Thyroid hormones and changes in body weight and metabolic parameters in response to weight loss diets: the POUNDS LOST trial.

BACKGROUND: The role of thyroid hormones in diet-induced weight loss and subsequent weight regain is largely unknown. OBJECTIVES: To examine the associations between thyroid hormones and changes in body weight and resting metabolic rate (RMR) in a diet-induced weight loss setting. SUBJECTS/METHODS: Data analysis was conducted among 569 overweight and obese participants aged 30-70 years with normal thyroid function participating in the 2-year Prevention of Obesity Using Novel Dietary Strategies (POUNDS) LOST randomized clinical trial. Changes in body weight and RMR were assessed during the 2-year intervention. Thyroid hormones (free triiodothyronine (T3), free thyroxine (T4), total T3, total T4 and thyroid-stimulating hormone (TSH)), anthropometric measurements and biochemical parameters were assessed at baseline, 6 months and 24 months. RESULTS: Participants lost an average of 6.6 kg of body weight during the first 6 months and subsequently regained an average of 2.7 kg of body weight over the remaining period from 6 to 24 months. Baseline free T3 and total T3 were positively associated, whereas free T4 was inversely associated, with baseline body weight, body mass index and RMR. Total T4 and TSH were not associated with these parameters. Higher baseline free T3 and free T4 levels were significantly associated with a greater weight loss during the first 6 months (P<0.05) after multivariate adjustments including dietary intervention groups and baseline body weight. Comparing extreme tertiles, the multivariate-adjusted weight loss±s.e. was -3.87±0.9 vs -5.39±0.9 kg for free T3 (Ptrend=0.02) and -4.09±0.9 vs -5.88±0.9 kg for free T4 (Ptrend=0.004). The thyroid hormones did not predict weight regain in 6-24 months. A similar pattern of associations was also observed between baseline thyroid hormones and changes in RMR. In addition, changes in free T3 and total T3 levels were positively associated with changes in body weight, RMR, body fat mass, blood pressure, glucose, insulin, triglycerides and leptin at 6 months and 24 months (all P<0.05). CONCLUSIONS: In this diet-induced weight loss setting, higher baseline free T3 and free T4 predicted more weight loss, but not weight regain among overweight and obese adults with normal thyroid function. These findings reveal a novel role of thyroid hormones in body weight regulation and may help identify individuals more responsive to weight loss diets.

Effects of dietary carbohydrate on 1,5-anhydroglucitol in a population without diabetes: results from the OmniCarb trial.

AIMS: To determine the effects of dietary changes in amount and type of carbohydrate on 1,5-anhydroglucitol levels. METHODS: We conducted an ancillary study to a completed, randomized clinical trial in overweight and obese adults without diabetes (N=159). Using a crossover design, participants were fed each one of four diets in turn for 5 weeks, with 2-week washout periods inbetween. The four diets were: high glycaemic index (≥65) with high proportion of carbohydrate (58% kcal) (GC); low glycaemic index (GI≤45) with low proportion of carbohydrate (40% kcal) (gc); low glycaemic index with high proportion of carbohydrate (gC); and high glycaemic index with low proportion of carbohydrate (Gc). Plasma 1,5-anhydroglucitol levels were measured at baseline and after each feeding period. RESULTS: At baseline, participants had a mean age of 53 years (53% women, 52% non-Hispanic black, 50% obese). Their mean fasting glucose and 1,5-anhydroglucitol levels were 97 mg/dl (5.4 mmol/l) and 18.6 µg/mL (113.3 µmol/l), respectively. Compared with baseline, each of the four diets reduced 1,5-anhydroglucitol by a range of -2.4 to -3.7 µg/mL (-14.6 to -22.5 µmol/l); all P <0.001). Reducing either glycaemic index or proportion of carbohydrate lowered 1,5-anhydroglucitol levels. These effects were additive, such that reducing both glycaemic index and proportion of carbohydrates decreased 1,5-anhydroglucitol by -1.31 µg/mL [95% CI: -1.63, -0.99; P<0.001 or -8.0 (-9.9, -6.0) µmol/l]. Furthermore, these effects were confirmed in a subgroup of participants with 12-h glucose monitoring and no documented hyperglycaemia (fasting glucose <160 mg/dl or 8.9 mmol/l). CONCLUSIONS: Both type and amount of dietary carbohydrate affect 1,5-anhydroglucitol plasma concentrations in adults without diabetes. This finding contradicts the long-standing notion that 1,5-anhydroglucitol remains at constant concentrations in the blood in the absence of hyperglycaemic excursions. (Clinical trials registry number: NCT00051350).

