Clinical and pathophysiological evidence supporting the safety of extremely low LDL levels—The zero-LDL hypothesis

doi:10.1016/j.jacl.2017.12.018

Journal of Clinical Lipidology

Volume 12, Issue 2, March–April 2018, Pages 292-299.e3

https://doi.org/10.1016/j.jacl.2017.12.018 Get rights and content

Highlights

•
Many patients on proprotein convertase subtilisin/kexin type 9 inhibitors achieve extremely low low-density lipoprotein cholesterol (LDL-C) levels.
•
Extremely low LDL-C levels are associated with even less cardiovascular risk.
•
Extremely low LDL-C concentrations cause no clinically relevant side effects.
•
Low LDL-C levels due to higher clearance are a marker of adequate LDL–LDLreceptor function.

Abstract

While the impact of very low concentrations of low–density lipoprotein cholesterol (LDL-C) on cardiovascular prevention is very reassuring, it is intriguing to know what effect these extremely low LDL-C concentrations have on lipid homoeostasis. The evidence supporting the safety of extremely low LDL levels comes from genetic studies and clinical drug trials. Individuals with lifelong low LDL levels due to mutations in genes associated with increased LDL-LDL receptor (LDLR) activity reveal no safety issues. Patients achieving extremely low LDL levels in the IMPROVE-IT and FOURIER, and the PROFICIO and ODYSSEY programs seem not to have an increased prevalence of adverse effects. The main concern regarding extremely low LDL-C plasma concentrations is the adequacy of the supply of cholesterol, and other molecules, to peripheral tissues. However, LDL proteomic and kinetic studies reaffirm that LDL is the final product of endogenous lipoprotein metabolism. Four of 5 LDL particles are cleared through the LDL-LDLR pathway in the liver. Given that mammalian cells have no enzymatic systems to degrade cholesterol, the LDL-LDLR pathway is the main mechanism for removal of cholesterol from the body. Our focus, therefore, is to review, from a physiological perspective, why such extremely low LDL-C concentrations do not appear to be detrimental. We suggest that extremely low LDL-C levels due to increased LDLR activity may be a surrogate of adequate LDL-LDLR pathway function.

Introduction

The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have changed the paradigm for lipid-lowering therapy to prevent cardiovascular disease. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER), the first completed outcome study with a PCSK9 inhibitor, showed the clinical benefit of lowering low-density lipoprotein cholesterol (LDL-C) below the current goal, extending the data obtained by the IMPROVE-IT study. In the FOURIER trial, 42% of patients achieved LDL-C levels <0.65 mmol/L (25 mg/dL).¹ While the impact of very low LDL-C concentration on cardiovascular prevention is very reassuring, it is intriguing to know what effect these extremely low LDL-C concentrations have on lipid homoeostasis.

Our focus, therefore, is to review, from a physiological perspective, why such extremely low LDL-C concentrations do not appear to be detrimental. We suggest that as the LDL-LDL receptor (LDLR) pathway is the main mechanism for removal of circulating cholesterol from the body, extremely low LDL-C levels due to increased LDLR activity may be a surrogate of LDL-LDLR pathway optimization. (Complete references list in online supplementary material)

Section snippets

Setting the stage: Evidence from trials

The direct correlation between LDL-C levels and cardiovascular events shown by epidemiological studies is indisputable.² Added to this, there is a wealth of data from randomized controlled trials with statin therapy showing that lowering LDL-C levels drives cardiovascular risk reduction³ underpinning “the lower is better” concept.⁴ The Cholesterol Treatment Trialists' Collaboration showed a 22% relative risk reduction per unit LDL-C mmol/L reduction with statin therapy.⁵ IMPROVE-IT (Examining

What is an LDL particle?

Before discussing this question, a background on LDL physiology is appropriate. LDL particles comprised lipid (∼80%, predominantly cholesterol as cholesteryl ester) and protein. The triglyceride content of LDL is relatively low under normal conditions (5%–10%) but increases with diabetes or obesity (Fig. 3A).

