FROM THE NEW ENGLAND JOURNAL OF MEDICINE

Empagliflozin was associated with a significant 39% decrease in risk of new or worsening nephropathy, compared with placebo among adults with type 2 diabetes at high risk for cardiovascular events, based on a secondary analysis of the phase III, randomized, double-blind EMPA-REG OUTCOME trial .

“Patients in the empagliflozin group also had a significantly lower risk of progression to macroalbuminuria or clinically relevant renal outcomes, such as a doubling of the serum creatinine level and initiation of renal-replacement therapy, than did those in the placebo group,” Dr. Christoph Wanner of Würzburg (Germany) University Clinic, and his associates reported in the June 14 New England Journal of Medicine.

Empagliflozin (Jardiance) is a selective sodium–glucose cotransporter-2 inhibitor that was approved in the United States in 2014 to improve glycemic control among patients with type 2 diabetes mellitus. In the initial analysis of the EMPA-REG OUTCOME trial, empagliflozin was associated with a significantly lower rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, as compared with placebo among patients with type 2 diabetes at high cardiovascular risk ( N Engl J Med. 2015 Nov 26 doi: 10.1056/NEJMoa1504720 ).

For the current secondary analysis, Dr. Wanner and his associates focused on renal microvascular outcomes, including new or worsening nephropathy (macroalbuminuria, defined as greater than 300 mg of urinary albumin/gram of creatinine), a doubling of the serum creatinine level accompanied by an epidermal growth factor receptor (eGFR) of less than or equal to 45 mL/minute per 1.73 m2 of body surface area, a new need for renal-replacement therapy, and death from renal disease. A total of 7,020 patients with type 2 diabetes and an eGFR of at least 30 mL/minute per 1.73 m2 of body-surface area received either 10 mg or 25 mg of empagliflozin or placebo once daily, plus standard diabetes care ( N Engl J Med. 2016 Jun 14. doi: 10.1056/NEJMoa1515920 ).

New or worsening nephropathy occurred among 525 (12.7%) patients who received empagliflozin, compared with 388 (18.8%) patients who received placebo, for a statistically significant 39% decrease in relative risk of this outcome (hazard ratio, 0.61; P less than .001). This benefit persisted at both doses of empagliflozin, among patients with and without baseline chronic kidney disease (eGFR greater than or equal to 60 mL/min/1.73m2), and across other subgroups stratified by sex, race, body mass index, number of cardiovascular risk factors, and diabetes history and treatment.

A total of 70 patients (1.5%) in the empagliflozin group had a doubling of serum creatinine, vs. 60 patients (2.6%) in the placebo group, for a significant relative risk reduction of 44% (hazard ratio, 0.56; P less than .001). In addition, the proportion of patients starting renal-replacement therapy was twice as high in the placebo group than in the empagliflozin group (0.6% and 0.3%, respectively; HR, 0.45; P less .01).

The groups did not significantly differ in the rate of incident albuminuria, the researchers said. “There were three deaths from renal disease in the empagliflozin group (0.1%) and none in the placebo group,” they added.

The study uncovered no safety signals related to hypoglycemia, diabetic ketoacidosis, thromboembolic events, bone fractures, or volume depletion, the investigators said. Rates of overall adverse events, serious adverse events, and adverse events leading to treatment discontinuation were similar across groups. Rates of complicated urinary tract infections did not significantly vary according to treatment or based on the presence or absence of chronic kidney disease (CKD).Although empagliflozin was associated with a doubling in the rate of urosepsis, these events were rare, affecting only 0.3% and 0.7% of patients with baseline CKD and 0.1% and 0.2% of patients without baseline CKD.

The study was funded by the Boehringer Ingelheim and Eli Lilly and the Diabetes Alliance. Dr. Wanner disclosed grant support from the European Foundation for the Study of Diabetes and personal fees from Boehringer Ingelheim, Janssen, and Novo Nordisk.

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