FARXIGA Study Showed Reduced Progression of Kidney Disease or Renal Death in Patients with Type 2 Diabetes

A pre-specified exploratory analysis of renal data from the Phase III DECLARE-TIMI 58 trial, the broadest cardiovascular outcomes trial of a sodium-glucose co-transporter 2 (SGLT2) inhibitor, showed that FARXIGA (dapagliflozin) reduced the progression of kidney disease or renal death in patients with type 2 diabetes (T2D).

These data, presented today at the American Diabetes Association (ADA) 79th Scientific Sessions, San Francisco, USA, and simultaneously published in TheLancet Diabetes & Endocrinology, showed a 47% reduction with FARXIGA in the relative risk of the composite renal-specific outcome of kidney function decline (sustained ≥40% decrease in estimated glomerular filtration rate [eGFR] to <60 mL/min/1.73m2), end-stage renal disease (ESRD), or renal death (excluding cardiovascular death) compared to placebo (1.5% vs. 2.8%; HR 0.53 [95% CI 0.43-0.66]).1

Additionally, FARXIGA reduced the relative risk of a cardio-renal composite of kidney function decline, ESRD, or renal or cardiovascular (CV) death by 24% compared to placebo (4.3% vs. 5.6%; HR 0.76 [95% CI 0.67-0.87]).1

This analysis evaluated 17,160 patients with T2D and predominantly preserved renal function, irrespective of underlying atherosclerotic CV disease (ASCVD). People with diabetes have a six-to-twelve times higher risk of developing ESRD and are approximately twice as likely to develop chronic kidney disease (CKD) than those without.2,3 FARXIGA is an inhibitor of SGLT2 indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D. FARXIGA is not approved to reduce the risk of renal or CV death, or to slow the progression of kidney disease.

Elisabeth Björk, Senior Vice President, Head of Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, said: “Heart failure and renal diseases are two of the most common and early complications experienced by people living with type 2 diabetes, and are too often overlooked. They contribute to a growing economic burden on the global healthcare system and can lead to fatal outcomes for patients. These data continue to offer clinically relevant evidence of the early cardio-renal effects of FARXIGA.”

While ESRD was a rare event in the trial, the incidence was lower in the FARXIGA arm compared to placebo (0.1% vs. 0.2%; HR 0.31 [95% CI 0.13 - 0.79]). The renal-specific outcome was consistent across subgroups regardless of eGFR or urinary albumin-to-creatinine ratio (UACR) category, whether they had established ASCVD or multiple CV risk factors.1

These data were presented alongside other clinically important renal outcomes data from the DECLARE-TIMI 58 trial, including positive results from another sub-analysis that evaluated UACR, a key marker of kidney health. FARXIGA improved renal function as measured by changes in UACR(improved from micro- to normo-albuminuria [HR 1.35, 95% CI {1.24, 1.47}], improved from macro- to micro- or normo-albuminuria [HR 1.55, 95% CI {1.34, 1.8}], and decreased deterioration from normo- to micro- or macro-albuminuria [HR 0.84, 95% CI {0.79, 0.89}]).4

Indication and Limitations of Use for FARXIGA® (dapagliflozin) tablets

FARXIGA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Important Safety Information for FARXIGA® (dapagliflozin) tablets

Contraindications

• Prior serious hypersensitivity reaction to FARXIGA
• Severe renal impairment (eGFR <30 mL/min/1.73 m2), end-stage renal disease, or patients on dialysis

