting agents exenatide (administered twice daily) and lixisenatide (Lund et al, 2014). Another beneficial aspect of GLP-1 receptor agonists is their potential to cause weight loss (Lund et al, 2014). This is in contrast to sulphonylureas, pioglitazone and insulin, which may encourage weight gain, a situation not ideal in those already overweight or obese (Inzucchi et al, 2012), and similar to sodium–glucose cotransporter 2 (SGLT2) inhibitors (Abdul-Ghani et al, 2012).

There is some debate about whether GLP-1 receptor agonists provide distinct cardiovascular benefits such as blood pressure decreases, lipid profile improvement and better endothelial and myocardial function. While clinical studies suggest that these agents can modestly but significantly lower systolic blood pressure (electronic Medicines Compendium [eMC], 2014a; 2014b; 2014c; 2014d; 2014e), results from randomised trials on cardiovascular mortality are not yet available. A number of ongoing trials are looking specifically at cardiovascular outcomes, but no conclusions can currently be drawn (Ryder, 2013). The positive impact on cardiovascular risk factors would certainly be advantageous for individuals with type 2 diabetes as the condition is often associated with hypertension, dyslipidaemia and obesity (Stranges and Khanderia, 2012).

The different agents
There are four currently available GLP-1 receptor agonists in the UK, all of which are administered via subcutaneous injection. They have a similar mode of action, with slight variations, but differ in their dosing schedules. Exenatide (Byetta®), the first in this class of drug to be launched in the UK (in 2007), is administered twice daily. This agent has since been joined in the class by exenatide prolonged release (Bydureon®), a once-weekly formulation, as well as the once-daily agents liraglutide (Victoza®) and lixisenatide (Lyxumia®; eMC 2014a; 2014b; 2014c; 2014d; 2014e). Albiglutide and dulaglutide, both with once-weekly formulations, are due to be launched in the near future (Lund, 2014).

Table 1 details some of the prescribing information for each of these agents. Choice of whether to use a GLP-1 receptor agonist, and which agent to use, may depend on: the other antidiabetes medications that a person is taking (all except exenatide prolonged release have a licence to be used with insulin); whether or not the person has renal impairment (and what stage it is); and whether there are any contraindicating factors.

The NICE (2009) type 2 diabetes guidelines only include exenatide twice daily (NICE, 2009), but the body has since published technology appraisals for liraglutide (NICE, 2010) and exenatide prolonged release (NICE, 2012) and an evidence summary for lixisenatide (NICE, 2013). Table 2 summarises NICE recommendations on when each agent can be prescribed in relation to other antidiabetes drugs.

Efficacy
While all of the GLP-1 receptor agonists have been shown to significantly reduce HbA_1c compared with a placebo, it is interesting to also consider if there are differences when comparing between different agents. There have only been a handful of such studies, the majority of which have compared exenatide in one or other of its formulations. While no significant differences were found between exenatide twice-daily and lixisenatide (Rosenstock et al, 2013), two studies found liraglutide to lower HbA_1c to a significantly greater extent compared with either exenatide formulation (Buse et al, 2009; 2013). However, in the one comparing liraglutide with exenatide twice daily, there were no differences between the agents with regard to postprandial measures (Buse et al, 2009). Furthermore, while the study comparing liraglutide with exenatide prolonged release favoured the former (Buse et al, 2013), an independent meta-analysis of randomised controlled trials of GLP-1 receptor agonists did not identify any significant differences in lowering of HbA_1c between these agents, suggesting they led to similar glycaemic effects (Scott et al, 2013).

Safety and tolerability
The most frequently reported adverse events with GLP-1 receptor agonists are gastrointestinal, including nausea, vomiting and diarrhoea; however, few people discontinue as a result of these events (Heine et al, 2005; Buse et al, 2011; 2013; Riddle et al, 2013a, 2013b; Rosenstock et al, 2013; eMC, 2014a; 2014b; 2014c; 2014d; 2014e; see Table 3). Nausea, the commonest adverse event, is most likely to occur after initiation and then typically subsides relatively quickly. For instance, in a study of lixisenatide and exenatide twice daily, nausea occurred most frequently in the first few weeks but was very limited by 8 weeks (Rosenstock et al, 2013).

