Dapagliflozin does not impair LDL catabolism and induces a shift towards a closer to normal VLDL1/VLDL2 catabolism in individuals with type 2 diabetes: a randomised in vivo kinetic study

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Abstract

AIMS/HYPOTHESIS: SGLT2 inhibitors reduce atherosclerosis, but their effect on lipid metabolism remains unclear. Animal studies have suggested that SGLT2 inhibitors may decrease LDL catabolism by reducing the hepatic expression of LDL receptors. However, the effect of SGLT2 inhibitors on LDL metabolism, and more widely on all ApoB-containing lipoproteins, remain unknown in humans. This prompted us to study the effect of the SGLT2 inhibitor dapagliflozin on the metabolism of ApoB100-containing lipoproteins in individuals with type 2 diabetes. METHODS: We performed a parallel double-blinded in vivo kinetic study using stable isotopes (tri-deuterated [2H3-labelled] L-leucine) in 24 individuals with type 2 diabetes before and after 6 months of treatment with dapagliflozin (10 mg/day) or placebo, given after randomisation. All individuals completed the study. RESULTS: Compared with placebo-treated individuals (n=7), those who received dapagliflozin (n=17) showed a significant reduction of body weight (p<0.001) and HbA1c (p=0.001). Plasma triglyceride, LDL-cholesterol and ApoB100 levels were not significantly modified by dapagliflozin treatment. LDL-ApoB100 fractional catabolism remained unchanged after dapagliflozin treatment (0.88 ± 0.37 vs 0.79 ± 0.31 pool/day, p=0.16). Similarly, no significant modification of the LDL-ApoB100 pool or LDL-ApoB100 production rate was observed. However, dapagliflozin induced a significant reduction in direct catabolism of VLDL1-ApoB100 (0.33 ± 0.65 vs 2.37 ± 2.31 pool/day, p=0.001) and a significant increase in the indirect catabolism of VLDL1-ApoB100 towards VLDL2 and IDL (2.71 ± 1.51 vs 1.68 ± 1.46 pool/day, p=0.001), and of VLDL2-ApoB100 towards IDL-ApoB100 (3.57 ± 1.68 vs 2.64 ± 1.90 pool/day, p=0.049), which is more representative of normal physiology. No significant side-effects were observed. CONCLUSIONS/INTERPRETATION: Dapagliflozin does not impair the catabolism of LDL in individuals with type 2 diabetes. It reduces direct catabolism of VLDL1 and increases indirect catabolism of VLDL1 towards VLDL2 and IDL, and of VLDL2 towards IDL, which is closer to normal metabolism. This may contribute to the reduction of atherosclerosis observed with use of SGLT2 inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov NCT03269058 FUNDING: The study was funded via grants and support from AstraZeneca, the French National Research Agency (ANR) under the programme 'Investissements d'Avenir', the University of Burgundy-Franche-Comté, the National Institute of Health and Medical Research (Inserm), the Region Burgundy - Franche Comté, and the Fonds Européens de Développement Régional.

Abstract as published, via PubMed.