Related Experiment Video
Updated: Mar 10, 2026
Differential Effects of Lipid-lowering Drugs in Modulating Morphology of Cholesterol Particles
Published on: November 10, 2017
Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism
Gerald F Watts1, Dick C Chan2, Ricardo Dent2
1From Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Australia (G.F.W.); School of Medicine and Pharmacology, University of Western Australia, Crawley (D.C.C., S.B., P.H.R.B.); Amgen Europe, Inc, Zug, Switzerland (R.D., R.S., S.M.W.); and Amgen Inc, Thousand Oaks, CA (R. Scott). gerald.watts@uwa.edu.au.
Background:
Monoclonal antibodies 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 monoclonal antibodies 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 conducted 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-apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was 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<0.001 and P.032, respectively), intermediate-density lipoprotein-apoB (P=0.021 and P=.002, respectively), and LDL-apoB (P<0.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of intermediate-density lipoprotein-apoB (P=0.043) and LDL-apoB (P<0.001), which contributed to the reduction 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<0.001). 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 intermediate-density lipoprotein 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 monoclonal antibodies incremental to statins in on-going clinical end point trials.
Clinical Trial Registration:
URL: http://www.clinicaltrials.gov. Unique identifier: NCT02189837.
Insights
Evolocumab, a PCSK9 monoclonal antibody, reduces LDL cholesterol by increasing lipoprotein catabolism and decreasing production. Combination therapy with atorvastatin showed greater LDL reduction than monotherapy, offering a distinct metabolic benefit.
Area of Science:
- Lipid Metabolism
- Pharmacodynamics
- Cardiovascular Research
Background:
- Proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibodies, like evolocumab, lower LDL cholesterol.
- The precise mechanism of PCSK9 inhibitors on lipoprotein metabolism requires further elucidation.
- Stable isotope tracer kinetics is a valuable tool for studying lipid-regulating pharmacotherapies.
Purpose of the Study:
- To investigate the effects of atorvastatin and evolocumab on the plasma kinetics of VLDL, IDL, and LDL apolipoprotein B-100 (apoB).
- To compare the metabolic mechanisms of action of atorvastatin and evolocumab, individually and in combination.
- To provide kinetic insights into the incremental benefits of PCSK9 inhibitors beyond statin therapy.
Main Methods:
- A 2x2 factorial trial involving 81 healthy men.
- Administration of atorvastatin (80 mg/day) and/or evolocumab (420 mg every 2 weeks) for 8 weeks.
- Stable isotope infusion of D3-leucine, GC/MS, and multicompartmental modeling to study apoB kinetics in VLDL, IDL, and LDL.
Main Results:
- Both atorvastatin and evolocumab accelerated the fractional catabolism of VLDL-apoB, IDL-apoB, and LDL-apoB.
- Evolocumab, but not atorvastatin, reduced the production rates of IDL-apoB and LDL-apoB, decreasing plasma lipoprotein levels.
- Combination therapy yielded significantly greater reductions in LDL-apoB and LDL cholesterol compared to monotherapy.
Conclusions:
- Evolocumab reduces atherogenic lipoproteins, primarily LDL, by enhancing their catabolism and decreasing their production.
- The kinetic profile of evolocumab demonstrates a distinct mechanism of action compared to atorvastatin.
- These findings support the potential for additive cardiovascular benefits of PCSK9 monoclonal antibodies when used with statins.
Related Concept Videos
01:20Lipid-Lowering Drugs: Statins and Miscellaneous Agents
01:29Cholesterol: Significance and Regulation
Considering cholesterol and...
01:25Lipid Catabolism
01:25Blood Studies for Cardiovascular System III: Serum Lipid Profile
Serum lipids are fats and fatty substances in the blood and are crucial for various bodily functions, including energy storage, cellular structure, and hormone production. Serum lipids consist of cholesterol, triglycerides, and phospholipids.
Cholesterol is a soft, fat-like substance found in all body cells. It is crucial for producing hormones, vitamin D, and substances that aid...
01:24Overview of Lipid Metabolism
Lipolysis: The Breakdown of Lipids:
Lipolysis is the process of breaking down lipids, particularly triglycerides, into glycerol and fatty acids. This process typically occurs in the adipose tissue and is triggered by various hormones, including glucagon and...
01:24Lipid Absorption
These breakdown products bind with bile salts and lecithin to form micelles, which quickly pass between microvilli to come in close contact with the apical...