Statin therapy for primary prevention in women: What is the role for coronary artery calcium?

By current guidelines, statin treatment decisions depend on multiple risk factor algorithms (e.g., pooled cohort equations [PCEs]). By available PCEs most older middle-aged women are statin eligible. But several studies cast doubt on reliability of available PCEs for ASCVD risk assessment. An alternative method for risk assessment is a coronary artery calcium (CAC) score. Many older women have zero CAC, which equates to low risk for ASCVD; these women can delay statin therapy for several years before re-scanning. When CAC is 1-99 Agatston units, risk is only borderline high and statin delay also is an option until re-scanning. When CAC is > 100 Agatston units, risk is high enough to warrant a statin. In most women, CAC is the best guide to treatment decisions. In high-risk women (e.g., diabetes and severe hypercholesterolemia), generally are indicated, but CAC can assist in risk assessment, but other risk factors also can aid in treatment decisions.

Utility of metabolic syndrome as a risk enhancing factor in decision of statin use.

BACKGROUND: Statins effectively reduce risk for atherosclerotic cardiovascular disease (ASCVD) when 10-year risk is ≥ 7.5%. In many patients at intermediate risk (7.5-<20% risk), there is uncertainty about reliability of risk assessment by current pooled cohort equations (PCE). A decision to initiate statin therapy is favored by several risk enhancing factors not employed in PCEs. OBJECTIVE: This study examines the scope of the metabolic syndrome, a risk enhancing factor, and its principal sequala, diabetes, in 26,796 US adults age 40-75 years from the NHANES survey data, 1999-2016. METHODS: The prevalence of metabolic syndrome without diabetes (MetS+) and of diabetes (DM+) were determined for 10-year risk categories estimated to be low (<7.5%), intermediate (7.5% -< 20%) and high (≥20%). Data were weighted to account for complex study design. RESULTS: 90.4% of the population was free of ASCVD. In subjects projected to be at low risk by PCEs, MetS+ was present in 15.0% and 17.6% of women and men, respectively. MetS + increased to 30.6% of women and 29.6% of men at intermediate risk, and to 21.5% of women and 32.2% of men at high risk. In addition, DM+ was present in 6.1%/5.3% (F/M) of low risk individuals, 20.1%/14.8% (F/M) of intermediate risk subjects, and 44.3%/39.4% (F/M) of high-risk persons. Prevalence of both MetS+ and DM + rose progressively with age in women and men. CONCLUSIONS: MetS+ and DM + are common multiplex risk factors that predispose to higher lifetime risk and support statin therapy in patients at intermediate and high risk.

Chronic kidney disease and statin eligibility.

BACKGROUND: Chronic kidney disease (CKD) is a risk factor for atherosclerotic cardiovascular disease (ASCVD). American cardiovascular societies consider CKD a risk-enhancing factor that supports statin therapy in intermediate-risk patients aged 40-75 years. In contrast, European cardiovascular societies recommend statins for all middle-aged adults with CKD. The Kidney Disease: Improving Global Outcomes lipid management guideline for CKD recommends statin therapy for all patients with CKD >50 years. Clinical implications for these differences have not been examined. OBJECTIVE: This study examines CKD prevalence and statin eligibility in non-ASCVD adults, representative of the US population, at 3 levels of 10-year risk of ASCVD estimated by pooled cohort equations. METHODS: National Health and Nutrition Examination Surveys 1999-2016 weighted data were evaluated for CKD defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2. Overall prevalence of low, intermediate, and high 10-year risk for ASCVD was determined. RESULTS: A total of 92.5% of all participants had estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2; 7.5% (confidence interval 6.9%, 8.1%) had CKD. Among participants with CKD, 46.3% had 10-year risk for ASCVD <7.5% (low risk); 31.7% had intermediate risk (7.5-< 20%), and 22.0% had high risk (≥20%). In participants with CKD, 62.5% were women. A total of 19.6% of all participants with CKD had diabetes. A total of 46.3% of participants with CKD at intermediate or high risk reported taking cholesterol-lowering drugs. CONCLUSION: A total of 46.3% of patients with CKD aged 40-75 years had 10-year risk <7.5% (low risk) and hence were statin eligible by European and Kidney Disease: Improving Global Outcomes (>50 years) guidelines. US cardiovascular guidelines limit statin eligibility to intermediate- and high-risk CKD. Statin eligibility in lower-risk patients may be best determined by measuring coronary artery calcium.

