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Biomedical subjects

James Shepherd

Publications and source records attributed to James Shepherd.

At least 37 records · Page 2Linked to original sources
PubMed2004

Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid--a position paper developed by the European Consensus Panel on HDL-C.

Reduction of low-density lipoprotein cholesterol (LDL-C) is presently the primary focus of lipid-lowering therapy for prevention and treatment of coronary heart disease (CHD). However, the high level of residual risk among statin-treated patients in recent coronary prevention studies indicates the need for modification of other major components of the atherogenic lipid profile. There is overwhelming evidence that a low plasma level of high-density lipoprotein cholesterol (HDL-C) is an important independent risk factor for CHD. Moreover, a substantial proportion of patients with or at risk of developing premature CHD typically exhibit distinct lipid abnormalities, including low HDL-C levels. Thus, therapeutic intervention aimed at raising HDL-C, within the context of reducing global cardiovascular risk, would benefit such patients, a viewpoint increasingly adopted by international treatment guidelines. Therapeutic options for patients with low HDL-C include treatment with statins, fibrates and nicotinic acid, either as monotherapy or in combination. Of these options, nicotinic acid is not only the most potent agent for raising HDL-C but is also effective in reducing key atherogenic lipid components including triglyceride-rich lipoproteins (mainly very low-density lipoproteins [VLDL] and VLDL remnants), LDL-C, and lipoprotein(a). The principal features of the atherogenic lipid profile in type 2 diabetes and the metabolic syndrome make them logical targets for nicotinic acid therapy, either alone or in combination with a statin. The lack of comprehensive European data on the prevalence of low HDL-C levels highlights a critical need for education on the importance of raising HDL-C in CHD prevention and treatment. The development of a reliable and accurate assay for HDL-C, as well as clarification of criteria for low and optimal levels of HDL-C in both men and women, constitute critical factors in the reliable identification and treatment of patients at elevated risk of CHD due to low HDL-C. Based on the available evidence, the European Consensus Panel recommends that the minimum target for HDL-C should be 40 mg/dL (1.03 mmol/L) in patients with CHD or with a high level of risk for CHD, including patients at high global risk with type 2 diabetes or the metabolic syndrome.

Cholesterol, HDL↗
PubMed2004

Lipid-modifying effects of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy.

OBJECTIVE: To evaluate the efficacy and safety of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy (HRT) in a randomized, double-blind, placebo-controlled trial. METHODS: After a 6-week dietary lead-in period, 135 postmenopausal women who had been taking a stable HRT regimen for at least 3 months were randomized to receive rosuvastatin 5 mg, 10 mg or placebo for 12 weeks. Fasting levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) were assessed at weeks 0, 2, 6, 10, and 12; apolipoprotein (Apo) B and Apo A-I were measured at weeks 0 and 12. RESULTS: Rosuvastatin 5 mg and 10 mg significantly reduced LDL-C by 38% (SE = 2.1) and 49% (SE = 2.1), respectively, compared with placebo (1% [SE = 2.1]; p < 0.001). TC, TG, Apo B, and all lipid ratios examined (LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, and Apo B/Apo A-I) were also reduced significantly by both rosuvastatin doses (p < 0.001). HDL-C levels increased significantly in the rosuvastatin groups (11% and 8% for 5 mg and 10 mg, respectively, vs. -0.5% for placebo; p < 0.001), as did Apo A-I levels (p < 0.05). The combination of rosuvastatin plus HRT was well tolerated with no apparent differences among treatments in the numbers or types of adverse events reported. CONCLUSIONS: Rosuvastatin 5 mg or 10 mg once daily is a well-tolerated and highly efficacious lipid-lowering therapy in postmenopausal women receiving HRT.

Administration, Oral↗
PubMed2004

Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the west of Scotland coronary prevention study.

