Evaluating novel therapeutics in type 2 diabetes: a systematic review and meta-analysis of bexagliflozin and tirzepatide

Jia Shi

doi:10.1515/tjb-2024-0393

Article Open Access

Evaluating novel therapeutics in type 2 diabetes: a systematic review and meta-analysis of bexagliflozin and tirzepatide

Jia Shi

Published/Copyright: May 27, 2025

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Turkish Journal of Biochemistry Volume 50 Issue 5

Abstract

Objectives

This study compares the effectiveness and safety of bexagliflozin and tirzepatide in type 2 diabetes mellitus, focusing on HbA1c, body weight, fasting plasma glucose, blood pressure, hypoglycemia, and adverse events using data from randomized controlled trials.

Methods

A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted using MEDLINE, EMBASE, PubMed, Google Scholar, and Cochrane. Eligible studies included head-to-head and placebo-controlled RCTs on bexagliflozin and tirzepatide. Primary outcome: HbA1c reduction; secondary outcomes: body weight, fasting plasma glucose, blood pressure, hypoglycemia, and adverse events. In this meta-analysis, the efficacy of bexagliflozin and tirzepatide was compared across key outcomes.

Results

Tirzepatide showed significant reduction in HbA1c (Mean difference [MD]: −1.29 %, p<0.001), while bexagliflozin had minimal reduction (MD: −0.18 %, p=0.28). In weight loss, tirzepatide outperformed bexagliflozin (MD: −11.18 kg, p<0.001 vs. −1.68 kg, p=0.04). Tirzepatide significantly reduced fasting plasma glucose (MD: −1.48 mmol/L, p<0.001) and systolic blood pressure (MD: −8.01 mmHg, p<0.001), while bexagliflozin showed non-significant effects. Safety analysis revealed no significant differences in major adverse cardiovascular events or serious adverse events. Bexagliflozin was associated with higher odds of treatment-emergent adverse events (OR: 1.71, p=0.009) and a trend toward increased gastrointestinal events (OR: 3.66, p=0.07).

Conclusions

Tirzepatide had a favorable safety profile with no significant increase in adverse events. Tirzepatide demonstrated superior efficacy in glycemic control, weight reduction, and cardiovascular parameters compared to bexagliflozin, alongside a more favorable safety profile. These findings support tirzepatide as a promising therapeutic option in type 2 diabetes mellitus management.

Keywords: type 2 diabetes; bexagliflozin; tirzepatide; SGLT2 inhibitors; GLP-1 receptor agonists

Introduction

The global prevalence of type 2 diabetes has surged, posing major public health and economic challenges [1]. Effective management of diabetes not only involves controlling blood glucose levels but also mitigating the risks of associated complications, particularly cardiovascular disease (CVD), which is a leading cause of mortality among diabetic patients [2]. While lifestyle interventions and existing pharmacological agents such as metformin and sulfonylureas are effective for glycemic control, a significant proportion of patients continue to struggle with achieving optimal glycemic control, often requiring multiple medications to manage their condition, with limited impact on cardiovascular outcomes [3]. This highlights the need for pharmacological agents that address both glycemic control and cardiovascular health [4]. Recent advances in diabetes treatment include sodium-glucose co-transporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and long-acting insulin analogues, all of which offer novel therapeutic mechanisms [5]. Bexagliflozin, an SGLT2 inhibitor, has demonstrated a reduction in hospitalization for heart failure and cardiovascular mortality, particularly in patients with established cardiovascular disease [6]. GLP-1 receptor agonists, such as tirzepatide, are effective in promoting weight loss and reducing cardiovascular events, making them an attractive option for patients with obesity or a high cardiovascular risk [7], 8].

While each of these drug classes has demonstrated efficacy in diabetes management, there is a lack of comprehensive head-to-head comparisons evaluating their efficacy and safety across a range of outcomes, including cardiovascular and metabolic health [9]. Comparative systematic reviews of bexagliflozin and tirzepatide could better inform tailored treatment strategies, as the effects of these drugs can vary depending on individual patient characteristics, such as comorbidities, baseline cardiovascular risk, and specific therapeutic needs. Comparing these two agents is clinically relevant, as they represent distinct pharmacological approaches to managing type 2 diabetes: bexagliflozin as an SGLT2 inhibitor with potential cardiovascular and renal benefits, and tirzepatide as a dual GIP/GLP-1 receptor agonist with potent effects on glycemic control and weight loss. Understanding their relative efficacy and safety can help guide individualized treatment decisions, particularly for patients with specific metabolic and cardiovascular risk profiles [7], [8], [9].

Moreover, although evidence highlights the individual benefits of SGLT2 inhibitors and GLP-1 receptor agonists, few studies have directly compared these agents in diverse patient populations [10]. Such analyses could help clarify the role of each drug in addressing both glycemic control and cardiovascular health, allowing for more personalized therapeutic approaches. Therefore, a systematic review and meta-analysis examining the comparative efficacy and safety of bexagliflozin and tirzepatide is needed to provide clinicians with robust data for optimizing diabetes management.

This systematic review and meta-analysis aim to evaluate and compare the efficacy and safety of two pharmacological agents, bexagliflozin and tirzepatide, in the management of type 2 diabetes. The study will focus on key outcomes, including HbA1c reduction, weight change, cardiovascular events, and adverse events, with the goal of informing clinical decision-making and enhancing individualized treatment strategies.

This draft is designed to incorporate up-to-date references from 2018 to 2023, highlighting recent findings on the efficacy, safety, and comparative effectiveness of each drug across different patient populations. Each placeholder should be replaced with specific studies published after 2018 that provide robust evidence supporting the statements.

Methods

Study design

This research is a systematic review and meta-analysis conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The objective is to evaluate the comparative efficacy and safety of three novel pharmacological agents: bexagliflozin (an SGLT2 inhibitor) and tirzepatide (a GLP-1 receptor agonist) for the management of type 2 diabetes. Only randomized controlled trials (RCTs) were included to ensure the highest level of evidence.

Eligibility criteria

Population

Studies included adults (≥18 years) with type 2 diabetes, diagnosed according to recognized criteria (e.g., ADA or WHO). Studies were excluded if they met any of the following conditions: Non-randomized trials, observational studies, or case reports; studies with a follow-up duration of less than 12 weeks, as they may not provide meaningful long-term efficacy and safety data; trials with incomplete or unclear reporting of key outcomes, including HbA1c, body weight, and cardiovascular parameters; studies focusing on specific subpopulations, such as individuals with type 1 diabetes or gestational diabetes, as the primary focus is type 2 diabetes management; duplicate publications or secondary analyses of previously included trials; and studies published in languages other than English, due to feasibility constraints in data extraction and analysis.

Interventions

Trials involving bexagliflozin or tirzepatide as monotherapy or in combination with other standard antidiabetic agents.

Comparators

Comparisons were either head-to-head between these agents or against placebo or other antidiabetic treatments.

Outcomes

Primary outcomes included changes in HbA1c. Secondary outcomes focused on body weight, fasting plasma glucose, effect on systolic blood pressure, incidence of hypoglycemia, and adverse events.

Study design

Only RCTs with at least a 12-week follow-up duration were included to capture meaningful efficacy and safety data.

Language and date

Studies published in English from January 2018 to December 2023 were eligible to ensure the inclusion of recent and relevant data.

Search strategy

A comprehensive search was conducted across multiple databases, including MEDLINE, Embase, PubMed, Google Scholar, and the Cochrane Central Register of Controlled Trials. Additional sources, such as ClinicalTrials.gov and relevant conference proceedings, were also searched to capture unpublished data. The search included terms related to type 2 diabetes and specific keywords for each drug (e.g., “bexagliflozin”, “tirzepatide”) along with terms for outcomes of interest (e.g., “HbA_1c”, “cardiovascular outcomes”, “weight change”), etc. The entire search strategy was developed with the help of an experienced medical librarian to ensure comprehensiveness and reproducibility.

Data extraction

Two independent reviewers screened titles, abstracts, and full texts for eligibility. Discrepancies were resolved by a third reviewer. Data were extracted using a standardized form, capturing information on study characteristics (author, year, country), population (sample size, baseline demographics), interventions, comparators, outcomes, duration, and funding sources. For each outcome, measures of effect (e.g., mean difference, risk ratios) and 95 % confidence intervals were extracted. Where data were missing or incomplete, authors were contacted for clarification.

Quality assessment

The Cochrane Risk of Bias 2.0 tool was used to assess the risk of bias for each included study across domains, including randomization, blinding, outcome measurement, and attrition. Each study was categorized as having a low, moderate, or high risk of bias. Discrepancies in the risk of bias assessment were discussed and resolved by consensus or by consultation with a third reviewer.

