Inequalities in the management of diabetic kidney disease in UK primary care: A cross-sectional analysis of a large primary care database.

AIMS: To determine differences in the management of diabetic kidney disease (DKD) relevant to patient sex, ethnicity and socio-economic group in UK primary care. METHODS: A cross-sectional analysis as of January 1, 2019 was undertaken using the IQVIA Medical Research Data dataset, to determine the proportion of people with DKD managed in accordance with national guidelines, stratified by demographics. Robust Poisson regression models were used to calculate adjusted risk ratios (aRR) adjusting for age, sex, ethnicity and social deprivation. RESULTS: Of the 2.3 million participants, 161,278 had type 1 or 2 diabetes, of which 32,905 had DKD. Of people with DKD, 60% had albumin creatinine ratio (ACR) measured, 64% achieved blood pressure (BP, <140/90 mmHg) target, 58% achieved glycosylated haemoglobin (HbA1c, <58 mmol/mol) target, 68% prescribed renin-angiotensin-aldosterone system (RAAS) inhibitor in the previous year. Compared to men, women were less likely to have creatinine: aRR 0.99 (95% CI 0.98-0.99), ACR: aRR 0.94 (0.92-0.96), BP: aRR 0.98 (0.97-0.99), HbA1c : aRR 0.99 (0.98-0.99) and serum cholesterol: aRR 0.97 (0.96-0.98) measured; achieve BP: aRR 0.95 (0.94-0.98) or total cholesterol (<5 mmol/L) targets: aRR 0.86 (0.84-0.87); or be prescribed RAAS inhibitors: aRR 0.92 (0.90-0.94) or statins: aRR 0.94 (0.92-0.95). Compared to the least deprived areas, people from the most deprived areas were less likely to have BP measurements: aRR 0.98 (0.96-0.99); achieve BP: aRR 0.91 (0.8-0.95) or HbA1c : aRR 0.88 (0.85-0.92) targets, or be prescribed RAAS inhibitors: aRR 0.91 (0.87-0.95). Compared to people of white ethnicity; those of black ethnicity were less likely to be prescribed statins aRR 0.91 (0.85-0.97). CONCLUSIONS: There are unmet needs and inequalities in the management of DKD in the UK. Addressing these could reduce the increasing human and societal cost of managing DKD.

Risk of progression from pre-diabetes to type 2 diabetes in a large UK adult cohort.

AIMS: People with pre-diabetes are at high risk of progressing to type 2 diabetes. This progression is not well characterised by ethnicity, deprivation and age, which we describe in a large cohort of individuals with pre-diabetes. METHODS: A retrospective cohort study with The Health Improvement Network (THIN) database was conducted. Patients aged 18 years and over and diagnosed with pre-diabetes [HbA1c 42 mmol/mol (6.0%) to 48 mmol/mol (6.5%) were included]. Cox proportional hazards regression was used to calculate adjusted hazard rate ratios (aHR) for the risk of progression from pre-diabetes to type 2 diabetes for each of the exposure categories [ethnicity, deprivation (Townsend), age and body mass index (BMI)] separately. RESULTS: Of the baseline population with pre-diabetes (n = 397,853), South Asian (aHR 1.31; 95% CI 1.26-1.37) or Mixed-Race individuals (aHR 1.22; 95% CI 1.11-1.33) had an increased risk of progression to type 2 diabetes compared with those of white European ethnicity. Likewise, deprivation (aHR 1.17; 95% CI 1.14-1.20; most vs. least deprived) was associated with an increased risk of progression. Both younger (aHR 0.63; 95% CI 0.58-0.69; 18 to <30 years) and older individuals (aHR 0.85; 95% CI 0.84-0.87; ≥65 years) had a slower risk of progression from pre-diabetes to type 2 diabetes, than middle-aged (40 to <65 years) individuals. CONCLUSIONS: South Asian or Mixed-Race individuals and people with social deprivation had an increased risk of progression from pre-diabetes to type 2 diabetes. Clinicians need to recognise the differing risk across their patient populations to implement appropriate prevention strategies.

How to manage weight loss in women with obesity and PCOS seeking fertility?