Genetic variation of fasting glucose and changes in glycemia in response to 2-year weight-loss diet intervention: the POUNDS LOST trial.

OBJECTIVE: Weight-loss intervention through diet modification has been widely used to improve obesity-related hyperglycemia; however, little is known about whether genetic variation modifies the intervention effect. We examined the interaction between weight-loss diets and genetic variation of fasting glucose on changes in glycemic traits in a dietary intervention trial. RESEARCH DESIGN AND METHODS: The Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial is a randomized, controlled 2-year weight-loss trial. We assessed overall genetic variation of fasting glucose by calculating a genetic risk score (GRS) based on 14 fasting glucose-associated single nucleotide polymorphisms, and examined the progression in fasting glucose and insulin levels, and insulin resistance and insulin sensitivity in 733 adults from this trial. RESULTS: The GRS was associated with 6-month changes in fasting glucose (P<0.001), fasting insulin (P=0.042), homeostasis model assessment of insulin resistance (HOMA-IR, P=0.009) and insulin sensitivity (HOMA-S, P=0.043). We observed significant interaction between the GRS and dietary fat on 6-month changes in fasting glucose, HOMA-IR and HOMA-S after multivariable adjustment (P-interaction=0.007, 0.045 and 0.028, respectively). After further adjustment for weight loss, the interaction remained significant on change in fasting glucose (P=0.015). In the high-fat diet group, participants in the highest GRS tertile showed increased fasting glucose, whereas participants in the lowest tertile showed decreased fasting glucose (P-trend <0.001); in contrast, the genetic association was not significant in the low-fat diet group (P-trend=0.087). CONCLUSIONS: Our data suggest that participants with a higher genetic risk may benefit more by eating a low-fat diet to improve glucose metabolism.

Two-year changes in circulating adiponectin, ectopic fat distribution and body composition in response to weight-loss diets: the POUNDS Lost Trial.

BACKGROUND/OBJECTIVES: Adiponectin has a pivotal role in linking fat distribution with cardiometabolic disorders. We investigated the associations of long-term changes in circulating adiponectin with body composition and fat distribution at different abdominal depots in response to weight-loss dietary interventions, as well as the modification effect of sex. SUBJECTS/METHODS: In the 2-year Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) Trial, 811 overweight or obese adults were randomly assigned to one of four diets varying in macronutrient intakes. Circulating concentrations of adiponectin were repeatedly measured at baseline, 6 months and 2 years. Body composition and fat distribution were repeatedly measured by dual-energy X-ray absorptiometry scan (n=424) and computed tomography (n=195). RESULTS: Over the 2-year intervention, after adjustment for age, sex, ethnicity, follow-up time, diet group, baseline body mass index and baseline level of respective outcome trait, increase of adiponectin was significantly associated with reduction of total fat mass (FM), total fat-free mass (FFM), whole body total percentage of fat mass (FM%), percentage of trunk fat (TF%), total adipose tissue (TAT), and adipose tissue mass at different depots including visceral (VAT), deep subcutaneous (DSAT) and superficial subcutaneous (SSAT; P<0.03 for each). The relations with FM, FM%, TF%, VAT and DSAT were significantly modified by sex (P for interaction=0.02, 0.005 and <0.001, 0.002, 0.03, respectively) with greater reductions associated with increase of adiponectin in men than in women. CONCLUSIONS: Long-term changes in circulating adiponectin were differentially associated with improvement of body composition and abdominal fat distribution in men and women.

Effect of diet composition on energy expenditure during weight loss: the POUNDS LOST Study.

