Among patients with diabetes, cardiovascular disease (CVD), and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, taking empagliflozin, 10 or 25 mg/d, was associated with lower rates of all-cause and cardiovascular mortality and all-cause and heart-failure hospitalization. The drug was compared to placebo in EMPA-REG OUTCOME, an industry-sponsored randomized controlled trial (RCT), and the new findings come from a post hoc subgroup analysis.
The study was published online Sept. 13, 2017, and in the Jan. 9 issue of Circulation. The following commentary by Louise Moist, MD, ACP Member, was published in the ACP Journal Club section of the May 15 Annals of Internal Medicine.
This post hoc subgroup analysis of the EMPA-REG OUTCOME trial by Wanner and colleagues showed reductions in major, validated, clinical outcomes in patients with type 2 diabetes, established CVD, and chronic kidney disease (CKD) treated with empagliflozin. However, we must be cautious when interpreting these results and consider them hypothesis-generating.
In its favor, the EMPA-REG trial included CKD as a baseline characteristic defined by eGFR and urine albumin–to–creatinine ratio categories. In this post hoc analysis, the positive treatment effects seen in EMPA-REG were consistent across these categories and across the 2 dosages of empagliflozin. Additionally, the subgroup of patients with CKD was relatively large (2,250 patients, 32% of the study population), the magnitude of effect was clinically and statistically significant, and a physiologic mechanism supports the effect.
Sodium–glucose co-transporter-2 inhibitors (SGLT2Is) have been game-changers for patients who have diabetes, with consistent evidence from RCTs of reduced mortality, all-cause cardiovascular events, and hospitalization. It is too early to apply the same optimism to patients with CKD. At baseline, mean eGFR in EMPA-REG OUTCOME was 83 mL/min/1.73 m2 for patients without CKD and 54 mL/min/1.73 m2 in the CKD subgroup. These results are not generalizable to patients with lower levels of kidney disease, and previous cardiovascular protective interventions have not shown a consistent benefit as eGFR declines. Although evidence shows that empagliflozin slows progression of kidney disease, these were exploratory outcomes and not designed to provide definitive information related to renoprotection. While encouraging, these results require confirmation in dedicated kidney outcome trials that are currently under way (ClinicalTrials.gov NCT03036150, NCT01032629, NCT02065791).
If the results of the above studies are confirmed, SGLT2Is will become a dominant strategy over standard glucose-lowering therapies for treating diabetic kidney disease, with reduced health care costs and improved clinical outcomes.