Obesity exacerbates the phenotype of polycystic ovarian syndrome (PCOS) including infertility as well as reducing the efficacy and access to fertility treatments. Weight management is, therefore, a key component of treatment for women with PCOS and coexistent obesity. Many women with PCOS describe significant difficulty losing weight and treatment options are limited. The first-line treatment is lifestyle interventions though the weight loss and any impact on fertility are limited. No one dietary strategy can be preferentially recommended based on current evidence. While very low energy diets can result in significant weight loss the evidence for impact on fertility is limited. Pharmacotherapy, including a range of treatments can result in marked weight loss and there is some evidence of improved rates of conception including spontaneous and in response to assisted reproduction treatment. As with pharmacotherapy, data regarding bariatric surgery is largely from nonrandomized studies and though the significant weight loss is anticipated to improve fertility the available data prevents firm conclusions. Clinicians and patients must consider the magnitude of weight loss to be targeted as well as the anticipated fertility treatment required and the timeline of treatment when deciding upon the personalized weight loss strategy. Clinicians and patients should be confident in targeting the most appropriate treatment early in the patient's management to avoid unnecessary delays.

Markers of adipose tissue hypoxia are elevated in subcutaneous adipose tissue of severely obese patients with obesity hypoventilation syndrome but not in the moderately obese.

It has been suggested that metabolic dysfunction in obesity is at least in part driven by adipose tissue (AT) hypoxia. However, studies on AT hypoxia in humans have shown conflicting data. Therefore we aimed to investigate if markers of AT hypoxia were present in the subcutaneous AT of severly obese individuals (class III obesity) with and without hypoventilation syndrome (OHS) in comparison to moderately obese (class I obesity) and lean controls. To provide a proof-of-concept study, we quantified AT hypoxia by hypoxia inducible factor 1 A (HIF1A) protein abundance in human participants ranging from lean to severly obese (class III obesity). On top of that nightly arterial O2 saturation in individuals with obesity OHS was assessed. Subjects with class III obesity (BMI > 40 kg/m2) and OHS exhibited significantly higher adipose HIF1A protein levels versus those with class I obesity (BMI 30-34.9 kg/m2) and lean controls whereas those with class III obesity without OHS showed an intermediate response. HIF1A gene expression was not well correlated with protein abundance. Although these data demonstrate genuine AT hypoxia in the expected pathophysiological context of OHS, we did not observe a hypoxia signal in lesser degrees of obesity suggesting that adipose dysfunction may not be driven by hypoxia in moderate obesity.

Hepatitis C virus infection is associated with hepatic and adipose tissue insulin resistance that improves after viral cure.

BACKGROUND: Chronic hepatitis C (CHC) is associated with systemic insulin resistance, yet there are limited data on the tissue-specific contribution in vivo to this adverse metabolic phenotype, and the effect of HCV cure. METHODS: We examined tissue-specific insulin sensitivity in a cohort study involving 13 patients with CHC compared to 12 BMI-matched healthy control subjects. All subjects underwent a two-step clamp incorporating the use of stable isotopes to measure carbohydrate and lipid flux (hepatic and global insulin sensitivity) with concomitant subcutaneous adipose tissue microdialysis and biopsy (subcutaneous adipose tissue insulin sensitivity). Investigations were repeated in seven patients with CHC following antiviral therapy with a documented sustained virological response. RESULTS: Adipose tissue was more insulin resistant in patients with CHC compared to healthy controls, as evidence by elevated glycerol production rate and impaired insulin-mediated suppression of both circulating nonesterified fatty acids (NEFA) and adipose interstitial fluid glycerol release during the hyperinsulinaemic euglycaemic clamp. Hepatic and muscle insulin sensitivity were similar between patients with CHC and controls. Following viral eradication, hepatic insulin sensitivity improved as demonstrated by a reduction in endogenous glucose production rate. In addition, circulating NEFA decreased with sustained virological response (SVR) and insulin was more effective at suppressing adipose tissue interstitial glycerol release with a parallel increase in the expression of insulin signalling cascade genes in adipose tissue consistent with enhanced adipose tissue insulin sensitivity. CONCLUSION: Chronic hepatitis C patients have profound subcutaneous adipose tissue insulin resistance in comparison with BMI-matched controls. For the first time, we have demonstrated that viral eradication improves global, hepatic and adipose tissue insulin sensitivity.

Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis. METHODS: This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1·8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119. FINDINGS: Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4·3 [95% CI 1·0-17·7]; p=0·019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]). INTERPRETATION: Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies. FUNDING: Wellcome Trust, National Institute of Health Research, and Novo Nordisk.

