Type 2 diabetes patients at high risk of cardiovascular events receiving empagliflozin along with standard care experienced slower progression of kidney disease and lower rates of renal events, according to a study published online by the New England Journal of Medicine

For the EMPA-REG OUTCOME trial, Christoph Wanner, MD, from Würzburg University in Germany, and colleagues randomly assigned patients with type 2 diabetes, established cardiovascular disease, and an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m² to once daily placebo or empagliflozin at a dose of 10 mg or 25 mg (median treatment duration, 2.6 years). Patients also received standard of care comprised of glucose-lowering and cardiovascular drugs, such as hypertension and lipid-lowering medication. 

Secondary renal outcomes of the trial included nephropathy, development or worsening (i.e., macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy [RRT], or death from renal disease), and incident albuminuria.

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Results showed that nephropathy developed or worsened in 525 of 4124 patients (12.7%) in the pooled empagliflozin group and in 388 of 2061 patients (18.8%) in the placebo group over a median 3.1 years. The difference represents a significant 39% risk reduction. By components:

  • Doubling of serum creatinine occurred in 1.5% of the empagliflozin group vs 2.6% of the placebo group, for a significant 44% risk reduction.
  • RRT commenced in 0.3% of empagliflozin users vs 0.6% of placebo users, for a significant 55% risk reduction.

The researchers observed no significant difference in the rate of incident albuminuria (51.5% vs 51.2%). Three patients in the empagliflozin group (0.1%) and none in the placbo group died from renal disease. 

“The mechanisms behind the renal effects of empagliflozin are probably multifactorial, but direct renovascular effects may play an important role,” Dr Wanner and colleagues suggested. The drug was used along with background blockade of the renin–angiotensin–aldosterone system (RAAS), which supports its potential use in type 2 diabetes patients with kidney disease, they noted.

Empagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, lowers elevated blood glucose by reducing the renal reabsorption of glucose and increasing its urinary excretion. The drug’s adverse-event profile in patients with impaired kidney function at baseline was similar to that of the overall trial population. In line with previous reports, more patients taking empagliflozin experienced genital infection. Fewer occurrences of acute renal failure or hyperkalemia were reported with the drug. 

The purported renal benefits of empagliflozin cannot be extended to type 2 diabetes patients at lower cardiovascular risk, the investigators stated. They recommended further research in broader populations, including on black patients who comprised only a small percentage of the EMPA-REG OUTCOME sample. 

In an accompanying editorial, Julie R. Ingelfinger, MD, and Clifford J. Rosen, MD, commented: “We are left with differences that appear encouraging, yet are not a ‘home run’ with regard to the management of diabetes. In the coming years, controlled and comparative effectiveness trials that uniformly combine newer agents with older agents may help to delineate an even more effective treatment plan…”

Several study authors disclosed financial relationships with Boehringer Ingelheim and Eli Lilly, the makers of empagliflozin (Jardiance®), which provided partial funding for the study.

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1. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. doi:10.1056/NEJMoa1515920. 

2. Ingelfinger JR and Rosen CJ. Cardiac and Renovascular Complications in Type 2 Diabetes — Is There Hope? N Engl J Med. doi:10.1056/NEJMe1607413.