¹ Shaikh Khalifa Bin Zayed Al Nahyan Medical and Dental College, Lahore, Punjab, Pakistan
² King Edward Medical University, Lahore, Punjab, Pakistan
³ Rawalpindi Medical University, Rawalpindi, Punjab, Pakistan
⁴ The University of Lahore University College of Medicine and Dentistry, Lahore, Punjab, Pakistan
⁵ Fatima Jinnah Medical University, Lahore, Punjab, Pakistan
⁶ Suleman Roshan Medical College, Tando Adam, Pakistan
⁷ Islam Medical College, Sialkot, Punjab, Pakistan
⁸ Khairpur Medical College, Khairpur, Sindh, Pakistan
⁹ Oli Health Magazine Organization Kigali, Kigali, Kigali City, Rwanda

Affaf Mahmood
Roles: Conceptualization, Data Curation, Investigation, Project Administration, Validation

Noor Us Sehar
Roles: Conceptualization, Data Curation, Formal Analysis

Aimen Farooq
Roles: Investigation, Methodology, Software

Sajila Latif
Roles: Data Curation, Software, Visualization

Minahil Rasul
Roles: Writing – Original Draft Preparation, Writing – Review & Editing

Shanza Abbasi
Roles: Investigation, Validation, Visualization

Amna Muhammad Ali
Roles: Methodology, Software

Eman Arshad
Roles: Data Curation, Investigation

Mohammad Azeem Malik
Roles: Methodology, Visualization

Kawish Nenwani
Roles: Formal Analysis, Methodology

Intzar Ahmed
Roles: Software, Validation

Muhammad Sarmad
Roles: Data Curation, Formal Analysis

Rohma Khan
Roles: Conceptualization, Writing – Review & Editing

Sagar Kumar
Roles: Investigation, Software

Abdul Haseeb Hasan
Roles: Validation, Visualization

Ahmad Hassan
Roles: Supervision

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines.¹⁵ The completed PRISMA 2020 checklist is available in the external repository. A comprehensive literature search was performed in PubMed, Embase, the Cochrane Library, and ScienceDirect from database inception through May 2026 to identify randomized controlled trials comparing mazdutide with placebo in patients with type 2 diabetes mellitus (T2DM). The search strategy incorporated both controlled vocabulary terms and free-text keywords related to mazdutide and placebo. The terms used included “Mazdutide,” “IBI362,” “LY3305677,” “GLP-1/glucagon receptor agonist,” “dual GLP-1 glucagon agonist,” “GLP-1 glucagon co-agonist,” “twincretin,” “IBI362,” “Glucagon like peptide 1 receptor agonist,” “Glucagon receptor agonist,” “GLP-1 agonist,” “Incretin agonist,” “Dual Incretin glucagon agonist,” and related synonyms. Database-specific search strategies were adapted as appropriate for each platform. The detailed search strategies for each database are provided in extended data in the external repository. Reference lists of relevant reviews and eligible studies were also screened manually to identify additional potentially eligible articles. No restrictions were applied regarding publication status, while only studies published in English were considered for inclusion.

Studies were included if they met the following criteria: (1) enrolled adult patients (≥18 years) diagnosed with type 2 diabetes mellitus (T2DM); (2) compared mazdutide, administered at any dose, frequency, or treatment duration, with placebo; (3) were randomized controlled trials (RCTs); (4) reported at least one efficacy outcome (e.g., glycated hemoglobin [HbA1c], fasting plasma glucose, body weight, waist circumference, or other metabolic parameters) or safety outcome (e.g., adverse events, serious adverse events, gastrointestinal adverse events, or treatment discontinuation); and (5) provided sufficient data for extraction and quantitative synthesis. Only studies published in the English language were considered.

Studies were excluded if they: (1) enrolled participants without T2DM; (2) did not directly compare mazdutide with placebo; (3) were non-randomized studies, observational studies, case reports, case series, reviews, editorials, conference abstracts without sufficient data, letters, or animal studies; (4) lacked relevant efficacy or safety outcomes; or (5) contained insufficient data for analysis.

