Health Outcomes Associated with Hypolipidemia: a Scoping Review

Seungcheol Hong; Dong-jun Choi*; Ji-cheon Jeong*

doi:10.22246/jikm.2025.46.1.61

The Journal of Internal Korean Medicine > Volume 46(1); 2025 > Article

Hong, Choi*, and Jeong*: Health Outcomes Associated with Hypolipidemia: a Scoping Review

Original Article

The Journal of Internal Korean Medicine 2025; 46(1): 61-94.

Published online: March 30, 2025

DOI: https://doi.org/10.22246/jikm.2025.46.1.61

Health Outcomes Associated with Hypolipidemia: a Scoping Review

Seungcheol Hong, Dong-jun Choi*, Ji-cheon Jeong*

Dept. of Internal Korean Medicine, College of Korean Medicine, Dongguk University

·Corresponding author: Ji-cheon Jeong Dept. of Internal Korean Medicine, Dongguk Ilsan Oriental Hospital, Dongguk University Medical Centre. 27, Dongguk-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea TEL: 031-961-9046 FAX: 031-961-9049 E-mail: kyjjc1931@daum.net

·Corresponding author: Dong-jun Choi Dept. of Internal Korean Medicine, Dongguk Ilsan Oriental Hospital, Dongguk University Medical Centre. 27, Dongguk-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea TEL: 031-961-9044 FAX: 031-961-9049 E-mail: juni@dumc.or.kr

Received February 28, 2025 Revised March 26, 2025 Accepted March 26, 2025

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective:

This review summarizes current evidence on the possible effects of hypolipidemia, a state of low concentration of blood lipids, on health outcomes.

Methods:

A review was conducted of articles published across 5 electronic databases (PubMed, EMBASE, Cochrane Central Resister of Controlled Trials, RISS, and ScienceON). Prospective and retrospective clinical studies were included.

Results:

In total, 84 studies were assessed. Depending on the subtypes of hypolipidemia, hypocholesterolemia and hypobetalipoproteinemia were associated with severity of liver disease and sepsis, mortality of COVID-19, and prevalence of cancer and mental illness. Hypoalphalipoproteinemia showed similar findings but was also associated with cardiovascular and cerebrovascular disease.

Conclusions:

Hypolipidemia may mediate lipid metabolism in the liver, immune activation, metabolic function, and recovery, contributing to disease severity and mortality. This highlights the need to monitor and assess hypolipidemia in patients with specific health conditions, as well as incorporate treatment plans accordingly.

Keywords: hypolipidemia, cholesterol, health outcomes, scoping review

I. Introduction

Dyslipidemia is a metabolic disorder characterized by abnormally elevated or reduced levels of one or more blood lipids, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG)¹. It is widely recognized as a major contributor to complications such as atherosclerosis, metabolic syndrome, hepatic dysfunction, ischemic heart disease, and stroke. Additionally, dyslipidemia can limit activities of daily life (ADL), quality of life (QoL), and increase mortality². In 2006, the Medical Subject Headings (MeSH) database replaced “hyperlipidemia” with “dyslipidemia,” reflecting extensive evidence since the 1980s linking HDL-C deficiency to various complications and mortality.

Hypolipidemia, defined as decreased blood lipid levels, lacks a universally accepted definition and reference levels. Previous studies have suggested that total cholesterol (TC) levels <150 mg/dL and LDL-C levels <70 mg/dL are indicative of hypolipidemia, though these thresholds vary among researchers^1-³. Primary hypolipidemia is a genetic disorder, including familial hypobetalipoproteinemia (FHBL), which can be further categorized into FHBL-SD1 (abetalipoproteinemia, ABL) caused by MTTP gene deficiency, FHBL-SD2 due to APOB gene deficiency, FHBL-EC1 (familial combined hypolipidemia, FCHL) associated with ANGPTL3 gene deficiency, and FHBL-EC2 linked to PCSK9 gene deficiency. Lecithin-cholesterol acyltransferase deficiency (LCAT) combines hypoalphalipoproteinemia and hypertriglyceridemia. Secondary hypolipidemia may arise from number of circumstances, such as nutritional deficiencies, malabsorption, anemia, neoplasms, liver disease, heart failure, hyperthyroidism, severe infections, chronic inflammation, or medication use. Drug-induced hypolipidemia may also be exacerbated by individual genetic factors⁴.

Clinically, blood lipid levels are associated with immunological status in infections, neoplasms, and sepsis, and are influenced by nutrition and liver function, which in turn affect cardiovascular (CV) health. Lowering LDL-C and increasing HDL-C are known to reduce the risk of stroke; however, the long-term effects and target serum concentrations require further investigation. Previous research indicates a U-shaped mortality rate concerning blood lipid levels, with CV disease risk increasing in higher quantiles and non-CV disease risk in lower quantiles⁵. Bandyopadhyay⁶ have reported findings suggesting that maintaining excessively low LDL-C levels due to hyperlipidemia management may elevate the risk of CV disease. Given the potential for a non-linear relationship between serum lipid levels and health outcomes, there is ongoing debate regarding the benefits of hypolipidemia. Therefore, synthesizing current clinical research data to identify health outcomes requiring further investigation is essential.

From the perspective of Korean medicine, hypolipidemia can be understood within the category of the Deficiency syndromes (虛證), which is recognized as a medical condition frequently observed in chronic disease patients, long-term hospitalization, nutritional deficiencies, and elderly patients. Although dyslipidemia has asymptomatic nature and was not described in traditional Korean Medicine textbooks, previous study demonstrated that hypolipidemic state of stroke patients is related with the Deficiency syndrome rather than the Excessive syndrome (實證)⁷^,8. Dyslipidemia, CV diseases, and diabetes are described as results of the weakened states of the Liver, Heart, Spleen, and Kidneys (肝, 心, 脾, 腎), leading to various health outcomes through the relationship of the Root deficiency and manifest excess (本虛標實)⁹. Following those concepts, hypolipidemia which belong to dyslipidemia can similarly be understood within pathology of Qi Blood Yin Yang Deficiency (氣血陰陽虛損). This perspective provides a theoretical basis for understanding the health outcomes associated with hypolipidemia as a decline in immune and lipid metabolic functions in modern Korean medicine.

Herbal medicine in Korean medicine has advantages employing its personalized approach based on syndrome differentiation, pathogenesis, and a multicomponent-multitarget mechanism¹⁰. This approach is not only rooted in historical literature but is also widely applied to various chronic and metabolic diseases in modern Korean medicine. Herbal medicine has already been utilized clinically for dyslipidemia, with numerous evidence reported. Previous studies, Mehraban¹¹ have documented the lipid-lowering effects of plant oils and phytosterols on dyslipidemia, while Fang¹² conducted a systematic review of 76 clinical trials, demonstrating that the administration of herbal medicine for dyslipidemia showed significant effects without adverse reactions.

Therefore, it is anticipated that Korean medicine may play a crucial clinical role in improving health outcomes related to hypolipidemia and in preventing complications and side effects. As highlighted in existing literature, hypolipidemia observed in clinical practice may influence treatment duration, prognosis, health outcomes, and readmission rates compared to patients without this condition. Thus, it is essential to explore the extent of these impacts through literature review, identify relevant characteristics, and propose future research directions.

This study is designed as a scoping review, conducting a literature review of clinical research which aimed to collect health outcomes such as mortality and complications, associated with hypolipidemic states of patients, while also examining differences based on the subtype of blood lipid and patient characteristics. The findings will serve as preliminary data for future systematic literature reviews or analyses of healthcare databases.

II. Methods

The study was conducted by referring to methodological procedures and recommendations for scoping literature reviews proposed by Arksey and O’Malley¹³, Levac et al.¹⁴, as well as the checklists provided by the PRISMA and JBI groups¹⁵. A comprehensive review of clinical studies that satisfied the inclusion criteria was conducted, on the basis of the following research questions.

1. Research Questions

This study aimed to determine whether there is a need to improve the state of hypolipidemia, and thus, the following two research questions were established:

1) “What health outcomes (complications, hospitalization, mortality, etc.) are associated with patients in a hypolipidemic state?”
2) “Which demographic and medical characteristics (comorbidities, physio-pathological parameters, medications, etc.) of hypolipidemic patients influence health outcomes?”

2. Search Strategy

Three English databases (MEDLINE, Embase, Cochrane CENTRAL) and two Korean databases (RISS, ScienceON) were selected for the search, and all the searches ended in February 2025. The search terms included “hypolipidemia”, “hypocholesterolemia” in English and Korean respectively, and bibliographic information was collected using Endnote 21 (Clarivate Analytics, United States). Two authors (S. Hong, D. Choi) independently conducted the search and literature selection. After screening the abstracts, if there were disagreements between the authors, the full texts of the relevant studies were obtained for discussion, and decisions were made through consensus based on their selection or exclusion reasons.

1) Inclusion Criteria

Clinical studies were selected based on the review of abstracts, including randomized controlled trials, prospective clinical studies, retrospective observational or medical record studies, and cross-sectional studies. The published year is restricted from 2005 to 2025, to review focused on updated evidence.

The target study population consisted of patients in a hypolipidemic state. Any hypolipidemia defined from the diagnostic criteria of each study was comprehensively included, since the reference level of hypolipidemia is not currently established so far. No restrictions were placed on the interventions collected. The health outcomes of interest included changes in medication usage involving lipid-lowering agents, complications such as CV disease, cerebrovascular disease, and metabolic syndrome, quality of life, disease severity, hospitalization and mortality differences. Additionally, demographic characteristics of hypolipidemic patients, such as age and sex, as well as medical characteristics including serum lipid levels, medications, and comorbidities, were examined for their additional impact on health outcomes. Factors contributing to the hypolipidemic state (diseases, medications, age, sex, etc.) were also collected.

2) Exclusion Criteria

Research protocols, case reports, and non-clinical studies such as literature reviews and animal or cell experiment studies were excluded. While no specific diseases other than hypolipidemia were restricted, studies that only observed changes in serum lipid levels for genomic analysis aimed at elucidating pathological mechanisms, without collecting other related health outcomes, were excluded. Studies for which the full text was not available or where the study design and outcome data could not be available were also excluded. If the study was published in both abstract presentation and full-length article, the abstract presentation was excluded as duplication.