Coronary and peripheral artery plaques: do differences in plaque characteristics translate to differences in lipid management?

Optimal medical management of patients with peripheral arterial disease (PAD) includes statin therapy, which has been shown to decrease the risk of major cardiovascular events. However, the relationship between low-density lipoprotein (LDL) lowering, PAD progression and limb outcomes remains controversial. Although prevention of coronary and cerebrovascular events is a priority, limb outcomes are still important determinants of quality of life and healthcare spending. This review will highlight differences between coronary artery disease (CAD) and PAD, and in particular, the more prevalent role of lipids and LDL cholesterol in CAD versus calcification in PAD. This difference may contribute to the differential impact of LDL cholesterol levels on coronary events and outcomes versus limb outcomes. Beyond LDL lowering, immune modulators have emerged as another agent to treat atherosclerosis in CAD, however similar data in PAD are lacking. Small studies have suggested that other lipids besides LDL cholesterol, such as triglycerides or small dense LDL, may have a greater impact on limb outcomes in patients with PAD. Although statin therapy is central in the management of patients with PAD, current understanding of the distinctions between PAD and CAD suggest that there may be other non-LDL targets for risk reduction that require further study.

Temporal decline in non-high-density lipoprotein cholesterol in subjects with diabetes mellitus without atherosclerotic cardiovascular disease.

BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-C) includes atherogenic cholesterol and low-density lipoproteins (LDL) and triglyceride-rich lipoproteins. Patients with diabetes frequently have elevations in non-HDL-C. OBJECTIVE: This study examines temporal trends in the levels of non-HDL-C in free-living subjects with diabetes but a negative history of atherosclerotic cardiovascular disease. METHODS: National Health and Nutrition Examination Surveys conducted between 1999 and 2016 had data from 3,219 adults (aged 40-75 years) with diabetes. Temporal trends in changes in the distribution of total cholesterol, non-HDL-C, LDL cholesterol (LDL-C), and HDL-C were evaluated. Data were weighted to account for complex survey design. RESULTS: Significant decreases were observed in non-HDL-C (20.1%; P < .0001) and total cholesterol (16.1%; P < .0001) levels between 1999 and 2016. No significant changes were noted in HDL-C levels. LDL-C was reduced by 29.6% in a subset of subjects. The reduction in non-HDL-C and LDL-C occurred simultaneously, with an increase of 4.4% of subjects per year taking cholesterol-lowering drugs and statins. In contrast, the fraction of subjects taking antihypertensives or hypoglycemia agents rose at a rate of 2.2% per year. There was also a significant trend for increases in weight gain (P ≤ .013). CONCLUSIONS: In subjects with diabetes, non-HDL-C levels have declined over time in parallel with reported increases in cholesterol-lowering drugs. Nonetheless, treatment targets for lipids in subjects with diabetes lag behind current recommendations. Reported intakes for antihypertensive agents and hypoglycemia agents were relatively high throughout the period of study, with little change over time. However, there was a trend for weight increase in diabetic subjects, which may offset some of the benefits of pharmacotherapy.

Traditional signs and symptoms commonly attributed to hypogonadism do not correlate with testosterone levels: the Cooper Center Longitudinal Study Experience.

Evidence suggests that substantial testosterone therapy is occurring without checking levels of testosterone, presumably based on the presence of symptoms alone. We sought to explore the relationship between total testosterone level and non-specific symptoms, metabolic abnormalities, and sexual dysfunction associated with hypogonadism. This cross-sectional study included 2994 generally healthy men aged 50-79 years examined at a preventive medicine clinic in Dallas, TX from January 2012 to March 2016. Symptoms of hypogonadism were assessed. Screening morning total testosterone levels were measured and categorized into low (<250 ng/dL), low normal (250-399 ng/dL), and normal (≥400 ng/dL). Multiple logistic regression models were used to test the associations between total testosterone and signs and symptoms of hypogonadism. When considering symptoms and signs of hypogonadism, only decreased libido (OR 1.31, 95% CI 1.00 to 1.70), fasting glucose ≥100 mg/dL (OR 1.47, CI 1.15 to 1.88), and hemoglobin A1c over 6% (OR 1.47, 95% CI 1.06 to 2.03) were associated with increased odds of low testosterone after adjustment for age, body mass index, and cardiorespiratory fitness. Testosterone levels were not associated with fatigue, depression, or erectile dysfunction in our study (p>0.6). In this preventive medicine cohort, symptoms commonly attributed to testosterone deficiency were not associated with low total testosterone levels.

