Selective SGLT2 inhibition exhibits nephroprotective effects in high risk diabetes patients

Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial

Literature - Wanner C, Heerspink HJL, Zinman B, et al; on behalf of the EMPA-REG OUTCOME Investigators - J Am Soc Nephrol 2018;29:published online ahead of print

Introduction and methods

Despite improvements in glycemic control, patients with diabetic chronic kidney disease (CKD) continue to have a high renal and cardiovascular (CV) risk [1]. In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG) OUTCOME trial [2], empagliflozin, a selective sodium glucose cotransporter 2 (SGLT2) inhibitor, decreased the risk of CV and delayed the progression of CKD in patients with type 2 diabetes (T2DM) and established CV disease [3,4].

This pre-specified slope analysis of the EMPA-REG OUTCOME Trial evaluated the effect of empagliflozin on acute changes in estimated glomerular filtration rate (eGFR) after treatment initiation (baseline – week 4), during chronic maintenance treatment (week 4 – last value on treatment), and after study drug discontinuation (last value on treatment – follow up) in the overall trial population and in individuals at higher risk of progressive CKD.

The EMPA-REG OUTCOME Trial (Sept 2010 – Apr 2013) was a double-blind, placebo-controlled, multinational trial in which 7,020 adults with T2DM, HbA1c ≥7% and established CV disease were randomized in a 1:1:1 ratio to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo, on top of standard of care, during a median treatment period of 2.6 years (median observation time: 3.1 years). Data of both empagliflozin doses were pooled for these analyses. Eligible patients had an eGFR of ≥30 ml/min per 1.73 m² at screening. The primary endpoint was a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke.

Main results

  • When analyzing estimated individual patient eGFR slopes, empagliflozin showed a consistent shift to the left across the distribution of individual eGFR changes compared with the placebo group during treatment initiation (baseline to week 4), indicating a reduction in mean eGFR. During chronic maintenance treatment and follow-up, the eGFR slope curve of empagliflozin shifted rightward, indicating slower loss of kidney function, followed by an increase in mean eGFR.
  • From baseline to week 4, the adjusted mean slope (eGFR change per week) was -0.77 ml/min/1.73m² in the empagliflozin group (95%CI: -0.83 to -0.71) and 0.01 in the placebo group (95%CI: -0.08 to 0.10; P<0.001).
  • From week 4 to study end, the annual adjusted mean change of eGFR was 0.23 ml/min/1.73 m² (95%CI: 0.05-0.40) in the empagliflozin group and -1.46 (95%CI: -1.74 to -1.17) in the placebo group (P<0.001).
  • Post-treatment, the adjusted mean change of eGFR per week was 0.56 ml/min/1.73 m² in the empagliflozin group (95%CI: 0.49-0.62) and -0.02 (95%CI: -0.12 to 0.08) in the placebo group (P<0.001).
  • In patients with prevalent CKD at baseline, the differences in mean adjusted annual eGFR slope rates during chronic therapy were in favor of empagliflozin compared with placebo, with no significant difference between patients with or without prevalent CKD.
  • Treatment with empagliflozin resulted in a more pronounced effect to slow eGFR decline in patients with prevalent macroalbuminuria (empagliflozin vs. placebo slope: 4.769, P-interaction<0.001) compared with normoalbuminuria (2.305) or microalbuminuria (1.226), or in those with elevated blood pressure (≥140/90 mmHg: 2.193 vs. 1.355, P-interaction <0.02).


In T2DM patients at high CV risk, empagliflozin significantly slowed eGFR decline over a treatment period of approximately 3 years, compared with placebo, in patients with or without higher risk for CKD, with a more pronounced effect observed in patients with albuminuria or elevated blood pressure. An initial decrease in eGFR relative to placebo is seen shortly after drug initiation, indicative of an acute hemodynamic response, followed by slowing of the loss of eGFR, suggesting preservation of kidney function. After treatment discontinuation, eGFR slopes tended to return to baseline values. These data suggest that empagliflozin slows the progression of CKD, probably through reductions in intraglomerular pressure and long-term preservation of kidney function.


1. Heise T, Seewaldt-Becker E, Macha S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab 15: 613–621, 2013.

2. Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPAREG OUTCOME). Cardiovasc Diabetol 13: 102, 2014.

3. Zinman B, Wanner C, Lachin JM, et al. EMPAREG OUTCOME Investigators: Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373: 2117–2128, 2015.

4. Wanner C, Inzucchi SE, Lachin JM, et al.: EMPA-REG OUTCOME Investigators: Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 375: 323–334, 2016.

Find this article online at J Am Soc Nephrol

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