3. Data extraction and analysis

From the full text of each included studies, two authors (S. Hong, D. Choi) independently extracted the data to predefined characteristics table. The first author’s name, published year, region, study period, sample size was recorded respectively. The study design was classified by using literature classification tool (Study Design Algorithm for Medical Literature of Intervention, DAMI)¹⁶ and methods that the authors had reported in the article. Patients, interventions or exposures, and outcomes were extracted if available and appropriate with the scope of the review. Therefore, outcomes that are irrelevant with research questions were not recorded. Finally, the major findings of each study were characterized by reviewing results and conclusions respectively.

Based on the characteristics data, recategorization with subgroups was conducted to investigate the trend of included studies. Each subgroup was categorized by the subtypes of hypolipidemia, related health condition, and benefit or risk, and was supported by findings from included studies.

III. Results

1. Results of the search

From the five electronic databases, 1,501 articles were identified after excluding duplicate studies. Articles were screened with inclusion criteria, and the full texts of 190 articles were retrieved and evaluated based on the title and abstract. Following browsing full texts of the articles, 106 were excluded including case reports and case series. As a result, eighty-four studies were finally included for this review process and data analysis (Fig. 1).

Fig. 1

PRISMA flow diagram.

2. Characteristics of the included studies

1) Study design

Three randomized controlled trials were included, and thirty-three other prospective studies including cohort, case-control, and observational studies were identified. Thirty-five retrospective studies including cohort, medical records reviews, observational studies were conducted, and thirteen cross-sectional studies were followed.

2) Topic

The topic of included studies varies in patient’s diseases, subtypes of hypolipidemia, and their benefit or risk on the outcomes. Primary outcomes were mostly overall or all-cause mortality, and disease severity, but also included risk, incidence, prevalence, morbidity of various diseases and conditions as well.

3) Publication year

Publication years were evenly distributed from 2005 to 2025, however, studies of COVID-19 infection newly associated with hypolipidemia since its breakout. The trend is mostly consistent throughout years, but hypobetalipoproteinemia is reported inconsistently the effect on health outcomes.

4) Sample size

Sample size depended on the study design, from 4 to 419,488. The median sample size of all included studies was 226 patients. Eight studies that have samples above 10,000, and ten studies have samples from 1,000 to 10,000, fifty-two studies have samples from 100 to 1,000, and fourteen studies have below 100. By the study designs, median sample size of retrospective studies was the most, followed by RCTs; however, mean sample size of prospective studies was exclusively larger than others, as four prospective studies had sample size more than 10,000. Cross-sectional studies were mostly conducted with fewer than 1,000 samples (Fig. 2).

Fig. 2

Summary of included studies.

3) Summary of the study topics and the results

(1) Patients

The research topic encompasses a variety of patient conditions, including CV diseases, cerebrovascular diseases, liver diseases, renal failure, various infections, neoplasms, and mental health issues. The subtypes of hypolipidemia considered in the studies include hypobetalipoproteinemia, hypoalphalipoproteinemia, hypocholesterolemia, and hypotriglyceridemia, along with their hereditary aspects.

(2) Intervention or exposure, controls

Most studies included observational research based on serum lipid concentrations rather than interventional studies. However, in cases where interventions were established, research focused on the administration of lipid-lowering agents and vitamin supplementation. Control groups were diverse according to research objectives, utilizing normal serum lipid control groups and external control groups.

(3) Outcomes

Outcome measures primarily included mortality rates, disease severity, risk of complications, prevalence, and incidence rates, with the majority of studies being prognostic observational studies.

This review categorizes the research topics based on the subtypes of hypolipidemia and the corresponding patient conditions, summarized as follows (Table 1).

Table 1

Study Results of Health Outcomes by Subtypes of Hypolipidemia

Related condition	Benefit/ risk	Study ID	Study results
A. hypo-LDL-cholesterolemia (hypobetalipoproteinemia)
cardiovascular disease	beneficial	B30, B33	reduction in the risk of coronary artery disease cardiovascular protective effect through decreased arterial wall stiffness

	neutral	C33	no negative impact in stable patients after acute coronary syndrome

	risk	C10, C23	independent, dose-response association with diabetes risk in patients with coronary artery disease undergoing intervention associated with the risk of cardiovascular events

cerebrovascular disease	beneficial	D01	associated with ischemic stroke and reduction in complications and mortality

	neutral	C25	no association with the incidence of intracerebral hemorrhage

hepatic steatosis	risk	B01, B15, B17, B22, B33, C08, C14, C25	associated with the prevalence of fatty liver disease increased risk and severity of fatty liver disease significantly associated with fatty liver despite lower obesity levels higher incidence of alcoholic liver disease

liver cancer	risk	C01	associated with the incidence of liver complications, including primary liver cancer

liver cirrhosis	risk	B01, B17	associated with the prevalence of liver fibrosis

COVID-19	risk	C03, C06, B08, C11	associated with severity in COVID-19 patients higher 30-day mortality and associated with inflammatory markers associated with worsening COVID-related acute kidney injury through immune response inhibition and fibrosis

sepsis	risk	C34	associated with severity in meningococcal sepsis patients

ESRD	risk	B31	associated with mortality prediction in dialysis patients

diabetes	risk	C05	independent risk factor for diabetes

cancer	risk	B29	associated with the incidence of various cancers

mental health	risk	C15	associated with schizophrenia, autism, hetero-aggression, violent behavior, and impulsivity

B. hypo-HDL-cholesterolemia (hypoalphalipoproteinemia)

cardiovascular disease	neutral	A02	no significant effect of HDL mimetics in patients with carotid atherosclerosis

	risk	B20, C13, C16, C26, D11, D13	risk factor in male patients with myocardial infarction independent predictor of in-hospital mortality in patients with acute coronary syndrome associated with the prevalence of atherosclerotic coronary artery disease associated with risk factors for myocardial infarction increased atherosclerosis index in female college students

cerebrovascular disease	risk	B06	associated with the risk of stroke recurrence after revascularization in moyamoya disease patients

liver cirrhosis	risk	C29	associated with severity in patients with cirrhosis and severe sepsis

COVID-19	risk	B04, C03	associated with severity in COVID-19 patients

sepsis	risk	B07, B19, C29, C30, C34	associated with long-term organ failure and poor prognosis significantly associated with disease severity, inflammatory marker and increased mortality associated with severity in patients with severe sepsis, meningococcal sepsis associated with mortality and sepsis risk

inflammation	risk	B32	associated with inflammatory states

CKD	risk	C16	associated with the prevalence of renal failure depending on genetic variations

urolithiasis	risk	C21	increased risk in patients with urinary stones

diabetes	risk	B14, D10	associated with cognitive impairment in elderly patients with type 2 diabetes threefold increased risk of microvascular complications in patients with type 1 diabetes

obesity	risk	B16	associated with decreased health-related quality of life scores in obese women

lipid metabolism	risk	B26	associated with low fecal sterol excretion

hematologic disorder	risk	D07	associated with increased endothelial injury markers in sickle cell patients

cancer	risk	B11, B29, C30	associated with the risk of various cancers associated with pediatric leukemia and Hodgkin’s disease associated with the risk of neoplasms

mental health	risk	D05	associated with increased depressive symptoms and EPDS scores in postpartum women

peripheral polyneuropathy	risk	D06	associated with peripheral neuropathy

psoriasis	risk	B05	associated with the incidence of psoriasis

C. hypocholesterolemia

cardiovascular disease	neutral	B21	no significant impact on the risk of ischemic heart disease

	risk	C10	independent, dose-response association with diabetes risk in patients with coronary artery disease undergoing intervention

cerebrovascular disease	beneficial	D01	protective effect against intracerebral hemorrhage

	neutral	D03	no association with hypertensive hemorrhagic stroke

liver cirrhosis	neutral	B21	risk impact of liver disease is not confirmed

	risk	C35, D08, D09, D12	associated with poor prognosis in cirrhosis patients with infection associated with disease progression in patients with cirrhosis associated with severe sepsis in patients with alcoholic cirrhosis associated with the severity of liver dysfunction and Child-Pugh classification in patients with cirrhosis

liver cancer	risk	B09	increased risk of primary liver cancer

amebic liver abscesses	risk	B18	associated with the severity of amoebic liver disease

COVID-19	risk	C03, C11, D02	associated with severity in COVID-19 patients higher mortality in COVID-19 patients

sepsis	risk	C24, C34	associated with mortality risk in patients admitted to the intensive care unit with sepsis associated with severity in patients with meningococcal sepsis

surgical site infection	neutral	B03	no significant effects on the risk of surgical site infections

	risk	B02, B12	increased risk of surgical site infections risk factor for surgical site infections and related to nutritional deficiencies

post-surgical complications	risk	C09, C17, C20, C22	associated with complication rates and survival after gastric cancer surgery independent predictor of in-hospital mortality in patients undergoing emergency surgery for diffuse peritonitis significantly higher in-hospital mortality in patients undergoing emergency gastrointestinal surgery for intra-abdominal sepsis potential predictor of decreased survival after emergency surgery for abdominal aortic aneurysm

trauma	neutral	C27	reduction in mechanical ventilation and mortality in trauma patients

	risk	C32	associated with increased mortality risk in patients with multiple severe trauma

ICU inpatient	risk	B24	associated with early mortality in patients admitted to the intensive care unit

AKI	risk	B27	higher mortality in patients with acute kidney injury admitted to the intensive care unit

HD patients	risk	C07	associated with decreased systemic vascular responsiveness and blood pressure reduction in dialysis patients

drug-induced hypolipidemia	risk	A01	no effect on mortality despite reduced emergency room visits due to dyslipidemia prevention guidance with lipid-lowering agents

hematologic disorder	risk	C31, B28, D07	independent association with decreased survival in patients with myelodysplastic syndromes associated with intravascular hemolysis and vascular dysfunction in sickle cell patients associated with increased endothelial injury markers in sickle cell patients

cancer	neutral	B21, C18	risk impact of tumors is not confirmed no association with postoperative pain in patients undergoing laparoscopic surgery for primary colorectal cancer

	risk	B29, C02, C09	associated with pediatric leukemia and Hodgkin’s disease associated with the risk of early mortality in pediatric patients with hemophagocytic lympho-histiocytosis associated with complication rates and survival after gastric cancer surgery

mental health	risk	B13, C12	associated with depressive disorders and suicide attempts potential association between autism spectrum disorder and intellectual disability

