Empagliflozin Slows Progression of Renal Disease in Diabetes

This renal end point consisted of a combination of progression to macroalbuminuria, a doubling of serum creatinine, the start of renal-replacement therapy, or renal death.

However, the benefit was primarily driven by the reduction in new-onset albuminuria, which occurred in 459 of 4091 patients taking empagliflozin compared with 330 of 2033 patients on placebo (11.2% vs 16.2%; HR, 0.62; P < .001).

Kidney dialysis was also reduced by more than half among those taking empagliflozin, although the absolute numbers affected were small (HR, 0.45; P = .0409).

In an editorial accompanying the renal findings in the published paper, Julie R Ingelfinger, MD, from Massachusetts General Hospital, Boston, Massachusetts, and Clifford J Rosen, MD, from the Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, say: “This new report indicates that empagliflozin was associated with a slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care in [type 2 diabetes] patients at high cardiovascular risk.”

And commenting on both EMPA-REG overall and LEADER, “We are left with differences that are encouraging yet are not a home run with regard to the management of diabetes,” they point out.

Is Empagliflozin a Renal Drug?

There was also some discussion at the ADA meeting about the mechanism of action of empagliflozin, both in lowering cardiovascular risk and now with regard to these renal benefits.

Most newer agent for diabetes will require dose adjustment in diabetic kidney disease because the majority are renally excreted; this includes DPP-4 inhibitors other than linagliptin, most GLP-1 agonists with the exception of liraglutide, and the SGLT2 inhibitors.

The latter, including empagliflozin, have required dose adjustment in patients with diabetic kidney disease. The current licenses for most SGLT-2 inhibitors precludes their use in patients with renal failure (eGFR < 60 mL/min/1.73 m2 in some cases or < 45 mL/min/1.73 m2 in others).

Dr Wanner said that 25% of the patients in EMPA-REG had eGFR < 60 mL/min/1.73 m2, more than a third already had albuminuria, and almost a third already had prevalent kidney damage.

Yet, paradoxically, they seem to provide some renal protection. These newest findings from EMPA-REG bolster excitement about the potential for SGLT2 inhibitors to provide a renoprotective effect, despite being metabolized by the kidney.

“The effect of empagliflozin on renal outcomes was there early and continued for the whole of the study, with both doses showing an effect. Empagliflozin works at lower stages of kidney function too,” Dr Wanner stressed.

Silvio Inzucchi, MD, of Yale University, New Haven, Connecticut, the lead investigator of EMPA-REG, added also that, regarding the overall cardiovascular benefit of empagliflozin seen in the trial, “there was no heterogeneity of effect based on eGFR; cardiovascular disease was reduced even in stage 3b renal-disease [eGFR 30–45 mL/min/1.73 m2] patients.”

Another SGLT2 inhibitor, canagliflozin (Invokana, Janssen) is being specifically tested in a diabetic kidney-disease population in the large multicenter randomized Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial.

This will enroll 3000 patients with stage 2 or 3 chronic kidney disease and macroalbuminuria already receiving standard of care. They will be randomized to canagliflozin 100 mg daily or placebo for 5 years, and results are not expected until 2019.

It is not known whether the latest caution from the Food and Drug Administration, strengthening the warning regarding acute kidney injury for canagliflozin and dapagliflozin, will affect this trial. This states that healthcare providers should consider factors that might predispose patients to acute kidney injury prior to starting them on canagliflozin or dapagliflozin.

Dr Wanner reports grant support from the Foundation for the Study of Diabetes (EFSD) and personal fees from Boehringer Ingelheim during the conduct of the study, and personal fees from Janssen and Novo Nordisk outside the submitted work. Dr Inzucchi reports personal fees and nonfinancial support from Boehringer Ingelheim during the conduct of the study; personal fees from Merck, Janssen, Novo Nordisk, Sanofi and Sanofi/Regeron, Intarcia, Lexicon, Poxel, Boehringer Ingelheim, Eli Lilly, and AstraZeneca; and nonfinancial and other support from Takeda outside the submitted work. In addition, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbott, Merck and Sanofi have provided CME funding to Dr Inzucchi’s employer, Yale University. Disclosures for the coauthors are listed on the journal website.Dr Ingelfinger is employed by the New England Journal of Medicine as deputy editor; Dr Rosen reports that he is an associate editor at the New England Journal of Medicine.

SOURCE / Reference : http://www.medscape.com/viewarticle/864857

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