Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are glucose lowering drugs which inhibit renal tubular reabsorption of primary filtrated glucose leading to urinary glucose excretion and osmotic diuresis. SGLT2 inhibitors reduce CV events in patients with type 2 diabetes (T2D) and atherosclerotic CV disease. Irrespective, several studies have found treatment with SGLT2 inhibitors to increase the proatherogenic low density lipoprotein cholesterol (LDL-C). The mechanism relevant for LDL-C increase currently remains unclear while some studies have suggested diuresis-dependent hemoconcentration as a potential mechanism. In addition, modulation of lipoprotein subfractions and apolipoproteins in response to SGLT2 inhibition has not been studied.   

Aim: This study examined early and delayed effects of empagliflozin on LDL-C, lipoprotein subfractions and apolipoproteins including LDL particle size and composition.
   
Methods: In this placebo-controlled, randomized, double blind study patients with T2D were randomized to empagliflozin 10 mg (n=20) or placebo (n=22). Blood was taken after day 1 and day 3 in addition to 3 months of treatment and compared to baseline values for lipoprotein profiles. Composition of lipoprotein subfractions was assessed before and after 3 months of treatment. Lipoproteins were separated using a combined ultracentrifugation-precipitation method (β-quantification).   

Results: Empagliflozin did not increase LDL-C (baseline: 103 ± 36 mg/dL) after day 1 (102 ± 36 mg/dL; p=0.915) or day 3 (102 ± 40 mg/dL; p=0.477) of treatment despite augmentation of urinary glucose excretion and urinary volume. LDL-C however increased after 3 months of empagliflozin treatment (112 ± 47 mg/dL; p<0.001) suggesting hemoconcentration to be an unlikely mechanism. Analyses of lipoprotein subfractions revealed LDL phospholipids, LDL free (unesterified) cholesterol and LDL apolipoprotein B to be increased by empagliflozin after 3 months of treatment while LDL particle size was not affected (baseline: 16.6 ± 0.3 nm; month 3: 16.7 ± 0.3 nm; p=0.246). In addition empagliflozin increased free fatty acid concentrations but had no effect on high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C) or apolipoprotein concentrations.     

Conclusion: In conclusion we found empagliflozin to increase LDL-C in a delayed manner independent of its diuretic effects.