Effect of the Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes: Pooled Analysis of SUSTAIN 6 and LEADER

Abstract

Background: We assessed the effect of once-weekly semaglutide and once-daily liraglutide on kidney outcomes in type 2 diabetes (T2D). Methods: Pooled (N=12,637) and by-trial data from SUSTAIN 6 (N=3297) and LEADER (N=9340) were assessed for albuminuria change, annual slope of estimated glomerular filtration rate (eGFR) change, and time to persistent eGFR reduction (30%, 40%, 50%, and 57%) from baseline. Results: The median follow-up durations were 2.1 and 3.8 years for SUSTAIN 6 and LEADER, respectively. In the pooled analysis, semaglutide/liraglutide lowered albuminuria from baseline to 2 years post-randomization by 24% versus placebo (95% confidence interval [CI] [20%,27% ], p <0.001). Significant reductions were also observed in by-trial data analyses ( p <0.001 for all), the largest being with semaglutide 1.0 mg: 33% (95% CI [24%,40% ], p <0.001) at 2 years. With semaglutide 1.0 mg and liraglutide, eGFR slope decline was significantly slowed by 0.87 and 0.26 mL/min/1.73 m 2 /year ( p <0.0001 and p <0.001), respectively, versus placebo. Effects appeared larger in those with baseline eGFR <60 versus ≥60 mL/min/1.73m 2 ( p interaction =0.06 and 0.008 for semaglutide 1.0 mg and liraglutide, respectively). Semaglutide/liraglutide significantly lowered risk of persistent 40% and 50% eGFR reductions versus placebo (hazard ratio [HR] 0.86, 95% CI [0.75,0.99], p =0.039, and HR 0.80, 95% CI [0.66,0.97], p =0.023, respectively). Similar, non-significant, directional results were observed for 30% and 57% eGFR reductions (HR 0.92, 95% CI [0.84, 1.02], p =0.10, and HR 0.89, 95% CI [0.69, 1.13], p =0.34). In those with baseline eGFR 30−<60mL/min/1.73m 2 , the likelihood of persistent reduction for all thresholds was increased, ranging from a HR 0.71 for 30% reduction (95% CI [0.59,0.85], p =0.0003, pinteraction=0.017) to 0.54 for 57% reduction (95% CI [0.36,0.81], p =0.003, pinteraction=0.035). Conclusions: In patients with T2D, semaglutide/liraglutide offered kidney-protective effects, which appeared more pronounced in those with pre-existing chronic kidney disease.

Evidence for Cardiorenal Protection with SGLT-2 Inhibitors and GLP-1 Receptor Agonists in Patients with Diabetic Kidney Disease

“…Notably, treatment-induced improvement in the eGFR slope was greater in the subgroup of patients with eGFR < 60 mL/min/1.73 m 2 than in those with preserved kidney function at baseline. Compared with placebo, therapy with semaglutide or liraglutide provoked a 14% (HR: 0.86; 95% CI: 0.75-0.99) and 20% (HR: 0.80; 95% CI: 0.66-0.97) reduction in the risk for sustained 40% and 50% declines in eGFR during follow-up, respectively [43]. Similarly, directional but not statistically significant reductions were evident for the risk of sustained 30% and 57% decline in eGFR.…”

“…Similarly, directional but not statistically significant reductions were evident for the risk of sustained 30% and 57% decline in eGFR. Once again, when the analysis was restricted to patients with eGFR of 30-60 mL/min/1.73 m 2 at baseline, the renoprotective benefit of GLP-1 receptor agonists was greater in magnitude (HR: 0.71, 0.67, 0.56, and 0.54 for sustained 30%, 40%, 50%, and 57% decline in eGFR, respectively) [43]. Taken together, this exploratory analysis of LEADER and SUSTAIN-6 trials suggests that the renoprotection afforded by GLP-1 receptor agonists is likely more pronounced in patients with T2DM and pre-existing CKD than in those with preserved kidney function.…”

“…Further insights on the kidney protective effects of GLP-1 receptor agonists were provided by a combined analysis of 12,637 patients with T2DM enrolled in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) and SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) trials [43]. From baseline to 2 years postrandomization, the placebo-subtracted reduction in albuminuria with GLP-1 receptor agonists was 24% (95% CI: 20-27%).…”

A Glimpse of Inflammation and Anti-Inflammation Therapy in Diabetic Kidney Disease

“…The half-life of natural GLP-1 is very short (1–2 min) because it is rapidly degraded by the ubiquitous proteolytic enzyme DPP-4 ( Bell et al, 1983 ; Hansen et al, 1999 ). Recently, dipeptidyl peptidase-4 inhibitor (DDP-4i) and GLP-1 receptor agonists (GLP1RA) have been widely used in anti-hyperglycemic medications by interfering with GLP-1 expression ( McGuire et al, 2019 ; Shaman et al, 2022 ). Recent studies demonstrated that DDP-4i and GLP-1RA could not only control blood sugar by regulating the secretion of insulin, but also exert anti-inflammatory and reno-protective effects in DKD ( Gangadharan et al, 2016 ; Coppolino et al, 2018 ; Shaman et al, 2022 ).…”

The Impact of Novel Anti-Diabetic Medications on CV Outcomes: A New Therapeutic Horizon for Diabetic and Non-Diabetic Cardiac Patients

“…Contrary to the above-mentioned trials, both in the LEADER trial [ 16 ] and the SUSTAIN-6 trial [ 20 ], evaluating Liraglutide and Semaglutide, respectively, there were no prespecified renal outcomes. In a recent pooled analysis of these trials, a decrease in albuminuria and eGFR decline was noted [ 35 ]. These effects were pronounced in patients with preexisting renal failure.…”