A 58-year-old man is seen in the clinic 6 months after undergoing right coronary artery stent placement due to unstable angina. His father died at age 50 from coronary artery disease. The patient follows a healthy diet and exercise plan and is compliant with his current medication regimen. BMI is 29 kg/m². Physical examination is unremarkable. After extensive discussion with the patient, evolocumab is added to his treatment plan. Which of the following is expected as an immediate result of this treatment?

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11ec160b_3bb6_ce68_9249_a3657ce191ee_MD0001_00 Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease that regulates the concentration of low-density lipoprotein receptor (LDL-R) on the hepatocyte cell surface. Binding of PCSK9 to LDL-R causes increased lysosomal degradation of LDL-R, which leads to decreased uptake of circulating LDL into hepatocytes. PCSK9 inhibitors (eg, evolocumab, alirocumab) are monoclonal antibodies that inhibit binding of PCSK9 to LDL-R, which decreases LDL-R degradation and increases the concentration of LDL-R remaining on the cell surface. This results in greater uptake of LDL in the liver and lower circulating LDL levels. When statins are used to treat high LDL levels, circulating levels of PCSK9 are upregulated, suggesting that PCSK9 pathway inhibition may complement the LDL-lowering effect of statins. Therefore, PCSK9 inhibitors are indicated for high-risk patients who have persistently elevated LDL despite statin therapy; PCSK9 inhibitors reduce the risk of cardiovascular events (eg, myocardial infarction, stroke) in these patients. (Choice A) Statins (eg, atorvastatin) are the primary, first-line lipid-lowering agents for patients who have atherosclerotic cardiovascular disease or are at increased atherosclerotic risk. They decrease hepatic cholesterol synthesis by inhibiting HMG-CoA reductase. (Choice B) Ezetimibe is a lipid-lowering drug that directly inhibits absorption of cholesterol in the small intestine. PCSK9 inhibitors do not inhibit intestinal cholesterol absorption. (Choice D) Insulin upregulates lipoprotein lipase, which hydrolyzes triglycerides in chylomicrons and VLDL; the liberated fatty acids are taken up in adipose tissue, leading to reduced plasma triglyceride levels. In contrast, PCSK9 inhibitors have little effect on triglycerides. (Choice E) Thyroid hormone increases expression of LDL-R, as does estrogen and various dietary factors (eg, low saturated fat diet). However, the increase in cell-surface LDL-R from PCSK9 inhibitors is due to decreased lysosomal degradation, not increased transcription (synthesis). Educational objective: Binding of proprotein convertase subtilisin kexin 9 (PCSK9) to low-density lipoprotein receptor (LDL-R) on the hepatocyte cell surface increases degradation of LDL-R, leading to decreased uptake of circulating LDL. PCSK9 inhibitors (eg, evolocumab, alirocumab) decrease LDL-R degradation, resulting in greater uptake of LDL in the liver and lower circulating LDL levels. __________ References: PCSK9 inhibitors: clinical evidence and implementation. (http://www.ncbi.nlm.nih.gov/pubmed/30420622)

A 58-Year-Old Man Is Seen in the Clinic 6 Months