Obstructive sleep apnea and its management in patients with atrial fibrillation: An International Collaboration of Sleep Apnea Cardiovascular Trialists (INCOSACT) global survey of practicing cardiologists.

Background: Among international cardiologists it is unclear whether equipoise exists regarding the benefit of diagnosing and managing obstructive sleep apnea (OSA) to improve atrial fibrillation (AF) outcomes and whether clinical practice and equipoise are linked. Methods: Between January 2019 and June 2020 we distributed a web-based 12-question survey regarding OSA and AF management to practicing cardiologists in 16 countries. Results: The United States, Japan, Sweden, and Turkey accounted for two-thirds of responses. 863 cardiologists responded; half were general cardiologists, a quarter electrophysiologists. Responses regarding treating OSA with CPAP to improve AF endpoints were mixed. 33% of respondents referred AF patients for OSA screening. OSA was diagnosed in 48% of referred patients and continuous positive airway pressure (CPAP) was prescribed for 59% of them. Nearly 70% of respondents believed randomized controlled trials (RCTs) of OSA treatment in AF patients were necessary and indicated willingness to contribute to such trials. Conclusions: There was no clinical equipoise among surveyed cardiologists; a majority expressed certainty that combined OSA and AF treatment is superior to AF treatment alone for improving AF outcomes. However, a minority of surveyed cardiologists referred AF patients for OSA testing, and while half of screened AF patients had OSA, CPAP was prescribed in little more than half of them, reflecting the view that better clinical trial evidence is needed to support this practice. Our results underscore the need for larger, multi-national prospective studies of OSA treatment and AF outcomes to inform more uniform society guideline recommendations.

Oral 11ß-HSD1 inhibitor AZD4017 improves wound healing and skin integrity in adults with type 2 diabetes mellitus: a pilot randomized controlled trial.

BACKGROUND: Chronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by the enzyme 11ß-hydroxysteroid dehydrogenase type 1, 11ß-HSD1) impair wound healing. OBJECTIVES: Efficacy, safety, and feasibility of 11ß-HSD1 inhibition for skin function and wound healing. DESIGN: Investigator-initiated, double-blind, randomized, placebo-controlled, parallel-group phase 2b pilot trial. METHODS: Single-center secondary care setting. Adults with type 2 diabetes mellitus without foot ulcers were administered 400 mg oral 11ß-HSD1 inhibitor AZD4017 (n = 14) or placebo (n = 14) bi-daily for 35 days. Participants underwent 3-mm full-thickness punch skin biopsies at baseline and on day 28; wound healing was monitored after 2 and 7 days. Computer-generated 1:1 randomization was pharmacy-administered. Analysis was descriptive and focused on CI estimation. Of the 36 participants screened, 28 were randomized. RESULTS: Exploratory proof-of-concept efficacy analysis suggested AZD4017 did not inhibit 24-h ex vivoskin 11ß-HSD1 activity (primary outcome; difference in percentage conversion per 24 h 1.1% (90% CI: -3.4 to 5.5) but reduced systemic 11ß-HSD1 activity by 87% (69-104%). Wound diameter was 34% (7-63%) smaller with AZD4017 at day 2, and 48% (12-85%) smaller after repeat wounding at day 30. AZD4017 improved epidermal integrity but modestly impaired barrier function. Minimal adverse events were comparable to placebo. Recruitment rate, retention, and data completeness were 2.9/month, 27/28, and 95.3%, respectively. CONCLUSION: A phase 2 trial is feasible, and preliminary proof-of-concept data suggests AZD4017 warrants further investigation in conditions of delayed healing, for example in diabetic foot ulcers. SIGNIFICANCE STATEMENT: Stress hormone activation by the enzyme 11ß-HSD type 1 impairs skin function (e.g. integrity) and delays wound healing in animal models of diabetes, but effects in human skin were previously unknown. Skin function was evaluated in response to treatment with a 11ß-HSD type 1 inhibitor (AZD4017), or placebo, in people with type 2 diabetes. Importantly, AZD4017 was safe and well tolerated. This first-in-human randomized, controlled, clinical trial found novel evidence that 11ß-HSD type 1 regulates skin function in humans, including improved wound healing, epidermal integrity, and increased water loss. Results warrant further studies in conditions of impaired wound healing, for example, diabetic foot ulcers to evaluate 11ß-HSD type 1 as a novel therapeutic target forchronic wounds.

