The Peripheral Neuropathy Prevalence and Characteristics Are Comparable in People with Obesity and Long-Duration Type 1 Diabetes.

INTRODUCTION: Peripheral neuropathy is reported in obesity even in the absence of hyperglycaemia. OBJECTIVE: To compare the prevalence and characterise the phenotype of peripheral neuropathy in people living with obesity (OB) and long-duration type 1 diabetes (T1D). PATIENTS AND METHODS: We performed a prospective cross-sectional study of 130 participants including healthy volunteers (HV) (n = 28), people with T1D (n = 51), and OB (BMI 30-50 kg/m2) (n = 51). Participants underwent assessment of neuropathic symptoms (Neuropathy Symptom Profile, NSP), neurological deficits (Neuropathy Disability Score, NDS), vibration perception threshold (VPT) and evaluation of sural nerve conduction velocity and amplitude. RESULTS: Peripheral neuropathy was present in 43.1% of people with T1D (age 49.9 ± 12.9 years; duration of diabetes 23.4 ± 13.5 years) and 33.3% of OB (age 48.2 ± 10.8 years). VPT for high risk of neuropathic foot ulceration (VPT ≥ 25 V) was present in 31.4% of T1D and 19.6% of OB. Participants living with OB were heavier (BMI 42.9 ± 3.5 kg/m2) and had greater centripetal adiposity with an increased body fat percentage (FM%) (P < 0.001) and waist circumference (WC) (P < 0.001) compared to T1D. The OB group had a higher NDS (P < 0.001), VAS for pain (P < 0.001), NSP (P < 0.001), VPT (P < 0.001) and reduced sural nerve conduction velocity (P < 0.001) and amplitude (P < 0.001) compared to HV, but these parameters were comparable in T1D. VPT was positively associated with increased WC (P = 0.011), FM% (P = 0.001) and HbA1c (P < 0.001) after adjusting for age (R2 = 0.547). Subgroup analysis of respiratory quotient (RQ) measured in the OB group did not correlate with VPT (P = 0.788), nerve conduction velocity (P = 0.743) or amplitude (P = 0.677). CONCLUSION: The characteristics of peripheral neuropathy were comparable between normoglycaemic people living with obesity and people with long-duration T1D, suggesting that metabolic factors linked to obesity play a pivotal role in the development of peripheral neuropathy. Further studies are needed to investigate the mechanistic link between visceral adiposity and neuropathy.

Mechanisms, screening modalities and treatment options for individuals with non-alcoholic fatty liver disease and type 2 diabetes.

Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum of disease ranging from excessive accumulation of fat within the liver (simple steatosis), inflammation (non-alcoholic steatohepatitis) through to fibrosis, cirrhosis and end-stage liver disease. There is also an increased risk of hepatocellular carcinoma. The principal risk factor for NAFLD is overweight or obesity, along with type 2 diabetes, and NAFLD itself is also a risk factor for incident type 2 diabetes. Overweight/obesity is synergistic with alcohol consumption in causing progressive and insidious liver damage. Recent consensus advocates a change in nomenclature from NAFLD to 'metabolic associated fatty liver disease' (MAFLD), reflective of the associated metabolic abnormalities (insulin resistance/type 2 diabetes and metabolic syndrome components). Additional extra-hepatic manifestations of NAFLD include cardiovascular disease, chronic kidney disease and certain cancers. Unlike other micro- and macrovascular complications of type 2 diabetes, systematic screening or surveillance protocols have not been widely adopted in routine diabetes care to assess for presence/severity of NAFLD. Various screening tools are available (non-invasive tests and biochemical indices) combined with imaging techniques (e.g. transient elastography) to detect steatosis and more importantly advanced fibrosis/cirrhosis to facilitate appropriate surveillance. Liver biopsy may be sometimes necessary. Treatment options for type 2 diabetes, including lifestyle interventions (dietary change and physical activity), glucose-lowering therapies and metabolic surgery, can modulate hepatic steatosis and to a lesser extent fibrosis. Awareness of the impact of liver disease on the choice of glucose-lowering medications in individuals with type 2 diabetes is also critical.

Correction to: Adipokines and the insulin resistance syndrome in familial partial lipodystrophy caused by a mutation in lamin A/C.

