Four new metformin/gliptin fixed-dose combinations (FDCs) for the treatment of type 2 diabetes are now available on the PBS:
- metformin with alogliptin (Nesina Met), which was listed on 1 February 2014
- metformin XR with saxagliptin (Kombiglyze XR) and linagliptin with metformin (Trajentamet), which were both listed on 1 March 2014
- metformin XR and sitagliptin (Janumet XR) listed from 1 May 2014 (Table 1).
All four products are listed as Authority required (Streamlined) benefit for treatment of patients whose HbA1c is > 7% before starting a dipeptidyl peptidase 4 inhibitor (gliptin), despite treatment with metformin.
It should be noted that there is no requirement in the listing restriction for patients to have trialled, or have contraindications to, sulfonylurea (Table 1).
Metformin extended release versus immediate release
Two of the four new combinations contain the metformin extended-release (XR) formulation. In clinical trials metformin XR has been shown to have efficacy comparable to that of immediate-release (IR) metformin.1, 2
In addition to comparable efficacy it is claimed that the metformin XR formulation results in fewer GI side effects than metformin IR.2-4 Metformin XR may therefore be an option for patients who experience an unacceptable level of GI side effects with metformin IR.2, 4, 5
However, a retrospective cohort study investigating relative GI tolerability only showed a lower incidence of GI side effects for patients who had been switched from metformin IR to metformin XR after GI upset, or for treatment-naïve patients who had been started on metformin XR.6 The study did not show any difference overall in GI adverse events between groups given IR or XR formulations.6
In addition to fewer GI side effects, use of metformin XR is purported to result in improved adherence through once-daily dosing3, 4 compared with metformin IR, which may have 2–3 times daily dosing. A population-based study demonstrated improved adherence in patients taking XR compared with IR formulations but it is unclear from this small observational study whether the improvement in adherence was attributable to once-daily dosing or to reduced side effects.5
Fixed-dose combination products
As with all FDC products, stabilise patients on the individual components taken separately before switching to the combination product.
While improved adherence through simplified dosing is a potential benefit of FDC products, other issues may impact efficacy and safety. There is a risk that use of a once-daily FDC product may result in inadvertent double dosing through patient confusion over which products the FDC replaces and/or because people who are used to multiple daily dosing may mistakenly take more doses than prescribed. In addition, as with all FDC products, there are limited options for dose adjustment.
Metformin combination products
All four products are subject to the same PBS restrictions for subsidy, as follows.
Authority Required (STREAMLINED)
Diabetes mellitus type 2
- Patient must have, or have had, an HbA1c measurement > 7% despite treatment with metformin; OR
- Patient must have, or have had, where HbA1c measurement
is clinically inappropriate, blood glucose levels > 10 mmol/L in
more than 20% of tests over a 2-week period despite treatment with
The date and level of the qualifying HbA1c measurement must be, or must have been, documented in the patient's medical records at the time treatment with a dipeptidyl peptidase 4 inhibitor (gliptin), a thiazolidinedione (glitazone), a glucagon‐like peptide‐1-related (GLP-1-related) drug or a sodium–glucose co-transporter-2 (SGLT2) inhibitor is initiated.
- The HbA1c must be no more than 4 months old at the time treatment with a gliptin, a glitazone, a GLP‐1-related drug or an SGLT2 inhibitor was initiated.
- Blood glucose monitoring may be used as an alternative assessment to HbA1c levels in the following circumstances:
a) a clinical condition with reduced red blood cell survival, including haemolytic anaemias and haemoglobinopathies; and/or
b) red cell transfusion within the previous 3 months.
The results of the blood glucose monitoring, which must be no more than 4 months old at the time of initiation of treatment with a gliptin, a glitazone, a GLP‐1-related drug or an SGLT2 inhibitor, must be documented in the patient's medical records.
- A patient whose diabetes was previously demonstrated unable to be controlled with metformin does not need to requalify on this criterion before being eligible for PBS‐subsidised treatment with this fixed-dose combination.
Authority required (STREAMLINED)
Diabetes mellitus type 2
Treatment Phase: Continuing
Patient must have previously received, and been stabilised on, a PBS‐subsidised regimen of oral diabetic medicines which includes metformin and gliptin specific to the combination product.
The fixed-dose combination tablets are not PBS subsidised for use in combination with a sulfonylurea (triple oral therapy), as initial therapy or in combination with a thiazolidinedione (glitazone), a GLP-1-related drug or an SGLT2 inhibitor.
Table 1 Metformin/gliptin fixed-dose combination products
|Combination||Brand name||PBS listing: key differences|
|Newly listed metformin/gliptin combinations|
No requirement for intolerance of, or contraindication to, sulfonylurea
|Existing metformin/gliptin combinations|
From 1 April 2014 there will be no requirement for intolerance of, or contraindication to, sulfonylurea
* Modified-release metformin = metformin XR
- Fujioka K, Pans M, Joyal S. Glycemic control in patients with type 2 diabetes mellitus switched from twice-daily immediate-release metformin to a once-daily extended-release formulation. Clin Ther 2003;25:515\u201329. [PubMed]
- Schwartz S, Fonseca V, Berner B, et al. Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes. Diabetes Care 2006;29:759\u201364. [PubMed]
- Ali S, Fonseca V. Overview of metformin: special focus on metformin extended release. Expert Opin Pharmacother 2012;13:1797\u2013805. [PubMed]
- Chacra AR. Evolving Metformin Treatment Strategies in Type-2 Diabetes: From Immediate-Release Metformin Monotherapy to Extended-Release Combination Therapy. Am J Ther 2012. [PubMed]
- Donnelly LA, Morris AD, Pearson ER. Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study. Diabetes Obes Metab 2009;11:338\u201342. [PubMed]
- Blonde L, Dailey GE, Jabbour SA, et al. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin 2004;20:565\u201372. [PubMed]