HIV	risk	B23	inhibits the effectiveness of HAART treatment in HIV patients

myelofibrosis	risk	A03	ruxolitinib treatment in patients with myelofibrosis is associated with changes in total cholesterol and increased survival

Takayasu arteritis	risk	C19	identified as the sole predictor of recurrence in Takayasu arteritis patients

TB	risk	D04	associated with the duration of treatment in patients with pulmonary tuberculosis

wasp sting	risk	C04	associated with severity in patients with wasp stings

D. hypotriglyceridemia

ischemic stroke	neutral	B10	no impact on the severity and prognosis of acute ischemic stroke

liver cirrhosis	risk	D12	associated with the severity of liver dysfunction and Child-Pugh classification

COVID-19	risk	C03	associated with severity and prevalence

AKI : acute kidney injury, CKD : chronic kidney disease, EPDS : Edinburgh Postnatal Depression Scale, ESRD : end-stage renal disease, HAART : highly active antiretroviral therapy, HD : hemodialysis, HDL, high-density lipoprotein, HIV : human immunosuppressive virus, ICU : intensive care unit, TB, tuberculosi

4. Details of the study topics and the results

1) hypo-LDL-cholesterolemia (hypobetalipoproteinemia)

In the realm of CV disease, low LDL-C is associated with a reduction in the risk of coronary artery diseaseB30 and a CV protective effect through decreased arterial wall stiffnessB33. Moreover, it shows no negative impact in stable patients following acute coronary syndromeC33. However, there exists an independent, dose-response association with diabetes risk in patients with coronary artery disease undergoing interventionC10, as well as an association with the risk of CV eventsC23. Regarding cerebrovascular disease, low LDL-C is beneficial as it is associated with ischemic stroke and a reduction in complications and mortalityD01.

In the context of liver diseases, low LDL-C is linked to several risks. It is associated with the incidence of primary liver cancerC01, and the prevalence of liver fibrosis in cirrhotic patientsB01,B17. Furthermore, it correlates with hepatic steatosis, indicating an increased risk and severity of fatty liver disease significantly associated with fatty liver despite lower obesity levelsB01,B15,B17,B22,B33,C08, and a higher incidence of alcoholic liver diseaseC14,C25. The implications of low LDL-C extend to COVID-19, where it is associated with increased severity in patientsC03,C11, higher 30-day mortalityC06, and an association with inflammatory markers. Additionally, it is linked to worsening COVID-related acute kidney injury through immune response inhibition and fibrosisB08.

Other risk associations include end-stage renal disease (ESRD), where low LDL-C is associated with mortality in dialysis patientsB31, and diabetesC05, where it is identified as an independent risk factor. Low LDL-C is also associated with the incidence of various cancersB29 and the severity of meningococcal sepsisC34. Finally, mental health outcomes are impacted as well, with associations found between low LDL-C and conditions such as schizophrenia, autism, hetero-aggression, violent behavior, and impulsivityC15 (Table 1-A).

2) hypo-HDL-cholesterolemia (hypoalphalipoproteinemia)

In the domain of CV disease, low HDL-C is identified as a risk factor in male patients with myocardial infarctionB20 and serves as an independent predictor of in-hospital mortality in patients with acute coronary syndromeC13. Low HDL-C is associated with the prevalence of atherosclerotic coronary artery disease and risk factors for myocardial infarctionC16,C26,D11, and similarly, is linked to an increased atherosclerosis index in female college studentsD13. Within cerebrovascular disease, low HDL-C is associated with an increased risk of stroke recurrence, particularly in patients with moyamoya disease following revascularizationB06.

In liver cirrhosis, it is associated with severity in patients suffering from both cirrhosis and severe sepsisC29. The implications of low HDL-C extend to COVID-19, where it is associated with increased severity in affected patientsB04,C03. Sepsis is another critical area, where low HDL-C is associated with long-term organ failure, poor prognosisB07,B19,C29, and increased mortalityC30, particularly in patients with severe sepsis and meningococcal sepsisC34. Moreover, low HDL-C is connected to inflammatory statesB32.

Additionally, in chronic kidney disease (CKD), it is linked with the prevalence of renal failure, influenced by genetic variationsC16. The risk of urolithiasis is also increased in patients with low HDL-CC21, while diabetes is linked to cognitive impairment in elderly patients with type 2 diabetesB14 and presents a threefold increased risk of microvascular complications in patients with type 1 diabetesD10. Obesity is another area of concern, as low HDL-C is associated with decreased health-related quality of life scores in obese womenB16, and lipid metabolism issues particularly low fecal sterol excretionB26. In hematologic disorders, low HDL-C correlates with increased endothelial injury markers in sickle cell patientsD07. Cancer risk is significantly impacted as well, with low HDL-C associated with various cancersB11, including pediatric leukemia and Hodgkin’s diseaseB29, as well as the overall risk of neoplasmsC30. In the context of mental health outcomes reveal an association with heightened depressive symptoms and elevated EPDS scores in postpartum womenD05. It is also associated with peripheral polyneuropathy and the incidence of psoriasisB05 (Table 1-B).

3) hypocholesterolemia

In the context of CV disease, low cholesterol level showed no significant impact on the risk of ischemic heart diseaseB21. However, it is identified as an independent, dose-response risk factor for diabetes in patients with coronary artery disease undergoing interventionC10. Within cerebrovascular disease, low cholesterol level exhibits beneficial effects, particularly a protective effect against intracerebral hemorrhageD01, while barely associated with hypertensive hemorrhagic stroke in the other studyD03.

In liver-related conditions, the risk impact of low total cholesterol on liver cirrhosis remains unconfirmedB21; however, it is associated with poor prognosisC35, disease progressionD08, and severe sepsis in patients with alcoholic cirrhosisD09. Additionally, low cholesterol level is linked to the severity of liver dysfunction and Child-Pugh classification in cirrhosis patientsD12. Furthermore, it presents an increased risk of primary liver cancerB09 and is associated with the severity of amoebic liver diseaseB18. The implications of low cholesterol extend to COVID-19, where it is associated with increased severity and mortality in patientsC03,C11,D02. In sepsis, low cholesterol is linked to mortality risk and severityC24, especially in patients admitted to the intensive care unit and those with meningococcal sepsisC34. Regarding surgical site infections, low cholesterol is associated with increased risk and nutritional deficiencies as a risk factor for surgical site infectionsB02,B12. Post-surgical complications are notably influenced by hypocholesterolemia, as it is associated with complication rates and survival after gastric cancer surgeryC09 It serves as an independent predictor of in-hospital mortality in patients undergoing emergency surgery for diffuse peritonitisC17 and is linked to significantly higher in-hospital mortality in emergency gastrointestinal surgeries for intra-abdominal sepsisC20, as well as being a potential predictor of decreased survival after emergency surgery for abdominal aortic aneurysmC22. In trauma patients, low cholesterol level was not affected a reduction in mechanical ventilation and mortalityC27, yet it is associated with increased mortality risk in patients with multiple severe traumasC32. Among ICU inpatients, low cholesterol is linked to early mortalityB24.

In acute kidney injury (AKI), low cholesterol level correlates with higher mortality in patients admitted to the intensive care unitB27. In dialysis patients, it is linked to decreased systemic vascular responsiveness and blood pressure reductionC07. Hematologic disorders reveal a concerning association, as low cholesterol level is linked to decreased survival in patients with myelodysplastic syndromesC31 and associated with intravascular hemolysisB28 and increased endothelial injury markers in sickle cell patientsD07. Cancer outcomes demonstrate a neutral impact regarding tumors, as the risk is not confirmed in some contextsB21, such as postoperative pain following laparoscopic surgery for primary colorectal cancerC18. However, low cholesterol level is associated with pediatric leukemia, Hodgkin’s diseaseB29, and increased risk of early mortality in pediatric patients with hemophagocytic lympho-histiocytosisC02. It is also linked to complication rates and survival after gastric cancer surgeryC09. Mental health was affected as well, with associations between low cholesterol level and depressive disorders, suicide attemptsB13, and potential connections to autism spectrum disorder and intellectual disabilityC12. In HIV patients, it inhibits the effectiveness of HAART treatmentB23. For myelofibrosis, ruxolitinib treatment is associated with changes in total cholesterol and improved survival outcomes in patientsA03. For Takayasu arteritis, it is identified as the sole predictor of recurrenceC19. Finally, Low cholesterol level is also associated with the duration of treatment in patients with pulmonary tuberculosisD04 and the severity of wasp stingsC04 (Table 1-C).

4) hypotriglyceridemia

In the context of ischemic stroke, low triglycerides level has a neutral effect, as it demonstrates no impact on the severity and prognosis of acute ischemic stroke. This finding suggests that while triglycerides level may fluctuate, they do not significantly alter the clinical outcomes in these patientsB10.

Conversely, in liver cirrhosis, low triglycerides level is associated with increased severity of liver dysfunction and correlates with the Child-Pugh classification. This relationship indicates that lower triglycerides level may reflect or contribute to the deterioration of liver function, highlighting the need for careful monitoring of lipid profiles in patients with liver diseaseD12.

Additionally, in the realm of COVID-19, low triglycerides level is linked to both severity and prevalence of the disease. This association raises important considerations regarding the role of lipid metabolism in the immune response and disease progression in COVID-19 patientsC03. (Table 1-D)

5. Summary of the study designs and the results

1) RCTs

Only three studies have been conducted and have applied interventions for hypolipidemia to assess health outcomes, including mortality. Among them, one unique RCT that utilized alert emails for hypolipidemia as an intervention and collected data from over 3,000 participants to compare differences in mortality and emergency room admission rates. The remaining two RCTs were conducted with sample sizes ranging from approximately 30 to 300 participants, and they observed changes in health outcomes related to the improvement of hypolipidemia itself, as well as atherosclerosis and mortality rates, through interventions such as HDL mimetics or targeted chemotherapy agents.

2) Prospective studies

A total of 33 studies measured baseline lipid profiles for various medical conditions, selecting either hypolipidemia or specific exposures as a comparator to observe health outcomes, complications, and prognoses over periods ranging from as short as 1 year to as long as 10 years. However, due to the prospective enrollment and observation methodology, most of these studies had sample sizes of less than 1,000 participants, with a median of 172, which was the smallest among the study designs. Health outcomes measured included changes in blood lipids, mortality, morbidity, disease severity, and length of hospitalization.

