Uncertain benefits of BNP blood tests to monitor heart failure treatment

In specialist clinics, using B-type natriuretic peptide (BNP) blood levels to guide treatment in people with chronic heart failure shows promise but did not improve survival for all groups. In this review, the benefit was only seen in patients aged less than 75, who survived an extra 1.5 years on average, and possibly those with poor heart function (reduced ejection fraction). However, there was a reduction in hospital admissions for heart failure for everyone. 


BNP is a hormone released from the heart muscle, and higher levels may indicate more severe disease. It is currently used for diagnosis, but its use in monitoring treatment has become the subject of recent research interest.


From the NIHR Dissemination Centre

Pancreatic cancer in adults: diagnosis and management [NG85]

New: Nice Guideline


This guideline covers diagnosing and managing pancreatic cancer in adults aged 18 and over. It aims to improve care by ensuring quicker and more accurate diagnosis, and by specifying the most effective treatments for people depending on how advanced their cancer is.

1.1 Diagnosis

1.2 Specialist pancreatic multidisciplinary teams

1.3 Staging

1.4 Psychological support

1.5 Pain management

1.6 Nutritional management

1.7 Relieving biliary and duodenal obstruction

1.8 Managing resectable and borderline resectable pancreatic cancer

1.9 Managing unresectable pancreatic cancer

UHCW publication: Differential expression of Lp-PLA2 in obesity and type 2 diabetes and the influence of lipids

Differential expression of Lp-PLA2 in obesity and type 2 diabetes and the influence of lipids.
Jackisch L, Kumsaiyai W, Moore JD, Al-Daghri N, Kyrou I, Barber TM, Randeva H, Kumar S, Tripathi G, McTernan PG.
Diabetologia 2018 Feb 9. doi: 10.1007/s00125-018-4558-6. [Epub ahead of print]


Abstract
AIMS/HYPOTHESIS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulatory macrophage-derived factor that increases with obesity and leads to a higher risk of cardiovascular disease (CVD). Despite this, its role in adipose tissue and the adipocyte is unknown. Therefore, the aims of this study were to clarify the expression of Lp-PLA2 in relation to different adipose tissue depots and type 2 diabetes, and ascertain whether markers of obesity and type 2 diabetes correlate with circulating Lp-PLA2. A final aim was to evaluate the effect of cholesterol on cellular Lp-PLA2 in an in vitro adipocyte model.METHODS: Analysis of anthropometric and biochemical variables from a cohort of lean (age 44.4 ± 6.2 years; BMI 22.15 ± 1.8 kg/m2, n = 23), overweight (age 45.4 ± 12.3 years; BMI 26.99 ± 1.5 kg/m2, n = 24), obese (age 49.0 ± 9.1 years; BMI 33.74 ± 3.3 kg/m2, n = 32) and type 2 diabetic women (age 53.0 ± 6.13 years; BMI 35.08 ± 8.6 kg/m2, n = 35), as part of an ethically approved study. Gene and protein expression of PLA2 and its isoforms were assessed in adipose tissue samples, with serum analysis undertaken to assess circulating Lp-PLA2 and its association with cardiometabolic risk markers. A human adipocyte cell model, Chub-S7, was used to address the intracellular change in Lp-PLA2 in adipocytes. RESULTS: Lp-PLA2 and calcium-independent PLA2 (iPLA2) isoforms were altered by adiposity, as shown by microarray analysis (p < 0.05). Type 2 diabetes status was also observed to significantly alter gene and protein levels of Lp-PLA2 in abdominal subcutaneous (AbdSc) (p < 0.01), but not omental, adipose tissue. Furthermore, multivariate stepwise regression analysis of circulating Lp-PLA2 and metabolic markers revealed that the greatest predictor of Lp-PLA2 in non-diabetic individuals was LDL-cholesterol (p = 0.004). Additionally, in people with type 2 diabetes, oxidised LDL (oxLDL), triacylglycerols and HDL-cholesterol appeared important predictors, accounting for 59.7% of the variance (p < 0.001). Subsequent in vitro studies determined human adipocytes to be a source of Lp-PLA2, as confirmed by mRNA expression, protein levels and immunochemistry. Further in vitro experiments revealed that treatment with LDL-cholesterol or oxLDL resulted in significant upregulation of Lp-PLA2, while inhibition of Lp-PLA2 reduced oxLDL production by 19.8% (p < 0.05).CONCLUSIONS/INTERPRETATION: Our study suggests adipose tissue and adipocytes are active sources of Lp-PLA2, with differential regulation by fat depot and metabolic state. Moreover, levels of circulating Lp-PLA2 appear to be influenced by unfavourable lipid profiles in type 2 diabetes, which may occur in part through regulation of LDL-cholesterol and oxLDL metabolism in adipocytes.


