Nonfasting Triglyceride Levels Research Articles

Replacing ritonavir by nelfinavir or nelfinavir/saquinavir as part of highly active antiretroviral therapy leads to an improvement of triglyceride levels

In a randomized, parallel arm, open-label study, the effect of switching from ritonavir to either nelfinavir or nelfinavir plus saquinavir as part of a triple antiretroviral regimen was investigated in 16 patients with undetectable HIV-1 loads. Patients continued to use the same nucleoside reverse transcriptase inhibitors as before the switch of protease inhibitor. The period of follow-up was 48 weeks. In all patients HIV-1 load remained undetectable, whereas CD4 cell counts remained stable. Furthermore, lipid markers improved after the switch.

A pilot trial of indinavir, ritonavir, didanosine, and lamivudine in a once-daily four-drug regimen for HIV infection.

To evaluate the tolerance, pharmacokinetics, and virologic and immunologic outcomes of once-daily indinavir, ritonavir, didanosine, and lamivudine in HIV-seropositive individuals. Open-label 24-week pilot study. Ten HIV-seropositive subjects who were either antiretroviral-naive or minimally experienced with short-term single-or dual-nucleoside therapy provided informed consent and were enrolled. All subjects received didanosine (400 mg) 30 to 60 minutes before a meal followed by indinavir (1200 mg), ritonavir (400 mg), and lamivudine (300 mg) concurrent with the aforementioned meal. Safety laboratory tests, including a complete blood cell count and amylase, lipase, liver transaminase, and nonfasting lipid monitoring as well as plasma HIV viral load and CD4+ lymphocyte count, were carried out at monthly intervals. Genotyping was performed at baseline. Pharmacokinetic studies for indinavir and ritonavir were performed at week 8. Nine of 10 subjects completed 24 weeks of therapy. No subject demonstrated primary protease inhibitor mutations at baseline. Toxicities experienced by subjects were typically mild and consistent with those commonly reported for each of the medications, including two cases of hematuria. By week 24, median nonfasting cholesterol and triglyceride levels increased by 49% and 108%, respectively. Median baseline plasma HIV viral load and CD4+ lymphocyte count were 29,292 (4.47 log10) copies/ml and 224 cells/mm3, respectively. Eight of 10 subjects had a plasma HIV viral load of <50 copies/ml by week 12. The 2 subjects with a detectable HIV viral load reached <50 copies/ml by week 28. Median CD4+ lymphocyte counts increased by 193 cells/mm3 at week 24. Indinavir and ritonavir plasma concentrations remained above respective inhibitory and effective concentrations (IC95 and EC50) (uncorrected for protein binding) throughout the 24-hour dosing interval for 6 of 10 and 8 of 10 subjects, respectively. Our pilot study demonstrates excellent virologic suppression despite low minimum protease inhibitor concentrations during a dosing interval in some patients and is supportive of further study.

