Comparative Effectiveness and Toxicity of Statins Among HIV-Infected Patients.

BACKGROUND: dyslipidemia is common and is often treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins). Little is known about the comparative effectiveness of statins among human immunodeficiency virus (HIV)-infected patients. This study compared the effectiveness and toxicity of statins among HIV-infected patients in clinical care. METHODS: we conducted a retrospective cohort study of patients starting their initial statin medications at 2 large HIV clinics (N = 700). The primary observation was change in lipid levels during statin therapy. Secondary observations included whether individualized National Cholesterol Education Program (NCEP) goals for low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) levels were reached, and toxicity rates. We used linear regression to examine change in lipid levels, controlling for baseline lipid values and demographic and clinical characteristics. We conducted secondary analyses using propensity scores to address confounding by indication. RESULTS: the most commonly prescribed statins were atorvastatin (N = 303), pravastatin (N = 280), and rosuvastatin (N = 95). One year after starting a statin therapy, patients who received atorvastatin or rosuvastatin had significantly greater decreases in total cholesterol, LDL-C, and non-HDL-C than patients on pravastatin. The likelihood of reaching NCEP goals for LDL-C levels was higher with the use of rosuvastatin (OR 2.1; P = .03) and atorvastatin (odds ratio [OR], 2.1; P = .001) compared with that of pravastatin. The likelihood of reaching NCEP goals for non-HDL-C levels was higher for rosuvastatin (OR 2.3; P = .045) but not atorvastatin (OR, 1.5; P = .1) compared with pravastatin. Toxicity rates were similar for all 3 statins: 7.3% for atorvastatin, 6.1% for pravastatin, and 5.3% for rosuvastatin. CONCLUSIONS: our findings suggest that atorvastatin and rosuvastatin are preferable to pravastatin for treatment of HIV-infected patients with dyslipidemia, due to greater declines in total cholesterol, LDL-C, and non-HDL-C, with similar lower toxicity rates.

Low clusterin levels in high-density lipoprotein associate with insulin resistance, obesity, and dyslipoproteinemia.

OBJECTIVE: To determine whether obesity and insulin resistance associate with changes in the protein content of high-density lipoprotein (HDL) in 2 different groups of men by using targeted proteomics. METHODS AND RESULTS: Insulin resistance and obesity are hallmarks of type 2 diabetes mellitus and the metabolic syndrome, which confer an increased risk of cardiovascular disease. Recent studies suggest that the protein cargo of HDL makes important contributions to the lipoprotein's cardioprotective effects. In a discovery study, we used isotope dilution mass spectrometry to quantify the relative concentrations of 5 proteins previously implicated in HDL's cardioprotective effects in 3 groups of healthy subjects: lean insulin-sensitive, lean insulin-resistant, and obese insulin-resistant individuals. We validated our findings in a different group of subjects. The clusterin concentration in HDL strongly and negatively associated with insulin resistance and body mass index in both populations. HDL clusterin levels were lower in subjects with low HDL and high triglycerides, key components of the metabolic syndrome. There was an inverse correlation between clusterin levels in HDL and very-low-density lipoprotein/low-density lipoprotein. CONCLUSIONS: Clusterin levels in HDL are lower in men with reduced insulin sensitivity, higher body mass index, and an unfavorable lipid profile. Our observations raise the possibility that clusterin depletion contributes to the loss of HDL's cardioprotective properties.

Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.

HDL lowers the risk for atherosclerotic cardiovascular disease by promoting cholesterol efflux from macrophage foam cells. However, other antiatherosclerotic properties of HDL are poorly understood. To test the hypothesis that the lipoprotein carries proteins that might have novel cardioprotective activities, we used shotgun proteomics to investigate the composition of HDL isolated from healthy subjects and subjects with coronary artery disease (CAD). Unexpectedly, our analytical strategy identified multiple complement-regulatory proteins and a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity. Many acute-phase response proteins were also detected, supporting the proposal that HDL is of central importance in inflammation. Mass spectrometry and biochemical analyses demonstrated that HDL3 from subjects with CAD was selectively enriched in apoE, raising the possibility that HDL carries a unique cargo of proteins in humans with clinically significant cardiovascular disease. Collectively, our observations suggest that HDL plays previously unsuspected roles in regulating the complement system and protecting tissue from proteolysis and that the protein cargo of HDL contributes to its antiinflammatory and antiatherogenic properties.

Combined statin and niacin therapy remodels the high-density lipoprotein proteome.

