What’s in the web for family physicians ‒ Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9I)

Sio-pan Chan 陳少斌，Wilbert WB Wong 王維斌，Alfred KY Tang 鄧權恩

Proprotein convertase subtilisin kexin 9 (PCSK9) is a natural protein mostly found in the liver. It plays a key role in plasma cholesterol metabolism.

In 2011, the first study on PCSK9 was published by Canadian researchers on the loss-of-function mutation P CS K9 gene s pecific to a few F rench Canadian families. Such mutation was generally associated with significant longevity with a much lower incidence of cardiovascular diseases than average. Typically people with such mutations have very low levels of LDL cholesterol and are leading otherwise completely normal lives. Further studies revealed that the gene encoding PCSK9 is highly polymorphic. Two categories of PCSK9 sequence variant produce mild to moderate (and opposing) phenotypes. Gain-of-function sequence variant cause a reduction in the Low Density Lipoprotein Receptor (LDL-R) that leads to hypercholesterolaemia or autosomal dominant hypercholesterolaemia in severe phenotypic variants. PCSK9 loss-of-function sequence variant decrease LDLR degradation, thereby reducing LDL cholesterol (LDL-C) concentrations.

Pharmaceutics companies soon developed specific monoclonal antibodies to block the function of PCSK9 protein, which was shown to be working wonders in lowering LDL-C, by as much as 60% and without much apparent side effects. It can be used alone or in combination with other standard cholesterol lowering medication such as statins and ezetimibe. It is particularly suitable for secondary prevention in patients who are statin intolerant, or when maximum standard oral treatment fails to achieve treatment target.

PCSK9 Inhibitors (PCSK9I) utilise a completely different mechanism from statins, they do not involve the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) pathway. Theoretically they do not share the side effects of statin, such as CoQ10 depletion. PCSK9I are monoclonal antibodies so they are really a kind of targeted or gene therapy. The main drawbacks are cost and the need for subcutaneous injection.

However, the whole idea of using PCSK9I treatment is based on the “dogma” that lowering LDL-C will reduce cardiovascular disease, as we have discussed in our previous article “The cholesterol and stain controversy' (The Hong Kong Practitioners, March 2023 issue), the lipid hypothesis in atherosclerosis pathogenesis is still controversial and far from being settled. PCSK9Is were only marketed in 2015, present data suggests they are highly effective in lowering LDL-C and in secondary prevention of CVD. It is far too early to tell the long term side effects of very low LDL-C. A reanalysis was published in January 2023 on an important trial which raised safety concerns and efficacy of the results from FOURIER cardiovascular outcomes trial. This trial was one of the key trials for the approval of evolocumab, one of the two PCSKI on the market. After re-adjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm. Perhaps the true efficacy of PCSK9I and whether their high cost is justifiable remain to be seen. As a cautionary tale, we also did a search on the internet on the possible harmful effects of a very low level of LDL-C. They include haemorrhagic stroke, cancer and infectious diseases, references of which will be given below.

An update on the role of PCSK9 in atherosclerosis

Atherosclerosis is initiated by functional changes in the endothelium accompanied by accumulation, oxidation, and glycation of LDL-cholesterol in the inner layer of the arterial wall and continues with the expression of adhesion molecules and release of chemoattractants.

PCSK9 is a proprotein convertase that increases circulating LDL levels by directing hepatic LDL receptors into lysosomes for degradation. The effects of PCSK9 on hepatic LDL receptors and contribution to atherosclerosis via the induction of hyperlipidaemia are well defined. Monoclonal PCSK9 antibodies that block the effects of PCSK9 on LDL receptors demonstrated beneficial results in cardiovascular outcome trials. This review focuses on the molecular roles of PCSK9 in atherosclerotic plaque formation.

PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis

The aim of this article was to compare the impact of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on cardiovascular outcomes in adults taking maximally tolerated statin therapy or those who are statin intolerant. The authors identified 14 trials assessing ezetimibe and PCSK9 inhibitors among 83 660 adults using statins. They concluded that Ezetimibe or PCSK9 inhibitors may reduce non-fatal MI and stroke in adults at very high or high cardiovascular risk who are receiving maximally tolerated statin therapy or are statin-intolerant, but not in those with moderate and low cardiovascular risk.

Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolaemia: A meta- analysis of 35 randomised controlled trials

The aim of this article is to examine the efficacy and safety of two PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab. A systematic review and meta-analysis of randomised controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomised controlled trials comprising 45,539 patients (mean follow-up: 85.5 weeks) were included.

The authors concluded that treatment with a PCSK9 inhibitor was well tolerated and improved cardiovascular outcomes. Although no overall benefit was noted in all-cause or cardiovascular mortality, such benefit may be seen in patients with higher baseline low-density lipoprotein cholesterol.

Evolocumab and clinical outcomes in patients with cardiovascular disease

This paper concluded that at 48 weeks, the mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%. Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval (CI), 0.79 to 0.92; P < 0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P < 0.001).

Cognitive function in a randomised trial of evolocumab

In a randomised trial involving patients who received either evolocumab or placebo in addition to statin therapy, no significant between-group difference in cognitive function was observed over a median of 19 months. However, we think that the trial period of 19 months was probably far too short to make a definitive conclusion on such an important issue.

Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data.

The authors concluded “After re-adjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm. At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our re-adjudication. A complete restoration of the FOURIER trial data is required. In the meantime, clinicians should be sceptical about prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Low-density lipoprotein cholesterol and risk of intracerebral haemorrhage: A prospective study

The authors in this paper concluded that there is a significant association between lower LDL-C and higher risk of ICH when LDL-C was < 1.8mmol/L. The association became nonsignificant when LDL-C ≥ 1.8mmol/L. These data can help in the determination of the ideal LDL range in patients who are at increased risk of both atherosclerotic disease and haemorrhagic stroke, and guide the planning of future lipid-lowering studies. The level of LDL-C achieved by PCSK9I is far below 1.8mmol/L.

Low serum LDL cholesterol levels and the risk of fever, sepsis, and malignancy

The authors investigated the association of low serum LDL cholesterol levels (< or = 70 mg/dl) and the incidences of fever, sepsis, and malignancy. A retrospective analysis of 203 patients' charts was carried out. The result demonstrated increased odds of haematological cancer with LDL-C < 70mg/dl by more than 15-fold (OR 15.7, 95% CI 1.78-138.4, p = 0.01). Each 1 mg/dl increase in LDL was associated with a relative reduction of 2.4% in the odds of haematological cancer (OR 0.976, 95% CI 0.956-0.997, p = 0.026). Low LDL levels also increased the odds of fever and sepsis. In summary, low serum LDL cholesterol level was associated with increased risks of haematological cancer, fever, and sepsis. This study was published before the introduction of PCSK9I.