FORXIGA (dapagliflozin) and chronic kidney disease (CKD)

Dapagliflozin is an SGLT2i recommended by NICE for the treatment of CKD as an add-on to optimised standard care

Dapagliflozin remains the only SGLT2i to reduce the risk of all cause mortality in patients with CKD on top of SoC vs placebo²

The approval of dapagliflozin for the treatment of CKD was a significant advancement in CKD Dapagliflozin provides a once daily oral treatment for patients with CKD.

The unmet need in CKD

CKD is a progressive disease that significantly impacts quality of life and increases the risk of:⁵

Poor cardiovascular (CV) and renal outcomes

Premature death

Heart Failure

Early intervention is important

CKD leads to a gradual loss of kidney function, and can influence the progression of type 2 diabetes (T2D) and heart failure (HF), worsening overall prognosis^5-9

On top of SoC vs placebo, in people with CKD with and without T2D, dapagliflozin reduces the composite risk of:^2*

Declining kidney function (≥50% sustained decline in eGFR)

Renal or CV death

End-stage kidney disease (ESKD)

CKD Prevalence

7.2 million

people were living with CKD in the United Kingdom (UK) in 2022¹⁰

~45,000

premature deaths occur every year in individuals with CKD in the UK⁵

Impact of CKD on the National Health Service (NHS)

£6.4 billion

is the estimated cost of kidney disease to the NHS in 2023¹⁰

Almost 50%

of all CKD-related hospitalisations are accounted for by frequently-hospitalised non-dialysis patients, of which most cases are attributed to HF and hyperkalemia¹¹

113,000

is the extra number of patients requiring dialysis in 2033, which is a growth rate of 375% on 2023 (30,000)¹²

£34,000

is the estimated cost to the NHS for one patient on dialysis per year¹²

Unplanned (emergency) hospital admissions are common in people with CKD, and are more likely as CKD worsens.¹⁰

39 more

unplanned hospital admissions occur annually per 100 patients with Stage 4 vs. Stage 3 CKD¹³

12 more

patients die annually per 100 patients with Stage 4 vs. Stage 3 CKD¹³

DAPA-CKD was a landmark study that investigated the use of dapagliflozin in the treatment of chronic kidney disease (CKD) patients, with or without type 2 diabetes (T2D)²

DAPA-CKD was a randomised, double-blind, placebo-controlled, multicentre clinical trial in patients with CKD, to determine the long-term efficacy and safety of the SGLT2i, dapagliflozin in patients, with and without T2D, on top of standard care^2,10

DAPA-CKD inclusion criteria:²

Estimated glomerular filtration rate (eGFR) range: 25–75 mL/min/1.73m²
Urine albumin creatinine ratio range: 22.6–565 mg/mmol
Participants were required to be receiving a stable and maximum-tolerated labelled dose of an angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) for at least 4 weeks prior to screening

Key exclusion criteria:^2*

Patients with polycystic kidney disease, lupus nephritis, or antineutrophil cytoplasmic antibody-associated vasculitis
Recent treatment with, or unacceptable side effects associated with a SGLT2i within 8 weeks prior to enrolment²
Patients treated with cytotoxic or immunosuppressive therapy for primary or secondary kidney disease 6 months prior to study enrolment
Patients with a history of organ (including kidney) transplantation
Patients with type 1 diabetes

*This list is not exhaustive, please refer to the supplementary appendix for the full list of key exclusion criteria²

DAPA-CKD was a landmark study that investigated the use of dapagliflozin in the treatment of chronic kidney disease (CKD) patients, with or without type 2 diabetes (T2D)²

Dapagliflozin in patients with CKD, with or without type 2 diabetes (T2D):

Dapagliflozin reduces the risk of the composite of declining kidney function, ESKD and renal or CV death on top of standard of care compared with placebo^2,14

Cumulative incidence of sustained decline in the eGFR of at least 50%, ESKD, or death from CV or renal causes in patients with CKD, with or without type 2 diabetes (T2D)^2,14

Dapagliflozin in patients with CKD, with or without a history of HF:

Prespecified analysis: There were fewer events of declining kidney function, ESKD, and renal or CV death with dapagliflozin 10 mg compared with placebo²

Cumulative incidence of the composite of a sustained decline in eGFR of at least 50%, ESKD, or death from renal causes in patients with or without type 2 diabetes (T2D), shown first in patients with no history of HF and then shown in patients with HF¹⁶

Adapted from McMurray et al. 2021

Adapted from Heerspink et al. 2020

first
second

Help delay dialysis even when eGFR is at 30 mL/ min/1.73m² in patients with or without type 2 diabetes²²

third
fourth

Watch Dr Will Hinchliffe deepdive into this data, and the impact it could have to people living with CKD

Key secondary efficacy endpoints:

31% RRR

in all-cause mortality vs. placebo¹

2.1% ARR

(4.7% vs. 6.8%) HR 0.69; 95% CI, 0.53, 0.88; p=0.004.

