Low-density lipoprotein (LDL) is the primary target of lipid lowering therapy and in many ways, LDL and cholesterol in general are relatively simple, not unlike blood pressure. From a conceptual point of view, LDL cholesterol is largely about LDL. We have good drugs to lower LDL. LDL lowering reduces risk for heart attack and stroke. All of those are like blood pressure lowering.

This is a major conceptual advance over the past 2 decades based on a large number of clinical trials. It has carried us a long way in the prevention of coronary heart disease and it's the foundation of the National Cholesterol Education Program guidelines.

I've been assigned the task to talk about triglycerides. Triglycerides are not so simple. We don't understand them as well. They have been the subject of a lot of disagreement through the years, and it's important to try to understand something about their complexity to understand what triglycerides are all about.

This shows that there are a variety of different triglyceride-rich lipoproteins that include chylomicrons, large very low-density lipoprotein (VLDL), small VLDL, beta-VLDL, and intermediate-density lipoprotein (IDL). All of these are present throughout the day, all of them have some role to play, and in some patients they are present more than in others.

Another important point that makes the matter even more complex is that elevated triglycerides usually go together with other abnormalities in lipoprotein metabolism. There's a condition that we call the lipid triad, or atherogenic dyslipidemia, which is characterized by elevated triglycerides or elevated VLDL, small LDL particles, and low high-density lipoprotein (HDL). These tend to run together and when you have high triglycerides, you have these other abnormalities in lipoprotein metabolism.

What we call atherogenic dyslipidemia, or this lipid triad, results in large part from the elevation in triglycerides. It is because of these high triglycerides and VLDL that we have the generation of these other abnormalities, small LDL and low HDL.

There's a difference in atherogenicity of the different triglyceride-rich lipoproteins. This has been a topic of a lot of discussion and some disagreement through the years, but I think a general pattern has emerged so that we know that different forms of triglyceride-rich lipoproteins differ in their atherogenic potential.

For example, beta-VLDL are perhaps the most atherogenic, and the other smaller particles are more atherogenic than the larger; IDL more than small VLDL, the small VLDL and IDL, what we call remnants, more than large VLDL and chylomicrons. So when considering the atherogenic potential in particular patients, it's important to know what kind of triglyceride-rich lipoproteins you have.

Another point is that, in view of the growing evidence that VLDL in its different forms is atherogenic, if we would combine the VLDL with LDL, we might have a better indication of the atherogenic potential of cholesterol and perhaps have a more definitive target. This is what we call non-HDL, which is the sum of VLDL plus LDL. And we believe that has more atherogenicity than just LDL.

Why don't we always use non-HDL? We could but there are several reasons why we stick with LDL. First of all, in most people who don't have elevated triglycerides, LDL is a good measure of the atherogenic potential of the lipoproteins. In addition, we have a lot of clinical trial evidence that relates to LDL lowering and its benefit.

Nonetheless, there's growing evidence that in people with high triglycerides, over 150 mg/dL, if you would add the VLDL cholesterol to the LDL to get the non-HDL, measured by total cholesterol minus HDL, you may have a better indication of the atherogenicity of the apolipoprotein (apo) B-containing lipoproteins.

Let's go through some of the different forms of hypertriglyceridemia that we face in clinical practice and see how we would approach them. A rare condition is severe chylomicronemia. When triglycerides are over 1000 mg/dL, the patients are at increased risk for acute pancreatitis, and they have a marked increase in chylomicrons. This is usually due to a defective lipolysis due to a defective breakdown of the triglycerides, either due to a low level of lipoprotein lipase or apo CII. This is a relatively rare condition but it's important to recognize and differentiate it from hypercholesterolemia.

How do we manage patients with severe chylomicronemia? The first goal is to prevent acute pancreatitis because elevated chylomicrons are not particularly atherogenic. The primary therapy then is to reduce the formation of chylomicrons, which is done by very low-fat diet, and patients with severe chylomicronemia should have less than 10% of their calories as dietary fat. A secondary approach would be to use medium-chain triglycerides because they don't produce chylomicrons. In general, lipid-lowering drugs such as fibrates are not very effective and the dietary approach is necessary.

