Lower MACE and renal outcomes with reduction in albuminuria in T2DM
Changes in Albuminuria Predict Cardiovascular and Renal Outcomes in Type 2 Diabetes: A Post Hoc Analysis of the LEADER Trial
Introduction and methods
In the LEADER and SUSTAIN-6 trials, use of the GLP-1RAs liraglutide and semaglutide resulted in both CV and renal benefits in patients with T2DM and high CV risk [1-3]. Albuminuria was significantly reduced and development of macroalbuminuria was prevented in those who received GLP-1RA treatment. More recently, the REWIND trial showed that use of the GLP-1RA dulaglutide resulted in 18% reduction of urinary albumin-to-creatinine ratio (UACR) and 15% reduction in the composite renal outcome compared to placebo in patients with T2DM with and without established CVD .
This study examined whether reduction in UACR is associated with a reduction of CV and renal risks in a cohort of T2DM patients using data from the LEADER trial. Participants were randomized to liraglutide or placebo on a background of control of established CV risk factors and continuous use of RAAS blockade in the majority of participants (>80%).
LEADER was a randomized, double-blind, placebo-controlled trial enrolling 9340 patients with T2DM. The treatment period was 3.5-5 years. Primary outcome was time to first occurrence of a composite of major adverse events (MACE). In this post hoc analysis, risk of MACE and a three-component nephropathy composite (doubling of serum creatinine and eGFR <45 ml/min/1.73 m2, renal replacement therapy or renal death) was evaluated in 8270 participants with a UACR measurement at baseline and at 1 year after randomization. Participants were stratified according to change in UACR from baseline to 1 year (>30% reduction [n=2928, 35%], 30-0% reduction (n=1218, 15%] and any increase from baseline [reference group, n=4124, 50%]). In addition, analyses were done in subgroups with baseline normo-, micro-, and macroalbuminuria.
- Patients with a decrease in UACR up to 30% had a similar risk of MACE compared to those with any increase in UACR (HR 0.99, 95%CI: 0.82-1.19). For the composite nephropathy outcome HR was 0.97 (95%CI: 0.66-1.43).
- For patients with a reduction in UACR of >30%, HR for MACE was 0.82 (95%CI: 0.71-0.94, P=0.006) and 0.67 (95%CI: 0.49-0.93, P=0.02) for the composite nephropathy outcome.
- Associations between early change and subsequent MACE and renal outcomes were consistent in the liraglutide and placebo groups (Pinteraction=0.516 and 0.839 for MACE and renal outcomes, respectively).
- In patients with normoalbuminuria at baseline, after 1 year, there was a reduction of 14% in UACR (95%CI: 9-18). In patients with microalbuminuria, an increase in UACR of 12% (95%CI: 4-20) was observed and in those with macroalbuminuria UACR was increased (121%, 95%CI:92-153).
- UACR change of >-30% was associated with reduction in MACE in patients with micro- or macroalbuminuria.
- Change in UACR of >-30% was associated with renal benefits in patients with micro- or macroalbuminuria.
This post hoc analysis of the LEADER trial confirmed that reductions in UACR were associated with reduced risk for MACE and renal outcomes in patients with T2DM and high CV risk and moderate renal risk. This reduced risk was independent of treatment and baseline UACR. The authors state: “These data strongly support the concept of a randomized controlled trial testing lower and higher target levels of UACR on major CV and renal outcomes.”