Key points

  • On 1 April 2022, a new indication and clinical criteria were added to the Authority Required (Streamlined) PBS listing for empagliflozin (Jardiance).
    The new indication is symptomatic (NYHA class II–IV) heart failure and LVEF ≤ 40%. The treatment must be an add-on therapy to optimal standard treatment, which must include, unless contraindicated or cannot be tolerated, a beta blocker and ACE inhibitor or ARB or ARNI.
  • Empagliflozin is the second PBS-listed SGLT2 inhibitor for heart failure with reduced ejection fraction (LVEF ≤ 40%)
    The new indication and clinical criteria for empagliflozin are the same as for dapagliflozin, whose PBS listing was changed on 1 January 2022.
  • Current Australian guidelines define HFrEF as LVEF < 50% and symptoms with or without signs of heart failure and recommend that the standard treatment for HFrEF is a combination of an ACE inhibitor (or ARB), heart failure beta blocker and MRA, each up-titrated to the maximum tolerated or target dose.
    The guidelines only recommend empagliflozin and other SGLT2 inhibitors to reduce the risk of heart failure-related hospitalisation for people with cardiovascular disease and type 2 diabetes with insufficient glycaemic control despite receiving metformin.
  • Updated international guidance recommends an expanded role for empagliflozin and other SGLT2 inhibitors for HFrEF with LVEF ≤ 40%.
    SGLT2 inhibitors are included as standard treatment for HFrEF with LVEF ≤ 40% in combination with an ACE inhibitor (or ARB or ARNI), heart failure beta blocker and MRA.
  • The clinical place of empagliflozin in the treatment of HFrEF is for people who have persistent LVEF ≤ 40% despite receiving optimal standard treatment that may or may not include an MRA.
    Adding empagliflozin or dapagliflozin, or changing the ACE inhibitor (or ARB) to an ARNI are three PBS-listed options for these patients. However, there is limited evidence to guide which option to select first.

Abbreviations

HFrEF – heart failure with reduced ejection fraction

HFpEF – heart failure with preserved ejection fraction

LVEF – left ventricular ejection fraction

ACE – angiotensin-converting enzyme

ARB – angiotensin receptor II blocker

ARNI – angiotensin receptor neprilysin inhibitor

MRA – mineralocorticoid receptor antagonist

SGLT2 – sodium–glucose co-transporter-2

NYHA – New York Heart Association

TGA – Therapeutic Goods Administration

PBS – Pharmaceutical Benefits Scheme

PBAC – Pharmaceutical Benefits Advisory Committee

 

Heart failure

Classification of heart failure

An estimated 480,000 people in Australia have heart failure.1 Clinical diagnosis is made following a patient history, physical examination and investigations. An echocardiogram is recommended to confirm the diagnosis and classify heart failure. Classification helps guide management of the condition.2

Just under half of all people with heart failure can be classified as having reduced ejection fraction (HFrEF).1 HFrEF (previously called systolic heart failure) is defined by the 2018 National Heart Foundation and Cardiac Society of Australia and New Zealand: Guidelines for the Prevention, Detection, and Management of Heart Failure in Australia, as:2

  • left ventricular ejection fraction (LVEF) < 50%, in the presence of symptoms with or without signs of heart failure, where the diagnosis is confirmed with an echocardiogram.

Over half of all people with heart failure can be classified as having preserved ejection fraction (HFpEF).1 HFpEF (previously called diastolic heart failure) is defined as:2

  • LVEF ≥ 50%, in the presence of symptoms with or without signs of heart failure and objective evidence of relevant structural heart disease and/or diastolic dysfunction without an alternative cause.

Type 2 diabetes is an independent risk factor for heart failure.2 Australian and overseas studies have found that for all people with heart failure, 10% to 47% also have type 2 diabetes.3,4

 

What’s new?

Authority Required (Streamlined)

On 1 April 2022, a new indication and clinical criteria were added to the General Schedule (Section 85) Authority Required (Streamlined) listing for empagliflozin (Jardiance).5 It was previously only listed for type 2 diabetes.6

The new indication for empagliflozin is chronic heart failure. The new clinical criteria are, the patient must:5

  • be symptomatic with New York Heart Association (NYHA) classes II, III or IV, and
  • have a documented LVEF ≤ 40%.