BACKGROUND: Boosting low high-density lipoprotein (HDL) levels is a current strategy for preventing clinical events that result from cardiovascular disease. We previously showed that HDL(3) of subjects with coronary artery disease is enriched in apolipoprotein E and that the lipoprotein carries a distinct protein cargo. This observation suggests that altered protein composition might affect the antiatherogenic and antiinflammatory properties of HDL. We hypothesized that an intervention that increases HDL levels-combined statin and niacin therapy-might reverse these changes. METHODS AND RESULTS: HDL(3) isolated from 6 coronary artery disease subjects before and 1 year after combination therapy was analyzed by liquid chromatography-Fourier transform-mass spectrometry. Alterations in protein composition were detected by spectral counting and confirmed with extracted ion chromatograms. We found that combination therapy decreased the abundance of apolipoprotein E in HDL(3) while increasing the abundance of other macrophage proteins implicated in reverse cholesterol transport. Treatment-induced decreases in apolipoprotein E levels of HDL(3) were validated biochemically in a second group of 18 coronary artery disease subjects. Interestingly, the changes in HDL(3) proteome with niacin/statin treatment resulted in a protein composition that more closely resembled that of HDL(3) in healthy control subjects. CONCLUSIONS: Combined statin and niacin therapy partially reverses the changes in the protein composition seen in HDL(3) in coronary artery disease subjects. Our observations raise the possibility that quantifying the HDL proteome could provide insights into the therapeutic efficacy of antiatherosclerotic interventions.

Comprehensive lipid management versus aggressive low-density lipoprotein lowering to reduce cardiovascular risk.

Five lines of evidence justify comprehensive lipoprotein management over aggressive low-density lipoprotein (LDL) lowering alone in most cases of cardiovascular disease (CVD) prevention. First, lipoprotein lipid transport consists of a single, recycling system involving very-low-density lipoprotein, LDL, and high-density lipoprotein (HDL). Single lipid interventions affect all lipoprotein classes to varying degrees. These effects can be expanded by using different drug classes in combination. Second, observational studies support the unitary nature of lipoprotein risk. A family of curves describes increasing CVD risk from increasing LDL as other risk factors are present. Conversely, a family of curves describes increasing CVD risk from decreasing levels of HDL in mirror image to LDL. The LDL and HDL risks are additive. Third, clinical trials that raise HDL and lower triglyceride ameliorate CVD, as does lowering LDL. Lowering LDL prevents heart disease, but by only 22%-36% with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor therapy. Studies indicate that better CVD prevention is obtained when drugs for triglyceride and HDL reduction are combined with LDL reduction. Fourth, HDL and its apolipoprotein (apo), apo A-I, as well as apo A-I analogues, decrease atherosclerosis. Each modality decreases atherosclerosis in animal models, and apo A-I Milano acutely decreases human coronary luminal stenosis. Apo A-I analogues have similar promise. Fifth, combined hyperlipidemia is the most common lipid disorder, has the strongest risk for CVD, and combines elevated LDL, hypertriglyceridemia, and low HDL. This condition requires the comprehensive treatment approach described above. In conclusion, 5 lines of evidence justify comprehensive diet and drug treatment for combined hyperlipidemia and, at lesser LDL elevations, the atherogenic dyslipidemias of obesity, diabetes mellitus, and the metabolic syndrome.

Survey correlations: proficiency and adequacy of nutrition training of medical students.

OBJECTIVE: The majority of graduating US medical students reported inadequate nutrition training over the past decade. This trend could in part be due to the lack of valid measures to assess the relationship between adequacy of nutrition training and proficiency on nutrition topics deemed essential. The study's objective was to test the hypothesis that self-reported nutrition proficiency is positively correlated with the perceived adequacy (quality, quantity, coverage and importance) of nutrition training of University of Washington medical students. METHOD: Cross-sectional e-mail survey of 1st to 4th year medical students (n = 708), including a survey prompt and three e-mail follow-up measures. To reduce and interpret the survey data, principal components analysis was employed, followed by Varimax rotation with Kaiser normalization. To assess internal consistency reliability, alpha (alpha) of nutrition proficiency items and factors was determined. RESULTS: A 44.5% response rate was achieved (n = 315 respondents). The 31-item questionnaire was reduced to 6 factors, explaining 60.2% of the total variance (alpha = 0.947). Self reported nutrition proficiency was positively correlated with the perceived quality, quantity and coverage of nutrition training in all 6 essential nutrition factors or topics determined after factor analysis (P < 0.01). CONCLUSION: Quality and coverage may be effective gauges of adequacy of nutrition training and related nutrition proficiency in medical education. Current national medical education evaluation measures focus on the quantity of nutrition instruction. The lowest reported proficiency topics; nutrition and disease management, micronutrients and complementary and alternative medicine are recommended for particular curricular emphasis.

