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.

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.

aSt George's University of London, London bUniversity Hospital of Wales, Cardiff, UK Correspondence to Alan Rees, University Hospital of Wales, Cardiff, UK. Tel: +0 783 118 4551; e-mail: [email protected]

aSt George's Medical School, University of London, London bUniversity Hospital of Wales, Cardiff, UK Correspondence to Alan Rees, University Hospital of Wales, Cardiff, UK. E-mail: [email protected]

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 Reactive hyperaemia induces a slowing of pulse wave velocity (PWV) in conduit arteries of healthy subjects (flow-mediated slowing (FMS)). This could be an alternative method for assessing peripheral vasomotor function to the gold standard method of flow-mediated dilatation (FMD) a more expensive and technically demanding technique. We aimed to assess the reproducibility of FMS in healthy participants and to test its ability to detect differences in vasomotor function in patients with familial hypercholesterolaemia (FH) and post-lipoprotein apheresis (LA) treatment. Methods Altogether 25 healthy participants were studied on two occasions to assess reproducibility of FMS. In a case control study of 22 patients with FH and matched healthy controls, FMD and FMS were compared. An intervention study in 12 patients with FH looked at the impact of a single LA treatment on FMS assessed pre and post treatment. Results FMS demonstrated good reproducibility (coefficient of variation (CoV) 7.3%). Patients with FH had reduced FMS in comparison to matched healthy controls (FMS% FH −15.13 ± 5.04% vs controls −18.41 ± 5.15%, p = 0.023), with no difference in FMD% between the two groups. A single LA treatment significantly improved FMS (pre −18.81 ± 9.84 vs post −24.09 ± 7.61%, p = 0.016). Conclusions FMS is a reproducible technique, which is able to detect differences in vasomotor function both in a condition associated with endothelial dysfunction and following an acute intervention known to improve endothelial function. This simple technique has potential for accessible assessment of vasomotor function in clinical studies.

Department of Diabetes and Endocrinology, University Hospital of Wales, Cardiff, UK Correspondence to Dr L.N. Rao Bondugulapati, Specialist Registrar, Department of Diabetes and Endocrinology, University Hospital of Wales, Cardiff CF14 4XW, UK. Tel: +44 7727041264; e-mail: [email protected]

aDepartment of Diabetes and Endocrinology, Prince Charles Hospital, Cwm Taf University Health Board, Gurnos, Merthyr Tydfil bDepartment of Diabetes and Endocrinology, University Hospital of Wales, Cardiff and Vale University Health Board, Cardiff, Wales, UK Correspondence to Dr Gautam Das, Consultant in Diabetes and Endocrinology, Department of Diabetes and Endocrinology, Prince Charles Hospital, Gurnos, Merthyr Tydfil CF47 9DT, UK. Tel: +44 16 8572 8353; fax: +44 16 8572 8448; e-mail: [email protected];[email protected]

Department of Diabetes and Endocrinology, University Hospital of Wales, Cardiff, UK Correspondence to Dr Vinay S. Eligar, Specialist Registrar, Department of Diabetes and Endocrinology, University Hospital of Wales, Cardiff CF14 4XW, UK. Tel: +44 7809118031; e-mail: [email protected]

Department of Diabetes and Endocrinology, University Hospital of Wales, Cardiff, UK Correspondence to Dr Gautam Das, Department of Diabetes and Endocrinology (B7 corridor), University hospital of Wales, Cardiff CF14 4XW, UK. Tel: +442920743000; fax: +442920744581; e-mail: [email protected],[email protected]

Despite impressive advances in treatment, cardiovascular disease (CVD) remains a significant healthcare burden in the UK and worldwide. The clustering of CVD risk factors in patients with type 2 diabetes underlines the need for a multifactorial treatment approach, yet even when receiving optimal therapy according to best standards of care, there remains a substantial risk of CVD and microvascular disease. Risk prediction tools traditionally provide an estimate of risk over 10 years, however this approach is dominated by chronological age and gender and has a number of recognised limitations. A move from 10-year to lifetime risk calculation has been proposed, and should encourage intervention at a much earlier stage. This move, alongside aggressive and broad control of modifiable risk factors, aims to ease the burden of atherosclerosis prior to the manifestations of CVD. This will be of particular benefit to those with type 2 diabetes, who have been exposed to hyperglycaemia and other risk factors for extended periods of time. The atherogenic dyslipidaemia common in this group also ensures they will benefit most from treatment strategies under investigation to further reduce macrovascular and microvascular risk.

