Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism
Background—Monoclonal antibodies (mAbs) against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 mAbs on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid regulating pharmacotherapies.
Methods—We carried out a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very low-density lipoprotein (VLDL)-apolipoprotein B-100 (apoB), intermediate-density lipoprotein (IDL)-apoB, and LDL-apoB in 81 healthy, normolipidemic, non-obese men. The kinetics of apoB in these lipoproteins were studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling.
Results—Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB (P<.001 and P.032, respectively), IDL-apoB (P=.021 and P=.002, respectively), and LDL-apoB (P<.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of IDL-apoB (P=.043) and LDL-apoB (P<.001), which contributed to the reductions in the plasma pool sizes of these lipoprotein particles. The reduction in LDL-apoB and LDL-cholesterol concentrations was significantly greater with combination versus either monotherapy (P<.001). Whereas evolocumab but not atorvastatin lowered the concentration of free PCSK9, atorvastatin lowered the lathosterol/campesterol ratio (a measure of cholesterol synthesis/absorption) and apoC-III concentration. Both interventions decreased plasma apoE, but neither significantly altered lipoprotein lipase and cholesteryl ester protein mass or measures of insulin resistance.
Conclusions—In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in IDL and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 mAbs incremental to statins in on-going clinical endpoint trials.
Clinical Trial Registration—NCT02189837; https://clinicaltrials.gov
- Received August 23, 2016.
- Revision received October 20, 2016.
- Accepted November 23, 2016.