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The association between severe mental illness (SMI) and cardiovascular and metabolic disease (CMD) is poorly understood. PCSK9 is expressed in systems critical to both SMI and CMD and influences lipid homeostasis and brain function. We systematically investigated relationships between genetic variation within the PCSK9 locus and risk for both CMD and SMI. UK Biobank recruited ~500,000 volunteers and assessed a wide range of SMI and CMD phenotypes. We used genetic data from white British ancestry individuals of UK Biobank. Genetic association analyses were conducted in PLINK, with statistical significance defined by the number of independent SNPs. Conditional analyses and linkage disequilibrium assessed the independence of SNPs and the presence of multiple signals. Two genetic risk scores of lipid-lowering alleles were calculated and used as proxies for putative lipid-lowering effects of PCSK9. PCSK9 variants were associated with central adiposity, venous thrombosis embolism, systolic blood pressure, mood instability, and neuroticism (all p < 1.16 × 10 -4 ). No secondary signals were identified. Conditional analyses and high linkage disequilibrium (r 2  = 0.98) indicated that mood instability and central obesity may share a genetic signal. Genetic risk scores suggested that the lipid-lowering effects of PCSK9 may be causal for greater mood instability and higher neuroticism. This is the first study to implicate the PCSK9 locus in mood-disorder symptoms and related traits, as well as the shared pathology of SMI and CMD. PCSK9 effects on mood may occur via lipid-lowering mechanisms. Further work is needed to understand whether repurposing PCSK9-targeting therapies might improve SMI symptoms and prevent CMD., (© 2022. The Author(s).)