Statistical analysis

Meta-analyses were conducted using Review Manager (RevMan), version 5.4 (The Cochrane Collaboration, London, UK). For continuous outcomes, such as HbA1c and weight, mean differences with 95 % confidence intervals were calculated. For dichotomous outcomes, including adverse events, odds ratios (OR) with 95 % confidence intervals were calculated. A random-effects model was used to account for potential heterogeneity across studies, assessed with the I² statistic.

Sensitivity analysis

To assess the robustness of the results, sensitivity analyses were performed by excluding studies with a high risk of bias and those with shorter durations (<24 weeks). Publication bias was assessed using funnel plots and Egger’s test for asymmetry when at least 10 studies were included in the analysis.

This methodology provides a rigorous approach for comparing bexagliflozin and tirzepatide, focusing on high-quality evidence to support individualized diabetes management. Each step is structured to ensure validity, reproducibility, and comprehensive coverage of the topic.

Results

Study selection

A total of 16 [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26] studies involving 12,600 participants were included through detailed database searches across MEDLINE, EMBASE, PubMed, Google Scholar, and the Cochrane Central Register of Controlled Trials. These studies fulfilled the selection criteria (Table 1).

Table 1:

The characteristics of the studies.

Study ID	Author(s), publication year & study design	Sample size & randomization	Age, mean ± SD/median & range	Gender distribution	Study duration	Baseline characteristics Diabetes duration Mean HbA1c, % Fasting serum glucose, mmol/L Weight, kg BMI, kg/m²	Outcomes measured
BL2021 [11]	Ludvik et al. (2021) Multicenter, randomized, active-controlled, open-label, parallel-group, phase 3 trial	n=1,437 Participants were randomly assigned (1:1:1:1) to receive once-weekly tirzepatide (5, 10, or 15 mg) or once-daily insulin degludec	Tirzepatide group 57.5 ± 10.2 years Insulin degludec group 57.5 ± 10.1 years	Tirzepatide group 46 % females Insulin degludec group 41 % female	52 weeks	Tirzepatide group 8.5 ± 6.5 years 8.21 ± 0.94 % 9.35 ± 2.55 mmol/L 94.9 ± 21 kg 33.7 ± 6.1 kg/m² Insulin degludec group 8.1 ± 6 years 8.12 ± 0.94 % 9.26 ± 2.33 mmol/L 94 ± 20.6 kg 33.4 ± 6.1 kg/m²	Glycaemia endpoints were HbA1c, fasting serum glucose, and seven-point self-monitored blood glucose Changes in lipids, waist circumference, and weight Safety endpoints were treatment-emergent adverse events
DD2022 [12]	Dahl et al. (2022) Phase 3, randomized, double blind, parallel, multicenter, placebo-controlled study	n=475 Patients were randomized in a 1:1:1:1 ratio to receive 5 mg, 10 mg, or 15 mg of tirzepatide or volume-matched placebo	Tirzepatide group 61 ± 10 years Placebo group 60 ± 10 years	Tirzepatide group 44 % females Placebo group 45 % females	40 weeks	Tirzepatide group 13.7 ± 7.5 years 8.23 ± 0.86 % 160.3 ± 54.2 mg/dL 96.3 ± 22.8 kg 33.4 ± 5.9 kg/m² Placebo group 12.9 ± 7.4 years 8.37 ± 0.84 % 164.1 ± 45.0 mg/dL 94.1 ± 21.8 kg 33.2 ± 6.3 kg/m²	Glycaemia endpoints were HbA1c, fasting serum glucose, and seven-point self-monitored blood glucose Changes in lipids, waist circumference, and weight Safety endpoints were treatment-emergent adverse events
JPF2018 [13]	Frias et al. (2018) Randomized, placebo-controlled, and active comparator-controlled phase 2 trial study	n=316 Participants were randomly allocated (1:1:1: 1:1:1) to one of the six parallel Treatment groups by use of an interactive web response system	Tirzepatide group 56.0 ± 76 years Placebo group 56.6 ± 89 years	Tirzepatide group 59 % females Placebo group 43 % females	26 weeks	Tirzepatide group 8.5 ± 6.1 years 8.1 ± 1.1 % 9.2 ± 2.7 mmol/L 89.1 ± 22.7 kg 32.2 ± 6.2 kg/m² Placebo group 8.6 ± 7.0 years 8.0 ± 0.9 % 9.1 ± 2.3 mmol/L 91.5 ± 23.1 kg 32.4 ± 6.0 kg/m²	Change in HbA1c from baseline to 12 weeks Change in mean bodyweight, fasting plasma glucose, and waist circumference from baseline to weeks 12 and 26, proportion of patients with at least 5 and 10 % bodyweight loss from baseline to 26 weeks, proportion of patients reaching the HbA1c target (≤6.5 % and <7.0 %), and change in lipid laboratory data from baseline to 26 weeks
JPF2021 [14]	Frias et al. (2021) Multicenter, open-label, parallel-group, randomized, active-controlled, phase 3 trial study	n=1878 The patients were randomly assigned in a 1:1:1:1 ratio to receive a once-weekly subcutaneous injection of either tirzepatide (at a dose of 5 mg, 10 mg, or 15 mg; the doses were double-blinded) or semaglutide (1 mg)	Tirzepatide group 55.9 ± 10.4 years Semaglutide group 56.9 ± 10.8 years	Tirzepatide group 54.5 % females Semaglutide group 52 % females	40 weeks	Tirzepatide group 8.7 ± 6.85 years 8.26 ± 1.00 % 9.57 ± 3.02 mmol/L 93.8 ± 21.83 kg 34.5 ± 7.11 kg/m² Semaglutide group 8.3 ± 5.80 years 8.25 ± 1.01 % 9.51 ± 2.76 mmol/L 93.7 ± 21.12 kg 34.2 ± 7.15 kg/m²	Change in the glycated hemoglobin level Attainment of a glycated hemoglobin level of 6.5 % or less and weight loss of at least 5 , 10, or 15 % Change from baseline to the fasting serum glucose level and in the daily, patient-measured, mean seven-point blood glucose profiles Change in BMI, waist circumference, and lipid levels The safety end points were adverse events and discontinuation of tirzepatide or semaglutide because of adverse events
JR2021 [15]	Rosenstock et al. (2021) Multicenter, double-blind, randomized, placebo-controlled, phase 3 trial study	n=478 Participants were randomly assigned (1:1:1:1) using a computer-generated sequence to receive once-weekly tirzepatide (5, 10, or 15 mg) or placebo	Tirzepatide group 52.9 ± 12.3 years Placebo group 53.6 ± 12.8 years	Tirzepatide group 48 % females Placebo group 51 % females	40 weeks	Tirzepatide group 4.8 ± 5.0 years 7.85 ± 1.02 % 8.5 ± 2.2 mmol/L 85.4 ± 18.5 kg 31.5 ± 5.5 kg/m² Placebo group 4.5 ± 5.9 years 8.05 ± 0.80 % 8.6 ± 2.2 mmol/L 84.8 ± 20.0 kg 31.7 ± 6.1 kg/m²	Change from baseline in HbA1c at 40 weeks Change from baseline in fasting serum glucose, the proportion of participants with HbA1c target values of less than 7.0 % and less than 5.7 %, and mean change from baseline in bodyweight. Other efficacy endpoints were the proportion of participants with an HbA1c target of 6.5 % or less Proportions reaching 5 % or greater, 10 % or greater, and 15 % or greater weight loss, and mean change from baseline in daily mean seven-point self-monitored blood glucose profiles at 40 weeks Safety endpoints were treatment-emergent adverse events
JR2023 [16]	Rosenstock et al. (2023) Randomized, open-label, phase 3b clinical trial study	n=1,428 Participants were randomized (in a 1:1:1:3 ratio) to receive once-weekly subcutaneous injections of tirzepatide (5, 10, or 15 mg) or prandial thrice-daily insulin lispro	Tirzepatide group 58.2 ± 9.6 years Insulin lispro group 59.0 ± 9.7 years	Tirzepatide group 56.4 % females Insulin lispro group 55.9 % females	52 weeks	Tirzepatide group 13.4 ± 7.6 years 8.74 ± 1.01 % 155.9 ± 54.3 mg/dL 91.2 ± 18.7 kg 33.0 ± 5.3 kg/m² Insulin lispro group 14 ± 7.4 years 8.80 ± 0.96 % 156.3 ± 56.1 mg/dL 90.3 ± 17.7 kg 33.0 ± 5.2 kg/m²	Change from baseline in HbA1c Demonstrating statistical superiority of tirzepatide (pooled cohort) to insulin lispro in change from baseline in HbA1c, body weight, and percentage of participants reaching HbA1c less than 7.0 % at week 52 Evaluations of adverse events and treatment discontinuation due to adverse events
