Can LDL cholesterol be too low? Possible risks of extremely low levels.

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.

Long-term neurodevelopmental outcome of children from euploid pregnancies with increased nuchal translucency in the first trimester screening.

OBJECTIVE: To assess the long-term neurodevelopmental outcome of children born from singleton euploid pregnancies with increased fetal nuchal translucency (NT) in the first trimester ultrasound screening and without structural anomalies in the second trimester ultrasound screening. STUDY DESIGN: This is a register-based retrospective cohort study carried out at a tertiary referral centre from 2002 to 2007. Children were followed up until 2012. All fetuses had increased NT (>95th percentile) at the first trimester ultrasound screening and normal findings in the second trimester ultrasound screening. Data about the neurodevelopmental outcome was retrieved from the hospital databases, The National Institute for Health and Welfare, and the Finnish Causes of Death Statistics Database. Information about received disability allowances was gathered from the Social Insurance Institute of Finland. RESULTS: The study population consists of 691 children. The mean follow-up time was 6.5 years. Neurodevelopmental disorders occurred in 29 children (4.2%). Twelve of these 29 children (1.7%) had severe neurodevelopmental impairment. CONCLUSIONS: The long-term neurodevelopmental outcome of children after increased fetal NT is reassuring. This information should be added to the parental counselling of such cases. © 2014 John Wiley & Sons, Ltd.

Blood pressure levels but not hypertensive complications have increased in Type 1 diabetes pregnancies during 1989-2010.

AIMS: The pre-pregnancy BMI and the third trimester HbA(1c) levels increased in Finnish parturients with Type 1 diabetes during 1989-2008. The aim of the present study was to investigate whether these trends have been accompanied by increases in blood pressure or hypertensive complications. Hypertension trends were analysed using the definitions of hypertension of both the American College of Obstetricians and Gynecologists and the American Diabetes Association. The associations of hypertension, as defined by the latter criteria, with perinatal complications were also studied. METHODS: The records of a cohort of 1007 consecutive patients with Type 1 diabetes with a singleton live childbirth during 1989-2010 at the Helsinki University Central Hospital were studied. RESULTS: The frequencies of hypertensive pregnancy complications did not change, but the mean diastolic blood pressure increased in normotensive parturients in all trimesters. The proportion of patients with systolic blood pressure > 130 mmHg or diastolic blood pressure > 80 mmHg in the first, second and third trimesters of pregnancy increased from 25 to 33%, from 26 to 35% and from 57 to 71%, respectively. Systolic blood pressure of 131-139 mmHg or diastolic blood pressure of 81-89 mmHg in the third trimester was associated with umbilical artery pH < 7.15. CONCLUSIONS: Blood pressure of patients with Type 1 diabetes during pregnancy is increasing. A growing proportion of women with Type 1 diabetes exceed the American Diabetes Association's definition of hypertension during pregnancy.

Trends in maternal BMI, glycaemic control and perinatal outcome among type 1 diabetic pregnant women in 1989-2008.

AIMS/HYPOTHESIS: Our objective was to examine the trends in prepregnancy BMI and glycaemic control among Finnish type 1 diabetic patients and their relation to delivery mode and perinatal outcome. METHODS: We analysed the obstetric records of 881 type 1 diabetic women with a singleton childbirth during 1989-2008. Maternal prepregnancy weight and height were obtained from the maternity cards, where they are recorded as reported by the mother. RESULTS: Maternal BMI increased significantly during 1989-2008 (p < 0.001). The mean HbA(1c) in the first trimester remained unchanged, but the midpregnancy and the last HbA(1c) before delivery increased (p = 0.009 and 0.005, respectively). Elective Caesarean sections (CS) decreased (p for trend <0.001), while emergency CS increased (p for trend <0.001). The mean umbilical artery (UA) pH decreased in vaginal deliveries (p for trend <0.001). The frequency of UA pH <7.15 and <7.05 increased (p for trend <0.001 and 0.008, respectively). The macrosomia rate remained at 32-40%. Neonatal intensive care unit (NICU) admissions increased (p for trend 0.03) and neonatal hypoglycaemia frequency decreased (p for trend 0.001). In multiple logistic regression analysis, maternal BMI was associated with macrosomia and NICU admission. The last HbA(1c) value before delivery was associated with delivery before 37 weeks' gestation, UA pH <7.15, 1 min Apgar score <7, macrosomia, NICU admission and neonatal hypoglycaemia. CONCLUSIONS/INTERPRETATION: Self-reported pregestational BMI has increased and glycaemic control during the second half of pregnancy has deteriorated. Poor glycaemic control seems to be associated with the observed increases in adverse obstetric and perinatal outcomes.

