Table 7.3. Recommendations for use of SGLT2 inhibitors in the treatment of HFrEF patients.

Recommendations	Class	LE	Comments	Table 2018	Ref.
SGLT2 inhibitors (dapagliflozin or empagliflozin) in symptomatic HFrEF patients with diabetes or not, receiving maximum optimized tolerate dose of beta-blocker, aldosterone antagonist, ACEI/ARB or ARNI to lower cardiovascular outcomes and progression of renal dysfunction.	I	A	NEW: SGLT2i are useful to reduce cardiovascular death and hospitalization for heart failure.	New	95–98
In DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), 4,744 HFrEF patients were randomly assigned to dapagliflozin or a placebo in addition to standard therapy, and 41.8% of them had DM2.95 The primary endpoint of cardiovascular death or worsening HF was significantly lower in the dapagliflozin group (26% reduction). When analyzed separately, there was a significant reduction in both cardiovascular death (18%) and worsening HF (30%), regardless the presence of DM2. The results reveal a new therapy for HF, already approved for that purpose. The EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction) trial assessed empagliflozin vs. a placebo, in addition to standard therapy, in 3,730 patients with HFrEF, 50.2% of which had DM2.96 Patients had more severe HF than those in DAPA-HF, with average LVEF of 27% vs. 31%, and over 70% of patients had LVEF under 30%, in addition to higher median NT-proBNP levels (1907 versus 1437 pg/mL). There was a 25% decrease in the primary endpoints of cardiovascular death or hospitalization for HF in favor of empagliflozin. When analyzed separately, there was no reduction in cardiovascular death, unlike the results from DAPA-HF. The benefit was once again observed regardless of the presence of DM2. The data confirm the results from DAPA-HF and reinforce the justification for using sodium-glucose cotransporter-2 inhibitors (SGLT2i) in HFrEF patients to reduce symptoms, improve quality of life, and lower the risk of hospitalization and cardiovascular death. The meta-analysis using results from the DAPA-HF and EMPEROR-Reduced trials, totaling 8,474 patients, found a 13% reduction in all-cause mortality (combined HR 0.87, 95% CI 0.77-0.98; p = 0.018) and a 14% reduction in death from cardiovascular disease (0.86, 95% CI 0.76 - 0.98; p = 0.027).(94) The use of SGLT2i was accompanied by a 26% relative reduction in combined risk for cardiovascular death or first hospitalization for HF (0.74,0.68–0.82; p < 0.0001), and a 25% eduction in the composite outcome of recurring hospitalizations for HF or cardiovascular death (0.75, 0.68–0.84; p < 0.0001). The risk of composite renal outcome was also lowered (0.62, 0.43–0.90; p = 0.013). The DAPA-HF subanalysis assessed the efficacy and safety of dapagliflozin use in HFrEF patients by baseline glomerular filtration rate (GFR) as well as the effects on dapagliflozin after randomization. The effect of dapagliflozin on primary (CV death or worsening HF) and secondary endpoints did not change with GFR (< 60 and ≥ 60 mL/min/1.73m2). A prespecified composite renal outcome (sustained > 50% reduction in GFR, terminal kidney disease or renal death) was also analyzed, along with worsening GFR throughout the study. Though dapagliflozin did not lower the composite renal outcome (RR = 0.71, 95% CI 0.44-1.16, p = 0.17), rates of worsening GFR were lower for dapagliflozin (-1.09) as compared to the placebo (-2.87), p < 0.001, for patients with our without DM2 (interaction p = 0.92).95 In the EMPEROR-Reduced trial, the annual rate of decline in 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 Data from a subanalysis of the DAPA-HF and EMPEROR-Reduced trials suggest the use of SGLT2 inhibitors is safe in patients with HFrEF and those with altered GFR, regardless of the presence or absence of DM2.

ACEI: angiotensin-converting enzyme II inhibitors; ARB: angiotensin II receptor blockers; ARNI: angiotensin II receptor-neprilysin inhibitors; DM2: type 2 diabetes mellitus; GFR: glomerular filtration rate; HF: heart failure; HFrEF: heart failure with reduced ejection fraction; LVEF: left ventricular ejection fraction; SGLT2i: sodium-glucose cotransporter-2 inhibitors.