Hypertriglyceridemia: A Review of Clinical Relevance and Treatment Options: Focus on Cerivastatin

Hans-Willi M. Breuer, Abteilung für Innere Medizin, St. Carolus-Krankenhaus Görlitz, Carolusstr. 212, 02827 Görlitz, Germany 

Curr Med Res Opin. 2001;17(1):60-73. 

In This Article

Triglyceride - An Independent Risk Factor?

Among the lipid parameters, the role of TG as an independent risk predictor of CHD is controversial.TG is present as TG, TG-rich lipoproteins (TGRLP)and as LDL-C- and HDL-C-associated TG[1,4]. Its action is complex and high TG levels appear to compound the risk associated with other lipid parameters. For example, high TG levels are thought to increase the risk associated with a high LDLC/HDL-C ratio[3]. The TG level is affected by many different factors, some of which are CHD risk factors[1,4,6,45]. There is wide variation of 'normal' TG levels between individuals and fluctuation within the same individual[3,25]. In addition, many other disease states and treatments can cause an increase in TG levels[25,46].

Patients with raised TG levels often have high blood pressure and insulin-resistance as well as aprocoagulant state and a lipid profile known as the 'lipid triad' - high TG (> 2.3 mmol/l, > 200 mg/dl),low HDL-C (< 0.9 mmol/l, < 35 mg/dl) and small dense LDL-C[47]. In the PROCAM study[3,24], 15.7% of subjects with the lipid triad suffered a myocardial infarction during the eight years of the study. The association between these factors is typical of the metabolic syndrome. Therefore, as a high TG level in itself predicts a higher risk of cardiovascular events,and individuals with high TG levels are more likely to suffer from the other associated risk factors of the metabolic syndrome than those with normal TG levels[3], it is not surprising that TG levels are so predictive for CHD[3,41,46]. The LDL-C level tends to be low in patients with the lipid triad, and consequently the TC/HDL-C ratio may be a more accurate indicator of the 'dysmetabolic state' than the LDL-C/HDL-C ratio, especially among overweight hyperinsulinemic patients[48].

The retrospective Baltimore Study[21] of patients with coronary artery disease (CAD) evaluated long-term predictors of CHD risk. Of the survivors at the 18-year follow-up, the HDL-C levels were lower and the TGs higher compared to normal controls.Independent predictors of CAD were calculated to be diabetes mellitus (relative risk [RR] 2.1), HDL-C< 0.9 mmol/l (< 35 mg/dl) (RR 1.5), and raised TG level > 1.1 mmol/l (> 100 mg/dl) (RR 1.5). There was significant reduction in survival ( p 0.008)from CAD in patients with baseline TG 1.1mmol/l( 100mg/dl) compared with those with baseline TG< 1.1 mmol/l (< 100 mg/dl).

Low HDL-C and high TG levels have been found to contribute to the risk associated with raised LDLC levels[49]. The PROCAM study[3,24] investigated the incidence of mortality and cardiovascular events in 4849 males aged 40-64 years over an eight-year period. The PROCAM study showed that in middle-aged men, the fasting TG level was an independent risk factor for CHD irrespective of serum levels of LDL-C or HDL-C. A synergistic relationship between high TG and LDL-C baseline levels and CHD risk was seen at all concentrations of LDL-C.The prevalence of a TG level > 2.2 mmol/l(> 200 mg/dl) in CHD patients was almost double that of non-CHD patients (Figure 1), emphasising that in prevention of CHD it is important to identify individuals with high TG and high LDL-C levels since these individuals are at the highest risk.

Figure 1.

Prevalence of subjects with TG > 2.2 mmol/l (> 200 mg/dl) in CHD and control populations

For patients with raised LDL-C levels, an increase in TG level correlated with a higher incidence of CHD[3,42,50]. This effect was more pronounced the higher the LDL-C level (Figure 2).

