Changes in the metabolome after treatment with canagliflozin in patients with type 2 diabetes

Sodium glucose co-transporter-2 inhibitors (SGLT2i) such as canagliflozin have been shown to have beneficial cardiovascular and renal effects, independent of the anti-glycaemic effects. This study aimed to improve understanding of the mechanism of action of SGLT2i by investigating changes in the metabolome after treatment with canagliflozin in order to confirm metabolite changes in prior smaller studies and discover novel metabolic pathways for further investigation.

Comprehensive metabolomic analyses of baseline and 52-week follow-up plasma samples were done for 955 of the 10 142 Canagliflozin Cardiovascular Assessment Study Programme participants (629 intervention and 326 control), who have type 2 diabetes and high cardiovascular risk, using high performance liquid chromatography coupled to mass spectrometry. A total of 165 metabolites were included in the final analysis. Analysis of metabolites was done with linear models with adjustment by age, gender and body mass index.

Treatment with canagliflozin compared with placebo was associated with upregulation of 19 metabolites, downregulation of 13 metabolites and no change in the remainder 133 metabolites. The most upregulated were malonate (fold change 1.31), involved in the tricarboxylic acid cycle; 3-hydroxybutyrate (fold change 1.33), a ketone body; and 2-oxobutanoate (fold change 1.31), a keto acid. The most downregulated were glucose (fold change 1.12); prephenate (fold change 1.38), an aromatic acid precursor; and glyceraldehyde (fold change 1.12), a glycolytic intermediate. Pathway analysis demonstrated upregulation of the lipid pathways and downregulation of amino acid pathway. Metabolites in novel pathways were also seen to be altered such as 3-indol-propionic acid in the antioxidant system.

In the largest metabolomics study of SGLT2i in humans performed to date, treatment with canagliflozin was associated with significant changes in 32 metabolites, of which 21 were reported for the first time. These may have importance for understanding the beneficial effects of SGLT2i on cardiovascular, metabolic and renal outcomes that occur independently of glucose alterations.