Impaired hepatic ketogenesis in moderately obese men with hypertriglyceridemia.

BACKGROUND: Several studies suggest that increased nonesterified fatty acid flux and increased de novo lipogenesis may contribute to hypertriglyceridemia, but few studies have examined fatty acid oxidation as a factor. RATIONALE: Endogenous hypertriglyceridemia (increased very low density lipoprotein triglyceride) could result from (a) re-esterification of excess nonesterified fatty acids entering the liver, (b) activation of hepatic lipogenesis, and/or (c) defective oxidation of hepatic fatty acids leading to greater triglyceride synthesis. Therefore, this study used plasma levels of 3-hydroxybutyrate as a marker for fatty acid oxidation. The study was carried out in hypertriglyceridemic and normotriglyceridemic subjects under 3 conditions: (a) in the fasting state, (b) after a fatty meal that should enhance fatty acid oxidation, and (c) after an oxandrolone challenge, which we recently showed increases fatty acid oxidation. RESULTS: In the fasting state, 3-hydroxybutyrate concentrations in hypertriglyceridemic patients were only 53% of levels in normotriglyceridemic subjects. After a fatty meal, moderate increases in 3-hydroxybutyrate were observed, but values for patients with hypertriglceridemia remained 62% of the levels in the normotriglyceridemic group. A similar pattern of response was observed with oxandrolone challenge. There were no significant changes in fasting or postprandial levels of nonesterfified fatty acids, glycerol, or triglycerides before and during the oxandrolone challenge. CONCLUSION: Patients with endogenous hypertriglyceridemia seem to have a defect in fatty acid oxidation as indicated by reduced levels of 3-hydroxybutyrate. This defect was observed during fasting, postprandially, and during oxandrolone challenge. We propose that this defect contributes to the development of hypertriglyceridemia.

Current trends in non-HDL cholesterol and LDL cholesterol levels in adults with atherosclerotic cardiovascular disease.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) are targets for prevention of atherosclerotic cardiovascular disease (ASCVD). The American Heart Association and American College of Cardiology recently modified recommendations for clinical management of cholesterol in secondary and primary prevention. Accordingly, the present article examines the need for cholesterol-lowering drugs in the U.S. population with ASCVD. OBJECTIVE: This study examines trends in non-HDL-C and LDL-C levels in a free living population of ASCVD subjects between 1999 and 2016. METHODS: National Health and Nutrition Examination Surveys database included 4920 adults with ASCVD aged 40 to 85 years. Complete data were available for 4226. Trend analysis of changes in lipids is shown in box plots. RESULTS: Mean age was 67 years with 57% males. Over 17 years, LDL-C decreased significantly by 24% and non-HDL-C by 21%. Over the period of study, reported intake of cholesterol-lowering drugs rose from 37% in 1999-2000 to 69% in 2015 to 2016. Over this same period, serum triglycerides decreased by 29% (P < .001) and HDL-C rose by 6%. CONCLUSIONS: The changes in LDL-C and non-HDL-C in patients with ASCVD over a 17-year period probably are related to increased treatment with statins. However, the changes are too small to be explained by widespread use of high-intensity statins, which is the current recommendation for patients with ASCVD. These findings pose a challenge for professional education to support implementation of current guidelines for cholesterol-lowering therapies.

Metabolic syndrome is a sequela of radiation exposure in hypothalamic obesity among survivors of childhood brain tumors.

