Applied Evidence

Newer cholesterol-lowering agents: What you must know

J Fam Pract. 2018 June;67(6):339-341,344-345

From The Journal of Family Practice | 2018;67(6):339-341,344-345.

References

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7. GoodRx. Ezetimibe. Available at: https://www.goodrx.com/ezetimibe. Accessed May 2, 2018.

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18. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5:941-950.

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A new class to lower LDL-C: PCSK9 inhibitors

It is clear that additional approaches to LDL-C reduction are needed. A new drug class that effectively lowers LDL-C levels is monoclonal antibodies that inhibit PCSK9 (proprotein convertase subtilisin/kexin type 9). PCSK9 activity is directly proportional to the circulating LDL-C level: gene mutations that increase PCSK9 function are one cause of elevated LDL-C and CVD risk in familial hypercholesterolemia (FH),¹⁴ whereas mutations that decrease PCSK9 activity are associated with a decrease in LDL-C levels and risk of ASCVD.¹⁵

Circulating PCSK9 initiates LDL-receptor clearance by binding to the LDL receptor; the complex is then taken into the hepatocyte, where it undergoes degradation, and the receptor is not recycled to the cell’s surface. The resultant decreased level of cholesterol within the hepatocyte upregulates HMG-CoA reductase (the enzyme that controls the rate-limiting step in cholesterol production and is targeted by statin therapy) and LDL-receptor activity to increase the available cholesterol in the hepatocyte. Unfortunately, statins promote the upregulation of both the LDL receptor and PCSK9, thereby limiting their LDL-C-lowering potency. Combined inhibition of HMG-CoA reductase with statins and PCSK9 with monoclonal antibodies exerts additive reductions in LDL-C.¹⁶

Evolocumab and alirocumab—monoclonal antibodies that prevent circulating PCSK9 from binding to the LDL receptor—have been approved by the US Food and Drug Administration (FDA) for use as adjuncts to diet and maximally-tolerated statin therapy in adults who have heterozygous familial hypercholesterolemia (HeFH) or clinical ASCVD and who must further lower LDL-C levels. The addition of a PCSK9 inhibitor to statin therapy consistently results in an incremental decrease in LDL-C of around 60%.^10,11 Much of the data supporting the use of PCSK9 inhibitors are disease-oriented. Among patients with angiographic coronary disease treated with statins, the addition of evolocumab resulted in regression of atherosclerotic plaque measured by intravascular ultrasound after 18 months of treatment.¹⁰

Continue to: PCSK9 inhibitors reduce adverse CVD events when added to a statin