Effect of combined sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonist therapy in patients with chronic kidney disease: a real-world analysis

Q: What are the key findings of this study?

Combined SGLT2i and GLP-1RA therapy was associated with a lower risk of major adverse kidney events (aHR 0.62, 95% CI 0.48–0.80; p<0.01) compared with SGLT2i monotherapy in patients with CKD.

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Chronic kidney disease (n=2300). Intervention: Combined SGLT2 inhibitor and GLP-1 receptor agonist therapy vs. SGLT2 inhibitor monotherapy. Primary outcome: Major adverse kidney events (MAKE: composite of all-cause death, CKD stage 5, end-stage kidney disease, or dialysis dependence) (aHR 0.62, 95% CI 0.48-0.80, p=<0.01).

Q: What does this research mean for the field?

Combined therapy with SGLT2 inhibitors and GLP-1 receptor agonists is associated with a lower risk of major adverse kidney events and all-cause mortality compared with SGLT2 inhibitor monotherapy in patients with chronic kidney disease. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To evaluate major adverse kidney, cardiovascular, and mortality outcomes associated with initiating combined SGLT2 inhibitor and GLP-1 receptor agonist therapy compared with SGLT2 inhibitor monotherapy in patients with chronic kidney disease.

Cheng-Wei Ho; Min‐Hsiang Chuang; Vin‐Cent Wu; Yu-Kuan Tu; Yea‐Chwen Wu; Jui‐Yi Chen

doi:10.23876/j.krcp.26.241

November 2, 2026Kidney Research and Clinical PracticeOpen Access

Effect of combined sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonist therapy in patients with chronic kidney disease: a real-world analysis

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Key result

Adding GLP-1RA to SGLT2i is linked to ~38% lower risk of major adverse kidney events.

aHR 0.62
95% CI 0.48-0.80
P<0.01
n=2,300

Why the study?

The kidney, cardiovascular, and mortality outcomes of combined SGLT2i and GLP-1RA therapy compared with SGLT2i monotherapy in patients with CKD needed evaluation.

Does simultaneous initiation of combined SGLT2i and GLP-1RA therapy reduce the risk of major adverse kidney events (MAKE), major adverse cardiovascular events (MACE), and all-cause mortality compared with SGLT2i monotherapy in patients with chronic kidney disease?

Key Points

To evaluate major adverse kidney, cardiovascular, and mortality outcomes associated with initiating combined SGLT2 inhibitor and GLP-1 receptor agonist therapy compared with SGLT2 inhibitor monotherapy in patients with chronic kidney disease.
Retrospective 1:1 propensity score-matched cohort analysis of electronic health records from the TriNetX Research Network (December 5, 2017–September 1, 2024) in patients aged ≥18 years with chronic kidney disease.
Included 1,150 matched patients per group who maintained their assigned treatment strategy (combined therapy vs. SGLT2i monotherapy) for the first 6 months, with follow-up extending from 6 months to 2 years after initiation.
Combined therapy was associated with a significantly lower risk of major adverse kidney events compared with monotherapy (8.87% [102/1,150] vs. 12.70% [146/1,150]; aHR, 0.62; 95% CI, 0.48–0.80; p < 0.01).
All-cause mortality was significantly lower in the combined therapy group than in the monotherapy group (4.00% [46/1,150] vs. 6.26% [72/1,150]; aHR, 0.58; 95% CI, 0.40–0.83; p < 0.01).
Risk of major adverse cardiovascular events showed no significant difference between combined therapy and monotherapy (12.35% [142/1,150] vs. 12.78% [147/1,150]; aHR, 0.88; 95% CI, 0.70–1.11; p = 0.29).

Study Design

Type

Cohort (n=2,300)

Multicenter

Yes

Structured PICO

Does simultaneous initiation of combined SGLT2i and GLP-1RA therapy reduce the risk of major adverse kidney events (MAKE), major adverse cardiovascular events (MACE), and all-cause mortality compared with SGLT2i monotherapy in patients with chronic kidney disease?

P

Population

2,300 propensity-score-matched adults with chronic kidney disease (mean age 63.9 years, 45.3% female), free of recent cardiovascular or kidney events, who initiated and maintained combined SGLT2i and GLP-1RA therapy or SGLT2i monotherapy for 6 months and were followed for up to 2 years.

