James Shepherd

• BSc MB ChB PhD
• Professor Emeritus at University of Glasgow

Statins may have nephroprotective as well as cardioprotective effects in patients with cardiovascular disease. In the Treating to New Targets (TNT) study (NCT00327691), patients with coronary heart disease (CHD) were randomized to atorvastatin 10- or 80-mg/day and followed for 4.9 years. The relationship between intra-study change in estimated glom...

Aims: This analysis of the Treating to New Targets study investigated the impact of intensive lipid-lowering with high-dose atorvastatin on the cardiovascular risk associated with individual metabolic syndrome (MetS) components (high body mass index [BMI], elevated triglycerides, low high-density lipoprotein cholesterol [HDL-C], hypertension and e...

Unlabelled: Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We cond...

Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for...

Background: Studies show that renal function improves with statin therapy in coronary patients with CKD, but few studies show a relationship between cholesterol and CKD. As many patients with CKD have dyslipidemia there is a need to evaluate the relationship between lipoproteins and CKD.

Intensive lowering of low-density lipoprotein cholesterol (LDL-C) with statins reduces cardiovascular risk but can cause liver-, muscle-, and possibly renal-related adverse events (AEs). We assessed the effects of rosuvastatin on the risk of developing renal impairment or renal failure among participants in the rosuvastatin clinical development pro...

Single nucleotide polymorphisms (SNPs) at the KIF6 (kinesin like protein 6, rs20455 or 719Arg), LPA (lipoprotein(a), rs3798220), TAS2R50 (taste receptor type 2, member 50, rs1376251) and VAMP8 (vesicle-associated membrane protein 8, rs1010) have previously been associated with low density lipoprotein cholesterol (LDL-C) lowering response to statins...

Background: Statins have been shown to significantly lower the risk of coronary heart disease morbidity and mortality, and these benefits have been related t lowering of low density lipoprotein (LDL) cholesterol lowering. Statin metabolism is affected by the liver X receptor alpha ( LXRA ) and the solute carrier organic anion transporter ( SLCO1B1...

Our goal was to determine whether genetic variation at genes affecting statin metabolism or targets of statin therapy would influence low density lipoprotein (LDL) cholesterol lowering with pravastatin, baseline heart disease, or cardiac endpoints on trial. We examined associations of single nucleotide polymorphisms (SNPs) at the liver X receptor a...

The effect of body mass index (BMI) on coronary heart disease (CHD) risk is attenuated when mediators of this risk (such as diabetes, hypertension and hyperlipidaemia) are accounted for. However, there is now evidence of a differential effect of risk factors on fatal and non-fatal CHD events, with markers of inflammation more strongly associated wi...

Atrial fibrillation/flutter (AF) is the most common arrhythmia in older people. It associates with reduced exercise capacity, increased risk of stroke, and mortality. We aimed to determine retrospectively whether pravastatin reduces the incidence of AF and whether any electrocardiographic measures or clinical conditions might be risk factors for it...

The aim of this study was to investigate the relationship between lipid and nonlipid biomarker levels achieved during statin therapy and the incidence of major cardiovascular events (MCVEs) in patients with stable coronary heart disease (CHD). Several plasma nonlipid biomarkers have been shown to predict MCVEs in population studies. This is a neste...

This study was designed to investigate the counterbalancing influence of genetic variation in the promoter of the gene encoding P300/CBP associated factor (PCAF), a lysine acetyltransferase (KAT), on coronary heart disease (CHD) and mortality. The association of genetic variation in the PCAF-gene with CHD, restenosis and mortality was investigated...

A single nucleotide polymorphism (SNP) in KIF6, a member of the KIF9 family of kinesins, is associated with differential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investigated whether othe...

The evidence base for fasting plasma glucose (FPG) in the non-diabetic range as a risk factor for cardiovascular disease (CVD) is inconclusive. We investigated this question in the West of Scotland Coronary Prevention Study (WOSCOPS). In WOSCOPS, we related FPG in 6447 men (mean age 55 years) with hypercholesterolaemia, but no history of CVD or dia...

Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. We assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration,...

Randomized data on statins for primary prevention in older persons are limited, and the relative hazard of cardiovascular disease associated with an elevated cholesterol level weakens with advancing age. To assess the efficacy and safety of rosuvastatin in persons 70 years or older. Secondary analysis of JUPITER (Justification for the Use of statin...

Background: Evidence suggests that obesity increases the risk of cardiovascular disease due to chronic kidney disease (CKD). This sub-analysis of the TNT study determined the frequency of CKD in CHD patients with obesity, analyzed the effect of CKD on major CV events (MCVE) in these subjects, and examined'the effect of intensive lipid lowering with...

