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The case reports a woman in her 70s, with type 2 diabetes and chronic kidney disease in G4 stage. The patient had elevated HbA1c, and she was switched from linagliptin, a dipeptidyl peptidase 4 inhibitor, to dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA). Thereafter, the HbA1c level decreased; however, since the dulaglutide supply became a problem, the patient was switched to tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA. To date, no clinical studies have evaluated the efficacy and safety of switching from GLP-1RA to GIP/GLP-1RA, but we report this case because efficacy was observed in this patient. The therapeutic effects after switching to tirzepatide included decrease in HbA1c, increase in eGFR, and decrease in BUN, when compared to when dulaglutide was used. A change from dulaglutide to tirzepatide, could inhibit renal impairment progression and improve renal function.

Given the limited head-to-head comparison of cardiovascular and renal outcomes between liraglutide and dulaglutide, our study aimed to investigate the clinical outcomes between dulaglutide and liraglutide in a real-world setting. In this new-user design, comparative and retrospective cohort study, patients with type 2 diabetes mellitus with prescription for GLP-1RAs from January 1, 2016 to December 31, 2022 (n = 8,278) were included. Primary outcome was composite cardiovascular outcomes which was composed of cardiovascular death, non-fatal myocardial infarction, and non-fatal ischemic stroke. The composite renal outcome was also interested, including new macroalbuminuria, doubling of serum creatinine, worsening of estimated glomerular filtration rate (eGFR), and progression to dialysis. A total of 3,210 subjects receiving liraglutide and 5,068 subjects receiving dulaglutide were identified. In the adjusted cohort by applying inverse probability of treatment weighting, the incidence of composite cardiovascular outcomes was 18.4 and 18.7 events per 1000 person-years in the liraglutide and dulaglutide groups, respectively. The risk of cardiovascular outcomes did not significantly differ between groups (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.85-1.15). Moreover, the risk of composite renal outcomes was also comparable between groups (subdistribution HR 1.07, 95% CI 0.995-1.16). Liraglutide and dulaglutide demonstrated comparable cardiovascular and renal outcomes in a real-world setting., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Tobacco use represents the leading preventable risk factor for premature deaths worldwide. A meta-analysis of 74 epidemiological studies, including 3.2 million individuals with type 2 diabetes mellitus (T2DM) from 33 countries, reported a pooled prevalence of smoking of 20.8% among individuals with T2DM. Cigarette smoking further aggravates existing deleterious vascular effects of T2DM. Namely, chronic hyperglycemia and exposure to cigarette smoke cause additive injurious effect on the endothelium, leading to an acceleration of vascular complications seen in persons with T2DM and tobacco use disorders (TUD). In a recent study, Wang and colleagues found that semaglutide use was associated with a significantly lower risk for medical encounters for TUD, when compared to other antidiabetic drug classes; indeed, this effect was strongest compared with insulins and weakest compared with other glucagon-like peptide-1 receptor agonists. Semaglutide was associated with reduced smoking cessation medication prescriptions and counseling. Similar findings were observed irrespective of the presence of obesity. Therefore, semaglutide use might be useful in terms of smoking cessation among individuals with T2DM, thus offering an additional benefit for this constantly growing population. However, those interesting findings should be confirmed through dedicated, large-scale randomized controlled trials.

Aims: To investigate the impact of baseline characteristics on the efficacy of once-weekly subcutaneous semaglutide 0.5 and 1.0 mg in participants with type 2 diabetes (T2D) from the SUSTAIN China trial., Methods: In this post hoc analysis, data for semaglutide 0.5 and 1.0 mg versus sitagliptin 100 mg were analysed in the total (n = 868) and Chinese-only (n = 605) populations. Changes from baseline to end of treatment (EOT) in glycated haemoglobin (HbA1c) and body weight were analysed by baseline age, sex, body mass index, HbA1c, diabetes duration, and homeostatic model assessment of β-cell function (HOMA-β) tertile. Proportions of participants achieving HbA1c <7.0% (53 mmol/mol) by baseline HbA1c, change from baseline to EOT in standard deviation of seven-point self-monitored plasma glucose (SMPG), derived time-in-range (dTIR) of seven-point SMPG at Week 30, and HOMA-β ratio to baseline at Week 30 were assessed for both populations., Results: In both populations the efficacy of once-weekly subcutaneous semaglutide 0.5 and 1.0 mg versus sitagliptin was not significantly affected by most of the baseline characteristics studied. The proportion of participants achieving the target HbA1c <7% was not affected by baseline HbA1c (p interaction  > 0.05). SMPG fluctuation and dTIR indicated less glucose variability in participants treated with semaglutide 0.5 and 1.0 mg versus sitagliptin, and the HOMA-β ratios to baseline at EOT were greater with semaglutide 0.5 and 1.0 mg versus sitagliptin (p < 0.05)., Conclusions: These results support the effectiveness of once-weekly subcutaneous semaglutide 0.5 and 1.0 mg across a broad range of baseline characteristics, in participants with T2D from SUSTAIN China., (© 2024 John Wiley & Sons Ltd.)

Aim: To analyse data from the All of Us Research Program to evaluate the real-world application and long-term effectiveness of semaglutide in treating type 2 diabetes and obesity patients in a large population., Materials and Methods: We identified patients prescribed semaglutide and analysed differences in route of administration and the time on semaglutide. For individuals diagnosed with obesity, we measured changes in body mass index (BMI) and weight from baseline, while measured changes in HbA1c for those patients with type 2 diabetes. We also examined the occurrence of newly diagnosed common adverse events from taking semaglutide., Results: For 3739 semaglutide patients, those on injectable semaglutide (3364 patients) averaged 301.54 days on the medication, with 20.36% having no end date, while those on oral semaglutide (435 patients) averaged 172.48 days, with 24.60% having no end date. We found average decreases of 1.54 kg/m 2 in BMI, 4.65 kg in weight and 0.75% in HbA1c for semaglutide users. The decreases were larger in participants taking injectable formulation, probably because of higher starting values. Over time, improvements in these outcomes diminished, but the values remained significantly lower than baseline levels. Approximately only 1.0% of patients reported newly diagnosed common adverse events., Conclusions: Consistent with clinical trial findings, this real-world data analysis showed that semaglutide was well tolerated and that, for a large population, it effectively reduced BMI, body weight and HbA1c, albeit to smaller magnitudes than observed in clinical trials. These findings provide valuable insights into real-world experience and the long-term effectiveness of semaglutide., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Importance: Obesity is associated with numerous psychosocial complications, making psychiatric safety a consideration for treating people with obesity. Few studies have investigated the psychiatric safety of newly available antiobesity medications., Objective: To evaluate the psychiatric safety of subcutaneous semaglutide, 2.4 mg, once weekly in people without known major psychopathology., Design, Setting, and Participants: This post hoc analysis of pooled data from the randomized, double-blind, placebo-controlled, multicenter phase 3a STEP 1, 2, and 3 trials (68 weeks; 2018-2020) and phase 3b STEP 5 trial (104 weeks; 2018-2021) included adults with overweight or obesity; STEP 2 participants also had type 2 diabetes. Trial designs have been published previously., Interventions: Semaglutide, 2.4 mg, vs placebo., Main Outcomes and Measures: Depressive symptoms and suicidal ideation/behavior were assessed using the Patient Health Questionnaire (PHQ-9) and Columbia-Suicide Severity Rating Scale, respectively. Psychiatric and nervous system disorder adverse events were investigated., Results: This analysis included 3377 participants in the STEP 1, 2, and 3 trials (2360 women [69.6%]; mean [SD] age, 49 [13] years) and 304 participants in STEP 5 (236 women [77.6%]; mean [SD] age, 47 [11] years). In the STEP 1, 2, and 3 trials, mean (SD) baseline PHQ-9 scores for the semaglutide, 2.4 mg, and placebo groups were 2.0 (2.3) and 1.8 (2.3), respectively, indicating no/minimal symptoms of depression. PHQ-9 scores at week 68 were 2.0 (2.9) and 2.4 (3.3), respectively; the estimated treatment difference (95% CI) between groups was -0.56 (-0.81 to -0.32) (P < .001). Participants treated with semaglutide vs placebo were less likely to shift (from baseline to week 68) to a more severe category of PHQ-9 depression (odds ratio, 0.63; 95% CI, 0.50-0.79; P < .001). Based on the Columbia-Suicide Severity Rating Scale, 1% or fewer of participants reported suicidal ideation/behavior during treatment, with no differences between semaglutide, 2.4 mg, and placebo. Psychiatric disorder adverse events were generally balanced between groups. Similar results were observed in STEP 5., Conclusions and Relevance: The results of this post hoc analysis suggest that treatment with semaglutide, 2.4 mg, did not increase the risk of developing symptoms of depression or suicidal ideation/behavior vs placebo and was associated with a small but statistically significant reduction in depressive symptoms (not considered clinically meaningful). People with obesity should be monitored for mental health concerns so they can receive appropriate support and care., Trial Registration: ClinicalTrials.gov Identifiers: STEP 1 (NCT03548935), 2 (NCT03552757), 3 (NCT03611582), and 5 (NCT03693430).

