Hepatorenal crosstalk perspective on differential renal effects of SGLT‑2 inhibitors and GLP‑1 receptor agonists in type 2 diabetes

Agreement: I AgreeBody:

Dear Editor,

We read with great interest the target‑trial‑emulation analysis reported by Turchin and colleagues¹. Their work demonstrates that SGLT‑2 inhibitors or GLP‑1 receptor agonists exert renal‑protective effects only in type 2 diabetes patients with albuminuria, with no detectable hard renal benefit observed among normoalbuminuric participants; sulfonylureas were additionally linked to accelerated renal function decline in normoalbuminuric individuals. We provide a complementary mechanistic interpretation from the perspective of hepatorenal crosstalk and metabolic‑dysfunction‑associated steatotic liver disease (MASLD)².

Bidirectional liver‑kidney metabolic interaction is prominent in type 2 diabetes. Hepatic steatosis‑driven lipotoxicity and low‑grade inflammation propagate renal injury, while renal impairment in turn exacerbates hepatic metabolic dysregulation. Patients with albuminuria often carry more advanced MASLD‑related metabolic disturbances, potentially rendering kidneys responsive to metabolic modulation by these anti‑diabetic agents³. By comparison, normoalbuminuric subjects may only exhibit early hepatic metabolic perturbation without overt glomerular damage; hard endpoints such as creatinine doubling might not materialise within the study’s median 32‑month follow‑up window.

Beyond well‑characterised tubular actions, SGLT‑2 inhibitors trigger direct hepatic metabolic reprogramming, restraining lipogenesis and suppressing intrahepatic inflammatory stress independent of renal haemodynamic shifts. These liver‑directed pleiotropic pathways may indirectly mitigate lipotoxic kidney insults in albuminuria‑positive patients. Pooled analysis of SGLT‑2 inhibitors and GLP‑1 RAs could obscure their divergent hepatoprotective signalling. Importantly, absence of hard‑endpoint benefit cannot rule out subtle subclinical renal protection in normoalbuminuric cohorts⁴.

Since baseline MASLD status was not adjusted for in this study¹, we propose both albuminuria and hepatic steatosis burden should be incorporated into risk‑stratified therapeutic decision‑making for type 2 diabetes. Further investigations are required to separate tubular‑renal versus direct hepatic contributions to organ‑protective drug effects.

Yours sincerely,
Hanwen Yang

References

1. 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
2. Angelidi AM, Boutari C, Kokkorakis M, , et al. MASLD and the Cardiovascular-Kidney-Liver-Metabolic syndrome. Endocr Rev. 2026 Jul 15:bnag023.
3. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380(24):2295‑2306.
4. 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(3):233‑244.

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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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Hepatorenal crosstalk perspective on differential renal effects of SGLT‑2 inhibitors and GLP‑1 receptor agonists in type 2 diabetes

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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

Check this box if you would like your letter to appear anonymously:: Last Name: YangFirst name and middle initial: HanwenEmail:

2640315153@mail.ccmu.edu.cn

Address: No. 8, Gongti South Road, Chaoyang District, BeijingOccupation: surgeonOther Authors: Zhili JiAffiliation: Beijing Chaoyang Hospital，Capital Medical UniversityBMJ: Additional Article Info: Rapid response