SGLT-2 Inhibition: A Potential New Treatment for Diabetic Kidney Disease?

Diabetic nephropathy is the leading cause of kidney failure. Treatments with drugs that block the renin-angiotensin system have proven beneficial in slowing kidney disease progression among those with diabetes; their benefit is limited and they do not stop disease progression. Despite multiple clinical trials of various interventions including dual blockade of the renin-angiotensin system over the past 15 years, no new therapies have emerged to slow kidney disease progression in diabetes. SGLT-2 inhibitors are a new class of antiglycemic drugs that have been shown to lower blood glucose by inhibition of the sodium-glucose transporter 2 in the proximal tubule of the kidney. Several of these inhibitors have been marketed for treatment of hyperglycemia in patients with type 2 diabetes mellitus. In a recent double-blind randomized and placebo-controlled trial of cardiovascular outcomes, an SGLT-2 inhibitor-based intervention using empagliflozin was shown to be superior to placebo-based regimen for reducing the risk of major cardiovascular events among people with type 2 diabetes and established cardiovascular disease. In a pre-specified secondary analysis of renal outcomes from this trial, Wanner et al. [N Engl J Med 2016;375:323-334] recently reported that empagliflozin administration was also associated with significant reductions in the progression of kidney disease including the rate of decline in estimated glomerular filtration rate (eGFR), progression of albuminuria and initiation of renal replacement therapy. While the results of this trial are striking and impressive, the majority of those enrolled in the trial did not have evidence of diabetic kidney disease as assessed by eGFR or albuminuria. Thus, whether or not they represent a breakthrough in the treatment of diabetic nephropathy remains to be determined. Several ongoing clinical trials are in the planning stages to evaluate SGLT-2 inhibition in a population of patients with overt kidney disease. These trials will help to substantiate, or not, the potential for this class of drugs to be added to the armamentarium of therapeutic strategies to prevent progression of kidney disease in diabetes.