Long-term safety and efficacy of a combination of niacin extended release and simvastatin in patients with dyslipidemia: the OCEANS study.

INTRODUCTION: High-dose HMG-CoA reductase inhibitors (statins) fail to prevent approximately two-thirds of cardiovascular events. This fact has focused increased attention on treating abnormalities of non-high-density lipoprotein-cholesterol (non-HDL-C), HDL-C, and triglycerides in national guidelines and has intensified interest in combination therapy. METHODS: The OCEANS study (Open-label evaluation of the safety and efficacy of a Combination of niacin ER and simvAstatin in patieNts with dySlipidemia; ClinicalTrials.gov identifier: NCT00080275) evaluated the safety and efficacy of a combination of niacin extended release and simvastatin (NER/S; SIMCOR) over 52 weeks in 520 patients with mixed dyslipidemia. After a >or=4-week run-in phase of diet modification and simvastatin 40 mg/day, median baseline values (mg/dL) were: non-HDL-C = 141, low-density lipoprotein-cholesterol (LDL-C) = 110, HDL-C = 45, and triglyceride = 151. Patients were randomized to an 8- or 12-week niacin titration scheme to a maximum NER/S dosage of 2,000/40 mg/day. RESULTS: Differences between titration groups in tolerability, safety, and efficacy were minimal; therefore, all results are for pooled titration groups. The safety of NER/S was consistent with the safety profile of each individual component. Treatment with NER/S was well tolerated: 71% of patients experienced flushing and 92% of flushing episodes were mild or moderate in intensity. Overall, 61% of patients experienced flushing episodes that were rated as mild or moderate in intensity. Flushing decreased over time: <40% of those who had flushing during titration experienced flushing during the final 12 weeks. A total of 20% of patients discontinued treatment because of a treatment-related adverse event, including 7% who discontinued because of flushing. Median changes from baseline (following the simvastatin 40 mg/day run-in phase) to 24 weeks were: non-HDL-C = -27.3%, LDL-C = -25.0%, HDL-C = +23.9%, and triglycerides = -35.9% (all p < 0.0001 vs baseline). In lipid-treatment-naive patients, NER/S 2,000/40 mg/day decreased non-HDL-C, LDL-C, and triglycerides by approximately 50% and increased HDL-C by approximately 25% when week-24 lipid values were compared with lipid values obtained prior to the simvastatin 40 mg/day run-in. All three therapeutic lipid targets (LDL-C [risk-adjusted goal], HDL-C >or=40 mg/dL, and triglycerides <150 mg/dL) were achieved concurrently by 65% of patients treated with NER/S. CONCLUSION: Treatment with NER/S 2,000/40 mg/day is well tolerated, has no unanticipated adverse events, and provides additional, clinically relevant improvements in multiple lipid parameters beyond statin monotherapy.

Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study).

International guidelines recommend lower target cholesterol levels and treatment of low high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides for patients at moderately high to high coronary heart disease (CHD) risk. Combination therapy is often required to achieve multiple lipid treatment goals, and > or =50% reduction in low-density lipoprotein cholesterol (LDL-C) is needed in some patients to achieve aggressive LDL-C targets. In this context, we evaluated comparative effects on lipid levels of combination therapy at low to moderate doses with a statin plus extended-release niacin (niacin ER), a statin plus ezetimibe, and a highly potent statin alone. This was an open-label, multicenter, 12-week study in 292 patients (50% women) who qualified for drug therapy based on number of CHD risk factors. Patients were randomized to four parallel arms, titrated from low to moderate or high doses: atorvastatin/niacin ER, rosuvastatin/niacin ER, simvastatin/ezetimibe, or rosuvastatin alone. Baseline mean values were, for LDL-C 197 mg/dL (5.1 mmol/L), HDL-C 49 mg/dL (1.3 mmol/L), triglycerides 168 mg/dL (1.9 mmol/L). There were no significant differences among treatment groups in the change from baseline in LDL-C at pre-specified timepoints during treatment. All groups lowered LDL-C by approximately 50% or more (range -49 to -57%), achieving mean levels of 82-98 mg/dL (2.1-2.5 mmol/L). Changes in non-HDL-C (range -46 to -55%) mirrored those for LDL-C and did not differ among treatment groups. Statin/niacin ER combination regimens also increased HDL-C and large HDL (HDL2) and lowered triglycerides and lipoprotein (a) significantly more than other regimens. No drug-related myopathy or hepatotoxicity was observed. In this study, low to moderate dose combination therapy with a statin and niacin ER provided broad control of lipids and lipoproteins independently associated with CHD.

