Exenatide triple therapy, an option for type 2 diabetes add-on treatment

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 HbA_1c from baseline (or randomisation) at 30 weeks.^3,4

Key features and results of clinical trials

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 HbA_1c, 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 gain^3,5 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

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 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 HbA_1c (>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.