Do You Prescribe PCSK9 Inhibitors Properly?

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibits the recycling of low-density lipoprotein (LDL) receptors to the cell surface and escorts them to lysosomes for degradation. Gain-of-function mutations in the PCSK9 gene cause high LDL cholesterol (LDL-C) levels, with an autosomal dominant form of inheritance.¹ In contrast, patients with loss-of-function mutations in PCSK9 are healthy, despite markedly low LDL-C levels, and have a reduced risk of developing coronary artery disease.^2–5

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Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, and deplete intracellular cholesterol, resulting in activation of sterol regulatory element-binding protein 2 (SREBP2), which senses decreased intracellular cholesterol and promotes LDL uptake from the blood via increased LDL-receptor expression downstream of SREBP2. Consequently, blood LDL-C levels are reduced, and intracellular cholesterol levels are restored.

However, SREBP2 also stimulates PCSK9 secretion so that LDL-receptor expression does not continuously increase. Therefore, PCSK9 partially contributes to the “6% rule of statins” (i.e., doubling the statin dose does not reduce LDL-C levels by more than 6%).⁶

Understanding these mechanisms, the best LDL-C lowering efficiency is when PCSK9 inhibitors are used after maximally increasing both the LDL receptor and PCSK9 by administering the maximum tolerated dose of statins.⁷ In Japan, it is clearly stated that a PCSK9 inhibitor should be added to the maximum tolerated dose of statin.⁸

Do you prescribe PCSK9 inhibitors properly?

In this issue of the Journal, Sheng (an employee of Amgen Inc.) et al use a medical database to report the characteristics of 4,022 patients prescribed evolocumab in real-world practice settings in Japan.⁹ They found that most of the prescriptions for evolocumab were initiated in the outpatient setting of large hospitals with more than 200 beds. This result may reflect the fact that evolocumab is mainly prescribed by physicians specializing in cardiology and lipid metabolism. (Unfortunately, the drug is still too difficult for general practitioners to access.) They also found that 23.4% of the patients prescribed the drug were patients with familial hypercholesterolemia (FH), 40.6% were post-acute myocardial infarction, and 14.0% were post-unstable angina, which suggests that prescribers are familiar with strict LDL-C control targets set out in the Japan Atherosclerosis Society’s guidelines (2022 edition)¹⁰ for these patients.

Sheng et al⁹ also report that the prescription period for evolocumab was short. It is possible that in some cases the drug was discontinued after consultation between the physician and patient due to its high cost. Unfortunately, there are no data provided by these authors on the percentage of patients prescribed evolocumab who achieved LDL-C control targets.

The biggest concern is the concomitant medications with evolocumab. This study found that as many as 22.3% (898 patients) were not prescribed any lipid-lowering medications before using evolocumab, which further increased to 29.6% (1,190 patients) after starting evolocumab. Considering the frequency of statin intolerance,¹¹ it is probable that not all of the patients were statin intolerant. It may have been the case that some patients received other oral medications such as statins at their medical clinic and only evolocumab at a large hospital, but not many, considering the characteristics of this drug, which can be self-injected at home.

It is also likely that many patients were not taking the maximum tolerated dose of statins, based on the medication history shown in table 3 of this paper. Furthermore, the increase in the number of patients receiving no concomitant treatment (i.e., evolocumab only) after starting evolocumab implies that some patients had discontinued drugs other than evolocumab or had their dosages reduced. I am concerned that an understanding of the link between statins, LDL receptors, and PCSK9, as I mentioned at the beginning of this editorial, is not widespread among doctors who prescribe evolocumab (Figure).

Figure.

The link between statins, low-density lipoprotein (LDL) receptors, and PCSK9. (A) Statins enhance SREBP2-mediated LDL receptor and PCSK9 expression by inhibiting cholesterol synthesis. Statins promote blood LDL uptake via enhanced LDL-receptor expression, but this effect is attenuated by concurrently enhanced PCSK9 expression. (B) Evolocumab is a monoclonal antibody against PCSK9. Therefore, if evolocumab is administered with both LDL-receptor expression and PCSK9 secretion maximized by prescribing the maximum tolerated statin dose, LDL-C-lowering will be more efficient. PCSK, proprotein convertase subtilisin/kexin type 9; SREBP2, sterol regulatory element-binding protein 2.

Because evolocumab is a costly drug, it is understandable that patients would want to reduce healthcare costs as much as possible if the LDL-C level were sufficiently lower than the control target. However, this may be a flawed way of reducing healthcare costs. Based on a scientific and economic rationale, the dose of a low-cost statin should be maintained at the maximum tolerated dose, and the dosing interval of high-cost evolocumab should be extended.

Inclisiran, a small interfering RNA for PCSK9, has recently been launched in Japan. Because this drug is administered 2–3 times a year, it is particularly critical to have a routine oral treatment regimen for maintaining LDL-C control targets in high-risk patients. Amgen provided important real-world data when its new PCSK9 inhibitor was launched.⁹ However, in order to balance the excellent LDL-C lowering effect (+ ASCVD prevention effect) of such PCSK9 inhibitors with the sustainability of the insurance healthcare system, companies that market them should continue to work with academic societies to educate doctors and the public on the correct way of prescribing them.

Funding

This work is supported by a grant from the Labor and Welfare Sciences Research Grant for Research on Rare and Intractable Diseases (21FC1009).

Disclosures

M.O. received lecture fees from Amgen, Ultragenyx Japan, and Kowa.

References

• 1.   Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34: 154–156.
• 2.   Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: Its role in LDL metabolism. Trends Biochem Sci 2007; 32: 71–77.
• 3.   Lambert G, Charlton F, Rye KA, Piper DE. Molecular basis of PCSK9 function. Atherosclerosis 2009; 203: 1–7.
• 4.   Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006; 79: 514–523.
• 5.   Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2007; 193: 445–448.
• 6.   Pearson TA, Laurola I, Chu H, Kafonek S. The lipid treatment assessment project (L-TAP): A multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000; 160: 459–467.
• 7.   Ogura M. PCSK9 inhibition in the management of familial hypercholesterolemia. J Cardiol 2018; 71: 1–7.
• 8.   Nohara A, Ohmura H, Okazaki H, Ogura M, Kitagawa K, Koseki M, et al. Statement for Appropriate Clinical Use of PCSK9 Inhibitors. J Atheroscler Thromb 2018; 25: 747–750.
• 9.   Sheng F, Wang AY, Miyawaki K, Tsuchiya T, Osada N, Miller R, et al. Real-world clinical profile of patients prescribed evolocumab in Japan. Circ J 2024, doi:10.1253/circj.CJ-23-0814.
• 10.   Okamura T, Tsukamoto K, Arai H, Fujioka Y, Ishigaki Y, Koba S, et al. Japan Atherosclerosis Society (JAS) Guidelines for prevention of atherosclerotic cardiovascular diseases 2022. J Atheroscler Thromb 2023, doi:10.5551/jat.GL2022.
• 11.   Kajinami K, Tsukamoto K, Koba S, Inoue I, Yamakawa M, Suzuki S, et al. Statin intolerance clinical guide 2018. J Atheroscler Thromb 2020; 27: 375–396.