Survivors of childhood brain tumors may be at risk for early onset of metabolic syndrome, possibly secondary to surgery and/or radiation exposure. This study examines effects of radiation exposure to hypothalamus-pituitary-adrenal axis (HPA) on metabolic risk among survivors of childhood brain tumors. One hundred forty-two met inclusion criteria; 60 had tumor surgery plus radiation exposure (>1 Gray (Gy)) to HPA. The second subgroup of 82 subjects had surgery only and were not exposed to radiation. Both subgroups had survived for approximately 5 years at the time of study. All had clinical evaluation, vital signs, anthropometry, measurement of body composition by dual X-ray absorptiometry and fasting laboratory assays (metabolic panel, insulin, C-peptide, insulin-like growth factor-1, leptin and adiponectin). Body composition data for both subgroups was compared with the National Health and Nutrition Survey (NHANES) subgroup of similar age, gender and body mass index. Cranial surgery was associated with obesity of similar severity in both subgroups. However, survivors exposed to radiation to the HPA also had increased visceral fat mass and high prevalence of growth hormone deficiency and metabolic syndrome. Fat mass alone did not explain the prevalence of the metabolic syndrome in radiation exposure subgroup. Other factors such as growth hormone deficiency may have contributed to metabolic risk. We conclude that prevalence of metabolic syndrome among subjects exposed to hypothalamic radiation was higher than expected from hypothalamic obesity alone. Radiation exposure may exert untoward endocrinopathies due to HPA exposure that worsens metabolic risk. Early screening for metabolic syndrome in this population is indicated.

Oxandrolone enhances hepatic ketogenesis in adult men.

BACKGROUND: Immediate administration of oxandrolone markedly increases hepatic lipase activity and reduces levels of plasma high-density lipoprotein. RATIONALE FOR THE STUDY: We postulated that oxandrolone should increase hepatic lipase and that the nonesterified fatty acids generated would enhance hepatic ketogenesis during an extended fat tolerance test. MAIN RESULTS: Eighteen men participated in the study using short-term administration of oxandrolone (10 mg/d) over a week. Subjects had evaluation of hepatic ketogenesis at baseline and after 7 days of administration of oxandrolone. Ketogenesis was assessed by measuring plasma levels of 3-hydroxybutyrate during a fat tolerance test. Oxandrolone increased fasting levels of 3-hydroxybutyrate by 70%, and increased the area under the curve during an FFT by 53% above pretreatment levels without affecting the areas under the curve for nonesterified fatty acids, glycerol, or triglycerides. Fasting 3-hydroxybutyrate levels correlated with nonesterified fatty acids and with triglycerides; however, there were no significant correlations with any other parameter. CONCLUSIONS: This study shows that short-term administration of oxandrolone results in marked increases in hepatic ketogenesis. This finding is consistent with an increased influx of fatty acids into the liver secondary to lipoprotein lipolysis by increased hepatic lipase. However, the possibility cannot be ruled out that oxandrolone acts directly in the liver to stimulate fatty acid oxidation. Therefore, the observation of increased ketogenesis will require further studies to determine the molecular basis of the response.

Effects of N-3 fatty acids on hepatic triglyceride content in humans.

BACKGROUND: Because dietary N-3 fatty acids reduce plasma triglycerides, they may also decrease hepatic triglyceride content. If so, N-3 fatty acids might constitute a therapy for fatty liver. METHODS: Twenty-two subjects were recruited into a study designed to test the effects of N-3 fatty acids on liver fat content. Seventeen completed the trial that had a sequential design of 4-week placebo followed by an 8-week treatment with 9 g/d of fish oil. Liver fat was measured during placebo and treatment by magnetic resonance spectroscopy. Compliance was assessed by capsule count at the end of each study phase and measurement of fatty acid composition in plasma triglyceride and phospholipid. Plasma lipoproteins and adiponectin were also measured. RESULTS: Treatment with fish oils reduced significantly levels of plasma triglyceride by 46% (P <.03), very low-density lipoprotein + intermediate density lipoprotein cholesterol by 21% (P <.03), total apolipoprotein B by 15% (P <.03). In contrast to the changes in plasma triglycerides, hepatic triglyceride content was not significantly reduced by fish oil treatment. CONCLUSIONS: N-3 fatty acids at high doses lower plasma triglyceride levels, but there are no significant decreases in hepatic content of triglyceride for the group as a whole. Whereas the triglyceride lowering is uniform, the liver response is more variable.

Ten-year risk of cardiovascular incidence related to diabetes, prediabetes, and the metabolic syndrome.

