--- arxiv_id: PMC12230154 title: "Efficacy and Safety of GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes Mellitus: A Systematic Review and Network Meta-Analysis" authors: - Xiaoyu Ren - Honghao Hua - Yuanqin Wu - Wei Zhang - Xianzhen Long - Yana Bai - Ning Cheng difficulty: Intermediate tags: - GLP-1 - Diabetes - NMA - Clinical published_at: 2025-01-01 flecto_url: https://flecto.zer0ai.dev/papers/PMC12230154/ lang: en --- ## Hero, Element=Badge ### Scientific Reports · Nature Portfolio · 2025 ## Hero, Element=Title ### Efficacy and Safety of GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes Mellitus ## Hero, Element=Subtitle ### A Systematic Review and Network Meta-Analysis · 64 RCTs · 25,572 Participants · Bayesian NMA ## Hero, Element=Author ### Xiaoyu Ren et al. ## Hero, Element=Doi Link ### DOI: 10.1038/s41598-025-09807-0 ## Abstract, Element=H1 ### Key Findings ## Abstract, Element=Caption The largest head-to-head comparison integrating data from 64 randomized controlled trials and 25,572 participants via Bayesian network meta-analysis ## Abstract, Element=Metric Number 1 ### HbA1c −2.3% ## Abstract, Element=Metric Label 1 ### Tirzepatide HbA1c reduction vs. placebo ## Abstract, Element=Badge 1 ### #1 RANKED ## Abstract, Element=Metric Sub 1 ### Semaglutide −1.5% · Liraglutide −1.2% ## Abstract, Element=Metric Number 2 ### −9.1 kg ## Abstract, Element=Metric Label 2 ### Tirzepatide body weight reduction vs. placebo ## Abstract, Element=Badge 2 ### MAX EFFECT ## Abstract, Element=Metric Sub 2 ### Semaglutide −2.8 kg · Liraglutide −1.2 kg ## Abstract, Element=Metric Number 3 ### 64 RCTs ## Abstract, Element=Metric Label 3 ### Randomized controlled trials included ## Abstract, Element=Badge 3 ### LARGEST NMA ## Abstract, Element=Metric Sub 3 ### 25,572 patients · Systematic search through October 2024 ## Abstract, Element=P1 GLP-1 receptor agonists (GLP-1 RAs) — including tirzepatide, semaglutide, and liraglutide — represent a new generation of treatments for type 2 diabetes mellitus (T2DM). These agents work by mimicking the incretin hormone GLP-1, stimulating insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting satiety. Beyond glycemic control, they offer meaningful reductions in body weight, a major comorbidity in T2DM. ## Abstract, Element=P2 This study represents the most comprehensive Bayesian network meta-analysis (NMA) to date, integrating 64 randomized controlled trials (RCTs) encompassing 25,572 participants. Using NMA methodology, the researchers were able to compare drugs that have never been directly tested against each other — providing clinically critical indirect comparisons across nine GLP-1 RA formulations and multiple conventional antidiabetic agents. ## Abstract, Element=P3 The primary analysis focused on HbA1c (glycated hemoglobin, the 3-month average blood glucose indicator) and FPG (fasting plasma glucose). Secondary outcomes included body weight, BMI, blood pressure, lipid profiles, and adverse events including hypoglycemia and gastrointestinal symptoms. The results provide evidence-based guidance for individualized treatment selection in clinical practice. ## Introduction, Element=H1 ### Background ## Introduction, Element=H2 ### Type 2 Diabetes and GLP-1 Receptor Agonists ## Introduction, Element=P1 Type 2 diabetes mellitus (T2DM) is a major global health challenge. According to the International Diabetes Federation (IDF), the number of adults living with diabetes worldwide is projected to reach 643 million by 2030 and 783 million by 2045. The disease carries enormous human and economic costs, encompassing cardiovascular complications, renal failure, neuropathy, and retinopathy. ## Introduction, Element=P2 GLP-1 receptor agonists have emerged as a transformative class of antidiabetic agents. They act by binding to and activating the glucagon-like peptide-1 receptor, thereby stimulating glucose-dependent insulin secretion from pancreatic beta cells, suppressing inappropriate glucagon secretion, slowing gastric emptying to reduce postprandial glucose spikes, and signaling satiety to the brain. These mechanisms combine to produce both glycemic improvement and clinically