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 journalArticle

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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)
JournalDiabetes, Obesity and Metabolism
DOIs
StatePublished - Jan 1 2019

Fingerprint

Type 2 Diabetes Mellitus
Sodium-Glucose Transporter 2
Symporters
Placebos
Confidence Intervals
Albumins
Creatinine
Urine
Placebo Effect
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Gas Chromatography-Mass Spectrometry
Cross-Over Studies
Therapeutics
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Kidney

Keywords

  • albuminuria
  • dapagliflozin
  • metabolomics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Effects of dapagliflozin on urinary metabolites in people with type 2 diabetes. / Mulder, Skander; Heerspink, Hiddo J.L.; Darshi, Manjula; Kim, Jiwan J.; Laverman, Gozewijn D.; Sharma, Kumar; Pena, Michelle J.

In: Diabetes, Obesity and Metabolism, 01.01.2019.

Research output: Contribution to journalArticle

Mulder, Skander ; Heerspink, Hiddo J.L. ; Darshi, Manjula ; Kim, Jiwan J. ; Laverman, Gozewijn D. ; Sharma, Kumar ; Pena, Michelle J. / Effects of dapagliflozin on urinary metabolites in people with type 2 diabetes. In: Diabetes, Obesity and Metabolism. 2019.
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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.",
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AU - Laverman, Gozewijn D.

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N2 - 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.

AB - 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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