Managing Hypertriglyceridemia in Daily Practice
Laurentius A. Pramono, Dante S. Harbuwono
Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia Correspondence mail:
Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo. Jl. Diponegoro no. 71, Jakarta 10430, Indonesia. email: [email protected], [email protected].
ABSTRAK
Hipertrigliseridemia merupakan salah satu jenis dislipidemia yang umumnya terjadi bersamaan dengan hiperkolesterolemia, kadar kolesterol LDL tinggi, atau kadar kolesterol HDL rendah. Sebagian besar penelitian menyebutkan bahwa hipertrigliseridemia berhubungan dengan berbagai kelainan metabolik, antara lain sindrom metabolik, diabetes, obesitas, dan penyakit kardio-serebrovaskular. Terapi terhadap hipertrigliseridemia seringkali tidak diberikan secara komprehensif oleh dokter yang hanya memberikan obat tanpa edukasi terhadap aktivitas fisik, diet sehat bagi pasien dislipidemia, dan penghentian merokok. Tinjauan ini mendiskusikan evaluasi, diagnosis, dan manajemen hipertrigliseridemia secara komprehensif, namun sederhana, yang dapat diaplikasikan sebagai panduan dalam praktek klinis sehari-hari.
Kata kunci: hipertrigliseridemia, dislipidemia, manajemen, panduan klinis ABSTRACT
Hypertriglyceridemia is a form of dyslipidemia, which usually occurs in combination with hypercholesterolemia, high-LDL or low-HDL cholesterol level. Most studies suggest that hypertriglyceridemia is associated with many metabolic disorders such as metabolic syndrome, diabetes, obesity, and also cardio-cerebrovascular diseases.
Treatment of hypertriglyceridemia is often not comprehensively addressed by many physicians, who usually only include prescribing drugs without encouraging patients to perform physical activity, to take a true healthy diet for dyslipidemia and to stop smoking. This review article discusses evaluation, diagnosis and a comprehensive, yet simple management of hypertriglyceridemia, which can be easily applied in daily clinical practice.
Key words: hypertriglyceridemia, dyslipidemia, management, clinical guidelines.
INTRODUCTION
Hypertriglyceridemia, a common form of dyslipidemia, is often stated as an independent risk factor for cardiovascular disease;1,2 however, several studies are still debating this statement.1,3 Almost all epidemiologic studies suggest that hypertriglyceridemia is associated with metabolic syndrome, diabetes, obesity, and coronary artery disease; while some clinical studies demonstrate that lowering triglyceride level can reduce the
risk of coronary artery disease.1,2,4-6
It is clear that hypertriglyceridemia is strongly associated with atherosclerosis.5,7,8 Hypertriglyceridemia is also associated with increased risk of acute pancreatitis.8-10 Nowadays, triglyceride level has become one of target biomarkers, which should be reduced in many patients at daily clinical practice.
Several consensus recommend an optimal triglyceride level of less than 150 mg/dL.4-6 A
report demonstrated that the mean triglyceride level among US population was 114 mg/
dL between 1976 and 1980. It was 116 mg/
dL in 1988-1994 and became 122 mg/dL in 1999-2002.3 A study conducted by Ford ES et al.3 showed that the unadjusted prevalence of triglyceride level of ≥150 mg/dL was 33.1%.
The prevalence was 17.1% for triglyceride level of ≥200 mg/dL, 1.7% for triglyceride level of
≥500 mg/dL and 0.4% for triglyceride level of
≥1000 mg/dL. In conclusion, we can say that the prevalence of hypertriglyceridemia remains high in Western population.
Very few studies have been done in Indonesian population. Kamso S et al.11 studied groups of executive workers in Jakarta and they found that the mean triglyceride levels in executive workers who had metabolic syndrome was 210.29 mg/dL; while in those without metabolic syndrome, the triglyceride level was 145.06 mg/dL. Another study has also been conducted in Indonesia. It was performed in Padang City, West Sumatera with a population, which is famous for its high cholesterol diet.
The prevalence of hypertriglyceridemia (with cut off point of 200 mg/dL) in that particular population was 6.9% in elderly men and 5.7%
in elderly women.12 Further study has also been done in Purwokerto, Central Java, which found that the mean triglyceride level in women with metabolic syndrome is 218.13 mg/dL.13 Those studies indicate that hypertriglyceridemia also affects populations of many cities in Indonesia.