All records retrieved from the electronic databases were imported into Zotero, where duplicate records were identified and removed prior to screening. Two reviewers independently screened the titles and abstracts of all retrieved studies according to the predefined eligibility criteria. The full texts of potentially eligible studies were then independently assessed by the same reviewers to determine their eligibility for inclusion. Any disagreements regarding study selection were resolved through discussion and consensus. If consensus could not be reached, a third reviewer was consulted to make the final decision. The study selection process was documented using the PRISMA 2020 flow diagram.

A structured Google Sheet was used for data extraction. A standardized data extraction form was developed to collect study-level information, including the first author’s name, year of publication, study design, sample size, duration of follow-up, intervention and comparator dosages, and baseline patient characteristics. Baseline characteristics extracted included age, sex, body mass index (BMI), duration of type 2 diabetes mellitus, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, and other relevant clinical variables.

Outcome data were categorized into efficacy and safety endpoints. Primary efficacy outcomes included change from baseline (CFB) in HbA1c, the proportion of participants achieving HbA1c <7.0%, and CFB in body weight expressed as both percentage and absolute change (kg). Secondary efficacy outcomes included the proportions of participants achieving HbA1c ≤6.5% and <5.7%, CFB in FPG, proportions of participants achieving ≥5% and ≥10% weight loss, the proportion achieving both ≥5% weight loss and HbA1c <7.0%, CFB in BMI and waist circumference, measures of beta-cell function and insulin resistance (HOMA2-B and HOMA2-IR), cardiovascular parameters including systolic blood pressure (SBP), diastolic blood pressure (DBP), and lipid profile, hepatic parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and renal parameters including serum uric acid.

Safety outcomes were categorized as primary and secondary endpoints. The primary safety outcome was the incidence of treatment-emergent adverse events (TEAEs). Secondary safety outcomes included serious adverse events (SAEs), TEAEs leading to treatment discontinuation, gastrointestinal adverse events (diarrhea, nausea, vomiting, abdominal distention, and decreased appetite), systemic adverse events (asthenia), metabolic adverse events (hypoglycemia, hyperuricemia, and increased lipase), cardiovascular adverse events (tachycardia, bradycardia, atrioventricular block, and arrhythmia), allergic reactions (injection-site reactions and hypersensitivity), hepatobiliary events (cholecystitis and cholelithiasis), diabetic ketosis, and infectious complications including upper respiratory tract infections (URTIs) and urinary tract infections (UTIs).

Data extraction was performed independently by four reviewers using the predefined extraction form. The extracted data were subsequently reviewed and cross-checked by an additional group of four authors to ensure completeness, accuracy, and consistency. Any discrepancies were resolved through discussion and consensus among the investigators. The standardized data extraction sheet containing all extracted baseline characteristics and outcome data is available as a separate file in the external repository.

The methodological quality of the included randomized controlled trials was assessed using the Cochrane revised Risk of Bias tool for randomized trials (RoB 2).¹⁶ This tool evaluates potential sources of bias across five domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of outcomes, and bias in the selection of the reported results. Each domain was rated as “low risk of bias,” “some concerns,” or “high risk of bias,” and an overall risk-of-bias judgment was assigned for each study. Risk-of-bias assessments were conducted separately for efficacy and safety outcomes, recognizing that the risk profile may differ according to the outcome evaluated. The assessments were performed independently by two reviewers, and any disagreements were resolved through discussion and consensus. Risk-of-bias summary figures and traffic-light plots were generated to visually present the methodological quality of the included studies.

The certainty of evidence for the predefined efficacy and safety outcomes was evaluated independently by two reviewers using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.¹⁷ The certainty of evidence for each outcome was categorized as high, moderate, low, or very low based on the domains of risk of bias, inconsistency, indirectness, imprecision, and publication bias. Randomized controlled trials were initially rated as high-certainty evidence and were downgraded where appropriate according to GRADE recommendations. Disagreements between reviewers were resolved through discussion or consultation with a third reviewer. A Summary of Findings (SoF) table was generated using GRADEpro GDT (McMaster University and Evidence Prime) and is provided in the extended data in external repository.