We examined the association of serum alanine aminotransferase (ALT) with features of the metabolic syndrome and whether it predicted incident diabetes independently of routinely measured factors in 5,974 men in the West of Scotland Coronary Prevention Study. A total of 139 men developed new diabetes over 4.9 years of follow-up. ALT, but not aspartate aminotransferase, levels increased progressively with the increasing number of metabolic syndrome abnormalities from (means +/- SD) 20.9 +/- 7.6 units/l in those with none to 28.1 +/- 10.1 units/l in those with four or more (P < 0.001). In a univariate analysis, men with ALT in the top quartile (ALT >/=29 units/l) had an elevated risk for diabetes (hazard ratio 3.38 [95% CI 1.99-5.73]) versus those in the bottom quartile (<17 units/l). ALT remained a predictor with adjustment for age, BMI, triglycerides, HDL cholesterol, systolic blood pressure, glucose, and alcohol intake (2.04 [1.16-3.58] for the fourth versus first quartile). In stepwise regression, incorporating ALT and C-reactive protein (CRP) together with metabolic syndrome criteria, elevated ALT (>/=29 units/l), and CRP (>/=3 mg/l) predicted incident diabetes, but low HDL cholesterol and hypertension did not. Thus, elevated ALT levels within the "normal" range predict incident diabetes. The simplicity of ALT measurement and its availability in routine clinical practice suggest that this enzyme activity could be included in future diabetes prediction algorithms.

Alanine Transaminase↗
PubMed2003

Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study.

BACKGROUND: The National Cholesterol Education Program (NCEP) recently proposed a simple definition for metabolic syndrome. Information on the prospective association of this definition for coronary heart disease (CHD) and type 2 diabetes is currently limited. METHODS AND RESULTS: We used a modified NCEP definition with body mass index in place of waist circumference. Baseline assessments in the West of Scotland Coronary Prevention Study were available for 6447 men to predict CHD risk and for 5974 men to predict incident diabetes over 4.9 years of follow-up. Mean LDL cholesterol was similar but C-reactive protein was higher (P<0.0001) in the 26% of men with the syndrome compared with those without. Metabolic syndrome increased the risk for a CHD event [univariate hazard ratio (HR)=1.76 (95% CI, 1.44 to 2.15)] and for diabetes [univariate HR=3.50 (95% CI 2.51 to 4.90)]. Metabolic syndrome continued to predict CHD events (HR=1.30, 95% CI, 1.00 to 1.67, P=0.045) in a multivariate model incorporating conventional risk factors. Men with 4 or 5 features of the syndrome had a 3.7-fold increase in risk for CHD and a 24.5-fold increase for diabetes compared with men with none (both P<0.0001). C-reactive protein enhanced prognostic information for both outcomes. With pravastatin, men with the syndrome had similar risk reduction for CHD as compared with those without (HR, 0.73 and 0.69; pravastatin versus placebo). CONCLUSIONS: A modified NCEP metabolic syndrome definition predicts CHD events, and, more strikingly, new-onset diabetes, and thus helps identify individuals who may receive particular benefit from lifestyle measures to prevent these diseases.

Body Mass Index↗
PubMed2003

Guidelines for lowering lipids to reduce coronary artery disease risk: a comparison of rosuvastatin with atorvastatin, pravastatin, and simvastatin for achieving lipid-lowering goals.

Both the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III and the Second Joint Task Force of European Societies guidelines have established low-density lipoprotein (LDL) cholesterol goals for lipid-lowering treatment to reduce the risk of coronary artery disease. Data from 3 trials that compared rosuvastatin 10 mg (n = 389) with atorvastatin 10 mg (n = 393) and 2 trials that compared rosuvastatin 10 mg (n = 226) with pravastatin 20 mg (n = 252) and simvastatin 20 mg (n = 249) were pooled separately to compare the achievement of LDL cholesterol goals over 12 weeks of treatment in hypercholesterolemic patients. Noncomparative pooling of rosuvastatin 10 mg results from all 5 trials (n = 615) showed that 80% achieved NCEP ATP III goals and 81% achieved the European goal of <3.0 mmol/L. Compared with atorvastatin 10 mg, significantly more patients treated with rosuvastatin 10 mg achieved their ATP III (76% vs 53%) and European (82% vs 51%) goals (p <0.001). Also, in comparisons with simvastatin 20 mg and pravastatin 20 mg, 86% of patients treated with rosuvastatin 10 mg achieved ATP III goals, compared with 64% of simvastatin-treated patients and 49% of pravastatin-treated patients (p <0.001). The proportions of patients who achieved the European goal were 80%, 48%, and 16% for rosuvastatin 10 mg, simvastatin 20 mg, and pravastatin 20 mg, respectively, in this comparison (all p <0.001). A total of 71% of patients treated with rosuvastatin 10 mg who had triglyceride levels > or =200 mg/dL met both their LDL cholesterol and their non-high-density lipoprotein cholesterol goals.

Adult↗
PubMed2003

Preventing the next event in the elderly: the PROSPER perspective.

Statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals but their efficacy and safety in elderly people has not been confirmed. Several clinical trials including the Cholesterol and Recurrent Events (CARE) and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), have sub-analysed their results for the 'elderly' cohort, but the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial is the first trial to specifically evaluate the benefits of statin therapy on vascular risk in elderly men and women. The results have shown that pravastatin, given for 3 years, reduced the risk of coronary heart disease in elderly individuals. Within this same time frame, there was no significant benefit on the risk reduction of stroke but there was a trend to reduce the risk of transient ischemic attacks. It was discovered that those patients with the lowest baseline high-density lipoprotein cholesterol gained the most benefit from the intervention. Drug interactions between pravastatin and the concomitant medications seen in this elderly cohort, was not a significant clinical issue. Therefore, PROSPER extends to elderly individuals the treatment strategy currently used in middle-aged people.

Aged↗
PubMed2003

Statin therapy in the elderly: does it make good clinical and economic sense?

HMG-CoA reductase inhibitors (statins) have been established as the dominant treatment for coronary heart disease (CHD). This dominance is based on an impressive body of clinical trial evidence showing significant benefits in primary prevention of cardiovascular events in individuals at risk for CHD and in secondary prevention of such events in patients with CHD and high or normal plasma cholesterol levels. There is, however, significant room for improvement in the treatment of CHD with respect both to drug efficacy and to the disparity between evidence-based medicine and actual clinical practice particularly in relation to treatment strategies for the elderly. Current statins fall short of requirements for 'ideal' lipid-lowering treatment in several respects; 'super' statins and other agents currently in development may satisfy more of these requirements. Moreover, available therapies are not applied optimally, because of physician nonacceptance and/or patient noncompliance; thus, the majority of patients with CHD or its risk factors still have cholesterol levels that exceed guideline targets. There is also evidence that older patients with CHD, or at high risk of CHD, are undertreated - possibly because of concerns regarding the increased likelihood of adverse events or drug interactions or doubts regarding the cost effectiveness of statin therapy in this population. This group is of particular clinical relevance, since it is showing a proportionate rapid expansion in most national populations. To address their potential healthcare needs, the ongoing Pravastatin in the Elderly at Risk (PROSPER) study is assessing the effects of pravastatin in elderly patients (5804 men and women aged 70-82 years) who either have pre-existing vascular disease or are at significant risk for developing it, with the central hypothesis that statin therapy (pravastatin 40 mg/day) will diminish the risk of subsequent major vascular events compared with placebo. After a 3.2-year treatment period, a primary assessment will be made of the influence of statin treatment on major cardiovascular events (a combination of CHD death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Optimal deployment of the currently available agents and of newer agents (no matter how well they satisfy requirements for ideal treatment) ultimately depends on the establishment of an evidence base and may require far-reaching educational programmes that change the way risk factor management is viewed by caregivers and patients alike.

Aged↗
PubMed2002

Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.

BACKGROUND: Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. METHODS: We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. FINDINGS: Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006). Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8), but the hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. INTERPRETATION: Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people.

Aged↗
PubMed2002

Factors affecting low-density lipoprotein and high-density lipoprotein cholesterol response to pravastatin in the West Of Scotland Coronary Prevention Study (WOSCOPS).

Statins are regarded as efficacious in general but there is a wide variation in individual response. We sought demographic and lifestyle factors that influenced the response to pravastatin 40 mg/day in moderately hypercholesterolemic men in the West Of Scotland Coronary Prevention Study (WOSCOPS). Changes in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol after 6 months of treatment were examined in 1,604 highly compliant subjects. LDL cholesterol decreased by a mean of 30.4%. The magnitude of the change was influenced, albeit to a small extent, by baseline plasma triglyceride levels and alcohol intake and age; subjects with low plasma triglyceride levels, older subjects, and subjects with low alcohol intake had the greatest reductions. The mean response in HDL cholesterol in the group was an 8.3% increase (0.09 mmol/L). The percent increase in HDL cholesterol was affected by baseline HDL level, plasma triglyceride levels, decrease in plasma triglyceride levels during the administration of pravastatin, and body mass index. The absolute increase in HDL cholesterol was influenced by the decrease in plasma triglyceride levels, body mass index, and alcohol intake. All of these associations were weak (r <0.2) although highly significant. In conclusion, plasma lipid phenotype, obesity, and alcohol consumption appear to influence the response of LDL and HDL cholesterol to statin treatment. The absolute increment in HDL cholesterol is relatively constant across a range of baseline values, hence the percent change is largely a function of the starting value.

Alcohol Drinking↗
PubMed2002

A Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): Screening Experience and Baseline Characteristics.

