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Empagliflozin May Have Beneficial Long-Term Renal Effects

Empagliflozin and long-term renal effects: it might not only decrease the risk of cardiovascular events in patients with type 2, but also renal events.

The EMPA-REG study demonstrated that empagliflozin decreased the risk of first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes (T2D) at high risk for cardiovascular events. However, there is a concern that sodium–glucose cotransporter 2 inhibitors, such as empagliflozin, may be associated with long-term adverse renal outcomes. Furthermore, approximately 35% of patients with T2D develop renal disease, increasing their risk of mortality.

The objective of this current study is to better understand the long-term renal effects of empagliflozin through analysis of the secondary microvascular outcomes of the EMPA-REG trial.  This was a phase III, multicenter, randomized, parallel group, double blind study. The median duration of treatment was 2.6 years with long-term analysis starting at 4 weeks and ending with the last week of treatment. Patients with T2D and an estimated glomerular filtration rate of at least 30 ml/min were randomly assigned to receive empagliflozin (10 or 25 mg) or placebo once daily in addition to standard care (including glucose-lowering therapy, antihypertensive therapy, lipid-lowering therapy, and anticoagulants). The prespecified secondary renal outcomes included incident or worsening nephropathy [defined as progression to macroalbuminuria (urinary albumin-to-creatinine ratio, >300 mg of albumin per gram of creatinine), a doubling of the serum creatinine level, the initiation of renal-replacement therapy, or death from renal disease] and incident albuminuria [defined as urinary albumin-to-creatinine ratio ≥30 in patients with a normal albumin level (urinary albumin-to-creatinine ratio, <30) at baseline]. Outcomes were assessed with the Cox proportional-hazards model.

Incident or worsening nephropathy occurred in 525 of 4,124 patients (12.7%) in the empagliflozin group and in 388 of 2,061 (18.8%) in the placebo group (HR 0.61; 95% CI, 0.53 to 0.70; P<0.001). In particular, progression to macroalbuminuria occurred in 459 of 4,091 patients (11.2%) in the empagliflozin group and in 330 of 2033 (16.2%) in the placebo group (HR 0.62; 95% CI, 0.54-0.72; P<0.001); doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group (HR 0.56; 95% CI, 0.38-0.79; P<0.001); renal-replacement therapy was initiated in 13 of 4,687 patients (0.3%) in the empagliflozin group and in 14 of 2,333 patients (0.6%) in the placebo group (HR 0.45; 95% CI, 0.21-0.97; P 0.04); and finally, there were three deaths from renal disease in the empagliflozin group (0.1%) and none in the placebo group. No significant between-group difference in the rate of incident albuminuria was found (HR 0.95; 95% CI, 0.87-1.04; P 0.25).

In this analysis, empagliflozin slowed progression of kidney disease and lowered rates of clinically relevant renal outcomes compared to placebo when added to standard of care in patients with T2D at high cardiovascular risk. This study was funded by the manufacturer of empagliflozin, and was an analysis of secondary outcomes from the EMPA-REG trial. Additionally, these results may not be generalizable to black patients (due to the small proportion in this study) or patients with T2D at a lower cardiovascular event risk. Future studies are needed to validate these findings in broader populations at risk for adverse renal outcomes.

Practice Pearls:

  • This RCT evaluated the long-term renal effects of empagliflozin in patients with T2D at high cardiovascular risk.
  • Compared to placebo, patients on empagliflozin had lower risk of worsening nephropathy, doubling of serum creatinine, and renal replacement therapy, but no significant difference in the rate of incident albuminuria.
  • Further research is needed in patients that have T2D at lower risk for cardiovascular events.

Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):323-34. doi: 10.1056/NEJMoa1515920. Epub 2016 Jun 14. PubMed PMID: 27299675.

 

Researched and prepared by Meghan Kelly, Pharm.D. Candidate Class of 2017. Reviewed by Michelle Caetano, Pharm.D, BCPS, BCACP, CDOE, CVDOE