significant weight loss. ## Introduction, Element=P3 Despite the growing number of approved GLP-1 RAs, direct head-to-head trial data comparing these agents to each other — and to conventional antidiabetic drugs such as metformin, sulphonylureas, DPP-4 inhibitors, and SGLT-2 inhibitors — remain limited. Previous meta-analyses have been constrained by smaller sample sizes, narrower drug comparisons, or shorter follow-up periods. ## Introduction, Element=P4 Tirzepatide (Mounjaro/Zepbound) represents a particularly important advance as a dual GIP/GLP-1 receptor agonist — the first in its class. By activating both glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors simultaneously, tirzepatide achieves greater metabolic effects than single-receptor agonists, as demonstrated in the SURPASS clinical trial program. ## Introduction, Element=Problem Box This study conducted the largest network meta-analysis to date comparing 8 GLP-1 receptor agonist formulations against each other, conventional antidiabetic agents, and placebo — including both direct and indirect comparisons — to provide comprehensive evidence for optimal treatment selection in T2DM. ## Introduction, Element=P5 The PRISMA-NMA reporting guidelines were followed throughout. The systematic search was prospectively registered in the PROSPERO database (CRD42024595773), ensuring methodological transparency and reproducibility. Five major databases were searched through October 2024, capturing the most current evidence including recently approved agents. ## Introduction, Element=P6 The clinical importance of this NMA lies in its ability to inform individualized treatment decisions: which drug offers the best glycemic control for a given patient profile, which carries the lowest risk of hypoglycemia, and how the magnitude of weight loss differs across agents. These are questions that individual RCTs cannot fully answer. ## Introduction, Element=Drug Heading ### GLP-1 Receptor Agonists Compared ## Introduction, Element=Info Box Heading ### Long-Acting vs. Short-Acting ## Introduction, Element=Info Box Li1 Long-acting: Tirzepatide, Semaglutide, Liraglutide, Dulaglutide, Albiglutide — once-weekly or once-daily dosing ## Introduction, Element=Info Box Li2 ### Short-acting: Exenatide BID, Lixisenatide — twice-daily dosing, stronger postprandial effect ## Methods, Element=H1 ### Methods ## Methods, Element=Caption ### PRISMA-NMA Guidelines · PROSPERO Registration: CRD42024595773 ## Methods, Element=Figure Heading Prisma ### Literature Search and Selection Process ## Methods, Element=Figure Caption Prisma ### PRISMA flow diagram: 12,074 records identified across 5 databases → 64 RCTs finally included. ## Methods, Element=Figure Note Prisma Database breakdown: PubMed (n=1,596) · Embase (n=3,496) · Cochrane (n=4,639) · Web of Science (n=2,265) · Chinese databases (n=78) → After deduplication: 8,523 → After title/abstract screening: 151 full-texts reviewed → Final inclusion: 64 RCTs (25,572 patients) ## Methods, Element=Card1 Heading ### Systematic Literature Search ## Methods, Element=Card1 Body Searched PubMed, Cochrane Library, Embase, Web of Science, and Chinese databases (CNKI, Wanfang) through October 2024. Only RCTs with parallel-group design were eligible. Two independent reviewers screened all titles, abstracts, and full texts. ## Methods, Element=Card1 Badge ### RCTs ONLY ## Methods, Element=Card2 Heading ### Bayesian Network Meta-Analysis ## Methods, Element=Card2 Body NMA integrates both direct (head-to-head) and indirect (via common comparator) evidence, enabling comparisons between drugs never directly tested against each other. SUCRA (Surface Under the Cumulative Ranking Curve) values rank treatments probabilistically. Consistency between direct and indirect evidence was assessed. ## Methods, Element=Card2 Badge ### Bayesian NMA ## Methods, Element=Card3 Heading ### Cochrane Risk of Bias Assessment ## Methods, Element=Card3 Body All 64 RCTs were independently evaluated by two reviewers using the Cochrane Risk of Bias (RoB) tool across 7 domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. ## Methods, Element=Card3 Badge ### Cochrane RoB ## Methods, Element=H2 Eligibility ### Eligibility Criteria and Outcomes ## Methods, Element=P1 Eligible studies were parallel-group RCTs in adults (aged ≥18 years) with confirmed T2DM comparing at least one GLP-1 RA (tirzepatide, semaglutide, liraglutide, dulaglutide, albiglutide, lixisenatide, exenatide QW, or exenatide BID) against placebo or another antidiabetic treatment (insulin, metformin, sulphonylureas, DPP-4 inhibitors, or SGLT-2 inhibitors). Minimum follow-up duration was 12 weeks. ## Methods, Element=P2 Primary outcomes were changes from baseline in HbA1c (%) and fasting plasma glucose (FPG, mmol/L). Secondary outcomes included body weight (kg), body mass index (BMI, kg/m²), systolic and diastolic blood pressure, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, and safety outcomes including hypoglycemia, nausea, diarrhea, vomiting, constipation, and decreased appetite. ## Methods, Element=P3 Statistical analysis employed a Bayesian random-effects NMA model. Heterogeneity was assessed using the I² statistic. Sensitivity analyses were conducted by merging semaglutide injection and oral formulations with conventional drug classes where appropriate, to test the robustness of primary findings. Publication bias was assessed with funnel plots for outcomes with sufficient studies. ## Results Primary, Element=H1 ### Primary Results: Glycemic Control ## Results Primary, Element=Caption ### Head-to-head comparison on HbA1c (glycated hemoglobin) and FPG (fasting plasma glucose) ## Results Primary, Element=Figure Heading Network ### Network Comparison Structure ## Results Primary, Element=Figure Caption Network Each node represents a treatment; edge thickness indicates the number of direct comparison trials. Placebo is the most common comparator. Panel A: HbA1c network. Panel B: FPG network. ## Results Primary, Element=H2 Ranking ### Top 3 Performers vs. Placebo (HbA1c Reduction) ## Results Primary, Element=Rank1 Badge ### TOP PERFORMER ## Results Primary, Element=Rank1 Drug ### Tirzepatide ## Results Primary, Element=Rank1 Label Hba1C ### HbA1c reduction: ## Results Primary, Element=Rank1 Val Hba1C ### −2.3% (95% CrI: −2.7, −1.9) ## Results Primary, Element=Rank1 Label Fpg ### FPG reduction: ## Results Primary, Element=Rank1 Val Fpg ### −3.1 mmol/L vs. placebo ## Results Primary, Element=Rank1 Label Wt ### Weight change: ## Results Primary, Element=Rank1 Val Wt ### −9.1 kg vs. placebo ## Results Primary, Element=Rank2 Badge ### 2ND ## Results Primary, Element=Rank2 Drug ### Semaglutide (injectable) ## Results Primary, Element=Rank2 Label Hba1C ### HbA1c reduction: ## Results Primary, Element=Rank2 Val Hba1C ### −1.5% (95% CrI: −1.8, −1.2) ## Results Primary, Element=Rank2 Label Fpg ### FPG reduction: ## Results Primary, Element=Rank2 Val Fpg ### −2.0 mmol/L vs. placebo ## Results Primary, Element=Rank2 Label Wt ### Weight change: ## Results Primary, Element=Rank2 Val Wt ### −2.8 kg vs. placebo ## Results Primary, Element=Rank3 Badge ### 3RD ## Results Primary, Element=Rank3 Drug ### Liraglutide ## Results Primary, Element=Rank3 Label Hba1C ### HbA1c reduction: ## Results Primary, Element=Rank3 Val Hba1C ### −1.2% (95% CrI: −1.4, −0.96) ## Results Primary, Element=Rank3 Label Fpg ### FPG reduction: ## Results Primary, Element=Rank3 Val Fpg ### −1.6 mmol/L vs. placebo ## Results Primary, Element=Rank3 Label Wt ### Weight change: ## Results Primary, Element=Rank3 Val Wt ### −1.2 kg vs. placebo ## Results Primary, Element=Figure Heading Forest ### Comparison vs. Placebo (Sensitivity Analysis Forest Plot) ## Results Primary, Element=Figure Caption Forest Vertical axis: individual GLP-1 RA agents. Horizontal axis: mean difference (MD) in HbA1c. Diamond shapes show pooled estimates; horizontal bars represent 95% credible intervals. Agents whose confidence intervals do not cross zero show statistically significant effects. ## Results Primary, Element=Reading Guide 1 How to read a forest plot: A point to the LEFT of zero means the drug lowers blood glucose more than placebo (beneficial effect). ## Results Primary, Element=Reading Guide 2 If the whiskers (confidence interval) do NOT cross zero, the difference is statistically