Changes in Albuminuria Predict Cardiovascular and Renal Outcomes in Type 2 Diabetes: A Post Hoc Analysis of the LEADER Trial

Literature - Persson F, Bain SC, Mosenzon O et al., - Diabetes Care. 2021, doi: 10.2337/dc20-1622

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 [4].

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.

Main results

• 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.

Conclusion

References

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