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Objectif Nutrition N°56 (March 2001)
Hypertriglyceridemia and vascular risk
Prof. Olivier ZIEGLER
Although LDL-cholesterol continues to be the principal lipid factor for vascular risk, the atherogenic role of hypertriglyceridemia is today recognized. Atherogenic hypertriglyceridemia management is above all dietary related.
In the structured classification of lipid factors for cardiovascular risk, LDL-cholesterol continues to rank number one. However, increasing epidemiologic clinical and pathophysiological evidence suggest that certain types of hypertriglyceridemia (HTG) are dangerous for the arterial wall: thus some recommendations, which deal little with the role of HTG, would be insufficient.
EPIDEMIOLOGIC DATA
Many studies have demonstrated a positive correlation between plasma triglyceride concentration levels and the risk of cardiovascular disease, especially in subjects with diabetes. And yet, some authors consider that triglycerides are not truly an independent risk factor because HTG is often associated with decreased HDL-cholesterol levels (the protective moiety of cholesterol). A meta-analysis by Austin and Hokanson (involving 18 prospective studies combining a total of over 45,000 men and 10,000 women) shows that an elevation of 1 mmol/l in triglyceride levels results in a 31% increase in cardiovascular risk in men and a 76% increased risk in women (whose overall risk, however, continues to be three times lower).
When HDL-cholesterol levels are taken into account in the analysis, the risks associated with triglycerides decrease but remain significant. This was recently confirmed by the Copenhagen study (an 8-year follow up of 2096 men, mean age of 63 years): triglycerides are an independent risk factor in men regardless of the HDL-cholesterol levels. However, no intervention study, specifically aimed at hypertriglyceridemia, has been conducted to date.
PATHOPHYSIOLOGY
The atherogenicity of hypertriglyceridemia results from several mechanisms :
- Triglyceride-rich lipoproteins (TRL).
TRL include chylomicrons, VLDL and of chylomicron and VLDL remnants (figure 1). Chylomicrons, produced by the small intestine after the ingestion of lipids, are rapidly taken up and metabolized by the liver. They cannot enter the arterial wall because they are too large. Moreover, no premature atherosclerosis exists in type I familial hyperchylomicronemia. On the other hand, chylomicron and VLDL remnants are potentially atherogenic since they can penetrate the tunica intima of the arterial wall and be captured by the macrophages.
All types of hypertriglyceridemia involve an increased production of TRL and/or their decreased plasma clearance. An increase in the "pool" of TRL promotes exchanges of triglycerides and cholesterol between these lipoproteins on the one hand and HDL and LDL on the other hand, producing a change in the composition of LDL and a decrease in HDL-cholesterol.
- Small dense LDL
In some subjects with hypertriglyceridemia, the increased production of VLDL by the liver give rise to LDL with an abnormal composition: small dense LDL, which easily penetrate the artery wall. Their low affinity for the LDL receptor and their susceptibility to oxidation promote their capture by macrophages, subsequently which one converted them into foam cells.
In the "Quebec Cardiovascular Study" (2013 men followed up for 5 years), the presence of small dense LDL was in itself a coronary risk factor (relative risk = 3.6).
- Postprandial lipidemia
The excess levels of TRL are especially frequent during the postprandial period, at which time exogenous lipoproteins (chylomicrons) and those of endogenous origin (VLDL) compete for their clearence. The use, after standardization, of an standardized oral lipid load test in subjects with a high vascular risk has provided much information :
- Thus TRL abnormalities detected with test were not demonstrated by measurement of fasting plasma lipid levels.
- A delay in clearence of TRL can be considered as a marker for insulin-resistance in different clinical conditions: android or visceral obesity, menopause, hypertension.
- According to certain studies conducted in subjects with coronary heart disease with normal fasting serum cholesterol and serum triglyceride levels, the increase in postprandial lipidemia is a prognostic factor for the progression of coronary lesions.
- The decrease in HDL-cholesterol
HDL-cholesterol has a protective function against atherosclerosis: its function is to return cholesterol not used by the peripheral tissue to the liver where it is subsequently eliminated. One of the most important consequences of hypertriglyceridemia is the decrease in HDL-cholesterol. Certainly, primary types of HDL hypercholesterolemia exist, but most of them are secondary to abnormalities in triglyceride metabolism, such as android obesity. The excess level of triglycerides in VLDL and their remnants promote a marked transfer of triglycerides to the HDLs and a transfer of cholesterol from HDLs to the VLDL remnants (Figure 1).
PRACTICAL MANAGEMENT
- How to recognize hypertriglyceridemia :
To confirm hypertriglyceridemia, which often fluctuates (for example, from 150 to 400 mg/ dl) and define its level, 3 measurements are required. For the 2nd and 3rd repeat measurements, a strict minimum 12-hour fast should be required of the patient. These plasma measurements specify whether there is a concomitant decrease in HDL-cholesterol and/or an increase in LDL-cholesterol: these abnormalities will markedly enhance the vascular risk associated with hypertriglyceridemia.
- Discovering the cause of hypertriglyceridemia:
Contrary to what one might think, generally hypertriglyceridemia is not associated with an excess dietary intake of lipids. Three factors can, in predisposed subjects, induce hypertriglyceridemia carried by the VLDLs :
- an overall excess energy intake, often associated with obesity (which tends to be of the android type)
- alcohol abuse
- excessive ingestion of simple sugars (above all sucrose and fructose)
This dietary sensitivity can be tested by measuring triglycerides before and after elimination of the suspect factor. Triglycerides are measured, the intake of the factor incriminated is completely eliminated (sugar or alcohol, starting with the most likely one) and a repeat measurement is made 3 to 4 weeks later: if the triglycerides have decreased by more than 50%, most likely this factor was responsible. Hypertriglyceridemia is also very sensitive to moderate body weight loss in an obese subject.
