Low-density Lipoprotein Triglyceride Levels Research Articles

Advanced Quantitative Lipoprotein Characteristics Do Not Relate to Healthy Dietary Patterns in Adults from a Mediterranean Area.

We aimed to assess the potential relationship between dietary patterns (i.e., Mediterranean diet and healthy eating) and the advanced lipoprotein profile (ALP) in a representative cohort of the Mediterranean population. Thus, ALP data from 1142 participants, including 222 with type 1 (19.4%) and 252 type 2 diabetes (22.1%), and 668 subjects without diabetes were used to study cross-sectional associations between quantitative characteristics of lipoproteins and adherence to the Mediterranean diet. The alternate Mediterranean diet score (aMED) and the alternate healthy eating index (aHEI) were calculated. The ALP was determined by nuclear magnetic resonance (NMR) spectrometry. Bivariable and multivariable analyses were performed. Participants in the third tertile of the aMED showed higher levels of low-density lipoprotein triglycerides (LDL-TG) (mean (SD) 17.5 (5.0); p = 0.037), large high-density lipoprotein particles (HDL-P) (0.3 (0.1); p = 0.037), and medium low-density lipoprotein particles (LDL-P) (434.0 (143.0); p = 0.037). In comparison with participants in the second and first tertiles of the aHEI, participants in the third tertile had higher levels of LDL-TG (17.7 (5.0); p = 0.010), and large HDL-P (0.3 (0.1); p = 0.002), IDL-C (11.8 (5.0); p = 0.001), intermediate-density lipoprotein triglycerides (IDL-TG) (13.2 (4.2); p < 0.001), LDL-TG (17.7(5.0); p = 0.010), high-density lipoprotein triglycerides (HDL-TG) (14.5 (4.4); p = 0.029,) large HDL-P (0.3 (0.1); p = 0.002) and very–low-density lipoprotein particles (VLDL-P) size (42.1 (0.2); p = 0.011). The adjusted-multivariable analysis for potential confounding variables did not show any association between the lipoproteins and dietary patterns (i.e., aMED and aHEI). In conclusion, none of the quantitative characteristics of lipoproteins were concomitantly associated with the extent of adherence to the Mediterranean diet measured using the aMED or aHEI scores in the studied population. Our findings also revealed that people with the highest adherence were older, had a higher body mass index (BMI) and more frequently had dyslipidemia, hypertension, or diabetes than those with the lowest adherence to the Mediterranean diet (MDiet). Thus, further research may be needed to assess the potential role of the dietary pattern on the ALP.

Abstract 15533: Long-term Prognostic Utility of Low-density Lipoprotein (ldl) Triglyceride in Real-world Patients With Coronary Artery Disease and Diabetes or Prediabetes

Introduction: Recent guidelines highlighted the association between atherosclerosis and triglyceride-enriched lipoproteins in patients with impaired glucose metabolism. However, evidence from prospective studies for long-term prognostic utility of low-density lipoprotein triglyceride (LDL-TG) in real-world patients with prediabetes (Pre-DM) or diabetes mellitus (DM) and coronary artery disease (CAD) is currently not available. Hypothesis: LDL-TG had impact on major adverse cardiovascular events (MACEs) in patients with stable CAD under different glucose metabolism status. Methods: A total of 4381 patients with CAD were consecutively enrolled and categorized according to both status of glucose metabolism [DM, Pre-DM, normal glycaemia regulation (NGR)] and tertiles of LDL-TG. Plasma LDL-TG level was measured by an automated homogeneous assay. All subjects were followed up for the occurrence of MACEs. Results: During a median 5.1 (interquartile range 3.9 to 5.9) year follow-up, 507 (11.6%) MACEs occurred. Cubic spline models showed a significant association between LDL-TG and MACEs in DM and Pre-DM but not in NGR. When the combined effect of elevated LDL-TG and glucose disorders was considered for risk stratification, the medium tertile of LDL-TG plus DM, the highest tertile of LDL-TG plus Pre-DM or plus DM subgroups were associated with significantly higher risk of MACEs after adjustment of confounders including triglyceride[hazard ratios (95% confidence intervals): 1.843(1.149-2.955), 1.828(1.165-2.867), 2.212(1.396-3.507), all p&lt;0.05]. Moreover, adding LDL-TG in the original model increased the C-statistic from 0.687 to 0.704 (ΔC-statistic=0.016, p=0.028) and from 0.734 to 0.749 (ΔC-statistic =0.014, p=0.002) in Pre-DM and DM respectively. Conclusions: In this longitudinal cohort study on real-world practice, higher LDL-TG was associated with worse outcomes among Pre-DM and DM patients with stable CAD.