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH. METHODS: Fourteen patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes. RESULTS: Liraglutide reduced BMI (-1.9 vs. +0.04kg/m(2); p<0.001), HbA1c (-0.3 vs. +0.3%; p<0.01), cholesterol-LDL (-0.7 vs. +0.05mmol/L; p<0.01), ALT (-54 vs. -4.0IU/L; p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin; p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8pmol/L insulin required to ½ maximally suppress serum non-esterified fatty acids; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic de novo lipogenesis in vivo (-1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01). CONCLUSIONS: Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.

Advanced non-alcoholic fatty liver disease and adipose tissue fibrosis in patients with Alström syndrome.

BACKGROUND AND AIMS: Alström syndrome (AS) is a recessive monogenic syndrome characterized by obesity, extreme insulin resistance and multi-organ fibrosis. Despite phenotypically being high risk of non-alcoholic fatty liver disease (NAFLD), there is a lack of data on the extent of fibrosis in the liver and its close links to adipose in patients with AS. Our aim was to characterize the hepatic and adipose phenotype in patients with AS. METHODS: Observational cohort study with comprehensive assessment of metabolic liver phenotype including liver elastography (Fibroscan® ), serum Enhanced Liver Fibrosis (ELF) Panel and liver histology. In addition, abdominal adipose histology and gene expression was assessed. We recruited 30 patients from the UK national AS clinic. A subset of six patients underwent adipose biopsies which was compared with control tissue from nine healthy participants. RESULTS: Patients were overweight/obese (BMI 29.3 (25.95-34.05) kg/m2 ). A total of 80% (24/30) were diabetic; 74% (20/27) had liver ultrasound scanning suggestive of NAFLD. As judged by the ELF panel, 96% (24/25) were categorized as having fibrosis and 10/21 (48%) had liver elastography consistent with advanced liver fibrosis/cirrhosis. In 7/8 selected cases, there was evidence of advanced NAFLD on liver histology. Adipose tissue histology showed marked fibrosis as well as disordered pro-inflammatory and fibrotic gene expression profiles. CONCLUSIONS: NAFLD and adipose dysfunction are common in patients with AS. The severity of liver disease in our cohort supports the need for screening of liver fibrosis in AS.

A comparative quality assessment of evidence-based clinical guidelines in endocrinology.

CONTEXT: Evidence-based clinical guidelines in endocrinology attempt to improve and standardize patient care. There has been an expansion in guideline production although some of the heterogeneous methods used to assess the quality of the underlying evidence base might limit interpretation and implementation. DESIGN: Current and archived guidelines from major endocrine organizations were accessed. The organizations used six different methods to rate underlying evidence, including Grading of Recommendations Assessment, Development and Evaluation (GRADE). To allow direct comparison between guidelines produced by different organizations, the levels of evidence used to generate them were graded according to the standardized system: 'high' based on randomized, controlled trials and meta-analyses, 'moderate' based on nonrandomized studies and 'low' based on expert opinion. RESULTS: There was an increase in guideline production over time (1995-2000 = 9, 2001-2005 = 12, 2006-2011 = 36). Three guidelines were updated with an average delay of 4·3 years and an increase in recommendations per guideline (21·1%). Encouragingly, whilst updates had similar levels of 'high'-quality evidence, there was increased reliance on 'moderate'-category evidence and less on 'low''-quality evidence' ('high', 6·3% vs 6·5%; 'moderate', 46·1% vs 59·1%; 'low', 47·7% vs 34·4%). A high proportion of 'low'-category evidence was seen throughout all organizations. Rarer conditions and recommendations concerning treatment efficacy were particularly reliant on 'low'-category evidence. CONCLUSIONS: The level of evidence underpinning current guidelines highlights areas in need of well-designed, collaborative clinical research. Furthermore, criteria to define when guideline updates are necessary are currently lacking. A standardized method of assessment, such as GRADE, would promote understanding and compliance by guideline users with the ultimate aim of enhancing patient care.

Impact of coronavirus disease 2019 on patients with primary adrenal insufficiency: a cross-sectional study.

