Introduction Dyslipidaemia accelerates atherosclerosis. Patients with genetic dyslipidaemias, Familial Hypercholesterolaemia (FH) being the most common, are at heightened risk of premature cardiovascular events. However, this risk is heterogeneous within identical genotype diseases, and modifiable with treatment. Coronary imaging identifies subclinical atherosclerosis, personalises risk stratification and treatment targets. Coronary artery calcium scoring (CACS) is first-line for primary prevention. However, calcification is a late-stage process in CAD pathogenesis and the CACS has low specificity in young patients with severe FH. CT coronary angiography (CTCA) may identify non-calcific CAD and high risk plaque (HRP) features unseen with CACS. This study aimed to quantify the impact of CTCA vs traditional CACS on clinical management in real-world asymptomatic Lipid Clinic patients. Methods A retrospective single-centre review of asymptomatic Lipid Clinic electronic patient records with both CACS and CTCA from May 2019 to December 2020. A vignette was compiled for each patient providing all relevant clinical data. CACS was recorded as Agastston score and CTCA as the Coronary Artery Disease - Reporting and Data System (CAD RADS) grading of anatomical stenosis with a modifier for HRP features.Findings were compiled into an anonymised online survey which Consultant Biochemists from across the UK were invited to complete. Data was revealed in a step-wise fashion to the participating clinician: (i) vignette only, (ii) CACS, and (iii) CAD RADS. Clinicians were asked their lipid target and management after each data-point was unblinded. Background information on CACS and CTCA result interpretation was provided prior to participation. Statistical analysis was performed using SPSS v.21 and significance was defined as two-tailed p<0.05. Results 45 asymptomatic patients (55±9 years, 49% female) were included. 7 Consultant Biochemists from 6 institutions (4 [67%] tertiary/teaching hospitals and 2 [33%] district general hospitals) participated.CACS and CAD RADS assessment of disease burden is presented in Figure 1, with CTCA re-classifying CAD severity vs CACS in 28/45 (62%) patientsLipid targets were altered significantly more frequently with CTCA vs CACS (19% vs 12%; χ2 57.0, p<0.005), even after CACS result available (Figure 2). The LDL target selected was altered by CACS in 12%, and in a further 19% when CAD RADS result was unblinded, which was statistically significant (χ2 57.0, p<0.005). This finding was consistent across FH and non-FH patients. Increasing CACS and CAD RADS severity were significantly associated with change in lipid target (χ2 54.2, p<0.001; χ2 27, p<0.001), the latter even after a high CACS result was available, as did presence of HRP (χ2 9.3, p=0.002). Conclusion In high-risk asymptomatic dyslipidaemia, CTCA alters treatment targets beyond CACS by demonstrating higher CAD severity burden and HRP. This may differentiate high risk and very high risk patients in an important population. Conflict of Interest Nil

Repurposing established medicines for a new therapeutic indication potentially has important global and societal impact. The high costs and slow pace of new drug development have increased interest in more cost-effective repurposed drugs, particularly in the cancer arena. The conventional drug development pathway and evidence framework are not designed for drug repurposing and there is currently no consensus on establishing the evidence base before embarking on a large, resource intensive, potential practice changing phase III randomised controlled trial (RCT). Numerous observational studies have suggested a potential role for statins as a repurposed drug for cancer chemoprevention and therapy, and we review the strength of the cumulative evidence here. In the setting of cancer, a potential repurposed drug, like statins, typically goes through a cyclical history, with initial use for several years in another disease setting, prior to epidemiological research identifying a possible chemo-protective effect. However, further information is required, including review of RCT data in the initial disease setting with exploration of cancer outcomes. Additionally, more contemporary methods should be considered, such as Mendelian randomization and pharmaco-epidemiological research with “target” trial design emulation using electronic health records. Pre-clinical and traditional observational data potentially support the role of statins in the treatment of cancer; however, randomised trial evidence is not supportive. Evaluation of contemporary methods provides little added support for the use of statin therapy in cancer. We provide complementary evidence of alternative study designs to enable a robust critical appraisal from a number of sources of the go/no-go decision for a prospective phase III RCT of statins in the treatment of cancer.

