Combo GLP-1 RA, SGLT2 Therapy Linked to Lower Kidney, CV Risks

Adding a glucagon-like peptide-1 receptor agonist (GLP-1 RA) to ongoing SGLT2 inhibitor therapy was associated with lower risks of kidney disease progression, cardiovascular events, and death in adults with chronic kidney disease (CKD), according to a real-world cohort study recently published in Diabetes, Obesity and Metabolism.¹

Evidence Gap Limits Guideline Support for Dual Therapy

Although SGLT2 inhibitors have reduced the risk of CKD progression, kidney failure, and mortality, residual kidney and cardiovascular risk remains. GLP-1 RAs have also demonstrated kidney benefits, including in the FLOW trial (NCT03819153), which supported the FDA's approval of semaglutide for patients with type 2 diabetes and CKD.² In addition, GLP-1 RAs may provide complementary effects through mechanisms such as anti-inflammatory and natriuretic actions.¹

Despite increasing use of both drug classes, investigators noted that evidence supporting their combined use remains limited. Major SGLT2 inhibitor trials included few patients taking GLP-1 RAs, and only a small proportion of participants in the FLOW trial were receiving SGLT2 inhibitors at baseline. Although post hoc analyses suggest GLP-1 RAs retain their benefits when used with SGLT2 inhibitors, the researchers emphasized that small sample sizes and potential selection bias limit these findings.

To address this gap, the researchers conducted a study to assess whether adding a GLP-1 RA to ongoing SGLT2 inhibitor therapy reduces CKD progression and improves cardiovascular outcomes. They used the TriNetX Global Collaborative Network, which draws electronic health record data from 152 health care organizations, most of them in the US. They compared adults with CKD who initiated a GLP-1 RA while on active SGLT2 inhibitor therapy between June 2020 and December 2023 with those who remained on SGLT2 inhibitor monotherapy.

Combo Therapy Linked to Lower Kidney, Cardiovascular Risks

The researchers identified 112,596 adults with CKD receiving an SGLT2 inhibitor, 16,460 of whom later started a GLP-1 RA. After 1:1 propensity score matching, the analytic cohort included 32,448 patients (16,224 per group). The primary outcome was major adverse kidney events (MAKE), a composite of all-cause mortality, progression to end-stage kidney disease (ESKD), dialysis, stage 5 CKD, or kidney transplant.

Over a median follow-up of 12 months, combination therapy was associated with a lower risk of MAKE compared with SGLT2 inhibitor monotherapy (HR, 0.70; 95% CI, 0.65-0.74; P < .001). The reduction was driven by lower risks of progression to stage 5 CKD (HR, 0.77; 95% CI, 0.66-0.89), incident dialysis/ESKD (HR, 0.83; 95% CI, 0.76-0.91), and all-cause mortality (HR, 0.55; 95% CI, 0.50-0.61; P < .001). However, the researchers did not observe a significant difference in kidney transplant rates (HR, 1.44; 95% CI, 0.51-4.04).

Combination therapy was also associated with a lower risk of major adverse cardiovascular events (HR, 0.83; 95% CI, 0.78-0.87; P < .001) than SGLT2 inhibitors alone, largely reflecting reductions in mortality and cardiac arrest (HR, 0.58; 95% CI, 0.47-0.71). By contrast, associations with acute myocardial infarction (HR, 0.95; 95% CI, 0.88-1.03) and stroke (HR, 0.92; 95% CI, 0.85-1.01) did not reach statistical significance.

Although benefits were broadly consistent across CKD stages and age groups, they were significantly larger in patients with obesity and heart failure. Specifically, the mortality reduction was more pronounced among patients with a body mass index (BMI) of 30 kg/m² or higher (HR, 0.49 vs 0.63; P for interaction = .021) and those with a history of heart failure (HR, 0.59 vs 0.79; P for interaction = .026). The MAKE reduction was also greater for patients with obesity (HR, 0.70 vs 0.82; P for interaction = .037).

“This suggests that BMI could serve as a clinical biomarker for prioritizing combination therapy,” the authors wrote.

Regarding safety, consistent with the known adverse event profile of GLP-1 RAs, combination therapy was associated with higher risks of gastrointestinal symptoms (HR, 1.09; 95% CI, 1.04-1.13), genital mycotic infections (HR, 1.29; 95% CI, 1.08-1.55), and progression of diabetic retinopathy (HR, 1.48; 95% CI, 1.40-1.57). At the same time, combination therapy was associated with significantly lower risks for several other adverse events, including hypotension/syncope (HR, 0.92; 95% CI, 0.87-0.98), palpitations (HR, 0.88; 95% CI, 0.83-0.93), and dehydration (HR, 0.87; 95% CI, 0.79-0.95).

Findings Point to Need for Randomized Trials

Still, the authors acknowledged several limitations. The differing index dates between groups may have introduced immortal-time bias, and the observational design leaves room for residual confounding and misclassification. In addition, data on dosing, titration, and adherence were unavailable, and follow-up was short; as a result, these data cannot establish causality.

The authors concluded that the findings highlight both the potential benefits of combination therapy and the need for further research.

"The addition of a GLP-1 RA to ongoing SGLT2 [inhibitor] therapy is associated with a substantial reduction in the risk of kidney disease progression and cardiovascular events in a real-world setting,” they wrote. "…While confirmatory randomized trials are awaited, these data support the early adoption of combination therapy to address the high residual risk in patients with CKD.”

References

1. Salim H, Qureshi S, Gulsin GS, et al. Effectiveness of adding GLP-1 receptor agonists to SGLT2 inhibitor therapy in chronic kidney disease: a population based study. Diabetes Obes Metab. Published online September 2026. doi:10.1111/dom.71375
2. Munz K. FDA expands semaglutide use for CV, kidney risks in T2D, CKD. AJMC^®. January 28, 2025. Accessed September 28, 2026. https://www.ajmc.com/view/fda-expands-semaglutide-use-for-cv-kidney-risks-in-t2d-ckd