SGLT2 inhibitor listings: indications and combinations

Under changes to PBS restrictions that took effect from 1 December 2014, dapagliflozin is now available as a second-line treatment (with either metformin or a sulfonylurea), after either metformin or a sulfonylurea have been demonstrated to inadequately control blood glucose.^{2, 3} The dapagliflozin listing has also been changed to Authority required (streamlined).^{2, 3}

Inadequate glycaemic control from a combination of metformin and a sulfonylurea is no longer a requirement to receive PBS-subsidised dapagliflozin, allowing this treatment option to move from third-line to second-line dual combination therapy.^1-3

Previously, although approved by the Therapeutic Goods Administration as a first-line option in combination with metformin, PBS-subsidised dapagliflozin (with metformin or a sulfonylurea) was only available after insufficient glycaemic control had been shown with a combination of metformin and a sulfonylurea.^{1, 7}

From 1 January 2015, empagliflozin (Jardiance, 10 mg and 25 mg tablets) joined dapagliflozin and canagliflozin on the PBS, and from 1 April 2015 the listing for empagliflozin was revised to align with dapagliflozin.⁴

Empagliflozin is now listed as an option for dual combination therapy with metformin or a sulfonylurea in people with type 2 diabetes who have shown insufficient glycaemic control using metformin or a sulfonylurea.^{4, 5}

Eligibility criteria also require HbA_1c to be, or to have been, > 7% (53 mmol/mol), or, when HbA_1c measurement is clinically inappropriate, blood glucose concentration to be, or to have been, > 10 mmol/L in more than 20% of tests over a 2-week period despite treatment with metformin or a sulfonylurea.⁴

The empagliflozin listing is designated Authority required (streamlined).^{4, 5} Note that there is no requirement in the listing restriction for patients to be intolerant of, or contraindicated to, a sulfonylurea.

Empagliflozin is not PBS subsidised for use as an add-on combination therapy with other anti-hyperglycaemic medicines, including insulin, although these uses are approved by the TGA.^{4, 5, 8}

Similar safety, efficacy and contraindications to those of other SGLT2 inhibitors

A recent meta-analysis of empagliflozin clinical trials (10 studies involving > 6200 participants) found HbA_1c (placebo adjusted) was reduced by 0.62% and 0.66% in groups treated with the 10 mg and 25 mg doses, respectively.⁹

Compared with metformin or sitagliptin, both 10 mg and 25 mg empagliflozin had similar efficacy, with no significant difference in HbA_1c reduction.⁹

There have been no head-to-head comparisons of empagliflozin with other SGLT2 inhibitors.

As for the other SGLT2 inhibitors, empagliflozin was associated with at least a threefold higher risk of genital tract infections for both the 10 mg and 25 mg doses, and should not be started in patients with impaired kidney function ( eGFR < 45 mL/min/1.73 m² or CrCL < 45 mL/min).^{8, 9} Refer to the Product Information for a full list of contraindications for empagliflozin. ⁸

The SGLT2 inhibitor canagliflozin (Invokana) remains on the PBS as a third-line treatment option in people with type 2 diabetes who have shown insufficient glycaemic control using metformin and a sulfonylurea but, after a decision by the sponsor, it will be delisted from the PBS effective 1 August 2015.^{6, 10}

Subsequent to its delisting, cost considerations may result in people previously taking canagliflozin to seek alternatives.

Alternatives for people who wish to switch

For people previously treated with canagliflozin who wish to switch, PBS-listed oral alternatives include other SGLT2 inhibitors such as dapagliflozin or empagliflozin, or a DPP-4 inhibitor (gliptin).^{2, 5, 11-15}

Considerations for switching medicines

Because of the importance of renal elimination, assess kidney function in patients before switching. Also evaluate liver function if indicated. Refer to the Product Information for a full list of precautions and contraindications.^{7, 8, 16-20}

Alternative SGLT2 inhibitors

Dapagliflozin and empagliflozin are SGLT2 inhibitors that may be considered as alternatives to canagliflozin.

Issues to consider before switching to dapagliflozin⁷

• Renal function: people with moderate to severe kidney impairment should not use dapagliflozin ( eGFR < 60 mL/min/1.73m² or CrCL < 60 mL/min).
• Risk to pregnant or lactating women: dapagliflozin is not for use in pregnant or lactating women because of increased risk of malformations and irreversible damage (pregnancy category D).
• Concurrent medicines: dapagliflozin has not been studied in combination with GLP-1 analogues, and concomitant use of dapagliflozin with loop diuretics is not recommended.^a
• Age: starting dapagliflozin is not recommended in people aged 75 years or over because of limited therapeutic experience in this population.

Precautions to be considered before switching patients to empagliflozin⁸

• Age: prescribe with caution in patients aged 75 years or over because of potential increased risk of volume depletion. Do not start treatment in patients aged 85 or over because of limited therapeutic experience in this population.
• Avoid combination with GLP-1 analogues: concomitant use of empagliflozin with GLP-1 analogues has not been studied.

Consult the current clinical guidelines for managing type 2 diabetes to more fully assess options for patients who wish to switch to a PBS-listed alternative.²¹