Statistical analyses were performed using Review Manager (RevMan) software. For dichotomous outcomes, effect sizes were calculated as odds ratios (ORs) with 95% confidence intervals (CIs), whereas continuous outcomes were summarized using mean differences (MDs) with corresponding 95% CIs. Heterogeneity among studies was assessed using the Cochrane Q test (Chi-square test) and quantified using the I² statistic. An I² value ≤50% with P ≥0.05 was considered to indicate low heterogeneity, and a fixed-effect model was applied in such cases. For outcomes with substantial heterogeneity (I² >50% and P <0.05), a random-effects model was used to account for between-study variability, in accordance with established meta-analytic guidelines.

Predefined subgroup analyses were performed for all efficacy outcomes to explore potential sources of heterogeneity. These included dose-based subgroup analyses comparing 3 mg, 4/4.5 mg, and 6 mg mazdutide versus placebo, as well as treatment duration–based subgroup analyses stratified by follow-up duration of ≥20 weeks.

Sensitivity analyses were conducted to evaluate the robustness of the pooled results and to identify potential sources of heterogeneity. A leave-one-out approach was applied by sequentially excluding each study to assess its influence on the overall effect size. These analyses were performed only for outcomes demonstrating substantial statistical heterogeneity, defined as I² >75%. The impact of individual studies on heterogeneity and pooled estimates was examined across these key high-heterogeneity outcomes to assess the stability of the results.

A total of 1,371 references were identified from four databases, namely PubMed, Cochrane, ScienceDirect, and Embase. After removal of 263 duplicate records, 1,108 records underwent title and abstract screening, of which 1,097 were excluded. Eleven reports underwent full-text evaluation, of which eight were excluded due to wrong comparison (n=6), insufficient data (n=1), and wrong outcome (n=1). Ultimately, three RCTs met the inclusion criteria and were included in the review. The PRISMA flowchart summarizing the process is shown in Figure 1.

All three included RCTs^11,12,18 were conducted in Chinese adults with type 2 diabetes mellitus. One study was a phase 3 double-blind, placebo-controlled trial (DREAMS-1), one was a phase 2 double-blind, placebo-controlled, active-referenced trial, and one was a phase 1b randomized, placebo-controlled, multiple ascending-dose trial. A total of 613 participants, including placebo recipients, were enrolled across the three studies. All trials evaluated once weekly subcutaneous mazdutide (IBI362/LY3305677) at doses of 3mg, 4/4.5mg and 6mg compared with placebo. Treatment duration ranged from 12 to 24 weeks, with Zhu 2026 including an additional 24-week extension phase.

Baseline characteristics were generally comparable across the included studies. Participants were middle-aged adults with inadequately controlled type 2 diabetes mellitus. Mean HbA1c ranged from 7.94% to 8.9%, fasting plasma glucose from 9.2 to 11.7 mmol/L, and BMI from 24.1 to 28.6 kg/m². Mean duration of diabetes ranged from 1.8 to 6.1 years. Background metformin use varied across studies, ranging from none reported in Zhu 2026 to 65–69% in Zhang 2024 and 38–58% in Jiang 2022. Baseline characteristics were well balanced between treatment groups within each study ( Table 1).

A total of 51 outcomes were evaluated and categorized into primary and secondary efficacy outcomes, as well as primary and secondary safety outcomes. Primary efficacy outcomes included glycemic and weight reduction parameters. Secondary efficacy outcomes included additional glycemic control outcomes, metabolic, anthropometric, beta-cell function, cardiovascular, hepatic, and renal biomarker outcomes. Treatment-emergent adverse events (TEAEs) were assessed as the primary safety outcome. Secondary safety outcomes included a broad range of gastrointestinal, cardiovascular, hepatobiliary, metabolic and other systemic adverse effects. A comprehensive list of all outcomes is presented in Table 2. The main manuscript presents the analyses of the following outcomes: HbA1c change from baseline (%), achievement of HbA1c <7.0%, body weight change from baseline (%), fasting plasma glucose change from baseline, participants achieving ≥5% and ≥10% weight loss, body mass index, waist circumference, HOMA2-B, HOMA2-IR, systolic and diastolic blood pressure, triglycerides, alanine aminotransferase, serum uric acid, treatment-emergent adverse events, severe treatment-emergent adverse events, serious adverse events, gastrointestinal adverse events (diarrhea, nausea, vomiting, abdominal distention, and decreased appetite), and cardiovascular adverse events (cardiac disorders, sinus tachycardia, and first-degree atrioventricular block). Subgroup analyses based on mazdutide dosage (3 mg, 4/4.5 mg, and 6 mg) and follow-up duration (12 weeks and ≥20 weeks) are also presented for these outcomes, where applicable. Forest plots for the remaining outcomes, including HbA1c change from baseline (mmol/mol), body weight change from baseline (kg), achievement of HbA1c ≤6.5% and <5.7%, the composite outcome of ≥5% weight loss with HbA1c <7.0%, total cholesterol, LDL cholesterol, HDL cholesterol, percentage changes in all lipid parameters, aspartate aminotransferase, systemic adverse events (asthenia and dizziness), metabolic adverse events (hyperuricaemia, hyperlipidemia, lipase increased, and hypoglycemia including Levels 1 and 2), injection-site reactions, hepatobiliary adverse events (hepatic function abnormal), and infectious adverse events (upper respiratory tract infection and urinary tract infection), are provided in the extended data and are not discussed in the main manuscript.

