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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
PCSK9 inhibitors: A new era of lipid lowering therapy
Rahul Chaudhary1, Jalaj Garg1, Neeraj Shah1
1Rahul Chaudhary, Department of Medicine, Sinai Hospital of Baltimore, Johns Hopkins University, Baltimore, MD 21209, United States.
Insights
New PCSK9 inhibitors offer effective LDL-cholesterol reduction for patients intolerant to statins or with severe hypercholesterolemia. These novel medications provide a significant additional benefit beyond statin therapy for cardiovascular disease risk management.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Biochemistry
Background:
- Hyperlipidemia is a major risk factor for cardiovascular disease (CVD).
- Current guidelines recommend statins for high-risk individuals, but treatment options are limited for statin-intolerant patients or those with severe hypercholesterolemia.
- Novel therapies are needed for advanced lipid management.
Purpose of the Study:
- To review the biology of proprotein convertase subtilsin-kexin type 9 (PCSK9).
- To explore mechanisms for altering PCSK9 activity.
- To discuss clinical trials and current availability of PCSK9 inhibitors for LDL-cholesterol reduction.
Main Methods:
- Review of scientific literature on PCSK9 biology and lipid-lowering therapies.
- Analysis of clinical trial data for PCSK9 inhibitors.
- Examination of FDA-approved PCSK9-targeting medications.
Main Results:
- PCSK9 inactivation by novel agents like Evolocumab and Alirocumab prevents LDL receptor degradation.
- This mechanism leads to significant additional LDL-cholesterol reduction (50%-60%) beyond statin therapy.
- PCSK9 inhibitors represent a new class of drugs for managing hyperlipidemia.
Conclusions:
- PCSK9 inhibitors provide a valuable therapeutic option for specific patient populations with hyperlipidemia.
- These agents offer enhanced LDL-cholesterol lowering for patients with statin intolerance or severe hypercholesterolemia.
- Further research and clinical application of PCSK9 inhibitors are expected to impact CVD prevention.
Abstract:
Hyperlipidemia is a well-established risk factor for developing cardiovascular disease (CVD). The recent American College of Cardiology and American Heart Association guidelines on lipid management emphasize treatment of individuals at increased risk for developing CVD events with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) at doses proven to reduce CVD events. However, there are limited options for patients who are either intolerant to statin therapy, develop CVD despite being on maximally tolerated statin therapy, or have severe hypercholesterolemia. Recently the Food and Drug Administration approved two novel medications for low-density lipoprotein (LDL)-cholesterol reduction: Evolocumab and Alirocumab. These agents target and inactivate proprotein convertase subtilsin-kexin type 9 (PCSK9), a hepatic protease that attaches and internalizes LDL receptors into lysosomes hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone. This review explores PCSK-9 biology and the mechanisms available to alter it; clinical trials targeting PCSK9 activity, and the current state of clinically available inhibitors of PCSK9.
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