Further analysis of EMPA-REG OUTCOME trial uncovers that Jardiance improves albuminuria in adults with type 2 diabetes suffering from cardiovascular disease. Benefits were seen in all three groups with baseline; normal albuminuria (<30 mg/d), micro-albuminuria (30-300 mg/d) and macro-albuminuria (>300 mg/d). About 7,000 patients were followed for 3 years.

As expected, the biggest reduction was seen in advanced disease: -25% in micro-alb and -32% in macro-alb vs. -7% normo-alb. Abnormal albuminuria, a marker of endothelial dysfunction, is an established independent contributor to cardiovascular events. It is reasonable to speculate that albuminuria reduction from Jardiance is a driving mechanism of CVD prevention in diabetes.

Lancet, Diabetes & endocrinology

EMPA-REG OUTCOME

June 2017

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 CVD, 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 CVD (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 randomization with a computer-generated random-sequence and interactive voice-response and web-response system, stratified by HbA1c, 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 baseline albuminuria (UACR <30, 30-300, >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 normo-albuminuria, 2013 (29%; 675 assigned to placebo and 1338 assigned to empagliflozin) had micro-albuminuria, and 769 (11%; 260 assigned to placebo and 509 assigned to empagliflozin) had macro-albuminuria.

Median treatment duration was 2·6 years and median observation time was 3·1 years. After short-term treatment at week 12, the placebo-adjusted geometric mean ratio of UACR change from baseline with empagliflozin was −7% (p=0·013) in patients with normo-albuminuria, −25% (p<0·0001) in patients with micro-albuminuria, and −32% (p<0·0001) in patients with macro-albuminuria.

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 micro-albuminuria (placebo-corrected adjusted geometric mean ratio of relative change from baseline with empagliflozin: −22%, p=0·0003) or macro-albuminuria (−29%, p=0·0048), but not for patients with baseline normo-albuminuria (1%, p=0·8911).

Patients treated with empagliflozin were more likely to experience a sustained improvement from microalbuminuria to normoalbuminuria (hazard ratio [HR] 1·43, p<0·0001) or from macroalbuminuria to microalbuminuria or normoalbuminuria (HR 1·82, p<0·0001), and less likely to experience a sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria (HR 0·84, 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.