BACKGROUND: Weight loss reduces energy expenditure, but the contribution of different macronutrients to this change is unclear. HYPOTHESIS: We tested the hypothesis that macronutrient composition of the diet might affect the partitioning of energy expenditure during weight loss. DESIGN: A substudy of 99 participants from the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial had total energy expenditure (TEE) measured by doubly labeled water, and resting energy expenditure (REE) measured by indirect calorimetry at baseline and repeated at 6 months in 89 participants. Participants were randomly assigned to one of four diets with either 15 or 25% protein and 20 or 40% fat. RESULTS: TEE and REE were positively correlated with each other and with fat-free mass and body fat, at baseline and 6 months. The average weight loss of 8.1 ± 0.65 kg (least-square mean ± s.e.) reduced TEE by 120 ± 56 kcal per day and REE by 136 ± 18 kcal per day. A greater weight loss at 6 months was associated with a greater decrease in TEE and REE. Participants eating the high-fat diet (HF) lost significantly more fat-free mass (1.52 ± 0.55 kg) than the low-fat (LF) diet group (P<0.05). Participants eating the LF diet had significantly higher measures of physical activity than the HF group. CONCLUSION: A greater weight loss was associated with a larger decrease in both TEE and REE. The LF diet was associated with significant changes in fat-free body mass and energy expenditure from physical activity compared with the HF diet.

Diet type and changes in food cravings following weight loss: findings from the POUNDS LOST Trial.

Few well-controlled trials have evaluated the effects that macronutrient composition has on changes in food cravings during weight loss treatment. The present study, which was part of the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial, investigated whether the fat and protein content of four different diets affected changes in specific food cravings in overweight and obese adults. A sample of 811 adults were recruited across two clinical sites, and each participant was randomly assigned to one of four macronutrient prescriptions: 1) low fat (20% of energy), average protein (15% of energy); 2) moderate fat (40%), average protein (15%); 3) low fat (20%), high protein (25%); 4) moderate fat (40%), high protein (25%). With few exceptions, the type of diet that participants were assigned did not differentially affect changes in specific food cravings. Participants assigned to the high-fat diets, however, had reduced cravings for carbohydrates at month 12 (p<0.05) and fruits and vegetables at month 24. Also, participants assigned to high-protein diets had increased cravings for sweets at month 6 and month 12 (ps<0.05). Participants in all four dietary conditions reported significant reductions in food cravings for specific types of foods (i.e., high fat foods, fast food fats, sweets, and carbohydrates/starches; all ps<0.05). Cravings for fruits and vegetables, however, were increased at month 24 (p<0.05). Calorically restricted diets (regardless of their macronutrient composition) yielded significant reductions in cravings for fats, sweets, and starches whereas cravings for fruits and vegetables were increased.

Protein-based HDL subspecies: Rationale and association with cardiovascular disease, diabetes, stroke, and dementia.

HDL-cholesterol is associated with reduced risk of cardiovascular disease, and is used in clinical practice for risk stratification. HDL is composed of many protein-defined subspecies that each comprises just a few percent of the total, some associated with lower and some with higher risk of CVD. HDL that contains apoC3 or apoE are subspecies that have opposing actions on HDL reverse cholesterol transport and opposing associations with risk of future CVD, apoC3 adverse and apoE beneficial. In addition to coronary heart disease, HDL that contains apoC3 is associated with risk of future type 2 diabetes and insulin resistance; ischemic stroke and cerebral infarction; dementia and the deposition of beta-amyloid in the brain. HDL that contains apoE and apoE itself are associated with lower risk of dementia. Other HDL subspecies that contain complement C3, alpha-2 macroglobulin, plasminogen, or haptoglobin are associated with higher future risk of coronary heart disease, whereas others such as HDL that contains apoC1 are associated with lower risk. At this time, these findings provide improved understanding of the multifaceted HDL system to better determine risk and targeting of therapy for the most prevalent chronic lifestyle diseases in our society.

Effects of low dose oral contraceptives on very low density and low density lipoprotein metabolism.

Oral contraceptives (OC) raise plasma triglyceride and VLDL levels, which may be of concern, since some conditions characterized by elevated triglycerides are associated with atherosclerosis. To identify the responsible mechanism, we studied 11 healthy premenopausal women, 5 of whom were taking OC containing 0.035 mg ethinyl estradiol, and 6 of whom were not. Their rates of VLDL and LDL metabolism were measured by endogenously labeling apoB, the protein component of VLDL and LDL, by an intravenous infusion of deuterated leucine. OC use had the greatest effect on the large, triglyceride-rich VLDL subfraction (Sf 60-400), increasing plasma levels threefold and production rates fivefold (P < 0.05). Among OC users, small VLDL (Sf 20-60) levels were 2.2 times higher, and production rates were 3.4-fold higher (P < 0.05). The fractional catabolic rates of large and small VLDL were similar among OC users and nonusers. LDL levels and metabolic rates were not significantly different between the two groups. Thus, contemporary low dose OC substantially raise VLDL levels by increasing the production rate of large, triglyceride-rich VLDL, and not by slowing VLDL catabolism. Since VLDL catabolism is not impaired, we speculate that the hypertriglyceridemia induced by OC may be less atherogenic than that of hypertriglyceridemia resulting from impaired lipolysis. This may explain why long-term OC use does not appear to promote atherosclerosis.