Long-term prognostic utility of low-density lipoprotein (LDL) triglyceride in real-world patients with coronary artery disease and diabetes or prediabetes

BackgroundRecent guidelines highlighted the association between atherosclerosis and triglyceride-enriched lipoproteins in patients with impaired glucose metabolism. However, evidence from prospective studies for long-term prognostic utility of low-density lipoprotein triglyceride (LDL-TG) in real-world patients with prediabetes (Pre-DM) or diabetes mellitus (DM) and coronary artery disease (CAD) is currently not available. The aim of the present study was to evaluate the impact of LDL-TG on major adverse cardiovascular events (MACEs) in patients with stable CAD under different glucose metabolism status.MethodsA total of 4381 patients with CAD were consecutively enrolled and plasma LDL-TG level was measured by an automated homogeneous assay. They were categorized according to both status of glucose metabolism [DM, Pre-DM, normal glycaemia regulation (NGR)] and tertiles of LDL-TG. All subjects were followed up for the occurrence of MACEs.ResultsDuring a median of 5.1 (interquartile range 3.9 to 5.9) years’ follow-up, 507 (11.6%) MACEs occurred. Cubic spline models showed a significant association between LDL-TG and MACEs in DM and Pre-DM but not in NGR. When the combined effect of elevated LDL-TG and glucose disorders was considered for risk stratification, the medium tertile of LDL-TG plus DM, and the highest tertile of LDL-TG plus Pre-DM or plus DM subgroups were associated with significantly higher risk of MACEs after adjustment of confounders including triglyceride [hazard ratios (95% confidence intervals): 1.843 (1.149–2.955), 1.828 (1.165–2.867), 2.212 (1.396–3.507), all p < 0.05]. Moreover, adding LDL-TG into the original model increased the C-statistic from 0.687 to 0.704 (∆C-statistic = 0.016, p = 0.028) and from 0.734 to 0.749 (∆C-statistic = 0.014, p = 0.002) in Pre-DM and DM, respectively.ConclusionsIn this longitudinal cohort study on real-world practice, higher LDL-TG was associated with worse outcomes among Pre-DM and DM patients with stable CAD.

Low-Density Lipoprotein (LDL)-Triglyceride and Its Ratio to LDL-Cholesterol as Diagnostic Biomarkers for Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease, but it is difficult to distinguish its pathogenic phenotype, nonalcoholic steatohepatitis (NASH), from nonalcoholic fatty liver (NAFL) without a liver biopsy. We analyzed serum lipids, including low-density lipoprotein triglyceride (LDL-TG), to elucidate their usefulness for diagnosing NASH. Serum samples obtained from 35 NASH and 9 NAFL biopsy-confirmed patients and 6 healthy volunteers (HLT) were studied for 13 lipid-related markers and compared between HLT, NAFL, and NASH groups. The relationship between histological findings and the lipid markers was also analyzed. There were significant differences in triglyceride, LDL-TG, the ratio of LDL-TG to the LDL-cholesterol (LDL-TG/LDL-C), small dense LDL-C, and apolipoprotein E between the three groups. Among the 5 lipid components, serum LDL-TG level and the ratio of LDL-TG to the LDL-cholesterol (LDL-TG/LDL-C) were significantly elevated in NASH. The median concentrations of LDL-TG in HLT, NAFL, and NASH were 9, 15, and 20 mg/dL (P < 0.001), and those of LDL-TG/LDL-C were 0.097, 0.102, and 0.173 (P < 0.001), respectively. Although the degree of steatosis was not correlated with the LDL-TG/LDL-C, the ratio was significantly higher in patients with lobular inflammation (P = 0.071), ballooning (P = 0.031), and fibrosis (P < 0.001). The area under the receiver operating characteristic curve of the ratio for distinguishing NASH from NAFL was 0.857. The rest of studied markers showed no significant utility. Serum LDL-TG levels and the LDL-TG/LDL-C ratio might serve as simple and noninvasive diagnostic biomarkers for NASH.

