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Empagliflozin reduces albuminuria in type 2 diabetes, CVD
In patients with type 2 diabetes and established cardiovascular disease, treatment with the SGLT2 inhibitor empagliflozin reduced urinary albumin to creatinine ratio compared with those assigned placebo, regardless of patients’ baseline albuminuria status or use of renin-angiotensin system inhibition, according to an exploratory analysis of the EMPA-REG Outcome trial.
“Beyond its effect on glycemic control, SGLT2 inhibition has important effects that might be related to changes in proximal tubular sodium reabsorption,” David Cherney, MD, PhD, FRCPC, from the division of nephrology, department of medicine, University Health Network at the University of Toronto, and colleagues wrote. “These effects include reductions in blood pressure and in interglomerular hypertension that probably mediate the characteristic early, small decrease in [estimated glomerular filtration rate] and the rapid and sustained reduction in albuminuria associated with SGLT2 inhibition.”
In a post hoc, exploratory analysis, Cherney and colleagues analyzed data from 7,028 patients with type 2 diabetes and established CVD participating in the EMPA-REG Outcome trial, a randomized, double blind, placebo-controlled trial conducted across 590 sites in 42 countries. Included patients had HbA1c between 7% and 10% and eGFR of at least 30 mL/min/1.73 m² and were either treatment-naive or on stable glucose-lowering therapy for at least 12 weeks before randomization. Between September 2010 and April 2013, researchers assigned patients to either 10 mg or 25 mg empagliflozin (Jardiance, Boehringer Ingelheim) or placebo once daily until at least 691 patients experienced a prespecified CV outcome, defined as a composite of death from CV causes, nonfatal MI or nonfatal stroke. Researchers measured serum creatinine and urinary albumin to creatinine ratio (UACR) at baseline and weeks 4, 12, 28 and 52, and then every 14 weeks until end-of-study visits.
For this analysis, prespecified exploratory outcomes included UACR over 192 weeks, stratified by baseline UACR status, time to new onset of normoalbuminuria in patients with baseline microalbuminuria or macroalbuminuria and time to new onset of microalbuminuria or macroalbuminuria in patients with normoalbuminuria at baseline.
Researchers had baseline UACR data for 6,953 patients; 4,171 had normoalbuminuria at baseline (2,789 assigned empagliflozin); 2,013 had microalbuminuria at baseline (1,338 assigned empagliflozin) and 769 had macroalbuminuria at baseline (509 assigned empagliflozin). Median treatment duration was 2.6 years.
In patients with baseline microalbuminuria or macroalbuminuria, researchers observed a rapid reduction in UACR in those assigned empagliflozin vs. placebo at week 12 and week 164. In patients without microalbuminuria or macroalbuminuria at baseline, UACR increased in those assigned empagliflozin, but remained lower in those patients vs. those assigned placebo, researchers noted.
Patients with baseline microalbuminuria or macroalbuminuria assigned empagliflozin also experienced new onset of sustained normoalbuminuria in greater numbers vs. those assigned placebo, independent of the use of angiotensin-converting enzyme or angiotensin receptor blocker inhibitors at baseline, according to researchers.
In further analysis, researchers found that the risk for new-onset microalbuminuria or macroalbuminuria in patients with normoalbuminuria at baseline was attenuated with empagliflozin therapy vs. placebo (HR = 0.84; 95% CI, 0.74-0.95).
Across all baseline UACR subgroups, treatment with empagliflozin also resulted in an increase and stabilization of eGFR in the first 12 months in patients with normoalbuminuria, with similar patterns observed in patients with microalbuminuria or macroalbuminuria.
“By contrast, eGFR in the placebo group gradually decreased over time,” the researchers wrote.
“The effect of empagliflozin on UACR appeared to be, in large part, beyond the effects on glycemic control,” they wrote. “These results suggest a persistent renal hemodynamic effect of empagliflozin, which may confer short-term and long-term renal effects on UACR when used in addition to current standard of care.” – by Regina Schaffer
Disclosures: Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance funded the EMPA-REG Outcome Trial. Cherney reports receiving consultant fees, honoraria or research funding from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck and Sanofi. Please see the full study for the other authors’ relevant financial disclosures.