Cholesterol is a fundamental molecule for the functioning of the human body. It is an essential component of cell membranes and a precursor for the synthesis of steroid hormones. However, cholesterol has also been linked to various types of cancer. The relationship between cholesterol and cancer is complex and varies depending on the type of tumor. This article will explore in detail how cholesterol affects the development and progression of cancer, analyzing different types of tumors and the mechanisms involved.

Numerous studies have shown that cholesterol metabolism is altered in cancer cells. This leads to increased uptake, biosynthesis, and accumulation of cholesterol in cancer cells. These changes support cancer cell proliferation, invasion, metastasis, and resistance to chemotherapy. Deregulation of cholesterol metabolism in cancer cells can be due to various factors, including genetic mutations, epigenetic alterations, and interactions with the tumor microenvironment.

One of the primary mechanisms through which cholesterol influences cancer is its ability to modulate cell membranes. Cholesterol is a key component of cell membranes, where it forms structures called lipid rafts. These membrane microdomains are important for cell signaling as they host various receptors and signaling molecules. The accumulation of cholesterol in cell membranes can influence cell signaling, promoting the proliferation and survival of cancer cells.

Another mechanism through which cholesterol affects cancer is its ability to modulate inflammation. Chronic inflammation is a known risk factor for many types of cancer. Cholesterol can influence inflammation by modulating the activity of immune cells. For example, cholesterol can promote the formation of reactive oxygen species (ROS), which can damage DNA and promote carcinogenesis. Additionally, cholesterol can modulate antitumor immune responses by influencing the activity of T cells and macrophages.

The relationship between cholesterol and cancer has been studied in various types of tumors, including colorectal cancer, breast cancer, prostate cancer, hepatocellular carcinoma, pancreatic cancer, lung cancer, gastric cancer, ovarian cancer, and blood cancer.

In the case of colorectal cancer, clinical and preclinical studies have shown that blood cholesterol levels significantly decrease in patients with this type of cancer. This decrease in blood cholesterol is correlated with higher tumor grades. The expression of the low-density lipoprotein receptor (LDLR) is higher in colon tumor tissues compared to normal tissues. This increased LDLR expression facilitates cholesterol uptake by cancer cells, contributing to their proliferation. Additionally, cholesterol can support the stemness of colon cancer cells through MAPK signaling and ROS generation.

Regarding breast cancer, epidemiological studies have shown a significant association between dietary cholesterol intake and an increased risk of breast cancer. However, the results of clinical studies on the correlation between blood cholesterol levels and breast cancer are inconsistent. Some studies have reported elevated blood cholesterol levels in breast cancer patients regardless of body mass index (BMI), while others have reported decreased blood cholesterol levels. A large-scale population study conducted in Korea showed that high blood cholesterol levels increase the risk of breast cancer. Additionally, a positive correlation has been reported between high-density lipoprotein cholesterol (HDLc) and an increased risk of breast cancer, along with an increase in mammographic density. Elevated LDL cholesterol (LDLc) levels at the time of diagnosis were associated with poorer disease-free survival. Clinical studies have also shown that the increased expression of mevalonate pathway genes in p53-mutant breast tumors is correlated with worse prognosis and survival. The overexpression of LDLR and the accumulation of cholesterol esters have been observed in advanced-grade breast tumors.

In prostate cancer, the relationship between blood cholesterol levels and cancer risk is complex. Some clinical studies have indicated a link between high blood cholesterol levels and an increased risk of high-grade prostate cancer and prostate-specific antigen (PSA) levels. However, most epidemiological studies show weak evidence or no relationship between blood cholesterol levels and prostate cancer risk. Racial differences may influence this correlation, with some populations showing a stronger correlation between blood cholesterol levels and PSA levels. Preclinical studies have shown that a hypercholesterolemic diet increases tumor progression and angiogenesis in mouse models of prostate cancer. Additionally, cholesterol can support androgen synthesis in prostate cancer cells, making them self-sufficient for rapid cell division.

In hepatocellular carcinoma (HCC), the liver is the primary site of cholesterol biosynthesis and lipoprotein synthesis. Large-scale epidemiological studies in Korea have reported that an increase in blood cholesterol levels is associated with a decrease in liver cancer incidence. However, many studies have reported a positive association between HCC and hypercholesterolemia, which is likely a consequence of the tumor. The alteration of the blood lipid profile in HCC patients can be attributed to an abnormality in lipid metabolism influenced by the tumor. Patients with hepatitis B and C-associated HCC have shown decreased serum lipid levels, including cholesterol, LDLc, HDLc, and triglycerides, compared to normal counterparts. Low serum LDL cholesterol levels have been associated with an increased risk of liver cancer mortality. Preclinical studies have demonstrated that rats bearing hepatomas exhibit an alteration in the cholesterol feedback mechanism. Mouse models of hypercholesterolemia have shown decreased tumor growth in chemically induced cancer models.

In pancreatic cancer, high dietary cholesterol intake has been linked to an increased risk of cancer. The expression of the enzyme ACAT1 and the accumulation of cholesterol esters in tumor tissue samples have been correlated with poor survival. Inhibition of ACAT activity has been shown to reduce tumor progression in mice. Additionally, preclinical models of pancreatic cancer have demonstrated increased cholesterol uptake in tumors, associated with elevated LDLR expression.

In lung cancer, the relationship between blood cholesterol levels and cancer risk is complex. Recent studies have reported that abnormally high or low blood cholesterol levels increase the risk of lung cancer. However, most studies suggest that higher blood cholesterol levels are associated with a reduced risk of lung cancer, while lower blood cholesterol levels are associated with increased risk and worse survival. Some studies have reported that dietary cholesterol intake does not significantly impact lung cancer risk, while others have suggested that increased dietary cholesterol may slightly increase the risk.

In gastric cancer, clinical studies have shown that blood cholesterol levels decrease in patients with this type of cancer. This decrease has been correlated with worse prognosis. Infection with Helicobacter pylori, a bacterium that utilizes cholesterol to survive, is a known risk factor for gastric cancer. Increased dietary cholesterol consumption may favor Helicobacter pylori infection and increase the risk of gastric cancer. However, the relationship between blood cholesterol levels and gastric cancer risk remains unclear, with some studies reporting a positive association and others a negative association.

In ovarian cancer, most studies have shown that blood cholesterol levels decrease in patients with this type of cancer. However, some studies have reported that elevated LDL cholesterol levels increase the risk of ovarian cancer. The accumulation of cholesterol in malignant ascites has been associated with poor prognosis. Additionally, the expression of the enzyme ACAT1 has been found to be elevated in ovarian cancer cells, contributing to their proliferation and invasion. Inhibition of ACAT1 has been shown to reduce the proliferation of ovarian cancer cells by inducing apoptosis.

In blood cancer, including leukemia, lymphoma, and myeloma, blood cholesterol levels are generally decreased. Clinical studies have shown that total cholesterol, HDL, and LDL levels significantly decrease in patients with chronic leukemia, lymphoma, and myeloma compared to healthy subjects. However, in some cases of chronic lymphocytic leukemia, cholesterol levels were elevated. Preclinical studies have demonstrated that cancerous blood cells accumulate cholesterol in the cytoplasm and nucleus, supporting their survival and proliferation. The removal of cholesterol from the cell membrane has been shown to reduce signaling and migration of leukemic cells.

Cholesterol can also influence the functionality of cancer-associated immune cells. Studies have shown that hypercholesterolemia can modulate the response of T cells and macrophages, affecting tumor growth. For example, cholesterol can promote the formation of regulatory T cells, which suppress the antitumor immune response. Additionally, cholesterol derivatives like 27-HC can modulate breast cancer metastasis by reducing the number of CD8+ T cells and increasing the number of polymorphonuclear neutrophils and γδ T cells at metastatic sites.

Alteration of cholesterol metabolism in cancer cells is considered one of the emerging hallmarks of cancer. Preclinical and clinical studies have shown that targeting cholesterol metabolism can be an effective strategy for cancer treatment. For example, inhibition of the enzyme HMG-CoA reductase, the main enzyme in cholesterol biosynthesis, with drugs like statins has shown positive effects in the management of various cancers. However, some studies have suggested that low-dose statin treatment can promote the aggressiveness of prostate cancer and reduce sensitivity to chemotherapeutic drugs in ovarian cancer. Combining statins with other chemotherapeutic drugs has shown a synergistic effect in reducing tumor progression in preclinical models of colon cancer, lung cancer, and hepatocellular carcinoma.

Other strategies for targeting cholesterol metabolism include the use of cholesterol uptake inhibitors, such as ezetimibe, which has been shown to reduce prostate cancer progression in mouse models. Inhibition of the enzyme ACAT1 has been shown to reduce the proliferation of prostate cancer and chronic myeloid leukemia cells. Additionally, depletion of membrane cholesterol with compounds like methyl-β-cyclodextrin has been shown to increase the cytotoxicity of chemotherapeutic drugs in preclinical models of melanoma, breast cancer, and hepatocellular carcinoma.

Alteration of cholesterol metabolism can also contribute to resistance to antitumor therapy. Studies have shown that increased mitochondrial cholesterol levels can cause chemoresistance in hepatocellular carcinoma. Additionally, increased cholesterol uptake through upregulation of LDLR and decreased endogenous cholesterol biosynthesis can contribute to chemoresistance in ovarian cancer. Drug resistance has also been associated with the accumulation of cholesterol esters due to ACAT1 activity.

