Fig. 2

Exploring possible HF benefits with glucose-lowering drugs (mainly SGLT2 inhibitors). All clinical trials shown are of SLGT2 inhibitors, except for AMPLITUDE-O (efpeglenatide, GLP-1 RA). A consistent pattern of fewer HHF events, with a large effect size, has been seen across the SGLT2 inhibitor class [13, 62, 139]. These reductions were closely mirrored in a dedicated renal outcomes study of canagliflozin in patients with diabetic kidney disease [36], and in dedicated HF outcomes studies of dapagliflozin and empagliflozin in patients with HFrEF with or without diabetes [69, 71] and of empagliflozin in patients with HFpEF with or without diabetes [86] (A). Results from these trials are shown to illustrate the consistency of findings regarding HHF; they should not be directly compared, due to differences in study design, definitions and populations. Note that HHF as a standalone endpoint was not a primary outcome measure in any of the studies shown and has not been reported for the SOLOIST-WHF HF outcomes study, DAPA-CKD renal outcomes or SCORED cardiorenal studies. Diabetes CVOTs were not initially designed to assess any protective effect on HHF (for example, most patients were not diagnosed with HF at baseline (B) [16, 18, 27, 30, 36, 37, 63, 69, 70, 72]). International guidelines for the treatment of patients with T2D now recommend SGLT2 inhibitors to protect patients from HF [38, 40, 42] (C), while real-world studies have confirmed the pattern of fewer HHF events in the more diverse patients seen in routine clinical practice [73, 74, 77,78,79,80,81,82, 89, 90] (D). ACC, American College of Cardiology; ADA, American Diabetes Association; CI, confidence interval; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase-4; EASD, European Association for the Study of Diabetes; ESC, European Society of Cardiology; GLD, glucose lowering drug; GLP-1 RA, glucagon-like peptide-1 receptor agonist; Hb1Ac, haemoglobin A1c; HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; HHF, hospitalisation for HF; HR, hazard ratio; SGLT2, sodium–glucose transporter 2; T2D, type 2 diabetes; TZD, thiazolidinedione. *p < 0.05. ^†Exploratory analysis. ^‡Efpeglenatide is not a currently licensed treatment