Target Triglycerides: The Neglected Lipids

CV Risk Increases Considerably in Diabetic Patients

NEW YORK CITY—When it comes to reducing cardiovascular (CV) morbidity and mortality, the focus has been on low-density lipoprotein cholesterol (LDL-C), and to a much lesser extent on high-density lipoprotein cholesterol (HDL-C), but little attention has been paid to the role of triglycerides in cardiovascular disease (CVD). This trend is beginning to shift, with triglycerides emerging as a strong predictor of CV risk, especially in women, experts reported at a recent meeting titled “Tipping the Scale: The Forgotten Fat.”

“We have ignored triglycerides, because the focus has been on the success of statins in reducing cardiovascular morbidity and mortality, mainly by controlling high LDL cholesterol levels,” said Kathleen Wyne, MD, PhD, assistant professor, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas. “Patients with a modest increase in LDL cholesterol, especially if it accompanies diabetes or the metabolic syndrome, are more likely to achieve benefit with use of fibric acid derivatives [fibrates].”

Niacin is another effective therapy, but it has been associated with a greater side-effect profile, and many physicians avoid niacin therapy for that reason.

Dr Wyne emphasized that diabetes imposes a 2- to 4-fold excess risk for CV events. This risk has been linked to the presence of what is known as mixed dyslipidemia, primarily a disorder of the triglyceride/HDL-C axis, which produced an elevation of triglyceride-rich lipoproteins and a decline in HDL-C levels.

Dyslipidemia is also a major component in patients with the metabolic syndrome, manifested by a cluster of risk factors, including elevated triglyceride levels, abdominal obesity, reduced HDL-C levels, impaired glucose tolerance, and hypertension (or patients taking antihypertensive medications).

Insulin resistance, which is central to diabetes and the metabolic syndrome, leads to an overproduction of very- low-density lipoprotein (LDL) particles. The resulting increase in triglyceride levels sparks an increase in small, dense LDL particles.

“The associated risks with the metabolic syndrome are not only for cardiovascular disease, but for all kinds of vascular disease and stroke as well,” Dr Wyne warned.

Circulation

Investigators in Denmark showed that enlarged waist circumference (≥88 cm) and elevated triglycerides (≥1.45 mmol/L) are the “best indicators” of CV risk (. 2005; 111:1883-1890) in women. In that study, more than 550 postmenopausal women were followed for a median of 8.5 years. The combination of a large waist circumference and elevated triglyceride levels was associated with a 4.7-fold increased risk of CV death during follow-up.

Am J Cardiol

Clin Chem

An earlier meta-analysis of 17 prospective studies of the role of triglycerides in CVD showed that women with elevated triglycerides were at a 37% increased risk for CVD, after adjusting for HDL-C and other risk factors; CVD risk among men increased by 14% (. 1998; 81:7B-12B). And another study showed that postmenopausal women with elevated triglycerides were twice as likely to die prematurely (before age 60) because of coronary heart disease (. 1998; 44: 1224-1232).

Circulation.

The presence of the metabolic syndrome has been significantly associated with increased risk for myocardial infarction (MI) and stroke, based on data from more than 10,000 participants in the Third National Health and Nutrition Examination Survey ( 2004; 109: 42-46).

Evidence from recent clinical trials supports the hypothesis that patients with insulin-resistant syndromes would benefit most from fibrate therapy. Fibrate therapy helps to change the typical lipid profile of a patient with type 2 diabetes by reducing triglyceride levels and raising HDL-C levels, thus reversing the tendency to form the small, dense, highly atherogenic LDL particles.

N Engl J Med.

Arch Intern Med.

In the Veterans Affairs High-Density Lipoprotein Intervention Trial (1999; 341:410-418), more than 2500 men with a history of CVD were assigned to treatment with gemfibrozil (Lopid) or matching placebo. Approximately 25% of each cohort had diabetes. The primary end point was a composite of nonfatal MI or death from coronary causes during a 5-year follow-up. This occurred in 17.3% of those receiving gemfibrozil and 21.7% of the placebo group—a relative risk reduction of 22%. In a subgroup analysis of participants with diabetes, the cohort receiving gemfibrozil had a 32% reduction in relative risk, attributable to a 22% decrease in MI and a 41% decrease in CV death ( 2002; 162: 2597-2604).

Lancet

The more recent randomized, placebo-controlled FIELD trial (Fenofibrate Intervention and Event Lowering in Diabetes; .?2005; 366:1849-1861) included nearly 10,000 participants with or without previous coronary heart disease. No patient was taking a statin at entry. Fenofibrate (Tricor) therapy failed to achieve statistical significance for the primary end point—risk reduction for CVD, CV death, or nonfatal MI.

However, this treatment did reduce the total CV events, mainly thanks to fewer infarctions and revascularizations. There were also fewer diabetic- related microvascular complications, such as progression of albuminuria and retinopathy.

The FIELD investigators pointed to the higher rate of statin therapy in the patients assigned to placebo (statins could be added during the study at the discretion of the patient’s primary physician or specialist), which might have masked a greater benefit of fibrate therapy.

Another explanation could be the lack of a sustained effect on HDL-C levels, despite improvements in triglyceride and LDL-C levels. But the true reasons for the lack of meaningful treatment effects are unknown.

Commenting on the need to address elevated triglyceride levels, Dr Wyne commented, “Lifestyle changes are the first priority in treatment. Reducing triglycerides in the diet is the most important factor in weight loss. Eat less, exercise more. When it is time for drug therapy, fibrates have the best outcomes data. Niacin is effective, but there are a lot of side effects. Statins are sometimes used to lower triglyceride levels, but they really don’t work very well. When the patient is at high risk, I am going to treat aggressively to restore lipid balance.”

This meeting was sponsored by Abbott Laboratories.

How to Lower Triglycerides with Lifestyle Changes

• Overweight person: lose 7%-10% of body weight, usually 10-15 lb

• Reduce the number of calories consumed—any calories, but mainly those coming from high-sugar foods and soda

• Using monounsaturated fats instead of saturated fats and excess carbohydrates will have a beneficial effect on triglycerides and perhaps on HDL-C; replace butter/margarine or large servings of rice, pasta, or bread with olive oil, canola oil, avocado, olives, or nuts

• Follow a diet low in transfatty acids and carbohydrates; cut down on snacks

• Increase physical activity; the American Heart Association recommends 60 min/day of exercise for weight loss

• It is difficult to raise HDL-C levels. Exercise (running 7-10 miles per week) may result in a small increase; regardless, exercise is cardioprotective.