BACKGROUND: PROSPER was designed to investigate the benefits of treatment with pravastatin in elderly patients for whom a typical doctor might consider the prescription of statin therapy to be a realistic option. METHODS: The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomised, double blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) will reduce the risk of coronary heart disease death, non-fatal myocardial infarction, and fatal or non-fatal stroke in elderly men and women with pre-existing vascular disease or with significant risk of developing this condition. RESULTS: In Scotland, Ireland, and the Netherlands, 23,770 individuals were screened, and 5,804 subjects (2,804 men and 3,000 women), aged 70 to 82 years (average 75 years) and with baseline cholesterol 4.0-9.0 mmol/l, were randomised. Randomised subjects had similar distributions with respect to age, blood pressure, and body mass index when compared to the entire group of screenees, but had a higher prevalence of smoking, diabetes, hypertension, and a history of vascular disease. The average total cholesterol level at baseline was 5.4 mmol/l (men) and 6.0 mmol/l (women). CONCLUSIONS: Compared with previous prevention trials of cholesterol-lowering drugs, the PROSPER cohort is significantly older and for the first time includes a majority of women. The study, having achieved its initial goal of recruiting more than 5,500 elderly high-risk men and women, aims to complete all final subject follow-up visits in the first half of 2002 with the main results being available in the fourth quarter of 2002.

Journal Article↗
PubMed2002

Coronary heart disease in patients with low LDL-cholesterol: benefit of pravastatin in diabetics and enhanced role for HDL-cholesterol and triglycerides as risk factors.

BACKGROUND: In two large secondary prevention trials of pravastatin, risk reduction was not significant in participants who had low baseline LDL-C concentrations (that is, <125 mg/dL). We conducted exploratory analyses of participant characteristics, lipid risk factors, and risk reduction in this group. METHODS AND RESULTS: Among 13 173 participants with coronary heart disease (CHD), 2607 had baseline LDL-C <125 mg/dL. Those with LDL-C <125 compared with > or =125 mg/dL were more likely to be diabetic (15% versus 9%), hypertensive (46 versus 41%), and male (89% versus 83%); they had higher triglycerides (169 versus 154 mg/dL), lower HDL-C (36.5 versus 38 mg/dL), and similar body mass index (27 kg/m2); and pravastatin lowered their LDL-C by 36 mg/dL (32%) versus 45 mg/dL (29%). During 5.8-year (mean) follow-up, HDL-C and triglycerides were both significantly stronger predictors of recurrent CHD events in participants with LDL-C <125 than > or =125 mg/dL. In diabetic participants with low LDL-C, pravastatin decreased CHD events from 34% to 22% (relative risk, 0.56; 95% CI, 0.37 to 0.83; P=0.004), significantly different from the effect in nondiabetic participants with low LDL-C (P interaction, 0.005) (event rate, 21%; relative risk, 1.06 [95% CI, 0.89 to 1.27]). There were trends toward risk reduction in smokers and in those with low HDL-C, <40 mg/dL. CONCLUSIONS: Among patients with CHD who have low LDL-C, diabetics have much higher subsequent CHD event rates than do nondiabetics. Pravastatin reduced the event rate in diabetics to that of nondiabetic participants. The results also suggest enhanced therapeutic potential for improving HDL-C and triglycerides in patients with CHD who have low LDL-C concentrations.

Adult↗
PubMed2002

Influence of atorvastatin and simvastatin on apolipoprotein B metabolism in moderate combined hyperlipidemic subjects with low VLDL and LDL fractional clearance rates.

