In fact, mediation analyses performed suggested that only approximately 25% of the benefit on renal outcomes may be mediated by improved glycemic control and 922% by changes on blood pressure,92,106 suggesting the role of direct mechanisms: reduction of hyperfiltration, oxidative stress and inflammation, antifibrotic effects, improvement of endothelial dysfunction and/or possible reduction of angiotensin II levels.52,54,107109 In experimental studies of DKD, treatment with arGLP-1 has been associated with histological improvements (reduction of glomerular hypertrophy, mesangial expansion, thickening of the glomerular basement membrane and tubulointerstitial damage).110,111 In fact, the KDIGO guidelines for the management of patients with diabetes and CKD rank arGLP-1 as a second line of treatment and suggest its use in patients with DM2 and CKD who have not reached individualized glycemic targets despite the use of metformin and iSGLT2, or in those who cannot use these drugs since liraglutide, semaglutide and dulaglutide (results with epfeglenatide have not been published) have demonstrated cardiovascular benefits, especially among patients with established cardiovascular disease, associated with favorable renal benefits with a substantial reduction in albuminuria and probable preservation of eGFR,112 as well as other guidelines in patients with DM2 and high/very high cardiovascular risk, such as patients with DKD.19,113 Furthermore, arGLP-1 s are more potent antihyperglycemic agents than iSGLT2s in patients with DKD, and some such as semaglutide also confer greater potential for weight loss
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