Sodium-glucose co-transporter 2 inhibitors in heart failure: an updated evidence-based practical guidance for clinicians

Abstract

The sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce risks of clinical events in patients with heart failure (HF), with early and sustained benefits regardless of ejection fraction, diabetic status, and care setting. As part and parcel of the modern foundational HF therapy, clinicians should be familiar with these drugs, in order to implement their use and limit the potential adverse effects. We present an up-to-date review of current evidence and a practical guide for the prescription of SGLT2 inhibitors in patients with HF, highlighting important elements for patient selection, treatment initiation, dosing, and problem solving.

Keywords: Cardiovascular outcome trials; Clinical practical guide; Heart failure; SGLT2 inhibitors.

Figure 1

Timeline of SGLT2 inhibitor trials targeting patients with heart failure (HF). Large and narrow boxes show enrolment and follow-up period, respectively. The result for the primary outcome is reported below the trial name. Modified from Tromp et al. Abbreviations: CHF, chronic heart failure; HR, hazard ratio; IV, intravenous; WR, win ratio. The primary endpoint was defined as (A) EMPULSE—clinical benefit, defined as a hierarchical composite of death from any cause, number of HF events and time to first HF event, or a ≥5 point difference in change from baseline KCCQ score at 90 days, as assessed using a WR; (B) SOLOIST-WHF—composite of deaths from cardiovascular causes, HF hospitalizations and urgent visits for HF (first and subsequent events); (C) EMPEROR-Reduced and EMPEROR-Preserved—composite of cardiovascular death or hospitalizations for HF; (D) DAPA-HF and DELIVER—composite of worsening HF (defined as either an unplanned hospitalization for HF or an urgent visit for HF) or cardiovascular death. *minimum time to randomization from the withdrawal of intravenous HF therapy in acute decompensated HF patients [EMPULSE—off inotropes for 24 h and no vasodilators or escalating diuretics for 6 h; SOLOIST-WHF—off IV inotropes or IV vasodilators (except for nitrates) for 48 h and having transitioned from IV to oral diuretic therapy; DELIVER—off intravenous HF therapy (including diuretics) for at least 24 h]. ^#enrolled only type 2 diabetic patients.

Figure 2

Practical guide to initiation of SGLT2 inhibitors in patients with heart failure. Abbreviations: AHF, acute heart failure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HF, heart failure; IV, intravenous; LD, loop diuretics; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure. ^aeGFR calculated by CKD-EPI formula. ^bInitial decline in eGFR of 3–4 mL/min/1.73 m² or 10–15% from baseline (mainly in patients with initial low eGFR) is common/expected, does not reflex acute kidney injury and therapy should be continued unless major fall in eGFR. ^cFDA recommend to withhold SGLT2 inhibitors in case of prolonged fasting or 3 days before major surgery. The treatment can be restarted only once the patient’s oral intake is restored and any other risk factors for ketoacidosis are resolved. ^dSymptoms of volume depletion are weakness, orthostatic hypotension, weight decrease >1 kg over 24 h or >2 kg in 1 week. ^eSymptoms of uro-genital infections are pain or burning on urination, redness, swelling, itching in the genital area, nasty-smelling vaginal or penile secretion, and fever. ^fSymptoms of diabetic ketoacidosis are excessive thirst, sweet-smelling breath, a change in urine or sweat odour, nausea, vomiting, abdominal pain, confusion, weakness, and fever. Note that it could also manifest with relatively normal glucose levels (euglycemic diabetic ketoacidosis).