Andrew Neil

University of Oxford | OX · Wolfson College

Introduction: Childhood-onset type 1 diabetes (T1D) is associated with an increased risk of premature cardiovascular mortality. Objectives: This study aimed to assess the evolution of subclinical vascular damage in young people with T1D as they transitioned through adolescence. Methods: Repeated vascular phenotyping was performed in early adolescen...

Identifying genetic determinants for longitudinal changes in albumin excretion in individuals with type 1 diabetes may help identify those that are predisposed to renal, retinal and cardiovascular complications. Most studies have focussed on genetic predisposition to diabetic kidney disease and used cross-sectional measurements of urinary albumin e...

Background Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in la...

Aims/hypothesis We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. Methods This was a prospective observational study in 710 normoalbuminuric...

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 Sta...

An increased albumin-creatinine ratio within the normal range can identify adolescents at higher risk of developing adverse cardio-renal outcomes as they progress into adulthood. Utilizing a parallel randomized controlled trial and observational cohort study, we characterized the progression of vascular phenotypes throughout this important period a...

Objectives To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D. Methods Twenty‐five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median[interquartile range] age: 13.9[12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardiorenal...

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...

OBJECTIVE Suboptimal adherence to insulin treatment is a main issue in adolescents with type 1 diabetes. However, to date, there are no available data on adherence to adjunct noninsulin medications in this population. Our aim was to assess adherence to ACE inhibitors and statins and explore potential determinants in adolescents with type 1 diabetes...

Diabetes vascular complications, including cardiovascular disease, diabetic nephropathy and retinopathy, have a negative effect on the long-term prognosis of young people with type 1 diabetes mellitus (T1DM). Poor glycaemic control and consequent increased HbA 1c levels are major risk factors for the development of vascular complications. HbA 1c le...

Background: Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages. Methods: In this...

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...

BACKGROUND AND AIMS: Patients with familial hypercholesterolaemia (FH) have an elevated risk of coronary heart disease (CHD). Here we compare changes in CHD mortality in patients with heterozygous (FH) pre 1992, before lipid-lowering therapy with statins was used routinely, and in the periods 1992–2008 and 2008–2016. METHODS: 1903 Definite (DFH) an...

Objective: Baseline data from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) indicated that tertiles of urinary albumin-to-creatinine ratios (ACRs) in the normal range at age 10-16 years are associated with risk markers for diabetic nephropathy (DN) and cardiovascular disease (CVD). We aimed to determine whether the top ACR...

Background and aims: Patients with familial hypercholesterolaemia (FH) have an elevated risk of coronary heart disease (CHD). Here we compare changes in CHD mortality in patients with heterozygous (FH) pre 1992, before lipid-lowering therapy with statins was used routinely, and in the periods 1992-2008 and 2008-2016. Methods: 1903 Definite (DFH)...

Background Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long-term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin-converting–enzyme...

BACKGROUND & para;& para;Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long-term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin-conv...

Background: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. Methods and results: We performed a meta-analysis of genome-wide association stud...

Background: Traditional cardiovascular risk factors, such as hypertension and dyslipidemia, predispose individuals to cardiovascular disease, particularly patients with diabetes. We investigated the predictive value of baseline systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) on the risk of vascular outcomes in a large...

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% m...

Heterozygous familial hypercholesterolaemia (FH) is a common autosomal dominant disorder. The vast majority of affected individuals remain undiagnosed, resulting in lost opportunities for preventing premature heart disease. Better use of routine primary care data offers an opportunity to enhance detection. We sought to develop a new predictive algo...

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 stati...

Background Familial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation. Methods and...

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and con...

OBJECTIVE Diabetes-associated autoantibodies can be detected in adult-onset diabetes, even when initially non-insulin requiring, i.e., with latent autoimmune diabetes. We aimed to identify adult-onset autoimmune diabetes in patients with established "type 2 diabetes" participating in the Collaborative Atorvastatin Diabetes Study (CARDS) to characte...

Annual screening for adults with type 2 diabetes to detect the early onset of kidney disease is widely recommended, but the recommendations are based on a limited methodological approach. In addition, there are continuing uncertainties about underlying rates of progression of the condition and the benefits of treatments with angiotensin-converting...

To replicate the associations of leukocyte telomere length (LTL) with variants at four loci and to investigate their associations with coronary heart disease (CHD) and type II diabetes (T2D), in order to examine possible causal effects of telomere maintenance machinery on disease aetiology. Four SNPs at three loci BICD1 (rs2630578 GγC), 18q12.2 (rs...

Objective To assess the association between early increases in albumin excretion and cardiovascular (CV) and renal markers in a large cohort of young people with type 1 diabetes.Research Design and Methods As part of preliminary screening for a multicentre, randomized controlled trial of statins/ACE inhibitors, we measured albumin-creatinine ratio...

Supplemental Fig. 1. 3D structure of LDL-R extracellular domains (Protein Database 1N7D, http://www.ebi.ac.uk/pdbsum/1N7D) viewed using Jmol, overlaid with conservation scores. Red indicates high conservation, purple moderate conservation, blue poor conservation. Calcium cations are shown as black dots. Residues deleted in p.(Lys223_Cys231) are sho...

Supplemental Fig. 2. Pre-treatment LDL cholesterol in patients with mutation in LDLR or APOB genes, or with no mutation identified. The difference between the groups was significant (ANOVA p = 7.76 × 10−05).