3) Retrospective studies

A total of 35 studies have tracked long-term health outcomes, complications, and prognoses for various health conditions over periods ranging from mostly 1-5 years, up to 15 years. Due to the retrospective methodologies, most studies collected large sample sizes, ranging from 100 to 10,000 participants, with a median of 674, which was the largest among the study designs. Health outcomes primarily included mortality, length of hospitalization, biochemical markers, and incidence such as cardiovascular events.

4) Cross-sectional studies

Thirteen studies compared health conditions at a specific point in time with the presence of hypolipidemia, reporting differences in health outcomes without employing interventions or exposures. The sample sizes were mostly under 1,000, like those in prospective studies. Health outcomes primarily focused on changes in serum lipids and biochemical markers (Table 2).

Table 2

Study Characteristics by Study Designs

ID	Author (year)	Design	Region	Periods	Sample size	Criteria of hypolipidemia	Patients	Interventions Exposures	Outcomes	Results
A. Randomized controlled trials

A01	Tsabar (2020)	Randomized controlled trial	Israel	September 2015 to November 2016	1. 1,791 2. 1,804	TC<160 mg/dl	drug-induced hypocholesterolemia	1. patient-specific reminder e-mail letter (sent to the clinic staff) 2. control (no letter)	1. annual death rate from any cause 2. changes in 1) dispensed cholesterol-lowering drugs doses 2) total drug use 3) emergency department visit rate.	The prevention guidance for hypolipidemia in patients taking lipid-lowering agents reduced emergency room visit rates but had no impact on mortality.

A02	Zheng (2020)	Randomized controlled trial phase 3	Multi-center	December 2015 to October 2017	1. 20 2. 10	1) HDL-C≤0.9 mmol/L 2) ApoAI≤1.1 g/L	carotid atherosclerosis with primary HBL	1. CER-001 2. placebo treatment	1. 3T-MRI at baseline, weeks 8, 24 and 48 for carotid mean vessel wall area measurements 2. F-FDG PET/CT : 18F-FDG uptake in the common carotid arteries	In patients with carotid atherosclerosis and low HDL-C, the administration of HDL mimetics showed no significant effects.

A03	Mesa (2012)	Randomized controlled trial	US	N/A	1. 155 2. 154	TC<150 mg/dl	myelofibrosis	1. ruxolitinib 2. placebo	1) Body weight 2) Total serum cholesterol 3) overall survival	Ruxolitinib treatment in patients with myelofibrosis is associated with changes in TC and increased survival rates.

B. Prospective studies

B01	Smati (2025)	Prospective observational study	France	N/A	104	LDL-C<5th percentile	primary HBL	Lipid profiles	1) liver steatosis, detected with FibroScan 2) BMI, DM, elevated plasma TG concentrations, presence of pathogenic ApoB variant	Low HDL-C is associated with the prevalence of fatty liver disease and liver fibrosis.

B02	Wani (2024)	Prospective observational study	India	January 2023 to March 2024	100	1) TC<100 mg/dl 2) TG≤160 mg/dl 3) HDL-C≤40 mg/dl	surgical site infection	elective or emergency surgeries	serum albumin, TG, TC, HDL levels	Hypolipidemia and hypocholesterolemia increase the risk of infections in surgical site patients.

B03	Paliwal (2023)	Prospective observational study	India	February 2023 to September 2023	150	TC<100 mg/dl	post-surgical infection	1) elective surgery : inguinal hernia surgery, appendectomy and colorectal surgery, cholecystectomy, breast surgeries and other major elective procedures 2) CBC, LFT, Lipid profile, bleeding time, clotting time, urine examination, chest x-ray and ECG	1) the duration of surgery & number of hospitalization days 2) Any surgical site infection 3) wound condition was graded according to the Southampton Wound Grade system 4) variables related with postoperative complications (albumin, TG, TC, HDL, etc)	The impact of hypolipidemia on surgical site infections was not observed and was influenced by hypoalbuminemia.

B04	Parra (2023)	Prospective observational study	Spain	March to June 2020	125	N/A	COVID-19	lipid profile : HDL-C, LDL-C	1) comorbidities, CV risk factors 2) WHO classification was applied to grade the severity of illness 3) all-cause mortality	Low HDL-C is associated with the severity of COVID-19.

B05	Xiao (2022)	Prospective cohort study	UK	2006 to 2010	1. 2,796 2. 416,692	1) HDL-C<1.0 mmol/L (men) 2) HDL-C<1.3 mmol/L (women)	1. psoriasis 2. no psoriasis	serum lipid concentrations	the risk of incident psoriasis	Low HDL-C and hypertriglyceridemia are associated with the incidence of psoriasis.

B06	Yu (2022)	Prospective case-control study	China	July to December 2019	123	HDL-C<0.9 mmol/L	Moyamoya disease	1) Direct bypass and combined bypass 2) Serum HDL levels	1) Recurrent stroke: Follow-up accidents concluded transient ischemia attack, ischemic stroke, hemorrhagic stroke, and loss of life. 2) The mRS was to assess the neurological status	Low HDL-C is linked to the risk of stroke recurrence after revascularization in moyamoya disease patients.

B07	Guirgis (2021)	Prospective cohort study	US	November 2016 to June 2018	172	N/A	Sepsis	1) TC, HDL-C, TG, LDL-C levels 2) dys-HDL measured via HII, PON-1, ApoA-I, inflammatory biomarkers, endothelial markers	1) early death within 2 weeks 2) CCI (ICU stay>14 days with organ dysfunction or discharged to long-term care) 3) rapid recovery	Low HDL-C in septic patients is associated with long-term organ failure and poor prognosis.

B08	Henry (2021)	Prospective observational study	US	N/A	1. 50 2. 30	1) LDL-C<50 mg/dl 2) TC<120 mg/dl	COVID-19 1. RT-PCR confirmed 2. matched sick controls with RT-PCR negative	HDL-C, LDL-C, TG, and TC	1) severe AKI during course of illness, defined as KDIGO Stage 2 and 3 2) need for hospitalization or ICU admission within 30 days of index ED presentation	Low LDL-C in COVID patients is associated with worsening COVID-related acute kidney injury through immune response inhibition and fibrosis.

B09	Ma (2021)	Prospective cohort study	China	2006 to 2007	98,936	TC<4.14 mmol/L	PLC	1) normal FBG & non-hypocholesterolemia 2) normal FBG & hypocholesterolemia 3) elevated FBG & non-hypocholesterolemia 4) elevated FBG & hypocholesterolemia	1) The annual human incidence of PLC 2) The accumulative incidence of PLC	Patients with primary liver cancer and impaired fasting glucose in the low cholesterol group had a higher risk of primary liver cancer compared to the control group.

B10	Ziroǧlu (2021)	Prospective observational study	Turkey	January 2012 to October 2014	564	TG<50 mg/dl	acute ischemic stroke	TG, TC, HDL-C, and LDL-C	1) NIHSS scores 2) mortality in hospital, recurrent stroke 3) mRS scores	Low TG levels in acute ischemic stroke patients had no effect on stroke severity and prognosis.

B11	Pedersen (2020)	Prospective cohort study	Denmark	1991 to 1994, 2003 to 2015	116,728	HDL-C<1.0 mmol/L	general population	HDL-C and ApoA1	Cancer endpoints : All cancer diagnoses (ICD-7 : 140-205 and ICD-10: C00-D09)	Low HDL-C is associated with the risk of various cancers.

B12	Manjunath (2018)	Prospective cohort study	India	January 2017 to August 2017	217	TC<160 mg/dl	open elective hernia repairs with mesh placement	1) TC levels, serum Albumin 2) Antibiotic prophylaxis of Inj. Ceftriaxone 1g i.v.	SSI : defined according to CDC criteria	Hypocholesterolemia appears to be a risk factor for surgical site infections and is related to nutritional deficiencies.

B13	Segoviano- Mendoza (2018)	Prospective case-control study	Mexico	June 2015 to December 2016	1. 261 2. 206	TC<150 mg/dl	1. MDD adult patients 2. healthy adult volunteer controls	TC, HDL-C, LDL-C and TG	1) the risk of MDD 2) suicide behaviors	Low cholesterol levels are associated with depressive disorders and suicide attempts.

B14	Bruce (2017)	Prospective observational study	Austrailia	1993 to 1996, 2008 to 2011	217	N/A	type 2 DM	1. FSG, HbA1c 2. serum lipids : HDL-C	A score≥27/30 on the MMSE identified normal cognition and a lower score led to an assessment with the CDR	Midlife low HDL-C is associated with cognitive impairment in elderly patients with type 2 diabetes.

B15	Di Costanzo (2017)	Prospective cohort study	Italy	N/A	1. 130 2. 220	1) TC<5^th percentile 2) LDL-C<5^th percentile	1. hypocholesterolemic subjects 2. normo-cholesterolemic controls	ALT, AST, plasma lipids : LDL-C levels, non-HDL-C, ApoB and ApoAI	The presence of hepatic steatosis was determined by ultrasound examination	The prevalence of fatty liver disease is associated with familial HBL.

B16	Chen (2014)	Prospective cohort study	Taiwan	January 2010 to December 2010	1. 50 2. 177	1) HDL-C<40 mg/dl 2) HDL-C<50 mg/dl	1. obese women 2. control	HDL-C level 1. HDL-C<40 mg/dl 2. HDL-C>=40 mg/dl	1) HRQoL : self-administered life quality questionnaires and brief version of the WHOQOL-BREF 2) the levels of obesity-related hormone peptides, including leptin, insulin, ghrelin, and adiponectin	Low HDL-C is associated with decreased health-related quality of life scores in obese women.

B17	Di Filippo (2014)	Prospective cohort study	Europe and North Africa	N/A	1. 7 2. 7	1) LDL-C<5^th percentile 2) ApoB<5^th percentile	1. ABL 2. familial HBL	N/A	1) LFT 2) ultrasound transient elastography using FibroScan® 3) liver biopsy	In primary hypolipidemia, the risk of fatty liver and liver fibrosis is high, necessitating genetic screening in patients with fatty liver.