The authors regret that Alexandra Bargiota's name was spelt incorrectly in the author list. The details given in this correction are correct.

Obesity in the global haemophilia population: prevalence, implications and expert opinions for weight management.

Overweight and obesity may carry a significant disease burden for patients with haemophilia (PWH), who experience reduced mobility due to joint inflammation, muscle dysfunction and haemophilic arthropathy. This review aimed to define the prevalence and clinical impact of overweight/obesity in the global population of PWH. A detailed literature search pertaining to overweight/obesity in haemophilia in the last 15 years (2003-2018) was conducted, followed by a meta-analysis of epidemiological data. The estimated pooled prevalence of overweight/obesity in European and North American PWH was 31%. Excess weight in PWH is associated with a decreased range in motion of joints, accelerated loss of joint mobility and increase in chronic pain. Additionally, the cumulative disease burden of obesity and haemophilia may impact the requirement for joint surgery, occurrence of perioperative complications and the prevalence of anxiety and depression that associates with chronic illness. Best practice guidelines for obesity prevention and weight management, based on multidisciplinary expert perspectives, are considered for adult and paediatric PWH. Recommendations in the haemophilia context emphasize the importance of patient education and tailoring engagement in physical activity to avoid the risk of traumatic bleeding.

Beyond lifestyle interventions: exploring the potential of anti-obesity medications in the UK.

In the UK, over one-quarter of the adult population have obesity (body mass index ≥30 kg m-2 ). This has major implications for patients' health and the National Health Service. Despite published studies showing that significant weight loss can be achieved and maintained in primary care, and guidance from the National Institute for Health and Care Excellence, weight management services are inconsistently implemented. This may be due primarily to workload and financial constraints. There is also a lack of belief that specialist weight management services and anti-obesity medications (AOMs) are a viable alternative to bariatric surgery for long-term maintenance of weight loss. This article discusses the challenges facing obesity management and explores the reasons for the lack of investment in AOMs in the UK to date. The aim of this article is to identify whether the newer AOMs, such as naltrexone/bupropion and liraglutide 3.0 mg, are likely to perform better in a real-world setting than current or withdrawn AOMs. In addition, it considers whether the equitable provision of specialist weight management services and future clinical trial design could be improved to help identify those individuals most likely to benefit from AOMs and, thus, improve outcomes for people with obesity in the UK.

Evaluation of Aintree LOSS, a community-based, multidisciplinary weight management service: outcomes and predictors of engagement.

Aintree LOSS is a community-based, multidisciplinary weight management programme for patients with severe and complex obesity, focusing on a flexible and individualized service with follow-up for up to 2 years. We evaluated all 2472 patients referred to the service between October 2009 and 2013. Demographic data were recorded at baseline, with the Index of Multiple Deprivation (IMD) used to measure socioeconomic deprivation. Weight was recorded at each visit. Mean body mass index at baseline was 45.6 (standard deviation 6.8), and 58.9% of patients lived in areas in the most deprived decile nationally. Of 2315 appropriate referrals, 1249 (55.1%) attended >2 visits; mean final weight loss was 3.50 ± 8.55 kg, and 24.1% achieved ≥5% weight loss. Of the patients, 754 (33.3%) attended for over 6 months; mean final weight loss was 4.94 ± 10 kg, and 34% achieved 5% weight loss. Multivariate logistic regression analysis showed increasing age, residence in a less deprived area and sleep apnoea to be independently associated with attendance for >6 months, and there was a linear relationship between 6-month attendance and deprivation quintile. Year-on-year analyses showed improvement in engagement over time, coinciding with efforts to improve access to the service. This work shows a multidisciplinary, community-based weight loss programme prioritizing a fully flexible and individualized approach functioning effectively in real-world practice. Maintaining engagement remains a challenge in weight loss programmes, and our results suggest younger patients living in areas with greater deprivation should be a target for efforts to improve engagement.

Arrhythmogenic gene remodelling in elderly patients with type 2 diabetes with aortic stenosis and normal left ventricular ejection fraction.