significant. All major GLP-1 RAs show significant HbA1c reductions vs. placebo. ## Results Primary, Element=Figure Heading Forest4 ### HbA1c: GLP-1 RAs vs. Conventional Treatments ## Results Primary, Element=Figure Caption Forest4 Forest plot comparing GLP-1 RAs against insulin, metformin, sulphonylureas, DPP-4 inhibitors, and SGLT-2 inhibitors. Tirzepatide demonstrates statistically significant HbA1c advantages over all conventional comparators. ## Results Primary, Element=Figure Heading League ### All-Drug Comparison: League Table ## Results Primary, Element=Figure Caption League Upper triangle: FPG comparisons. Lower triangle: HbA1c comparisons. The Tirzepatide (Tir) row shows the greatest improvements across all pairwise comparisons. Values represent mean differences with 95% credible intervals. ## Results Primary, Element=H2 Detailed ### Detailed HbA1c Results ## Results Primary, Element=Detail P1 In the primary NMA for HbA1c, all GLP-1 RAs demonstrated statistically significant reductions compared to placebo. Tirzepatide showed the largest effect (MD: −2.3%, 95% CrI: −2.7 to −1.9), followed by semaglutide injection (MD: −1.5%), semaglutide oral (MD: −1.4%), liraglutide (MD: −1.2%), dulaglutide (MD: −1.1%), albiglutide (MD: −0.88%), exenatide QW (MD: −0.93%), exenatide BID (MD: −0.82%), and lixisenatide (MD: −0.56%). ## Results Primary, Element=Detail P2 Compared to conventional antidiabetic agents, tirzepatide significantly outperformed insulin (MD: −1.5%), metformin (MD: −1.4%), sulphonylureas (MD: −1.7%), DPP-4 inhibitors (MD: −1.6%), and SGLT-2 inhibitors (MD: −1.6%). Semaglutide injection and liraglutide also showed significant advantages over sulphonylureas (MD: −0.91% and −0.58%, respectively). ## Results Primary, Element=Detail P3 SUCRA rankings for HbA1c reduction placed tirzepatide first (SUCRA: 97.6%), followed by semaglutide injection (87.2%), semaglutide oral (79.4%), liraglutide (65.1%), and dulaglutide (60.3%). The long-acting GLP-1 RAs consistently ranked above short-acting formulations and conventional treatments, reflecting their superior once-weekly dosing and extended receptor engagement. ## Results Primary, Element=H2 Fpg ### Fasting Plasma Glucose (FPG) Results ## Results Primary, Element=Fpg P1 For FPG reduction, tirzepatide again demonstrated the greatest effect among all treatments (MD: −3.1 mmol/L vs. placebo). Semaglutide injection (MD: −2.0 mmol/L), liraglutide (MD: −1.6 mmol/L), and dulaglutide (MD: −1.5 mmol/L) followed. All long-acting GLP-1 RAs showed significant FPG reductions compared to placebo. ## Results Primary, Element=Fpg P2 The consistency between direct and indirect evidence was satisfactory for most treatment comparisons. Where inconsistency was identified, it was limited to comparisons with sparse direct evidence, which is expected in any large-scale NMA and does not substantially affect the primary conclusions. ## Results Secondary, Element=H1 ### Secondary Results: Weight Loss and Safety ## Results Secondary, Element=H2 Weight ### Body Weight Effects ## Results Secondary, Element=Tir Weight ### −9.1 kg ## Results Secondary, Element=Tir Ci ### 95% CrI: −11.0 to −7.4 kg ## Results Secondary, Element=Sema Weight ### −2.8 kg ## Results Secondary, Element=Sema Ci ### 95% CrI: −3.9 to −1.8 kg ## Results Secondary, Element=Lira Weight ### −1.2 kg ## Results Secondary, Element=Lira Ci ### 95% CrI: −2.2 to −0.12 kg ## Results Secondary, Element=Info Note Note: BMI, blood pressure, and lipid parameters (total cholesterol, HDL-C, LDL-C) showed no statistically significant differences versus placebo across GLP-1 RA treatments in this analysis. ## Results Secondary, Element=Figure Caption Weight Forest plot for body weight change (kg vs. placebo). Tirzepatide demonstrates the largest weight reduction across all comparisons. ## Results Secondary, Element=Figure Heading Fpg ### Fasting Plasma Glucose: Full Forest Plot ## Results Secondary, Element=Figure Caption Fpg NMA forest plot for FPG reduction across all GLP-1 RAs and conventional comparators vs. placebo and active comparators. ## Results Secondary, Element=H2 Safety ### Safety Profile (Adverse Events) ## Results