Fig. (2).

Does metformin protect kidney function? Concerns over hepatotoxicity and lactic acidosis resulted in the almost universal withdrawal in 1978 of the biguanides phenformin and busformin from clinical use. Metformin inherited these concerns, although the incidence of lactic acidosis associated with the use of metformin is very low, with the risk greatly reduced by avoiding use in patients with severe chronic kidney disease (CKD) where eGFR is <30 mL/min/1.73 m². As depicted in the figure, an accumulation of evidence from both pre-clinical and clinical studies supports the view that metformin has both indirect and direct renoprotective actions. Extra-kidney protective effects can be linked, at least in part, to the activation of AMPK, reduction of insulin resistance, enhanced peripheral glucose utilization, and protection of vascular function. Evidence, primarily from studies with rodent models of diabetes, also supports direct renoprotective effects of metformin that involve the activation of AMPK. The downstream effects of AMPK protect multiple cell types in the kidney via enhanced endothelial/vascular function, reduced NFκB activation, inhibition of mammalian target for rapamycin (mTOR) and autophagy, and reduced inflammation and fibrosis. This figure was created with BioRender.