In conclusion, cholesterol plays a complex and multifaceted role in the development and progression of cancer. Understanding the mechanisms through which cholesterol influences cancer can lead to better management strategies, including new therapeutic approaches targeting cholesterol metabolism. However, further research is needed to elucidate the specific molecular pathways involved and develop effective therapeutic interventions.

Cholesterol and Cancer: Detailed Analysis

Cholesterol, a vital component of cell membranes and a precursor for steroid hormones, has been linked to various cancers. This relationship is complex and varies across different cancer types. The role of cholesterol in cancer involves altered cholesterol metabolism, leading to enhanced uptake, biosynthesis, and accumulation in cancer cells. These changes support cancer cell proliferation, invasion, metastasis, and resistance to chemotherapy.

Mechanisms Linking Cholesterol and Cancer

• Cell Proliferation and Survival: Cholesterol contributes to the structure and function of cell membranes, influencing cell signaling pathways that regulate proliferation and survival.
• Metastasis: Cholesterol accumulation aids in the formation of lipid rafts in cell membranes, facilitating cell migration and invasion.
• Chemoresistance: Elevated cholesterol levels can interfere with drug delivery and efficacy, contributing to chemoresistance.
• Hormone Synthesis: Cholesterol is a precursor for steroid hormones, which can promote the growth of hormone-dependent cancers such as breast and prostate cancer.

The Impact of Low Cholesterol Levels on Cancer Incidence, Recurrence, and Mortality: A Comprehensive Analysis

Cholesterol, a vital component of cell membranes and precursor for steroid hormones, has a complicated role in human health. While traditionally, high cholesterol levels have been implicated in cardiovascular diseases, recent research has increasingly highlighted the nuanced impact of cholesterol levels on cancer incidence, progression, and mortality. Numerous studies have examined the relationship between cholesterol metabolites and cancer, revealing significant associations with various cancer types, including pancreatic, breast, and prostate cancers. This document aims to provide a detailed and comprehensive analysis of the effects of cholesterol levels, particularly low cholesterol, on cancer outcomes, supported by the latest data and research findings available as of today.

Cholesterol and Cancer: A Complex Relationship

Cholesterol Metabolites and Cancer Formation

Cholesterol metabolites, such as oxysterols, play critical roles in various biological processes, including lipid metabolism, cell proliferation, and apoptosis. Several studies have established links between cholesterol metabolites and the development of cancers, suggesting that disruptions in cholesterol metabolism may contribute to tumorigenesis.

• Pancreatic Cancer: High cholesterol levels have been linked to an increased risk of pancreatic cancer. Cholesterol metabolites may influence pancreatic cancer cell proliferation and survival by modulating key signaling pathways involved in cancer development, such as the Hedgehog signaling pathway.
• Breast Cancer: In breast cancer, cholesterol metabolites like 27-hydroxycholesterol (27HC) act as estrogen receptor modulators, promoting tumor growth and metastasis. Studies have shown that higher serum cholesterol levels correlate with an increased risk of breast cancer recurrence.
• Prostate Cancer: Elevated cholesterol levels are associated with a higher probability of prostate cancer recurrence. Each 10 mg/dL increase in cholesterol levels increases the likelihood of recurrence by approximately 9%.

Biochemical and Molecular Mechanisms

Alterations in lipid metabolism and the balance between cell proliferation and apoptosis are central to the relationship between cholesterol and cancer. The biochemical and molecular mechanisms underlying this relationship include:

• Lipid Metabolism: Dysregulation in lipid metabolism, often associated with metabolic syndrome and obesity, can lead to increased lipid accumulation in tissues, promoting cancer development. Excessive lipid accumulation can result in oxidative stress and inflammation, which are conducive to cancer progression.
• Cell Proliferation and Apoptosis: Cholesterol and its metabolites can modulate signaling pathways that regulate cell proliferation and apoptosis. For instance, 27HC has been shown to activate the estrogen receptor in breast cancer cells, promoting cell proliferation and inhibiting apoptosis.
• Immune System Dysfunction: Dysregulated cholesterol levels can impair immune function, reducing the body’s ability to detect and eliminate cancer cells. Studies have shown that patients with low cholesterol levels often have compromised immune responses, making them more susceptible to infections and possibly cancer.

Cohort Studies and Meta-Analyses

Numerous cohort studies and meta-analyses have explored the association between serum cholesterol levels and cancer outcomes. These studies provide valuable insights into the complex relationship between cholesterol and cancer:

• Overall Survival: A systematic review and meta-analysis found a substantial association between total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and overall survival among cancer patients. Low levels of HDL-C were consistently associated with poorer survival outcomes.
• Low-Density Lipoprotein Cholesterol (LDL-C): Recent studies have observed a U-shaped association between LDL-C levels and all-cause mortality. While extremely low LDL-C levels are associated with increased mortality, moderate levels appear to have a protective effect.
• Triglycerides (TG): Elevated blood triglycerides have been identified as a poor prognostic indicator in some studies, although the evidence is not conclusive. The impact of triglyceride levels on cancer outcomes requires further investigation.

The U-Shaped Association Between Cholesterol Levels and Mortality

Study Overview

In a large-scale longitudinal analysis of 59,217 cancer patients, researchers identified a U-shaped association between baseline total cholesterol levels and mortality risk. Both low and high cholesterol levels were associated with an elevated risk of death, highlighting the importance of maintaining balanced cholesterol levels for optimal health outcomes.

• Low LDL-C Levels: Low LDL-C levels, particularly in the first and second centiles, were associated with a significantly increased risk of death. This finding underscores the potential dangers of excessively low LDL-C levels in cancer patients.
• HDL-C Levels: Decreased HDL-C levels were consistently linked to a higher risk of death, reinforcing the protective role of HDL-C in cancer outcomes.
• Triglyceride Levels: No significant association was found between triglyceride levels by quartile and mortality risk in cancer patients, suggesting that triglycerides may play a less critical role in cancer prognosis compared to other lipid fractions.

Mechanisms Underlying the U-Shaped Association

Several mechanisms have been proposed to explain the U-shaped association between cholesterol levels and mortality in cancer patients:

• Reverse Causation: Low serum cholesterol levels may be indicative of underlying frailty, illness, or malnutrition, which can contribute to non-cardiovascular mortality. Undiagnosed cancers may also lower cholesterol levels, creating a reverse causation effect.
• Immune System Function: Dysregulated cholesterol homeostasis can impair immune function, increasing vulnerability to infections and potentially facilitating cancer progression. Low cholesterol levels have been linked to reduced total T and CD8+ cell counts, critical components of the immune response.
• Oxidative Stress: Patients with low cholesterol levels often exhibit lower serum antioxidant activity, making them more susceptible to oxidative stress. Oxidative stress can damage cellular components, promoting cancer development and progression.
• Inflammation and Cytokines: Elevated levels of pro-inflammatory cytokines, such as interleukin-6, have been observed in patients with low cholesterol levels. Chronic inflammation is a well-established risk factor for cancer and can exacerbate disease progression.

Prognostic Role of Baseline Lipid Levels in Cancer Patients

Clinical Implications

The findings of the large-scale longitudinal study have significant clinical implications for the management of cancer patients:

• Risk Stratification: Baseline lipid levels can serve as valuable prognostic markers, helping clinicians identify patients at higher risk of mortality. Regular monitoring of cholesterol levels should be integrated into routine cancer care to guide treatment decisions.
• Tailored Interventions: Understanding the relationship between lipid levels and cancer outcomes enables the development of tailored interventions aimed at optimizing cholesterol levels. Lifestyle modifications, dietary interventions, and pharmacological treatments can be employed to maintain cholesterol within optimal ranges.
• Comprehensive Care: Given the interplay between lipid metabolism, immune function, and cancer progression, a holistic approach to patient care is essential. Addressing comorbidities, such as diabetes and hypertension, and ensuring adequate nutritional support are critical components of comprehensive cancer management.

Limitations and Future Directions

While the study provides valuable insights, it is important to acknowledge potential limitations and areas for future research:

• Population Specificity: The study’s findings are based on a sample of Korean individuals, which may limit the generalizability of the results to other populations. Further research is needed to validate these findings in diverse demographic groups.
• Residual Confounding: Despite multivariable analyses, residual confounding factors, such as cancer medication or surgical interventions, may influence the results. Future studies should aim to account for these potential confounders.
• Longitudinal Follow-Up: Long-term follow-up is essential to fully understand the impact of cholesterol levels on cancer outcomes. Continued research should focus on tracking changes in lipid levels over time and their association with cancer prognosis.

In conclusion, the relationship between cholesterol levels and cancer outcomes is complex and multifaceted. The U-shaped association between total cholesterol levels and mortality risk highlights the importance of maintaining balanced cholesterol levels in cancer patients. Low LDL-C levels are significantly associated with an increased risk of all-cause mortality, while decreased HDL-C levels are linked to higher mortality risk. Triglyceride levels, however, do not appear to have a significant impact on cancer prognosis.