Secondary, Element=Safety Card1 H3 ### Gastrointestinal Events ## Results Secondary, Element=Safety Card1 Badge ### CAUTION ## Results Secondary, Element=Safety Card1 Body Semaglutide, tirzepatide, liraglutide, and dulaglutide all showed significantly higher rates of nausea, diarrhea, vomiting, constipation, and decreased appetite compared to placebo. These GI effects are class-characteristic for long-acting GLP-1 RAs. ## Results Secondary, Element=Safety Card1 Muted GI symptoms are typically transient, occurring most often during dose titration and improving over time. ## Results Secondary, Element=Safety Card2 H3 ### Hypoglycemia Risk ## Results Secondary, Element=Safety Card2 Badge ### DRUG-DEPENDENT ## Results Secondary, Element=Safety Card2 Li1 ### Higher risk: Semaglutide inj. (RR: 4.6, 95% CI: 1.6–10.0) and Exenatide BID (RR: 3.3) vs. placebo ## Results Secondary, Element=Safety Card2 Li2 Protective effect: Liraglutide significantly REDUCES hypoglycemia risk vs. conventional drugs — a unique advantage ## Results Secondary, Element=Safety Card3 H3 ### Treatment Selection Guide ## Results Secondary, Element=Safety Card3 Badge ### CLINICAL GUIDANCE ## Results Secondary, Element=Safety Card3 Li1 ### Obese T2DM → Tirzepatide (−9.1 kg additional weight benefit) ## Results Secondary, Element=Safety Card3 Li2 ### Normal-weight T2DM → Semaglutide or Liraglutide ## Results Secondary, Element=Safety Card3 Li3 ### Hypoglycemia concern → Liraglutide as first choice ## Results Secondary, Element=Safety Card3 Li4 ### GI disease history → Use semaglutide and liraglutide with caution ## Results Secondary, Element=H2 Other ### Other Secondary Outcomes ## Results Secondary, Element=Other P1 Beyond weight, several GLP-1 RAs demonstrated effects on cardiometabolic risk factors. Semaglutide injection showed significant reductions in systolic blood pressure versus some comparators. However, across the full NMA, differences in BMI, total cholesterol, HDL-C, LDL-C, and triglycerides between GLP-1 RAs and placebo did not consistently reach statistical significance, suggesting these outcomes may require larger or longer trials to detect. ## Results Secondary, Element=Other P2 For all adverse events analyzed, the safety signals were consistent with known class effects and product labels. No unexpected safety findings emerged from this NMA. The overall benefit-risk profile favored GLP-1 RAs over conventional antidiabetic agents for patients with T2DM, particularly when both glycemic and weight-related outcomes are considered together. ## Discussion, Element=H1 ### Discussion ## Discussion, Element=H2 1 ### Long-Acting vs. Short-Acting GLP-1 RAs ## Discussion, Element=P1 A key finding of this NMA is the consistent superiority of long-acting GLP-1 receptor agonists — particularly tirzepatide and semaglutide — over short-acting formulations in reducing HbA1c. Long-acting agents maintain sustained GLP-1 receptor occupancy, which more effectively suppresses hepatic glucose production overnight and reduces fasting glucose, while short-acting agents primarily blunt postprandial glucose excursions. ## Discussion, Element=P2 Tirzepatide's exceptional performance — the highest SUCRA rankings across HbA1c, FPG, and body weight — is attributable to its unique dual mechanism as both a GLP-1 and GIP receptor agonist. The GIP component enhances insulin secretion and may directly promote adipose tissue lipolysis, contributing to the substantially greater weight loss (−9.1 kg) observed compared to single-receptor GLP-1 RAs (−1.2 to −2.8 kg). ## Discussion, Element=H2 2 ### Semaglutide: Injection vs. Oral Formulations ## Discussion, Element=P3 Both injectable and oral semaglutide formulations demonstrated comparable glycemic efficacy (HbA1c reduction: injection −1.5%, oral −1.4%). The oral formulation, which uses the absorption enhancer SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) to enable intestinal absorption, provides a needle-free option that may improve adherence in patients with needle phobia or injection fatigue. ## Discussion, Element=P4 The once-weekly dosing schedule of both semaglutide formulations aligns with patient preference data