To determine whether activation of hemostatic function (thrombosis and fibrinolysis) is associated with cognitive decline in older people. We studied 5804 people (age, 70-82 years) in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Mean follow-up was 3.2 years, including annual measurement of speed of information processing (...

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studi...

Statin therapy has been found to substantially and significantly reduce coronary events in carriers of the KIF6 719Arg variant (rs20455) but not in noncarriers. We investigated whether, among the elderly, statin therapy also significantly reduced coronary events in carriers but not in noncarriers. Among 5,752 patients of the PROspective Study of Pr...

Analyses of randomized clinical trials are usually restricted to examination of time to first event. However, because many patients have multiple events, this approach precludes much potentially useful clinical and economic data. To assess the effect on overall disease burden in the Treating to New Targets (TNT) study, we evaluated the effect of tr...

Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes. We searched Medline, Embase, and the Cochrane Central Register of Con...

Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances. We meta-analysed individual records of 160 309 people...

Context Associations of major lipids and apolipoproteins with the risk of vascular disease have not been reliably quantified. Objective To assess major lipids and apolipoproteins in vascular risk. Design, Setting, and Participants Individual records were supplied on 302 430 people without initial vascular disease from 68 long-term prospective studi...

Observational studies have shown an association between low plasma cholesterol levels and increased risk of cancer, whereas most randomized clinical trials involving cholesterol-lowering medications have not shown this association. Between 1997 and 2002, the authors assessed the association between plasma cholesterol levels and cancer risk, free fr...

Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven. The aim of the study was to explore the causal direction of the relationship between adiposity and inflammation using a bidirectional Mendelian randomization approach. In the PROSPER study of...

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an inflammatory biomarker that circulates mainly bound to LDL. We evaluated the association of Lp-PLA(2) with vascular events in the elderly where the importance of LDL is diminished as a risk factor for coronary disease. Mass and activity of Lp-PLA(2) were related to risk over 3.2 years for...

As recently demonstrated, random allocation to rosuvastatin results in large relative risk reductions for first cardiovascular events among apparently healthy men and women with low levels of low-density lipoprotein cholesterol but elevated levels of high-sensitivity C-reactive protein. However, whether the absolute risk reduction among such indivi...

Two previous trials have reported that the best clinical outcomes in treatment of acute coronary ischemia among patients receiving statins occurred in those who achieved low-density lipoprotein (LDL) cholesterol <1.8 mmol/L (<70 mg/dL) and high-sensitivity C-reactive protein (hsCRP) <2 mg/L. Despite these findings, the added benefits of reduced hsC...

Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Our objective was to examine whether five variants (-133A>G, -18A>C, L272L, V1296V, and U3_28650A>G) at the NPC1L1 gene have effects on lipid levels, prevalence, and incidence of coronary heart disease (CHD) and lipid-lowering response to pravastatin...

Cholesterol homeostasis, defined as the balance between absorption and synthesis, influences circulating cholesterol concentrations and subsequent coronary heart disease (CHD) risk. Statin therapy targets the rate-limiting enzyme in cholesterol biosynthesis and is efficacious in lowering CHD events and mortality. Nonetheless, CHD events still occur...

Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke. To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes. Long-term prospective studies that recorded Lp(...

Observational studies have given conflicting results about the effect of statins in preventing dementia and cognitive decline. Moreover, observational studies are subject to prescription bias, making it hard to draw definite conclusions from them. Randomized controlled trials are therefore the preferred study design to investigate the association b...

Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke. In t...

Statins lower high-sensitivity C-reactive protein (hsCRP) and cholesterol concentrations, and hypothesis generating analyses suggest that clinical outcomes improve in patients given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1.8 mmol/L (<70 mg/dL). However, the benefit of lowering both LDL cho...

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohort...

Controversy persists regarding the extent of shared pathways between arterial and venous thrombosis and whether treatments of known efficacy for one disease process have consistent benefits for the other. Observational studies have yielded variable estimates of the effect of statin therapy on the risk of venous thromboembolism, and evidence from ra...

Previous studies have shown that statin therapy reduces high-sensitivity C-reactive protein levels as well as cholesterol, but no prospective trials have directly addressed the issue of whether elevated levels of high-sensitivity C-reactive protein are beneficial for apparently healthy persons with levels of LDL cholesterol below current thresholds...

IntroductionLipids and CVDImproving the lipid profileStatins and other lipid-lowering agentsLipid intervention goalsMonitoringConclusion References

To investigate whether statins reduce all cause mortality and major coronary and cerebrovascular events in people without established cardiovascular disease but with cardiovascular risk factors, and whether these effects are similar in men and women, in young and older (>65 years) people, and in people with diabetes mellitus. Meta-analysis of rando...

Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants...

To clarify the association of circulating levels of leptin with risk for cardiovascular disease (CVD) events and new-onset diabetes in men and women. We related baseline leptin levels to CVD events (n = 864) and incident diabetes (n = 289) in an elderly population (n = 5,672) over 3.2 years of follow-up. In treatment-, age-, and country-adjusted mo...

The aim of this prospective study was to determine whether circulating intercellular adhesion molecule (ICAM) 1, as a potential surrogate of 'endothelial activation', is more strongly associated with risk of vascular events than with incident diabetes. We related baseline ICAM-1 levels to vascular events (866 CHD and stroke events in 5,685 particip...

BACKGROUND: Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from sta...

Background: Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from st...

The Treating to New Targets (TNT) clinical trial found that intensive 80 mg atorvastatin (A80) treatment reduced cardiovascular events by 22% when compared to 10 mg atorvastatin (A10) treatment. We evaluated the cost-effectiveness of intensive A80 vs A10 treatment in the United Kingdom (UK), Spain, and Germany. A lifetime Markov model was developed...

To investigate the effect of intensive lipid lowering with high-dose atorvastatin on the incidence of major cardiovascular events compared with low-dose atorvastatin in patients with coronary artery disease and type 2 diabetes, with and without chronic kidney disease (CKD). Following 8 weeks' open-label therapy with atorvastatin (10 mg/d), 10,001 p...

Clinical use of criteria for metabolic syndrome to simultaneously predict risk of cardiovascular disease and diabetes remains uncertain. We investigated to what extent metabolic syndrome and its individual components were related to risk for these two diseases in elderly populations. We related metabolic syndrome (defined on the basis of criteria f...

Inflammation plays a prominent role in the development of atherosclerosis, which is the most important risk factor for vascular events. Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine and is found to be expressed in atherosclerotic lesions. We investigated the association between the C804A polymorphism within the LTA gene and coronary and ce...

The aim of this post hoc analysis from the TNT (Treating to New Targets) trial is to determine whether patients with previous coronary artery bypass grafting (CABG) surgery achieved clinical benefit from intensive low-density lipoprotein (LDL)-cholesterol lowering. The development and progression of atherosclerosis is accelerated in coronary venous...

Inflammation is thought to play an important role in the development of cognitive decline and dementia in old age. The interleukin-1 signalling pathway may play a prominent role in this process. The gene encoding for interleukin-1 beta-converting enzyme (ICE) is likely to influence IL-1 beta levels. Inhibition of ICE decreases the age-related incre...

Hyperchylomicronaemia was identified in a four-week-old Siamese kitten with lethargy, in-appetence, hindlimb ataxia and profound anaemia. The kitten was euthanased and at necropsy a thrombus was found occluding the caudal aorta. Two littermates later presented with lethargy, inappetence and hypertriglyceri-daemia which resolved after being weaned o...

This subanalysis of the TNT (Treating to New Targets) study investigates the effects of intensive lipid lowering with atorvastatin in patients with coronary heart disease (CHD) with and without pre-existing chronic kidney disease (CKD). Cardiovascular disease is a major cause of morbidity and mortality in patients with CKD. A total of 10,001 patien...

The purpose of this study was to investigate the association between the Ala227Pro polymorphism in the ADAMTS1 metalloproteinase gene and coronary heart disease and benefit from statin therapy in 2 independent cohorts. The frequency of the ADAMTS1 227Pro minor allele was 0.24 in 2421 male subjects from CARE, a randomized trial of pravastatin versus...

Dyslipidemia conveys a major increased risk of future cardiovascular events in older persons. Data from large randomized controlled trials confirm that statin therapy is as beneficial in older adults as it is in younger persons in both primary and secondary prevention. National guidelines support the use of statin therapy to reduce low-density lipo...

To determine whether aspirin and antioxidant therapy, combined or alone, are more effective than placebo in reducing the development of cardiovascular events in patients with diabetes mellitus and asymptomatic peripheral arterial disease. Multicentre, randomised, double blind, 2x2 factorial, placebo controlled trial. 16 hospital centres in Scotland...

Our purpose was to evaluate associations of single nucleotide polymorphisms (SNPs) at the low density lipoprotein (LDL) receptor (LDLR C44857T, minor allele frequency (MAF) 0.26, and A44964G, MAF 0.25, both in the untranslated region) and HMG-CoA reductase (HMGCR i18 T>G, MAF 0.019) gene loci with baseline lipid values, statin-induced LDL-cholester...