These findings underscore the need for a comprehensive approach to cancer care that includes regular monitoring and management of lipid levels. By integrating lipid assessments into routine cancer care, clinicians can better stratify risk, tailor interventions, and ultimately improve patient outcomes. Continued research is essential to further elucidate the mechanisms underlying the relationship between cholesterol and cancer and to develop effective strategies for optimizing lipid levels in cancer patients.

New Cholesterol Guidelines

In recent years, a new approach to treating abnormal cholesterol levels has been developed. Previous guidelines recommended that doctors use specific target goals for LDL (low-density lipoprotein) cholesterol based on patient risk factors. The newer guidelines take a somewhat different approach, focusing on reducing the overall risk of diseases caused by atherosclerosis, including abnormal cholesterol, rather than targeting specific cholesterol lab results precisely.

Several cardiovascular risk calculators are available that consider a person’s gender, age, race, total cholesterol, HDL (high-density lipoprotein), blood pressure, diabetes, and smoking status to estimate their risk of having a heart attack or stroke within the next 10 years. Based on these results, a doctor may recommend treatment with a cholesterol-lowering statin or other drugs. Despite the availability of drug therapy, heart-healthy lifestyle changes (diet, exercise, smoking cessation, and weight control) remain the foundation for cholesterol treatment at all ages, both before and during drug therapy.

Drug Therapy

The guidelines recommend drug therapy based on a person’s risk for heart disease, stroke, and other problems caused by atherosclerosis:

• Primary prevention refers to risk reduction in those who do not yet have evidence of cardiovascular disease.
• Secondary prevention refers to risk reduction in those who have evidence of cardiovascular disease.

Statins are the first choice in virtually all patients with abnormal LDL cholesterol levels to prevent cardiovascular disease. When to start statins and what dose to use is based on a patient’s risk and current atherosclerotic cardiovascular disease. Newer biological drugs have been approved for reducing LDL cholesterol levels in certain high-risk scenarios.

Lifestyle Changes

The key lifestyle changes to improve unhealthy cholesterol levels are:

• A heart-healthy diet (emphasizing vegetables, fruits, and whole grains).
• Regular physical activity (The American Heart Association recommends performing 30 minutes of moderate exercise five days a week for a total of 150 minutes a week, or 75 minutes of vigorous exercise a week).
• Maintaining a healthy body weight (with a doctor’s help when necessary).
• Avoiding smoking.
• Controlling high blood pressure and diabetes (for patients who also have these conditions).

Lipids are the building blocks of fats and fatty substances found in animals and plants. They include cholesterol, triglycerides, fatty acids, phospholipids, and others. Lipids do not dissolve in water and are usually transported in blood and other body fluids in the form of lipoproteins. Lipids serve essential functions in the body, including:

• Structural components of all cell membranes.
• Energy source.
• Signaling molecules involved in multiple cellular processes.
• Precursors for other lipid molecules, hormones, and vitamins.

Cholesterol

Cholesterol is present in all animal cells and animal-based foods but not in plants. Despite its negative reputation, cholesterol is an essential nutrient necessary for many functions, including:

• Repairing cell membranes.
• Manufacturing vitamin D in the skin.
• Producing hormones such as estrogen and testosterone.
• Possibly aiding in cell connections in the brain that are important for learning and memory.

However, when cholesterol levels rise in the blood, they can have dangerous consequences depending on the type of cholesterol. Although the body acquires some cholesterol through diet, about two-thirds is manufactured in the liver, stimulated by saturated fat. Saturated fats are found in animal products (meat, egg yolks, high-fat dairy products) and tropical plant oils (palm, coconut).

Triglycerides

Triglycerides are composed of glycerol and fatty acid molecules. They are the basic chemicals contained in fats in both animals and plants. High levels of triglycerides, especially in combination with low levels of HDL, are associated with an increased risk of heart disease, stroke, diabetes, and fatty liver disease.

Lipoproteins

Lipoproteins are protein spheres that transport cholesterol, triglycerides, or other lipid molecules through the bloodstream. Most of the vascular effects of cholesterol and triglycerides depend on lipoproteins. Lipoproteins are categorized into five types according to size and density, further defined by whether they carry cholesterol or triglycerides.

Cholesterol-Carrying Lipoproteins

These lipoproteins are commonly referred to as cholesterol:

• Low-density lipoproteins (LDL), often called “bad” cholesterol.
• High-density lipoproteins (HDL), the smallest and densest, often called “good” cholesterol.

Triglyceride-Carrying Lipoproteins

• Intermediate-density lipoproteins (IDL) tend to carry triglycerides.
• Very low-density lipoproteins (VLDL) tend to carry triglycerides.
• Chylomicrons or ultra low-density lipoproteins (UDL) are the largest in size and lowest in density. Chylomicrons tend to carry triglycerides.

Effects of Lipoproteins and Triglycerides on Heart Disease

Low-Density Lipoproteins (LDL), the “Bad” Cholesterol

The main villain in the cholesterol story is low-density lipoprotein (LDL). Heart disease is least likely to occur among people with the lowest LDL levels. Lowering LDL is the primary goal of cholesterol drug and lifestyle therapy.

Low-density lipoprotein (LDL) transports about 75% of the blood’s cholesterol to the body’s cells. It is normally harmless. However, if exposed to oxidation, LDL can penetrate and interact dangerously with the artery walls, producing a harmful inflammatory response. Oxidation is a natural process in the body that occurs from chemical combinations with unstable molecules known as oxygen-free radicals or oxidants.

In response to oxidized LDL, the body releases various immune factors aimed at protecting the damaged arterial walls. Unfortunately, in excessive quantities, they cause inflammation and promote further injury to the targeted areas.

High-Density Lipoproteins (HDL), the “Good” Cholesterol

High-density lipoprotein (HDL) appears to benefit the body in several ways:

• It removes cholesterol from the walls of the arteries and returns it to the liver for disposal from the body.
• It helps prevent the oxidation of LDL. (HDL may have antioxidant properties.)
• It may also fight inflammation.

HDL helps keep arteries open and reduces the risk of heart attack. High levels of HDL (above 60 mg/dL) may be nearly as protective for the heart as low levels of LDL. HDL levels below 40 mg/dL are associated with an increased risk of heart disease.

Triglycerides

Triglycerides interact with HDL cholesterol in such a way that HDL levels fall as triglyceride levels rise. High triglycerides may pose other dangers regardless of cholesterol levels. For example, they may be associated with blood clots that form and block the arteries. High triglyceride levels are also associated with the inflammatory response, the harmful effect of an overactive immune system that can cause considerable damage to cells and tissues, including the arteries. Very high triglycerides can also cause pancreatitis, a potentially life-threatening condition.

Risk Factors

Unhealthy cholesterol levels (low HDL, high LDL, and high triglycerides) increase the risk of heart disease and heart attack. Some risk factors for cholesterol can be controlled (such as diet, exercise, and weight) while others cannot (such as age, gender, and family history).

Age and Sex

From puberty on, men tend to have lower HDL (good cholesterol) levels than women. One reason is that the female sex hormone estrogen is associated with higher HDL levels. Because of this, premenopausal women generally have lower rates of heart disease than men. After menopause, as estrogen levels decline, women catch up in their rates of heart disease. Throughout the postmenopausal years, HDL levels decrease and LDL (bad cholesterol) and triglyceride levels increase. For men, LDL and triglyceride levels also rise with age, increasing heart disease risks. Heart disease is the main cause of death for both men and women.

Children and Adolescents

Children with abnormal cholesterol levels are at increased risk of developing heart disease later in life. However, it is difficult to distinguish “normal” cholesterol levels in children. Cholesterol levels, which are normally very low at birth, tend to naturally rise sharply until puberty, decrease sharply, and then rise again later in life.

Genetic Factors and Family History

Genetics can play a major role in determining a person’s blood cholesterol levels. (Children from families with a history of premature heart disease should be tested for cholesterol levels after age 2.) Genes may influence whether a person has low HDL levels, high LDL levels, high triglycerides, or high levels of other lipoproteins, such as lipoprotein(a). Several types of inherited cholesterol disorders exist.

• Familial hypercholesterolemia (FH) is a genetic disorder that causes high cholesterol levels, particularly LDL, and premature heart disease. There are two forms of FH:
• Heterozygous FH, where the genetic mutation is inherited from one parent, occurs in about 1 in 500 people. It increases the risk of heart attack between ages 40 to 60.
• Homozygous FH, where the genetic mutation is inherited from both parents, is much rarer, occurring in about 1 in 1 million people. People with homozygous FH risk extremely severe hypercholesterolemia, with many experiencing heart attack or death before age 30.
• Familial lipoprotein lipase deficiency is a group of rare genetic disorders causing depletion of the enzyme lipoprotein lipase. This enzyme helps remove lipoproteins rich in triglycerides. People deficient in lipoprotein lipase have high levels of cholesterol and fat in their blood.

Lifestyle Factors

• Diet: The primary dietary elements leading to unhealthy blood cholesterol include saturated fats (found mainly in red meat and high-fat dairy products) and trans fatty acids (found in fried foods and some commercially baked food products). Shellfish and egg yolks are also high in dietary cholesterol

. Large amounts of added sugars raise triglyceride levels.

• Weight: Being overweight or obese increases the risks for unhealthy cholesterol levels.
• Exercise: Lack of exercise can contribute to weight gain, decreases in HDL levels, and increases in LDL, triglycerides, and total cholesterol levels.
• Smoking: Smoking reduces HDL cholesterol and promotes the buildup of fatty deposits in the coronary arteries.
• Alcohol: Heavy consumption of alcohol can increase triglyceride levels.

Obesity, Metabolic Syndrome, and Type 2 Diabetes

In the United States, obesity is at epidemic levels in all age groups. The effect of obesity on cholesterol levels is complex. Overweight individuals tend to have high triglyceride and LDL levels and low HDL levels, a combination that poses a risk for heart disease. Obesity also causes other effects, such as high blood pressure and increased inflammation, posing significant risks to the heart.

Obesity is particularly dangerous when it is one of the components of the metabolic syndrome. Metabolic syndrome consists of:

• Obesity marked by abdominal fat.
• Unhealthy lipid levels (low HDL levels, high triglycerides).
• High blood pressure.
• Insulin resistance.

Metabolic syndrome is a pre-diabetic condition significantly associated with heart disease and higher mortality rates from all causes. Obesity is also strongly associated with type 2 diabetes, which itself poses a significant risk for high cholesterol levels and heart disease.

Children who are overweight are at higher risk for high triglycerides and low HDL, which may be directly related to later unhealthy cholesterol levels. Childhood LDL levels and body mass index (BMI) are strongly associated with cardiovascular risk during adulthood. Overweight and obese children who have high cholesterol should also get tested for high blood pressure, diabetes, and other conditions associated with metabolic syndrome.

Other Medical Conditions

• High Blood Pressure: High blood pressure (hypertension) does not affect cholesterol levels but contributes to the thickening of heart blood vessel walls, worsening atherosclerosis. High blood pressure, high cholesterol, and diabetes all act together to increase the risk of developing heart disease.
• Hypothyroidism: Low thyroid levels (hypothyroidism) are associated with elevated total and LDL cholesterol and triglyceride levels. Treating the thyroid condition can significantly reduce cholesterol levels. Research is mixed on whether mild hypothyroidism (subclinical hypothyroidism) is associated with unhealthy cholesterol levels.
• Polycystic Ovarian Syndrome: Women with this endocrine disorder may have increased risks for high triglyceride and low HDL levels, possibly due to the higher levels of the male hormone testosterone associated with this disease.

Other Risk Factors

• Medications: Certain medications, such as specific antiseizure drugs, corticosteroids, and isotretinoin (Accutane), may increase lipid levels.

Complications

Heart Disease

Atherosclerosis is a common disorder of the arteries where fat, cholesterol, and other substances collect in the artery walls. Larger accumulations, called atheromas or plaque, can damage artery walls and block blood flow. Severely restricted blood flow in the heart muscle leads to symptoms such as chest pain.

Unhealthy cholesterol, particularly LDL cholesterol, forms a fatty substance called plaque, which builds up on the arterial walls of the heart. Smaller plaques remain soft, but older, larger plaques tend to develop fibrous caps with calcium deposits. The long-term result is atherosclerosis.

The heart is endangered in two ways by this process:

• The calcified and inelastic arteries eventually become narrower (a condition known as stenosis). As this process continues, blood flow slows, preventing sufficient oxygen-rich blood from reaching the heart. This condition can lead to angina (chest pain) and, when atherosclerotic plaques are damaged (e.g., rupture), can lead to sudden blockages and heart attack. When damage is sufficient to impair the heart’s pumping, heart failure can result.
• Smaller unstable plaques may rupture, triggering the formation of blood clots on their surface. The blood clots block the arteries and are significant causes of heart attacks.

This process is accelerated by other risk factors, including high blood pressure, smoking, obesity, diabetes, and a sedentary lifestyle. When more than one of these risk factors is present, the risk is compounded.

Coronary Artery Disease

The end result of atherosclerosis is coronary artery disease. Coronary artery disease, sometimes referred to simply as “heart disease” or ischemic heart disease, is the leading cause of death in the U.S.

Studies consistently report a higher risk of death from heart disease with high LDL cholesterol levels. Even moderate elevation of LDL levels increases the chance of heart disease when other risk factors are present. The higher the cholesterol, the greater the risk.

Peripheral Artery Disease (PAD)

Peripheral artery disease (PAD) is caused by plaque buildup in the feet, legs, hands, and arms, most often occurring in the legs. PAD is associated with atherosclerosis. Lower levels of HDL and high triglyceride levels also increase the risk for PAD.

Stroke

Having adequate levels of HDL may be the most crucial lipid-related factor for preventing ischemic stroke, a type of stroke caused by blockage of the arteries that carry blood to the brain. HDL may even reduce the risk of hemorrhagic stroke, a much less common type of stroke caused by bleeding in the brain associated with low overall cholesterol levels.

The build-up of plaque in the internal carotid artery may lead to narrowing and irregularity of the artery’s channel, preventing proper blood flow to the brain. More commonly, as the narrowing worsens, clots form on the plaque and can break free, travel to the brain, and block blood vessels that supply blood to the brain. This leads to stroke, with possible paralysis, speech impairment, or other deficits.

The effects of high total cholesterol and LDL levels on ischemic stroke are less clear. Some research suggests that the risk for ischemic stroke increases when total cholesterol is high. Other studies suggest that high cholesterol poses a risk for stroke only when specific proteins associated with inflammation are present.

Symptoms

There are no warning signs for high LDL and other unhealthy cholesterol levels. When symptoms finally occur, they usually take the form of angina (chest pain), heart attack, or stroke. When buildups occur in leg arteries, patients may have discomfort with walking (claudication). In men, erectile dysfunction may be another symptom of atherosclerosis.

Atherosclerosis is a disease of the arteries in which fatty material is deposited in the vessel wall, resulting in narrowing and eventual impairment of blood flow. Severely restricted blood flow in the arteries to the heart muscle leads to symptoms such as chest pain. Atherosclerosis shows no symptoms until a complication occurs.

Diagnosis

Blood tests can easily measure cholesterol levels. A lipid profile includes LDL, total cholesterol, HDL, and triglycerides. It is also possible to measure LDL levels by themselves, but LDL levels can be reliably calculated using the other values unless the triglycerides are very high.

To obtain an accurate cholesterol reading, doctors advise:

• Do not eat or drink anything but water for 8 to 12 hours before the test. (Some recent studies indicate that fasting is unnecessary for routine screening. Check with your doctor.)
• If the test results are abnormal, a second test should be performed between 1 week and 2 months after the first test.

Screening Guidelines

Periodic cholesterol testing is recommended in all adults, but the major national guidelines differ on the age to start testing. Recommended starting ages are between 20 to 35 for men and 20 to 45 for women. Adults with normal cholesterol levels do not need to have the test repeated for 5 years unless lifestyle changes occur (including weight gain and diet). Adults with a history of elevated cholesterol, diabetes, kidney problems, heart disease, and other conditions require more frequent testing.

Screening with a fasting lipid profile is recommended for children who:

• Have risk factors such as a family history of high cholesterol and a history of heart attacks before age 55 for men and before age 65 for women. Screening should begin as early as age 2 and no later than age 10.
• Are overweight or obese (above the 85th percentile for weight) or have diabetes. If the child’s cholesterol level tests normal, retesting is recommended in 3 to 5 years.

People already being treated for high cholesterol may have tests periodically to ensure treatment is working and tolerated (especially by the liver). However, the new guidelines de-emphasize repeat testing.

Other Tests

If the risk-based calculation for statin therapy is uncertain, the doctor may order three additional tests recommended by the ACC/AHA guidelines:

• C-reactive Protein (CRP): CRP is produced in the liver. CRP levels increase when there is inflammation throughout the body. A CRP level of 2.0 mg/L or greater indicates increased risk for heart disease. CRP is measured by a blood test.
• Ankle-Brachial Index (ABI): The ABI test compares blood pressure readings in the ankles and arms to evaluate circulation. Measurements below 0.9 suggest possible blockage of the arteries. The ABI test is similar to a blood pressure exam, but the cuff is placed around the ankles. This test is typically used to diagnose peripheral artery disease.
• Coronary Calcium Scan: A computed tomography (CT) scan is used to detect calcium deposits on the arterial walls. A high coronary artery calcification score (above 300 Agatston units) indicates increased risk for heart disease. Routine screening with this test is not recommended.

Other possible tests your doctor may order include:

• Carotid Intima-Media Thickness: This test uses an ultrasound scan to obtain a very precise measurement of the wall of the carotid artery. If the thickness is high, a doctor may prescribe drug therapy.
• Lp(a): Lipoprotein(a) is a lipoprotein associated with coronary artery disease and stroke. However, there is no proven benefit to date that lowering these levels will result in fewer cardiovascular events. If levels are elevated, a doctor may prescribe lipid-lowering therapy.
• LP PLA2: Lipoprotein-associated phospholipase A2 is a marker of vascular inflammation associated with heart disease and stroke. If levels are elevated, a doctor may prescribe lipid-lowering therapy.
• Apolipoprotein B (apoB or apoB 100): Apolipoprotein B is a component of lipoproteins like LDL and is associated with cardiovascular disease risk. Similar to LDL-C, apoB may be used to help with decisions on lipid-lowering therapy.

Treatment

General Treatment Approaches

Lifestyle changes (such as diet, weight control, exercise, and smoking cessation) are the first line of defense for treating unhealthy cholesterol levels. If levels and other risk factors remain high, drug treatment is an effective next step.

Statins are the first-line drugs for lowering high LDL levels and reducing the risk of heart disease and stroke. A statin drug is used along with healthy lifestyle habits, not in place of them.

In the past, choices regarding when and how aggressively to treat hyperlipidemia were driven largely by LDL and HDL cholesterol levels. Doctors advised most adults to target a total cholesterol level of less than 200 mg/dL and an LDL of less than 100 mg/dL. In some people at very high risk, the targeted level was even lower.

However, experts on cholesterol realized there was no solid scientific evidence to support the target number treatment approach, especially in people with no cardiovascular disease. As a result, newer guidelines take a risk-based approach, treating the patient rather than just treating the lab result. Along with the cholesterol level, other factors that may increase a patient’s risk for heart disease are considered. All of this information is then used to decide the following:

• Whether to use statin drugs to treat unhealthy cholesterol levels.
• How to choose between lower and higher doses of lower and higher potency statins.
• Which other drugs may be used.

Candidates for Statin Therapy

Secondary prevention refers to treating unhealthy cholesterol levels in those with a history of heart disease, stroke, or narrowing of the arteries to the brain, intestines, kidneys, or legs (cardiovascular disease). Almost all people with these health problems will be treated with higher doses of statins if tolerated. For most of these patients, the aim is to reduce LDL cholesterol by at least half. In people with a very high risk of these problems, the aim with statin therapy is to reduce LDL-C to below 70 mg/dL. Other drugs may be needed to reach these goals, such as PCSK9 inhibitors and ezetimibe.

Primary prevention refers to treating people who have no known cardiovascular disease but are thought to be at increased risk. Treatment recommendations differ based on a person’s risk of cardiovascular disease and the risk of side effects caused by statins.

• If someone has diabetes and an LDL-C level between 70 and 189 mg/dL (1.8 to 4.9 mmol/L):
• In those aged 40 to 75, moderate doses of statins are recommended. The goal is to reduce LDL-C by a little less than half.
• In those with many risk factors for ASCVD or those aged 50 to 75, higher doses of statins may be recommended. The goal is to reduce LDL-C by over half.
• If someone does not have diabetes, is between the ages of 40 and 75, and has an LDL-C level between 70 and 189 mg/dL (1.8 to 4.9 mmol/L):
• A healthcare provider should calculate the risk of having a heart attack or stroke within 10 years. In those who have a 7.5% or higher risk, moderate doses of statins are most often recommended. The goal is to reduce LDL-C by a little less than half.
• In those with a very high risk of heart attack or stroke, higher doses of statins may be used.
• In those who have less than a 7.5% risk of heart attack or stroke, lifestyle changes are often recommended.
• Adults with an LDL-C of 190 mg/dL (4.9 mmol/L) or higher are likely to be given higher doses of statins. If the LDL-C level remains above 100 mg/dL (2.6 mmol/L), adding ezetimibe or a PCSK9 inhibitor may be considered.
• Adults over 75 who are otherwise healthy may be candidates for drug therapy for elevated cholesterol levels. However, careful consideration should be taken for older adults with a limited lifespan due to other illnesses.

Heart Disease Risk Calculation

The ACC/AHA has designed a “risk calculator” that healthcare providers can use to calculate a person’s 10-year cardiovascular disease risk. The calculator can be found at tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate.

The ACC/AHA recommends that doctors enter the following factors into the “risk calculator” to determine a person’s overall risk for cardiovascular disease:

• Sex
• Age
• Race (white, African American, or other)
• Total cholesterol
• LDL (bad cholesterol)
• HDL (good cholesterol)
• Blood pressure (systolic and diastolic blood pressure)
• Currently treated for blood pressure
• Currently treated with a statin
• Currently treated with aspirin
• Diabetes
• Smoking

This risk calculator is designed for people aged 40 to 79 who do not have existing or prior heart disease.

If the risk calculation seems uncertain, a doctor may consider additional factors, including family history of premature heart disease, increased lifetime heart disease risk, and sometimes the results of other diagnostic tests such as C-reactive protein level, ankle-brachial index, and coronary artery calcification score.

The ACC/AHA emphasizes that individual patient preferences are an essential part of the new guidelines. All treatment options should begin with a conversation between the doctor and patient, including discussing how people feel about the risks and benefits of drug therapy. Lifestyle modification is the most critical component of heart disease risk reduction. Recommendations are likely to change in the future as more information becomes available from extensive research studies.

Lifestyle Changes

The most important first step for improving cholesterol levels and reducing the risk of heart disease and stroke is to make heart-healthy lifestyle changes. Even when drug therapy is used, lifestyle measures are critical companions.

General Guidelines for Healthy Lifestyle

The main lifestyle principles to reduce unhealthy cholesterol levels include:

• Consume a heart-healthy diet (emphasizing vegetables, fruits, and whole grains).
• Engage in regular physical activity (30 minutes per day for a total of 150 minutes per week of moderate intensity or 75 minutes per week of vigorous exercise).
• Maintain a healthy body weight (under a doctor’s supervision when necessary).
• Avoid smoking.
• Control high blood pressure and diabetes (for people who also have these conditions).

Heart-Healthy Diets

The American College of Cardiology (ACC) and American Heart Association (AHA) joint dietary guidelines for reducing unhealthy cholesterol levels recommend:

• Making vegetables, fruits, and whole grains the focus of the diet.
• Including low-fat dairy products, poultry, fish, legumes (beans), nontropical vegetable oils, and nuts.
• Limiting intake of sweets, sugar-sweetened beverages, and red meats.

Many dietary approaches protect heart health, such as the Mediterranean Diet, which emphasizes fruits, vegetables, and healthy fats. The DASH diet is very effective for patients with high blood pressure and others who need to restrict sodium (salt) intake. Other heart-healthy diet plans include the American Heart Association diet and the USDA Food Pattern.

Doctors generally agree on the following recommendations for heart protection:

• Choose fiber-rich food (whole grains, legumes, and nuts) as the primary source of carbohydrates, along with a high intake of fruits and vegetables. Walnuts, in particular, have cholesterol-lowering properties and are a good source of antioxidants and alpha-linolenic acid.
• Avoid saturated fats (found mostly in animal products and tropical plant oils) and trans fatty acids (found in hydrogenated fats and many commercial products and fast foods). Choose unsaturated fats (particularly omega-3 fatty acids found in vegetable [olive, canola] and fish oils). For dairy products, choose nonfat or low-fat over whole fat.
• For proteins, choose fish, poultry, and beans instead of red meat.
• Fish is particularly heart protective. It contains the omega-3 fatty acids docosahexaenoic (DHA) and eicosapentaenoic (EPA), which have significant benefits for the heart, particularly for lowering triglyceride levels. Fish oil supplements do not generally provide the same benefits as fish.
• Avoid added sugars such as those found in sugar-sweetened beverages.
• Limit sodium (salt) intake to no more than 2,400 mg a day. Some people, such as those with high blood pressure, may need to restrict sodium intake to no more than 1,500 mg/day.

After starting a heart-healthy diet, it generally takes an average of 3 to 6 months before any noticeable reduction in cholesterol occurs. However, some people see improved levels in as few as 4 weeks.

Weight Management

A healthy weight is vital for healthy cholesterol levels. For people who are overweight or obese, losing even a modest amount of weight has significant health benefits, even if an ideal weight is not achieved. There is a direct relationship between the amount of weight lost and an improvement in cholesterol.

In particular, triglyceride is closely linked to weight: a sustained 3% to 5% weight loss can significantly reduce unhealthy triglyceride levels. Even greater amounts of weight loss can help improve LDL and HDL levels. Weight loss also helps reduce the need for blood pressure medication, improves blood glucose (sugar) levels, and lowers the risk of developing type 2 diabetes.

Obesity is now considered

and treated as a disease, not a lifestyle issue. Doctors’ understanding of weight issues has evolved. Scientific evidence has shown that weight gain is a complex process, and weight loss involves more than simple willpower. Excess weight contributes to many health problems, including increased risk of cardiovascular disease.

Doctors should check body mass index (BMI) at least once a year. The BMI estimates how much someone should weigh based on height:

• Overweight is a BMI of 25 to 29.9.
• Obese is a BMI of over 30.

Guidelines recommend doctors create individualized weight loss plans for overweight or obese patients. The plan should include three components:

• Reduced Calorie Diet: A doctor should help select an eating plan that will cut calories and perhaps restrict certain food types (such as fats or carbohydrates). The doctor may make specific recommendations depending on the cholesterol profile and other factors. For example, a low-calorie, low-fat diet can be very effective for reducing LDL levels. The plan should consider personal and cultural food preferences. Doctors may refer patients to a registered dietician or nutritionist for counseling.
• Behavioral Strategies: People need to consider how to set weight loss goals, monitor weight, track food and calorie intake, change shopping habits and food storage environments, and establish fitness routines. People may benefit from individual, group, or telephone counseling sessions.
• Increased Physical Activity: People should aim for 200 to 300 minutes of physical activity a week (about 40 minutes a day of moderate to intensive aerobic exercise).

A weight loss of 5% to 10% within the first 6 months of starting these changes can help improve cholesterol levels and other health indicators. If someone has risk factors for heart disease or diabetes and does not achieve weight loss from diet and lifestyle changes alone, a doctor may recommend adding a prescription medication to the weight loss plan. For people with a very high BMI and several cardiovascular risk factors (such as diabetes and high blood pressure), bariatric surgery may be considered.

Exercise

Inactivity is a significant risk factor for coronary artery disease, on par with smoking, unhealthy cholesterol, and high blood pressure. Studies suggest that people who change their diet to control cholesterol only achieve a lower risk of heart disease when they also follow a regular aerobic exercise program. Resistance (weight) training offers a complementary benefit to aerobics.

Even moderate exercise reduces the risk of heart attack and stroke. Current guidelines recommend at least 40 minutes of moderate-intensity physical activity on three or more days per week for a total of 200 to 300 minutes per week.

Quitting Smoking

Cigarette smoking lowers HDL and is directly responsible for many deaths from heart disease. The importance of breaking this habit cannot be emphasized enough. Once a person quits smoking, HDL cholesterol levels rise within weeks or months to levels that are equal to their nonsmoking peers. Passive smoking also reduces HDL levels and increases the risk of heart disease in people exposed to second-hand smoke. Cigarette smoking is also associated with high blood pressure.

Alcohol

Numerous studies have found heart protection from moderate alcohol intake (one or two drinks a day). Moderate amounts of alcohol may help raise HDL levels. Although red wine is most often cited for healthful properties, any type of alcoholic beverage appears to have similar benefits. However, the potential benefits of moderate drinking may be offset by the risk of alcohol use disorder and other diseases. People with high triglyceride levels should drink sparingly or not at all, as even small amounts of alcohol can significantly increase blood triglycerides. Pregnant women, women at risk for breast cancer, anyone who cannot drink moderately, and people with liver disease should not drink at all. Because alcohol can be toxic to the heart muscle, some patients with heart disease, specifically heart failure, may be counseled to avoid alcohol. Drinking alcohol in any amount may increase the risk of certain types of cancer.

Herbs and Supplements

Manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Like drugs, herbs and supplements can affect the body’s chemistry and potentially produce harmful side effects. Numerous reported cases exist of serious and even lethal side effects from herbal products. Always check with a doctor before using any herbal remedies or dietary supplements.

The following natural remedies are of interest for cholesterol control:

• Garlic: Contrary to popular belief, neither raw garlic nor garlic supplements significantly reduce LDL cholesterol levels.
• Policosanol: Policosanol is a nutritional supplement derived from sugar cane, promoted for its lipid-lowering benefits. However, rigorous research has not shown policosanol to have any effect on reducing LDL levels.
• Red Yeast Rice: Red yeast rice is used in traditional Chinese medicine. The FDA warns that red yeast rice dietary supplement products sold as treatments for high cholesterol contain the same chemicals as statin drugs, but these products are not standardized for purity, safety, and effectiveness.

Medications

Statins

Statins are the most effective drugs for lowering LDL (bad cholesterol) levels and reducing the risk of heart disease and stroke. Statins inhibit the liver enzyme HMG-CoA reductase, which the body uses to manufacture cholesterol.

Current guidelines from the American College of Cardiology and American Heart Association recommend a statin drug as the first-line treatment for patients at risk for cardiovascular disease. Other cholesterol-lowering medications are not as effective as statins and are not recommended, except in rare cases.

Depending on LDL cholesterol levels, the presence of atherosclerotic heart disease, 10-year risk for heart disease, and whether or not someone has diabetes, a doctor will recommend either a moderate-intensity or high-intensity statin therapy dosage plan. The exact dosage will depend on the statin drug prescribed.

Once someone starts a statin, the recommended dosage is maintained. For the most part, there is no need to monitor LDL levels for response.

If a particular statin drug does not work or if someone experiences significant side effects, a doctor may switch to a different statin drug. In general, if multiple statins are not tolerated, other statin-lowering medicines are generally not recommended.

Brands

Statins approved in the U.S. include:

• Lovastatin (Mevacor, generic)
• Pravastatin (Pravachol, generic)
• Simvastatin (Zocor, generic)
• Atorvastatin (Lipitor, generic)
• Fluvastatin (Lescol)
• Pitavastatin (Livalo)
• Rosuvastatin (Crestor)

Some statins come as fixed-dose combination drugs, combining two drugs in one pill. Examples include:

• Sitagliptin/simvastatin (Juvisync) for people with high cholesterol and diabetes.
• Amlodipine/atorvastatin (Caduet) for people with high cholesterol and high blood pressure.
• Ezetimibe/simvastatin (Vytorin) and ezetimibe/atorvastatin (Liptruzet), which combines two lipid-lowering drugs that act through different mechanisms: statins lower cholesterol synthesis in the body, and ezetimibe lowers cholesterol absorption from the intestine.
• Simvastatin/niacin (Simcor) and lovastatin/niacin (Advicor) combine a statin with another lipid-lowering drug, niacin, which lowers LDL and triglycerides and raises HDL levels.

Side Effects

Statin side effects may include diarrhea, constipation, upset stomach, muscle and joint pain, tendon problems, headache, fatigue, and forgetfulness or memory loss. More serious side effects include liver and muscle damage. People should immediately tell their doctor about any unusual muscle discomfort or weakness, fever, nausea or vomiting, or darkening of urine color.

Statins can affect the results of liver tests. Liver enzyme tests should be performed before starting statin therapy. Liver damage is rare but can occur, particularly at higher doses. People should tell their doctor if they have symptoms indicating liver problems, such as unusual fatigue, loss of appetite, upper belly pain, dark-colored urine, or yellowing of the skin or whites of the eyes.

A specific safety concern with statins is an uncommon muscle disease called myopathy, in which a person may experience muscle pains, and certain lab tests may be elevated. Severe myopathy called rhabdomyolysis can lead to kidney failure, but fortunately, its occurrence is very rare. The risk for myopathy/rhabdomyolysis is highest at higher doses and in older people (over 65 years), those with hyperthyroidism, and those with renal insufficiency (kidney disease).

Rosuvastatin (Crestor) may increase the risk of myopathy, especially when given at the highest dose level (40 mg). The FDA advises that people should not start therapy at a high dose. Additionally, people of Asian heritage appear to metabolize the drug differently and should start treatment at the lowest rosuvastatin dose (5 mg), with 20 mg generally considered the maximum dose for these people. Maximal doses of simvastatin and lovastatin also appear to increase the risk of myopathy.

Other Safety Concerns

Statins are recommended as the best drugs for improving cholesterol and lipid levels in people with type 1 or type 2 diabetes. However, they may increase blood glucose levels in some people, especially when taken in high doses. They may also increase the risk of developing type 2 diabetes in people with risk factors.

There is evidence that statins may increase the risk of developing cataracts.

Interactions with Drugs and Food

Statins may have some adverse interactions with other drugs. People should tell their doctors about any other medications they are taking. Medications that should not be taken along with statins include protease inhibitors, telaprevir, cyclosporine, macrolide antibiotics, and certain antifungals. Grapefruit juice and Seville oranges can increase the blood levels of certain statins.

Other Cholesterol-Lowering

Drugs

Statins are the primary drugs for treating cholesterol and reducing cardiovascular disease risk. They have replaced other drugs that were used for lowering cholesterol. These other drugs are still available, but the value of their use when statins have not been tolerated or successful enough remains unclear.

Fibrates

Fibrates are generally reserved for people with extremely high triglyceride levels or high cholesterol who cannot tolerate a statin drug.

Gemfibrozil (Lopid, generic) is the most commonly prescribed fibrate. Other fibrates include fenofibrate (TriCor, Lofibra) and fenofibric acid (Trilipix). These drugs have many side effects, including gallstones, abnormal heart rhythms, and muscle problems (myopathy), which may lead to kidney damage. A fibrate should only be carefully used in combination with a statin because of increased risk for myopathy.

Niacin

For many years, high doses of niacin (nicotinic acid or vitamin B3) were considered a treatment option for low HDL cholesterol and high LDL cholesterol and triglyceride levels. Research now suggests that niacin does not add to the benefit of a statin alone for reducing the risk of cardiovascular events, including heart attacks and strokes. Additionally, niacin can cause unpleasant and potentially dangerous side effects, leading to its declining use. Niacin/statin combinations include simvastatin/niacin (Simcor) and lovastatin/niacin (Advicor).

Bile-Acid Binding Drugs

Bile-acid binding drugs, also known as bile acid resins or bile acid sequestrants, reduce LDL levels. Brands include cholestyramine (generic), colesevelam (Welchol), and colestipol (Colestid, generic).

Bile acid resins commonly cause constipation, heartburn, gas, and other gastrointestinal problems, side effects that many people cannot tolerate. These drugs may increase the risk of osteoporosis, elevate triglyceride levels, and interfere with the absorption of other medications.

Ezetimibe

Ezetimibe (Zetia) blocks the absorption of cholesterol from food. It helps reduce LDL cholesterol and is often used with statins. Ezetimibe is used in people with cardiovascular disease who are at very high risk if high-intensity statin therapy does not lower LDL-cholesterol enough. Ezetimibe can also be used in patients without cardiovascular disease but with very high LDL-cholesterol that is not reduced enough with statins alone.

Vytorin is a combination of ezetimibe and the statin simvastatin in a single pill. Liptruzet combines ezetimibe and the statin atorvastatin in a single pill.

Prescription Fish Oil Supplements

Lovaza and Vascepa are prescription forms of omega-3 fish oil, which may be prescribed to help lower triglycerides in people with very high levels. Recent research has questioned the benefits of fish oil supplements for preventing heart attacks and strokes.

Other Drugs

Mipomersen (Kynamro) and lomitapide (Juxtapid) are approved specifically for treating homozygous familial hypercholesterolemia, a very rare genetic condition that can cause heart attacks and strokes before age 30.

Proprotein Convertase Subtilisin Kexin 9 (PCSK9) Inhibitors

A new group of drugs that inhibit a specific enzyme have been released. These drugs can reduce LDL cholesterol by 60% to 70% and appear to reduce the rate of heart attacks, deaths from heart disease, and overall mortality.

Two drugs have been approved by the FDA: evolocumab (Repatha) and alirocumab (Praluent). They are a type of drug called monoclonal antibodies. These drugs are expensive, and their exact role in treating elevated LDL cholesterol levels remains to be fully determined. They are used for people with inherited cholesterol disorders and those who cannot take statin drugs. PCSK9 inhibitors are also recommended for people with very high risk or very high LDL-cholesterol for whom high-intensity statin treatment does not lower LDL-cholesterol levels enough.

In conclusion, the new cholesterol guidelines emphasize a more holistic approach to treating abnormal cholesterol levels, focusing on overall cardiovascular risk rather than specific cholesterol targets. This approach includes the use of cardiovascular risk calculators, heart-healthy lifestyle changes, and appropriate drug therapy, with statins being the first-line treatment. Other medications and lifestyle interventions are considered based on individual patient risk factors and responses to treatment.

Cholesterol Levels and Cancer Correlation: Analytical Table

Cancer Type	Cholesterol Level	Correlation with Cancer Development	Mechanisms and Findings
Colorectal Cancer	Decreased blood cholesterol	Negative correlation with higher tumor grade	Increased uptake by cancer cells, high LDLR expression in tumors, blood cholesterol decreases before diagnosis.
Breast Cancer	High blood cholesterol (varied findings)	Positive correlation with risk and progression	Increased LDLc linked to higher grade and Her2-neu positive subtypes, 27-HC as estrogen receptor modulator.
Prostate Cancer	High blood cholesterol (varied findings)	Positive correlation with high-grade cancer and PSA levels	Increased LDLR expression, cholesterol biosynthesis in tumors, androgen synthesis from cholesterol.
Hepatocellular Cancer	High blood cholesterol (varied findings)	Mixed findings, generally high cholesterol linked to HCC	Altered lipid metabolism in HCC, correlation with hepatitis-related HCC, elevated cholesterol in cirrhotic liver patients.
Pancreatic Cancer	High dietary cholesterol	Positive correlation with risk and progression	Increased ACAT1 expression, cholesterol ester accumulation, LDLR expression in tumors.
Lung Cancer	Abnormally high or low cholesterol	Increased risk with abnormal levels	Low blood cholesterol linked to worse survival, mixed findings on dietary cholesterol impact.
Gastric Cancer	Low blood cholesterol	Negative correlation with progression	Decreased blood cholesterol linked to poor prognosis, dietary cholesterol supports Helicobacter pylori infection.
Ovarian Cancer	Decreased blood cholesterol	Mixed findings, generally low cholesterol linked to poor prognosis	High LDL cholesterol linked to risk, elevated cholesterol in malignant ascites, ACAT1 overexpression.
Blood Cancer (Leukemia, Lymphoma, Myeloma)	Decreased blood cholesterol	Negative correlation with tumor stage	Decreased cholesterol linked to higher tumor stages, altered cholesterol metabolism in cancer cells.

Detailed Role of Cholesterol in Various Cancers

Colorectal Cancer

• Key Findings: Blood cholesterol levels decrease significantly in patients, correlating with higher tumor grades. LDLR expression is higher in tumor tissues.
• Mechanism: Enhanced cholesterol uptake by cancer cells reduces blood cholesterol. Cholesterol supports stemness and proliferation through MAPK signaling and ROS generation.

Breast Cancer

• Key Findings: Elevated blood cholesterol correlates with higher risk and worse prognosis, particularly in postmenopausal women.
• Mechanism: Cholesterol metabolites like 27-HC act as selective estrogen receptor modulators, promoting cancer cell proliferation. LDLc and VLDLc enhance cell proliferation via pAKT and pERK pathways.

Prostate Cancer

• Key Findings: Mixed findings with race-specific correlations. High blood cholesterol associated with higher PSA levels in some studies.
• Mechanism: Increased LDLR expression and cholesterol biosynthesis support rapid cell division. Cholesterol contributes to androgen synthesis in cancer cells.

Hepatocellular Cancer

• Key Findings: High blood cholesterol generally linked to HCC, with altered lipid metabolism observed in patients.
• Mechanism: Tumor cells may disrupt cholesterol feedback mechanisms, leading to high cholesterol levels. Hepatitis-related HCC shows decreased serum lipids.

Pancreatic Cancer

• Key Findings: High dietary cholesterol linked to increased risk. ACAT1 expression and cholesterol ester accumulation correlate with poor survival.
• Mechanism: LDLR-mediated cholesterol uptake supports cell proliferation. ACAT1 inhibition reduces tumor growth by inducing ER stress and apoptosis.

Lung Cancer

• Key Findings: Both high and low cholesterol levels increase cancer risk. Low blood cholesterol linked to worse outcomes.
• Mechanism: Cholesterol impacts cell migration and invasion. Dietary cholesterol has mixed effects on cancer risk.

Gastric Cancer

• Key Findings: Low blood cholesterol associated with higher cancer risk and worse prognosis. Dietary cholesterol supports bacterial infection.
• Mechanism: Helicobacter pylori infection, aided by dietary cholesterol, increases cancer risk. Low serum cholesterol may result from increased tumor uptake.

Ovarian Cancer

• Key Findings: Decreased blood cholesterol generally linked to poor prognosis. Elevated cholesterol in ascites fluid.
• Mechanism: Overexpression of ACAT1 and HMGCR supports tumor growth. Altered cholesterol metabolism contributes to cancer progression.

Blood Cancer

• Key Findings: Decreased blood cholesterol observed in various types. High cholesterol linked to worse outcomes in some studies.
• Mechanism: Altered cholesterol metabolism supports cancer cell survival and proliferation. Increased LDLR and cholesterol biosynthesis observed in cancer cells.

The relationship between cholesterol and cancer is multifaceted, with cholesterol metabolism playing a critical role in cancer cell proliferation, survival, and resistance to therapy. Understanding these mechanisms can lead to better management strategies, including targeting cholesterol metabolism in cancer treatment. Further research is needed to elucidate the specific molecular pathways involved and to develop effective therapeutic interventions.

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APPENDIX 1 – The Role of Cholesterol in Cancer