PIP: At Brigham and Women's Hospital in Boston, Massachusetts, data on 5 women aged 22-24 years using low-dose oral contraceptives (OCs) containing .035 mg ethinyl estradiol were compared with data on 6 women aged 23-27 years not using OCs so researchers could study the metabolism of individual very low density lipoprotein (VLDL) subfractions of low density lipoprotein (LDL) in users of low-dose OCs and nonusers. Specifically, they wanted to determine the mechanisms by which OC use increases plasma VLDL and triglyceride levels. They infused a nonradioactive amino acid tracer (D3-leucine) intravenously into the 11 women to endogenously label the primary protein component of VLDL and of LDL, apoB, allowing them to measure VLDL and LDL synthesis and catabolism. OC users had large triglyceride-rich VLDL subfraction plasma levels 3 times higher than those of nonusers (20.2 nmol/l vs. 6.7 nmol/l; p , .05). OC use increased large, triglyceride-rich VLDL subfraction production rates 5-fold (16.7 nmol/kg/d vs. 3.4 nmol/kg/d; p .005). OC users had 2.2 times higher small VLDL subfraction levels (36.7 nmol/l vs. 16.7 nmol/l; p .05) and 3.4 times higher small VLDL subfraction production rates (22.5 nmol/kg/d vs. 6.7 nmol/kg/d; p .01) than nonusers. The fractional catabolic rates of large and small VLDL were essentially the same for OC users and nonusers (19.4 pool/d vs. 18.2 pool/d and 15.1 pool/d vs. 17 pool/d). Thus, low-dose OC use increases VLDL levels via a rise in the production rate of large VLDL and not by impeding VLDL catabolism. Learning that low-dose OCs do not curb VLDL catabolism, the researchers proposed that the OC-induced hypertriglyceridemia is less likely to be atherogenic than impaired lipolysis induced hypertriglyceridemia. This hypothesis may provide the answer as to why longterm OC use does not apparently foster atherosclerosis.

A trilogy of primary prevention statin trials. Panel discussion.

Presented is a report of a panel discussion held as part of the ISA 2006 Sankyo Forum titled "A Trilogy of Primary Prevention Statin Trials--The Impact of These Landmark Studies on Clinical Practice," Rome, Italy, June 2006. The themes of the panel discussion were the design features of three trials, WOSCOPS, AFCAPS/TexCAPS, and Japan's MEGA Study; comparison of their primary endpoints; and the implications of their results. Among the topics discussed by the panel of experts from Japan, USA, and UK were observations on the benefits associated with pravastatin at low dose as demonstrated in the MEGA Study as well as that study's implications for women, who represented the majority of subjects. Several suggestions were put forth to explain how the low dose used in MEGA elicited similar LDL-C reductions to those observed in WOSCOPS and AFCAPS/TexCAPS at higher doses including the body size hypothesis, genetic variation, and statin-diet interaction. It was felt that in Japan, the current guidelines are adequate; there seemed no merit in radically reducing LDL-C levels since in the Japanese population the risk is generally low. Japanese physicians tend to use small doses of statin and believe that these are effective in lowering cholesterol sufficiently with few side effects and encourage good compliance.

Markers of dietary protein intake are associated with successful weight loss in the POUNDS Lost trial.

To assess the association of markers for dietary protein intake, measures of dietary adherence and demographic variables with weight loss in the POUNDS Lost study over the first 6 months and again between 6 and 24 months using data from those who completed each period. This is a secondary analysis of pooled data on completers assigned to one of four diets: 65%C/15%P/20%F (AP/LF), 55%C/25%P/20%F (HP/LF), 45%C/15%P/40%F (AP/HF) or 35%C/25%P40%F (HP/HF) in the POUNDS Lost study. Urinary nitrogen excretion, dietary adherence measured by 24-h recall and attendance at sessions, age (above and below 50 years), gender, race/ethnicity and activity by pedometry were analysed. Increased spread between protein intake at baseline and protein at 6 or 24 months, assessed by urinary nitrogen excretion, was associated with greater weight loss from baseline to 2 years. At 6 and 24 months, older age, male gender, body mass index > 30 kg m-2 and adherence to the fat and protein diets were associated with more weight loss. None of these variables was associated with a regain from 6 to 24 months. Weight regain for women in the highest carbohydrate (65%) group was significantly greater (-4.4 kg [95% CI: -5.9, -3.0]) than for women in the lowest carbohydrate group (-1.8 kg [95% CI: -3.2, -0.4 kg]) (P for interaction = 0.012). An increased spread in the difference between baseline and follow-up protein intake was associated with greater weight loss, consistent with the 'protein spread theory'. Women eating the highest carbohydrate diet regained more weight from 6 to 24 months.

Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects.

BACKGROUND: Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed. METHODS AND RESULTS: A meta-analysis was performed on individual patient data from 7 large, population-based studies (each >500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, P<0.0001) higher HDL-C levels than did B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD (odds ratio=0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals (P for linearity=0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance (P=0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated. CONCLUSIONS: The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therapy.

Prospective study of plasma fatty acids and risk of prostate cancer.

BACKGROUND: Although some evidence suggests that dietary fat intake is related to prostate cancer, epidemiologic studies have been inconsistent. PURPOSE: Our purpose was to assess the association between plasma lipid levels, particularly linoleic and alpha-linolenic acids, and the development of prostate cancer. METHODS: In 1982, at the start of the Physicians' Health Study, 14916 U.S. male physicians provided plasma samples, which were frozen at -82 degrees C. Data accumulated from a series of questionnaires were used to assess the intake of various foods. We used a nested case-control design to compare the fatty acid compositions in plasma from 120 men who later developed prostate cancer with 120 matched controls who did not. Individual fatty acids were measured in plasma as a percentage of total fatty acids, using capillary gas chromatography. Conditional logistic regression models were used to obtain odds ratio estimates while adjusting simultaneously for the effects of one or more potential confounders. RESULTS: The relative risks (RRs) of prostate cancer for men in successively higher quartiles of plasma alpha-linolenic acid level were 3.0 (95% confidence interval [CI] = 1.2-7.3), 3.4 (95% CI = 1.6-7.5), and 2.1 (95% CI = 0.9-4.9), compared with those with levels below the detection threshold (P trend = .03). For linoleic acid, RRs in successively higher quartiles were 0.7 (95% CI = 0.4-1.5), 0.8 (95% CI = 0.4-1.6), and 0.6 (95% CI = 0.3-1.3), with the lowest quartile as referent (P trend = .24). The effect estimates were not notably altered by adjustment for exercise, body mass, meat and dairy consumption, or other fatty acid levels in the plasma. The RR for eating red meat at least five times per week compared with less than once a week was 2.5 (95% CI = 0.9-6.7) and was little changed by adjustment for alpha-linolenic acid, although alpha-linolenic acid levels were correlated with intake of red meat and butter. The association of alpha-linolenic acid levels with prostate cancer was greater among men with low linoleic acid and reduced meat intake. CONCLUSIONS: These results suggest that low plasma levels of alpha-linolenic acid might be associated with reduced risk of prostate cancer, independently of high meat intake. High linoleic acid and low marine fatty oils were not associated with increased risk, as previously hypothesized. IMPLICATIONS: The effects of dietary alpha-linolenic acid, particularly from vegetable sources, warrant further study. The effects of dietary linoleic acid and marine fatty acids seen in animal bioassays might not apply to human prostate cancer.

Fatty acid composition of the subcutaneous adipose tissue and risk of proliferative benign breast disease and breast cancer.