Caucasian carriers of the T allele at R46L in the proprotein convertase subtilisin/kexin type 9 (PCSK9) locus have been reported to have 15% lower low-density lipoprotein (LDL) cholesterol (C) levels and 47% lower coronary heart disease (CHD) risk. Our objective was to examine two PCSK9 single nucleotide polymorphisms (SNPs), R46L and E670G, in 578...

We asked whether 35 genetic polymorphisms, previously found to be associated with cardiovascular disease, were associated with myocardial infarction (MI) in the CARE (Cholesterol and Recurrent Events) trial and with coronary heart disease (CHD) in the WOSCOPS (West of Scotland Coronary Prevention Study) trial and whether the risk associated with th...

In the West of Scotland Coronary Prevention Study (WOSCOPS), treatment of hypercholesterolemic men with pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, reduced their likelihood to progress to diabetes mellitus by 30%. However, the mechanism of this effect of pravastatin has not been investigated. In the curre...

The Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is a randomized, double-blind, placebo-controlled primary prevention trial of statin therapy among persons with average to low levels of low-density lipoprotein (LDL) cholesterol who are at increased cardiovascular risk due to ele...

Data suggest that atorvastatin may be nephroprotective. This subanalysis of the Treating to New Targets study investigated how intensive lipid lowering with 80 mg of atorvastatin affects renal function when compared with 10 mg in patients with coronary heart disease. A total of 10,001 patients with coronary heart disease and LDL cholesterol levels...

To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women. Prospective study. Scotland, Ireland, and the Netherlands. Five thousand eight hundred four subjects aged 70 to 82 from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Subjects were assessed at baseline and over a mean 3....

The West of Scotland Coronary Prevention Study was a randomized clinical trial comparing pravastatin with placebo in men with hypercholesterolemia who did not have a history of myocardial infarction, with an average follow-up of approximately 5 years. The combined outcome of death from definite coronary heart disease or definite nonfatal myocardial...

Patients with type 2 diabetes have a marked increase in the risk of premature coronary heart disease (CHD). One of the underlying reasons for this increased risk is atherogenic dyslipidaemia, which is common in this patient group and characterized by low plasma levels of high-density lipoprotein cholesterol (HDL-C), increased levels of serum trigly...

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;...

The appearance of statins was key to our understanding of the pathologic effects of hypercholesterolemia. Before statins were available, physicians did not know whether cholesterol lowering improved cardiovascular health. Pioneering studies such as the Framingham Study and MR FIT identified high blood cholesterol as a risk factor for cardiovascular...

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Proinflammatory cytokines, like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), are implicated in the development of atherosclerosis. The role of anti-inflammatory cytokines, like IL-10, is largely unknown. We investigated the association of four single nucleotide polymorphisms (SNPs) in the promoter region of the IL-10 gene (4259...

To examine metabolic changes (lipids, liver enzymes, blood pressure, and weight) potentially associated with conversion to diabetes, we analyzed serial glucose and other metabolic measures obtained every 6 months within the West of Scotland Coronary Prevention Study trial. Changes in parameters for 86 men who converted to new-onset diabetes ("conve...

Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration h...

The safety and tolerability of rosuvastatin were assessed using data from 16,876 patients who received rosuvastatin 5-40 mg in a multinational phase II/III/IIIb/IV program, representing 25,670 patient-years of continuous exposure to rosuvastatin. An integrated database, consisting of 33 trials whose databases were locked up to and including Septemb...

The role of C-reactive protein (CRP) in predicting vascular events and response to statin therapy remains uncertain. Additional large prospective studies are required. Baseline CRP was related to risk over 3.2 years for primary a combined end point (definite or suspected death from coronary heart disease, nonfatal myocardial infarction, and fatal o...

Inter-individual differences in biological ageing could affect susceptibility to coronary heart disease. Our aim was to determine whether mean leucocyte telomere length is a predictor of the development of coronary heart disease. We compared telomere lengths at recruitment in 484 individuals in the West of Scotland Primary Prevention Study (WOSCOPS...

OBJECTIVE: To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women.DESIGN: Prospective study.SETTING: Scotland, Ireland, and the Netherlands.PARTICIPANTS: Five thousand eight hundred four subjects aged 70 to 82 from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).MEASUREMENTS: S...

Statins reduce inflammation and risk of myocardial infarction (MI). Because the myeloid IgA Fc receptor encoded by FCAR mediates inflammation, we hypothesized that the FCAR Asp92Asn polymorphism is associated with risk of MI and that this risk would be modified by pravastatin. In the placebo arm of the Cholesterol and Recurrent Events (CARE) study,...