Enhancing recruitment of healthy African American volunteers in a city with a small African American community: results from a dietary supplement crossover trial.

OBJECTIVE: To describe strategies for enhancing recruitment of African Americans to a longterm intervention study requiring frequent blood draws and follow-up visits, in a city with relatively few African Americans. DESIGN: The intervention study was a 14-month, double-blind, crossover study evaluating the effects of three oral folic acid doses on blood homocysteine levels. The goal was to have 40 African Americans complete the study, in addition to 160 participants from other races and ethnicities. RESULTS: Of 707 healthy, adult men and women recruited, 57 were African Americans. Recruitment advice was sought from African American community leaders interested in health research and the advice can be attributable to the success of recruitment. As suggested by the community leaders, our female African American project manager made oral presentations to select community groups. Word-of-mouth support from community leaders and study participants helped recruitment. Although the adult Seattle population is 7.4% African American, the group completing the study comprised 15% African Americans. Retention in the dietary intervention was 74% (31 out of 42) among African Americans, 81% (158 out of 196) among non-African Americans--a statistically non-significant difference. CONCLUSIONS: Advice from African American community leaders about targeting appropriate civic/professional groups, churches, and community organizations can lead to effective recruitment of African Americans. Advice should be sought before beginning recruitment and endorsement for the study should be obtained. Effective retention of African American participants is possible for intervention studies requiring multiple blood draws and follow-up visits.

Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN).

OBJECTIVE: Cardiovascular disease (CVD) risk is increased in type 2 diabetes. The purpose of this study was to assess the effect of 10 mg of atorvastatin versus placebo on CVD prevention in subjects with type 2 diabetes and LDL cholesterol levels below contemporary guideline targets. RESEARCH DESIGN AND METHODS: Subjects were randomly assigned to receive 10 mg of atorvastatin or placebo in a 4-year, double-blind, parallel-group study. The composite primary end point comprised cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, recanalization, coronary artery bypass surgery, resuscitated cardiac arrest, and worsening or unstable angina requiring hospitalization. RESULTS: A total of 2,410 subjects with type 2 diabetes were randomized. Mean LDL cholesterol reduction in the atorvastatin group over 4 years was 29% versus placebo (P < 0.0001). When we compared atorvastatin versus placebo, composite primary end point rates were 13.7 and 15.0%, respectively (hazard ratio 0.90 [95% CI 0.73-1.12]). In the subset of 1,905 subjects without prior myocardial infarction or interventional procedure, 10.4% of atorvastatin- and 10.8% of placebo-treated subjects experienced a primary end point (0.97 [0.74-1.28]). In the 505 subjects with prior myocardial infarction or interventional procedure, 26.2% of atorvastatin- and 30.8% of placebo-treated subjects experienced a primary end point (0.82 [0.59-1.15]). Relative risk reductions in fatal and nonfatal myocardial infarction were 27% overall (P = 0.10) and 19% (P = 0.41) and 36% (P = 0.11) for subjects without and with prior myocardial infarction or interventional procedure, respectively. CONCLUSIONS: Composite end point reductions were not statistically significant. This result may relate to the overall study design, the types of subjects recruited, the nature of the primary end point, and the protocol changes required because of changing treatment guidelines. For these reasons, the results of the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) did not confirm the benefit of therapy but do not detract from the imperative that the majority of diabetic patients are at risk of coronary heart disease and deserve LDL cholesterol lowering to the currently recommended targets.

Impact of differences in fasting glucose and glucose tolerance on the hyperbolic relationship between insulin sensitivity and insulin responses.