Hypertriglyceridemia: new insights and new approaches to pharmacologic therapy

I t has long been recognized that elevated triglyceride levels are associated with increased risk for coronary heart disease (CHD). However, it has not been determined whether elevated triglycerides are an independent risk factor for CHD. Thus, the predictive power of triglyceride levels are often reduced or lost when other risk factors, particularly high-density lipoprotein (HDL) cholesterol or diabetes mellitus, are taken into account.1,2 A number of recent findings, however, have provided compelling evidence of the independent association of elevated triglycerides and major coronary events, including a meta-analysis documenting an independent incremental risk of such events with triglyceride elevation.3,4 A persistent caveat is, however, the lack of clear identification of diabetic subjects in these studies. In the large, population-based Munster Heart Study (Prospective Cardiovascular Munster Study [PROCAM]),5 an 8-year follow-up of nearly 5,000 men aged 40 to 65 years without evidence of myocardial infarction (MI) at entry showed that the risk for MI or sudden cardiac death increased markedly as triglyceride levels increased from ,2.26 mmol/L (,200 mg/ dl) to 9.02 mmol/L (799 mg/dl) (Figure 1). (There were too few subjects with triglycerides .9.02 mmol/L to analyze this group.) The association of triglyceride levels with major coronary events remained significant after adjustment for low-density lipoprotein (LDL) and HDL cholesterol levels, and other important coronary risk factors. The association of elevated triglyceride levels (.2.26 mmol/L) with risk of CHD was particularly strong when the LDL/ HDL ratio was .5. This finding corroborated an earlier result from the Helsinki Heart Study,6 a randomized, placebo-controlled primary prevention trial involving .4,000 middle-aged men. Placebo recipients with an LDL/HDL cholesterol ratio .5 and triglyceride level .2.30 mmol/L had a relative risk [RR] for CHD of 3.8. They had the greatest protection with hypolipidemic therapy (gemfibrozil); there was a 71% decrease in CHD events compared with the corresponding placebo subgroup. Similar findings have been reported in the Physicians’s Health Study, a prospective nested case-control study of the effect of nonfasting triglyceride levels and LDL particle diameter on the risk for MI.7 The men who experienced a MI had significantly smaller LDL particle diameter and significantly higher triglyceride levels than control subjects. After adjustment for lipid levels and other coronary risk factors, the significant association of LDL size disappeared, whereas the association with elevated triglycerides remained (RR 1.40 per 1.13 mmol/L [100 mg/dl] increase).7 As in PROCAM,5 the triglyceride/total cholesterol interaction in the Physicians’ Health Study was significant, with the highest risk for MI observed in patients with triglyceride levels and total/HDL cholesterol ratios in the highest tertiles (Figure 2).7 Other recent studies have shown associations between LDL particle size and CHD risk (with some data showing it to be an independent risk factor),8–10 and there is a clear physiologic basis for a link between triglyceride elevation and reduced LDL particle size. The Copenhagen Male Study11 reported 8-year follow-up data showing that elevated fasting triglycerides are a strong and independent risk factor for incident CHD. In 2,906 white men initially free of overt cardiovascular disease, increasing triglycerides were significantly associated with CHD; incidence rates of disease were 4.6% in the lowest triglyceride tertile From the Division of Preventive Medicine and Nutrition, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York. This work was supported in part by an unrestricted educational grant from Parke-Davis, Ann Arbor, Michigan. Manuscript received September 4, 2000; revised manuscript received and accepted December 21, 2000. Address for reprints: Henry N. Ginsberg, MD, Irving Center for Clinical Research, 630 West 168th Street, New York, New York 10032. E-mail: hng1@columbia.edu. FIGURE 1. Incidence of major coronary events per 1000 men according to triglyceride level during 8-year follow-up in the Munster Heart Study (n 5 4,639 men aged 40 to 65 years; 258 events). Reprinted with permission from Assmann et al.5

Dietary fatty acids effects on sucrose-induced cardiovascular syndrome in rats

Cardiovascular disease is one of the leading causes of morbidity and mortality in Mexico. We investigated the effects of omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids on the metabolic syndrome associated with cardiovascular disease in a high-sucrose-fed rat model. The metabolic syndrome-induced rats showed a significant increase in systolic blood pressure, serum insulin, nonfasting serum triglyceride and serum cholesterol levels. Experimental high-sucrose-fed animals received either a n-3 or n-6 enriched diet or a control diet during 6 weeks. Animals fed the n-3 enriched diet had a significant reduction in blood pressure and serum insulin and triglyceride levels. Serum triglyceride levels were also significantly reduced in the n-6-rich diet animals.

Context-dependent and invariant associations between lipids, lipoproteins, and apolipoproteins and apolipoprotein E genotype

Variation in apolipoprotein (apo)E genotypes predicts variation in plasma cholesterol and apoB; however, the context-dependent associations between high density lipoprotein (HDL) cholesterol, apoA-I, triglycerides, and lipoprotein[a] (Lp[a]) and this polymorphism remain unsettled. We genotyped 5,025 women and 4,035 men sampled to represent a white general population in the age range 20 to 80+ years (mean ages 58 and 57 years for women and men, respectively). The relative frequencies of the ε22, ε32, ε42, ε33, ε43, and ε44 genotypes were 0.005, 0.127, 0.027, 0.564, 0.251, and 0.027, respectively. Variations in apoE genotype (in the order listed above) predicted stepwise increases in cholesterol and apoB in both genders (all ANOVAs: P < 0.001), and stepwise decreases in HDL cholesterol and apoA-I in women (both ANOVAs: P < 0.001), but not in men. In both genders ε33 individuals had the lowest levels of nonfasting triglycerides, whereas the highest levels were found in individuals with ε22 and ε44 genotypes (both ANOVAs: P < 0.001). Finally, a stepwise increase in Lp[a] was seen in women (ANOVA: P < 0.001), but not in men. In women, the association between variation in nonfasting triglycerides and Lp[a], and variation in apoE genotypes was mainly seen in those with the highest alcohol consumption, similar to the consumption of most men. Variations in apoE genotype predicted 5% and 11% in women, and 2% and 6% in men, of the total variation in plasma cholesterol and apoB, respectively. Variation in levels of plasma lipoproteins is associated with variation in apoE genotypes in the population at large, with the most pronounced association in women, except for nonfasting triglycerides, for which the association is most pronounced in men. Whereas the associations between variation in plasma cholesterol and apoB and the variation in apoE genotypes seem invariant, the associations with variation in plasma HDL cholesterol, apoA-I, nonfasting triglycerides, and Lp[a] seem context dependent.—Frikke-Schmidt, R., B. G. Nordestgaard, B. Agerholm-Larsen, P. Schnohr, and A. Tybjærg-Hansen. Context-dependent and invariant associations between lipids, lipoproteins, and apolipoproteins and apolipoprotein E genotype. J. Lipid Res. 2000. 41: 1812–1822.