Glycemic Control (HbA1c and Target Achievement):

All three included RCTs (n=525) reported mean change in HbA1c from baseline (%). Using a fixed effect model, a statistically significant reduction in HbA1c was observed in the mazdutide group compared with the placebo group (MD -1.53; 95% CI -1.70 to -1.35; p<0.00001; I²=14%) ( Figure 2).

Achievement of the glycemic target of HbA1c <7% was reported by the 3 RCTs (n=521). Participants receiving mazdutide were significantly more likely to achieve the glycemic target than those in the placebo group in the random effects model (OR 9.04; 95% CI 3.05 to 26.76; p<0.0001). Considerable heterogeneity was observed across the studies (I²=76%) ( Figure 3).

Weight reduction efficacy:

Mean change in body weight from baseline (%) was reported by 3 studies (n= 526). Our pooled analysis revealed statistically significant reduction in body weight in the mazdutide group compared with the placebo group in random effect model (MD -4.22; 95% CI -5.71 to -2.73; p<0.00001; I²=59%) ( Figure 4).

Forest plots for the mean change in HbA1c level from baseline (mmol/mol) and body weight (kg) are presented in the extended data in external repository (Fig S1.1and 1.2).

Fasting Plasma Glucose and Glycemic Variability:

Glycemic control was further assessed using the mean change in fasting plasma glucose level from baseline (mmol/L). Analysis of data from all three RCTs (n=526) revealed a statistically significant reduction in FPG levels in the mazdutide group compared with the placebo group in the random-effects model (MD -2.09; 95% CI -2.74 to -1.45; p<0.00001; I²=66%) ( Figure 5).

Anthropometric Outcomes (Weight loss thresholds, BMI and Waist Circumference):

Weight reduction efficacy was further assessed by the proportion of participants achieving ≥5% and ≥10% weight loss. Both of these outcomes were reported by two RCTs (n=490). Participants receiving mazdutide were significantly more likely to achieve ≥5% reduction in weight than those in the placebo group in the random-effect model (OR 10.61; 95% CI 3.72 to 30.29; p<0.0001; I²=63%) ( Figure 6). Similarly, the odds of achieving ≥10% weight loss were significantly higher in the mazdutide group than in the placebo group in the fixed-effect model (OR 42.56; 95% CI 5.98 to 302.89; p=0.0002; I²=0%) ( Figure 7).

Three studies (n=553) reported mean change in BMI (kg/m²) from baseline and waist circumference (cm) from baseline. A random-effect analysis of data revealed that participants receiving mazdutide showed significant reduction in BMI as compared with the placebo group (MD -1.16; 95% CI -1.54 to -0.78; p<0.00001; I²=60%) ( Figure 8). A significant reduction in waist circumference was also observed in the mazdutide group compared with the placebo group in a fixed-effect model (MD -3.19; 95% CI -3.92 to -2.46; p<0.00001; I²=34%) ( Figure 9).