Hypertriglyceridemia is found more prominent in patients with type-2 diabetes.14,15 Soebardi S et al.15 found that the prevalence of hypertrigliseridemia was 54.3% in patients with newly diagnosed diabetes. Furthermore, the mean triglyceride level in subjects with normal glucose tolerance, newly diagnosed diabetes and those with diabetes were 124.5 mg/dL, 186.3 mg/
dL and 169.9 mg/dL, respectively.15 Untreated diabetes group, which was represented by newly diagnosed diabetes patient group, showed the highest triglyceride level. The high triglyceride level was improved following diabetes treatment, which suggests that providing diabetes treatment may have great contribution to improve lipid profiles.14,15
Hypertriglyceridemia must be assessed completely, especially by history taking of other cardiovascular risks, physical examination, and laboratory data on lipid profiles.1 There are some criteria and consensus of triglyceride level for establishing the diagnosis of hypertriglyceridemia.4-6 Several management and treatment choices for hypertriglyceridemia can be seen in many reviews and guidelines.
For severe cases, plasmapheresis can be an option.10 Our review article emphasizes on the management of hypertriglyceridemia in daily practice based on several guidelines.
Since there are many options of medication and non-pharmacological treatment in treating hypertriglyceridemia, it can be expected that physician not only treating hypertriglyceridemia with statin; but more options can be suggested for the patients.
EVALUATION
The evaluation of hypertriglyceridemia always starts with an interview about family history of dyslipidemia and premature coronary artery disease,1,6 as well as secondary causes of hypertriglyceridemia such as untreated diabetes, other lipid metabolism disorders, drugs that can alter lipid metabolism, alcohol consumption, pregnancy, and renal disease.2,8 Brunzell JD2 stated that the presence of premature coronary artery disease in parents or sibling indicates familial combined hyperlipidemia or familial hypoalphalipoproteinemia. Special medications must be considered in this situation.
Unfortunately, for patients with low to moderate socio-economic level, which are the majority in Indonesian population, family history are difficult to be obtained by physicians.
Physician should ask patients about their past cardiovascular and medical history, prior medical tests or examinations, which have been performed earlier (electrocardiogram, echocardiography, treadmill test), their physical activity (frequency, duration, and type of sport or physical activity), diet profile, smoking habit, and simple anthropometry profile, which can be measured by the patients themselves.
It seems that dyslipidemia patients also usually take over the counter (OTC) medicines
or traditional herbs to lower their cholesterol level or take medications from other physician or perform self-medication (buying medicine illegally in drug stores or drug markets). It is also important to ask their previous lipid profile found in their past laboratory data; they probably can remember the number of their cholesterol, LDL cholesterol, or triglyceride levels.
Physical examinations that should be concerned in patients with dyslipidemia, diabetes, metabolic syndrome and risk factors for cardiovascular disease include blood pressure, body mass index (BMI) calculation (patient’s height and weight), and waist circumference.2
Large waist circumference, in Western population 101.6 cm for men and 88.9 cm for women;2 while in Indonesian population, we found 88 cm for men and 86 cm for women.16 The waist circumference may help the doctors to distinguish familial hypertriglyceridemia from familial combined hyperlipidemia or familial hypoalphalipoproteinemia.2
Lipid profiles (total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride) are the most important laboratory data and other metabolic parameters must also be tested including fasting blood glucose level, 2 hours post-prandial blood glucose level, and kidney function (ureum and creatinin level).2,6
Apolipoprotein B is associated with metabolic syndrome; however, the use is still restricted for specific situation.2,17 Measurement of apolipoprotein B level may help doctors to estimate the total number of LDL particles (large and small). Elevated level is found in familial combined hyperlipidemia and lower level indicates familial hypertriglyceridemia. It is well-known that apolipoprotein B level provides better prediction for evaluating cardiovascular risk than non-HDL cholesterol.2 Other specific lipid parameters such as lipoprotein (a) and apolipoprotein A-I still have not been popular as laboratory tests for daily practice. Table 1 shows key points for evaluation of hypertriglyceridemia using history taking, physical examination, and other examinations.