Regional Adiposity, Adipokines, and Insulin Resistance in Type 2 Diabetes

The prevalence of obesity is rapidly increasing worldwide, and obesity is a well-known risk factor for type 2 diabetes involving insulin resistance. In recent decades, marked environmental and lifestyle changes have occurred and led to increased obesity and obesity-related cardiovascular diseases in Korea. Obesity is a heterogeneous condition, and body fat location may have a more important impact on the development of cardiovascular risk factors and related diseases than total excess adiposity [1]. Excessive accumulation of visceral adipose tissue causes low-grade chronic inflammation, dyslipidemia, insulin resistance, type 2 diabetes, and cardiovascular diseases. Recently, regional distribution of fat mass seems to correlate with risk level; fat mass in the lower extremities has a protective effect against insulin resistance and dyslipidemia [2,3]. Gluteofemoral fat, as measured by thigh circumference, hip circumference or leg adipose tissue mass, is independently associated with low total- and low-density lipoprotein triglyceride levels and high high-density lipoprotein cholesterol levels. A small amount of adiposity in the lower extremities is associated with higher insulin resistance and unfavorable glucose level [4]. Increased leg adipose tissue mass is associated with lower aortic calcification and arterial stiffness as well as with a decreased progression of aortic calcification [5,6]. Hip circumference was positively associated with plasma ascorbic acid level, an anti-oxidant marker, and might contribute to endothelial protection [7]. There are a few possible mechanisms to explain the protective role of lower extremity fat deposition. First, subcutaneous adipose tissue acts as a buffer for the daily influx of dietary lipids, protecting other tissues from a lipid overflow associated with lipotoxicity [8]. Second, there is differential secretion of adipose tissue-related proteins, called adipokines. Gluteofemoral adipose tissue could contribute to a protective adipokine profile by secreting more beneficial adipokines and fewer inflammatory molecules compared with abdominal fat. However, even though the negative association between lower extremity fat mass and insulin resistance is established, it is still unclear whether the lower extremity fat mass per se exerts beneficial effects on glucose metabolism independent of the mere absence of trunk fat. Several metabolic characteristics of adipocyte size and location might influence their metabolic consequences. Adipocytes in the lower extremities are larger, less sensitive to lipolytic stimuli, and more sensitive to insulin compared with those in the abdomen [9,10]. Although increases in adipocyte number and size can occur with increasing obesity level, larger adipocytes are also associated with higher secretion of adipokines which favorably influence insulin resistance [11]. The large adipocytes in the femoral region can result in higher insulin sensitivity and increased secretion of metabolically beneficial adipokines. This combination of factors may partially offset the detrimental influence of abdominal adiposity and offer metabolic defense against additional glucose dysregulation [12]. Trunk to leg fat ratio may have a different impact according to age and gender. With aging, this ratio increased more markedly in women than men, because the women's lower extremity fat mass remained much the same at all ages. According to the literature, the relationship between leg and trunk fat mass is associated with the risk of insulin resistance and dyslipidemia in obese women, both before and after menopause [2]. Adipokines are biomarkers for fat mass, fat distribution, adipose tissue function, liver fat content, insulin sensitivity, and subclinical chronic inflammation associated with metabolic diseases. Circulating biomarkers for abdominal fat accumulation include adiponectin, retinol binding protein-4 (RBP4), vaspin, chemerin, progranulin, and fetuin-A and others [13]. RBP4 is predominantly secreted from the liver, but is also expressed in adipocytes. Increased RBP4 expression in visceral adipose induces the increased serum RBP4 levels in tissues of patients with insulin resistance [14]. Adiponectin and letptin are more likely to be associated with impaired insulin sensitivity or insulin secretion, while RBP4 is associated with adverse fat distribution and insulin resistance. In a recent issue of Diabetes & Metabolism Journal, Kim et al. [15] presented an article regarding the relationship of absolute or relative adiposity to insulin resistance in obese women with type 2 diabetes. They measured the trunk fat mass and lower extremities fat mass and found that relative adiposity (defined by peripheral fat mass/trunk fat mass) was correlated with insulin resistance. They also observed the positive association of total, central, and peripheral fat mass with adiponectin and leptin levels, but not with RBP4 level. The regional adiposity was positively associated with serum adiponectin level and negatively associated with RBP4 level, suggesting the favorable effect of regional adiposity. However, regional adiposity was also positively associated with insulin resistance. Although the authors did not discuss these conflicting results, they may be due to the age distribution of the study subject's considering that peripheral fat mass does not change with age, while visceral adiposity is markedly increased after menopause. Additional studies in various conditions such as age, gender, obesity degree, and underlying disease condition will be helpful for understanding the metabolic effects of regional adiposity.

Partnership of PGC-1α and HNF4α in the Regulation of Lipoprotein Metabolism

Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator involved in several aspects of energy metabolism. It is induced or activated under different stimuli in a highly tissue-specific manner and subsequently partners with certain transcription factors in those tissues to execute various biological programs. In the fasted liver, PGC-1alpha is induced and interacts with hepatocyte nuclear factor 4alpha (HNF4alpha) and other transcription factors to activate gluconeogenesis and increase hepatic glucose output. Given the broad spectrum of liver genes responsive to HNF4alpha, we sought to determine those that were specifically targeted by the combination of PGC-1alpha and HNF4alpha. Coexpression of these two molecules in murine stem cells reveals a high induction of mRNA for apolipoproteins A-IV and C-II. Forced expression of PGC-1alpha in mouse and human hepatoma cells increases the mRNA of a subset of apolipoproteins implicated in very low density lipoprotein and triglyceride metabolism, including apolipoproteins A-IV, C-II, and C-III. Coactivation of the apoC-III/A-IV promoter region by PGC-1alpha occurs through a highly conserved HNF4alpha response element, the loss of which completely abolishes activation by PGC-1alpha and HNF4alpha. Adenoviral infusion of PGC-1alpha into live mice increases hepatic expression of apolipoproteins A-IV, C-II, and C-III and increases serum and very low density lipoprotein triglyceride levels. Conversely, knock down of PGC-1alpha in vivo causes a decrease in both apolipoprotein expression and serum triglyceride levels. These data point to a crucial role for the PGC-1alpha/HNF4alpha partnership in hepatic lipoprotein metabolism.

