Effects of dapagliflozin on urinary metabolites in people with type 2 diabetes
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Aim: To assess the effects of the sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor dapagliflozin on a pre‐specified panel of 13 urinary metabolites linked to mitochondrial metabolism in people with type 2 diabetes and elevated urine albumin levels. Materials and methods: Urine and plasma samples were used from a double‐blind, randomized, placebo‐controlled crossover trial in 31 people with type 2 diabetes, with an albumin:creatinine ratio >100 mg/g, and who were on a stable dose of an angiotensin‐converting enzyme inhibitor or an angiotensin receptor blocker. Dapagliflozin or placebo treatment periods each lasted 6 weeks, with a 6‐week washout period in between. Urinary and plasma metabolites were quantified by gas‐chromatography mass spectrometry, corrected for creatinine level, and then combined into a single‐valued urinary metabolite index. Fractional excretion of the metabolites was calculated. Results: All 13 urinary metabolites were detectable. After 6 weeks of dapagliflozin therapy, nine of the 13 metabolites were significantly increased from baseline. The urinary metabolite index increased by 42% (95% confidence interval [CI] 8.5 to 85.6; P = .01) with placebo versus 121% (95% CI 69 to 189; P < .001) with dapaglifozin. The placebo‐adjusted effect was 56% (95% CI 11 to 118; P = .012). In plasma, seven of the 13 metabolites were detectable, and none was modified by dapagliflozin. Conclusions: Dapagliflozin significantly increased a panel of urinary metabolites previously linked to mitochondrial metabolism. These data support the hypothesis that SGLT2 inhibitors improve mitochondrial function, and improvements in mitochondrial function could be a mechanism for kidney protection. Future studies with longer treatment duration and clinical outcomes are needed to confirm the clinical impact of these findings.
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Urinary beta-OH-butyrate rises significantly after dapagliflozin, and the rise correlates with changes in erythropoietin and hematocrit in type 2 diabetes and CKD patients.
“Indeed, urinary b -OH-butyrate concentrations were significantly increased following treatment with the SGLT2 inhib- Perspective itors dapagliflozin, and the rise in b -OH-butyrate correlated with changes in erythropoietin and hematocrit in patients with T2D and CKD (Kim et al., 2019a; Mulder et al., 2019).”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Mulder et al., 2019
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Self-citationWang, G., Zhao, Y., Liu, G., Du, Y., Liu, S., Yang, Y., Bu, S., & Zhao, B. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27198451
- Authors
- Mulder, S., Heerspink, H. J. L., Darshi, M., Kim, J. J., Laverman, G. D., Sharma, K., & Pena, M. J.
- Affiliations
- University Medical Center Groningen (NL)
- The University of Texas at San Antonio Health Science Center (US)
- Ziekenhuis Groep Twente (NL)
- Corresponding author
- Pena, Michelle J.
- ORCID
- Venue
- Diabetes, Obesity and Metabolism
- Publisher
- Wiley
- Published
- 2019-07-18
- Volume
- 21
- Issue
- 11
- Pages
- 2422-2428
- ISSN
- 1462-8902 (ISSN-L)
- 1463-1326
- OpenAlex
- W2954378976
- Cited by
- 65
- References
- 25
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 12 · 2023: 9 · 2022: 9 · 2021: 13 · 2020: 9 · 2019: 3
- FWCI
- 6.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes Obesity and Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Funders
- Sanofi
- European Federation of Pharmaceutical Industries and Associations
- European Commission (HORIZON2020, 115974)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (917.15.306)
- Novo Nordisk
- Astellas Pharma
- Innovative Medicines Initiative (115974)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- dapagliflozin, SGLT2 inhibitors, type 2 diabetes, urinary metabolites, mitochondrial metabolism, albuminuria, diabetic nephropathy, renal protection, fractional excretion, plasma metabolites
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Aged, Albuminuria, Benzhydryl Compounds, Diabetes Mellitus, Type 2, Female, Glucosides, Humans, Ketone Bodies, Male, Middle Aged, Metabolomics, Metabolome
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