Aims: To investigate the risk of cardiovascular disease (CVD) events and all-cause mortality in patients with statin-related adverse drug reaction (ADR) consultation in primary care and examine whether different treatments following the ADR affect subsequent outcomes., Methods: This was a retrospective cohort study of statin users between 2004 and 2019 using IQVIA Medical Research Data (formally known as the THIN database). Patients with statin-related ADR consultation were matched by propensity score (1:1) to statin users without ADR consultation based on demographics, comorbidities and concomitant medication. Cox proportional hazard regression was used to compare the risk of subsequent CVD event and all-cause mortality, stratified by history of CVD. In the secondary analysis among patients with statin-related ADR, treatment changes within a 1-year period following the ADR were examined and the outcomes were compared between different treatment groups., Results: Among 1 564 687 statin users, 19 035 (1.22%) had a statin-related ADR consultation in primary care. The mean (standard deviation) follow-up time was 6.32 (3.74) years and 5.31 (3.83) years for CVD primary and secondary prevention cohorts, respectively. Statin-related ADR consultation was associated with subsequent CVD events in both cohorts (adjusted hazard ratio [HR] of 1.39 [95% CI 1.23, 1.57] and 1.34 [95% CI 1.25,1.42], respectively). In the secondary analysis among patients with statin-related ADR consultation, we found that (i) continued statin prescription or combination of any statin with additional lipid-lowering treatment (LLT) and (ii) other LLT only were associated with lower risks of CVD event (adjusted HR 0.71 [95% CI 0.64, 0.78] and 0.75 [95% CI 0.62, 0.92], respectively) and all-cause mortality (adjusted HR 0.46 [95% CI 0.42, 0.50] and 0.52 [95% CI, 0.43, 0.64], respectively), compared to discontinuation of all LLT., Conclusion: Statin-related ADR was associated with an increased risk of subsequent CVD event, indicating that these patients should be monitored more closely. Continued lipid-lowering medication is of importance to protect against CVD events and mortality., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Nuclear magnetic resonance (NMR) spectroscopy allows triglycerides to be subclassified into 14 different classes based on particle size and lipid content. We recently showed that these subfractions have differential associations with cardiovascular disease events. Here we report the distributions and define reference interval ranges for 14 triglyceride-containing lipoprotein subfraction metabolites., Methods: Lipoprotein subfractions using the Nightingale NMR platform were measured in 9073 participants from four cohort studies contributing to the UCL-Edinburgh-Bristol consortium. The distribution of each metabolite was assessed, and reference interval ranges were calculated for a disease-free population, by sex and age group (<55, 55-65, >65 years), and in a subgroup population of participants with cardiovascular disease or type 2 diabetes. We also determined the distribution across body mass index and smoking status., Results: The largest reference interval range was observed in the medium very-low density lipoprotein subclass (2.5th 97.5th percentile; 0.08 to 0.68 mmol/L). The reference intervals were comparable among male and female participants, with the exception of triglyceride in high-density lipoprotein. Triglyceride subfraction concentrations in very-low density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein and high-density lipoprotein subclasses increased with increasing age and increasing body mass index. Triglyceride subfraction concentrations were significantly higher in ever smokers compared to never smokers, among those with clinical chemistry measured total triglyceride greater than 1.7 mmol/L, and in those with cardiovascular disease, and type 2 diabetes as compared to disease-free subjects., Conclusion: This is the first study to establish reference interval ranges for 14 triglyceride-containing lipoprotein subfractions in samples from the general population measured using the nuclear magnetic resonance platform. The utility of nuclear magnetic resonance lipid measures may lead to greater insights for the role of triglyceride in cardiovascular disease, emphasizing the importance of appropriate reference interval ranges for future clinical decision making.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a major development in the prevention of cardiovascular disease (CVD) and is one of the most significant discoveries since the development of statin therapy. Administration of two human monoclonal antibodies to PCSK9 (alirocumab and evolocumab) can significantly reduce low-density lipoprotein cholesterol (LDL-c) concentrations, thus improving lipid management. Accordingly, guidelines on the specific indications for alirocumab and evolocumab usage have been released. This multicentre study aimed to estimate the proportion of patients treated for an acute myocardial infarction (MI) who could be considered for PCSK9 inhibitors under the current National Institute for Health and Care Excellence (NICE) lipid targets criteria., Methods: The records of 596 patients in two large hospitals in Liverpool, UK were analysed. Information was collected on lipid profiles during and after admission, lipid-lowering therapy and previous CVD., Results: At least 2.2% of patients were eligible for PCSK9 inhibitors post-MI under the current NICE guidance. Additionally, 29% of patients failed to achieve LDL-c concentrations <2.0 mmol/L despite maximum statin therapy and failed to meet eligibility for PCSK9 inhibitors as per the NICE criteria. This cohort represents a group of patients 'in limbo', in which statin therapy alone is not sufficient to reduce LDL-c., Conclusions: PCSK9 inhibitors are expensive and so their use must be highly selective. At present, in a real-world setting with ezetimibe underprescribing, ~2% of patients are eligible and a further 30% are deprived of benefit and improved outcomes by lack of optimisation and/or potential use of PCSK9 inhibitors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The UK Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS-OM) developed using 30-year (1977-2007) data from the UKPDS is widely used for health outcomes' projections and economic evaluations of therapies for patients with type 2 diabetes (T2D). Nevertheless, its reliability for contemporary UK T2D populations is unclear. We assessed the performance of version 2 of the model (UKPDS-OM2) using data from A Study of Cardiovascular Events in Diabetes (ASCEND), which followed participants with diabetes in the UK between 2005 and 2017.Methods: The UKPDS-OM2 was used to predict the occurrence of myocardial infarction (MI), other ischemic heart disease, stroke, cardiovascular (CV) death, and other death among the 14 569 participants with T2D in ASCEND, all without previous CV disease at study entry. Calibration (comparison of predicted and observed year-on-year cumulative incidence over 10 years) and discrimination (c-statistics) of the model were assessed for each endpoint. The percentage error in event rates at year 7 (mean duration of follow up) was used to quantify model bias.Results: The UKPDS-OM2 substantially overpredicted MI, stroke, CV death, and other death over the 10-year follow-up period (by 149%, 42%, 269%, and 52%, respectively, at year 7). Discrimination of the model for MI and other ischemic heart disease (c-statistics 0.58 and 0.60, respectively) was poorer than that for other outcomes (c-statistics ranging from 0.66 to 0.72).Conclusions: The UKPDS-OM2 substantially overpredicted risks of key CV outcomes and death in people with T2D in ASCEND. Appropriate adjustments or a new model may be required for assessments of long-term effects of treatments in contemporary T2D cohorts. [ABSTRACT FROM AUTHOR]

Despite widespread evidence of the effectiveness of lipid modification for the reduction of cardiovascular disease (CVD) risk, lipid modification goals are commonly underachieved in the United Kingdom (UK). In order to understand current UK lipid management guidance and the corresponding attainment of recommended lipid lowering goals relating to treatment with statins and ezetimibe, a literature review was conducted using PubMed focusing on publications between January 2017 and February 2020 in order to capture the most up-to-date literature. Identified publications were reviewed against key clinical guidelines for lipid management in relation to CVD risk from the National Institute for Health and Care Excellence (NICE, CG181), the Scottish Intercollegiate Guidelines Network (SIGN, 149) and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS). Cholesterol lowering goals are central to current lipid lowering therapy guidance, although specific goals vary depending on the guideline and patients' individual risk profile. Current guidance by NICE and SIGN specifies that treatment should achieve a greater than 40% reduction in non-high-density lipoprotein cholesterol (non-HDL-C) at 3 months of treatment, while the ESC/EAS place emphasis on the lowering of low-density lipoprotein (LDL-C) and total cholesterol. Yet, despite widespread availability of guidance and consistent messaging that lipid lowering goals should be ambitious, current evidence suggests a significant proportion of UK patients have sub-optimal reductions in cholesterol/non-HDL-C/LDL-C. The reasons for this are reported to be multifactorial, including a lack of compliance with guidelines, particularly regarding high-intensity statin prescribing, patient adherence, statin intolerance and statin reluctance as well as wider genetic factors. A number of possible strategies to improve current lipid management and attainment of lipid-lowering goals were identified, including improving the patient-healthcare professional partnership, conducting audits of local prescribing versus guidance, implementing plans for the refinement of current services and considering alternative options such as cost-effective single pill combinations for improving adherence. [ABSTRACT FROM AUTHOR]