In head-to-head studies, nausea was found to be higher with exenatide twice daily compared with the prolonged-release formulation (34.5% versus 26.4%; Drucker et al, 2008) or with lixisenatide (35.1% versus 24.5%; Rosenstock et al, 2013). In a study comparing exenatide twice daily and liraglutide, occurrences were similar initially (28.0% and 25.5%, respectively) but took longer to subside with exenatide (Buse et al, 2009). However, when comparing liraglutide with exenatide prolonged release, less nausea was found with the latter (21% versus 9%; Buse et al, 2013). Useful tips to help combat nausea are shown in Box 1.

Fear of hypoglycaemia can be a major concern for people commencing insulin therapy (Gherman et al, 2011). With GLP-1 receptor agonists, incidences of hypoglycaemia, especially major hypoglycaemia, are relatively low, when used as monotherapy or with some oral antidiabetes agents, including metformin (Heine et al, 2005; Buse et al, 2013; Rosenstock et al, 2013). However, the incidence of hypoglycaemia can increase when combined with a sulphonylurea or basal insulin (Buse et al, 2011; 2013; Riddle et al, 2013a; 2013b; see Table 3). If a GLP-1 receptor agonist is given in combination with a sulphonylurea, the dose should be at least temporarily reduced and the person monitored. When a GLP-1 receptor agonist is combined with basal insulin, the insulin dose should be evaluated and reduced if necessary (eMC, 2014a; 2014b; 2014c; 2014d; 2014e).

A potential relationship between treatment with GLP-1 receptor agonists and acute pancreatitis has been the subject of recent debate. The agents’ summaries of product characteristics do report a risk of developing this condition, albeit a rare one (eMC, 2014a; 2014b; 2014c; 2014d; 2014e). In 2013, however, the European Medicines Agency (EMA) published an assessment on GLP-1-based therapies in which it examined the incidence of acute pancreatitis, as reported in a journal article, as well as other clinical data. They concluded that currently available data “do not confirm recent concerns over an increased risk of pancreatic adverse events with these medicines” (EMA, 2013).

The characteristic symptom of acute pancreatitis is persistent, severe abdominal pain. If an individual experiences this they should stop using the GLP-1 receptor agonist and urgently seek medical help. If it is acute pancreatitis then the person cannot be restarted on GLP-1 receptor agonist therapy. These agents are not suitable for someone with a history of pancreatitis (eMC, 2014a; 2014b; 2014c; 2014d; 2014e).

Another adverse event associated with injectable therapies are injection site reactions. With GLP-1 receptor agonists these are usually mild (see Table 3), with most individual nodules being asymptomatic and resolving. They are most frequently observed with exenatide prolonged release and are consistent with the known properties of poly(d,l-lactide-co-glycolide) polymer microsphere formulations, which allow the GLP-1 receptor agonist to be absorbed over a week’s duration (eMC, 2014a). This should be discussed with all individuals suitable for prolonged-release formulations of GLP-1 receptor agonists.

Other concerns include cardiovascular safety, but while current clinical trial results do not suggest adverse cardiovascular effects (eMC, 2014a; 2014b; 2014c; 2014d; 2014e), ongoing outcome studies will provide a more robust evaluation (Ryder, 2013). These outcome studies will also be reporting on incidences of pancreatic and thyroid cancer (Ryder, 2013). With regard to any potential malignancy, while rat studies have shown a link between long-term, very-high-dose GLP-1-receptor agonist administration and non-lethal thyroid C-cell tumours, current studies in humans do not suggest any such link (eMC, 2014a; 2014b; 2014c; 2014d; 2014e). There is also no direct evidence, from both animal and human studies, of a link between GLP-1 receptor agonists and the development of pancreatic cancer (Ryder, 2013).

Summary
GLP-1 receptor agonists are effective in improving glycaemic control, and while they are not clinically indicated for weight loss, this may be an additional benefit. The practice of using GLP-1 receptor agonists with insulin is becoming more common as this allows blood glucose levels to be reduced while potentially negating weight gain experienced with insulin therapy. Patients commenced on GLP-1 receptor agonist therapy need the right information and support to help ensure that they get the maximum benefit.

Note: The authors are writing on behalf of TREND-UK