- On 1 September 2022, a new indication and clinical criteria were added to the Authority Required (Streamlined) PBS listing for dapagliflozin (Forxiga).
The new indication is for treatment of CKD and must be an addition to standard care. The patient must be stabilised on an ACE inhibitor or ARB for at least 4 weeks prior to initiation, unless contraindicated.
- There is a high and urgent unmet clinical need for effective CKD treatments, with limited effective therapies on the PBS specifically for CKD.
When added to standard care, for some patients, dapagliflozin provided a significant improvement in efficacy over standard care alone.
- Dapagliflozin’s role in the treatment of CKD for patients without type 2 diabetes is not yet reflected by Australian guidelines.
Evidence shows that patients with CKD (with or without type 2 diabetes) have a reduced risk of CKD progression when dapagliflozin is added to standard care.
- International guidelines and KDIGO recommend dapagliflozin be considered in addition to standard care for the management of CKD (with and without type 2 diabetes).
The new PBS listing is in line with international guidelines. Consider prescribing dapagliflozin for patients with CKD (eGFR 25–75 mL/min/1.73 m2 and urine ACR 22.6–565 mg/mmol [200–5000 mg/g]) that has been stable using an ACE inhibitor or ARB for at least 4 weeks.
- Dapagliflozin does not need to be up-titrated and a standard oral dose of 10 mg daily, with or without food, is recommended for all patients.
This dose does not need to be reduced due to age, or kidney or hepatic function.
ACE – angiotensin-converting enzyme
ACR – albumin-to-creatinine ratio
ANCA – anti-neutrophil cytoplasmic autoantibody
ARB – angiotensin receptor II blocker
BP – blood pressure
CKD – chronic kidney disease
CVD – cardiovascular disease
eGFR – estimated glomerular filtration rate
GLP-1 – glucagon-like peptide-1
HbA1c – glycated haemoglobin
KDIGO – Kidney Disease Improving Global Outcomes
NICE – National Institute for Health and Care Excellence
PBS – Pharmaceutical Benefits Scheme
PBAC – Pharmaceutical Benefits Advisory Committee
SGLT2 – sodium–glucose co-transporter-2
The Australasian Proteinuria Consensus Working Group 2012 position statement on proteinuria recommends that the reporting units for albumin-to-creatinine ratio (ACR) should be in mg/mmol.1 Where ACR is referred to in both mg/g and mg/mmol, the article will refer to ACR in the recommended units for the remainder of the article.
Authority Required (Streamlined)
On 1 September 2022, a new indication and clinical criteria were added to the General Schedule (Section 85) Authority Required (Streamlined) listing for dapagliflozin (Forxiga).2 It was previously listed only for type 2 diabetes and heart failure.3
The new indication for dapagliflozin is chronic kidney disease (CKD). According to the clinical criteria, the patient must have:2
- a diagnosis of CKD, defined as abnormalities of kidney structure or function present for 3 months or more, prior to initiating treatment with dapagliflozin, and
- an estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2 inclusive, prior to initiating treatment with dapagliflozin, and
- a urine ACR 22.6–565 mg/mmol (200–5000 mg/g) inclusive, prior to initiating treatment with dapagliflozin, and
- stabilised disease for at least 4 weeks on the maximum tolerated dose of an:
- angiotensin-converting enzyme (ACE) inhibitor, or
- angiotensin receptor II blocker (ARB)
that is continued as a combination treatment with dapagliflozin, unless contraindicated.
Patients must not be receiving treatment with another sodium–glucose co-transporter-2 (SGLT2) inhibitor and must discontinue treatment with dapagliflozin prior to initiating kidney replacement therapy (dialysis or kidney transplant).2
Patients not eligible for treatment with dapagliflozin for CKD include those:2
- with polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis
- requiring, or with a recent history of, cytotoxic or immunosuppressive therapy for kidney disease
- with an organ transplant.
See the PBS website for complete details for this 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.2 See the PBS website for more information on nurse practitioner PBS prescribing.
What is dapagliflozin?
- empagliflozin and ertugliflozin (currently TGA-registered)6,7
- canagliflozin (previously TGA-registered).8
- type 2 diabetes (October 2012)
- type 2 diabetes with established cardiovascular disease (CVD) or risk factors for CVD, to reduce the risk of hospitalisation for heart failure (April 2020)
- symptomatic heart failure with reduced ejection fraction, as an adjunct to standard care (November 2020).
See the NPS MedicineWise RADAR article Dapagliflozin (Forxiga) for heart failure with reduced ejection fraction (LVEF ≤ 40%) for more information.