The effect of high-fiber rye bread enriched with nonesterified plant sterols on major serum lipids and apolipoproteins in normocholesterolemic individuals.

BACKGROUND AND AIMS: Plant sterols are naturally occurring cholesterol-lowering compounds which are industrially incorporated in various foods. A novel food carrier is rye bread, the intake of which can be monitored in trials utilizing newly defined plasma biomarkers. Our aim was to determine the effects of plant sterols incorporated into high-fiber rye bread on serum total and LDL cholesterol, apoB/apoA1 and total cholesterol/HDL cholesterol ratios and lipophilic (pro)vitamins in healthy free-living normocholesterolemic individuals. METHODS AND RESULTS: In this double-blind, dietary intervention trial the subjects (n=68) were randomized to receive a rye bread (9.3g/d fiber) with added plant sterols (2g/d) (active) or without (control). In the second phase of the study the amount of rye bread was doubled providing 18.6g/d fiber and in the active group 4g/d plant sterols. Compliance was monitored utilizing 3-day food diaries and a novel rye fiber-derived biomarker in plasma. Intake of rye bread enriched with 2g/d of plant sterols during two weeks reduced significantly serum total and LDL cholesterol, apoB/apoA1 and total cholesterol/HDL cholesterol ratios by 5.1%, 8.1%, 8.3% and 7.2%, respectively, compared to controls. Correspondingly, the following two-week treatment with 4g/d of plant sterols resulted in 6.5%, 10.4%, 5.5% and 3.7% difference compared to controls, being most pronounced for LDL (0.33 mmol/L). The treatments did not affect lipophilic (pro)vitamin levels. CONCLUSION: Rye bread enriched with 2-4g/d of nonesterified plant sterols beneficially modifies cardiovascular lipid risk factors in normocholesterolemic subjects compared to controls.

Cardiovascular outcomes and their relationships to lipoprotein components in patients with and without chronic kidney disease: results from the IDEAL trial.

OBJECTIVES: In Incremental Decrease in Endpoints through Aggressive Lipid-lowering (IDEAL), we compared cardiovascular outcomes in patients with and without chronic kidney disease (CKD) (estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2)) and analysed relationships between lipoprotein components (LC) and major coronary events (MCE) and other cardiovascular (CV) events. DESIGN: Exploratory analysis of CV endpoints in a randomized trial comparing high dose of atorvastatin to usual dose of simvastatin on MCE. SETTINGS: Patients with CKD were compared with the non-CKD patients. Cox regression models were used to study the relationships between on-treatment levels of LC and incident MCE. FINDINGS: Chronic kidney disease was strongly associated with cardiovascular end-points including total mortality. In patients with CKD, a significant benefit of high dose atorvastatin treatment was found for any CV events, stroke and peripheral artery disease, but not for MCE. However, all cardiovascular end-points except stroke and CV mortality were reduced in the non-CKD group. Differential changes in LC or relationships to LC could not explain the different treatment outcomes in MCE in the two groups. INTERPRETATION: Chronic kidney disease was a powerful risk factor for all cardiovascular end-points. The reason why the significant reductions achieved by high-dose statin treatment in most CV end-points in the non-CKD group were only in part matched by similar reductions in the CKD patients is not apparent. This difference did not result from differential changes in or relations to LC, but limited power may have increased the possibility of chance findings.

Hot flushes and biochemical markers for cardiovascular disease: a randomized trial on hormone therapy.