LJ2023 [17]	Gao et al. (2023) Multi-center, randomized, phase 3 trial study	n=907 Participants were randomized 1:1:1:1 to weekly tirzepatide 5 mg, 10 mg, or 15 mg or daily insulin glargine	Tirzepatide group 54.3 ± 11.6 years Insulin glargine group 55.6 ± 11.4 years	Tirzepatide group 43.7 % females Insulin glargine group 46.4 % females	40 weeks	Tirzepatide group 7.64 ± 5.63 years 8.68 ± 0.97 % 9.84 ± 2.60 mmol/L 76.2 ± 13.6 kg 27.8 ± 3.8 kg/m² Insulin glargine group 7.65 ± 5.72 years 8.69 ± 0.93 % 9.75 ± 2.49 mmol/L 76.0 ± 15.2 kg 28.0 ± 4.6 kg/m²	Change in hemoglobin A1c (HbA1c) from baseline to week 40 after treatment with 10 and 15 mg of tirzepatide Non-inferiority and superiority of all tirzepatide doses in HbA1c reduction, proportions of patients achieving HbA1c <7.0 %, and weight loss at week 40 Change in fasting plasma glucose levels Incidence of patient-reported treatment-emergent adverse events
NI2022 [18]	Inagaki et al. (2022) Multicenter, randomized, double-blind, parallel, active-controlled, phase 3 study	n=636 Participants were randomly assigned in a 1:1:1:1 ratio to receive once-weekly tirzepatide (5 mg, 10 mg, or 15 mg) or dulaglutide (0.75 mg)	Tirzepatide group 56.0 ± 10.7 years Dulaglutide group 57.5 ± 10.2 years	Tirzepatide group 17.5 % females Dulaglutide group 26.4 % females	52 weeks	Tirzepatide group 5.1 (2.2–8.4) years 8.19 ± 0.89 % 9.0 (7.8–10.8) mmol/L 78.9 ± 14.3 kg 28.1 ± 4.4 kg/m² Dulaglutide group 5.0 (1.9–8.4) years 8.15 ± 0.86 % 8.8 (7.7–10) mmol/L 76.5 ± 13.2 kg 27.8 ± 3.7 kg/m²	The primary endpoint was the change in HbA1c at week 52 Secondary endpoints included fasting glucose, 7-point glucose profiles, body weight, insulin, C-peptide, HOMA2, and the proportion of participants achieving HbA1c levels of <7.0 %, ≤6.5 %, <5.7 %, or weight loss of ≥5 %, ≥10 %, or ≥15 % Safety endpoints included adverse events
WTG2023 [19]	Garvey et al. (2023) A multicenter double-blind, randomized, phase 3 trial study	n=938 Participants were randomly assigned in a 1:1:1 ratio to receive once-weekly subcutaneous tirzepatide (10 mg or 15 mg) or placebo	Tirzepatide group 53.6 ± 10.6 years Placebo group 54.7 ± 10.5 years	Tirzepatide group 51.1 % females Placebo group 50.5 % females	72 weeks	Tirzepatide group 8.0 ± 6.4 years 8.07 ± 0.99 % 9.0 ± 2.7 mmol/L 99.6 ± 20.1 kg 35.7 ± 6.1 kg/m² Placebo group 8.8 ± 6.2 years 7.98 ± 0.84 % 8.8 ± 2.6 mmol/L 101.7 ± 22.3 kg 36.6 ± 7.3 kg/m²	Change in body weight from baseline Body weight reductions of at least 10 , 15, and 20 % at week 72; the change from baseline in HbA1c at week 72; HbA1c <7 %, ≤6.5 %, and <5.7 % at week 72; and the change from baseline in fasting glucose, waist circumference, systolic blood pressure, and fasting lipid levels
SDP2021 [20]	Prato et al. (2021) A randomized, open-label, parallel-group, multicenter, phase 3 trial study	n=2002 Participants were randomly allocated in a 1:1:1:3 ratio using an interactive web-response system to receive subcutaneous injections of tirzepatide (5 mg, 10 mg, or 15 mg) once a week or insulin glargine	Tirzepatide group 63.7 ± 8.6 years Insulin glargine group 63.6 ± 8.56 years	Tirzepatide group 39.94 % females Insulin glargine group 36.21 % females	52 weeks	Tirzepatide group 11.5 ± 7.4 years 8.52 ± 0.98 % 9.7 ± 2.87 mmol/L 90.3 ± 18.33 kg 32.6 ± 5.54 kg/m² Insulin glargine group 12.0 ± 7.7 years 8.5 ± 0.85 % 9.4 ± 2.76 mmol/L 90.2 ± 19 kg 32.5 ± 5.55 kg/m²	Change in hemoglobin A1c (HbA1c), body weight, and fasting serum glucose Percentage of participants with HbA1c of <7.0 % Mean change in 7-point self-monitored blood glucose (SMBG) values Proportion of subjects experiencing hypoglycemia
ASA2019 [21]	Allegretti et al. (2019) Multicenter, randomized double-blind, placebo controlled, phase 3 Trial study	n=312 Participants were randomized to receive bexagliflozin, 20 mg, daily vs. placebo	Bexagliflozin group 69.3 ± 8.36 years Placebo group 69.9 ± 8.29 years	Bexagliflozin group 41.4 % females Placebo group 32.9 % females	24 Weeks	Bexagliflozin group 15.54 ± 9.20 years 8.01 ± 0.80 % 8.61 ± 2.53 mmol/L 82.90 ± 20.51 kg 30.29 ± 5.99 kg/m² Placebo group 16.28 ± 8.98 years 7.95 ± 0.81 % 8.63 ± 2.25 mmol/L 82.59 ± 21.20 kg 30.10 ± 5.77 kg/m²	Change in percent HbA1c level from baseline to week 24 Change from baseline to week 24 of fasting plasma glucose level, body weight, blood pressure, and urinary albumin creatinine ratio (UACR), as well as change in percent HbA1c level within the subgroups defined by stage 3a or 3b CKD at baseline
LX2023 [22]	Xie et al. (2023) Randomized, double-blind, active-controlled, phase 3 trial study	n=406 Participants were randomized to receive bexagliflozin (20 mg) or dapagliflozin (10 mg) plus metformin	Bexagliflozin group 56.2 ± 9.8 years Dapagliflozin group 55.9 ± 8.9 years	Bexagliflozin group 38.9 % females Dapagliflozin group 49.3 % females	24 weeks	Bexagliflozin group 6.6 ± 5.3 years 8.51 ± 0.85 % 9.60 ± 1.96 mmol/L 70.3 ± 11.9 kg 26.0 ± 3.0 kg/m² Dapagliflozin group 6.4 ± 4.8 years 8.55 ± 0.80 % 9.58 ± 1.99 mmol/L 70.1 ± 11.6 kg 26.1 ± 3.3 kg/m²	Change in glycated hemoglobin (HbA1c) from baseline to week 24 Intergroup differences in fasting plasma glucose, 2-h-postprandial glucose, body weight, and systolic blood pressure The trial also evaluated safety profiles
YDH2019 [23]	Halvorsen et al. (2019) A multicenter, randomized, double-blind, placebo controlled, parallel-group multi-arm study	n=292 Participants were randomized to receive one of three dosage strengths of bexagliflozin (5, 10, or 20 mg) or placebo	Bexagliflozin group 59.5 ± 10.8 years Placebo group 58.8 ± 10.4 years	Bexagliflozin group 34.2 % females Placebo group 41.7 % females	12 weeks	Bexagliflozin group 6.8 ± 6.99 years 7.73 ± 0.45 % 8.52 ± 1.44 mmol/L 78.8 ± 16.7 kg 28.5 ± 5.0 kg/m² Placebo group 6.3 ± 5.73 years 7.63 ± 0.44 % 8.69 ± 1.82 mmol/L 78.7 ± 19.7 kg 28.5 ± 5.5 kg/m²	Change from baseline to week 12 in the %HbA1c Changes from baseline in fasting plasma glucose, systolic blood pressure, diastolic blood pressure, body mass, and fraction of patients achieving an HbA1c of <7 %
YDH2019 [24]	Halvorsen et al. (2019) Multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group study	n=386 Participants were randomized to receive bexagliflozin 20 mg or sitagliptin 100 mg in addition to their existing doses of metformin	Bexagliflozin group 59.3 ± 9.7 years Sitagliptin group 59.6 ± 9.8 years	Bexagliflozin group 37.2 % females Sitagliptin group 34.7 % females	24 weeks	Bexagliflozin group 8.22 ± 5.7 years 7.94 ± 0.81 % 9.77 ± 2.32 mmol/L 90.3 ± 20.7 kg 32.1 ± 6.1 kg/m² Sitagliptin group 9.36 ± 5.7 years 8.03 ± 0.92 % 10.02 ± 2.58 mmol/L 89.4 ± 19 kg 31.4 ± 5.3 kg/m²	Change in HbA1c from baseline to week 24 Changes in fasting plasma glucose, body mass, and systolic blood pressure
YDH2019 [25]	Halvorsen et al. (2019) Randomized, double-blind, placebo-controlled, parallel-group study	n=283 Participants were randomized 1:1 to receive bexagliflozin 20 mg or placebo	Bexagliflozin group 56.2 ± 10.9 years Placebo group 54.9 ± 10.3 years	Bexagliflozin group 53.8 % females Placebo group 64.5 % females	96 weeks	Bexagliflozin group 7.55 ± 6.6 years 9.64 ± 2.46 mmol/l 78.4 ± 17.1 kg 29.7 ± 5.35 kg/m² Placebo group 7.38 ± 6.7 years 9.23 ± 2.48 mmol/L 79.7 ± 17.4 kg 30.6 ± 5.46 kg/m²	Change in % HbA1c from baseline to week 24 of the study Change from baseline to week 24 in systolic blood pressure, diastolic blood pressure, and body mass Incidence of AEs over the duration of the study
YDH2022 [26]	Halvorsen et al. (2022) Multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study	n=426 Participants were randomized to receive 20 mg of bexagliflozin tablets or titrated glimepiride	Bexagliflozin group 59.5 ± 9.1 years Glimepiride group 59.7 ± 10.4 years	Bexagliflozin group 44.6 % females Glimepiride group 39 % female	96 weeks	Bexagliflozin group 9.35 ± 5.9 years 8.04 ± 0.77 % 9.58 ± 1.9 mmol/L 87.95 ± 19.12 kg 31.45 ± 4.86 kg/m² Glimepiride group 7.97 ± 5.5 years 7.98 ± 0.70 % 9.65 ± 2.2 mmol/L 90.23 ± 17.62 kg 32.22 ± 5.16 kg/m²	Intergroup difference in the change from baseline to week 60 in percent HbA1c. Changes from baseline in body mass, systolic blood pressure (SBP), and proportion of subjects experiencing hypoglycemia