Mechanisms of action
- a glucose-lowering effect that is well understood; it increases glucose excretion (glucosuria)
- cardioprotective effects for heart failure that are not yet fully understood
- renoprotective effects for CKD that are not yet fully understood.
A key proposed mechanism for renoprotective effects is reduction of intraglomerular pressure through tubuloglomerular feedback.5 In this mechanism, SGLT2 inhibitors cause more sodium to pass along the nephron, which is sensed by macula cells that act via adenosine to constrict afferent glomerular arterioles.15,17
It is proposed that enhanced sodium excretion in the urine (natriuresis) and osmotic diuresis, coupled with reductions in extracellular volume and plasma volume, contribute to the blood pressure (BP)-lowering efficacy of SGLT2 inhibitors, which may preserve kidney function.14
SGLT2 inhibitors may also improve kidney oxygenation and promote anti-inflammatory and antifibrotic pathways, thereby slowing the progression of kidney function decline.18
Why was the new listing made?
Key study evidence
The 2020 DAPA-CKD trial enrolled 4304 adults from 21 countries, with an eGFR 25–75 mL/min/1.73 m2 and urine ACR 22.6–565 mg/mmol. All participants were on a stable, maximum tolerated dose of standard care (ACE inhibitor or ARB), unless contraindicated, for at least 4 weeks.19
The primary composite outcome was worsening kidney function, defined as a decline of at least 50% in eGFR or onset of kidney failure (dialysis, kidney transplant or GFR < 15 mL/min/1.73 m2), or death due to kidney disease or CVD. This outcome was reduced by 39% with dapagliflozin in comparison to placebo (9.2% with dapagliflozin vs 14.5% with placebo). This corresponds to a number needed to treat of 19 (95% confidence interval [CI] 15 to 27) to prevent one primary outcome event. Sub-group analyses showed that the treatment effect was consistent in patients with and without type 2 diabetes.19
The DAPA-CKD trial also showed a reduced risk of all-cause mortality by 31% with dapagliflozin in comparison to placebo (4.7% with dapagliflozin vs 6.8% with placebo).19
Reasons for PBS listing
At the March 2022 Meeting, the PBAC recommended listing dapagliflozin for the treatment of CKD.20
The PBAC recognised that there was a high and urgent unmet clinical need for effective CKD treatments, noting that there were limited effective therapies on the PBS specifically for CKD.21
The PBAC was satisfied that dapagliflozin added to standard care provided a significant improvement in efficacy over standard care alone for some patients based on the DAPA-CKD trial. The PBAC considered that dapagliflozin provided a substantial added benefit in terms of a reduction in kidney failure and death.21
The PBAC agreed that dapagliflozin would be an addition to standard care in CKD, administered concurrently with an ACE inhibitor or ARB, unless contraindicated.21
Will the changes affect current prescribing?
CKD pharmacological management
Table 1: Medicines shown to slow CKD progression and reduce cardiovascular risk
|Pharmacological management||Who to prescribe to||Benefit||Treatment target|
|ACE inhibitor/ARB||↓ albuminuria, CKD progression and cardiovascular events27,28|
|SGLT2 inhibitor||↓ risk of decline in eGFR, kidney failure or death from kidney causes and ↓ risk of cardiovascular death in patients with CKD +/- type 2 diabetes (dapagliflozin)19|
|Statin (+/- ezetimibe)||↓ cardiovascular events/death (statin alone)32|
↓ major atherosclerotic events (simvastatin + ezetimibe)33
|GLP-1 receptor agonist||↓ CKD progression for patients with type 2 diabetes and high cardiovascular risk (semaglutide)35|
a Check your patients’ CVD risk using the Australian absolute cardiovascular disease risk calculator.
CKD and dapagliflozin
Australian guidelines currently recommend dapagliflozin and other SGLT2 inhibitors as a preferred second-line agent after metformin (unless contraindicated or not tolerated) for patients with CKD and type 2 diabetes to manage blood glucose levels.8,36 The Kidney Disease Improving Global Outcomes (KDIGO) 2020 clinical practical guidelines on management of diabetes in CKD recommend metformin combined with an SGLT2 inhibitor as first-line therapy.29
The United Kingdom NICE guidelines for the treatment of CKD were updated in March 2022, with the recommendation that dapagliflozin be considered as an addition to standard therapy for patients with CKD, with or without type 2 diabetes.37
Following the PBS listing for dapagliflozin to manage CKD in patients with or without type 2 diabetes, the PBAC has estimated there will be an increase in the incidence of diagnosed CKD.38
What else should health professionals know?
