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Abstract Diabetes mellitus (DM) is one of the most prevalent medical conditions, affecting over 415 million people worldwide with estimated increase in prevalence by 2040 to 642 million adults. Traditional risk factors for the development of tpye 2 diabetes mellitus (T2DM), represented by obesity, age, physical inactivity and genetics (Trinh et al., 2021). Type 2 diabetes mellitus, an eterogeneous metabolic disorder, has characteristics of insulin resistance or insufficient secretion (Xinyun et al., 2020). Diabetic kidney disease (DKD) is a worldwide danger because it causes end stage renal disease (ESRD) and affects mortality in diabetic patients. So, slowing down its onset and progression is an urgent issue, and the development of therapeutic approaches against DKD is required. Furthermore, DKD is an established risk factor for cardiovascular disease (CVD) (Yasuda-Yamahara et al., 2021). Understanding the mechanisms of diabetic complications constitutes the cornerstone of the evaluation of drug regimens used for the treatment of T2DM (Jingyi et al., 2021). Until now, there is no definite theory on its pathological mechanism. Inflammation is thought to be the most likely pathogenesis of diabetes. This theory holds that inflammatory factors can inhibit glucose transporters on cell membranes and therefore causes hyperinsulinemia, excessive inflammatory factors could directly inhibit insulin signal transduction and cause insulin resistance. The inflammatory cytokines involved are tumour necrosis factor α (TNF-α), interleukin 6 ,8 (IL-6, 8), C-reactive protein (CRP), adiponectin, type-I interferons (IFN) and transforming growth factor- β-1 (TGF-β1), Introduction 15 improvement of these inflammatory cytokines are an important strategy for treatment of T2DM (Xu et al., 2017; Chen et al., 2020). On the other hand, Hyperglycemia, the hallmark of DM, is accompanied by significant changes in glucose and lipid metabolism as well as the induction of oxidative stress (Othman et al., 2020), which is involved to a great extent in the development of DM complications as it promote the activation of NF-κB, which leads to inflammatory cytokines such as TNF-α and IL-6 (Khan et al., 2017), apoptosis is another theory (Kim et al., 2021). Treatments with better control of blood glucose, more reduction of oxidative stress and modulation of pro-inflammatory cytokines are beneficial for controlling diabetic complications. To date, kidney dialysis and renal transplantation are the only final options for the management of end-stage kidney disease that leads to a significant burden on the health organizations. Hence new strategies are needed for prevention and treatment of CKD. Metformin is the most widely accepted first-line treatment to lower blood glucose levels in patients who have type 2 diabetes mellitus. In addition to its role in lowing blood glucose levels, recent reports suggested it has anti-oncogenic (Leone et al., 2020), cardio-protective and anti-inflammatory effects. Metformin can attenuate cyclosporine A- induced renal fibrosis in rats (Lin et al., 2019), modulate immune cell infiltration into the kidney during unilateral ureteral obstruction in mice (Christensen et al., 2019), significantly ameliorates diabetic nephropathy in a rat model of low-dose streptozotocin-induced diabetes (Zhang et al., 2017), which suggest an antifibrotic effect. However, Metformin use is currently limited to patients with Type 2 diabetes mellitus and normal Introduction 16 renal function or stage 1–3 CKD, as its administration is not recommended in patients with advanced renal impairment because it may increase the risk of lactic acidosis. However, the potential efficacy of metformin on reducing the cardiovascular disease (CVD) risk in T2D patients with moderate chronic kidney disease (CKD) has also been suggested (Hao Yi et al.,2021). Thus, the world is waiting for anti-diabetic agents that can attenuate both DKD and CVD. Like glucagon-like 1 receptor agonists (GLP-1RAs) which have favorable effects on the cardiorenal outcomes in (T2D) (Giugliano et al., 2019; Kristensen et al., 2019). GLP-1RAs improve glucose metabolism by stimulating glucose- dependent insulin secretion and inhibiting the release of glucagon. They have also beneficial effects on cardiovascular risk factors by improving obesity, hypertension, and the lipid profile. Recent CV outcome trials utilizing GLP-1RAs have also investigated renal outcomes (Drucker, 2018). In addition, the elucidation of basic mechanisms underlying the renoprotective effect of GLP-1RAs is progressing. In this work, we hope to understand more the renoprotective effects of GLP-1RAs from clinical and mechanistic standpoints. |