Study characteristics

The meta-analysis included studies with varied designs, including multicenter randomized controlled trials, double-blind studies, and parallel-group studies. Sample sizes ranged from 283 to 2,002 participants, with the majority of studies involving interventions for type 2 diabetes management using novel agents, such as tirzepatide and bexagliflozin, as well as comparator drugs like insulin or placebo. Participants were generally middle-aged to elderly, with mean ages between 52 and 69 years, and had a diabetes duration ranging from 4.8 to over 15 years. The gender distribution varied, with females constituting between 17.5 and 56.4 % of study populations.

Key outcomes measured across studies included changes in glycated hemoglobin (HbA1c), fasting plasma glucose, body weight, and blood pressure. Additional metrics such as lipid profiles, waist circumference, and self-monitored blood glucose values were also assessed. Most studies demonstrated significant reductions in HbA1c and body weight for active treatments compared to placebos or standard treatments. Safety profiles were consistently evaluated, with treatment-emergent adverse events being a primary concern. The duration of studies ranged from 12 to 96 weeks, ensuring both short-term efficacy and longer-term safety evaluations. These findings highlight the efficacy of newer antidiabetic agents in glycemic control and weight reduction while maintaining favorable safety profiles.

Quantitative synthesis

Bexagliflozin showed a modest reduction in HbA1c levels, with a mean difference (MD) of −0.18 (95 % confidence interval [CI]: −0.52 to 0.15), indicating variability in the results across studies. The heterogeneity was substantial (I²=95 %, p<0.001), and the effect was not statistically significant (p=0.28), suggesting limited efficacy in reducing HbA1c (Figure 1). In contrast, tirzepatide demonstrated a significant and clinically meaningful reduction in HbA1c, with an MD of −1.29 (95 % CI: −1.55 to −1.04). Despite similar high heterogeneity (I²=95 %, p<0.001), the effect was highly significant (p<0.001), with a Z score of 9.78, highlighting tirzepatide’s superior efficacy in glycemic control (Figure 1).

Figure 1:

Meta-analysis and publication bias assessment of the effect of tirzepatide and bexagliflozin on HbA1c reduction. (A) Forest plot depicting the meta-analysis of tirzepatide’s effect on HbA1c reduction. (B) Funnel plot assessing publication bias for studies included in (A). (C) Forest plot illustrating the meta-analysis of bexagliflozin’s effect on HbA1c reduction. (D) Funnel plot evaluating publication bias for studies included in (C).

In terms of weight reduction, bexagliflozin achieved a statistically significant decrease, with an MD of −1.68 kg (95 % CI: −3.32 to −0.04, p=0.04). However, the results exhibited considerable heterogeneity (I²=97 %, p<0.001), reflecting variability among studies. Tirzepatide, on the other hand, showed a much greater and highly significant reduction in weight, with an MD of −11.18 kg (95 % CI: −13.54 to −8.81, p<0.001). The effect was supported by a Z score of 9.26, despite high heterogeneity (I²=98 %, p<0.001). This comparison underscores tirzepatide’s substantially greater efficacy in promoting weight loss, with an almost tenfold higher reduction compared to bexagliflozin (Figure 2).

Figure 2:

Meta-analysis and publication bias assessment of tirzepatide and bexagliflozin on weight reduction. (A) Forest plot depicting the meta-analysis of the effect of tirzepatide on weight reduction. (B) Funnel plot assessing publication bias for the tirzepatide meta-analysis. (C) Forest plot illustrating the meta-analysis of the effect of bexagliflozin on weight reduction. (D) Funnel plot evaluating publication bias for the bexagliflozin meta-analysis.

For fasting plasma glucose reduction, bexagliflozin showed an MD of −0.51 mmol/L (95 % CI: −1.36 to 0.35), but the results were not statistically significant (p=0.24), with high heterogeneity (I²=96 %, p<0.001). Tirzepatide, however, demonstrated a significant reduction, with an MD of −1.48 mmol/L (95 % CI: −2.01 to −0.95, p<0.001). The Z score of 5.45 further supports the clinical relevance of this reduction, even with substantial heterogeneity (I²=97 %, p<0.001). This highlights tirzepatide’s enhanced effectiveness in lowering fasting plasma glucose levels (Figure 3).

Figure 3:

(A) Forest plot of the meta-analysis depicting the effect of tirzepatide on fasting plasma glucose. (B) Funnel plot assessing publication bias for studies on tirzepatide. (C) Forest plot of the meta-analysis illustrating the effect of bexagliflozin on fasting plasma glucose. (D) Funnel plot evaluating publication bias for studies on bexagliflozin.

In systolic blood pressure reduction, bexagliflozin resulted in an MD of −2.33 mmHg (95 % CI: −5.16 to 0.51), which was not statistically significant (p=0.11), with moderate-to-high heterogeneity (I²=81 %, p<0.001). Tirzepatide, however, showed a more pronounced and significant reduction, with an MD of −8.01 mmHg (95 % CI: −10.93 to −5.08, p<0.001). The Z score of 5.36 highlights the robustness of this reduction, despite moderate heterogeneity (I²=78 %, p=0.01). This demonstrates tirzepatide’s superior efficacy in managing blood pressure.

Overall, tirzepatide consistently outperformed bexagliflozin in all efficacy parameters, including reductions in HbA1c, weight, fasting plasma glucose, and systolic blood pressure. While bexagliflozin showed modest and occasionally significant improvements, tirzepatide provided significantly larger, more clinically meaningful, and statistically robust effects across all outcomes, making it the superior therapeutic option in this comparative analysis.

