Summary: In this prespecified subgroup analysis of the FLOW randomized trial (3,533 adults with type 2 diabetes and chronic kidney disease), semaglutide reduced the primary composite kidney outcome by 24% versus placebo overall (95% CI: 34%, 12%). The benefit was statistically demonstrated in participants not taking an SGLT2 inhibitor at baseline (hazard ratio 0.73), whereas no benefit was detected in the smaller, underpowered SGLT2 inhibitor subgroup (hazard ratio 1.07); the interaction was not significant (P = 0.109).
PICO Summary
| Element | Detail |
|---|---|
| Population | 3,533 adults with type 2 diabetes and chronic kidney disease enrolled in the international, double-blind FLOW trial (NCT03819153), stratified by baseline SGLT2 inhibitor use (n = 550) versus no use (n = 2,983). |
| Intervention | Once-weekly subcutaneous semaglutide (GLP-1 receptor agonist), titrated to 1.0 mg. SGLT2i subgroup n = 277; non-SGLT2i subgroup n = 1,490. |
| Comparison | Matching placebo, analysed within the same baseline SGLT2 inhibitor strata. SGLT2i subgroup n = 273; non-SGLT2i subgroup n = 1,493. |
| Outcome | Primary composite (kidney failure, ≥50% eGFR decline, kidney death or cardiovascular death) was 24% lower overall with semaglutide (95% CI: 34%, 12%; equivalent HR 0.76, 95% CI 0.66–0.88). By subgroup: SGLT2i at baseline 41/277 vs 38/273, HR 1.07 (95% CI 0.69–1.67), P = 0.755; no SGLT2i 290/1,490 vs 372/1,493, HR 0.73 (95% CI 0.63–0.85), P < 0.001; P interaction = 0.109. eGFR slope, major cardiovascular events and all-cause death also favoured semaglutide regardless of SGLT2i use (P interaction 0.237, 0.741 and 0.901). Authors note power was limited to detect smaller but clinically relevant effects within the SGLT2i subgroup. |
FLOW: Semaglutide ± SGLT2i in T2D With CKD
RCT subgroup analysis · type 2 diabetes + CKD
Semaglutide cut the primary kidney composite by 24% overall. The benefit held in patients not on an SGLT2 inhibitor; the on-SGLT2i subgroup was too small (79 events) to confirm or exclude added benefit, with no significant interaction.
Expert Commentary
The overall FLOW result is robust: in a double-blind randomized trial, semaglutide produced a clinically meaningful 24% reduction in the primary kidney composite. This prespecified analysis was undertaken to ask whether that benefit persists alongside an SGLT2 inhibitor, the other agent class proven to protect the kidney. The honest verdict is reassuring but not definitive. No significant interaction was found, the eGFR slope, cardiovascular and mortality endpoints moved consistently in both strata, and the directionally divergent kidney hazard ratios are best read as a power artifact rather than true effect modification. The single most important limitation is precisely that: only 550 participants were taking an SGLT2 inhibitor at baseline, yielding 79 primary events and wide confidence intervals (0.69 to 1.67) that neither confirm nor exclude added benefit. The point estimate of 1.07 should therefore not be interpreted as loss of efficacy. Industry context also warrants disclosure, as the trial was sponsored by the manufacturer and several authors are employees. Can I use this with my patients? Yes, for a patient with type 2 diabetes and chronic kidney disease already on an SGLT2 inhibitor, adding semaglutide remains reasonable, as nothing here signals harm or redundancy. A dedicated, adequately powered combination trial would settle the question more cleanly.
References
Mann JFE, Rossing P, Bakris G, et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med. 2024;30(10):2849-2856. doi:10.1038/s41591-024-03133-0