It has been brought to our attention that the wording of the German reimbursement criteria for apheresis is not clear in the above paper (Section 7. Management of patients with raised Lipoprotein(a), Subheading: Apheresis). This should read: "In Germany, Lp(a) levels exceeding 60 mg/dl and LDL-cholesterol in normal range along with progressive CVD has been approved as an indication for regular lipoprotein apheresis since 2008." HEART UK consensus statement on Lipoprotein(a): A call to actionAtherosclerosisVol. 291PreviewLipoprotein(a), Lp(a), is a modified atherogenic low-density lipoprotein particle that contains apolipoprotein(a). Its levels are highly heritable and variable in the population. This consensus statement by HEART UK is based on the evidence that Lp(a) is an independent cardiovascular disease (CVD) risk factor, provides recommendations for its measurement in clinical practice and reviews current and emerging therapeutic strategies to reduce CVD risk. Ten statements summarise the most salient points for practitioners and patients with high Lp(a). Full-Text PDF Open Access

The emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes Coronavirus Disease 2019 (COVID-19) has resulted in a pandemic. SARS-CoV-2 is highly contagious and its severity highly variable. The fatality rate is unpredictable but is amplified by several factors including advancing age, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension and obesity. A large proportion of patients with these conditions are treated with lipid lowering medication and questions regarding the safety of continuing lipid-lowering medication in patients infected with COVID-19 have arisen. Some have suggested they may exacerbate their condition. It is important to consider known interactions with lipid-lowering agents and with specific therapies for COVID-19. This statement aims to collate current evidence surrounding the safety of lipid-lowering medications in patients who have COVID-19. We offer a consensus view based on current knowledge and we rated the strength and level of evidence for these recommendations. Pubmed, Google scholar and Web of Science were searched extensively for articles using search terms: SARS-CoV-2, COVID-19, coronavirus, Lipids, Statin, Fibrates, Ezetimibe, PCSK9 monoclonal antibodies, nicotinic acid, bile acid sequestrants, nutraceuticals, red yeast rice, Omega-3-Fatty acids, Lomitapide, hypercholesterolaemia, dyslipidaemia and Volanesorsen. There is no evidence currently that lipid lowering therapy is unsafe in patients with COVID-19 infection. Lipid-lowering therapy should not be interrupted because of the pandemic or in patients at increased risk of COVID-19 infection. In patients with confirmed COVID-19, care should be taken to avoid drug interactions, between lipid-lowering medications and drugs that may be used to treat COVID-19, especially in patients with abnormalities in liver function tests.

Purpose of review The role of non-HDL-C in the identification and management of lipid disorders is not clearly defined, although UK guidelines recommend its wider use in assessing the need for lipid-lowering therapy and as a treatment target. Recent findings We examined the implications of the use of non-HDL-C as opposed to LDL-C in 253 people with hypercholesterolaemia before treatment and 573 after treatment in whom fasting total serum cholesterol, HDL-C and LDL-C had been recorded and the diagnosis of heterozygous familial hypercholesterolemia (heFH) was investigated by genetic testing. The difference and the limits of agreement between non-HDL-C and LDL-C calculated using the Friedewald formula were assessed in those with and without heFH-causing mutations. There were 147 mutation-positive and 106 mutation-negative pretreatment participants and 395 mutation-positive and 178 mutation-negative patients receiving treatment. The difference between non-HDL-C and LDL-C pretreatment in mutation-positive people (mean LDL-C 7.73 mmol/l) was 0.67 mmol/l (95% CI 0.62-0.73) and posttreatment (mean LDL-C 4.71 mmol/l) was 0.62 mmol/l (95% CI 0.59-0.65) with wide limits of agreement of -0.02 to 1.37 and 0.07-1.18 mmol/l, respectively. Among patients with heterozygous familial hypercholesterolaemia, use of estimated LDL-C derived from non-HDL-C in place of calculated LDL-C may result in diagnostic misclassification and difficulty in assessing the true reduction in LDL-C with treatment, because of the wide inter-individual limits of agreement around the mean difference between non-HDL-C and LDL-C.

