Camilleri, Michael

SummaryBackgroundObesity has reached epidemic proportions, with >40% of the US population affected. Although traditionally managed by lifestyle modification, and less frequently by bariatric therapies, there are significant pharmacological advancements.AimsTo conduct a narrative review of the neurohormonal and physiological understanding of weight gain and obesity, and the development, clinical testing, indications, expected clinical outcomes, and associated risks of current FDA‐approved and upcoming anti‐obesity medications (AOMs).MethodsWe conducted a comprehensive review in PubMed for articles on pathophysiology and complications of obesity, including terms ‘neurohormonal’, ‘obesity’, ‘incretin’, and ‘weight loss’. Next, we searched for clinical trial data of all FDA‐approved AOMs, including both the generic and trade names of orlistat, phentermine/topiramate, bupropion/naltrexone, liraglutide, and semaglutide. Additional searches were conducted for tirzepatide and retatrutide ‐ medications expecting regulatory approval. Searches included combinations of terms related to mechanism of action, indications, side effects, risks, and future directions.ResultsWe reviewed the pathophysiology of obesity, including specific role of incretins and glucagon. Clinical data supporting the use of various FDA‐approved medications for weight loss are presented, including placebo‐controlled or, when available, head‐to‐head trials. Beneficial metabolic effects, including impact on liver disease, adverse effects and risks of medications are discussed, including altered gastrointestinal motility and risk for periprocedural aspiration.ConclusionAOMs have established efficacy and effectiveness for weight loss even beyond 52 weeks. Further pharmacological options, such as dual and triple incretins, are probable forthcoming additions to clinical practice for combating obesity and its metabolic consequences such as metabolic dysfunction‐associated steatotic liver disease.

LINKED CONTENTThis article is linked to Borup et al paper. To view this article, visit https://doi.org/10.1111/apt.17739

Objective High rectal sensory thresholds (RSTs) are associated with chronic constipation (CC), especially in older patients. Bile acids (BAs) affect the RSTs of healthy individuals. Here, we aimed to investigate the effects of the BA transporter inhibitor elobixibat in patients with CC aged ≥60 years. Design We prospectively compared the RSTs of 17 patients with CC aged ≥60 years with those of 9 healthy individuals of the same age range. We next performed a prospective, randomised, parallel-group, double-blind, placebo-controlled clinical trial of 17 patients with CC who administered elobixibat or placebo daily for 1 week. Using barostat methodology, their first constant sensation volume (FCSV), defaecatory desire volume (DDV), and maximum tolerable volume (MTV) thresholds; their rectal compliance; and their faecal BA concentrations were measured before and after treatment. Results There were no significant differences in the RSTs of healthy individuals and patients with CC, but all of these tended to be higher in the latter group. Elobixibat increased the desire to defaecate, significantly reduced the threshold for FCSV (p=0.0018), and tended to reduce the threshold for DDV (p=0.0899) versus placebo. However, there were no differences in the MTV or rectal compliance of the two groups. The total faecal BA concentration increased, and particularly that of secondary BAs in the elobixibat group. Elobixibat was most efficacious in participants with a longer duration of CC and a history of treatment for CC. Conclusion Elobixibat reduces the RSTs of patients with CC aged ≥60 years, which may be important for its therapeutic effects. Trial registration number jRCTs061200030.

AbstractBackgroundFood intake is regulated by homeostatic and hedonic systems that interact in a complex neuro‐hormonal network. Dysregulation in energy intake can lead to obesity (OB) or anorexia nervosa (AN). However, little is known about the neurohormonal response patterns to food intake in normal weight (NW), OB, and AN.Material & MethodsDuring an ad libitum nutrient drink (Ensure®) test (NDT), participants underwent three pseudo‐continuous arterial spin labeling (pCASL) MRI scans. The first scan was performed before starting the NDT after a > 12 h overnight fast (Hunger), the second after reaching maximal fullness (Satiation), and the third 30‐min after satiation (postprandial fullness). We measured blood levels of ghrelin, cholecystokinin (CCK), glucagon‐like peptide (GLP‐1), and peptide YY (PYY) with every pCASL‐MRI scan. Semiquantitative cerebral blood flow (CBF) maps in mL/100 gr brain/min were calculated and normalized (nCBF) with the CBF in the frontoparietal white matter. The hypothalamus (HT), nucleus accumbens [NAc] and dorsal striatum [DS] were selected as regions of interest (ROIs).ResultsA total of 53 participants, 7 with AN, 17 with NW (body‐mass index [BMI] 18.5–24.9 kg/m2), and 29 with OB (BMI ≥30 kg/m2) completed the study. The NW group had a progressive decrease in all five ROIs during the three stages of food intake (hunger, satiation, and post‐prandial fullness). In contrast, participants with OB showed a minimal change from hunger to postprandial fullness in all five ROIs. The AN group had a sustained nCBF in the HT and DS, from hunger to satiation, with a subsequent decrease in nCBF from satiation to postprandial fullness. All three groups had similar hormonal response patterns with a decrease in ghrelin, an increase in GLP‐1 and PYY, and no change in CCK.ConclusionConditions of regulated (NW) and dysregulated (OB and AN) energy intake are associated with distinctive neurohormonal activity patterns in response to hunger, satiation, and postprandial fullness.

The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide‐1 (GLP‐1), glucose‐dependent insulinotropic peptide (GIP) and glucagon. There are several approved single or dual incretin agonists which can be administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and other experimental dual or triple incretin agonists. Analogues of amylin, peptide YY and oxyntomodulin, as well as the combination of a GLP1R agonist and GIPR antagonist also are in development. Oral semaglutide (administered daily) is approved for type 2 diabetes mellitus and is on track for regulatory review for obesity. The review includes specifically perspectives on the effects of these mechanisms and pharmacological agents on gastric emptying, which contribute to satiation and weight loss, in addition to the established evidence on effects on central mechanisms controlling appetite. In the future, it is anticipated that small molecule GLP‐1 receptor agonists (e.g., oral danuglipron) will be developed for treating obesity. These pharmacological agents are having significant impact on glycaemic control and obesity and on their co‐morbidities.