Aim To determine the frequency and spectrum of mutations causing Familial Hypercholesterolaemia (FH) in patients attending a single UK specialist hospital lipid clinic in Oxford and to identify characteristics contributing to a high mutation detection rate. Methods 289 patients (272 probands) were screened sequentially over a 2-year period for mut...

Telehealth-supported clinical interventions may improve diabetes self-management. We explored the feasibility of stepwise self-titration of oral glucose-lowering medication guided by a mobile telephone-based telehealth platform for improving glycemic control in type 2 diabetes. We recruited 14 type 2 diabetes patients to a one-year feasibility stud...

Background: Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be cause...

Aim: Type 1 diabetes guidelines recommend annual monitoring of albumin-creatinine ratio (ACR) to detect nephropathy. Annual monitoring for conditions such as dyslipidemia leads to high rates of false-positive diagnoses. We estimated rates of false-positive and false-negative diagnoses under annual, biennial and triennial monitoring. Methods: Usi...

Background Familial Hypercholesterolaemia (FH) is an autosomal dominant disease, caused by mutations in LDLR, APOB or PCSK9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease. An autosomal recessive form of FH is also known, due to homozygous mutations in LDLRAP1. This study assessed the utility of an e...

To assess the relationship of levels of inflammatory risk markers to presence of clinical coronary artery disease (CAD) in patients with treated heterozygous familial hypercholesterolaemia. A cross-sectional study of patients on the Simon Broome Familial Hyperlipidaemia Register. Six hospital outpatient clinics in the UK. A total of 211 men and 199...

A sequence variant, rs7025486[A], in DAB2IP on chromosome 9q33 has recently been associated with coronary heart disease (CHD). We sought to replicate this finding and to investigate associations with a panel of inflammatory and haemostatic biomarkers. We also sought to examine whether this variant, in combination with a chromosome 9p21 CHD variant...

In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the...

We carried out a genome-wide association study (GWAS) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed atorvastatin 10 mg. Following...

We examined the effect of atorvastatin (and placebo) on tumour necrosis factor (TNF)α, soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular cell adhesion molecule-1 (sICAM-1) in patients with type 2 diabetes without prior cardiovascular disease (CVD) and investigated whether adhesion molecules were associated with incident...

Circulating levels of soluble receptor for advanced glycation end products (sRAGE) likely comprise both a secreted isoform (esRAGE) and wild-type RAGE cleaved from the cell membrane. Both sRAGE and esRAGE have been proposed as biomarkers of cardiovascular disease (CVD), but prospective data are limited. We examined the relationship of sRAGE and esR...

A sequence variant, rs7025486[A], in DAB2IP on chromosome 9q33 has recently been associated with coronary heart disease (CHD). We sought to replicate this finding and to investigate associations with a panel of inflammatory and haemostatic biomarkers. We also sought to examine whether this variant, in combination with a chromosome 9p21 CHD variant...

We investigated the feasibility of a mobile-phone based system for patients with type 2 diabetes who had recently commenced insulin therapy but remained poorly controlled. The system was evaluated in a feasibility study in a general practice setting with 23 patients over six months. A total of 22 patients successfully completed the study and used t...

To determine the effects of statin treatment and omega-3 polyunsaturated fatty acid supplementation on plasma plant sterol concentrations and cholesterol synthesis in patients with type 2 diabetes. Plant sterol concentrations and lanosterol (a marker of cholesterol synthesis) were measured using a high sensitivity assay to assess the effect of doub...

Familial hypercholesterolemia (FH) meets internationally agreed criteria for screening, and systematic national screening programs should, therefore, be initiated. Cascade testing (to screen at-risk relatives) of known index cases with FH (using a combination of mutation information and lipid levels) is cost effective, and is an evidence-based meth...

Shorter telomeres have been reported in premature myocardial infarction (MI) patients. Our work aimed at confirming the association of shorter telomere with MI in two case–control studies and in familial hypercholesterolemia (FH) patients with coronary heart disease (CHD). The HIFMECH study compared 598 white male patients (<60 years) who survived...

To examine all-cause and cardiovascular mortality in patients with severe hypertriglyceridaemia. 337 patients aged less than 80 years (47 with diabetes, 75 women) with a fasting triglyceride concentration on at least two occasions of >5.0mmol/l were registered by 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 200...

To estimate, using probabilistic decision-analytic modelling techniques, the cost effectiveness of treating familial hypercholesterolaemia (FH) patients with high-intensity statins compared to treatment with low-intensity statins. For the purpose of this economic analysis, and based on their known differences, statins were categorised as high inten...

Familial predisposition to hypertension has been associated with the development of diabetic nephropathy in adults, but there are limited data in adolescents. Our aim was to assess whether parental ambulatory blood pressure (ABP) was associated with ABP and albumin excretion in young offspring with type 1 diabetes. Twenty-four-hour ABP monitoring w...

We measured plasma PCSK9 concentrations in healthy men with a PCSK9 (proprotein convertase subtilisin/kexin type 9) loss-of-function variant (p.R46L), in statin-treated patients with a clinical diagnosis of familial hypercholesterolemia (FH) and carrying a PCSK9 gain-of-function mutation (p.D374Y), and in statin-treated patients with FH due to diff...