LDL subspecies and lipidome change by evolocumab add-on therapy to empagliflozin in patients with type 2 diabetes: A prespecified secondary analysis of a randomized clinical trial.

BACKGROUND

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce cardiovascular risk in type 2 diabetes. Whether these benefits are partly mediated by modifications in low-density lipoprotein (LDL) phenotype, beyond changes in LDL-cholesterol levels, remains unknown.

METHODS

In this prespecified analysis of the EXCEED-BHS3 randomized trial, 110 individuals with type 2 diabetes were assigned to 16 weeks of empagliflozin (E) or empagliflozin plus evolocumab (EE). Changes in LDL subspecies profiles were assessed in the full cohort, while LDL lipidomic alterations were evaluated in a randomly selected subset of 50 participants. Associations between lipidomic features and endothelial function were subsequently explored.

RESULTS

Empagliflozin monotherapy did not affect LDL cholesterol levels or LDL subfraction proportions. As expected, EE therapy reduced LDL cholesterol by 61 ± 27% (intragroup and intergroup p < 0.001) and shifted LDL subspecies composition, increasing LDL1 (+49 ± 32%), LDL2 (+22 ± 12%), and LDL5 (+27 ± 18%), while reducing LDL3 (-18 ± 9%) and LDL4 (-17 ± 6%). Lipidome profiling revealed 118 altered species with E and 189 with EE. E therapy decreased phosphatidylcholine (-59%), phosphatidylethanolamine (-67%), phosphatidylinositol (-73%), and cholesteryl esters (-20%), while increased phytosteryl esters (+33%), a marker of intestinal cholesterol absorption. EE therapy increased triglyceride-polyunsaturated fatty acids (+47%), ceramides (+74%), phosphatidylcholine (+41%), phosphatidylethanolamine (+100%), and vitamin E (+100%), and reduced cholesteryl esters (-70%), cholesteryl oxyesters (-43%), phosphatidylethanolamine (-89%), and 2H- (-75%) and 3H-ceramides (-100%). Improvement in endothelial function correlated with reductions in cholesteryl esters and oxyesters, and with increases in phosphatidylcholine, ceramides, vitamin E, and triglyceride-polyunsaturated fatty acids.

CONCLUSIONS

These findings indicate that the addition of PCSK9i to SGLT2i therapy elicits remodeling of LDL subspecies and lipid composition, with mechanistic implications for vascular protection in type 2 diabetes.