Impact of obesity and metabolic health status in the development of non-alcoholic fatty liver disease (NAFLD): A United Kingdom population-based cohort study using the health improvement network (THIN).

BACKGROUND: With the obesity epidemic reaching crisis levels, there has been attention around those who may be resilient to the effects of obesity, termed metabolically healthy obesity (MHO), who initially present without associated metabolic abnormalities. Few longitudinal studies have explored the relationship between MHO and non-alcoholic fatty liver disease (NAFLD), which we address using over 4 million primary care patient records. METHODS: A retrospective population-based longitudinal cohort was conducted using The Health Improvement Network (THIN) database incorporating adults with no history of NAFLD or alcohol excess at baseline. Individuals were classified according to BMI category and metabolic abnormalities (diabetes, hypertension and dyslipidaemia). Diagnosis of NAFLD during follow-up was the primary outcome measure. NAFLD was identified by Read codes. RESULTS: During a median follow-up period of 4.7 years, 12,867 (0.3%) incident cases of NAFLD were recorded in the cohort of 4,121,049 individuals. Compared to individuals with normal weight and no metabolic abnormalities, equivalent individuals who were overweight, or obese were at significantly greater risk of incident NAFLD (Adjusted HR 3.32 (95%CI 2.98-3.49), and 6.92 (6.40-7.48, respectively). Metabolic risk factors further increased risk, including in those with normal weight and 1 (2.27, 1.97-2.61) or = < 2 (2.39, 1.99-2.87) metabolic abnormalities. CONCLUSIONS: MHO individuals are at greater risk of developing NAFLD compared to those with normal weight. This finding supports that the MHO phenotype is a temporary state, and weight must be considered a risk factor even before other risk factors develop. Being normal weight with metabolic abnormalities was also associated with risk of NAFLD.

Impact of bariatric surgery on cardiovascular outcomes and mortality: a population-based cohort study.

BACKGROUND: Cohort studies have shown that bariatric surgery may reduce the incidence of and mortality from cardiovascular disease (CVD), but studies using real-world data are limited. This study examined the impact of bariatric surgery on incident CVD, hypertension and atrial fibrillation, and all-cause mortality. METHODS: A retrospective, matched, controlled cohort study of The Health Improvement Network primary care database (from 1 January 1990 to 31 January 2018) was performed (approximately 6 per cent of the UK population). Adults with a BMI of 30 kg/m2 or above who did not have gastric cancer were included as the exposed group. Each exposed patient, who had undergone bariatric surgery, was matched for age, sex, BMI and presence of type 2 diabetes mellitus (T2DM) with two controls who had not had bariatric surgery. RESULTS: A total of 5170 exposed and 9995 control participants were included; their mean(s.d.) age was 45·3(10·5) years and 21·5 per cent (3265 of 15 165 participants) had T2DM. Median follow-up was 3·9 (i.q.r. 1·8- 6·4) years. Mean(s.d.) percentage weight loss was 20·0(13·2) and 0·8(9·5) per cent in exposed and control groups respectively. Overall, bariatric surgery was not associated with a significantly lower CVD risk (adjusted hazard ratio (HR) 0·80; 95 per cent c.i. 0·62 to 1·02; P = 0·074). Only in the gastric bypass group was a significant impact on CVD observed (HR 0·53, 0·34 to 0·81; P = 0·003). Bariatric surgery was associated with significant reduction in all-cause mortality (adjusted HR 0·70, 0·55 to 0·89; P = 0·004), hypertension (adjusted HR 0·41, 0·34 to 0·50; P < 0·001) and heart failure (adjusted HR 0·57, 0·34 to 0·96; P = 0·033). Outcomes were similar in patients with and those without T2DM (exposed versus controls), except for incident atrial fibrillation, which was reduced in the T2DM group. CONCLUSION: Bariatric surgery is associated with a reduced risk of hypertension, heart failure and mortality, compared with routine care. Gastric bypass was associated with reduced risk of CVD compared to routine care.

