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

Skander Mulder, Hiddo J.L. Heerspink, Manjula Darshi, Jiwan J. Kim, Gozewijn D. Laverman, Kumar Sharma, Michelle J. Pena

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2422-2428
Number of pages7
JournalDiabetes, Obesity and Metabolism
Volume21
Issue number11
DOIs
StatePublished - Nov 1 2019

Keywords

  • albuminuria
  • dapagliflozin
  • metabolomics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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