Efficacy and safety of semaglutide 2.4 mg by race and ethnicity: A post hoc analysis of three randomized controlled trials.

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of semaglutide 2.4 mg, a glucagon-like peptide-1 receptor agonist, by race and ethnicity, across three phase 3 trials. METHODS: The Semaglutide Treatment Effect in People with Obesity (STEP) clinical trials evaluated the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg. Here, STEP 1 and 3 data were pooled for analysis; STEP 2 data were examined separately. All analyses were conducted using data from racial and ethnic subgroups. The primary outcome was the estimated treatment difference in percent body weight change for semaglutide 2.4 mg versus placebo. RESULTS: Participants reported race as White (STEP 1 and 3, 75.3%; STEP 2, 59.4%), Black (8.8%; 8.9%), Asian (10.6%; 27.3%), or other racial group (5.3%; 4.4%); and ethnicity as Hispanic or Latino (13.9%; 11.9%) or not Hispanic or Latino (83.9%; 88.1%). There were no significant interactions between treatment effect and race (STEP 1 and 3: p ≥ 0.07; STEP 2: p ≥ 0.15) or ethnicity (p ≥ 0.40; p ≥ 0.85). The safety of semaglutide 2.4 mg was consistent across subgroups. CONCLUSIONS: The treatment effect of semaglutide was statistically significant versus placebo and clinically relevant across all racial and ethnic subgroups in STEP 1 and 3 and STEP 2. All subgroups across both samples demonstrated good tolerability.

Seventeen years since rimonabant's downfall: reassessing its suicidality risk profile.

Targeting the cannabinoid type 1 receptor (CB1) is a clinically validated antiobesity therapeutic approach. The only such drug approved, rimonabant, was launched in 2006 in Europe but subsequently rejected by the US Food and Drug Administration (FDA) in 2007. The FDA cited the increased risk of suicidality in its opposition to rimonabant's approval, leading to the drug's eventual worldwide withdrawal and the abandonment of this class of therapeutics. Seventeen years later, a new class of CB1-targeting drugs is emerging, but the impact of the 2007 FDA decision remains a formidable obstacle to its clinical development. We revisit the suicidality data presented by the FDA in light of the evolution of suicidality assessment and cross-reference this with the data in the subsequently published clinical trials. We conclude that the publicly available data do not support the FDA's conclusion that the use of rimonabant was associated with an increase in the risk of suicidality.

Interventions for Weight Management in Children and Adolescents: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Body mass index (BMI) of the 95th or greater percentile for age and sex is common among young people, and its prevalence has increased in recent decades. Objective: To examine the benefits and harms of weight management interventions initiated in health care settings among children and adolescents with high BMI. Data Sources: MEDLINE via Ovid, PsycINFO via Ovid, and the Cochrane Central Registry of Controlled Trials through January 12, 2023; ongoing surveillance through January 26, 2024. Study Selection: English-language studies of weight management interventions (behavioral and pharmacologic, including liraglutide, semaglutide, orlistat, and phentermine/topiramate) among children aged 2 to 18 years with high BMI (eg, ≥85th or ≥95th percentile for age and sex) conducted in or recruited from health care settings. Data Extraction and Synthesis: One investigator abstracted data; a second checked for accuracy. Outcomes with sufficient evidence for meta-analysis were pooled using random-effects models. Main Outcomes and Measures: BMI and other weight-related outcomes, cardiometabolic measures, quality of life, physical activity, dietary pattern scores, and harms. Results: Fifty-eight randomized clinical trials (RCTs) were included (N = 10 143). Behavioral interventions were associated with small reductions in BMI and other weight outcomes after 6 to 12 months (28 RCTs [n = 4494]; mean difference in change between groups, -0.7 [95% CI, -1.0 to -0.3]). Larger effects were seen in interventions with higher contact hours and that offered physical activity sessions. Reporting was sparse for outcomes other than BMI, with few significant findings. Semaglutide and phentermine/topiramate had the largest effects on BMI (eg, 1 RCT [n = 201] for semaglutide; mean difference, -6.0 [95% CI, -7.3 to -4.6]). The very few studies that evaluated outcomes after medication discontinuation showed immediate weight regain. Gastrointestinal adverse effects were common with liraglutide, semaglutide, and orlistat. Serious adverse effects were rare, but no studies had follow-up longer than 17 months. Conclusions and Relevance: In the short term, weight management interventions led to lower BMI in children and adolescents, with no evidence of serious harm. Evidence is lacking about how weight management interventions affect BMI beyond 1 year and after medication discontinuation and about longer-term effects on other outcomes.