showing strong associations between less frequent dosing and treatment adherence in T2DM. This pharmacokinetic advantage, combined with efficacy comparable to daily-dosing agents, reinforces semaglutide's position as a second-line option behind tirzepatide. ## Discussion, Element=H2 3 ### Body Weight and Metabolic Effects ## Discussion, Element=P5 Tirzepatide's weight loss effect (−9.1 kg vs. placebo) is substantially larger than other GLP-1 RAs analyzed and approaches the weight reductions seen with dedicated anti-obesity medications. This finding has important clinical implications for the substantial proportion of T2DM patients with concomitant obesity, for whom weight loss is an equally important therapeutic target alongside glycemic control. ## Discussion, Element=P6 The lack of statistically significant differences in BMI, blood pressure, and lipid parameters (TC, HDL-C, LDL-C) compared to placebo across most GLP-1 RAs is notable and contrasts with findings from some individual trials and earlier meta-analyses. This may reflect the heterogeneity of study populations, varying baseline cardiovascular risk profiles, and the shorter follow-up periods common in glycemic control trials compared to dedicated cardiovascular outcomes trials (CVOTs). ## Discussion, Element=H2 4 ### Safety Considerations ## Discussion, Element=P7 The gastrointestinal adverse event profile — dominated by nausea, diarrhea, vomiting, and constipation — is consistent across all long-acting GLP-1 RAs and represents the primary tolerability challenge. These effects are believed to result from slowed gastric motility mediated by GLP-1 receptor activation in the enteric nervous system and are dose-dependent. They typically peak during dose escalation and diminish with continued treatment. ## Discussion, Element=P8 The differential hypoglycemia risk across agents is a clinically meaningful finding. Semaglutide injection's increased hypoglycemia risk (RR: 4.6 vs. placebo) warrants attention, particularly when used in combination with insulin or sulphonylureas. In contrast, liraglutide's significant protective effect against hypoglycemia — a finding that has been observed in some prior cardiovascular outcomes trials — suggests it may be particularly suitable for patients at high hypoglycemia risk. ## Discussion, Element=H2 Limitations ### Study Limitations ## Discussion, Element=Limit P1 This NMA has several limitations. Network sparsity in some treatment comparisons limited the power of inconsistency testing. The analysis used aggregate-level data rather than individual patient data (IPD), which precludes subgroup analyses by age, sex, diabetes duration, or baseline HbA1c. Regional and ethnic variation in pharmacogenomics and dietary patterns may influence outcomes not fully captured by pooling international RCTs. ## Discussion, Element=Limit P2 The risk of bias assessment found moderate-to-low risk overall, but performance bias (participant and personnel blinding) was rated high or unclear in a subset of studies — an inherent challenge in trials of injectable agents. The time horizons of included trials (typically 24–52 weeks) may not fully reflect long-term cardiovascular and renal outcomes that have been demonstrated in dedicated CVOTs for some agents. ## Discussion, Element=Side Card1 H3 ### STUDY STRENGTHS ## Discussion, Element=Side Card1 Body Largest NMA in class (64 RCTs, 25,572 patients). PRISMA-NMA compliant. Bayesian random-effects model. Covers all major GLP-1 RAs plus conventional comparators. PROSPERO pre-registered. ## Discussion, Element=Side Card2 H3 ### LIMITATIONS ## Discussion, Element=Side Card2 Body Network sparsity · Aggregate data only · Regional variation · Moderate performance bias risk · Short-term follow-up in some trials ## Discussion, Element=Side Card3 H3 ### CLINICAL IMPLICATION ## Discussion, Element=Side Card3 Body Personalized medicine approach: match drug selection to patient obesity status, hypoglycemia risk tolerance, injection preference, and cost/access considerations. ## Conclusion, Element=H1 ### Conclusion ## Conclusion, Element=P1 GLP-1 receptor agonists significantly improve glycemic control in type 2 