Purpose of review The role of non-HDL-C in the identification and management of lipid disorders is not clearly defined, although UK guidelines recommend its wider use in assessing the need for lipid-lowering therapy and as a treatment target. Recent findings We examined the implications of the use of non-HDL-C as opposed to LDL-C in 253 people with hypercholesterolaemia before treatment and 573 after treatment in whom fasting total serum cholesterol, HDL-C and LDL-C had been recorded and the diagnosis of heterozygous familial hypercholesterolemia (heFH) was investigated by genetic testing. The difference and the limits of agreement between non-HDL-C and LDL-C calculated using the Friedewald formula were assessed in those with and without heFH-causing mutations. Summary There were 147 mutation-positive and 106 mutation-negative pretreatment participants and 395 mutation-positive and 178 mutation-negative patients receiving treatment. The difference between non-HDL-C and LDL-C pretreatment in mutation-positive people (mean LDL-C 7.73 mmol/l) was 0.67 mmol/l (95% CI 0.62–0.73) and posttreatment (mean LDL-C 4.71 mmol/l) was 0.62 mmol/l (95% CI 0.59–0.65) with wide limits of agreement of −0.02 to 1.37 and 0.07–1.18 mmol/l, respectively. Among patients with heterozygous familial hypercholesterolaemia, use of estimated LDL-C derived from non-HDL-C in place of calculated LDL-C may result in diagnostic misclassification and difficulty in assessing the true reduction in LDL-C with treatment, because of the wide inter-individual limits of agreement around the mean difference between non-HDL-C and LDL-C.

Background and aims: The UK Simon Broome (SB) familial hypercholesterolaemia (FH) register previously reported 3-fold higher standardised mortality ratio for cardiovascular disease (CVD) in women compared to men from 2009 to 2015. Here we examined sex differences in CVD morbidity in FH by national linkage of the SB register with Hospital Episode Statistics (HES). Methods: Of 3553 FH individuals in the SB register (aged 20-79 years at registration), 2988 (52.5% women) had linked HES records. Standardised Morbidity Ratios (SMbR) compared to an age and sex-matched UK general practice population were calculated [95% confidence intervals] for first CVD hospitalisation in HES (a composite of coronary heart disease (CHD), myocardial infarction (MI), stable or unstable angina, stroke, TIA, peripheral vascular disease (PVD), heart failure, coronary revascularisation interventions). Results: At registration, men had significantly (p < 0.001) higher prevalence of previous CHD (24.8% vs 17.6%), previous MI (13.2% vs 6.3%), and were commenced on lipid-lowering treatment at a younger age than women (37.5 years vs 42.3 years). The SMbR for composite CVD was 6.83 (6.33-7.37) in men and 7.55 (6.99-8.15) in women. In individuals aged 30-50 years, SMbR in women was 50% higher than in men (15.04 [12.98-17.42] vs 10.03 [9.01-11.17]). In individuals >50 years, SMbR was 33% higher in women than men (6.11 [5.57-6.70] vs 4.59 [4.08-5.15]). Conclusions: Excess CVD morbidity due to FH remains markedly elevated in women at all ages, but especially those aged 30-50 years. This highlights the need for earlier diagnosis and optimisation of lipid-lowering risk factor management for all FH patients, with particular attention to young women with FH.

Lipoprotein(a), Lp(a), is a modified atherogenic low-density lipoprotein particle that contains apolipoprotein(a). Its levels are highly heritable and variable in the population. This consensus statement by HEART UK is based on the evidence that Lp(a) is an independent cardiovascular disease (CVD) risk factor, provides recommendations for its measurement in clinical practice and reviews current and emerging therapeutic strategies to reduce CVD risk. Ten statements summarise the most salient points for practitioners and patients with high Lp(a). HEART UK recommends that Lp(a) is measured in adults as follows: 1) those with a personal or family history of premature atherosclerotic CVD; 2) those with first-degree relatives who have Lp(a) levels >200 nmol/l; 3) patients with familial hypercholesterolemia; 4) patients with calcific aortic valve stenosis and 5) those with borderline (but <15%) 10-year risk of a cardiovascular event. The management of patients with raised Lp(a) levels should include: 1) reducing overall atherosclerotic risk; 2) controlling dyslipidemia with a desirable non-HDL-cholesterol level of <100 mg/dl (2.5 mmol/l) and 3) consideration of lipoprotein apheresis.

