High Triglyceride Low High-density Lipoprotein Research Articles

Adverse Events Related to Muraglitazar Use in Diabetes

To the Editor: The study of muraglitazar and adverse events by Dr Nissen and colleagues points out why physicians need hard outcomes data obtained in a blinded fashion before prescribing a new therapy for patients. The study, however, raises broader concerns beyond muraglitazar. Mortality data are needed prior to US Food and Drug Administration (FDA) approval for peroxisome proliferator–activated receptor (PPAR) agonists, and current practices that use combined therapy for patients with diabetes who have lipid abnormalities need to be examined. There is a relative paucity of mortality data for fibric acid derivatives compared with data on statins. One of the 3 large studies examining the use of gemfibrozil in the secondary prevention of cardiovascular disease showed a nonstatistically significant 7% increase in total mortality. Another study showed a nonsignificant benefit for gemfibrozil, with a 10% reduction in total mortality. Bezafibrate was reported to have a nonsignificant 6% higher mortality. These studies were not designed as mortality trials, but there are no published data demonstrating convincing mortality benefit with the use of fibric acid derivatives. Diabetic dyslipidemia typically refers to patients with a high triglyceride–low high-density lipoprotein (HDL) profile, who are the patients most suitable for PPARagents. These patients may receive PPARand PPARagents as 2 different pills, and the interaction of these was not previously known. The fibric acid studies were all conducted in different patient populations, and it is not clear how many patients in each group were also taking PPARagents. However, with limited data supporting a mortality benefit for fibric acids alone, and the apparent increase in mortality seen with muraglitazar, caution should be used in prescribing any fibric acid along with any PPARagent because this combination may have the same propensity to increased mortality.

Role of fibric acid derivatives in the management of risk factors for coronary heart disease.

Although elevated low-density lipoprotein (LDL)-cholesterol is a well established coronary heart disease (CHD) risk factor, the ability to adequately discriminate high-risk individuals by this risk factor alone is limited and other metabolic risk variables are known to modulate CHD risk. For instance, it has been reported that the cluster of metabolic disturbances observed among individuals with abdominal obesity, the so-called metabolic syndrome, is associated with a substantially increased risk of CHD. Among the features of the dyslipidaemic profile observed in these individuals, the high triglyceride-low high-density lipoprotein (HDL)-cholesterol dyslipidaemia is predictive of an elevated risk of CHD. Fibric acid derivatives (fibrates) have been used in clinical practice for more than 2 decades as a class of agents known to decrease triglyceride levels while substantially increasing HDL-cholesterol levels, with a limited but significant additional lowering effect on LDL-cholesterol levels. Although the clinical benefits of HMG-CoA reductase inhibitors (statins) have been well documented by primary and secondary prevention trials that justify their widespread use, it was not until the publication of the VA-HIT (Veterans Affairs High-Density Lipoprotein Intervention Trial) that the relevance of identifying HDL-cholesterol as a therapeutic target to reduce the risk of recurrent CHD events was finally confirmed. The clinical benefits of fibrate therapy are especially important in the subpopulation of patients with low HDL-cholesterol levels with the metabolic syndrome, particularly in patients with type 2 diabetes mellitus or in abdominally obese, hyperinsulinaemic patients. Evidence also suggests that there is a 'fibrate effect' that mediates the reduction in CHD risk beyond the favourable impact of these agents on HDL-cholesterol levels. This last notion is consistent with the pleiotropic effects of fibrates which are known to be related to their mechanisms of action. Through peroxisome proliferator-activated alpha-receptors, fibrates have a significant impact on the synthesis of several apolipoproteins (apo) and enzymes of lipoprotein metabolism as well as on the expression of several genes involved in fibrinolysis and inflammation. Fibrate therapy has been reported to decrease apo CIII levels (a powerful inhibitor of lipoprotein lipase) and increase apo AI levels, as well as to increase lipoprotein lipase activity. Such changes contribute to improve the catabolism of triglyceride-rich lipoproteins, leading to a substantial increase in HDL-cholesterol levels accompanied by a shift in the size and density of LDL particles (from small, dense LDL particles to larger, more buoyant cholesteryl ester-rich LDL). It is proposed that some of these pleiotropic effects could explain some of the clinical benefits of fibrate therapy beyond its HDL-raising properties, particularly among patients with abdominal obesity, hyperinsulinaemia or type 2 diabetes with both low HDL- and low/normal LDL-cholesterol levels.