- The recommended dose of dapagliflozin for CKD is 10 mg taken once daily, with or without food.
- No adjustments are required for those with reduced kidney function, mild-to-moderate hepatic impairment or based on age.
- Not recommended to be initiated if:
- eGFR < 25 mL/min/1.73 m2 (note: may continue established dapagliflozin therapy at 10 mg once daily unless dialysis is commenced)
- patient has a history of hypotension or dehydration with diuretic therapy
- patient is currently experiencing an acute illness.
There are limited post-market safety data for SGLT2 inhibitors in the treatment of CKD in a population without type 2 diabetes. The DAPA-CKD trial showed a lower rate of serious adverse events (severe hypoglycaemia and diabetic ketoacidosis) among people without type 2 diabetes.19
- with polycystic kidney disease; lupus nephritis; ANCA-associated vasculitis; or those requiring or with a recent history of immunosuppressive therapy due to expected lack of effectiveness in these groups
- with severe hepatic impairment (Child–Pugh class C)
- < 18 years old
- with a known hypersensitivity to any of the ingredients
- with type 1 diabetes
- for the treatment of diabetic ketoacidosis.
- Volume-depleted patients
- Patients with a history of hypotension
- History of diabetic ketoacidosis while taking a SGLT2 inhibitor
- eGFR < 45 mL/min/1.73 m2 (glucose-lowering effect is reduced)
- eGFR < 25 mL/min/1.73 m2: starting treatment with dapagliflozin is not recommended; treatment may be continued if eGFR falls below this unless dialysis is commenced.
Pregnancy and breastfeeding
- Dapagliflozin is not recommended during pregnancy (Category D) and must not be used during the second and third trimesters. If pregnancy is detected during treatment, dapagliflozin should be discontinued.4
- Dapagliflozin must not be used by women who are breastfeeding.4
- Genitourinary infectionsb
- Dehydration (volume depletion)
- Transiently reduced kidney function
- Euglycaemic ketoacidosisb
- Fractures and amputations
b Patients with type 2 diabetes are at higher risk of experiencing this adverse effect compared to patients without type 2 diabetes.
The adverse event profile for dapagliflozin for CKD is consistent with other indications such as type 2 diabetes and heart failure. Note that the incidence of adverse effects was higher for patients that had type 2 diabetes compared to those without.37
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.
What should patients know?
- Dapagliflozin may cause some people to feel dizzy or light-headed. Low blood sugar levels may also slow their reaction time and affect how they drive or use machinery.
- Do not drive a car, use machinery or perform other actions that have a high chance of harm if feeling dizzy or light-headed.
- Urine tests will show presence of glucose while taking dapagliflozin.
- Drink enough water to control thirst and avoid dehydration.
- Taking dapagliflozin can increase the chances of genital infection (eg, thrush). 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 region).
- Dapagliflozin can be taken with or without food.
- Kidney Health Australia Chronic Kidney Disease (CKD) Management in Primary Care (4th Edition 2020)
- NPS MedicineWise Chronic kidney disease: early detection and management
- NPS MedicineWise News CKD – Integrating kidney health into patient care
- NICE Guidelines Dapagliflozin for treating chronic kidney disease
- Australian Prescriber Sodium-glucose co-transporter 2 inhibitors beyond diabetes
- Johnson DW, Jones GR, Mathew TH, et al. Chronic kidney disease and measurement of albuminuria or proteinuria: a position statement. Med J Aust 2012;197:224-5.
- Pharmaceutical Benefits Scheme. PBS Schedule: Summary of Changes (September 2022). Canberra: Australian Government Department of Health, 2022 (accessed 1 September 2022).
- Pharmaceutical Benefits Scheme. PBS General Schedule (July 2022). Canberra: Australian Government Department of Health, 2022 (accessed 1 July 2022).
- Australian Medicines Handbook. Dapagliflozin. Adelaide: AMH Pty Ltd, 2022 (accessed 4 July 2022).
- AstraZeneca Pty Ltd. Dapagliflozin (Forxiga) product information. Macquarie Park, NSW: AstraZeneca Pty Ltd, 2021 (accessed 29 June 2022).
- Boehringer Ingelheim Pty Ltd. Empagliflozin (Jardiance) product information. North Ryde, NSW: Boehringer Ingelheim Pty Ltd, 2022 (accessed 15 July 2022).
- Merck Sharp & Dohme (Australia) Pty Ltd. Ertugliflozin (Steglatro) product information. Macquarie Park, NSW: Merck Sharp & Dohme (Australia) Pty Ltd, 2022 (accessed 1 July 2022).