Objective: Patients with primary adrenal insufficiency (PAI) are thought to be particularly vulnerable to coronavirus disease 2019 (COVID-19); however, little is known about its true impact on this group. We assessed morbidity and health promotion attitudes during the pandemic amongst a large cohort of patients with PAI. Design: Cross-sectional, single-centre study. Methods: In May 2020, COVID-19 advice on social distancing and sick-day rules was distributed to all patients with PAI registered with a large secondary/tertiary care centre. A semi-structured questionnaire was used to survey patients in early 2021. Results: Of 207 contacted patients, 162 responded (82/111 with Addison's disease, AD; 80/96 with congenital adrenal hyperplasia, CAH). Patients with AD were older than those with CAH (median age 51 vs 39 years; P < 0.001) and had more comorbidities (Charlson comorbidity index ≥2 47.6% vs 10.0%; P< 0.001). By the time of the survey, 47 patients (29.0%) had been diagnosed with COVID-19, the second commonest cause of sick-day dosing during the study and the leading trigger of adrenal crises (4/18 cases). Patients with CAH had a higher risk of COVID-19 compared to AD (adjusted odds ratio 2.53 (95% CI 1.07-6.16), P= 0.036), were less inclined to have the COVID-19 vaccine (80.0% vs 96.3%; P = 0.001), and were less likely to have undergone hydrocortisone self-injection training (80.0% vs 91.5%; P = 0.044) or wear medical alert jewellery (36.3% vs 64.6%; P = 0.001). Conclusions: COVID-19 was a principal trigger for adrenal crises and sick-day dosing in patients with PAI. Despite a higher risk of COVID-19, patients with CAH showed less engagement with self-protective attitudes. Significance statement: We conducted a cross-sectional study on a large and well-characterised group of patients with PAI and demonstrated that COVID-19 was a leading cause of morbidity during the early phases of the pandemic. Patients with AD were older and had a greater burden of comorbidity than those with CAH, including non-adrenal autoimmune disorders. However, patients with CAH were more likely to develop COVID-19 and demonstrated reduced engagement with healthcare services and health promotion strategies.

Interventions for the prevention of adrenal crisis in adults with primary adrenal insufficiency: a systematic review.

Objective: The incidence of adrenal crisis (AC) remains high, particularly for people with primary adrenal insufficiency, despite the introduction of behavioural interventions. The present study aimed to identify and evaluate available evidence of interventions aiming to prevent AC in primary adrenal insufficiency. Design: This study is a systematic review of the literature and theoretical mapping. Methods: MEDLINE, MEDLINE in Process, EMBASE, ERIC, Cochrane CENTRAL, CINAHL, PsycINFO, the Health Management Information Consortium and trial registries were searched from inception to November 2021. Three reviewers independently selected studies and extracted data. Two reviewers appraised the studies for the risk of bias. Results: Seven observational or mixed methods studies were identified where interventions were designed to prevent AC in adrenal insufficiency. Patient education was the focus of all interventions and utilised the same two behaviour change techniques, 'instruction on how to perform a behaviour' and 'pharmacological support'. Barrier and facilitator themes aiding or hindering the intervention included knowledge, behaviour, emotions, skills, social influences and environmental context and resources. Most studies did not measure effectiveness, and assessment of knowledge varied across studies. The study quality was moderate. Conclusion: This is an emerging field with limited studies available. Further research is required in relation to the development and assessment of different behaviour change interventions to prevent AC.

Metformin maintains intrahepatic triglyceride content through increased hepatic de novo lipogenesis.

OBJECTIVE: Metformin is a first-line pharmacotherapy in the treatment of type 2 diabetes, a condition closely associated with non-alcoholic fatty liver disease (NAFLD). Although metformin promotes weight loss and improves insulin sensitivity, its effect on intrahepatic triglyceride (IHTG) remains unclear. We investigated the effect of metformin on IHTG, hepatic de novo lipogenesis (DNL), and fatty acid (FA) oxidation in vivo in humans. DESIGN AND METHODS: Metabolic investigations, using stable-isotope tracers, were performed in ten insulin-resistant, overweight/obese human participants with NAFLD who were treatment naïve before and after 12 weeks of metformin treatment. The effect of metformin on markers of s.c. adipose tissue FA metabolism and function, along with the plasma metabolome, was investigated. RESULTS: Twelve weeks of treatment with metformin resulted in a significant reduction in body weight and improved insulin sensitivity, but IHTG content and FA oxidation remained unchanged. Metformin treatment was associated with a significant decrease in VLDL-triglyceride (TG) concentrations and a significant increase in the relative contribution of DNL-derived FAs to VLDL-TG. There were subtle and relatively few changes in s.c. adipose tissue FA metabolism and the plasma metabolome with metformin treatment. CONCLUSIONS: We demonstrate the mechanisms of action of metformin whereby it improves insulin sensitivity and promotes weight loss, without improvement in IHTG; these observations are partly explained through increased hepatic DNL and a lack of change in FA oxidation.