NEW FINDINGS: What is the central question of this study? Type 2 diabetes is associated with a higher rate of ventricular arrhythmias compared with the non-diabetic population, but the associated myocardial gene expression changes are unknown; furthermore, it is also unknown whether any changes are attributable to chronic hyperglycaemia or are a consequence of structural changes. What is the main finding and its importance? We found downregulation of left ventricular ERG gene expression and increased NCX1 gene expression in humans with type 2 diabetes compared with control patients with comparable left ventricular hypertrophy and possible myocardial fibrosis. This was associated with QT interval prolongation. Diabetes and associated chronic hyperglycaemia may therefore promote ventricular arrhythmogenesis independently of structural changes. Type 2 diabetes is associated with a higher rate of ventricular arrhythmias, and this is hypothesized to be independent of coronary artery disease or hypertension. To investigate further, we compared changes in left ventricular myocardial gene expression in type 2 diabetes patients with patients in a control group with left ventricular hypertrophy. Nine control patients and seven patients with type 2 diabetes with aortic stenosis undergoing aortic valve replacement had standard ECGs, signal-averaged ECGs and echocardiograms before surgery. During surgery, a left ventricular biopsy was taken, and mRNA expressions for genes relevant to the cardiac action potential were estimated by RT-PCR. Mathematical modelling of the action potential and calcium transient was undertaken using the O'Hara-Rudy model using scaled changes in gene expression. Echocardiography revealed similar values for left ventricular size, filling pressures and ejection fraction between groups. No difference was seen in positive signal-averaged ECGs between groups, but the standard ECG demonstrated a prolonged QT interval in the diabetes group. Gene expression of KCNH2 and KCNJ3 were lower in the diabetes group, whereas KCNJ2, KCNJ5 and SLC8A1 expression were higher. Modelling suggested that these changes would lead to prolongation of the action potential duration with generation of early after-depolarizations secondary to a reduction in density of the rapid delayed rectifier K+ current and increased Na+ -Ca2+ exchange current. These data suggest that diabetes leads to pro-arrythmogenic changes in myocardial gene expression independently of left ventricular hypertrophy or fibrosis in an elderly population.

Dapagliflozin therapy for type 2 diabetes in primary care: Changes in HbA1c, weight and blood pressure over 2 years follow-up.

AIMS: To investigate prescribing patterns and effect of dapagliflozin among individuals with T2DM using UK primary care data. METHODS: Adult patients with T2DM initiating dapagliflozin treatment were identified from the Clinical Practice Research Datalink. Changes in HbA1c, body weight and systolic blood pressure were assessed in subgroups defined by glucose lowering treatment at baseline and compliance with the Summary of Product Characteristics. Logistic regression examined the association of baseline characteristics with achievement of target HbA1c (≤53mmol/mol) and weight reduction (by ≥3.0%). RESULTS: Among 5828 eligible individuals, HbA1c was reduced from a baseline mean of 80.0mmol/mol (SD 17.6) by -12.8 (95% CI -13.8, -11.8)mmol/mol at >12-24 months. The corresponding value for weight reduction (baseline mean 101.7kg) was -5.0 (-5.4, -4.5)kg, and for systolic blood pressure reduction (baseline mean 134.1mmHg) was -3.1 (-4.0, -2.2) mmHg. Lower baseline HbA1c values (<69; 69-85 versus ≥86mmol/mol) were positively associated with achievement of target HbA1c <53mmol/mol. CONCLUSIONS: Treatment with dapagliflozin in T2DM was associated with reductions in HbA1c, weight and systolic blood pressure over time periods up to 2 years. Changes in these parameters were consistent with those reported in RCTs.

Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation.

This paper considers the argument for obesity as a chronic relapsing disease process. Obesity is viewed from an epidemiological model, with an agent affecting the host and producing disease. Food is the primary agent, particularly foods that are high in energy density such as fat, or in sugar-sweetened beverages. An abundance of food, low physical activity and several other environmental factors interact with the genetic susceptibility of the host to produce positive energy balance. The majority of this excess energy is stored as fat in enlarged, and often more numerous fat cells, but some lipid may infiltrate other organs such as the liver (ectopic fat). The enlarged fat cells and ectopic fat produce and secrete a variety of metabolic, hormonal and inflammatory products that produce damage in organs such as the arteries, heart, liver, muscle and pancreas. The magnitude of the obesity and its adverse effects in individuals may relate to the virulence or toxicity of the environment and its interaction with the host. Thus, obesity fits the epidemiological model of a disease process except that the toxic or pathological agent is food rather than a microbe. Reversing obesity will prevent most of its detrimental effects.

