P N Durrington

The University of Manchester, Manchester, England, United Kingdom

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Publications (450)2860.1 Total impact

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    ABSTRACT: Background: High-density lipoprotein (HDL) particles have an important role in atheroprotection, with properties including antioxidation, antiglycation and promotion of cholesterol efflux. Obese patients have increased systemic inflammation and thus higher risk of vascular disease. Little is known of the changes in HDL particles and HDL functionality associated with obesity. We aimed to assess the effects of obesity itself and bariatric surgery-induced weight loss on both HDL quantity and quality. Methods: We measured HDL-C, oxidised HDL (Ox-HDL), apolipoprotein AI (ApoAI), apolipoprotein AII (ApoAII), apolipoprotein M (ApoM), Myeloperoxidase (MPO) mass, HDL-apolipoprotein E (apoE), serum paraoxonase-1 (PON1) activity and capacity of HDL to promote cholesterol efflux in vitro for 37 obese patients at baseline and at 6 and 12 months following bariatric surgery. We compared HDL functionality in obese patients with age and sex matched controls. Results: At baseline, HDL-C, ApoAI and cholesterol efflux capacity were significantly lower among obese patients than healthy controls. Six months after bariatric surgery, although ApoAII and HDL-ApoE were significantly decreased (both p < 0.05), HDL-C, ApoA1, MPO mass, PON1 activity and cholesterol efflux were unchanged compared to baseline. At 12 months after bariatric surgery HDL quantity and quality were considerably improved. HDL-C and cholesterol efflux capacity were significantly increased compared with their baseline (both p < 0.001), as were PON1 activity and HDL-apoE concentration (both p < 0.01). MPO mass decreased and a further reduction in ApoAII was observed (both p < 0.01). ApoAI, ApoM and ox-HDL were unchanged. We used biological systems analysis to identify factors influencing HDL functionality. Conclusions: Bariatric surgery significantly increases circulating HDL cholesterol levels and improves HDL quality, but effects are not apparent until 12 months after treatment.
    No preview · Conference Paper · Feb 2016
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    ABSTRACT: Aims/hypothesis: In an individual-level analysis we examined the effect of atorvastatin on glycaemia progression in type 2 diabetes and whether glycaemia effects reduce the prevention of cardiovascular disease (CVD) with atorvastatin. Methods: The study population comprised 2,739 people taking part in the Collaborative Atorvastatin Diabetes Study (CARDS) who were randomised to receive atorvastatin 10 mg or placebo and who had post-randomisation HbA1c data. This secondary analysis used Cox regression to estimate the effect of atorvastatin on glycaemia progression, defined as an increase in HbA1c of ≥0.5% (5.5 mmol/mol) or intensification of diabetes therapy. Mixed models were used to estimate the effect of atorvastatin on HbA1c as a continuous endpoint. Results: Glycaemia progression occurred in 73.6% of participants allocated placebo and 78.1% of those allocated atorvastatin (HR 1.18 [95% CI 1.08, 1.29], p < 0.001) by the end of follow-up. The HR was 1.22 (95% CI 1.19, 1.35) in men and 1.11 (95% CI 0.95, 1.29) in women (p = 0.098 for the sex interaction). A similar effect was seen in on-treatment analyses: HR 1.20 (95% CI 1.07, 1.35), p = 0.001. The net mean treatment effect on HbA1c was 0.14% (95% CI 0.08, 0.21) (1.5 mmol/mol). The effect did not increase through time. Diabetes treatment intensification alone did not differ with statin allocation. Neither baseline nor 1-year-attained HbA1c predicted subsequent CVD, and the atorvastatin effect on CVD did not vary by HbA1c change (interaction p value 0.229). Conclusions/interpretation: The effect of atorvastatin 10 mg on glycaemia progression among those with diabetes is statistically significant but very small, is not significantly different between sexes, does not increase with duration of statin and does not have an impact on the magnitude of CVD risk reduction with atorvastatin.
    No preview · Article · Nov 2015 · Diabetologia
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    Handrean Soran · Jonathan D. Schofield · Paul N. Durrington
