Renal effects of sodium–glucose cotransporter-2 inhibitors in patients with type 2 diabetes and renal impairment

Figures & data

Table 1. Major renal outcomes with sodium-glucose cotransporter-2 inhibitors in cardiovascular outcomes trials of patients with type 2 diabetes.

EMPA-REG OUTCOME [15] (N = 7020)		CANVAS [16] (N = 10,142)		DECLARE-TIMI 58 [17] (N = 17,160)
Renal outcomes, rate/1000 PY (HR [95% CI])	EMPA vs. PBO	Renal outcomes, rate/1000 PY (HR [95% CI])	CANA vs. PBO	Renal outcomes, rate/1000 PY (HR [95% CI])	DAPA vs. PBO
Incident or worsening nephropathy^a or CV death	60.7 vs. 95.9 (0.61 [0.55–0.69])**	New-onset microalbuminuria^b	96.7 vs. 127.3 (0.80 [0.73–0.87])	≥40% reduction in eGFR to <60 mL/min/1.73 m^2, new ESRD, or death from renal or CV causes	10.8 vs. 14.1 (0.76 [0.67–0.87])
Incident or worsening nephropathy	47.8 vs. 76.0 (0.61 [0.53–0.70])**	New-onset macroalbuminuria^c	15.1 vs. 27.6 (0.58 [0.50–0.68])	≥40% reduction in eGFR to <60 mL/min/1.73 m^2, new ESRD, or death from renal causes	3.7 vs. 7.0 (0.53 [0.43–0.66])
Progression to macroalbuminuria^d	41.8 vs. 64.9 (0.62 [0.54–0.72])**	New-onset albuminuria^e	100.4 vs. 130.8 (0.80 [0.73–0.88])
Incident albuminuria^f	252.5 vs. 266.0 (0.95 [0.87–1.04])	Doubling of sCr, ESRD, or death from renal causes	1.5 vs. 2.8 (0.53 [0.33–0.84])
Doubling of sCr plus eGFR ≤45 mL/min/1.73m^2, initiation of RRT, or death from renal causes	6.3 vs. 11.5 (0.54 [0.40–0.75])**	Doubling of sCR, ESRD, death from renal causes, or new-onset macroalbuminuria	15.1 vs. 27.4 (0.58 [0.50–0.67])
Doubling of sCr plus eGFR ≤45 mL/min/1.73 m^2	5.5 vs. 9.7 (0.56 [0.39–0.79])**	Doubling of sCr, ESRD, or death from renal or CV causes	13.2 vs. 15.8 (0.82 [0.68–0.97])
Initiation of RRT	1.0 vs. 2.1 (0.45 [0.21–0.97])*	40% eGFR reduction, ESRD, or death from renal causes	5.5 vs. 9.0 (0.60 [0.47–0.77])
		40% eGFR reduction, ESRD, death from renal causes, or new-onset macroalbuminuria	18.6 vs. 33.3 (0.57 [0.50–0.66])
		40% eGFR reduction, ESRD, or death from renal or CV causes	16.9 vs. 21.6 (0.77 [0.66–0.89])
		40% eGFR reduction	5.3 vs. 8.7 (0.60 [0.47–0.78])
		Doubling of sCr	1.2 vs. 2.4 (0.50 [0.30–0.84])
		ESRD	0.4 vs. 0.6 (0.77 [0.30–1.97])
		ESRD or death from renal causes	0.4 vs. 0.8 (0.56 [0.23–1.32])

*p < 0.05 vs. placebo; **p < 0.001 vs. placebo.^aProgression to macroalbuminuria, doubling of sCr plus eGFR ≤45 mL/min/1.73 m², initiation of RRT, or death from renal causes.^bUACR 30–300 mg/g in patients with normal UACR (<30 mg/g) at baseline or with ≥30% increase in UACR.^cUACR >300 mg/g in patients with normal UACR (<30 mg/g) or microalbuminuria (30–300 mg/g) at baseline or with ≥30% increase in UACR.^dUACR >300 mg/g.^eDevelopment of microalbuminuria or macroalbuminuria (based on UACR ranges or ≥30% increase in UACR) in patients with normal UACR (<30 mg/g) at baseline.^fUACR ≥30 mg/g in patients with normal UACR (<30 mg/g) at baseline.CANA: canagliflozin; CANVAS: Canagliflozin Cardiovascular Assessment Study; CI: confidence interval; CV: cardiovascular; DAPA: dapagliflozin; DECLARE-TIMI 58: Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58; eGFR: estimated glomerular filtration rate; EMPA: empagliflozin; EMPA-REG OUTCOME: Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; ESRD: end-stage renal disease; HR: hazard ratio; PBO: placebo; PY: patient-years; RRT: renal replacement therapy; sCr: serum creatinine; UACR: urinary albumin-to-creatinine ratio.

Figure 1. Effect of T2D and SGLT-2is on afferent and efferent arteriolar modulation, GFR, and sodium excretion in the renal tubule. (A) In individuals without diabetes, all of the filtered glucose is reabsorbed (along with Na⁺) by SGLT-2 and SGLT-1, and TGF is maintained; (B) in patients with T2D, glucose reabsorption is increased by SGLT-2 and SGLT-1; and (C) in patients with T2D receiving SGLT-2is, reabsorption of glucose and Na⁺ is increased and glucose is excreted in the urine. Reproduced with permission from DeFronzo et al. Nat Rev Nephrol. 2017;13:11–26 [29]. GFR, glomerular filtration rate; JGA, juxtaglomerular apparatus; Na⁺, sodium; SGLT, sodium–glucose cotransporter; SGLT-2is, SGLT-2 inhibitors; T2D, type 2 diabetes; TGF, tubuloglomerular feedback.

Figure 2. Synergistic effects of SGLT-2is and RAASis proposed for cardiorenal benefit. SGLT-2is and RAASis can inhibit the activity of NHE isoforms in the kidney, leading to favorable tubuloglomerular feedback and multiple cardiorenal benefits, and in the heart and vasculature, leading to favorable myocardial metabolism and energetics and mitigating cardiac hypertrophy, injury, and fibrosis. NHE, sodium-hydrogen exchanger; RAASi, renin-aldosterone-angiotensin system inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

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