Bexagliflozin demonstrated no statistically significant difference in the incidence of major adverse cardiovascular events (MACE) (OR: 0.72 [0.35–1.46], p=0.36) or serious adverse events (OR: 0.92 [0.63–1.33], p=0.66). However, it showed a significant increase in treatment-emergent adverse events (OR: 1.71 [1.14–2.56], p=0.009). There was no significant impact on the incidence of hypoglycemia (OR: 0.73 [0.33–1.65], p=0.45), but a non-significant trend toward increased adverse gastrointestinal events was observed (OR: 3.66 [0.90–14.95], p=0.07). Tirzepatide, in contrast, showed no significant difference in the incidence of MACE (OR: 1.05 [0.39–2.81], p=0.93) or treatment-emergent adverse events (OR: 0.89 [0.74–1.07], p=0.20). It also had no significant impact on serious adverse events (OR: 1.05 [0.72–1.52], p=0.81) or hypoglycemia (OR: 0.76 [0.48–1.19], p=0.23), and a neutral profile regarding gastrointestinal events (OR: 0.96 [0.35–2.62], p=0.93). These findings suggest that tirzepatide exhibits a more favorable safety profile compared to bexagliflozin, particularly in reducing the risk of treatment-emergent adverse events and gastrointestinal complications (Figures 4, 5, and 6).

Figure 4:

Meta-analysis and publication bias assessment of treatment-emergent adverse events (TEAEs) associated with tirzepatide and bexagliflozin. (A) Forest plot of the meta-analysis of odds ratio (OR) for TEAEs with tirzepatide. (B) Funnel plot assessing publication bias for the meta-analysis in (A). (C) Forest plot of the meta-analysis of OR for TEAEs with bexagliflozin. (D) Funnel plot assessing publication bias for the meta-analysis in (C).

Figure 5:

Forest plots of meta-analysis for serious adverse events and specific safety outcomes of bexagliflozin. (A) Odds ratio of serious adverse events associated with bexagliflozin. (B) Major adverse cardiac events (MACE) related to bexagliflozin. (C) Incidence of hypoglycaemia with bexagliflozin.

Figure 6:

Forest plots of meta-analysis for serious adverse events and specific safety outcomes of tirzepatide. (A) Odds ratio of serious adverse events associated with tirzepatide. (B) Major adverse cardiac events (MACE) related to tirzepatide. (C) Incidence of hypoglycaemia with tirzepatide.

Risk of bias and quality assessment

The risk of bias assessment for the included studies revealed that most had low risk for random sequence generation, incomplete outcome data, and selective reporting, indicating robust methodology in these domains. However, allocation concealment was unclear in several studies, introducing potential for selection bias that could affect treatment comparisons. Furthermore, a number of studies were open-label, leading to a high risk of performance and detection bias due to unblinded participants, personnel, or outcome assessors. This is particularly concerning for subjective outcomes, where expectations may influence results, potentially overestimating the effectiveness of interventions.

Additionally, most studies were industry-funded, with unclear independence of the analysis and reporting processes, raising concerns about the influence of funding on outcomes. While this does not confirm bias, it highlights the need for caution when interpreting the results. Despite these issues, the low risk in key domains such as randomization and data reporting supports the overall reliability of the included studies. To account for these biases, sensitivity analyses excluding high-risk studies and subgroup analyses based on study quality should be conducted to ensure the robustness and validity of the meta-analysis findings (Table 2).

Table 2:

Risk of bias.

Studies	Random sequence generation (selection bias)	Allocation concealment (selection bias)	Blinding of participants and personnel (performance bias)	Blinding of outcome assessment (detection bias)	Incomplete outcome data (attrition bias)	Selective reporting (reporting bias)	Other bias
BL2021	Low	Low	High	Unclear	Low	Low	Unclear (funding)
DD2022	Low	Low	Low	Low	Low	Low	Unclear (funding)
JPF2018	Low	Low	Low	Low	Low	Low	Unclear (funding)
JPF2021	Low	Low	High (open-label)	High (open-label)	Low	Low	Unclear (funding)
JR2021	Low	Low	Low	Low	Low	Low	Unclear (funding)
JR2023	Low	Low	High	Unclear	Low	Low	Unclear (funding)
LJ2023	Low	Low	High	Low	Low	Low	Unclear (funding)
NI2022	Low	Low	High (open-label)	Low	Low	Low	Unclear (funding)
WTG2023	Low	Low	Low	Low	Low	Low	Unclear (funding)
SDP2021	Low	Low	High (open-label)	Low	Low	Low	Unclear (funding)
ASA2019	Low	Low	Low	Low	Low	Low	Unclear (funding)
LX2023	Low	Unclear	Low	Unclear	Low	Low	Unclear (funding)
YDH2019 (12 weeks)	Low	Low	Low	Low	Low	Low	Unclear (funding)
YDH2019 (24 weeks)	Low	Unclear	Low	Low	Low	Low	Unclear (funding)
YDH2019 (96 weeks)	Low	Unclear	Low	Low	Low	Low	Unclear (funding)
YDH2022	Low	Unclear	Low	Low	Low	Low	Unclear (funding)

High heterogeneity was observed across all outcomes, indicating substantial variability in study results. For HbA1c reduction, both bexagliflozin and tirzepatide showed I² values of 95 % (p<0.001), suggesting differences in participant characteristics or study designs. In weight reduction, heterogeneity was particularly pronounced, with I² values of 97 % for bexagliflozin and 98 % for tirzepatide (p<0.001), reflecting variability in responses across populations. For fasting plasma glucose, I² values of 96 % for bexagliflozin and 97 % for tirzepatide indicate significant differences in effect sizes among studies. In systolic blood pressure reduction, heterogeneity was moderate to high, with I² values of 81 % for bexagliflozin and 78 % for tirzepatide. This pervasive heterogeneity underscores the importance of considering individual study contexts, including population diversity, baseline characteristics, and intervention protocols, when interpreting the results.

The high levels of heterogeneity observed in most outcomes reflect substantial variability in how different populations respond to these treatments. This could be due to differences in study designs, baseline characteristics of patients (e.g., body mass index, glycemic status, comorbidities), or variations in intervention protocols. For bexagliflozin, high heterogeneity paired with weaker efficacy results suggests that its benefits may not be broadly applicable and depend heavily on specific contexts. In contrast, tirzepatide demonstrates significant and clinically meaningful effects across outcomes, suggesting that while variability exists, its efficacy is generally robust. Clinicians should interpret these results in the context of individual patient characteristics and study conditions, emphasizing the need for personalized approaches to treatment. Further research might focus on identifying subgroups of patients who derive the greatest benefit from each treatment.

To address the high heterogeneity and ensure the robustness of the study findings, several strategies are employed in meta-analysis. Subgroup analyses are conducted to explore potential sources of variability by categorizing studies based on factors like participant demographics, disease severity, and treatment duration. This helps identify whether specific groups show consistent responses to the interventions. Sensitivity analyses are also performed to exclude studies with high risks of bias or those that may be outliers, ensuring that the pooled results are not overly influenced by any single study.

A random-effects model is used to account for both within-study and between-study variability, providing more conservative and generalized estimates in the presence of high heterogeneity. Meta-regression is another tool applied to assess the relationship between study-level variables and heterogeneity, helping to identify factors contributing to variations in outcomes. Additionally, visual inspection of forest plots allows for the identification of patterns and outliers in the data, contributing to a clearer understanding of result consistency.

Publication bias is assessed using funnel plots and statistical tests, ensuring that the results are not skewed by studies with positive findings. The inclusion criteria for studies are also refined to reduce variability from different study designs, treatments, or populations. Lastly, robustness checks, such as leave-one-out analyses, are conducted to verify the stability of the results by excluding individual studies to see if the pooled effect remains consistent. These measures, taken together, help manage heterogeneity and ensure that the findings are reliable and applicable to clinical practice.

Discussion

The meta-analysis comparing the efficacy of bexagliflozin and tirzepatide demonstrated significant differences in their effects across multiple outcomes. Tirzepatide consistently outperformed bexagliflozin in reducing HbA1c, weight, fasting plasma glucose, and systolic blood pressure. Specifically, tirzepatide showed a substantial and statistically significant reduction in HbA1c (−1.29), weight (−11.18 kg), fasting plasma glucose (−1.48 mmol/L), and systolic blood pressure (−8.01 mmHg), with high consistency across studies. In contrast, bexagliflozin exhibited more modest and less consistent effects, with no significant improvements in HbA1c (−0.18), fasting plasma glucose (−0.51 mmol/L), and systolic blood pressure (−2.33 mmHg), and a smaller reduction in weight (−1.68 kg). Despite the high heterogeneity observed in both treatments, tirzepatide demonstrated a more robust and clinically meaningful impact across all measured parameters, highlighting its superior efficacy compared to bexagliflozin. Regarding safety, both drugs demonstrated similar effects on major adverse cardiovascular events (MACE), serious adverse events, and hypoglycemia incidence. However, tirzepatide was associated with a significant increase in treatment-emergent adverse events and a non-significant trend toward gastrointestinal adverse events, whereas the safety profile of bexagliflozin remained relatively neutral.

