Table 7.5. Recommendations for use of SGLT2 inhibitors in preventing worsening of renal function in HFrEF patients.

Recommendations	Class	LE	Comments	Table 2018	Ref.
SGLT2 inhibitors (dapagliflozin or empagliflozin) in patients with HFrEF to prevent worsening of renal function in patients with and without diabetes, with GFR ≥ 20 mL/min/1.73 m2.	IIa	A	NEW: SGLT2i are useful to reduce progressive worsening of renal function in HFrEF.	New	95, 96, 98–104
In the EMPEROR-Reduced trial, the annual rate of decline in glomerular filtration rate (GFR) was slower in the empagliflozin group than in the placebo group (-0.55 vs. −2.28 mL/min/1,73 m2 per year, p < 0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes, regardless of the presence or absence of DM2.96 The DAPA-HF subanalysis assessed the efficacy and safety of dapagliflozin use in HFrEF patients by baseline GFR as well as the effects on dapagliflozin after randomization.98 In the DAPA-HF trial, dapagliflozin did not lead to lower composite renal outcomes (RR = 0.71, 95% CI 0.44-1.16, p = 0.17).95 However, in a subanalysis, rates of worsening GFR were lower for dapagliflozin (-1.09) as compared to a placebo (-2.87), p < 0.001, in patients with or without DM2. The DAPA-CKD (Dapagliflozin in Patients with Chronic Kidney Disease) trial randomized 4,304 patients with chronic kidney disease, GFR 25-75 mL/min/73 m2, and urinary albumin-creatinine ratio 200-5,000. Dapagliflozin led to lower rates of primary endpoints (consisting of sustained reduction in GFR of at least 50%, terminal kidney disease or CV or renal death) (9.2% with dapagliflozin vs. 14.5% with a placebo; [RR = 0.61, CI = 9%, 0.51-0.72; p < 0.001]. Death occurred for 101 members (4.5%) of the dapagliflozin group vs. 146 (6.8%) of the placebo group (RR = 0.69, 95% CI = 0.53-0.88, p = 0.004). Dapagliflozin lowered cardiovascular death or hospitalization for HF (0.67, 0.40-1.13 vs. 0.70, 0.52-0.94, respectively, P-interaction = 0,88). The results were consistent, both with and without DM2.104 Data from EMPEROR-Reduced, DAPA-CKD and the subanalysis of DAPA-HF suggest the use of SGLT2 inhibitors is safe in HFrEF and GFR alterations, regardless of the presence of DM2. They also show that SGLT2i may decrease renal function impairment in HFrEF patients.

DM2: type 2 diabetes mellitus; GFR: glomerular filtration rate; HFrEF: heart failure with reduced ejection fraction; SGLT2i: sodium-glucose cotransporter-2 inhibitors.