Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome.

BACKGROUND: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III. METHODS: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis. RESULTS: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group. CONCLUSIONS: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.).

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Ethnic Diversity and Distinctive Features of Familial Versus Multifactorial Chylomicronemia Syndrome: Insights From the UK FCS National Registry.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS). METHODS: The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project. RESULTS: FCS was relatively common in non-Europeans and those with parental consanguinity (P<0.001 for both). LPL variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; P=0.001), recurrent pancreatitis (92% versus 63%; P<0.001), unexplained abdominal pain (84% versus 52%; P<0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; P<0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; P<0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS (P<0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS (P=0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS. CONCLUSIONS: The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS.

Paraoxonase 1: evolution of the enzyme and of its role in protecting against atherosclerosis.

PURPOSE OF REVIEW: To review the discoveries which led to the concept that serum paraoxonase 1 (PON1) is inversely related to atherosclerotic cardiovascular disease (ASCVD) incidence, how this association came to be regarded as causal and how such a role might have evolved. RECENT FINDINGS: Animal models suggest a causal link between PON1 present on HDL and atherosclerosis. Serum PON1 activity predicts ASCVD with a similar reliability to HDL cholesterol, but at the extremes of high and low HDL cholesterol, there is discordance with PON1 being potentially more accurate. The paraoxonase gene family has its origins in the earliest life forms. Its greatest hydrolytic activity is towards lactones and organophosphates, both of which can be generated in the natural environment. It is active towards a wide range of substrates and thus its conservation may have resulted from improved survival of species facing a variety of evolutionary challenges. SUMMARY: Protection against ASCVD is likely to be the consequence of some promiscuous activity of PON1, but nonetheless has the potential for exploitation to improve risk prediction and prevention of ASCVD.

Pancreatic and cardiometabolic complications of severe hypertriglyceridaemia.

PURPOSE OF REVIEW: This review endeavours to explore the aetiopathogenesis and impact of severe hypertriglyceridemia (SHTG) and chylomicronaemia on cardiovascular, and pancreatic complications and summarizes the novel pharmacological options for management. RECENT FINDINGS: SHTG, although rare, presents significant diagnostic and therapeutic challenges. Familial chylomicronaemia syndrome (FCS), is the rare monogenic form of SHTG, associated with increased acute pancreatitis (AP) risk, whereas relatively common multifactorial chylomicronaemia syndrome (MCS) leans more towards cardiovascular complications. Despite the introduction and validation of the FCS Score, FCS continues to be underdiagnosed and diagnosis is often delayed. Longitudinal data on disease progression remains scant. SHTG-induced AP remains a life-threatening concern, with conservative treatment as the cornerstone while blood purification techniques offer limited additional benefit. Conventional lipid-lowering medications exhibit minimal efficacy, underscoring the growing interest in novel therapeutic avenues, that is, antisense oligonucleotides (ASO) and short interfering RNA (siRNA) targeting apolipoprotein C3 (ApoC3) and angiopoietin-like protein 3 and/or 8 (ANGPTL3/8). SUMMARY: Despite advancements in understanding the genetic basis and pathogenesis of SHTG, diagnostic and therapeutic challenges persist. The rarity of FCS and the heterogenous phenotype of MCS underscore the need for the development of predictive models for complications and tailored personalized treatment strategies. The establishment of national and international registries is advocated to augment disease comprehension and identify high-risk individuals.

Established and potential cardiovascular risk factors in metabolic syndrome: Effect of bariatric surgery.