Category	Subcategory	Details
Introduction	Lipids	Lipids are the building blocks of fats and fatty substances found in animals and plants.
Introduction	Lipids	They include cholesterol, triglycerides, fatty acids, phospholipids, and others.
Introduction	Lipids	Lipids do not dissolve in water and are usually transported in blood and other body fluids in the form of lipoproteins.
Introduction	Lipids	Lipids serve essential functions in the body, including structural components of all cell membranes, energy source, signaling molecules involved in multiple cellular processes, and precursors for other lipid molecules, hormones, and vitamins.
Cholesterol	Cholesterol	Cholesterol is present in all animal cells and in animal-based foods but not in plants.
Cholesterol	Cholesterol	Cholesterol is an essential nutrient necessary for many functions, including repairing cell membranes, manufacturing vitamin D in the skin, producing hormones such as estrogen and testosterone, and possibly aiding in cell connections in the brain that are important for learning and memory.
Cholesterol	Cholesterol	When cholesterol levels rise in the blood, they can have dangerous consequences depending on the type of cholesterol.
Cholesterol	Cholesterol	Although the body acquires some cholesterol through diet, about two-thirds is manufactured in the liver, stimulated by saturated fat.
Cholesterol	Cholesterol	Saturated fats are found in animal products (meat, egg yolks, high-fat dairy products) and tropical plant oils (palm, coconut).
Cholesterol	Cholesterol	Saturated fats are strongly associated with higher cholesterol levels.
Cholesterol	Cholesterol	Tropical oils, such as palm, palm kernel, coconut, and cocoa butter, are also high in saturated fats.
Triglycerides	Triglycerides	Triglycerides are composed of glycerol and fatty acid molecules.
Triglycerides	Triglycerides	They are the basic chemicals contained in fats in both animals and plants.
Lipoproteins	Lipoproteins	Lipoproteins are protein spheres that transport cholesterol, triglyceride, or other lipid molecules through the bloodstream.
Lipoproteins	Lipoproteins	Most of the vascular effects of cholesterol and triglyceride depend on lipoproteins.
Lipoproteins	Lipoproteins	Lipoproteins are categorized into five types according to size and density, further defined by whether they carry cholesterol or triglycerides.
Cholesterol-Carrying Lipoproteins	Cholesterol-Carrying Lipoproteins	These are the lipoproteins commonly referred to as cholesterol.
Cholesterol-Carrying Lipoproteins	Cholesterol-Carrying Lipoproteins	Low-density lipoproteins (LDL), often called ‘bad’ cholesterol, and high-density lipoproteins (HDL), the smallest and densest, often called ‘good’ cholesterol.
Triglyceride-Carrying Lipoproteins	Triglyceride-Carrying Lipoproteins	Intermediate-density lipoproteins (IDL) tend to carry triglycerides.
Triglyceride-Carrying Lipoproteins	Triglyceride-Carrying Lipoproteins	Very low-density lipoproteins (VLDL) tend to carry triglycerides.
Triglyceride-Carrying Lipoproteins	Triglyceride-Carrying Lipoproteins	Chylomicrons or ultra low-density lipoproteins (UDL) are the largest in size and lowest in density. Chylomicrons tend to carry triglycerides.
Effects of Lipoproteins on Heart Disease	Low-Density Lipoproteins (LDL)	Low-density lipoprotein (LDL) transports about 75% of the blood’s cholesterol to the body’s cells.
Effects of Lipoproteins on Heart Disease	Low-Density Lipoproteins (LDL)	LDL is normally harmless. However, if it is exposed to a process called oxidation, it can penetrate and interact dangerously with the walls of the artery, producing a harmful inflammatory response.
Low-Density Lipoproteins (LDL)	Low-Density Lipoproteins (LDL)	The main villain in the cholesterol story is low-density lipoprotein (LDL). Heart disease is least likely to occur among people with the lowest LDL levels.
Low-Density Lipoproteins (LDL)	Low-Density Lipoproteins (LDL)	Lowering LDL is the primary goal of cholesterol drug and lifestyle therapy.
High-Density Lipoproteins (HDL)	High-Density Lipoproteins (HDL)	High-density lipoprotein (HDL) appears to benefit the body in several ways.
High-Density Lipoproteins (HDL)	High-Density Lipoproteins (HDL)	HDL removes cholesterol from the walls of the arteries and returns it to the liver for disposal from the body.
High-Density Lipoproteins (HDL)	High-Density Lipoproteins (HDL)	HDL helps prevent the oxidation of LDL and may have antioxidant properties.
High-Density Lipoproteins (HDL)	High-Density Lipoproteins (HDL)	HDL may also fight inflammation.
High-Density Lipoproteins (HDL)	High-Density Lipoproteins (HDL)	HDL helps keep arteries open and reduces the risk of heart attack.
Triglycerides	Triglycerides	High levels of HDL (above 60 mg/dL) may be nearly as protective for the heart as low levels of LDL.
Triglycerides	Triglycerides	HDL levels below 40 mg/dL are associated with an increased risk of heart disease.
Risk Factors	Risk Factors	Triglycerides interact with HDL cholesterol in such a way that HDL levels fall as triglyceride levels rise.
Risk Factors	Risk Factors	High triglycerides may pose other dangers, regardless of cholesterol levels.
Risk Factors	Risk Factors	They may be associated with blood clots that form and block the arteries.
Age and Sex	Age and Sex	High triglyceride levels are also associated with the inflammatory response, the harmful effect of an overactive immune system that can cause considerable damage to cells and tissues, including the arteries.
Age and Sex	Age and Sex	From puberty on, men tend to have lower HDL (good cholesterol) levels than women.
Age and Sex	Age and Sex	The female sex hormone estrogen is associated with higher HDL levels.
Age and Sex	Age and Sex	Premenopausal women generally have lower rates of heart disease than men.
Children and Adolescents	Children and Adolescents	After menopause, as estrogen levels decline, women catch up in their rates of heart disease.
Children and Adolescents	Children and Adolescents	Throughout the post-menopausal years, HDL levels decrease and LDL (bad cholesterol) and triglyceride levels increase.
Genetic Factors and Family History	Genetic Factors and Family History	For men, LDL and triglyceride levels also rise as they age and the risks for heart disease increase.
Genetic Factors and Family History	Genetic Factors and Family History	There is some evidence that high triglyceride levels carry more risks for women than men.
Genetic Factors and Family History	Genetic Factors and Family History	Heart disease is the main cause of death for both men and women.
Genetic Factors and Family History	Genetic Factors and Family History	Children who have abnormal cholesterol levels are at increased risk of developing heart disease later in life.
Genetic Factors and Family History	Genetic Factors and Family History	Cholesterol levels which are normally very low at birth tend to naturally rise sharply until puberty, decrease sharply, and then rise again later in life.
Lifestyle Factors	Lifestyle Factors	Genetics can play a major role in determining a person’s blood cholesterol levels.
Lifestyle Factors	Lifestyle Factors	Children from families with a history of premature heart disease should be tested for cholesterol levels after they are 2 years old.
Lifestyle Factors	Lifestyle Factors	Genes may influence whether a person has low HDL levels, high LDL levels, high triglycerides, or high levels of other lipoproteins, such as lipoprotein(a).
Lifestyle Factors	Lifestyle Factors	There are several types of inherited cholesterol disorders.
Lifestyle Factors	Lifestyle Factors	Familial hypercholesterolemia (FH) is a genetic disorder that causes high cholesterol levels, particularly LDL, and premature heart disease.
Obesity, Metabolic Syndrome, and Diabetes	Obesity, Metabolic Syndrome, and Diabetes	There are two forms of FH: Heterozygous FH, in which the genetic mutation is inherited from one parent, occurs in about 1 in 500 people. Homozygous FH, in which the genetic mutation is inherited from both parents, is much rarer.
Obesity, Metabolic Syndrome, and Diabetes	Obesity, Metabolic Syndrome, and Diabetes	Obesity is at epidemic levels in all age groups.
Obesity, Metabolic Syndrome, and Diabetes	Obesity, Metabolic Syndrome, and Diabetes	The effect of obesity on cholesterol levels is complex.
Obesity, Metabolic Syndrome, and Diabetes	Obesity, Metabolic Syndrome, and Diabetes	Overweight individuals tend to have high triglyceride and LDL levels and low HDL levels.
Obesity, Metabolic Syndrome, and Diabetes	Obesity, Metabolic Syndrome, and Diabetes	This combination is a risk factor for heart disease.
Other Medical Conditions	High Blood Pressure	High blood pressure does not affect your cholesterol level, but it does contribute to the thickening of the heart’s blood vessel walls, which can worsen atherosclerosis.
Other Medical Conditions	Hypothyroidism	Low thyroid levels (hypothyroidism) are associated with elevated total and LDL cholesterol and triglyceride levels.
Other Medical Conditions	Polycystic Ovarian Syndrome	Women with this endocrine disorder may have increased risks for high triglyceride and low HDL levels.
Other Medical Conditions	Medications	Certain medications such as specific antiseizure drugs, corticosteroids, and isotretinoin (Accutane) may increase lipid levels.
Complications	Heart Disease	Atherosclerosis is a common disorder of the arteries. Fat, cholesterol, and other substances collect in the walls of arteries. Larger accumulations are called atheromas or plaque and can damage artery walls and block blood flow. Severely restricted blood flow in the heart muscle leads to symptoms such as chest pain.
Complications	Coronary Artery Disease	The end result of atherosclerosis is coronary artery disease. Coronary artery disease, sometimes referred to simply as ‘heart disease’ or ischemic heart disease, is the leading cause of death in the U.S. Studies consistently report a higher risk for death from heart disease with high LDL cholesterol levels. Even moderate elevation of LDL levels increases the chance of heart disease when other risk factors are present. The higher the cholesterol, the greater the risk.
Complications	Peripheral Artery Disease (PAD)	Peripheral artery disease (PAD) is caused by the buildup of plaque in the feet, legs, hands, and arms. It most often occurs in the legs. PAD is associated with atherosclerosis. Lower levels of HDL and high triglyceride levels also increase the risk for PAD.
Complications	Stroke	Having adequate levels of HDL may be the most important lipid-related factor for preventing ischemic stroke, a type of stroke caused by blockage of the arteries that carry blood to the brain. HDL may even reduce the risk for hemorrhagic stroke, a much less common type of stroke caused by bleeding in the brain that is associated with low overall cholesterol levels.
Symptoms	Symptoms	There are no warning signs for high LDL and other unhealthy cholesterol levels. When symptoms finally occur, they usually take the form of angina (chest pain), heart attack, or stroke. When buildups occur in leg arteries, patients may have discomfort with walking (called ‘claudication’). In men, erectile dysfunction may be another symptom of atherosclerosis.
Diagnosis	Diagnosis	Blood tests can easily measure cholesterol levels. A lipid profile includes: LDL, total cholesterol, HDL, and triglycerides. It is also possible to measure LDL levels by themselves, but LDL levels can be reliably calculated using the other values, unless the triglycerides are very high.
Screening Guidelines	Screening Guidelines	Periodic cholesterol testing is recommended in all adults, but the major national guidelines differ on the age to start testing. Recommended starting ages are between 20 to 35 for men and 20 to 45 for women. Adults with normal cholesterol levels do not need to have the test repeated for 5 years unless changes occur in lifestyle (including weight gain and diet).

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reference :

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010885/
• https://www.mountsinai.org/health-library/report/cholesterol
• https://www.nature.com/articles/s41598-023-50931-6

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