Acute intermittent hypoxia drives hepatic de novo lipogenesis in humans and rodents.

Background and aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. Methods: Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. Results: Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. Conclusions: These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD.

AKR1D1 knockout mice develop a sex-dependent metabolic phenotype.

Steroid 5ß-reductase (AKR1D1) plays important role in hepatic bile acid synthesis and glucocorticoid clearance. Bile acids and glucocorticoids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype in vivo is unknown. Akr1d1-/- mice were generated on a C57BL/6 background. Liquid chromatography/mass spectrometry, metabolomic and transcriptomic approaches were used to determine effects on glucocorticoid and bile acid homeostasis. Metabolic phenotypes including body weight and composition, lipid homeostasis, glucose tolerance and insulin tolerance were evaluated. Molecular changes were assessed by RNA-Seq and Western blotting. Male Akr1d1-/- mice were challenged with a high fat diet (60% kcal from fat) for 20 weeks. Akr1d1-/- mice had a sex-specific metabolic phenotype. At 30 weeks of age, male, but not female, Akr1d1-/- mice were more insulin tolerant and had reduced lipid accumulation in the liver and adipose tissue yet had hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was associated with sexually dimorphic changes in bile acid metabolism and composition but without overt effects on circulating glucocorticoid levels or glucocorticoid-regulated gene expression in the liver. Male Akr1d1-/- mice were not protected against diet-induced obesity and insulin resistance. In conclusion, this study shows that AKR1D1 controls bile acid homeostasis in vivo and that altering its activity can affect insulin tolerance and lipid homeostasis in a sex-dependent manner.

wEight chanGes, caRdio-mEtabolic risks and morTality in patients with hyperthyroidism (EGRET): a protocol for a CPRD-HES linked cohort study.

INTRODUCTION: Hyperthyroidism is a common condition affecting up to 3% of the UK population. Treatment improves symptoms and reduces the risk of atrial fibrillation and stroke that contribute to increased mortality. The most common symptom is weight loss, which is reversed during treatment. However, the weight regain may be excessive, contributing to increased risk of obesity. Current treatment options include antithyroid drugs, radioiodine and thyroidectomy. Whether there are differences in either weight change or the long-term cardiometabolic risk between the three treatments is unclear. METHODS AND ANALYSIS: The study will establish the natural history of weight change in hyperthyroidism, investigate the risk of obesity and risks of cardiometabolic conditions and death relative to the treatment. The data on patients diagnosed with hyperthyroidism between 1 January 1996 and 31 December 2015 will come from Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office of National Statistics Death Registry. The weight changes will be modelled using a flexible joint modelling, accounting for mortality. Obesity prevalence in the general population will be sourced from Health Survey for England and compared with the post-treatment prevalence of obesity in patients with hyperthyroidism. The incidence and time-to-event of major adverse cardiovascular events, other cardiometabolic outcomes and mortality will be compared between the treatments using the inverse propensity weighting model. Incidence rate ratios of outcomes will be modelled with Poisson regression. Time to event will be analysed using Cox proportional hazards model. A competing risks approach will be adopted to estimate comparative incidences to allow for the impact of mortality. ETHICS AND DISSEMINATION: The study will bring new knowledge on the risk of developing obesity, cardiometabolic morbidity and mortality following treatment for hyperthyroidism to inform clinical practice and public health policies. The results will be disseminated via open-access peer-reviewed publications and directly to the patients and public groups (Independent Scientific Advisory Committee protocol approval #20_000185).

Diet and physical activity in pregnancy to prevent gestational diabetes: a protocol for an individual participant data (IPD) meta-analysis on the differential effects of interventions with economic evaluation.