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    ABSTRACT: High-density lipoprotein (HDL) provides a pathway for the passage of lipid peroxides and lysophospholipids to the liver via hepatic scavenger receptors. Perhaps more importantly, HDL actually metabolizes lipid hydroperoxides preventing their accumulation on low-density lipoprotein (LDL), thus impeding its atherogenic structural modification. A number of candidates have been suggested to be responsible for HDL's antioxidant function, with paraoxonase-1 (PON1) perhaps the most prominent. Here we review the evidence for HDL anti-oxidative function and the potential contributions of apolipoproteins, lipid transfer proteins, paraoxonases and other enzymes associated with HDL.
    Full-text · Article · Oct 2015 · Frontiers in Pharmacology
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    ABSTRACT: Background: The aim of this study was to explore the influence of extended-release niacin/laropiprant (ERN/LRP) versus placebo on high-density lipoprotein (HDL) antioxidant function, cholesterol efflux, apolipoprotein B100 (apoB)-containing lipoproteins, and mediators of vascular inflammation associated with 15% increase in high-density lipoprotein cholesterol (HDL-C). Study patients had persistent dyslipidemia despite receiving high-dose statin treatment. Methods and results: In a randomized double-blind, placebo-controlled, crossover trial, we compared the effect of ERN/LRP with placebo in 27 statin-treated dyslipidemic patients who had not achieved National Cholesterol Education Program-ATP III targets for low-density lipoprotein cholesterol (LDL-C). We measured fasting lipid profile, apolipoproteins, cholesteryl ester transfer protein (CETP) activity, paraoxonase 1 (PON1) activity, small dense LDL apoB (sdLDL-apoB), oxidized LDL (oxLDL), glycated apoB (glyc-apoB), lipoprotein phospholipase A2 (Lp-PLA2), lysophosphatidyl choline (lyso-PC), macrophage chemoattractant protein (MCP1), serum amyloid A (SAA) and myeloperoxidase (MPO). We also examined the capacity of HDL to protect LDL from in vitro oxidation and the percentage cholesterol efflux mediated by apoB depleted serum. ERN/LRP was associated with an 18% increase in HDL-C levels compared to placebo (1.55 versus 1.31 mmol/L, P<0.0001). There were significant reductions in total cholesterol, triglycerides, LDL cholesterol, total serum apoB, lipoprotein (a), CETP activity, oxLDL, Lp-PLA2, lyso-PC, MCP1, and SAA, but no significant changes in glyc-apoB or sdLDL-apoB concentration. There was a modest increase in cholesterol efflux function of HDL (19.5%, P=0.045), but no change in the antioxidant capacity of HDL in vitro or PON1 activity. Conclusions: ERN/LRP reduces LDL-associated mediators of vascular inflammation, but has varied effects on HDL functionality and LDL quality, which may counter its HDL-C-raising effect. Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01054508.
    Full-text · Article · Sep 2015 · Journal of the American Heart Association
  • Handrean Soran · Jonathan D Schofield · Paul N Durrington
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    ABSTRACT: Guidelines for primary prevention of cardiovascular disease (CVD) with statins, including the most recent, fail to make the best use of the evidence from clinical trials by concentrating on absolute CVD risk as a statin indication and not also considering that a major determinant of therapeutic benefit is the magnitude of the low-density lipoprotein (LDL) (or non-HDL) cholesterol reduction achieved. This decrease is proportional to the pretreatment concentration. We set out to apply this knowledge to the calculation of the number needed to treat to prevent one event (NNT) and to assess critically how current guidelines performed at different degrees of CVD risk across a range of LDL (or non-HDL) cholesterol concentrations. Number needed to treat to prevent one event revealed exclusion from the treatment of some people with higher cholesterol levels, who may benefit more than others needlessly exposed to statins with no realistic prospect of benefit. Furthermore, abandonment of cholesterol therapeutic goals disadvantaged people with higher levels. These problems can be overcome by basing the decision to treat on the NNT calculated both from absolute CVD risk and also on the LDL (or non-HDL) cholesterol reduction achievable with statin treatment. This need not adds an additional layer of complexity for the clinician, because computer programmes already used to estimate CVD risk could be easily amended, thus permitting more effective deployment of statins in the population. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    No preview · Article · Aug 2015 · European Heart Journal
