From 1 October 2015 the PBS listing of exenatide twice daily is extended to allow triple therapy with exenatide in combination with insulin and metformin (unless contraindicated or not tolerated) for the treatment of type 2 diabetes mellitus.1

The new listing is an extension to the previous PBS listings in which exenatide was subsidised in dual therapy with either metformin or a sulfonylurea and in triple therapy with metformin and a sulfonylurea.2

The Pharmaceutical Benefits Advisory Committee accepted that exenatide in combination with insulin is at least as effective as insulin intensification (with rapid- or short-acting insulin) and has some clinical advantages, including reductions in weight gain and small reductions in minor hypoglycaemic episodes.1

Efficacy of exenatide in combination with insulin

The PBAC recommended exenatide as an add-on to insulin therapy based on two clinical studies of exenatide twice daily in combination with insulin glargine (with or without oral diabetes medicines), compared with insulin lispro (intensification)3 or placebo.4

The primary outcome was mean change in HbA1c from baseline (or randomisation) at 30 weeks.3,4

Key features and results of clinical trials

Trial ID

Trial design

Background therapya

Mean change in HbA1c %
(standard error)

twice daily

Insulin lispro


(n = 627)

Randomised, open label, 12 weeks' run-in, 30 weeks' duration

Metformin + insulin glargine ± sulfonylurea

–1.13 (0.053)

–1.10 (0.051)

twice daily


GWCO4 (n = 261)

Randomised, double blinded, 30 weeks' duration

Insulin glargine ± metformin ± pioglitazone


–1.00 (0.09)

  1. Background therapy: patients taking other antidiabetic medicines were allowed to take them concurrently during the trial

The results demonstrated exenatide add-on therapy to be as effective as (non-inferior to) insulin intensification (basal-bolus regimen) and superior to titrated basal insulin alone in reducing HbA1c, on a background of insulin glargine with or without metformin and/or pioglitazone and/or a sulfonylurea.1,3,4

Other clinical health benefits over insulin intensification

The studies have shown some clinical advantages of exenatide with insulin, including reductions in weight gain3,5 and small reductions in the frequency of minor hypoglycaemic episodes.3,4

The GWDM trial showed that treatment with exenatide twice daily was associated with a net improvement in fasting plasma glucose levels and systolic blood pressure, compared with insulin intensification.1,3

The PBAC noted that the open-label nature of the study would result in the rates of hypoglycaemia being biased, as participants on treatment would be more likely to test for hypoglycaemic events.1

Different safety profile to that of insulin intensification

Although the combination use of exenatide, insulin and metformin has a different safety profile to that of insulin intensification, the adverse events are tolerable.1 Clinical evidence reported common adverse events of nausea, vomiting and diarrhoea for add-on exenatide therapy.3,4

The GWDM study reported fewer major or minor hypoglycaemic events in the exenatide treatment arm compared with insulin intensification.3 However, a potential bias in reporting adverse events may have been introduced by the open-label design of this study.

Additional data on safety obtained from postmarketing experience with exenatide identified risks of pancreatitis and altered kidney function (see the November 2010 NPS RADAR review of exenatide for further information). While these adverse events are serious, the occurrence associated with exenatide is low. 6

PBS listing

PBS listing broader than TGA indication

The extension to the PBS listing is broader than the Therapeutic Goods Administration indication for exenatide.

Exenatide is TGA approved as an adjunctive therapy to improve glycaemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea, or a combination of metformin and basal insulin, but who are not achieving adequate glycaemic control.7

The PBS criteria for use of exenatide in combination with insulin does not require concurrent use of metformin if it is contraindicated or not tolerated.2

When to consider prescribing

Australian guidelines recommend exenatide in combination with insulin and metformin (if tolerated) as a third-line option when blood glucose targets are not reached after 6 months of treatment with current therapies at the maximum tolerated doses.8

Current guidelines recommend exenatide as an alternative strategy to insulin intensification for patients using basal insulin.8

PBS-subsidised place in therapy

The latest listing extension for triple therapy provides PBS-subsidised add-on exenatide in combination with insulin and metformin (if tolerated and not contraindicated) when inadequate glycaemic control has been shown despite treatment with:

  • insulin and oral diabetes medicines, or
  • insulin alone when metformin is contraindicated or not tolerated.2

In summary, exenatide is now available on the PBS for people who have clinically inappropriate HbA1c (>7%):

  • and the combination of metformin and a sulfonylurea is contraindicated or not tolerated
  • despite treatment with maximally tolerated doses of metformin and a sulfonylurea
  • despite treatment with a combination of insulin and other antidiabetic agents, or insulin alone when metformin is contraindicated or not tolerated.1

The availability of exenatide on the PBS is shown in Figure 1.

Figure 1Pathways to PBS-subsidised exenatide.a

  1. Refer to for a full list of PBS criteria for access to PBS-subsidised exenatide.
  2. Combination treatment with metformin unless contraindicated or not tolerated.


  1. Australian Government Department of Health. Public Summary Document. Exenatide (Byetta). March 2015 PBAC Meeting. [PBS] (accessed 6 August 2015).
  2. Australian Government Department of Health. PBS: Exenatide. [PBS] (accessed 24 July 2015).
  3. Diamant M, Nauck MA, Shaginian R, et al. Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care 2014;37:2763–73. .
  4. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2011;154:103–12. .
  5. Buse JB, Han J, Miller S, et al. Addition of exenatide BID to insulin glargine: a post-hoc analysis of the effect on glycemia and weight across a range of insulin titration. Curr Med Res Opin 2014;30:1209–18. .
  6. U.S. Food and Drug Administration. Byetta Safety Update for Healthcare Professionals. 2013. [FDA] (accessed 20 July 2015).
  7. Therapeutic Goods Administration. Public Summary. 2015. [TGA] (accessed 20 July 2015).
  8. Royal Australian College of General Pracitioners. Clinical Guidelines. 2014. [RACGP] (accessed 20 July 2015).