Sodium‐glucose cotransporter 2 inhibitor effects on heart failure hospitalization and cardiac function: systematic review

Abstract

Aims To systematically review randomized controlled trials assessing effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on hospitalization for heart failure (HHF) and cardiac structure/function and explore randomized controlled trial (RCT)-derived evidence for SGLT2i efficacy mechanisms in heart failure (HF). Methods and results Systematic searches of Medline and Embase were performed. In seven trials [3730-17 160 patients; low risk of bias (RoB)], SGLT2is significantly reduced the relative risk of HHF by 27-39% vs. placebo, including in two studies in patients with HF with reduced ejection fraction with or without type-2 diabetes mellitus (T2DM). Improvements in conventional cardiovascular risk factors, including glycaemic levels, cannot account for these effects. Five trials (56-105 patients; low RoB) assessed the effects of 6-12 months of SGLT2i treatment on left ventricular structure/function; four reported significant improvements vs. placebo, and one did not. Five trials (low RoB) assessed SGLT2i treatment effects on serum N-terminal pro B-type natriuretic peptide levels; significant reductions vs. placebo were reported after 8-12 months (two studies; 3730-4744 patients) but not ≤12 weeks (three studies; 80-263 patients). Limited available RCT-derived evidence suggests various possible cardioprotective SGLT2i mechanisms, including improved haemodynamics (natriuresis and reduced interstitial fluid without blood volume contraction/neurohormonal activation) and vascular function, enhanced erythropoiesis, reduced tissue sodium and epicardial fat/inflammation, decreased sympathetic tone, and beneficial changes in cellular energetics. Conclusions Sodium-glucose cotransporter 2 inhibitors reduce HHF regardless of T2DM status, and reversal of adverse left ventricular remodelling likely contributes to this efficacy. Hypothesis-driven mechanistic trials remain sparse, although numerous trials are planned or ongoing.

Sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials

“…Some of the outcomes of interest were not consistently reported, which might have introduced bias. There are several ongoing large trials examining effects of SGLT-2 inhibitors in HFpEF patients [45] . These trials will address the efficacy as well as safety of SGLT-2 inhibitors in these patients.…”

Benefit of natriuresis and cardiac resynchronisation therapy in acute decompensated heart failure with cardiorenal syndrome and hypernatraemia

“…A thiazide diuretic and a mineralocorticoid receptor antagonist were added to increase the natriuresis-to-diuresis ratio. Sodium-glucose co-transporter-2 inhibitors also intensify natriuresis and reduce mortality in heart failure 6. However, these were contraindicated by poor oral intake and AKI.…”

Sodium-glucose co-transporter 2 inhibitors beyond diabetes

“…It may relate to the drug’s natriuretic effect, enhanced erythropoiesis, beneficial changes in cellular energetics or reversal of adverse ventricular remodelling. 5 …”

“…It may relate to the drug's natriuretic effect, enhanced erythropoiesis, beneficial changes in cellular energetics or reversal of adverse ventricular remodelling. 5 The DAPA-HF trial reported a 26% relative risk reduction in cardiovascular death or worsening heart failure in patients randomised to receive dapagliflozin. 3 The magnitude of benefit was similar irrespective of the patient's background therapy for heart failure.The EMPEROR-Reduced trial compared empagliflozin to placebo.…”