B18	Flores (2014)	Prospective case-control study	Mexico	2002 to 2011	1. 108 2. 140	TC <100 mg/dl	1. ALA 2. healthy volunteers	1) standard treatment : antibiotics and supportive care 2) TC and TG	1) size, number, and localization of the amebic abscesses 2) days of hospital stay	Hypocholesterolemia is associated with the severity of ALA.

B19	Lekkou (2014)	Prospective observational study	Greece	N/A	50	N/A	severe sepsis	TC, TG and HDL-C, LDL-C	1) inflammatory markers : TNF-α and IL-10, IL-6 and IL-8, TGF-β1, CRP 2) mortality	Low HDL-C in patients with severe sepsis is significantly associated with disease severity, inflammatory marker and increased mortality.

B20	Estrada-Garcia (2013)	Prospective case-control study	Mexico	N/A	1. 210 2. 607	N/A	1. first acute non-fatal MI 2. matched controls from a MCUP	lipid profiles	prevalence of CCVRF	Low HDL-C is a risk factor in male patients with MI compared to the control group.

B21	Minicocci (2012)	Prospective cohort study	Italy	2008 to 2009	1. 63 2. 339	N/A	1. primary hypocholesterolemia 2. normocholesterolemic noncarriers	1) lipid profile, ApoB, FBG, LFT 2) Angiopoietin-like 3 serum levels 3) non-cholesterol sterols	The risk of liver disease, tumors, CV disease	The risk impact of liver disease, tumors, and ischemic heart disease has not been confirmed in patients with hereditary hypolipidemia.

B22	Gutiérrez- Cirlos (2011)	Prospective observational study	Mexico	N/A	4	1) TC<3.88 mmol/L 2) TC<150 mg/dl 3) TC<5th percentile	Familial heterozygous HBL	N/A	1) ApoB kinetics 2) LFT 3) abdominal ultrasonography	In primary HBL, the risk of fatty liver varies among individuals.

B23	Míguez (2010)	Prospective cohort study	US	January 2005	165	TC<150 mg/dl	HIV-infected participants starting HAART	TC, HDL-C, LDL-C, and TG	1) CD4 and CD8 T-cell counts 2) thymus volume, viral load	In HIV patients, hypocholesterolemia inhibits the effectiveness of HAART treatment.

B24	Sanchez (2010)	Prospective observational study	Venezuella	January to April 2010	41	N/A	ICU patients	levels of TC	1) APACHE II score 2) ICU mortality	In critically ill patients, early admission to the intensive care unit shows low cholesterol levels and is associated with mortality.

B25	Barlage (2009)	Prospective observational study	Germany	N/A	1. 104 2. 47	N/A	Sepsis 1. survivors 2. non-survivors	1) TC, TG and HDL-C, LDL-C 2) ApoAI, B, E, CI, CII, and CIII	1) SAPS II scores 2) sepsis-related mortality within 30 days	In septic patients, HDL-associated apolipoprotein AI is linked to 30-day mortality, and low HDL-C is associated with platelet activation.

B26	Harchaoui (2009)	Prospective observational study	Netherland	N/A	1. 12 2. 11	N/A	1. familial HAL 2. healthy controls	Fasting TC, LDL-C, HDL-C, TG, Apo	fecal neutral sterols and bile acid	Fecal sterol excretion is low in patients with primary HAL.

B27	Guimarães (2008)	Prospective cohort study	Brazil	N/A	1. 39 2. 17	TC≤96 mg/dl	Patients with AKI at ICU admission 1. non-survivor 2. survivor	1) anthopometric evaluation 2) SGA of nutritional status 3) IGF-1, serum albumin, TC, serum urea, and creatinine	1) 28-day mortality 2) sepsis: APACHE II score 3) need for mechanical ventilation, presence of oliguria, AKI etiopathogenesis 4) demographic data, comorbidity conditions, primary and concomitant diagnoses. 5) organ failures	In patients with acute kidney injury admitted to the intensive care unit, hypocholesterolemia is associated with higher mortality.

B28	Zorca (2008)	Prospective cohort study	US	N/A	1. 405 2. 32	N/A	1. SCD patients 2. healthy African American controls	TC, HDL-C, LDL-C TG, ApoAI, ApoB and the ratio ApoAI/ ApoB.	battery of markers of intravascular hemolysis and vascular dysfunction : reticulocyte count, total bilirubin, LDH	Low cholesterol levels in SCD patients are associated with intravascular hemolysis and vascular dysfunction.

B29	Naik (2006)	Prospective case-control study	India	N/A	1. 105 2. 52	N/A	1. children with leukemia or Hodgkin’s disease 2. healthy children	serum TC, TG, HDL-C, LDL-C	Incidence of cancer	Hypolipidemia is associated with leukemia and Hodgkin’s disease in pediatric patients.

B30	Cohen (2006)	Prospective cohort study	US	up to January 2003	1. 3,363 2. 9,524	N/A	CAD 1. black patients 2. white patients	lipid profiles	1) hospitalizations and death 2) The incidence of CHD 3) Carotid IMT	Low LDL-C resulting from PCSK9 mutations in Black individuals significantly reduces the risk of CAD.

B31	Chiang (2005)	Prospective observational study	Taiwan	in September 2002	210	LDL-C<80 mg/dl	ESRD patients with maintenance HD	Blood urea nitrogen, creatinine, albumin, TC, TG, HDL-C, LDL-C	annual mortality and hospitalization	Low LDL-C in HD patients is associated with mortality prediction.

B32	Mostaza (2005)	Prospective case-control study	Spain	N/A	1. 86 2. 86	HDL-C<40 mg/dl	1. patients with HAL 2. control	N/A	CRP concentrations	Patients with low HDL-C are associated with inflammatory states.

B33	Sankatsing (2005)	Prospective observational study	Netherland	N/A	1. 41 2. 41	ApoB<5th percentile	1. Familial HBL 2. healthy controls	N/A	1) Liver Ultrasound: extent of hepatic fatty infiltration was classified 2) Carotid Ultrasound: B-mode ultrasound IMT	In low LDL-C, the prevalence and severity of fatty liver disease increase, while arterial stiffness decreases, providing CV protective effects.

C. Retrospective studies

C01	Wargny (2024)	Retrospective cohort study	1. France 2. UK	1. February 2012 to December 2019 2. 2006 to 2010	1. 34,653 2. 94,666	1) LDL-C<70 mg/dl 2) LDL-C<1.81 mmol/L 3) LDL-C<5^th percentile	primary hypocholesterolemia 1. French CONSTANCES cohort 2. UK Biobank (UKBB) as a replication cohort	TC, TG, HDL-C, LDL-C, FPG, Hb, WBC and platelet counts and ALT	1) hepatic diseases at baseline and hepatic complications during follow-up 2) in the UKBB only, the fibrosis-4 index (FIB-4) : risk of advanced liver fibrosis	Low LDL-C is associated with an increased incidence of liver complications, including primary liver cancer.

C02	Xiao (2023)	Retrospective observational study	China	January 2008 to December 2020	353	TC≤3.11 mmol/L	children with hemophagocytic lymphohistiocytosis	Lipid evaluation: TC, TG, HDL-C, LDL-C	1) early death as death within 30 days of diagnosis 2) Survival time	In pediatric patients with hemophagocytic lymphohistiocytosis, hypocholesterolemia is linked to an increased risk of early mortality.

C03	Almas (2022)	Retrospective cohort study	Pakistan	April 2020 to January 2021	1. 1,067 2. 688	N/A	1. COVID-19 positive 2. healthy adult controls	1) Hb, and WBC 2) ALT, AST, LDL-C, HDL-C, TC, and TG 3) Free T3, free T4, TSH, IL-6, and Procalcitonin	1) severity markers: acute phase reactants like IL-6, Procalcitonin, CRP, and D-dimers 2) hospital stay	In COVID-19 patients, hypolipidemia is significantly more prevalent compared to controls and is associated with disease severity.

C04	Quan (2022)	Retrospective observational study	China	June 2018 to December 2021	1. 212 2. 1,060	N/A	1. patients with wasp stings 2. healthy controls	1) severity rating of wasp stings 2) allergic reaction grade 3) lipid tests (TG, TC, HDL-C, LDL-C, ApoA1 and ApoB), routine blood tests	1) LFT, RFT, and inflammatory markers such as IL-6 and CRP 2) the APACHE II score, SOFA score and mortality at 28 days	Hypolipidemia in patients with wasp stings is associated with severity.

C05	Yang (2022)	Retrospective cohort study	China	January to May 2019	22,557	1) LDL-C<1.48 mmol/L 2) LDL-C<2.5^th percentile	DM	TC, LDL-C concentration	The risk of DM	Both hypocholesterolemia and low LDL-C are independent risk factors for DM.

C06	Aparisi (2021)	Retrospective observational study	Spain	March to May 2020	654	N/A	COVID-19	TC, HDL-C, LDL-C, TG	1) inflammatory markers 2) all-cause mortality at 30-days	In COVID-19 patients, low LDL-C is associated with a higher 30-day mortality rate and inflammatory markers.

C07	Matsuo (2021)	Retrospective cohort study	Japan	November 2012 to August 2018	1. 19 2. 82	N/A	HD patients 1. Decreased BP during HD group 2. Non-decreased BP during HD group	lipid profiles	Blood volume and blood velocity: calculated from changes in impedance heart rate, MAP, CI, and SVRI	In HD patients, hypocholesterolemia is associated with decreased systemic vascular responsiveness, leading to lower blood pressure.

C08	Rimbert (2021)	Retrospective cohort study	France	N/A	111	LDL-C<5^th percentile	HBL	TC, TG, HDL-C, ApoA1, ApoB, and FPG	1) Liver steatosis was diagnosed by abdominal ultrasonography. 2) ALT, AST, and gamma-GT	In primary low LDL-C cases, single-gene mutations are associated with a higher risk of liver complications compared to polygenic cases.

C09	Shin (2021)	Retrospective observational study	Korea	January 2005 to December 2008	1251	TC≤117.6 mg/dl	gastric cancer	1) gastric cancer surgery 2) serum albumin, total protein, serum TC level, and CBC	1) overall survival, recurrence free survival, and surgical outcomes, such as hospital stays, blood loss, type and incidence of complications. 2) the log hazard of death	Preoperative hypocholesterolemia in gastric cancer patients is associated with postoperative complication rates and survival.

