Dapagliflozin for chronic kidney disease

• 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.

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.

Dapagliflozin belongs to a class of medicines called SGLT2 inhibitors.^4,5 Other medicines in this class include:

• empagliflozin and ertugliflozin (currently TGA-registered)^6,7
• canagliflozin (previously TGA-registered).⁸

CKD

Dapagliflozin is indicated as 10 mg tablets for proteinuric CKD (stage 2, 3 or 4 and urine ACR ≥ 30 mg/mmol) to reduce the risk of progressive decline in kidney function.^5,9

Other indications

Dapagliflozin is also indicated for adults with:^5,10

• 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

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.^11,12

Inhibition of SGLT2 leads to multiple effects, including:^11,13,14

• 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.

Renoprotective effects

SGLT2 inhibition reduces resorption of glucose and also sodium from the glomerular filtrate in the proximal kidney tubule. This leads to urinary excretion of glucose and osmotic diuresis.^5,15,16

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

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

Treatment goals should include pharmacological and lifestyle management²² of the risk factors underlying CKD progression, including hyperglycaemia, hypertension, albuminuria, and obesity.²³

CKD pharmacological management

Prescribe medicines shown to slow CKD progression and reduce cardiovascular risk.^24,25

Table 1: Medicines shown to slow CKD progression and reduce cardiovascular risk

CKD and dapagliflozin

The clinical place of dapagliflozin (and SGLT2 inhibitors more broadly) in the treatment of people with CKD who do not have type 2 diabetes continues to evolve.^14,23

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

Dosing^4,5

• 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.

Safety issues

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

Contraindications

Dapagliflozin should not be used to treat CKD for patients:^5,19

• 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.

Precautions^4,5

• Surgery
• 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

Adverse effects^5,34

• Genitourinary infections^b
• Hypoglycaemia^b
• Dehydration (volume depletion)
• Hypotension
• Transiently reduced kidney function
• Euglycaemic ketoacidosis^b
• 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.

Prescribers and pharmacists are encouraged to discuss the following with patients and carers:^4,39

• 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