Lixisenatide may delay kidney disease progression in T2D patients with macroalbuminuria
The GLP-1* receptor agonist lixisenatide may slow the progression of micro- and macroalbuminuria in patients with type 2 diabetes (T2D) and acute coronary syndrome, based on an exploratory analysis of the ELIXA** trial presented at EASD 2018.
“[A]fter 108 weeks, lixisenatide given in addition to standard of care, reduced progression of albuminuria beyond glucose lowering in patients with T2D who had a recent acute coronary event, with significant effects in those with macroalbuminuria at baseline,” said the researchers.
The multinational (828 sites in 49 countries), double-blind ELIXA trial involved 6,068 individuals with T2D and recent history of acute coronary syndrome (within 180 days pre-screening) who were randomized 1:1 to receive either subcutaneous lixisenatide (10–20 μg/day) or placebo, plus usual care.
Baseline UACR*** data from 5,978 patients followed for a median 108 weeks showed that 74 percent of the patients had normoalbuminuria (UACR <30 mg/g), while 19 and 7 percent had microalbuminuria (≥30 to <300 mg/g) and macroalbuminuria (≥300 mg/g), respectively. Seventy-seven percent of patients had baseline eGFR# levels <90 mL/min/1.73 m2, and 23 percent had eGFR <60 mL/min/1.73 m2.
While there were no significant changes in UACR with lixisenatide in patients with normoalbuminuria (placebo-adjusted least-squares mean percentage change from baseline, -1.69 percent; p=0.7398), patients with microalbuminuria and macroalbuminuria treated with lixisenatide experienced significant reductions in UACR (placebo-adjusted least-squares mean percentage change from baseline, -21.10 percent; p=0.0502 and -39.18 percent; p=0.0070, respectively). [EASD 2018, abstract 77; Lancet Diabetes Endocrinol 2018;doi:10.1016/S2213-8587(18)30268-7]
An analysis of patients who completed 108 weeks of treatment showed that treatment with lixisenatide resulted in a 46.39 percent greater reduction in UACR among patients with macroalbuminuria at baseline compared with treatment with placebo (p=0.0146). Patients at high risk for chronic kidney disease (UACR ≥300 mg/g or UACR >30 mg/g plus eGFR <60 or <45 mL/min/1.73 m2) also experienced a greater benefit with lixisenatide over placebo (-44.28 percent; p=0.0005).
After adjusting for baseline HbA1c, patients on lixisenatide had a reduced risk of developing new-onset macroalbuminuria compared with those on placebo (hazard ratio [HR], 0.808; p=0.0404).
There was no significant difference between treatment groups with regard to change in eGFR from baseline at 108 weeks regardless of baseline UACR. The largest decline in eGFR during this period occurred in patients with macroalbuminuria, with no difference between treatments. Doubling of serum creatinine levels was also comparable between treatment groups (1 percent in each group, HR, 1.163; p=0.5127), as was progression from normoalbuminuria to macroalbuminuria or regression from macroalbuminuria to microalbuminuria or normoalbuminuria.
The incidence of serious renal adverse events was low and comparable between patients on lixisenatide and placebo (1.6 percent in each group), as was incidence of end-stage kidney disease (ESKD, eGFR ≤15 mL/min/1.73 m2; <1 percent in each group).
However, as the number of patients assessed for ESKD and serum creatinine doubling was low, the researchers recommended further study into identifying the effect of lixisenatide on these outcomes in patients with T2D and macroalbuminuria. They also highlighted the comparable baseline HbA1c levels between patients on lixisenatide and placebo which may have had an impact on the lack of difference on the outcomes between treatment arms.
The mechanism behind the impact of lixisenatide on albuminuria has not been identified, said the researchers, with reduction in glomerular hyperfiltration and intraglomerular pressure, stimulation of anti-inflammatory pathways, and direct effects on the renal vascular endothelium proposed as potential mechanisms.
They recommended research into the impact of combination therapies, particularly with GLP-1 agonists and SGLT-2## inhibitors, seeing as how both classes appear to have renoprotective effects and together, may “induce additive or even synergistic benefits on renal outcomes”.