Review article: Pharmacologic management of obesity - updates on approved medications, indications and risks.

BACKGROUND: Obesity 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. AIMS: To 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). METHODS: We 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. RESULTS: We 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. CONCLUSION: AOMs 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.

Recent developments in diagnosing bile acid diarrhea.

INTRODUCTION: Bile acid diarrhea (BAD) commonly causes chronic diarrhea. Symptoms may be mistaken for disorders of gut brain interaction. Due to the lack of widely available diagnostic tests and poor recognition of BAD, there is a delay in diagnosis leading to increased healthcare system burden and decreased patient quality of life. AREAS COVERED: A thorough review of the literature was conducted using PubMed for articles on the biological functions of bile acids, pathophysiology and management of BAD, but focusing on diagnostic testing including 75SeHCAT retention, 7αC4, FGF-19, fecal bile acids, and single stool tests. This narrative review discusses available modalities focusing on noninvasive stool and serum testing that are more widely available and show good sensitivity and specificity for diagnosis of BAD. 75SeHCAT retention is not available in many countries. Alternative diagnostic tests include total and primary fecal bile acid (BA) excretion in 48-hour collection or a single stool sample, serum7αC4 >46 or 52.5 ng/mL, and combination of single stool and serum 7αC4 ±watery stools (Bristol Stool Form Scale 6-7). EXPERT OPINION: Given the ease of serum and single stool sample acquisition and diagnostic advances, clinical practice should embrace positive diagnosis, rather than BAS therapeutic trial. BAD needs to be considered in diverse gastrointestinal diseases.

Optimal measurement of gastric emptying of solids in gastroparesis or functional dyspepsia: evidence to establish standard test.

OBJECTIVE: Symptoms in gastroparesis (Gp) and functional dyspepsia (FD) overlap; using egg protein substitute to measure gastric emptying of solids (GES), ~40% of patients are reclassified from Gp to FD, and vice versa. Our aim was to assess inter-individual and intra-individual coefficients of variation (COV) in GES in symptomatic patients with Gp or FD with documented slow or normal GES, respectively. DESIGN: Scintigraphic GES (T1/2 and GE% at 2 and 4 hours) using a 320 kcal real egg meal (30% fat) was tested in the following: single measurements in 20 patients with diabetes mellitus (10 each type 1 and type 2); repeat GES to estimate COVintra measured: 3 days apart in 9 Gp, 4 weeks apart in 21 Gp and 18 with FD with normal GE assigned to placebo and in 70 patients at 94.3 weeks (median) apart. RESULTS: COVinter for GE% at 4 hours and GE T1/2 were respectively 14.2% and 23.5% in FD and 27.5% and 33% in Gp; COVintra for GE% at 4 hours and GE T1/2 up to 4 weeks apart were 23.4% and 37.9% in FD and 20.1% and 33% in Gp. GE% at 2 hours showed less consistent results. However, >85% retained original diagnosis as normal or delayed. From clinical GES to baseline research for Gp group, repeat GES (after treatment) showed the COVintra for GE% at 4 hours was 37.3% at median 94.3 weeks, with 26/70 changed diagnoses. CONCLUSION: The 320 kcal (30% fat) GES scintigraphic test provides consistent diagnosis in >85% and should be the standard test for suspected gastric emptying disorders.

A Randomized, Controlled Trial of Efficacy and Safety of Cannabidiol in Idiopathic and Diabetic Gastroparesis.

BACKGROUND & AIMS: Cannabis (delta-9-tetrahydrocannabinol), a nonselective cannabinoid-receptor agonist, relieves nausea and pain. Cannabidiol (CBD), a cannabinoid receptor 2 inverse agonist with central effects, also reduces gut sensation and inflammation. We compared the effects of 4 weeks of treatment with pharmaceutical CBD vs placebo in patients with idiopathic or diabetic (diabetes mellitus) gastroparesis. METHODS: We performed a randomized, double-blinded, placebo-controlled study of CBD twice daily (Epidiolex escalated to 20 mg/kg/d; Jazz Pharmaceuticals, Dublin, Ireland) in patients with nonsurgical gastroparesis with delayed gastric emptying of solids (GES). Symptoms were assessed by the Gastroparesis Cardinal Symptom Index Daily Diary. After 4 weeks of treatment, we measured GES, gastric volumes, and Ensure (Abbott Laboratories, Abbott Park, IL) satiation test (1 kcal/mL, 30 mL/min) to assess volume to comfortable fullness and maximum tolerance. Patients underwent specific FAAH and CNR1 genotyping. Statistical analysis compared 2 treatments using analysis of variance including baseline measurements and body mass index as covariates. RESULTS: Among 44 patients (32 idiopathic, 6 diabetes mellitus type 1, and 6 diabetes mellitus type 2), 5 patients did not tolerate full-dose escalation; 3 withdrew before completing 4 weeks of treatment (2 placebo, 1 CBD); 95% completed 4 weeks of treatment and diaries. Compared with placebo, CBD reduced the total Gastroparesis Cardinal Symptom Index score (P = .008), inability to finish a normal-sized meal (P = .029), number of vomiting episodes/24 hours (P = .006), and overall symptom severity (P = .034). Patients treated with CBD had a higher volume to comfortable fullness and maximum tolerance and slower GES. FAAH rs34420 genotype significantly impacted nutrient drink ingestion. The most common adverse events reported were diarrhea (14 patients), fatigue (8 patients), headache (8 patients), and nausea (7 patients). CONCLUSIONS: CBD provides symptom relief in patients with gastroparesis and improves the tolerance of liquid nutrient intake, despite slowing of GES. CLINICALTRIALS: gov NCT #03941288.

