Effects of Empagliflozin on the Urinary Albumin-to-creatinine Ratio in Patients with Type 2 Diabetes and Established Cardiovascular Disease: an Exploratory Analysis from the EMPA-REG OUTCOME Randomised, Placebo-controlled Trial

Background: In a pooled analysis of short-term trials, short-term treatment with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin reduced albuminuria in patients with type 2 diabetes and prevalent albuminuria. In this exploratory analysis of the EMPA-REG OUTCOME trial, we report the short-term and long-term effects of empagliflozin on albuminuria in patients with type 2 diabetes and established cardiovascular disease, according to patients' baseline albuminuria status.

Methods: In this randomised, double-blind, placebo-controlled trial at 590 sites in 42 countries, we randomly assigned patients aged 18 years and older with type 2 diabetes and established cardiovascular disease (1:1:1) to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in addition to standard of care until at least 691 patients experienced an adjudicated event included in the primary outcome. We did the randomisation with a computer-generated random-sequence and interactive voice-response and web-response system, stratified by HbA, BMI, region, and estimated glomerular filtration rate. Patients, investigators, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary efficacy and safety endpoints of this trial have been reported previously. Here, we report urinary albumin-to-creatinine ratio (UACR) data for the pooled empagliflozin group versus placebo according to albuminuria status at baseline (normoalbuminuria: UACR <30 mg/g; microalbuminuria: UACR ≥30 to ≤300 mg/g; and macroalbuminuria: UACR >300 mg/g). We did the analysis with mixed-model repeated measures including prespecified and post-hoc tests. This study is completed and registered with ClinicalTrials.gov, number NCT01131676.

Findings: Between Sept 1, 2010, and April 22, 2013, we randomly assigned 7028 patients to treatment groups and 7020 patients received treatment. At baseline, we had UACR data for 6953 patients: 4171 (59% of treated patients; 1382 assigned to placebo and 2789 assigned to empagliflozin) had normoalbuminuria, 2013 (29%; 675 assigned to placebo and 1338 assigned to empagliflozin) had microalbuminuria, and 769 (11%; 260 assigned to placebo and 509 assigned to empagliflozin) had macroalbuminuria. Median treatment duration was 2·6 years (IQR 2·0-3·4; 136 weeks) and median observation time was 3·1 years (2·2-3·6; 164 weeks). After short-term treatment at week 12, the placebo-adjusted geometric mean ratio of UACR change from baseline with empagliflozin was -7% (95% CI -12 to -2; p=0·013) in patients with normoalbuminuria, -25% (-31 to -19; p<0·0001) in patients with microalbuminuria, and -32% (-41 to -23; p<0·0001) in patients with macroalbuminuria. The reductions in UACR were maintained with empagliflozin in all three groups compared with placebo during long-term treatment when measured at 164 weeks. At follow-up, after cessation of treatment for a median of 34 or 35 days, UACR was lower in the empagliflozin versus placebo group in those with baseline microalbuminuria (placebo-corrected adjusted geometric mean ratio of relative change from baseline with empagliflozin: -22%, 95% CI -32 to -11; p=0·0003) or macroalbuminuria (-29%, -44 to -10; p=0·0048), but not for patients with baseline normoalbuminuria (1%, -8 to 10; p=0·8911). Patients treated with empagliflozin were more likely to experience a sustained improvement from microalbuminuria to normoalbuminuria (hazard ratio [HR] 1·43, 95% CI 1·22 to 1·67; p<0·0001) or from macroalbuminuria to microalbuminuria or normoalbuminuria (HR 1·82, 1·40 to 2·37; p<0·0001), and less likely to experience a sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria (HR 0·84, 0·74 to 0·95; p=0·0077). The proportions of patients with any adverse events, serious adverse events, and adverse events leading to discontinuation increased with worsening UACR status at baseline, but were similar between treatment groups. The proportion of patients with genital infections was greater with empagliflozin than placebo in all subgroups by UACR status.

Interpretation: These results support short-term and long-term benefits of empagliflozin on urinary albumin excretion, irrespective of patients' albuminuria status at baseline.

Funding: Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance.