Patients with elevated levels of triglycerides in their blood has a significantly higher mortality rate

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Doctors interested in ways to minimize the risk of cardiovascular disease have long had blood cholesterol levels in their sights.

But other types of blood fats (also known as ‘lipids’) can also be damaging to health. “Our work has involved studying a special group of lipids, the triglycerides.

We’ve been able to show that when these naturally occurring fats are present at elevated concentrations they can alter our defence cells in such a way that the body reacts as if responding to a bacterial infection.

This leads to inflammation, which, if it becomes chronic, can damage the kidneys or cause atherosclerosis – the narrowing of arteries due to a build up of deposits on the inner arterial wall.

And atherosclerosis is one of the main causes of heart attacks and strokes,” explains Timo Speer of Saarland University.

Speer, who has a doctorate in medicine as well as biology, is the lead author of the work just published in Nature Immunology.

The large-scale study was able to demonstrate that patients with elevated levels of triglycerides in their blood had a significantly higher mortality rate than comparison groups with a similar health history.

“Put another way, we can now say that adopting a low-fat diet can significantly extend the life expectancy of high-risk patients, such as those with diabetes or those whose blood pressure is too high,” says Timo Speer.

Blood triglyceride levels rise substantially in people who eat a high-fat diet.

“As a result of biochemical changes, the triglycerides develop toxic properties that activate the body’s innate immune system.

This initiates a series of self-destructive processes including those in which the walls of the arteries are attacked and the blood vessels become occluded, reducing blood flow,” explains Speer.

The study has established a definitive link between the chronic inflammation triggered by an elevated triglyceride concentration in the blood and secondary diseases such as kidney failure or heart attack.

“We hope that our results will help in developing new strategies for treating and preventing these life-threatening diseases,” says Timo Speer.

The publication in Nature Immunology is one of the results of the diverse range of scientific investigations being carried out as part of a Transregional Collaborative Research Centre between Saarland University and RWTH Aachen University.

The focus of the work performed within the Collaborative Research Centre is to discover which cardiac and vascular diseases can be caused by chronic kidney disease. The German Research Foundation (DFG) is funding this major research programme with ten million euros over a three-year period.

Timo Speer is the lead researcher for one the research projects. He is also a senior physician at Saarland University Hospital and laboratory director for experimental and translational nephrology.


Lipids are circulating as lipoproteins, consisting of unesterified cholesterol, triglycerides, phospholipids, and protein. There are five major lipoproteins in blood: (1) chylomicrons; (2) very low-density lipoprotein (VLDL); (3) intermediate-density lipoprotein (IDL); (4) low-density lipoprotein (LDL); and (5) high-density lipoprotein (HDL).

Each of these classes of lipoproteins transports cholesterol and triglyceride to its designated destinations.

The level of cholesterol plays a vital role in cardiovascular diseases process. A high level of lipids, including cholesterol and triglycerides in the serum, which also termed as hyperlipidemia, leads to a higher risk of developing atherosclerotic cardiovascular disease (CVD). Clinically, obtaining a lipid profile assists in the screening, diagnosing, and managing diseases. Here, we will discuss the indications for testing, the role of lipid profiles, and the relevant health care issues. Generally, a lipid profile or lipid panel consists of the following,

  • Total cholesterol
  • High-density lipoprotein (HDL) cholesterol
  • Low-density lipoprotein (LDL) cholesterol
  • Triglycerides

Specimen Collection

Cholesterol level measurement is from serum. A non-fasting lipid test can be done anytime without fasting; a fasting lipid test requires a 12-hour fast except for water. Total and HDL cholesterol are measured directly from serum. First developed in the 1960s, Friedewald equation has been used widely to estimate LDL-C which is (total cholesterol) – (high-density lipoprotein cholesterol [HDL-C]) – (triglycerides/5) in mg/dL for research as well as clinical purpose. A fixed factor of 5 for the ratio of fasting triglyceride level(up to 4.5mmol/l ) to very low-density lipoprotein cholesterol(TG: VLDL-C) is the assumption from the equation[1]

Optimizing LDL-C level has been the main target for current guidelines, including the European Society of Cardiology, European Atherosclerosis Society,[2] and the American Heart Association and American College of Cardiology.[3] There are several limitations of the Friedewalk equation as follows[4]:

  • The estimated LDL-C level is not accurate in patients with hypertriglyceridemia(up to 4.5mmol/l or 400 mg/dL) – such a setting warrants ultracentrifugal single spin analysis or immunoprecipitation technique
  • There is an underestimation of LDL-C level in patients with lower LDL-C (less than 25 mg/dL or 0.6 mmol/L)
  • There is an underestimation of intermediate-density lipoprotein(IDL), and some VLDL remnants which are considered atherogenic

In an extensive cross-sectional analysis, Martin SS et al. proposed a novel calculation that is more accurate than the Friedewald equation regardless of fasting/nonfasting blood samples.[5]Fasting or non-fastingWhile fasting LDL-C is still the standard for initiating lipid-lowering therapy, there has been a heated debate over fasting or non-fasting lipid profile among specialists. The rationale behind the discussion of fasting or non-fasting is because the triglycerides level can be affected by the last intake and the limitations of the Friedewald equation per se.[6][7] 

Advantages of the non-fasting lipid profile are its accessibility clinically, simplicity for both patients and medical practitioners; whereas the fasting lipid profile is inconvenient for patients and clinicians as it requires an additional visit.

Also, the accuracy of the fasting lipid profile depends on patients’ compliance.Many current guidelines propose that nonfasting LDL-C holds similar significance to that of fasting LDL-C.[8][9] A fasting lipid panel is a strong recommendation for patients with type 2 diabetes, obesity, medications that may affect lipid levels, such as thiazides and beta blockers,[10] and excessive intake of alcohol.[11] Apolipoproteins 

The 2010 American College of Cardiology Foundation/American Heart Association guideline does not recommend measurement of apolipoproteins, size of lipid particles, and density for cardiovascular risk assessment. (Level III)

Indications

Indications for screening or obtaining lipid profile varies between adults and children. 

  • The National Health and Nutrition Examination Survey (NHANES) for 1999 to 2006 reports a 20% prevalence rate of dyslipidemia among adolescents with a statistically significant higher level of lipids in higher BMI adolescents.[12] Among those adolescents with dyslipidemia, only 0.8% of them might need pharmacological treatment.[13] The guideline by the United States National Heart, Lung, and Blood Institute (NHLBI) expert panel in 2011 recommend that all children should be screened for dyslipidemia to identify children with familial hypercholesterolemia (FH). FH patients are at higher risk for morbidity and early mortality.[14] Fasting lipid test is the recommendation for children with cardiovascular risks, such as hypertension, obesity, diabetes, and family history; non-fasting lipid test is preferable for those without known cardiovascular risks.
  • In adults, the most common indications are[15][16]:
    • Screening due to a family history of lipid disorder, such as familial hypercholesterolemia
    • Establish the risk of 10-year cardiovascular disease, such as the 2008 Framingham general cardiovascular risk score or JBS3 risk score
    • Pancreatitis
    • Management for atherosclerotic cardiovascular diseases
    • Evaluation for lipid-lowering therapy

Potential Diagnosis

DyslipidemiasPrimary disorders of lipid metabolism such as familial hypercholesterolemia (FH), chylomicronemia, familial combined hyperlipidemia, familial dysbetalipoproteinemia classify according to Fredrickson phenotype.[17] 

Secondary dyslipidemia can result from diabetes mellitus, hypothyroidism, obstructive liver diseases, chronic renal failure, drugs that increase LDL-C including retinoids, cyclosporine A, and phenothiazines and drugs that decrease HDL-C including progestins, androgens, beta-blockers, and anabolic steroids.Based on the types of lipid abnormalities, dyslipidemias can be categorized into high total cholesterol (TC), High low-density lipoprotein cholesterol (LDL-C), High non-high-density lipoprotein cholesterol (non-HDL-C), High triglycerides (TG), and Low high-density lipoprotein cholesterol (HDL-C). According to the Adult Treatment Panel III (ATP III), the standard levels per guideline as following[18]:

  • Fasting triglyceride level:
    • Normal: less than 150 mg/dL 
    • Mild hypertriglyceridemia: 150 to 499 mg/dL
    • Moderate hypertriglyceridemia: 500 to 886 mg/dL 
    • Very high or severe hypertriglyceridemia: greater than 886 mg/dL
  • LDL-C level:
    • Optimal: less than 100 mg/ dL
    • Near optimal/above optimal:100 to 129 mg/dL
    • Borderline high: 130 to 159 mg/dL
    • High: 160 to 189 mg/dL
    • Very high: greater than 190 mg/dL 
  • HDL level: 
    • Low: less than 40
    • High: greater than or equal to 60

Metabolic syndrome There are five definitions of the metabolic syndrome:

  1. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), 2005
  2. International Diabetes Federation(IDF), 2006
  3. Group for the Study of Insulin Resistance (EGIR), 1999
  4. World Health Organization, 1999
  5. American Association of Clinical Endocrinologists (AACE), 2003;

Among these, The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) is the most widely used. Parameters for the definitions of metabolic syndrome are triglycerides, HDL cholesterol, glucose, hypertension, and obesity, and metabolic syndrome is diagnosed when three or more the followings are abnormal:

  • HDL cholesterol: less than 1.0 mmol/L (40 mg/dL) (men); less than 1.3 mmol/L (50 mg/dL) (women) or pharmaceutical treatment for low HDL cholesterol, i.e., treatment with one or more of niacin or fibrates
  • Triglycerides: greater than or equal to 1.7 mmol/L (150 mg/dL) or drug treatment for elevated triglycerides, i.e., treatment with one or more of niacin or fibrates
  • Glucose: greater than or equal to 5.6 mmol/L (100 mg/dL) or drug treatment for elevated blood glucose
  • Obesity: Waist greater than or equal to 102 cm (men) or 88 cm (women)
  • Blood pressure: greater than or equal to 130/85 mmHg or drug treatment for hypertension

Atherosclerotic Cardiovascular disease (ASCVD)

  1. Coronary heart disease presents as myocardial infarction, angina pectoris, heart failure, or coronary death
  2. Cerebrovascular disease presents as a stroke or transient ischemic attack
  3. Peripheral artery disease, such as intermittent claudication
  4. Aortic atherosclerosis and thoracic or abdominal aortic aneurysm, the diseases as mentioned earlier are often generalized as the term cardiovascular disease(CVD)

Atherosclerosis is the major culprit in most of the coronary heart disease.[19] Lipids and lipoproteins are established risk factors for developing atherosclerotic cardiovascular diseases(ASCVD). Large clinical trials reported lipid-lowering therapy to reduce the risk of ASCVD events.[20][21]

Several factors are taken into account in 10-year risk cardiovascular assessment as following, 

  • Age (between 20 to 79)
  • Sex
  • Race
  • Systolic blood pressure  
  • Diastolic blood pressure  
  • Total cholesterol  
    1. LDL cholesterol  
    2. HDL cholesterol  
  • History of diabetes
  • On hypertension treatment?
  • On a statin?
  • On aspirin therapy?

The 10-year risk for ASCVD falls into the following categories:

  • Low-risk (less than 5%)
  • Borderline risk (5% to 7.4%)
  • Intermediate risk (7.5% to 19.9%)
  • High risk (greater than or equal to 20%)

Risk-enhancing factors such as family history of premature ASCVD, metabolic syndrome, chronic kidney disease, premature menopause, chronic inflammatory disorders, high-risk ethnic groups (e.g., South Asian), persistent elevations of LDL-C greater than or equal to 160 mg/dL or triglycerides greater than or equal to 175 mg/dL, high-sensitivity C-reactive protein greater than or equal to 2.0 mg/L, and ankle-brachial index less than 0.9. 

Normal and Critical Findings

For dyslipidemia, obtaining a detailed family history is crucial. By identifying family members with any abnormal deposits of cholesterol in the skin or eyes, premature CHD, or those who have elevated cholesterol during childhood assist in establishing a diagnosis. Perform physical examination with attention to abnormal deposits of cholesterol in the skin or eyes, such as tendon xanthomata which mostly present in the Achilles tendons and dorsum of the hands, and xanthelasmas, which are soft and yellow plaques that often present on the eyelids. Fasting lipid profile revealed the majority of the abnormalities.

However, an evaluation for causes resulted in secondary hyperlipidemia is warranted. The clinician can offer genetic testing of LDLR, APOB, and PCSK9 gene mutations, even though the benefits are still not well-established. 

Patient Safety and Education

First and foremost, it is essential to educate individuals on a heart-healthy lifestyle. LDL-C is one of the major culprits in the development of atherosclerotic heart disease. The target level of LDL-C is between 50 to 70mg/dl to prevent plaque formation in the blood vessels.

Patients should undergo evaluation for 10-year risk and those with more than 10 percent risk; guidelines strongly recommend statin therapy. Low levels of HDL-C are related to an increased risk of CVD; however, according to recent studies, HDL-C raising therapy showed no clinical benefit; therefore, routine use is not recommended.

Clinical Significance

Primary prevention recommendations for adults age between 40 to 75 years old With an LDL Level of 70 to 189 mg/dL. High levels of low-density lipoprotein-cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C) are risk factors for coronary heart disease.[22][23] Large clinical trials have shown that lowering LDL-C levels significantly reduce cardiovascular events and mortality rate[24]; whereas, according to current consensus, HDL-C is not a target for primary prevention in coronary artery diseases(CAD). Nevertheless, recent studies proposed the prognostic value of serum cholesterol efflux capacity in patients with coronary artery disease.[25]

According to the 2018 Guideline on the Management of Blood Cholesterol,[26], clinicians should target at lowering LDL-C levels by more than 50% with maximally tolerated statin therapy in ASCVD. In very high-risk ASCVD individuals who are already under statin therapy and remain an increased LDL-C level (more than 70mg/dL); clinicians should then initiate additional non-statin therapy such as ezetimibe.

Furthermore, individuals on maximally tolerated statin along with ezetimibe, a PCSK9 inhibitor should then be considered. Ezetimibe is preferred before initiating a PCSK9 inhibitor due to its cost and convenience. Begin high-intensity statin therapy despite 10-year ASCVD risk in severe hypercholesterolemia( LDL-C level greater than or equal to 190 mg/dL ).

Start moderate-intensity statin therapy regardless of 10-year ASCVD risk in 40 to 75-year-old diabetic patients with a level of LDL-C greater than or equal to 70 mg/dL; for those non-diabetic patients with a level of LDL-C greater than or equal to 70 mg/dL and a 10-year ASCVD risk more than 7.5%, consider a moderate-intensity statin. Statin Intensity 

Moderate-intensity statin therapy is expected to have a 30 to 50 percent LDL-C reduction, as following, 

  • Lovastatin 40mg daily;
  • Pravastatin 40mg daily
  • Simvastatin 40 mg daily; 
  • Atorvastatin 10 to 20 mg daily; 
  • Rosuvastatin 5 to 10 mg daily; 
  • Pitavastatin 4 mg

High-intensity statin therapy is expected to have a greater than or equal to 50 percent LDL-C reduction, as following, 

  • Atorvastatin 40 to 80 mg
  • Rosuvastatin 20 to 40 mg

In most of the cases, do not intensify statin therapy for patients who are on moderate-intensity statin therapy.

The efficacy of statin therapy should undergo evaluation in six to eight weeks after the initiation.

Statin therapy management should take place when statin-induced muscle adverse events, elevated aminotransferase, or renal dysfunction such as proteinuria have developed. However, routine monitoring of serum creatine kinase (CK) levels is not currently a reocmmendation for patients on statins. 

For medical practitioners, obtaining a baseline CK level should be considered before initiating statin therapy. Education on lifestyle modification, medication compliance, and awareness of new onset of muscle discomforts or weakness is crucial. 


More information: Zewinger, S., Reiser, J., Jankowski, V. et al. Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.Nat Immunol (2019) DOI: 10.1038/s41590-019-0548-1 , https://nature.com/articles/s41590-019-0548-1

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