Adding a GLP-1 Receptor Agonist to SGLT2 Inhibitor Therapy in CKD

Key Finding Adding a GLP-1 receptor agonist to background SGLT2 inhibitor therapy was associated with a 30% reduction in major adverse kidney events (HR 0.70), a 17% reduction in MACE (HR 0.83), and a 45% reduction in all-cause mortality (HR 0.55) in adults with chronic kidney disease.

Two drug classes — SGLT2 inhibitors and GLP-1 receptor agonists — have each demonstrated independent benefits for kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD). A question that inevitably follows is whether combining them produces additive or synergistic effects.

A new population-based study published in Diabetes, Obesity & Metabolism provides a real-world look at that question, drawing on data from over 100,000 patients with CKD [PMID 42802242].

What the study did

The authors conducted a retrospective cohort analysis using the TriNetX Global Collaborative Network, a large federated health data platform. They identified adults with CKD who were receiving SGLT2 inhibitor therapy between June 2020 and December 2023. Within that population, they compared patients who remained on SGLT2i monotherapy with those who subsequently initiated a GLP-1 receptor agonist.

Because treatment assignment was not randomized, the analysis used 1:1 propensity score matching to adjust for differences in demographics, comorbidities, concurrent medications, and baseline laboratory values. The matched cohort included 32,448 patients evenly split between the two groups. The primary outcome was major adverse kidney events (MAKE); secondary endpoints included major adverse cardiovascular events (MACE) and all-cause mortality.

Kidney outcomes

Over a median follow-up of 12 months, the addition of a GLP-1RA was associated with a significantly lower rate of the primary kidney outcome. The hazard ratio for MAKE was 0.70 (95% CI 0.65–0.74, p < 0.001) — a 30% relative reduction compared with SGLT2i monotherapy.

The kidney benefit was consistent across CKD stages and regardless of diabetes status, suggesting the combination’s effect is not limited to patients with diabetic kidney disease.

Cardiovascular and mortality findings

The combination group also showed lower risks on the cardiovascular and mortality endpoints:

MACE: HR 0.83 (95% CI 0.78–0.87)
All-cause mortality: HR 0.55 (95% CI 0.50–0.61)

The mortality finding is notable in magnitude — a 45% relative reduction — though observational comparisons of mortality should always be read with the caveat that unmeasured confounders (healthier patients may be more likely to receive additional therapy) could contribute.

Subgroups worth watching

The analysis identified several subgroups in which the benefit appeared more pronounced:

Patients with obesity
Patients with heart failure
Patients with ischemic heart disease

These are biologically plausible enrichment signals. The combination of SGLT2i’s hemodynamic and metabolic effects with GLP-1RA’s weight-independent cardiorenal actions may produce the largest net benefit in patients with the highest baseline cardiometabolic risk.

Safety considerations

Combination therapy was associated with some increased risks: gastrointestinal symptoms, genital infections, and retinopathy progression were more frequent in the combination group. However, the combination arm had lower rates of volume-depletion events and acute kidney injury compared with SGLT2i monotherapy — a finding that may reflect GLP-1RA’s hemodynamic profile offsetting some of SGLT2i’s volume-related effects.

What this means for the evidence base

This is an observational study, not a randomized trial. Propensity score matching reduces but does not eliminate confounding by indication — clinicians may add a GLP-1RA to SGLT2i therapy for reasons that correlate with better outcomes. The median 12-month follow-up also cannot speak to whether the benefits and risks remain balanced over years of combined therapy.

What the study does provide is real-world data at a scale that no single randomized trial has yet matched. The consistency of the effect across kidney, cardiovascular, and mortality endpoints, and across multiple CKD stages and comorbidity subgroups, makes a reasonable case for prospective evaluation in a dedicated trial. Several such trials are underway or planned, and their results will determine whether the additive benefit observed here survives randomization.

For researchers tracking the incretin class, the key question is no longer whether GLP-1RAs benefit the kidney — the evidence for that is established — but whether combination with SGLT2i produces the kind of additive protection that would shift treatment paradigms for the large population of patients with CKD.