Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects

Abstract

Sodium-glucose cotransporter 2 inhibition with canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that canagliflozin confers renoprotection. We determined whether canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride uptitrated to 6-8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, canagliflozin 100 mg, and canagliflozin 300 mg groups had eGFR declines of 3. versus glimepiride). In the subgroup of patients with baseline urinary albumin-to-creatinine ratio $30 mg/g, urinary albumin-to-creatinine ratio decreased more with canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P=0.01) or canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P,0.001) than with glimepiride. Patients receiving glimepiride, canagliflozin 100 mg, or canagliflozin 300 mg had reductions in HbA1c of 0.81%, 0.82%, and 0.93%, respectively, at 1 year and 0.55%, 0.65%, and 0.74%, respectively, at 2 years. In conclusion, canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and canagliflozin may confer renoprotective effects independently of its glycemic effects. 28: 368-375, 201728: 368-375, . doi: 10.1681 Many patients with type 2 diabetes present with hyperglycemia, hypertension, and excess weight, and develop increased albuminuria, all of which increase the risk of micro-and macrovascular complications. Current practice guidelines recommend targeting these risk factors with a range of different drugs. 1 However, despite the many drugs used, many patients do not reach treatment targets and develop potentially preventable micro-and macrovascular complications. Emerging interest in the role of the kidney in glucose homeostasis has led to the development of sodium-glucose cotransporter inhibitors. 2 These drugs are designed to inhibit sodium-glucose cotransporter 2 (SGLT2), which is located in the S1 segment of the proximal tubule. Previous phase 2 and phase 3 studies have shown that administration of SGLT2 inhibitors augments urinary glucose and sodium excretion and decreases glycated hemoglobin A1c (HbA1c), body weight, and BP in patients with type 2 diabetes. 3,4 Moreover, reductions in albuminuria have been observed after administration of SGLT2 inhibitors. 5,6 J Am Soc Nephrol

Are SGLT2 Inhibitors Ready for Prime Time for CKD?

“…These data suggest that SGLT2i may have beneficial kidney effects, even in people with reduced kidney function, where glycemic benefits are limited (5). Interestingly, a recent study suggested that canagliflozin slows the progression of kidney function decline independently of effects on glycemia (6).…”

“…Finally, SGLT2i has been shown to slow the progression of kidney function decline independently of glycemic effects (6). Together with the unique mechanism of action of these drugs, which impact the kidney hemodynamics, this observation raises the hypothesis that their impact could also translate into improved kidney outcomes in nonpatients with diabetes.…”

Cardiovascular benefits of the newer medications for treating type 2 diabetes mellitus

“…In a study of 1450 T2DM patients on metformin randomly assigned to either canagliflozin or glimepiride, canagliflozin treated patients had significantly less decline in estimated glomerular filtration rate and greater reduction in urinary albuminto-creatinine ratio compared to glimepiride (47). The authors concluded that canagliflozin, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with T2DM, and canagliflozin may confer renoprotective effects independently of its glycemic effects (47). This study was not designed nor powered to compare the renoprotective effects of canagliflozin versus glimepiride, so the results should be interpreted as hypothesis-generating (47).…”

Sodium-Glucose Co-Transporter 2 Inhibitors could Improve the Bioavailability of Vitamin C at the Kidney in Diabetes Treatment

“…It seems plausible that reabsorbed ascorbic acid protects renal proximal tubular cells from reactive oxygen species and exits the cells as dehydroascorbic acid, as indicated in the neurons [7]. Most recently, it has been demonstrated that SGTL 2 inhibitors slow progression of kidney disease in type 2 diabetes [8,9], where improvement of the bioavailability of vitamin C is not included in the putative mechanisms behind their renal effects. If this hypothesis is verified, SGLT2 inhibitors would be expected to have beneficial effects on the kidney still unknown beyond glucose lowering.…”