Comparison of Specific Glucagon-Like Peptide-1 Receptor Agonists on Kidney Outcomes Among Patients With Type 2 Diabetes.
Semaglutide may be associated with better kidney outcomes compared to other GLP-1 receptor agonists, but no differences were found for the primary kidney outcome.
Where it sits
this study against the rest of the exenatide corpusSummary and findings
This study examined the effects of GLP-1 receptor agonists on kidney outcomes in adults with type 2 diabetes and moderate cardiovascular risk. The primary outcome showed no differences among dulaglutide, exenatide, liraglutide, and semaglutide. Semaglutide was associated with an 8% reduced risk for the secondary kidney composite outcome compared to dulaglutide and a 12% reduced risk compared to exenatide.
Abstract
<h4>Rationale & objective</h4>Glucagon-like peptide 1 (GLP-1) receptor agonist treatment is associated with a lower risk for incident chronic kidney disease (CKD) and death relative to treatment with a dipeptidyl peptidase 4 inhibitor or sulfonylurea. This study examined within class effects of GLP-1 receptor agonists on kidney outcomes in type 2 diabetes mellitus (T2DM) and moderate cardiovascular risk.<h4>Study design</h4>Retrospective observational study using the target trial emulation framework.<h4>Setting & participants</h4>This study used claims data from OptumLabs Data Warehouse and 100% sample of Medicare fee-for-service claims. Participants were adults ≥21 years of age, at moderate cardiovascular risk, who filled a new prescription for a GLP-1 receptor agonist between January 1, 2019 and December 31, 2021.<h4>Exposure</h4>GLP-1 receptor agonists dulaglutide, exenatide, liraglutide, or semaglutide.<h4>Outcome</h4>A primary kidney composite outcome inclusive of incident diagnosis codes for CKD stages 3-4 and kidney failure (inclusive of CKD stage 5 and kidney replacement therapy). A secondary kidney composite outcome included the elements of the primary composite outcome plus death from any cause. Components of the kidney composite outcomes were also evaluated independently.<h4>Analytical approach</h4>Random treatment assignment was emulated using inverse probability of treatment weighting (IPTW) with propensity scores estimated using the SuperLearner ensemble method. Primary analyses were time-to-event models under the intention-to-treat framework using cause-specific IPTW Cox proportional hazards models.<h4>Results</h4>There was no difference among dulaglutide, exenatide, liraglutide, and semaglutide with respect to the primary outcome. When compared to dulaglutide and exenatide, semaglutide was associated with a reduced risk for the secondary kidney composite outcome by 8% (HR, 0.92 [95% CI, 0.87-0.97]) and 12% (HR, 0.88 [95% CI, 0.79-0.99]), respectively. Compared to dulaglutide, semaglutide was also associated with reduced risk of death (HR, 0.81 [95% CI, 0.70-0.93]).<h4>Limitations</h4>Potential for residual confounding, lack of hemoglobin A<sub>1c</sub> and weight data, and uncertainty about the indication for GLP-1 receptor agonist prescriptions.<h4>Conclusions</h4>No differences were observed among different GLP-1 receptor agonists for the primary outcome, but semaglutide initiation was associated with a lower risk of the secondary kidney composite outcome and of death.<h4>Plain-language summary</h4>Chronic kidney disease (CKD) is a common complication of diabetes that increases the risk for poor health outcomes. Glucagon-like peptide-1 (GLP-1) receptor agonists were found to improve kidney outcomes in people with type 2 diabetes mellitus (T2DM) and moderate cardiovascular risk when compared with dipeptidyl peptidase-4 inhibitors and sulfonylureas. Although there has been no head-to-head comparison of individual GLP-1 receptor agonists, randomized controlled trials have suggested that there may be variation among members of this drug class on kidney disease outcomes. In this study, we tested whether there were differences in kidney outcomes when comparing individual GLP-1 receptor agonist medications. We found that semaglutide compared favorably to other drugs in the class and may represent the preferred GLP-1 receptor agonist for delaying or preventing CKD in this population.
Background
The study addresses the comparative effects of GLP-1 receptor agonists on kidney outcomes in patients with type 2 diabetes mellitus (T2DM) and moderate cardiovascular risk. Prior studies suggested that GLP-1 receptor agonists may lower the risk of chronic kidney disease (CKD) compared to other diabetes medications. This research is significant as it seeks to clarify whether specific GLP-1 receptor agonists differ in their impact on kidney health.
Methods
This was a retrospective observational study utilizing claims data from OptumLabs Data Warehouse and Medicare fee-for-service claims. Participants included adults aged 21 and older with moderate cardiovascular risk who filled a new prescription for a GLP-1 receptor agonist between January 1, 2019, and December 31, 2021. The primary outcome was a composite of incident CKD stages 3-4 and kidney failure, while the secondary outcome included death from any cause. The study employed inverse probability of treatment weighting (IPTW) and cause-specific Cox proportional hazards models for analysis.
Results
The primary outcome showed no difference among the GLP-1 receptor agonists. Semaglutide was associated with an 8% reduced risk for the secondary kidney composite outcome compared to dulaglutide (HR, 0.92 [95% CI, 0.87-0.97]) and a 12% reduced risk compared to exenatide (HR, 0.88 [95% CI, 0.79-0.99]). Additionally, semaglutide was linked to a lower risk of death compared to dulaglutide (HR, 0.81 [95% CI, 0.70-0.93]).
Interpretation
The findings indicate that while semaglutide may offer some advantages over other GLP-1 receptor agonists regarding secondary kidney outcomes and mortality, the primary outcome did not show significant differences among the drugs. The effect sizes for the secondary outcomes, while statistically significant, may not be clinically meaningful given the potential for confounding factors. Limitations such as the observational design and lack of certain clinical data suggest caution in interpreting these results for clinical practice.
Key findings
- No difference among dulaglutide, exenatide, liraglutide, and semaglutide with respect to the primary outcome.
- Semaglutide associated with reduced risk for secondary kidney composite outcome by 8% (HR, 0.92 [95% CI, 0.87-0.97]) compared to dulaglutide.
- Semaglutide associated with reduced risk for secondary kidney composite outcome by 12% (HR, 0.88 [95% CI, 0.79-0.99]) compared to exenatide.
- Semaglutide associated with reduced risk of death compared to dulaglutide (HR, 0.81 [95% CI, 0.70-0.93]).
Limitations
- Potential for residual confounding.
- Lack of hemoglobin A1c and weight data.
- Uncertainty about the indication for GLP-1 receptor agonist prescriptions.
- Observational design limits causal inference.