ANTECEDENTES: Estudios de cohortes han mostrado que la cirugía bariátrica puede reducir la incidencia de enfermedad cardiovascular (cardiovascular disease, CVD) y la mortalidad, pero los estudios basados en datos del mundo real son limitados. Este estudio examinaba el impacto de la cirugía bariátrica (bariatric surgery, BS) en la incidencia de CVD, hipertensión, fibrilación auricular (FA) y mortalidad por cualquier causa. MÉTODOS: Se realizó un estudio retrospectivo de cohortes, controlado por emparejamiento, a partir de la base de datos de atención primaria del The Health Improvement Network (THIN) (1/1/1990 y 31/1/2018) (aproximadamente el 6% de la población del Reino Unido UK). En el grupo de exposición, se incluyeron adultos con un índice de masa corporal (IMC) ≥ 30 kg/m2 que no tenían cáncer gástrico. Cada paciente expuesto (había sido operado de BS) fue emparejado por edad, sexo, IMC y presencia de diabetes tipo 2 (T2D) con 2 controles (sin BS). RESULTADOS: Se incluyeron un total de 5.170 sujetos expuestos y 9.995 participantes controles. La edad media (DE) fue 45,3 (10,5) años, 21,5% (n = 3.265) tenían T2D. La mediana de seguimiento era de 3,9 años (rango intercuartílico 1,8- 6,4). La media ± desviación estándar del % de pérdida de peso fue del 20,0 ± 13,2% en el grupo BS versus 0,8 ± 9,5% en los grupos control. Globalmente, la BS no se asoció con una CVD significativamente más baja (cociente de riesgos instantáneos ajustados, adjusted hazard ratio, HR 0,80; i.c. del 0,62- 1,02, P = 0,074). Solo en el grupo del bypass gástrico se observó un impacto significativo en CVD (0,53, 0,34- 0,81, P = 0,003). BS se asoció con una reducción significativa en la mortalidad de cualquier causa (0,70; i.c. Del 95% 0,55- 0,89, P = 0,004), hipertensión (0,41; 0,34- 0,50, P < 0,001), e insuficiencia cardiaca (0,57, 0,34- 0,96; P = 0.033). Los resultados fueron similares en aquellos pacientes con y sin T2D (expuesto versus control) excepto en la FA incidental que se redujo en el grupo T2D. CONCLUSIONES: La práctica de BS se asoció con una reducción del riesgo de insuficiencia cardiaca y mortalidad.

Changes in glycaemic control, blood pressure and lipids 5 years following laparoscopic adjustable gastric banding combined with medical care in patients with type 2 diabetes: a longitudinal analysis.

The long-term outcomes of weight loss maintenance induced by laparoscopic adjustable gastric band (LAGB) followed by multidisciplinary medical care in patients with type 2 diabetes mellitus (T2DM) (beyond 3 years) are scarcely reported. Study aims were to determine the longer term metabolic outcomes following LAGB combined with medical care in patients with T2DM. This is a longitudinal analysis of 200 adults with T2DM who had LAGB between 2003 and 2008 and were followed up till 2013 at a single bariatric unit in a tertiary UK centre. A total of 200 patients (age 47 ± 9.7 years; body mass index [BMI] 52.8 ± 9.2 kg m-2 ; glycosylated haemoglobin (HbA1c) 7.9 ± 1.9% [62.8 mmol mol-1 ]; women, n = 123 [61.5%]; insulin treatment, n = 71 [35.5%]) were included. The mean follow-up was 62.0 ± 13.0 months (range 18-84 months). There were significant reductions in body weight (-24.4 ± 12.3% [38 ± 22.7 kg]), HbA1c (-1.4 ± 2.0%), systolic blood pressure [BP] (-11.7 ± 23.5 mmHg), total cholesterol and triglyceride levels. The proportion of patients requiring insulin reduced from 36.2% to 12.3%. The overall band complication rate was 21% (21 patients). LAGB when combined with multidisciplinary medical care significantly improved metabolic outcomes in patients with T2DM independent of diabetes duration, and baseline BMI over 5 years. Diabetes duration and baseline BMI did not predict changes in glycaemic control, BP or lipids following LAGB.