Poorly controlled diabetes can induce hypertriglyceridemia: it will be detected by measuring fasting blood glucose at the time of the blood test. HTG can also be secondary to other diseases (renal, hepatic, endocrine) or iatrogenic (therapy with estrogen-progestins, diuretics, etc.)
- Management of hypertriglyceridemia :
Initial treatment and maintenance treatment are above all dietary measures: there is no effective medical therapy without strictly adherence to dietary measures.
Fibrates, which are the reference medications and produce both effects on the production and catabolism of TRLs, represent the only treatment of isolated hypertriglyceridemia. In the presence of mixed dyslipidemia and little increased triglyceride levels, statins can be used as first line therapy, especially if coronary heart disease already exists. Statins are more effective than fibrates in decreasing LDL-cholesterol levels. On the other hand, fibrates have a better effect on hypertriglyceridemia in the fasting stage, on postprandial lipidemia and small dense LDLs; they also have the advantage of producing a higher increase in HDL-cholesterol levels.
CONCLUSION
Treatment of lipid for vascular risk factors should not be limited solely to LDL-cholesterol level monitoring, but should also involve monitoring of abnormalities associated with triglyceride metabolism, a risk factor which has long been overlooked in the recommendations made by Scientific Societies or Health Authorities.
To provide precise recommendations in this field, it is necessary to plan new intervention studies, in primary as well as in secondary prevention. In the immediate future, the practitioner should take into account, in his/her choices of therapy, the four basic parameters measured after a fast: cholesterol, triglycerides, HDL-cholesterol and LDL-cholesterol levels.
Prof. Olivier ZIEGLER
CHU, Nancy
Bibliography
Chanu B. Hypertriglycéridémies: un danger pour les artères.
Presse Med., 1999, 28: 2011-2017.
Gotto AMJ. Triglyceride: the forgotten risk factor.
Circulation, 1998, 97: 1027-8.
Ziegler O, Guerci B, Drouin P. Le "deuxième phénotype athérogène" ou le rôle de l'insulino- résistance dans le risque vasculaire.
Arch. Mal. Cœur Vaisseaux, 1998, 91 (spécial V): 33-9.
La prise en charge thérapeutique du patient dyslipémique. Recommandations de l'AFSSAPS.
Insert: The second atherogenic phenotype.
| Even if LDL-cholesterol levels are the principal lipid factor for vascular risk, the atherogenic role of triglycerides has now been established. It is practical to define the following abnormalities: moderate hypertriglyceridemia (often between 150-400 mg/dl), decrease in HDL-cholesterol levels (< 35 mg/dl), moderate increase in LDL-cholesterol levels (between 130 - 159 mg/dl), and alterations in the composition of LDL (in particular small dense LDLs) as "the second atherogenic phenotype". Insulin resistance may constitute the common denominator in these disorders because it promotes the increase in production of triglyceride-rich lipoproteins and a decrease in their catabolism. Obesity, physical inactivity or smoking increase the occurrence of these lipoprotein metabolism abnormalities. |
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Abbreviations
EC : esterified cholesterol
CETP : cholesterol ester transfert protein
CM : chylomicrons
HDL : high density lipoprotein
LDL : low density lipoprotein
LPL : lipoprotein lipase
PL: phospholipids
R : receptor
R-LDL : LDL receptor
TG : triglycerides
VLDL : very low density lipoprotein
Figure 1: Intravascular metabolism of TRL and formation of small dense LDL.
Chylomicrons produced by the small intestine and VLDL produced by the liver give rise, under the effect of lipoprotein lipase, to smaller particles called "remnants." Exchanges of triglycerides and cholesterol occur in the circulation between these lipoproteins on one hand and HDL and LDL on the other hand, in particular under the effect of a cholesterol transfer protein, i.e. CETP. The LDL become rich in triglycerides and under the action of hepatic lipase, which hydrolyzes these triglycerides, are converted into small dense LDL.
Simplified classification of primary hypertriglyceridemia
| Type |
Plasma cholesterol |
Plasma TG* |
Associated factors |
Atherogenic risk |
| Chylomicron HTG (rare) |
N* or little elevated |
500-1000 mg/dl up to over 10000 mg/dl |
Genetic
Sensitive to dietary lipids |
very low |
| Isolated HTG with normal HDL-chol (rare) |
N or little elevated |
2-5 g/l |
Genetic
Alcohol (leads to an increase in HDL) |
probably low |
| HTG with low HDL-chol (frequent) |
N or little elevated |
200-500 mg/dl |
Genetic
Alcohol
Simple sugars
Obesity |
high |
| Mixed dyslipidemia: HTG, elevated LDL- chol +/- , low HDL- chol (frequent) |
200-300 mg/dl |
150-300 mg/dl |
Genetic
Alcohol
Simple sugars
Obesity
Insulin resistance |
very high |
| VLDL and chylomicron HTG (rare) |
N or little elevated |
> 500-1000 mg/dl up to over 10000 mg/dl |
Genetic
Dietary lipids
Alcohol
Simple sugars
Diabetes |
high |
* plasma concentrations given as an example
- HTG: hypetriglyceridemia
- chol: cholesterol
- N: Normal values
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