C10	Ndrepepa (2020)	Retrospective observational study	Germany	2000 to 2011	1. 8,592 2. 6,360	1) TC<1st quintile 2) TC<157 mg/dl	patients with CAD 1. statin-naïve 2. statin-treated	1) percutaneous coronary intervention 2) TC, TG, LDL-C and HDL-C	1) CRP, Creatinine 2) the risk of DM	In patients with CAD undergoing intervention, hypocholesterolemia is independently and dose-responsively associated with DM risk, primarily linked to low LDL-C.

C11	Wei (2020)	Retrospective cohort study	China	February to March 2020	1. 597 2. 1,574	TC<174 mg/dl	1. COVID-19 positive 2. normal subjects	1) CBC 2) ALT, AST, ALP, gamma-GT, LDL-C, HDL-C, TC, and TG	IL-6, T cell subpopulations	In COVID-19 patients, hypolipidemia is associated with disease severity.

C12	Benachenou (2019)	Retrospective observational study	Canada	2007 to 2017	1. 79 2. 79	TC, HDL-C, LDL-C, TG 1) <5th percentiles 2) 10th percentiles	1. individuals with ASD 2. control group consists of outpatients	TC, HDL-C, TG, LDL-C levels	1) anthropometric measurements: age, weight, height, and BMI 2) developmental, medical/genetic, psychiatric/behavioral disorders, prevalence of ASD, ASD-associated ID 3) medications	In patients with ASD, low cholesterol levels may be potentially linked to ASD and ID.

C13	Ishida (2019)	Retrospective observational study	Japan	October 2009 to July 2013	623	1) HDL-C<45 mg/dl (men) 2) HDL-C<55 mg/dl (women)	acute coronary syndrome patients : STEMI, non-STEMI and unstable angina.	troponin T, serum creatinine, FPG, LDL-C, HDL-C and TG levels	1) in-hospital mortality 2) ECG, echocardiography	In patients with acute coronary syndrome, low HDL-C is identified as an independent predictor of in-hospital mortality.

C14	Mouzaki (2019)	Retrospective cohort study	US	August 2010 to October 2017	740	LDL-C<50 mg/dl	nonalcoholic fatty liver disease	lipid profiles	1) hepatic profile, lipid profile, HbA1c 2) BMI, Waist circumference to height ratio 3) The NAFLD activity score	In patients with non-alcoholic fatty liver disease, the severity of low LDL-C is similar to that of the control group; however, low LDL-C significantly correlates with lower obesity levels and fatty liver.

C15	Cariou (2018)	Retrospective observational study	France	course of the year 2014	1. 20 2. 817	LDL-C≤50 mg/dl	1. HBL 2. non-HBL	N/A	1) physical characteristics 2) psychiatric characteristics: history of aggressive behaviors (hetero-aggression, suicidal attempts and other self-injuries), current psychotropic drugs use	Low LDL-C is associated with schizophrenia, autism, altruistic aggression, violent behavior, and impulsivity.

C16	Geller (2018)	Retrospective observational study	US	2014 to 2016	1. 112,776 2. 145,476	HDL-C<20 mg/dl	general population 1. male 2. female	1) TC, TG, LDL-C, sdLDL-C, HDL-C, ApoAI, ApoB, HDL, FBG, hsCRP, insulin, adiponectin, fibrinogen, MPO, and LFT 2) genetic mutations	prevalence rates of ASCAD, kidney failure	In cases of low HDL-C with genetic mutations, there is an association with the prevalence of kidney failure and ASCAD.

C17	Lee (2018)	Retrospective observational study	Korea	January 2007 to December 2015	1. 871 2. 55	TC<61 mg/dl	critically ill patients with diffuse peritonitis 1. survivor 2. non-survivor	1) emergency surgery 2) postoperative TC level	1) in-hospital mortality 2) ASA physical status classification, APACHE II score, comorbidities, lesion location, diagnosis, perioperative shock, preoperative blood cultures, intraoperative peritoneal fluid cultures, preoperative laboratory findings, postoperative complications 3) septic shock, Pulmonary complications, Anastomotic leakage, Wound complications, SSI; Postoperative AKI according to the RIFLE definition, postoperative ileus, newly developed sepsis	In critically ill patients undergoing emergency surgery for diffuse peritonitis, hypocholesterolemia is an independent predictor of in-hospital mortality.

C18	Oh (2018)	Retrospective observational study	Korea	January 2011 to June 2017	1,944	TC<160 mg/dl	primary colorectal cancer	1) elective laparoscopic colorectal surgery 2) preoperative TC levels	1) difference in postoperative pain outcome 2) BMI, ASA classification, history of hypertension or DM, type of surgery, preoperative TC, surgery duration, length of hospital stay, total opioid usage (PODs 0–2), and postoperative pain score (PODs 0-2).	There is no association between postoperative pain and preoperative hypocholesterolemia in patients undergoing laparoscopic surgery for primary colorectal cancer.

C19	Fukui (2016)	Retrospective observational study	Japan	April 2000 to July 2015	1. 18 2. 15	TC<150 mg/dl	Takayasu arteritis 1. relapse 2. non-relapse	1) symptoms, BMI, history of smoking, and complications 2) HLA typing, WBC count, Hb, platelet count, ESR, CRP, IgG, Alb, TC, LDL-C, HDL-C, and TG 3) MMP-3 and MMP-9 4) corticosteroid doses	1) subsequent relapse 2) survival rate	In Takayasu arteritis patients, low cholesterol levels are confirmed as the sole predictor of recurrence.

C20	Lee (2015)	Retrospective observational study	Korea	January 2007 to December 2012	1. 366 2. 45	TC<60 mg/dl	patients with intra-abdominal sepsis 1. survivor 2. non-survivor	1) emergency gastrointestinal surgery 2) postoperative TC level	in-hospital mortality	In patients undergoing emergency gastrointestinal surgery for intra-abdominal sepsis, low cholesterol levels significantly increase in-hospital mortality.

C21	Kang (2014)	Retrospective observational study	Korea	2005 to 2011	1. 665 2. 1,965	1) HDL-C<40 mg/dl (men) 2) HDL-C<50 mg/dl (women)	1. stone formers 2. control subjects	1) CBC, urine analyses, abdominal ultrasonography 2) lipid battery : TC, TG, and HDL-C, LDL-C	The risk of urinary stones	Patients with urolithiasis showed a higher risk associated with low HDL-C.

C22	Nakayama (2014)	Retrospective cohort study	Japan	January 2003 to December 2011	1. 186 2. 869	TC<120 mg/dl	AAA	1. emergency infrarenal repair 2. elective infrarenal repair	1) ECG abnormalities, Laboratory data 2) postoperative survival	In patients undergoing emergency surgery for abdominal aortic aneurysm, low cholesterol levels may be a potential predictor of decreased survival.

C23	Albers (2013)	Retrospective cohort study	US	N/A	3,196	LDL-C<40 mg/dl	atherothrombotic CV disease with low levels of HDL-C and elevated TG	the impact of intensive LDL-lowering therapy alone or in combination with ERN on ApoA-1, ApoB, and Lp (a)	CV events 1) death from coronary disease 2) nonfatal MI 3) ischemic stroke 4) hospitalization for acute coronary syndrome 5) symptom driven coronary or cerebrovascular revascularization	Low LDL-C is associated with the risk of CV events.

C24	Tadeu (2013)	Retrospective cohort study	Portugal	January 2009 to December 2012	225	N/A	admitted in the ICU, with severe sepsis or septic shock	serum TC and CRP levels	1) ICU mortality 2) LOS	In septic patients admitted to the intensive care unit, hypocholesterolemia is associated with an increased risk of mortality.

C25	Lee (2012)	Retrospective observational study	Korea	January 2005 to March 2011	1. 250 2. 709	1) LDL-C≤40 mg/dl 2) LDL-C≤70 mg/dl	HBL 1. very low LDL-C group 2. low LDL-C group	1) biochemical tests, lipid profiles (including LDL-C) 2) body anthropometry 3) vital sign assessments	1) incidence of chronic diseases 2) incidence of ICH	Patients with low LDL-C had a higher incidence of viral hepatitis and alcoholic liver disease; however, there was no association with the incidence of intracerebral hemorrhage.

C26	Tietjen (2012)	Retrospective cohort study	Netherlands and Canada	N/A	1. 89 2. 89	HDL-C<10^th percentile	unrelated probands of Caucasian ancestry with HAL 1. Familial 2. Unknown	1) HDL-C level 2) genetic mutations : ABCA1, APOA1, LCAT	1) CAD prevalence	Genetic mutations in patients with low HDL-C are associated with the prevalence of CAD.

C27	Dunham (2011)	Retrospective observational study	US	August 2006 to June 2008	152	TC<90 mg/dl	brain-injured patients underwent phenytoin loading on the day of injury	1) injury mechanism, chest injury, brain injury, ISS, shock, hypoxemia, RBC transfusion 2) TC level	1) requiring emergency tracheal intubation, mechanical ventilation 2) mortality	In trauma patients, the resolution of hypocholesterolemia may signal mechanical ventilation and mortality.

C28	Sok (2009)	Retrospective observational study	Slovenia	January 1992 to April 1994	198	1) TC≤1^st quartile 2) TC≤4.5 mmol/L	who underwent operations for non-small-cell lung cancer	1) TC level 2) physical examination and chest radiography by CT scanning, bronchoscopy or ultrasound	survival, The date of death	In patients undergoing surgery for non-small cell lung cancer, hypocholesterolemia is an important predictor of postoperative survival.

C29	Tsai (2009)	Retrospective observational study	Taiwan	May 2005 to April 2006	1. 37 2. 66	1) HDL-C<16.5 mg/dl 2) ApoAI<47.5 mg/dl	cirrhotic patients with severe sepsis 1. survivors 2. non-survivors	TC, TG, HDL, LDL, APO A-I	TNF-a, IL-6, CRP	Low HDL-C is associated with severity in patients with severe sepsis and cirrhosis.