Lipoprotein alterations in hemodialysis: Differences between diabetic and nondiabetic patients

Both renal failure and type 2 diabetes may contribute synergistically to the dyslipemia of diabetic renal failure with the development of atherosclerosis as the possible consequence. It has not yet been conclusively evaluated whether diabetic patients with end-stage renal failure under maintenance hemodialysis (HD) show accentuated alterations in plasma lipids and lipoproteins in comparison to nondiabetics under HD. These abnormalities would involve hepatic lipase activity and the regulation of triglyceride-rich lipoprotein metabolism. The purpose of the present study was to evaluate whether type 2 diabetic patients undergoing HD exhibited a lipid-lipoprotein profile different from that of nondiabetic hemodialyzed patients. We compared plasma lipids, apoprotein (apo) A-I and B, and lipoprotein parameters among 3 groups: 25 type 2 diabetics, 25 nondiabetics, both undergoing HD, and 20 healthy control subjects. Intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) were isolated by sequential ultracentrifugation. Hepatic lipase activity was measured in postheparin plasma. Both groups of HD patients showed higher triglyceride and IDL cholesterol (P <.001), and lower high-density lipoprotein (HDL) cholesterol (P <.01) and apo A-I (P <.001) levels compared to the control group, even after adjustment for age and body mass index (BMI). However, no differences were found in lipid, lipoprotein, and apoprotein concentrations between diabetic and nondiabetic HD patients, except for high LDL triglyceride content of diabetic HD patients (P <.01). Nondiabetics undegoing HD also presented higher LDL triglyceride levels than controls (P <.05). LDL triglyceride correlated with plasma triglycerides (r = 0.51, P <.001). A lower LDL cholesterol/apo B ratio was found in each group of HD patients in comparison to controls (P <.02). Comparing the diabetic and nondiabetic patients, hepatic lipase activity remained unchanged, but significantly lower than control subjects (P <.001). Hepatic lipase correlated with log-triglyceride (r = −0.31, P <.01), IDL cholesterol (r = −0.41, P <.001), and LDL triglyceride (r = −0.32, P <.01). In conclusion, both diabetic and nondiabetic HD patients shared unfavorable alterations in lipid-lipoprotein profile not different between them but different from a healthy control group. The only difference between the groups of HD patients was a significant LDL triglyceride enrichment, which correlated negatively with hepatic lipase activity. Lipoprotein abnormalities in HD patients would enhance their risk for the development of atherosclerosis. Copyright 2003, Elsevier Science (USA). All rights reserved.

Analysis of the Ileal Bile Acid Transporter Gene, SLC10A2 , in Subjects With Familial Hypertriglyceridemia

Familial hypertriglyceridemia (FHTG), a disease characterized by elevated plasma very low density lipoprotein triglyceride levels, has been associated with impaired intestinal absorption of bile acids. The aim of this study was to test the hypothesis that defects in the active ileal absorption of bile acids are a primary cause of FHTG. Single-stranded conformation polymorphism analysis was used to screen the ileal Na(+)/bile acid cotransporter gene (SLC10A2) for FHTG-associated mutations. Analysis of 20 hypertriglyceridemic patients with abnormal bile acid metabolism revealed 3 missense mutations (V98I, V159I, and A171S), a frame-shift mutation (646insG) at codon 216, and 4 polymorphisms in the 5' flanking sequence of SLC10A2. The SLC10A2 missense mutations and 5' flanking sequence polymorphisms were not correlated with bile acid production or turnover in the hypertriglyceridemic patients and were equally prevalent in the unaffected control subjects. In transfected COS cells, the V98I, V159I, and A171S isoforms all transported bile acids similar to the wild-type SLC10A2. The 646insG frame-shift mutation abolished bile acid transport activity in transfected COS cells but was found in only a single FHTG patient. These findings indicate that the decreased intestinal bile acid absorption in FHTG patients is not commonly associated with inherited defects in SLC10A2.

Cardiovascular risk factors associated with insulin resistance cluster in families with early-onset coronary heart disease.

Coronary heart disease (CHD) is a multifactorial disease caused by environmental and genetic factors. CHD clusters in families, but it is not known whether susceptibility to early-onset CHD is associated with the clustering of cardiovascular risk factors. Therefore, we determined the levels of cardiovascular risk factors among siblings with and without severe early-onset CHD drawn from 101 Finnish families. Probands with CHD, compared with their siblings without CHD, had, respectively, higher 2-hour insulin levels (475.7 versus 331.8 pmol/L, P=0.011) and 2-hour insulin areas (796.2 versus 640.4 pmol/L per hour, P=0.031) in an oral glucose tolerance test, lower high density lipoprotein cholesterol levels (1.22 versus 1.42 mmol/L, P=0.001), higher total triglyceride levels (1.91 versus 1.68 mmol/L, P=0.018), higher very low density lipoprotein triglyceride levels (1.25 versus 1.06 mmol/L, P=0.011), and higher fibrinogen levels (3.8 versus 3.4 g/L, P= 0.008). No significant differences were found in cardiovascular risk factors between affected siblings and probands with CHD. Environmental or lifestyle factors did not differ between siblings with or without early-onset CHD. We conclude that cardiovascular risk factors associated with the insulin resistance syndrome (hyperinsulinemia, low high density lipoprotein cholesterol, high total and very low density lipoprotein triglycerides, and high fibrinogen) are likely to contribute indirectly to early-onset CHD.