A much more common form and one that we see all the time in clinical practice is atherogenic dyslipidemia: high VLDL remnants or moderately high triglycerides, small LDL, and low HDL. In most patients who have atherogenic dyslipidemia, this is elicited by the presence of the metabolic syndrome. Most people who have this constellation, the lipid triad with moderately high triglycerides, have the metabolic syndrome, and thus the presence of elevated triglycerides is an important marker for the metabolic syndrome. That's not very well recognized and most people tend to think of triglycerides independent of other factors, but it goes along with metabolic syndrome.

What is the metabolic syndrome? It's a condition in which there are multiple metabolic risk factors that include atherogenic dyslipidemia, higher blood pressure, insulin resistance, a prothrombotic state, and a proinflammatory state.

We know increasing amounts about its origins. It arises in large part from abdominal obesity, acting in a person who's genetically susceptible. With abdominal obesity, there's increased production of free fatty acids that enter the liver and stimulate the production of VLDL triglycerides. There's increased release of cytokines and plasminogen activator inhibitor-1 (PAI-1), which contribute to the other inflammatory and coagulable states that are present as part of this syndrome. So it's extremely important to recognize this syndrome and to know that higher triglycerides are a very good marker for its presence.

How do we manage atherogenic dyslipidemia and metabolic syndrome? First-line therapy is therapeutic lifestyle changes, weight reduction and increased physical activity, which all of our patients with these disorders should start on. This will reduce all the metabolic risk factors, and there's no single drug that can do that anywhere near as well as therapeutic lifestyle changes.

For second-line therapy, we may have to resort to using drugs for treating specific risk factors, and in the case of atherogenic dyslipidemia, statins, fibrates, and nicotinic acid are important therapeutic agents as second-line therapy.

There is a condition also associated with elevated triglycerides that is less common than metabolic syndrome called familial hypertriglyceridemia. Some people have moderately elevated triglycerides, in the range of 150 to 500 mg/dL, but they don't have metabolic syndrome. They're thin, they're active people, and they still have high triglycerides. They often have low HDL.

The problem is not an overproduction of triglycerides by the liver, but a defective lipolysis. In other words, they have abnormalities that lead to a defect in the breakdown of their triglycerides, so the triglycerides accumulate in their plasma. This is not a common problem, but we do see it in our patients and we wonder what to do about it.

How do we manage patients with familial hypertriglyceridemia who don't have the metabolic syndrome? Risk for coronary heart disease is variable. Some of these people are not at increased risk at all if they just have elevated triglycerides and none of the other components of the metabolic syndrome.

How do we find out whether they're at increased risk? We don't have a perfect way, but factors that indicate increased risk include family history of premature coronary disease. And if you do measures of subclinical atherosclerosis, such as carotid atherosclerosis or electron beam computed tomography (CT) of coronary calcium, and these are increased, the person is at increased risk if they have a lot of atherosclerotic burden, and they might be considered for more aggressive treatment.

It's probably good to avoid high carbohydrate diets, which raise triglyceride levels, and drugs should be reserved only for those patients for whom we have some evidence that they are at increased risk.

Sometimes familial hypertriglyceridemia is combined with the metabolic syndrome, and when this occurs, we have a condition called type 5 hyperlipidemia in which there's an increase in both chylomicrons and VLDL. We often see this in patients who have type 2 diabetes, and certainly people with type 2 diabetes have metabolic syndrome. They have an overproduction of triglycerides, an overproduction of VLDL, and in the presence of a moderate defect in the breakdown of triglycerides, they accumulate large amounts of VLDL and even chylomicrons. They are at increased risk for pancreatitis, but also for coronary heart disease, and this has been called, by the old nomenclature, type 5 hyperlipidemia. It represents a therapeutic management problem.

Many physicians are not familiar with how to approach this problem and have trouble controlling elevated triglycerides. We believe that these people are at increased risk for both coronary heart disease and acute pancreatitis.