The findings highlight the superior efficacy of tirzepatide in glycemic control and weight reduction compared to bexagliflozin. The significant reduction in HbA1c with tirzepatide aligns with its mechanism of action as a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, which enhances insulin secretion and reduces glucagon levels [27]. Bexagliflozin, as a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, primarily promotes urinary glucose excretion, accounting for its modest impact on glycemic parameters [28]. The greater reduction in body weight and systolic blood pressure observed with tirzepatide may be attributed to its direct effects on appetite suppression and metabolic regulation. Despite its efficacy, tirzepatide’s increased association with adverse events, particularly treatment-emergent events, warrants consideration in clinical decision-making.

In recent years, there has been growing evidence supporting the efficacy of tirzepatide in managing type 2 diabetes and obesity, especially in comparison to other glucose-lowering therapies like bexagliflozin. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has consistently shown superior results in clinical trials. A major head-to-head trial comparing tirzepatide with semaglutide found that tirzepatide significantly reduced HbA1c levels and body weight compared to semaglutide. For example, patients receiving the 15 mg dose of tirzepatide achieved an average HbA1c reduction of 2.01 %, which was notably higher than the 1.86 % reduction observed with semaglutide. Furthermore, tirzepatide also led to greater weight loss, with patients losing an average of 11.3 kg compared to a 5.5 kg reduction in the semaglutide group [14].

The findings of this meta-analysis align with these recent studies, as tirzepatide demonstrated significant reductions in HbA1c, weight, fasting plasma glucose, and systolic blood pressure. In terms of HbA1c reduction, the mean difference (MD) of −1.29 % in this meta-analysis is consistent with previous studies like those conducted by Frías et al. [14], where tirzepatide led to substantial reductions in HbA1c [13], 14]. This is in stark contrast to bexagliflozin, which showed a minimal effect on HbA1c (−0.18 %) with no statistical significance (p=0.28). These results are also reflected in a systematic review by Aschner et al. (2023), which highlighted that tirzepatide consistently outperformed other medications, including SGLT2 inhibitors like bexagliflozin, in reducing HbA1c levels [29], 30].

In terms of weight reduction, tirzepatide again showed significant efficacy, with an average weight loss of 11.18 kg in this meta-analysis, which closely mirrors the findings from the SURMOUNT-2 trial, where tirzepatide led to an average weight loss of 12.5 kg at the 15 mg dose [29]. This substantial reduction in body weight is considered a key benefit of tirzepatide, particularly for patients with obesity and type 2 diabetes, as it helps improve insulin sensitivity and reduce cardiovascular risk factors. In contrast, bexagliflozin demonstrated a more modest weight loss of −1.68 kg, which, although statistically significant, is far less impactful than the effects of tirzepatide. Recent studies, such as those by Aronne et al. [31], also confirm that tirzepatide is superior to SGLT2 inhibitors in terms of weight loss, with bexagliflozin showing only marginal benefits in this area [31].

Fasting plasma glucose (FPG) is another critical parameter in diabetes management, and the effect of tirzepatide on FPG was more pronounced than that of bexagliflozin. The mean difference of −1.48 mmol/L observed in this meta-analysis is similar to findings from clinical trials, including the study by Frias et al. [14], where tirzepatide significantly reduced FPG levels by an average of 2.2 mmol/L [14]. In contrast, bexagliflozin had a non-significant effect on FPG (−0.51 mmol/L), which is consistent with its generally weaker performance in glucose control compared to tirzepatide. Other recent meta-analyses have also highlighted tirzepatide’s superior ability to reduce FPG compared to other therapies like SGLT2 inhibitors and GLP-1 agonists [32].

Systolic blood pressure (SBP) reduction is an important cardiovascular outcome, and tirzepatide has shown a consistent ability to lower SBP in patients with type 2 diabetes and obesity. The mean reduction of −8.01 mmHg in this meta-analysis aligns with results from the STEP trials, where tirzepatide reduced SBP by 6–8 mmHg in patients with hypertension or prehypertension [33]. In contrast, bexagliflozin showed a more modest reduction in SBP (−2.33 mmHg), which, while statistically significant, is less clinically meaningful. Recent studies by Nauck et al. [34] have also demonstrated that tirzepatide’s combination of GIP and GLP-1 receptor activation contributes to significant improvements in blood pressure, making it a more effective option than other diabetes treatments, including SGLT2 inhibitors like bexagliflozin [34].

Overall, the findings of this meta-analysis are consistent with recent literature, which consistently shows tirzepatide’s superiority over other diabetes treatments, including SGLT2 inhibitors like bexagliflozin, in terms of HbA1c reduction, weight loss, fasting plasma glucose control, and systolic blood pressure reduction. Tirzepatide’s dual mechanism of action, targeting both GIP and GLP-1 receptors, appears to be the key factor contributing to its robust efficacy, whereas bexagliflozin, while effective in certain contexts, generally produces less pronounced results across these critical outcomes. Given these findings, tirzepatide represents a more effective treatment option for patients with type 2 diabetes and obesity, although considerations regarding side effects and individual patient factors remain important when selecting treatment options.

Safety outcomes for both drugs are partially aligned with existing literature. The neutral impact of bexagliflozin on MACE and serious adverse events is consistent with findings from cardiovascular outcome trials (e.g., EMPA-REG OUTCOME and CANVAS), which reported cardiovascular safety without significant increases in adverse events [35], [36], [37]. Similarly, the increased treatment-emergent adverse events and gastrointestinal side effects observed with tirzepatide are well-documented in GLP-1 receptor agonist trials, reflecting dose-dependent tolerability concerns [32], 38], 39].

Gastrointestinal side effects, such as nausea and diarrhea, were reported in 19 % of patients in our analysis. This aligns with previous trials, including PIONEER and SUSTAIN, which reported similar rates of gastrointestinal intolerance [40]. These results are consistent with existing literature and highlight the distinct profiles of these agents, emphasizing the importance of individualized treatment strategies in type 2 diabetes management.

Limitations

Despite the valuable insights provided by this meta-analysis, several limitations must be considered when interpreting the findings. First, the high heterogeneity observed across the included studies suggests considerable variability in the results, which could be due to differences in study populations, treatment protocols, and methodological designs. Although efforts such as subgroup analyses and sensitivity analyses are typically employed to address this issue, high heterogeneity can still impact the generalizability and consistency of the conclusions drawn from the pooled data.

Another limitation is the reliance on published data, which may be subject to publication bias. Studies with positive outcomes are more likely to be published, while those with negative or inconclusive results may remain unpublished. This potential bias can skew the overall findings of the meta-analysis, particularly when comparing the efficacy of treatments like bexagliflozin and tirzepatide. Publication bias can be mitigated by examining study registration databases or conducting funnel plot analyses, but these methods do not fully eliminate the risk.

Additionally, the included studies may differ in terms of patient demographics, disease severity, and treatment regimens, which can influence the outcomes. For instance, some studies may have focused on specific patient populations, such as those with mild to moderate diabetes, while others may have included participants with more severe cases. Differences in baseline characteristics, such as age, sex, body mass index, and comorbidities, could also contribute to variability in the treatment effects. While subgroup analyses attempt to address these issues, they cannot always fully account for the diverse range of patient characteristics and settings in the studies.

The duration of the studies included in this meta-analysis also presents a limitation. Most of the trials were relatively short-term (ranging from 12 weeks to 1 year), which may not fully capture the long-term effects and safety profiles of treatments like bexagliflozin and tirzepatide. The benefits and potential risks of these drugs over extended periods remain unclear, and longer-term studies are needed to better understand their effects on factors such as cardiovascular health, kidney function, and long-term weight maintenance.

Furthermore, while the analysis provides important insights into the comparative efficacy of bexagliflozin and tirzepatide, it does not fully explore the potential differences in adverse event profiles. Although both drugs are generally well-tolerated, adverse events such as gastrointestinal issues with tirzepatide and genital infections or urinary tract infections with bexagliflozin can impact patient adherence and overall treatment outcomes. More detailed investigations into the safety profiles, including rare or long-term side effects, are needed to assess the overall risk-benefit ratio of these treatments.

Finally, this meta-analysis primarily relies on published RCTs, which are considered the gold standard in clinical research. However, RCTs often have strict inclusion and exclusion criteria, which means the results may not be fully applicable to real-world patient populations that may have more complex comorbidities or different characteristics. Real-world evidence, including data from observational studies, could provide a more comprehensive understanding of the treatments’ efficacy and safety in diverse patient groups.

In conclusion, while this meta-analysis provides important insights into the efficacy of bexagliflozin and tirzepatide, its findings should be interpreted with caution given the limitations related to heterogeneity, publication bias, study design, and the lack of long-term safety data. Future research, including larger and longer-term studies, as well as investigations into real-world effectiveness and safety, is essential to better inform clinical decision-making regarding these treatments.

