Journal Article

Dapagliflozin modulates plasma lipidomic profile and urinary metabolite excretion in type 2 diabetes

Gastaldelli, Amalia, Mengozzi, Alessandro, Pezzica, Samantha, Carli, Fabrizia, Sabatini, Silvia, Pratesi, Filippo, Solini, Anna

2025

Overview

Background Dapagliflozin (DAPA) has shown major nephroprotective effects, improving kidney metabolism and oxigenation. Lipidomics and metabolomics are powerful tools for understanding such effects, providing a comprehensive look at how SGLT2 inhibitors might change the metabolic landscape beyond their primary glucose-lowering action. We investigated changes in plasma metabolomic/lipidomic profile and urinary excretion of metabolites that could occur independent of increased diuresis. Methods A two-armed, parallel-design, randomized clinical trial was conducted in subjects with type 2 diabetes and hypertension who received treatment with DAPA 10 mg/day or hydrochlorothiazide 12.5 mg/day for four weeks. Lipidomics and metabolomics were performed by high resolution mass spectrometry in fasting plasma and 24-hour urine samples collected before and after treatment. Results Compared to hydrochlorothiazide, DAPA significantly increased plasma isoleucine, methionine, citrate, β-hydroxybutyrate and decreased lactate. DAPA induced plasma lipid remodeling towards a significant raise in free fatty acids (FFAs) and some sphingomyelins and lysophosphatidylcholines containing these fatty acids. A significant change was observed in plasma medium- and short-chain acylcarnitines, positively correlated with changes in plasma FFAs and β-hydroxybutyrate. In addition, DAPA, but not hydrochlorothiazide, significantly increased 24-h urinary excretion of several amino-acids, lactate, TCA cycle metabolites, β-hydroxybutyrate and electrolytes, except for a decrease in malate excretion. Conclusions DAPA treatment has major effects on the plasma lipidomic and the urine metabolomic profiles, with significant increased renal excretion of several metabolites, especially amino-acids, independently of increased diuresis. These data offer insights into the complex metabolic pathways leading to kidney protection by SGLT2 inhibitors. Clinical Trial Information European Union Drug Regulating Authorities Clinical Trials No. 2015-004164-11. Graphical abstract

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Aged / Amino acids / Angiology / Antihypertensive Agents - adverse effects / Antihypertensive Agents - therapeutic use / Benzhydryl Compounds - adverse effects / Benzhydryl Compounds - therapeutic use / Biomarkers - blood / Biomarkers - urine / Blood Glucose - drug effects / Blood Glucose - metabolism / Cardiology / Cholesterol / Chromatography / Clinical trials / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - blood / Diabetes Mellitus, Type 2 - diagnosis / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - urine / Diuresis / Excretion / Fatty acids / Female / Glucagon / Glucose / Glucosides - adverse effects / Glucosides - therapeutic use / High density lipoprotein / Humans / Hydrochlorothiazide / Hydrochlorothiazide - therapeutic use / Hypertension - blood / Hypertension - diagnosis / Hypertension - drug therapy / Hypertension - urine / Isoleucine / Kidney / Kidneys / Lactic acid / Lipid Metabolism - drug effects / Lipidomic / Lipidomics - methods / Lipids / Lipids - blood / Lipoproteins / Male / Mass spectrometry / Mass spectroscopy / Medicine / Medicine & Public Health / Metabolic pathways / Metabolism / Metabolites / Metabolomic / Metabolomics / Metabolomics - methods / Methionine / Middle Aged / Plasma / Renal Elimination - drug effects / Renal function / Scientific imaging / SGLT2 inhibitors / Sodium-Glucose Transporter 2 Inhibitors - adverse effects / Sodium-Glucose Transporter 2 Inhibitors - therapeutic use / Software / Statistical analysis / Time Factors / Treatment Outcome / Tricarboxylic acid cycle / Type 2 diabetes / Urine