Summary: In a prespecified secondary analysis of the FLOW trial (N=3,533 adults with type 2 diabetes and chronic kidney disease), once-weekly semaglutide reduced the primary kidney and cardiovascular composite by 24% overall (95% CI 12% to 34%). The benefit appeared consistent whether or not participants were taking a sodium-glucose cotransporter-2 inhibitor (SGLT2i) at baseline, with no significant treatment-by-subgroup interaction (P interaction 0.109).
PICO Summary
| Element | Detail |
|---|---|
| Population | Adults with type 2 diabetes and chronic kidney disease (N=3,533) from the multinational, double-blind FLOW randomised controlled trial, stratified by baseline SGLT2i use (n=550 on SGLT2i; n=2,983 not on SGLT2i). |
| Intervention | Once-weekly subcutaneous semaglutide (a glucagon-like peptide-1 receptor agonist). On SGLT2i subgroup: 277 randomised to semaglutide. Not on SGLT2i: 1,490 randomised to semaglutide. |
| Comparison | Matching placebo. On SGLT2i subgroup: 273 to placebo. Not on SGLT2i: 1,493 to placebo. |
| Outcome | Primary composite (kidney failure, ≥50% eGFR decline, kidney death, or cardiovascular death): 24% relative risk reduction overall with semaglutide (95% CI 12% to 34%). SGLT2i subgroup: 41/277 vs 38/273, HR 1.07 (95% CI 0.69 to 1.67; P=0.755). Non-SGLT2i subgroup: 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). eGFR slope, major cardiovascular events, and all-cause death showed no significant interaction by SGLT2i use (P interaction 0.237, 0.741, and 0.901, respectively). Absolute risk reductions and NNT were not reported in the abstract. |
FLOW: Semaglutide +/- SGLT2i in T2D + CKD
Prespecified secondary analysis · T2D + CKD
Semaglutide's kidney and cardiovascular benefit was consistent regardless of baseline SGLT2i use, with no significant treatment-by-subgroup interaction. The on-SGLT2i subgroup was underpowered (n=550), so the HR of 1.07 should not be read as loss of benefit.
Expert Commentary
This prespecified secondary analysis was designed to answer a practical question: does the kidney and cardiovascular benefit of semaglutide hold when patients are already taking an SGLT2 inhibitor? The honest verdict is that the data are reassuring but not definitive. The treatment-by-subgroup interaction was not statistically significant for the primary composite (P interaction 0.109) or for any of the three confirmatory secondary outcomes, which is the statistically correct basis for concluding that the benefit is broadly consistent regardless of background SGLT2i use. The hazard ratio of 1.07 seen in the SGLT2i subgroup should not be read as evidence that semaglutide stops working in these patients; it is far more likely to reflect the dominant limitation of this analysis, namely that only 550 of 3,533 participants were taking an SGLT2 inhibitor at baseline, leaving the subgroup substantially underpowered with wide confidence intervals. The authors are explicit that power was limited to detect smaller but clinically relevant effects. Industry sponsorship by the drug’s manufacturer also warrants routine caution, although FLOW was double-blind and placebo-controlled, which mitigates performance and detection bias. Can I use this with my patients? Yes, with appropriate framing: for a patient with type 2 diabetes and chronic kidney disease already established on an SGLT2 inhibitor, this analysis supports adding semaglutide for additive organ protection rather than withholding it. A dedicated, adequately powered combination trial remains the necessary next step to confirm the magnitude of incremental benefit.
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