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Highlighted articles October

Volume 277 Issue October 2018

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

This issue of Atherosclerosis contains 41 peer-reviewed articles on “Improving the Global Care of Familial Hypercholesterolaemia: the FHSC Perspective” assembled by Kausik K Ray and Gerald F Watts as the Guest Editors. Beyond this thematic series, this issue contains several highly interesting original articles which address the measurement of LDL cholesterol, the modification of risk in familial hypercholesterolemia by circulating lipoprotein(a) and PCSK9, as well as state of the art and novel developments in the therapeutic management of hypercholesterolemia.

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Special Issue Section: Improving the Global Care of Familial Hypercholesterolaemia: the FHSC Perspective

The thematic series on the care of familial hypercholesterolaemia (FH) is opened by the Familial Hypercholesterolaemia Studies Collaboration (FHSC) report on the outcome of a survey on awareness, prevalence, management and treatment of FH across member countries and highlights a general lack of information on the prevalence of FH in most of the participating countries, and universally low rates of identification. Five invited reviews from leading experts in the field and more than 30 original papers add to the evolving corpus of information on FH, discussing current knowledge and gaps of information and data to be filled in in order to manage the worldwide burden of cardiovascular disease imposed by under-detected and under-treated FH. For more details, we invite the readers to read the editorial by our Guest Editors related to this special section.


Performance of LDL-C calculated with Martin's formula compared to the Friedewald equation in familial combined hyperlipidemia

Low density lipoprotein cholesterol (LDL-C) remains the principle goal of therapy in the management of dyslipidemia. Conventionally, LDL-C is calculated with the Friedewald equation, which estimates LDL-C as (total cholesterol) – (high-density lipoprotein cholesterol [HDL-C]) – (triglycerides/5) in mg/dL. The final term assumes a fixed ratio of triglyceride levels to very low-density lipoprotein cholesterol (TG:VLDL-C) of 5:1. This estimate is unreliable in patients with triglycerides ≥150 mg/dL, due to the fixed triglyceride to VLDL-C ratio, and does not consider the variance of this ratio across different concentrations of triglycerides and non-HDL-C. Martin et al. have developed a novel method to estimate LDL-C using an adjustable factor for the TG: VLDL-C ratio (using triglyceride and non-HDL-C concentrations). This method may permit a more accurate estimation of cardiovascular risk; however, external validation is needed. Here, Mehta et al. compared the performance of LDL-C using this new method (LDL-N) with LDL-C estimated with Friedewald equation (LDL-F) in familial combined hyperlipidemia (FCHL), a common primary dyslipidemia in which apolipoprotein B (Apo B) containing particle composition is abnormal and interferes with LDL-C estimation.

A total of 410 FCHL subjects were included. LDL-C was estimated with both LDL-F and the novel formula. Apo B levels and non- HDL-C were recorded. The correlation and concordance between LDL-F and LDL-N and both Apo B and non-HDL-C levels were calculated. An analysis stratifying for triglyceride tertiles and FCHL lipid phenotypes was carried out.

The correlations between LDL-N and Apo B and non-HDL-C were ρ = 0.777 and ρ = 0.735, respectively. The corresponding correlations for LDL-F were ρ = 0.551 and ρ = 0.394, respectively. In mixed dyslipidemia or isolated hypertriglyceridemia, these correlations were significantly better using LDL-N. With respect to concordance, LDL-N performed significantly better than LDL-F when considering ApoB <90 mg/dL and non-HDL-C <130.

In FCHL, LDL-C estimation using Martin's formula showed greater correlation and concordance with non-HDL-C and Apo B compared with the Friedewald equation.

The different relations of PCSK9 and Lp(a) to the presence and severity of atherosclerotic lesions in patients with familial hypercholesterolemia

The association of lipoprotein a [Lp(a)] and proprotein convertase substilisin/kexin type 9 (PCSK9) levels with coronary artery disease (CAD) has been well established in the general population, while little is known about the association of Lp(a) or PCSK9 and atherosclerotic lesions at different artery sites in patients with familial hypercholesterolemia (FH). In this study, Cao et al. aimed at investigating the potential relationships of PCSK9 and Lp(a) with clinically relevant atherosclerosis affecting different sites, in a cohort with heterozygous FH (HeFH).

One hundred and fifty-one HeFH patients were enrolled, with available data on coronary angiography and carotid ultrasonography and femoral ultrasonography. Coronary and carotid severity was evaluated by Gensini score and Crouse score. PCSK9 and Lp(a) concentrations were determined by ELISA and immunoturbidimetry, respectively. Moreover, the correlation of PCSK9 and Lp(a) with the presence and severity of CAD and peripheral artery disease (PAD) was assessed.

PCSK9 levels were significantly elevated in patients with coronary and carotid atherosclerotic lesions compared to the non-atherosclerotic groups, while no difference was found in the femoral atherosclerotic lesion groups. Lp(a) levels only differed between patients with or without coronary atherosclerotic lesions. Patients with the highest PCSK9 and Lp(a) concentrations had the highest prevalence and severity of atherosclerotic lesions. Multivariate regression analysis showed that PCSK9 was independently associated with CAD and PAD, while Lp(a) was only associated with CAD.

