Albuminuria may mark renal risk without defining a treatment threshold
Agreement: I Agree Body: Dear Editor, Turchin and colleagues report an important target trial emulation in which glucagon-like peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter-2 (SGLT2) inhibitors were associated with a lower five-year risk of renal deterioration than dipeptidyl peptidase-4 inhibitors among people with albuminuria (3.2% v 5.4%; risk ratio 0.60), but not among those without albuminuria (2.4% v 2.1%; risk ratio 1.10).[1] The latter finding is informative for
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Agreement: I AgreeBody:
Dear Editor,
Turchin and colleagues report an important target trial emulation in which glucagon-like peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter-2 (SGLT2) inhibitors were associated with a lower five-year risk of renal deterioration than dipeptidyl peptidase-4 inhibitors among people with albuminuria (3.2% v 5.4%; risk ratio 0.60), but not among those without albuminuria (2.4% v 2.1%; risk ratio 1.10).[1] The latter finding is informative for the population studied, but whether 30 mg/g represents a boundary of treatment responsiveness remains uncertain.
Albuminuria is not only a potential treatment-effect modifier but also a powerful marker of baseline renal risk. In the group without albuminuria, baseline estimated glomerular filtration rate was high and only 783 renal events occurred among 61 583 participants; the primary outcome required doubling of serum creatinine or an estimated glomerular filtration rate below 15 mL/min/1.73 m².[1] Such low event velocity could attenuate separation of hard endpoints without implying absence of biological renal benefit.
Randomised evidence makes this distinction clinically relevant. In the SMART-C meta-analysis, SGLT2 inhibitors reduced chronic kidney disease progression even at urinary albumin-to-creatinine ratio (UACR) ≤30 mg/g (hazard ratio 0.58), without evidence of a graded attenuation of relative benefit across UACR categories.[2] EMPA-KIDNEY similarly showed preservation of chronic eGFR slope among participants with UACR <30 mg/g despite their slower underlying progression.[3] Conversely, GRADE found no material kidney-outcome differences between liraglutide, sitagliptin, glimepiride, and glargine in a predominantly low-UACR population.[4] These findings suggest that apparent heterogeneity at low UACR may be both drug-class dependent and estimand dependent.
An informative extension would therefore model baseline UACR continuously and estimate both relative and absolute treatment effects separately for SGLT2 inhibitors and GLP-1RAs. A stable relative effect with increasing absolute benefit as UACR rises would support prognostic enrichment; a changing relative effect would support genuine effect modification. Only a clear change around 30 mg/g would support interpreting that cut-off as a therapeutic threshold.
References
- Turchin A, Petito LC, Hegermiller E, et al. Renal outcomes in people with type 2 diabetes with and without albuminuria treated with SGLT-2 inhibitors and GLP-1 receptor agonists: target trial emulation. BMJ 2026;394:e100574. doi:10.1136/bmj-2026-100574.
- Neuen BL, Fletcher RA, Anker SD, et al. SGLT2 inhibitors and kidney outcomes by glomerular filtration rate and albuminuria: a meta-analysis. JAMA 2026;335:233-244. doi:10.1001/jama.2025.20834.
- EMPA-KIDNEY Collaborative Group. Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the EMPA-KIDNEY trial. Lancet Diabetes Endocrinol 2024;12:39-50. doi:10.1016/S2213-8587(23)00321-2.
- Wexler DJ, de Boer IH, Ghosh A, et al. Comparative effects of glucose-lowering medications on kidney outcomes in type 2 diabetes: the GRADE randomized clinical trial. JAMA Intern Med 2023;183:705-714. doi:10.1001/jamainternmed.2023.1487.
No competing Interests: YesThe following competing Interests: Electronic Publication Date: Friday, September 18, 2026 - 04:29AI use: No, I have not used AIHighwire Comment Subject:
Renal outcomes in people with type 2 diabetes with and without albuminuria treated with SGLT-2 inhibitors and GLP-1 receptor agonists: target trial emulation
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Albuminuria may mark renal risk without defining a treatment threshold
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Renal outcomes in people with type 2 diabetes with and without albuminuria treated with SGLT-2 inhibitors and GLP-1 receptor agonists: target trial emulation
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- September 18, 2026
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