View details on PubMed at https://www.ncbi.nlm.nih.gov/pubmed/29427237

UHCW publication: Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy

Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy.

Georgios K. Dimitriadis, Harpal S. Randeva, Saboor Aftab, Asad Ali, John G. Hattersley, Sarojini Pandey, Dimitris K. Grammatopoulos, Georgios Valsamakis

Georgios Mastorakos, T. Hugh Jones, Thomas M. Barber.

Endocrine. 2018 Feb 2. doi: 10.1007/s12020-017-1516-x
Abstract
AIM:
To explore the metabolic phenotype of obesity-related secondary hypogonadism (SH) in men pre-replacement and post-replacement therapy with long-acting intramuscular (IM) testosterone undecanoate (TU).
METHODS:
A prospective observational pilot study on metabolic effects of TU IM in male obesity-related SH (hypogonadal [HG] group, n = 13), including baseline comparisons with controls (eugonadal [EG] group, n = 15). Half the subjects (n = 7 in each group) had type 2 diabetes mellitus (T2D). Baseline metabolic assessment on Human Metabolism Research Unit: fasting blood samples; BodPod (body composition), and; whole-body indirect calorimetry. The HG group was treated with TU IM therapy for 6-29 months (mean 14.8-months [SD 8.7]), and assessment at the Human Metabolism Research Unit repeated. T-test comparisons were performed between baseline and follow-up data (HG group), and between baseline data (HG and EG groups). Data reported as mean (SD).
RESULTS:
Overall, TU IM therapy resulted in a statistically significant improvement in HbA1C (9 mmol/mol, P = 0.03), with 52% improvement in HOMA%B. Improvement in glycaemic control was driven by the HG subgroup with T2D, with 18 mmol/mol [P = 0.02] improvement in HbA1C. Following TU IM therapy, there was a statistically significant reduction in fat mass (3.5 Kg, P = 0.03) and increase in lean body mass (2.9 kg, P = 0.03). Lipid profiles and energy expenditure were unchanged following TU IM therapy. Comparisons between baseline data for HG and EG groups were equivalent apart from differences in testosterone, SHBG and basal metabolic rate (BMR).
CONCLUSION:
In men with obesity-related SH (including a subgroup with T2D), TU IM therapy improved glycaemic control, beta cell function, and body composition.

Open access full text available at: https://link.springer.com/article/10.1007/s12020-017-1516-x

Pathogenesis and Management of Adiposity and Insulin Resistance in Polycystic Ovary Syndrome (PCOS)

In: Freemark M. (eds) Pediatric Obesity. Contemporary Endocrinology. Humana Press, Cham
Polycystic ovary syndrome (PCOS) is a common condition that often presents during adolescence with characteristic reproductive and hyperandrogenic features. Activation of the hypothalamic-pituitary (HP)-adrenal and HP-ovarian axes during adolescence often coexists with weight gain and heightened insulin resistance; PCOS manifests in those girls who are genetically predisposed. The association of PCOS (the subgroup with both oligo-amenorrhoea and hyperandrogenic features) with metabolic dysfunction, although not contributory as a diagnostic feature, deserves particular focus in adolescent girls. Given the increased risks for development of type 2 diabetes mellitus and dyslipidaemia, it is important that screening for metabolic dysfunction is applied, that “metabo-vigilance” is maintained, and that any emergent metabolic risk factor is managed accordingly. Weight loss remains the most important strategy for both prevention and management of PCOS in obese adolescent girls. With the burgeoning obesity epidemic, it is incumbent upon all of us to promote a healthy lifestyle amongst our children, to avoid excessive weight gain and the associated obesity-related morbidities such as PCOS.

UHCW Research: Thomas M Barber

Screening for malnutrition in patients with gastro-entero-pancreatic neuroendocrine tumours: a cross-sectional study

BMJ Open. 2016 May 4;6(5):e010765. doi: 10.1136/bmjopen-2015-010765.

OBJECTIVES: To investigate whether screening for malnutrition using the validated malnutrition universal screening tool (MUST) identifies specific characteristics of patients at risk, in patients with gastro-entero-pancreatic neuroendocrine tumours (GEP-NET).

CONCLUSIONS: Given the frequency of patients identified at malnutrition risk using MUST in our relatively large and diverse GEP-NET cohort and the clinical implications of detecting malnutrition early, we recommend routine use of malnutrition screening in all patients with GEP-NET, and particularly in patients who are treated with long-acting somatostatin analogues.

UHCW Research: Qureshi SA, Burch N, Hattersley JG, Khan S, Gopalakrishnan K, Darby C, Wong JL, Davies L, Fletcher S, Shatwell W, Sothi S, Randeva HS, Dimitriadis GK and Weickert MO.

Ribociclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer [TA496]

New:  Technology appraisal guidance

Evidence-based recommendations on ribociclib (Kisqali) as initial endocrine-based therapy for hormone-receptor positive, human epidermal growth factor receptor 2 (HER2)‑negative, locally advanced or metastatic (secondary) breast cancer in adults.

Marketing authorisation

Ribociclib in combination with an aromatase inhibitor is indicated for the treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer as initial endocrine-based therapy.

Palbociclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer [TA495]

New technology appraisal guidance from NICE. Palbociclib (Ibrance) as initial endocrine-based therapy for hormone-receptor positive, human epidermal growth factor receptor 2 (HER2)‑negative, locally advanced or metastatic (secondary) breast cancer in adults.

Recommendations:
Palbociclib, with an aromatase inhibitor, is recommended within its marketing authorisation, as an option for treating hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer as initial endocrine-based therapy in adults. Palbociclib is recommended only if the company provides it with the discount agreed in the patient access scheme.

British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice

The aim of this guidance is to review the available literature on testosterone deficiency and provide evidence-based statements for UK clinical practice.

UHCW audit on SGLT2 inhibitor (SGLT2-i) use

Endocrine Abstracts (2017) 50 P224 DOI:10.1530/endoabs.50.P224

After almost 2 centuries, SGLT2-i have made their comeback in human pharmacology through successful re-introduction in diabetes type 2 (T2D). Via restriction of renal glucose reabsorption, SGLT2-i have shown promising results. The aim of this audit was to ensure that current practice at UHCW NHS Trust is in line with the agreed national standards, whilst collecting clinical data from the use of SGLT2-i.

UHCW Research: Maria Mytilinaiou, Georgios K Dimitriadis, Allan Davasgaium, Diane Sambrook, Claire Hewins, Nilisha Nalawade, Dimitris K Grammatopoulos and Harpal S Randeva

Significant improvement in response to the GLP1-agonist 'Liraglutide' following change in injection site

Endocrine Abstracts (2017) 50 EP054 DOI:10.1530/endoabs.50.EP054

Variability in treatment response with respect to GLP1 agents is well-accepted but incompletely understood. In a specialist GLP-1 clinic at UHCW, we describe a case of improved therapeutic response following change in injection site. Currently, advice is injection in the abdomen or thigh.

A 61 year old man was commenced on Liraglutide 1.2 mg subcutaneous OD injection, in 2013. Previously managed with glimepiride 4 mg and metformin 1 g BD, with suboptimal HbA1c of 93 mmol/mol, weight 111.4 kg.

This case highlights, therefore, anecdotal evidence suggesting site-specific efficacy with relation to liraglutide, and further work should focus on this and its potential mechanisms, including site-specific differences in absorption.

UHCW Research: Daniel Border, Wendy Clayton, Tom Barber & Harpal Randeva

Tumour diameter is not reliable for management of non-secreting pancreatic neuroendocrine tumours

doi: 10.1530/EC-17-0293 Endocr Connect 2017 vol. 6 no. 8 876-885 

Small non-functioning pancreatic NETs (pNETs) ≤2 cm can pose a management dilemma in terms of surveillance or resection. There is evidence to suggest that a surveillance approach can be considered since there are no significant radiological changes observed in lesions during long-term follow-up. However, other studies have suggested loco-regional spread can be present in ≤2 cm pNETs. The aim of this study was to characterise the prevalence of malignant features and identify any useful predictive variables in a surgically resected cohort of pNETs. 418 patients with pNETs were identified from 5 NET centres. Of these 227 were included for main analysis of tumour characteristics. Mean age of patients was 57 years, 47% were female. The median follow-up was 48.2 months. Malignant features were identified in 38% of ≤2 cm pNETs. ROC analysis showed that the current cut-off of 20 mm had a sensitivity of 84% for malignancy. The rate of malignant features is in keeping with other surgical series and challenges the belief that small pNETs have a low malignant potential. This study does not support a 20 mm size cut-off as being a solitary safe parameter to exclude malignancy in pNETs.