PURPOSE OF REVIEW: The aim of this review was to provide an overview of the role of novel biomarkers in metabolic syndrome, their association with cardiovascular risk and the impact of bariatric surgery on these biomarkers. RECENT FINDINGS: Metabolic syndrome encompasses an intricate network of health problems, and its constituents extend beyond the components of its operational definition. Obesity-related dyslipidaemia not only leads to quantitative changes in lipoprotein concentration but also alteration in qualitative composition of various lipoprotein subfractions, including HDL particles, rendering them proatherogenic. This is compounded by the concurrent existence of obstructive sleep apnoea (OSA) and nonalcoholic fatty liver disease (NAFLD), which pave the common pathway to inflammation and oxidative stress culminating in heightened atherosclerotic cardiovascular disease (ASCVD) risk. Bariatric surgery is an exceptional modality to reverse both conventional and less recognised aspects of metabolic syndrome. It reduces the burden of atherosclerosis by ameliorating the impact of obesity and its related complications (OSA, NAFLD) on quantitative and qualitative composition of lipoproteins, ultimately improving endothelial function and cardiovascular morbidity and mortality. SUMMARY: Several novel biomarkers, which are not traditionally considered as components of metabolic syndrome play a crucial role in determining ASCVD risk in metabolic syndrome. Due to their independent association with ASCVD, it is imperative that these are addressed. Bariatric surgery is a widely recognized intervention to improve the conventional risk factors associated with metabolic syndrome; however, it also serves as an effective treatment to optimize novel biomarkers.

Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study.

BACKGROUND: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally. METHODS: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005. FINDINGS: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12·0 years (IQR 5·5-27·0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14·7 mmol/L (IQR 11·6-18·4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3·93 mmol/L, IQR 2·6-5·8) versus non-high-income countries (9·3 mmol/L, 6·7-12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24·5 years (IQR 17·0-34·5) versus 37·0 years (29·0-49·0) in high-income countries (adjusted hazard ratio 1·64, 95% CI 1·13-2·38). INTERPRETATION: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH. FUNDING: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society.

Impact of Bariatric Surgery on Subtilisin/Kexin Type 9 (PCSK9) Gene Expression and Inflammation in the Adipose Tissue of Obese Diabetic Rats.

Bariatric surgery improves dyslipidaemia and reduces body weight, but it remains unclear how bariatric surgery modulates gene expression in fat cells to influence the proprotein convertase subtilisin/kexin type 9 (PCSK-9) and low-density lipoprotein receptor (LDLR) gene expression. The expression of the PCSK9/LDLR/tumor necrosis factor-alpha (TNFα) gene in adipose tissue was measured in two groups of Zucker Diabetic Sprague Dawley (ZDSD) rats after Roux-en-Y gastric bypass (RYGB) surgery or 'SHAM' operation. There was lower PCSK9 (p = 0.02) and higher LDLR gene expression (p = 0.02) in adipose tissue in rats after RYGB. Weight change did not correlate with PCSK9 gene expression (r = -0.5, p = 0.08) or TNFα gene expression (r = -0.4, p = 0.1). TNFα gene expression was positively correlated with PCSK9 gene expression (r = 0.7, p = 0.001) but not correlated with LDLR expression (r = -0.3, p = 0.3). Circulating triglyceride levels were lower in RYGB compared to the SHAM group (1.1 (0.8-1.4) vs. 1.5 (1.0-4.2), p = 0.038) mmol/L with no difference in cholesterol levels. LDLR gene expression was increased post-bariatric surgery with the potential to reduce the number of circulating LDL particles. PCSK9 gene expression and TNFα gene expression were positively correlated after RYGB in ZDSD rats, suggesting that the modulation of pro-inflammatory pathways in adipose tissue after RYGB may partly relate to PCSK9 and LDLR gene expression.

What should be the goal of cholesterol-lowering treatment? A quantitative evaluation dispelling guideline myths.