BACKGROUND: Studies in animals and geographic correlations across populations suggest that fatty acid intake may have a positive relationship with breast cancer risk, but analytic epidemiologic studies of fat intake have been less supportive. Adipose tissue analysis provides a more objective assessment of intakes of fatty acids that are not endogenously synthesized than do the questionnaire survey methods used in many epidemiologic studies. PURPOSE: This case-control study of postmenopausal women was designed to examine the relationship between fatty acid composition of subcutaneous adipose tissue and risk of breast cancer and proliferative benign breast disease. In addition, we examined specific hypotheses that breast cancer risk is negatively associated with long-chain N-3 fatty acid intake, positively associated with trans fatty acid intake, and positively associated with increased intake of polyunsaturated fat together with low intake of antioxidants. METHODS: Aspirates of subcutaneous fat from the buttocks were obtained from 380 women with newly diagnosed stage I or II breast cancer and 176 with proliferative benign breast disease. A total of 397 women who were evaluated for breast abnormalities at the same institutions but did not require breast biopsy or whose biopsy revealed nonproliferative benign breast disease served as the control group. We examined associations between saturated, monounsaturated, polyunsaturated, trans, or long-chain N-3 fatty acids and breast cancer, atypical hyperplasia, or proliferative benign breast disease without atypia. RESULTS: We observed no consistent patterns of association between breast cancer risk and any of the categories of fatty acids or the individual constituent fatty acids in the adipose tissue. Saturated fatty acids were inversely associated with risk of proliferative benign breast disease without atypia but not with atypical hyperplasia or breast cancer. This association was not observed, however, when total fat intake was taken into account. Women with high levels of polyunsaturated fatty acids in adipose tissue and low serum or dietary levels of antioxidants were not observed to be at higher risk of breast cancer. CONCLUSIONS: Using an objective measure of intake, we observed no major associations between polyunsaturated fatty acids, including long-chain N-3 fatty acids and trans fatty acids, and risk of breast cancer or proliferative benign breast disease. IMPLICATIONS: These data do not support the hypothesis that intake of specific fatty acids, particularly polyunsaturated and trans fatty acids, is an important risk factor for malignant or benign breast disease.

Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis.

Dietary consumption of the carotenoid lycopene (mostly from tomato products) has been associated with a lower risk of prostate cancer. Evidence relating other carotenoids, tocopherols, and retinol to prostate cancer risk has been equivocal. This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. We conducted a nested case-control study using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. We quantified the five major plasma carotenoid peaks (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol using high-performance liquid chromatography. Results for plasma beta-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active beta-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls (P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54-1.06; P, trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34-0.91; P, trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P, trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to beta-carotene supplements. However, in the beta-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher alpha-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming beta-carotene supplements. For men with low lycopene, beta-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide further evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer.

VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial.

BACKGROUND: Plasma triglyceride concentration has been an inconsistent independent risk factor for coronary heart disease, perhaps because of the metabolic heterogeneity among VLDL particles, the main carriers of triglycerides in plasma. METHODS AND RESULTS: We conducted a prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin in 4159 patients with myocardial infarction and average LDL concentrations at baseline (115 to 174 mg/dL, mean 139 mg/dL). Baseline concentrations of VLDL-apolipoprotein (apo) B (the VLDL particle concentration), VLDL lipids, and apoCIII and apoE in VLDL+LDL and in HDL were compared in patients who had either a myocardial infarction or coronary death (cases, n=418) with those in patients who did not have a cardiovascular event (control subjects, n=370) in 5 years of follow-up. VLDL-cholesterol, VLDL-triglyceride, VLDL-apoB, apoCIII and apoE in VLDL+LDL and apoE in HDL were all interrelated, and each was a univariate predictor of subsequent coronary events. The significant independent predictors were VLDL-apoB (relative risk [RR] 3.2 for highest to lowest quintiles, P:=0.04), apoCIII in VLDL+LDL (RR 2.3, P:=0.04), and apoE in HDL (RR 1.8, P:=0.02). Plasma triglycerides, a univariate predictor of coronary events (RR 1.6, P:=0.03), was not related to coronary events (RR 1.3, P:=0.6) when apoCIII in VLDL+LDL was included in the model, whereas apoCIII remained significant. Adjustment for LDL- and HDL-cholesterol did not affect these results. CONCLUSIONS: The plasma concentrations of VLDL particles and apoCIII in VLDL and LDL are more specific measures of coronary heart disease risk than plasma triglycerides perhaps because their known metabolic properties link them more closely to atherosclerosis.

Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project.

