Effect of alirocumab on postprandial hyperlipidaemia in patients with type 2 diabetes: A randomized, double‐blind, placebo‐controlled, cross‐over trial

Postprandial hyperlipidaemia (PPL), characterized by elevated triglyceride (TG) concentrations after a meal, is common in type 2 diabetes (T2D) and is often recognized as an independent cardiovascular risk factor. Here, we aimed to assess the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition by alirocumab on PPL in patients with T2D. EUTERPE is a randomized, double-blind, placebo-controlled cross-over trial conducted in male patients with T2D. Participants received sequentially two sequences of 10-week treatment (alirocumab 75 mg Q2W or placebo s/c) with a wash-out period of 10 weeks. The primary end-point was the percentage reduction in plasma TG response after an oral fat load (incremental area under the curve [iAUC]0-8h TG). Secondary end-points included mass spectrometry-based apolipoprotein measurements and nuclear magnetic resonance (NMR)-based lipoprotein profiling. Fourteen participants were included: age 59 ± 9 years, BMI 32.8 ± 5.5 kg/m2, HbA1C 6.7 ± 0.5%. Compared to placebo, alirocumab did not reduce PPL (iAUC0-8h TG: -5% [CI 95%: -28, +25], p = 0.68). Alirocumab decreased fasting non-HDL cholesterol (-38.5 ± 5.6%, p = 0.0003), remnant cholesterol (-20.0 ± 13.3%, p = 0.04), apoB100 (-21.2 ± 6.4%, p = 0.004) and apoE (-15.3 ± 6.6%, p = 0.02) concentrations. NMR analyses showed that alirocumab decreased both postprandial VLDL2 cholesterol (-42% [-55, -25], p < 0.001) and IDL cholesterol (-26% [-38, -12], p = 0.0007), without effect on VLDL1 cholesterol or TG concentrations. Inhibition of PCSK9 by alirocumab did not reduce PPL in T2D, confirming that PCSK9 controls remnant cholesterol catabolism rather than intestinal chylomicron production.