COMMENTARY

New Data on Empagliflozin in Treating Diabetic Kidney Disease

Tejas P. Desai, MD

Disclosures

September 29, 2016

Empagliflozin and Its Potential Effects in Treating Kidney Disease

For decades, investigators have searched for a new therapeutic agent against diabetic kidney disease. While angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been reliable therapeutics, nephrology providers have earnestly waited for the development of new pharmacologic agents that can further halt the progression of kidney disease in conjunction with standard therapies. History, however, has not been kind to this endeavor, as drugs that were initially heralded as active kidney-healing agents were later shown to have little therapeutic effect and perhaps significant adverse effects (eg, bardoxolone). Today, we report on a new agent that may finally bring us what we have all been waiting for: empagliflozin.

Empagliflozin is a new class of antihyperglycemic agents that inhibits the resorption of sodium and glucose in the proximal tubules of the kidney. In the randomized, controlled EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) trial, which was published in the New England Journal of Medicine, the glycosuric and natriuretic effects of empagliflozin were shown to reduce major cardiac events.[1] These exciting results made investigators wonder if empagliflozin could protect kidney function in patients with diabetes and chronic kidney disease (CKD). This new follow-up study tries to answer that question.

The study examines the data from the EMPA-REG OUTCOME trial as it relates to patients with CKD.[2] Though not reported in great detail in the parent trial, data were collected in a prespecified subset of patients to determine the rate of incident or worsening of kidney disease, development of macroalbuminuria, initiation of renal replacement therapy, or death from kidney failure. In this subset analysis, patients with type 2 diabetes and an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73 m2 were randomly assigned to either a daily placebo or empagliflozin (at a dose of 10 mg or 25 mg). Approximately 81% of the patients in this subset were either treated with an ACE inhibitor or an ARB, and nearly 26% of the patients had an eGFR between 30 and 59 mL/min/1.73 m2. These patients were treated for a median of 2.6 years and observed for a median of approximately 3 years.

So how did empagliflozin perform? Over 7000 patients with kidney disease who took the medication saw a relative risk reduction of 39% in incident or worsening of kidney disease, a 38% reduction in progression to macroalbuminuria, and a lower rate of progression to renal replacement therapy. Perhaps more interesting is that after 4 weeks of therapy and an initial decrease in eGFR in both treatment arms, patients receiving empagliflozin had no further decline in renal function (eGFR), while those receiving the placebo had a steady decline.

Indeed, this investigation shines a positive light on the possible future role that empagliflozin will have in the treatment of diabetic kidney disease. Unfortunately, the study has a few notable nuances that gave me pause for concern. For starters, this investigation is, at its core, a subset analysis that was prepared for a manuscript separate from the parent trial (EMPA-REG OUTCOME). One should adopt the same cautious interpretations of this report as one would of any trial that reports subgroup analyses within the main manuscript itself. Perhaps even more surprising was the exclusion of two statistical tools used to help validate clinical trial results from a subset of data. Despite worsening kidney function being a prespecified subgroup outcome, neither a power calculation to determine the number of patients needed to see this difference between groups nor a corrected statistical significance level to correct for multiple hypothesis testing were performed. These omissions were not explained in the report. Saving the most shocking for last is that a public relations firm helped write this report.

There are a lot of points to take away from this report. Empagliflozin may be the next efficacious drug against diabetic kidney disease. Hopefully, the drug receives a fair shake from investigators and is studied for its effects against kidney disease in its own randomized, controlled trial and reported solely by the investigators leading the study with the appropriate statistical analyses conducted. Tell us what you think and whether you'd begin prescribing the drug today to your patients with diabetes and CKD in the comments section below.

Abstract

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