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    Full-text · Article · Jul 2015 · Atherosclerosis
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    ABSTRACT: Dyslipidaemia is an important cardiovascular disease risk factor. Many drugs affect lipid profile and lipoprotein metabolism. We reviewed unintended effects of nonlipid modifying, commonly used medications on lipid profile and lipoprotein metabolism. Several detrimental effects of many drug classes such as diuretics, antidepressant, anticonvulsant and antiretroviral drugs have been reported, whereas other drug classes such as antiobesity, alpha 1-blockers, oestrogens and thyroid replacement therapy were associated with positive effects. Dyslipidaemia is a common side-effect of many medications. This should be taken into consideration, especially in patients at high risk of cardiovascular disease. Other drugs demonstrated positive effects on circulating lipids and lipoproteins. The impact of these unintended effects on atherosclerotic disease risk and progression is unclear.
    Full-text · Article · Jun 2015 · Current opinion in lipidology
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    Handrean Soran · Jonathan D Schofield · Yifen Liu · Paul N Durrington
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    ABSTRACT: To summarize the current evidence about how HDL impedes the oxidative and glycative atherogenic modification of LDL. Paraoxonase 1 (PON1) is located on HDL. Meta-analysis of clinical epidemiological investigations reveals a substantial association of low serum PON1 activity with coronary heart disease incidence independent of other risk factors including HDL cholesterol and apolipoprotein AI (apoAI). Transgenic animal models also indicate an antiatherosclerotic role for PON1. However, highly purified and recombinant PON1 do not retain their antioxidant properties. The therapeutic potential of PON1 should be recognized in preventing atherosclerosis and combating infection and organophosphate toxicity. In unleashing this potential, it is important to consider that both highly purified and recombinant PON1 are dissociated from the lipid phase and other components of HDL, such as apoAI and apoM, all of which may be required for HDL (through its PON1 component) to hydrolyze more lipophilic substrates.
    Full-text · Article · Jun 2015 · Current opinion in lipidology
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    ABSTRACT: We investigated whether atorvastatin 10 mg daily lowered C-reactive protein (CRP) and whether the effects of atorvastatin on cardiovascular disease (CVD) varied by achieved levels of CRP and LDL-cholesterol. CRP levels were measured at baseline and 1 year after randomisation to atorvastatin in 2,322 patients with type 2 diabetes (40-75 years, 69% males) in a secondary analysis of the Collaborative Atorvastatin Diabetes Study, a randomised placebo-controlled trial. We used Cox regression models to test the effects on subsequent CVD events (n = 147) of CRP and LDL-cholesterol lowering at 1 year. After 1 year, the atorvastatin arm showed a net CRP lowering of 32% (95% CI -40%, -22%) compared with placebo. The CRP response was highly variable, with 45% of those on atorvastatin having no decrease in CRP (median [interquartile range, IQR] per cent change -9.8% [-57%, 115%]). The LDL-cholesterol response was less variable, with a median (IQR) within-person per cent change of -41% (-51%, -31%). Baseline CRP did not predict CVD over 3.8 years of follow-up (HRper SD log 0.89 [95% CI 0.75, 1.06]), whereas baseline LDL-cholesterol predicted CVD (HRper SD 1.21 [95% CI 1.02, 1.44]), as did on-treatment LDL-cholesterol. There was no significant difference in the reduction in CVD by atorvastatin, with above median (HR 0.57) or below median (HR 0.52) change in CRP or change in LDL-cholesterol (HR 0.61 vs 0.50). CRP was not a strong predictor of CVD. Statin efficacy did not vary with achieved CRP despite considerable variability in CRP response. The use of CRP as an indicator of efficacy of statin therapy on CVD risk in patients with type 2 diabetes is not supported by these data. Trial registration NCT00327418.
    Preview · Article · Apr 2015 · Diabetologia