LDL transports cholesterol in the blood and extracellular fluids, and this is largely controlled by the interactions of surface proteins with lipid transport proteins, enzymes, and cell

Transporting liposoluble vitamins

Among the liposoluble vitamins, only vitamin E (α-tocopherol) is strongly associated with LDL metabolism. Vitamin E is absorbed via chylomicrons, and also HDL, in enterocytes and its transport in the blood largely follows that of cholesterol within lipoprotein metabolism, with subsequent transport into the liver by chylomicron remnants through LRP1, and VLDL and LDL by the LDLR pathway.⁴² One of the main physiological roles of vitamin E is linked to LDL protection because of its antioxidant

Lessons from homozygous FH

The main concern about very low LDL-C plasma concentrations is that cholesterol and other molecules transported by LDL will not be properly supplied to peripheral organs and tissues. Homozygous FH (HoFH), which is characterized by absent or defective LDLR function, provides an opportunity to evaluate the impact of the lack of LDLR-mediated peripheral delivery of cholesterol and other molecules associated with LDL.

Systematic studies of liposoluble vitamin or steroid hormone synthesis in HoFH

Conclusion

In conclusion, the clinical and physiological evidence makes the case that extremely low LDL-C plasma concentrations mediated by increased LDLR activity are not associated with significant adverse effects, within the limitations of the available clinical trial data. Given that the main function of LDL metabolism is cholesterol excretion, therapies that increase LDLR activity could provide optimization of this physiological role. In other words, extremely low LDL-C concentrations due to

Acknowledgments

The authors thank Jane Stock for helping us in the article editing.

Authors' contributions: All authors have contributed to the conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content, and all have approved the final version of the article.

References (51)

Cholesterol Treatment Trialists' (CTT) Collaboration et al.
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials
Lancet
(2010)
I. Gouni-Berthold et al.
Mipomersen and lomitapide: two new drugs for the treatment of homozygous familial hypercholesterolemia
Atheroscler Suppl
(2015)
Z. Zhao et al.
Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote
Am J Hum Genet
(2006)
I. Ramasamy
Update on the molecular biology of dyslipidemias
Clin Chim Acta
(2016)
D.I. Swerdlow et al.
HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials
Lancet
(2015)
J.G. Robinson et al.
Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials
J Am Coll Cardiol
(2017)
R.P. Giugliano et al.
Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial
Lancet
(2017)
D. Borchman et al.
Lipids and the ocular lens
J Lipid Res
(2010)
J.M. Dietschy et al.
Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans
J Lipid Res
(1993)
S.J. Robins et al.
Origin of biliary cholesterol and lecithin in the rat - contribution of new synthesis and preformed hepatic stores
J Lipid Res
(1982)

J.J. Albers et al.

Role of plasma phospholipid transfer protein in lipid and lipoprotein metabolism

Biochim Biophys Acta

(2012)

M. Hoekstra

SR-BI as target in atherosclerosis and cardiovascular disease - A comprehensive appraisal of the cellular functions of SR-BI in physiology and disease

Atherosclerosis

(2017)

S. Tonstad et al.

Fat-soluble vitamin levels in familial hypercholesterolemia

J Pediatr

(1997)

M. Blaha et al.

Pregnancy in homozygous familial hypercholesterolemia - Importance of LDL-apheresis

Atheroscler Suppl

(2015)

M.S. Sabatine et al.

Evolocumab and clinical outcomes in patients with cardiovascular disease

N Engl J Med

(2017)

W.B. Kannel et al.

Risk factors in coronary heart disease: an evaluation of several serum lipids as predictors of coronary heart disease: the Framingham Study

Ann Intern Med

(1964)

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)

Lancet

(1994)

J.C. LaRosa et al.

Intensive lipid lowering with atorvastatin in patients with stable coronary disease

N Engl J Med

(2005)

C.P. Cannon et al.

Ezetimibe added to statin therapy after acute coronary syndromes

N Engl J Med

(2015)

S.E. Nissen et al.

Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial

JAMA

(2006)

S.J. Nicholls et al.

Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial

JAMA

(2016)

M.G. Silverman et al.

Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis

JAMA

(2016)

B.A. Ference et al.

Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel

Eur Heart J

(2017)

D.A. Raichlen et al.

Physical activity patterns and biomarkers of cardiovascular disease risk in hunter-gatherers

Am J Hum Biol

(2016)

V. Sorrentino et al.

Identification of a loss-of-function inducible degrader of the low-density lipoprotein receptor variant in individuals with low circulating low-density lipoprotein

Eur Heart J

(2013)

Cited by (45)

When to treat hypercholesterolaemia
2024, Medicina Clinica
Dietary fat quality, plasma atherogenic lipoproteins, and atherosclerotic cardiovascular disease: An overview of the rationale for dietary recommendations for fat intake
2024, Atherosclerosis
The scientific evidence supporting the current dietary recommendations for fat quality keeps accumulating; however, a paradoxical distrust has taken root among many researchers, clinicians, and in parts of the general public. One explanation for this distrust may relate to an incomplete overview of the totality of the evidence for the link between fat quality as a dietary exposure, and health outcomes such as atherosclerotic cardiovascular disease (ASCVD). Therefore, the main aim of the present narrative review was to provide a comprehensive overview of the rationale for dietary recommendations for fat intake, limiting our discussion to ASCVD as outcome. Herein, we provide a core framework – a causal model – that can help us understand the evidence that has accumulated to date, and that can help us understand new evidence that may become available in the future. The causal model for fat quality and ASCVD is comprised of three key research questions (RQs), each of which determine which scientific methods are most appropriate to use, and thereby which lines of evidence that should feed into the causal model. First, we discuss the link between low-density lipoprotein (LDL) particles and ASCVD (RQ1); we draw especially on evidence from genetic studies, randomized controlled trials (RCTs), epidemiology, and mechanistic studies. Second, we explain the link between dietary fat quality and LDL particles (RQ2); we draw especially on metabolic ward studies, controlled trials (randomized and non-randomized), and mechanistic studies. Third, we explain the link between dietary fat quality, LDL particles, and ASCVD (RQ3); we draw especially on RCTs in animals and humans, epidemiology, population-based changes, and experiments of nature.
Additionally, the distrust over dietary recommendations for fat quality may partly relate to an unclear understanding of the scientific method, especially as applied in nutrition research, including the process of developing dietary guidelines. We therefore also aimed to clarify this process. We discuss how we assess causality in nutrition research, and how we progress from scientific evidence to providing dietary recommendations.
Observational study of patients from a Lipid Unit on lipid-modifying therapy for primary and secondary prevention: ULFI Study
2023, Clinica e Investigacion en Arteriosclerosis
Evaluar la consecución de los objetivos de colesterol unido a lipoproteínas de baja densidad (cLDL) establecidos por las guías europeas de manejo de las dislipemias de 2019 y de prevención cardiovascular de 2021, describir el tratamiento hipolipemiante realizado, analizar el logro de los objetivos según el tratamiento hipolipemiante recibido y estudiar los factores asociados al éxito terapéutico.
Estudio observacional con 185 pacientes de ambos sexos de 18 años o más en tratamiento hipolipemiante para prevención primaria o secundaria, atendidos en la Unidad de Lípidos.
El 62,1% de los pacientes presentó un riesgo cardiovascular (RCV) muy alto según la guía de 2019, y el 60,5% según la de 2021. Del total de casos, el 22,7% logró un control adecuado del cLDL según la guía de 2019 y el 20% lo hizo de acuerdo con la de 2021. El 47,6% de los pacientes recibió tratamiento hipolipemiante de muy alta intensidad y el 14,1% lo recibió de extremadamente alta intensidad. El 76% de los sujetos con muy alto RCV en tratamiento hipolipemiante de extremadamente alta intensidad logró los objetivos terapéuticos de ambas guías. En el análisis multivariante, los factores asociados al éxito terapéutico fueron la presencia de enfermedad cardiovascular arteriosclerótica, la intensidad del tratamiento hipolipemiante, la diabetes mellitus y el consumo bajo o moderado de alcohol.
El control de la dislipemia es mejorable. Los tratamientos hipolipemiantes de alta o extremadamente alta intensidad pueden contribuir a optimizar el control de los pacientes con mayor RCV.
To evaluate the achievement of low-density lipoprotein cholesterol (LDLc) goals established by the 2019 European Guidelines for the Management of Dyslipidemias and 2021 Cardiovascular Disease Prevention Guidelines, describe the lipid-lowering treatment received, analyze the achievement of goals according to the lipid-lowering treatment received and study the factors associated with therapeutic success.
Observational study that included 185 patients of both sexes aged 18 or over undergoing lipid-lowering treatment for primary or secondary prevention, attended at the Lipid Unit.
62.1% of the patients had a very high cardiovascular risk (CVR) according to the 2019 guidelines, and 60.5% according to the 2021 guidelines. Of the total cases, 22.7% achieved adequate control of LDLc according to the 2019 guidelines and 20% according to the 2021 guidelines. 47.6% of the patients received very high intensity lipid-lowering treatment, and 14.1% received extremely high intensity lipid-lowering treatment. 76% of subjects with very high CVR on extremely high intensity lipid-lowering treatment achieved the therapeutic objectives of both guides. In the multivariate analysis, factors associated with therapeutic success were the presence of arteriosclerotic cardiovascular disease, the intensity of lipid-lowering treatment, diabetes mellitus, and low to moderate alcohol consumption.