PURPOSE OF REVIEW: Guidelines for cholesterol-lowering treatment generally include extensive review of epidemiological and clinical trial evidence. However, the next logical step, the translation of evidence into clinical advice, occurs not entirely by reasoning, but by a form of consensus in which the prejudices and established beliefs of the societies with interests in cardiovascular disease convened to interpret the evidence are prominent. Methods, which are the subject of this review, have, however, been developed by which clinical trial evidence can be translated objectively into best practice. RECENT FINDINGS: Guidelines differ in their recommended goals for cholesterol-lowering treatment in the prevention of atherosclerotic cardiovascular disease (ASCVD). Proposed goals are LDL-cholesterol 2.6 mmol/l (100 mg/dl) or less in lower risk, LDL-cholesterol 1.8 mmol/l (70 mg/dl) or less in higher risk, non-HDL-cholesterol decrease of at least 40% or LDL-cholesterol 1.8 mmol/l (70 mg/dl) or less or decreased by at least 50% whichever is lower. Evidence from clinical trials of statins, ezetimibe and proprotein convertase subtilisin/kexin type 9-inhibitors can be expressed in simple mathematical terms to compare the efficacy on ASCVD incidence of clinical guidance for the use of cholesterol-lowering medication. The target LDL-cholesterol of 2.6 mmol/l (100 mg/dl) is ineffective and lacks credibility. Cholesterol-lowering medication is most effective in high-risk people with raised LDL-cholesterol. The best overall therapeutic target is LDL-cholesterol 1.8 mmol/l (70 mg/dl) or less or decreased by at least 50% whichever is lower. The use of non-HDL-cholesterol as a therapeutic goal is less efficacious. Aiming for LDL-cholesterol 1.4 mmol/l (55 mg/dl) or less as opposed to 1.8 mmol/l produces only a small additional benefit. Evidence for apolipoprotein B targets in hypertriglyceridaemia and in very high ASCVD risk should be more prominent in future guidelines. SUMMARY: The LDL-cholesterol goal of 2.6 mmol/l or less should be abandoned. Percentage decreases in LDL-cholesterol or non-HDL-cholesterol concentration are better in people with initial concentrations of less than 3.6 mmol/l. The LDL-cholesterol target of 1.8 mmol/l is most effective when initial LDL-cholesterol is more than 3.6 mmol/l in both primary and secondary prevention.

Lipoprotein (a) in familial hypercholesterolaemia.

PURPOSE OF REVIEW: The role of lipoprotein (a) in atherogenesis has been the subject of argument for many years. Evidence that it is raised in familial hypercholesterolaemia has been disputed not least because a mechanism related to low density lipoprotein (LDL) receptor mediated catabolism has been lacking. Whether lipoprotein (a) increases the already raised atherosclerotic cardiovascular disease (ASCVD) risk in familial hypercholesterolaemia is also more dubious than is often stated. We review the evidence in an attempt to provide greater clarity. RECENT FINDINGS: Lipoprotein (a) levels are raised as a consequence of inheriting familial hypercholesterolaemia. The mechanism for this is likely to involve increased hepatic production, probably mediated by PCSK9 augmented by apolipoprotein E. The extent to which raised lipoprotein (a) contributes to the increased ASCVD risk in familial hypercholesterolaemia remains controversial.Unlike, for example, statins which are effective across the whole spectrum of LDL concentrations, drugs in development to specifically lower lipoprotein (a) are likely to be most effective in people with the highest levels of lipoprotein (a). People with familial hypercholesterolaemia may therefore be in the vanguard of those in whom theses agents should be exhibited. SUMMARY: Inheritance of familial hypercholesterolaemia undoubtedly increases the likelihood that lipoprotein (a) will be raised. However, in familial hypercholesterolaemia when ASCVD incidence is already greatly increased due to high LDL cholesterol, whether lipoprotein (a) contributes further to this risk cogently needs to be tested with drugs designed to specifically lower lipoprotein (a).

Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome.

BACKGROUND: Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels. METHODS: We conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months. RESULTS: Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P<0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001). At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter). A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000 per microliter. No patient had platelet counts below 50,000 per microliter after enhanced platelet-monitoring began. CONCLUSIONS: Volanesorsen lowered triglyceride levels to less than 750 mg per deciliter in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection-site reactions were common adverse events. (Funded by Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical Trials.gov number, NCT02211209.).

Elevated plasma triglyceride concentration and risk of adverse clinical outcomes in 1.5 million people: a CALIBER linked electronic health record study.