Progression of coronary artery disease in young male post-infarction patients is linked to disturbances of carbohydrate and lipoprotein metabolism and to impaired fibrinolytic function.

To assess determinants of coronary artery disease progression in men with previous myocardial infarction. A total of 102 unselected non-diabetic Swedish men (age 40.4 +/- 3.6, range 23-44 years) entered the study 3-6 months after a first myocardial infarction. The programme included metabolic and haemostatic investigations and routine coronary angiography at baseline, followed by re-angiography 5 years later. Of the original cohort, 76 patients underwent a second angiogram. Separate semiquantitative scoring systems were used for diffuse coronary atherosclerosis and distinct stenoses in 15 proximal coronary segments. Smoking, global severity of coronary atherosclerosis and presence of multi-vessel disease at baseline (P < 0.001) characterized patients with severe progression of both diffuse and focal lesions. Higher plasma levels of low density lipoprotein cholesterol (P < 0.01) and low density lipoprotein triglycerides (P < 0.05), a lower plasma high density lipoprotein2 cholesterol level (P < 0.05) and higher plasma plasminogen activator inhibitor-1 activity (P < 0.05), together with a high baseline stenosis score (P < 0.001) characterized patients with severe progression of coronary atherosclerosis. On the other hand, more pronounced fasting and post-prandial glycaemia (P < 0.05), together with higher plasma plasminogen activator inhibitor-1 activity (P < 0.01) characterized severe progressors with respect to coronary stenosis. Multivariate analysis identified the presence of multi-vessel disease as an independent predictor of progression of both coronary atherosclerosis (P = 0.008) and stenoses (P = 0.007), whereas a high low density lipoprotein triglyceride level (P < 0.01) was independently related to progression of coronary atherosclerosis and a high fasting glucose level (P = 0.02) to progression of coronary stenoses. Disturbances in carbohydrate and lipoprotein metabolism and impaired fibrinolytic function are associated with progression of coronary artery disease in young male post-infarction patients.

High-density lipoprotein: Relations to metabolic parameters and severity of coronary artery disease

The regulation of plasma high-density lipoprotein (HDL) cholesterol level by the joint influence of plasma lipoprotein lipids, lipoprotein lipase (LPL), hepatic lipase (HL), cholesteryl ester transfer protein (CETP), oral glucose tolerance, and postload plasma insulin and proinsulin levels was investigated in young postinfarction patients and healthy population—based control subjects. In addition, the association between HDL cholesterol and the number and severity of coronary stenoses previously reported in this cohort of young postinfarction patients was further investigated by analyzing the determinants and angiographic relations of HDL subclasses measured by gradient gel electrophoresis. The following parametres showed significant univariate relations with HDL choleterol level in the patient group: very—low-density lipoprotein (VLDL) cholesterol and triglyceride, low-density lipoprotein (LDL) triglyceride, and postload plasma insulin concentrations, preheparin plasma LPL mass, and postheparin plasma HL activity. In the control group, significant correlations with HDL cholesterol concentration in addition to those noted among the patients were found for body mass index (BMI), LDL cholesterol level postload plasma intact proinsulin concentration, and LPL activity in postheparin plasma. In contrast to the patients, no significant relations were noted for postload plasma insulin level and preheparin plasma LPL mass. Multiple stepwise regression analysis showed that 42% of the variability of HDL cholesterol in the patients could be accounted for by VLDL cholesterol concentration (29%), LDL triglyceride level (7%), and postheparin plasma HL activity (6%), whereas the corresponding figure in controls was 35% (VLDL cholesterol concentration [9%] and postheparin plasma HL activity [26%]). The strength of the relationships of HDL cholesterol and HDL subclasses to the coronary stenosis score was similar and statistically significant ( r = .25 to .36). When the metabolic parameters that correlated with HDl cholesterol and HDL subclass concentrations in univariate analysis were used as covariates, all relations to the coronary stenosis score disappeared. This clearly indicates that the influence of triglyceride-rich lipoproteins and lipolytic enzymes needs to be considered when assessing the association between HDL cholesterol and coronary artery disease (CAD).