BACKGROUND: The relative contributions of the metabolic syndrome (MetS) and dysglycemia on the risk of cardiovascular disease (CVD) have not been dissected. We aimed to compare MetS with dysglycemia in their association with the 10-year incidence risk of CVD. METHODS: A total of 30,378 subjects were recruited from 11 provinces in the CMCS and followed-up for new coronary heart disease (CHD) and stroke events (ischemic stroke and hemorrhagic stroke) for 10 years. Incidence rates and HRs were estimated by the presence or absence of MetS, impaired fasting glucose (IFG) and diabetes, and by the various traits of MetS. RESULTS: Among the subjects, 18.2% were defined as having MetS; 21.1% had IFG, and 6.8% had diabetes. Metabolic syndrome prevalence in IFG and diabetes was 38.1% and 48.7%, respectively, and the prevalence of IFG and diabetes in MetS was 44.1% and 18.3%, respectively. After adjusting for nonmetabolic risk factors, HRs of total CVD, CHD, and ischemic stroke in MetS were significant and higher than those in non-MetS, regardless of glycemic status. In the absence of MetS, the impact of dysglycemia was found only in IFG to CHD and diabetes to ischemic stroke. Hyperglycemia without any concomitant disorders was not associated with significantly higher risk of CVD. CONCLUSIONS: The increased CVD risk in individuals with IFG or diabetes was largely driven by the coexistence of multiple metabolic disorders rather than hyperglycemia per se. Identification of clustering of metabolic abnormalities should be given more consideration in CVD prevention.

Plasma 24S hydroxycholesterol response to statins in Alzheimer's disease patients: effects of gender, CYP46, and ApoE polymorphisms.

A number of epidemiologic studies suggest an association between plasma total cholesterol and risk for Alzheimer's disease (AD). Additionally, it has been suggested that treatment with statins, drugs that block cholesterol biosynthesis, lower the incidence and prevalence of AD and of vascular dementia. This review provides an overview of cholesterol transport within the central nervous system and the impact of statins on brain cholesterol metabolism in subjects with AD. Brain cholesterol is converted to 24-S-hydroxycholesterol, a reaction catalyzed by CYP46. The oxysterol traverses the blood-brain barrier and is transported to the liver by plasma lipoproteins. The levels of 24-S-hydroxy-cholesterol are a reflection of brain cholesterol turnover. Subjects with AD reportedly have high levels of the oxysterol possibly reflecting neuronal death with release of cell membrane cholesterol. We show gender dimorphism in plasma levels of 24-S-hydroxycholesterol in subjects with AD and significant reductions in plasma levels of the oxysterol during treatment with standard doses of statins (lovastatin, simvastatin, and pravastatin). Polymorphisms of apolipoprotein E and CYP46 do not influence the effect of statins on plasma levels of 24-S-hydroxycholesterol. There were no untoward effects of the standard doses of statin for the duration of treatment. Statins are currently in trial to determine their effect on the course of AD.

Relationship of apolipoprotein B levels to the number of risk factors for metabolic syndrome.

Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipid-lowering therapy. However, all lipoproteins containing apolipoprotein B (apo B) appear to be atherogenic. Preferred targets of therapy therefore may include either the cholesterol in all apo B-containing lipoproteins (non-high-density lipoprotein cholesterol [non-HDL-C]) or total apo B itself. Apo B can be measured by three methods: chemically, by nuclear magnetic resonance (NMR), and by immunoassay. This study compares the first two methods as a function of the number of metabolic risk factors in patients with metabolic syndrome. Plasma lipid, lipoprotein cholesterol, and apo B levels were measured in 274 adults with varying numbers of metabolic syndrome components. Low-density lipoprotein (LDL) particle sizes were measured by gel electrophoresis and by NMR. Total apo B was estimated chemically and by conversion of NMR lipoprotein particle number, assuming one apo B molecule per lipoprotein particle. As the number of metabolic syndrome components increased, apo B rose by both chemical and NMR methods, but by chemical methods, increases were in the triglyceride-rich fraction, whereas by NMR, they were in LDL. The correlation between total apo B measured by the two methods was only moderate (r = .73). Further, non-HDL-C was more highly correlated with total apo B measured chemically than either LDL-C or total apo B by NMR. Non-HDL-C correlates highly with total apo B in patients with metabolic syndrome and had advantages as a target of therapy over LDL-C or NMR apo B.

Variability in postheparin hepatic lipase activity is associated with plasma adiponectin levels in African Americans.