- Australian Diabetes Society. Australian type 2 diabetes glycaemic management algorithm. Sydney: Australian Diabetes Society, 2021 (accessed 1 July 2022).
- Therapeutic Goods Administration. Australian Public Assessment Report for Dapagliflozin (as propanediol monohydrate). Canberra: Australian Government Department of Health, 2022 (accessed 29 August 2022).
- Therapeutic Goods Administration. Prescription medicines: new or extended uses, or new combinations of registered medicines, 2020. Canberra: Australian Government Department of Health, 2021 (accessed 15 July 2022).
- Joshi SS, Singh T, Newby DE, et al. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart 2021;107:1032-1038.
- Thynne T, Doogue M. Sodium-glucose co-transporter inhibitors. Australian Prescriber 2014;37:14-6.
- Chesterman T, Thynne TR. Harms and benefits of sodium-glucose co-transporter 2 inhibitors. Aust Prescr 2020;43:168-71.
- Sen T, Heerspink HJL. A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors. Cell Metab 2021;33:732-9.
- Toyama T, Neuen BL, Jun M, et al. Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis. Diabetes Obes Metab 2019;21:1237-50.
- Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: Cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 2016;134:752-72.
- Bailey CJ, Day C, Bellary S. Renal protection with SGLT2 inhibitors: Effects in acute and chronic kidney disease. Curr Diab Rep 2022;22:39-52.
- Heerspink HJL, Kosiborod M, Inzucchi SE, et al. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int 2018;94:26-39.
- Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46.
- Pharmaceutical Benefits Scheme. Public Summary Document: Dapagliflozin (March 2022 PBAC Meeting). Canberra: Australian Government Department of Health, 2022 (accessed 4 July 2022).
- Pharmaceutical Benefits Scheme. Public Summary Document: Dapagliflozin (July 2021 PBAC Meeting). Canberra: Australian Government Department of Health, 2021 (accessed 29 June 2022).
- Kidney Health Australia. Chronic kidney disease (CKD) management in primary care. 4th. Melbourne: Kidney Health Australia, 2020 (accessed 5 January 2022).
- Mende CW. Chronic kidney disease and SGLT2 inhibitors: A review of the evolving treatment landscape. Adv Ther 2022;39:148-64.
- Dwyer KD, Robson B, Sum C. How to treat chronic kidney disease. AusDoc. How to Treat. Australian Doctor, 2021 (accessed 24 May 2022).
- Bezabhe WM, Kitsos A, Saunder T, et al. Medication prescribing quality in Australian primary care patients with chronic kidney disease. Journal of Clinical Medicine 2020;9:783.
- Johnson DW, Atai E, Chan M, et al. KHA-CARI guideline: Early chronic kidney disease: detection, prevention and management. Nephrology (Carlton) 2013;18:340-50.
- Xu R, Sun S, Huo Y, et al. Effects of ACEIs versus ARBs on proteinuria or albuminuria in primary hypertension: a meta-analysis of randomized trials. Medicine (Baltimore) 2015;94:e1560.
- Xie X, Liu Y, Perkovic V, et al. Renin-angiotensin system inhibitors and kidney and cardiovascular outcomes in patients with CKD: a Bayesian network meta-analysis of randomized clinical trials. Am J Kidney Dis 2016;67:728-41.
- Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int 2020;98:S1-s115.
- CARI Living Guideline Lipid Work Group. CARI Guidelines: Management of cholesterol-lowering therapy in people with chronic kidney disease. Westmead NSW: CARI Guidelines, 2022 (accessed 14 July 2022).
- Palmer SC, Navaneethan SD, Craig JC, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev 2014:CD007784.
- Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181-92.
- Australian Medicines Handbook. Australian Medicines Handbook. Adelaide: AMH Pty Ltd, 2022 (accessed 20 June 2022).
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44.
- Diabetes Expert Group. Therapeutic Guidelines: Type 2 diabetes in adults. East Melbourne: Therapeutic Guidelines Ltd, 2019 (accessed 12 July 2022).
- National Institute for Health and Care Excellence. Dapagliflozin for treating chronic kidney disease. UK: NICE, 2022 (accessed 29 June 2022).
- Pharmaceutical Benefits Scheme. Public Summary Document: Dapagliflozin (November 2021 PBAC Meeting). Canberra: Australian Government Department of Health, 2021 (accessed 29 June 2022).
- AstraZeneca Pty Ltd. Dapagliflozin (Forxiga) consumer medicine information. Macquarie Park, NSW: AstraZeneca Pty Ltd, 2021 (accessed 4 July 2022).