BACKGROUND: Assessing the spectrum of disease risk associated with hypertriglyceridemia is needed to inform potential benefits from emerging triglyceride lowering treatments. We sought to examine the associations between a full range of plasma triglyceride concentration with five clinical outcomes. METHODS: We used linked data from primary and secondary care for 15 M people, to explore the association between triglyceride concentration and risk of acute pancreatitis, chronic pancreatitis, new onset diabetes, myocardial infarction and all-cause mortality, over a median of 6-7 years follow up. RESULTS: Triglyceride concentration was available for 1,530,411 individuals (mean age 56·6 ± 15·6 years, 51·4% female), with a median of 1·3 mmol/L (IQR: 0.9.to 1.9). Severe hypertriglyceridemia, defined as > 10 mmol/L, was identified in 3289 (0·21%) individuals including 620 with > 20 mmol/L. In multivariable analyses, a triglyceride concentration > 20 mmol/L was associated with very high risk for acute pancreatitis (Hazard ratio (HR) 13·55 (95% CI 9·15-20·06)); chronic pancreatitis (HR 25·19 (14·91-42·55)); and high risk for diabetes (HR 5·28 (4·51-6·18)) and all-cause mortality (HR 3·62 (2·82-4·65)) when compared to the reference category of ≤ 1·7 mmol/L. An association with myocardial infarction, however, was only observed for more moderate hypertriglyceridaemia between 1.7 and 10 mmol/L. We found a risk interaction with age, with higher risks for all outcomes including mortality among those ≤ 40 years compared to > 40 years. CONCLUSIONS: We highlight an exponential association between severe hypertriglyceridaemia and risk of incident acute and chronic pancreatitis, new diabetes, and mortality, especially at younger ages, but not for myocardial infarction for which only moderate hypertriglyceridemia conferred risk.

Corneal nerve loss is related to the severity of painful diabetic neuropathy.

BACKGROUND AND PURPOSE: Previously it has been shown that patients with painful diabetic neuropathy (PDN) have greater corneal nerve loss compared to patients with painless diabetic neuropathy. This study investigated if the severity of corneal nerve loss was related to the severity of PDN. METHODS: Participants with diabetic neuropathy (n = 118) and healthy controls (n = 38) underwent clinical and neurological evaluation, quantitative sensory testing, nerve conduction testing and corneal confocal microscopy and were categorized into those with no (n = 43), mild (n = 34) and moderate-to-severe (n = 41) neuropathic pain. RESULTS: Corneal nerve fibre density (p = 0.003), corneal nerve fibre length (p < 0.0001) and cold perception threshold (p < 0.0001) were lower and warm perception threshold was higher (p = 0.002) in patients with more severe pain, but there was no significant difference in the neuropathy disability score (p = 0.5), vibration perception threshold (p = 0.5), sural nerve conduction velocity (p = 0.3) and amplitude (p = 0.7), corneal nerve branch density (p = 0.06) and deep breathing heart rate variability (p = 0.08) between patients with differing severity of PDN. The visual analogue scale correlated significantly with corneal nerve fibre density (r = -0.3, p = 0.0002), corneal nerve branch density (r = -0.3, p = 0.001) and corneal nerve fibre length (r = -0.4, p < 0.0001). Receiver operating curve analysis showed that corneal nerve fibre density had an area under the curve of 0.78 with a sensitivity of 0.73 and specificity of 0.72 for the diagnosis of PDN. CONCLUSIONS: Corneal confocal microscopy reveals increasing corneal nerve fibre loss with increasing severity of neuropathic pain and a good diagnostic outcome for identifying patients with PDN.

The impact of atherosclerotic cardiovascular disease, dyslipidaemia and lipid lowering therapy on Coronavirus disease 2019 outcomes: an examination of the available evidence.

PURPOSE OF REVIEW: Coronavirus Disease 2019 (COVID19) has caused significant global morbidity and mortality, especially in persons with underlying cardiovascular disease. There have been concerns that lipid-lowering therapy (LLT) increases angiotensin-converting enzyme 2 levels. Conversely, pleiotropic effects of statins can theoretically protect against severe COVID19 infection, supporting evidence from other respiratory illnesses in which statin use probably confers benefit. RECENT FINDINGS: There is an abundance of studies that show that statins are safe and potentially protect against severe COVID19 infection (critical illness and death), even when adjustment for potential confounders is undertaken. However, the evidence is limited to retrospective cohorts. The benefit for patients with diabetes is less clear. There is a paucity of evidence for other LLT agents. Available clinical guidelines recommend the ongoing use of LLT in patients with COVID19 (unless specifically contra-indicated) and the data from available studies support these. SUMMARY: In patients with COVID19 infection, LLT should be continued. However, the current findings need substantiating in larger prospective clinical studies with specific examination of the possible mechanisms by which LLT confers benefit from COVID19.

Lipids and peripheral neuropathy.