C30	Shor (2008)	Retrospective observational study	Israel	January 2005 to December 2005	1. 108 2. 96	HDL-C≤20 mg/dl	1. patients with HAL 2. patients with hyperalphalipoproteinemia	CBC, FBG, urea, albumin, uric acid, electrolytes, LFT, total protein, lipid profile (TC, TG, LDL-C, HDL-C), creatinine	1) sepsis : ACCP/SCCM consensus conference definition 2) patient survival, fever, risk of neoplasm	Low HDL-C is associated with risks of mortality, sepsis, fever, and neoplasms.

C31	Mesa (2007)	Retrospective observational study	US	N/A	558	1) TC<150 mg/dl 2) HDL-C<60 mg/dl	myeloproliferative disorders (primary myelofibrosis, polycythemia vera, and essential thrombocythemia)	Serum TC, LDL-C, HDL-C, and TG	Survival rates	In patients with bone marrow disorders, hypocholesterolemia is independently associated with decreased survival rates.

C32	Nie (2007)	Retrospective observational study	China	January 2005 to December 2006	1. 61 2. 28	N/A	patients with severe multiple injuries 1. survival group 2. death group	serum TC	the risk of mortality	In patients with multiple severe trauma, hypocholesterolemia is associated with increased mortality risk.

C33	Wiviott (2005)	Retrospective cohort study	US	N/A	1,656	N/A	acute coronary syndrome after stabilization 1) acute MI 2) non-STEMI	1. intensive therapy (atorvastatin) 2. standard therapy (pravastatin) 3. gatifloxacin 4. placebo LDL-C level	death, MI, and total stroke	In stabilized patients after acute coronary syndrome, the administration of lipid-lowering agents showed no negative impact on low LDL-C levels.

C34	Vermont (2005)	Retrospective observational study	Netherland	July 1997 to March 2000	57	N/A	meningococcal sepsis	1. protein C concentrate 2. placebo Serum TC, HDL-C, and LDL-C	1) Disease Severity Scores : PRISM, SOFA, and the DIC score 2) Levels of IL-6 and TNF-α 3) WBC counts, lactate concentrations, and serum CRP	In patients with meningococcal sepsis, hypolipidemia is associated with severity.

C35	Kim (2005)	Retrospective observational study	Korea	January 2002 to June 2004	674	N/A	liver cirrhosis	total protein, albumin, AST, ALT, LDH, total bilirubin, TC, TG, PT, aPTT	1) severity of cirrhosis : CPC 2) in-hospital day, mortality	In cirrhosis patients, hypocholesterolemia is present with infections and correlates with poor prognosis.

D. Cross-sectional studies

D01	Andgi (2023)	Cross-sectional study	India	N/A	50	1) TC<200 mg/dl 2) LDL<130 mg/dl 3) HDL<40 mg/dl 4) TG<150 mg/dl	patients with acute stroke (cerebral infraction or intra-cerebral hemorrhage)	N/A	1) Lipid profile : TC, LDL, HDL, TG 2) the carotid IMT of the CCA by B-mode ultrasound	Hypercholesterolemia exhibits a protective effect against intracerebral hemorrhage. Elevated LDL levels are associated with ischemic stroke, and improvement in high LDL levels reduces complications and mortality.

D02	Armonis (2023)	Cross-sectional study	Greece	during the year 2021	301	N/A	COVID-19	N/A	1) blood sugar, HbA1c 2) lipid values : TC, TG, LDL and HDL 3) Mortality	In COVID-19 patients, hyperglycemia and hypolipidemia are associated with increased mortality.

D03	Amin (2018)	Cross-sectional study	Iraq	April 2014 to October 2016	1. 93 2. 93	TC<131 mg/dl	1. patients who developed non-traumatic, hypertensive hemorrhagic stroke 2. healthy control	N/A	serum TC, LDL-C, HDL-C, VLDL-C, and TG	There is no association between hypocholesterolemia and hypertensive hemorrhagic stroke in affected patients.

D04	Mukisa (2018)	Cross-sectional study	Uganda	February to April 2016	323	TC<3.7 mmol/L	pulmonary tuberculosis	N/A	1) laboratory tests : lipid profile, random blood sugar 2) pre-tested structured questionnaire.	In patients with pulmonary tuberculosis, hypocholesterolemia is linked to the duration of tuberculosis treatment.

D05	Ramachandran Pillai (2018)	Cross-sectional study	India	September 2014 to October 2015	1. 186 2. 503	N/A	1. women with postpartum depressive symptoms 2. without postpartum depression	N/A	1) TC TG, HDL-C 2) Tamil version of EPDS to assess depression	In postpartum women, low HDL-C is associated with increased depressive symptoms and higher EPDS scores.

D06	Nienov (2017)	Cross-sectional study	Brazil	January to December 2014	218	1) HDL-C<40 mg/dl (men) 2) HDL-C<50 mg/dl (women)	patients with severe obesity with metabolic syndrome	N/A	1) anthropometric data 2) blood pressure, serum blood glucose 3) HDL-C, LDL-C, TG, creatinine, TSH, and vitamin B12	Multiple peripheral neuropathy is associated with low HDL-C levels.

D07	Ataga (2015)	Cross-sectional study	US	N/A	1. 117 2. 11	N/A	1. SCD 2. healthy African American controls	N/A	TC, HDL, ProHDL	In SCD patients, hypocholesterolemia is associated with elevated markers of endothelial injury, and inflammatory HDL is linked to liver dysfunction.

D08	Boemeke (2015)	Cross-sectional study	Brazil	2010	150	1) TC<100 mg/dl 2) HDL-C<40 mg/dl 3) LDL-C<70 mg/dl 4) VLDL<16 mg/dl 5) TG<70 mg/dl	liver cirrhosis	N/A	1) TC, HDL-C, LDL-C, and TG 2) clinical outcome (liver transplantation or death pre-transplant	Hypocholesterolemia in cirrhosis patients is associated with disease progression.

D09	Nair (2015)	Cross-sectional study	India		1. 60 2. 60	N/A	1. alcoholic cirrhosis 2. healthy controls	N/A	1) CPC, MELD 2) Serum TG levels, TC, HDL, LDL, VLDL, ApoA1, Apo B100 and Lp (a)	In alcoholic cirrhosis patients, hypocholesterolemia is linked to severe sepsis.

D10	Chillarón (2013)	Cross-sectional study	Spain	2008	291	1) HDL-C<40 mg/dl (men) 2) HDL-C<50 mg/dl (women)	type 1 DM	N/A	HDL-C, and TG	In patients with type 1 diabetes, low HDL-C increases the risk of microvascular complications threefold.

D11	López-Hern ández (2012)	Cross-sectional study	Mexico	N/A	1. 826 2. 98	HDL-C≤35 mg/dl	MI 1. mestizos 2. indigos	N/A	serum glucose, TC, LDL-C, HDL-C, and TG	Low HDL-C is associated with an increased risk of MI.

D12	Abbasi (2012)	Cross-sectional study	Pakistan	June to December 2010	114	TC≤100 mg/dl	liver cirrhotic patients	N/A	1) serum TC, CBC, LFT, prothrombin time, albumin and total protein 2) dysfunction was categorized according to CPC	In cirrhosis patients, hypocholesterolemia and low triglyceride levels are correlated with the severity of liver dysfunction and Child-Pugh classification.

D13	Jung (2008)	Cross-sectional study	Korea	N/A	94	HDL-C<50 mg/dl	female college students		HDL-C, BMI, body weight, body fat, waist circumference	In female college students, low HDL-C is associated with an increased atherosclerosis index.

AAA : abdominal aortic aneurysm, ABL : abetalipoproteinemia, Apo : Apolipoprotein, AKI : Acute Kidney Injury, ALA : amoebic liver abscess, ALP : Alkaline Phosphatase, ASA : American Society of Anesthesiologists, ASCAD : atherosclerotic coronary artery disease, ASD : autism spectrum disorder, BMI : Body Mass Index, CAD : coronary artery disease, CBC : complete blood cell count, CCA : common carotid artery, CCVRF : Classic Cardiovascular Risk Factors, CCI : chronic critical illness, CDR : Clinical Dementia Rating, CHD : Coronary Heart Disease, CPC : Child Pugh Classification, CRP : C-Reactive Protein, CV : Cardiovascular, DIC : Disseminated Intravascular Coagulation, EPDS : Edinburgh Postnatal Depression Scale, ERN : extended-release niacin, ESR : Erythrocyte Sedimentation Rate, F-FDG PET/CT : Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography, Free T3 : Free Triiodothyronine, Free T4 : Free Thyroxine, GM-CSF : Granulocyte Macrophage Stimulating Factor, G-CSF : Granulocyte Colony Stimulating Factor, GRO : Growth Related Oncogene, HAART : highly active antiretroviral therapy, Hb : Hemoglobin, HAL : hypoalphalipoproteinemia, HBL : hypobetalipoproteinemia HD : Hemodialysis, HDL-C : High-Density Lipoprotein Cholesterol, hsCRP : High-Sensitivity C-Reactive Protein, IBD : inflammatory bowel diseases, ICAM-1 : Intercellular Adhesion Molecule-1, IFN : Interferon, IMT : Intima-Media Thickness, ID : Intellectual Disability, ISS : Injury Severity Score, IL : Interleukin, KDIGO : Kidney Disease Improving Global Outcomes, LDL-C : Low-Density Lipoprotein Cholesterol, LFT : Liver Function Tests, LOS : Length of Stay, Lp (a) : lipoprotein (a), MCUP : middle class urban population, MDD : major depressive disorder, MELD : Model End-Stage Liver Disease, MI : myocardial infarction, MIP-1α : Macrophage Inflammatory Protein-1α, MMP : Matrix Metalloproteinase, MMSE : Mini Mental State Examination, MPO : Myeloperoxidase, MRI : Magnetic Resonance Imaging, mRS : Modified Rankin Scale, NIHSS : National Institutes of Health Stroke Scale, PG : pyoderma gangrenosum, PODs : Postoperative Days, PRISM : Pediatric Risk of Mortality, RFS : Recurrence Free Survival, RFT : renal function test, RIFLE : Risk : Injury : Failure : Loss and End-Stage Renal Disease, SAPS : Simplified Acute Physiology Score, SCD : sickle cell disease, SGA : Subjective Global Nutritional Assessment, SOFA : Sepsis-Related Organ Failure Assessment, SSI : Surgical Site Infection, STEMI : ST-elevated myocardial infarction, SVRI : Systemic Vascular Resistance Index, TC : Total Cholesterol, TG : Triglycerides, TSH : Thyroid-Stimulating Hormone, VLDL-C : Very Low-Density Lipoprotein Cholesterol, WBC : white blood cell, WC : Waist Circumference, WHOQOL-BREF : World Health Organization Quality of Life Instrument (Brief Version)