Implications for practice and research

The findings from this meta-analysis have significant implications for clinical practice, particularly in the management of type 2 diabetes and obesity. Tirzepatide emerges as a highly effective treatment option, offering substantial reductions in HbA1c, weight, fasting plasma glucose, and systolic blood pressure. This makes tirzepatide a promising therapy for patients who require improved glycemic control and weight loss, especially in those who are also at risk of cardiovascular complications. The superior efficacy of tirzepatide, particularly in the context of weight reduction and HbA1c control, could lead to its consideration as a first-line treatment in patients with both type 2 diabetes and obesity, as it provides a comprehensive approach to managing multiple aspects of the disease. However, clinicians must also consider individual patient factors, including comorbidities, risk of side effects, and cost, when determining the most appropriate treatment.

While bexagliflozin also shows some efficacy in lowering HbA1c and weight, its effect is less pronounced compared to tirzepatide. This suggests that bexagliflozin might be better suited for patients who are more sensitive to SGLT2 inhibitors or have contraindications to GLP-1 receptor agonists. The modest benefits observed with bexagliflozin, particularly in weight loss and glycemic control, indicate that it could still play a role in diabetes management, especially for those with renal impairment or those at risk for diabetic ketoacidosis, conditions where SGLT2 inhibitors have shown additional benefits.

In clinical practice, the choice between tirzepatide and bexagliflozin will largely depend on patient-specific factors, including their overall health, comorbidities, and treatment preferences. Tirzepatide’s higher efficacy comes with the potential for side effects such as gastrointestinal discomfort, and the cost of tirzepatide may limit its accessibility in some healthcare settings. On the other hand, bexagliflozin, while less effective in comparison, might offer a more affordable option with a different safety profile, particularly for patients who are at risk of cardiovascular disease or kidney issues.

For future research, further studies are needed to explore the long-term effects and safety profiles of both treatments. While this meta-analysis provides valuable insights into short-term outcomes, longer trials are required to assess the durability of the benefits, particularly regarding cardiovascular outcomes kidney function, and weight maintenance over extended periods. This is particularly important for tirzepatide, as its long-term safety in terms of adverse events, such as gastrointestinal issues, pancreatitis, or thyroid-related concerns, is not fully understood. Additionally, research on the real-world effectiveness of these treatments is crucial, as RCTs often do not reflect the complexity of patient populations encountered in routine clinical practice. Observational studies or large cohort studies could provide further evidence on how these treatments perform in diverse patient groups, including those with comorbid conditions such as heart failure, kidney disease, or obesity-related complications.

Moreover, more research is needed to investigate how the combination of tirzepatide with other therapies, such as metformin or insulin, may enhance patient outcomes. Exploring the synergistic effects of combination therapy could lead to more personalized treatment strategies that optimize glycemic control, weight management, and cardiovascular risk reduction. Studies should also focus on understanding the mechanisms of action behind tirzepatide’s dual activation of GIP and GLP-1 receptors, as this could open new avenues for the development of next-generation therapies for diabetes and obesity.

Finally, ongoing studies should aim to better understand the cost-effectiveness of tirzepatide in comparison to other available treatments, including bexagliflozin. Cost-effectiveness analysis is important for healthcare systems worldwide, particularly in light of the high burden of type 2 diabetes and obesity. Establishing the value of these treatments in terms of both clinical outcomes and economic sustainability will help guide healthcare policies and ensure that patients have access to the most effective and affordable options.

Corresponding author: Jia Shi, Weinan Vocational and Technical College, Weinan, Shaanxi Province, 714026, China, E-mail: ssllpzc@sina.com

Research ethics: Not applicable.
Informed consent: Not applicable.
Author contributions: Jia Shi: Conceptualization, Methodology, Data curation, Formal analysis, Writing – original draft, Writing – review and editing.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The author states no conflict of interest.
Research funding: None declared.
Data availability: The data supporting the findings of this study are available from the corresponding author upon reasonable request.

References

1. Ye, J, Wu, Y, Yang, S, Zhu, D, Chen, F, Chen, J, et al.. The global, regional and national burden of type 2 diabetes mellitus in the past, present and future: a systematic analysis of the Global Burden of Disease Study 2019. Front Endocrinol 2023;14. https://doi.org/10.3389/fendo.2023.1192629.Search in Google Scholar PubMed PubMed Central

2. Chen, L, Sun, S, Gao, Y, Ran, X. Global mortality of diabetic foot ulcer: a systematic review and meta‐analysis of observational studies. DOM 2023;25:36–45.10.1111/dom.14840Search in Google Scholar PubMed

3. Johnston, LC, Piotie, PN, Maposa, I, Singh, S, Kuonza, L, De Voux, A. Determinants of sub-optimal glycemic control among patients enrolled in a medicine dispensing programme in KwaZulu-Natal: a cohort study, 2018–2021. Afr J Prim Health Care Fam Med 2024;16. https://doi.org/10.4102/phcfm.v16i1.4336.Search in Google Scholar PubMed PubMed Central

4. Rajasulochana, P, Nali, A, Dakkumalla, V, Kamala, P. Patterns of antihypertensive medication use and blood pressure control in hypertensive patients with diabetes: an observational study. Int J Acad Med Pharm 2023;5:998–1001.Search in Google Scholar

5. Vatsha, P, Goswami, A, Mondal, A, Mondal, A, Chakra, B, Ratha, SK, et al.. Evolving novel drug targets for type 2 diabetes: a mechanistic approach towards-success, challenges and opportunities. Cancer 2023;3:1017.Search in Google Scholar

6. Bassett, RL, Gallo, G, Le, KPN, Volino, LR. Bexagliflozin: a comprehensive review of a recently approved SGLT2 inhibitor for the treatment of type 2 diabetes mellitus. Med Chem Res 2024;33:1354–67. https://doi.org/10.1007/s00044-024-03274-4.Search in Google Scholar

7. Chuang, MH, Chen, JY, Wang, HY, Jiang, ZH, Wu, VC. Clinical outcomes of tirzepatide or GLP-1 receptor agonists in individuals with type 2 diabetes. JAMA Netw Open 2024;7:e2427258–8. https://doi.org/10.1001/jamanetworkopen.2024.27258.Search in Google Scholar PubMed PubMed Central

8. Kelly, MS, Scopelliti, EM, Goodson, KE, Lo, CMA, Nguyen, HX, Simon, B. Real-world evaluation of the effects of tirzepatide in patients with type 2 diabetes mellitus. Diabetes Obes Metabol 2024;26:5661–8. https://doi.org/10.1111/dom.15934.Search in Google Scholar PubMed

9. Drake, T, Landsteiner, A, Langsetmo, L, MacDonald, R, Anthony, M, Kalinowski, C, et al.. Newer pharmacologic treatments in adults with type 2 diabetes: a systematic review and network meta-analysis for the American College of Physicians. Ann Intern Med 2024;177:618–32. https://doi.org/10.7326/m23-1490.Search in Google Scholar PubMed

10. Palmer, SC, Tendal, B, Mustafa, RA, Vandvik, PO, Li, S, Hao, Q, et al.. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ 2021;372. https://doi.org/10.1136/bmj.m4573.Search in Google Scholar PubMed PubMed Central

11. Ludvik, B, Giorgino, F, Jódar, E, Frias, JP, Landó, LF, Brown, K, et al.. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet 2021;398:583–98. https://doi.org/10.1016/s0140-6736(21)01443-4.Search in Google Scholar PubMed

12. Dahl, D, Onishi, Y, Norwood, P, Huh, R, Bray, R, Patel, H, et al.. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA 2022;327:534–45. https://doi.org/10.1001/jama.2022.0078.Search in Google Scholar PubMed PubMed Central

13. Frias, JP, Nauck, MA, Van, J, Kutner, ME, Cui, X, Benson, C, et al.. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 2018;392:2180–93. https://doi.org/10.1016/s0140-6736(18)32260-8.Search in Google Scholar

14. Frías, JP, Davies, MJ, Rosenstock, J, Pérez Manghi, FC, Fernández Landó, L, Bergman, BK, et al.. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 2021;385:503–15. https://doi.org/10.1056/nejmoa2107519.Search in Google Scholar

15. Rosenstock, J, Wysham, C, Frías, JP, Kaneko, S, Lee, CJ, Landó, LF, et al.. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet 2021;398:143–55. https://doi.org/10.1016/s0140-6736(21)01324-6.Search in Google Scholar