OBJECTIVE: To determine whether the hyperbolic relationship between insulin sensitivity and the acute insulin response to glucose (AIRg) exists in subjects with impaired fasting glucose (IFG) or decreased glucose tolerance. RESEARCH DESIGN AND METHODS: We studied 219 healthy subjects (88 male and 131 female subjects, aged 26-75 years) with fasting plasma glucose (FPG) <6.11 mmol/l. Subjects underwent an intravenous glucose tolerance test to determine the insulin sensitivity index (Si), AIRg, and the glucose disappearance constant (Kg), the latter a measure of intravenous glucose tolerance. RESULTS: Si and AIRg were inversely related for the entire cohort, and this relationship was not significantly different from hyperbolic. The inverse relationship between Si and AIRg was not significantly different when compared between groups based on fasting glucose (normal fasting glucose [NFG], FPG <5.56 mmol/l vs. IFG, FPG 5.56-6.11 mmol/l) or by the Kg quartile. However, the curve relating Si and AIRg was left shifted in the IFG compared with NFG group (P < 0.001) and was progressively more left shifted with decreasing Kg (P < 0.001), consistent with decreasing beta-cell function. These changes were not observed for the curves relating Si and fasting insulin, suggesting that in the fasting state beta-cell function is maintained even in patients with mild IFG. Finally, the disposition index (DI) (Si x AIRg) was calculated as a measure of beta-cell function. The DI progressively decreased with increasing FPG, even in the group of subjects classified as NFG. CONCLUSIONS: The inverse relationship between insulin sensitivity and AIRg is consistent with a hyperbola not only in subjects with normal glucose tolerance but also with mild IFG or decreased Kg. Based on a hyperbolic relationship, a decrease in beta-cell function can be detected as FPG increases, even in patients who are normal glucose tolerant.

Cholesterol feeding increases C-reactive protein and serum amyloid A levels in lean insulin-sensitive subjects.

BACKGROUND: Inflammatory markers associated with elevated cardiovascular risk are increased by cholesterol feeding in animal models. However, whether dietary cholesterol increases inflammatory marker levels in humans is not known. METHODS AND RESULTS: C-reactive protein (CRP), serum amyloid A (SAA), and lipoprotein levels were compared in 201 healthy subjects on an American Heart Association-National Cholesterol Education Program step 1 diet at baseline and after addition of 4 eggs per day for 4 weeks. Subjects were classified a priori into 3 groups based on their body mass index (BMI) and insulin sensitivity index (SI): lean insulin sensitive (LIS), mean+/-SEM BMI, 23.2+/-0.3 kg/m2, and SI, 6.7+/-0.3x10(-4)min(-1)/(microU/mL), n=66; lean insulin resistant (LIR), BMI, 24.5+/-0.2 kg/m2 and SI, 2.9+/-0.1x10(-4)min(-1)/(microU/mL), n=76; or obese insulin resistant (OIR), BMI, 31.4+/-0.5 kg/m2 and SI, 2.1+/-0.1x10(-4)min(-1)/(microU/mL), n=59. Insulin resistance and obesity each were associated with increased baseline levels of both CRP (P for trend, <0.001) and SAA (P for trend=0.015). Egg feeding was associated with significant increases in both CRP and SAA in the LIS group (both P<0.01) but not in the LIR or OIR groups. Egg feeding also was associated with a significant increase in non-HDL cholesterol (P<0.001) in LIS subjects; however, there was no correlation between the change in non-HDL cholesterol or changes in either CRP or SAA in this group. CONCLUSIONS: A high-cholesterol diet leads to significant increases in both inflammatory markers and non-HDL cholesterol levels in insulin-sensitive individuals but not in lean or obese insulin-resistant subjects.

Lipoprotein effects of combined ezetimibe and colesevelam hydrochloride versus ezetimibe alone in hypercholesterolemic subjects: a pilot study.

Two drug classes act in the intestine to lower cholesterol. Ezetimibe inhibits cholesterol absorption, whereas bile acid-binding resins enhance cholesterol excretion via enhanced conversion to bile acids. Combining these 2 classes may be beneficial, but cholestyramine binds ezetimibe, and the combined effect of colesevelam hydrochloride and ezetimibe was little studied. The aim of the study was to determine if adding colesevelam HCl to ezetimibe provides additional lowering of low-density lipoprotein- and apolipoprotein B-containing lipoproteins or alters ezetimibe levels. Twenty subjects with low-density lipoprotein cholesterol (LDL-C) levels of 130 mg/dL or higher were enrolled and taught a National Cholesterol Education Program Step I diet. At a second baseline visit, lipoproteins were measured and subjects were randomly allocated to (1) ezetimibe 10 mg daily with placebo colesevelam HCl twice daily (E) or (2) ezetimibe 10 mg daily with 1.875 g colesevelam HCl twice daily (E + C). Lipoproteins were measured 6 and 12 weeks after initiating treatment. Baseline characteristics (mean +/- SD) were statistically indistinguishable in E vs E + C: LDL-C (mg/dL), 167 +/- 26 and 158 +/- 27; triglyceride, 134 +/- 75 and 140 +/- 67; and BMI, 29.4 +/- 4.9 and 27.8 +/- 6.6 kg/m(2), respectively. Percent changes after 12 weeks in E vs E + C were as follows: LDL-C, -24 +/- 12 vs -30 +/- 11 (P = .102); triglyceride, -19 +/- 34 vs 36 +/- 85 (P = .054; at 6 weeks, P = .009); total cholesterol, -19 +/- 9 vs -15 +/- 8 (P = .50); non-high-density lipoprotein cholesterol, -25 +/- 10 vs -21 +/- 11 (P = .70); apolipoprotein B, -31 +/- 14 vs -22 +/- 14 (P = .41). Plasma ezetimibe levels at 12 weeks were 21% lower in E + C vs E, a nonsignificant difference (P = .54). In conclusion, in the short term, colesevelam HCl may not consistently add cholesterol-lowering benefit to ezetimibe. This observation requires confirmation.