Ciprofibrate versus gemfibrozil in the treatment of primary hyperlipidaemia

The efficacy and short-term safety of ciprofibrate and gemfibrozil were compared in a 12-week, double-blind, randomised study. One-hundred-and-ten primary, type II hyperlipidaemic patients were randomised to receive either ciprofibrate, 100 mg/day once daily, or gemfibrozil, 1200 mg/day twice daily. Treatment efficacy was measured by complete lipid and lipoprotein profiles and by plasma fibrinogen levels. Tolerability was assessed by drug compliance and safety was evaluated by laboratory safety parameters, physical examination and evaluation of adverse events. Mean reductions of plasma TC and low density lipoprotein cholesterol levels were similar in the two treatment groups. In contrast, the mean relative reduction of plasma total triglyceride and very low density lipoprotein triglyceride levels was significantly higher in patients receiving Gmfbrozil as compared with ciprofibrate ( P < 0.05). The absolute reduction of the last two parameters was higher in the ciprofibrate group compared with the gemfibrozil group; furthermore, the mean concentrations of these parameters were within normal limits at the end of the study. The clinical relevance of the statistically significant difference mentioned should, therefore, be questioned. Ciprofibrate therapy significantly reduced (−8.33%) and gemfibrozil therapy significantly increased (+6.97%) plasma fibrinogen levels ( P < 0.0001 compared with baseline in each case). Adverse events were rare, mild and equally distributed between the two treatment groups. Laboratory safety parameters did not show any significant changes. Ciprofibrate and Gmfbrozil have comparable short-term efficacy and safety profiles. Furthermore, ciprofibrate reduces fibrinogen levels and benefits from a once daily regimen.

Lowering of triglycerides by gemfibrozil affects neither the glucoregulatory nor antilipolytic effect of insulin in Type 2 (non-insulin-dependent) diabetic patients

Hypertriglyceridaemia and insulin resistance are closely associated but it is unknown whether hypertriglyceridaemia per se contributes to insulin resistance. In the present study we examined whether gemfibrozil, by lowering triglyceride levels, improves the glucoregulatory and antilipolytic action of insulin in Type 2 (non-insulin-dependent) diabetes mellitus. Twenty patients were randomly allocated to receive either placebo or gemfibrozil 1200 mg daily for 12 weeks in a double-blind study. Very low density lipoprotein triglyceride levels decreased in the gemfibrozil group by 42 +/- 12% (p < 0.01). Gemfibrozil had no effect on the diurnal concentration of non-esterified fatty acids (NEFA). At the randomization HbA1c levels were comparable (7.6 +/- 0.3 vs 7.8 +/- 0.2%, NS) and increased slightly both in the gemfibrozil (8.2 +/- 0.4%, p < 0.05) and placebo groups (8.0 +/- 0.3%, NS). Pre- and post-treatment diurnal glucose and insulin concentrations remained unchanged. Basal pre- and post-treatment hepatic glucose production rates were comparable in both groups and similarly suppressed by insulin. Rate of whole body glucose disposal during a low-dose insulin infusion (serum insulin -90 pmol/l) (pre- vs post-gemfibrozil 11.9 +/- 1.1 vs 11.1 +/- 0.7, pre- vs post-placebo 9.9 +/- 1.1 vs 10.8 +/- 0.8 mumol.kg-1.min-1, NS for both) and a high-dose insulin infusion (serum insulin approximately 500 pmol/l) (16.2 +/- 1.7 vs 17.7 +/- 2.7, 17.1 +/- 4.2 vs 17.4 +/- 2.9 mumol.kg-1 x min-1, respectively, NS for both) remained unchanged. Basal pre- and post-treatment NEFA turnover rates were comparable in both groups and similarly suppressed by insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Early abnormalities in coronary heart disease risk factors in relatives of subjects with non-insulin-dependent diabetes.

Coronary heart disease risk factor levels were studied in 184 first-degree relatives (sisters and brothers) of non-insulin-dependent diabetic subjects (124 relatives with normoglycemia, 34 relatives with impaired glucose tolerance [IGT], and 26 relatives with non-insulin-dependent diabetes mellitus [NIDDM]) and in 215 relatives of nondiabetic subjects (194 relatives with normoglycemia and 21 relatives with IGT). Subjects with IGT exhibited the highest insulin responses to an oral glucose load. Systolic blood pressure was significantly higher; serum high density lipoprotein cholesterol level was significantly lower; and total, low density lipoprotein, and very low density lipoprotein triglyceride levels were higher in the relatives with a family history of diabetes who had IGT or NIDDM than in the normoglycemic relatives without a family history of diabetes. These abnormal changes were not seen in normoglycemic relatives or relatives with IGT who had no family history of NIDDM. Thus, in relatives of diabetics, abnormal glucose tolerance seems to induce changes in cardiovascular heart disease risk factor levels that are similar to those observed in NIDDM. Therefore, a family history of diabetes adds substantially to the risk for atherosclerosis, particularly in subjects with IGT.

Effects of a monounsaturated rapeseed oil and a polyunsaturated sunflower oil diet on lipoprotein levels in humans.

