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Aim: N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) concentrations are lower in patients with obesity. The interaction between body mass index (BMI) and NT‐proBNP with respect to heart failure risk remains incompletely defined. Methods and results: Data were pooled across three randomized clinical trials enrolling predominantly patients who were overweight or obese with established cardiometabolic disease: SAVOR‐TIMI 53, DECLARE‐TIMI 58 and CAMELLIA‐TIMI 61. Hospitalization for heart failure (HHF) was examined across strata of baseline BMI and NT‐proBNP. The effect of dapagliflozin versus placebo was assessed for a treatment interaction across BMI categories in patients with or without an elevated baseline NT‐proBNP (≥125 pg/ml). Among 24 455 patients, the median NT‐proBNP was 96 (interquartile range [IQR]: 43–225) pg/ml and the median BMI was 33 (IQR 29–37) kg/m2, with 68% of patients having a BMI ≥30 kg/m2. There was a significant inverse association between NT‐proBNP and BMI which persisted after adjustment for all clinical variables (p < 0.001). Within any range of NT‐proBNP, those at higher BMI had higher risk of HHF at 2 years (comparing BMI <30 vs. ≥40 kg/m2 for NT‐proBNP ranges of <125, 125–<450 and ≥450 pg/ml: 0.0% vs. 0.6%, 1.3% vs. 4.0%, and 8.1% vs. 13.8%, respectively), which persisted after multivariable adjustment (adjusted hazard ratio [HRadj] 7.47, 95% confidence interval [CI] 3.16–17.66, HRadj 3.22 [95% CI 2.13–4.86], and HRadj 1.87 [95% CI 1.35–2.60], respectively). In DECLARE‐TIMI 58, dapagliflozin versus placebo consistently reduced HHF across BMI categories in those with an elevated NT‐proBNP (p‐trend for HR across BMI = 0.60), with a pattern of greater absolute risk reduction (ARR) at higher BMI (ARR for BMI <30 to ≥40 kg/m2: 2.2% to 4.7%; p‐trend = 0.059). Conclusions: The risk of HHF varies across BMI categories for any given range of circulating NT‐proBNP. These findings showcase the importance of considering BMI when applying NT‐proBNP for heart failure risk stratification, particularly for patients with low‐level elevations in NT‐proBNP (125–<450 pg/ml) where there appears to be a clinically meaningful absolute and relative risk gradient. [ABSTRACT FROM AUTHOR]

Obesity is a chronic, progressive and relapsing disease with a rising global prevalence associated with increased morbidity and mortality and reduced quality of life. Treatment of obesity requires a comprehensive medical approach that includes behavioural interventions, pharmacotherapy and bariatric surgery. The degree of weight loss with all approaches is highly heterogeneous, and long‐term weight maintenance remains challenging. For years, antiobesity medications have been limited in number, often delivering meagre efficacy and raising numerous safety concerns. Therefore, there is a need for the development of highly efficacious and safe new agents. Recent insights into the complex pathophysiology of obesity have increased our understanding of intervenable targets for pharmacotherapies to treat obesity and improve weight‐related cardiometabolic complications, namely, type 2 diabetes, hyperlipidaemia and hypertension. As a result, novel potent therapies have emerged, such as semaglutide, a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) recently approved for the treatment of obesity. Semaglutide 2.4 mg once weekly significantly reduces body weight by approximately 15%, with simultaneous improvement in cardiometabolic risk factors and physical functioning in people with obesity. Tirzepatide, the first dual glucose‐dependent insulinotropic polypeptide (GIP)/GLP‐1RA, has recently demonstrated that body weight reduction exceeding 20% in people with obesity and coupled with improved cardiometabolic measures is feasible. Thus, these novel agents promise to narrow the gap between the weight‐loss effects of behaviour interventions, previous pharmacotherapies, and bariatric surgery. In this narrative review, we highlight established and emerging therapeutic treatments for long‐term obesity management and position them in a framework according to their weight loss effects. [ABSTRACT FROM AUTHOR]

Aim: To undertake a cost‐effectiveness analysis of dapagliflozin in treating high‐risk patients with type 2 diabetes mellitus (T2DM), using both directly observed events in the DECLARE‐TIMI 58 trial and surrogate risk factors to predict endpoints not captured within the trial. Methods: An established T2DM model was adapted to integrate survival curves derived from the DECLARE‐TIMI 58 trial, and extrapolated over a lifetime for all‐cause mortality, hospitalization for heart failure, stroke, myocardial infarction, hospitalization for unstable angina, and end‐stage kidney disease. The economic analysis considered the overall DECLARE trial population, as well as reported patient subgroups. Total and incremental costs, life‐years and quality‐adjusted life‐years associated with dapagliflozin versus placebo were estimated from the perspective of the UK healthcare payer. Results: In the UK setting, treatment with dapagliflozin compared to placebo was estimated to be dominant, with an expected increase in quality‐adjusted life‐years from 10.43 to 10.48 (+0.06) and a reduction in lifetime total costs from £39 451 to £36 899 (−£2552). Across all patient subgroups, dapagliflozin was estimated to be dominant, with the greatest absolute benefit in the prior heart failure subgroup (incremental lifetime costs −£4150 and quality‐adjusted life‐years +0.11). Conclusions: The results of this study demonstrate that dapagliflozin compared to placebo appears to be cost‐effective, when considering evidence reported from the DECLARE‐TIMI 58 trial, at established UK willingness‐to‐pay thresholds. The findings highlight the potential of dapagliflozin to have a meaningful impact in reducing the economic burden of T2DM and its associated complications across a broad T2DM population. [ABSTRACT FROM AUTHOR]