Elevated pregnancy losses at high and low extremes of maternal glucose in early normal and diabetic pregnancy: evidence for a protective adaptation in diabetes.

OBJECTIVE: Early pregnancy losses increase with marked hyperglycemia in diabetic pregnancy. However, mean loss rates do not differ from those of nondiabetic pregnancy. This observation might be explained by increased fetal losses at the extremes of glycemia in diabetic and nondiabetic pregnancy. To test this hypothesis, we examined relationships of proximate measures of prior glycemia, glycated protein and fructosamine, to pregnancy loss. RESEARCH DESIGN AND METHODS: A total of 389 diabetic and 429 nondiabetic pregnant subjects participated in the Diabetes In Early Pregnancy study. Glycated protein and fructosamine measurements were standardized as multiples of control values for each center (Z score). The logarithm of odds of pregnancy loss were plotted against Z scores and tested by logistic models. RESULTS: Mean pregnancy loss rates were 12% in diabetic and 13% in normal pregnancies. However, over six intervals of glycated protein in diabetic pregnancy, fetal loss rates at the upper and lower extremes (24 and 33%, respectively) were approximately threefold higher than the four intervening rates (8-14%). The odds ratio of pregnancy loss for these extreme intervals to the intervening intervals is 3.0 (P = 0.01). Nondiabetic losses showed a similar pattern. In confirmation, logit pregnancy losses were increased in a J-shaped curve at the glycemic extremes in normal (P < 0.019) and diabetic (P < 0.015) pregnancy. The upper glycemic extreme in diabetic pregnancy was two- to fivefold higher than in control pregnancy. CONCLUSIONS: Pregnancy losses are increased at the extremes of glycemia in both normal and diabetic pregnancy but at higher levels in diabetic pregnancy. The data suggest defensive adaptations against hyperglycemia in diabetic pregnancy.

Effect of raloxifene on serum triglycerides in women with a history of hypertriglyceridemia while on oral estrogen therapy.

OBJECTIVE: Raloxifene hydrochloride is a selective estrogen receptor modulator that to date has not been shown to cause hypertriglyceridemia in normal, diabetic, or hypertriglyceridemic women. This study was designed to assess the effect of raloxifene on serum triglycerides in postmenopausal women who have a history of increased hypertriglyceridemia with oral estrogen therapy. RESEARCH DESIGN AND METHODS: This was a single-center, uncontrolled, open-label study investigating the effects of 8 weeks of raloxifene (60 mg/day) therapy on plasma lipids. The study subjects were 12 postmenopausal women, ages 49-73 years, with a documented history of oral estrogen-induced hypertriglyceridemia (serum triglycerides > or =3.39 mmol/l [> or =300 mg/dl]). RESULTS: At week 2 of the study, three (25%) of the subjects withdrew from the trial because they developed marked hypertriglyceridemia (>or =11.3 mmol/l [> or =1,000 mg/dl]) during raloxifene therapy. These three women had higher baseline triglyceride and glucose levels, were not being treated with lipid-lowering agents, and were more likely to have diabetes than the other study subjects. The remaining nine patients (75%) completed the 8-week trial and experienced a nonsignificant increase in mean triglyceride levels from baseline to end point. Raloxifene treatment also resulted in a significant 16% decrease in hepatic lipase activity and a 26% increase in HDL(2) levels (P = 0.013 and 0.03, respectively). CONCLUSIONS: Patients with a previous history of hypertriglyceridemia on oral estrogen therapy should have serum triglyceride levels monitored closely after beginning raloxifene therapy and may even require fibrate therapy before beginning raloxifene.

