Effects of dapagliflozin on urinary metabolites in people with type 2 diabetes

• Published in: Diabetes, obesity & metabolism Vol. 21; no. 11; pp. 2422 - 2428
• Main Authors: Mulder, Skander, Heerspink, Hiddo J. L., Darshi, Manjula, Kim, Jiwan J., Laverman, Gozewijn D., Sharma, Kumar, Pena, Michelle J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-2019; Wiley Subscription Services, Inc
• Subjects: Aged; Albumin; albuminuria; Albuminuria - urine; Angiotensin-converting enzyme inhibitors; Antidiabetics; Benzhydryl Compounds - pharmacology; Benzhydryl Compounds - therapeutic use; Creatinine; dapagliflozin; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - urine; Female; Glucose transporter; Glucosides - pharmacology; Glucosides - therapeutic use; Humans; Ketone Bodies - urine; Male; Mass spectroscopy; Metabolism; Metabolites; Metabolome - drug effects; Metabolomics; Middle Aged; Mitochondria; Sodium; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Urine; albuminuria; metabolomics; dapagliflozin
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.13823

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.