Relative importance of various risk factors for asymptomatic carotid atherosclerosis versus coronary heart disease incidence: the Atherosclerosis Risk in Communities Study.

Major risk factors for coronary heart disease are also associated with early carotid artery thickening, but no studies have yet examined patterns of risk factors to see whether they differ for the two outcomes. Assuming similar pathogenesis for both coronary and carotid atherosclerosis, one could interpret risk factor pattern differences as relating to differences in staging, i.e., early atheroma versus later stenotic or occlusive atherothrombosis. This study included 12,193 Atherosclerosis Risk in Communities Study participants aged 45-64 years who were free of clinical cardiovascular disease in 1987-1989, in whom 420 myocardial infarctions or coronary heart disease deaths occurred over the next 6 years. Plasma low density lipoprotein cholesterol, systolic blood pressure, and smoking were major risk factors for both outcomes. Compared with these factors, triglycerides and high density lipoprotein (HDL) cholesterol were associated only weakly with carotid atherosclerosis but were associated strongly with coronary heart disease incidence. No other risk factors, including those associated with diabetes mellitus, hemostasis, and inflammation, differed in their relative contribution to the two outcomes. These results suggest that the high triglyceride-low HDL cholesterol pattern is involved in the transition from atheroma to atherothrombosis, and that control of this pattern may be important in persons with detectable subclinical disease.

Gemfibrozil treatment of the high triglyceride‐low high‐density lipoprotein cholesterol trait in men with established atherosclerosis

To study the short-term efficacy, tolerability and safety of the treatment with gemfibrozil 600 mg twice daily or placebo in male patients with established atherosclerosis, with a lipid profile matching the 'high triglyceride-low high-density lipoprotein (HDL) cholesterol trait'. Double-blind randomized placebo controlled prospective trial. Amsterdam Lipid Research Clinic at the Academic Medical Centre of the University of Amsterdam and the Slotervaart Training Hospital affiliated to the University of Amsterdam, Amsterdam, the Netherlands. Thirty-five male patients, age 30-70, with established atherosclerosis and the high triglyceride-low HDL cholesterol trait. Plasma total cholesterol, triglycerides, lipoproteins, apolipoproteins A1 and B100, clinical and laboratory safety parameters. Seventeen patients in the gemfibrozil group and 16 patients in the placebo group completed the study period. Compliance was considered adequate. Mean (+/- standard deviation) plasma HDL cholesterol levels increased 20.3% (+/- 12.22) from 0.82 to 0.99 mmol L-1 in the gemfibrozil group against 9.9% (+/- 18.31) from 0.79 to 0.87 mmol L-1 in the placebo group (P = 0.001). Mean plasma triglyceride level fell 49.5% (+/- 14.27) from 3.65 to 1.82 mmol L-1 in the gemfibrozil group against an increase of 13.6% (+/- 40.31) from 3.62 to 4.01 mmol L-1 in the placebo group (P < 0.001). Although plasma HDL cholesterol and triglyceride levels improved in all patients, normalization of these lipoproteins was only observed in approximately half of them. Plasma total and low-density lipoprotein (LDL) cholesterol levels, as well as plasma levels of apolipoprotein (apo) A1, B100 and lipoprotein [Lp(a)], did not show significant alterations compared to the placebo. All safety parameters were comparable between the two groups and remained within the reference limits. Gemfibrozil was well tolerated during treatment. Minor inconveniences were equally distributed between the two treatment groups. Gemfibrozil is an effective and safe drug in patients with coronary heart disease (CHD) and the high triglyceride-low HDL cholesterol trait.

Epidemiology of triglycerides: A view from Framingham

New analyses from the Framingham Heart Study are presented showing that men and women who have high triglyceride levels (>1.7 mmol/liter) and a low high-density lipoprotein (HDL) level (<1.03 mmol/liter) run a significantly higher rate of coronary artery disease and can be identified, and that this risk group (high triglyceride-low HDL) is, independently of the major risk factors (including low HDL), related to occurrence of coronary artery disease. Further, this trait appears to be common in our society, producing twice as many cases of coronary artery disease during the 14 years of the Framingham study as the next highest disease-producing lipid abnormality. This trait of high triglyceride-low HDL is associated in the medical literature with increased insulin resistance, higher blood sugars (within the normal range), higher uric add levels, hypertension, and centrally mediated obesity. Because total cholesterol in people with these traits may be less than or just slightly greater than 5.2 mmol/liter, they are missed or neglected by most cholesterol screening programs.