Background and aims: The International Atherosclerosis Society (IAS) has proposed that patients with "severe" FH (SFH) would warrant early and more aggressive cholesterol-lowering treatment such as with PCSK9 inhibitors. SFH is diagnosed if LDL-cholesterol (LDLC) > 10 mmol/L, or LDLC > 8.0 mmol/L plus one high-risk feature, or LDLC > 5 mmol/L plus two high-risk features. Here we compare CHD mortality in SFH and non-SFH (NSFH) patients in the UK prospective Simon Broome Register since 1991, when statin use became routine. Methods: 2929 definite or possible PFH patients (51% women) aged 20-79 years were recruited from 21 UK lipid clinics and followed prospectively between 1992 and 2016. The excess CHD standardised mortality ratio (SMR) compared to the England and Wales population was calculated (with 95% confidence intervals). Results: 1982 (67.7%) patients met the SFH definition. Compared to the non-SFH, significantly (p < 0.001) more SFH patients had diagnosed CHD at baseline (24.6% vs. 17.5%), were current smokers (21.9% vs 10.2%) and had a BMI > 30 kg/m(2) (14.9% vs. 7.8%). The SMR for CHD mortality was significantly (p = 0.007) higher for SFH (220 (184-261) (34,134 person years, 129 deaths observed, vs. 59 expected) compared to NSFH of 144 (98-203) (15,432 person years, 32 observed vs. 22 expected). After adjustment for traditional risk factors, the Hazard Ratio for CHD mortality in SFH vs. NSFH was 1.22 (0.80-1.87) p = 0.36, indicating that the excess risk was largely accounted for by these factors. Conclusions: CHD mortality remains elevated in treated FH, especially for SFH, emphasising the importance of optimal lipid-lowering and management of other risk factors.

This consensus statement on the management of children and young people with heterozygous familial hypercholesterolaemia (FH) addresses management of paediatric FH in the UK, identified by cascade testing when a parent is diagnosed with FH and for those diagnosed following incidental lipid tests. Lifestyle and dietary advice appropriate for children with FH; suggested low density lipoprotein cholesterol (LDL-C) targets and the most appropriate lipid-lowering therapies to achieve these are discussed in this statement of care. Based on the population prevalence of FH as ~1/250 and the UK paediatric population, there are approximately 50,000 FH children under 18 years. Currently only about 550 of these children and young people have been identified and are under paediatric care.

Dyslipidaemia is a key risk factor for cardiovascular disease, and its identification and treatment is important for both primary and secondary prevention. This article discusses how to screen for dyslipidaemia and optimise lipid‐lowering therapy to improve cardiovascular outcomes.

Homozygous familial hypercholesterolaemia (HoFH) is an inherited disease causing an approximately fourfold increase in blood low-density lipoprotein cholesterol (LDLC) from birth compared with the age-matched normal population owing to reduced low-density lipoprotein receptor (LDLR) activity. Such elevated cholesterol is associated with accelerated atheromatous disease, particularly of the aortic root and coronary arteries. However, HoFH is clinically heterogeneous, reflecting residual low-density lipoprotein receptor (LDLR) activity. The main objective in treating children may be stated to be the avoidance of irreversible cardiac damage requiring heart transplantation by sufficient lowering of blood cholesterol. Lipoprotein apheresis or plasmapheresis are safe means of lowering cholesterol but may be insufficient on their own. Statin drugs, PCSK9 inhibitors ezetimibe and bile acid sequestrants are relatively ineffective if LDLR activity is lacking, but should be used if effective. Two new drugs, lomitapide and mipomersen, have been licensed specifically for HoFH by some regulatory authorities. They work by reducing LDL production rate. They have been associated with fatty liver in adults. Evidence of safety in children is lacking. An alternative is liver transplantation, which replaces the missing LDLR and normalises cholesterol. Clinicians are faced with a dilemma in choosing between these options or deferring such treatment associated with potential harm. Individual case descriptions are an important means of informing clinical judgement. Management of the two cases described in this issue is discussed in the light of modern developments in transplantation and pharmacotherapy.

BACKGROUND AND AIMS:Untreated individuals with familial hypercholesterolaemia (FH) are at increased risk of developing premature cardiovascular disease (CVD). Early diagnosis and treatment can result in a normal life expectancy. A recent survey commissioned by the European Atherosclerosis Society (EAS) reported a lack of awareness of FH in the general population. We conducted a survey to assess knowledge among healthcare professionals involved in the assessment and management of cardiovascular risk and disease in the United Kingdom.METHODS:A survey designed to assess knowledge of diagnostic criteria, risk assessment, the role of cascade screening, and management options for patients with FH was distributed to 1000 healthcare professionals (response rate 44.3%). The same survey was redistributed following attendance at an educational session on FH.RESULTS:151 respondents (40.5%) reported having patients under their care who would meet the diagnostic criteria for FH, but just 61.4% recognized that cardiovascular risk estimation tools cannot be applied in FH, and only 22.3% understood the relative risk of premature CVD compared to the general population. Similarly, just 65.9% were aware of recommendations regarding cascade screening.CONCLUSIONS:The prevalence and associated risk of FH continue to be underestimated, and knowledge of diagnostic criteria and treatment options is suboptimal. These results support the recent Consensus Statement of the EAS and production of quality standards by the National Institute for Health and Care Excellence. Further work is required to formulate interventions to improve FH awareness and knowledge, and to determine the effect these interventions have on patient outcomes.