Summary: Obesity is a global epidemic associated with over 200 health complications and a significant risk of developing cardiovascular disease (CVD), partly by increasing classical risk factors such as lipid and glucose levels and blood pressure. Weight loss through lifestyle interventions, pharmacotherapy and/or bariatric surgery improves CV risk factors. Cardiovascular outcome trials (CVOTs) of anti‐obesity medications aim to evaluate the CV safety and benefits of pharmacotherapy. Many CVOTs in obesity have either failed to demonstrate a CV benefit or have been terminated prematurely because of safety issues, prompting regulatory agencies to define new requirements (based on those for CVOTs in type 2 diabetes [T2D]). CVOTs of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) in T2D have demonstrated that some GLP‐1RAs reduce CV risk and may help inform future CVOTs in obesity, given the approval of liraglutide 3.0 mg for obesity. In this review, the evidence for the link between obesity and CVD is considered in the context of studies showing that weight loss improves markers of CV risk and risk of adverse CV events. The review also examines the CVOTs in obesity that have been conducted to date and those under way, such as the SELECT trial with subcutaneous semaglutide of 2.4 mg. [ABSTRACT FROM AUTHOR]

Objective: The obesity epidemic is a public health concern, warranting further research into pharmacological treatments for weight management (WM) as an adjunct to lifestyle interventions. The Semaglutide Treatment Effect in People with obesity (STEP) program aims to investigate the effect of semaglutide versus placebo on weight loss, safety, and tolerability in adults with obesity or overweight.Methods: Across five phase 3 trials (NCT03548935, WM; NCT03552757, WM in type 2 diabetes; NCT03611582, WM with intensive behavioral therapy; NCT03548987, sustained WM; and NCT03693430, long-term WM), ~5,000 participants are being randomly assigned to receive semaglutide 2.4 mg once weekly subcutaneously versus placebo. Results will be available in 2020/2021. For all trials, the primary end point is change from baseline to end of treatment in body weight.Results: Participants have a mean age of 46.2 to 55.3 years, are mostly female (mean: 74.1%-81.0%), and have a mean BMI of 35.7 to 38.5 kg/m2 and a mean waist circumference of 113.0 to 115.7 cm.Conclusions: The STEP program evaluates the efficacy and safety of semaglutide 2.4 mg subcutaneously once weekly in a broad population. The trials will provide insights on WM in people with obesity with and without type 2 diabetes and on long-term follow-up. [ABSTRACT FROM AUTHOR]

Summary: We are facing a global epidemic of obesity and type 2 diabetes. Weight loss, in the context of obesity and type 2 diabetes, may improve glycaemic control and weight‐related comorbidities, and in some cases, induce diabetes remission. Although lifestyle‐based weight loss strategies may be initially successful, most are not effective long‐term. There is an increasing need to consider pharmacological approaches to assist weight loss in diabetes‐obesity. Older glucose‐lowering agents may cause weight gain, whereas the newer drug classes, sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) and glucagon‐like peptide receptor agonists (GLP‐1 RAs), concomitantly target weight loss and glycaemic control. Clinical trial data suggest that both SGLT2i and GLP1 RAs cause a mean weight loss of approximately 2 to 3 kg but real‐world evidence and clinical experience suggests a significant heterogeneity in the magnitude of the weight loss (GLP‐1 RAs) or the magnitude of the actual weight loss is significantly less than anticipated (SGLT2i). Why do some individuals lose more weight than others in response to these pharmacological treatments? This review will first explore mechanisms by which body weight is regulated through control of energy balance and its dysregulation in obesity, and then consider how these mechanisms may be modulated therapeutically with SGLT2i and GLP1 RAs. [ABSTRACT FROM AUTHOR]

