INTRODUCTION:With new advancements in obesity medicine, clarity on goals and expectations for successful disease management is limited. This post hoc analysis assessed application of proposed treat-to-target (TtT) thresholds for obesity to the outcome measures of SURMOUNT-5, which randomised participants with obesity to tirzepatide or semaglutide. METHODS:The proportion of participants in each treatment group reaching proposed TtT thresholds for waist to height ratio (WHtR) <0.53, body mass index (BMI) <27 kg/m2, or a combination was evaluated. The associations between the thresholds and achieving low disease activity to remission (meeting goals for at least four of five defined cardiometabolic risk parameters) and normalisation or improvement in SF-36v2 physical component score (PCS) from baseline to week 72 were explored. RESULTS:About 23.1%-33.9% of participants treated with tirzepatide and 14.2%-20.7% treated with semaglutide reached the TtT thresholds, with greater weight reduction than the overall population. About 77% of participants who reached WHtR <0.53 achieved low disease activity to remission, with an odds ratio of 2.31 (p < 0.001) compared to those who did not reach this target. The BMI threshold was not statistically associated with the assessed outcomes for SF-36v2 PCS. CONCLUSION:In this post hoc analysis of SURMOUNT-5, most participants who reached the proposed TtT thresholds achieved the goal of low disease activity to remission defined by cardiometabolic risk parameters. These data suggest that TtT thresholds in obesity medicine may clarify goals in shared decision-making and improve clinical outcomes.

The global rise in obesity has led to an increasing need for pharmacologic therapies as adjuncts to lifestyle interventions for weight management. While obesity medications (OMs) produce meaningful weight loss (∼5%-24%) and improve cardiometabolic health, up to half of patients discontinue treatment within 1 to 2 years due to side effects, limited access, cost, or inadequate response. Discontinuation of OMs, however, often results in weight regain and reversal of associated health benefits, posing considerable clinical challenges. Understanding the outcomes following cessation of pharmacotherapy and identifying effective interim strategies are essential to maintaining progress in weight management and minimizing long-term health risks. This approach to the patient article demonstrates 2 cases of patients in the real-world setting who experience disruption of their obesity regimen with either a blunted response to reintroduction of therapy and/or weight regain and outlines practical approaches to mitigate weight regain and sustain health improvements long term in patients with obesity.

BACKGROUND:Monlunabant, a novel cannabinoid receptor 1 (CB1R) inverse agonist, has shown encouraging weight loss efficacy and tolerability. We aimed to evaluate the efficacy and safety of monlunabant in individuals with obesity and metabolic syndrome. METHODS:This 16-week, randomised, double-blind, placebo-controlled, dose-ranging phase 2a trial, conducted at 25 outpatient research centres in Canada, enrolled adults with obesity and metabolic syndrome. Participants were randomly assigned (1:1:1:1) by means of an interactive response system to once-daily oral tablets of monlunabant 10 mg, 20 mg, 50 mg, or placebo. The participants, site staff, sponsor, and contract research organisation were masked to treatment allocation. The primary endpoint was mean bodyweight (kg) change from baseline at week 16 versus placebo, assessed in all eligible randomised participants, whereas the safety analysis was done in all randomised participants who received at least one dose of trial product. The estimator for the primary estimand was analysed using a mixed model for repeated measures, assuming missing data are missing at random. This trial is registered with ClinicalTrials.gov (NCT05891834) and is complete. FINDINGS:From Sept 8, 2023, to Jan 26, 2024, 409 individuals were screened for eligibility. In total, 243 individuals were randomly assigned to monlunabant 10 mg (n=61), monlunabant 20 mg (n=61), monlunabant 50 mg (n=60), and placebo (n=61); 242 participants received treatment, including 167 (69%) females and 75 (31%) males. 183 (76%) of 242 participants completed the trial: 50 (82%) of 61 received monlunabant 10 mg, 42 (70%) of 60 received monlunabant 20 mg, 34 (57%) of 60 received monlunabant 50 mg, and 57 (93%) of 61 received placebo. At week 16, participants receiving monlunabant showed statistically significant weight loss compared with those receiving placebo (least squares mean difference vs placebo of -6·4 kg [95% CI -8·0 to -4·9] for monlunabant 10 mg, -6·9 kg [-8·5 to -5·3] for monlunabant 20 mg, and -8·0 kg [-9·7 to -6·4] for monlunabant 50 mg). Adverse events were mostly mild to moderate gastrointestinal and psychiatric disorders and were seen in 42 (69%) of 61 participants in the monlunabant 10 mg group, 47 (78%) of 60 participants in the monlunabant 20 mg group, 55 (92%) of 60 participants in the monlunabant 50 mg group, and 42 (69%) of 61 participants in the placebo group. Withdrawals due to adverse events appeared dose-dependent, occurring in eight (13%) participants who received monlunabant 10 mg, 16 (27%) who received monlunabant 20 mg, 25 (42%) who received monlunabant 50 mg, and none who received placebo, driven by nausea, anxiety, diarrhoea, irritability, and sleep disorder. No deaths were reported. INTERPRETATION:Participants receiving monlunabant showed statistically significant and clinically meaningful weight loss compared with those receiving placebo for all tested doses. Only slightly greater weight loss was observed at higher doses, whereas adverse events appeared dose dependent. Further investigation is needed to assess the safety and efficacy of lower doses of monlunabant, to evaluate its potential as a medication for obesity. FUNDING:Inversago Pharma (a Novo Nordisk company).