Cardiometabolic Outcomes (BP, Lipids, Liver Enzymes):

Mean change in systolic and diastolic blood pressure (mmHg) from baseline was reported by all the three included RCTs (n=553). Pooled analysis revealed that mazdutide was associated with significant reduction in both systolic (MD -4.77; 95% CI -6.71 to -2.84; p<0.00001; I²=0%) and diastolic (MD -2.32; 95% CI -3.59 to -1.05; p=0.0004; I²=0%) blood pressure compared with placebo in fixed-effect model ( Figure 10, Figure 11). Three studies (n=553) reported the mean change in triglycerides (mmol/L) from baseline. A statistically significant reduction was observed in mazdutide group compared with the placebo group in a fixed-effect model (MD -0.65; 95% CI -0.82 to -0.47; p<0.00001; I²=23%) ( Figure 12). Additionally, mean change in ALT (U/L) from baseline reported in 3 studies (n= 553) revealed no significant difference between the mazdutide and the placebo groups (MD -1.09; 95% CI -6.91 to 4.73; p=0.71; I²=83%) ( Figure 13).

Forest plots for additional outcomes are reported in extended data in external repository (Fig S1.3 – 1.16).

Treatment emergent adverse effects (TEAEs) were evaluated across all three RCTs (n= 555). Our pooled fixed effect estimate showed that mazdutide was associated with significantly higher odds of TEAEs as compared with placebo (OR 2.20; 95% CI 1.42 to 3.41; p=0.0004; I²=0%) ( Figure 14).

Severe treatment-emergent adverse effects were reported by two RCTs (n=519). Our analysis revealed no significant difference between the mazdutide and the placebo groups (OR 0.68; 95% CI 0.06 to 7.66; p=0.76) ( Figure 15). Similarly, serious adverse events were evaluated across three RCTs (n=555). Pooled analysis revealed no significant difference between the treatment groups (OR 1.24; 95% CI 0.14 to 10.93; p=0.85; I²=67%) ( Figure 16).

Gastrointestinal Safety outcomes:

Gastrointestinal adverse effects were reported across all three RCTs. Compared with placebo, participants receiving mazdutide had significantly higher odds of diarrhea (OR 4.65; 95% CI 2.68 to 8.08; p<0.00001; I²=0%), nausea (OR 7.43; 95% CI 1.49 to 37.06; p=0.01; I²=58%), vomiting (OR 7.47; 95% CI 2.49 to 22.41; p=0.0003; I²=0%), decreased appetite (OR 8.31; 95% CI 4.05 to 17.05; p<0.00001; I²=0%) and abdominal distention (OR 3.81; 95% CI 1.40 to 10.38; p=0.009; I²=0%) ( Figure 17 to Figure 21).

Cardiac safety outcomes:

Cardiac adverse effects were assessed across the included studies. For the composite outcome of any cardiac disorder, no significant difference was found between the mazdutide and the placebo groups (OR 1.71; 95% CI 0.55 to 5.29; p=0.35; I²=0%) ( Figure 22). Similarly, no significant difference was observed between the treatment groups for sinus tachycardia (OR 1.17; 95% CI 0.27 to 5.15; p=0.83; I²=0%) and first-degree AV block (OR 1.82; 95% CI 0.20 to 16.65; p=0.60; I²=0%) ( Figure 23, Figure 24).

All primary and secondary efficacy outcomes, together with their pooled effect estimates and statistical analyses, are summarized in Table 3. Additional safety outcomes are presented in the extended data in external repository (Fig S 1.17 – 1.28)

Glycemic outcomes:

Subgroup analyses based on mazdutide dose were conducted for the mean change in HbA1c (%) from baseline and participants achieving HbA1c <7%. No significant subgroup differences were identified for either outcome.

Subgroup analysis by treatment duration demonstrated a significant reduction in HbA1c (%) from baseline (MD −1.56; 95% CI −1.73 to −1.38; p<0.00001; I²=0%) and significantly higher odds of achieving HbA1c <7% (OR 14.04; 95% CI 5.52 to 35.70; p<0.00001; I²=68%) (Fig S5.1, Fig S5.2). Findings were consistent with the primary pooled analysis.

Weight and metabolic outcomes:

Although the combined analysis of body weight change % favored mazdutide, the 3 mg dose subgroup did not reach statistical significance (MD −1.56; 95% CI −4.38 to 1.27; p=0.28; I²=59%) (Fig S2.6). Likewise, despite significant reductions in BMI and waist circumference in the overall pooled analyses, the 3 mg dose subgroup demonstrated no significant reductions in BMI (MD −0.43; 95% CI −1.00 to 0.14; p=0.14; I²=64%) or waist circumference (MD −0.65; 95% CI −3.31 to 2.01; p=0.63; I²=61%) (Fig S 2.7, Fig S2.8).