29% RRR

in the composite of CV death or hospitalisation for heart failure (hHF) vs. placebo, driven by hHF¹

1.8% ARR

(4.6% vs. 6.4%) HR 0.71; 95% CI, 0.55, 0.92; p=0.009.

Review dapagliflozin's safety profile information.

Dapagliflozin is recommended for the management of CKD by a number of major guidelines and treatment recommendations

Evaluating CKD guideline implementation: insights from the UK

National guidelines (UKKA, NICE and ABCD) recommends SGLT2i such as dapagliflozin for the management of CKD in patients with or without type 2 diabetes (T2D)^{1, 17-21}

For people with CKD¹⁷

UKKA recommend initiating SGLT-2 inhibition in people with chronic kidney disease, irrespective of primary kidney disease,* for any of the following clinical scenarios (Grade 1A):
a. eGFR of ≥20 mL/min/1.73m² and a urinary albumin-to-creatinine ratio (uACR) of ≥25 mg/mmol^†
b. Symptomatic heart failure, irrespective of ejection fraction

^*excludes people with polycystic kidney disease, type 1 diabetes, or a kidney transplant
^†urinary protein-to-creatinine ratio of 35 mg/mmol can be considered equivalent

UKKA recommend initiating SGLT-2 inhibition to slow rate of kidney function decline in people with an eGFR of 20-45 mL/min/1.73m² and a uACR of <25 mg/mmol^* (Grade 1B)

^*urinary protein-to-creatinine ratio of 35 mg/mmol can be considered equivalent

UKKA suggest clinicians consider initiating SGLT-2 inhibition in people with an eGFR below 20 mL/min/1.73m² to slow progression of kidney disease (Grade 2B)^**

^**There is limited experience with initiating FORXIGA (dapagliflozin) treatment in patients with eGFR <25 mL/min/1.73m², and no experience in patients with eGFR <15 mL/min/1.73m². Therefore, it is not recommended to initiate treatment in patients with eGFR <15 mL/min/1.73m²

For people with CKD and T2D¹⁷

Due to the benefits of SGLT-2 inhibitors on kidney outcomes (CKD and AKI) and cardiovascular risk:

UKKA recommend initiating an SGLT2 inhibitor in people with chronic kidney disease and type 2 diabetes, irrespective of primary kidney disease,* for any of the following 4 clinical scenarios (Grade 1A):

(a) eGFR of 20-45 mL/min/1.73m²
(b) eGFR of >45 mL/min/1.73m² and a urinary albumin-to-creatinine ratio (uACR) of ≥25 mg/mmol^†
(c) Symptomatic heart failure, irrespective of ejection fraction
(d) Established coronary disease

^*excludes people with polycystic kidney disease, type 1 diabetes, or a kidney transplant
^†urinary protein-to-creatinine ratio of 35 mg/mmol can be considered equivalent

UKKA suggest initiating SGLT-2 inhibition to modify cardiovascular risk and slow rate of kidney function decline in people with an eGFR >45-60 mL/min/1.73m² and a uACR of <25 mg/mmol, recognising effects on glycaemic control will be limited (Grade 2B)

UKKA suggest clinicians consider initiating SGLT-2 inhibition in people with an eGFR below 20 mL/min/1.73m² to slow progression of kidney disease (Grade 2B)^**

Current NICE guidelines include recommendations for multifactional interventional approaches for the management of CKD (NG203; Chronic kidney disease: assessment and management) and associated comorbidities, such as diabetes (NG28; Type 2 diabetes in adults: management), hypertension, heart failure (HF) (TA679; Dapagliflozin for treating chronic heart failure with reduced ejection fraction; TA902; Dapagliflozin for treating chronic heart failure with preserved or mildly reduced ejection fraction), and dyslipidaemia^18–20

Dapagliflozin is recommended as an option for treating CKD in adults.

