Impact of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab on the postprandial responses of triglyceride-rich lipoproteins in type II diabetic subjects

Abstract

Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly lower the levels of low-density lipoprotein and very-low-density lipoproteins (VLDL), but their effect on postprandial lipoprotein metabolism in dyslipidemic subjects is unclear. This study aimed to investigate the effects of evolocumab on postprandial lipid responses, ectopic fat depots, whole-body cholesterol synthesis, hepatic lipogenesis, and fat oxidation in patients with type II diabetes. The trial was a single-phase, nonrandomized study of 12-week treatment with evolocumab 140mgsubcutaneously every 2weeks in 15 patients with type II diabetes on background statin therapy. Cardiometabolic responses to a high-fat mixed meal were assessed before and at the end of the intervention period. Evolocumab treatment reduced significantly postprandial rises in plasma total triglyceride (by 21%; P<.0001) and VLDL1 triglyceride (by 15%; P=.018), but the increase in chylomicron triglyceride after the meal was not significantly perturbed (P=.053). There were reduced postprandial responses in plasma total apolipoprotein C-III (by 14%; P<.0001) and apolipoprotein B-48 concentration (by 17%; P=.0046) and in "remnant-like particles" cholesterol (by 29%; P<.0001) on the PCSK9 inhibitor. Treatment reduced the steady-state (ie, fasting and postprandial) concentrations of VLDL2 cholesterol by 50% (P<.0001) and VLDL2 triglyceride by 29% (P<.0001), in addition to the 78% reduction of low-density lipoprotein cholesterol (P<.001). The changes in apolipoprotein C-III associated significantly with reduction in postprandial responses of remnant-like particles cholesterol and triglyceride-rich lipoprotein cholesterol. Evolocumab therapy did not influence liver fat accumulation, hepatic de novo lipogenesis, or fasting β-hydroxybutyrate but did increase total body cholesterol synthesis (P<.01). Evolocumab treatment improved postprandial responses of triglyceride-rich lipoproteins and measures of cholesterol-enriched remnant particles in type II diabetic subjects. These results indicate that postprandial phenomena need to be taken into account in assessing the full range of actions of PCSK9 inhibitors in dyslipidemic individuals.