  • No preview · Conference Paper · Mar 2015
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    Full-text · Conference Paper · Mar 2015
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    ABSTRACT: Background: The global burden of coronary heart disease (CHD) is estimated to be the highest on the Indian subcontinent. The pathophysiology of this increased risk is complex, multifactorial, and its magnitude increases with migration from India to Britain. Haemoglobin disorders, which also frequent this ethnic group, have been linked to cardiovascular disease. We investigated the impact of migration and nutritional intake on haematological parameters amongst South Asians, with a focus on their relation to molecular indices of oxidative atherogenesis. Methods: Haematology, diet, oxidised low-density lipoprotein (LDL), and serum paraoxonase activity were measured in 230 migrant Indian Gujaratis (Britain), and 305 matched contemporaries living in rural villages (India).
    Full-text · Article · Jan 2015
  • Handrean Soran · Rahul Yadav · Basil Ammori · Paul Durrington

    No preview · Article · Jan 2015 · Journal of Clinical Endocrinology & Metabolism
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    ABSTRACT: Paraoxonase 1 (PON1) protects against the development of atherosclerosis by hydrolysing damaging lipid peroxides formed in low-density lipoprotein (LDL) and cell membranes. The effect of migration on PON1 activity is unknown. We have investigated the effect of migration on serum PON1 activity by comparing an Indian Gujarati community who had migrated to Sandwell (West Midlands, UK) with people still living in their villages of origin around the town of Navsari (Gujarat, NorthWest India) and determined biochemical and nutritional parameters which may correlate with PON1 activity. PON1 activity was almost double in men and women living in Sandwell compared to those in Navsari. In the Spearman's Rank correlation analysis, PON1 activity was significantly negatively correlated with fasting glucose and C-reactive protein, and positively with fasting non-esterified fatty acids, homeostasis model assessment (HOMA)-insulin sensitivity, and high-density lipoprotein (HDL) in rural Indian men, positively with HDL and apolipoprotein A1 (apo A1) in migrant Indian men, negatively with HOMA-cell activity and apo A1. It was positively correlated with HDL cholesterol, mean LDL particle diameter, and oxidised-LDL (ox-LDL) in rural Indian women and positively with HDL cholesterol, apo A1, and ox-LDL in migrant Indian women. Multivariate analysis with PON1 as the dependent variable indicated significant relationships with migrant status and HDL cholesterol only (both p<0.001). In conclusion, in the South Asian populations studied here, PON1 activity significantly correlated with measures of insulin sensitivity and the metabolic syndrome; however, by far the strongest determinant of PON1 activity was migration, or at least environmental and dietary changes which accompany migration. We also found an as yet unexplained lack of gender difference in HDL cholesterol, which requires further investigation.
    Full-text · Article · Nov 2014
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    ABSTRACT: Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
    Full-text · Article · Oct 2014 · Nature Communications

  • No preview · Article · Oct 2014 · Atherosclerosis
  • Paul N Durrington
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    ABSTRACT: Commentary on: Keene D, Price C, Shun-Shin MJ, et al. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ 2014;349:g4379. Context Decreasing low-density lipoprotein (LDL) cholesterol with statin treatment reduces cardiovascular disease (CVD) incidence. The National Institute for Health and Care Excellence (NICE) has recently recommended that first-line statin treatment in primary prevention should be atorvastatin 20 mg daily and in secondary prevention atorvastatin 80 mg daily, doses which typically decrease LDL cholesterol by 43% and 55%, respectively.1 In many patients this will leave little scope to reduce residual CVD risk by additional LDL lowering. Attention is therefore drawn to the epidemiological inverse association between HDL cholesterol and CVD risk. This is widely exploited in the …
    No preview · Article · Sep 2014 · Evidence-Based Medicine