INTRODUCTION: Menopausal hot flushes may affect the responses of various vascular risk factors to hormone therapy (HT). We compared the responses of biochemical markers for cardiovascular diseases to HT in recently postmenopausal women with tolerable or intolerable hot flushes. METHODS: Healthy, non-smoking freshly postmenopausal women (n = 150) with no previous HT use were studied. Seventy-two women reported intolerable hot flushes (> or =7 moderate/severe episodes/day) and 78 women tolerable hot flushes (< or =3 mild episodes/day). The participants were treated in randomized order with either transdermal estradiol gel (1 mg), oral estradiol valerate (2 mg) with or without medroxyprogesterone acetate (5 mg), or placebo for 6 months. Treatment-induced changes in lipids, lipoproteins, apolipoproteins, sex hormone binding globulin (SHBG) and high-sensitivity C-reactive protein were compared. The trial is registered in the US National Institutes of Health Clinical Research Registry (no. NCT00668603). RESULTS: Pretreatment hot flush status was not related to the responses of these markers to different forms of HT. However, when all active regimens were evaluated together as a post-hoc analysis, 7/10 markers showed a tendency toward greater beneficial changes in women with intolerable hot flushes. Furthermore, in women with intolerable hot flushes and with HT use, the increases in SHBG (Spearman's rho = - 0.570, p < 0.001) were related to the reductions in hot flushes during the use of HT. CONCLUSIONS: Hot flushes appear to be no significant determinant for the responses of vascular markers to HT use.

Prediction of placental abruption by testing for C-reactive protein and chlamydial antibody levels in early pregnancy.

OBJECTIVE: Placental abruption may be a manifestation of acute and chronic inflammatory process. We wanted to assess the association of first-trimester serum C-reactive protein (CRP), Chlamydia pneumoniae antibodies, Chlamydia trachomatis antibodies or chlamydial heat-shock protein 60 (CHSP60) antibodies to placental abruption. DESIGN: Retrospective case-control study. SETTING: University Hospital. POPULATION: A total of 181 women with subsequent placental abruption and 261 control women with normal pregnancy. METHODS: Serum samples collected at first trimester (mean 10.4 gestational weeks) were analysed for CRP levels, C. pneumoniae-specific immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies and C. trachomatis-specific IgG, IgA and CHSP60 antibodies. MAIN OUTCOME MEASURE: Placental abruption. RESULTS: The levels of CRP showed no difference between the cases and the controls (median 2.35 mg/l [interquartile range {IQR} 1.09-5.93] versus 2.28 mg/l [IQR 0.92-5.01], not significant). C. pneumoniae-specific IgG and IgA as well as C. trachomatis-specific IgG, IgA and CHSP60 antibody frequencies were similar between the groups. There was no association between CRP levels and chlamydial antibodies. CONCLUSION: These markers of inflammation in early pregnancy failed to predict subsequent placental abruption.

Roles of apolipoproteins B and E in the cellular binding of very low density lipoproteins.

Apoproteins B and E both interact with cellular low density lipoprotein (LDL) apolipoprotein B and E (apo B,E)-receptors, and very low density lipoproteins (VLDL) contain both apo B and apo E. Our aim was to study the relative importance of apo B and apo E in the binding of VLDL subfractions to cells. Two monoclonal anti-LDL-apo B antibodies (464B1B3 and 464B1B6, 2a and 2b, respectively) and two anti-apo E antibodies (1506 A1.4 and 1907 F6.4) were used to inhibit lipoprotein-cell interactions. In confirmation of previous findings, the binding and degradation of 125I-LDL by human fibroblasts were inhibited approximately 90% by antibodies 2a or 2b or the antigen-binding fragments of 2a, whereas the cellular processing of 125I-VLDL3 (Sf20-60), 125I-VLDL2 (Sf60-120), and 125I-VLDL1 (Sf greater than 120) were inhibited by only approximately 50%, approximately 25%, and less than 10%, respectively. The VLDL1-3 and LDL-dependent intracellular esterification of cholesterol with [3H]oleate were inhibited to a similar extent. Other monoclonal anti-human apo B antibodies inhibited lipoprotein-cell interactions much less effectively and nonimmune IgG isolated from mouse serum did not inhibit at all. 20-fold excesses of LDL produced about the same patterns of inhibition of degradation of 125I-VLDL1-3 and LDL by cells as did antibodies 2a and 2b, whereas homologous unlabeled VLDL1-3 in like amounts inhibited the matched 125I-VLDL subfraction more effectively. Two anti-apo E monoclonal antibodies and a polyclonal anti-apo E antibody inhibited cell-mediated degradation of and lipoprotein-dependent cholesterol esterification by VLDL1 but not VLDL3 or LDL. The results suggest that receptor recognition sites on apo E in preference to sites on apo B mediate the cellular binding of hypertriglyceridemic VLDL1. However, the proportion of particles bound via apo B seems to increase as VLDL decreases in size toward LDL, and virtually all of LDL binding is mediated by apo B.