PURPOSE OF REVIEW: Hyperlipidaemia is associated with the development of neuropathy. Indeed, a mechanistic link between altered lipid metabolism and peripheral nerve dysfunction has been demonstrated in a number of experimental and clinical studies. Furthermore, post hoc analyses of clinical trials of cholesterol and triglyceride-lowering pharmacotherapy have shown reduced rates of progression of diabetic neuropathy. Given, there are currently no FDA approved disease-modifying therapies for diabetic neuropathy, modulation of lipids may represent a key therapeutic target for the treatment of diabetic nerve damage. This review summarizes the current evidence base on the role of hyperlipidaemia and lipid lowering therapy on the development and progression of peripheral neuropathy. RECENT FINDINGS: A body of literature supports a detrimental effect of dyslipidaemia on nerve fibres resulting in somatic and autonomic neuropathy. The case for an important modulating role of hypertriglyceridemia is stronger than for low-density lipoprotein cholesterol (LDL-C) in relation to peripheral neuropathy. This is reflected in the outcomes of clinical trials with the different therapeutic agents targeting hyperlipidaemia reporting beneficial or neutral effects with statins and fibrates. The potential concern with the association between proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy and cognitive decline raised the possibility that extreme LDL-C lowering may result in neurodegeneration. However, studies in murine models and data from small observational studies indicate an association between increased circulating PCSK9 levels and small nerve fibre damage with a protective effect of PCSK9i therapy against small fibre neuropathy. Additionally, weight loss with bariatric surgery leads to an improvement in peripheral neuropathy and regeneration of small nerve fibres measured with corneal confocal microscopy in people with obesity with or without type 2 diabetes. These improvements correlate inversely with changes in triglyceride levels. SUMMARY: Hyperlipidaemia, particularly hypertriglyceridemia, is associated with the development and progression of neuropathy. Lipid modifying agents may represent a potential therapeutic option for peripheral neuropathy. Post hoc analyses indicate that lipid-lowering therapies may halt the progression of neuropathy or even lead to regeneration of nerve fibres. Well designed randomized controlled trials are needed to establish if intensive targeted lipid lowering therapy as a part of holistic metabolic control leads to nerve fibre regeneration and improvement in neuropathy symptoms.

High density lipoprotein-associated miRNA is increased following Roux-en-Y gastric bypass surgery for severe obesity.

Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed weight-loss procedures, but how severe obesity and RYGB affect circulating HDL-associated microRNAs (miRNAs) remains unclear. Here, we aim to investigate how HDL-associated miRNAs are regulated in severe obesity and how weight loss after RYGB surgery affects HDL-miRNAs. Plasma HDLs were isolated from patients with severe obesity (n = 53) before and 6 and 12 months after RYGB by immunoprecipitation using goat anti-human apoA-I microbeads. HDLs were also isolated from 18 healthy participants. miRNAs were extracted from isolated HDL and levels of miR-24, miR-126, miR-222, and miR-223 were determined by TaqMan miRNA assays. We found that HDL-associated miR-126, miR-222, and miR-223 levels, but not miR-24 levels, were significantly higher in patients with severe obesity when compared with healthy controls. There were significant increases in HDL-associated miR-24, miR-222, and miR-223 at 12 months after RYGB. Additionally, cholesterol efflux capacity and paraoxonase activity were increased and intercellular adhesion molecule-1 (ICAM-1) levels decreased. The increases in HDL-associated miR-24 and miR-223 were positively correlated with an increase in cholesterol efflux capacity (r = 0.326, P = 0.027 and r = 0.349, P = 0.017, respectively). An inverse correlation was observed between HDL-associated miR-223 and ICAM-1 at baseline. Together, these findings show that HDL-associated miRNAs are differentially regulated in healthy participants versus patients with severe obesity and are altered after RYGB. These findings provide insights into how miRNAs are regulated in obesity before and after weight reduction and may lead to the development of novel treatment strategies for obesity and related metabolic disorders.

Bariatric surgery leads to an improvement in small nerve fibre damage in subjects with obesity.

