June 15, 2018, Dr Chee L Khoo 
Insulin secretion is augmented by incretins following oral glucose intake. In healthy individuals, incretins are responsible for 70% of insulin secretion. However, in patients with type 2 diabetes (T2D), the incretin effect is significantly blunted thereby affecting glucose control. Glucagon like peptide 1 (GLP1) and gastric inhibitory peptide (GIP)s are the most studied of the incretins. GLP1 not only stimulates the secretion of insulin by beta cells, it is also a strong inhibitor of glucagon secretion.
Natural GLP1 is rapidly degraded by natural DPP4 enzymes. To date, there are 7 different GLP1 receptor analogues (GLP1-RA) on the market. They resist degradation by natural DPP4 enzymes because of the alteration in structure of the GLP1 molecule. They are all quite different molecules and differ in their pharmacokinetics and hence, their clinical effects.
GLP1-RAs are categorised into either short acting or long acting. Short acting agents (exenatide (Byetta®)) and lixisenatide (Lyxumia®)) are given once or twice a day and last a few hours. The long acting agents resist degradation and elimination by binding to microspheres, albumin or similar proteins and can be given daily (liraglutide (Victoza®)) or weekly (exenatide LAR (Bydureon®), albiglutide (Tanzeum®), dulaglutide (Trulicity®), semaglutide (Ozempic®). So far, Exenatide, Exenatide LAR, liraglutide, dulaglutide and lixisenatide are approved by the TGA for use in Australia but only Exenatide, Exenatide LAR and Dulaglutide are on the PBS. Dulaglutide was only approved for the PBS in June 2018. It might be a good time to review and compare these agents.
When should we use these agents?
GLP1-RAs have really changed the management of our patients with type 2 diabetes (T2D). It really is a game changer. It can be used:
- Second line after metformin. Yes, it is an injectable and most patients don’t really like needles but with education almost all patients can be “persuaded” to commence on an injectable. It is often not needles that they are scared of. Once you tell them that it helps with weight loss, suddenly it is “tell me more”.
- When oral therapy fails but before insulin. Once again, patient’s “phobia” with needles include phobias with hypoglycaemia and complicated dose regimens. GLP1-RA injectables don’t have those issues. Unfortunately, the PBS doesn’t allow us to use a GLP1-RA in conjunction with DPP4 inhibitors, SGLT2 inhibitors or glitazones.
- Add-on to basal insulins. In the early stages of oral failure, patients can adequately be managed on basal insulin once or twice a day. As beta cell decline continues, post prandial glucose eventually needs attention. Instead of adding a prandial insulin (Novorapid®, Humalog® rapid or Apidra®), one could add a GLP1-RA to basal insulin to cover the prandial needs. And PBS actually allows us to do that. In fact, an insulin-GLP1-RA combination is now the flavour of the month. There are fixed insulin-GLP1-RA combos in development with proven efficacy in clinical trials.
- Just add on to insulin whenever. GLP1-RA injectable when added to insulin often reduces insulin doses, reduce weight or helps to negate weight gain frequently associated with insulin therapy and reduce. It is an ideal combination.
How do they compare with insulin?
As mentioned above, these agents are now used at the same point in the treatment algorithm. Thus, we need to be know whether they as efficacious as basal insulin. It need not be more superior than insulin in reducing HbA1c but they just need to be as good as insulin therapy to reduce HbA1c. Indeed in a recent meta-analysis comparing GLP1-Rs with basal insulin, both the weekly Bydureon® and Truclicity® reduce HbA1c better than basal insulin while the daily Victoza® and Byetta® were as good as basal insulin with glycaemic control. All the GLP1-Rs were better than basal insulin in weight reduction. Both short-acting and long-acting GLP1RAs reduce body weight, whereas short-acting GLP1RAs have a greater effect on postprandial plasma levels of glucose and long-acting GLP1RAs predominantly lower fasting plasma concentrations of glucose. A note of warning though. In patients requiring large doses of prandial insulin, GLP1-RAs alone do not sufficiently cover the post prandial hyperglycaemia.
How safe are these agents?
In a recent systematic review comparing the short acting GLP1-Rs, exenatide and lixisenatide, with the longer acting agents, exenatide LAR, liraglutide, dulaglutide, albiglutide, all GLP-1RAs were found to improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short-acting agents were compared with each other or when long-acting agents were compared with each other, dulaglutide, liraglutide and once-weekly exenatide LAR were superior to twice-daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemic events between these 3 agents but once-weekly exenatide LAR had the lowest risk of vomiting.
There were some initial concerns of a link between exenatide and pancreatic cancer in 2011 but both preclinical and clinical studies regarding the risk of pancreatitis and pancreatic cancer have been extensively evaluated by the US food and Drug Authority (FDA) and the European Medicines Agency (EMA), with the conclusion that the data were inconsistent with a causal association between GLP1-RAs and pancreatic adverse effects. This conclusion is supported by a meta-analysis that was published in 2017, which included data from >9,000 patients treated with GLP1-RAs for a minimum of 24 months and found no evidence of an increased risk of pancreatitis.
Are they any other benefits?
In 2008, cardiovascular outcome trial (CVOT)s became an FDA requirement for approval of new treatments for type 2 diabetes( T2DM) and a similar requirement was subsequently put forward by the EMA. Since then, there have been many CVOTs completed with GLP1-RA – ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide). Lixisenatide and exenatide has been shown to be cardiovascularly safe while liraglutide and semaglutide has been shown to reduce major adverse cardiovascular events in patients with either established cardiac disease or high CV risks. We await outcomes from the REWIND (dulaglutide) and HARMONY (albiglutide) trials.
These agents are increasingly becoming mainstay treatment for many of our patients with T2D. There will be more agents on the PBS soon. While all of them are similar in their benefits, there are individual differences and it is worthwhile being familiar with them to choose the right agent for the right patient. We also need to consider the proven cardiovascular data available when selecting the agents for our patients with known cardiovascular disease or high cardiovascular risk. So far, liraglutide (not on PBS), exenatide (on PBS) and semaglutide (not available yet) have proven cardiovascular data.
Reference
Sonal Singh, Eugene E. Wright, Jr., Anita Y. M. Kwan, et al. Glucagon‐like peptide‐1 receptor agonists compared with basal insulins for the treatment of type 2 diabetes mellitus: a systematic review and meta‐analysis. Diabetes Obes Metab. 2017 Feb; 19(2): 228–23
Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017 Apr;19(4):524-536
Andreas Andersen, Asger Lund, Filip K. Knop, Tina Vilsbøll. Glucagon-like peptide 1 in health and disease. Nat Rev Endocrinol 2018 May 04