Safety aspects and cholesterol-lowering efficacy of low fat dairy products containing plant sterols.

OBJECTIVE: The aim of this study was to investigate whether a plant sterol mixture would reduce serum cholesterol when added to low fat dairy products in subjects with hypercholesterolaemia, and to examine the effects of the mixture on the serum plant sterol and fat-soluble vitamin levels. DESIGN: A parallel, double-blind study. SETTING: The study was performed in three different locations in Finland. SUBJECTS: In total, 164 mildly or moderately hypercholesterolaemic subjects participated in the study. METHODS: The subjects were randomly divided into two groups: a plant sterol group and a control group. The subjects consumed the products for 6 weeks after a 3-week run-in period. The targeted plant sterol intake was 2 g/day in the sterol group. RESULTS: During the treatment period, there was a 6.5% reduction in serum total cholesterol in the sterol group while no change was observed in the control group (P<0.0005). Serum low-density lipoprotein (LDL) cholesterol was reduced by 10.4% in the sterol group and by 0.6% in the control group (P<0.00005). There was no change during the trial in serum high-density lipoprotein (HDL) cholesterol or triacylglycerol concentrations. The HDL/LDL cholesterol ratio increased by 16.1% in the sterol group and by 4.3% in the control group (P=0.0001). Serum plant sterol levels increased significantly (P=0.0001) in the sterol group. None of the fat-soluble vitamin levels decreased significantly when changes in serum total cholesterol were taken into account. The hypocholesterolaemic effect of sterol administration was not influenced by apolipoprotein E phenotype. CONCLUSIONS: Yoghurt, low-fat hard cheese and low-fat fresh cheese enriched with a plant sterol mixture reduced serum cholesterol in hypercholesterolaemic subjects and no adverse effects were noted in the dietary control of hypercholesterolaemia.

Amniotic fluid rapid biomarkers are associated with intra-amniotic infection in preterm pregnancies regardless of the membrane status.

OBJECTIVE: The objective of this study was to evaluate the association of amniotic fluid lactate dehydrogenase and glucose concentrations with microbial invasion of amniotic cavity and histologic chorioamnionitis before 37 pregnancy weeks in women with or without preterm premature rupture of membranes. STUDY DESIGN: Amniocentesis was performed on 70 women with suspected intra-amniotic infection. Standard biochemical methods, molecular microbiology and culture techniques were used. Histopathological examination of the placenta was performed. RESULTS: Thirty (48%) women had microbial invasion of the amniotic cavity (MIAC), 53 (76%) women had histological chorioamnionitis and 28 women had both. The cutoff values for MIAC and histological chorioamnionitis were 429 IU l(-1) for lactate dehydrogenase and 0.7 mmol l(-1) for glucose. Both end points occurred equally often regardless of the membrane status. CONCLUSION: Increased amniotic fluid lactate dehydrogenase and decreased glucose were associated with MIAC and histological chorioamnionitis. However, test performance was of limited value.

Comparison of amniotic fluid matrix metalloproteinase-8 and cathelicidin in the diagnosis of intra-amniotic infection.