Screening methods for obstructive sleep apnoea in severely obese pregnant women.

Obstructive sleep apnoea (OSA) is an often-overlooked diagnosis, more prevalent in the obese population. Screening method accuracy, uptake and hence diagnosis is variable. There is limited data available regarding the obese pregnant population; however, many studies highlight potential risks of apnoeic episodes to mother and foetus, including hypertension, diabetes and preeclampsia. A total of 162 women with a body mass index (BMI) ≥ 35 were recruited from a tertiary referral hospital in the northwest of England. They were invited to attend three research antenatal clinics, completing an Epworth Sleepiness Scale (ESS) questionnaire at each visit. A monitor measuring the apnoea hypopnoea index (AHI) was offered at the second visit. Data taken from consent forms, hospital notes and hospital computer records were collated and anonymized prior to statistical analysis. A total of 12.1% of women had an ESS score of >10, suggesting possible OSA. Rates increased throughout pregnancy, although unfortunately, the attrition rate was high; 29.0% of women used the RUSleeping (RUS) meter, and only one (2.1%) met pre-specified criteria for OSA (AHI ≥ 15). This individual had OSA categorized as severe and underwent investigations for preeclampsia, eventually delivering by emergency caesarean section due to foetal distress. The accuracy of the ESS questionnaire, particularly the RUS monitor, to screen for OSA in the pregnant population remains unclear. Further research on a larger sample size using more user-friendly technology to confidently measure AHI would be beneficial. There are currently no guidelines regarding screening for OSA in the obese pregnant population, yet risks to both mother and foetus are well researched.

What have human experimental overfeeding studies taught us about adipose tissue expansion and susceptibility to obesity and metabolic complications?

Overfeeding experiments, in which we impose short-term positive energy balance, help unravel the cellular, physiological and behavioural adaptations to nutrient excess. These studies mimic longer-term mismatched energy expenditure and intake. There is considerable inter-individual heterogeneity in the magnitude of weight gain when exposed to similar relative caloric excess reflecting variable activation of compensatory adaptive mechanisms. Significantly, given similar relative weight gain, individuals may be protected from/predisposed to metabolic complications (insulin resistance, dyslipidaemia, hypertension), non-alcoholic fatty liver disease and cardiovascular disease. Similar mechanistic considerations underpinning the heterogeneity of overfeeding responses are pertinent in understanding emerging metabolic phenotypes, for example, metabolically unhealthy normal weight and metabolically healthy obesity. Intrinsic and extrinsic factors modulate individuals' overfeeding response: intrinsic factors include gender/hormonal status, genetic/ethnic background, baseline metabolic health and cardiorespiratory fitness; extrinsic factors include macronutrient (fat vs carbohydrate) content, fat/carbohydrate composition and overfeeding pattern. Subcutaneous adipose tissue (SAT) analysis, coupled with metabolic assessment, with overfeeding have revealed how SAT remodels to accommodate excess nutrients. SAT remodelling occurs either by hyperplasia (increased adipocyte number) or by hypertrophy (increased adipocyte size). Biological responses of SAT also govern the extent of ectopic (visceral/liver) triglyceride deposition. Body composition analysis by DEXA/MRI (dual energy X-ray absorptiometry/magnetic resonance imaging) have determined the relative expansion of SAT (including abdominal/gluteofemoral SAT) vs ectopic fat with overfeeding. Such studies have contributed to the adipose expandability hypothesis whereby SAT has a finite capacity to expand (governed by intrinsic biological characteristics), and once capacity is exceeded ectopic triglyceride deposition occurs. The potential for SAT expandability confers protection from/predisposes to the adverse metabolic responses to overfeeding. The concept of a personal fat threshold suggests a large inter-individual variation in SAT capacity with ectopic depot expansion/metabolic decompensation once one's own threshold is exceeded. This review summarises insight gained from overfeeding studies regarding susceptibility to obesity and related complications with nutrient excess.

Exposure-response analyses of liraglutide 3.0 mg for weight management.