E

Exposure

Combined initiation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) on the same day, maintained for at least the first 6 months after initiation

C

Comparator

Initiation of SGLT2i monotherapy without GLP-1RA, maintained for at least the first 6 months after initiation (1:1 propensity score-matched on demographics, comorbidities, medications, and laboratory measures; ~67% on statins and ~63% on ACEi/ARB in both groups)

O

Outcome

Co-primary outcomes of major adverse kidney events (MAKE: composite of death, CKD stage 5, end-stage kidney disease, or dialysis dependence) and major adverse cardiovascular events (MACE: composite of death, myocardial infarction, or stroke), assessed from 6 months to 2 years after treatment initiationcomposite

Main Result

Hazard Ratio: 0.62 (95% CI 0.48–0.8)

Absolute Event Rate: 8.87% vs 12.7%

p-value: p=<0.01

In a real-world propensity-matched cohort of patients with chronic kidney disease, simultaneous initiation of combined SGLT2i and GLP-1RA therapy was associated with a 38% lower risk of major adverse kidney events and a 42% lower risk of all-cause mortality compared with SGLT2i monotherapy, without a statistically significant difference in major adverse cardiovascular events.

Limitations

Retrospective observational design with potential for residual confounding and misclassification.
Persistence of laboratory abnormalities for at least 3 months could not be directly confirmed in all patients to verify chronicity of CKD.
Competing-risk analysis for death could not be applied to the propensity-score-matched cohorts within the TriNetX platform.
Lack of detailed information on cause-specific mortality, diabetes duration, longitudinal glycemic control, longitudinal kidney function measurements (eGFR decline, albuminuria), drug dosage, titration, and adherence.
Subgroup analyses by CKD stage and BMI could not be fully evaluated because outcome event numbers in the CKD stage 1-2 and BMI <30 kg/m² subgroups were below the TriNetX reporting threshold.
High baseline use of background cardioprotective medications (statins, ACEi/ARB) and active SGLT2i comparator may have limited the remaining modifiable cardiovascular risk and attenuated differences in MACE.

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Implication

Hypothesis-generating for combined SGLT2i/GLP-1RA in CKD; prospective RCTs needed before practice change.

Abstract

Background: This study aimed to evaluate the kidney, cardiovascular, and mortality outcomes of combined sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) therapy compared with SGLT2i monotherapy in patients with chronic kidney disease (CKD). Methods: Using TriNetX electronic health records, we compared patients initiating combined therapy with those initiating SGLT2i alone. Propensity score matching (1:1) was applied. The index date was defined as treatment initiation, with patients required to maintain the assigned treatment strategy during the first 6 months. Outcome follow-up began 6 months after the index date and continued to 2 years after the index date. Primary outcomes were major adverse kidney events (MAKE) and major adverse cardiovascular events (MACE), and the secondary outcome was all-cause mortality. Results: Among 178,930 patients, 1,154 (0.65%) initiated combined therapy of SGLT2i and GLP-1RA, and 24,134 (13.49%) initiated monotherapy of SGLT2i. After matching, each group included 1,150 patients. Combined therapy was associated with a lower risk of MAKE (adjusted hazard ratio [aHR], 0.62; 95% confidence interval [CI], 0.48-0.80; p < 0.01) and all-cause mortality (aHR, 0.58; 95% CI, 0.40-0.83; p < 0.01) compared with SGLT2i alone. There was no significant reduction in risk of MACE (aHR, 0.88; 95% CI, 0.70-1.11; p = 0.29). Conclusion: Among patients with CKD, initiation of combined SGLT2i and GLP-1RA therapy was associated with lower risks of MAKE and all-cause mortality compared with SGLT2i monotherapy. Further studies are needed to clarify effects on kidney and mortality outcomes.

Discussion

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Cite This Study

Ho et al. (2026) conducted a cohort in Chronic kidney disease (n=2,300). Combined SGLT2 inhibitor and GLP-1 receptor agonist therapy vs. SGLT2 inhibitor monotherapy was evaluated on Major adverse kidney events (MAKE: composite of all-cause death, CKD stage 5, end-stage kidney disease, or dialysis dependence) (aHR 0.62, 95% CI 0.48-0.80, p=<0.01). Combined SGLT2i and GLP-1RA therapy was associated with a lower risk of major adverse kidney events (aHR 0.62, 95% CI 0.48–0.80; p<0.01) compared with SGLT2i monotherapy in patients with CKD.

synapsesocial.com/papers/6aea772189a8acbed9c87acd https://doi.org/10.23876/j.krcp.26.241

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Effect of combined sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonist therapy in patients with chronic kidney disease: a real-world analysis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Effect of combined sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonist therapy in patients with chronic kidney disease: a real-world analysis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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