Corresponding Author
Key Words: familial hypercholesterolemia, lipid lowering therapy, prevention, statin intolerance, therapeutic inertia
Familial hypercholesterolemia (FH) is an autosomal codominant genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol (LDL-C) leading to a high risk for atherosclerotic cardiovascular disease (ASCVD).1,2 Despite the prevalence (∼1 in 250 individuals for heterozygous FH), this disorder remains underdiagnosed.2,3 Reassuringly, the current armamentarium of lipid-lowering therapeutics (LLTs) can now help patients with FH achieve guideline-directed LDL-C lowering. These drugs include hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins), ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs), and the newer agents bempedoic acid and the PCSK9 siRNA inclisiran.4,5
In this issue of JACC: Case Reports, Lin and Stone6 present the case of a 71-year-old woman with a history of heterozygous FH and coronary artery disease. Her therapeutic course was complicated by statin-associated muscle symptoms (SAMS) despite de-challenging and re-challenging with statins. Her condition was managed with ezetimibe, and she was started on evolocumab. After no improvement with evolocumab, she was switched to alirocumab. Despite initial improvement, she had a rise in LDL-C leading to suspicion for development of neutralizing antibodies against the PCSK9 mAbs. She was transitioned to inclisiran, with a significant and durable reduction in LDL-C.
This case highlights key points in the management of hypercholesterolemia: SAMS management, the use of newer LLTs (ie, bempedoic acid and inclisiran), and the differential diagnosis for poor response to PCSK9 mAbs. However, 2 aspects of this case warrant further discussion.
The first point is that high-risk patients are undertreated. In a U.S.-based cohort of patients with myocardial infarction, only ∼18% of patients with FH achieved an LDL-C level <70 mg/dL.7 A Spanish cohort found <10% of FH patients with cardiovascular disease attaining an LDL-C level <70 mg/dL.8 Data in primary prevention are only marginally better, with approximately one-third of patients achieving LDL-C control.8,9 Although this case highlights FH, unfortunately the same undertreatment applies to patients with ASCVD, as seen in large registries.10, 11, 12
The second, and more important, point is the concept of “therapeutic persistence.” To the best of my knowledge, this term is newly defined. Lin and Stone6 state that therapeutic persistence is the “continued effort by the provider to adjust or intensify therapy to achieve optimal therapeutic targets” (Figure 1). As they note, therapeutic inertia is the failure of clinicians to initiate or intensify guideline-directed therapy, and this is a barrier to the treatment of many conditions.13 Although many factors contribute to therapeutic inertia, I believe it is incumbent that we providers adopt “therapeutic persistence.” Lin and Stone6 state that this is a “crucial trait in the contemporary era of managing patients with high ASCVD risk, such as patients with FH”; I would extend this to specifically include secondary prevention patients, too.
Figure 1.
Therapeutic Persistence
Clinicians should engage patients in shared decision making to discuss therapeutic goals, available therapy, and adverse effects. This should be an ongoing conversation to ensure that personalized treatment of the right patients with the right medications to the right therapeutic goals is achieved.
The 2013 cholesterol guidelines, chaired by Dr Stone, brought the concept of a clinician-patient risk discussion to the foreground14 and reinforced the need to match the intensity of treatment to patients’ risk.14,15 Providers must help contextualize risk for patients and engage them in shared decision making about therapy. Given the multitude of LLTs, there is little reason we cannot achieve adequate LDL-C control.5 By regularly assessing risk, lipid control, and adverse effects, providers can persist in matching the right therapy to the patient.
On a personal note, as a fourth-year medical student, I had the privilege of working with Dr Stone during an elective best summarized as a master class on doctoring. Although this rotation fueled my interest in lipids and prevention and started me down my career path, my most valuable lessons were about the type of provider I wanted to be. Therefore, I am humbled to continue learning from Dr Stone and believe all of us should emulate Drs Lin and Stone: for those managing high-risk patients, we must be insistent that we be persistent.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The author attests they are in compliance with human studies committees and animal welfare regulations of the author’s institution and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
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