The treatment must be an add-on therapy to optimal standard chronic heart failure treatment, which must include, unless contraindicated according to the TGA-approved Product Information (PI) or cannot be tolerated, a:5

  • beta-blocker and
  • angiotensin converting enzyme (ACE) inhibitor or
  • angiotensin II antagonist (angiotensin II receptor blocker; ARB) or
  • angiotensin receptor with neprilysin inhibitor (sacubitril/valsartan; ARNI).

The patient must not be receiving treatment with another medicine from the same class of medicines: sodium–glucose co-transporter-2 (SGLT2) inhibitors.5

See the PBS website for complete details for each item.

May be prescribed by nurse practitioners (continuing therapy only)

Authorised nurse practitioners may only prescribe continuing therapy of this medicine after it has been initiated by a medical practitioner.5 See the PBS website for more information on nurse practitioner PBS prescribing.

Empagliflozin – the second PBS-listed SGLT2 inhibitor for heart failure with reduced ejection fraction (LVEF ≤ 40%)

The new indication and clinical criteria for empagliflozin are the same as those added to the PBS listing for dapagliflozin on 1 January 2022.5,7

See the NPS MedicineWise RADAR article Dapagliflozin (Forxiga) for heart failure with reduced ejection fraction (LVEF ≤ 40%) for more information.

 

What is empagliflozin?

Empagliflozin belongs to a class of medicines called SGLT2 inhibitors.8,9 Other medicines in this class include:

Indications

Empagliflozin is TGA registered as 10 mg tablets for:9

  • type 2 diabetes including:
    • glycaemic control as monotherapy and in combination with other glucose-lowering therapies
    • prevention of cardiovascular death for people who also have established cardiovascular disease
  • symptomatic heart failure with reduced ejection fraction, as an adjunct to standard of care therapy.

Mechanisms of action

SGLT2 is a protein primarily located in the proximal convoluted tubule of the nephrons in the kidneys. It is responsible for resorption of approximately 90% of filtered glucose in the kidneys.13,14

Inhibition of SGLT2 leads to multiple effects, including:13,15,16

  • a glucose-lowering effect that is well understood; increased glucose excretion (glucosuria)
  • cardioprotective effect for heart failure that is not yet fully understood – the effect was discovered in trials addressing cardiovascular safety concerns for people with type 2 diabetes that inadvertently found benefits such as reduced hospitalisation for heart failure that were independent of the glucose-lowering effect. See ‘Why was the new listing made? Background’ section below for more information about the trials.

See NPS MedicineWise RADAR article Dapagliflozin (Forxiga) for heart failure with reduced ejection fraction (LVEF ≤ 40%) ‘What is it?’ section for more information about the proposed mechanisms for the cardioprotective effect of SGLT2 inhibitors.

 

Why was the new listing made?

Background

Trials on the cardiovascular safety of SGLT2 inhibitors including empagliflozin for people with type 2 diabetes were published between 2015 and 2020.17-20

The safety trials consistently showed a 27% to 35% reduction in heart failure-related hospitalisations as a secondary outcome.17-20

These findings led to HFrEF efficacy trials being conducted for SGLT2 inhibitors for people with and without type 2 diabetes. The first was the 2019 Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial for dapagliflozin.13,21 It was followed by the 2020 EMPEROR-Reduced trial for empagliflozin, which was the key study evidence for this PBS listing.22

Key study evidence

The 2020 EMPEROR-Reduced trial enrolled people with symptomatic (NYHA class II–IV) HFrEF and LVEF ≤ 40% (mean LVEF 27.7%). At baseline, 49.8% of the 3730 participants had type 2 diabetes and there was high use of the standard treatment for HFrEF, which is a combination of three medicines: an ACE inhibitor; heart failure beta-blocker; and mineralocorticoid receptor antagonist (MRA).22

The primary composite outcome (hospitalisation for worsening heart failure or cardiovascular death) was reduced by 25% with empagliflozin in comparison to placebo: 19.4% vs 24.7% . This corresponds to a number needed to treat of 19 (95% confidence interval [CI], 13 to 37) to prevent one event (worsened heart failure or cardiovascular death). Sub-group analyses showed that the treatment effect was consistent in patients with and without type 2 diabetes.22

Reasons for PBS listing

At the November 2021 Meeting, the PBAC recommended listing empagliflozin for the treatment of people with chronic heart failure with reduced ejection fraction, NYHA class II-IV and LVEF ≤ 40%.23