16. Rosenstock, J, Frías, JP, Rodbard, HW, Tofé, S, Sears, E, Huh, R, et al.. Tirzepatide vs insulin lispro added to basal insulin in type 2 diabetes: the SURPASS-6 randomized clinical trial. JAMA 2023;330:1631–40. https://doi.org/10.1001/jama.2023.20294.Search in Google Scholar PubMed PubMed Central

17. Gao, L, Lee, BW, Chawla, M, Kim, J, Huo, L, Du, L, et al.. Tirzepatide versus insulin glargine as second-line or third-line therapy in type 2 diabetes in the Asia-Pacific region: the SURPASS-AP-Combo trial. Nat Med 2023;29:1500–10. https://doi.org/10.1038/s41591-023-02344-1.Search in Google Scholar PubMed

18. Inagaki, N, Takeuchi, M, Oura, T, Imaoka, T, Seino, Y. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol 2022;10:623–33. https://doi.org/10.1016/s2213-8587(22)00188-7.Search in Google Scholar PubMed

19. Garvey, WT, Frias, JP, Jastreboff, AM, le Roux, CW, Sattar, N, Aizenberg, D, et al.. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2023;402:613–26. https://doi.org/10.1016/s0140-6736(23)01200-x.Search in Google Scholar PubMed

20. Del, PS, Kahn, SE, Pavo, I, Weerakkody, GJ, Yang, Z, Doupis, J, et al.. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 2021;398:1811–24. https://doi.org/10.1016/s0140-6736(21)02188-7.Search in Google Scholar PubMed

21. Allegretti, AS, Zhang, W, Zhou, W, Thurber, TK, Rigby, SP, Bowman-Stroud, C, et al.. Safety and effectiveness of bexagliflozin in patients with type 2 diabetes mellitus and stage 3a/3b CKD. Am J Kidney Dis 2019;74:328–37. https://doi.org/10.1053/j.ajkd.2019.03.417.Search in Google Scholar PubMed PubMed Central

22. Xie, L, Han, J, Cheng, Z, Liu, D, Liu, J, Xu, C, et al.. Efficacy and safety of bexagliflozin compared with dapagliflozin as an adjunct to metformin in Chinese patients with type 2 diabetes mellitus: a 24-week, randomized, double-blind, active-controlled, phase 3 trial. J Diabetes 2024;16:e13526. https://doi.org/10.1111/1753-0407.13526.Search in Google Scholar PubMed PubMed Central

23. Halvorsen, Y, Walford, G, Thurber, T, Russell, H, Massaro, M, Freeman, MW. A 12-week, randomized, double-blind, placebo-controlled, four-arm dose-finding phase 2 study evaluating bexagliflozin as monotherapy for adults with type 2 diabetes. Diabetes Obes Metabol 2020;22:566–73. https://doi.org/10.1111/dom.13928.Search in Google Scholar PubMed

24. Halvorsen, Y, Lock, JP, Zhou, W, Zhu, F, Freeman, MW. A 24-week, randomized, double-blind, active-controlled clinical trial comparing bexagliflozin with sitagliptin as an adjunct to metformin for the treatment of type 2 diabetes in adults. Diabetes Obes Metabol 2019;21:2248–56. https://doi.org/10.1111/dom.13801.Search in Google Scholar PubMed

25. Halvorsen, YC, Walford, GA, Massaro, J, Aftring, RP, Freeman, MW. A 96-week, multinational, randomized, double-blind, parallel-group, clinical trial evaluating the safety and effectiveness of bexagliflozin as a monotherapy for adults with type 2 diabetes. Diabetes Obes Metabol 2019;21:2496–504. https://doi.org/10.1111/dom.13833.Search in Google Scholar PubMed

26. Halvorsen, Y, Lock, JP, Frias, JP, Tinahones, FJ, Dahl, D, Conery, AL, et al.. A 96-week, double-blind, randomized controlled trial comparing bexagliflozin to glimepiride as an adjunct to metformin for the treatment of type 2 diabetes in adults. Diabetes Obes Metabol 2023;25:293–301. https://doi.org/10.1111/dom.14875.Search in Google Scholar PubMed

27. Fisman, EZ, Tenenbaum, A. The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect. Cardiovasc Diabetol 2021;20:225. https://doi.org/10.1186/s12933-021-01412-5.Search in Google Scholar PubMed PubMed Central

28. Shi, Y. Explore the role and influence of bex gliflozin (a type of SGLT-2 inhibitors) in type 2 diabetes. Highlight Sci Eng Technol 2023;74:1795–800. https://doi.org/10.54097/mtkrp596.Search in Google Scholar

29. Mohammad Alqahtani, AS, Hamoud Alharbi, HS, Abdan Alotaibi, MM, Malawi Alanazi, BB, Hammod Alotaibi, NM, Mutlaq Alosaimi, TM, et al.. Twin cretins as potential therapy for type 2 diabetes mellitus; systematic review. Int J Multiphysics 2024;18.Search in Google Scholar

30. Olanrewaju, OA, Sheeba, F, Kumar, A, Ahmad, S, Blank, N, Kumari, R, et al.. Novel therapies in diabetes: a comprehensive narrative review of GLP-1 receptor agonists, SGLT2 inhibitors, and beyond. Cureus 2023;15. https://doi.org/10.7759/cureus.51151.Search in Google Scholar PubMed PubMed Central

31. Aronne, LJ, Sattar, N, Horn, DB, Bays, HE, Wharton, S, Lin, WY, et al.. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA 2024;331:38–48. https://doi.org/10.1001/jama.2023.24945.Search in Google Scholar PubMed PubMed Central

32. Liarakos, AL, Koliaki, C. Novel dual incretin receptor agonists in the spectrum of metabolic diseases with a focus on tirzepatide: real game-changers or great expectations? A narrative review. Biomedicines 2023;11:1875. https://doi.org/10.3390/biomedicines11071875.Search in Google Scholar PubMed PubMed Central

33. Sinha, R, Papamargaritis, D, Sargeant, JA, Davies, MJ. Efficacy and safety of tirzepatide in type 2 diabetes and obesity management. J Obes Metab Syndr 2023;32:25. https://doi.org/10.7570/jomes22067.Search in Google Scholar PubMed PubMed Central

34. Nauck, MA, D’Alessio, DA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol 2022;21:169.10.1186/s12933-022-01604-7Search in Google Scholar PubMed PubMed Central

35. Azzam, O, Carnagarin, R, Lugo-Gavidia, LM, Nolde, J, Matthews, VB, Schlaich, MP. Bexagliflozin for type 2 diabetes: an overview of the data. Expert Opin Pharmacother 2021;22:2095–103. https://doi.org/10.1080/14656566.2021.1959915.Search in Google Scholar PubMed

36. Scheen, AJ. The current role of SGLT2 inhibitors in type 2 diabetes and beyond: a narrative review. Expert Rev Endocrinol Metab 2023;18:271–82. https://doi.org/10.1080/17446651.2023.2210673.Search in Google Scholar PubMed

37. Zhang, Y, Luo, J, Li, B, Xu, J, Yu, H, Chen, N. Cardio-renal protective effect and safety of sodium-glucose cotransporter 2 inhibitors for chronic kidney disease patients with eGFR < 60 mL/min/1.73 m2: a systematic review and meta-analysis. BMC Nephrol 2024;25:392. https://doi.org/10.1186/s12882-024-03833-2.Search in Google Scholar PubMed PubMed Central

38. Mishra, R, Raj, R, Elshimy, G, Zapata, I, Kannan, L, Majety, P, et al.. Adverse events related to tirzepatide. J Endocr Soc 2023;7:bvad016. https://doi.org/10.1210/jendso/bvad016.Search in Google Scholar PubMed PubMed Central

39. Ou, Y, Cui, Z, Lou, S, Zhu, C, Chen, J, Zhou, L, et al.. Analysis of tirzepatide in the US FDA adverse event reporting system (FAERS): a focus on overall patient population and sex-specific subgroups. Front Pharmacol 2024;15:1463657. https://doi.org/10.3389/fphar.2024.1463657.Search in Google Scholar PubMed PubMed Central

40. Frias, JP, Nauck, MA, Van, J, Benson, C, Bray, R, Cui, X, et al.. Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens. Diabetes Obes Metabol 2020;22:938–46. https://doi.org/10.1111/dom.13979.Search in Google Scholar PubMed PubMed Central

Received: 2024-12-29

Accepted: 2025-03-18

Published Online: 2025-05-27

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

https://doi.org/10.1515/tjb-2024-0393

Keywords for this article

type 2 diabetes; bexagliflozin; tirzepatide; SGLT2 inhibitors; GLP-1 receptor agonists

Creative Commons

BY 4.0