INTRODUCTION: Subjects with obesity have metabolic risk factors for nerve fibre damage. Because bariatric surgery improves these risk factors we have assessed whether this can ameliorate nerve fibre damage. METHODS: Twenty-six obese subjects without diabetes (age: 46.23 ± 8.6, BMI: 48.7 ± 1.5, HbA1c: 38.0 ± 4.5) and 20 controls (age: 48.3 ± 6.2, BMI: 26.8 ± 4.2, HbA1c: 39.1 ± 2.6) underwent detailed assessment of neuropathy at baseline and 12 months after bariatric surgery. RESULTS: Obese subjects had normal peroneal (45.9 ± 5.5 vs. 48.1 ± 4.5, P = 0.1) and sural (46.9 ± 7.6 vs. 47.9 ± 10.6, P = 0.1) nerve conduction velocity, but a significantly higher neuropathy symptom profile (NSP) (4.3 ± 5.7 vs. 0.3 ± 0.6, P = 0.001), vibration perception threshold (VPT) (V) (10.2 ± 6.8 vs. 4.8 ± 2.7, P < 0.0001), warm threshold (C°) (40.4 ± 3.5 vs. 37.2 ± 1.8, P = 0.003) and lower peroneal (3.8 ± 2.2 vs. 4.9 ± 2.2, P = 0.02) and sural (8.9 ± 5.8 vs. 15.2 ± 8.5, P < 0.0001) nerve amplitude, deep breathing-heart rate variability (DB-HRV) (beats/min) (21.7 ± 4.1 vs. 30.1 ± 14, P = 0.001), corneal nerve fibre density (CNFD) (n/mm2) (25.6 ± 5.3 vs. 32.0 ± 3.1, P < 0.0001), corneal nerve branch density (CNBD) (n/mm2) (56.9 ± 27.5 vs. 111.4 ± 30.7, P < 0.0001) and corneal nerve fibre length (CNFL) (mm/mm2) (17.9 ± 4.1 vs. 29.8 ± 4.9, P < 0.0001) compared to controls at baseline. In control subjects there was no change in neuropathy measures over 12 months. However, 12 months after bariatric surgery there was a significant reduction in BMI (33.7 ± 1.7 vs. 48.7 ± 1.5, P = 0.001), HbA1c (34.3 ± 0.6 vs. 38.0 ± 4.5, P = 0.0002), triglycerides (mmol/l) (1.3 ± 0.6 vs. 1.6 ± 0.8, P = 0.005) and low-density lipoprotein cholesterol (mmol/l) (2.7 ± 0.7 vs. 3.1 ± 0.9, P = 0.02) and an increase in high-density lipoprotein cholesterol (mmol/l) (1.2 ± 0.3 vs. 1.04 ± 0.2, P = 0.002). There was a significant improvement in NSP (1.6 ± 2.7 vs. 4.3 ± 5.7, P = 0.004), neuropathy disability score (0.3 ± 0.9 vs. 1.3 ± 2.0, P = 0.03), CNFD (28.2 ± 4.4 vs. 25.6 ± 5.3, P = 0.03), CNBD (64.7 ± 26.1 vs. 56.9 ± 27.5, P = 0.04) and CNFL (20.4 ± 1.2 vs. 17.9 ± 4.1, P = 0.02), but no change in cold and warm threshold, VPT, DB-HRV or nerve conduction velocity and amplitude. Increase in CNFD correlated with a decrease in triglycerides (r = -0.45, P = 0.04). CONCLUSION: Obese subjects have evidence of neuropathy, and bariatric surgery leads to an improvement in weight, HbA1c, lipids, neuropathic symptoms and deficits and small nerve fibre regeneration without a change in quantitative sensory testing, autonomic function or neurophysiology.

Greater small nerve fibre damage in the skin and cornea of type 1 diabetic patients with painful compared to painless diabetic neuropathy.