BACKGROUND: Previous trials have had insufficient numbers of coronary events to address definitively the effect of lipid-modifying therapy on coronary heart disease in subgroups of patients with varying baseline characteristics. METHODS AND RESULTS: The data from 3 large randomized trials with pravastatin 40 mg were pooled and analyzed with the use of a prospectively defined protocol. Included were 19 768 patients, 102 559 person-years of follow-up, 2194 primary end points (coronary death or nonfatal myocardial infarction), and 3717 expanded end points (primary end point, CABG, or PTCA). Pravastatin significantly reduced relative risk in younger (<65 years) and older (>/=65 years) patients, men and women, smokers and nonsmokers, and patients with or without diabetes or hypertension. The relative effect was smaller, but absolute risk reduction was similar in patients with hypertension compared with those without hypertension. Relative risk reduction was significant in predefined categories of baseline lipid concentrations. Tests for interaction were not significant between relative risk reduction and baseline total cholesterol (5% to 95% range 177 to 297 mg/dL, 4.6 to 7.7 mmol/L), HDL cholesterol (27 to 58 mg/dL, 0.7 to 1.5 mmol/L), and triglyceride (74 to 302 mg/dL, 0.8 to 3.4 mmol/L) concentrations, analyzed as continuous variables. However, for LDL cholesterol, the probability values for interaction were 0.068 for the prespecified primary end point and 0.019 for the expanded end point. Relative risk reduction was similar throughout most of the baseline LDL cholesterol range (125 to 212 mg/dL, 3.2 to 5.5 mmol/L) with the possible exception of the lowest quintile of CARE/LIPID (<125 mg/dL) (relative risk reduction 5%, 95% CI 19% to -12%). CONCLUSIONS: Pravastatin treatment is effective in reducing coronary heart disease events in patients with high or low risk factor status and across a wide range of pretreatment lipid concentrations.

Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators.

BACKGROUND: The role of lipid modification in stroke prevention is controversial, although increasing evidence suggests that HMG-CoA reductase inhibition may reduce cerebrovascular events in patients with prevalent coronary artery disease. METHODS AND RESULTS: To test the hypothesis that cholesterol reduction with pravastatin may reduce stroke incidence after myocardial infarction, we followed 4159 subjects with average total and LDL serum cholesterol levels (mean, 209 and 139 mg/dL, respectively) who had sustained an infarction an average of 10 months before study entry and who were randomized to pravastatin 40 mg/d or placebo in the Cholesterol and Recurrent Events (CARE) trial. Using prospectively defined criteria, we assessed the incidence of stroke, a prespecified secondary end point, and transient ischemic attack (TIA) over a median 5-year follow-up period. Patients were well matched for stroke risk factors and the use of antiplatelet agents (85% of subjects in each group). Compared with placebo, pravastatin lowered total serum cholesterol by 20%, LDL cholesterol by 32%, and triglycerides by 14% and raised HDL cholesterol by 5% over the course of the trial. A total of 128 strokes (52 on pravastatin, 76 on placebo) and 216 strokes or TIAs (92 on pravastatin, 124 on placebo) were observed, representing a 32% reduction (95% CI, 4% to 52%, P=0.03) in all-cause stroke and 27% reduction in stroke or TIA (95% CI, 4% to 44%, P=0.02). All categories of strokes were reduced, and treatment effect was similar when adjusted for age, sex, history of hypertension, cigarette smoking, diabetes, left ventricular ejection fraction, and baseline total, HDL, and LDL cholesterol and triglyceride levels. There was no increase in hemorrhagic stroke in patients on pravastatin compared with placebo (2 versus 6, respectively). CONCLUSIONS: Pravastatin significantly reduced stroke and stroke or TIA incidence after myocardial infarction in patients with average serum cholesterol levels despite the high concurrent use of antiplatelet therapy.

A prospective study of plasma fish oil levels and incidence of myocardial infarction in U.S. male physicians.

OBJECTIVES: This study evaluated whether increased intake of fish oils (eicosapentaenoic and docosahexaenoic acids) might reduce the risk of coronary heart disease. BACKGROUND: Observational and clinical studies have suggested that increased intake of fish oils, as reflected in plasma levels of fish oils, may reduce the risk of myocardial infarction. METHODS: A nested case-control study was conducted among the 14,916 participants in the Physicians' Health Study with a sample of plasma before randomization. Each participant with myocardial infarction occurring during the first 5 years of follow-up was matched by smoking status and age with a randomly chosen control participant who had not developed coronary heart disease. RESULTS: Mean levels of fish oils (with 95% confidence interval [CI] for paired differences and p values) in case and control participants, expressed as percent of total fatty acids, were, for eicosapentaenoic acid, 0.26 versus 0.25 (95% CI -0.03 to 0.05, p = 0.70) in cholesterol esters and 0.56 versus 0.54 (95% CI -0.04 to 0.09, p = 0.44) in phospholipids, and for docosahexaenoic acid, 0.23 versus 0.24 (95% CI -0.07 to 0.04, p = 0.64) in cholesterol esters and 2.22 versus 2.14 (95% CI -0.10 to 0.27, p = 0.36) in phospholipids. Results adjusted for major cardiovascular risk factors showed a very similar lack of association between fish oil levels and the incidence of myocardial infarction. CONCLUSIONS: These results indicate no beneficial effect of increased fish oil consumption on the incidence of a first myocardial infarction. However, the effect of very high levels of fish oils could not be evaluated.

