CASE REVIEW

Evolocumab greatly reduces low-density lipoprotein cholesterol levels in familial hypercholesterolemia: A local case review

30 Oct 2020
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Prof. Brian Tomlinson

Faculty of Medicine,
Macau University of Science and Technology

Patients with familial hypercholesterolemia (FH) have an elevated low-density lipoprotein cholesterol (LDL-C) level, which translates into a higher risk of cardiovascular events.1 Although maximum standard treatment of statins and ezetimibe in FH patients helps reduce the LDL-C level by at least 50%, the recommended level is yet to be met.2 Phase 3 clinical trials have demonstrated that evolocumab plus stable lipid-lowering agents further lowered LDL-C level in both heterozygous FH (HeFH) and homozygous FH (HoFH).3,4 Professor Brian Tomlinson, from the Faculty of Medicine at the Macau University of Science and Technology, shared a case involving a patient with HeFH who achieved the satisfactory LDL-C level with evolocumab.

Background

FH is a genetic condition in which most patients harbor a mutation in the low-density lipoprotein (LDL) receptor gene. This causes disruption in the metabolism of LDL, resulting in an abnormally high serum LDL-C level in patients.1 The elevated LDL-C level in turn increases the risk of premature cardiovascular diseases.1 According to the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) 2019 guidelines, patients with FH are categorized into the high-risk group, whereas the very-high-risk group includes individuals with FH and other major risk factors.5 In addition to the target of at least 50% reduction from baseline, the LDL-C goals are <1.8mmol/L for the highrisk group and <1.4mmol/L for the very-high-risk group.5 Although the combination of statin and ezetimibe could help FH patients achieve at least 50% reduction of the LDL-C level from baseline, the target absolute LDL-C level could not be reached in some patients.2,5

Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors, such as evolocumab, are recommended for very-high-risk FH patients if the combination of ezetimibe and maximal tolerated statin fails to achieve the LDL-C goal.5 Phase 3 clinical trials of evolocumab illustrated the effectiveness of lowering LDL-C on top of the standard statin-based treatment in HeFH and HoFH.3,4 This highlights the potential of evolocumab in regulating LDL-C level and reducing cardiovascular risk in FH patients.

Prof. Tomlinson shared a case of a HeFH patient who could not achieve desirable LDL-C levels with the combination of statin and ezetimibe alone. Despite the patient’s high-risk profile, the addition of evolocumab to the standard treatment significantly reduced his LDL-C level.

Case report

The patient is a 62-year old male HeFH patient with a smoking habit. His mother had been diagnosed with HoFH and his sisters had been diagnosed with HeFH. In 1995, he was first referred to a lipid clinic due to asymptomatic hyperlipidemia. His baseline LDL-C level was 7.25mmol/L at initial presentation, and cholestyramine was prescribed as an early treatment. Three years later, the patient switched to the maximum dose of lovastatin, which helped reduce his LDL-C level to 4.8mmol/L. In 2004, the regimen was changed to rosuvastatin 20mg daily, which further lowered his LDL-C level to 4.3mmol/L. After six years, his LDL-C level showed additional decrease after adding ezetimibe 10mg daily to the statin therapy.

In 2011, the patient experienced chest pain and underwent computed tomography (CT) angiography. The diagnosis of three-vessel disease (3VD) was established and the possibility of acute myocardial infarction was excluded. The patient then received percutaneous coronary intervention (PCI) with four stents placed. His LDL-C level ranged from 3.2 to 3.5mmol/L with the maintenance of ezetimibe and rosuvastatin. However, Prof. Tomlinson considered such level unsatisfactory because the recommended LDL-C level goal for FH or established cardiac disease was 1.8mmol/L at that time.

Two years later, the patient was enrolled into the clinical trial of evolocumab specific to FH. In addition to the standard treatment of ezetimibe and rosuvastatin, he was first allocated to administer evolocumab 420mg monthly before switching to evolocumab 140mg biweekly. The lowest LDL-C level achieved was 0.49mmol/L, while the levels ranged from 0.9 to 1.9mmol/L during the treatment of evolocumab plus rosuvastatin and ezetimibe. During the clinical trial, his initial lipoprotein (a) [Lp(a)] level was 224nmol/L, which was much higher than the normal range (<35nmol/L). Prof. Tomlinson explained that Lp(a) was seldom measured in the local hospital setting, and this measurement from the clinical trial revealed an additional risk factor for the patient. Prof. Tomlinson added, “We can see that he has the three major risk factors: LDL cholesterol, smoking and Lp(a).”

After the end of the clinical trial in 2016, the patient discontinued evolocumab and switched to rosuvastatin 20mg daily, ezetimibe 10mg daily and cholestyramine 4g twice daily. Since then, his LDL-C level has returned to 3.4mmol/L (Figure 1). Prof. Tomlinson highlighted that the patient would likely deteriorate again as most patients with extensive disease would experience progression unless the LDL-C level is well-regulated below 1.8mmol/L.