Dyslipidemia control is improvable. High or extremely high intensity lipid-lowering treatments can contribute to optimizing control of patients with higher CVR.
Lipid lowering combination therapy: From prevention to atherosclerosis plaque treatment
2023, Pharmacological Research
Statins have contributed to the prevention of numerous atherosclerotic cardiovascular (CV) events and cardiovascular deaths in the past three decades. The benefit of statins is mainly mediated by the lowering of LDLc. According to scientific evidence, the current international guidelines recommend very low LDLc goals in patients at high/very high cardiovascular risk because they are associated with fewer CV events and improvements in atherosclerotic plaques. However, these goals often cannot be obtained with statins alone. Recent RCTs have demonstrated that these CV benefits can also be obtained with nonstatin LDLc-lowering drugs such as PCSK9 inhibitors (alirocumab and evolocumab), ezetimibe and bempedoic acid, while evidence with inclisiran is upcoming. Icosapent ethyl, a lipid metabolism modifier, has also shown an effect on event reduction. Physicians should take advantage of the currently available lipid-lowering therapies, choosing the drug or combination of drugs that is most appropriate for each patient according to his or her CV risk and baseline LDLc concentration. Strategies implementing combination therapies from early stages or even from the outset may increase the number of patients attaining LDLc goals, thereby preventing new CV episodes and improving existing atherosclerotic lesions.
There is urgent need to treat atherosclerotic cardiovascular disease risk earlier, more intensively, and with greater precision: A review of current practice and recommendations for improved effectiveness
2022, American Journal of Preventive Cardiology
Atherosclerotic cardiovascular disease (ASCVD) is epidemic throughout the world and is etiologic for such acute cardiovascular events as myocardial infarction, ischemic stroke, unstable angina, and death. ASCVD also impacts risk for dementia, chronic kidney disease peripheral arterial disease and mobility, impaired sexual response, and a host of other visceral impairments that adversely impact the quality and rate of progression of aging. The relationship between low-density lipoprotein cholesterol (LDL-C) and risk for ASCVD is one of the most highly established and investigated issues in the entirety of modern medicine. Elevated LDL-C is a necessary condition for atherogenesis induction. Basic scientific investigation, prospective longitudinal cohorts, and randomized clinical trials have all validated this association. Yet despite the enormous number of clinical trials which support the need for reducing the burden of atherogenic lipoprotein in blood, the percentage of high and very high-risk patients who achieve risk stratified LDL-C target reductions is low and has remained low for the last thirty years. Atherosclerosis is a preventable disease. As clinicians, the time has come for us to take primordial and primary prevention more serously. Despite a plethora of therapeutic approaches, the large majority of patients at risk for ASCVD are poorly or inadequately treated, leaving them vulnerable to disease progression, acute cardiovascular events, and poor aging due to loss of function in multiple visceral organs. Herein we discuss the need to greatly intensify efforts to reduce risk, decrease disease burden, and provide more comprehensive and earlier risk assessment to optimally prevent ASCVD and its complications. Evidence is presented to support that treatment should aim for far lower goals in cholesterol management, should take into account many more factors than commonly employed today and should begin significantly earlier in life.
LDL as a therapeutic target
2022, Clinica e Investigacion en Arteriosclerosis
La incidencia de las enfermedades arterioscleróticas ha aumentado en los países desarrollados. La dislipemia es un factor de riesgo cardiovascular mayor y el descenso del LDLc es el objetivo terapéutico. Hay que individualizar los objetivos en cada paciente y las estatinas han demostrado ser un tratamiento coste-efectivo tanto en prevención primaria como en secundaria. La aparición de los inhibidores de PSCK9, más potentes y por tanto consiguiendo un mayor descenso de las cifras de LDLc, son un avance en el tratamiento de la enfermedad cardiovascular. La publicación en 2019 de las Guías de Dislipemias (Sociedad Europea de Cardiología /Sociedad Europea de Arteriosclerosis) con el nivel de evidencia y fuerza de recomendación, pueden ayudar en la toma de decisiones y beneficios para nuestros pacientes en la práctica clínica diaria.
The incidence of atherosclerotic cardiovsacular disease (ASCVC) has increased in the developed countries. Dyslipidemia is a primary major risk factor for ASCVD and LDL lowering is one of the main objectives. Although treatment goals for dyslipidemias should be personalized in every patient, statins are cost-effective in primary and secondary prevention of ASCVD. New treatments with higher power and greater decreases in LDL, PSCK9 inhibitors, have made a new breakthrough in ASCVD treatment. The 2019 Guidelines for de Management of Dyslipidaemias: Lipid Modification to reduce Cardiovascular Risk (European Society of Cardiology/European Atherosclerosis Society) with the level of evidence and the strength of the recommendations can facilitate the best decisions and benefits to our patients in clinical practice.