Although the submission presented a modelled economic evaluation against standard care, the PBAC concluded that the main comparator that was most relevant for decision-making about this submission was dapagliflozin for chronic heart failure because of its recent listing on the PBS. Due to the lack of head-to-head trials comparing empagliflozin to dapagliflozin, the PBAC agreed on an indirect treatment comparison (ITC) between the 2020 EMPEROR-Reduced trial for empagliflozin vs the DAPA-HF trial for dapagliflozin, using placebo plus standard treatment as the common reference.23

Based on the ITC findings, the PBAC considered the claim of noninferior effectiveness and safety of empagliflozin compared with dapagliflozin was reasonable. It also considered that the benefits of the SGLT2 inhibitors for people with HFrEF are a class effect, which is reflected in clinical guidelines and practice.23

 

Will the changes affect current prescribing?

The clinical place of empagliflozin and other SGLT2 inhibitors in the treatment of people with HFrEF who do not have type 2 diabetes continues to evolve.23,24 There are differences between Australian guideline recommendations and international guidance.

Australian guidelines for HFrEF

Standard treatment for HFrEF

The 2018 National Heart Foundation and Cardiac Society of Australia and New Zealand: Guidelines for the Prevention, Detection, and Management of Heart Failure in Australia define HFrEF as LVEF < 50% in the presence of symptoms with or without signs of heart failure, where the diagnosis is confirmed with an echocardiogram.2

A combination of three medicines – an ACE inhibitor, heart failure beta-blocker and MRA – is recommended as standard treatment in the guidelines. Each medicine should be up-titrated to the maximum tolerated or target doses. If an ACE inhibitor is contraindicated or not tolerated, an ARB may be prescribed instead (see Figure 1).2

For people with HFrEF who have persistent LVEF ≤ 40%, despite receiving the maximum tolerated or target doses of an ACE inhibitor (or ARB) and heart failure beta blocker, with or without an MRA, an ARNI may be prescribed to replace the ACE inhibitor (or ARB).2

Figure 1: Initial pharmacological management for people with HFrEF2,25,26

Read an accessible version of this figure

See NPS MedicineWise News Up-titrating heart failure medicines: A practical guide for more details about the pharmacological management of HFrEF.

Limited role for empagliflozin and other SGLT2 inhibitors

There is no recommendation for empagliflozin and other SGLT2 inhibitors for the management of patients with HFrEF who do not have type 2 diabetes in the pharmacological management of heart failure in the Australian guidelines.2

The role of empagliflozin and other SGLT2 inhibitors to reduce the risk of heart failure-related hospitalisation is limited to patients with both cardiovascular disease and type 2 diabetes with insufficient glycaemic control despite receiving metformin.2

Expanded role in the international guidance for HFrEF with LVEF ≤ 40%

The pharmacological management for people with HFrEF who have LVEF ≤ 40% was updated in the US, European and Canadian guidelines in 2021. The National Institute for Health and Care Excellence in the United Kingdom also published guidance on empagliflozin in the management of HFrEF in 2022.27-30

All of them included an expanded role for SGLT2 inhibitors, including empagliflozin.27-30

They recommend that standard treatment for HFrEF with LVEF ≤ 40% include an SGLT2 inhibitor as a fourth medicine alongside the three existing recommended medicines – an ACE inhibitor (or ARB or ARNI), heart failure beta blocker and MRA – unless contraindicated.27-30

Clinical place of empagliflozin in the treatment of HFrEF with LVEF ≤ 40%

There are now three PBS-listed options for people with HFrEF who have persistent LVEF ≤ 40%, despite receiving optimal standard treatment that may or may not include an MRA:5,31

  • changing the ACE inhibitor (or ARB) to an ARNI, or
  • adding dapagliflozin, or
  • adding empagliflozin

In addition:5,31

  • for people who are already taking an ARNI, empagliflozin (or dapagliflozin) may be added
  • for people who have already added empagliflozin (or dapagliflozin) to standard treatment, the ACEI (or ARB) may also be changed later to an ARNI.

Which of the three PBS-listed options should be selected first?

There are no head-to-head trials for people with HFrEF who have persistent LVEF ≤ 40% comparing the three PBS-listed options and only limited evidence providing guidance.