The effects of high oleic acid rapeseed oil compared with polyunsaturated fats on serum lipoprotein levels are largely unknown. Therefore, we fed 30 women and 29 men a baseline diet rich in saturated fat, which was followed by a diet rich in high oleic and low erucic acid rapeseed oil (total energy content of fat, 38%; saturates, 12.4%; monounsaturates, 16%; n-6 polyunsaturates, 6%; and n-3 polyunsaturates, 2%) and one rich in sunflower oil (total energy content of fat, 38%; saturates, 12.7%; monounsaturates, 10%; n-6 polyunsaturates, 13%; and n-3 polyunsaturates, 0%). The oils were incorporated into mixed natural diets that were dispensed in a random order for 3.5 weeks each in a blinded crossover design. The diet composition was confirmed by analysis of duplicate diets. Both test diets reduced serum total cholesterol (TC) and low density lipoprotein (LDL) cholesterol levels from baseline, the monounsaturated rapeseed oil diet more than the polyunsaturated sunflower oil diet (TC: -15% versus -12%, p less than 0.01; LDL cholesterol: -23% versus -17%, p less than 0.01). Very low density lipoprotein (VLDL) cholesterol and total, VLDL, and LDL triglyceride levels were lower during the sunflower oil diet compared with the rapeseed oil diet. Total high density lipoprotein (HDL) cholesterol levels remained unchanged by both diets. The consumption of rapeseed oil resulted in a more favorable HDL2 to LDL cholesterol ratio (0.43 +/- 0.19 versus 0.39 +/- 0.18, p less than 0.01) and an apolipoprotein A-I to B ratio (3.0 +/- 1.4 versus 2.4 +/- 1.6, p less than 0.001) than did the sunflower oil.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoproteins and Acute Phase Response during Acute Infection. Interrelationships between C-reactive Protein and Serum Amyloid-A Protein and Lipoproteins

To study the interrelations between the changes of acute phase proteins and those of serum lipoproteins in acute infections we measured the concentrations of different lipoproteins, serum amyloid-A protein and C-reactive protein and activities of lipoprotein lipase and hepatic lipase during acute and convalescence phase and after complete recovery in 64 patients with infectious diseases (30 with viral infection and 34 with bacterial infection). The maximal decrements of both low density lipoprotein and high density lipoprotein cholesterol correlated significantly with the acute phase levels of C-reactive protein and serum amyloid-A protein. The acute phase concentration of very low density lipoprotein triglyceride correlated inversely to C-reactive protein level (r = -0.31, P less than 0.05) but not to serum amyloid-A protein level. Regression analysis showed that the concentration of C-reactive protein was a significant predictor of very low density lipoprotein triglyceride level in the acute phase of infection but not during convalescence. These results and the previous findings that C-reactive protein binds to low and very low density lipoproteins and that serum amyloid-A protein is associated with high density lipoprotein give credence to the view that C-reactive protein and serum amyloid-A protein interfere with the metabolism of serum lipoproteins during acute phase of infection.

Effects of nicotinic acid on concentrations of serum apolipoproteins B, C-I, C-II, C-III and E in hyperlipidemic patients.

Twenty-four patients with Type IIa, IIb, III and IV hyperlipoproteinemia (HLP) were treated with 4 g of nicotinic acid daily with the purpose to study its effect on serum apolipoprotein B, C-I, C-II, C-III and E concentrations. Triglyceride and total cholesterol concentrations of whole serum and of different serum lipoprotein fractions were also determined. Analyses were performed prior to and after a drug treatment period of 6 weeks, during which all the patients were weight stable. Treatment caused a decrease in serum concentrations of apolipoproteins C-I, C-II, C-III and E. These highly significant reductions were all positively correlated to a reduction of very low density lipoprotein triglyceride levels of serum (r-values greater than 0.76, p less than 0.001). There were highly significant decreases in serum levels of apolipoprotein B and low density lipoprotein total cholesterol. These reductions were positively intercorrelated (r = 0.55; p less than 0.01). Similar effects were observed in the different HLP types and in both sexes. Treatment resulted in normolipidemia in 12 patients, who were hypercholesterolemic (7 type IIa, 3 type IIb, 2 type III hyperlipoproteinemia) prior to treatment. The serum apolipoprotein B concentrations of these 12 patients fell after therapy to values which, however, remained abnormally high. We suggest that serum lipid adjusting treatment should aim at a normalization not only of serum lipid concentrations but also of the serum apolipoprotein B concentration in order to achieve a maximal antiatherogenic effect.

Potential use of fenofibrate and other fibric acid derivatives in the clinic

The fibric acid derivatives continue to have a place in the treatment of hyperlipidemia. The third generation of these drugs, including fenofibrate, appears to offer some advantages over those currently available in the United States. These drugs should be prescribed only after dietary and lifestyle changes have been offered as the preferable treatment. In severe hypertriglyceridemia, clofibrate, gemfibrozil, or fenofibrate may reduce the very low-density lipoprotein and chylomicron levels adequately. Dysbetalipoproteinemia may also be completely controlled by a combination of diet and any one of these drugs. When the low-density lipoprotein level is elevated, the newer fibric acid derivatives, such as fenofibrate, may be more effective in lowering the plasma cholesterol levels. This is true for those patients with elevated low-density lipoprotein and normal very low-density lipoprotein triglyceride levels, as well as those with elevated very low-density lipoprotein triglyceride levels. A 20 percent reduction in low-density lipoprotein cholesterol levels is expected when the triglyceride levels are not elevated. When the very low-density lipoprotein triglyceride levels are elevated, the low-density lipoprotein response is more variable, and on occasion the low-density lipoprotein cholesterol level may rise as the very low-density lipoprotein level is reduced. The average reduction in low-density lipoprotein cholesterol levels (about 6 percent) caused by fenofibrate may be greater in patients with elevated very low-density lipoprotein triglyceride levels than by other fibrates. In combination with other agents that lower low-density lipoprotein levels more specifically, such as the bile acid sequestrants and hydroxymethylglutaryl coenzyme A reductase inhibitors, fenofibrate may act to effect control of the triglycerides allowing management of those patients with disorders producing elevated very low-density lipoprotein triglyceride levels than by other fibrates. Extensive European experience with fenofibrate (six million patient-years) indicates that severe side effects are unlikely. However, the physician should monitor patients for skin rash, liver and renal function abnormalities, gastrointestinal dysfunction, and generalized muscle tenderness. All of these usually appear very early in the course of treatment and are reversible. Of greater concern is the possibility of an increased incidence of cholethiasis, since the bile becomes relatively enriched in cholesterol during therapy with any fibric acid derivative. The chance of experiencing this side effect may depend on the patient's propensity to the development of cholelithiasis, since the actual incidence of this problem during fenofibrate therapy appears to be quite small and has not been well defined.