BACKGROUND: African Americans commonly have normal high-density lipoprotein cholesterol (HDL-C) and low triglyceride levels despite having insulin resistance and obesity. The higher than expected HDL-C levels are usually attributed to low levels of hepatic triglyceride lipase (HTGL) activity. Factors that regulate HTGL in African Americans are not well delineated. METHODS: In the current study, HTGL activity was examined in relation to indices of body fat (body mass index [BMI] and waist circumference [WC]), insulin resistance (fasting plasma insulin and homeostasis model assessment of insulin resistance [HOMA-IR] index), and adipokines (adiponectin and leptin). Sixty-three African Americans (33 men, 30 women; median age 31 years, range 20-50 years; median BMI 28.6 kg/m2, range 19.7-54.7 kg/m2) had anthropometry and measurement of postheparin lipase activities (HTGL), plasma HDL-C, triglycerides, and plasma adiponectin. RESULTS: HTGL correlated strongly with HDL-C (r = -.52, p < .0001) and adiponectin (r = -.49, p < .001). HTGL increased with BMI and WC (r = .297, p = .018 and r = .301, p = .016, respectively). Adiponectin correlated strongly with HDL-C (r = .50, p < .0001) and triglycerides (r = -.493, p < .001). From multiple regression models, 28% of HTGL variability among African Americans can be explained by adiponectin levels in combination with gender and 35% of HTGL is explained with HDL-C included in the model. CONCLUSION: The data suggest that adiponectin is a significant metabolic concomitant of HTGL activity in African Americans.

Metabolic Concomitants of Obese and Nonobese Women With Features of Polycystic Ovarian Syndrome.

CONTEXT: Polycystic ovarian syndrome (PCOS) is often associated with obesity and diabetes. OBJECTIVE: The present study measured body fat distribution and metabolic risk factors in women with features of PCOS. DESIGN: Cross-sectional, multiethnic study of cardiovascular risks. SETTING: General community. STUDY PARTICIPANTS: 145 PCOS and 344 non-PCOS women. EXPOSURE MEASURES: Body composition by dual x-ray absorptiometry; abdominal fat masses measured by magnetic resonance imaging and hepatic triglyceride by magnetic resonance spectroscopy. OUTCOMES MEASURES: Body composition, liver fat content, homeostatic model assessment for insulin resistance (HOMA-IR), revised, and metabolic syndrome components. RESULTS: PCOS women had a higher free androgen index compared with the non-PCOS women. Nonobese PCOS and non-PCOS women had a similar body fat content and distribution, HOMA-IR, and hepatic triglyceride content. Obese PCOS women had a similar total body fat percentage compared with their non-PCOS counterparts (41.4% and 41.4% respectively). Both obese groups had similar intraperitoneal fat (1.4% of total body mass in PCOS vs 1.4% in non-PCOS). However, obese PCOS women had a greater ratio of truncal/lower body fat (1.42 vs 1.27; P < 0.016). They also had greater insulin resistance (HOMA-IR: PCOS, 2.24% vs non-PCOS, 1.91%; P < 0.016), higher liver triglyceride content (6.96% in PCOS vs 4.44% in non-PCOS; P < 0.016), and a greater incidence of hypertension (33% vs 24%; P < 0.05). No differences were observed in other metabolic risk factors. CONCLUSIONS: Both obese and nonobese women with PCOS features had a greater free androgen index compared with non-PCOS women, but neither had greater intraperitoneal fat or abnormal lipid levels. Obese, but not nonobese, women with PCOS had a greater truncal/lower extremity fat ratio, HOMA-IR, and liver triglyceride content.

Influence of body fat content and distribution on variation in metabolic risk.