Warnings and Precautions

• Hypotension: FARXIGA causes intravascular volume contraction, and symptomatic hypotension can occur. Assess and correct volume status before initiating FARXIGA in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for hypotension
• Ketoacidosis has been reported in patients with type 1 and type 2 diabetes receiving FARXIGA. Some cases were fatal. Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue FARXIGA, evaluate and treat promptly. Before initiating FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA may require monitoring and temporary discontinuation in situations known to predispose to ketoacidosis
• Acute Kidney Injury and Impairment in Renal Function: FARXIGA causes intravascular volume contraction and renal impairment, with reports of acute kidney injury requiring hospitalization and dialysis. Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat.
  FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating FARXIGA, evaluate renal function and monitor periodically. FARXIGA is not recommended when the eGFR is <45 mL/min/1.73 m2
• Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the risk for urinary tract infections [UTIs] and serious UTIs have been reported with FARXIGA. Evaluate for signs and symptoms of UTIs and treat promptly
• Hypoglycemia: FARXIGA can increase the risk of hypoglycemia when coadministered with insulin and insulin secretagogues. Consider lowering the dose of these agents when coadministered with FARXIGA
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Rare but serious, life-threatening cases have been reported in patients receiving SGLT2 inhibitors including FARXIGA. Cases have been reported in females and males. Serious outcomes have included hospitalization, surgeries, and death. Assess patients presenting with pain or tenderness, erythema, swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment and discontinue FARXIGA.
• Genital Mycotic Infections: FARXIGA increases the risk of genital mycotic infections, particularly in patients with prior genital mycotic infections. Monitor and treat appropriately
• Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur with FARXIGA. Monitor LDL-C and treat per standard of care
• Bladder cancer: An imbalance in bladder cancers was observed in clinical trials. There were too few cases to determine whether the emergence of these events is related to FARXIGA, and insufficient data to determine whether FARXIGA has an effect on pre-existing bladder tumors. FARXIGA should not be used in patients with active bladder cancer. Use with caution in patients with a history of bladder cancer
• Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA

Adverse Reactions

In a pool of 12 placebo-controlled studies, the most common adverse reactions (≥5%) associated with FARXIGA 5 mg, 10 mg, and placebo respectively were female genital mycotic infections (8.4% vs 6.9% vs 1.5%), nasopharyngitis (6.6% vs 6.3% vs 6.2%), and urinary tract infections (5.7% vs 4.3% vs 3.7%).

Use in Specific Populations

• Pregnancy: Advise females of potential risk to a fetus especially during the second and third trimesters.
• Lactation: FARXIGA is not recommended when breastfeeding.

Please see accompanying US Full Prescribing Information and Medication Guide for FARXIGA.

– ENDS –

NOTES TO EDITORS

About DECLARE-TIMI 58

DECLARE (Dapagliflozin Effect on Cardiovascular Events)-TIMI 58 is an AstraZeneca-sponsored, randomized, double-blinded, placebo-controlled, multicenter trial designed to evaluate the effect of FARXIGA compared with placebo on CV outcomes in adults with T2D at risk of CV events, including patients with multiple CV risk factors or established CV disease. DECLARE included more than 17,000 patients across 882 sites in 33 countries and was independently run in collaboration with academic investigators from the TIMI study group (Boston, USA) and the Hadassah Hebrew University Medical Center (Jerusalem, Israel).

About DapaCare

DECLARE is part of the extensive DapaCare clinical program for FARXIGA, which will enroll patients in randomized clinical trials including a wide range of mechanistic trials and is supported by a multinational real-world evidence study (CVD-REAL). The DapaCare clinical program will generate data across a spectrum of people with CV risk factors, established CV disease and varying stages of renal disease, both with and without T2D. DECLARE is paving the way for three Phase III trials: Dapa-HF, DELIVER, Dapa-CKD and DETERMINE. FARXIGA is not indicated to reduce the risk of CV events, CV death, or hHF, or the treatment of CKD.

About AstraZeneca in CV, Renal & Metabolism (CVMD)

CV, renal and metabolism together form one of AstraZeneca’s main therapy areas and a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. Our ambition is to modify or halt the natural course of CVMD diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.comand follow us on Twitter @AstraZenecaUS.

References
1. Mosenzon O et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: Analysis from DECLARE-TIMI 58 trial. The Lancet Diabetes & Endocrinology.
2. Narres M et al. The Incidence of End-Stage Renal Disease in the Diabetic (Compared to the Non-Diabetic) Population: A Systematic Review. PLoS ONE 2016; 11(1):e0147329.
3. Koye DN et al. The Global Epidemiology of Diabetes and Kidney Disease. Adv Chronic Kidney Dis. 2018; 25(2):121-132.
4. Mosenzon O et al. Effects of dapagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes: a predefined analysis from the DECLARE-TIMI 58 randomised, placebo-controlled trial. Oral Presentation at the American Diabetes Association 79th Scientific Sessions. (Oral 244-OR, Monday, June 10; 8:15 – 8:30 AM PST)

US-29104 Last Updated 6/19

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