  • No preview · Article · Aug 2014 · Atherosclerosis
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    Handrean Soran · Jonathan D Schofield · Paul N Durrington
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    ABSTRACT: Purpose of review: Guidelines seeking to deploy statin treatment rely heavily on the use of estimates of absolute cardiovascular disease (CVD) risk as an arbiter of who should receive statins. We question whether this is an effective strategy unless the LDL-cholesterol (LDL-C) response is also considered. Recent findings: Recently, meta-analyses of randomized clinical trials of statins have revealed that CVD risk decreases linearly by 22% for each 1 mmol/l reduction in LDL-C. Calculation of the number needed to treat with statins to prevent one CVD event using both the pretreatment absolute CVD risk and the LDL-C response that can be achieved is thus possible. Application of this evidence reveals that many people (including younger ones) with high LDL-C levels can benefit more than people currently receiving statin treatment solely on the basis of their absolute CVD risk, whereas others at higher CVD risk, but with lower LDL-C, will derive little benefit. This does not seem to have been adequately considered in recent clinical guidelines. Summary: A simple additional mathematical step in risk assessment to take account of the LDL-C response to statins and provide knowledge of number needed to treat would greatly improve individual management, cost-effectiveness and the population impact of statins.
    Full-text · Article · Jun 2014 · Current Opinion in Lipidology
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    ABSTRACT: Purpose of review: Despite being both the longest known and the most prevalent genetic risk marker for atherosclerotic cardiovascular disease (CVD), little progress has been made in agreeing a role for lipoprotein (a) [Lp(a)] in clinical practice and developing therapies with specific Lp(a)-lowering activity. We review barriers to progress, and discuss areas of controversy which are important to future research. Recent findings: Epidemiological and genetic studies have supported a causal role for Lp(a) in accelerated atherosclerosis, independent of other risk factors. Progress continues to be made in the understanding of Lp(a) metabolism, and Lp(a) levels, rather than apolipoprotein (a) isoform size, have been shown to be more closely related to CVD risk. Selective Lp(a) apheresis has offered some evidence that Lp(a)-lowering can improve cardiovascular end-points. Summary: We have acquired a great deal of knowledge about Lp(a), but this has not yet led to reductions in CVD. This is at least partially due to disagreement over Lp(a) measurement methodologies, its physiological role and the importance of the elevations seen in renal diseases, diabetes mellitus and familial hypercholesterolaemia. Renewed focus is required to bring assays into clinical practice to accompany new classes of therapeutic agents with Lp(a)-lowering effects.
    Full-text · Article · Jun 2014 · Current Opinion in Lipidology

Publication Stats

24k Citations
2,860.10 Total Impact Points

Institutions

  • 1980-2015
    • The University of Manchester
      • • School of Biomedicine
      • • Centre for Endocrinology and Diabetes
      Manchester, England, United Kingdom
  • 2014
    • Central Manchester University Hospitals NHS Foundation Trust
      Manchester, England, United Kingdom
  • 2008
    • The University of Sheffield
      • School of Health and Related Research (ScHARR)
      Sheffield, England, United Kingdom
  • 2005
    • Queen Mary, University of London
      Londinium, England, United Kingdom
  • 2004
    • Sandwell and West Birmingham Hospitals NHS Trust
      Birmingham, England, United Kingdom
  • 2003
    • University of Granada
      • Department of Legal Medicine, Toxicology and Psychiatry
      Granada, Andalusia, Spain
  • 2002
    • Manchester Memorial Hospital
      Manchester, Connecticut, United States
  • 1998
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
    • University of Birmingham
      Birmingham, England, United Kingdom
  • 1991
    • Newcastle University
      Newcastle-on-Tyne, England, United Kingdom
  • 1990
    • University Hospital Of South Manchester NHS Foundation Trust
      Manchester, England, United Kingdom
  • 1982
    • University of California, San Diego
      • Department of Medicine
      San Diego, California, United States