AIMS: Liraglutide 3.0 mg, an acylated GLP-1 analogue approved for weight management, lowers body weight through decreased energy intake. We conducted exposure-response analyses to provide important information on individual responses to given drug doses, reflecting inter-individual variations in drug metabolism, absorption and excretion. METHODS: We report efficacy and safety responses across a wide range of exposure levels, using data from one phase II (liraglutide doses 1.2, 1.8, 2.4 and 3.0 mg), and two phase IIIa [SCALE Obesity and Prediabetes (3.0 mg); SCALE Diabetes (1.8; 3.0 mg)] randomized, placebo-controlled trials (n = 4372). RESULTS: There was a clear exposure-weight loss response. Weight loss increased with greater exposure and appeared to level off at the highest exposures associated with liraglutide 3.0 mg in most individuals, but did not fully plateau in men. In individuals with overweight/obesity and comorbid type 2 diabetes, there was a clear exposure-glycated haemoglobin (HbA1c) relationship. HbA1c reduction increased with higher plasma liraglutide concentration (plateauing at ∼21 nM); however, for individuals with baseline HbA1c >8.5%, HbA1c reduction did not fully plateau. No exposure-response relationship was identified for any safety outcome, with the exception of gastrointestinal adverse events (AEs). Individuals with gallbladder AEs, acute pancreatitis or malignant/breast/benign colorectal neoplasms did not have higher liraglutide exposure compared with the overall population. CONCLUSIONS: These analyses support the use of liraglutide 3.0 mg for weight management in all subgroups investigated; weight loss increased with higher drug exposure, with no concomitant deterioration in safety/tolerability besides previously known gastrointestinal side effects.

Fit for Birth - the effect of weight changes in obese pregnant women on maternal and neonatal outcomes: a pilot prospective cohort study.

UNLABELLED: The 'Fit for Birth' study aimed to explore patterns of gestational weight gain and their relationship with pregnancy outcomes. The study had three aims: 1. To explore the feasibility of conducting a large cohort study in this setting. 2. To describe patterns of weight gain through pregnancy in obese women. 3. To explore associations of weight change during pregnancy with outcomes. STUDY POPULATION: Pregnant women with a BMI ≥ 30 kg m(-2) at first antenatal clinic visit. METHODS: This was a single centre pilot observational study based at the Liverpool Women's Hospital, a large UK maternity hospital.Women were recruited into the study at their antenatal booking visit and had weights measured throughout pregnancy. Patterns of weight gain were described and related to maternal and neonatal outcomes. MAIN OUTCOME MEASURE: The primary outcome was a composite measure consisting of any of 12 adverse maternal and foetal outcomes. This was compared by categorized pregnancy weight gain (<0 kg, 0-5 kg, 5.1-9 kg and >9 kg). RESULTS: Eight hundred and twenty four women consented to participation between June 2009 and June 2010. Weight data were collected on 756 women. Only 385 women had weights measured in all three study assessment periods (6-20 weeks, 20 + 1 to 32 weeks and >32 weeks gestation) while 427 women had weights measured in period 3. Individual patterns of weight gain varied widely and missing data were common and non-random. There was a significant association between increased weight gain during pregnancy and poor maternal and foetal outcome. CONCLUSIONS: Weight gain in obese women during pregnancy can be highly variable. Our study supports an association between increased weight gain in pregnancy and adverse perinatal outcomes.

Role of incretin-based therapies and sodium-glucose co-transporter-2 inhibitors as adjuncts to insulin therapy in Type 2 diabetes, with special reference to IDegLira.

The progressive nature of Type 2 diabetes necessitates treatment intensification over time in order to maintain glycaemic control, with many patients ultimately requiring insulin therapy. While insulin has unlimited potential efficacy, its initiation is often delayed and improvements in glycaemic control are typically accompanied by weight gain and an increased risk of hypoglycaemia, particularly as HbA1c approaches and falls below target levels. This may account for the sub-optimal control often achieved after insulin initiation. Combining insulin with antihyperglycaemic therapies that have a low risk of hypoglycaemia and are weight-neutral or result in weight loss is a therapeutic strategy with the potential to improve Type 2 diabetes management. Although the effects differ with each individual class of therapy, clinical trials have shown that adding a glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor to insulin regimens can offer a significant reduction in HbA1c without substantially increasing hypoglycaemia risk, or weight. The evidence and merit of each approach are reviewed in this paper. Once-daily co-formulations of a basal insulin and a glucagon-like peptide-1 receptor agonist have been developed (insulin degludec/liraglutide) or are under development (lixisenatide/insulin glargine). Insulin degludec/liraglutide phase III trials and a lixisenatide/insulin glargine phase II trial have shown robust HbA1c reductions, with weight loss and a low risk of hypoglycaemia. With insulin degludec/liraglutide now approved in Europe, an important consideration will be the types of patients who may benefit most from a fixed-ratio combination; this is discussed in the present review, and we also take a look toward future developments in the field.