Cardio metabolic outcomes:

In contrast to the combined analysis, which showed no significant difference in mean change in ALT (U/L) between the treatment groups, dose specific subgroup analysis revealed significant reductions in ALT levels with Mazdutide 4/4.5mg (MD −7.08; 95% CI −10.01 to −4.14; p<0.00001; I²=0%) (Fig S3.22) and 6mg (MD −7.04; 95% CI −9.97 to −4.10; p<0.00001; I²=35%) (Fig S4.22) compared with placebo.

Safety dose- response:

Subgroup analyses based on mazdutide dose demonstrated findings consistent with the overall pooled analysis. No significant subgroup differences were observed across the evaluated safety outcomes.

Treatment duration-dependent safety outcomes:

Subgroup analyses based on treatment duration (≥20 weeks) were conducted for all pre-specified safety outcomes. No significant subgroup differences were identified for any outcome.

See supplemental file Figure S2.1-S2.26, figure S3.1-S3.49, Figure S4.1-S4.49, and Figure S5.1-S5.42

Sensitivity analysis was performed using a leave-one-out approach to explore sources of heterogeneity, as substantial heterogeneity (I2 >75%) was observed across multiple outcomes. Zhu et al. was identified as the primary contributor to heterogeneity. Following exclusion of this study, heterogeneity was reduced for achievement of HbA1c <7% (I²: 76% to 54%), change in HOMA2-B from baseline (I²: 86% to 0%), change in ALT from baseline (I²: 83% to 0%), and change in AST from baseline (I²: 77% to 0%). While the results for achievement of HbA1c <7% (p<0.00001) and HOMA2-B (p=0.0003) remained statistically significant, mean change in ALT (p=0.01) and AST (p=0.03) changed from non-significant to statistically significant following removal of Zhu et al. Detailed results of the sensitivity analysis are presented in Table 4. Forest plots for sensitivity analyses are provided in the extended data in external repository (Fig S6.1 – Fig S6.8).

The methodological quality of the included randomized controlled trials was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. All three included RCTs were judged to be at low risk of bias across all five assessed domains, including bias arising from the randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of the reported results. Consequently, each study received an overall judgment of low risk of bias. The traffic-light plot and summary plot illustrating the domain-specific and overall risk-of-bias assessments are presented in Figure 25 and Figure 26, respectively.

The certainty of evidence for the evaluated efficacy and safety outcomes was assessed using the GRADE framework and is summarized in the Summary of Findings table ( Table 1 in extended data in external repository). High-certainty evidence supported the effects of mazdutide on HbA1c reduction, treatment-emergent adverse events, and diarrhea. Moderate-certainty evidence was observed for body weight reduction, hypoglycemia, and vomiting. In contrast, the certainty of evidence was low for HbA1c target achievement (<7.0%) and ≥5% weight loss, whereas serious adverse events and nausea were supported by very low-certainty evidence. Overall, the certainty of evidence ranged from very low to high, reflecting high confidence for several key efficacy and safety outcomes while indicating greater uncertainty for outcomes downgraded because of study limitations identified through the GRADE assessment ( Table 2 in extended data in external repository).

Several strengths of this study should be acknowledged. First, this represents the first quantitative synthesis focused exclusively on mazdutide in patients with T2DM. Second, only randomized controlled trials were included, providing evidence derived from the highest level of clinical study design currently available for this intervention. Third, a broad range of clinically relevant efficacy and safety outcomes were evaluated, allowing a comprehensive assessment of the therapeutic profile of mazdutide. Finally, subgroup and sensitivity analyses were performed to explore heterogeneity and assess the robustness of pooled estimates, while the use of GRADE methodology enhances the interpretability and clinical applicability of the findings.