Circulating PCSK9 concentrations were associated with an increased risk of CAD and PAD, while Lp(a) was only a marker for CAD in HeFH patients.

Lipoprotein-apheresis in familial hypercholesterolemia: Long-term patient compliance in a French cohort

Lipoprotein apheresis (LA) is a rescue therapy for the treatment of severe FH, in patients’ refractory to the available drugs. It is a complex therapeutic option, and poor compliance can adversely affect treatment outcome. In this study, Béliard et al. aim to describe long-term compliance to treatment in patients undergoing regular LA therapy and to investigate factors related to low compliance.

11,391 prescribed procedures of LA performed between 1990 and 2007 in 51 patients with familial hypercholesterolemia were assessed. Regular LA treatment was initiated in patients presenting with either homozygous familial hypercholesterolemia or severe heterozygous familial hypercholesterolemia, with elevated LDL-cholesterol levels and who did not respond adequately to diet and drug therapy; the majority of these patients had cardiovascular disease at initiation of therapy.

The overall observed compliance rate based on the number of achieved/programmed procedures was 87.5%. Main causes of missed procedure were holidays and/or concomitant illness. Neither cardiovascular history nor subtypes of hypercholesterolemia were associated with compliance. In addition, there was no impact of patient demography on compliance. The frequency of treatment was the only determinant of low-compliance, patients having more than 2 LA/month had a 3-fold increased risk of low-compliance. Interestingly, a non-significant decrease in compliance was observed among patients aged <20 years.

Despite the complexity of the LA procedure and its impact on the organization of patients' daily lives, overall compliance was very high. The choice of an appropriate and adequate frequency of treatment had a significant impact on patient compliance. Cardiovascular history and genotype were not associated with low-compliance.

Efficacy and safety of alirocumab in patients with or without prior coronary revascularization: Pooled analysis of eight ODYSSEY phase 3 trials

Patients with atherosclerotic cardiovascular disease (ASCVD) and prior revascularization are at high risk of further cardiovascular events and may require additional lipid-lowering therapies beyond maximally tolerated statin therapy. Kereiakes et al. assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in patients with ASCVD, with or without prior coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]).

Data were pooled from eight placebo/ezetimibe-controlled Phase 3 ODYSSEY trials: alirocumab 150 mg or 75 mg with possible dose increase to 150 mg every 2 weeks compared to placebo or ezetimibe.

Among 4629 randomized patients with hypercholesterolemia, 3382 had ASCVD, including 2191 with prior revascularization. Although baseline characteristics were comparable between alirocumab and control groups, revascularized patients were more likely to be male, with prior myocardial infarction/stroke, higher lipoprotein (a) and PCSK9 levels, and were more often treated with high-intensity statin therapy. Alirocumab significantly reduced low-density lipoprotein cholesterol, lipoprotein (a), non-high-density lipoprotein cholesterol, and apolipoprotein B levels regardless of prior PCI/CABG. Alirocumab had a similar safety profile regardless of revascularization status, and higher rates of injection-site reactions compared to controls.

These results suggest that alirocumab is generally well-tolerated and effective, with a similar safety profile in high-risk patients with or without prior revascularization.


Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study

(LDL-C) lowering. However, Statins have established their role as a first-line option for low-density lipoprotein cholesterol, some patients are unable to tolerate statin doses necessary to optimally lower LDL-C, most commonly due to muscle-related side effects, and they are at increased cardiovascular risk due to ongoing elevations in low-density lipoprotein cholesterol (LDL-C). Bempedoic acid (ETC-1002) is an oral, once-daily, first-in-class, small-molecule cholesterol synthesis inhibitor in development for the treatment of hyperlipidemia. Different doses of bempedoic acid were evaluated in phase 2 studies. The favorable efficacy and safety profile supported use of the 180 mg/day dose in phase 3 clinical trials. The first of the completed phase 3 studies, CLEAR Tranquility (NCT03001076), conducted by Ballantyne and colleagues, evaluated the efficacy and safety of bempedoic acid when added to background lipid-modifying therapy in patients with a history of statin intolerance who require additional LDL-C lowering.

This phase 3, multicenter, randomized, double-blind, placebo-controlled study enrolled 269 patients with a history of statin intolerance and LDL-C ≥100 mg/dl while on stable lipid-modifying therapy. After a 4-week ezetimibe 10 mg/day run-in period, patients were randomized 2:1 to treatment with bempedoic acid 180 mg or placebo once daily added to ezetimibe 10 mg/day for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C.

Bempedoic acid, added to background lipid-modifying therapy including ezetimibe, reduced LDL-C by 28.5% more than placebo. Significant reductions in secondary endpoints, including non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein, were observed with bempedoic acid compared to placebo. Bempedoic acid was well tolerated in statin intolerant patients: rates of treatment-emergent adverse events, muscle-related adverse events, and discontinuations were similar in the bempedoic acid and placebo treatment groups.

These results suggest that bempedoic acid may provide an oral therapeutic option complementary to ezetimibe in statin intolerant patients who require additional LDL-C lowering.


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