Energy balance and metabolic changes with sodium-glucose co-transporter 2 inhibition.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the latest addition to the class of oral glucose-lowering drugs. They have been rapidly adopted into clinical practice because of therapeutic advantages, including weight loss and reduction in blood pressure, in addition to glycaemic benefits and a low intrinsic risk of hypoglycaemia. Although there are extensive data on the clinical effects of SGLT2 inhibition, the metabolic effects of inhibiting renal glucose reabsorption have not been fully described. Recent studies have identified compensatory metabolic effects, such as an increase in endogenous glucose production, and have also shown an increase in glucagon secretion during SGLT2 inhibition. In addition, there is a discrepancy between the expected and observed weight loss found in clinical studies on SGLT2 inhibitors, probably as a result of changes in energy balance with this treatment approach. SGLT2 inhibition is likely to have intriguing effects on whole body metabolism which have not been fully elucidated, and which, if explained, might help optimize the use of this new class of medicines.

Cerebral activations during viewing of food stimuli in adult patients with acquired structural hypothalamic damage: a functional neuroimaging study.

BACKGROUND/OBJECTIVES: Obesity is common following hypothalamic damage due to tumours. Homeostatic and non-homeostatic brain centres control appetite and energy balance but their interaction in the presence of hypothalamic damage remains unknown. We hypothesized that abnormal appetite in obese patients with hypothalamic damage results from aberrant brain processing of food stimuli. We sought to establish differences in activation of brain food motivation and reward neurocircuitry in patients with hypothalamic obesity (HO) compared with patients with hypothalamic damage whose weight had remained stable. SUBJECTS/METHODS: In a cross-sectional study at a University Clinical Research Centre, we studied 9 patients with HO, 10 age-matched obese controls, 7 patients who remained weight-stable following hypothalamic insult (HWS) and 10 non-obese controls. Functional magnetic resonance imaging was performed in the fasted state, 1 h and 3 h after a test meal, while subjects were presented with images of high-calorie foods, low-calorie foods and non-food objects. Insulin, glucagon-like peptide-1, Peptide YY and ghrelin were measured throughout the experiment, and appetite ratings were recorded. RESULTS: Mean neural activation in the posterior insula and lingual gyrus (brain areas linked to food motivation and reward value of food) in HWS were significantly lower than in the other three groups (P=0.001). A significant negative correlation was found between insulin levels and posterior insula activation (P=0.002). CONCLUSIONS: Neural pathways associated with food motivation and reward-related behaviour, and the influence of insulin on their activation may be involved in the pathophysiology of HO.

Impact of bariatric surgery on physical functioning in obese adults.

Obesity is associated with a profound impairment in the ability to perform the basic physical activities required for everyday function. This impacts on quality of life and contributes to disability. Bariatric surgery leads to weight loss and metabolic improvements in severe obesity; however, less is known about its effect on physical functioning. This narrative review summarizes current evidence on the effect of bariatric surgery on this outcome with a consideration of the mechanisms involved. Nine longitudinal observational studies reporting objective measures of physical functioning were identified. Inclusion criteria, follow-up time and outcomes reported varied considerably between studies and sample sizes were small. They all showed a significant improvement in performance following surgery despite variations in baseline patient characteristics. Additionally, six studies were found in which subjects were subjected to exercise testing protocols. Performance of the test protocol improved in all. Where reported, peak oxygen uptake related to body weight improved; however, absolute values were either unchanged or decreased. In conclusion, observational evidence suggests that patients' physical functioning improves following bariatric surgery. More evidence is required regarding mechanisms involved; however, it may be due to improved efficiency in performing activities as opposed to absolute improvements in cardiorespiratory or muscle function.