INTRODUCTION: Mothers with gestational diabetes mellitus (GDM) are at increased risk of pregnancy-related complications and developing type 2 diabetes after delivery. Diet and physical activity-based interventions may prevent GDM, but variations in populations, interventions and outcomes in primary trials have limited the translation of available evidence into practice. We plan to undertake an individual participant data (IPD) meta-analysis of randomised trials to assess the differential effects and cost-effectiveness of diet and physical activity-based interventions in preventing GDM and its complications. METHODS: The International Weight Management in Pregnancy Collaborative Network database is a living repository of IPD from randomised trials on diet and physical activity in pregnancy identified through a systematic literature search. We shall update our existing search on MEDLINE, Embase, BIOSIS, LILACS, Pascal, Science Citation Index, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects and Health Technology Assessment Database without language restriction to identify relevant trials until March 2021. Primary researchers will be invited to join the Network and share their IPD. Trials including women with GDM at baseline will be excluded. We shall perform a one and two stage random-effect meta-analysis for each intervention type (all interventions, diet-based, physical activity-based and mixed approach) to obtain summary intervention effects on GDM with 95% CIs and summary treatment-covariate interactions. Heterogeneity will be summarised using I2 and tau2 statistics with 95% prediction intervals. Publication and availability bias will be assessed by examining small study effects. Study quality of included trials will be assessed by the Cochrane Risk of Bias tool, and the Grading of Recommendations, Assessment, Development and Evaluations approach will be used to grade the evidence in the results. A model-based economic analysis will be carried out to assess the cost-effectiveness of interventions to prevent GDM and its complications compared with usual care. ETHICS AND DISSEMINATION: Ethics approval is not required. The study is registered on the International Prospective Register of Systematic Reviews (CRD42020212884). Results will be submitted for publication in peer-reviewed journals.

Developing Integrated Clinical Pathways for the Management of Clinically Severe Adult Obesity: a Critique of NHS England Policy.

PURPOSE OF THE REVIEW: Pathways for obesity prevention and treatment are well documented, yet the prevalence of obesity is rising, and access to treatment (including bariatric surgery) is limited. This review seeks to assess the current integrated clinical pathway for obesity management in England and determine the major challenges. RECENT FINDINGS: Evidence for tier 2 (community-based lifestyle intervention) and tier 3 (specialist weight management services) is limited, and how it facilitates care and improve outcomes in tier 4 remains uncertain. Treatment access, rigidity in pathways, uncertain treatment outcomes and weight stigma seems to be major barriers to improved care. More emphasis must be placed on access to effective treatments, treatment flexibility, addressing stigma and ensuring treatment efficacy including long-term health outcomes. Prevention and treatment should both receive significant focus though should be considered to be largely separate pathways. A simplified system for weight management is needed to allow flexibility and the delivery of personalized care including post-bariatric surgery care for those who need it.

Co-administration of 5α-reductase Inhibitors Worsens the Adverse Metabolic Effects of Prescribed Glucocorticoids.

CONTEXT: Glucocorticoids (GCs) are commonly prescribed, but their use is associated with adverse metabolic effects. 5α-reductase inhibitors (5α-RI) are also frequently prescribed, mainly to inhibit testosterone conversion to dihydrotestosterone. However, they also prevent the inactivation of GCs. OBJECTIVE: We hypothesized that 5α-RI may worsen the adverse effects of GCs. DESIGN: Prospective, randomized study. PATIENTS: A total of 19 healthy male volunteers (age 45 ±â€…2 years; body mass index 27.1 ±â€…0.7kg/m2). INTERVENTIONS: Participants underwent metabolic assessments; 2-step hyperinsulinemic, euglycemic clamp incorporating stable isotopes, adipose tissue microdialysis, and biopsy. Participants were then randomized to either prednisolone (10 mg daily) or prednisolone (10 mg daily) plus a 5α-RI (finasteride 5 mg daily or dutasteride 0.5 mg daily) for 7 days; metabolic assessments were then repeated. MAIN OUTCOME MEASURES: Ra glucose, glucose utilization (M-value), glucose oxidation, and nonesterified fatty acids (NEFA) levels. RESULTS: Co-administration of prednisolone with a 5α-RI increased circulating prednisolone levels (482 ±â€…96 vs 761 ±â€…57 nmol/L, P = 0.029). Prednisolone alone did not alter Ra glucose (2.55 ±â€…0.34 vs 2.62 ±â€…0.19 mg/kg/minute, P = 0.86), M-value (3.2 ±â€…0.5 vs 2.7 ±â€…0.7 mg/kg/minute, P = 0.37), or glucose oxidation (0.042 ±â€…0.007 vs 0.040 ±â€…0.004 mmol/hr/kg/minute, P = 0.79). However, co-administration with a 5α-RI increased Ra glucose (2.67 ±â€…0.16 vs 3.05 ±â€…0.18 mg/kg/minute, P < 0.05) and decreased M-value (4.0 ±â€…0.5 vs 2.6 ±â€…0.4 mg/kg/minute, P < 0.05), and oxidation (0.043 ±â€…0.003 vs 0.036 ±â€…0.002 mmol/hr/kg, P < 0.01). Similarly, prednisolone did not impair insulin-mediated suppression of circulating NEFA (43.1 ±â€…28.9 vs 36.8 ±â€…14.3 µmol/L, P = 0.81), unless co-administered with a 5α-RI (49.8 ±â€…8.6 vs 88.5 ±â€…13.5 µmol/L, P < 0.01). CONCLUSIONS: We have demonstrated that 5α-RIs exacerbate the adverse effects of prednisolone. This study has significant translational implications, including the need to consider GC dose adjustments, but also the necessity for increased vigilance for the development of adverse effects.