Rhabdomyolysis secondary to a weight-loss prescription.

We present a case of a case of a man in his 70s on multiple medications (including treatment of ischemic heart disease and diabetes who developed significant rhabdomyolysis, complicated by acute kidney injury (AKI) and encephalopathy, while using a compounded medication for weight loss. The patient was admitted to the intensive care unit and progressed favourably after haemodialysis and supportive care. Information regarding the ingestion of weight-loss drugs was unknown at the time of admission and was only discovered after resolution of encephalopathy, raising the possibility of toxin-associated rhabdomyolysis. This case emphasises the need for a thorough clinical history and scrutiny of the safety of weight-loss prescriptions, including preparations that comprise a combination of drugs and supplements that may adversely interact with chronic medications, especially in polymedicated patients.

Semaglutide for management of obesity in adolescents: efficacy, safety, and considerations for clinical practice.

PURPOSE OF REVIEW: The purpose of this review is to describe the existing limited data related to the use of semaglutide in adolescents with obesity, supplementing with findings from adult studies of semaglutide use. RECENT FINDINGS: Semaglutide, as a once weekly subcutaneous injection for weight management, effectively reduces body mass index (BMI) while improving hyperglycemia, elevated alanine aminotransferase levels, hyperlipidemia, and quality of life in youth with obesity. As of this review, only one large randomized clinical trial of semaglutide in youth has been completed, with a follow-up duration of 68 weeks. Thus, long-term data on the safety in adolescents is limited, particularly regarding the risks of cholelithiasis, pancreatitis, suicidal ideation, and disordered eating. Due to the cost of semaglutide, particularly in the United States, limited cost effectiveness analyses have demonstrated unfavorable incremental cost-effectiveness ratios for semaglutide relative to phentermine-topiramate as an alternative antiobesity medication in adolescents. SUMMARY: Semaglutide represents an important advance in the pediatric obesity management, with clear short-term reductions in BMI and improvement in metabolic parameters. However, its long-term safety and efficacy for youth with obesity remain to be demonstrated. Additional research is needed to assess trends in utilization and adherence to minimize the risk of worsening socioeconomic disparities in pediatric obesity.

The association between weight loss medications and cardiovascular complications.

OBJECTIVE: Obesity and its cardiovascular complications are major causes of morbidity and mortality. Little is known in real-world settings about the effect of newly approved antiobesity medications (AOMs) on cardiovascular complications among patients with obesity. METHODS: This retrospective cohort study examined the association between newly approved AOM use and cardiovascular events among Medicare patients with obesity using data from 2020 to 2022. Patient age, gender, comorbidity scores, socioeconomic status, and baseline cardiovascular comorbidities were compared descriptively. Subgroup analysis compared variables by medication type. Relative risk and absolute risk of cardiovascular disease (CVD) events were estimated using Cox and Aalen regression models. RESULTS: The analysis included 5926 patients treated with semaglutide and tirzepatide, including Ozempic (5404 patients), Wegovy (375 patients), or Mounjaro (147 patients). Hypertension, type 2 diabetes, and hyperlipidemia were the most common comorbidities. For patients with AOMs, less incidence of heart failure (4.89% vs. 6.13%, p < 0.0001), atrial fibrillation (3.83% vs. 5.17%, p < 0.0001), arrhythmia (3.59% vs. 4.14%, p < 0.0153), and peripheral vascular disease (3.44% vs. 2.94%, p < 0.0395) was found versus patients without AOMs. Patients receiving AOMs showed an 8% risk reduction in any CVD. Protective effect on CVD was apparent over the first 375 days. CONCLUSIONS: Results suggest that utilization of AOMs effectively alleviates the high prevalence of CVD.

Efficacy and safety of orlistat in controlling the progression of prediabetes to diabetes: A meta-analysis and systematic review.