First of all, treat the chylomicronemia with very low-fat diets and by using fibrates. They are usually effective in reducing triglyceride levels.

Second treatment is to treat the metabolic syndrome with weight reduction, and since these people often have other risk factors, it's important to treat those as well.

But the first goal is to get the triglycerides down. In many people, it's not possible to get them down to normal, but if you can get them down to below 1000 or 500 mg/dL, then the risk for pancreatitis is greatly reduced.

Another condition that we often see is an elevated triglyceride and elevated cholesterol. This is what we might call combined hyperlipidemia. People who have an increase in both VLDL and LDL usually have metabolic syndrome in addition. They have an overproduction of VLDL associated with metabolic syndrome, but they also have something that's quite common, a defective clearance of LDL. We know that saturated fat in the diet and many other factors lead to a low clearance of LDL. So if you're overproducing lipoproteins and you can't remove the LDL through the LDL receptor, you'll get high levels of VLDL and LDL and end up with combined hyperlipidemia.

How do we approach the treatment of such patients? These people are at very high risk for coronary heart disease. They have both remnants and LDL. The first goal is to treat LDL, and statins are first-line therapy for this purpose. But it's also important to treat elevated VLDL in these people, and we can consider the use of combined drug therapy, either fibrates or nicotinic acid.

And most of these people have metabolic syndrome, so lifestyle changes are extremely important, as well as treating other risk factors.

Let me note what might be the approach with combined drug therapy using a statin and fibrate. It's important to remember that statins not only lower LDL, but they also lower VLDL. They produce similar reductions in VLDL cholesterol and LDL, so statins are efficacious in both.

Fibrates lower VLDL cholesterol, but they don't lower LDL cholesterol levels in general. They do raise the LDL particle size. Whereas statins lower the number of LDL particles, fibrates increase the size of the particles, which may also be beneficial. So you can see the potential benefit derived from using this combination therapy.

Niacin can also be used in combination with statins. Statins lower both VLDL and LDL, and niacin likewise lowers VLDL and LDL, but mainly lowers VLDL. Its ability to lower LDL is less than that of statins, but may have some additional effect. In addition, niacin raises LDL particle size. Niacin probably would be preferred over fibric acids for its effect on both VLDL and LDL, and even HDL. Unfortunately it has more side effects than fibrates, which makes most of us usually go to a fibrate first. But often in patients who can tolerate niacin, we would use that as a second drug in combined therapy.

Another relatively rare, but interesting condition is familial dysbetalipoproteinemia. This is type 3 hyperlipidemia and there's an increase in very atherogenic beta-VLDL. This disorder also is a result of a combined defect; overproduction of VLDL by metabolic syndrome combined with a defective clearance of beta-VLDL as a result of a particular form of apo E called apo E2. If you have apo E2 and metabolic syndrome, you'll end up with an increase in beta-VLDL type 3 and be at increased risk.

How do we manage patients with type 3 hyperlipidemia? They are at increased risk for coronary heart disease. They have a combined defect, metabolic syndrome plus apo E-2 genotype. It's important to treat the metabolic syndrome. Weight reduction is often extremely effective in patients with this disorder. But it's also important to treat the beta-VLDL with drugs, either statins or fibrates.

In summary, hypertriglyceridemia is a relatively complex problem, and you have to understand the mechanisms of its formation. It results from both an overproduction of triglyceride-rich lipoproteins and defective clearance of lipoproteins, very often in combination.

The overproduction most commonly occurs in patients with metabolic syndrome who have other metabolic risk factors, indicating that triglycerides are a marker for the presence of metabolic syndrome. But defective clearance can occur at several levels in the metabolism of these triglyceride-rich lipoproteins: defective lipolysis leading to larger particles being increased, defective clearance of beta-VLDL remnant removal leading to type 3 hyperlipidemia, or defective clearance of LDL leading to combined hyperlipidemia. And each of those requires a slight difference in the way to approach its management.