Discussion

Early diagnosis of FH is important. Since FH patients have high LDL-C level throughout their lives, the accumulated exposure to high LDL-C levels would pose a greater risk than those who develop high LDL-C levels due to dietary factors.5 When comparing individuals with the same LDL-C level, those who have a high LDL-C level because of genetic causes, such as FH patients, have a 3-fold increase in risk of further cardiovascular events.6 Therefore, more aggressive treatment at an earlier stage is recommended for these high-risk patients to reduce the risk of coronary artery disease.5 Another benefit of early diagnosis is to protect the family members of the diagnosed patient. Since FH is a genetic disease, there is a 50% chance for the patients’ offspring to develop FH. If FH patients could be identified early at younger adolescent ages and treated accordingly to reduce their LDL-C levels, the early intervention could prevent disease development and progression, and hence lessen the need for aggressive treatment in later stages.5 Therefore, patients may be referred to specific genetic counseling services if needed, while simple advice could be given by the physicians to highlight the inheritance of FH and the importance of screening for early treatment. Prof. Tomlinson remarked that, “The sooner you start the treatment, the better the prognosis.”

Despite the benefits of early diagnosis, FH remains underdiagnosed in Hong Kong. Prof. Tomlinson stated that while there is no data of local FH prevalence, the prevalence of HeFH was estimated to be about 1 in 250 people globally.5 Yet, the limited number of patients identified reveals the issue of underdiagnosis. Prof. Tomlinson cited the lack of physicians’ awareness and not having cholesterol measurements done as the primary reasons for FH underdiagnosis. Prof. Tomlinson continued by introducing the Dutch Lipid Clinic Network diagnostic criteria for FH diagnosis (Table 1).7 He highlighted that this common diagnostic algorithm primarily distinguished patients by using LDL-C level and family history, followed by an examination of physical signs and genetic testing, if available.7

 

After the diagnosis, patients would be advised about treatment and lifestyle change. Prof. Tomlinson pointed out that patients should initiate smoking cessation and reduce the uptake of certain types of saturated fats and cholesterol in addition to pharmacological intervention. Although some FH patients can achieve reasonable LDL-C level with statin alone, most patients cannot meet the target level and require the addition of ezetimibe. Prof. Tomlinson mentioned that while the target LDL-C level in ESC/EAS 2019 guidelines for primary prevention is potentially achievable, a substantial proportion of patients still requires the prescription of PCSK9 inhibitors for achieving the ideal LDL-C level.

In the RUTHERFORD-2 trial, patients with HeFH tolerated evolocumab well in addition to the standard treatment of statin with or without ezetimibe and yielded rapid 60% reductions in LDL-C level compared with placebo.3 For the TESLA trial part B, patients with HoFH who received evolocumab achieved significantly lower LDL-C level compared with placebo.4 Prof. Tomlinson shared that in his daily practice, similar clinical outcomes have been achieved in comparison to those reported in the clinical trials. Even though evolocumab showed consistent benefits of reducing LDL-C level in FH patients, Prof. Tomlinson added that, “It is important to look at the risk level in patients as not all patients with FH need a very low target (<1.4mmol/L).” Prof. Tomlinson further suggested that it is essential to assess the overall cardiovascular risk in order to plan treatment and reminded that having FH with high LDL-C level is just one of many important risk factors.

Treatment adherence is the major challenge for FH long-term management. Prof. Tomlinson explained that when patients do not show symptoms, they are less likely to adhere to the treatment because the benefits are less visible. Therefore, physicians should conduct regular follow-up and discussion with patients to explain the necessity of long-term treatment in order to lower the cardiovascular risk.

Prof. Tomlinson highlighted, “It is important to recognize the risk related to FH, the combination of risks, the additional risk of having high Lp(a) and being a smoker. These factors put the patients in such a high-risk category that you have to treat them very aggressively. We need to recognize the condition at an early stage, do not wait until it is too late.”

Conclusion

Patients with FH have a lifelong elevated LDL-C level, resulting in a higher risk of cardiovascular events. Although early diagnosis and intervention of FH could be beneficial in preventing disease progression and lowering cardiovascular risks, the disease remains largely underdiagnosed in Hong Kong, prompting the need for FH awareness and higher rate of serum cholesterol measurement. Moreover, evolocumab has been demonstrated to be suitable for FH patients who could not achieve the target LDL-C level with the combination of ezetimibe and maximal tolerated statin. However, for the optimal disease management, clinicians should not neglect other major risk factors, such as Lp(a) and the patient’s smoking status.

This is an independent editorial article, published and distributed through unrestricted educational support from Amgen Hong Kong Limited, for the purpose of continuing medical education only. The views expressed in this publication reflect the experience and/or opinion of the author(s) and are not necessarily those of editors, publisher and sponsor(s). Because of rapid advances in medicine, independent verification of clinical diagnoses, medical suitability and dosage should be made before treatment prescription. The appearance of advertisement, if any, has no influence on editorial content or presentation and does not imply the endorsement of products by the publication, or its authors and editors.


References
  1. Gidding SS et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation. 2015;132(22):2167-92.
  2. Nordestgaard BG et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478-90a.
  3. Raal FJ et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331-40.
  4. Raal FJ et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341-50.
  5. Mach F et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-88.
  6. Khera AV et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol. 2016;67(22):2578-89.
  7. Civerira F et al. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis. 2004 Mar;173(1):55-68.