Exploration of knowledge and understanding in patients with primary adrenal insufficiency: a mixed methods study.

BACKGROUND: Primary adrenal insufficiency (PAI) is a rare and severe condition requiring lifelong steroid replacement. During acute illness or stressful events, it is important to appropriately adjust glucocorticoid dose; failure to do so may lead to an adrenal crisis. The aim of the study was to explore patients PAI knowledge and understanding of the condition, steroid replacement adjustment during acute illness or stress and provided education. METHODS: Ten adult patients with PAI were purposefully recruited from two hospitals in a tertiary NHS Trust in England, UK. Data was collected using a mixed method approach utilising semi-structured audio-recorded interviews and hospital case note review. Interviews were transcribed verbatim and analysed using Burnard's content analysis framework. Information from the hospital case note review was captured using a matrix table based on pre-defined criteria. RESULTS: Four key themes emerged: 'Addison's disease and hydrocortisone replacement'; 'stress and corticosteroids'; 'patient compliance/adherence' and 'transition'. Patients reported feelings of 'going through a transition from uncertainty to adaption' following diagnosis. All participants had a good level of knowledge and understanding of required medication however application in times of need was poor. Medication adherence and prevention of a crisis relied not only on patient knowledge and application but also the support of family and health professionals. Health care professional knowledge required improvement to aid diagnosis and management of PAI. CONCLUSION: Patients with PAI did not apply existing knowledge to adjust steroid dose during acute illness or stress. Although a sample of limited size, our study identified there is a need to further explore why patients with Addison's disease do not apply existing knowledge during times of increased need. Future research should consider appropriate behaviour change interventions to promote medication adherence to reduce risk of an adrenal crisis.

Novel therapeutics for type 2 diabetes: insulin resistance.

Insulin resistance (IR) plays an important role in the pathogenesis of type 2 diabetes (T2D) and cardiovascular disease. Hence improving IR is a major target of treatment in patients with T2D. Obesity and lack of exercise are major causes of IR. However, recent evidence implicates sleep disorders and disorders of the circadian rhythm in the pathogenesis of IR. Weight loss and lifestyle changes are the cornerstone and most effective treatments of IR, but adherence and patient's acceptability are poor. Bariatric surgery results in significant and sustainable long-term weight loss associated with beneficial impact on IR and glucose metabolism, making this an attractive treatment option for patients with T2D. Currently available pharmacological options targeting IR (such as metformin and thiazolidinediones) do not maintain glycaemic measures within targets long term and can be associated with significant side effects. Over the last two decades, many pharmacological agents targeting different aspects of the insulin signalling pathway were developed to improve IR, but only a minority reached clinical trials. Such treatments need to be specific and reversible as many of the components of the insulin signalling pathway are involved in other cellular functions such as apoptosis. Recent evidence highlighted the role of circadian rhythm and sleep-related disorders in the pathogenesis of IR. In this article, we review the latest developments in the pharmacological and non-pharmacological interventions targeting IR including bariatric surgery. We will also review the role of circadian rhythm and sleep-related disorders in the development and treatment of IR.

In-patient diabetes care: the impact of diabetes outreach team on long-term glycaemic control.

