Cardiorenal Protection in Type 2 Diabetes Mellitus

Incidence and prevalence of ESRD are increasing. Number of people receiving renal replacement therapy is projected to double all over the world. Diabetes is the leading cause of ESRD. Moreover patients with T2DM and CKD are at greatly increased risk of mortality than diabetic patients without CKD. Unfortunately in spite of decreasing trend of diabetic related complications, end stage renal disease had smallest decline in recent decads.Tight control of glucose levels and blood pressure reduction especially with blockade of the renin–angiotensin– aldosterone system slows but does not prevent the onset of diabetic nephropathy. Therefore there is unmet need in prevention and treatment of DKD. Fortunately, during the past 4 years, the results of three large, multicentre, placebo-controlled trials (EMPA-REG OUTCOME, the CANVAS Program, and DECLARE–TIMI 58) have shown substantive kidney benefits in patients randomly assigned to receive an SGLT2 inhibitor. Each of these trials showed substantial reductions in the composite kidney outcomes of worsening kidney function (defined as either a doubling of serum creatinine or a 40% decrease in eGFR), end-stage kidney disease, or death due to kidney disease. It is important to note that, all of them already have provided cardiovascular benefit as well. However renal endpoints were not primary outcomes in these studies and less than %20 of included patients had eGFR less than 60 mL/min/1.73 m². As such, the CREDENCE trial, the first dedicated kidney outcomes trial of an SGLT2 inhibitor (canagliflozin), done in patients with type 2 diabetes and macroalbuminuric chronic kidney disease with a mean baseline eGFR of 56•2 mL/ min per 1•73 m², fills an important knowledge gap. In this study, reported in 2019, the investigators found a HR 0•70 (95% CI, 0•54–0•86) for the primary composite outcome of end-stage kidney disease, doubling of serum creatinine, or death from kidney or cardiovascular causes. The secondary analysis of the large, placebo-controlled, cardiovascular outcome trials of GLP-1 receptor agonists also have shown reduction of a composite kidney outcome of development of new-onset macroalbuminuria,decline in estimated glomerular filtration rate (or increase in creatinine), progression to end stage kidney disease, or death attributable to kidney causes. However these results were driven by a lowerincidence of new onset macroalbuminuria. In contrast to SGLT2 inhibitors, no significant reduction was observed regarding hard kidney outcomes. Therefore, we can conclude that two therapeutic tools (SGLT2i and GLP-IR) that simultaneously provide cardiorenal protection in type 2 diabetes are available now. However there is no doubt that SGLT2 inhibitors are more effective at mitigating loss of kidney function than GLP-1 receptor agonists.