Heart failure outcomes among reduced and preserved ejection fraction patients on sodium-glucose cotransporter-2 inhibitors with different dosing patterns of diuretics: a systematic review and meta-analysis

The current review was conducted to provide information on the best dosing strategy of background loop diuretics with sodium-glucose cotransporter-2 inhibitors (SGLT2i) for heart failure and safety outcomes among reduced and preserved ejection fraction patients with comorbid conditions. The search was conducted in four databases. Study eligibility was evaluated independently, and a total of four randomized controlled trials were included in this review. Data extraction was performed using the Cochrane-modified extraction template. Statistical analyses and risk of bias assessment were conducted with RevMan version 5.4.1, while the certainty of evidence was appraised using the GRADEpro tool. The primary composite outcomes and hospitalization or urgent heart failure (HF) with SGLT2i and placebo were consistent across all the doses of loop diuretics. The primary composite outcome when loop diuretics were dosed at <40 mg and >40 mg [hazard ratio (HR): 0.77 and HR: 0.81] and showed high significance (p=0.0002), similar for hospitalization and urgent HF (HR: 0.73 and HR: 0.81) with (p=0.0007 and p=0.002). However, when the loop diuretics were dosed at 40 mg, they showed highly significant (p<0.01) efficacies for all cardiovascular outcomes, such as primary composite outcome (HR: 0.76), hospitalization or urgent HF (HR: 0.68), and mortality due to any cause (HR: 0.81), and marginally significant efficacy (p=0.05) for cardiovascular death (HR: 0.86). Compared to the SGLT2i and placebo groups, patients receiving SGLT2i with 40 mg of loop diuretics and placebo were less likely to experience volume depletion, with the odds ratio of 1.56 (p<0.05). The adverse renal effects and discontinuation of the drug were the same across all the doses of loop diuretics. We conclude that SGLT2i plus dosing of loop diuretics at 40 mg with placebo among heart failure patients demonstrated superior cardiovascular and safety outcomes.