Summary: In a pre-specified subgroup analysis of the FLOW randomised trial (3,533 adults with type 2 diabetes and chronic kidney disease), semaglutide lowered the primary composite kidney and cardiovascular outcome by 24% overall versus placebo. The relative benefit appeared smaller in the 550 participants already taking an SGLT2 inhibitor (HR 1.07) than in the 2,983 who were not (HR 0.73), but the interaction was not statistically significant (P interaction 0.109), and the SGLT2i subgroup was underpowered.
PICO Summary
| Element | Detail |
|---|---|
| Population | 3,533 adults with type 2 diabetes and chronic kidney disease, pre-specified subgroup analysis of the FLOW randomised double-blind placebo-controlled trial (multinational; NCT03819153). Stratified by baseline SGLT2 inhibitor use: 550 on an SGLT2i, 2,983 not on an SGLT2i. |
| Intervention | Once-weekly subcutaneous semaglutide (target 1.0 mg). On SGLT2i at baseline: n=277. Not on SGLT2i: n=1,490. |
| Comparison | Matching placebo, both subgroups continuing standard care. On SGLT2i at baseline: n=273. Not on SGLT2i: n=1,493. |
| Outcome | Primary composite (kidney failure, ≥50% eGFR reduction, kidney death or cardiovascular death): 24% lower risk overall with semaglutide (95% CI 12% to 34% reduction). On SGLT2i: 41/277 vs 38/273, HR 1.07 (95% CI 0.69 to 1.67; P=0.755). Not on SGLT2i: 290/1,490 vs 372/1,493, HR 0.73 (95% CI 0.63 to 0.85; P<0.001). P interaction 0.109 (non-significant). Total eGFR slope difference (ml/min/1.73 m²/year): 0.75 (95% CI -0.01 to 1.5) on SGLT2i and 1.25 (95% CI 0.91 to 1.58) not on SGLT2i; P interaction 0.237. Major cardiovascular events and all-cause death favoured semaglutide similarly regardless of SGLT2i use (P interaction 0.741 and 0.901). No ARR or NNT for the subgroup comparison was reported. |
FLOW: Semaglutide kidney benefit by SGLT2i use
RCT subgroup · T2D + CKD
Semaglutide cut the composite kidney-CV outcome by 24% overall. The SGLT2i subgroup (n=550) showed no clear benefit, but the interaction test was non-significant and that stratum was underpowered, so effect modification is unproven.
Expert Commentary
This pre-specified subgroup analysis of FLOW asks a clinically pressing question: does background SGLT2 inhibition leave any room for added kidney protection from semaglutide? The honest answer from these data is that no effect modification was demonstrated. The point estimates differ between subgroups, with a hazard ratio of 1.07 in those already on an SGLT2 inhibitor and 0.73 in those who were not, but the interaction test was not significant (P=0.109), so a real biological difference cannot be claimed. The apparent absence of benefit in the SGLT2i subgroup is best read as imprecision rather than proof of no effect: only 550 participants and 79 events sat in that stratum, and the confidence interval (0.69 to 1.67) is wide enough to be compatible with a meaningful benefit. The principal limitation is therefore power; the authors themselves state the analysis could not detect smaller but clinically relevant effects. As a manufacturer-sponsored analysis (Novo Nordisk authorship), the framing of consistency warrants measured interpretation, although the design was double-blind and placebo-controlled, which strengthens the underlying randomised comparison. Can I use this with my patients? Yes, cautiously: for a patient with type 2 diabetes and CKD already established on an SGLT2 inhibitor, these data neither confirm nor exclude added renal benefit from semaglutide, so the decision should rest on the overall FLOW result and individual cardiometabolic goals. Adequately powered combination-therapy trials are needed to settle the question.
References
Mann JFE, Rossing P, Bakris G, Belmar N, Bosch-Traberg H, Busch R, 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