A Prospective Study of Triglyceride Level, Low-Density Lipoprotein Particle Diameter, and Risk of Myocardial Infarction

To test whether a predominance of small, dense low-density lipoprotein (LDL) particles and elevated triglyceride levels are independent risk factors for myocardial infarction (MI). Nested case-control study with prospectively collected samples. Prospective cohort study. Blood samples were collected at baseline (85% nonfasting samples) from 14916 men aged 40 to 84 years in the Physicians' Health Study. Myocardial infarction diagnosed during 7 years of follow-up. Cases (n=266) had a significantly smaller LDL diameter (mean [SD], 25.6 [0.9] nm) than did controls (n=308) matched on age and smoking (mean [SD], 25.9 [8] nm; P<.001). Cases also had higher median triglyceride levels (1.90 vs 1.49 mmol/L [168 vs 132 mg/dL]; P<.001). The LDL diameter had a high inverse correlation with triglyceride level (r=-0.71), and a high direct correlation with high-density lipoprotein cholesterol (HDL-C) level (r=0.60). We observed a significant multiplicative interaction between triglyceride and total cholesterol (TC) levels (P=.01). After simultaneous adjustment for lipids and a variety of coronary risk factors, LDL particle diameter was no longer a statistically significant risk indicator, with a relative risk (RR) of 1.09 (95% confidence interval [CI], 0.85-1.40) per 0.8-nm decrease. However, triglyceride level remained significant with an RR of 1.40 (95% CI, 1.10-1.77) per 1.13 mmol/L (100-mg/dL) increase. The association between triglyceride level and MI risk appeared linear across the distribution; men in the highest quintile had a risk about 2.5 times that of those in the lowest quintile. The TC level, but not HDL-C level, also remained significant, with an RR of 1.80 (95% CI, 1.44-2.26) per 1.03-mmol/L (40-mg/dL) increase. These findings indicate that nonfasting triglyceride levels appear to be a strong and independent predictor of future risk of MI, particularly when the total cholesterol level is also elevated. In contrast, LDL particle diameter is associated with risk of MI, but not after adjustment for triglyceride level. Increased triglyceride level, small LDL particle diameter, and decreased HDL-C levels appear to reflect underlying metabolic perturbations with adverse consequences for risk of MI; elevated triglyceride levels may help identify high-risk individuals.

Altered lipid profile after Kawasaki syndrome.

Delineation of lipid values in children after Kawasaki syndrome is important because of the predilection of this disease for the coronary arteries. We measured plasma concentrations of total cholesterol, high density lipoprotein (HDL) cholesterol, and triglycerides using enzymatic methods in 105 patients with a history of Kawasaki syndrome. Measurements were obtained during six time periods: 10 days or less, 11-31 days, 1-3 months, 3-12 months, 1-3 years, and more than 3 years. Total cholesterol was depressed in the first interval (122.0 +/- 19.8 mg/dl, mean +/- SD), but the mean values were normal in all periods after clinical recovery (overall mean, 149.0 +/- 24.0 mg/dl). High density lipoprotein cholesterol was also depressed in the first interval (15.2 +/- 9.9 mg/dl); although high density lipoprotein cholesterol increased significantly with duration since disease onset (p less than 0.001), it remained significantly lower than expected (p less than 0.001), even in the latest interval (47.2 +/- 10.9 mg/dl). Nonfasting triglyceride levels were high (162.5 +/- 63.4 mg/dl) in the first interval and then diminished steadily with time, but this relation did not achieve statistical significance. We compared adjusted lipid levels (z scores) of 46 Kawasaki patients after clinical recovery with those of their parents; patients had similar total cholesterol levels but significantly lower high density lipoprotein cholesterol levels (p = 0.021 for mothers, p = 0.001 for fathers). Mean high density lipoprotein cholesterol after clinical recovery tended to be lower in patients with persistent coronary abnormalities than in those without such lesions (p = 0.085). Kawasaki syndrome is associated with important abnormalities in lipid metabolism. Continued long-term surveillance of this population is necessary to monitor lipid levels and their relation to future development of coronary atherosclerosis.

