Will Glucagon-like peptide-1 agonists dominate the Type 2 Diabetes market?

Reviewed by Professor Anthony Barnett, Institute of Metabolism and Systems Research, University of Birmingham, UK.

Currently available GLP-1 agonists

The three biggest selling GLP-1 agonists on the market to date are Byetta and the once weekly Bydureon from AstraZeneca, and Novo Nordisk’s Victoza. Approved by the FDA in 2005, twice-daily Byetta was used most extensively in 2010. This figure declined following the 2009 approval of the competing, once-daily Victoza (liraglutide), now considered the “gold standard” with some 70% of the GLP-1 agonist market. This position has been bolstered by a recent meta-analysis showing that Victoza provides a greater HbA1c reduction with improved likelihood of reaching glycaemic goals, compared to SGLT2 inhibitors in people with type 2 diabetes who are inadequately controlled with metformin alone or in combination with sulfonylurea, DPP-4 inhibitors or thiazolidinedione.

GLP-1 agonists in development

Currently there are about 60 GLP-1 drugs in R&D, with the majority designed to offer improved convenience with less frequent or oral administration rather than daily subcutaneous injection. Among the most advanced is Sanofi’s once-daily Lyxumia, which was approved in the EU in 2013. Sanofi refiled the drug in the US in 2015 following an FDA request for additional cardiovascular data. The future in diabetes at Sanofi lies with a combination of Lyxumia and Lantus called LixiLan which is currently filed for approval in the US. Filing is planned in the EU in 2016. Since Lantus targets fasting glucose levels and Lyxumia post-prandial glucose levels this makes a potentially powerful approach to diabetes management.

Once-weekly Eperzan/Tanzeum (albiglutide) from GSK was approved in both the EU and US in 2014. Meanwhile Eli Lilly has high hopes for Trulicity (dulaglutide) which is US approved as a once weekly competitor to Victoza. One large-scale trial has shown that it is equal to Victoza, with a more convenient weekly dosing schedule. Whilst pricing is similar to Victoza at the median dose of the latter, Trulicty is cheaper if compared to the highest recommended dose of Victoza. These factors, plus delivery by an easy to use pen device with hidden needle, may mean that Trulicity could cut significantly into Victoza’s market share. In addition, clinical trials with Trulicity show the drug is superior to Byetta, Lantus and Tanzeum in terms of HbA1c control.

Novo Nordisk also has secured EU approval for Xultophy, a once-daily, single-injection combination of Victoza and Tresiba (insulin degludec), with the combination being more effective than each drug alone and also more effective than competitors, Lyxumia and Lantus. The reason: the components act in complementary ways, the weight loss provided by GLP-1 agonists can help overcome weight gain associated with long-acting insulin therapy, resulting in a lower risk of hypoglycaemia compared with intensified insulin regimes. In addition, the included GLP-1 component results in fewer injections per day than with intensified insulin regimes, where up to 4 injections may be needed each day. Xultophy was also filed with the FDA in September 2015.

Potential hurdles facing GLP-1 agonists

GLP-1 agonists provide significant glucose reductions, as well as offering weight loss and possibly other CV benefits without causing hypoglycaemia, yet they are rarely used to treat Type 2 Diabetes patients early in the disease as the treatment is administered by injection and costs more than oral drugs. Doctors commonly wait for patients to fail oral treatments before they move on to GLP-1 agonists. This may change with the advent of Novo Nordisk’s oral semaglutide which is currently in Phase III testing. Novo Nordisk plans to initiate seven clinical trials – including a cardiovascular outcomes study – to test the safety and efficacy of this oral GLP-1 treatment. Another route to increased patient convenience could be Intarcia’s Exenatide delivery system ITCA 650, currently in Phase III. This involves an annual subcutaneous implant of the matchstick-sized pump, which delivers daily doses of Exenatide. Researchers are also exploring ways to slow the release of GLP-1 agonists such as Exenatide to allow a monthly dosing schedule.

GLP-1 agonists are not risk free and have been associated with both tolerability and safety concerns. Gastrointestinal side effects such as nausea, vomiting and diarrhoea are common in the first few weeks of treatment but tend to disappear with time. These side effects may be less common with longer acting agents.

Pancreatitis may also be an issue. According to a study published in JAMA in 2013, Byetta may double patients' risk of pancreatitis though many studies have reported a lower risk while several show no increased risk at all. Claims that GLP-1 agonists as a class increase the risk of pancreatitis are under investigation. In 2015 analysts at AdverseEvents reported on safety issues with GLP-1 drugs: there were 1900 cases of pancreatitis associated with AstraZeneca's Byetta (750 cases of pancreatic cancer) and 1284 cases of pancreatitis associated with Novo Nordisk's Victoza (335 cases of pancreatic cancer). Indeed, some 154 plaintiffs in the US have started litigation alleging that use of Victoza led to pancreatic cancer. Clearly these figures must be balanced against the fact that type 2 diabetes itself is associated with a significantly increased risk of pancreatitis and pancreatic cancer. While the FDA and EMA are keeping these issues under review, current advice in early 2016 is that a convincing case has not been made linking GLP-1 RAs to pancreatitis and pancreatic cancer. It would seem sensible at present to withhold these drugs from patients with either a history of pancreatitis, or those at high risk of developing it, such as people known to have gallstones or alcoholism. Finally, liraglutide has been linked with thyroid C-cell tumours at clinically relevant exposures in rodents, although this has not been confirmed in humans. The FDA and EMA continue to review this issue.

Clearly GLP-1 agonists will continue to face stiff competition from other drugs with different mechanisms of action, particularly those that are orally medicated, which may be considerably cheaper or offer additional health benefits. For example, there are currently 3 sodium glucose co-transporter (SGLT2) inhibitors approved for use and one of them, Jardiance (empagliflozin), has been associated with positive CV outcome data. Dipeptidyl peptidase-4 (DPP-4) inhibitors could make a dent in their market share, in particular Tradjenta/Trajenta (linagliptin) which is not renally cleared and does not need dose adjustment.

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