It is recommended as an add-on to optimised standard care, including the highest tolerated licensed dose of ACEis/ARBs (unless contraindicated) in patients with:¹
- An eGFR of 25–75 ml/min/1.73 m² at the start of treatment and
- T2D or
- uACR ≥ 22.6 mg/mmol

In the presence of CKD, the first choice should be dapagliflozin once daily which has shown benefits in patients with CKD and macroalbuminuria with or without T2D²¹

Dose adjustments are not required based on renal function

Dapagliflozin offers simple, once daily dosing of 10mg¹¹ across the range of eGFR.
In patients with severe hepatic impairment, a starting dose of 5 mg is recommended. If well tolerated, the dose may be increased to 10 mg.

There is limited experience with initiating dapagliflozin treatment in patients with eGFR <25 mL/min/1.73m², and no experience in patients with eGFR <15 mL/min/1.73m². Therefore, it is not recommended to initiate treatment in patients with eGFR <15 mL/min/1.73m²

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Safety information

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ABCD, Association of British Clinical Diabetologists; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; ARR, absolute risk reduction; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; GFR, glomerular filtration rate; HF, heart failure; HR, hazard ratio; NICE, National Institute for Health and Care Excellence; NNT, number needed to treat; RRR, relative risk reduction; SGLT2i, Sodium/glucose cotransporter-2 inhibitors; SoC, standard of care; T2D, type 2 diabetes; uACR, urine albumin-creatinine ratio; UK, United Kingdom; UKKA, UK kidney association.

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Heerspink HJL et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436–1446.
Breyer MD et al. Nat Rev Drug Discov. 2016;15(8):568-588.
Tuttle KR. Lancet Diabetes Endocrinol. 2021;9(1):3-5.
Kerr M. Chronic Kidney Disease in England. the Human and Financial Cost. NHS. 2012.
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Rawshani A. et al. Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2018;379(7):633-644.
Alicic RZ, et al. Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032-2045.
Kidney disease: A UK public health emergency (2023) Kidney Research UK. Available at: https://www.kidneyresearchuk.org/about-us/influencing-change/health-economics-report/. Last accessed: November 2023.
Ronksley et al. Potentially Preventable Hospitalization among Patients with CKD and High Inpatient Use. Clin J Am Soc Nephrol. 2016 Nov 7;11(11):2022-2031
Economics of Kidney Disease Report. Available at https://www.kidneyresearchuk.org/wp-content/uploads/2023/06/Economics-of-Kidney-Disease-full-report_accessible.pdf. Last accessed August 2024
National Chronic Kidney Disease Audit, National Report: Part 2, 2017. Available at: http://allcatsrgrey.org.uk/wp/wpfb-file/final-ckd-audit-report-14-dec-2017-pdf. Last accessed: November 2023
FORXIGA (dapagliflozin) 10 mg film-coated tablets - Summary of Product Characteristics (SmPC).
Wheeler DC, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(1):22-31.
McMurray JJV, et al. Effects of Dapagliflozin in Patients With Kidney Disease, With and Without Heart Failure [published correction appears in JACC Heart Fail. 2022 Jun;10(6):446-447]. JACC Heart Fail. 2021;9(11):807-820.
UK Kidney Association Clinical Practice Guideline: Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease. Working Group co-chairs: Assoc. Prof William G. Herrington & Dr Andrew H. Frankel. Final Version: 13 April 2023. Available at: https://guidelines.ukkidney.org/2023-update/
NICE Technology Appraisal Guidance: TA679 (24th February 2021). Dapagliflozin for treating heart failure with reduced ejection fraction. Publication date: February 2021. Available from: https://www.nice.org.uk/guidance/ta679. Last accessed: November 2023. All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this material.
NICE guideline NG28: Type 2 diabetes in adults: management. Publication date 15th February 2022. Available from: https://www.nice.org.uk/guidance/ng28. Last accessed: November 2023. All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this material.
Chronic kidney disease: assessment and management NICE guideline [NG203]. Available from: https://www.nice.org.uk/guidance/ng203. Last accessed: November 2023. All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this material.
Basu A et al. Cardiovascular impact of new drugs (GLP-1 and gliflozins): the ABCD position statement BJD. 2021; 21(1):132-148.
Magdalena Madero et al. SGLT2 Inhibitor Use in Chronic Kidney Disease: Supporting Cardiovascular, Kidney, and Metabolic Health. Kidney Med. 6(8):100851. https://www.kidneymedicinejournal.org/article/S2590-0595(24)00062-1/fulltext

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