Using Semaglutide and Liraglutide To Protect the Kidney?

Semaglutide and liraglutide may offer a two-for-one deal: both cardiovascular benefits and kidney protection. 

Patients with type 2 diabetes are vulnerable to developing chronic kidney disease. To some degree, diabetes can impair blood vessels, which eventually can damage the kidneys. Even though kidney protection mechanisms are indistinct, two trials suggest that both semaglutide and liraglutide could provide renoprotection. This study used both the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER®) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN™ 6) to conclude results. In both the LEADER 0.78 (0.67-0.92) and SUSTAIN 6 0.64 (0.46- 0.88) trial, the secondary kidney outcomes were microalbuminuria, doubling serum creatine, or end-stage kidney disease or kidney death. It is possible that both direct effects such as anti-inflammatory properties, inhibition of renin-angiotensin-aldosterone system, and increased natriuresis and indirect effects like glycemic regulation, lowered blood pressure, and weight loss may arbitrate kidney results. Previous studies like Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) did have kidney benefits, but the trial did not adjust for systolic blood pressure.  

This study aims to investigate whether or not both semaglutide and liraglutide provide kidney protection based on the LEADER and SUSTAIN 6 trials. The goal is to determine if the kidney protective effects are stimulated by a direct or indirect impact of GLP-1RA. A post hoc analysis was done to explore changes in the patient’s hemoglobin A1c levels, systolic blood pressure, body weight as the possible facilitators for the kidney protective effects of semaglutide and liraglutide. The two treatment arms in this study were semaglutide and liraglutide vs. placebo. Within this particular study, the primary outcome was the first occurrence of 3-point major adverse cardiovascular events composed of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Crucial inclusion measures had type 2 diabetes, and hemoglobin A1c greater than 7%, antidiabetic drug naïve, greater than or equal to 50 years old with established cardiovascular disease, or estimated glomerular filtration rate less than 60 mL/min/1.73m2, or greater than or equal to 60 years old and one or more cardiovascular risk factors. A total of 3,297 patients’ data was used from the SUSTAIN 6 trial, and 9,340 patients’ data was used from the LEADER trial. Data from baseline results to 2 years was used from the SUSTAIN 6 trial, and baseline results to 3 years were used from the LEADER trial. A mediation model was used to incorporate a “what-if” method.  

The results implicated that the rate of a renal event was decreased by 36% (95% CI: 12%,54%; p=0.005) in the semaglutide group and by 22% (95% CI: 8%, 33%; P=0.003) in the liraglutide group. The hemoglobin A1c level was predicted to arbitrate 26% in the semaglutide group and 25% (CI: 7.1,67.3) in the liraglutide group. For systolic blood pressure the results were 22% and 9% [95% CI: 2.8,22.7]) and the body weight (-8% and 9% [95% CI: -7.9,35.5]) for semaglutide and liraglutide respectively. Once the results were adjusted, the hemoglobin A1c levels raised to 36% when systolic blood pressure was used as a cofounder in the semaglutide group. The hemoglobin A1c levels went to 30% when both systolic blood pressure and body weight were used as cofounders in the liraglutide group.  

Based on the mediation model used, there could be mediators that were left unmeasured. To better explore the relationship, further studies should explore direct mediators of both semaglutide and liraglutide. There was external steadiness between the LEADER and SUSTAIN 6 trials for hemoglobin A1c levels. It can be concluded that a patient’s hemoglobin A1c, systolic blood pressure, and body weight have a moderate effect on the kidney. 

Practice Pearls: 

• There was consistency in the indirect mediators between the two trials, LEADER and SUSTAIN 6.  
• Further studies have already begun to analyze chronic kidney disease development delay from semaglutide, with kidney functions as the primary measures.  
• Hemoglobin A1c, systolic blood pressure, and body weight effects propose that the reno-protective effects from semaglutide and liraglutide may also be caused by more direct mechanisms that were not measured.  

Mann J, Wolthers B, Vilsboll T, et al. Renoprotection with semaglutide and liraglutide: Direct or indirect effects? EASD Virtual Congress. Published 2020.  

Alexandria Bartley, PharmD. Candidate, Florida Agricultural & Mechanical University, College of Pharmacy and Pharmaceutical Sciences