IV. Discussions

Hypolipidemia refers to a state characterized by low levels of blood lipids¹. It can be classified as either genetic or secondary. While genetic disorders include such as abetalipoproteinemia and familial hypobetalipoproteinemia, secondary hypolipidemia is often attributed to the use of lipid-lowering agents in the treatment of hyperlipidemia¹⁷. The National Health and Nutrition Examination Survey (NHANES) indicates that blood lipid levels generally increase the age from 20s to 60s before declining in the age of 70s¹⁸. Although the mechanisms are not fully understood, hypolipidemia is theorized to cause deficiencies in thyroid hormones, adrenal hormones, sex hormones, and iron, and it has been associated with frailty in the context of lipid-lowering therapy. Previous research on hypolipidemia has been relatively limited compared to hyperlipidemia. Previous studies have explored the impact of hypolipidemia on health outcomes in populations with compromised health status, such as ICU admission and septic patients¹⁹^,20. However, these studies predominantly highlight the necessity for monitoring and clinical evaluation of hypolipidemia in specific contexts. This study aims to collect and identify trends related to health outcomes associated with hypolipidemia without restricting diseases.

The search results indicate that, while conflicting findings exist regarding certain disease groups such as CV and cerebrovascular diseases, numerous studies report an association between hypolipidemia and increased risks of mortality, disease severity, prevalence of various diseases, and adverse health outcomes. Through subgroup analyses, several trends from the included studies can be inferred.

First, in terms of immune and recovery functions, hypolipidemia may independently correlate with adverse health outcomes such as mortality, disease severity, increased incidence of infections, delayed recovery periods, and postoperative complications in specific health conditions characterized by impaired immune and recovery functions, including infections, sepsis, neoplasms, ICU admissions, and postoperative states. It has been hypothesized that decreased serum lipid levels may enhance cortisol and corticosterone synthesis in the adrenal glands²⁰, with cytokines like IL-6 related to chronic infections also associated with lower serum lipid levels²². Furthermore, Elmehdawi¹ and Mathew² have highlighted potential infection risks in septic conditions associated with hypolipidemia, while Falagas¹⁹ and Hofmaenner²⁰ have noted that hypolipidemia in septic patients could lead to increased intensive care unit (ICU) admissions and mortality rates. This suggests that, unlike healthy individuals, the lipid metabolism necessary for immune and recovery functions may be impaired in states of hypolipidemia due to genetic or secondary causes.

Regarding liver lipid metabolism, hypolipidemia has been associated with disease severity, prevalence, and prognosis in liver diseases such as fatty liver, cirrhosis, and liver cancer, as well as in conditions like sepsis, infections, and mental disorders. Reports suggest that abnormalities in liver lipid metabolism associated with hypolipidemia can affect immune function and may also influence the symptoms of mental disorders. The lipid metabolic response during immune reactions is identified as a key factor related to hypolipidemia, with the host lipid response to infections being influenced by sex hormones, age, and disease severity²³. Mechanisms linking hypolipidemia with major depressive disorder²⁴ and autism spectrum disorders²⁵ have been proposed, indicating that while liver dysfunction may contribute to the outcomes of hypolipidemia, similar findings in hereditary hypolipidemia suggest that specific genetic mutations leading to lipid synthesis disorders may also be associated with liver diseases.

While low LDL-C has been reported as a positive factor associated with CV protective effects, such as reduced arterial stiffness and decreased incidence of cerebrovascular diseases, it has been associated negatively with liver diseases, infections, neoplasms, and mental health. Karagiannis²⁶ reviewed the safety of low LDL-C levels, while a number of studies^27-³⁰ examined target levels for LDL-C regulation. There are also reports indicating that lipid-lowering agents are associated with increased hemorrhage in hemorrhagic strokes. Therefore, the negative associations of low LDL-C with non-CV diseases warrant further investigation. Conversely, low HDL-C, which is well recognized as components of dyslipidemia and metabolic syndrome, correlates with increased risks and prevalence of CV diseases such as myocardial infarction and coronary artery disease. However, HDL-C is similarly reported as a negative factor for non-CV diseases, like other cholesterols. The results of the included studies demonstrate the differences in CV health outcomes related to LDL-C and HDL-C.

Additionally, the study results suggest that hypolipidemia may influence various medical conditions that are caused or challenged by immune and lipid metabolic functions. This is reminiscent of the pathological mechanisms represented by the concepts of the Deficiency syndrome (虛證) in Korean Medicine. Although pathology and pattern identification still need to be investigated including lipid profile characteristics of each pattern syndrome; however, there is potential for utilizing Korean medical approaches to improve prognosis and enhance health outcomes for chronic diseases, long-term hospitalization, nutritional deficiencies, and elderly patients. Despite the inclusion of Korean databases in the search strategy, no research has been conducted in the realm of Korean medicine. Thus, further investigation into the effects of Korean medicine on hypolipidemia would be needed.

In analyzing the results according to the study design, it is observed that RCTs tend to have a relatively small sample size and limited publications. Although this can yield strong evidence of comparative effectiveness and efficacy, there are practical limitations regarding the feasibility of long-term follow-up observations extending over several years. Furthermore, there remains a need for further discussions about diagnostic criteria and the necessity for treatment of hypolipidemia, which appears to hinder the execution of RCTs focused on interventions and health outcomes related to hypolipidemia. In the case of prospective studies, long-term health outcomes were observed based on the collection of baseline lipid profiles, alongside hypolipidemia or various exposures. While this approach may provide prognostic data that can estimate the impact of hypolipidemia and its correction on health outcomes, it is limited by the potential confounding variables related to participant characteristics, chronic disease prevalence such as diabetes, and surgical conditions in specific studies, unlike RCTs that minimize heterogeneity. Conversely, retrospective studies, which typically involve larger sample sizes and extended observation periods, are more suitable for longitudinal analysis to demonstrate the impact of hypolipidemia on health outcomes. Such studies are often chosen as an epidemiological method to study the effects on health outcomes like prevalence and mortality of specific diseases, and the retrospective studies of this review included the largest sample sizes and various health conditions. Cross-sectional studies, in contrast, do not track long-term health outcome impacts but rather collect data on health outcomes at a single point in time. While they have reported associations between health conditions and hypolipidemia, the major limitation that the causation cannot be concluded is crucial. Most of the included studies reported differences in serum lipid levels or biochemical indicators rather than mortality or disease prevalence. Therefore, future research should be considered to investigate the long-term prognostic effects of hypolipidemia on health outcomes through a retrospective cohort design, considering the use of healthcare big-data to encompass a sufficiently large sample.

Several limitations must be discussed for careful interpretation of this review. First, comparisons of mortality and complication risks with hyperlipidemia are needed. Recent studies of hyperlipidemia have reported that the relation between lipid levels and health outcomes is U-shaped rather than L-shaped⁴^,31. Since the health outcomes of hyperlipidemia are already well-documented, it is advisable to explore the relative risks and discuss the lower limits of lipid level that may influence health outcomes in the hypolipidemia group. Second, there are conflicting research results regarding whether hypolipidemia itself exerts direct and independent effects on health. Included studies often focused on specific diseases, and when comparing groups against healthy controls, confounding factors related to diseases other than hypolipidemia may influence health outcomes. Third, this study did not specifically target patients taking lipid-lowering agents, making it challenging to interpret the health outcomes associated with hypolipidemia resulting from these medications. Given that studies associating hypolipidemia as a mediating factor for health outcomes are mixed, further health data analyses must be predicated on whether individuals are on lipid-lowering therapy. Fourth, there is no established clinical target threshold for the risks and optimal concentrations of hypolipidemia, indicating that studies reporting positive health impacts of hypolipidemia may not be widely published. Although this review aimed to encompass all health outcomes associated with hypolipidemia, most reports indicated negative effects, suggesting a tendency to prefer investigating risks over exploring lower target concentrations when studying hypolipidemia. Considering potential publication bias, the evidence supporting the risks of hypolipidemia remains insufficient.

In summary, this review of published clinical studies related to hypolipidemia and health outcomes indicates that hypolipidemia has elucidated the associations between various health conditions, and these findings are expected to have significant implications for clinical management. Effective management and prevention of hypolipidemia require an understanding of the characteristics of each disease and their relationship with hypolipidemia, necessitating a treatment approach based on this understanding. Future research may promote more in-depth clinical applications based on these findings.

V. Conclusions

Hypolipidemia may mediate lipid metabolism in the liver and immune function, contributing to the severity of conditions like sepsis, infections, and surgical complications, and is also a predictor of mortality risk. Low LDL-C levels are independent risk factors for fatty liver diseases, such as steatosis and fibrosis, but they may reduce CV risk by reducing arterial wall sclerosis. In contrast, low HDL-C levels promote arterial wall sclerosis and are associated with increased CV disease risk, while also linking to mortality of non-CV disease, such as infections and neoplasms. This underscores the importance of monitoring hypolipidemia in patients with specific health conditions. Further research is essential to explore the clinical implications of hypolipidemia, especially regarding its connections to various diseases.

Notes

Authors’ Contributions

Conceptualization : J. Jeong.

Methodology : S. Hong, D. Choi.

Software : S. Hong.

Validation : S. Hong.

Formal analysis : S. Hong

Investigation : S. Hong, D. Choi, J. Jeong.

Resources : S. Hong.

Data curation : S. Hong.

Writing - Original Draft : S. Hong.

Writing - Review & Editing : S. Hong, D. Choi, J. Jeong.

Visualization : S. Hong.

Supervision : D. Choi, J. Jeong.

Project administration : D. Choi, J. Jeong.

Funding acquisition : D. Choi.

Authors’ disclosure statement

The Authors declare that there is no conflict of interest.

Funding Statement

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : RS-2023-KH139286).

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethics Approval

Since the research is based on published literature and does not involve living subjects, informed consent and ethics approval were not required.

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