Objective:
To formulate clinical practice guidelines for the pharmacological management of obesity.
Participants:
An Endocrine Society-appointed Task Force of experts, a methodologist, and a medical ...writer. This guideline was co-sponsored by the European Society of Endocrinology and The Obesity Society.
Evidence:
This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence.
Consensus Process:
One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the European Society of Endocrinology, and The Obesity Society reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize some of the supporting evidence.
Conclusions:
Weight loss is a pathway to health improvement for patients with obesity-associated risk factors and comorbidities. Medications approved for chronic weight management can be useful adjuncts to lifestyle change for patients who have been unsuccessful with diet and exercise alone. Many medications commonly prescribed for diabetes, depression, and other chronic diseases have weight effects, either to promote weight gain or produce weight loss. Knowledgeable prescribing of medications, choosing whenever possible those with favorable weight profiles, can aid in the prevention and management of obesity and thus improve health.
: A hypothetical role of glucocorticoids in human obesity has been suggested since the abdominal obesity phenotype and syndromes of endogenous or exogenous hypercortisolism share several clinical, ...metabolic, and cardiovascular similarities. An emerging body of evidence indicates that both neuroendocrine dysregulation of the hypothalamic‐pituitary‐adrenal (HPA) axis as well as peripheral alterations of cortisol metabolism may play a role in the pathophysiology of abdominal obesity. Major alterations of the HPA axis in vivo may be identified in different ways. They include evaluation of hormone concentrations: (a) in basal conditions, in blood, urine, or saliva samples; (b) during dynamic studies following stimulation with different neuropeptides or psychological stress challenges, or suppression with inhibiting agents of the HPA axis at different levels; and (c) after mixed meals or meals containing different nutrient compositions. In addition, alteration of peripheral cortisol metabolism can be detected by direct measurement of cortisol metabolites in urine, although this is a matter of more complex investigation. Alterations of the HPA axis in abdominal obesity are associated with insulin resistance, which suggests a direct responsibility of these hormonal alterations in the susceptibility of affected patients to develop both metabolic and cardiovascular diseases. According to available data, no single marker probably has the power to detect subtle alterations of the HPA axis in conditions, such as the abdominal obesity and the metabolic syndrome. On the contrary, they indicate the need for multiple parameters. At present, evaluation of urinary free cortisol, particularly during the night‐time, and salivary‐free cortisol appear to be promising for these purposes, whereas dynamic tests should be reserved for specific clinical settings, involving well‐characterized patients.
During the last few years, the endocannabinoid system has emerged as a highly relevant topic in the scientific community. Many different regulatory actions have been attributed to endocannabinoids, ...and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors, named CB1 receptor and CB2 receptor, first discovered as the molecular targets of the psychotropic component of the plant Cannabis sativa, participate in the physiological modulation of many central and peripheral functions. CB2 receptor is mainly expressed in immune cells, whereas CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain. CB1 receptor is expressed in the hypothalamus and the pituitary gland, and its activation is known to modulate all the endocrine hypothalamic-peripheral endocrine axes. An increasing amount of data highlights the role of the system in the stress response by influencing the hypothalamic-pituitary-adrenal axis and in the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior.
The ability of the endocannabinoid system to control appetite, food intake, and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the gastrointestinal tract, and, possibly, skeletal muscle. The relevance of the system is further strenghtened by the notion that drugs interfering with the activity of the endocannabinoid system are considered as promising candidates for the treatment of various diseases, including obesity.
Immune checkpoint inhibitors (ICIs) show efficacy in the treatment of non-Hodgkin lymphomas (NHL). However, these agents are associated with a unique group of side effects called immune-related ...adverse events (irAEs). We conducted an observational retrospective/prospective study on patients with relapsed/refractory NHL treated with ICI to determine the incidence of irAEs assessing the type, severity, and timing of onset, outcome and relationship with study drugs of these events. Thirty-two patients underwent ICI as single agent (N = 20) or in combination (N = 12). Ten patients (31.3%) developed at least one irAE for a total of 17 irAEs. Median time to presentation of irAEs was 69 days (range 0-407) with a median resolution time of 16 days (range 0-98). Progression free survival at 24 months for patients who developed an irAE was 40% and 31.8% for who did not. Overall survival for the two groups did not differ (at 24 months 40.0% and 62.5% for patients without and with irAE, respectively), but the median for who developed an irAE was not reached. The incidence of irAEs was associated with better long-term survival in NHL treated with ICIs but patients' disease conditions need to be carefully evaluated to decide the optimal management.
Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a ...crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1-KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1-KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot-specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue. Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1-KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions. Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role.
Incidental discovery of adrenal masses has increased over the past few years. Mild alterations in cortisol secretion without clinical signs of overt hypercortisolism (subclinical Cushing's syndrome) ...are a common finding in patients with these tumours. Although metabolic alterations and increased cardiovascular risk have been noted in patients with subclinical Cushing's syndrome, incidence of cardiovascular events and mortality in the long term have not been assessed. We aimed to ascertain the frequency of new cardiovascular events and mortality in patients with non-secreting adrenal incidentalomas, tumours of intermediate phenotype, or those causing subclinical Cushing's syndrome.
From January, 1995, to September, 2010, consecutive outpatients with adrenal incidentalomas who were referred to the endocrinology unit of S Orsola-Malpighi Hospital, Bologna, Italy, were enrolled into our study. Individuals were assessed every 18-30 months for the first 5 years (mean follow-up 7·5 SD 3·2 years, range 26 months to 15 years). Cortisol concentrations after the 1 mg dexamethasone suppression test (DST) were used to define non-secreting (+50 nmol/L) and intermediate phenotype (50-138 nmol/L) adrenal incidentalomas and subclinical Cushing's syndrome (+138 nmol/L). At the end of follow-up, patients were reclassified as having either unchanged or worsened secreting patterns from baseline.
198 outpatients were assessed; at the end of follow-up, 114 patients had stable non-secreting adrenal incidentalomas, 61 had either a stable intermediate phenotype or subclinical Cushing's syndrome, and 23 had a pattern of secretion that had worsened. By comparison with patients with stable non-secreting adrenal incidentalomas, the incidence of cardiovascular events was higher in individuals with a stable intermediate phenotype or subclinical Cushing's syndrome (6·7% vs 16·7%; p=0·04) and in those with worsened secreting patterns (6·7% vs 28·4%; p=0·02). Cardiovascular events were associated independently with a change (from baseline to the end of follow-up) in cortisol concentrations post DST (hazard ratio 1·13, 95% CI 1·05-1·21; p=0·001). Survival rates for all-cause mortality were lower in patients with either stable intermediate phenotype adrenal incidentalomas or subclinical Cushing's syndrome compared with those with stable non-secreting masses (57·0% vs 91·2%; p=0·005). Factors associated with mortality were age (hazard ratio 1·06, 95% CI 1·01-1·12; p=0·03) and mean concentrations of cortisol post DST (1·10, 1·01-1·19; p=0·04). Compared with patients with stable non-secreting adrenal incidentalomas, unadjusted survival for cardiovascular-specific mortality was lower in patients with either a stable intermediate phenotype or subclinical Cushing's syndrome (97·5% vs 78·4%; p=0·02) and in those with worsened secreting patterns (97·5% vs 60·0%; p=0·01). Cancer mortality did not differ between groups.
Even when clinical signs of overt hypercortisolism are not present, patients with adrenal incidentalomas and mild hypercortisolism have an increased risk of cardiovascular events and mortality.
None.
Subclinical Cushing's syndrome (SCS) is defined as alterations in hypothalamic-pituitary-adrenal axis without classic signs/symptoms of glucocorticoid excess. Whether SCS leads to metabolic and ...cardiovascular diseases is still controversial.
To evaluate the prevalence of hypertension, type 2 diabetes (T2D), coronary heart disease (CHD), ischemic stroke, osteoporosis, and fractures, and their relationship to increasing patterns of subclinical hypercortisolism, in patients with nonsecreting adrenal adenomas (NSA) and SCS.