BACKGROUND:Tirzepatide and semaglutide are highly effective medications for obesity management. The efficacy and safety of tirzepatide as compared with semaglutide in adults with obesity but without type 2 diabetes is unknown. METHODS:In this phase 3b, open-label, controlled trial, adult participants with obesity but without type 2 diabetes were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly for 72 weeks. The primary end point was the percent change in weight from baseline to week 72. Key secondary end points included weight reductions of at least 10%, 15%, 20%, and 25% and a change in waist circumference from baseline to week 72. RESULTS:A total of 751 participants underwent randomization. The least-squares mean percent change in weight at week 72 was -20.2% (95% confidence interval [CI], -21.4 to -19.1) with tirzepatide and -13.7% (95% CI, -14.9 to -12.6) with semaglutide (P<0.001). The least-squares mean change in waist circumference was -18.4 cm (95% CI, -19.6 to -17.2) with tirzepatide and -13.0 cm (95% CI, -14.3 to -11.7) with semaglutide (P<0.001). Participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of at least 10%, 15%, 20%, and 25%. The most common adverse events in both treatment groups were gastrointestinal, and most were mild to moderate in severity and occurred primarily during dose escalation. CONCLUSIONS:Among participants with obesity but without diabetes, treatment with tirzepatide was superior to treatment with semaglutide with respect to reduction in body weight and waist circumference at week 72. (Funded by Eli Lilly; SURMOUNT-5 ClinicalTrials.gov number, NCT05822830.).

Introduction and Objective: During long-term obesity management fluctuations in body weight and waist circumference are expected. Waist-Height-Ratio (WHtR) is a practical estimate of central adiposity that predicts cardiometabolic disease. SURMOUNT-1 (SM-1) 3-year study evaluated the safety and efficacy of tirzepatide (TZP), a GIP and GLP-1 receptor agonist, in participants with prediabetes for the treatment of obesity. This post-hoc analysis aimed to determine sustainability of WHtR category from a participant’s nadir weight to end of study, week 176. Methods: This SM-1 3-year study post-hoc analysis included on-treatment data of 690 TZP-adherent participants (≥75% doses received over 176 weeks) with ≥5% weight reduction at nadir. Weight regain was calculated from nadir weight to Week 176 (percent weight change from baseline to Week 176 - percent weight change from baseline to nadir weight). The analysis evaluated the portion of participants who had WHtR categorical shift from nadir weight to Week 176 by weight regain categories <5%, 5-<10%, ≥10%. WHtR risk categories were defined as healthy (WHtR≤0.49), increased (WHtR>0.49 to ≤0.59) and high (WHtR>0.59). Results: Of TZP-treated participants with weight regain <5% from nadir weight to Week 176 (n=481, 70% of TZP-treated participants), 94% and 6% had an improved/sustained and worsened WHtR category, respectively. Of TZP-treated participants with weight regain of 5%-<10% (n=148, 22%) 76% and 24% had an improved/sustained and worsened WHtR category, respectively. Of TZP-treated participants with ≥10% weight regain (n=57, 8%), 63% and 37% had an improved/sustained and worsened WHtR category, respectively. Conclusion: Most participants sustained their WHtR category from nadir weight to end of study regardless of the weight regain from nadir. These findings suggest that for most participants treated with TZP the limited degree of weight regain from nadir weight to 3 years was not negatively associated with cardiometabolic risk as predicted by WHtR category. L.J. Aronne: Consultant; Novo Nordisk. Research Support; Novo Nordisk. Consultant; Lilly USA LLC. Research Support; Lilly USA LLC. J.F. Brumm: None. I. Jouravskaya: None. D. Cao: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J.P. Dunn: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

OBJECTIVE:SURMOUNT-MAINTAIN aims to evaluate the efficacy and safety of reducing the tirzepatide dose and/or continuing the maximum tolerated dose (MTD) versus placebo in maintaining body weight (BW) reduction achieved with tirzepatide MTD. METHODS:This Phase 3b, multicenter, randomized, parallel-arm, double-blinded, placebo-controlled, 52-week clinical trial is in progress comparing treatment with once weekly tirzepatide (5 mg and/or MTD of 15 mg or 10 mg) versus placebo in achieving BW reduction maintenance from the initial 60-week open-label weight-loss period on tirzepatide MTD, in adults with obesity (BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with ≥ 1 obesity-related comorbidity, excluding type 2 diabetes). The primary endpoint is percent maintenance of BW reduction achieved during the weight-loss period at Week 112 among those who reached a BW plateau (i.e., < 5% BW change) between Weeks 48 and 60. RESULTS:Participants are mostly female (65%) with a mean ± SD age of 47 ± 13 years, BW 114 ± 27 kg, BMI 40 ± 8 kg/m2, and waist circumference 119 ± 18 cm. CONCLUSIONS:The SURMOUNT-MAINTAIN trial will evaluate whether reducing or continuing the tirzepatide dose as a long-term treatment option may help maintain the reduced BW initially achieved with tirzepatide MTD versus switching to placebo. Combined, this study may provide additional evidence to help tailor patient-centered strategies for maintenance of BW reduction in adults living with obesity. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT06047548.

BACKGROUND:Orforglipron, a small-molecule, nonpeptide oral glucagon-like peptide-1 (GLP-1) receptor agonist, is being investigated as a treatment for obesity. METHODS:In this phase 3, multinational, randomized, double-blind trial, we examined the safety and efficacy of once-daily orforglipron at doses of 6 mg, 12 mg, or 36 mg, as compared with placebo (assigned in a 3:3:3:4 ratio) as an adjunct to healthy diet and physical activity for 72 weeks. All the patients had obesity without diabetes mellitus. The primary end point was the percent change in body weight from baseline to week 72, as assessed according to the treatment-regimen estimand in the intention-to-treat population. RESULTS:A total of 3127 patients underwent randomization. The mean change in body weight from baseline to week 72 was -7.5% (95% confidence interval [CI], -8.2 to -6.8) with 6 mg of orforglipron, -8.4% (95% CI, -9.1 to -7.7) with 12 mg of orforglipron, and -11.2% (95% CI, -12.0 to -10.4) with 36 mg of orforglipron, as compared with -2.1% (95% CI, -2.8 to -1.4) with placebo (P<0.001 for all comparisons with placebo). Among the patients in the orforglipron 36-mg group, 54.6% had a reduction of 10% or more, 36.0% had a reduction of 15% or more, and 18.4% had a reduction of 20% or more, as compared with 12.9%, 5.9%, and 2.8% of the patients, respectively, in the placebo group. Waist circumference, systolic blood pressure, triglyceride levels, and non-HDL cholesterol levels significantly improved with orforglipron treatment as compared with placebo. Adverse events resulted in treatment discontinuation in 5.3 to 10.3% of the patients in the orforglipron groups and in 2.7% of those in the placebo group. The most common adverse events with orforglipron were gastrointestinal effects, which were mostly mild to moderate. CONCLUSIONS:In adults with obesity, 72-week treatment with orforglipron led to significantly greater reductions in body weight than placebo; the adverse-event profile was consistent with that of other GLP-1 receptor agonists. (Funded by Eli Lilly; ATTAIN-1 ClinicalTrials.gov number, NCT05869903.).

BACKGROUND Obesity is a chronic disease and causal precursor to myriad other conditions, including type 2 diabetes. In an earlier analysis of the SURMOUNT-1 trial, tirzepatide was shown to provide substantial and sustained reductions in body weight in persons with obesity over a 72-week period. Here, we report the 3-year safety outcomes with tirzepatide and its efficacy in reducing weight and delaying progression to type 2 diabetes in persons with both obesity and prediabetes. METHODS We performed a phase 3, double-blind, randomized, controlled trial in which 2539 participants with obesity, of whom 1032 also had prediabetes, were assigned in a 1:1:1:1 ratio to receive tirzepatide at a once-weekly dose of 5 mg, 10 mg, or 15 mg or placebo. The current analysis involved the participants with both obesity and prediabetes, who received their assigned dose of tirzepatide or placebo for a total of 176 weeks, followed by a 17-week off-treatment period. The three key secondary end points, which were controlled for type I error, were the percent change in body weight from baseline to week 176 and onset of type 2 diabetes during the 176-week and 193-week periods. RESULTS At 176 weeks, the mean percent change in body weight among the participants who received tirzepatide was -12.3% with the 5-mg dose, -18.7% with the 10-mg dose, and -19.7% with the 15-mg dose, as compared with -1.3% among those who received placebo (P<0.001 for all comparisons with placebo). Fewer participants received a diagnosis of type 2 diabetes in the tirzepatide groups than in the placebo group (1.3% vs. 13.3%; hazard ratio, 0.07; 95% confidence interval [CI], 0.0 to 0.1; P<0.001). After 17 weeks off treatment or placebo, 2.4% of the participants who received tirzepatide and 13.7% of those who received placebo had type 2 diabetes (hazard ratio, 0.12; 95% CI, 0.1 to 0.2; P<0.001). Other than coronavirus disease 2019, the most common adverse events were gastrointestinal, most of which were mild to moderate in severity and occurred primarily during the dose-escalation period in the first 20 weeks of the trial. No new safety signals were identified. CONCLUSIONS Three years of treatment with tirzepatide in persons with obesity and prediabetes resulted in substantial and sustained weight reduction and a markedly lower risk of progression to type 2 diabetes than that with placebo.

Successful treatment of obesity requires a multidisciplinary approach including dietary strategy, physical activity, and behavioral modification. The seven FDA-approved anti-obesity medications are phentermine, orlistat, phentermine/topiramate ER, naltrexone SR/bupropion SR, liraglutide 3.0 mg, semaglutide 2.4 mg, and tirzepatide. Obesity is a chronic disease and these medications should be prescribed with the intention of long-term use. In this article, we summarize data from phase 3 clinical trials which led to drug approval, and we review the clinical indications, mechanism of action, dosing/administration, side effects, drug interactions and contraindications for each medication.

A 12-month multicentre randomized clinical trial finds that replacing added sugar in foods and beverages with sweeteners and sweetness enhancers supports modest weight loss maintenance and alters gut microbiota composition, with no safety concerns identified.

Introduction & Objective: Use of branded anti-obesity medications (bAOMs) has increased concurrently with the rise of telemedicine, a convenient, cost-effective modality for patient care. However, limited data exist regarding characteristics of telemedicine users in medical weight management. This study examines the profile and treatment course of patients prescribed bAOMs for overweight or obesity via telemedicine at an academic weight center in New York City. Methods: This is a retrospective observational study of patients who started telemedicine treatment between May 1, 2020, and September 30, 2022, received a bAOM prescription (Contrave®, Qsymia®, Saxenda®, or Wegovy®), and had ≥6 (±2) months’ follow-up. Data were abstracted by electronic medical record query using relevant ICD/diagnosis codes and biomarker data to curate a dataset of eligible patients for analysis. Results: Patients who met inclusion criteria (N=1286) had a mean age of 47.2 (SD=12.8) years, initial weight of 220.9 (50.6) lb (n=934), initial BMI of 35.2 (6.5) (n=930), and an average of 2.2 weight-related comorbidities (most commonly dyslipidemia [n=705], hypertension [n=355], and prediabetes [n=595]). Most patients identified as White (63.7%); 72.2% of patients were female. Patients had a mean (SD) of 9.5 (7.2) telemedicine visits with physicians, nurse practitioners, and registered dietitians over 17.7 (7.2) months; 36.2% used both telemedicine and in-person visits, and 63.8% used only telemedicine. The most frequently prescribed bAOM was Wegovy® (70.3% of patients), followed by Saxenda® (17.6%), Contrave® (13.6%), and Qsymia® (12.4%). Conclusion: In this study, Wegovy® was the most commonly prescribed bAOM, and telemedicine facilitated frequent appointments (every 1.9 months on average). Future research is necessary to examine the impact of this treatment model on obesity and obesity-related comorbidities. Disclosure A. Shukla: Research Support; Eli Lilly and Company, Novo Nordisk. Consultant; Sun Pharmaceutical Industries Ltd. D. Li: None. A.J. Casper: None. L. Aronne: Advisory Panel; Novo Nordisk. Consultant; Novo Nordisk. Advisory Panel; Lilly Diabetes, Altimmune Inc. Consultant; Lilly Diabetes. Advisory Panel; Pfizer Inc. Consultant; UnitedHealth Group. Advisory Panel; Boehringer-Ingelheim. Board Member; AstraZeneca. Advisory Panel; Amgen Inc. D. D'Angelo: None. K.H. Saunders: Other Relationship; Intellihealth. L.I. Igel: Consultant; Novo Nordisk. Employee; Intellihealth. E. Lucas: Consultant; Intellihealth. K. Palepu: None. E. Zacherle: Employee; Novo Nordisk. A. Traina: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. K. Olsson: Employee; Novo Nordisk.