ArticleBMC medicine2026
Urea cycle modulation by combined SGLT2 inhibitors and metformin.
Article in BMC medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
21 authors.
Funding
Abstract
backgroundSodium-glucose co-transporter 2 inhibitors (SGLT2i), when combined with metformin (COMBI), offer multi-organ protective effects in patients with type 2 diabetes (T2D), particularly those at high risk of cardiovascular or renal complications. However, the underlying molecular mechanisms remain poorly understood.
methodsWe profiled 303 targeted serum metabolites in 1494 participants of the KORA study, including T2D patients treated with COMBI therapy, metformin monotherapy, or no glucose-lowering medication. Additionally, metabolomic profiling was quantified on seven tissues (plasma, liver, adrenal glands, adipose tissue, testis, lung, and cerebellum), and related hepatic transcripts were evaluated in 40 mice. Multivariable linear regression analyses, adjusted for age, sex, BMI, lifestyle, glycemic, and cardiovascular risk factors, were applied to human data; tissue-specific regression analyses were conducted for murine samples. Identified metabolites were further investigated using biochemical pathway analyses and literature review.
resultsCOMBI therapy was associated with significant changes in metabolite profiles. In humans, 10 metabolites were significantly altered compared to metformin monotherapy. In mice, 82 altered metabolites were identified in plasma, 52 in liver, 30 in adrenal glands, 12 in adipose tissue, seven in testis, seven in lung, and six in cerebellum. COMBI therapy lowered threonine concentrations in both human serum and murine plasma but raised threonine, glycine, and urea cycle metabolites (citrulline, asymmetric dimethyl arginine (ADMA), and ornithine) in murine liver. This was accompanied by enhanced hepatic expression of Slc38a2, a threonine transporter gene. In humans, urea cycle metabolites correlated strongly with the fibrosis-4 index, a marker of liver fibrosis. Additionally, COMBI therapy elevated ketone body markers, such as hydroxybutyrylcarnitine, across murine liver, plasma, adrenal glands, adipose tissue, and testis.
conclusionsCOMBI therapy modulates amino acid metabolism, the urea cycle, and ketone body production, suggesting potential mechanisms underlying its protective effects against liver fibrosis and male subfertility. These findings provide novel insights into the systemic metabolic actions of COMBI therapy and highlight its translational potential to improve clinical outcomes in T2D patients.
Indexed as
Identifiers
What Socratic holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.