Kidney Week

Abstract: SA-OR082

Renoprotection with Semaglutide and Liraglutide: Direct or Indirect Effects?

Session Information

• Moving the Needle for Treatment of Diabetic Kidney Disease
  November 09, 2019 | Location: Ballroom C, Walter E. Washington Convention Center
  Abstract Time: 05:18 PM - 05:30 PM

Category: Diabetic Kidney Disease

• 602 Diabetic Kidney Disease: Clinical

Authors

• Mann, Johannes F., Friedrich Alexander University of Erlangen, Erlangen, Germany

Johannes F. Mann, MD

• Buse, John, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States

John Buse,

• Idorn, Thomas, Novo Nordisk A/S, Søborg, Denmark

Thomas Idorn,

• Leiter, Lawrence A., St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

Lawrence A. Leiter,

• Pratley, Richard E., AdventHealth Translational Research Institute for Metabolism and Diabetes, Orlando, Florida, United States

Richard E. Pratley,

• Rasmussen, Soren, Novo Nordisk A/S, Søborg, Denmark

Soren Rasmussen,

• Vilsbøll, Tina, Steno Diabetes Center Copenhagen, Gentofte; University of Copenhagen, Hellerup, Hellerup, Denmark

Tina Vilsbøll,

• Wolthers, Benjamin, Novo Nordisk A/S, Søborg, Denmark

Benjamin Wolthers,

• Perkovic, Vlado, The George Institute, UNSW, Sydney, New South Wales, Australia

Vlado Perkovic,

Background

The SUSTAIN 6 and LEADER cardiovascular (CV) outcome trials indicated that the glucagon-like peptide-1 analogues semaglutide and liraglutide may provide renal as well as CV benefits. This post-hoc analysis investigated the degree to which the observed renoprotective effects could be mediated by glycated hemoglobin (A1C), systolic blood pressure (SBP) and body weight (BW).

Methods

SUSTAIN 6 (N=3297, NCT01720446) and LEADER (N=9340, NCT01179048) assessed CV, renal and safety outcomes for semaglutide and liraglutide versus placebo in patients with type 2 diabetes and high CV risk. A prespecified secondary outcome in these trials was a renal composite of new onset persistent macroalbuminuria, persistent doubling of serum creatinine, need for continuous renal-replacement therapy or death due to renal disease. We performed counterfactual mediation analyses of A1C, SBP and BW using absolute values at each trial visit. The direct contribution of semaglutide/liraglutide to time to first renal event was estimated assuming that the mediator values changed to those observed in the placebo group (from baseline to 2 and 3 years in SUSTAIN 6 and LEADER, respectively). In the adjusted model for A1C, both SBP alone and in combination with BW were included as confounders. Due to the limited number of events in SUSTAIN 6, 95% confidence intervals (CIs) could not be calculated.

Results

In SUSTAIN 6 and LEADER, the rate of a renal event was reduced by 36% (95% CI 12%;54%; P=0.005) and 22% (95% CI 8%;33%; P=0.003) in the semaglutide and liraglutide groups, respectively, versus placebo. A1C was estimated to mediate 26% and 25% (95% CI -7.1;67.3) of the benefits of semaglutide and liraglutide, respectively, whereas the contributions of SBP (22% and 9% [95% CI 2.8;22.7]) and BW (-8% and 9% [95% CI -7.9;35.5]) were smaller. In adjusted analyses, the contribution of A1C increased to 36% (SBP as confounder) and 30% (95% CI -4.5;81.1; SBP and BW as confounders) in the semaglutide and liraglutide groups, respectively.

Conclusion

The renal benefits of semaglutide and liraglutide appear mediated to a modest extent by changes in A1C, SBP and BW, and are therefore likely to be also driven by other, potentially direct, mechanisms.

Funding

• Commercial Support –