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BACKGROUND Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagonlike peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity. METHODS In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point). RESULTS A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from - 8 . 6% to - 1 2 . 6% across the orforglipron dose cohorts and was - 2 . 0% in the placebo group. At week 36, the mean change ranged from - 9 . 4% to - 1 4 . 7% with orforglipron and was - 2 . 3% with placebo. A weight reduction of at least 1 0% by week 36 occurred in 46 to 7 5% of the participants who received orforglipron, as compared with 9 % who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class. C O N C L U S I O N S Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. [ABSTRACT FROM AUTHOR]

Aim: To compare the efficacy of tirzepatide 10 and 15 mg with semaglutide 2.4 mg using an indirect treatment comparison. Materials and Methods: Using SURMOUNT‐1 and STEP 1 trial data, mean percentage change in body weight from baseline and odds ratio (OR) of achieving 5% or greater weight loss were compared between tirzepatide 10 and 15 mg at week 72 and semaglutide 2.4 mg at week 68 using matching‐adjusted indirect comparison of the efficacy estimand. Sensitivity analyses were completed using different methods, including the Bucher method, also using different estimands and/or time points. Results: Greater reductions in percentage change in body weight were observed with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg (tirzepatide 10 mg mean difference: −4.67% [95% CI −5.91%, −3.43%]; tirzepatide 15 mg mean difference: −5.92% [95% CI −7.16%, −4.68%]; both P <.001). Similarly, more participants achieved 5% or greater weight loss with tirzepatide 10 mg (OR 2.61 [95% CI 1.48, 4.57]; P <.001) and 15 mg (OR 2.75 [95% CI 1.57, 4.81]; P <.001) compared with semaglutide 2.4 mg. All sensitivity analyses were consistent, except for an OR of achieving 5% or greater weight loss with tirzepatide 10 mg using the Bucher method to analyse the treatment regimen estimand (P =.074). Conclusions: Currently there are no direct comparisons of tirzepatide and semaglutide for weight management. Using the matching‐adjusted indirect treatment comparison method to compare the efficacy of tirzepatide and semaglutide for chronic weight management, this analysis showed greater weight loss with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg. [ABSTRACT FROM AUTHOR]

Objective: This study evaluated the effect of once‐weekly semaglutide 2.4 mg on 2‐year control of eating. Methods: In STEP 5, adults with overweight/obesity were randomized 1:1 to semaglutide 2.4 mg or placebo, plus lifestyle modification, for 104 weeks. A 19‐item Control of Eating Questionnaire was administered at weeks 0, 20, 52, and 104 in a subgroup of participants. P values were not controlled for multiplicity. Results: In participants completing the Control of Eating Questionnaire (semaglutide, n = 88; placebo, n = 86), mean body weight changes were −14.8% (semaglutide) and −2.4% (placebo). Scores significantly improved with semaglutide versus placebo for Craving Control and Craving for Savory domains at weeks 20, 52, and 104 (p < 0.01); for Positive Mood and Craving for Sweet domains at weeks 20 and 52 (p < 0.05); and for hunger and fullness at week 20 (p < 0.001). Improvements in craving domain scores were positively correlated with reductions in body weight from baseline to week 104 with semaglutide. At 104 weeks, scores for desire to eat salty and spicy food, cravings for dairy and starchy foods, difficulty in resisting cravings, and control of eating were significantly reduced with semaglutide versus placebo (all p < 0.05). Conclusions: In adults with overweight/obesity, semaglutide 2.4 mg improved short‐ and longer‐term control of eating associated with substantial weight loss. [ABSTRACT FROM AUTHOR]

Aim: To explore changes in body weight and cardiometabolic risk factors after treatment withdrawal in the STEP 1 trial extension. Materials and Methods: STEP 1 (NCT03548935) randomized 1961 adults with a body mass index ≥ 30 kg/m2 (or ≥ 27 kg/m2 with ≥ 1 weight‐related co‐morbidity) without diabetes to 68 weeks of once‐weekly subcutaneous semaglutide 2.4 mg (including 16 weeks of dose escalation) or placebo, as an adjunct to lifestyle intervention. At week 68, treatments (including lifestyle intervention) were discontinued. An off‐treatment extension assessed for a further year a representative subset of participants who had completed 68 weeks of treatment. This subset comprised all eligible participants from any site in Canada, Germany and the UK, and sites in the United States and Japan with the highest main phase recruitment. All analyses in the extension were exploratory. Results: Extension analyses included 327 participants. From week 0 to week 68, mean weight loss was 17.3% (SD: 9.3%) with semaglutide and 2.0% (SD: 6.1%) with placebo. Following treatment withdrawal, semaglutide and placebo participants regained 11.6 (SD: 7.7) and 1.9 (SD: 4.8) percentage points of lost weight, respectively, by week 120, resulting in net losses of 5.6% (SD: 8.9%) and 0.1% (SD: 5.8%), respectively, from week 0 to week 120. Cardiometabolic improvements seen from week 0 to week 68 with semaglutide reverted towards baseline at week 120 for most variables. Conclusions: One year after withdrawal of once‐weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two‐thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health. [ABSTRACT FROM AUTHOR]

To assess changes in weight by calendar month and sex in patients enrolled in a weight loss intervention. Adults participating in a lifestyle weight loss intervention at the Wharton Medical Clinic from January 1st, 2007 to July 4th, 2019 were examined (N = 19,153). A linear generalized estimating equation was used to examine the association between weight change (baseline, month 1, month 2) and calendar month with adjustment for age, sex and baseline body mass index. A first order interaction between sex and calendar was included to assess if the association between calendar month and weight loss differs by sex. Patients lost 1.3 ± 2.0 kg (1.2 ± 1.8%) of their body weight per month. As compared to the mean monthly weight loss, patients lost slightly less weight in September (mean, 95% confidence interval (CI): −0.3, −0.4 to −0.2 kg) and slightly more weight in October (0.2, 0.1–0.3 kg). With adjustment for age, body mass index and calendar month, men lost 0.4 kg/month (95% CI: 0.3, 0.5 kg/month) than women. There were no other significant differences in the monthly weight change between men and women (sex*calendar month P-value = 0.24). While there were slight differences in the amount of weight change achieved by patients in September, and October, it was not of a magnitude that is likely clinically relevant. In addition, men consistently lost more weight than women across all calendar months. Taken together, this suggest that calendar month is not associated with differences in weight loss for men and women enrolled in a structured weight management program. [ABSTRACT FROM AUTHOR]

Background: Our objective was to identify factors that are independently associated with early attrition and successful weight loss (WL) in an obesity-management program. Methods: Participants were 9,498 patients enrolled in treatment at the Wharton Weight Management Clinic for at least 6 months. Predictors of early attrition (<6 months) and successful WL (=5%) were analyzed using relative risk (RR) in men and women separately. Pearson's correlation was used to determine the relationship between WL and treatment time Weight loss and attrition analysis was restricted to patients who had more than two visits (n = 5415). Results: Older individuals had lower early attrition (RR Range:0.74-0.92, P < 0.05) and greater WL success (RR Range:1.40-1.65, P < 0.05) than younger individuals. Males with hypertension and females with depression had greater early attrition (RR Range:1.09-1.20, P < 0.05) and lower WL success (RR Range:0.48-0.57, P < 0.05) than those without these health conditions. Males with lower education had greater early attrition (RR = 1.11[1.03-1.19]) than males with higher education, but did not differ in WL. Females who smoked had greater early attrition (RR = 1.06[1.01-1.11]) than females who did not smoke, but did not differ in WL. Ethnicity was not related to early attrition, however, females of Black and Other ethnicities had lower WL success compared to White females (RR Range:0.58-0.74, P < 0.05). After adjusting for treatment time, all above associations were no longer significant and treatment time remained as the only independent predictor of WL success (P < 0.0001). Conclusion: As WL is positively and independently related with treatment time, individuals at risk for early attrition may need alternative treatment options, in order to improve patient retention and improve WL success. [ABSTRACT FROM AUTHOR]

Background: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.Methods: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.Results: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).Conclusions: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935). [ABSTRACT FROM AUTHOR]