IntroductionObesity and overweight are prevalent and growing global public health concerns that significantly increase the risk of long-term complications, including type 2 diabetes, cancer, hypertension, cardiovascular disease, and other serious health issues, compromising quality of life and life expectancy.1 The escalating prevalence of these conditions has placed an increasing burden on healthcare systems worldwide, necessitating urgent and effective public health interventions. Among the nations grappling with this epidemic, China stands out as having the highest absolute numbers of individuals affected by excess body weight. According to recent national data, the prevalence of overweight and obesity among Chinese adults has reached 34.3% and 16.4%, respectively.2 This rapid rise in obesity prevalence reflects the combined effects of sedentary lifestyles, dietary transitions toward high-calorie processed foods, and rapid urbanization over the past several decades. More concerning is the finding that obesity now ranks as the sixth leading risk factor for death and disability in China, posing a substantial challenge to the country’s healthcare system.3 Without effective and scalable interventions, the obesity epidemic is projected to worsen, further threatening public health and overwhelming healthcare resources in the coming decades.In response to this growing burden of obesity and its associated complications, effective and sustainable pharmacological interventions have gained increasing prominence beyond comprehensive lifestyle management. Over the last decade, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the therapeutic landscape of obesity and overweight, firmly establishing GLP-1RA-based pharmacotherapy as a cornerstone of body weight management.4 Several GLP-1RAs, including liraglutide, semaglutide, and the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, have been approved for obesity treatment by health authorities. Despite their clinical success, most GLP-1RAs require subcutaneous injections, which raise concerns about injection-site reactions and poor long-term adherence. While oral semaglutide has been approved for type 2 diabetes, its clinical application for weight loss in overweight and obesity is still under investigation in clinical trials.5,6 Although oral semaglutide represents a key milestone in expanding oral peptide-based therapy, its clinical use is limited by low bioavailability, strict administration requirements (e.g., fasting and specific timing relative to meals), and tolerability issues. These challenges can undermine patient compliance, highlighting the urgent need for alternative oral GLP-1RAs that bypass these barriers. Consequently, developing novel, nonpeptide GLP-1RAs with improved oral bioavailability and short titration algorithms could significantly enhance weight management outcomes and patient adherence.7The small-molecule compound VCT220 was developed as a nonpeptide GLP-1RA for managing obesity and type 2 diabetes. As a once daily, orally administered agent, VCT220 eliminates the need for injections, thereby increasing the willingness to initiate treatment, enhancing the convenience of use, and improving long-term adherence. Unlike oral semaglutide, which requires absorption enhancers and strict fasting administration, VCT220 does not rely on specialized delivery technologies and can be taken with meals, further supporting sustained patient compliance.7 Phase I trials submitted to the Chinese health authority involving healthy participants (CTR20222374) and individuals with overweight, obesity (CTR20231482), or type 2 diabetes (CTR20230826) have shown favorable safety and tolerability profiles, comparable with those of established injectable GLP-1RAs. These initial findings laid the groundwork for the current phase II trial, which further evaluates the efficacy and safety of VCT220 in weight management.To further rigorously investigate the optimized flexible titration regimen of oral GLP-1RA and body weight loss potential at high target maintenance dose, we conducted a randomized, double-blind, placebo-controlled, multicenter phase II trial across 13 clinical sites in China to assess the efficacy and safety of VCT220 in Chinese adults who had obesity or overweight with at least one weight-related comorbidity. All participants received once-daily oral VCT220 (80 mg, 120 mg, or 160 mg) or placebo, alongside standardized lifestyle counseling, over a 16-week treatment period, followed by a 2-week safety follow-up. Notably, a short dose escalation period (4–6 weeks) was designed in this study to fully leverage the flexible titration advantages of oral nonpeptide GLP‑1RA. This trial represents the first controlled evaluation of VCT220 in a Chinese population and addresses an urgent clinical need for effective and convenient oral anti-obesity therapies tailored to local demographics.ResultsParticipant characteristicsBetween December 25, 2023 and March 22, 2024, 328 participants were screened, and 250 were randomized to receive VCT220 at doses of 80 mg, 120 mg, or 160 mg (62–65 participants per group, including 31 in each 160 mg titration subgroup) or a dose-matched placebo (n = 61) (Fig. 1). The baseline characteristics were well-balanced across the treatment groups (Table 1). The mean age of the participants was 32.4±7.46 years, with a mean body weight of 91.76±13.80 kg and a mean BMI of 32.03±3.27 kg/m2; 146 participants (58.4%) were male, and 104 (41.6%) were female. Among them, 237 participants (94.8%) completed the 16-week treatment, and 236 participants (94.4%) completed the study. All 250 participants met the inclusion criteria of both the full analysis set and the safety analysis set. Treatment was discontinued in 13 participants (5.2%). The most common reason for discontinuation was participant withdrawal (n = 7, 2.8%). Specific data on discontinuations due to adverse events (AEs), which occurred in 4 participants, is presented in Table 3.Fig. 1Full size imageFlow diagram of the participants. The flow diagram illustrates the disposition of the participants screened and enrolled. ST slow titration, FT fast titration, AE adverse eventTable 1 Demographic and clinical characteristics of the participants at baselineFull size tableWeight-related outcomesVCT220 reduced weight in a dose-dependent manner and no apparent plateau was observed until week 16 (Fig. 2a). At week 16, the mean percentage weight reductions from baseline were significantly greater with VCT220 at all doses than with the pooled placebo: –5.75% (95% CI: –6.71 to –4.80) for 80 mg, –7.42% (95% CI: –8.41 to –6.44) for 120 mg, –9.40% (95% CI: –10.79 to –8.02) for 160 mg slow titration (ST), –9.73% (95% CI: –11.16 to –8.29) for 160 mg fast titration (FT), versus –1.61% (95% CI: –2.59 to –0.63) for the pooled placebo. The estimated treatment differences ranged from –4.14% (95% CI: –5.51 to –2.77) for 80 mg to –8.11% (95% CI: –9.85 to –6.38) for 160 mg-FT (Table 2). The absolute weight reductions (kg) reflected these percentage reductions (Fig. 2b, Table 2). Sensitivity analyses confirmed consistency with the results of the primary analysis (supplementary Tables 2, 3). Subgroup analysis results of weight changes using Chinese BMI category and comorbidity status were comparable with those using U.S. benchmark criteria (supplementary Table 8–11).Fig. 2Full size imageComparison of body weight parameters with VCT220 versus placebo during the treatment period. a Observed mean percentage change in body weight over time. Numbers below the panels are the number of participants contributing to the mean. b Observed mean change in body weight (kg) over time. Numbers below the panels are the number of participants contributing to the mean. c Observed proportions of participants who had body weight reductions of at least 5%, 10%, and 15% at week 16. d Observed proportions of participants who had body weight reductions of at least 5% at week 8, week 12, and week 16. All data were analyzed using FAS with multiple imputation. Changes from baseline data are reported as the least squares mean ± SE. ST slow titration, FT fast titration, SE standard error, FAS full analysis setTable 2 Primary and selected secondary endpointsFull size tableAt week 16, 55.4% (80 mg) to 90.3% (160 mg-ST) of participants treated with VCT220 achieved at least 5% weight loss, compared to 13.1% in the placebo group. The results were dose-dependent, with the following proportions of participants achieving ≥ 5% weight loss: 80 mg: 55.4%, 120 mg: 72.6%, 160 mg-FT: 77.4%, 160 mg-ST: 90.3%. For the ≥ 10% weight loss threshold, the response ranged from 4.6% (80 mg) to 45.2% (160 mg-FT) across VCT220 doses, while only 1.6% of placebo participants achieved this level. Similarly, 1.5% (80 mg) to 9.7% (160 mg-FT) of participants in the VCT220 groups achieved ≥ 15% weight loss, whereas no participants in the placebo group did so. These results demonstrate a clear dose-dependent effect of VCT220 on clinically meaningful weight loss (Fig. 2c, d). Only participants in the 160 mg-FT group (1.6%) achieved weight loss of 20% or more. Moreover, while the study duration of 16 weeks did not show a plateau in weight loss, the ongoing trends, particularly in the higher-dose groups, suggest that longer-term treatment may lead to even greater weight loss. Furthermore, the decrease in BMI and waist circumference was dose-dependent, with VCT220 consistently leading to greater reductions compared to the placebo group. The mean changes from baseline in BMI and waist circumference at week 16 ranged from –1.80 to –3.21 kg/m2 and from –5.15 to –7.61 cm, respectively, across VCT220 doses, whereas the values were –0.49 kg/m2 and –1.99 cm, respectively, in the placebo group (Table 2).Cardiometabolic parametersImprovements were also observed in several exploratory cardiometabolic parameters, including blood pressure, glycemic markers and lipid measures. At the end of treatment, participants receiving VCT220 showed mean reductions in systolic blood pressure (SBP) ranging from −5.2 mmHg to −9.7 mmHg and in diastolic blood pressure (DBP) ranging from −3.8 mmHg to −5.3 mmHg, whereas the corresponding reductions were −3.1 mmHg and −1.2 mmHg in the placebo group (Fig. 3a, b; supplementary Tables 4, 5). These improvements in the blood pressure did not result in significant changes in the heart rate until the end of treatment.Fig. 3Full size imageComparison of cardiometabolic parameters with VCT220 versus placebo during the treatment period. a Observed mean change in systolic pressure (mmHg) over time. Numbers below the panels are the number of participants contributing to the mean. b Observed mean change in diastolic pressure (mmHg) over time. Numbers below the panels are the number of participants contributing to the mean. c Mean change in HbA1c (%) from baseline at week 16. d Mean change in fasting insulin (mIU/L) from baseline at week 16. All data were analyzed using FAS with multiple imputation. Changes from baseline data are reported as the least squares mean ± SE. ST slow titration, FT fast titration, HbA1c glycated hemoglobin A1c, SE standard error, FAS full analysis setSignificant improvements in HbA1c and fasting insulin were observed with VCT220 treatment compared to placebo (Fig. 3c, d; Table 2). HbA1c levels decreased from baseline to week 16 across all VCT220 dose groups, with more significant reductions than placebo. The estimated mean treatment differences were –0.17% for VCT220 80 mg, –0.21% for VCT220 120 mg, –0.25% for VCT220 160 mg-ST and –0.35% for VCT220 160 mg-FT. Fasting insulin concentrations decreased significantly in a dose-dependent manner as VCT220 dose levels increased. Higher doses of VCT220 tended to produce greater reductions in total cholesterol and triglycerides. The mean changes from baseline in total cholesterol and triglycerides at week 16 ranged from –0.31 to –0.58 mmol/L and from –0.05 to –0.48 mmol/L, respectively, across VCT220 doses, whereas the values were –0.23 mmol/L and 0.11 mmol/L, respectively, in the placebo group (Table 2).Safety outcomesVCT220 was well tolerated across all dose groups, without any identified new safety signals. The proportion of participants reporting treatment-emergent adverse events (TEAEs) was similar between the VCT220 groups (89.2–100%) and the placebo group (93.4%) (Table 3). Treatment-related adverse events (TRAEs) of VCT220 were 78.5% for 80 mg, 91.9% for 120 mg, 80.6% for 160 mg-ST and 87.1% for 160 mg-FT, versus 60.7% for placebo. Most TEAEs and TRAEs were mild or moderate, transient, and manageable. Treatment discontinuation because of TEAEs occurred in one participant each in the 80 mg, 120 mg, 160 mg-FT, and placebo groups.Table 3 Adverse events during the trial period (safety analysis set)Full size tableGastrointestinal adverse events (GI-AEs) were the most frequently reported AEs, with an overall incidence of 58.4% (146 participants). The incidence of GI-AEs increased in a dose-dependent manner, ranging from 58.5% at 80 mg to 74.2% at 120 mg and 72.6% at pooled 160 mg, compared to 27.9% in the placebo group, representing a 2.1- to 2.7-fold increase in GI-AE rates with VCT220 relative to placebo. Within the 160 mg dose group, the incidence of GI-AEs was significantly higher in participants receiving fast titration (80.6%) compared to placebo (27.9%). Notably, slow titration reduced this incidence to 64.5%, highlighting the impact of dosing strategy on tolerability. Nausea, vomiting, and diarrhea were the common GI-AEs with a dose-dependent manner in incidence. Nausea of VCT220 groups ranged from 41.5% (80 mg) to 58.1% (160 mg-FT), versus 8.2% in the placebo group. Vomiting of VCT220 groups ranged from 13.8% (80 mg) to 41.9% (160 mg-FT), versus 8.2% in the placebo group. Diarrhea of VCT220 groups ranged from 17.7% (120 mg) to 29.0% (160 mg-FT), versus 8.2% in the placebo group.As expected for GLP-1RAs, the incidence of GI-AEs peaked during the dose titration phase (weeks 4-6) and decreased from week 4 to week 16. Most GI-AEs were mild (grade 1, 50.4%) or moderate (grade 2, 17.2%), with only the 120 mg group experiencing three instances (1.2%) of grade 3 GI-AEs. Importantly, permanent discontinuation due to gastrointestinal events was rare, occurring in only two participants across all VCT220 groups. VCT220 treatment reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, with more significant reductions observed in the 120 mg and 160 mg groups than in the 80 mg and placebo groups (supplementary Tables 6, 7). No significant safety concerns related to liver function were identified. As for hypoglycemic events, a total of 9 episodes among 5 (2.0%) participants were reported, with 1 participant in the placebo group, 1 participant in the 80 mg group, 2 participants in the 120 mg group, and 1 participant in the 160 mg group, respectively. All events were mild, and no severe hypoglycemia was reported. There were no significant differences in the incidence of hypoglycemia between groups.Cardiovascular events were infrequent and mild (Grade 1), comparable between the VCT 220 groups and placebo group, with palpitation being the most common event. The proportion of different degrees of change in QTcF relative to baseline (ΔQTcF) in all VCT220 groups showed no significant difference from that in the placebo group, suggesting that VCT220 tablets do not increase the risk of QT interval prolongation. An increase in the calcitonin levels was rare, mild, transient, and resolved without intervention. No significant safety concerns were identified in the renal, hepatic, gallbladder, or psychiatric assessments. Additionally, no deaths and drug-related SAEs occurred during the trial.DiscussionIn this randomized, placebo-controlled phase II trial, the nonpeptide oral GLP-1RA VCT220 produced dose-dependent and clinically meaningful reductions in body weight, waist circumference, HbA1c, fasting insulin, total cholesterol, triglycerides and blood pressure over 16 weeks in adults with overweight or obesity without diabetes. The magnitude of weight loss was notable given the short treatment duration, and the high proportion of participants achieving ≥5% and ≥10% weight loss reinforces the potential clinical utility of this agent.Injectable GLP-1RAs typically achieve peak weight loss after 40-68 weeks.8,9,10,11,12,13 Similarly, orforglipron, another nonpeptide GLP-1RAs, resulted in a body weight reduction of 11.2%, with a placebo-corrected reduction of 9.1% in participants with obesity at week 72 at the highest dose of 36 mg in phase III trial ATTAIN−1.11 In phase III trial OASIS1, Oral semaglutide 50 mg showed a treatment difference of -12.7% of mean body weight change from baseline compared with placebo at week 68 in adults with overweight or obesity without type 2 diabetes.6 As a once-daily, orally administered, nonpeptide agent, VCT220 eliminates the need for injections, which may improve patient acceptance, convenience, and long-term adherence. In this phase II trial, VCT220 reduced weight in a dose-dependent manner and achieved a weight reduction of 9.73% in the highest 160 mg-FT group without an apparent plateau at week 16.The safety profile was consistent with other GLP-1RAs, with GI-AEs such as nausea, vomiting and diarrhea being the most common TEAEs.10,14,15,16 GI-AEs were dose-dependent and predominantly occurred during the dose-escalation phase, particularly in the first four weeks. The rapid titration group (160 mg-FT) showed higher GI-AE rates than the slow titration group (160 mg-ST), suggesting that slower titration improves tolerability—a finding consistent with other GLP-1RA trials.11,17,18,19,20 Additionally, SBP and DBP reductions ranged from −5.2 to −9.7 mmHg and from −3.8 to −5.3 mmHg, respectively, surpassing placebo (−3.1 mmHg and −1.2 mmHg), which may suggest a potentially greater antihypertensive effect with VCT220 compared to other GLP-1 receptor agonists, a finding that warrants confirmation in further studies.21 The incidence of hypoglycemic events was infrequent, with no severe cases reported, consistent with the known safety profiles of this drug class. Discontinuation due to AEs was rare, occurring in only one participant from each of the VCT220 80 mg, 120 mg, and 160 mg groups and the placebo group. No significant safety concerns were identified in the renal, hepatic, gallbladder, or psychiatric assessments, comparable with semaglutide, dulaglutide, and orforglipron.11,15,19,20 Furthermore, the high trial completion rate (>94%) and low discontinuation rates strengthen the robustness of these results.Oral nonpeptide, small-molecule GLP-1RAs may differ from oral peptide GLP-1RAs (e.g., oral semaglutide) in receptor engagement, desensitization, and tissue distribution.22 In contrast to oral semaglutide, which requires absorption enhancers and strict fasting administration, VCT220 does not depend on specialized delivery technologies and can be taken with meals.6 VCT220 also showed slow systemic clearance, prolonging plasma exposure and restricted tissue distribution, reducing off-target retention.23 While the extent of CNS penetration and long-term receptor kinetics is not fully characterized, our in-house preliminary animal experiments have indicated measurable but low brain concentrations of VCT220. These findings support the hypothesis of combined central and peripheral metabolic effects of GLP-1RAs, meriting confirmation in future studies. The good tolerability and favorable dose-dependent efficacy of VCT220 provide a strong rationale for testing higher doses in future trials, aiming to fully explore its therapeutic potential.This study had several limitations. The 16-week duration, along with the time required to reach the target dose, especially for participants in the VCT220 160 mg slow titration group who did not reach the target dose until week 7, may not have fully captured the weight loss potential or long-term safety profile of VCT220. The U.S. FDA and EMA require anti-obesity drugs to demonstrate ≥5% placebo-subtracted weight loss sustained over at least one year, along with an acceptable cardiovascular and metabolic safety profile. While the observed weight loss over just 16 weeks is promising for a short-term proof of concept, information on durability, plateau, and long-term safety is limited, as well as the comparisons with other GLP-1RA trials should be interpreted cautiously. Longer-term trials for at least one year are essential to determine whether VCT220 meets these regulatory benchmarks. The favorable tolerability and low discontinuation rate in this trial provide preliminary support for proceeding to phase III evaluation. Improvements of numerous metabolic parameters were exploratory results, which also need to be further confirmed in phase III evaluation with a prespecified hierarchy for the analysis. Besides, this multi-center phase II trial explored several different titration algorithms with corresponding placebo, leading to potential bias raised from pooled placebo cohorts, site effects and the confounding introduced by different titration cadences. Moreover, the study participants were predominantly Han Chinese under Chinese criteria of overweight and obesity, limiting the generalizability of the findings to more diverse ethnic groups by using different obesity and overweight diagnosis criteria (BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with comorbidity). The low burden of baseline comorbidities seen in East Asian obesity populations may also limit extrapolation to Western populations with higher cardiometabolic risk. Furthermore, pharmacological responses to GLP-1RAs may vary by ethnicity due to differences in body composition, insulin sensitivity, and genetic factors. Additionally, as is typical for phase II trials, participants with significant comorbidities, such as advanced heart failure (New York Heart Association class 3 or 4) or severe renal dysfunction (eGFR