The effects of dapagliflozin on urinary metabolites in patients with type 2 diabetes

AIMS: Previously, a panel of 13 urinary metabolites linked to mitochondrial metabolism was found to be significantly reduced in patients with diabetic kidney disease and eGFR>60 ml/min/1.73m2 . The beneficial effects of SGLT-2 inhibition on cardio-renal outcomes are hypothesized in part due to improved work efficiency at the mitochondrial level. We therefore assessed the effects of the SGLT-2 inhibitor dapagliflozin, on this pre-specified panel of 13 urinary metabolites linked to mitochondrial metabolism in patients with type 2 diabetes and elevated albuminuria.MATERIALS AND METHODS: Urine and plasma samples were used from a double-blind, randomized, placebo controlled crossover trial in 31 patients with type 2 diabetes, albumin:creatinine ratio >100 mg/g, and on a stable dose of an Angiotensin Converting Enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). Dapagliflozin or placebo treatment periods each lasted for 6 weeks, with 6 weeks wash-out in between. Urinary and plasma metabolites were quantified by gas-chromatography mass spectrometry, corrected for creatinine, 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%CI: 8.5 - 85.6, p=0.01) with placebo compared to 121% (69 - 189, p<0.001) with dapaglifozin. Accordingly, the placebo-adjusted effect was 56% (11 - 118, p=0.012). In plasma, seven of the 13 metabolites were detectable, and none were modified by dapagliflozin.CONCLUSIONS: Dapagliflozin significantly increased a panel of urinary metabolites previously linked to mitochondrial metabolism. These data support the hypothesis that SGLT-2 inhibitors may improve mitochondrial function, and improvements in mitochondrial function may be a mechanism for kidney protection. Future studies of longer treatment duration and clinical outcomes are needed to confirm the clinical impact of these findings. This article is protected by copyright. All rights reserved.