OBJECTIVES: Several reports indicate that the body fat compartments, especially ip fat, predict metabolic risk better than total body fat. The objective of the study was to determine whether this can be confirmed and generalized throughout the population. PARTICIPANTS: A representative sample of 1934 Black and White women and men of the Dallas Heart Study participated in the study. DESIGN: We measured the fat in total body, trunk, and lower body with dual-energy x-ray absorptiometry and in abdominal compartments (sc, ip, and retroperitoneal) with magnetic resonance imaging. Other measurements included body mass index (BMI), waist circumference, blood pressure, plasma lipids, glucose, insulin (including homeostasis model), and C-reactive protein. RESULTS: In all groups, total body fat correlated positively with key metabolic risk factors, i.e. homeostasis model, triglyceride/high-density lipoprotein-cholesterol ratios, C-reactive protein, and blood pressure; however, it explained less than one third of the variability of all the risk factors. After adjustment for total body fat, truncal fat conferred additional positive correlation with risk factors. Furthermore, with multivariable regression analysis, ip fat conferred independent correlation with plasma lipids beyond a combination of other compartments including truncal fat. Still, except for insulin levels, all combinations including ip fat still explained less than one third of the variability in risk-factor levels. Conversely, lower body fat correlated negatively with risk factors; i.e. lower body fat appeared to offer some protection against risk factors. CONCLUSIONS: Body fat distribution has some influence on risk factors beyond total body fat content. Both waist circumference and BMI significantly predicted risk factors after adjustment for total body fat, and for clinical purposes, most of the predictive power for men was contained in waist circumference, whereas for women, BMI and waist circumference were similarly predictive. Finally, even though the correlations between combined body fat parameters and risk factors explained only a portion of the variation in the latter, the average number of categorical metabolic risk factors increased progressively with increasing obesity. Hence, obesity seemingly has more clinical impact than revealed in these correlative studies.

Combination of fenofibrate plus low-dose nicotinic acid added to statin treatment in type 2 diabetes: An open-label, crossover study.

BACKGROUND: Plasma lipid abnormalities commonly persist in patients with diabetic dyslipidemia in spite of statin monotherapy. OBJECTIVE: The aim of this study was to determine whether fenofibrate plus low-dose nicotinic acid adequately improves the lipoprotein profile in patients with diabetic dyslipidemia who are being treated with a statin. METHODS: In this open-label, crossover study, patients with type 2 diabetes mellitus who were receiving statin treatment were enrolled at the Lipid Clinic of the Veterans Affairs Medical Center, Dallas, Texas, and administered simvastatin 20 mg/d for 8 weeks. At the end of the 8-week period, fenofibrate 160 mg/d was added for 8 weeks, followed by the addition of extended-release nicotinic acid 1 g/d for an additional 8 weeks. The first subject was recruited on September 25, 2003, and the last subject was recruited on September 28, 2004. Liver function tests, creatine phosphokinase activity, and blood glucose levels were assessed every 4 weeks to assess tolerability. Levels of fasting plasma lipids and lipoprotein cholesterol were measured every 8 weeks on 3 consecutive days in each patient; C-reactive protein, lipoprotein pattern, and glycosylated hemoglobin levels were assessed once every 8 weeks. Plasma levels of total cholesterol, triglycerides, very-low-density lipoprotein plus intermediate-density lipoprotein cholesterol (VLDL+IDL-C), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B were also measured. RESULTS: Twenty-six patients were enrolled in the study and 20 patients (18 men, 2 women; mean [SD] age, 58.8 [6.5] years) completed it. The mean plasma triglyceride level was significantly decreased (-29.2%; P= 0.004) and the mean HDL-C level was significantly increased (+13.5%; P < 0.001) with 3-drug treatment (simvastatin + fenofibrate + extended-release nicotinic acid) compared with simvastatin monotherapy. Significant reductions in plasma levels of VLDL+IDL-C (-35.7%; P = 0.001), VLDL+IDL-apolipoprotein B (-30%; P = 0.005), non-HDL-C (-12.9%; P = 0.001), and total-apolipoprotein B (-17.9%; P < 0.001) were seen with the 3-drug treatment compared with simvastatin alone. Compared with simvastatin monotherapy, simvastatin + fenofibrate-treated (2-drug treatment) patients had significantly lower plasma levels of triglycerides (-24.9%; P = 0.014) and significantly higher levels of HDL-C (+5.4%; P = 0.008). Significant reductions were also seen in levels of VLDL+IDL-C (-28.6%; P = 0.004), VLDL+IDL-apolipoprotein B (-26.7%; P < 0.001), non-HDL-C (-9.1 %; P= 0.004), and total-apolipoprotein B (-12.3%; P < 0.001) in the 2-drug treatment group compared with the simvastatin monotherapy group. The administration of 3-drug treatment was associated with improved responses in all lipoprotein fractions, although only the increase in HDL-C level was statistically significant (+7.7%; P = 0.008) compared with 2-drug treatment. CONCLUSIONS: Treatment with the 3-drug regimen was associated with a significant reduction in triglyceride levels compared with simvastatin monotherapy. However, there was not a significant incremental reduction in triglyceride levels when nicotinic acid was added to the 2-drug treatment, suggesting that the triglyceride-lowering effect of fenofibrate + nicotinic acid is not cumulative. To obtain clinically meaningful responses, particularly for the treatment of elevated HDL-C, higher doses of nicotinic acid might be required.

