Association between GLP-1 receptor agonist therapy and decreased CV risk in T2DM patients with CKD
Effects of Liraglutide versus Placebo on Cardiovascular Events in Patients with Type 2 Diabetes and Chronic Kidney Disease: Results from the LEADER TrialLiterature - Mann JFE, Fonseca V, Mosenzon O et al. - Circulation 2018; published online ahead of print
Introduction and methods
Patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD) have an increased cardiovascular (CV) risk. Furthermore, low estimated glomerular filtration rate (eGFR) and albuminuria are independent predictors of CV outcomes [1,2]. However, it is unclear whether therapeutic interventions to decrease CV risk improve outcomes in these patients. In the Liraglutide Effect and Action in Diabetes: Evaluation of CV outcome Results (LEADER) trial [3,4], liraglutide therapy was associated with a reduced risk of CV outcomes, all-cause death and renal outcomes compared with placebo, in T2DM patients with established CV disease on standard of care.
LEADER was a multicenter, double-blind, placebo-controlled trial, which randomized T2DM patients at high CV risk to receive 1:1 liraglutide (1.8 mg daily or maximum tolerated dose) or placebo, on top of standard of care. The study was designed to recruit a subgroup of at least 660 patients with an eGFR<60 mL/min/1.73 m2, approximately 220 patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), and at least 440 patients with moderate renal impairment (CKD stage 3; eGFR 30–60 mL/min/1.73 m2).
This posthoc analysis assessed the effect of liraglutide versus placebo on CV and safety outcomes in subgroups of patients with eGFR <60 mL/min/1.73 m2 versus eGFR ≥60 mL/min/1.73 m2, and those with micro/macroalbuminuria (<30 mg/g versus ≥30 mg/g creatinine), versus those without albuminuria at randomization. The primary outcome was a composite of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke.
- Overall, 2,158 patients had baseline eGFR <60, and 7,182 patients had baseline eGFR >60 mL/min/1.73 m2.
- The primary composite CV outcome occurred in a lower proportion of patients taking liraglutide compared with placebo (15.4% vs 21.4% in those with eGFR <60 mL/min/1.73 m2, and 12.3% vs 13.0% in those with eGFR ≥60 mL/min/1.73 m2).
- For the primary composite outcome, the risk reduction with liraglutide was greater in the subgroup of patients with eGFR <60 mL/min/1.73 m2 (HR: 0.69; 95%CI: 0.57-0.85) than in those with eGFR ≥60 mL/min/1.73 m2 (HR: 0.94; 95%CI: 0.83-1.07; interaction P=0.01).
- When eGFR was grouped in intervals of 15 ml/min/1.73 m2, there was no consistent difference in the treatment effect of liraglutide on the primary outcome, across eGFR subgroups (interaction P=0.13). Nor was an interaction seen between eGFR at baseline and the treatment effect, with eGFR as a continuous variable.
- The HRs for the primary and key secondary outcomes for the micro/macroalbuminuria and normoalbuminuria subgroups by baseline eGFR and time to primary composite CV outcome in patients according to baseline eGFR were 0.83 (95%CI: 0.71-0.97) and 0.92 (95%CI: 0.79-1.07; P-interaction=0.36), respectively.
In patients with T2DM and CKD at high CV risk, liraglutide treatment was associated with fewer CV outcomes, similarly to patients without CKD.