Background It is recognised that sleep-disordered breathing ( SDB), in particular, obstructive sleep apnoea ( OSA) is associated with obesity and diabetes. The complications of OSA include dysregulation of metabolic and cardiovascular homeostasis. With the growing population of diabetes and obesity globally, it is becoming apparent that identifying and screening patients who are at risk is becoming increasingly crucial. Many patients may remain unaware of the potential diagnosis and continue to be undiagnosed. The high prevalence of OSA poses a demanding challenge to healthcare providers in order to provide sufficient resources and facilities for patient diagnosis and treatment. Design In this article, we review the evidence in favour of screening populations deemed to be at increased risk of OSA, with particular reference to patients with obesity and diabetes. We consider the recent advances in potential screening methods that may allow new prognostic and predictive tools to be developed. A detailed search of Medline and Web of Science electronic databases for relevant articles in English was performed. Results Apart from the use of screening tools such as questionnaires and clinical decision models, there is increasing evidence to suggest that there are differences in biological parameters in patients with OSA. Although further studies are required, there may be potential for such biomarkers to contribute to and augment the screening process. However, the significance of such biological tools remains to be elucidated. Conclusions A fundamental role for improved screening in patients with conditions such as obesity and diabetes can enable early interventions that may improve health outcomes relating to the adverse consequences of OSA. The future will see further research being carried out in the development of potential screening methods with emphasis on the selection of patients at risk of sleep disorders, thereby allowing more detailed physiological studies to be carried out where needed. [ABSTRACT FROM AUTHOR]

Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R) and potently stimulates GH release in humans. Ghrelin is found in the hypothalamus, but most circulating ghrelin is derived from the stomach. Ghrelin stimulates food intake but circulating levels are low in obesity. We hypothesized that GH deficiency (GHD) might be associated with increased circulating ghrelin concentrations as a result of low GH levels. We therefore measured circulating ghrelin concentrations, leptin and body composition in subjects with GHD and healthy controls. Subjects with GHD ( n = 18) were compared to healthy control subjects ( n = 18), matched for body mass index (BMI). They underwent assessment of body composition [waist circumference, BMI and percentage body fat (using bioimpedance)]. Plasma ghrelin, leptin, insulin, GH and IGF-1 were measured in the fasting state. Plasma ghrelin was measured using a specific radioimmunassay, and the other hormones using commercially available assays. The groups were well-matched for BMI (GHD vs. control; 32·9 ± 10·8 vs. 31·3 ± 11·7, P = ns) and waist circumference (GHD vs. control; 102·9 ± 20·0 vs. 99·8 ± 25·2, P = ns), but percentage body fat (GHD vs. control; 37·0 ± 9·1 vs. 29·4 ± 13·0, P = 0·06) tended to be higher in the GHD group. As expected, IGF-1 was lower in GHD (GHD vs. control; 12·5 ± 6·8 vs. 19·2 ± 5·8 nmol/l, P = 0·003). Ghrelin [GHD vs. controls; geometric mean (95% CI); 828·8 (95% CI 639·9–1074·2) vs. 487·9 (95% CI 297·2–800·2) pmol/l] and leptin [GHD vs. controls; 13·2 (95% CI 6·6–26·5) vs. 7·9 (95% CI 3·7–16·9) ng/ml] were similar in the two groups. Plasma ghrelin correlated inversely with waist circumference and waist hip ratio in GHD subjects ( r = −0·6, P = 0·02) but not with IGF-1 or GH concentrations. There was no significant correlation in the control subjects. Circulating ghrelin concentrations are influenced by body fat distribution, but not by levels of either GH or IGF-1. However, given that obesity is associated with reduced ghrelin concentrations and that GHD is commonly associated with increased body fat, it is possible that these two opposing influences on circulating ghrelin levels result in normal concentrations in subjects with GHD. [ABSTRACT FROM AUTHOR]

OBJECTIVE Growth hormone (GH) deficiency is associated with increased cardiovascular morbidity and mortality. Abnormalities in heart rate variability (HRV), a surrogate marker of cardiac autonomic tone, have also been found in untreated growth hormone deficient (GHD) patients. Similar abnormalities have been found in patients with complications postmyocardial infarction. DESIGN AND MEASUREMENTS This study was designed to investigate whether GH treatment leads to normalization of cardiac autonomic tone. HRV measurements were obtained from 15 minute resting ECG recordings in 11 untreated adult GHD patients (7 females; mean age 39·2 years), 10 GHD patients (6 females; mean age 46·2 years) reCENving GH replacement (mean duration, 52·7 months) and 12 healthy controls (7 females; mean age 44·6 ± 2·9 years) who were all of similar age, weight and BMI. The untreated GHD patients were then commenced on GH and HRV measurements repeated after 3 and 6 months of treatment. RESULTS In accord with our previous findings, HRV analysis using Fast Fourier Transform (FFT) showed a distinct pattern of abnormality in GHD patients compared with controls. Specifically, there was an increase in nHF power (P = 0·04) and a reduction in nLF power (P = 0·04) (representing parasympathetic and sympathetic activity, respectively), a reduction in nVLF power (P = 0·03) and a 50% reduction in LF/HF ratio (P = 0·02) (a measure of sympathovagal balance) in GHD patients when compared with controls. HRV results in patients who have been on long-term GH replacement were indistinguishable from controls. After 3 months GH replacement in the untreated GHD patient group, nVLF power had increased by 28% (P = 0·03) at 3 months and this was sustained at 6 months. However, no significant changes in LF and HF power were seen. CONCLUSIONS These results suggest that abnormalities of the cardiac autonomic system in GHD patients may be correctable. Longer duration of prospective follow-up will be required to determine at what time point improvements in the other frequency bands occur. [ABSTRACT FROM AUTHOR]