The Endocrine and Metabolic Characteristics of a Large Bardet-Biedl Syndrome Clinic Population.

Context: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder in which previous reports have described obesity and a metabolic syndrome. Objective: We describe the endocrine and metabolic characteristics of a large BBS population compared with matched control subjects. Design: We performed a case-control study. Setting: This study was performed at a hospital clinic. Patients: Study patients had a clinical or genetic diagnosis of BBS. Main Outcome Measurements: Our study determined the prevalence of a metabolic syndrome in our cohort. Results: A total of 152 subjects were studied. Eighty-four (55.3%) were male. Mean (± standard deviation) age was 33.2 ± 1.0 years. Compared with age-, sex-, and body mass index-matched control subjects, fasting glucose and insulin levels were significantly higher in subjects with BBS (glucose: BBS, 5.2 ± 1.2 mmol/L vs control, 4.9 ± 0.9 mmol/L, P = 0.04; insulin: BBS, 24.2 ± 17.0 pmol/L vs control, 14.2 ± 14.8 pmol/L, P < 0.001). Serum triglycerides were significantly higher in subjects with BBS (2.0 ± 1.2 mmol/L) compared with control subjects (1.3 ± 0.8 mmol/L; P < 0.001), but total cholesterol, high-density lipoprotein, and low-density lipoprotein were similar in both groups. Systolic blood pressure was higher in the BBS group (BBS, 135 ± 18 mm Hg vs control subjects, 129 ± 16 mm Hg; P = 0.02). Alanine transaminase was raised in 34 (26.8%) subjects with BBS, compared with five (8.9%) control subjects (P = 0.01). The rate of metabolic syndrome, determined using International Diabetes Federation criteria, was significantly higher in the BBS group (54.3%) compared with control subjects (26% P < 0.001). Twenty-six (19.5%) of male subjects with BBS were hypogonadal (serum testosterone, 9.9 ± 5.3 mmol/L), but significant pituitary abnormalities were uncommon. Subclinical hypothyroidism was present in 24 of 125 (19.4%) patients with BBS, compared with 3 of 65 (4.6%) control subjects (P = 0.01). Conclusions: Insulin resistance and the metabolic syndrome are increased in adult patients with BBS compared with matched control subjects. Increased subclinical hypothyroidism in the BBS cohort needs further investigation.

Non-alcoholic fatty liver disease and diabetes.

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) are common conditions that regularly co-exist and can act synergistically to drive adverse outcomes. The presence of both NAFLD and T2DM increases the likelihood of the development of complications of diabetes (including both macro- and micro- vascular complications) as well as augmenting the risk of more severe NAFLD, including cirrhosis, hepatocellular carcinoma and death. The mainstay of NAFLD management is currently to reduce modifiable metabolic risk. Achieving good glycaemic control and optimising weight loss are pivotal to restricting disease progression. Once cirrhosis has developed, it is necessary to screen for complications and minimise the risk of hepatic decompensation. Therapeutic disease modifying options for patients with NAFLD are currently limited. When diabetes and NAFLD co-exist, there are published data that can help inform the clinician as to the most appropriate oral hypoglycaemic agent or injectable therapy that may improve NAFLD, however most of these data are drawn from observations in retrospective series and there is a paucity of well-designed randomised double blind placebo controlled studies with gold-standard end-points. Furthermore, given the heterogeneity of inclusion criteria and primary outcomes, as well as duration of follow-up, it is difficult to draw robust conclusions that are applicable across the entire spectrum of NAFLD and diabetes. In this review, we have summarised and critically evaluated the available data, with the aim of helping to inform the reader as to the most pertinent issues when managing patients with co-existent NAFLD and T2DM.