Serious flaws in targeting LDL-C reduction in the management of cardiovascular disease in familial hypercholesterolemia

ABSTRACT

Recently, Polychronopoulos and Tziomalos reviewed research on the use of inclisiran and bempedoic acid in the management of cardiovascular disease (CVD) risk in people with familial hypercholesterolemia (FH). Their treatment recommendations were based on the general premise that high LDL-cholesterol (LDL-C) is inherently atherogenic, and that low levels of LDL-C need to be achieved to reduce CVD risk in FH individuals. However, their perspective on LDL-C is flawed at two levels of analysis: 1) They ignored the extensive literature demonstrating that CVD is not caused by high LDL-C; and 2) they failed to consider CVD treatment strategies that take into account the extensive literature that has shown that coagulation factors are more closely related to coronary events in FH than is LDL-C. In the following, we have briefly addressed each of these flaws in their review.

KEYWORDS:

• Familial hypercholesterolemia
• LDL-cholesterol
• inclisiran
• bempedoic acid
• cardiovascular disease
• atherosclerosis
• myocardial infarction
• coagulation

Recently, Polychronopoulos and Tziomalos reviewed research on the use of inclisiran and bempedoic acid in the management of cardiovascular disease (CVD) risk in people with familial hypercholesterolemia (FH) [1]. Their treatment recommendations were based on the general premise that high LDL-cholesterol (LDL-C) is inherently atherogenic, and that low levels of LDL-C need to be achieved to reduce CVD risk in FH individuals. However, they have ignored the many studies having shown that high LDL-C is not the cause of atherosclerosis or CVD. In the following, we have briefly addressed each of these flaws.

In a recent paper we have reviewed the extensive evidence that high LDL-C is not the cause of CVD [2]. For example, there is no exposure-response in the statin trials between the degree of LDL-C lowering and total mortality. Several studies have shown that degree of atherosclerosis is not associated with LDL-C, neither in people with FH [3] nor in non-FH people [4]. Moreover, the LDL-C of patients with acute myocardial infarction is lower than normal, and the risk increases if it is lowered even more [2]. The reason for these contradictions to the common view about CVD is most likely that LDL is an important participants in the immune system [5], and there is much evidence that infectious diseases may increase the risk of atherosclerosis [6].

Further evidence that high LDL-C is not inherently atherogenic was provided in a systematic review of 19 follow-up studies on mortality rate in relation to LDL-C levels. This study demonstrated that most people over 60 years of age with the highest LDL-C lived longer than those with low LDL-C; none of the reviewed studies found the opposite [7]. Since then, many studies have confirmed these findings [8].

A pathophysiological mechanism that was ignored by Polychronopoulos and Tziomalos is the extensive evidence of hypercoagulopathy in the small subset of FH individuals that develop premature CVD, as reviewed by Ravnskov et al [3]. and Diamond et al [9]. In brief, people with FH have significantly higher sensitivity to platelet aggregating agents than the general population. In a study of 62 subjects with FH, half of whom had CVD, plasma fibrinogen and factor VIII were significantly higher among those with CVD, whereas there was no significant difference with regards to LDL-C [3]. In a genotype study of 1940 FH people, polymorphism in the prothrombin gene was significantly higher among those with CVD, independent of LDL-C levels [10]. Finally, mean platelet volume is significantly greater in FH subjects [3], and larger platelets are more active and thereby prone to adhesion and aggregation [11].

The hypothesis that increased coagulability is the cause of premature CVD in FH is in accordance with an experiment on rabbits with FH [12]. These rabbits have significantly higher levels of factor VIII and fibrinogen compared with normal rabbits, and treatment of them with probucol, which has anticoagulant effects, lowered factor VIII and fibrinogen and prevented atherosclerosis in the absence of a significant reduction of plasma cholesterol.

In the context of hypercoagulation as a well-established contributor to CVD in FH, it is surprising that in their review, Polychronopoulos and Tziomalos did not include the extensive literature on lipoprotein a [Lp(a)] and CVD. Lp(a) is a major prothrombotic and antifibrinolytic agent and is a well-established risk factor for CVD [13]. Unlike LDL-C, Lp(a) is one of the most robust of all markers of CHD risk in FH and non-FH populations. In FH, elevated levels of Lp(a) are more closely associated with CHD than is LDL-C. For example, Seed et al. showed that FH individuals with CHD had significantly greater levels of Lp(a) compared to FH individuals without CHD, and the association of Lp(a) with CHD was independent of their LDL-C levels [14].

The misdirection in targeting LDL-C reduction as prevention of CVD is compounded by combining the adverse effects of statins with adverse effects caused by bempedoic acid. As Polychronopoulos and Tziomalos [1] stated in their review, ‘treatment with this agent (bempedoic acid) is associated with an increase in uric acid, creatinine, and hepatic enzyme levels and with a 3.5-times increase in the incidence of gout. … Moreover, the incidence of adverse events leading to discontinuation was 44% higher in patients treated with bempedoic acid than those who received placebo … ’. Thus, the obsession with LDL-C reduction puts FH individuals at risk of developing serious adverse effects from treatments that have not been shown to produce significant benefits.

Our conclusions are in accord with a recent review of 35 cholesterol-lowering trials by DuBroff et al [15]. Contrary to the general view, some of the trials with a very modest reduction of LDL-C reported cardiovascular benefits, while most of the trials with a substantial reduction of LDL-C reported no benefit. Therefore, the small benefit in coronary events with statins cannot have been due to cholesterol-lowering, and as pointed out by DuBroff et al., ‘the LDL-C-centric approach to cardiovascular disease prevention may have distracted us from investigating other pathophysiologic mechanisms and treatments.’ We have suggested that one of the pathophysiologic mechanisms that has been largely ignored in FH treatment is their predisposition toward hypercoagulopathy. This is a critical issue in the day-to-day management of families with high cholesterol. Practitioners should identify FH individuals with evidence of hypercoagulability, such as high levels of fibrinogen, Lp(a) or increased platelet volume, and treat them accordingly to more effectively prevent CVD events.

Declaration of interest

U. Ravnskov and M. Kendrick have declared writing books with criticism of the cholesterol campaign. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

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Funding

This paper was not funded.