Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes

Abstract

Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. This analysis explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation ( 115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose cotransporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.

Efficacy and Safety of Ertugliflozin in Patients with Type 2 Diabetes Inadequately Controlled by Metformin and Sulfonylurea: A Sub-Study of VERTIS CV

“…Changes from baseline in laboratory parameters including lipids, hematocrit and hemoglobin, and analytes (magnesium, phosphate, uric acid) observed in this sub-study were consistent with the findings in other VERTIS program studies [38]. The increases in hemoglobin and hematocrit and decreases in uric acid may be important mediators of the beneficial effects of SGLT2 inhibitors on heart failure, CV death, and kidney events [39][40][41].…”

Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial

“…31 Furthermore, SGLT2 inhibitors restore impaired tubuloglomerular feedback and reduce hyperfiltration in diabetes, which could preserve long-term kidney function and reduce hypoxia. 32,33 Prior long-term and large clinical trials of SGLT2 inhibitors have reported similar increase in haemoglobin and haematocrit over follow-up in patients with type 2 diabetes and relatively normal kidney function 13,34,35,36 These studies also demonstrated that changes in haemoglobin and haematocrit from baseline explained nearly half of the effects of SGLT2 inhibitors versus placebo on the risk of cardiovascular death, heart failure, and kidney failure. [34][35][36] These data suggest a strong association between erythropoiesis parameters with cardiovascular and kidney outcomes which is supported by the findings from the current analysis demonstrating that development of anaemia was statistically significantly associated with subsequent risk of kidney and cardiovascular outcomes.…”

Impact of sodium glucose linked cotransporter‐2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus

“…It has been estimated that the associated increase in systemic hematocrit (~5%) may be responsible for as much as 50% of the increase in patient survival observed in clinical trials (Inzucchi et al, 2018). Thus, mild renal hypoxia may protect the kidney, while initiating a systemic response (EPO derived erythrogenesis), which may improve systemic oxygen delivery and organism survival (Inzucchi et al, 2018;Li et al, 2020). With respect to other studies which report measurement of renal P k O 2 utilizing different experimental models; these studies have a number of limitations.…”