OBJECTIVE: To evaluate the association of amniotic fluid (AF) matrix metalloproteinase-8 (MMP-8) and cathelicidin concentrations with microbial invasion of the amniotic cavity (MIAC) in pregnancies with preterm prelabor rupture of the membranes or intact membranes. STUDY DESIGN: Amniocentesis was performed in 54 singleton pregnancies between 22+0 and 34+2 gestational weeks with suspected intra-amniotic infection. AF-MMP-8 was analysed by immunoassay and AF-cathelicidin by commercial ELISA. Standard biochemical methods, molecular microbiology and culture techniques were used. RESULTS: MIAC was present in 18 (33%) women. The cutoff value for the diagnosis of MIAC was 41.5 ng ml-1 for AF-MMP-8, and 11.6 ng ml-1 for AF-cathelicidin. With these cutoff values AF-MMP-8 had a sensitivity of 100%, specificity of 69%, positive predictive value of 62% and negative predictive value of 100% for MIAC. The corresponding values for AF-cathelicidin were 89, 81, 70 and 94%. CONCLUSION: The performance of AF-cathelicidin in the prediction of MIAC is comparable to AF-MMP-8.

Incorporation of esterified soybean isoflavones with antioxidant activity into low density lipoprotein.

We have recently reported that dietary intake of soybean isoflavone phytoestrogens resulted in increased oxidation resistance of isolated low density lipoprotein (LDL). In order to explore the underlying mechanisms we designed two types of in vitro experiments. First, we prepared several different isoflavone fatty acid esters to increase their lipid solubility and studied their incorporation into LDL. Second, the oxidation resistance of the isoflavone-containing LDLs was investigated with Esterbauer's 'conjugated diene' method using Cu2+ as prooxidant. Unesterified daidzein and genistein as well as genistein stearic acid esters were incorporated into LDL to a relatively small extent (0.33 molecules per LDL particle, or less) and they did not significantly influence oxidation resistance. The oleic acid esters of isoflavones were incorporated more effectively, reaching a level of 2.19 molecules per LDL particle or more, and the 4',7-O-dioleates of daidzein and genistein exhibited prolongations of lag times by 46% (P<0.05) and 202% (P<0.01), respectively. A smaller but significant increase in lag time (20.5%, P<0.01) was caused by daidzein 7-mono-oleate. In summary, esterification of soybean isoflavones daidzein and genistein with fatty acids at different hydroxyl groups provided lipophilicity needed for incorporation into LDL. Some isoflavone oleic acid esters increased oxidation resistance of LDL following their incorporation.

Antioxidant protection of lipoproteins containing estrogens: in vitro evidence for low- and high-density lipoproteins as estrogen carriers.

Some recent studies have reported that low-density lipoprotein (LDL) isolated from estrogen-treated postmenopausal women exhibited increased oxidation resistance ex vivo. However, the underlying mechanisms responsible for this effect are not clear. We explored the possibility that lipophilic derivatives of 17beta-estradiol (E(2)) could be incorporated into LDL and high-density lipoprotein (HDL) particles inhibiting lipoprotein oxidation. Introduction of small amounts of esterified E(2) into lipoproteins by means of incubation of free E(2) and E(2) 17-stearate in plasma did not result in any antioxidant effect. Using an artificial transfer system (Celite dispersion), larger amounts of E(2) esters could be incorporated into lipoproteins. Concentrations ranging between 0.27 and 1.38 molecules/LDL particle for E(2) 17-stearate and between 0.36 and 1.93 molecules/LDL particle for E(2) 17-oleate resulted in increased Cu(2+)-induced oxidation resistance of LDL as indicated by statistically significant lag time prolongations. Significant prolongations of lag times were also observed for HDL following incorporation of E(2) esters using Celite as transfer system. Our results suggest that free E(2) can be esterified and incorporated into lipoproteins during incubation in plasma. However, incorporation of supraphysiologic concentrations of E(2) esters into lipoproteins by means of the artificial transfer system was required in order to reduce their oxidation susceptibility.

Levels of serum C-reactive protein during oral and transdermal estradiol in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy.

Liver dysfunction may affect the production and release of C-reactive protein (CRP). We designed a double-blind prospective crossover study involving 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), where we compared the basal levels of CRP and their responses to increasing doses of oral and transdermal estradiol (E2), followed by addition of oral medroxyprogesterone acetate (MPA). Serum samples collected at baseline, on the last day of each E2 period, and on the last day of the E2 + MPA combination were assayed for CRP, estrogens, and liver enzymes. There was no difference in basal CRP between the study groups. Both regimens (oral and transdermal E2) were accompanied by significant rises in estrone and E2 concentrations; the former were 16 times higher during the oral than during the transdermal regimen. Oral E2 elevated CRP dose dependently, and this response was unaffected by a history of ICP or the use of MPA. The activities of liver transaminases varied but were in normal ranges during E2 use, in women with and without a history of ICP. In conclusion, the synthesis of CRP is not affected by a history of ICP. It is readily and dose dependently stimulated by oral but not by transdermal E2 in as soon as 2 wk.