BACKGROUND: The aim of this study is to examine the impact of the Orlistat on glucose levels and glucose tolerance in individuals with prediabetes, as well as assess its efficacy and safety in preventing the progression to diabetes. METHODS: For achieving the appropriate randomized controlled trials, we enrolled the public datas from the following electronic databases: The Cochrane library, Embase, China National Knowledge Infrastructure, VIP, Wan-Fang, and China Biology Medicine disc. The article focused on the orlistat intervention of glucose tolerance and glycemic status in prediabetic patients. We restricted the publication time from the creation to May 2023. RESULTS: Six subjects were included in the study, with a total of 1076 participants (532 in the control group vs 544 in the experimental group). The results indicated that the orlistat can reduce the fasting blood glucose [relative risk (RR) = -2.18, 95% confidence intervals (CI) (-2.471, -1.886)], as well as the 2 hour postprandial blood glucose [RR = -1.497, 95% CI (-1.811, -1.183)]. Furthermore, it can prevent the impaired glucose tolerance patients to type 2 diabetes mellitus [RR = 0.605, 95% CI (0.462, 0.791)], and reversal the impaired glucose tolerance [RR = 2.092, 95% CI (1.249, 3.503)]. CONCLUSIONS: In prediabetic people, the orlistat can control weight, reduce the fasting blood glucose and the 2 hour postprandial blood glucose, and then delay the progression of diabetes. However, due to the quantitative restrictions, additional high-quality study needs to be conducted to improve the reliability of the results.

Exploring the association between suicidal thoughts, self-injury, and GLP-1 receptor agonists in weight loss treatments: Insights from pharmacovigilance measures and unmasking analysis.

INTRODUCTION: The study addresses concerns about potential psychiatric side effects of Glucagon-like peptide-1 receptor agonists (GLP-1 RA). AIM: The aim of this work was to analyse adverse drug reports (ADRs) from the Food and Drug Administration Adverse Events Reporting System (FAERS) using metformin and orlistat as comparators. METHODS: Descriptive and pharmacovigilance disproportionality analyses was performed. RESULTS: A total of 209,354 ADRs were reported, including 59,300 serious cases. Of those, a total of 5378 psychiatric disorder cases, including 383 'serious' cases related to selected ADRs were registered during 2005-2023. After unmasking, 271 cases where individual GLP-1 RA were implicated showing liraglutide (n = 90; Reported Odds Ratio (ROR) = 1.64), exenatide (n = 67; ROR = 0.80), semaglutide (n = 61; ROR = 2.03), dulaglutide (n = 45; ROR = 0.84), tirzepatide (n = 5; ROR = 1.76) and albiglutide (n = 2; ROR = 0.04). A greater association between these ADRs with metformin was observed, but not orlistat. With regards to selected preferred terms (PTs), 42 deaths including 13 completed suicides were recorded. Suicidal ideation was recorded in n = 236 cases for 6/7 GLP-1 RA (excluding lixisenatide). DISCUSSION: Suicide/self-injury reports pertaining to semaglutide; tirzepatide; and liraglutide were characterised, although lower than metformin. It is postulated that rapid weight loss achieved with GLP-1 RA can trigger significant emotional, biological, and psychological responses, hence possibly impacting on suicidal and self-injurious ideations. CONCLUSIONS: With the current pharmacovigilance approach, no causality link between suicidal ideation and use of any GLP-1 RA can be inferred. There is a need for further research and vigilance in GLP-1 RA prescribing, particularly in patients with co-existing psychiatric disorders.

Effectiveness and safety of drugs for obesity.

Recent publicity around the use of new antiobesity medications (AOMs) has focused the attention of patients and healthcare providers on the role of pharmacotherapy in the treatment of obesity. Newer drug treatments have shown greater efficacy and safety compared with older drug treatments, yet access to these drug treatments is limited by providers' discomfort in prescribing, bias, and stigma around obesity, as well as by the lack of insurance coverage. Now more than ever, healthcare providers must be able to discuss the risks and benefits of the full range of antiobesity medications available to patients, and to incorporate both guideline based advice and emerging real world clinical evidence into daily clinical practice. The tremendous variability in response to antiobesity medications means that clinicians need to use a flexible approach that takes advantage of specific features of the antiobesity medication selected to provide the best option for individual patients. Future research is needed on how best to use available drug treatments in real world practice settings, the potential role of combination therapies, and the cost effectiveness of antiobesity medications. Several new drug treatments are being evaluated in ongoing clinical trials, suggesting that the future for pharmacotherapy of obesity is bright.