Using the 1 mg dexamethasone suppression test (DST), 348 patients were classified as follows: 203 were defined as NSA and 19 SCS, using the most stringent cutoff values (<50 and >138 nmol/l respectively). Patients with cortisol post-DST (50-138 nmol/l) were considered as intermediate phenotypes and classified as minor (n=71) and major (n=55) using plasma ACTH and/or urinary free cortisol as additional diagnostic tools.
SCS patients showed higher prevalence of T2D, CHD, osteoporosis, and fractures with respect to NSA. Intermediate phenotypes also showed higher prevalence of CHD and T2D with respect to NSA. The prevalence of all clinical outcomes was not different between intermediate phenotype patients, which were therefore considered as a single group (IP) for multivariate logistic regression analysis: both IP and SCS-secreting patterns showed a significant association with CHD (odds ratio (OR), 4.09; 95% confidence interval (CI), 1.47-11.38 and OR, 6.10; 95% CI, 1.41-26.49 respectively), independently of other potential risk factors. SCS was also independently associated with osteoporosis (OR, 5.94; 95% CI, 1.79-19.68).
Patterns of increasing subclinical hypercortisolism in adrenal adenomas are associated with increased prevalence of adverse metabolic and cardiovascular outcomes, independently of other potential risk factors.
The mineralocorticoid receptor (MR) controls adipocyte function, but its role in the conversion of white adipose tissue (WAT) into thermogenic fat has not been elucidated. We investigated responses ...to the MR antagonists spironolactone (spiro; 20 mg/kg/d) and drospirenone (DRSP; 6 mg/kg/d) in C57BL/6 mice fed a high‐fat (HF) diet for 90 d. DRSP and spiro curbed HF diet‐induced impairment in glucose tolerance, and prevented body weight gain and white fat expansion. Notably, either MR antagonist induced up‐regulation of brown adipocyte‐specific transcripts and markedly increased protein levels of uncoupling protein 1 (UCP1) in visceral and inguinal fat depots when compared with the HF diet group. Positron emission tomography and magnetic resonance spectroscopy confirmed acquisition of brown fat features in WAT. Interestingly, MR antagonists markedly reduced the autophagic rate both in murine preadipocytes in vitro (10‐5 M) and in WAT depots in vivo, with a concomitant increase in UCP1 protein expression. Moreover, the autophagy repressor bafilomycin A1 (10‐8 M) mimicked the effect of MR antagonists, increasing UCP1 protein expression in primary preadipocytes. Hence, we showed that adipocyte MR regulates brown remodeling of WAT through a modulation of autophagy. These results provide a rationale for the use of MR antagonists to prevent the adverse metabolic consequences of adipocyte dysfunction.—Armani, A., Cinti, F., Marzolla, V., Morgan, J., Cranston, G. A., Antelmi, A., Carpinelli, G., Canese, R., Pagotto, U., Quarta, C., Malorni, W., Matarrese, P., Marconi, M., Fabbri, A., Rosano, G., Cinti, S., Young, M. J., Caprio, M. Mineralocorticoid receptor antagonism induces browning of white adipose tissue through impairment of autophagy and prevents adipocyte dysfunction in high‐fat‐diet‐fed mice. FASEB J. 28, 3745–3757 (2014). www.fasebj.org
The advent of new insights into phosphate metabolism must urge the endocrinologist to rethink the pathophysiology of widespread disorders, such as primary hyperparathyroidism, and also of rarer ...endocrine metabolic bone diseases, such as hypoparathyroidism and tumor-induced hypophosphatemia. These rare diseases of mineral metabolism have been and will be a precious source of new information about phosphate and other minerals in the coming years. The parathyroid glands, the kidneys, and the intestine are the main organs affecting phosphate levels in the blood and urine. Parathyroid disorders, renal tubule defects, or phosphatonin-producing tumors might be unveiled from alterations of such a simple and inexpensive mineral as serum phosphate. This review will present all these disorders from a 'phosphate perspective'.