AIM: Our aim is to assess the impact of inpatient diabetes services on glycaemic control in patient with diabetes admitted to a secondary care hospital in UK. METHODS: We performed a retrospective analysis of all diabetes mellitus (DM) in-patients who were seen by our Diabetes Outreach Team from June 2007 to December 2010. Those with an admission diagnosis of hypoglycaemia were excluded. Blood samples including HbA1c at the initial visit and subsequent outpatient follow-up at 3-6 months were collected. Patients admitted with newly diagnosed diabetes were analysed separately. RESULTS: In total 2002 patient data were captured. 778 patients were eliminated initially because of failure to attend follow-up clinic, lack of follow-up HbA1c data, and because of planned discharge to the community. Complete blood samples were available for 1224 patients. Of this, 235 patients (19.2% of those with complete data) were analysed separately as their primary diagnosis was hypoglycaemia. In the remaining 989 patients, 31 (3.1%) new onset Type 1 DM patients and 91 (9.2%) new onset Type 2 patients were analysed separately. In patients with known DM (n = 867) HbA1c improved from 75 mmol/mol (9.0% ± 2.39) to 69 mmol/mol (8.46% ± 2.0) (p < 0.001). In the newly diagnosed Type 1 DM (n = 31) patients HbA1c improved from 114 mmol/mol (12.55% ± 2.27) to 58 mmol/mol (7.43% ± 2.05) (p < 0.001). In the newly diagnosed Type 2 DM (n = 91) patients HbA1c improved from 93 mmol/mol (10.70% ± 3.04) to 56 mol/mol (7.29% ± 1.74) (p < 0.001). In those who presented with hypoglycaemia (n = 235) HbA1c changed from 58 mmol/mol (7.48% ± 1.59) to 59 mmol/mol (7.59% ± 1.57) (p = 0.2). CONCLUSION: By providing a comprehensive care, structured education and appropriate intervention through our Diabetes Outreach Team, we have shown a significant reduction in HbA1c for recently hospitalised patients.

Management strategies for gastrointestinal, erectile, bladder, and sudomotor dysfunction in patients with diabetes.

There are substantial advances in understanding disordered gastrointestinal autonomic dysfunction in diabetes. It occurs frequently. The underlying pathogenesis is complex involving defects in multiple interacting cell types of the myenteric plexus as well. These defects may be irreversible or reversible. Gastrointestinal symptoms represent a major and generally underestimated source of morbidity for escalating health care costs in diabetes. Acute changes in glycaemia are both determinants and consequences of altered gastrointestinal motility. 35-90% of diabetic men have moderate-to-severe erectile dysfunction (ED). ED shares common risk factors with CVD. Diagnosis is based on medical/sexual history, including validated questionnaires. Physical examination and laboratory testing must be tailored to patient's complaints and risk factors. Treatment is based on PDE5-inhibitors (PDE5-I). Other explorations may be useful in patients who do not respond to PDE5-I. Patients at high cardiovascular risk should be stabilized by their cardiologists before sexual activity is considered or ED treatment is recommended. Estimates on bladder dysfunction prevalence are 43-87% of type 1 and 25% of type 2 diabetic patients, respectively. Common symptoms include dysuria, frequency, urgency, nocturia and incomplete bladder emptying. Diagnosis should use validated questionnaire for lower urinary tract symptoms. The type of bladder dysfunction is readily characterized with complete urodynamic testing. Sudomotor dysfunction is a cause of dry skin and is associated with foot ulcerations. Sudomotor function can be assessed by thermoregulatory sweat testing, quantitative sudomotor axon reflex test, sympathetic skin response, quantitative direct/indirect axon reflex testing and the indicator plaster.

Predicting dysglycaemia in patients under investigation for acute coronary syndrome.