Fatty acid oxidation in normotriglyceridemic men.

BACKGROUND: Moderate hypertriglyceridemia is frequently associated with central obesity, insulin resistance, and atherogenic dyslipidemia. We showed previously that moderately obese men with hypertriglyceridemia have reduced fatty acid oxidation postabsorptively and postprandially. In the present study, we examined the oxidation of fatty acids in normotriglyceridemic men. OBJECTIVE: The study objective was to determine the relation between plasma triglyceride levels and fatty acid oxidation in normotriglyceridemic men. STUDY DESIGN: Twenty-four healthy, nonobese White and African American men participated in a cross-sectional metabolic study for evaluation of fatty acid oxidation. Men were healthy, and none took hypolipidemic or hypoglycemic agents. They ingested 200 mg of fat/hour/kg of body weight over a 10-hour period. Plasma levels of triglyceride, nonesterified fatty acids, 3-ß-hydroxybutyrate, insulin, and glucagon were measured postabsorptively and postprandially. Chylomicron-triglyceride halflife was also calculated. RESULTS: Nonobese White and African-American men had similar anthropometry, levels of plasma triglyceride, lipoprotein cholesterol, nonesterified fatty acids, 3-ß-hydroxybutyrate, insulin, and glucagon postabsorptively and postprandially. For the group as a whole, there was a positive and significant correlation between plasma fatty acids and 3-ß-hydroxybutyrate and an inverse association between plasma triglyceride levels and 3-ß-hydroxybutyrate at baseline. All subjects had increased levels of metabolites of interest postprandially. However, there were no significant changes in plasma insulin, glucagon, or the ratio of insulin to glucagon. The postprandial levels of 3-ß-hydroxybutyrate correlated positively with nonesterified fatty acids and inversely with the half-life of chylomicron triglyceride. CONCLUSION: Normotriglyceridemia is strongly associated with oxidation of fatty acids by the liver suggesting the possibility that the fatty acid oxidation pathway is a potential target of intervention to prevent hypertriglyceridemia and concomitant fatty liver.

Association of triglyceride-to-high density lipoprotein cholesterol ratio to cardiorespiratory fitness in men.

BACKGROUND: Both triglyceride-to-high density lipoprotein cholesterol (TG/HDL-C) and cardiorespiratory fitness (CRF) impart risk for all-cause morbidity and mortality independently of conventional risk factors. OBJECTIVE: To determine prevalence and/or incidence of high TG/HDL-C ratio in men with low CRF. METHODS: Clinical characteristics and CRF were used to determine prevalence of a TG/HDL-C ratio ≥ 3.5 (high ratio) in 13,954 men of the Cooper Center Longitudinal Study. High-ratio conversion was determined in 10,424 men with normal baseline TG/HDL-C ratio. Hazard ratio (HR) of incident high TG/HDL-C was adjusted for age and waist girth. RESULTS: Men with low CRF had the highest prevalence of a high TG/HDL-C ratio. In the population with normal TG/HDL-C, age-adjusted HR of incident high TG/HDL-C ratio was 2.77 times higher in men with lowest CRF than in those with highest CRF. Incidence of conversion of normal to high ratio was 5.5% per year in low CRF population, compared with 1.7% in high CRF subjects. Incidence HR was independent of waist girth. Men who converted from normal to high TG/HDL-C ratio during the follow-up period had increased number of metabolic risk factors and a higher prevalence of metabolic syndrome. Men who did not convert to a high TG/HDL-C ratio retained a low prevalence of metabolic syndrome risk factors. CONCLUSION: A high TG/HDL-C ratio is common in men with low CRF. Metabolic syndrome also is common among those with a high ratio.