Dapagliflozin in type 2 diabetes: effectiveness across the spectrum of disease and over time.

BACKGROUND: Despite many available therapies, patients with type 2 diabetes mellitus (T2DM) frequently do not achieve/maintain glycaemic control. Furthermore, side effects such as hypoglycaemia and weight gain may limit therapy choices. Dapagliflozin, a selective sodium-glucose cotransporter-2 inhibitor, reduces hyperglycaemia by increasing glucosuria independently of insulin, representing a novel approach in T2DM. Dapagliflozin efficacy, safety and tolerability were evaluated across a wide range of clinical trials. METHODS: Dapagliflozin 10-mg efficacy data from (i) two short-term, active-comparator studies (vs. metformin-XR over 24 weeks and vs. glipizide over 52 weeks), (ii) pooled 24-week analyses of five placebo-controlled trials (as monotherapy or add-on therapy), and (iii) long-term studies over 2 years; dapagliflozin 5- and 10-mg pooled safety data from 12 placebo-controlled trials; and cardiovascular safety and malignancy data from 19 dapagliflozin studies were evaluated. RESULTS: In treatment-naïve patients (baseline HbA1c 9%), dapagliflozin reduced HbA1c (-1.45%) similarly to metformin-XR (-1.44%). In metformin-treated patients (baseline HbA1c 7.7%), dapagliflozin achieved a clinically significant reduction (-0.52%) similar to glipizide (-0.52%). In pooled 24-week analyses, dapagliflozin vs. placebo differences in HbA1c, weight and systolic blood pressure (SBP) were -0.60%, -1.61 kg and -3.6 mmHg, respectively. At 2 years, dapagliflozin vs. placebo differences in HbA1c and weight were -0.44 to -0.80% and -2.41 to -3.19 kg, respectively, and vs. glipizide, differences in HbA1c, weight, and SBP were -0.18%, -5.06 kg, and -3.89 mmHg, respectively. Major hypoglycaemia with dapagliflozin was rare (< 0.1%). Urinary tract and genital infections were more common with dapagliflozin, but responded to standard care and rarely led to study discontinuation. Events of renal failure/impairment and malignancies were rare and balanced across treatment groups. Pooled analyses did not indicate that dapagliflozin increased cardiovascular event risk. CONCLUSIONS: Dapagliflozin improved glycaemic control, decreased body weight, and lowered blood pressure across the spectrum of T2DM disease, with maintenance of these benefits over time.

Characteristics and perspectives of night-eating behaviour in a severely obese population.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Night-eating syndrome (NES) can be a feature of severe obesity. NES is a dysfunction of circadian rhythm and is associated with impaired sleep. WHAT THIS STUDY ADDS: Night eaters with severe obesity are more likely to be low in mood and unemployed compared with non-night eaters. Night eaters with severe obesity describe compulsive and uncontrolled eating. Research interest in night-eating syndrome (NES) has grown in recent years in line with increased rates of obesity. This study used a mixed-methods approach to investigate its characteristics in severe obesity. Eighty-one individuals (mean [standard deviation] age 44.6 [11.6] years, [body mass index] 50.0 [10.7] kg m(-2) ; 43% men) from a hospital-based UK obesity clinic were interviewed for NES based on 2003 criteria. Full and partial NES were combined into one night-eating behaviour (NEB) group (n = 31). Demographic and clinical characteristics were compared with those of non-NEB individuals (n = 50). NEB characteristics were also identified through exploratory thematic analysis of interview data. NEB individuals had lower mood (P = 0.01) and were less likely to be employed (P = 0.03). Differences in mean age and reported sleep duration were not significant. Thematic analysis of patient perceptions of NEB highlighted the potential heterogeneity of NEB development: NEB developed in childhood, adolescence and adulthood. Individuals reported long-standing and current sleep difficulties, negative affect and conflictful relationships. Night eating was solitary, compulsive and uncontrolled, and daytime eating patterns were chaotic. Accounts of awareness of night eating were conflicting. Severely obese night eaters are characterized by low mood and lack of employment. Further studies are required to explore behavioural and cognitive influences on night eating in severe obesity.