Effects of oral and transdermal estradiol administration on levels of sex hormone-binding globulin in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy.

SHBG, the most important transport protein for sex steroids, is produced in the liver under the control of estrogen action. In a randomized, double-blind, prospective crossover study we compared basal levels of serum SHBG and their responses to increasing doses of oral and transdermal estradiol (E2), followed by E2 plus oral progestin (medroxyprogesterone acetate [MPA]), in 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), which could affect the synthesis of SHBG. Serum samples collected at baseline, on the last day of each E2 period, and on the last day of the E2 plus MPA combination were assayed for SHBG and E2. Basal levels of SHBG showed no difference between the study groups. Oral but not transdermal E2 increased SHBG concentrations by 67-171% in the control group, but the response was smaller (42-121%) in the ICP group. Addition of MPA decreased SHBG levels by 14-18% in both groups during both treatments. In conclusion, a history of ICP is associated with blunted responses of SHBG to oral estrogen.

Effects of vitamin E on the toxicity of oxidized LDL on endothelial cells in vitro in smokers vs nonsmokers on diets rich in fish.

OBJECTIVE: To clarify whether supplementation of vitamin E can alter the low density lipoprotein (LDL) oxidation properties and thereby affect endothelial cell function and prostacyclin production in smokers compared to nonsmokers on diets rich in fish in a pilot study. DESIGN: The LDL of six smokers and six nonsmokers on habitual high fish diet was isolated before and after an 8-week supplementation of vitamin E (800 IU/day). LDL was oxidized by incubation with CuSO4. Cytotoxicity of LDL oxidized to different degrees on endothelial cells was investigated in vitro in these two groups. SETTING: Helsinki University Central Hospital; Institute of Biomedicine, Pharmacology, University of Helsinki. RESULTS: At baseline, the rate of oxidation was higher in nonsmokers than in smokers. The lag phase increased significantly after the supplementation of vitamin E both in smokers and nonsmokers. Native LDL dose dependently tended to reduce the viability of endothelial cells in vitro more markedly when isolated from smokers than from nonsmokers. Vitamin E supplementation had no beneficial effect on the cytotoxicity of oxidized LDLs in endothelial cell culture. On the other hand, simultaneous administration of Trolox, the water-soluble analogue of vitamin E, attenuated the LDL cytotoxicity on endothelial cells. The vitamin E supplementation to LDL donors attenuated the increase in prostacyclin production both in smokers and nonsmokers. CONCLUSION: Supplementation of LDL donors (healthy male volunteers on habitual fish diet) with vitamin E increased the lag phase of LDL oxidation, but, on the other hand, did not influence in vitro cytotoxicity of LDL, or prostacyclin production.

Plant sterols and stanols.

The expanding market of 'functional foods' containing plant sterols and stanols has focused interest on their cholesterol-lowering effects as well on possible adverse effects. Trials of cholesterol lowering demonstrate that intake of 2 g/day of plant sterols and stanols reduces serum low-density lipoprotein (LDL) cholesterol concentrations by approximately 10%. Safety concerns regarding elevations in serum plant sterol levels, or effects on fat-soluble vitamin absorption or hypothetical effects on serum sex hormone balance have received attention and been addressed in studies. Plant sterol (but not stanol) supplementation increased serum plant sterol concentrations but these levels remained much lower than those observed in homozygous sitosterolemia making an adverse health effect unlikely. Prolonged statin therapy also causes elevations in all cholesterol-adjusted plant sterol levels as well as small but significant elevations in serum unadjusted campesterol levels from baseline. This is probably caused by a statin-induced reduction in biliary cholesterol efflux resulting in a diminished intestinal cholesterol pool. The diminished competition with cholesterol molecules allows more plant sterol molecules to become incorporated in mixed micelles facilitating their uptake in enterocytes. With the exception of beta-carotene, reductions in serum concentrations of fat-soluble (pro)vitamins are usually abolished by adjustment for cholesterol suggesting that they reflect reductions in carrier lipoproteins, mainly LDL. The small reductions in serum beta-carotene are not regarded as a major concern, nor have any adverse effects on sex hormone metabolism been demonstrated apart from parenteral administration of large doses in experimental animals. However, as increasing consumer populations become exposed to a large variety of food products enriched with plant sterols and stanols the likelihood of rare adverse effects increases and surveillance is necessary.