Cell membrane trans-fatty acids and the risk of primary cardiac arrest.

BACKGROUND: The relation of trans-fatty acid intake to life-threatening arrhythmias and primary cardiac arrest is unknown. METHODS AND RESULTS: We investigated the association of trans-fatty acid intake, assessed through a biomarker, with the risk of primary cardiac arrest in a population-based case-control study. Cases, aged 25 to 74 years, were out-of-hospital cardiac arrest patients attended by paramedics in Seattle, Washington from 1988 to 1999 (n=179). Controls, matched to cases by age and sex, were randomly identified from the community (n=285). Participants were free of previous clinically diagnosed heart disease. Blood was obtained at the time of cardiac arrest (cases) or at the time of an interview (controls) to assess trans-fatty acid intake. Higher total trans-fatty acids in red blood cell membranes was associated with a modest increase in the risk of primary cardiac arrest after adjustment for medical and lifestyle risk factors (odds ratio for interquintile range, 1.5; 95% CI, 1.0 to 2.1). However, trans isomers of oleic acid were not associated with risk (odds ratio for interquintile range, 0.8; 95% CI, 0.5 to 1.2), whereas higher levels of trans isomers of linoleic acid were associated with 3-fold increase in risk (odds ratio for interquintile range, 3.1; 95% CI, 1.7 to 5.4). CONCLUSIONS: These findings suggest that dietary intake of total trans-fatty acids is associated with modest increase and trans isomers of linoleic acid with a larger increase in the risk of primary cardiac arrest. These associations need to be confirmed in future studies that distinguish between trans isomers of linoleic acid and trans isomers of oleic acid.

The atherogenic lipoprotein profile associated with obesity and insulin resistance is largely attributable to intra-abdominal fat.

Obesity and insulin resistance are both associated with an atherogenic lipoprotein profile. We examined the effect of insulin sensitivity and central adiposity on lipoproteins in 196 individuals (75 men and 121 women) with an average age of 52.7 years. Subjects were subdivided into three groups based on BMI and their insulin sensitivity index (S(I)): lean insulin sensitive (n = 65), lean insulin resistant (n = 73), and obese insulin resistant (n = 58). This categorization revealed that both obesity and insulin resistance determined the lipoprotein profile. In addition, the insulin-resistant groups had increased central adiposity. Increasing intra-abdominal fat (IAF) area, quantified by computed tomography scan and decreasing S(I), were important determinants of an atherogenic profile, marked by increased triglycerides, LDL cholesterol, and apolipoprotein B and decreased HDL cholesterol and LDL buoyancy (Rf). Density gradient ultracentrifugation (DGUC) revealed that in subjects who had more IAF and were more insulin resistant, the cholesterol content was increased in VLDL, intermediate-density lipoprotein (IDL), and dense LDL fractions whereas it was reduced in HDL fractions. Multiple linear regression analysis of the relation between the cholesterol content of each DGUC fraction as the dependent variable and IAF and S(I) as independent variables revealed that the cholesterol concentration in the fractions corresponding to VLDL, IDL, dense LDL, and HDL was associated with IAF, and that S(I) additionally contributed independently to VLDL, but not to IDL, LDL, or HDL. Thus an atherogenic lipoprotein profile appears to be the result primarily of an increase in IAF, perhaps via insulin resistance.

Impact of intra-abdominal fat and age on insulin sensitivity and beta-cell function.

The prevalence of glucose intolerance and type 2 diabetes increases with age. To determine whether the hyperbolic relationship between insulin sensitivity and the insulin response is affected by age and whether the decline in beta-cell function with age is related to increases in intra-abdominal fat or age per se, we studied 220 healthy subjects with fasting glucose <6.1 mmol/l (89 men and 131 women, aged 26-75 years, BMI 18.7-40.4 kg/m(2)). The insulin sensitivity index (S(i)) and the acute insulin response to glucose (AIRg) were determined, and from these beta-cell function was estimated as the disposition index (S(i) x AIRg). Intra-abdominal fat and subcutaneous fat areas were quantified by computed tomography. S(i) (5.40 +/- 0.5 vs. 7.86 +/- 0.7 x10(-5) min(-1)/[pmol/l]), P < 0.01) was decreased and intra-abdominal fat (117 +/- 10 vs. 81 +/- 9 cm(2), P < 0.05) was increased in the oldest (age 60-75 years) versus the youngest (age 26-44 years) quartile. The hyperbolic relationship between S(i) and AIRg was present independent of age; thus, beta-cell function measured as the disposition index (1,412 +/- 120 vs. 2,125 +/- 150 x10(-5) min(-1), P < 0.01) was lower in the oldest versus the youngest quartile. In multiple regression, intra-abdominal fat (r = -0.470, P < 0.001) but not age was associated with S(i), but both intra-abdominal fat (r = -0.198, P = 0.003) and age (r = -0.131, P = 0.05) were correlated with the disposition index. These data suggest that although intra-abdominal fat is a strong determinant of insulin sensitivity and beta-cell function, age has an independent effect on beta-cell function that may contribute to the increased prevalence of type 2 diabetes in older populations.

Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome.

The underlying pathophysiology of the metabolic syndrome is the subject of debate, with both insulin resistance and obesity considered as important factors. We evaluated the differential effects of insulin resistance and central body fat distribution in determining the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. In addition, we determined which NCEP criteria were associated with insulin resistance and central adiposity. The subjects, 218 healthy men (n = 89) and women (n = 129) with a broad range of age (26-75 years) and BMI (18.4-46.8 kg/m2), underwent quantification of the insulin sensitivity index (Si) and intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas. The metabolic syndrome was present in 34 (15.6%) of subjects who had a lower Si [median: 3.13 vs. 6.09 x 10(-5) min(-1)/(pmol/l)] and higher IAF (166.3 vs. 79.1 cm2) and SCF (285.1 vs. 179.8 cm2) areas compared with subjects without the syndrome (P < 0.001). Multivariate models including Si, IAF, and SCF demonstrated that each parameter was associated with the syndrome. However, IAF was independently associated with all five of the metabolic syndrome criteria. In multivariable models containing the criteria as covariates, waist circumference and triglyceride levels were independently associated with Si and IAF and SCF areas (P < 0.001). Although insulin resistance and central body fat are both associated with the metabolic syndrome, IAF is independently associated with all of the criteria, suggesting that it may have a pathophysiological role. Of the NCEP criteria, waist circumference and triglycerides may best identify insulin resistance and visceral adiposity in individuals with a fasting plasma glucose <6.4 mmol/l.

The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations : distinct metabolic effects of two fat compartments.

Obesity is associated with insulin resistance, particularly when body fat has a central distribution. However, insulin resistance also frequently occurs in apparently lean individuals. It has been proposed that these lean insulin-resistant individuals have greater amounts of body fat than lean insulin-sensitive subjects. Alternatively, their body fat distribution may be different. Obesity is associated with elevated plasma leptin levels, but some studies have suggested that insulin sensitivity is an additional determinant of circulating leptin concentrations. To examine how body fat distribution contributes to insulin sensitivity and how these variables are related to leptin levels, we studied 174 individuals (73 men, 101 women), a priori classified as lean insulin-sensitive (LIS, n = 56), lean insulin-resistant (LIR, n = 61), and obese insulin-resistant (OIR, n = 57) based on their BMI and insulin sensitivity index (S(I)). Whereas the BMI of the two lean groups did not differ, the S(I) of the LIR subjects was less than half that of the LIS group. The subcutaneous and intra-abdominal fat areas, determined by computed tomography, were 45 and 70% greater in the LIR subjects (P < 0.001) and 2.5- and 3-fold greater in the OIR group, as compared with the LIS group. Fasting plasma leptin levels were moderately increased in LIR subjects (10.8 +/- 7.1 vs. 8.1 +/- 6.4 ng/ml in LIS subjects; P < 0.001) and doubled in OIR subjects (21.9 +/- 15.5 ng/ml; P < 0.001). Because of the confounding effect of body fat, we examined the relationships between adiposity, insulin sensitivity, and leptin concentrations by multiple regression analysis. Intra-abdominal fat was the best variable predicting insulin sensitivity in both genders and explained 54% of the variance in S(I). This inverse relationship was nonlinear (r = -0.688). On the other hand, in both genders, fasting leptin levels were strongly associated with subcutaneous fat area (r = 0.760) but not with intra-abdominal fat. In line with these analyses, when LIS and LIR subjects were matched for subcutaneous fat area, age, and gender, they had similar leptin levels, whereas their intra-abdominal fat and insulin sensitivity remained different. Thus, accumulation of intra-abdominal fat correlates with insulin resistance, whereas subcutaneous fat deposition correlates with circulating leptin levels. We conclude that the concurrent increase in these two metabolically distinct fat compartments is a major explanation for the association between insulin resistance and elevated circulating leptin concentrations in lean and obese subjects.