Introduction Glitazones (also known as thiazolidinediones) are a class of drugs used to treat type 2 diabetes mellitus. They bind to and activate PPARγ, a ligand-activated nuclear transcription factor expressed in adipose tissue, endothelial cells, skeletal muscle liver cells and other tissues. The activated PPARγ leads to changes in expression/transcription of several genes involved in glucose and lipid metabolism. The two currently available glitazones, rosiglitazone and pioglitazone, have been shown to raise HDL-C and lower TG levels in several clinical studies as well as increasing insulin sensitivity. Separate meta-analyses of the effects of rosiglitazone and pioglitazone on cardiovascular events were reported in 2007. It was seen that while rosiglitazone appeared to be associated with an increased risk of myocardial infarction pioglitazone showed a beneficial effect. Although no explanation for these disparate observations has been provided the possibility of significant differences between the two glitazones exists. We recently reported five case studies in which the addition of rosiglitazone in patients already on a fibrate led to unexpected reductions in HDL-C but with improvements in glycaemic control. Although the reasons for this were not clear we suggested that thiazolidinediones cross-reacted with PPAR-α and either decreased synthesis of ApoA1 or increased catabolism of ApoA1 leading to lower levels of HDL-C. Three of the patients were switched from rosiglitazone to pioglitazone and the HDL-C returned to normal levels. This pointed to differences between the two drugs in their actions on lipid metabolism. We now report a case which showed a paradoxical decrease in HDL-C when treated with rosiglitazone, but unlike the other patients reported by us also demonstrated a similar change when switched to pioglitazone.

General practice characteristics are important for healthcare providers to maximise outcomes. Although different aspects of general practice characteristics have been studied previously, the impact of practice size on the delivery of care has been sparsely studied, particularly in relation to diabetes care. This brief report presents a longitudinal study in Shropshire (66 practices, 16,858 patients with diabetes) to assess the impact of practice size on diabetes care before and after implementation of the Quality and Outcomes Framework (QOF). Achievement of glycaemic control targets was better before the QOF for larger as compared to smaller practices (P=0.02 and P=0.003 for haemoglobin A1c [HbA1c]<or=7.4% and 10% respectively). This difference disappeared following QOF implementation. Repeated measures analysis showed significant improvement in achieving glycaemic control targets following QOF implementation in both large and small practices (P<0.001 for HbA1c<or=7.4% and 10%). The study failed to reveal an impact of practice size on achieving the HbA1c target<or=7.4% (P=0.1) by this analysis. However, it did show an impact on reaching the target of HbA1c<10% (P=0.04) in favour of smaller practices. There was a significant difference in favour of smaller practices for achievement of prescription of angiotensin-converting enzyme inhibitors (P=0.001).

To examine the changes in coronary, all-cause, and cancer mortality in patients with heterozygous familial hypercholesterolaemia (FH) before and after lipid-lowering therapy with statins.A total of 3382 patients (1650 men) aged < 80 years were recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2006 for 46 580 person-years. There were 370 deaths, including 190 from coronary heart disease (CHD) and 90 from cancer. The standardized mortality ratio (compared with the population in England and Wales) was calculated before and from 1 January 1992. In patients aged 20-79 years, CHD mortality fell significantly by 37% (95% CI = 7-56) from 3.4- to 2.1-fold excess. Primary prevention resulted in a 48% reduction in CHD mortality from 2.0-fold excess to none, with a smaller reduction of nearly 25% in patients with established disease. Coronary mortality was reduced more in women than in men. In patients without known CHD at registration, all-cause mortality from 1992 was 33% (21-43), lower than in the general population, mainly due to a 37% (21-50) lower risk of fatal cancer.The results emphasize the importance of early identification of FH and treatment with statins.

The aim of this study was to assess the impact of the Quality and Outcomes Framework (QOF) of the new GP contract on diabetes care in Shropshire, which has a total population of approximately 460 000. The mean percentage of patients achieving each of the quality indicators in each practice in Shropshire, before and after the implementation of the QOF was calculated. All 16 867 patients with diabetes from all 66 Shropshire practices were included. There were significant improvements in the percentage of patients achieving targets for all quality indicators between April 2004 to March 2006 (P < 0.001).