Diabetes mellitus is in epidemic proportions around the world. A leading complication is diabetic kidney disease, which accounts, at least in the Western Hemisphere, for over 40% of all patients currently undergoing renal replacement therapy. Many therapies have been tried to slow progression of diabetic kidney disease, without much success.

The mainstay for treatment remains renin-angiotensin blockade using either an angiotensin-converting enzyme inhibitor, such as lisinopril, or an angiotensin receptor blocker, such as losartan. A recent publication in the New England Journal of Medicine (NEJM) by Wanner and colleagues sets the stage for a new and probably substantially more effective approach to preventing progression of kidney disease.1

Wanner and colleagues investigated the effect of treating patients with established type 2 diabetes with nephropathy using a sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin. Their findings reflect the emergence of the most exciting new class of agents for diabetic kidney disease in over two decades.

SGLT2 inhibitors block kidney-specific SGLT2 channels competitively in the proximal nephron and prevent renal glucose, uric acid, and sodium resorption. The clinical effects are reduced plasma glucose levels and hemoglobin A1C, lower blood pressure, and lower uric acid level.

SGLT2 inhibitors have emerged as a very promising class of agents because of the results of the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) program. Zinman and colleagues had earlier reported the results of a placebo–controlled, randomized, controlled trial of 7,020 subjects with type 2 diabetes at high risk for cardiovascular events.2 The study reported the beneficial effect of empagliflozin versus placebo given in addition to standard care on the primary outcome of a composite of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. Empagliflozin was used at a once-daily dose of 10 or 25 mg.

In a recent follow-on paper published in NEJM, Wanner and colleagues asked the question: Could treatment with empagliflozin superimposed on standard therapy result in improved renal and cardiovascular outcomes?1 They reported on a prespecified secondary analysis of kidney outcomes following the Zinman and colleagues primary publication.2 Wanner and colleagues examined the effect of empagliflozin on the following outcomes: new-onset or worsening nephropathy, including new onset of macroalbuminuria (defined as a urine albumin to creatinine ratio > 300 mg/g); doubling of serum creatinine accompanied by an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or less; initiation of renal replacement therapy; or death due to renal disease. There was also a composite outcome of doubling of serum creatinine, initiation of renal replacement therapy, or death due to renal disease.

Empagliflozin’s effect on kidney outcomes was impressive, to say the least. Empagliflozin resulted in a 39% reduction in new-onset or worsening of nephropathy (hazard ratio [HR] 0.61; p < .0001). Furthermore, empagliflozin compared with placebo demonstrated a 46% reduced risk in the composite outcome of doubling of serum creatinine, initiation of renal replacement therapy, or death due to renal disease (HR 0.54; p = .0002). These findings applied to patients with or without chronic kidney disease at baseline.

Empagliflozin was well tolerated compared with placebo, with no worrisome safety signal, although there was a higher risk of genital infections, likely because of a high level of glucosuria.

These results are impressive and likely to have far-reaching consequences on the treatment of patients with nephropathy from type 2 diabetes mellitus. At long last, we have progress, and it is certainly time to pop open the champagne!

WRITTEN BY

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AJAY K. SINGH, MBBS, FRCP(UK), MBA

Co-Editor, Neurology Section, Scientific American Medicine
Co-Editor, Scientific American Neurology
Chair, Department of Neurology, Brigham and Women’s Hospital
Miriam Sydney Joseph Professor of Neurology, Harvard Medical School


SAM-CTA


REFERENCES
1. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323–34.
2. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28.