The international guidance suggests either dapagliflozin or empagliflozin may be prescribed for people with HFrEF who have LVEF ≤ 40%, alongside other optimal standard treatments – an ACE inhibitor (or ARB or ARNI), heart failure beta blocker and MRA.27-29

A 2020 meta-analysis comparing the 2019 DAPA-HF trial and 2020 EMPEROR-Reduced trial found the two medicines were consistent in their cardiovascular effects, reducing the relative risk of heart failure-related hospitalisations and/or cardiovascular death by 25%.32

Medicine choice may be influenced by certain conditions, for example empagliflozin (or dapagliflozin) may be more appropriate than an ARNI in people with hyperkalaemia (serum potassium > 5.5 mmol/L) or a history of ACE inhibitor- or ARB-associated angioedema.2,25

Alternatively, an ARNI may be appropriate ifor some people when empagliflozin should not be prescribed, eg, people with comorbid type 1 diabetes.9,33

Empagliflozin may be more appropriate than dapagliflozin for patients with estimated glomerular filtration rate (eGFR) 20 to < 25 mL/min/1.73 m2. Dapagliflozin is not recommended for patients with eGFR < 25 mL/min/1.73 m2, while empagliflozin may be initiated and continued down to 20 mL/min/1.73 m2.9,10

 

What else should health professionals know?

Dosing

The recommended dose of empagliflozin for heart failure is a 10 mg tablet taken orally once daily, with or without food.9

Unlike the standard treatment medicines for heart failure, empagliflozin (like dapagliflozin) does not have a starting dose followed by up-titration to the maximum tolerated dose or target dose.27

No adjustments are required for people with hepatic impairment or aged < 85 years.9

Contraindications

Empagliflozin for the treatment of heart failure should not be taken by people with:9

  • type 1 diabetes
  • eGFR < 20 mL/min/1.73 m2
  • creatinine clearance (CrCl) < 20 mL/min
  • age ≥ 85 years.

Safety issues

The precautions and adverse effects for SGLT2 inhibitors including empagliflozin and dapagliflozin may be regarded as a class effect.8,15

See the NPS MedicineWise RADAR article Dapagliflozin (Forxiga) for heart failure with reduced ejection fraction (LVEF ≤ 40%) ‘Safety’ section for detailed information about these precautions and adverse effects.

For information about reporting adverse reactions to the TGA, or to report suspected adverse reactions online, see the TGA website.

 

What should patients know?

Prescribers and pharmacists are encouraged to discuss the following with patients and carers:8,9,15

  • Empagliflozin may cause dizziness in some people. Low blood sugar levels may also slow reaction times and affect the ability to drive or operate machinery.
  • Do not drive a car, operate machinery or perform other activities that have a high chance of injury if feeling dizzy or lightheaded.
  • Urine will test positive for glucose while taking empagliflozin.
  • Make sure to drink enough water to control thirst and avoid dehydration.
  • Taking empagliflozin can increase the chances of genital infection (eg, thrush). To reduce the chance of infection, it is important to maintain good hygiene and be aware of the signs and symptoms of infection. Seek medical help if infection occurs (eg, if there is fever and pain, tenderness or swelling in the genital area).
  • Empagliflozin can be taken with or without food.
 

More information

 

References

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  2. Atherton JJ, Sindone A, De Pasquale CG, et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Guidelines for the prevention, detection, and management of heart failure in Australia 2018. Heart Lung Circ 2018;27:1123-208.
  3. Atherton JJ, Hayward CS, Wan Ahmad WA, et al. Patient characteristics from a regional multicenter database of acute decompensated heart failure in Asia Pacific (ADHERE International-Asia Pacific). J Card Fail 2012;18:82-8.
  4. Dunlay SM, Givertz MM, Aguilar D, et al. Type 2 Diabetes Mellitus and Heart Failure: A Scientific Statement From the American Heart Association and the Heart Failure Society of America: This statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update. Circulation 2019;140:e294-e324.
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  18. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377:644-57.
  19. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57.
  20. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383:1425-35.
  21. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.
  22. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-24.
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  26. Cardiovascular Expert Group. Therapeutic Guidelines: Heart failure. East Melbourne: Therapeutic Guidelines Ltd 2018 (accessed 29 October 2020).
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  28. McDonald M, Virani S, Chan M, et al. CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction. Can J Cardiol 2021;37:531-46.
  29. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599-726.
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  31. Pharmaceutical Benefits Scheme. PBS General Schedule (April 2022). Canberra: Australian Government Department of Health, 2022 (accessed 18 March 2022).
  32. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020;396:819-29.
  33. Novartis Pty Ltd. Sacubitril/valsartan (Entresto) product information. Macquarie Park, NSW: Novartis Pty Ltd, 2020 (accessed 23 November 2021).