AIMS: To examine methods for the identification of previously undetected dysglycaemia [diabetes and impaired glucose tolerance (IGT)] in patients investigated for possible acute coronary syndrome. Specifically, we wished to examine whether the recently advocated use of glycosylated haemoglobin (HbA1c) would enhance detection rates for diabetes in these patients. METHODS: Patients (n = 200) investigated for possible acute coronary syndrome and not previously known to have diabetes were recruited and anthropometric data collected. Random plasma glucose concentrations followed by oral glucose tolerance tests, HbA1c, fasting lipids, high sensitivity C-reactive protein and homeostatic modular assessment-insulin resistance were obtained during admission. Following discharge, the fasting plasma glucose (FPG) was repeated to determine the importance of sequential fasting levels. The accuracy of individual tests, combinations and sequential testing was assessed using receiver operating characteristic curves. A predictive index (PI) was generated using stepwise logistic regression models. RESULTS: The prevalence of diabetes and IGT were 21 and 32%, respectively. FPG >6.0 mmol/l and HbA1c ≥ 6.0% had specificities of 94.9% and 93.6% but sensitivities of only 31.7 and 39.0%, respectively. Combination and sequential testing provided little additional benefit. Use of a PI comprising FPG, HbA1c and age provided the best overall performance (75.6% sensitivity, 77.1% specificity, negative predictive value 92.4%). CONCLUSION: Our data confirm the high prevalence of dysglycaemia in this cohort. The commonly advocated screening tools have significant limitations if used in isolation, combination or sequentially. Our approach using a PI offers improved performance partly as it uses continuous data rather than arbitrary cut-off values.

The prevalence of vitamin D abnormalities in South Asians with type 2 diabetes mellitus in the UK.

BACKGROUND: The high prevalence of both hypovitaminosis D and type 2 diabetes (T2DM) in the Asian community is well recognised, but the impact of diabetes on vitamin D status and vice versa, has not been well reported. AIMS: To determine the prevalence of hypovitaminosis D in Asian patients with T2DM and its impact on glycaemic control. METHODS: A cross-sectional study was conducted in a tertiary referral centre in the UK. Two hundred and ten Asian patients aged more than 40 years were included (170 with and 40 without T2DM). Each had a standard bone profile (serum calcium, phosphate and alkaline phosphatase), serum parathyroid hormone and 25-hydroxycholecalciferol. RESULTS: The prevalence of low serum 25-hydroxyvitamin D (< 50 nmol/l) was high in the group as a whole (> 80%) and more common in diabetics compared with controls (83% vs. 70%; p = 0.07). This was particularly so in men (82.5% vs. 57.9%; p = 0.02). HbA1c was higher in women with vitamin D deficiency (< 12.5 nmol/l) (8.11 +/- 1.11% vs. 7.33 +/- 1.32%, p = 0.046). In logistic regression analysis, T2DM was an independent predictor of hypovitaminosis D. In linear regression analysis, vitamin D deficiency was independently related to HbA1c in women with T2DM. CONCLUSIONS: Hypovitaminosis D remains a major public health issue in the Asian population and is exaggerated in patients with T2DM. The fact that vitamin D deficient women had higher HbA1c levels raises the possibility that vitamin D replacement may improve glycaemic control.

Once weekly thyroxine treatment as a strategy to treat non-compliance.

Hypothyroidism is a common disorder, which is mainly treated in primary rather than secondary care. Once daily thyroxine replacement restores euthyroidism in most patients; some patients, however, remain hypothyroid despite adequate thyroxine replacement. Non-compliance is the most common cause of lack of response to thyroxine treatment. We describe two cases of primary hypothyroidism in which daily thyroxine treatment did not restore biochemical euthyroidism but once weekly thyroxine treatment was successful. In addition we review the evidence and discuss the differential diagnosis of lack of response to thyroxine treatment. Once weekly thyroxine treatment can be a safe, well-tolerated, and effective therapy for patients with non-compliance.

Grave's Eye disease developing following radioiodine treatment for toxic nodular goitre.

The development of Grave's ophthalmopathy (GO) following radioiodine (RI) treatment for Grave's thyrotoxicosis, though controversial, is well described. The development of ophthalmopathy following RI treatment for toxic nodular goitre is much less recognised. We report a 49 year-old female patient who developed thyrotoxicosis and GO after receiving RI treatment for toxic nodular goitre and we also review the relevant literature.