(62). GLP-1RAs can control blood sugar and decrease body weight without increasing the risk of hypoglycemia (64). GLP-1RAs can lower systolic, and to a minor degree, diastolic blood pressure (65). In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, liraglutide use significantly decreased mortality from any cause and cardiovascular events in patients with T2DM at high risk for cardiovascular events. This benefit is more pronounced in patients with eGFR 30 mL/min/1.73m2 over a median duration of 3.1 years (107). In RENAAL trial, losartan treatment of a similar population having DN led to a 28% delay in the onset of ESRD over a mean follow-up of 3.4 years (108). In addition, empagliflozin caused a 39% reduction of incident or worsening nephropathy, a 38% reduction in progression to overt albuminuria, and a 44% reduction in doubling of serum creatinine (109). The favorable outcome of SGLT2Is is attributable to their effect on glomerular hyperfiltration, blood pressure, body weight, and serum UA in diabetic patients (109-111). SGLT2Is also inhibit NHEs on the surface of cardiomyocytes, endothelial cells, and renal tubular epithelial cells. NHE inhibition can explain the distinguished cardioprotective and renoprotective actions of SGLT2Is (112-114). Decreased renal blood flow induced by SGLT2Is is related to tubuloglomerular feedback and not related to the RAS blockade. Empagliflozin and dapagliflozin increase plasma aldosterone and angiotensin II (115, 116), together with increased activity of urinary angiotensin converting enzyme and angiotensin converting enzyme2 (117). Figure 8. The beneficial effects of DPP4Is on the kidney are muffled by the bad effect induced by stromal cells derived factor 1(SDF-1). DPP-4: dipeptidyl peptidase; TGF: transforming growth factor; EndMT: endothelial mesenchymal transition Antioxidant effect Inhibition of NHE3 in PCT Stop inhition of megalin within PCT Inhibit DPP4 mediated stimulation of immune and inflammatory cells Inhibition of endothelial DPP4 Inhibition of fibrosis potentiation of SDF-1 within the kidney podocyte injury and glomerulosclerosis natriuresis in the distal tubules Figure 9. Mechanism of hyperfitration induced by hyperglycemia and how do SGLT2Is control it. UF: ultrafiltrate; SGLT: sodium glucose transporter; Na+: sodium; PCT: proximal convoluted tubules; DCT: distal convoluted tubules; ATP: adenosine triphosphate; MD: macula densa; AMP: adenosine monophosphate; VD: vasodilatation; AA: afferent arteriole; VC: vaso-constriction hyperglycemia Hyperfiltration Hyperfiltration SGLT2Is é Glucose in UF é SGLT2 activity ê SGLT2 activity é Na+ absorption (PCT) ê Na+ absorption (PCT) ê ê ê ê DCT Na+ delivery é DCT Na+ delivery ê DCT Na+ absorption é DCT Na+ absorption ê DCT ATP consumption é DCT ATP consumption ê MD AMP é MD AMP ê MD Adenosine é MD Adenosine VD of AA VC of AA Sharaf El Din et al. Diabetic Nephropathy Prevention Turk J Nephrol 2020; 29(2): 161-73 166 When T2DM patients (total of 1,450 cases) already on metformin were treated for 2 years with either once-daily canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride titrated to 6-8 mg, the eGFR declined by 0.5, 0.9, and 3.3 mL/min/1.73 m2 /year respectively (p90, 45.1% had GFR between 60 and 90, whereas only 7.4% of the patients had GFR 300 to 5,000 mg/g) that were receiving RAS blockers. The primary outcome was a composite of ESRD (dialysis, transplantation, or a sustained eGFR of 90, in cases with GFR between 60 and 90, in normo-albuminuric patients, in patients with microalbuminuria, and in those with overt proteinuria. These favorable effects were only observed in patients already maintained on either ACE inhibitors or ARBs (12). Role of Free Oxygen Radicals Scavengers Many preclinical studies have underlined the role of ROS in the pathogenesis of diabetic complications. However, the less favorable outcomes of different antioxidants to prohibit the development or progression of diabetic complications in large clinical trials have dampened the enthusiasm for the use of antioxidant agents in diabetes (126). Clinical studies using vitamin A, C, and E as antioxidant agents in pre-diabetic and T2DM patients were disappointing. Recommendations of Diabetes Associations In October 2018, the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) issued an updated consensus on management of T2DM patients. In this consensus, patients with clinical CV disease should receive one of SGLT2Is or GLP-1RAs, whereas in patients with CKD or clinical HF and ASCVD, SGLT2Is should be considered (127). The choice of diabetes therapies as recommended by the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) must be individualized on the basis of many attributes including the risk reduction in heart and kidney disease (128). Novel Markers of Diabetic Complications Mannose-binding lectin (MBL), a recognized protein of the innate immune system is independently associated with HbA1c in diabetic patients (129). MBL is a possible independent predictor of DR, DN and other vascular complications in type 1 and type 2 diabetes (130-134). In 297 newly diagnosed T2DM patients, serum fibrinogen was a