An overview of therapeutic options of obesity management in India: the Integrated Diabetes and Endocrinology Academy (IDEA) 2023 Congress update.

INTRODUCTION: With newer anti-obesity medications (AOMs) being introduced at a rapid pace, it is prudent to make a concise and updated clinical practice document that may help busy clinicians in daily clinical practice. A group of metabolic physicians, diabetologists, endocrinologists, and bariatric surgeons assembled during the Integrated Diabetes and Endocrine Academy 2023 Congress (IDEACON, July 2023, Kolkata, India) to compile an update of pharmacotherapeutic options for managing people with obesity in India. AREAS COVERED: After an extensive review of the literature by experts in different domains, this update provides all available information on the management of obesity, with a special emphasis on both currently available and soon-to-be-available AOMs, in people with obesity. EXPERT OPINION: Several newer AOMs have been shown to reduce body weight significantly, thus poised to make a paradigm shift in the management of obesity. While the tolerability and key adverse events associated with these AOMs appear to be acceptable in randomized controlled trials, pharmacovigilance is vital in real-world settings, given the absence of sufficiently long-term studies. The easy availability and affordability of these drugs is another area of concern, especially in developing countries like India.

The association between previous use of anti-obesity medication and semaglutide weight loss outcomes.

AIMS: To compare weight loss outcomes between patients starting semaglutide who had previously been on another anti-obesity medication (AOM) compared to those who were AOM-naïve. MATERIALS AND METHODS: We performed a retrospective study in patients with overweight or obesity taking semaglutide for weight loss for a duration of 3 to 12 months. Our primary endpoint was assessment of percentage of total body weight loss (TBWL) in patients who started semaglutide as their first AOM (AOM-naïve) compared to those who started semaglutide and had previously taken another AOM (non-AOM-naïve). The secondary outcome was a comparison of the proportions of patients achieving ≥5%, ≥10%, ≥15% and ≥20% TBWL between the groups. Our endpoints were analysed using independent t-tests and ANOVA/ANCOVA for continuous variables and Pearson's test for categorical variables. RESULTS: This study included 305 patients. Outcomes of semaglutide treatment were superior in AOM-naïve patients (n = 231) compared to non-AOM-naïve patients (n = 74) at 3 (6.3% vs. 3.8%), 6 (10.6% vs. 6.7%), 9 (14.0% vs. 9.1%) and 12 months (14.3% vs. 10.6%; p < 0.0001 at 3, 6 and 9 months, and p = 0.01 at 12 months). A greater proportion of patients in the AOM-naïve group achieved a TBWL ≥ 15% (48% vs 21%; p = 0.02) and ≥20% (27% vs 4% p < 0.01) at 12 months. CONCLUSION: The use of semaglutide in patients with previous intake of other AOMs was associated with inferior weight loss outcomes in comparison to patients who were AOM-naïve.

Effects of meal type on the bioavailability of vutiglabridin, a novel anti-obesity agent, in healthy subjects.

Vutiglabridin, which affects the pharmacokinetics (PKs) of food, is currently under clinical development for the treatment of obesity. This study aimed to evaluate the effects of low- and high-fat meals on PKs of vutiglabridin in healthy male subjects. A randomized, open-label, single-dose, three-period, six-sequence crossover study was conducted. The subjects received a single oral dose of vutiglabridin 480 mg in a fasted state, 30 min after the intake of a low-fat meal (total 500-600 kcal, fat content 100-125 kcal) and high-fat meal (total 800-1000 kcal, fat content 500-600 kcal), with a 21-day washout period. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve to the last measurable timepoint (AUClast ) were calculated. After intake of low- and high-fat meals, systemic exposure to vutiglabridin was increased, and the time to reach Cmax (Tmax ) was delayed compared to that in the fasted state. The GMRs (90% CIs) of low-fat meal to fasted state for Cmax and AUClast were 2.14 (1.76-2.60) and 2.15 (1.92-2.42), respectively, and those of high-fat meal to fasted state were 3.07 (2.53-3.72) and 3.00 (2.67-3.37), respectively. The median Tmax was delayed by 1.5 h in both fed states compared with that in the fasted state. The study drug was well-tolerated after administration in both the fed and fasted states. Food ingestion substantially increased the extent of oral vutiglabridin absorption in healthy subjects, and this enhancement increased with the fat content of the meal.

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.