Summary: In a prespecified subgroup analysis of the double-blind FLOW trial (3,533 participants with type 2 diabetes and chronic kidney disease), once-weekly semaglutide reduced the primary composite kidney outcome by 24% overall versus placebo (95% CI 12% to 34%). The interaction with baseline SGLT2 inhibitor use was not significant (P interaction 0.109), but the SGLT2i subgroup (n=550) showed no benefit (hazard ratio 1.07, 95% CI 0.69 to 1.67) and was acknowledged to be underpowered.
PICO Summary
| Element | Detail |
|---|---|
| Population | 3,533 adults with type 2 diabetes and chronic kidney disease at high risk for kidney failure and cardiovascular events; prespecified subgroup analysis of the international, double-blind FLOW randomised controlled trial (NCT03819153), stratified by baseline SGLT2 inhibitor use (n=550) versus no use (n=2,983). |
| Intervention | Once-weekly subcutaneous semaglutide 1.0 mg, a glucagon-like peptide-1 receptor agonist, added to standard care (semaglutide arm n=1,767). |
| Comparison | Matching placebo added to standard care (placebo arm n=1,766), analysed within and across baseline SGLT2 inhibitor strata. |
| Outcome | Primary composite (kidney failure, ≥50% eGFR reduction, kidney death or cardiovascular death): overall 24% relative risk reduction with semaglutide (95% CI 12% to 34%; equivalent to HR approximately 0.76). Baseline SGLT2i subgroup: 41/277 vs 38/273 events, HR 1.07 (95% CI 0.69 to 1.67; P=0.755). No baseline SGLT2i subgroup: 290/1,490 vs 372/1,493 events, HR 0.73 (95% CI 0.63 to 0.85; P<0.001). P interaction 0.109. eGFR slope, major cardiovascular events and all-cause death favoured semaglutide with no significant interaction by SGLT2i use; the authors state power was limited to detect smaller but clinically relevant effects in the SGLT2i subgroup. |
FLOW: semaglutide by baseline SGLT2i use
RCT subgroup · T2D + CKD · median 3.4 y
Semaglutide cut the primary kidney outcome 24% overall, driven by SGLT2i-naive patients. The 550-patient SGLT2i subgroup (HR 1.07) was underpowered, so additive benefit on top of an SGLT2 inhibitor stays unproven.
Expert Commentary
This prespecified analysis was designed to ask whether the kidney and cardiovascular benefit of semaglutide is preserved when an SGLT2 inhibitor is already on board. The honest verdict is that the trial cannot answer this question with confidence. The overall result is genuine and important, but the interpretation that benefit is “consistent regardless of” baseline SGLT2 inhibitor use rests on a non-significant interaction test rather than on demonstrated efficacy within the SGLT2i stratum. In that stratum the point estimate (hazard ratio 1.07) actually pointed away from benefit, with a confidence interval wide enough to include both meaningful harm and meaningful benefit. The single most important limitation is statistical power: only 550 of 3,533 participants were taking an SGLT2 inhibitor at baseline, and the authors themselves concede the analysis could not detect clinically relevant effects in that group. A non-significant interaction is not evidence of equivalence. Industry sponsorship by the manufacturer, Novo Nordisk, with several employee co-authors, is a further reason for measured reading. Can I use this with my patients? Cautiously yes for SGLT2-inhibitor-naive patients with type 2 diabetes and chronic kidney disease, where the benefit is robust; for those already established on an SGLT2 inhibitor, additive kidney protection from semaglutide remains plausible but unproven. A properly powered combination trial is needed before firm guidance can be given.
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