Efficacy and safety of metformin versus empagliflozin on chronic kidney disease progression (MET-EMPA-CKD): a randomized controlled trial

Abstract

Abstract Background Chronic kidney disease (CKD) is a devastating progressive condition accompanied with high morbidity and mortality rates. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have recently proven their renoprotective effects, whereas evidence for metformin remains limited but suggestive of potential benefit. This study aimed at comparing the efficacy and safety of metformin versus empagliflozin, a SGLT2 inhibitor, on retarding CKD progression with exploring supposed mechanistic pathways in clinical settings. Methods In this 12-month randomized controlled trial, 120 moderate CKD patients were randomized into three groups: metformin 1000 mg/day ( n = 40) or empagliflozin 10 mg/day ( n = 40), both added orally to standard treatment, or control who continued standard of care ( n = 40). The primary outcome was changes in estimated glomerular filtration rate (eGFR). Secondary analyses assessed percent changes of urinary albumin-to-creatinine ratio (uACR), transforming growth factor-β1 (TGF-β1), kidney injury molecule (KIM)-1, and beclin-1 (an autophagy biomarker). Other metabolic and safety issues were also assessed. Results 118 patients completed the study with comparable baseline data. Metformin and empagliflozin halted the decline in eGFR at study end with adjusted mean difference ± SE: 8.91 ± 1.92 ( p ˂0.001) and 5.1 ± 1.89 ( p = 0.03), respectively, compared to control group. Metformin preserved its effect in diabetics and non-diabetics, with superiority than empagliflozin in non-diabetics. uACR was lowered by metformin and empagliflozin than control. Both of them tended to halt the deterioration of intermediates with %relative change of -28.8% (95% CI, -44.4 to -9, p = 0.003) and 179.3% (95% CI, 32.2 to 490, p = 0.003), for metformin versus control in TGF-β1 and beclin-1 levels, respectively. Empagliflozin reduced KIM-1 compared to control [-29% (95% CI, -49.3 to -0.5, p = 0.045)]. Study treatments showed benefits on lipid profile without changing urate levels significantly compared to the control arm. No significant changes were found between metformin and empagliflozin. Adverse effects were comparable across groups with tolerable increased urination frequency by empagliflozin. Conclusion 12-month metformin therapy demonstrated renoprotective effects comparable to empagliflozin, with a greater effect observed among non-diabetics as an exploratory insight. Metformin’s renal actions were linked to antifibrotic and favorable autophagy effects while, empagliflozin preserved mainly tubular injury. Safety issues were generally comparable. Clinicaltrials.Gov identifier NCT05373680, registered on 13/5/2022 “retrospectively”. Graphical abstract

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Affiliated Institutions

• Tanta University EG
• Mansoura University EG

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