Objective: To examine the association between age at period cessation and trajectories of anthropometry, blood pressure, lipids and glycated haemoglobin (HbA1c) from midlife to age 69 years.Methods: We used data from the UK Medical Research Council National Survey of Health and Development to examine the association between age at period cessation and trajectories of systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI) and waist circumference (WC) from 36 to 69 years and trajectories of triglyceride, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and HbA1c from 53 to 69 years.Results: We found no evidence that age at period cessation was associated with trajectories of log triglyceride, LDL-C and HDL-C from 53 to 69 years and trajectories of SBP or DBP from 36 to 69 years, regardless of whether period cessation occurred naturally or due to hysterectomy. While we found some evidence of associations of age at period cessation with log BMI, log WC and log HbA1c, patterns were not consistent and differences were small at age 69 years, with confidence intervals that spanned the null value.Conclusion: How and when women experience period cessation is unlikely to adversely affect conventional cardiovascular risk factors across mid and later life. Women and clinicians concerned about the impact of type and timing of period cessation on conventional cardiovascular intermediates from midlife should be reassured that the impact over the long term is small. [ABSTRACT FROM AUTHOR]

Background: Stroke is a leading cause of death and disability; worldwide it is estimated that 16.9 million people have a first stroke each year. Lipid-lowering, anticoagulant, and antihypertensive drugs can prevent strokes, but may be underused.Methods and Findings: We analysed anonymised electronic primary care records from a United Kingdom (UK) primary care database that covers approximately 6% of the UK population. Patients with first-ever stroke/transient ischaemic attack (TIA), ≥18 y, with diagnosis between 1 January 2009 and 31 December 2013, were included. Drugs were considered under-prescribed when lipid-lowering, anticoagulant, or antihypertensive drugs were clinically indicated but were not prescribed prior to the time of stroke or TIA. The proportions of strokes or TIAs with prevention drugs under-prescribed, when clinically indicated, were calculated. In all, 29,043 stroke/TIA patients met the inclusion criteria; 17,680 had ≥1 prevention drug clinically indicated: 16,028 had lipid-lowering drugs indicated, 3,194 anticoagulant drugs, and 7,008 antihypertensive drugs. At least one prevention drug was not prescribed when clinically indicated in 54% (9,579/17,680) of stroke/TIA patients: 49% (7,836/16,028) were not prescribed lipid-lowering drugs, 52% (1,647/3,194) were not prescribed anticoagulant drugs, and 25% (1,740/7,008) were not prescribed antihypertensive drugs. The limitations of our study are that our definition of under-prescribing of drugs for stroke/TIA prevention did not address patients' adherence to medication or medication targets, such as blood pressure levels.Conclusions: In our study, over half of people eligible for lipid-lowering, anticoagulant, or antihypertensive drugs were not prescribed them prior to first stroke/TIA. We estimate that approximately 12,000 first strokes could potentially be prevented annually in the UK through optimal prescribing of these drugs. Improving prescription of lipid-lowering, anticoagulant, and antihypertensive drugs is important to reduce the incidence and burden of stroke and TIA. [ABSTRACT FROM AUTHOR]

The article discusses a study that discusses the role of a workplace-based risk assessment in improving a lifetime cardiovascular disease risk in male steelworkers in Great Britain. It informs that the study included a sample of male employees from a local steelworks in Carmarthenshire, South Wales, and undergone cardiovascular disease (CVD) and diabetes risk assessment and the results showed that workplace-based CVD initiatives were beneficial to shift workers.

