Is a PCSK9 Inhibitor Right for Your Patient? A Review of Treatment Data for Individualized Therapy

Abstract

Introduction: In the United States, a significant amount of the population is affected by hyperlipidemia, which is associated with increased levels of serum low-density lipoprotein (LDL-C) and risk of cardiovascular disease. As of 2019, the guidelines set by the American College of Cardiology/American Heart Association advocate for the use of statins as the major contributor to lowering serum LDL-C. While proven to be effective, side effects, including muscle-related symptoms and new-onset diabetes mellitus, can make patients unable to tolerate statin therapy. Additionally, there is a subset of the population which does not approach a recommended LDL-C goal on statin treatment. Due to these findings, it was deemed necessary to review the literature of current statin-alternative lipid-lowering therapies.

Methods: A systematic review of preclinical and clinical papers, and a current meta-analysis, was performed using PubMed and Google Scholar. Following the literature review, a meta-analysis was conducted using ProMeta 3.

Results: Through systematic review and meta-analysis of the current literature, it is suggested that newer lipid-lowering therapies such as proprotein convertase subtilsin-kixen type 9 (PCSK9) inhibitors are a safe and effective statin alternative for the population with statin intolerance. PCSK9 inhibitors were shown to have no significant effect in causing myalgia in patients and showed no increase in adverse cardiovascular outcomes compared to a control of a current antilipemic medication regimen.

Discussion: There are many statin-alternative therapies that should be investigated further as a potential replacement for patients with statin intolerance or as an addition for patients with statin resistance.

Keywords: 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA); cardiovascular; hyperlipidemia; low-density lipoprotein; proprotein convertase subtilsin-kixen type 9 inhibitor (PCSK9i); statin intolerance; statin resistance; statin-associated muscle symptoms (SAMS).

Figure 1

Inhibition of cholesterol synthesis pathway by bempedoic acid and statins. Bempedoic acid inhibits ACL upstream of HMG CoA reductase (top of figure). Statins inhibit HMG CoA reductase downstream of ACL (center of figure). BA and statins promote the upregulation of LDL receptors thereby increasing LDL-C clearance and reducing plasma LDL-C (bottom of figure). ACL, ATP citrate lyase; BAA, bempedoic acid; HMG-CoA, β-hydroxy β-methylglutaryl-CoA; LDL-C, low-density lipoprotein cholesterol; LDL-R, low-density lipoprotein receptor.

Figure 2

Proposed mechanism for statin-induced myopathy. Impaired calcium signaling increases mitochondrial caspase activity, and apoptosis results in CLC-1 channel inhibition and hyperexcitation of cell membrane (left of figure). Inhibition of the cholesterol synthesis pathway alters membrane composition, promoting membranolysis (right of figure). ATP, adenosine triphosphate; CLC-1, chloride channel 1; FAD, flavin adenine dinucleotide; HMG-CoA, β-hydroxy β-methylglutaryl-CoA; MPT pore, mitochondrial permeability transition pore; PKC, protein kinase C; TCA, tricarboxylic acid.

Figure 3

Proposed pathways for statin-induced type 2 diabetes mellitus via inhibition of the cholesterol synthesis pathway. Reductions in GLUT 4 receptors results in decreased insulin sensitivity (center of figure). Reduced translocation of insulin receptors results in decreased insulin sensitivity (center right of figure). Reduced calcium influx results in decreased insulin secretion (bottom right). ATP, adenosine triphosphate; GLUT 4, glucose transporter type 4; HMG-CoA, β-hydroxy β-methylglutaryl-CoA.

Figure 4

Proposed mechanisms of statin-induced type 2 diabetes mellitus. Hydrophobic statins (pravastatin, rosuvastatin) require active transport to enter the cell (left of figure). Lipophilic statins (atorvastatin, cerivastatin, lovastatin, simvastatin, pitavistatin) can freely diffuse across the cell membrane (right of figure). The first letter of each statin is listed where it acts in the insulin secretion pathway. Akt, protein kinase B; A, Atorvastatin; Cav1, caveolin 1; C, Cerivastatin; GF, growth factor; GLUT 4, glucose transporter type 4; IR, insulin receptor; IRS-1, insulin receptor substrate 1; L, Lovastatin; P, phosphate; PI3K, phosphoinositide 3 kinase; Rab4, ras-associated binding protein 4; Ras, rat sarcoma; S, Simvastatin.

Figure 5

The mechanism of action of PCSK9 inhibition in the hepatocyte. (1) PCSK9 marks the LDL receptor for endocytosis and lysosomal degradation. (2) An anti-PCSK9 antibody prevents PCSK9 binding to the LDL-R. (3) The free LDL-R clears more LDL particles. (4) A decrease in intracellular cholesterol due to statins will upregulate LDL-Rs and subsequent clearance. HMG-CoA, β-hydroxy β-methylglutaryl-CoA; LDL, low-density lipoprotein; PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL, very low-density lipoprotein.

Figure 6

Funnel plot for meta-analysis of incidence of myalgia. Funnel depicts no publication bias for meta-analysis of myalgia incidence in anti-PCSK9 group vs. control group.

Figure 7

Forest plot for meta-analysis of myalgia incidence. Forest plot depicting effect size and weight for each of the studies included in the meta-analysis of myalgia incidence in anti-PCSK9 group vs. placebo group. Graphically, the effect size is represented as the center of each box while the box size represents the weight of each study and the whiskers represent the 95% confidence interval for each study. Center line (ES = 1) is the line of no effect where intervention (PCSK9 inhibitors or placebo) has no effect on outcome (no incidence of myalgia). The overall ES of 0.91 favors PCSK9 inhibitors. ES, effect size; W, weight [49].

Figure 8

Funnel plot for meta-analysis of incidence of myocardial infarction. Funnel depicts no publication bias for meta-analysis of incidence of myocardial infarction in anti-PCSK9 group vs. control group.

Figure 9

Forest plot for metanalysis of incidence of myocardial infarction. Forest plot depicting effect size and weight for each of the studies included in the meta-analysis of myocardial infarction incidence in anti-PCSK9 group vs. placebo group. Graphically, the effect size is represented as the center of each box while the box size represents the weight of each study and the whiskers represent the 95% confidence interval for each study. Center line (ES = 1) is the line of no effect where intervention (PCSK9 inhibitors or placebo) has no effect on outcome (no incidence of myocardial infarction). The overall ES of 0.68 favors PCSK9 inhibitors. ES, effect size; W, weight.