Significance of Metformin Use in Diabetic Kidney Disease

Abstract

Metformin is a glucose-lowering agent that is used as a first-line therapy for type 2 diabetes (T2D). Based on its various pharmacologic actions, the renoprotective effects of metformin have been extensively studied. A series of experimental studies demonstrated that metformin attenuates diabetic kidney disease (DKD) by suppressing renal inflammation, oxidative stress and fibrosis. In clinical studies, metformin use has been shown to be associated with reduced rates of mortality, cardiovascular disease and progression to end-stage renal disease (ESRD) in T2D patients with chronic kidney disease (CKD). However, metformin should be administered with caution to patients with CKD because it may increase the risk of lactic acidosis. In this review article, we summarize our current understanding of the safety and efficacy of metformin for DKD.

The Current and Potential Therapeutic Use of Metformin—The Good Old Drug

“…The impact of metformin on the kidney in diabetics is also a consequence of both its glucose lowering-dependent and glucose-independent mechanism [ 230 ]. The toxic effect of hyperglycemia on the kidney is well recognized both in animal models and in humans.…”

“…Hyperglycemia increasing oxidative stress and generation of free radicals, inducing low-grade chronic inflammation, and autophagy is responsible for podocyte damage and its death and for the intensification of tubule-interstitial fibrosis. Therefore, metformin with its potent anti-hyperglycemic effect, inhibition of advanced glycation end products accumulation in various tissues and decreasing hyperglycemia -related inflammation and oxidative stress may slow down all these kidney damaging processes [ 229 , 230 , 231 ]. Experimental studies on mammalian cells have shown that metformin increases the level of anti-aging protein (klotho protein) which may inhibit the progression of various kidney diseases.…”

Metformin Protects against Podocyte Injury in Diabetic Kidney Disease

“…As in other tissues, also in the kidney metformin acts via both AMPK-dependent and -independent pathways as described in the following paragraphs, in which I will concentrate on the effects of metformin in podocytes. For comprehensive reviews covering the effects of metformin in the kidney beyond podocytes, see the following recent review articles [ 93 , 94 , 95 , 96 , 97 ]. The mechanisms of action of metformin in different tissues are reviewed in [ 98 ].…”

“…Metformin also ameliorates the senescence of renal tubular cells in culture and in diabetic db/db mice by up-regulating miR-130a-3p and down-regulating STAT3, a target gene of miR-130a-3p involved in the pathogenesis of DKD [ 136 ]. For recent reviews on the beneficial effects of metformin in the kidney at large, the readers are referred to [ 93 , 94 , 95 , 96 , 97 ].…”

“…The data also support the notion that adjusting the dose of metformin to the eGFR enables the use of metformin also when the kidney function is impaired, and that metformin should be contraindicated when eGFR falls < 30 mL/min/1.73 m 2 [ 2 ]. For a more detailed description of clinical studies on the use of metformin in DKD the readers are referred to a recent review article [ 94 ].…”