Subjects with moderate combined hyperlipidemia (n=11) were assessed in an investigation of the effects of atorvastatin and simvastatin (both 40 mg per day) on apolipoprotein B (apoB) metabolism. The objective of the study was to examine the mechanism by which statins lower plasma triglyceride levels. Patients were studied on three occasions, in the basal state, after 8 weeks on atorvastatin or simvastatin and then again on the alternate treatment. Atorvastatin produced significantly greater reductions than simvastatin in low density lipoprotein (LDL) cholesterol (49.7 vs. 44.1% decrease on simvastatin) and plasma triglyceride (46.4 vs. 39.4% decrease on simvastatin). ApoB metabolism was followed using a tracer of deuterated leucine. Both drugs stimulated direct catabolism of large very low density lipoprotein (VLDL(1)) apoB (4.52+/-3.06 pools per day on atorvastatin; 5.48+/-4.76 pools per day on simvastatin versus 2.26+/-1.65 pools per day at baseline (both P<0.05)) and this was the basis of the 50% reduction in plasma VLDL(1) concentration; apoB production in this fraction was not significantly altered. On atorvastatin and simvastatin the fractional transfer rates (FTR) of VLDL(1) to VLDL(2) and of VLDL(2) to intermediate density lipoprotein (IDL) were increased significantly, in the latter instance nearly twofold. IDL apoB direct catabolism rose from 0.54+/-0.30 pools per day at baseline to 1.17+/-0.87 pools per day on atorvastatin and to 0.95+/-0.43 pools per day on simvastatin (both P<0.05). Similarly the fractional transfer rate for IDL to LDL conversion was enhanced 58-84% by statin treatment (P<0.01) LDL apoB fractional catabolic rate (FCR) which was low at baseline in these subjects (0.22+/-0.04 pools per day) increased to 0.44+/-0.11 pools per day on atorvastatin and 0.38+/-0.11 pools per day on simvastatin (both P<0.01). ApoB-containing lipoproteins were more triglyceride-rich and contained less free cholesterol and cholesteryl ester on statin therapy. Further, patients on both treatments showed marked decreases in all LDL subfractions. In particular the concentration of small dense LDL (LDL-III) fell 64% on atorvastatin and 45% on simvastatin. We conclude that in patients with moderate combined hyperlipidemia who initially have a low FCR for VLDL and LDL apoB, the principal action of atorvastatin and simvastatin is to stimulate receptor-mediated catabolism across the spectrum of apoB-containing lipoproteins. This leads to a substantial, and approximately equivalent, percentage reduction in plasma triglyceride and LDL cholesterol.

Adult↗
PubMed2002

Regulation of small dense LDL concentration in Korean and Scottish men and women.

Small dense LDL is now emerging as an important risk factor for coronary artery disease. The amount of the LDL III has been reported to differ between ethnic groups. To investigate differences in the distribution of LDL subfractions between Korean and Scottish populations, we measured the plasma concentration and percent distribution of three major LDL subfractions in age-and sex-matched, middle aged, healthy 124 Korean and Scottish subjects (32 Korean men vs. 32 Scottish men; 30 Korean women vs. 30 Scottish women). Body mass index and waist circumference did not differ between the two ethnic groups. Total cholesterol and LDL cholesterol concentrations were higher in Scottish men compared with Korean men (P<0.01), while plasma triglyceride concentration was higher in Korean men and women (P<0.01 in men, P<0.05 in women). HDL cholesterol concentrations in both Korean men and women were lower than that of their Scottish counterparts (P<0.05 in men; P<0.001 in women). Korean men had lower concentrations of total LDL (242+/-65 vs. 325+/-122 mg/dl, P<0.01), LDL I (24+/-18 vs. 60+/-36 mg/dl, P<0.001) and LDL II (110+/-56 vs. 196+/-78 mg/dl, P<0.001). In contrast, LDL III concentration was markedly higher in Korean men (108+/-75 vs. 70+/-65 mg/dl, P<0.05). Likewise, the percent of LDL I (10.0+/-7.3 vs. 19.1+/-10.1%, P<0.001) and LDL II (47.2+/-20.7 vs. 60.1+/-10.9%, P<0.01) were lower in Korean men, while that of LDL III was higher (42.8+/-24.9 vs. 20.8+/-15.0%, P<0.001). In the female population, there were no differences in total LDL and LDL I concentrations between Korean and Scottish. LDL II concentration was lower in Korean women (106+/-53 vs. 151+/-57 mg/dl, P<0.01). Korean women showed a higher percent of LDL III (24.8+/-24.7 vs. 14.2+/-5.9%, P<0.05) and a lower LDL II (47.8+/-19.1 vs. 61.0+/-10.0%, P<0.01). Multiple linear regression revealed that plasma triglyceride concentration was the most important determinant of the LDL III subfraction concentration in Korean men and women and in Scottish men. In Korean men, the LDL III concentration rose linearly through the whole range of plasma triglyceride concentration, whereas in Scottish men, there was a threshold at 108 mg/dl triglyceride above which there was a positive association. Korean women showed the same pattern as Scottish men. We suggest that LDL concentrations and LDL subfraction distributions are regulated differently in these two ethnic groups. The different relationships between triglyceride and LDL III subfraction in Koreans versus Scots suggest that other factors, such as hepatic lipase or cholesteryl ester transfer protein may additionally play a role determining the LDL subfraction profile.

Adult↗