diabetes, with long-acting formulations demonstrating consistently greater HbA1c and FPG reductions compared to short-acting agents and conventional antidiabetic drugs. This comprehensive Bayesian NMA of 64 RCTs and 25,572 patients provides the most robust evidence base currently available for comparative treatment selection. ## Conclusion, Element=P2 Tirzepatide, semaglutide, and liraglutide emerge as the three most effective GLP-1 RAs for glycemic control. Tirzepatide's dual GIP/GLP-1 mechanism confers exceptional advantages in both HbA1c reduction (−2.3%) and body weight loss (−9.1 kg), making it the preferred option when significant weight reduction is a treatment goal. For patients prioritizing hypoglycemia safety, liraglutide offers a distinctive protective profile. ## Conclusion, Element=P3 Treatment decisions should be individualized based on patient-specific factors including obesity status, hypoglycemia risk, cardiovascular risk profile, tolerability of GI adverse effects, dosing convenience (injection vs. oral), and access. The evidence from this NMA supports GLP-1 RAs as a first-line or early combination option in T2DM management, particularly for patients where weight management is a co-equal goal. ## Conclusion, Element=Card1 Heading ### Obese T2DM ## Conclusion, Element=Card1 Drug ### Tirzepatide ## Conclusion, Element=Card1 Reason ### Maximum glycemic control (−2.3% HbA1c) plus the greatest weight loss (−9.1 kg) among all treatments ## Conclusion, Element=Card1 Badge ### FIRST LINE ## Conclusion, Element=Card2 Heading ### Normal-Weight T2DM ## Conclusion, Element=Card2 Drug ### Liraglutide ## Conclusion, Element=Card2 Reason Strong glycemic efficacy with the lowest hypoglycemia risk among GLP-1 RAs — protective vs. conventional drugs ## Conclusion, Element=Card2 Badge ### OPTIMAL SAFETY ## Conclusion, Element=Card3 Heading ### Normal-Weight T2DM (Alternative) ## Conclusion, Element=Card3 Drug ### Semaglutide ## Conclusion, Element=Card3 Reason High glycemic efficacy; oral formulation available for needle-averse patients. Note elevated hypoglycemia risk ## Conclusion, Element=Card3 Badge ### NOTE: Hypoglycemia risk ## Conclusion, Element=Footer 1 ### Scientific Reports | DOI: 10.1038/s41598-025-09807-0 | Xiaoyu Ren et al., 2025 ## Conclusion, Element=Footer 2 ### Published under Creative Commons Attribution 4.0 International (CC BY 4.0) ## Quality Assessment, Element=H2 ### Evidence Quality: Bias Risk Assessment ## Quality Assessment, Element=Caption ### Cochrane Risk of Bias (RoB) framework applied to all 64 included RCTs across 7 domains ## Quality Assessment, Element=Figure Caption Green = Low risk · Yellow = Unclear risk · Red = High risk. Performance bias (participant/personnel blinding) shows some high-risk entries, inherent to injection trials. Overall: moderate-to-low risk evidence base. ## Quality Assessment, Element=Card1 H3 ### Randomization Procedures ## Quality Assessment, Element=Card1 Badge ### LOW RISK DOMINANT ## Quality Assessment, Element=Card1 Body Sequence generation and allocation concealment were judged low-risk in the majority of included RCTs, supporting the integrity of randomization. ## Quality Assessment, Element=Card2 H3 ### Blinding ## Quality Assessment, Element=Card2 Badge ### SOME HIGH RISK ## Quality Assessment, Element=Card2 Body Participant and personnel blinding was rated high-risk or unclear in some studies, as blinding to injectable treatments is inherently challenging. This represents the primary quality concern. ## Quality Assessment, Element=Card3 H3 ### Selective Reporting ## Quality Assessment, Element=Card3 Badge ### LOW RISK DOMINANT ## Quality Assessment, Element=Card3 Body Selective outcome reporting was judged low-risk in most studies. The overall evidence base is considered suitable for drawing comparative conclusions. ## Metadata, Element=Authors Heading ### Authors ## Metadata, Element=Journal Heading ### Publication & Funding ## Metadata, Element=Journal Name ### Scientific Reports (Nature Portfolio), 2025 ## Metadata, Element=Pmc Id ### PMC ID: PMC12230154 ## Metadata, Element=Coi ### Competing interests: The authors declare no competing interests.