Pharmacogenetic interactions of medications administered for weight loss in adults: a systematic review and meta-analysis.

Aim: To analyze roles of single nucleotide variants (SNVs) on weight loss with US FDA-approved medications. Materials & methods: We searched the literature up until November 2022. Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were followed. Results: 14 studies were included in qualitative analysis and seven in meta-analysis. SNVs in CNR1, GLP-1R, MC4R, TCF7L2, CTRB1/2, ADIPOQ, SORCS1 and ANKK1 were evaluated relative to weight loss with glucagon-like peptide-1 agonists (13 studies) or naltrexone-bupropion (one study). CNR1 gene (rs1049353), GLP-1R gene (rs6923761, rs10305420), TCF7L2 gene (rs7903146) were associated with weight loss in at least one study involving glucagon-like peptide-1 agonist(s). The meta-analysis did not identify any consistent effect of SNVs. Conclusion: Pharmacogenetic interactions for exenatide, liraglutide, naltrexone-bupropion and weight loss were identified, but the directionality was inconsistent.

Update on treatment of abdominal pain in irritable bowel syndrome: A narrative review.

The objectives of this narrative review are to update readers on the current state-of-the-art regarding diverse approaches for the treatment of pain, global symptoms, or adequate relief in irritable bowel syndrome (IBS). The article appraises medications, dietary interventions including low fermentable oligosaccharides, disaccharides, and monosaccharides and polyols (FODMAP) diet, fecal microbial transplantation (FMT), electrical approaches, and behavioral therapies including cognitive behavioral therapy (CBT), gut-directed hypnotherapy (GDH), mindfulness, and open-label placebo. Current evidence demonstrates only modest benefit in global IBS symptoms and pain relief. A future approach that identifies pathophysiological mechanisms of IBS through validated biomarkers has the potential to individualize treatment of patients rather than sequential therapeutic trial and error approaches.

Epidemiology and Healthcare Utilization in Patients With Gastroparesis: A Systematic Review.

BACKGROUND & AIMS: The authors performed a systematic review of epidemiologic data to understand the prevalence, incidence, etiologies, and hospitalizations related to gastroparesis (GP). METHODS: Studies of the epidemiology of GP published in all languages, years, and countries from 5 databases in January 2022 were studied using prespecified search strategies. RESULTS: Thirteen studies (data from 1994 to 2019) were included. All but one study (from the United Kingdom) were based in the United States. Prevalence of definite GP (symptoms plus delayed gastric emptying) ranged from 13.8 to 267.7 per 100,000 adults, and incidence was 1.9-6.3 per 100,000 person-years. The estimated 10-year cumulative incidence of GP in type 1 diabetes (DM) and type 2 DM was 5.2% and 1.0%, respectively. Across studies, GP was more common among female patients and those with DM. Rates of hospitalizations and emergency department visits for GP are increasing, ranging from 2- to 18-fold over approximately 2 decades. Mortality rates for patients with possible or definite GP were higher compared with the general population, with primary causes of death in GP being cardiovascular, respiratory failure, and malignancy. Multiple studies observed improved inpatient mortality over the mid-1990s to late 2000s. Limitations include the case identification in most studies (76.9%) used solely International Classification of Diseases codes or clinical record diagnoses; 2 studies (15.4%) used objective evaluation to diagnose GP. Only 4 studies (30.8%) used non-specialized community databases; the remaining 9 studies used inpatient, emergency department, or disease-specific databases. CONCLUSIONS: There is a paucity of high-quality, demographically diverse, and population-based studies to accurately describe the epidemiology of GP. Future studies with valid gastric emptying measurement are needed to better characterize the epidemiology and natural history of GP.

Factors associated with successful weight loss after liraglutide treatment for obesity.

AIM: To identify patient factors, including gastrointestinal functions, that are predictive or associated with weight loss in response to once-daily 3 mg liraglutide administered subcutaneously (SQ) or placebo in obesity. METHODS: One hundred and thirty-six obese adults (87% female) were randomized in a placebo-controlled, 16-week trial of liraglutide, escalated to 3 mg administered SQ daily. Gastrointestinal functions were measured at baseline and 16 weeks: gastric emptying of solids (GET1/2 ); fasting and postprandial gastric volumes; kcal ingested during ad libitum buffet meal and the nutrient drink test. GET1/2 was also measured at 5 weeks. A multiple variable regression model examined variables associated with weight loss of more than 4 kg at 16 weeks. A parsimonious model using backward selection identified the final model. RESULTS: Weight loss of more than 4 kg at 16 weeks occurred in 71% of liraglutide- and 16% of placebo-treated patients. In all participants combined, parameters univariately associated with a weight loss of more than 4 kg were GET1/2 at 5 and 16 weeks, weight loss at 5 weeks and kcal intake during the buffet meal at 16 weeks. The final parsimonious model (area under the receiver operator characteristics [AUROC] curve = 0.832) identified that factors associated with more than 4-kg weight loss were GET1/2 at 5 weeks (OR = 2.505; 95% CI: 1.57-3.997) per 50 minutes and kcal intake during ad libitum meal at 16 weeks (OR = 0.721; 95% CI: 0.602-0.864) per 100 kcal. Among only the 60 liraglutide-treated subjects, kcal intake at 16 weeks was associated with 4-kg weight loss (AUROC = 0.757). CONCLUSIONS: Slower GET1/2 and weight loss at 5 weeks predicted a weight loss of more than 4 kg at 16 weeks in all participants. Among liraglutide-treated adults, weight loss of more than 4 kg was associated with ad libitum meal kcal intake at 16 weeks.

Defining the Long-Term Clinical Course and Need for Repeat Dilation for Patients With Schatzki Rings.

Schatzki rings (SRs) are a well-known cause of intermittent solid-food dysphagia.1 Although some patients sustain improvement after 1 endoscopic dilation, others require repeated dilations for recurrent symptoms.2-4 SRs are believed to be distinct from strictures caused by gastroesophageal reflux disease. SRs are sharply localized lesions with clearly defined margins, whereas peptic strictures have a more gradual transition between normal and abnormal esophagus to produce a funnel-shaped narrowing.5,6 Consequently, it has been assumed that repeat dilation is less common in SRs dissimilar from medically untreated peptic strictures. The study aim was to identify clinical and radiologic predictors for repeated esophageal dilations in patients with SRs and to assess if peptic stricture-like characteristics of rings correspond to need for repeat dilation.

Severity of dysphagia is associated with hospitalizations and mortality in patients with Parkinson's disease.

BACKGROUND: Aspiration pneumonia is the commonest cause of hospitalizations and death in patients with Parkinson's disease (PD). Among these patients, the relationships between severity of dysphagia, hospitalizations for related complications, and death are not robustly defined. Our aim was to characterize the relationship between PD-related oropharyngeal dysfunction and clinically relevant outcomes. METHODS: Retrospective cohort study of 312 patients with PD at a tertiary center who underwent videofluoroscopic swallow studies conducted by expert therapists between 2010 and 2015. Level of swallowing function was represented using the 7-point Functional Oral Intake Scale (FOIS) (7 = normal function). Significance and relative risk calculations utilized Poisson regression. Time to composite outcome of first hospitalization or death was summarized using Kaplan-Meier curve with log-rank test. KEY RESULTS: One hundred thirty eight patients had a recorded FOIS score. The prevalence of oropharyngeal dysfunction was 76.1%. The median duration of follow-up was 26.8 months. In multivariate analyses, patients with FOIS 5 (RR = 2.01 [95% CI: 1.22, 3.32]), FOIS 3 (RR = 2.78 [95% CI: 1.75, 4.40]), and FOIS 1 (RR = 2.50 [95% CI: 1.49, 4.20]) were significantly associated with increased risk of hospitalization or death compared to FOIS 7 after co-variate adjustments. GERD was also associated with a significant increased risk of hospitalization or death (RR = 1.28 [95% CI: 1.01, 1.64]). Time to first hospitalization or death was shorter in patients with lower FOIS scores (p < 0.00005). CONCLUSIONS AND INFERENCES: Severity of oropharyngeal dysphagia, as measured by the FOIS, is associated with poorer survival and shorter time to hospitalization for dysphagia-related complications, pneumonia, or death in PD.