Relationship of angiographically defined coronary artery disease to serum lipoproteins and apolipoproteins in young survivors of myocardial infarction.

The relationship of serum lipoprotein and apolipoprotein concentrations to angiographically determined coronary artery disease was investigated in 105 consecutive male survivors of myocardial infarction under the age of 45. Concentrations and composition of lipoproteins, lipid indexes, and nonlipid risk factors (tobacco consumption, hypertension, reduced glucose tolerance, and obesity) were related to a recently developed scoring system for semiquantitative estimation of diffuse coronary atheromatosis, as well as to the number and severity of significant coronary artery stenoses. The concentrations of cholesterol in very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), in combination with serum triglyceride or VLDL triglyceride level, comprised the best set of independent discriminatory lipid variables between patients and control subjects. In the patients, LDL cholesterol and apolipoprotein B levels showed strong relationships to the extent and severity of coronary atheromatosis but not to the number and severity of distinct coronary stenoses. HDL2 cholesterol concentration correlated inversely with the coronary atheromatosis score, whereas other variables reflecting HDL concentration and composition or VLDL lipids were not independently related to any of the coronary scores. The LDL triglyceride level, an index of intermediate-density lipoprotein (IDL) accumulation, was significantly correlated to the coronary atheromatosis score in univariate analysis. Nonlipid risk factors were correlated neither to coronary atheromatosis nor to severity of stenoses. Stepwise multiple regression analyses of data adjusted for age, cumulative tobacco consumption, and weight indicated that 18% of the variation in the coronary atheromatosis score could be accounted for by levels of apolipoprotein B. Addition of other lipoprotein variables or the nonlipid variables hypertension and glucose tolerance did not significantly increase the value of R2. When ratios of lipoprotein lipids and apolipoproteins were included in the regression model, the highest multiple correlation coefficient was obtained with the LDL/HDL cholesterol ratio alone (R2 = .22). The present data demonstrate the importance of elevated LDL cholesterol and apolipoprotein B concentrations for the development of coronary atheromatosis in young male survivors of myocardial infarction. The lack of correlations between the levels of lipoprotein lipids and serum apolipoproteins and the severity of coronary stenoses suggests that mechanisms other than disturbances of lipoprotein metabolism may be involved in the progression of more advanced coronary lesions.

Plasma lipids and lipoproteins in young insulin-dependent diabetic patients: relationship with control.

Plasma and lipoprotein cholesterol and triglycerides, glucose and haemoglobin A1c concentrations were measured in 106 patients (56 males) with insulin-dependent diabetes mellitus (age range 2–22 years) and 36 normal volunteers (19 males) with similar age and sex distribution. The diabetic patients were further divided into three subgroups: “good”, fair and poor control, based on 24 h glycosuria and haemoglobin A1c concentrations. Total, low density lipoprotein and very low density lipoprotein cholesterol levels were significantly increased in male patients in poor control when compared with the group in “good” control and with normal subjects. Triglyceride and very low density lipoprotein triglyceride levels were also significantly increased in poorly controlled males. The most significant difference however was a decrease of high density lipoprotein cholesterol in male patients in poor control. There was a significant inverse correlation between haemoglobin A1c and high density lipoprotein cholesterol (r = -0.63) and a direct correlation between haemoglobin A1c and low density lipoprotein cholesterol (r = 0.35) and triglycerides (r = 0.62) in the male diabetics. The findings were similar in females. The most striking change was observed in low density lipoprotein cholesterol levels, which were more markedly increased in poorly controlled females than in poorly controlled males. No statistical singificant differences were found between the groups in good and fair control for any of the plasma and lipoprotein lipids studied. A significant difference however was found between the groups in poor and fair control. There was a significant correlation in females between haemoglobin A1c and low density lipoprotein cholesterol levels (r = 0.43), haemoglobin A1c and triglycerides levels (r = 0.54) and an inverse correlation between haemoglobin A1c and high density lipoprotein cholesterol (r = -0.59).