DOI:10.1097/MOL.0000000000000134 Microsomal triglyceride transfer protein (MTP) is a key element involved in the assembly and secretion of apolipoprotein B (ApoB) containing lipoproteins. It mediates the transfer of triglycerides and cholesterol esters from the cytosol to the endoplasmic reticulum containing nascent ApoB during the formation of VLDLs and chylomicrons in the liver and intestinal cells, respectively [1 & ]. In abetalipoproteinemia, a rare autosomal recessive disorder, patients have mutations in the MTP gene, which leads to defective and nonfunctional MTP activity. As a consequence, patients have very low plasma concentrations of triglycerides and cholesterol and undetectable levels of LDL-cholesterol (LDL-C) and ApoB [2]. This concept was utilized to develop an effective therapeutic strategy of MTP inhibition, which can significantly lower LDL-C in patients with severe dyslipidemia. For any new therapeutic intervention to succeed, benefits must outweigh risk. Several pharmacological preparations, which were developed and aimed at MTP inhibition, have demonstrated the predictable side-effects of hepatic fat accumulation, elevation of liver enzymes, steatorrhea and deficiencies of fat-soluble vitamins [3]. Historically, this has been the case for the last decade. Thus, adverse events generally outweigh benefits apart from in the very highest risk patients. Patients with homozygous familial hypercholesterolemia (HoFH) constitute one such very high-risk group and are characterized by abnormally high levels of LDL-C, which cannot be lowered by conventional therapies. Moreover, these patients have a 10-fold to 13-fold risk of cardiovascular disease, leading to premature and untimely death in a young population [4]. Familial hypercholesterolemia is a dominantly inherited lipoprotein disorder caused by mutations in the LDL receptor (LDLR), ApoB and proprotein convertase subtilisin/kexin type 9 gene loci. HoFH, more correctly termed compound heterozygote familial hypercholesterolemia, is characterized by severe hypercholesterolemia (total cholesterol range from 15 to 30 mmol/l) since childhood and the presence of early-onset cutaneous and tendon xanthomas and corneal arcus [5].

Carl Henry Alstrom first described the syndrome in 1959.1 It is a rare autosomal recessive, single gene, multi system disorder characterised by early onset retinal (progressive cone rod) dystrophy with profound visual loss, childhood obesity with insulin resistance, hyperinsulinaemia and diabetes, sensorineural hearing loss, dilated cardiomyopathy as well as progressive renal and hepatic dysfunction. We present a case of Alstrom syndrome diagnosed in a 34 year old male subject followed by a brief review of its clinical presentation

Consultant Diabetes & Endocrinology, University hospital of Wales, Cardiff, UK Correspondence to Dr Atul Kalhan, Department of Diabetes & Endocrinology, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK. Tel: +44 2920744687; fax: +44 2920745131; e-mail: [email protected]

University Hospital of Wales, Cardiff, UK Correspondence to Dr Atul Kalhan, Department of Diabetes and Endocrinology, University Hospital of Wales, Cardiff, CF14 4XW, UK. Tel: +44 2920715021; fax: +44 2920715689; e-mail: [email protected]

Aims Metformin is associated with lowering of vitamin B12 levels. We hypothesise that holotranscobalamin (holoTC) and methylmalonic acid (MMA) are more sensitive indicators of B12 deficiency in patients receiving metformin therapy, and that these correlate with declining peripheral neurological function. Methods Patients with type 2 diabetes were recruited and divided into those receiving metformin for greater than 6 months and a non-metformin group. Baseline characteristics were measured in both groups including vitamin B12, holoTC and MMA concentrations. Neurological function was assessed using neurothesiometry, monofilament, Neuropathy Total Symptom Score-6 questionnaire and the Self-administered Leeds Assessment of Neuropathic Symptoms and Signs questionnaire. Results In total, 202 patients were recruited: 152 in the metformin group and 50 in the non-metformin group. Vitamin B12 levels were lower in the metformin group (219.1±105.4 ng/L, 281.4±95.1 ng/L, p<0.001). HoloTC was significantly lower in the metformin group (54.8±30.5 pmol/L, 70.1±26.0 pmol/L, p=0.002). No significant difference in serum MMA was observed between the two groups (0.40±0.26 μmol/L, 0.35±0.22, p=0.23). No significant difference in neurological function was observed between the groups. Conclusion Although metformin therapy is associated with lower vitamin B12 status there does not appear to be any significant effect on peripheral neuropathy in those receiving metformin. We do not recommend changing current practice to routinely monitor or replace patients receiving metformin with vitamin B12 unless clinically indicated.