Aims: To evaluate the efficacy and safety of oral semaglutide for type 2 diabetes mellitus (T2DM) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD)., Materials and Methods: This was a single-arm, multicentre, prospective study. Among 80 consecutive patients with MASLD and T2DM who newly received oral semaglutide, 70 completed 48-week oral semaglutide treatment as scheduled and were included in an efficacy analysis. Dose adjustments of oral semaglutide were determined by each physician while monitoring efficacy and adverse events., Results: Significant improvements in body weight, liver enzymes, lipid profile, and glycaemic control were found at 48 weeks compared with baseline values (all p < 0.01). Controlled attenuation parameter values significantly decreased from baseline to 48 weeks (p < 0.01). Changes in alanine aminotransferase concentrations (r = 0.37, p < 0.01) and controlled attenuation parameter values (r = 0.44, p < 0.01) were significantly correlated with changes in body weight. Liver fibrosis markers, such as type IV collagen 7S, Wisteria floribunda agglutinin-positive Mac-2-binding protein, fibrosis-4 index, and liver stiffness measurement, significantly decreased from baseline to 48 weeks (all p < 0.01). The most common adverse events were Grades 1-2 transient gastrointestinal symptoms, such as nausea (23 patients, 28.8%), dyspepsia (12, 15.0%) and appetite loss (4, 5.0%)., Conclusions: Oral semaglutide treatment for T2DM in patients with MASLD leads to an improvement in liver steatosis and injury, surrogate markers of fibrosis, diabetic status, and lipid profile, and reduces body weight., (© 2024 John Wiley & Sons Ltd.)

Aims/introduction: PIONEER REAL Japan was a non-interventional prospective study of oral semaglutide in adults with type 2 diabetes in Japanese clinical practice., Materials and Methods: Adults naïve to injectable glucose-lowering therapies initiated oral semaglutide in routine clinical practice and were followed for 34-44 weeks. The primary endpoint was change in glycated hemoglobin (HbA 1c ) from baseline to end of study; the co-primary endpoint was number of adverse events (AEs). Secondary endpoints included change in bodyweight from baseline to end of study. Analyses were also carried out for subgroups aged <75 and ≥75 years., Results: A total of 624 participants initiated oral semaglutide; 578 completed the study. Mean baseline HbA 1c and bodyweight were 7.7% and 72.4 kg, respectively. At end of study, estimated change (95% confidence interval [CI]) in HbA 1c from baseline was -0.7 percentage points (-0.77, -0.61) overall, -0.8 percentage points (-0.86, -0.67) in the <75 years subgroup and -0.5 percentage points (-0.68, -0.41) in the ≥75 years subgroup (all P < 0.0001). Estimated change (95% CI) in bodyweight was -2.8 (-3.19, -2.50) kg overall, -2.9 (-3.38, -2.49) kg in the <75 years subgroup and - 2.7 (-3.18, -2.14) kg in the ≥75 years subgroup (all P < 0.0001). AEs occurred in 161 (25.8%) participants: 99 of 423 (23.4%) and 62 of 201 (30.8%) participants in the <75 and ≥75 years subgroups, respectively. Gastrointestinal AEs were the AEs most frequently leading to oral semaglutide discontinuation., Conclusions: In routine clinical practice, HbA 1c and bodyweight were significantly reduced from baseline in adults initiating oral semaglutide, including those aged ≥75 years, with no new safety concerns., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Purpose: Novel therapies for diabetes have potent effects on glycemic control, obesity, and cardiovascular risk reduction, but some, including the popular drug semaglutide, have also been implicated in worsening of diabetic retinopathy (DR). Given the ubiquity of these new agents, understanding the risks to vision is important. Here, we review the data for several newly available agents in terms of systemic efficacy and retinal safety., Methods: Literature review., Results: Novel antihyperglycemic treatments include incretin mimetics and enhancers, sodium-glucose cotransporter inhibitors, long-acting insulins, and insulin delivery systems. All improve glycemic control, and some have been shown to reduce major cardiovascular outcomes. In a pivotal trial, semaglutide was associated with approximately 75% increased risk of DR worsening. The novel long-acting insulin icodec, formulated for once weekly dosing, showed increased risk of DR worsening over a once daily insulin. No other recent antihyperglycemic agent was associated with DR worsening, although following the semaglutide trials, nearly all studies excluded patients with preexisting DR. Cases of DR worsening were rare in all instances. Dedicated safety studies for semaglutide in DR are currently underway., Conclusion: For most patients being considered for treatment with a novel antihyperglycemic agent, benefits on systemic metabolic and cardiovascular health are very likely to outweigh potential retinal harms. Although the true risks of the new agents on DR are unclear because their safety data come from secondary end points, the most vulnerable patients are those with preexisting high-risk DR, poor baseline glycemic control, and using insulin., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Background & Objectives: Obesity is a common comorbidity in heart failure, yet effective pharmacological options for weight loss in these patients are limited. Semaglutide, a glucagon-like peptide 1 receptor agonist, has shown promise for weight reduction in obese adults. This study aims to evaluate semaglutide's impact on weight loss, functional status, and clinical outcomes in obese patients with heart failure., Methods: A retrospective analysis was conducted on all consecutive obese (BMI > 30 kg/m²) patients with heart failure at the University Hospital Bonn outpatient clinic from July 2019 to July 2022. Propensity score matching paired patients receiving semaglutide as an add-on therapy (SEMA) with those on medical therapy alone (Control)., Results: Among 1,942 patients with heart failure screened, 26 matched pairs were identified. At one year, the SEMA group exhibited significant weight loss, with a mean BMI reduction of -2.91 kg/m² (95% CI: -4.27 to -1.55; p < 0.001), while the control group showed a non-significant mean change of -0.41 kg/m² (95% CI: -1.08 to 0.26; p = 0.22). The difference in BMI between the two groups was statistically significant (mean difference: 3.42 kg/m², 95% CI: 1.43 to 5.42; p = 0.001). Improvements by at least one NYHA class were observed in 65% of the SEMA group (p < 0.001) compared to 15% of the control group (p = 0.18). The SEMA group also showed a significant increase in 6-minute walk distance (6MWD), with a mean difference of 75 m between the groups at one year (95% CI: 0.53 to 150.02; p = 0.049). NT-proBNP levels significantly decreased in the SEMA group (p < 0.001) compared to the control group (p = 0.78), with a statistically significant difference in NT-proBNP between the groups (p = 0.048). Both improvements in 6MWD and reductions in NT-proBNP were significantly correlated with BMI percentage reductions., Conclusions: Semaglutide was associated with significant weight reduction in obese patients with heart failure, accompanied by improved NYHA classification and 6-minute walk distance. Larger, multi-center trials and prospective, randomized controlled trials are warranted. These studies should focus on assessing long-term outcomes, optimizing dosage, and exploring the potential cardiovascular benefits beyond weight reduction., (© 2024. The Author(s).)

This large community-based cohort study investigates the impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), specifically Liraglutide and Semaglutide, on the risk of developing psychiatric conditions such as depression, anxiety, and suicidal behaviors in patients with obesity. Utilizing post-marketing data, this research compares patients prescribed GLP-1 RAs (cases) with those not taking these medications (controls). The analysis spanned data from January 1, 2015, to December 31, 2023. To minimize selection bias, we employed 1:1 propensity score matching to account for demographic factors such as age, sex, race, and comorbidities. After matching, the study included 162,253 case and control patients. This study showed a significant association between GLP-1 RA treatment and an 98% increased risk of any psychiatric disorders. Notably, patients on GLP-1 RAs exhibited a 195% higher risk of major depression, a 108% increased risk for anxiety, and a 106% elevated risk for suicidal behavior. These findings underscore the critical need for physicians to thoroughly assess patient history before prescribing GLP-1 RAs and highlight the urgent requirement for further prospective clinical trials to fully understand the implications of GLP-1 RA use on mental health in the obese patient population., (© 2024. The Author(s).)

