Empagliflozin and Kidney Disease Progression in Diabetes

Study Questions:

What are the effects of empagliflozin on microvascular outcomes and, in particular, progression of kidney disease in patients with type 2 diabetes who are at high risk for cardiovascular events?

Methods:

This was a prespecified analysis of the EMPA-REG OUTCOME trial. The study population of this trial included patients who had type 2 diabetes, established cardiovascular disease, and an estimated glomerular filtration rate of ≥30 ml/min 1.73 m2 of body surface area. Patients were randomly assigned to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily in addition to standard care. The primary outcome of the EMPA-REG OUTCOME trial was a composite of major adverse cardiovascular events. The secondary outcomes examined in this prespecified analysis were incident or worsening nephropathy, doubling of the serum creatinine level, initiation of renal replacement therapy, or death from renal disease.

Results:

A total of 7,020 patients at 590 sites in 42 countries received at least one dose of a study drug. Incident or worsening nephropathy occurred in 525 of 4,124 patients (12.7%) in the empagliflozin group and in 388 of 2,061 patients (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53-0.70; p < 0.001). Progression to macroalbuminuria occurred in 459 of 4,091 patients (11.2%) in the empagliflozin group and in 330 of 2,033 (16.2%) in the placebo group, a significant relative risk reduction of 38%. There was no significant between-group difference in the rate of incident albuminuria.

Conclusions:

In patients with type 2 diabetes and at escalated risk for cardiovascular events, those who received empagliflozin in addition to standard care had a significantly lower risk of incident or worsening nephropathy than did those receiving placebo.

Perspective:

This is a valuable analysis that helps establish empagliflozin as being associated with a significantly lower risk of clinically relevant renal events. While the mechanisms underlying the renal effects of empagliflozin are likely multifactorial, the authors report that “direct renovascular effects may play an important role.” Although there is a reduction in proximal tubular sodium re-absorption, empagliflozin may lead to afferent vasomodulation and a decrease in hyperfiltration. Further studies will help more precisely establish in whom empagliflozin should be used.

Clinical Topics: Diabetes and Cardiometabolic Disease, Prevention

Keywords: Albuminuria, Cardiovascular Diseases, Creatinine, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Glomerular Filtration Rate, Kidney Diseases, Metabolic Syndrome X, Primary Prevention, Renal Replacement Therapy


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