ABSTRACT The aim of this study is to assess the effects of once-daily oral orforglipron on weight and metabolic markers in adult patients. PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were systematically searched until February 2024 for randomized controlled trials (RCTs) comparing orforglipron versus placebo or other anti-obesity medications in adult patients. Weighted mean differences (WMDs) for continuous outcomes and risk ratios (RRs) or risk differences for binary endpoints were computed, with 95% confidence intervals (CIs). Heterogeneity and risk of bias were assessed with I2 statistics and Rob-2, respectively. Statistical analyses were performed using R, version 4.2.2. A total of four studies were included, comprising 815 patients, of whom 620 (76.1%) were prescribed orforglipron. Compared with placebo, orforglipron reduced body weight (WMD -6.14 kg, 95% CI -9.62 to -2.66 kg), body mass index (WMD -2.87 kg/m2, 95% CI -4.65 to -1.10 kg/m2), and waist circumference (WMD -5.32 cm, 95% CI -9.13 to -1.51 cm). More patients treated with orforglipron than placebo achieved a weight loss of ≥ 5% (RR 3.31, 95% CI 2.23-4.93), ≥ 10% (RR 5.24, 95% CI 2.07-13.31), and ≥ 15% (RR 9.53, 95% CI 1.26-71.89). The most common adverse events were related to the gastrointestinal tract. In this meta-analysis, the use of once-daily oral orforglipron by adult patients was associated with a significant decrease in body weight, as compared with placebo, with an increase in non-severe gastrointestinal adverse events. Phase 3 RCTs are expected to shed further light on the efficacy and safety of once-daily oral orforglipron over the long term. oncedaily once daily PubMed Embase Library ClinicalTrialsgov ClinicalTrials gov 202 (RCTs antiobesity anti obesity WMDs (WMDs RRs (RRs computed 95 CIs. CIs . (CIs) I Rob2, Rob2 Rob 2, 2 Rob-2 respectively R 422 4 4.2.2 included 81 62 76.1% 761 76 1 (76.1% WMD 6.14 614 6 14 -6.1 kg 9.62 962 9 -9.6 2.66 266 66 -2.6 , kg) 2.87 287 87 -2.8 kgm2 kgm m2 m kg/m2 4.65 465 65 -4.6 1.10 110 10 -1.1 kg/m2) 5.32 532 5 32 -5.3 cm 9.13 913 13 -9.1 1.51 151 51 -1.5 cm. cm) RR 331 31 3.31 2.234.93, 223493 2.23 4.93 23 93 2.23-4.93) 524 24 5.24 2.0713.31, 2071331 2.07 13.31 07 2.07-13.31) 15 953 53 9.53 1.2671.89. 1267189 1.26 71.89 26 71 89 1.26-71.89) tract metaanalysis, metaanalysis meta analysis, analysis meta-analysis nonsevere non severe term 20 (CIs Rob- 42 4.2. 8 76.1 7 (76.1 6.1 61 -6. 9.6 96 -9. 2.6 -2. 2.8 28 kg/m 4.6 46 -4. 1.1 11 -1. 5.3 -5. 9.1 91 1.5 33 3.3 234 2.234.93 22349 223 2.2 493 4.9 2.23-4.93 52 5.2 0713 2.0713.31 207133 207 2.0 1331 13.3 0 2.07-13.31 9.5 2671 1.2671.89 126718 126 1.2 7189 71.8 1.26-71.89 4.2 76. (76. 6. -6 9. -9 2. -2 4. -4 1. -1 5. -5 3. 2.234.9 2234 22 49 2.23-4.9 071 2.0713.3 20713 133 13. 2.07-13.3 267 1.2671.8 12671 12 718 71. 1.26-71.8 (76 - 2.234. 2.23-4. 2.0713. 2071 2.07-13. 1.2671. 1267 1.26-71. (7 2.234 2.23-4 2.0713 2.07-13 1.2671 1.26-71 ( 2.23- 2.071 2.07-1 1.267 1.26-7 2.07- 1.26-