Nevertheless, several limitations should be considered. Only three randomized controlled trials met the eligibility criteria, resulting in a relatively modest sample size and limiting the precision of certain estimates, particularly for uncommon adverse events. The duration of follow-up ranged from 12 to 24 weeks, with only one study incorporating a longer extension phase; therefore, the long-term durability of treatment effects and safety profile remain uncertain. In addition, all included studies were conducted in Chinese populations, which may limit the generalizability of these findings to other ethnic groups and healthcare settings. Variations in treatment duration and dose regimens may also have contributed to heterogeneity across several outcomes. Furthermore, the included studies were not designed to evaluate major adverse cardiovascular events, cardiovascular mortality, or long-term hepatic outcomes, precluding definitive conclusions regarding these clinically important endpoints. Finally, assessment of publication bias was limited by the small number of available studies. Although several clinically important outcomes were supported by moderate- to high-certainty evidence, the certainty for some efficacy and safety outcomes was downgraded because of heterogeneity, imprecision, and the limited number of available randomized controlled trials.

• 1.  Genitsaridi I, Salpea P, Salim A, et al.: 11th edition of the IDF Diabetes Atlas: global, regional, and national diabetes prevalence estimates for 2024 and projections for 2050. Lancet Diabetes Endocrinol. 2026; 14(2): 149–156. PubMed Abstract | Publisher Full Text
• 2.  Defronzo RA: Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009; 58(4): 773–795. PubMed Abstract | Publisher Full Text | Free Full Text
• 3.  Davies MJ, Aroda VR: Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD); 2022; 45(11): 2753–86.
• 4.  Schroeder EB: Management of Type 2 Diabetes: Selecting Amongst Available Pharmacological Agents.Feingold KR, Adler RA, Ahmed SF, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000. Copyright © 2000-2026, MDText.com, Inc.
• 5.  Lingvay I, Sumithran P, Cohen RV, et al.: Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation. Lancet (London, England). 2022; 399(10322): 394–405. PubMed Abstract | Publisher Full Text
• 6.  Nauck MA, Quast DR, Wefers J, et al.: GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Molecular metabolism. 2021; 46: 101102. PubMed Abstract | Publisher Full Text | Free Full Text
• 7.  Baggio LL, Drucker DJ: Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Molecular metabolism. 2021; 46: 101090. PubMed Abstract | Publisher Full Text | Free Full Text
• 8.  Wen J, Nadora D, Truong A, et al.: Next generation dual GLP-1/GIP, GLP-1/glucagon, and triple GLP-1/GIP/glucagon agonists: a literature review. Nutr. Metab. Cardiovasc. Dis. 2025; 35(12): 104213. PubMed Abstract | Publisher Full Text
• 9.  Sánchez-Garrido MA, Brandt SJ, Clemmensen C, et al.: GLP-1/glucagon receptor co-agonism for treatment of obesity. Diabetologia. 2017; 60(10): 1851–1861. PubMed Abstract | Publisher Full Text | Free Full Text
• 10.  Tham L-S, Thomas MK, Benson C, et al.: 106-OR: A First-in-Human Single Ascending Dose Study of Oxyntomodulin Analog LY3305677 in Healthy Subjects. Diabetes. 2021; 70(Supplement_1). Publisher Full Text
• 11.  Zhu D, Zhao J: Mazdutide versus placebo in Chinese adults with type 2 diabetes.2026; 652(8108): 174–180.
• 12.  Jiang H, Pang S, Zhang Y, et al.: A phase 1b randomised controlled trial of a glucagon-like peptide-1 and glucagon receptor dual agonist IBI362 (LY3305677) in Chinese patients with type 2 diabetes.2022; 13(1): 3613.
• 13.  Azam MH, Azam MH, Azam KU, et al.: Efficacy and Safety of Mazdutide in Managing Overweight and Obesity Among Non-Diabetic Adults: A Meta-Analysis of Randomised Controlled Trials.2026; 28(6): 4464–4473.
• 14.  Deng B, Ruan T, Lu W, et al.: Safety and efficacy of GLP-1 and glucagon receptor dual agonist for the treatment of type 2 diabetes and obesity: a systematic review and meta-analysis of randomized controlled trials. Endocrine. 2024; 86(1): 15–27. PubMed Abstract | Publisher Full Text