Controlled trial of fish oil for regression of human coronary atherosclerosis. HARP Research Group.

OBJECTIVES: This randomized clinical trial tested whether fish oil supplements can improve human coronary atherosclerosis. BACKGROUND: Epidemiologic studies of populations whose intake of oily fish is high, as well as laboratory studies of the effects of the polyunsaturated fatty acids in fish oil, support the hypothesis that fish oil is antiatherogenic. METHODS: Patients with angiographically documented coronary heart disease and normal plasma lipid levels were randomized to receive either fish oil capsules (n = 31), containing 6 g of n-3 fatty acids, or olive oil capsules (n = 28) for an average duration of 28 months. Coronary atherosclerosis on angiography was quantified by computer-assisted image analysis. RESULTS: Mean (+/- SD) baseline characteristics were age 62 +/- 7 years, plasma total cholesterol concentration 187 +/- 31 mg/dl (4.83 +/- 0.80 mmol/liter) and triglyceride levels 132 +/- 70 mg/dl (1.51 +/- 0.80 mmol/liter). Fish oil lowered triglyceride levels by 30% (p = 0.007) but had no significant effects on other plasma lipoprotein levels. At the end of the trial, eicosapentaenoic acid in adipose tissue samples was 0.91% in the fish oil group compared with 0.20% in the control group (p < 0.0001). At baseline, the minimal lumen diameter of coronary artery lesions (n = 305) was 1.64 +/- 0.76 mm, and percent narrowing was 48 +/- 14%. Mean minimal diameter of atherosclerotic coronary arteries decreased by 0.104 and 0.138 mm in the fish oil and control groups, respectively (p = 0.6 between groups), and percent stenosis increased by 2.4% and 2.6%, respectively (p = 0.8). Confidence intervals exclude improvement by fish oil treatment of > 0.17 mm, or > 2.6%. CONCLUSIONS: Fish oil treatment for 2 years does not promote major favorable changes in the diameter of atherosclerotic coronary arteries.

Pravastatin prevents clinical events in revascularized patients with average cholesterol concentrations. Cholesterol and Recurrent Events CARE Investigators.

OBJECTIVES: This analysis was carried out to determine if revascularized patients derive benefit from the 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin. BACKGROUND: The HMG-CoA reductase inhibitors result in substantial reductions in serum cholesterol and stabilization of atherosclerotic plaques in patients with coronary artery disease. METHODS: Pravastatin was found to reduce clinical cardiovascular events in the Cholesterol and Recurrent Events (CARE) trial consisting of 4,159 patients with a documented myocardial infarction and an average cholesterol level (mean 209 mg/dl and all <240 mg/dl). A total of 2,245 patients underwent coronary revascularization before randomization including 1,154 patients with percutaneous transluminal coronary angioplasty (PTCA) alone, 876 patients with coronary artery bypass graft (CABG) alone, and 215 patients with both procedures. Clinical events in revascularized patients were compared between patients on placebo and on pravastatin. RESULTS: In the 2,245 patients who had undergone revascularization, the primary endpoint of coronary heart disease death or nonfatal myocardial infarction (MI) was reduced by 4.1% with pravastatin (relative risk [RR] reduction 36%, 95% confidence interval [CI] 17 to 51, p = 0.001). Fatal or nonfatal MI was reduced by 3.3% (RR reduction 39%, 95% CI 16 to 55, p = 0.002), postrandomization repeat revascularization was reduced by 2.6% (RR reduction 18%, 95% CI 1 to 33, p = 0.068) and stroke was reduced by 1.5% (RR reduction 39%, 95% CI 3 to 62, p = 0.037) with pravastatin. Pravastatin was beneficial in both the 1,154 PTCA patients and in the 1,091 CABG patients who had undergone revascularization before randomization. CONCLUSIONS: Pravastatin reduced clinical events in revascularized postinfarction patients with average cholesterol levels. This therapy was well tolerated and its use should be considered in most patients following coronary revascularization.