Summary | What are the key lessons from the EMPA-REG OUTCOME trial?
May 25, 2018 - Prof. Christoph Wanner
The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG) OUTCOME trial was published in 2015. This trial randomly assigned type 2 diabetes mellitus (T2DM) patients with established cardiovascular disease (CVD) to receive placebo, or 10 mg or 25 mg of the SGLT2 inhibitor empagliflozin after a placebo run-in period. The treatment period was followed by 30 days consisting of a wash-out period and serum creatinine measurements for the kidney endpoint. 7020 Adults with body mass index ≤45 kg/m2, hemoglobin (Hb) A1c of 7-10% and an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73m2 were included. The CV results of this trial were surprisingly positive as will be discussed next [1].
A reduction in CV outcomes was observed in the EMPA-REG OUTCOME trial after treatment with the SGLT2 inhibitor. Treatment of only 39 patients with empagliflozin on top of standard care (ACE-inhibitors, statins and aspirin), prevents one death over a period of three years [1]. This compares favorably with treating 56 persons over a period of five years with ramipiril [2] and 30 persons over a period of 5.4 years after treatment with simvastatin [3]. Prof. Wanner therefore concluded: 'The EMPA-REG OUTCOME has been an important study in the field of cardiovascular outcomes'.
Next, prof. Wanner discussed the secondary endpoints of the study , starting with the effect of empagliflozin on the kidneys. Treatment with empagliflozin in T2DM patients with well-preserved kidney function and a mean eGFR of 74 ml/min/1.73m2 initially resulted in eGFR reduction by about 3 to 4 mL/min/1.73m2 and then eGFR normalized over time by gradually increasing about 2 mL/min/1.73m2/year, whereas the placebo group more often showed progression of CKD. During the follow-up after the treatment period (median: 34 days) without the use of empagliflozin, eGFR increased and returned to baseline. At the follow up visit, the difference in eGFR from baseline between placebo and empagliflozin was 4.7 ml/min/1.73m2, which translated into a reduction of kidney endpoints with empagliflozin[4].
The secondary kidney endpoint new onset or worsening of nephropathy was significantly reduced by 39% after treatment with empagliflozin compared with placebo (HR: 0.61, 95%CI: 0.53-0.70, P<0.0001). Also, new onset macroalbuminuria was significantly decreased by 38% in the empagliflozin group, suggesting that nephropathy is driven by macroalbuminuria. Although only a few patients showed doubled creatinine levels, a reduction of 44% was observed after treatment with empagliflozin as compared with placebo. Initiation of renal replacement therapy occurred in 0.3% of the patients treated with empagliflozin and in 0.6% of the patients treated with placebo (relative risk reduction: 55%) [4].
In macroalbuminuria patients (UACR ratio of 800 mg/gram) albuminuria was prominently reduced by 50% at the end of empagliflozin treatment, but albuminuria returned to half of baseline levels when patients stopped using the drug, suggesting there might be a structural benefit over time. When comparing different risk populations, macroalbuminuria patients (N=764) showed lower eGFR levels at a later stage of the study in comparison with normoalbuminuria (N=4042) and microalbuminuria patients (N=1995). This risk population mainly consisted of older patients, with more comorbid diseases, more long-standing diabetes, and their eGFR was reduced by 7 mL/min/1.73m2/year with placebo. This reduction in eGFR was stabilized after treatment with empagliflozin, showing a prominent and significant difference with placebo treatment [5].
A next step was to investigate the effect of empagliflozin in patients with pre-existing CKD, the so-called renal population. CKD was defined by an eGFR of 30-60 mL/min/1.73m2 and/or macroalbuminuria at baseline and the study included 2250 patients. To study the effect of the drug in this subpopulation, HbA1c levels were evaluated and compared with patients with normal kidney function (eGFR ≥60 mL/min/1.73m2 at baseline). HbA1c was reduced in patients with normal kidney function, whereas only 0.3% of the CKD patients showed a reduction, possibly due to lower glucose excretion. Thus, it might be that empagliflozin does not effectively lower HbA1c in patients with CKD. To further study this, a subanalysis was done focusing on groups with different eGFRs (≥90, 60 to <90, 45 to <60, 30 to <45 mL/min/1.73m2) and albuminuria patients. Surprisingly, the hazard ratio risk reduction for new onset or worsening of nephropathy was almost the same for each subgroup with different eGFRs, suggesting that patients with an eGFR of at least 30 ml/min/173m2 would benefit from the drug. Also, according to the results, albuminuria patients can benefit from treatment with empagliflozin [6].
Kaplan-Meyer survival curves showed a reduced incidence of nephropathy in prevalent CKD patients after treatment with empagliflozin as compared with placebo (HR: 0.58, 95%CI: 0.47-0.71, P<0.001). Similarly, CV death was decreased in CKD patients with empagliflozin (HR: 0.70, 95%CI: 0.51-0.96, P=0.0265).Of note, the curves for CV death separate after one year, indicating that treatment with empagliflozin is effective in later stages of CKD. When looking at hospitalization for heart failure (HF), again CKD patients showed reduced risk after treatment with empagliflozin compared to placebo (HR: 0.60, 95%CI: 0.42-0.86, P=0.0056), with a prominent effect already in a very early stage of the trial [6].
Prof. Wanner finished with a last slide about safety of empagliflozin. 'It is important to look at acute renal failure and acute kidney injury when evaluating the safety of this drug. In randomized trials there is no evidence of harm with empagliflozin in terms of kidney outcomes' [4].
In summary, the EMPA-REG OUTCOME trial results showed a reduction of new onset or worsening of nephropathy, CV death and hospitalization for HF in CKD patients after treatment with empagliflozin, as compared with placebo, on top of standard care.
1.	Bernard Zinman et al., N Engl J Med, 2015. 373(22): p. 2117-2128.
2.	Yusuf S, S.P et al., N Engl J Med, 2000. 342(3): p. 145-53.
3.	Pedersen TR et al., Lancet, 1994. 344(8934): p. 1383-9.
4.	Wanner C et al., N Engl J Med, 2016. 375(4): p. 323-34.
5.	Cherney DZI et al., Lancet Diabetes Endocrinol, 2017. 5(8): p. 610-621.
6.	Wanner C et al., Circulation, 2018. 137(2): p. 119-129.
This is a summary of the presentation given by prof. Wanner, during the PACE symposium entitled 'Diabetic Kidney Disease: Exploring mechanisms and outcomes of SGLT2 inhibition', held during ERA-EDTA in Copenhagen, Denmark, on May 25, 2018
View lectures of this symposium