Aim/introduction: The recent adverse reactions associated with semaglutide have led the Food and Drug Administration (FDA) to issue a "black box warning", and it is necessary to analyze all reports of adverse reactions to improve the safety of its clinical use., Materials and Methods: Statistical analyses and signal mining were performed by obtaining the adverse event reports related to semaglutide in the FAERS database from the first quarter of 2018 to the fourth quarter of 2023. We used disproportionality and Bayesian analysis to examine clinical and demographic attributes, trends reported quarterly, and contrasts between two distinct indications (obesity and type 2 diabetes)., Results: We found 10 unexpected adverse signals related to "pancreatic cancer", "intestinal obstruction", "cholecystitis", and "polycystic ovary" and both the two different indications had the same serious adverse reaction events occurring., Conclusions: This study identified many unexpected signals of serious adverse reactions, suggesting the importance of continuous post-marketing surveillance of semaglutide to understand its potential risks., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aim: Recently, the development of the oral glucagon-like peptide-1 receptor agonist semaglutide has drawn a great deal of attention. This study aimed to compare the effectiveness of oral glucagon-like peptide-1 receptor agonist semaglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors on glycaemic control and several metabolic parameters in patients with type 2 diabetes mellitus over a 6-month period., Methods: Fifty-nine participants were included, and we compared various clinical parameters between before and after switching from DPP-4 inhibitors to oral semaglutide in 'study 1' (pre-post comparison) and set the control group using the propensity score matching method in 'study 2'., Results: In 'study 1', 6 months after the switching, the glycated haemoglobin value was significantly reduced from 7.5% to 7.0%, and the body mass index was also decreased from 29.7 kg/m 2 to 28.8 kg/m 2 . Such effects were more clearly observed in participants whose glycaemic control was poor. In 'study 2', after 1:1 propensity score matching, 51 participants from each group were matched, and glycaemic control as well as body weight management were improved in the switching group compared with the DPP-4 inhibitor continuation group over the 6-month observation period., Conclusion: In this study, including obese participants with poor glycaemic control, switching DPP-4 inhibitors to oral semaglutide showed more beneficial effects on both glycaemic and weight control, irrespective of age, body weight and diabetes duration. Therefore, we should bear in mind that it would be better to start using an oral semaglutide in clinical practice, particularly in obese participants with poor glycaemic control with DPP-4 inhibitors., (© 2024 John Wiley & Sons Ltd.)

Aim: To investigate, through post hoc analysis of nine studies from the SemaglUtide Real-world Evidence (SURE) programme, the safety of once-weekly (OW) semaglutide in adults with type 2 diabetes (T2D) and in subpopulations in routine clinical practice, complementing findings from the phase 3 randomized clinical trial (RCT) SUSTAIN programme., Methods: The SURE studies had a duration of ~30 weeks and included adults with diagnosed T2D treated with OW semaglutide. Safety information, including hypoglycaemic events, were collected and analysed for the total study population and for patient subgroups based on baseline patient characteristics, baseline co-medication and prescriber specialty., Results: Of the total 3505 patients, 24.3% reported adverse events (AEs), with most patients reporting non-serious (22.3%) and mild (17.1%) AEs. AEs mainly belonged to the gastrointestinal disorders system organ class (16.3% of patients). In total, 5.1% of patients reported AEs that led to treatment discontinuation, 0.5% reported serious adverse drug reactions and 0.2% had an AE with a fatal outcome, reported as unrelated to treatment. Overall, 1.1% and 0.1% of patients reported level 2 and 3 hypoglycaemic events, respectively. A higher rate of level 2 hypoglycaemia was observed in patients with baseline microvascular complications treated with insulin versus those on insulin without these complications., Conclusions: Safety data reported in the real-world SURE studies were generally consistent with observations in phase 3 OW semaglutide RCTs. No new safety concerns were identified, highlighting that OW semaglutide is well tolerated by adults with T2D and in subpopulations in routine clinical practice., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To investigate real-world treatment adherence and persistence in people with type 2 diabetes newly initiating oral semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), or a dipeptidyl peptidase-4 inhibitor (DPP-4i)., Methods: This retrospective cohort study used the Merative™ MarketScan® Commercial and Medicare databases. Index date was the first fill for the cohort medication. Adherence was defined as proportion of days covered (PDC) over the 12-month post-index period ('adherent' = ≥0.8). Persistence was number of days until discontinuation, based on a 45-day gap. Results were compared between cohorts using inverse probability treatment weighting., Results: Oral semaglutide (n=5485) and DPP-4i (n=4980) cohorts had similar percentages of people who were adherent (PDC ≥0.8; 41.6 % vs. 42.9 %; P = 0.182) and persistent for ≥9 months (45.0 % vs. 46.3 %; P = 0.185). The DPP-4i cohort used significantly more anti-diabetic medication (ADM) classes over the post-index period (mean±SD: 2.6±1.0 vs. 2.9±1.1, P < 0.001), with 23.2 % filling a GLP-1 RA in the post-period., Conclusions: Adherence and persistence were similar between cohorts. However, there are potential benefits to prescribing oral semaglutide over DPP-4is, including reduced need for additional ADM., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may have neuroprotective effects in patients with type 2 diabetes (T2D). However, their comparative effectiveness in preventing dementia remains uncertain., Objective: To compare the risk for dementia between SGLT2 inhibitors and dulaglutide (a GLP-1 RA)., Design: Target trial emulation study., Setting: Nationwide health care data of South Korea obtained from the National Health Insurance Service between 2010 and 2022., Patients: Patients aged 60 years or older who have T2D and are initiating treatment with SGLT2 inhibitors or dulaglutide., Measurements: The primary outcome was the presumed clinical onset of dementia. The date of onset was defined as the year before the date of dementia diagnosis, assuming that the time between the onset of dementia and diagnosis was 1 year. The 5-year risk ratios and risk differences comparing SGLT2 inhibitors with dulaglutide were estimated in a 1:2 propensity score-matched cohort adjusted for confounders., Results: Overall, 12 489 patients initiating SGLT2 inhibitor treatment (51.9% dapagliflozin and 48.1% empagliflozin) and 1075 patients initiating dulaglutide treatment were included. In the matched cohort, over a median follow-up of 4.4 years, the primary outcome event occurred in 69 participants in the SGLT2 inhibitor group and 43 in the dulaglutide group. The estimated risk difference was -0.91 percentage point (95% CI, -2.45 to 0.63 percentage point), and the estimated risk ratio was 0.81 (CI, 0.56 to 1.16)., Limitation: Residual confounding is possible; there was no adjustment for hemoglobin A 1c levels or duration of diabetes; the study is not representative of newer drugs, including more effective GLP-1 RAs; and the onset of dementia was not measured directly., Conclusion: Under conventional statistical criteria, a risk for dementia between 2.5 percentage points lower and 0.6 percentage point greater for SGLT2 inhibitors than for dulaglutide was estimated to be highly compatible with the data from this study. However, whether these findings generalize to newer GLP-1 RAs is uncertain. Thus, further studies incorporating newer drugs within these drug classes and better addressing residual confounding are required., Primary Funding Source: Ministry of Food and Drug Safety of South Korea., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-3220.

This study aims to systematically review the efficacy and safety of oral semaglutide in the treatment of type 2 diabetes mellitus (T2DM) and provide a basis for the rational use of the drug in clinical practice. From the database's inception until February 2023, a systematic search was conducted in PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang Database, and China Science and Technology Journal Database to identify randomized controlled trials (RCTs) comparing the efficacy of oral semaglutide at dosages of 3, 7, and 14 mg (trial group) against placebo or other positive control drugs (control group) for the treatment of T2DM. Following literature screening and data extraction, the bias risk assessment tool in the Cochrane reviewer handbook 5.1.0 was used to evaluate the literature quality. Meta-analysis was carried out with RevMan 5.4 software. A total of 10 RCTs with 9541 patients were included. The meta-analysis results revealed that compared with placebo or positive control drugs (empagliflozin, sitagliptin, liraglutide, and dulaglutide), oral semaglutide significantly reduced the hemoglobin A1c (HbA1c) in patients (compared to placebo, 3 mg [MD = -0.61%, 95% CI (-0.89, -0.34)], 7 mg [MD = -1.12%, 95% CI (-1.45, -0.79)], 14 mg [MD = -1.08%, 95% CI (-1.32, -0.85)]; compared to positive control drugs (7 mg [MD = -0.26%, 95% CI (-0.38, -0.15)], 14 mg [MD = -0.37%, 95% CI (-0.52, -0.23)]). Oral semaglutide also showed certain advantages over placebo or positive control drugs in terms of weight loss, HbA1c reduction achievement rate, fasting plasma glucose level, and body mass index with overall dose-dependent efficacy. The incidence of nausea, diarrhea, and vomiting caused by oral semaglutide was higher than that of the placebo or positive control drugs, and the incidence of appetite decrease or constipation was higher than that of the placebo. Severe or symptomatic hypoglycemic episodes were reduced compared to positive control drugs. Oral semaglutide has definite clinical benefits of reducing blood glucose, body weight, reducing the risk of hypoglycemia, and with good safety., (© 2024, The American College of Clinical Pharmacology.)

