Summary: In a post hoc substudy of a 32-week randomised trial (n=80, type 2 diabetes, high cardiovascular risk), semaglutide and empagliflozin monotherapy each significantly lowered cortical apparent diffusion coefficient (ADC) versus placebo (semaglutide -0.20, p<0.001; empagliflozin -0.15, p=0.01), whereas the combination group showed no significant ADC change (p=0.29). Total kidney volume fell modestly in all active arms (-3% to -5%). These are exploratory imaging signals, not clinical kidney outcomes.
PICO Summary
| Element | Detail |
|---|---|
| Population | n=80 adults with type 2 diabetes and high cardiovascular risk; post hoc MRI substudy of a randomised, placebo-controlled trial conducted in Denmark (EudraCT 2019-000781-38). |
| Intervention | Three active arms (n=20 each): empagliflozin for 32 weeks; semaglutide for 16 weeks then placebo added for 16 weeks (“semaglutide”); semaglutide for 16 weeks then empagliflozin added for 16 weeks (“combination”). |
| Comparison | Tablet placebo for 32 weeks (n=20). Primary surrogate endpoints were change in renal cortical/medullary ADC on diffusion-weighted MRI and total kidney volume (TKV). |
| Outcome | Cortical ADC vs placebo: semaglutide -0.20×10⁻³ mm²/s (95% CI -0.30, -0.10; p<0.001); empagliflozin -0.15 (95% CI -0.26, -0.04; p=0.01); combination -0.05 (95% CI -0.15, 0.05; p=0.29, non-significant). Medullary ADC unchanged in all arms; only semaglutide changed cortico-medullary ΔADC (-0.13; 95% CI -0.22, -0.04; p=0.01). TKV vs placebo: semaglutide -3% (95% CI -5%, -0.3%; p=0.04), empagliflozin -3% (95% CI -5%, -0.4%; p=0.02), combination -5% (95% CI -8%, -2%; p<0.001). Cortical ADC changes were not associated with GFR, albuminuria, TKV or inflammation; TKV changes were associated with GFR, albuminuria and HbA1c. No ARR/NNT (surrogate imaging endpoints). |
GLP-1 / SGLT2 and renal diffusion MRI
RCT substudy · type 2 diabetes · 32 weeks
Semaglutide and empagliflozin each lowered cortical ADC versus placebo, while the combination did not. These are exploratory imaging surrogates, not clinical kidney outcomes.
Expert Commentary
This is a mechanistic, hypothesis-generating substudy rather than an efficacy trial, and it should be read as such. Cortical ADC was reduced by semaglutide and by empagliflozin monotherapy, while the combination arm showed no significant cortical ADC change, an inconsistency the authors do not resolve and which argues against any simple additive interpretation. Total kidney volume fell by a modest 3% to 5% across active arms, a change plausibly reflecting reduced glomerular hyperfiltration rather than structural protection. Two cautions deserve emphasis. First, these are imaging surrogates: ADC was proposed as a marker of kidney microstructure and possible fibrosis, yet the authors explicitly note their findings may reflect effects unrelated to fibrosis, so the biological meaning remains uncertain. Second, with only 20 participants per arm and post hoc analysis of multiple ADC and volume measures, the risk of chance findings and limited precision is real, as the wide confidence intervals show. Can I use this with my patients? Not yet in any direct sense. Nothing here changes prescribing, since established renal benefit for these agents rests on hard-outcome trials, not on diffusion MRI. The signal is most relevant to researchers designing mechanistic studies. The trial was investigator-led with disclosed manufacturer involvement, which warrants the usual scrutiny. What is needed is larger imaging-anchored work linking ADC and TKV changes to validated histology and to clinical kidney endpoints before these measures can inform care.
References
Vernstrøm L, Gullaksen S, Sørensen SS, Ringgaard S, Laustsen C, Birn H, et al. Effects of semaglutide, empagliflozin and their combination on renal diffusion-weighted MRI and total kidney volume in patients with type 2 diabetes: a post hoc analysis from a 32 week randomised trial. Diabetologia. 2024;67(10):2175-2187. doi:10.1007/s00125-024-06228-y