View all citing articles on Scopus

View full text

Review ArticleClinical and pathophysiological evidence supporting the safety of extremely low LDL levels—The zero-LDL hypothesis

Highlights

Abstract

Introduction

Section snippets

Setting the stage: Evidence from trials

What is an LDL particle?

Transporting liposoluble vitamins

Lessons from homozygous FH

Conclusion

Acknowledgments

Lancet

Atheroscler Suppl

Am J Hum Genet

Clin Chim Acta

Lancet

J Am Coll Cardiol

Lancet

J Lipid Res

J Lipid Res

J Lipid Res

Biochim Biophys Acta

Atherosclerosis

J Pediatr

Atheroscler Suppl

Evolocumab and clinical outcomes in patients with cardiovascular disease

N Engl J Med

Risk factors in coronary heart disease: an evaluation of several serum lipids as predictors of coronary heart disease: the Framingham Study

Ann Intern Med

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)

Lancet

Intensive lipid lowering with atorvastatin in patients with stable coronary disease

N Engl J Med

Ezetimibe added to statin therapy after acute coronary syndromes

N Engl J Med

Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial

JAMA

Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial

JAMA

Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis

JAMA

Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel

Eur Heart J

Physical activity patterns and biomarkers of cardiovascular disease risk in hunter-gatherers

Am J Hum Biol

Identification of a loss-of-function inducible degrader of the low-density lipoprotein receptor variant in individuals with low circulating low-density lipoprotein

Eur Heart J

Review Article
Clinical and pathophysiological evidence supporting the safety of extremely low LDL levels—The zero-LDL hypothesis