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ELIXA: Lixisenatide slows, reduces macroalbuminuria risk in type 2 diabetes with CVD

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Adults with type 2 diabetes, established cardiovascular disease and macroalbuminuria assigned to the GLP-1 receptor agonist lixisenatide experienced a reduction in urinary albumin to creatinine ratio vs. similar patients assigned to placebo, according to an exploratory analysis of the ELIXA cardiovascular outcomes trial presented at the European Association for the Study of Diabetes annual meeting.

“This is the first analysis of a clinical trial to assess the effect of a short-acting GLP-1 receptor agonist on renal outcomes in patients with type 2 diabetes at high risk for cardiovascular disease, and suggests that short-acting GLP-1 receptor agonists might have similar renal benefit as long-acting GLP-1 receptor agonists, which have been reported in previous cardiovascular outcome trials in this target population,” Marcel H.A. Muskiet, MD, of the Diabetes Center at VU University Medical Center in Amsterdam, and colleagues wrote. “By contrast with the LEADER and SUSTAIN-6 trials, in the ELIXA trial, glycemic differences were small, suggesting that the observed renal benefit in the macroalbuminuria subgroup is not fully explained by improvements in glycemic control or other hemodynamic and metabolic risk factors.”

In the ELIXA outcomes trial, presented at the American Diabetes Association Scientific Sessions in 2015 and reported by Endocrine Today, researchers found that lixisenatide (Adlyxin, Sanofi) lowered HbA1c without any CV risk or benefit in adults with type 2 diabetes at high risk for acute CV events, with no increased risk for hypoglycemia or pancreatic injury after 3 years vs. those assigned to placebo.

In a prespecified exploratory analysis of the intention to treat population in ELIXA (n = 5,978), researchers assessed progression of urinary albumin to creatinine ratio (UACR) and estimated glomerular filtration rate in patients assigned lixisenatide (n = 3,031) or placebo (n = 3,034) stratified by baseline albuminuria status. Time to new onset macroalbuminuria and doubling of serum creatinine were also determined. Mean follow-up time was 25 months.

At baseline, 74% of patients had normoalbuminuria, 19% had microalbuminuria and 7% had macroalbuminuria.

After 108 weeks, researchers observed a reduction in UACR for patients with microalbuminuria and macroalbuminuria in the lixisenatide group, whereas UACR increased or remained stable in the placebo group. In the lixisenatide group, researchers found that the least squares mean percentage change for UACR approached statistical significance for patients with microalbuminuria (–21.1%; 95% CI, –42.25 to 0.04) and rose to significance for patients with macroalbuminuria (–39.2%; 95% CI, –68.53 to –9.84).

Additionally, lixisenatide was associated with a borderline statistically significant 16% reduction in risk of incidence for macroalbuminuria, whereas eGFR declined throughout the study across all albuminuria categories, with the largest decrease observed among patients with macroalbuminuria.

There were no between-group differences in eGFR decline between treatment arms in the overall population or among UACR subgroups, according to the researchers.

In commentary published in The Lancet Diabetes & Endocrinology accompanying the study, Muh Geot Wong, MBBS, FRACP, PhD, senior research fellow at The George Institute for Global Health in Sydney, and colleagues wrote that the findings are consistent with data for other GLP-1 receptor agonists, SGLT2 inhibitors and DPP-IV inhibitors that suggest the three drug classes all seem to reduce albuminuria levels in people with type 2 diabetes, with potentially greater effects in those with macroalbuminuria.

“Trials specifically assessing the effects of these drugs on kidney failure in people with type 2 diabetes and macroalbuminuria should therefore be a priority for the future, since the albuminuria-lowering effects seem to be greatest in people with raised levels at baseline,” Wong and colleagues wrote. “Additionally, studies of companion therapies, such as SGLT2 inhibitors with GLP-1 receptor agonists, will be key.” – by Regina Schaffer

References:

Muskiet MHA. Abstract 77. Presented at: European Association for the Study of Diabetes Annual Meeting; Oct. 1-5, 2018; Berlin.

Muskiet MHA, et al. Lancet Diabetes Endocrinol. 2018;doi:10.1016/s2213-8587(18)30268-7.

Wong MG, et al. Lancet Diabetes Endocrinol. 2018;doi:10.1016/s2213-8587(18)30291-2.

Disclosures: Muskiet reports he has received consultant fees from Eli Lilly and Novo Nordisk, with all honoraria paid to the VU Medical Center. Wong reports he has received honorarium for scientific lectures from Amgen, AstraZeneca, Baxter and Retrophin. Please see the study and commentary for the other authors’ relevant financial disclosures.