Deborah Robertson provides an overview of recently published articles that may be of interest to non-medical prescribers. Should you wish to look at any of the papers in more detail, a full reference is provided [ABSTRACT FROM AUTHOR]

Abstract: Background: Although low-density lipoprotein cholesterol (LDL-C) is the primary lipid target for cardiovascular disease (CVD) risk reduction, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) have also emerged as risk factors. This study evaluated attainment of goal/normal lipid levels in current clinical practice among high-risk patients following lipid-modifying therapy (LMT). Methods: Data for patients aged ≥35years and on LMT for ≥12months were identified from electronic medical records (United Kingdom and Sweden) and extracted from medical charts (Canada and Spain). High CVD risk was defined according to the Adult Treatment Panel III guidelines. An index period was defined, from January 1995–July 2008, during which patients received an initial LMT prescription. Prevalence of lipid abnormalities was assessed 12months before and after the index date. Multivariate logistic regressions evaluated predictors of attaining goal/normal lipid levels. Results: Among 12,768 high-risk patients, 75% had elevated LDL-C, 37% low HDL-C, and 30% elevated TG before LMT. Despite therapy (97% statins only), 23% had elevated LDL-C, 36% low HDL-C, 16% elevated TG, and 17% had ≥2 abnormal lipid levels. Framingham risk score >20% (Odds Ratio, 95% confidence interval: 0.37,0.31–0.43), diabetes (0.75,0.64–0.88), hypertension (1.26,1.09–1.46), current smoker (0.82,0.70–0.95) and increased body mass index (0.95,0.94–0.96) were associated with the likelihood of attaining ≥2 normal lipid levels (vs. LDL-C goal only). Conclusion: Current approaches to lipid management improve LDL-C goal attainment; however, control of multiple lipid risk factors remains poor. Patients may benefit from more comprehensive approaches to lipid management, which treat multiple lipid abnormalities, as suggested in clinical guidelines. [Copyright &y& Elsevier]

Abstract: Here the impact of APOE genotype on CHD risk in UK adults is reported, along with an analysis of APOE genotype×BMI/age/sex interactions. APOE genotype had a significant impact on fasting total:LDL-cholesterol (TC:LDL-C) ratio, triglycerides, % HDL3, and the Framingham 10-year CVD risk score (P <0.05), with an overall trend towards lower and higher risk in E2- and E4-carriers, respectively, relative to the wild-type E3/E3 genotype. A greater impact of genotype on TC:HDL-C was observed in females, which explained 16% of the variability in this outcome versus 6% in males. APOE genotype was also associated with plasma C-reactive protein and adhesion molecule concentrations (P <0.05), with significant genotype×BMI interactions observed. Our observations indicate that the association between the APOE genotype and CHD risk is unlikely to be homogenous and highlights the risk of inaccurate estimations of genotype–phenotype associations in population subgroups without appropriate stratification for sex and adiposity. [Copyright &y& Elsevier]

The article discusses various issues concerning lipid modification in relation to cardiovascular disease (CVD). It cites the guidance on lipid modification published by Great Britain National Institute for Clinical Excellence (NICE). An explanation on the value of lipid modification in the primary prevention of CVD is offered, along with the factors that affect cholesterol measurement. The article also discusses the pharmacological management of CVD.

Background and objectives: Lipid management in UK general practice targets the achievement of total cholesterol (TC) targets in high-risk individuals. Statins alone have a modest effect on non-LDL-C components of the lipid profile, leaving these patients at significant residual cardiovascular (CV) risk. Improving risk further would require the addition of non-statin therapies. This analysis explores what proportion of the UK population with cardiovascular disease (CVD) and TC levels at or below target may still be at risk because of residual dyslipidaemia.Methods: CV risk profiles were extracted from a research database of 602 222 patients from 98 UK general practices. Patients were categorised according to their prior CV history and use of statins. Mean values and proportions achieving treatment targets were assessed for TC, low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) and triglycerides (TG).Results: In all, 48 499 patients with pre-existing CVD or diabetes were identified. 73% of statin-treated patients and 63% of untreated patients had a TC ≤5 mmol/L. 28.6% of patients treated to a TC target had LDL-C>3 mmol/L. Amongst those with both TC and LDL-C treated to target, 22.5% had low HDL-C and 37.2% had high triglyceride (TG). Within this group, more women than men had abnormal HDL-C (25.4 vs. 20.7%; p<0.0001). Patients with diabetes were more likely than non-diabetics to have abnormalities of both HDL-C (28.9 vs. 16.4%; p<0.0001) and triglyceride (44.9 vs. 29.5%; p<0.0001) despite normal TC and LDL-C.Conclusions: Around 60% of high-risk patients have residual dyslipidaemias despite achieving the Quality and Outcomes Framework (QOF) TC target. New patterns of treatment are required in order to extend lipid management beyond simple total cholesterol lowering. [ABSTRACT FROM AUTHOR]

The article reports that practice nurses in Great Britain will be expected to hit tough new targets on the identification of people at risk of cardiovascular disease (CVD) and for lipid modification, following the publication of new guidance from the National Institute for Clinical Excellence (NICE). NICE says that practices must adopt a more systematic strategy to identify people who are likely to be at high risk of CVD.