UHCW Research: Saboor Khan, Martin O. Weickert

Hypertestosteronemia and primary infertility from a mediastinal extragonadal germ cell tumor

Case study poster on Hypertestosteronemia and primary infertility from a mediastinal extragonadal germ cell tumor from GK Dimitriadis, A Davasgaium, M Mytilinaiou, C Hewit, N Nalawade, D Sambrook and H S Randeva

Fat Hormones, Adipokines

Endocrinology of the Heart in Health and Disease in Integrated, Cellular, and Molecular Endocrinology of the Heart 2017, Pages 167–205

Adipose tissue functions as a dynamic endocrine organ secreting multiple proteins, factors, and hormones into the systemic circulation that are collectively described as adipokines. Adipokines exert pleiotropic effects on target tissues/organs thereby regulating energy homeostasis, metabolism, and insulin sensitivity, as well as immune and cardiovascular functions. Expanding adipose tissue in obesity undergoes a change in the adipokine secretion profile characterized by an increase of proinflammatory adipokines and suppression of anti-inflammatory adipokines increasing proinflammatory pathways within adipose tissue depots and creating an adverse circulating adipokine profile, resulting in a chronic, low-grade, systemic inflammatory state. Compelling evidence directly links the adverse proinflammatory adipokine profile in obesity with a spectrum of detrimental cardio-metabolic effects including hepatic, skeletal muscle, and myocardial insulin resistance, hypertension, atherosclerosis, hypercoagulability, thrombosis, and endothelial and cardiac dysfunction. This chapter presents a brief overview of the nature of adipose tissue in obesity and focuses on selected adipokines that have direct and indirect effects on the heart and cardiovascular system.

UHCW Research: I Kyrou, H. S. Mattu and H. S. Randeva

New Getting It Right First Time leads announced

Clinical leads for three areas of the Getting It Right First Time programme have been announced.

The £60m clinical efficiency and safety programme is run by NHS Improvement and sees clinician led teams look at service lines in every trust in England to determine whether they are operating at sufficient scale, among other factors.

Some trusts change their practices or stop providing some services as a result of the subject area GIRFT reports published so far on orthopaedics and general surgery.

The programme announced clinical leads for endocrinology, rheumatology and stroke medicine last week.

To obtain this article copy and past it into an email and send to: librasryw@uhcw.nhs.uk

NEOD001 for amyloid light-chain (AL) amyloidosis

Current treatments for AL amyloidosis target the plasma cells in the bone marrow, stopping the production of amyloid. NEOD001 has the potential to target amyloid protein directly in the bloodstream as well as within the organs. It would make the amyloid protein that is in the bloodstream ineffective, and would also clear amyloid protein deposits in tissues, nerves and organs. This has the potential to be the first treatment for AL amyloidosis that could restore organ function.

From the NIHR Innovation Observatory

Sotagliflozin tablets as an adjuct therapy to insulin for Type 1 diabetes mellitus

Sotagliflozin is a drug being developed to lower blood sugar levels in type 1 diabetes by increasing the amount of sugars excreted in the urine. It is taken once a day tablet in conjunction with insulin to prevent large rises and falls in blood sugar levels. This may be especially useful for people who cannot control their blood sugar levels with insulin alone. Sotagliflozin is currently in clinical trials which have shown that sotagliflozin has the potential to reduce and control blood sugar levels when taken with insulin.


from the NIHR Innovation Observatory

Setmelanotide for pro-opiomelanocortin deficiency obesity

Body fat and food intake are regulated by signals from the brain to the gut. One of the important hormones that is responsible for this is pro-opiomelanocortin (POMC). In a very small group of people there is a lack of this hormone (due to a genetic mutation), referred to as POMC deficiency. This causes severe overeating which leads to obesity and high blood sugar in children. Very few adults have been observed with this condition, which may be due to high death rates in adolescence. Pale skin that does not tan and red hair are common signs of POMC deficiency obesity.
Currently there are no licensed treatment options for POMC deficiency obesity, however weight loss medicines orlistat and methylcellulose are the only treatment options offered. Setmelanotide is being developed to treat pro-opiomelanocortin (POMC) deficiency obesity. If marketed setmelanotide could be the first effective treatment option aimed specifically at this patient group as it replaces one of the key hormones that is lacking in POMC deficiency patients (melanocytestimulating hormone). It has been shown to reduce hunger and has resulted in substantial weight loss in previous patients.


From NIHR Innovation Observatory

Males with prolactinoma are at increased risk of incident cardiovascular disease

Clin Endocrinol. Accepted Author Manuscript. doi:10.1111/cen.13498

The aim of this study was to investigate whether the risk of incident cardiovascular disease (CVD) is increased in patients with prolactinoma.

UHCW Research: Tim Robbins

Adiponectin circulating levels and 10-year (2002–2012) cardiovascular disease incidence: the ATTICA Study

Endocrine (2017). https://doi.org/10.1007/s12020-017-1434-y

Adiponectin is an adipokine with anti-inflammatory and cardiovascular-protective properties. Existing epidemiological evidence is conflicting on the exact relationship between adiponectin and long-term cardiovascular disease (CVD) risk. Our aim was to prospectively assess whether circulating adiponectin is associated with long-term incident CVD.

UHCW Research: Ioannis Kyrou