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Background:
Systematic Review

Risk of Hearing Loss in Patients Treated with Exendin-4 Derivatives: A Network Meta-Analysis of Glucagon-like Peptide-1 Receptor Agonists and Sodium–Glucose Cotransporter 2 Inhibitors

by
Jiann-Jy Chen
1,2,†,
Chih-Wei Hsu
3,†,
Chao-Ming Hung
4,5,
Chih-Sung Liang
6,7,
Kuan-Pin Su
8,9,10,
Andre F. Carvalho
11,
Brendon Stubbs
12,13,
Yen-Wen Chen
1,
Tien-Yu Chen
14,15,
Wei-Te Lei
16,17,
Bing-Yan Zeng
18,19,*,‡ and
Ping-Tao Tseng
1,18,20,*,‡
1
Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 81166, Taiwan
2
Department of Otorhinolaryngology, E-Da Cancer Hospital, I-Shou University, Kaohsiung 82445, Taiwan
3
Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
4
Division of General Surgery, Department of Surgery, E-Da Cancer Hospital, I-Shou University, Kaohsiung 82445, Taiwan
5
School of Medicine, College of Medicine, I-Shou University, Kaohsiung 84001, Taiwan
6
Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei 112003, Taiwan
7
Department of Psychiatry, National Defense Medical Center, Taipei 11490, Taiwan
8
Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung 404328, Taiwan
9
College of Medicine, China Medical University, Taichung 404328, Taiwan
10
An-Nan Hospital, China Medical University, Tainan 709, Taiwan
11
Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC 3220, Australia
12
Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London WC2R 2LS, UK
13
Department of Sport, University of Vienna, 1010 Vienna, Austria
14
Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei 114, Taiwan
15
Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
16
Section of Immunology, Rheumatology, and Allergy Department of Pediatrics, Municipal MacKay Children’s Hospital, Hsinchu 300046, Taiwan
17
Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan
18
Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
19
Department of Internal Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung 807, Taiwan
20
Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
 
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*
Authors to whom correspondence should be addressed.
†
These authors contributed equally as first authors to this work.
‡
These authors contributed equally as corresponding authors to this work.
Pharmaceuticals 2025, 18(5), 735; https://doi.org/10.3390/ph18050735
Submission received: 20 March 2025 / Revised: 30 April 2025 / Accepted: 10 May 2025 / Published: 16 May 2025
(This article belongs to the Special Issue Small-Molecule Inhibitors for Novel Therapeutics)
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Abstract

:
Background/Objectives: Emerging evidence suggests an association between glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose co-transporter 2 (SGLT2) inhibitors with altered risk of damage in the inner ear system. However, limited research exists on the relationship between these medications and subsequent irreversible hearing loss. We conducted this network meta-analysis (NMA) to evaluate the comparative risk of hearing loss associated with such medications. Methods: In this NMA, we used a confirmatory approach to specifically focus on particular adverse effects of interest (i.e., incidence of hearing loss here) based on the Cochrane recommendation. A Bayesian-based NMA of randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors was conducted. The primary outcome was the hearing loss events. Results: Our NMA of 29 RCTs with 145,895 participants found that only two exendin-4 derivatives—lixisenatide and high-dose efpeglenatide (i.e., 6 mg/week)—showed increased hearing loss events compared to controls. No other GLP-1 receptor agonists or SGLT2 inhibitors demonstrated significantly elevated hearing loss risk. Lixisenatide ranked highest in risk among all investigated regimens. Conclusions: This comprehensive NMA identifies a significant association between exendin-4 derivatives (lixisenatide and efpeglenatide) and potential ototoxicity. Clinicians should carefully consider this potential ototoxicity when prescribing exendin-4 derivatives, particularly in patients with pre-existing hearing loss risk factors.

1. Introduction

Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose co-transporter 2 (SGLT2) inhibitors have emerged as novel glucose-lowering agents, featuring mechanisms of action distinct from those of conventional treatments [1]. However, along with their widespread prescription, there have been more and more reports regarding irreversible end-organ damage [2]. For example, Lee et al. found a significantly increased risk of retinal vein occlusion and SGLT2 inhibitor use [3]. Similarly, the prescription of exendin-4, one type of the GLP-1 receptor agonist, would increase the risk of formation of a micro-platelet-erythrocyte clot via suppression of matrix metalloproteinase-9 activity [4,5].
Although not clearly clarified, one of the potential etiologies of hearing loss, either sudden onset or chronic course, was associated with the disturbance of microcirculation in the inner ear system. For example, in addition to the direct injury related to noise exposure, loud sounds could affect red blood cell velocity and blood vessel diameter in the cochlea and lead to disturbances in cochlear micro-circulation [6]. Furthermore, there have been several reports addressing the formation of micro-platelet-erythrocyte clots and consequent occlusion of micro-circulation in the inner ear in subjects with various autoimmune diseases, which would finally lead to irreversible sensorineural hearing loss [7,8,9]. Therefore, theoretically, the prescription of GLP-1 receptor agonists and SGLT2 inhibitors might be associated with risk of irreversible hearing loss via disturbance of micro-circulation in inner ear.
However, there are currently few reports addressing the relationship between hearing loss and GLP-1 receptor agonists/SGLT2 inhibitor use. Although there was a trend of an association between them in large-scale randomized controlled trials (RCTs) [10,11], this issue has still not caught clinicians’ attention. A well-designed network meta-analysis (NMA) of GLP-1 receptor agonists and SGLT2 inhibitors, which allows for direct comparisons among different medications, could enhance the ability to make multiple treatment efficacy comparisons and assess the potential superiority of specific interventions at various dosages [12]. This approach offers a more detailed and evidence-based framework for guiding future clinical practices. To the best of our knowledge, no NMA has yet assessed the potential risk of hearing loss related to different GLP-1 receptor agonists and SGLT2 inhibitors used in various dosages. Therefore, following the rationale in our previous NMA addressing the risk of neurodegenerative diseases related to GLP-1 receptor agonists and SGLT2 inhibitor use [13], this NMA aims to provide evidence about the comparative risk of hearing loss by GLP-1 receptor agonists and SGLT2 inhibitor use.

2. Methods

In this study, we used a confirmatory approach to specifically focus on particular adverse effects of interest (i.e., incidence of hearing loss here) based on the Cochrane recommendation [14] in order to repurpose drugs for new roles [15,16]. This study followed the rationales of our recent article, which addressed the risk of neurodegenerative diseases related to GLP-1 receptor agonists and SGLT2 inhibitor use [13]. This NMA adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including the extension for network meta-analyses (PRISMA NMA) (Table S1) [17]. The study protocol was registered in PROSPERO under registration number CRD42025645560. The study protocol was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB E202516007).

2.1. Database Searches and Study Identification

We conducted comprehensive searches across multiple databases, including PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ProQuest, ScienceDirect, Web of Science, and ClinicalTrials.gov (Table S2), covering publications up to 1 February 2025. Regarding the sources of unpublished trials, we actually used several databases, including ScienceDirect (in which several important poster abstract will be posted here), ProQuest (in which some thesis would be posted here), and ClinicalTrials.gov (in which some gray literature would be uploaded here). Two independent researchers (PT Tseng and BY Zeng) carried out these searches, screened titles and abstracts, and resolved disagreements through discussion. We also manually reviewed reference lists from relevant review articles and meta-analyses for additional studies [18,19]. No language restrictions were applied.

2.2. Inclusion and Exclusion Criteria

This NMA was guided by the PICOS framework (Population, Intervention, Comparison, Outcome, Study Design): Population: Individuals without documented hearing loss at baseline; Intervention: Use of GLP-1 receptor agonists or SGLT2 inhibitors at any dose; Comparison: Placebo, standard care, or active comparator; Outcome: Incidence of hearing loss, either sensorineural hearing loss or conductive hearing loss; Study design: RCTs.
To minimize selective reporting bias, only RCTs with systematic adverse event assessments or targeted outcome evaluations were included [20]. Further, RCTs exclusively enrolling participants with documented hearing loss at baseline were excluded to maintain focus on causative or prophylactic evaluation. Therefore, to reduce the potential heterogeneity and bias, the inclusion criteria were strictly set as: (1) RCTs with participants free from documented hearing loss at baseline; (2) RCTs evaluating GLP-1 receptor agonists or SGLT2 inhibitors; (3) Studies involving human subjects; and (4) RCTs with systematic adverse event monitoring or direct evaluation of target outcomes.
Exclusion criteria included the following: (1) non-RCT studies; (2) RCTs specifically enrolling participants with documented hearing loss at baseline; (3) RCTs lacking direct comparisons of GLP-1 receptor agonists or SGLT2 inhibitors; (4) RCTs lacking information on target outcomes; and (5) animal studies.

2.3. Methodological Quality Appraisal

Two independent reviewers assessed the risk of bias using the Cochrane Risk of Bias Tool 1.0 [21], achieving an inter-rater reliability score of 0.86. Discrepancies were resolved by consulting a third reviewer.

2.4. Outcome Definition

Due to variations in event reporting methods, the primary outcome was defined as “total hearing loss events recorded in registry systems”. Event counts rather than individual patient numbers were considered. The hearing loss included sensorineural hearing loss or conductive hearing loss because they were frequently comorbid. Since the cut-off point between complete hearing loss and hearing impairment varied widely across different regions and years, we pooled these two diagnoses into one group but did not separate them. We calculated the dropout rates, indicating study withdrawals for any reason.
In order to provide more clinically relevant information to clinicians (i.e., the potential dose-dependent risk of hearing loss), we conducted a subgroup analysis by grouping RCTs by various dosages of individual medication, which procedures had been widely accepted in various fields of research [22,23,24]. The dose definitions followed original RCT classifications [10,11,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]. However, if there was only one uniform dose used in the recruited RCTs, we would not subdivide them into subgroups. Rather, we will count them as single groups, such as dapagliflozin, lixisenatide, and liraglutide.
  • Canagliflozin: low: 100 mg; high: 300 mg.
  • Efpeglenatide: low: 4 mg; high: 6 mg.
  • Ertugliflozin: low: 5 mg; high: 15 mg.
  • Injectable Semaglutide: low: 0.5 mg; Medium: 1.0 mg; high: 2.4 mg.
  • Empagliflozin: low: 1–10 mg; high: 25–50 mg.
  • Tirzepatide: low: 5 mg; Medium: 10 mg; high: 15 mg.
  • Dulaglutide: low: 0.75 mg; high: 1.5 mg
If RCTs applied an escalating titrating dosage strategy in the study design, we would use the “highest dosage (the final dosage)” as our recording. However, if RCTs consisted of a parallel low-dose arm and high-dose arm at the same time, we would use both dosages in our recording.

2.5. Data Extraction, Management and Conversion

Two independent authors (PT Tseng and BY Zeng) extracted relevant data, including demographics, study design, treatment details, primary outcomes, and drop-out data. Missing information was requested by the corresponding authors. Data extraction followed protocols from the Cochrane Handbook for Systematic Reviews of Interventions and other medical literature standards [51].

2.6. Statistical Analyses

We conducted network meta-analyses using MetaInsight (version 4.0.2, Complex Reviews Support Unit, National Institute for Health Research, London, UK), implementing a random-effects model within a Bayesian framework. The analyses were performed using the package of gemtc, BUGSNET, and bnma in R. For categorical data management, the procedures of corrections to single-zero-event studies would be operated by the MetaInsight programs [52]. We would exclude studies with zero events in both treatment and control arms to minimize bias [53,54]. Effect sizes were calculated using odds ratios (ORs) with 95% credible intervals (95% CrIs) and presented in forest plots. We performed Bayesian analysis using four Markov Chain Monte Carlo (MCMC) chains, each with a total of 25,000 iterations, discarding the first 5000 as burn-in. A thinning interval of 1 was applied, resulting in a total of 80,000 posterior samples for inference. Similarly, the relative effects of treatments compared to placebo were assigned normal priors with a mean of zero and the same precision. Model fit and consistency were assessed using residual deviance plots, per-arm residual deviance, and leverage plots. Convergence was visually inspected using Gelman convergence assessment plots for all studies.
Treatment rankings and effect sizes for both direct and indirect comparisons were generated and systematically tabulated. We assessed the consistency between direct and indirect evidence using the ‘node-splitting’ method, which is particularly valuable for network meta-analyses with available trial-level data. To evaluate the relative superiority of individual regimens, we conducted Bayesian-based surface under the cumulative ranking (SUCRA) evaluations, visualized through Litmus Rank-O-Gram and radial SUCRA plots.
Finally, we evaluated the heterogeneity with the tau value, I2, and related p value. Publication bias would be assessed with a funnel plot.

2.7. Sensitivity Analyses

To validate the reliability and convergence of treatment estimates, we employed a deviation-model analysis [55]. Specifically, each bar represents the residual deviance for an individual study arm; larger residual deviance values indicate poorer model fit for that arm in the per-arm models. Points positioned towards the upper-right corner suggest study arms with potentially poorer model fit and/or higher influence on the network meta-analysis results in the leverage plot. Further, we evaluated the overall quality of evidence in our NMA with the GRADE, which was a recognized framework to evaluate the certainty of evidence [56]. Finally, to re-validate the results of our NMA, we re-analyze our data with risk ratio (RR) and related 95% CrIs. To reduce the potential bias related to heterogeneous baseline illnesses across the recruited RCTs, we arranged subgroup analysis focusing on those RCTs recruiting subjects with a baseline illness of diabetes, which was the major indication of GLP-1 receptor agonists and SGLT2 inhibitors.

2.8. General Declaration

This study complies with the principles outlined in the Declaration of Helsinki.

3. Results

3.1. Eligibility of the Studies

Figure 1 illustrates the flowchart summarizing the literature search and screening process for this NMA. After excluding 118 articles for various reasons (Table S3), a total of 28 articles encompassing 29 RCTs were included in the analysis (Table S4) [10,11,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]. The selected studies involved 145,895 participants (mean age = 64.0 years, range: 50.8 to 71.9 years; mean female proportion = 35.3%, range: 20.8% to 53.6%). The average study duration was 146.6 weeks (range: 13 to 281 weeks). The investigated GLP-1 receptor agonists included tirzepatide, efpeglenatide, liraglutide, albiglutide, dulaglutide, exenatide, semaglutide, and lixisenatide. The investigated SGLT2 inhibitors included bexagliflozin, canagliflozin, empagliflozin, ertugliflozin, dapagliflozin, and sotagliflozin.

3.2. Primary Outcome: Incidence of Hearing Loss

The main results of the primary outcome revealed that lixisenatide (number needed to harm = 757.75) was associated with increased events of hearing loss in comparison with the controls. In contrast, only albiglutide was associated with fewer hearing loss events than the controls. Among the investigated regimens, the risk of lixisenatide ranked the highest (Figure 2A, Figure 3A and Figure S3A, and Table 1A). There was no significant heterogeneity detected (tau < 0.001, I2 = 0%, p value = 0.9934). The funnel plot revealed symmetry (Figure S7A).

3.3. Subgroup Analyses of Various Dosage

In our subgroup analysis of various dosages, lixisenatide and high-dose efpeglenatide (i.e., 6 mg/week) (number needed to harm = 757.75 and 679.00, respectively) were associated with increased events of hearing loss in comparison with the controls, whereas oral semaglutide revealed only a borderline association. In contrast, only low-dose tirzepatide, sotagliflozin, albiglutide, and low-dose injectable semaglutide were associated with fewer hearing loss events than the controls. Among the investigated regimens, the risk of lixisenatide ranked the highest (Figure 2B, Figure 3B and Figure S3B, and Table 1B). There was no significant heterogeneity detected (tau < 0.001, I2 = 0%, p value = 0.8874). The funnel plot revealed symmetry (Figure S7B).

3.4. Sensitivity Analysis with Re-Validation by RR

In our sensitivity test with re-validation by RR, the main results of the current NMA would not be changed. Specifically, lixisenatide was still the only regimen associated with increased events of hearing loss in comparison with the controls (Figure S2A and Table S5A). When subgrouping according to various dosages, the lixisenatide and high-dose efpeglenatide (i.e., 6 mg/week) were still associated with increased events of hearing loss in comparison with the controls (Figure S2B and Table S5B).

3.5. Subgroup Analysis of RCTs Recruiting Subjects with Baseline Illness of Diabetes

In this part of the subgroup analysis, the main results of the current NMA would not be changed. Specifically, lixisenatide was still the only regimen associated with increased events of hearing loss in comparison with the controls (Figures S1A and S2C and Table S5C). When subgrouping according to various dosages, the lixisenatide and high-dose efpeglenatide (i.e., 6 mg/week) were still associated with increased events of hearing loss in comparison with the controls (Figures S1B and S2D and Table S5D).

3.6. Drop-Out Rate

None of the investigated regimens were associated with different drop-out rates compared to controls (Figures S1C, S2E and S3C, and Table S5E).

3.7. Sensitivity Analysis with Deviation-Model Evaluation

The Bayesian-based SUCRA ranking list is depicted in Table S6A–C and Figure S4A–F. The deviation-model assessment did not demonstrate significant deviation among the current NMA (Figure S5A–I).

3.8. Risk of Bias and Inconsistency

We identified that 81.8% (166/203 items), 17.2% (35/203 items), and 1.0% (2/203 items) of the included studies had low, unclear, and high risks of bias, respectively (Figure S6A,B). The inconsistency test, evaluating the assumption of consistency, showed no significant inconsistencies in the subgroup analysis of various dosages. In contrast, the inconsistency could not be evaluated in the main NMA because of its star-shaped in-network geometry (Table S7A–C). The overall quality of evidence of this NMA falls within the moderate-high range (Table S8A–C).

4. Discussion

To our knowledge, this is the first NMA addressing the potential risk of hearing loss related to GLP-1 receptor agonists and SGLT2 inhibitor use. The main results of the current NMA are summarized in Table 2. In brief, in this work, we observed that the lixisenatide and high-dose efpeglenatide, which are both exendin-4 derivatives, were associated with increased events of hearing loss in comparison with the controls.
The most important finding of the current NMA was the increased risk of hearing loss related to both exendin-4 derivative use (i.e., lixisenatide and high-dose efpeglenatide) compared to controls. Although the exendin-4 itself (i.e., exenatide) did not achieve statistical significance, it still had a trend of increased risk of hearing loss (Figure 3). This issue was clinically relevant since subjects who needed such medications had underlying risk factors of hearing loss [19]. Although there is little knowledge regarding the etiology of hearing loss, the disturbance to micro-circulation (i.e., labyrinthine artery) in the inner ear, especially the cochlea, was one of the important etiologies [57]. The disturbance to micro-circulation in the inner ear might result from the formation of a micro-platelet-erythrocyte clot, which frequently contributes to sudden sensorineural hearing loss [7,8,9]. Specifically, the formation of a micro-platelet-erythrocyte clot, either related to autoimmune diseases or medication adverse effects, would follow the blood flow and result in occlusion in the small arterioles or micro-circulation in the end organ. This thromboembolism would finally lead to ischemic damage to the affected organs, specifically the audiologic system in this NMA. There is accumulating evidence addressing the potentially increased risk of formation of a micro-platelet-erythrocyte clot related to exendin-4 derivative use. For example, Kuroki and colleagues found that exendin-4 administration would inhibit the matrix metalloproteinase-9 activation in the animal model, with the suppressing effects persisting at least 7 days [4]. Researchers have demonstrated that the matrix metalloproteinase-9 could inhibit or prolong platelet aggregation and prevent the platelet plug formation in in vitro and in vivo studies [58]. Further, matrix metalloproteinases-9 has been found to be abundant in the resistance-sized (approximately 200 µm) arteries [59]. The cochlear micro-circulation vessels (approximately diameters of 9.1 ± 0.8 µm) were in the downstream of the aforementioned resistance-sized arteries [60] so that the formation of micro-platelet-erythrocyte clots in the upstream would result in occlusion in the downstream vessels. Taken together, the suppressed matrix metalloproteinase-9 activity related to exendin-4 administration would finally result in the pro-thromboembolism environment in the micro-circulation in the inner ear [4,5]. Regardless of the potential of anti-inflammatory properties of GLP-1 receptor agonists [61] and SGLT2 inhibitors [62] to ameliorate hearing impairment [7,8,9,63], this physiopathology might not be able to reverse the potential ototoxicity effect mentioned above. We had drawn a schematic diagram to depict the physiopathology of exendin-4 related micro-platelet-erythrocyte clot formation (Figure 4). However, as addressed before, the hypothesis remained theoretical and lacked direct supporting evidence. Future direct human trials should be warranted to provide more information regarding the pro-thromboembolic effects related to exendin-4 derivative use.

Strengths and Limitations

This NMA offers several methodological strengths that enhance the reliability and clinical utility of our findings. First, the NMA designation could enable statistical comparisons between different GLP-1 receptor agonists and SGLT2 inhibitors, providing more comprehensive evidence than RCTs or traditional pairwise meta-analyses. Our rigorous methodology included exclusively focusing on RCTs, ensuring high-quality evidence while minimizing potential bias. By specifically excluding participants with pre-existing hearing loss at baseline, we were able to isolate true causative or prophylactic effects. Furthermore, our detailed subgroup analyses across various dosages offer clinicians granular evidence to select the optimal dosage for specific patient populations who already had risk factors of hearing loss at baseline.
Some limitations warrant consideration. First, there were only a few studies addressing hearing loss related to GLP-1 receptor agonists or SGLT2 inhibitor use so that the included RCTs and recruited participants were relatively few (29 RCTs involving 145,895 participants). Second, our stringent focus on RCTs, while ensuring methodological rigor, potentially excluded valuable observational data from long-term cohort studies. Third, the variation in diagnostic approaches across multi-country trials presents a notable limitation. The lack of structural and uniform diagnostic methods to detect hearing loss may have introduced heterogeneity in case identification, potentially affecting the precision of our effect estimates. Although meta-analyses may raise concerns about “inconsistencies in diagnostic tools and baseline illnesses”, the nature of these studies is rooted in large databases or numerous clinical studies, making them more reflective of clinical experience. Therefore, many meta-analyses on drug side effects [15,16] have become a benchmark for guiding future research [64,65]. Fourth, the star-shaped network geometry in the main outcome would limit the evaluation of inconsistency. Fifth, the main results of this NMA mainly came from a few RCTs [10,11] so that the clinicians should pay special attention when interpreting the results of our study in their clinical practice. Finally, all the recruited RCTs were designed based on various underlying diseases (i.e., diabetes or obesity) but not specifically to examine hearing loss occurrence, which might lead to ignorance of the occurrence of mild hearing loss. Because adverse effects data are often handled with less rigor than the primary beneficial outcomes of a study, incomplete reporting might still exist when synthesizing data. Therefore, future studies using various audiometric tests to routinely follow patients’ hearing function should be warranted. These limitations suggest the need for large-scale studies specifically designed to assess causative or preventive effects in hearing loss.

5. Conclusions

This comprehensive NMA reveals a potential relationship between hearing loss and exendin-4 derivative prescription (i.e., lixisenatide and high-dose efpeglenatide). Since hearing loss is an irreversible disease and subjects who need such medications had underlying risk factors of hearing loss, this potentially ototoxicity related to exendin-4 derivative prescription would be important for clinicians to choose the most suitable regimens for patients with an underlying risk of hearing loss. Future research should prioritize large-scale studies specifically designed to assess causative or preventive effects in hearing loss.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ph18050735/s1, Figure S1: (A) Network structure of primary outcome: incidence of hearing loss (focus on diabetes), (B) Network structure of primary outcome: incidence of hearing loss in subgroup of dosage (focus on diabetes) (C) Network structure of NMA of drop-out rate; Figure S2: (A) Forest plot of primary outcome: incidence of hearing loss (risk ratio), (B) Forest plot of primary outcome: incidence of hearing loss in subgroup of dosage (risk ratio), (C) Forest plot of primary outcome: incidence of hearing loss (focus on diabetes), (D) Forest plot of primary outcome: incidence of hearing loss in subgroup of dosage (focus on diabetes),(E) Forest plot of NMA of drop-out rate; Figure S3: (A) Individual study result of primary outcome: incidence of hearing loss, (B) Individual study result of primary outcome: incidence of hearing loss in subgroup of dosage, (C) Individual study result of drop-out rate; Figure S4: (A) Bayesian-based Litmus Rank-O-Gram rank plot of primary outcome: incidence of hearing loss, (B) Bayesian-based radial surface under the cumulative ranking of primary outcome: incidence of hearing loss, (C) Bayesian-based Litmus Rank-O-Gram rank plot of primary outcome: incidence of hearing loss in subgroup of dosage, (D) Bayesian-based radial surface under the cumulative ranking of primary outcome: incidence of hearing loss in subgroup of dosage, (E) Bayesian-based Litmus Rank-O-Gram rank plot of drop-out rate, (F) Bayesian-based radial surface under the cumulative ranking of drop-out rate; Figure S5: (A) Bayesian-based residual deviance NMA/UME model of primary outcome: incidence of hearing loss, (B) Bayesian-based per-arm residual deviance of primary outcome: incidence of hearing loss, (C) Bayesian-based leverage plot of primary outcome: incidence of hearing loss, (D) Bayesian-based residual deviance NMA/UME model of primary outcome: incidence of hearing loss in subgroup of dosage, (E) Bayesian-based per-arm residual deviance of primary outcome: incidence of hearing loss in subgroup of dosage, (F) Bayesian-based leverage plot of primary outcome: incidence of hearing loss in subgroup of dosage, (G) Bayesian-based residual deviance NMA/UME model of drop-out rate, (H) Bayesian-based per-arm residual deviance of drop-out rate, (I) Bayesian-based leverage plot of drop-out rate; Figure S6: (A) Overview of risk of bias, (B) Detailed risk of bias in each study; Figure S7: (A) Funnel plot of the primary outcome: incidence of hearing loss, (B) Funnel plot of the primary outcome: incidence of hearing loss in subgroup of dosage; Table S1: PRISMA 2020 checklist of the current network meta-analysis; Table S2: Keyword used in each database and search results; Table S3: Excluded studies and reason; Table S4: Characteristics of the included studies; Table S5: (A) League table of NMA of primary outcome: incidence of hearing loss (risk ratio), (B) League table of NMA of primary outcome: incidence of hearing loss in subgroup of dosage (risk ratio), (C) League table of NMA of primary outcome: incidence of hearing loss (focus on diabetes), (D) League table of NMA of primary outcome: incidence of hearing loss in subgroup of dosage (focus on diabetes), (E) League table of NMA of drop-out rate; Table S6: (A) SUCRA (Surface under the cumulative ranking) of primary outcome: incidence of hearing loss, (B) SUCRA (Surface under the cumulative ranking) of primary outcome: incidence of hearing loss in subgroup of dosage, (C) SUCRA (Surface under the cumulative ranking) of drop-out rate; Table S7: (A) Inconsistency within the network meta-analysis of primary outcome: incidence of hearing loss, (B) Inconsistency within the network meta-analysis of primary outcome: incidence of hearing loss in subgroup of dosage, (C) Inconsistency within the network meta-analysis of drop-out rate; Table S8: (A) GRADE of primary outcome: incidence of hearing loss, (B) GRADE of primary outcome: incidence of hearing loss in subgroup of dosage, (C) GRADE of drop-out rate. (References in Supplementary Materials [10,11,18,19,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182]).

Author Contributions

Conceptualization, Y.-W.C., C.-S.L. and P.-T.T.; Methodology, B.S., T.-Y.C. and K.-P.S.; Software, Y.-W.C. and T.-Y.C.; Validation, C.-M.H. and C.-S.L.; Formal analysis, B.-Y.Z. and T.-Y.C.; Investigation, C.-W.H., A.F.C., Y.-W.C. and K.-P.S.; Resources, A.F.C. and W.-T.L.; Data curation, J.-J.C. and A.F.C.; Writing—original draft, J.-J.C., B.-Y.Z. and C.-W.H.; Writing—review & editing, C.-S.L., K.-P.S. and P.-T.T.; Visualization, B.S. and W.-T.L.; Supervision, C.-M.H. and B.S.; Project administration, C.-M.H. and W.-T.L. All authors have read and agreed to the published version of the manuscript.

Funding

The authors of this work were supported by the following grants: Brendon Stubbs is supported by the NIHR. Brendon Stubbs is part funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust. Brendon Stubbs is also supported by the Maudsley Charity, King’s College London.

Institutional Review Board Statement

This study complies with the principles outlined in the Declaration of Helsinki. Trial registration: PROSPERO CRD42025645560. The study protocol was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB E202516007).

Informed Consent Statement

The current study did not directly involve individual participant so that we did not have the chance to approach individual participant or explore individual participant’s information. Therefore, it is impossible to obtain consent to participate in the current study.

Data Availability Statement

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to all the data of this study were extracted from an open-source website (https://clinicaltrials.gov/) (accessed on 28 October 2024).

Acknowledgments

This paper presents independent research. The views expressed in this publication are those of the authors and not necessarily those of the acknowledged institutions.

Conflicts of Interest

The authors report no financial interests or potential conflicts of interest.

References

  1. Avogaro, A.; de Kreutzenberg, S.V.; Morieri, M.L.; Fadini, G.P.; Del Prato, S. Glucose-lowering drugs with cardiovascular benefits as modifiers of critical elements of the human life history. Lancet Diabetes Endocrinol. 2022, 10, 882–889. [Google Scholar] [CrossRef]
  2. Hathaway, J.T.; Shah, M.P.; Hathaway, D.B.; Zekavat, S.M.; Krasniqi, D.; Gittinger, J.W., Jr.; Cestari, D.; Mallery, R.; Abbasi, B.; Bouffard, M.; et al. Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide. JAMA Ophthalmol. 2024, 142, 732–739. [Google Scholar] [CrossRef]
  3. Lee, M.K.; Kim, B.; Han, K.; Lee, J.H.; Kim, M.; Kim, M.K.; Baek, K.H.; Song, K.H.; Kwon, H.S.; Roh, Y.J. Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Retinal Vein Occlusion Among Patients with Type 2 Diabetes: A Propensity Score-Matched Cohort Study. Diabetes Care 2021, 44, 2419–2426. [Google Scholar] [CrossRef]
  4. Kuroki, T.; Tanaka, R.; Shimada, Y.; Yamashiro, K.; Ueno, Y.; Shimura, H.; Urabe, T.; Hattori, N. Exendin-4 Inhibits Matrix Metalloproteinase-9 Activation and Reduces Infarct Growth After Focal Cerebral Ischemia in Hyperglycemic Mice. Stroke 2016, 47, 1328–1335. [Google Scholar] [CrossRef]
  5. Mastenbroek, T.G.; Feijge, M.A.; Kremers, R.M.; van den Bosch, M.T.; Swieringa, F.; De Groef, L.; Moons, L.; Bennett, C.; Ghevaert, C.; Johnson, J.L.; et al. Platelet-Associated Matrix Metalloproteinases Regulate Thrombus Formation and Exert Local Collagenolytic Activity. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 2554–2561. [Google Scholar] [CrossRef]
  6. Quirk, W.S.; Avinash, G.; Nuttall, A.L.; Miller, J.M. The influence of loud sound on red blood cell velocity and blood vessel diameter in the cochlea. Hear. Res. 1992, 63, 102–107. [Google Scholar] [CrossRef]
  7. Chen, J.J.; Hsu, C.W.; Chen, Y.W.; Chen, T.Y.; Zeng, B.S.; Tseng, P.T. Audiovestibular Dysfunction in Systemic Lupus Erythematosus Patients: A Systematic Review. Diagnostics 2024, 14, 1670. [Google Scholar] [CrossRef]
  8. Chen, J.J.; Hsu, C.W.; Chen, Y.W.; Chen, T.Y.; Zeng, B.Y.; Tseng, P.T. Audiovestibular Dysfunction Related to Anti-Phospholipid Syndrome: A Systematic Review. Diagnostics 2024, 14, 2522. [Google Scholar] [CrossRef]
  9. Chen, J.J.; Hsu, C.W.; Chen, Y.W.; Chen, T.Y.; Zeng, B.S.; Tseng, P.T. Audiological Features in Patients with Rheumatoid Arthritis: A Systematic Review. Int. J. Mol. Sci. 2024, 25, 13290. [Google Scholar] [CrossRef]
  10. Gerstein, H.C.; Sattar, N.; Rosenstock, J.; Ramasundarahettige, C.; Pratley, R.; Lopes, R.D.; Lam, C.S.P.; Khurmi, N.S.; Heenan, L.; Del Prato, S.; et al. Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes. N. Engl. J. Med. 2021, 385, 896–907. [Google Scholar] [CrossRef]
  11. Pfeffer, M.A.; Claggett, B.; Diaz, R.; Dickstein, K.; Gerstein, H.C.; Kober, L.V.; Lawson, F.C.; Ping, L.; Wei, X.; Lewis, E.F.; et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N. Engl. J. Med. 2015, 373, 2247–2257. [Google Scholar] [CrossRef] [PubMed]
  12. Higgins, J.P.; Welton, N.J. Network meta-analysis: A norm for comparative effectiveness? Lancet 2015, 386, 628–630. [Google Scholar] [CrossRef]
  13. Tseng, P.T.; Zeng, B.Y.; Hsu, C.W.; Hung, C.M.; Carvalho, A.F.; Stubbs, B.; Chen, Y.W.; Chen, T.Y.; Lei, W.T.; Chen, J.J.; et al. The pharmacodynamics-based prophylactic benefits of GLP-1 receptor agonists and SGLT2 inhibitors on neurodegenerative diseases: Evidence from a network meta-analysis. BMC Med. 2025, 23, 197. [Google Scholar] [CrossRef]
  14. Peryer, G.; Golder, S.; Junqueira, D.; Vohra, S.; Loke, Y.K.; Group, C.A.E.M. Chapter 19: Adverse effects. In Cochrane Handbook for Systematic Reviews of Interventions; Higgins, J.P.T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M.J., Welch, V.A., Eds.; Cochrane: London, UK, 2023. [Google Scholar]
  15. Hinkle, J.T.; Graziosi, M.; Nayak, S.M.; Yaden, D.B. Adverse Events in Studies of Classic Psychedelics: A Systematic Review and Meta-Analysis. JAMA Psychiatry 2024, 81, 1225–1235. [Google Scholar] [CrossRef]
  16. Pillinger, T.; McCutcheon, R.A.; Vano, L.; Mizuno, Y.; Arumuham, A.; Hindley, G.; Beck, K.; Natesan, S.; Efthimiou, O.; Cipriani, A.; et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: A systematic review and network meta-analysis. Lancet Psychiatry 2020, 7, 64–77. [Google Scholar] [CrossRef] [PubMed]
  17. Hutton, B.; Salanti, G.; Caldwell, D.M.; Chaimani, A.; Schmid, C.H.; Cameron, C.; Ioannidis, J.P.; Straus, S.; Thorlund, K.; Jansen, J.P.; et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations. Ann. Intern. Med. 2015, 162, 777–784. [Google Scholar] [CrossRef] [PubMed]
  18. Panfili, E.; Frontino, G.; Pallotta, M.T. GLP-1 receptor agonists as promising disease-modifying agents in WFS1 spectrum disorder. Front. Clin. Diabetes Healthc. 2023, 4, 1171091. [Google Scholar] [CrossRef]
  19. Samocha-Bonet, D.; Wu, B.; Ryugo, D.K. Diabetes mellitus and hearing loss: A review. Ageing Res. Rev. 2021, 71, 101423. [Google Scholar] [CrossRef]
  20. Phillips, R.; Hazell, L.; Sauzet, O.; Cornelius, V. Analysis and reporting of adverse events in randomised controlled trials: A review. BMJ Open 2019, 9, e024537. [Google Scholar] [CrossRef]
  21. Higgins, J.; Green, S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2; The Cochrane Collaboration: London, UK, 2009. [Google Scholar]
  22. Tseng, P.T.; Yang, C.P.; Su, K.P.; Chen, T.Y.; Wu, Y.C.; Tu, Y.K.; Lin, P.Y.; Stubbs, B.; Carvalho, A.F.; Matsuoka, Y.J.; et al. The association between melatonin and episodic migraine: A pilot network meta-analysis of randomized controlled trials to compare the prophylactic effects with exogenous melatonin supplementation and pharmacotherapy. J. Pineal Res. 2020, 69, e12663. [Google Scholar] [CrossRef]
  23. Tseng, P.T.; Zeng, B.Y.; Chen, Y.W.; Yang, C.P.; Su, K.P.; Chen, T.Y.; Wu, Y.C.; Tu, Y.K.; Lin, P.Y.; Carvalho, A.F.; et al. The dose- and duration-dependent association between melatonin treatment and overall cognition in Alzheimer’s dementia: A network meta-analysis of randomized placebo-controlled trials. Curr. Neuropharmacol. 2022, 20, 1816–1833. [Google Scholar] [CrossRef] [PubMed]
  24. Yang, C.P.; Tseng, P.T.; Pei-Chen Chang, J.; Su, H.; Satyanarayanan, S.K.; Su, K.P. Melatonergic agents in the prevention of delirium: A network meta-analysis of randomized controlled trials. Sleep Med. Rev. 2020, 50, 101235. [Google Scholar] [CrossRef]
  25. Anker, S.D.; Butler, J.; Filippatos, G.; Ferreira, J.P.; Bocchi, E.; Bohm, M.; Brunner-La Rocca, H.P.; Choi, D.J.; Chopra, V.; Chuquiure-Valenzuela, E.; et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N. Engl. J. Med. 2021, 385, 1451–1461. [Google Scholar] [CrossRef]
  26. Cannon, C.P.; Pratley, R.; Dagogo-Jack, S.; Mancuso, J.; Huyck, S.; Masiukiewicz, U.; Charbonnel, B.; Frederich, R.; Gallo, S.; Cosentino, F.; et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N. Engl. J. Med. 2020, 383, 1425–1435. [Google Scholar] [CrossRef] [PubMed]
  27. Dahl, D.; Onishi, Y.; Norwood, P.; Huh, R.; Bray, R.; Patel, H.; Rodriguez, A. 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, 534–545. [Google Scholar] [CrossRef]
  28. Gallo, S.; Charbonnel, B.; Goldman, A.; Shi, H.; Huyck, S.; Darekar, A.; Lauring, B.; Terra, S.G. Long-term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104-week VERTIS MET trial. Diabetes Obes. Metab. 2019, 21, 1027–1036. [Google Scholar] [CrossRef]
  29. Gerstein, H.C.; Colhoun, H.M.; Dagenais, G.R.; Diaz, R.; Lakshmanan, M.; Pais, P.; Probstfield, J.; Riesmeyer, J.S.; Riddle, M.C.; Ryden, L.; et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): A double-blind, randomised placebo-controlled trial. Lancet 2019, 394, 121–130. [Google Scholar] [CrossRef] [PubMed]
  30. Hernandez, A.F.; Green, J.B.; Janmohamed, S.; D’Agostino, R.B., Sr.; Granger, C.B.; Jones, N.P.; Leiter, L.A.; Rosenberg, A.E.; Sigmon, K.N.; Somerville, M.C.; et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo-controlled trial. Lancet 2018, 392, 1519–1529. [Google Scholar] [CrossRef]
  31. Holman, R.R.; Bethel, M.A.; Mentz, R.J.; Thompson, V.P.; Lokhnygina, Y.; Buse, J.B.; Chan, J.C.; Choi, J.; Gustavson, S.M.; Iqbal, N.; et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2017, 377, 1228–1239. [Google Scholar] [CrossRef]
  32. Ji, L.; Lu, Y.; Li, Q.; Fu, L.; Luo, Y.; Lei, T.; Li, L.; Ye, S.; Shi, B.; Li, X.; et al. Efficacy and safety of empagliflozin in combination with insulin in Chinese patients with type 2 diabetes and insufficient glycaemic control: A phase III, randomized, double-blind, placebo-controlled, parallel study. Diabetes Obes. Metab. 2023, 25, 1839–1848. [Google Scholar] [CrossRef] [PubMed]
  33. Kadowaki, T.; Chin, R.; Ozeki, A.; Imaoka, T.; Ogawa, Y. Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): A multicentre, randomised, open-label, parallel-group, phase 3 trial. Lancet Diabetes Endocrinol. 2022, 10, 634–644. [Google Scholar] [CrossRef] [PubMed]
  34. Lee, B.W.; Cho, Y.M.; Kim, S.G.; Ko, S.H.; Lim, S.; Dahaoui, A.; Jeong, J.S.; Lim, H.J.; Yu, J.M. Efficacy and Safety of Once-Weekly Semaglutide Versus Once-Daily Sitagliptin as Metformin Add-on in a Korean Population with Type 2 Diabetes. Diabetes Ther. 2024, 15, 547–563. [Google Scholar] [CrossRef] [PubMed]
  35. Lincoff, A.M.; Brown-Frandsen, K.; Colhoun, H.M.; Deanfield, J.; Emerson, S.S.; Esbjerg, S.; Hardt-Lindberg, S.; Hovingh, G.K.; Kahn, S.E.; Kushner, R.F.; et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N. Engl. J. Med. 2023, 389, 2221–2232. [Google Scholar] [CrossRef]
  36. Marso, S.P.; Bain, S.C.; Consoli, A.; Eliaschewitz, F.G.; Jodar, E.; Leiter, L.A.; Lingvay, I.; Rosenstock, J.; Seufert, J.; Warren, M.L.; et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N. Engl. J. Med. 2016, 375, 1834–1844. [Google Scholar] [CrossRef]
  37. Marso, S.P.; Daniels, G.H.; Brown-Frandsen, K.; Kristensen, P.; Mann, J.F.; Nauck, M.A.; Nissen, S.E.; Pocock, S.; Poulter, N.R.; Ravn, L.S.; et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2016, 375, 311–322. [Google Scholar] [CrossRef]
  38. Natale, P.; Tunnicliffe, D.J.; Toyama, T.; Palmer, S.C.; Saglimbene, V.M.; Ruospo, M.; Gargano, L.; Stallone, G.; Gesualdo, L.; Strippoli, G.F. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes. Cochrane Database Syst. Rev. 2024, 5, CD015588. [Google Scholar] [CrossRef]
  39. Neal, B.; Perkovic, V.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Shaw, W.; Law, G.; Desai, M.; Matthews, D.R.; et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N. Engl. J. Med. 2017, 377, 644–657. [Google Scholar] [CrossRef] [PubMed]
  40. Packer, M.; Anker, S.D.; Butler, J.; Filippatos, G.; Pocock, S.J.; Carson, P.; Januzzi, J.; Verma, S.; Tsutsui, H.; Brueckmann, M.; et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N. Engl. J. Med. 2020, 383, 1413–1424. [Google Scholar] [CrossRef]
  41. Rosenstock, J.; Allison, D.; Birkenfeld, A.L.; Blicher, T.M.; Deenadayalan, S.; Jacobsen, J.B.; Serusclat, P.; Violante, R.; Watada, H.; Davies, M.; et al. Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults with Type 2 Diabetes Uncontrolled with Metformin Alone or with Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA 2019, 321, 1466–1480. [Google Scholar] [CrossRef]
  42. Solomon, S.D.; McMurray, J.J.V.; Claggett, B.; de Boer, R.A.; DeMets, D.; Hernandez, A.F.; Inzucchi, S.E.; Kosiborod, M.N.; Lam, C.S.P.; Martinez, F.; et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N. Engl. J. Med. 2022, 387, 1089–1098. [Google Scholar] [CrossRef]
  43. A Study of Tirzepatide (LY3298176) in Participants with Obesity Disease (SURMOUNT-J). Available online: https://clinicaltrials.gov/study/NCT04844918?cond=NCT04844918&rank=1 (accessed on 28 October 2024).
  44. EMPA-Kidney Collaborative Group; Herrington, W.G.; Staplin, N.; Wanner, C.; Green, J.B.; Hauske, S.J.; Emberson, J.R.; Preiss, D.; Judge, P.; Mayne, K.J.; et al. Empagliflozin in Patients with Chronic Kidney Disease. N. Engl. J. Med. 2023, 388, 117–127. [Google Scholar] [CrossRef] [PubMed]
  45. Voors, A.A.; Angermann, C.E.; Teerlink, J.R.; Collins, S.P.; Kosiborod, M.; Biegus, J.; Ferreira, J.P.; Nassif, M.E.; Psotka, M.A.; Tromp, J.; et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: A multinational randomized trial. Nat. Med. 2022, 28, 568–574. [Google Scholar] [CrossRef] [PubMed]
  46. Wada, T.; Mori-Anai, K.; Takahashi, A.; Matsui, T.; Inagaki, M.; Iida, M.; Maruyama, K.; Tsuda, H. Effect of canagliflozin on the decline of estimated glomerular filtration rate in chronic kidney disease patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III study in Japan. J. Diabetes Investig. 2022, 13, 1981–1989. [Google Scholar] [CrossRef]
  47. Wang, J.; Li, H.Q.; Xu, X.H.; Kong, X.C.; Sun, R.; Jing, T.; Ye, L.; Su, X.F.; Ma, J.H. The Effects of Once-Weekly Dulaglutide and Insulin Glargine on Glucose Fluctuation in Poorly Oral-Antidiabetic Controlled Patients with Type 2 Diabetes Mellitus. Biomed. Res. Int. 2019, 2019, 2682657. [Google Scholar] [CrossRef]
  48. Wason, S. Efficacy and Bone Safety of Sotagliflozin 400 and 200 mg Versus Placebo in Participants with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control (SOTA-BONE). Available online: https://clinicaltrials.gov/study/NCT03386344?cond=NCT03386344&rank=1 (accessed on 28 October 2024).
  49. Wiviott, S.D.; Raz, I.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Silverman, M.G.; Zelniker, T.A.; Kuder, J.F.; Murphy, S.A.; et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2019, 380, 347–357. [Google Scholar] [CrossRef]
  50. Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015, 373, 2117–2128. [Google Scholar] [CrossRef]
  51. Chaimani, A.; Caldwell, D.M.; Li, T.; Higgins, J.P.T.; Salanti, G. Chapter 11: Undertaking network meta-analyses. In Cochrane Handbook for Systematic Reviews of Interventions; The Cochrane Collaboration: London, UK, 2018; Volume 7. [Google Scholar]
  52. Lee, C.C.; Ju, T.R.; Lai, P.C.; Lin, H.T.; Huang, Y.T. Should We Use High-Flow Nasal Cannula in Patients Receiving Gastrointestinal Endoscopies? Critical Appraisals through Updated Meta-Analyses with Multiple Methodologies and Depiction of Certainty of Evidence. J. Clin. Med. 2022, 11, 3860. [Google Scholar] [CrossRef] [PubMed]
  53. Cheng, J.; Pullenayegum, E.; Marshall, J.K.; Iorio, A.; Thabane, L. Impact of including or excluding both-armed zero-event studies on using standard meta-analysis methods for rare event outcome: A simulation study. BMJ Open 2016, 6, e010983. [Google Scholar] [CrossRef]
  54. Brockhaus, A.C.; Bender, R.; Skipka, G. The Peto odds ratio viewed as a new effect measure. Stat. Med. 2014, 33, 4861–4874. [Google Scholar] [CrossRef]
  55. Dias, S.; Ades, A.E.; Welton, N.J.; Jansen, J.P.; Sutton, A.J. Chapter 3: Model fit, model comparison and outlier detection. In Network Meta-Anlaysis for Decision-Making; Scott, M., Barnett, V., Eds.; John Wiley & Sons Ltd.: Chichester, UK, 2002; pp. 59–92. [Google Scholar]
  56. Brignardello-Petersen, R.; Izcovich, A.; Rochwerg, B.; Florez, I.D.; Hazlewood, G.; Alhazanni, W.; Yepes-Nunez, J.; Santesso, N.; Guyatt, G.H.; Schunemann, H.J.; et al. GRADE approach to drawing conclusions from a network meta-analysis using a partially contextualised framework. BMJ 2020, 371, m3907. [Google Scholar] [CrossRef]
  57. Nakashima, T.; Naganawa, S.; Sone, M.; Tominaga, M.; Hayashi, H.; Yamamoto, H.; Liu, X.; Nuttall, A.L. Disorders of cochlear blood flow. Brain Res. Rev. 2003, 43, 17–28. [Google Scholar] [CrossRef]
  58. Sheu, J.R.; Fong, T.H.; Liu, C.M.; Shen, M.Y.; Chen, T.L.; Chang, Y.; Lu, M.S.; Hsiao, G. Expression of matrix metalloproteinase-9 in human platelets: Regulation of platelet activation in in vitro and in vivo studies. Br. J. Pharmacol. 2004, 143, 193–201. [Google Scholar] [CrossRef]
  59. Fernandez-Patron, C.; Martinez-Cuesta, M.A.; Salas, E.; Sawicki, G.; Wozniak, M.; Radomski, M.W.; Davidge, S.T. Differential regulation of platelet aggregation by matrix metalloproteinases-9 and -2. Thromb. Haemost. 1999, 82, 1730–1735. [Google Scholar] [CrossRef]
  60. Arpornchayanon, W.; Canis, M.; Suckfuell, M.; Ihler, F.; Olzowy, B.; Strieth, S. Modeling the measurements of cochlear microcirculation and hearing function after loud noise. Otolaryngol. Head Neck Surg. 2011, 145, 463–469. [Google Scholar] [CrossRef]
  61. Aktas, G.; Atak Tel, B.M.; Tel, R.; Balci, B. Treatment of type 2 diabetes patients with heart conditions. Expert Rev. Endocrinol. Metab. 2023, 18, 255–265. [Google Scholar] [CrossRef]
  62. Aktas, G.; Taslamacioglu Duman, T. Current usage of long-acting insulin analogs in patients with type 2 diabetes mellitus. Expert Rev. Endocrinol. Metab. 2024, 19, 155–161. [Google Scholar] [CrossRef]
  63. Chen, J.J.; Chen, Y.W.; Zeng, B.Y.; Hung, C.M.; Zeng, B.S.; Stubbs, B.; Carvalho, A.F.; Thompson, T.; Roerecke, M.; Su, K.P.; et al. Efficacy of pharmacologic treatment in tinnitus patients without specific or treatable origin: A network meta-analysis of randomised controlled trials. eClinicalMedicine 2021, 39, 101080. [Google Scholar] [CrossRef]
  64. Wang, S.D. Opportunities and challenges of clinical research in the big-data era: From RCT to BCT. J. Thorac. Dis. 2013, 5, 721–723. [Google Scholar] [CrossRef]
  65. Zhang, Z. Big data and clinical research: Perspective from a clinician. J. Thorac. Dis. 2014, 6, 1659–1664. [Google Scholar] [CrossRef]
  66. Ahmann, A.J.; Capehorn, M.; Charpentier, G.; Dotta, F.; Henkel, E.; Lingvay, I.; Holst, A.G.; Annett, M.P.; Aroda, V.R. Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects with Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes Care 2018, 41, 258–266. [Google Scholar] [CrossRef]
  67. Ahren, B.; