Diabetes (DM) is a global public health concern, and recent research indicates a substantial increase in the burden of the condition over the past decade, evolving into a growing epidemic. Specifically, 8.8% of adults are diagnosed with DM (1). If these trends persist, it is projected that by 2040, approximately 693 million individuals aged 18–99, comprising 9.9% of the world’s population, will have DM (1). The occurrence and progression of type 2 diabetes (T2DM) are closely linked to various modifiable risk factors (2). Among these factors, being overweight (body mass index [BMI] ≥ 25 kg/m²) and obesity (BMI ≥ 30 kg/m²) are the major influencers (3, 4). Additionally, limited physical activity, sedentary behaviour and certain habits (including high-calorie intake and smoking) contribute to the rising prevalence of T2DM (5, 6). In the clinical guidelines for managing T2DM without insulin use, recommended approaches include dietary adjustments and increased physical activity. If target blood glucose levels are not achieved, escalation to oral hypoglycaemic agents such as metformin or dipeptidyl peptidase-4 inhibitors is typically initiated (7).

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) provide a new avenue for treating T2DM. These agents activate the glucagon-like peptide-1 receptor (GLP-1 R), stimulating insulin secretion in a glucose-dependent manner and inhibiting glucagon secretion, thereby lowering blood sugar (8). Currently, several GLP-1 RAs are approved for treating T2DM, including liraglutide and semaglutide, known for their excellent glucose-lowering effects while also reducing body weight and blood pressure. However, their administration via subcutaneous injections may impact patient compliance. In comparison, patients may prefer and be more likely to adhere to an oral medication regimen. Presently, semaglutide is the only oral GLP-1 RA approved by the US Food and Drug Administration for T2DM treatment. However, patients taking oral semaglutide must do so at least 30 minutes before the first meal, drink or other medications of the day, limiting water intake to approximately 120 mL and avoiding food or drink for at least 30 minutes post-dose to ensure optimal absorption and efficacy (9). These restrictive intake conditions may affect patient compliance, highlighting the importance of seeking simpler oral GLP-1 RAs as a key treatment goal.

Danuglipron and orforglipron are both small molecule oral formulations of GLP-1 RAs, currently under development for treating T2DM and obesity. The recommendations are twice-daily oral intake for danuglipron and once-daily dosing for orforglipron. Due to orforglipron’s stronger impact on cyclic adenosine monophosphate (cAMP) signalling compared with beta (β)-cell recruitment, its lower risk of receptor desensitisation distinguishes it from other GLP-1 RAs (10). Recent clinical studies have explored the efficacy and safety of these two oral GLP-1 RAs, yet comprehensive evidence for their effectiveness and safety is lacking. Therefore, this study investigates the efficacy and safety of danuglipron and orforglipron in treating T2DM through meta-analysis, providing valuable insights for their clinical application.

In this meta-analysis of prospective studies, we systematically evaluated the effects of novel oral GLP-1 RAs, danuglipron and orforglipron, on glycaemic control and weight management in patients with T2DM and obesity compared with placebo, as well as comprehensively assessing their impacts on AEs, particularly gastrointestinal AEs. Our findings align with previous small-scale studies (22, 23), and this updated analysis provides robust evidence that not only adheres to biological plausibility but also expands clinical understanding through comprehensive quantitative synthesis, offering valuable insights for guiding the clinical use of these novel oral GLP-1 RAs.

In recent years, the GLP-1 R has emerged as a pivotal therapeutic target for T2DM. Although injectable GLP-1 RAs have demonstrated glycaemic benefits clinically, the development of oral formulations remains imperative to overcome limitations associated with injectable administration. This systematic review and meta-analysis synthesised evidence from eight rigorously conducted RCTs, indicating that both danuglipron and orforglipron achieve significant improvements in glycaemic parameters among patients with T2DM and obesity. The marked reductions in HbA1c (danuglipron: MD: −0.90%; orforglipron: MD: −1.02%) and FPG (danuglipron: MD: −24.66 mg/dL; orforglipron: MD: −26.91 mg/dL) are consistent with the established pharmacodynamic actions of GLP-1 RAs, which enhance glucose-dependent insulin secretion via cAMP signalling pathways and suppress α-cell glucagon release (24, 25). According to recent meta-analytic evidence, 7 and 14 mg of semaglutide once daily reduced HbA1c by 1.06% and 1.1%, respectively, compared with placebo in patients with T2DM (26). Furthermore, the same doses of semaglutide demonstrated superior HbA1c reductions of 0.26% and 0.38%, respectively, versus other glucose-lowering agents (26). The divergent effects on FPI (danuglipron increased FPI [MD + 2.94 μIU/mL] whereas orforglipron exhibited neutral effects) likely reflect differences in receptor binding affinities or tissue-specific activation patterns. Additionally, danuglipron’s FPI elevation may resemble early-phase insulinotropic effects observed with short-acting agents, raising concerns about its long-term implications for β-cell exhaustion.

Significant weight reduction was observed with both agents, particularly highlighting orforglipron’s superior efficacy in reducing body weight (MD: −6.28 kg) and BMI (MD: −2.64 kg/m²), underscoring their dual role in metabolic regulation. Previous studies reported that 7 mg of semaglutide induced a weight loss of 1.18 kg versus placebo and 1.47 kg compared with other glucose-lowering agents (26). However, the lack of FPI improvement with orforglipron warrants caution, as suppressed insulin levels in the context of weight loss may paradoxically exacerbate dyslipidaemia in susceptible individuals – a phenomenon observed in certain lifestyle intervention trials. Clinicians should therefore balance the benefits of weight reduction against potential metabolic trade-offs, particularly in patients with comorbid cardiovascular disease (27).

The safety profiles of both agents were dominated by gastrointestinal AEs, such as nausea and vomiting, consistent with the class effects of GLP-1 RAs. Mechanistically, these AEs arise from delayed gastric emptying and direct stimulation of GLP-1 Rs in the area postrema, a circumventricular organ mediating emesis. For danuglipron, gastrointestinal side effects may be target mediated, and the presence of a carboxylic acid moiety in its structure could contribute to these outcomes by influencing its pharmacokinetic properties, dosing regimen and direct gastrointestinal irritation (28). The incidence of danuglipron-related AEs exhibits dose dependency. Although Phase 1 trial data suggested no dose-dependent increase in gastrointestinal AEs (15), another Phase 1 trial observed the lowest AE rates at low doses (10–15 mg), with 100% AE incidence at 120 mg, indicating a clear dose–response relationship for gastrointestinal tolerability (14). Furthermore, danuglipron’s Phase 2 study demonstrated escalating discontinuation rates and AE frequencies as the target dose increased from 80 mg twice daily to 200 mg twice daily (18). Regarding orforglipron, most AE risks appear linked to rapid dose escalation and were more pronounced in aggressive titration groups (21). However, its Phase 1b trial revealed no significant dose-dependent effects, potentially due to the limited sample size and short exposure duration (17). Emerging pharmacogenomic evidence suggests that polymorphisms in the GLP-1 R gene (GLP1R) may modulate AE susceptibility, explaining interpatient variability. For example, carriers of the rs6923761 G-allele exhibit attenuated gastrointestinal responses to GLP-1 RAs, a finding that merits integration into personalised treatment algorithms (29, 30). Future trials should evaluate whether intermittent dosing or adjunctive antiemetics can mitigate AE-related discontinuations without compromising therapeutic efficacy.

We observed a modest increase in FPI among participants treated with danuglipron in our pooled analysis. Several non-mutually exclusive mechanisms may explain this finding. First, GLP-1 R agonism augments glucose-dependent insulin secretion, and early improvements in β-cell responsiveness could manifest as higher fasting insulin levels, particularly in short-term trials (31). Second, changes in hepatic insulin clearance or transient compensatory hyperinsulinemia related to concurrent background therapies (e.g. use of insulin secretagogues or withdrawal/alteration of other agents) might increase measured fasting insulin independently of insulin sensitivity (32). Third, methodological factors – including heterogeneity in assay methods, sampling timing, the relatively short duration of most included trials and limited sample sizes – could have contributed to an apparent rise in FPI (33). Importantly, the clinical importance of this short-term FPI increase is uncertain – an isolated rise in fasting insulin does not necessarily indicate progressive β-cell dysfunction and may reflect transient adaptations (34).

A contemporary and closely related meta-analysis by Karakasis et al. (35) examined randomised trials (n = 1,037) of oral small-molecule GLP-1 RAs (danuglipron and orforglipron) and reported broadly similar effects on glycaemia and body weight (HbA1c reduction = −1.03%, FPG = −28.5 mg/dL, weight = −4.3 kg), as well as an increased incidence of gastrointestinal AEs. Notably, Karakasis et al. complemented their synthesis with a dose–response meta-analysis using restricted cubic splines along with a GRADE assessment of evidence certainty, which provided useful insight into dose–effect relationships and the strength of available evidence. The present analysis is consistent with their principal findings; importantly, however, our study extends the evidence base by including more recent trials and a larger pooled sample (n = 1,454 in our review) and by reporting additional outcomes (e.g. fasting insulin and a more granular safety analysis). Although Karakasis et al. provided formal dose–response curves and GRADE ratings, these analyses were not included in the present manuscript due to differences in available dose-level reporting across the newly added trials. Nevertheless, the concordance between the two independent meta-analyses strengthens confidence in the emerging clinical profile of these oral GLP-1 RAs. We acknowledge that incorporating formal GRADE and dose–response meta-analyses into future revisions (or as supplementary analyses) would further increase the interpretability and clinical applicability of the results.

The findings suggest that oral small-molecule GLP-1 RAs achieve the class’s expected metabolic benefits (HbA1c and weight reduction) while offering the practical advantage of oral dosing, which may improve uptake and adherence among patients unwilling or unable to use injectables. However, several factors limit immediate translation into routine care. Large, long-term outcome data – including cardiovascular safety and durability of glycaemic/weight effects – are lacking for these oral agents, and head-to-head comparisons with established injectable GLP-1 RAs are not yet available. Tolerability concerns (notably gastrointestinal AEs) and a modest short-term signal of increased fasting insulin also warrant cautious interpretation and monitoring. To define the optimal place of these agents in clinical pathways, future priorities should include independent Phase 3 trials, pragmatic real-world studies, direct comparative trials against injectable GLP-1 RAs, standardised reporting of concomitant glucose-lowering therapies and metabolic dynamic measures, and formal cost-effectiveness and adherence evaluations. Until such evidence accrues, clinicians should weigh the convenience of oral therapy against unresolved questions regarding long-term safety, comparative effectiveness and patient selection.

Several limitations affect the interpretability of these findings. First, as most included studies were early-phase clinical trials, the pooled sample size (n = 1,454) and short trial durations (≤36 weeks) preclude definitive conclusions regarding rare safety outcomes or the durability of metabolic benefits. Second, considerable heterogeneity was observed in weight and fasting glucose outcomes; because the included trials were generally small and underpowered for detailed subgroup analyses, the sources of this heterogeneity could not be fully resolved. Third, heterogeneity in background therapies across trials – particularly variable use of SGLT2 inhibitors and metformin – may have confounded the observed treatment effects, but insufficient and inconsistently reported data precluded further exploration of these confounders’ potential impacts. Finally, all included trials were industry sponsored, which may introduce reporting or publication bias. Future research should prioritise large, independently funded Phase 3 trials, incorporate real-world evidence to evaluate these agents in underrepresented populations (e.g. advanced chronic kidney disease) and conduct cost-effectiveness analyses to inform healthcare resource allocation.

This study’s findings suggest that the novel small-molecule GLP-1 RAs danuglipron and orforglipron represent effective and safe options for glycaemic management in patients with T2DM. Notably, both agents also demonstrate considerable benefits in weight control. While orforglipron and similar oral GLP-1RAs show promise, current evidence is insufficient to conclude that they are ready alternatives to established therapies. Large, long-duration RCTs with thorough safety monitoring and independent outcome adjudication are required to define the long-term efficacy, tolerability and risk–benefit profile of oral small-molecule GLP-1RAs.