Can Glucose-Lowering Medications Improve Outcomes in Non-Diabetic Heart Failure Patients? A Bayesian Network Meta-Analysis

Aims The cardioprotective effects of glucose-lowering medications in diabetic patients with heart failure (HF) are well known. Several large randomized controlled trials (RCTs) have recently suggested that the cardioprotective effects of glucose-lowering medications extend to HF patients regardless of diabetic status. The aim of this study was to conduct a Bayesian network meta-analysis to evaluate the impact of various glucose-lowering medications on the outcomes of non-diabetic HF patients. Methods and results Medline and Embase were searched for RCTs investigating the use of glucose-lowering medications in non-diabetic HF patients in August 2021. Studies were included in accordance with the inclusion and exclusion criteria, and data were extracted with a pre-defined datasheet. Primary outcomes include serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, left ventricular ejection fraction (LVEF), and maximal oxygen consumption (PVO2). A Bayesian network meta-analysis was performed to compare the effectiveness of different classes of glucose-lowering medications in improving HF outcomes. Risk-of-bias was assessed using Cochrane Risk-of-Bias tool 2.0 for randomized trials (ROB2). Seven RCTs involving 2897 patients were included. Sodium-glucose transporter 2 inhibitor (SGLT2i) was the most favourable in lowering NT-proBNP, with the significant reduction in NT-proBNP when compared with glucagon-like peptide-1 receptor agonists (GLP1-RA) [mean differences (MD): −229.59 pg/mL, 95%-credible intervals (95%-CrI): −238.31 to −220.91], metformin (MD: −237.15 pg/mL, 95%-CrI: −256.19 to −218.14), and placebo (MD: −228.00 pg/mL, 95%-CrI: −233.99 to −221.99). SGLT2i was more effective in improving LVEF for HF with reduced ejection fraction patients relative to GLP1-RA (MD: 8.09%, 95%-CrI: 6.30 to 9.88) and placebo (MD: 6.10%, 95%-CrI: 4.37 to 7.84). SGLT2i and GLP1-RA were more favourable to placebo in improving PVO2, with significant increase of PVO2 at a MD of 1.60 mL/kg/min (95%-CrI: 0.63 to 2.57) and 0.86 mL/kg/min (95%-CrI: 0.66 to 1.06), respectively. All three drugs had comparable safety profiles when compared with placebo. Conclusions This Bayesian network meta-analysis demonstrated that SGLT2i, when compared with GLP1-RA and metformin, was superior in improving LVEF in HF with reduced ejection fraction patients, as well as improving PVO2 and NT-proBNP in non-diabetic HF patients. Further large-scale prospective studies are needed to confirm these preliminary findings.