Elevated triglycerides increase the risk of CHD in association with LDL-C. Triglyceride and LDL-C concentration ranges are given in mmol/l; TG 1.7 mmol/l (150 mg/dl), 2.2 mmol/l (200 mg/dl), 4.5 mmol/l (400 mg/dl); LDL-C 3.6 mmol/l (135 mg/dl), 4.0 mmol/l (155 mg/dl), 5.0 mmol/l (195 mg/dl)3

The Paris Prospective study[51,52] showed that men and women with diabetes have the same risk of CHD.This may be due to the greater increase in TG in women than in men with diabetes, which elevates the risk in women to equal that of the men. In patients with type 2 diabetes, the lipid profile of low HDL-C and high TG is a much more powerful CHD risk predictor in women: 200 times greater risk in women and three times greater in men[53]. The mechanism of the TG increase seen in diabetics is unknown. One study has shown that it is not due to the failure of insulin to inhibit TG production[54].

The TG level has been demonstrated to correlate extremely well with CHD risk in cases of familial hypertriglyceridemia (also known as post-prandiallipemia)[40,55]. In this group of patients, the postprandial elevation in TG level, assessed by using the total area under the TG time curve, has been associated with a transient impairment of endothelial function[56,57]. This finding points to the important role of impaired TG tolerance in the development of atherosclerosis[56,57]. The post-prandial elevation of TGs in these patients has been shown to be due to pathological metabolism of endogenous (liver derived)TGRLPs and not, as one might expect, an accumulation of dietary TGRLPs[56].

The Copenhagen Male Study (CMS) also showed elevated TG levels to be a strong risk factor independent of HDL-C level and other risk factors[23]. The study was carried out between 1970 and 1985 on 6125 males aged 40-59 years. In 1986, 3387 survivors aged 53-74 years were studied. A clear risk gradient was seen relating baseline fasting TG level with risk of ischemic heart disease, controlling the data for other confounding factors such as other lipid parameters and non-lipid factors (e.g. the use of antihypertensives, exercise levels, diet, age, social class and alcohol consumption).

The Framingham study[4,5] investigated the incidence of CHD in 5209 men and women aged 30-62 years. From the study data, TC correlated with the incidence of coronary events in low-risk patients,increasing with age, but this was the weakest correlation of all lipid parameters. The highest incidence of coronary events was seen in those with a moderately increased TC of 5.2-6.2 mmol/l (200-240 mg/dl). The HDL-C level and TC/HDL-Cratio were found to be better predictors of CHD than LDL-C. In men aged < 65 years, only TC/HDL-Cratio predicted CHD, whereas in women aged 50-79 years, LDL-C, HDL-C, TG levels and the TC/HDLC ratio were all strong predictors of risk. TG levels have been shown to correlate inversely with HDL-C levels and, although it is acknowledged that TG levels are an indicator of risk and can lead to the presence of atherogenic TGRLP particles in some individuals, the risk bestowed by the TG level is overshadowed by the greater significance of the HDL-C level[17].

The TG level is a stronger independent risk factor in women, in men with low HDL-C, and in all individuals with a high TC/HDL-C ratio > 3.55. Approximately 90% of patients with high TG levels also have a TC/HDL-C ratio > 3.5. Meta-analyses of several prospective studies[46] have also shown that increased TG is a risk factor for CHD independent of HDL-C level, especially in women[53]. An increase of 1 mmol/l (90 mg/dl) in TG relates to a 30% increase in CHD risk in men and a 75% increase in CHD risk in women. After adjustment to remove the effect of other risk factors, the relative risk was reduced but still highly significant: 14% in men and 37% in women[43,46]. The risk is significantly greater in postmenopausal women and men aged > 65 years[53].

The Helsinki Heart Study (HHS)[58] found in predominantly non-diabetic patients that the LDL/HDL-C ratio was the best single predictor of CHD risk. The subgroup with elevated TG(> 2.3 mmol/l, > 200 mg/dl) combined with an LDL/HDL-C ratio of > 5 had a relative risk (RR)factor of 3.8 compared with that of the control group and showed the most benefit from treatment with lipid-lowering drugs. A total of 71% of this patient group showed a reduction in CHD events.


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