Treatment of hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM. A multicenter comparison study.

OBJECTIVE: To compare the lipid-lowering efficacies of simvastatin and gemfibrozil in NIDDM patients with combined (mixed) hyperlipidemia (CHL) or isolated hypercholesterolemia (IHC). RESEARCH DESIGN AND METHODS: Patients with primary dyslipidemia and NIDDM were recruited for this double-blind, double-dummy comparison study from 10 Finnish centers. After a 4-week placebo run-in period, they were randomly assigned to simvastatin or gemfibrozil. The simvastatin group (n = 47) received 10 mg once nightly for 8 weeks, 20 mg for the next 8 weeks, and 40 mg for the third 8-week period. The gemfibrozil group (n = 49) received 600 mg twice daily throughout the 24 weeks. The lipid-lowering efficacies of both drugs were compared in all patients as well as separately in patients with CHL and IHC. RESULTS: In all patients, simvastatin reduced LDL and total cholesterol and the LDL-to-HDL cholesterol ratio more effectively, whereas gemfibrozil was more effective in elevating HDL cholesterol and decreasing triglyceride levels. The drug effects differed according to lipid phenotype at baseline. Simvastatin decreased LDL cholesterol levels by 30-40% in both phenotypes. Gemfibrozil caused a 15% reduction in LDL cholesterol in IHC but no change in CHL patients. Simvastatin produced 15-30% reductions in triglyceride levels in CHL but no change in IHC patients. Gemfibrozil caused reductions in triglycerides in CHL (50% and more) and in IHC (40%) patients, with 12-18% increases in HDL cholesterol in these groups. CONCLUSIONS: Simvastatin is useful in both CHL and IHC patients, whereas gemfibrozil can be used in patients with high triglyceride and low or normal LDL cholesterol levels.

Hyperinsulinemia 17 years after preeclamptic first pregnancy.

Insulin resistance syndrome predisposes to occlusive vascular disorders in nonpregnant subjects. Because preeclampsia, representing a pregnancy-specific occlusive vascular disorder, is known to be accompanied by metabolic changes similar to those in insulin resistance syndrome, we compared carbohydrate and lipid metabolism in 22 women who had a preeclamptic first pregnancy and in 22 control women who had normotensive first pregnancy, both, on the average, 17.0 +/- 0.7 yr earlier. The study groups were comparable in regard to body mass index at the follow-up study. Women with prior preeclampsia were normoglycemic (baseline, 3 h oral glucose tolerance), but showed a significant hyperinsulinemia, as seen from elevated immunoreactive insulin (IRI) levels at the baseline (mean +/- SE, 7.3 +/- 0.6 vs. 5.5 +/- 0.5 mU/L; P < 0.03), after 1 h (45.7 +/- 5.5 vs. 35.6 +/- 3.5 mU/L; P = 0.13), after 2 h (32.4 +/- 4.1 vs. 23.8 +/- 2.3 mU/L; P = 0.08), and after 3 h (10.1 +/- 1.4 vs. 6.4 +/- 0.6 mU/L; P = 0.02). The area under the IRI curve was larger in the women with prior preeclampsia (86.8 +/- 9.1 vs. 65.4 +/- 5.2 mU/h.L; P = 0.05). The serum levels of total cholesterol, high density lipoprotein (HDL) cholesterol (with its subfractions HDL2 and HDL3), low density lipoprotein cholesterol, triglyceride, or uric acid did not differ significantly between the study groups. In women with prior preeclamsia, the area under the IRI curve was negatively related to HDL2 cholesterol, but positively related to triglyceride and systolic blood pressure. We conclude that a history of preeclampsia is associated with mild hyperinsulinemia in nonpregnant women.