Is LDL the sole principal target of a lipid-modifying strategy for minimizing cardiovascular disease risk?

The importance of dyslipidemia in the development of cardiovascular disease is now recognized as a central factor of equal, if not greater, significance than any other risk factor.

After low density lipoprotein (LDL) was identified as an independent risk factor for cardiovascular disease, significant efforts have been made to decrease LDL levels. Results from the statin trials^1-3 have established that intervention leading to lower LDL levels produces a significant risk reduction. It was clear from these trials, however, that the extent of this reduction was incomplete: the decrease in the rate of coronary events was only 30% to 35%.4 A substantial number of individuals who received treatment and who achieved meaningful LDL reduction still had a cardiovascular disease event or evidence of disease progression, suggesting the presence of additional risk factors. Hence the challenge that we face today is to move beyond LDL and consider other risk factors that might explain the residual morbidity and mortality seen in these landmark studies. These potential risk factors include elevated triglycerides, low levels of high density lipoprotein (HDL), elevated levels of small dense LDL, elevated fibrinogen levels and increased lipoprotein (a) [Lp (a)] levels.

The extent of CHD risk reduction in landmark statin trials was only 30-35%. Hence the challenge that we face today is to move beyond LDL and consider other risk factors that might explain the significant residual morbidity and mortality seen in these landmark studies.

There is a growing body of evidence from epidemiologic, clinical and laboratory data that indicates that elevated triglyceride levels are an independent risk factor for cardiovascular disease.

The Prospective Cardiovascular Munster (PROCAM) study involved 4849 middle-aged men who were followed up for 8 years to record the incidence of CHD events according to the risk factors present at study entry. The study showed that fasting levels of triglycerides were an independent risk factor for CHD events, irrespective of serum levels of HDL or LDL (Figure 1).⁵

Recently published data that further substantiate this concept include the Copenhagen Male Study, in which investigators followed 2906 men between the ages of 52 and 74 who were initially free of cardiovascular disease, for a period of 8 years. The investigators reported finding a clear gradient of risk of CHD with increasing triglyceride levels.⁶

In addition, a comprehensive meta-analysis of 17 studies involving 46413 men and 10864 women showed that every l mmol/L (88.5 mg/dl) increase in triglycerides increases risk of CHD by 32% in men and 76% in women.⁷

Every 1 mmol/L (88.5 mg/dl) increase in triglycerides increases risk of CHD by 32% in men and 76% in women

Triglyceride is also increasingly accepted as a CHD risk factor synergistic with other lipid risk factors. Also, elevated levels of triglycerides may be a marker for a series of other potentially atherogenic and prothrombotic changes such as increased small dense LDL particles, low HDL cholesterol levels, and increased levels of procoagulant molecules.⁸

Classification

The classification of serum triglycerides as per Adult Treatment Panel (ATP) III is given in the table below:

Management (ATP III)⁹

• For all persons with elevated triglycerides, the primary aim of therapy is to achieve the target goal for LDL cholesterol.
• When triglycerides are borderline high (150-199 mg/dl), emphasis should also be placed on weight reduction and increased physical activity.
• For high triglycerides, non-HDL cholesterol (total cholesterol minus HDL cholesterol) becomes a secondary target of therapy (Table 2).