Common Etiologies of Hypertriglyceridemia

Henry N. Ginsberg, MD

Dr Ginsberg is the Irving Professor of Medicine at Columbia University College of Physicians and Surgeons, an Associate Dean for Clinical and Translational Research, and the Director of the Irving Institute for Clinical and Translational Research at Columbia University Medical Center, New York, New York.


At least 95% of people with type-2 diabetes are insulin resistant. In the adipose tissue, insulin-resistant cells release fatty acids, increasing fatty acid flux to the liver resulting in transformation of the excess into triglycerides (TG). The liver unloads the TG by combining with an Apolipoprotein B (ApoB), to produce very low density lipoprotein (VLDL). A basic central abnormality of people with a diabetic or insulin resistant dyslipidemia is increased production and secretion of VLDL. Overproduction of VLDL leads to increased levels of TG, via an exchange process mediated by cholesteryl ester transfer protein (CETP), resulting in low levels of high-density lipoprotein cholesterol (HDL-C) and Apolipoprotein A-I (apoA-1), and the generation of small, dense low density lipoprotein (LDL). Patients with diabetes or metabolic syndrome show a wide range of TG levels, due to the number of different modulators of lipoprotein lipase (LPL), the lipolytic enzyme essential for normal hydrolysis of TG in VLDL and variations in the LPL gene affecting these functions.

This type of patient must first be treated with a statin. There are three main possibilities for treating the rest of the lipid profile plus PPARγ agonists, such as pioglitazone, which has been shown to lower TG and raise HDL-C, with variable effects on LDL-C. Niacin is probably the best lipid modulator currently available. The Arterial Disease Multiple Intervention Trial (ADMIT) and Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial (ADVENT) studies suggested that niacin can be efficacious in patients with existing, treated diabetes; however, it may cause an increase in blood glucose or worsening of diabetic control. A secondary analysis of HDL-Atherosclerosis Treatment Study (HATS) trials showed that patients on niacin had an increase in glucose compared with placebo. Two critical hard outcome trials with niacin that will provide more information are Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health (AIM-HIGH) and Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE). Omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) lower TG by 25-35% at a dose of 4 mg/day. From animal and cell models, it is known that omega-3 fatty acids can cause apoB to be degraded, and in humans studies both TG and apoB secretion are reduced by large doses of omega-3 fatty acids.

Fibrates act as PPARγ receptor agonists that reduce TG by 35-50% and raise HDL-C by 35-50% in patients with high TG and low HDL-C. Clinical trials with fenofibrate produced variable results in preventing cardiovascular (CV) outcomes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial, which looked at fenofibrate plus simvastatin versus simvastatin alone in diabetic patients, was designed before the Bezafibrate Infarction Prevention (BIP) or Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study results became available. The trial showed a non-significant 8% reduction in major fatal or nonfatal CV events with fenofibrate.1 Subgroup analyses showed that women did less well than men, although there was no basis for this finding. Patients with TG levels in the highest third (≥ 204 mg/dL) and HDL-C level in the lowest third (≤ 34 mg/dL) (dyslipidemic subgroup), which made up 17% of the cohort, had 31% reduction in the primary outcome, whereas the other 83% without dyslipidemia had no benefit, with no effect of fenofibrate on their lipid profile. This finding was consistent with post-hoc analyses of the Helsinki Heart Study, BIP, and FIELD, where post-hoc analyses showed better benefit in dyslipidemics, than in the overall group, or the only benefit compared with nonstatistically significant outcomes in the overall group.

Dr Ginsberg concluded that in statin/multidrug treated patients, it worthwhile adding a fibrate if they have significant dyslipidemia, with TG >200 mg/dL, HDL-C <35 mg/dL (40 mg/dL) in women. This is about 10% of Caucasian population (less in nonwhites). Dr. Ginsberg noted that data suggests that only 2-3% of that 10% are being treated with that combination.

References:

  1. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. Apr 29 2010;362(17):1563-1574.