Potential Benefits of Sodium-Glucose Transporter-2 Inhibitors in the Symptomatic and Functional Status of Patients With Heart Failure: A Systematic Review and Meta-Analysis

Abstract

This review evaluates the potential benefits of sodium-glucose transporter-2 (SGLT-2) inhibitors on symptom burden/health-related quality of life (HRQoL), functional improvement, hospitalization for heart failure (HHF), cardiovascular mortality (CVM), and all-cause mortality (ACM) in patients with heart failure (HF) with reduced or preserved ejection fraction (EF). We analyzed 12 randomized clinical trials (RCTs) accessed through 11 records and three secondary analyses from PubMed and Scopus following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines. These studies evaluated 23,389 patients treated with either an SGLT-2 inhibitor or placebo in addition to the standard of care. Four studies recruited diabetic patients, some of whom had HF at the baseline and were evaluated as a subgroup. One study had diabetes and HF present in all patients at the baseline. Ten studies recruited patients with HF at their baseline irrespective of diabetic status. Eight studies evaluated the SGLT-2 inhibitors for a composite of hospitalization for heart failure or cardiovascular mortality (HHF/CVM) and ACM. Five of these studies showed a decreased risk for HHF/CVM, and two showed a reduced risk for ACM. One trial showed benefits in patients with heart failure with reduced ejection fraction (HFrEF) only and not in heart failure with preserved ejection fraction (HFpEF). Other studies revealed benefits but did not reach statistical significance. Ten studies assessed the SGLT-2 inhibitors for improvement in symptoms and HRQoL; four demonstrated a significant improvement, three showed a slight improvement, and three did not find any benefit. Five trials evaluated participants' functional progress by assessing for a six-minute walk test (6MWT). Two studies showed a significant increase in the distance walked by the patient, while three others did not. The SGLT-2 inhibitors reduce the risk of HHF/CVM irrespective of ejection fraction and result in a symptomatic improvement.

Obesity, diabetes mellitus, and cardiometabolic risk: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2023

“…Conversely, patients with marked increases in glucose and/or blood pressure, severe dyslipidemia (e.g., severe hypertriglyceridemia), acute thrombosis, cardiovascular disease (CVD), or cancer should have these acute metabolic abnormalities urgently assessed, managed, and treated – preferably with concomitant interventions that may also improve obesity. For example, while glucagon-like peptide-1 receptor agonist based therapies may reduce body weight and improve glycemic control in patients with overweight/obesity [ 20 ], if the patient with obesity and T2DM has heart failure, then beyond their indicated use as anti-diabetes medications, some sodium glucose transporter 2 inhibitors (SGLT1i) have clinical outcome data to support improvement in both CVD and heart failure [ 178 ], and may also facilitate mild weight reduction [ 179 , 180 ].

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NHC/ SHA 2023 Focused update of the 2019 guidelines for the management of heart failure

“…Both trials demonstrated that SGLT2-inhibitors reduce the combined risk of worsening heart failure or cardiovascular death, regardless of the presence of diabetes [ 130 , 131 ]. The benefit of SGLT2 inhibitors was also reported by several meta-analyses to be irrespective of EF [ 112 – 114 ]. SGLT2 inhibitors are therefore recommended for all patients with HFmrEF.…”

“…Empagliflozin was also associated with significant improvements in quality of life, and reduction in eGFR decline but no significant reduction of CV mortality [ 110 , 111 ]. This benefit was confirmed by several meta-analyses of RCTs, which reported that SGLT2 inhibitors lead to a reduction in the risk of both HF hospitalizations and cardiovascular mortality, in addition to symptomatic improved among patients irrespective of ejection fraction [ 112 – 114 ]. SGLT2 inhibitors are therefore recommended for all patients with HF along with standard therapy.…”

“…As with HFrEF and HFmrEF, diuretics are recommended for the relief of symptoms in congested patients. Currently, SGLT2-inhibitors is the only drug class with significant benefit in terms of mortality and HF worsening in HFpEF patients [ 112 – 114 , 130 , 131 ]. The DELIVER trial is the largest (6263 patients enrolled) and broadest global trial to date in patients with LVEF >40%.…”

“…SGLT2 inhibitors improve clinical outcomes in patients with established cardiovascular disease or ‘cardiovascular risk factors, as shown in several clinical trials (EMPA-REG OUTCOME, VERTIS-CV trials, CANVAS, DECLARE-TIMI 58, SCORED trial [ 66 – 70 ]). Meta-analyses of RCTs confirm that SGLT2 inhibitors lead to a reduction in the risk of both HF hospitalizations and cardiovascular mortality, in addition to symptomatic improvement among patients irrespective of ejection fraction [ 112 – 114 ]. the EMPEROR-Preserved and DELIVER-Preserved RCTs recently confirmed that SGLT2 inhibitors are effective in patients with mildly reduced and preserved ejection fraction (EF>40%), regardless of the presence of diabetes [ 130 , 131 ].…”