BACKGROUND AND AIM: Damage to small nociceptive fibres may contribute to painful diabetic neuropathy. We aimed to compare large and small nerve fibre measurements together with skin biopsy and corneal confocal microscopy in patients with type 1 diabetes and painful or painless diabetic neuropathy. METHODS: We have assessed the McGill pain questionnaire, neuropathy disability score, vibration perception threshold, warm and cold sensation thresholds, electrophysiology, corneal confocal microscopy and skin biopsy in participants with type 1 diabetes and painful (n = 41) or painless (n = 50) diabetic neuropathy and control subjects (n = 50). RESULTS: The duration of diabetes, body mass index, glycated haemoglobin (HbA1c), blood pressure and lipid profile did not differ between subjects with painful and painless neuropathy. Neuropathy disability score and vibration perception threshold were higher and sural nerve conduction velocity was lower, but sural nerve amplitude, peroneal nerve amplitude and conduction velocity and cold and warm sensation thresholds did not differ between patients with painful compared to painless diabetic neuropathy. However, intraepidermal nerve fibre density, corneal nerve fibre density, corneal nerve branch density and corneal nerve fibre length were significantly lower in subjects with painful compared to painless diabetic neuropathy. CONCLUSIONS: There is evidence of more severe neuropathy, particularly small fibre damage in the skin and cornea, of patients with painful compared to painless diabetic neuropathy.

No evidence of improvement in neuropathy after renal transplantation in patients with end stage kidney disease.

To assess the impact of renal transplantation on peripheral nerve damage in patients with chronic kidney disease (CKD). Fifteen patients with CKD (eGFR <15 mL/min/1.73 m2 ) underwent longitudinal assessment after renal transplantation (age: 56.88 ± 2.53 years, eGFR: 46.82 ± 4.86) and were compared with 15 age-matched controls (age: 58.25 ± 2.18 years, eGFR: 86.0 ± 2.0). The neuropathy symptom profile (NSP), neuropathy disability score (NDS), vibration perception threshold (VPT), cold and warm sensation threshold (CST and WST), cold and heat induced pain (CIP and HIP), deep breathing heart rate variability (DB-HRV), nerve conduction studies and corneal confocal microscopy (CCM) to quantify small nerve fibre pathology, were undertaken within 1-month of renal transplantation (baseline) and at 6, 12 and 24 months of follow up. There was no significant difference in NSP (P = .1), NDS (P = .3), VPT (P = .6), CST (P = .2), CIP (P = .08), HIP (P = .1), DB-HRV (P = .9) and sural (P = .4) and peroneal (P = .1) nerve amplitude between patients with CKD and controls at baseline. However, sural (P = .04), peroneal (P = .002) and tibial (P = .007) nerve conduction velocity and tibial nerve amplitude (P = .03) were significantly lower, WST (P = .02) was significantly higher and corneal nerve fibre density (P = .004) was significantly lower in patients with CKD compared with controls. There was no significant change in NSP, NDS, quantitative sensory testing, DB-HRV, nerve conduction or CCM parameters 24 months after renal transplantation. There is evidence of small and large fibre neuropathy in patients with CKD, but no change up to 24 months after successful renal transplantation.

Protection from neuropathy in extreme duration type 1 diabetes.

A proportion of individuals with type 1 diabetes mellitus for more than 50 years (medallists) may be protected from developing nephropathy, retinopathy and neuropathy. Detailed neuropathy phenotyping was undertaken in a cohort of 33 medallists aged 63.7 ± 1.4 years with diabetes for 58.5 ± 0.8 years and HbA1c of 65.9 ± 2.1 mmol/mmol. Medallists had a significantly higher HbA1c (P < .001), lower estimated glomerular filtration rate (eGFR) (P = .005) and higher albumin creatinine excretion ratio (ACR) (P = .01), but a lower total cholesterol (P < .001), triacylglycerols (P = .001), low density lipoprotein-cholesterol (P < .001) and higher high density lipoprotein-cholesterol (P = .03), compared to controls. Twenty-four percent of participants were identified as "escapers" without confirmed diabetic neuropathy. They had a lower neuropathy symptom profile (P = .002), vibration perception threshold (P = .02), warm threshold (P = .05), higher peroneal amplitude (P = .005), nerve conduction velocity (P = .03), heart rate variability (P = .001), corneal nerve fibre density (P = 0.001), branch density (P < .001) and length (P = .001), compared to medallists with diabetic neuropathy. Escapers had a shorter duration of diabetes (P = .006), lower alcohol consumption (P = .04), lower total cholesterol (P = .04) and LDL (P = .02), higher eGFR (P = .001) and lower ACR (P < .001). Patients with extreme duration diabetes without diabetic neuropathy have a comparable HbA1c, blood pressure and body mass index, but a more favourable lipid profile and consume less alcohol compared to those with diabetic neuropathy.