Concomitants of excess coronary deaths--major risk factor and lifestyle findings from 10,359 men and women in the Scottish Heart Health Study.

The Scottish Heart Health Study is a study of lifestyle and coronary heart disease risk factors in 10,359 men and women aged 40-59 years, in 22 districts of Scotland. The study was conducted during 1984-86, when Scotland had the highest national coronary heart disease mortality reported by the World Health Organisation. A self-completed questionnaire, complemented by a 40 minute visit to a survey clinic, staffed by nurses, enabled the classical major risk factors and some more newly described ones to be measured. The study emphasised quality control and representativeness, and incorporated a World Health Organisation protocol for measurement of key items to allow comparisons in place and time, and therefore also to provide a definitive baseline against which interventions can be assessed. This paper describes the overall findings. Current cigarette smokers constitute 39% of men and 38% of women, higher levels than those reported in England but lower than previous Scottish reports. Mean blood pressure levels were 134/84 mmHg for men and 131/81 mmHg in women, lower than in British studies of the 1960s and 1970s. Mean body mass index levels, 26.1 Kg/m2 in men and 25.7 Kg/m2 in women, were not high by international standards. However, mean serum cholesterol levels were 6.4 mmol/l in men and 6.6 mmol/l in women--as high as those in previous British studies and high by international standards. Levels of high density lipoprotein cholesterol, non-fasting triglycerides and fibrinogen are also reported. Physical activity both at work and in leisure time was low.(ABSTRACT TRUNCATED AT 250 WORDS)

Time-dependent pharmacokinetics and toxicity of cyclosporine.

Although the circadian pattern of cyclosporine (CSA) pharmacokinetics and toxicity has been described previously in both animal and clinical studies, the mechanism of this action is unknown. The present study compared the pharmacokinetics and experimental nephrotoxicity of chronic CSA in both the genetically-hyperlipidemic rat model and the lean litter-mate. Once daily dosing (25 mg/kg via gavage) was either at the start of the active (1900) or inactive (0700) cycle (Nov 1987 to Jan 1988). Serial serum samples following the final dose were assayed by both polyclonal (nonspecific) and monoclonal (specific for parent CSA) RIA. Renal toxicity was assessed by 24-hr creatinine clearances, fractional clearances of sodium and potassium, and inulin clearances (CIN). Despite a greater than 2-fold increase in serum CSA concentrations, there were no changes in renal function in obese rats dosed at the start of the active period compared to the inactive period. Furthermore, mean CIN of the lean group administered drug at the start of the active period was not significantly different from time-matched placebo-treated lean rats. However, there was an 80% drop in CIN in rats treated with CSA at the start of the inactive period compared to control group. There were no differences in electrolyte handling. Insulin concentrations, independent of time of dosing, were markedly elevated in obese rats dosed CSA compared to placebo-treated obese or both lean groups. Serum triglyceride levels were significantly correlated with pharmacokinetic parameters of total but not parent CSA. In summary, significant differences in toxicity were observed due to time of dosing and lipid profiles. Although the mechanism of this action remains unclear, it appears that increased non-fasting serum triglyceride levels following the active period most likely reduced CSA distribution into kidney tissue preventing the dose-limiting nephrotoxicity.

Charcoal sorbent-induced hypolipidemia in uremia and diabetes

Rats with hyperlipidemia associated with streptozotocin-induced diabetes or azotemia after subtotal nephrectomy were administered a diet containing 5% activated charcoal. Significant lowering of nonfasting serum cholesterol and triglyceride levels resulted. Charcoal-feeding also altered the abnormal high density lipoprotein electrophoresis pattern of diabetic rats toward normal.