EMPA-REG OUTCOME: The Initial "eGFR Dip" due to Empagliflozin does not affect its CV and Renal Benefits in T2DM Patients

6 Apr, 21

Introduction

Treatment with sodium-glucose co-transporter-2 inhibitors (SGLT-2i) is associated with an initial 3-5 ml/min/1.73 m² decline in estimated glomerular filtration rate (eGFR). Though this 'eGFR dip' is of hemodynamic origin and largely reversible, it has raised concerns in clinical practice. A better understanding on the incidence and clinical implications of eGFR dip is thus essential.

Aim

To determine whether the initial ‘eGFR dip’ observed with empagliflozin is influenced by baseline characteristics and/or has an impact on safety and cardiovascular (CV) and renal outcomes

Patient Profile

Participants from the EMPA-REG OUTCOME trial (treated type-2 diabetes mellitus [T2DM] patients with established CV disease [CVD] and eGFR ≥30 ml/min/1.73 m²) who received at least one dose of the study drug (n=6668)
The eGFR data at baseline and week 4 was available for all the study participants. Based on the percent eGFR from baseline at week 4, patients were categorized into 3 classes as follows:
- ‘eGFR dipper’: >10% decline
- ‘eGFR intermediate’: >0% to ≤10% decline
- ‘eGFR non-dipper’: no decline

Methods

Study Design

A post hoc analysis of EMPA-REG OUTCOME trial
EMPA-REG OUTCOME was a double-blind, placebo-controlled multinational trial

Treatment Strategy

The study participants were randomized 1:1:1 to receive empagliflozin 10 mg, empagliflozin 25 mg or placebo once daily in addition to the standard care

Outcomes

Association of an ‘eGFR dip’ from baseline at week 4 with CV-related death, hospitalization for heart failure (HHF), or renal outcomes after week 4

Median Treatment Duration

2.6 years

Median Observation Time

3.1 years

Results

The patient split for initial ‘eGFR dip’ observed in empagliflozin vs. placebo group (as per the eGFR categorization) are shown in table 1.

Table 1: Percentage of patients as per eGFR category

eGFR category	Empagliflozin Group (% participants)	Placebo Group (% participants)
eGFR Dipper	28.3%	13.4%
eGFR Intermediate	41.1%	39.5%
eGFR Non-dipper	30.5%	47.1%

From week 12 onward, the mean eGFR remained stable in all ‘eGFR dipping’ categories of the empagliflozin-treated patients, as well as in the subset of patients who experienced an initial empagliflozin-induced eGFR decline >30%. On the contrary, the mean eGFR levels declined across all categories of the placebo-treated patients.
In patients for whom the eGFR data during follow-up was available, increase in the mean eGFR values was evident after discontinuation of empagliflozin treatment as compared with the last value on treatment (LVOT). The mean eGFR did not change after discontinuation of placebo as compared with the LVOT.
As per a multivariate logistic regression analysis, diuretic use and higher KDIGO (Kidney Disease Improving Global Outcomes) risk category at baseline were independent predictors of an initial 'eGFR dip' in empagliflozin vs. placebo.
An ‘eGFR dip’ was associated with a significantly increased risk for incident or worsening nephropathy (HR, 1.22; 95% CI, 1.05–1.44) in participants treated with empagliflozin as well as placebo (all P values for treatment-by-‘eGFR dip’ interaction around 0.5–0.8).
The initial 'eGFR dip' did not have a major impact on the treatment effect of empagliflozin on subsequent cardiovascular death, hospitalization for heart failure, and incident or worsening kidney disease.
As compared to placebo, empagliflozin treatment was associated with a consistent reduction in the incidence of CV death, hospitalization for HHF, incident or worsening nephropathy, and CV and kidney outcomes.
The incidence of overall and serious adverse events from baseline to week 4 did not increase in any of the subgroups. Patients treated with empagliflozin had a slightly higher incidence of kidney-related adverse events.

Conclusions

Patients with T2DM with more advanced kidney disease and/or on diuretic therapy were more likely to experience an 'eGFR dip' of >10% with empagliflozin. A more pronounced initial eGFR decline of >30% was rare.
Empagliflozin treatment was safe and was associated with improved CV and renal outcomes, irrespective of identified baseline predictive factors.
The initial ‘eGFR dip” had no major impact on the long-term CV and renal benefits observed in empagliflozin-treated patients.

Kidney Int. 2021;99(3):750-762.