Latest Evidence on Efficacy and Safety of Combining SGLT2 Inhibitors with GLP-1 Agonists for Type 2 Diabetes Management in Patients with CKD Stage 3

Recent evidence from observational studies and meta-analyses (up to May 2025) supports the combination of SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin) and GLP-1 receptor agonists (e.g., semaglutide) as a promising strategy for cardiorenal protection in type 2 diabetes (T2D) patients with CKD stage 3 (eGFR 30–59 mL/min/1.73 m²), though direct randomized controlled trials (RCTs) are lacking.

Efficacy

• Cardiorenal Outcomes: Combination therapy is associated with a 52% lower risk of kidney composite endpoints (e.g., ESKD, eGFR decline ≥50%, doubling of serum creatinine, renal death; RR 0.48, 95% CI 0.32–0.73) compared to monotherapy, though evidence certainty is very low due to observational design and surrogate endpoints. Network meta-analyses show SGLT2 inhibitors may preserve eGFR better (21% greater reduction in composite kidney outcomes) than GLP-1 agonists alone, but combinations provide additive benefits via complementary mechanisms (e.g., SGLT2 reduces hyperfiltration; GLP-1 lowers inflammation and albuminuria).

• Key Trials (Including CKD Stage 3 Populations):

  • DAPA-CKD (Dapagliflozin): In eGFR 25–75 mL/min/1.73 m² (mean 43.1), reduced primary composite by 39% (HR 0.61, 95% CI 0.51–0.72; NNT 19), with eGFR slope benefit of 0.93 mL/min/1.73 m²/yr and 29% UACR reduction.

  • EMPA-KIDNEY (Empagliflozin): In eGFR 20–<90 mL/min/1.73 m² (mean 37.3), reduced progression/CV death by 28% (HR 0.72, 95% CI 0.64–0.82; NNT 28), with eGFR slope benefit of 0.75 mL/min/1.73 m²/yr.

  • FLOW (Semaglutide): In eGFR 25–75 mL/min/1.73 m² (mean 47.0), reduced primary composite by 24% (HR 0.76, 95% CI 0.66–0.88; NNT 20), with eGFR slope benefit of 1.16 mL/min/1.73 m²/yr and 32% UACR reduction; benefits consistent in those on SGLT2 inhibitors (P interaction=0.109).

• Additional Benefits: Reduced MACE (RR 0.56, 95% CI 0.43–0.71), all-cause mortality (RR 0.50, 95% CI 0.40–0.63), and hospitalization for heart failure (RR 0.67, 95% CI 0.64–0.71). Preclinical and smaller trials suggest improved kidney oxygenation and perfusion.

Safety

• Generally well-tolerated; no increased risks of severe hypoglycemia, diabetic ketoacidosis, genitourinary infections, or gastrointestinal side effects compared to monotherapy. SGLT2 risks (e.g., genital infections) and GLP-1 risks (e.g., GI events) are similar in CKD stage 3, with no specific signals for combinations. Monitor for dehydration and AKI.

Limitations and Gaps

• Evidence from 18 cohort studies (low certainty due to confounding, inconsistency; no direct RCTs in CKD stage 3). Gaps include long-term durability, predictors of response, and optimal strategies in high-risk groups. Ongoing trials (e.g., CONFIDENCE, TREASURE-CKD) may provide more data.