Lipid profile tests requires patients to fast in order to demonstrate the true endogenous triglyceride level.5,6 Indonesian Society for
Endocrinologists Concensus of Dyslipidemia recommends that patients who undergo lipid profiles examination to ideally fast 12-16 hours before blood withdrawal.6 Nowdays, many clinical laboratory use direct LDL cholesterol examination, and if it is not possible, Friedwald calculation can be used only if the triglyceride level is less than 400 mg/dL.6 However, this calculation can still be used in many areas in Indonesia since there is still lack of lipid profiles examinations in many rural and suburban hospitals (district II hospitals) nowadays.
Table 1. Key points for history taking, physical examination, and other examinations
History taking
Family history of dyslipidemia
Family history of coronary artery disease History of diabetes, disorders of lipid metabolism Renal and liver disease
Pregnancy
Symptoms of angina
Symptoms of peripheral artery disease Symptoms of pancreatitis
Alcohol consumption Cigarrette smoking Physical activity Diet profile Medication history
Physical examination Not specific
Blood pressure Body mass index Waist circumference
Other examinations
Lipid profile (total cholesterol, LDL-C, HDL-C, triglyceride)
Blood glucose and HbA1c
Thyroid function tests (for suspected hypothyroidism) Renal function
Liver function Electrocardiogram
Friedwald calculation:
LDL cholesterol = Total cholesterol – HDL cholesterol – Triglyceride/5
DIAGNOSIS
There are only several consensus have firmly defined the cut-off value for ‘hyper’ or high triglyceride level and one of them is the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), which recommends four categories for triglyceride level, i.e.
optimal level is defined when triglyceride level is less than 150 mg/dL; while the level is 150-199 mg/dL, it is called borderline high.
Triglyceride level between 200 and 499 mg/dL is called high level and when the level reaches more than (≥500 mg/dL), it is called very high level.4-6 Many physicians, including Indonesian physicians, and also clinical laboratories, use 150 mg/dL as the cut-off point for triglyceride level.6 Small differences are described by Endocrine Society in 2010 which classifies hypertriglyceridemia as moderate, severe, and very severe hypertriglyceridemia.4 Table 2 shows the differences between NCEP ATP III and Endocrine Society classification for hypertriglyceridemia.
Actually, for clinical application, aggressive LDL cholesterol lowering is more beneficial to reduce cardiovascular risk.4,6 Treatment of LDL cholesterol with statins will also reduce triglyceride level further. For diabetic hypertriglyceridemia, the triglyceride level is considered high when the level is more than 150 mg/dL.14 Mild to moderate hypertriglyceridemia has a range of 150-499 mg/dL, while severe hypertriglyceridemia has a cut off point ≥500 mg/dL.14
Hypertriglyceridemia, either alone or in combination with hypercholesterolemia
or low level of HDL cholesterol, is called dyslipidemia or hyperlipidemia. In fact, the term
‘hyperlipidemia’ is not suitable for low-HDL- cholesterol dyslipidemia type, which is should be simply known as the low-HDL. However, the terminology is a general diagnosis, which can be used for treatment in general and also for the purpose of education and socialization in the society. All types of dyslipidemia including hypertriglyceridemia must be categorized into primary and secondary dyslipidemia.6,8 Primary dyslipidemia is a term to point out the lipid disturbances caused by genetic factors, such as familial primary hypertriglyceridemia, remnant dyslipidemia, and familial hypercholesterolemia.
In contrast, secondary dyslipidemia is caused by many other conditions such as hypothyroidism, nephrotic syndrome, diabetes mellitus, metabolic syndrome, and drugs like steroids, hormones, and beta-blockers.6,8
MANAGEMENT
Before starting treatment for patients with dyslipidemia or hypertriglyceridemia, physician must always perform risk stratification of cardiovascular events that their patients about to have.6 The treatment target should follow the risk assessment. NCEP ATP III suggests that there are five risk factors for coronary heart disease, which must be assessed including cigarette smoking, hypertension (blood pressure above 140/90 mmHg, or those who are having anti-hypertensive medication), HDL cholesterol of less than 40 mg/dL, history of premature coronary heart disease (father <55 year-old or mother <65 year-old), and age (man ≥45 year-
Table 2. Triglyceride classification
Triglyceride classification ATP III levels Triglyceride classification Endocrine Society
Normal <150 mg/dL Normal <150 mg/dL
Borderline high 150-199 mg/dL Mild hypertriglyceridemia 150-199 mg/dL
High 200-499 mg/dL Moderate hypertriglyceridemia 200-999 mg/dL
Very high ≥500 mg/dL Severe hypertriglyceridemia 1000-1999 mg/dL
Very severe hypertriglyceridemia ≥2000 mg/dL Source: Robert C, Lanier IB. Management of hypertriglyceridemia. Am Fam Physician. 2007;75:1365-71; Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(9):2969-89.