Objective: Semaglutide, a glucagon-like peptide-1 receptor agonist is approved for weight loss and diabetes treatment, but limited literature exists regarding semaglutide use in patients with advanced chronic kidney disease (CKD). Therefore, this project assessed the safety and efficacy of semaglutide among patients with estimated glomerular filtration rate (eGFR) 15-29 mL/min/1.73 m 2 (CKD stage 4), eGFR<15 mL/min/1.73 m 2 (CKD stage 5) or on dialysis., Methods: This is a retrospective electronic medical record based analysis of consecutive patients with advanced CKD (defined as CKD 4 or greater) who were started on semaglutide (injectable or oral). Data was collected between January 2018 and January 2023. Investigators verified CKD diagnosis and manually extracted data. Data were analyzed using Fisher's exact test, paired t test, linear mixed effects models and Wilcoxon signed rank test., Results: Seventy-six patients with CKD 4 or greater who initiated semaglutide were included. Most patients had a history of type 2 diabetes mellitus (96.0%), and most were males (53.9%). The mean age was 66.8 y (SD 11.5) with the mean body mass index was 36.2 (SD 7.5). The initial doses were 3 mg orally and 0.25 mg by injection. Maximum prescribed dose was 1 mg (injectable) in 28 (45.2%) patients and 14 mg (orally) in 2 (14.2%) patients. Patients received semaglutide for a median duration of 17.4 (IQR 0.43, 48.8) months. Forty-eight (63.1%) patients reported no adverse effects associated with the therapy. Mean weight decreased from 106.2 (SD 24.2) to 101.3 (SD 27.3) kg (P < .001). Eight patients (16%) with type 2 diabetes mellitus T2DM discontinued insulin after starting semaglutide. Mean hemoglobin A1c (HbA1c) decreased from 8.0% (SD 1.7) to 7.1% (SD 1.3) (P < .001). Adverse effects were the primary reason for semaglutide discontinuation (37.0%), with nausea, vomiting, and abdominal pain being the most common complaints., Conclusions: Based on this retrospective study semaglutide appears to be tolerated by most individuals with CKD 4 or greater despite associated gastrointestinal side effects similar to those observed in patients with better kidney function and leads to an improvement of glycemic control and insulin discontinuation in patients with T2DM. Modest weight loss (approximately 4.6% of the total body weight) was observed on the prescribed doses. Larger prospective randomized studies are needed to comprehensively assess the risks and benefits of semaglutide in patients with CKD 4 or greater and obesity., Competing Interests: Disclosure Dr Aleksandra Kukla participated in NovoNordisk Advisory Board in 2020 but recieved no personal compensation. Dr Matthew M. Clark, Associate Editor, Obesity. Intellectual Property, Phenomix Science, Inc, Pheno-Diet: Individualized Lifestyle Intervention for Obesity Management Based on Obesity Phenotypes., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosures: Disclosure forms are available with the article online.

Background: The pericoronary fat attenuation index (FAI) has emerged as a novel and sensitive biomarker reflecting the degree of coronary artery inflammation. Semaglutide has been demonstrated to exert a cardiovascular protective effect independent of hypoglycemia; however, its impact on coronary artery inflammation remains elusive. This study aimed to investigate the association between semaglutide treatment and coronary artery inflammation based on FAI in patients with type 2 diabetes mellitus (T2DM)., Methods: This study enrolled 497 T2DM patients who underwent coronary computed tomography angiography (CCTA) at Hebei General Hospital, of whom 93 treated with semaglutide (Sema+) and 404 did not (Sema-). Clinical data, laboratory indicators, and CCTA parameters were collected and compared between the two groups at baseline. Propensity score matching (PSM) was used to adjust for confounders, and pericoronary FAI was compared. Multivariate linear regression models were used to analyze the association between semaglutide treatment and pericoronary FAI., Results: Before PSM, pericoronary FAI of the LAD and LCX was lower in patients treated with semaglutide than those without semaglutide treatment. The results of the PSM analysis revealed a lower FAI in all three major coronary arteries in the Sema + group compared to the Sema- group. Multivariate linear regression analyses revealed an independent association between semaglutide treatment and reduced FAI in all three major coronary arteries. This association varied across T2DM patients of differing profiles., Conclusion: Semaglutide treatment may be associated with lower coronary artery inflammation in patients with T2DM, which might partially explain its cardiovascular protective mechanism., (© 2024. The Author(s).)

Rationale: Glucagon-like peptide-1 is an endogenous incretin that plays an active role in weight loss and hypoglycemia. Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), which has been approved for the treatment of patients with type 2 diabetes (T2D). GLP-1RAs can increase insulin secretion and inhibit glucagon release, thereby leading to a decrease in blood glucose levels within the body. Specifically, GLP-1RAs control postprandial blood glucose levels by inhibiting hepatic glucose production and delaying gastric emptying. However, attention should be given to gastrointestinal adverse reactions. There are currently a few cases of GLP-1RA causing diabetic ketoacidosis (DKA)., Patient Concerns: The following report details the case of a 50-year-old Chinese female who has been living with diabetes for 12 years. Initially diagnosed with T2D, she was subsequently identified as a patient with latent autoimmune diabetes in adults (LADA) following treatment. The patient presented severe nausea, vomiting, and fatigue 1 day after injecting dulaglutide 1 time and discontinuing insulin therapy. She was diagnosed with severe DKA in the emergency department., Diagnoses: LADA and DKA., Interventions: Changed from dulaglutide to insulin therapy., Outcomes: After discontinuing dulaglutide and switching to insulin for blood glucose reduction, the patient's DKA was corrected, and blood glucose levels returned to normal., Lessons: This case suggests that clinicians should be alert to patients with severe DKA in cases of severe gastrointestinal adverse reactions after the use of GLP-1RAs. In addition, in most countries, GLP-1RAs are administered to patients with T2D, but we should consider the use of GLP-1RAs in patients with type 1 diabetes and LADA., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

GLP-1 (glucagon-like peptide-1) receptor agonists are a class of anti-diabetic agents that act by inducing insulin secretion and inhibiting glucagon release in a glucose-dependent manner. They are particularly promising because of their long duration of action, reduced risk of hypoglycaemia and the added benefit of weight loss. Trulicity ® dulaglutide is a GLP-1 receptor agonist approved for type II diabetes and chronic weight management in obese adults. A few rare cases of hypersensitivity reactions have been reported in patients taking the GLP-1 receptor agonists dulaglutide and liraglutide. Here we present a new case of cutaneous hypersensitivity reactions in a man taking dulaglutide for type II diabetes. A 52-year-old man who had been taking dulaglutide for 5 weeks developed a rash on the abdomen when the dose was increased for 3 months. The patient experienced resolution of symptoms within days of stopping dulaglutide., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: obesity affects many patients with inflammatory bowel disease (IBD). Glucagon-like peptide (GLP)-1 agonists are a promising therapy for obese patients. However, there is a lack of evidence of the use of these drugs in IBD patients. This study investigated the effectiveness and safety of GLP-1 agonists in a cohort of obese patients with IBD., Methods: a retrospective series of cases of consecutive IBD patients who received GLP-1 agonists indicated to treat obesity between 2019 and 2021 was analyzed. The GLP-1 agonists included were semaglutide 1.0 mg or liraglutide 3.0 mg. The coprimary endpoints were the percentage of change in body weight from baseline to six months and a weight reduction of 5 % or more at six months. In addition, the safety profile of GLP-1 agonist therapy and its impact on the IBD course were reviewed., Results: sixteen obese patients with IBD (nine with Crohn's disease [CD] and seven with ulcerative colitis [UC]) were included in the study. The median body mass index at baseline was 35 (32-37). The percentage of change in body weight was -6.2 % (-3.4-[-8.5]) at six months, and a 5 % or more weight reduction was achieved in 58.3 % (7/12) of patients at six months. The most common side effect was nausea (13.3 %), and one patient withdrew due to diarrhea. IBD activity score did not change significantly during follow-up., Conclusion: our results showed that GLP-1 agonists were effective and had a good safety profile in IBD patients. Most adverse effects were mild, and the IBD activity had no significant changes.

Aims/hypothesis: The aim of this study was to assess the efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment., Methods: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 12 trial was a randomised, double-dummy, active-controlled, parallel-group, Phase IIIa trial conducted over 26 weeks at 90 sites across the China region (including mainland China, Taiwan and Hong Kong) and five other countries. Adults aged ≥18 years (≥20 years in Taiwan) with a diagnosis of type 2 diabetes, HbA 1c between 53 and 91 mmol/mol (inclusive) and treated with a stable daily dose of metformin were eligible for inclusion. Participants were randomised (1:1:1:1) using a web-based randomisation system to either once-daily oral semaglutide (3 mg, 7 mg or 14 mg) or once-daily oral sitagliptin 100 mg. Treatment allocation was masked to both participants and investigators. Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary endpoint was change in HbA 1c from baseline to week 26. The confirmatory secondary endpoint was change in body weight (kg) from baseline to week 26. All randomised participants were included in the full analysis set (FAS). All participants exposed to at least one dose of trial product were included in the safety analysis (SAS)., Results: Of 1839 participants screened, 1441 were randomly assigned to oral semaglutide 3 mg (n=361), 7 mg (n=360), 14 mg (n=361) or sitagliptin 100 mg (n=359) and included in the FAS. A total of 1438 participants were included in the SAS. In total, 75.2% of participants were from the China region. A total of 1372 (95.2%) participants completed the trial and 130 participants prematurely discontinued treatment (8.3%, 8.6% and 15.0% for oral semaglutide 3 mg, 7 mg and 14 mg, respectively; 4.2% for sitagliptin 100 mg). Significantly greater reductions in HbA 1c from baseline to week 26 were reported for all doses of oral semaglutide vs sitagliptin 100 mg. For oral semaglutide 3 mg, 7 mg and 14 mg vs sitagliptin 100 mg, the estimated treatment differences (ETDs [95% CI]) were -2 (-4, -1) mmol/mol, -8 (-9, -6) mmol/mol and -11 (-12, -9) mmol/mol, respectively. The corresponding ETDs (95% CI) in percentage points vs sitagliptin 100 mg were -0.2 (-0.3, -0.1), -0.7 (-0.8, -0.6) and -1.0 (-1.1, -0.8), respectively. Reductions in body weight were significantly greater for all doses of oral semaglutide vs sitagliptin 100 mg (ETD [95% CI] -0.9 [-1.4, -0.4] kg, -2.3 [-2.8, -1.8] kg and -3.3 [-3.8, -2.8] kg for 3 mg, 7 mg and 14 mg, respectively). In the subpopulation of participants from the China region (75.2% of trial participants), reductions in HbA 1c and body weight from baseline to week 26 were similar to those seen in the overall population. The most frequent adverse events in the semaglutide treatment arms were gastrointestinal, although these were mostly transient and mild/moderate in severity., Conclusions/interpretation: Significantly greater reductions in both HbA 1c and body weight over 26 weeks were seen with oral semaglutide 3 mg, 7 mg and 14 mg than with sitagliptin 100 mg in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials., Trial Registration: ClinicalTrials.gov NCT04017832., Funding: This trial was funded by Novo Nordisk A/S, Søborg, Denmark., (© 2024. The Author(s).)

Purpose: Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is not cleared by the kidneys and has proven efficacy and safety in patients with diabetic kidney disease. We aimed to evaluate the 1-year efficacy of dulaglutide in patients with diabetic kidney disease who have used the drug for more than 1 year., Methods: This retrospective, observational study comprised 131 patients with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m 2 who had received dulaglutide for more than one year between June 2016 and May 2023. The primary outcome measures were changes in glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and body weight from baseline to the 12-month follow-up, with assessments performed at six-month intervals. Subgroup analyses were conducted based on age, sex, baseline body mass index, FPG, and HbA1c, and insulin administration at baseline and last follow-up., Findings: The mean age was 60.0 ± 10.2 years, and 61.1% of the participants were males. Baseline HbA1c, FPG, and body weight were 9.1% (76.0 mmol/mol), 186.8 mg/dL, and 79.3 kg, respectively. Dulaglutide significantly reduced HbA1c, FPG, and body weight from baseline to the 12-month follow-up (mean ± standard error: -1.2 ± 0.1%, -34.8 ± 6.9 mg/dL, and -2.3 ± 0.5 kg, respectively; P < 0.001). Subgroup analysis revealed significant differences in HbA1c reduction based on baseline HbA1c., Implications: Dulaglutide exhibited sustained glucose-lowering and weight-reduction effects during the initial 1 year of treatment in patients with diabetic kidney disease. Altogether, dulaglutide could serve as a favorable long-term therapeutic option for patients with diabetic kidney disease in real-world clinical settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone., Methods: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA 1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA 1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product., Results: Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA 1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA 1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA 1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation., Conclusions/interpretation: Oral semaglutide resulted in significantly greater reductions in HbA 1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials., Trial Registration: ClinicalTrials.gov NCT04109547., Funding: Novo Nordisk A/S., (© 2024. The Author(s).)

Semaglutide is found to be efficient for weight loss in patients with overweight or obesity with diabetes mellitus (DM). With a wide range of adverse events reported, the efficacy and safety of once-weekly subcutaneous semaglutide in individuals without DM, with overweight or obesity, is unclear. We conducted a comprehensive meta-analysis of randomized studies on once-weekly semaglutide in this patient population. We identified nine studies with 11,641 patients in the semaglutide group and 10,479 in the placebo group. We observed that semaglutide resulted in significant benefits, including change in body weight (%): mean difference (MD) of -11.49% (p < 0.0001), change in absolute body weight: MD of -11.74 kg (p < 0.0001), and change in waist circumference: MD of -9.06 cm (p < 0.0001). Gastrointestinal side effects are predominant including nausea: odds ratio (OR) of 4.06 (p < 0.0001), vomiting: OR of 4.43 (p < 0.0001), diarrhea: OR of 2.10 (p < 0.0001), constipation: OR of 2.43 (p < 0.0001), gallbladder disorders: OR of 1.26 (p = 0.010), and cholelithiasis: OR of 2.06 (p = 0.04). Serious adverse events were not statistically significant: OR of 1.06 (p = 0.82). However, the percentage of participants discontinuing due to adverse events and gastrointestinal side effects was statistically significant: ORs of 2.22 (p < 0.0001) and 3.77 (p < 0.0001), respectively. This study shows that in patients with overweight or obesity without DM, once-weekly subcutaneous semaglutide can significantly decrease body weight without risk of serious adverse events when compared with a placebo. However, gastrointestinal side effects are predominant with semaglutide, which can result in medication discontinuation., (© 2024 The Author(s). Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Introduction: Type 2 diabetes mellitus is the most common type of diabetes, characterized by varying degrees of insulin resistance and diminishing beta-cell function, which increases the risk of macrovascular and microvascular complications. Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is administered once weekly and approved for treating adults with type 2 diabetes mellitus. It can be used as a monotherapy or in addition to oral hypoglycemic or insulin therapy., Aim: This study aims to provide information contributing to assessing the efficacy and safety of weekly 1.5 mg dulaglutide therapy in Saudi adult patients with type 2 diabetes mellitus., Methods: A retrospective single-arm cohort study using a purposive sample to recruit type 2 diabetes mellitus patients on dulaglutide from endocrine and diabetic outpatient clinics in King Saud Medical City (N = 205). Data were collected from participants' medical profiles and through the phone using interview questionnaires., Results: Most participants were female and married; approximately 33% had had diabetes for more than 20 years, 41.4% of the sample had third-class obesity, and more than half had used dulaglutide for the last 1-2 years. With therapy, weight, body mass index, hemoglobin A1c, and fasting blood sugar were significantly improved after 6 and 12 months from baseline. The main side effects reported were nausea (52%) and fatigue (28%)., Conclusion: Dulaglutide is a safe and effective therapy that demonstrated favorable glycemic control and weight reduction in obese type 2 diabetes patients of Saudi origin., (© 2024. The Author(s).)

Introduction: Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis involving arterioles, capillaries and postcapillary venules. LCV is generally confined to the skin, with extracutaneous manifestations occurring less frequently. LCV has multiple potential etiologies. Indeed, histological LCV can be found in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex vasculitis, vasculitis associated with systemic diseases (i.e. sarcoidosis, Sjögren's syndrome, rheumatoid arthritis, and systemic lupus erythematosus), or in vasculitis associated with cancer, infections, sepsis and use of certain medications. LCV can also be idiopathic in up to 50% of cases., Case Report: Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist used for management of type 2 diabetes mellitus (T2DM), obesity and overweight associated with one or more weight-related comorbidities. A case of drug-induced LCV has already been described with the use of once-daily oral semaglutide. Herein, we describe the first case of skin-limited LCV induced by once-weekly subcutaneous semaglutide in a 73-year-old man with T2DM, who experienced the complete resolution of the skin lesions shortly after the discontinuation of semaglutide therapy., Conclusion: Future prospective studies, adverse event reporting and post-marketing surveillance will certainly contribute to establishing if LCV represents a less rare than expected side effect of both oral and subcutaneous semaglutide formulations.

Background: There are currently limited data regarding the effect of semaglutide 2·4 mg in individuals with obesity and prediabetes in clinical trials. We aimed to assess the efficacy and safety of semaglutide 2·4 mg for weight management and glycaemic control in participants with obesity and prediabetes., Methods: STEP 10 was a randomised, double-blind, parallel-group, phase 3 trial done across 30 trial sites in Canada, Denmark, Finland, Spain, and the UK and included participants aged 18 years or older with a BMI of 30 kg/m 2 or higher and prediabetes according to UK National Institute for Health and Care Excellence criteria (defined as having at least one of the following at screening: HbA 1c of 6·0-6·4% [42-47 mmol/mol] or fasting plasma glucose [FPG] of 5·5-6·9 mmol/L). Participants were randomly assigned (2:1) to once-weekly subcutaneous semaglutide 2·4 mg or placebo with diet and physical activity counselling for 52 weeks, followed by a 28-week off-treatment period. Primary endpoints were percentage change in bodyweight and proportion of participants reverting to normoglycaemia (HbA 1c <6·0% [<42 mmol/mol] and FPG <5·5 mmol/L) at week 52 (assessed in all randomly assigned participants by intention to treat). Selective safety data were collected for participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05040971, and is complete., Findings: Between Sept 16 and Dec 29, 2021, 138 participants were randomly assigned to semaglutide 2·4 mg and 69 to placebo. 147 (71%) were female and 60 (29%) were male; 183 (88%) were White. All randomly assigned participants received at least one dose of study drug. Baseline mean age was 53 years (SD 11), bodyweight 111·6 kg (22·2), BMI 40·1 kg/m 2 (6·9), waist circumference 120·1 cm (14·7), HbA 1c 5·9% (0·3; 41·3 mmol/mol [3·0]), and FPG 5·9 mmol/L (0·6). There was a significantly greater reduction in bodyweight with semaglutide 2·4 mg than with placebo at week 52 (-13·9% [SD 0·7] vs -2·7% [0·6]; estimated treatment difference -11·2% [95% CI -13·0 to -9·4]; p<0·0001). Greater proportions of participants reverted to normoglycaemia at week 52 with semaglutide 2·4 mg than with placebo (103 [81%] of 127 vs nine [14%] of 64; odds ratio 19·8 [95% CI 8·7 to 45·2]; p<0·0001). Serious adverse events occurred in 12 (9%) participants receiving semaglutide 2·4 mg versus six (9%) receiving placebo. Adverse events leading to treatment discontinuation occurred in eight (6%) participants in the semaglutide 2·4 mg group versus one (1%) participant in the placebo group. No new safety signals were reported., Interpretation: Semaglutide 2·4 mg provided superior reduction in bodyweight and reversion to normoglycaemia versus placebo in participants with obesity and prediabetes. The safety and tolerability profile was consistent with previous studies and with the GLP-1 receptor agonist class. These findings support the potential use of semaglutide 2·4 mg as a treatment option for individuals with obesity and prediabetes to achieve reversion to normoglycaemia., Funding: Novo Nordisk., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AV, HAKM, and MQ are employees and shareholders of Novo Nordisk. BMM received a research grant from Novo Nordisk; received honoraria as a consultant or speaker for Eli Lilly, Amgen, Novo Nordisk, Pfizer, and Johnson & Johnson; and is a shareholder of Reset Health. DCWL received clinical trial funding from Amgen and Novo Nordisk, and honoraria as a consultant or speaker for Amgen, Bayer, Boehringer Ingelheim, CME at Sea, Canada Collaborative Research Network, Eli Lilly, Novartis, Novo Nordisk, Viatris, and Zealand Pharma. JMB is a member of speakers bureaus for Merck, Boehringer Ingelheim, and Novo Nordisk, and has received research grants from the Novo Nordisk Foundation. KHP received honoraria for attendance or talks at meetings from AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk, and research funding from the Novo Nordisk Foundation. MC received research grants and honoraria as a speaker for and member of advisory boards, and support to attend meetings from Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. SDP received consulting fees from AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Merck, Abbott, HLS Therapeutics, Sanofi, Dexcom, Bayer, and Pfizer; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, GSK, Janssen, Boehringer Ingelheim, Sanofi, Merck, Abbott, Dexcom, HLS, Bayer, and Pfizer; support for attending meetings or travel from AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Merck, Abbott, HLS Therapeutics, Sanofi, Dexcom, and Bayer; and participation on data safety monitoring boards or advisory boards for AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Merck, Abbott, HLS Therapeutics, Sanofi, Dexcom, and Bayer., (Copyright © 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Importance: Although tirzepatide and semaglutide were shown to reduce weight in randomized clinical trials, data from head-to-head comparisons in populations with overweight or obesity are not yet available., Objective: To compare on-treatment weight loss and rates of gastrointestinal adverse events (AEs) among adults with overweight or obesity receiving tirzepatide or semaglutide labeled for type 2 diabetes (T2D) in a clinical setting., Design, Setting, and Participants: In this cohort study, adults with overweight or obesity receiving semaglutide or tirzepatide between May 2022 and September 2023 were identified using electronic health record (EHR) data linked to dispensing information from a collective of US health care systems. On-treatment weight outcomes through November 3, 2023, were assessed. Adults with overweight or obesity and regular care in the year before initiation, no prior glucagon-like peptide 1 receptor agonist receptor agonist use, a prescription within 60 days prior to initiation, and an available baseline weight were identified. The analysis was completed on April 3, 2024., Exposures: Tirzepatide or semaglutide in formulations labeled for T2D, on or off label., Main Outcomes and Measures: On-treatment weight change in a propensity score-matched population, assessed as hazard of achieving 5% or greater, 10% or greater, and 15% or greater weight loss, and percentage change in weight at 3, 6, and 12 months. Hazards of gastrointestinal AEs were compared., Results: Among 41 222 adults meeting the study criteria (semaglutide, 32 029; tirzepatide, 9193), 18 386 remained after propensity score matching. The mean (SD) age was 52.0 (12.9) years, 12 970 were female (70.5%), 14 182 were white (77.1%), 2171 Black (11.8%), 354 Asian (1.9%), 1679 were of other or unknown race, and 9563 (52.0%) had T2D. The mean (SD) baseline weight was 110 (25.8) kg. Follow-up was ended by discontinuation for 5140 patients (55.9%) receiving tirzepatide and 4823 (52.5%) receiving semaglutide. Patients receiving tirzepatide were significantly more likely to achieve weight loss (≥5%; hazard ratio [HR], 1.76, 95% CI, 1.68, 1.84; ≥10%; HR, 2.54; 95% CI, 2.37, 2.73; and ≥15%; HR, 3.24; 95% CI, 2.91, 3.61). On-treatment changes in weight were larger for patients receiving tirzepatide at 3 months (difference, -2.4%; 95% CI -2.5% to -2.2%), 6 months (difference, -4.3%; 95% CI, -4.7% to -4.0%), and 12 months (difference, -6.9%; 95% CI, -7.9% to -5.8%). Rates of gastrointestinal AEs were similar between groups., Conclusions and Relevance: In this population of adults with overweight or obesity, use of tirzepatide was associated with significantly greater weight loss than semaglutide. Future study is needed to understand differences in other important outcomes.

Background: Semaglutide is increasingly used in the management of type 2 diabetes mellitus and obesity. Ensuring the safety of this medication is crucial for its clinical use. This meta-analysis evaluates the safety profile of semaglutide across patient populations and treatment durations., Methods: Randomized controlled trials assessing the safety of semaglutide vs. placebo, with specified treatment durations were identified. The primary outcome was occurrence of any cardiovascular adverse events. Secondary outcomes included sudden cardiac death, adverse events leading to death, adverse events, gastrointestinal side effects, occurrence of hypoglycemia, and new-onset neoplasm., Results: A total of 23 studies met the inclusion criteria with a combined sample size of 57,911 participants. The meta-analysis revealed that the adverse event associated with semaglutide is gastrointestinal in nature (nausea and vomiting). No significant differences were observed between semaglutide and comparator groups., Conclusion: Semaglutide appears to have a favorable safety profile across diverse patient populations and treatment durations, supporting its continued use in the management of type 2 diabetes mellitus and obesity. It is generally well-tolerated, with a low incidence of adverse events. Clinicians should be aware of these findings and monitor patients accordingly. Further long-term studies are warranted to assess the safety of semaglutide in clinical practice.

Background: Heart failure (HF) is a major contributor to global health challenges, affecting mortality rates and healthcare expenditure. Glucagon-like peptide-1 receptor agonists (GLP-1RA) offer promise in HF management, though their precise impact is unclear. The main objective of this study was to evaluate the effect of semaglutide on HF-related outcomes., Methods: We conducted a meta-analysis of studies assessing the effects of semaglutide therapy on HF-related outcomes. This meta-analysis was performed according to PRISMA guidelines. Randomized clinical trials or observational cohorts studies with a follow-up duration ≥ 6 months were included. The random-effects model was performed., Results: Six randomised clinical trials (n = 28,762 patients) and two observational studies were identified and considered eligible for this systematic review. A total of 14,608 subjects were assigned to the semaglutide group and 14,716 individuals were assigned to control or placebo groups. Overall, this meta-analysis shows that semaglutide use was associated with an decreased risk of HF (OR: 0.74; 95 % CI: 0.58 to 0.94, I 2 45 %), compared to placebo or control groups. The analytical evaluation does not suggest publication bias, and the sensitivity analysis demonstrated that the result was robust., Conclusion: This meta-analysis demonstrates that the use of semaglutide is associated with a reduction in clinical events related to HF. As HF is a heterogeneous clinical condition, further studies will be necessary to analyze this association in different subgroups of patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: To compare the incidence of adverse events (AEs) related to antiobesity medications (AOMs; glucagon-like peptide-1 receptor agonists [GLP-1RAs] vs. non-GLP-1RAs) after bariatric surgery., Methods: This single-centre retrospective cohort included patients (aged 16-65 years) who had undergone laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy (cohort entry date) and initiated AOMs. Participants were categorized as users of US Food and Drug Administration (FDA)-approved, off-label, or GLP-1RA AOMs if documented as receiving the medication on or after cohort entry date. Non-GLP-1RA AOMs were phentermine, orlistat, topiramate, canagliflozin, dapagliflozin, empagliflozin, naltrexone, bupropion/naltrexone and phentermine/topiramate. GLP-1RA AOMs included: semaglutide, dulaglutide, exenatide and liraglutide. The primary outcome was AE incidence. Logistic regression was used to determine the association of AOM exposure with AEs., Results: We identified 599 patients meeting our inclusion criteria, 83% of whom were female. Their median (interquartile range [IQR]) age was 47.8 (40.9-55.4) years. The median duration of surgery to AOM exposure was 30 months. GLP-1RAs use was not associated with higher odds of AEs: adjusted odds ratio (aOR) 1.1 (95% confidence interval [CI] 0.5-2.6) and aOR 1.1 (95% CI 0.6-2.3) for GLP-1RA versus FDA-approved and off-label AOM use, respectively. AOM initiation ≥12 months after surgery was associated with lower risk of AEs compared to <12 months (aOR 0.01 [95% CI 0.0-0.01]; p < 0.001)., Conclusion: Our results showed that GLP-1RA AOMs were not associated with an increased risk of AEs compared to non-GLP-1RA AOMs in patients who had previously undergone bariatric surgery. Prospective studies are needed to identify the optimal timeframe for GLP-1RA initiation., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Heart failure with preserved ejection fraction (HFpEF) is a growing clinical challenge with limited treatment options. This review explores the potential of semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, for HFpEF treatment. Studies suggest promising benefits, including symptom improvement, weight management, and the potential for enhanced exercise capacity. However, the evidence for semaglutide's impact on exercise capacity and heart function remains inconclusive, and its anti-inflammatory effects require further investigation. The safety profile appears favorable, with gastrointestinal side effects being the most common adverse events. It is crucial to emphasize that additional research with longer follow-up, head-to-head comparisons, and exploration of optimal dosage and mechanisms of action are necessary to solidify semaglutide's role in HFpEF treatment. Semaglutide is promising to improve symptoms, promote weight loss, and potentially influence underlying HFpEF mechanisms. Future research can refine treatment strategies and unlock the full potential of semaglutide for this patient population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Aims: The combination of cagrilintide and semaglutide (CagriSema) is being developed for the treatment of obesity and type 2 diabetes. The objective of this thorough QT study was to confirm that cagrilintide does not result in a clinically relevant prolongation in cardiac repolarization compared with placebo., Materials and Methods: This was a double-blind study (NCT05804162) in which healthy participants were randomized to cagrilintide, administered as a once-weekly subcutaneous injection dose escalated to 4.5 mg, or a placebo. The primary end point was the time-matched change from baseline in Fridericia heart rate-corrected QT interval (QTcF) at 12-, 24-, 48- and 72 h after the last cagrilintide 4.5-mg dose. To conclude that cagrilintide does not induce a clinically relevant prolongation, the upper limit of the two-sided 90% confidence interval (CI) for the treatment difference at each of the four time points must fall below 10 ms. To establish QT assay sensitivity, participants in the placebo arms received a single 400-mg oral moxifloxacin dose as a positive control and moxifloxacin placebo in a nested cross-over fashion., Results: A total of 105 participants received cagrilintide (n = 53) or placebo (n = 52). No clinically relevant QTcF prolongation occurred after the last cagrilintide 4.5-mg dose; the upper limits of the two-sided 90% CIs of the placebo-adjusted QTcF changes from baseline were below 10 ms at all time points. QT assay sensitivity was demonstrated with moxifloxacin as a positive control., Conclusions: Cagrilintide did not result in clinically relevant QTcF prolongation, indicating no increased risk of ventricular tachyarrhythmias., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: The expanding roles and popularity of glucagon-like peptide-1 (GLP-1) and GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists has created access barriers to medication use. We sought to describe an adverse drug event which occurred after reinitiation of a GLP-1 receptor agonist following a prolonged lapse in therapy due to poor medication access. Case Summary : Once-weekly injectable semaglutide was prescribed to an outpatient 33-year-old male for chronic weight management. After a delayed initiation due to global shortage, semaglutide was initiated and titrated over five months before a seven week lapse in therapy due to prior authorization interruption. Despite the extended treatment gap, the patient was directed to reinitiate semaglutide at the target dose rather than starting dose, which was followed by recurrent, symptomatic nausea and vomiting requiring medical intervention. Practice Implications: A prolonged lapse in GLP-1 receptor agonist therapy, typically defined as missing three or more doses of a once-weekly injectable, warrants consideration of reinitiation at a reduced dose, personalized to the patient's prior gastrointestinal tolerability, efficacy goals, and therapy lapse duration. Therapy lapses with GLP-1 receptor agonists may be prevented by utilizing a multi-modal approach including extended dosing intervals, intermediate doses, agent interchange, efficient prior authorization communication, and cautious initiation of GLP-1 recent agonists while supply cannot meet demand., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Glucagon-like peptide-1 receptor agonists (GLP1RAs), originally developed for the treatment of type 2 diabetes mellitus, have attracted attention for their potential therapeutic benefits in asthma due to their anti-inflammatory properties and effects on airway smooth muscle function. However, concerns have been raised about the possibility of GLP1RAs inducing or exacerbating asthma symptoms., Methods: We reviewed data from the US Food and Drug Administration's (FDA) adverse event (AE) reporting system (FAERS) to examine reports of cases of asthma observed in the real-world during treatment with GLP1RAs., Results: Analysis of the FAERS reporting system database has shown that certain GLP1RAs, particularly exenatide, semaglutide and liraglutide, were associated with a higher proportion of respiratory AEs, particularly asthma or asthma-like events. This association was statistically significant at least for semaglutide and liraglutide. Serious asthma-related events and deaths were also reported, with exenatide having the highest proportion of deaths., Conclusions: The reasons for the observed differences in the AE profiles of the GLP1RAs remain unclear and may involve various factors such as pharmacological properties, patient characteristics and reporting biases. The complex interplay between the therapeutic benefits of GLP1RAs and the potential respiratory risks requires careful monitoring by clinicians, underpinned by ongoing research efforts to improve patient care and safety.

Postpartum mothers and their healthcare providers often face the challenge of limited data regarding the safety of drug therapies during lactation. Pregnancy can lead to sustained weight gain, and obesity can negatively impact both physical and psychological well-being. The introduction of GLP-1 agonists to augment weight loss has become a topic of interest for many postpartum mothers. Our study aims to investigate the transmission of semaglutide into human milk in the first steps to ensure the safety and health of both lactating mothers and their breastfed infants. Semaglutide quantification was performed using high-resolution liquid chromatography-mass spectrometry. InfantRisk Center Human Milk biorepository released milk samples from eight women collected at 0, 12 and 24 h post-semaglutide administration. Semaglutide was extracted using protein precipitation in methanol, followed by chromatographic separation. Linear calibration curves for the method ranged between 2.5-30 ng/mL, with a limit of detection of 1.7 ng/mL and a limit of quantification of 5.7 ng/mL (LLOQ). Semaglutide was not detected in any of the collected human milk samples. A worst-case scenario of the relative infant dose (RID) was calculated using the LLOQ as the drug concentration in milk when considering semaglutide's bioavailability and long-acting dose profile. The maximum RID projected was 1.26%, far below the standard 10% safety threshold. While questions about long-term infant outcomes, the safety of maternal nutrient intake, and the nutrient content of breast milk remain, our findings suggest that semaglutide concentrations in human milk are unlikely to pose clinical concerns for breastfed infants. These results support healthcare providers in making informed decisions regarding postpartum therapeutic interventions.

Background: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure., Methods: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m 2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597., Findings: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m 2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all p interaction >0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype., Interpretation: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group., Funding: Novo Nordisk., Competing Interests: Declaration of interests JD declares having received consulting honoraria from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, and Bayer, and research grants from British Heart Foundation, Medical Research Council (UK), National Institute for Health and Care Research, Public Health England, MSD, Pfizer, Aegerion, Colgate, and Roche. BMS declares having received institutional research grants to Brigham and Women's Hospital from Better Therapeutics, Merck, Novo Nordisk, and Pfizer, and consulting fees from Allergan, Boehringer Ingelheim, Better Therapeutics, Elsevier PracticeUpdate Cardiology, Esperion, Hanmi, Lexicon, Novo Nordisk, and equity in health at Scale and Doximity. SV reports speaking honoraria or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. DR declares having received consulting honoraria from Altimmune, Amgen, Biohaven, Boehringer Ingelheim, Calibrate, Carmot Therapeutics, CinRx, Eli Lilly, Epitomee, Gila Therapeutics, Ifa Celtic, Novo Nordisk, Pfizer, Rhythm, Scientific Intake, Wondr Health, and Zealand. DR also declares having received stock options from Calibrate, Epitomee, Scientific Intake, and Xeno Bioscience. IL declares having received research funding (paid to institution) from Novo Nordisk, Sanofi, Mylan, and Boehringer Ingelheim. IL received advisory or consulting fees or other support from Altimmune, AstraZeneca, Bayer, Biomea, Boehringer Ingelheim, Carmot, Cytoki Pharma, Eli Lilly, Intercept, Janssen/Johnson & Johnson, Mannkind, Mediflix, Merck, Metsera, Novo Nordisk, Pharmaventures, Pfizer, Regeneron, Sanofi, Shionogi, Structure Therapeutics, Target RWE, Terns Pharma, The Comm Group, Valeritas, WebMD, and Zealand Pharma. HMC declares being a stockholder and serving on an advisory panel for Bayer; receiving research grants from Chief Scientist Office, Diabetes UK, European Commission, IQVIA, Juvenile Diabetes Research Foundation, and Medical Research Council; serving on an advisory board and speakers bureau for Novo Nordisk; and holding stock in Roche Pharmaceuticals. SEK declares having received consulting honoraria from Anii Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, and Oramed and stock options from Altpep. JP declares having received consulting honoraria from Altimmune, Amgen, Esperion Therapeutics, Merck, MJH Life Sciences, Novartis, and Novo Nordisk; he has received a grant, paid to his institution, from Boehringer Ingelheim, and holds the position of Director, Preventive Cardiology, at Brigham and Women's Hospital. MNK declares having served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. MNK has also received other research support from AstraZeneca. SSE declares having received consulting honoraria from Amylyx, AstraZeneca, Avillion, Ayala, Bayer, BeiGene, Boehringer Ingelheim, 89 Bio, BioAge, BioAtla, Bristol Myers Squibb, BridgeBio, Daiichi Sankyo, Denovo, Fore Therapeutics, GlaxoSmithKline, Inovio, Insmed, Ipsen, Karuna, Lilly, Lundbeck, Mirati, Moderna, Novartis, Novavax, Novo Nordisk, National Surgical Adjuvant Breast and Bowel Project, Pfizer, Principia, Reata, Rebiotx, Roche, Sanofi, Solvd, Sutro Biopharma, and TG Therapeutics. AG declares having received honoraria from Novo Nordisk, AstraZeneca, Novartis, Boehringer Ingelheim, and Bayer. CCL declares having received consulting and research honoraria from Amarin, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Moderna, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics. MU-T declares having received consulting and research honoraria from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Frosst Laboratories, Johnson and Johnson, Menarini, Novartis, Novo Nordisk, Pfizer, Procaps, Sanofi-Aventis, Servier, and Tecnofarma. MP declares having received honoraria from Novo Nordisk. AML declares having received honoraria from Novo Nordisk, Eli Lilly, Akebia, Amgen, Ardelyx, Becton Dickson, Endologix, Fibrogen, GlaxoSmithkline, Medtronic, Neovasc, Provention Bio, ReCor, Brainstorm Cell, Alnylam, and Intarcia for consulting activities and research funding to his institution from AbbVie, Esperion, AstraZeneca, CSL Behring, Novartis, and Eli Lilly. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Importance: Obesity affects approximately 19% of women and 14% of men worldwide and is associated with increased morbidity. Antiobesity medications (AOMs) modify biological processes that affect appetite and significantly improve outcomes, such as type 2 diabetes, hypertension, and dyslipidemia., Observations: AOMs should be administered in combination with lifestyle interventions and can be classified according to their mechanisms of action. Orlistat modifies digestive tract absorption and causes gastrointestinal adverse effects, such as oily fecal spotting and urgency, in more than 25% of patients. Centrally acting drugs, such as phentermine-topiramate and naltrexone-bupropion, regulate appetite in the brain and are associated with constipation in approximately 20% of patients, although the incidence of other adverse effects (eg, paresthesia, nausea) varies by medication. Nutrient-stimulated hormone-based medications, such as liraglutide, semaglutide, and tirzepatide, mimic the actions of enteropancreatic hormones that modify central appetite regulation and provide multiple cardiometabolic weight-loss benefits. Adverse effects of these drugs include nausea (28%-44%), diarrhea (21%-30%), and constipation (11%-24%). The relative potency of adult obesity medications has been studied in meta-analyses. Compared with placebo, orlistat was associated with 3.1% greater weight loss (52 randomized clinical trials [RCTs]; 16 964 participants), phentermine-topiramate was associated with 8.0% greater weight loss (5 RCTs; 3407 participants), naltrexone-bupropion was associated with 4.1% greater weight loss (6 RCTs; 9949 participants), liraglutide was associated with 4.7% greater weight loss (18 RCTs; 6321 participants), semaglutide was associated with 11.4% greater weight loss (5 RCTs; 4421 participants), and tirzepatide 15 mg was associated with 12.4% greater weight loss (6 RCTs; 1972 participants)., Conclusion and Relevance: Obesity is associated with increased morbidity. Antiobesity medications are effective adjunctive therapy to lifestyle changes for improved weight loss and health outcomes.