Safety of Liraglutide in Type 2 Diabetes and Chronic Kidney Disease

Abstract

Background and objectives: The glucagon-like peptide-1 receptor agonist liraglutide demonstrated cardiovascular and kidney benefits in the LEADER trial, particularly in participants with CKD.

Design, setting, participants, & measurements: This post hoc analysis evaluated the safety of liraglutide treatment in patients with CKD in LEADER. Overall, 9340 patients were randomized to liraglutide or placebo, both in addition to standard of care. Of those, 2158 patients had CKD versus 7182 without CKD (defined as eGFR <60 versus ≥60 ml/min per 1.73 m², respectively); 966 patients had macroalbuminuria and 2456 had microalbuminuria (urine albumin-creatinine ratio >300 mg/g and ≥30 to ≤300 mg/g, respectively). At baseline, the mean eGFR in patients with CKD was 46±11 ml/min per 1.73 m² versus 91±22 ml/min per 1.73 m² in those without CKD. Time to first event within event groups was analyzed using Cox regression with treatment group, baseline eGFR group, or baseline albuminuria group as fixed factors.

Results: Overall, serious adverse events were more frequently recorded in patients with CKD compared with those without CKD (59% versus 50%; interaction P=0.11); however, they occurred to the same extent in those on liraglutide versus placebo. Similarly, no interaction of adverse events with randomized therapy was observed in patients with micro- or macro- versus normoalbuminuria (interaction P=0.11). Risk of severe hypoglycemia was significantly reduced with liraglutide versus placebo in patients with CKD or with micro- or macroalbuminuria (hazard ratio, 0.63 [95% CI, 0.43 to 0.91] and 0.57 [95% CI, 0.40 to 0.82], respectively).

Conclusions: In LEADER, the use of liraglutide in those with CKD was safe, with no difference between patients with and without CKD.

Clinical trial registry name and registration number: ClinicalTrials.gov; NCT01179048 (https://clinicaltrials.gov/ct2/show/NCT01179048).

Keywords: GFR; albumins; chronic kidney disease; chronic renal insufficiency; confidence intervals; creatinine; glucagon-like peptide-1 receptor; humans; hypoglycemia; kidney; liraglutide; microalbuminuria; standard of care; type 2 diabetes mellitus.

Graphical abstract

Figure 1.

Time to first serious adverse event in those with and without CKD, and with and without albuminuria at baseline. HR, hazard ratio; Lira, liraglutide; SAE, serious adverse event; UACR, urinary albumin-creatinine ratio.

Figure 2.

Treatment differences (liraglutide versus placebo) for selected adverse events by CKD class and albuminuria status at baseline. (A) Selected adverse events by CKD class at baseline. (B) Selected adverse events by albuminuria status at baseline. *All patients with eGFR at baseline; ^†all patients with albuminuria at baseline. Patients with CKD were defined as those with baseline eGFR <60 ml/min per 1.73 m²; patients without CKD were defined as those with baseline eGFR ≥60 ml/min per 1.73 m²; patients with albuminuria were defined as those with UACR ≥30 mg/g; patients without albuminuria were defined as those with UACR <30 mg/g; Diabetic foot ulcer (DFU) events included new foot ulcer events and worsening of existing foot ulcer.

Figure 3.

Time to first AKI in those with and without CKD, and with and without albuminuria at baseline.