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SGLT2 Inhibitors vs GLP-1 Receptor Agonists for Kidney Outcomes in Individuals With Type 2 Diabetes
Simon K Jensen1,2,3, Uffe Heide-Jørgensen1,2, Ina T Andersen1,2
1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark.
Importance:
No randomized clinical trial has directly compared the effectiveness of sodium-glucose cotransporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment in reducing acute and chronic kidney outcomes.
Objective:
To examine the comparative effectiveness of SGLT2i and GLP-1RA treatment for acute and chronic kidney outcomes in individuals with type 2 diabetes.
Design, Setting, And Participants:
This comparative effectiveness study with a target trial emulation design used nationwide, population-based data from Denmark. Participants were individuals with metformin-treated type 2 diabetes who initiated SGLT2i or GLP-1RA treatment from January 2014 to November 2020, with follow-up through October 2024.
Exposure:
Initiation of an SGLT2i or a GLP-1RA.
Main Outcomes And Measures:
The 2 coprimary outcomes were chronic kidney disease (CKD; 40% reduction in estimated glomerular filtration rate [eGFR], severe albuminuria, or kidney failure) and acute kidney injury (AKI). Secondary outcomes included the individual components of CKD, albuminuria, and death. Intention-to-treat effects were estimated using inverse probability of treatment weights, comparing risks for CKD assessed by the Aalen-Johansen estimator, and AKI burden by mean cumulative counts (MCCs; mean number of events per individual as multiple AKI events were possible). Subgroup analyses included stratification by preexisting cardiovascular or kidney disease.
Results:
The study included 36 279 individuals who initiated an SGLT2i and 18 782 who initiated a GLP-1RA (median [IQR] age, 63 [55-71] years vs 61 [52-70] years), with comparable diabetes duration, eGFR, and urine albumin-creatinine ratios. The weighted 5-year risk of CKD was 6.7% (95% CI, 6.4%-7.0%) for SGLT2i initiators and 8.2% (95% CI, 7.8%-8.6%) for GLP-1RA initiators (risk ratio: 0.81 [95% CI, 0.76-0.87]; risk difference: -1.5% [95% CI, -2.0% to -1.0%]). The 5-year MCC of AKI per 100 individuals was 25.2 (95% CI, 24.4-26.1) for SGLT2i initiators and 28.7 (95% CI, 27.4-30.0) for GLP-1RA initiators (MCC ratio: 0.88 [95% CI, 0.83-0.93]; MCC difference: -3.5 [95% CI, -5.0 to -2.0]). In contrast, the secondary outcomes of albuminuria and mortality were slightly reduced in GLP-1RA initiators. Results were consistent across subgroups, with the most pronounced CKD and AKI reductions with SGLT2i observed among individuals without preexisting kidney disease.
Conclusions And Relevance:
This comparative effectiveness study found that initiation of SGLT2i vs GLP-1RA treatment in individuals with type 2 diabetes was associated with a lower 5-year risk of CKD and a lower 5-year count of AKI. These findings underscore the potential of SGLT2i treatment for primary prevention of kidney disease in individuals with type 2 diabetes.
Insights
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) show greater effectiveness than glucagon-like peptide-1 receptor agonists (GLP-1RA) in preventing chronic kidney disease (CKD) and acute kidney injury (AKI) in type 2 diabetes patients.
Area of Science:
- Nephrology
- Endocrinology
- Pharmacology
Background:
- Randomized clinical trials directly comparing SGLT2i and GLP-1RA for kidney outcomes are lacking.
- Type 2 diabetes is a leading cause of chronic kidney disease (CKD) and acute kidney injury (AKI).
Purpose of the Study:
- To compare the effectiveness of SGLT2i versus GLP-1RA in reducing CKD and AKI in individuals with type 2 diabetes.
- To evaluate the impact of these treatments on secondary kidney-related outcomes and mortality.
Main Methods:
- Emulation of a target trial using nationwide Danish registry data from metformin-treated type 2 diabetes patients initiating SGLT2i or GLP-1RA.
- Coprimary outcomes: CKD (defined by eGFR decline, kidney failure, or severe albuminuria) and AKI.
- Intention-to-treat analysis using inverse probability of treatment weights, with Aalen-Johansen estimator for CKD and mean cumulative counts for AKI.
Main Results:
- SGLT2i initiation was associated with a lower 5-year risk of CKD (6.7% vs 8.2%) and a lower 5-year AKI burden (25.2 vs 28.7 events per 100 individuals) compared to GLP-1RA.
- GLP-1RA initiators showed slightly reduced risks of albuminuria and mortality.
- SGLT2i demonstrated greater benefits in individuals without pre-existing kidney disease.
Conclusions:
- SGLT2i treatment is associated with a reduced risk of CKD and AKI compared to GLP-1RA in type 2 diabetes.
- SGLT2i may be a preferred option for the primary prevention of kidney disease in this population.
- Further research should explore long-term comparative effectiveness and safety profiles.
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