Summary: In this pre-specified secondary analysis of the double-blind FLOW randomised controlled trial (N=3,533) in type 2 diabetes and chronic kidney disease, weekly semaglutide reduced the primary kidney-cardiovascular composite by 24% overall (95% CI 12% to 34%). The effect was directionally consistent across patients with and without baseline SGLT2 inhibitor use, with a non-significant test for interaction (P=0.109); the small SGLT2 inhibitor subgroup (n=550) was underpowered.
PICO Summary
| Element | Detail |
|---|---|
| Population | Adults with type 2 diabetes and chronic kidney disease (N=3,533) from the FLOW double-blind RCT, stratified by baseline SGLT2 inhibitor use (n=550 on SGLT2i; n=2,983 not on SGLT2i); multinational. Subgroups defined by baseline therapy, not by randomisation. |
| Intervention | Subcutaneous semaglutide 1.0 mg once weekly (a GLP-1 receptor agonist). On SGLT2i: n=277; not on SGLT2i: n=1,490. |
| Comparison | Matching placebo once weekly. On SGLT2i: n=273; not on SGLT2i: n=1,493. |
| Outcome | Primary composite (kidney failure, ≥50% eGFR decline, kidney death, or cardiovascular death). Overall: 24% relative risk reduction (95% CI 12% to 34%). Not on SGLT2i: 290/1,490 vs 372/1,493, HR 0.73 (95% CI 0.63 to 0.85; P<0.001). On SGLT2i: 41/277 vs 38/273, HR 1.07 (95% CI 0.69 to 1.67; P=0.755). Test for interaction P=0.109 (not significant). Total eGFR slope difference (ml/min/1.73 m²/year): 1.25 (0.91, 1.58) non-SGLT2i and 0.75 (-0.01, 1.5) SGLT2i (P interaction 0.237). Major cardiovascular events and all-cause death favoured semaglutide irrespective of SGLT2i use (P interaction 0.741 and 0.901). No ARR/NNT reported in the source. |
FLOW: Semaglutide ± SGLT2i in CKD
RCT subgroup · T2D + CKD · kidney-CV outcomes
Semaglutide cut the kidney-cardiovascular composite by 24% overall, with a directionally consistent effect regardless of baseline SGLT2 inhibitor use. The small SGLT2 inhibitor subgroup was underpowered (P interaction 0.109).
Expert Commentary
This pre-specified subgroup analysis of the FLOW trial is reassuring rather than definitive, and its headline should be read as consistency, not divergence. The overall 24% reduction in the kidney-cardiovascular composite is robust, and the central question here was whether that benefit is preserved when semaglutide is added to an SGLT2 inhibitor. The honest answer is that the data are compatible with a preserved benefit: the formal test for interaction was not significant (P=0.109), so the contrasting point estimates between subgroups (HR 0.73 versus HR 1.07) should not be over-read. The principal limitation is power. Only 550 participants were taking an SGLT2 inhibitor at baseline, yielding just 79 primary events, so the wide confidence interval crossing 1.0 reflects statistical uncertainty rather than demonstrated absence of effect. Because subgroups were defined by baseline prescribing and not by randomisation, the comparison is associational and vulnerable to confounding by indication. The trial was sponsored by the manufacturer of semaglutide, with several authors employed by the sponsor, which warrants the usual caution despite the double-blind design. Can I use this with my patients? Yes, for a person with type 2 diabetes and chronic kidney disease already on an SGLT2 inhibitor, these data support adding semaglutide rather than withholding it. A dedicated, adequately powered combination trial is needed to settle the magnitude of incremental benefit.
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