• 15.  Page MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ (Clinical research ed). 2021; 372: n71. Publisher Full Text
• 16.  Tool RoB: Risk of bias tools.[20th March, 2025]. Publisher Full Text
• 17.  Guyatt GH, Oxman AD, Vist GE, et al.: GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ (Clinical research ed). 2008; 336(7650): 924–926. PubMed Abstract | Publisher Full Text | Free Full Text
• 18.  Zhang B, Cheng Z, Chen J, et al.: Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2. Trial. 2024; 47(1): 160–168.
• 19.  Committee ADAPP: 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes—2024. Diabetes Care. 2023; 47(Supplement_1): S20–S42. Publisher Full Text
• 20.  Drucker DJ, Nauck MA: The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet (London, England). 2006; 368(9548): 1696–1705. Publisher Full Text
• 21.  Frías JP, Davies MJ, Rosenstock J, et al.: Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N. Engl. J. Med. 2021; 385(6): 503–515. PubMed Abstract | Publisher Full Text
• 22.  Kahn SE, Hull RL, Utzschneider KM: Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006; 444(7121): 840–846. Publisher Full Text
• 23.  Drozdz D, Alvarez-Pitti J, Wójcik M, et al.: Obesity and Cardiometabolic Risk Factors: From Childhood to Adulthood. Nutrients. 2021; 13(11): 4176. PubMed Abstract | Publisher Full Text | Free Full Text
• 24.  Day JW, Ottaway N, Patterson JT, et al.: A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 2009; 5(10): 749–757. PubMed Abstract | Publisher Full Text
• 25.  Müller TD, Finan B, Clemmensen C, et al.: The New Biology and Pharmacology of Glucagon. Physiol. Rev. 2017; 97(2): 721–766. Publisher Full Text
• 26.  Joseph JJ: Comprehensive Management of Cardiovascular Risk Factors for Adults With Type 2 Diabetes: A Scientific Statement From the American Heart Association.2022; 145(9): e722–e759.
• 27.  Stachteas P, Nasoufidou A, Karakasis P, et al.: Efficacy of Dual Glucagon and Glucagon-like Peptide-1 Receptor Agonists Across the Cardiometabolic Continuum: A Review of Current Clinical Evidence. Rev. Cardiovasc. Med. 2025; 26(7): 39691. PubMed Abstract | Publisher Full Text | Free Full Text
• 28.  Tenenbaum A, Klempfner R, Fisman EZ: Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor. Cardiovasc. Diabetol. 2014; 13: 159. PubMed Abstract | Publisher Full Text | Free Full Text
• 29.  Gorgojo-Martínez JJ, Mezquita-Raya P, Carretero-Gómez J: Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus.2022; 12(1).
• 30.  Müller TD, Finan B, Bloom SR, et al.: Glucagon-like peptide 1 (GLP-1). Molecular metabolism. 2019; 30: 72–130. PubMed Abstract | Publisher Full Text | Free Full Text
• 31.  Chen QQ, Yang Y, Xu JY, et al.: Dose-Response Relationship of Glucagon-like Peptide-1 Receptor Agonists on HbA1c and Body Weight in Type 2 Diabetes Mellitus: A Systematic Review and Network Meta-Analysis. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2025; 31(2): 188–197. PubMed Abstract | Publisher Full Text
• 32.  Nalisa DL, Cuboia N, Dyab E, et al.: Efficacy and safety of Mazdutide on weight loss among diabetic and non-diabetic patients: a systematic review and meta-analysis of randomized controlled trials. Front. Endocrinol. 2024; 15: 1309118. PubMed Abstract | Publisher Full Text | Free Full Text
• 33.  9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2025. Diabetes Care. 2025; 48(1 Suppl 1): S181–s206. PubMed Abstract | Publisher Full Text | Free Full Text
• 34.  Ekpor E, Akyirem S, Adade DP: Prevalence and associated factors of overweight and obesity among persons with type 2 diabetes in Africa: a systematic review and meta-analysis. Ann. Med. 2023; 55(1): 696–713. PubMed Abstract | Publisher Full Text | Free Full Text
• 35.  Gao L, Jiang H, Cai H, et al.: Treatment With 9-mg Mazdutide for Weight Reduction in Chinese Adults With Obesity: The GLORY-2 Randomized Clinical Trial. JAMA. 2026. PubMed Abstract | Publisher Full Text | Free Full Text
• 36.  Rasul M, Hassan A: Underlying and Extended Data for: Efficacy and Safety of Mazdutide for Type 2 Diabetes: a GRADE-assessed systematic review and meta-analysis of randomized controlled trials.2026.