Acute reversible decline in eGFR seen with SGTL2 inhibitor in T2DM patients with or without HF


News - Apr. 30, 2017

Paris, France | Empagliflozin decreases risk of kidney function decline in type 2 diabetes: slope analyses in patients with and without heart failure at baseline from the EMPA-REG OUTCOME trial

Presented at ESC Heart Failure 2017 by Alfred CHUENG (Salt Lake City, UT, USA)

The EMPA-REG OUTCOME trial evaluated the effect of the SGLT2 inhibitor empagliflozin (10 mg qd or 25 mgqd), in comparison to placebo, in 7020 patients with type 2 diabetes (T2DM) and established CV disease, for a median follow-up of 3.1 years. According to inclusion criteria, patients had eGFR (MDRD) ≥30 mL/min/1.73m2. Baseline characteristics overall were quite similar in placebo- or empagliflozin-treated patients, including the percentage of persons with eGFR <60 mL/ min/1.73m2, namely 26% in both groups.

The major results of the EMPA-REG OUTCOME trial included that compared to placebo, empagliflozin decreased the primary composite outcome of CV death, nonfatal MI or nonfatal stroke (HR: 0.86, 95%CI: 0.74-0.99, P=0.04) and the composite outcome of CV death or adjudicated heart failure (HF) hospitalisation (HR: 0.66, 95%CI: 0.55-0.79, P<0.0001).

The current study focusses on the observation that empagliflozin caused an acute, apparently reversible decline in eGFR, followed by long-term renoprotection. This study aims to assess effects of empagliflozin on the rate of change in eGFR over time in patients with (n=654) or without (n=6013) HF at baseline in the EMPA-REG OUTCOME trial. To this end, eGFR slopes were calculated using random-intercept and time-coefficient models, accounting for multiple baseline factors. eGFR slopes were calculated for three pre-specified time periods: acute phase (baseline to week 4 of treatment), chronic phase (week 4 to end of treatment) and post-treatment (to 1 month after the end of treatment).

Main results

  • When separating patients with or without HF at baseline, it became clear that those with HF at baseline more often had eGFR <60 mL/ min/1.73m2 (36.5% on placebo, 37.7% on empagliflozin) than those without HF (24.8% on placebo, 24.6% on empagliflozin).
  • Use of ACE inhibitors or ARBs was prevalent (with HF: 84.4% on placebo, 87.9% on empagliflozin, without HF: 79.6% and 80.3% respectively).
  • Adjusted mean eGFR dropped with empagliflozin in the acute phase, while on placebo it remained stable, both in those with and without HF (although the curves for those with HF were lower than those for patients without HF).
  • Throughout the chronic phase (week 4-week 206), eGFR was stable on empagliflozin treatment, while it declined on placebo. The same pattern, at different levels of eGFR, was seen for patients with or without HF at baseline.
  • In the post-treatment phase, eGFR increased on empagliflozin, and remained stable on placebo, in both HF groups.
  • When calculating the weekly slope in the acute phase, a decrease of -0.77 change in eGFR mL/ min/1.73m2 was seen with empagliflozin, as compared to 0.01 with placebo in those without HF, and -0.76 and -0.01 respectively in those with HF.
  • Calculating the annual slope in the chronic phase showed an increase by 0.24 mL/ min/1.73m2 in eGFR and a decrease of -1.37 mL/ min/1.73m2 on placebo in those without HF, and 0.12 mL/ min/1.73m2 increase with empagliflozin and -2.49 mL/ min/1.73m2 in those with HF.
  • In the post-treatment phase, empagliflozin showed an increased weekly slope by 0.55 mL/ min/1.73m2 as compared by a decrease (0.04) with placebo in those without HF, and of 0.58 mL/ min/1.73m2 vs. 0.13 on placebo in those with HF.
  • In the post-treatment phase, empagliflozin showed an increased weekly slope by 0.55 mL/ min/1.73m2 as compared by a decrease (0.04) with placebo in those without HF, and of 0.58 mL/ min/1.73m2 vs. 0.13 on placebo in those with HF.


These analyses show that eGFR slope analyses represent a useful method to investigate the effect of SGLT2 inhibitors on kidney function. Furthermore, it showed that the SGLT2 inhibitor empagliflozin caused an acute decline in eGFR (on a high background of ACEi/ARB use), which is apparently reversible upon stopping treatment. Empagliflozin appeared to prevent a decline in eGFR seen in patients receiving placebo. This pattern of eGFR changes was similar in patients with and without pre-existing HF.

Ongoing trials are further investigating the effects of empagliflozin on kidney function in patients (with or without diabetes) with HFrEF (EMPEROR-reduced) and with HFpEF (EMPEROR-preserved).

During the discussion, dr. Giuseppe M C ROSANO (London, GB) postulated that maybe an initial diuretic effect may explain the observations, as also an initial reduction of body weight was seen. Thus, the effect on eGFR may represent a diuretic effect rather than an effect of the drug itself. Also, he noted that while one would like to keep renal function in good shape, the drug lowers mortality and morbidity, which is outweighs the effects on renal function.


Our coverage of ESC HF 2017 is based on the information provided during the congress.

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