old, woman ≥55 year-old).6 Diabetes is a risk equivalent with coronary artery disease,6,18 in contrast, HDL cholesterol of more than 60 mg/
dL is a negative risk factor that can reduce one other risk factor.6
Mild risk is defined when the patient has 0-1 risk factor(s); while moderate risk is applied when the patient has ≥2 risk factors, and high risk is addressed when the patient has a history of coronary heart disease, or other risk equivalent, such as diabetes, stroke, or multiple risk factors.
Moreover, very high risk is defined when the patient has multiple risk factors, metabolic syndrome, and acute coronary sindrome.
Treatment targets are made based on the risk assessment and the target LDL cholesterol level instead of the triglycerides level. Mild, moderate, high, and very high risks are defined for target LDL cholesterol level of <160 mg/dL, <130 mg/
dL, <100 mg/dL, and <70 mg/dL, respectively.6,18 It should always be remembered that triglyceride level is not exclusively meaningful information for risk assessment of coronary heart disease.19 Moreover, it is also important in metabolic syndrome assessment, particularly for diagnosis. Simply said, physician should not ignore any information about triglyceride level. It should be considered and target should be included when performing the assessment.1,2 Table 3. shows metabolic syndrome diagnosis criteria according to NCEP ATP III.20
Many physicians give statins for the first line treatment of dyslipidemia, including hypertriglyceridemia.3 Furthermore, lowering LDL cholesterol is always followed by decreasing triglycerides level. Actually, there is nothing wrong with this treatment choice, especially when statin (simvastatin) is the only available drug in Indonesian primary health care facilities.
A study conducted by Ford ES et al.3 in US population has reported that 16% of participants with triglycerides level of 150 to 199 mg/dL had statin or ezetimibe; while 15.2% participants with triglycerides level more than 200 mg/dL had statin or ezetimibe. Therefore, statin is still the most popular medication for dyslipidemia worldwide.
Pharmacologic treatment alone for hypertriglyceridemia is not sufficient to lower the cholesterol and triglycerides levels. Physician must suggest non-pharmacologic treatment, which are divided into healthy diet, physical activity, and smoking cessation.1,4,5 Healthy diet seems to be a cliche suggestion; however, not all clinicians can define the healthy diet for hypertriglyceridemia patients. The evidence- based nutritional recommendation includes fish oil and a total dose of 2 to 4 gram of EPA/
DHA daily contained in an omega-3 capsule.1 The evidence level is C (based on consensus and expert opinion). Healthy diet also includes restriction of saturated fatty acid (SAFA) and increased diet of mono- and poly-unsaturated fatty acid (MUFA or PUFA).6
Physical activity or regular exercise is recommended with the level of evidence B.1 Every physical activity is beneficial for the patients, such as walking, jogging and sports.
Regular exercise can increase HDL cholesterol level and apoA1, lower triglycerides and LDL cholesterol level, increase insulin sensitivity and maintain ideal body mass index.6 The patients should decide which physical activity that can bring enjoyment and pleasure for them, so that it can be performed regularly without any pressure.
Along with healthy diet, regular exercise, and smoking cessation, drugs are the important parts of the treatment. Physician must have sufficient knowledge about several drugs available in the
Table 2. Metabolic syndrome diagnosis criteria Risk factors Defining level Abdominal obesity, given by waist circumference
- Men > 102 cm
- Women > 88 cm
Triglyceride level ≥ 150 mg/dL
HDL cholesterol
- Men < 40 mg/dL
- Women < 50 mg/dL
Blood pressure ≥ 130/ ≥ 85 mmHg
Fasting blood glucose ≥ 110 mg/dL Source: Grundy SM, Brewer B, Cleeman JI, Smith SC, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109(3):433-8.
market to treat hypertriglyceridemia. In addition to many traditional herbs, which had been demonstrated in many studies that these herbs have the potency to lower triglycerides level, there are only three classes of drugs that have been approved to treat hypertriglyceridemia, i.e. (1) statins, (2) fibrates (fenofibrate and gemfibrozil), and (3) niacin.1,2 Statins are the most popular, but fibrates have the highest triglyceride reduction.
Statins (atorvastatin 10-80 mg daily, fluvastatin 20-80 mg daily, lovastatin 10-80 mg daily, pravastatin 10-80 mg daily, simvastatin 5-80 mg daily, rosuvastatin 5-20 mg daily, and pitavastatin 2-4 mg daily)1,5 can reduce triglyceride level up to 20-40% and also gives 18-55% reduction of LDL cholesterol level and 5-15% increase of HDL cholesterol level.
Moreover, niacin (500 mg – 2 gram daily) has the highest capability to increase HDL cholesterol level (20-30%); however, it only has moderate reduction on triglycerides level (30-50%) and LDL cholesterol level (5-25%). Fibrates are divided into fenofibrate (48-145 mg daily) dan gemfibrozil (600 mg twice daily), which give 40-60% reduction of triglycerides level and 15- 25% increase of HDL cholesterol level; however, the increase the LDL cholesterol level is only about 5-30%.1 Fibrates, niacin, and fish oil are considered when triglyceride level is still higher than 200 mg/dL and the level of LDL cholesterol is near or has reached the target level. These three drugs are beneficial to achieve the non-HDL cholesterol goal.1
Drugs are usually used only in combination with non-pharmacological treatment. Physician must emphasize that drugs are not the first line treatment and patients should be encouraged to have healty lifestyle.6 Ideally, drugs are initiated for patients with high triglyceride levels (not borderline high levels).1 Do not forget to do the risk assessment and determine the target LDL cholesterol level.
For patients with combined dyslipidemia (hypertriglyceridemia and high LDL cholesterol level), combination treatment using statin/
gemfibrozil or statin/fenofibrate is recommended.1 The combination of statin and fenofibrate has lower rhabdomyolysis side effect. For long-term
treatment, it is better to use these drugs with caution. For diabetic patients, a review from Jialal I et al.14 indicates that combination of statin/
fibrate is disappointing; while the ACCORD Study recommends to use a combination of statin and niacin to treat hypertriglyceridemia in diabetic patients.14
Severe hypertriglyceridemia is defined when the triglycerides level is more than 1000 mg/dL.
Several patients can reach the level of 2000 mg/
dL.10 Lowering triglycerides level to less than 500 mg/dl is recommended to prevent acute pancreatitis.10 Endocrine Society recommends combining reduction of dietary fat and simple carbohydrate intake with drug treatment to reduce the risk of pancreatitis.4 The first line agent for treating severe hypertriglyceridemia is fibrate and statin; however, it should not be used as monotherapy for severe and very severe hypertriglyceridemia. Furthermore, Murphy M et al.9 found that statins are associated with reduced risk for acute pancreatitis, which is consistent with results of meta-analysis study. The data suggests physicians to provide combination therapy for patients with severe hypertriglyceridemia. Plasmapheresis treatment is indicated for medical emergencies such as hypertriglyceridemic pancreatitis.10 However, the use is still limited due to its high cost and limited availability in many health care center, especially in Indonesia.
CONCLUSION
Hypertriglyceridemia management should be integrated with the management of dyslipidemia, metabolic syndrome and diabetes as well as including the risk assessment of coronary heart disease. Evaluation of hypertriglyceridemia must include complete history taking of cardiovascular risks, performing physical examination, which is known as the metabolic physical examination (body mass index, waist circumference, blood pressure, etc), and evaluating laboratory data (lipid profiles, blood glucose level, etc). Hypertriglyceridemia treatment includes physical activity, healthy diet, smoking cessation, and drugs. Along with the Omega-3 capsules, which are nutriceutical agents, statins, fibrates (fenofibrate and
gemfibrozil), and niacin are the top four list drugs used in the management of hypertriglyceridemia.
For severe hypertriglyceridemia, combination of all modalities are recommended; while plasmapheresis is indicated for severe emergency cases of hypertriglyceridemic acute pancreatitis, which is still a great challenge for our health care centers.
CONFLICT OF INTEREST
Author declares that there is no conflict of interest in writing this manuscript.
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