Clinical Evaluation of Dapagliflozin in the Management of CKD: Focus on Patient Selection and Clinical Perspectives

Figures & data

Figure 1 KDIGO CKD staging by GFR and albuminuria categories.

Notes: Reprinted from Kidney Int Suppl, 3(1), Levin A, Stevens PE, Bilous RW, et al. Kidney Disease: Improving Global Outcomes CKD Working Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease, 1–150, Copyright (2013), with permission from Elsevier.¹

Table 1 Summary of Trials on SGLT2 Inhibitors with Kidney Outcomes

Trial	CREDENCE (n = 4401)	CANVAS Program (n = 10,142)	EMPA-REG OUTCOME (n = 7020)	DECLARE-TIMI 58 (n = 17,160)	DAPA-CKD (n = 4304)
Inclusion criteria	eGFR 30 to <90 mL/min/1.73 m^2; UACR >300–5000 mg/g	eGFR ≥30 mL/min/1.73 m^2	eGFR ≥ 30 mL/min/1.73 m^2	CLcr ≥60 mL/min	eGFR 25–75 mL/min/1.73 m^2; UACR 200–5000 mg/g
Drug	Canagliflozin	Canagliflozin	Empagliflozin	Dapagliflozin	Dapagliflozin
Median follow-up	2.6 yr	2.4 yr	3.1 yr	4.2 yr	2.4 yr
Outcomes: RR or HR Comparing SGLT2i with Placebo
Dialysis, Txp, or death from kidney disease	0.72 (0.54–0.97)	0.56 (0.23–1.32)	0.90 (0.30–2.67)	0.42 (0.20–0.87)	NA
Dialysis, Txp, or sustained eGFR <15 mL/min/1.73 m^2,d	0.68 (0.54–0.86)	0.77 (0.30–1.97)	0.60 (0.18–1.98)	0.31 (0.13–0.79)	0.64 (0.50–0.82)
Loss of kidney function; dialysis, Txp, or sustained eGFR <15 mL/min/1.73 m^2,d; or death from kidney disease	0.66 (0.53–0.81)	0.53 (0.33–0.84)	0.54 (0.40–0.75)	0.53 (0.43–0.66)	0.56 (0.45–0.68)

Abbreviations: eGFR, estimated glomerular filtration rate; CLcr, creatinine clearance.

Figure 2 Mechanisms of action of SGLT2 inhibitors.

Table 2 Patients Characteristics in Dapagliflozin Studies

Trial	DERIVE	DECLARE-TIMI 58 (n = 17,160)	DAPA-CKD (n = 4304)	DAPA-HF (n=4744)
Inclusion criteria	GFR>45 mL/min/1.73 m^2	CLcr ≥ 60 mL/min	eGFR 25–75 mL/min/1.73 m^2; UACR 200–5000 mg/g	eGFR ≥ 30 mL/min/1.73 m^2
Median follow-up, months	24	50.2	28.8	18
Baseline ACEI or ARB use	132 (82.0%)	13,950 (81%)	1354 (31%)^a; 2870 (67%)^b	1332(56.1%)^a 675 (28.4%)^b 250 (10.5%)^c
eGFR, mL/min/1.73 m^2
≥90	Mean 53.6 (10.6)	8162 (48%)	0 (0)	Mean 66±19.6
60 to <90		7732 (45%)	454 (11%)
45 to <60		1265 (7%)	1328 (31%)
30 to <45		NA	1898 (44%)
		0 (0)	624 (14%)
Missing		1 (<0.1%)	0 (0)
UACR, mg/g
	Mean 29.0 (3.8–8474.0)	11,644 (68%)	NAc	Not reported
30–300		4030 (24%)	NA
c		1169 (7%)	NA

Notes: ^aPatients receiving ACEI. ^bPatients receiving ARB. ^cPatients receiving sacubitril/valsartan.

Abbreviations: GFR, glomerular filtration rate; CLcr, creatinine clearance; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; UACR, urine albumin-to-creatinine ratio.

Table 3 SGLT-s Inhibitors Dosing and Indications

SGLT-2 Inhibitors Available in the United States	Dapagliflozin	Canagliflozin	Empagliflozin	Ertugliflozin
Doses	5–10 mg daily	100–300 mg daily	10–25 mg daily	5–15 mg daily
Renal dosing	eGFR >25 mL/min/1.73 m^2, 5–10 mg daily with no dose adjustment. eGFR <25 mL/min/1.73 m^2, initiation is not recommended but use is to be continued till need for kidney replacement therapy	eGFR >60 mL/min/1.73 m^2, 300 mg daily. eGFR 30–59 mL/min/1.73 m^2, 100 mg daily eGFR <30 mL/min/1.73 m^2, initiation is not recommened but use at 100 mg daily can be continued	eGFR <45 mL/min/1.73 m^2, avoid use	eGFR <30 mL/min/1.73 m^2, avoid use
Indications based on evidence
Diabetes Mellitus	Improves glycemic control	Improves glycemic control	Improves glycemic control	Improves glycemic control
Renal outcomes	Reduce the risk of kidney disease progression in patients with CKD with and without diabetes	Reduce the risk of end stage kidney disease and doubling of serum creatinine in adults with type 2 diabetes mellitus and diabetic nephropathy and albuminuria
Cardiovascular outcomes	Reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease. Reduce the risk of cardiovascular death and hospitalization for heart failure in adult patient with heart failure and reduced systolic ejection fraction	Reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease. Reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria	Reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease.

Table 4 Dapagliflozin Drug Characteristics

Features and Properties of Dapagliflozin
Indications
● Chronic kidney disease stages 1–4 (eGFR >25 mL/min/1.73 m^2) with proteinuria (>200 mg/g)  ● Diabetes mellitus type II  ● Congestive heart failure
Mechanism of Action
Selective sodium–glucose cotransporter 2
Dosage and administration
5–10 mg oral tablets once a day
Pharmacokinetic Profile
Bioavailability	78%
Mean half-life	12.9 hours
Volume of distribution	118 L
Excretion	75% urine and 21% feces
Contraindications
● Diabetes mellitus type 1  ● Advanced CKD with eGFR <25 mL/min/1.73m^2 (patients may continue 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and HF)  ● Prior diabetic ketoacidosis (DKA)
Side effects
● Genital yeast infections (vaginal and penile) and UTIs  ● Runny nose and sore throat  ● Changes in urination, urgency, nocturia and increased urine output.  ● Dehydration
Practical consideration when initiating therapy with dapagliflozin including patient education
● Ensure euvolemia and consider decreasing the dose of diuretics by 25–50%  ● Assess risk of hypoglycemia and the need to decrease the dose of other hypoglycemic agents or insulin therapy  ● Counsel the patient on “sick days” or “procedure day”  ● Educate the patient about foot care  ● Educate patient about symptoms of UTI and genital yeast infections. Assess kidney function in 1 month in selected high risk patients at risk of AKI

Figure 3 Management of CKD with proteinuria.

Kidney Disease: Improving Global Outcomes CKD Working Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3(1):1–150.

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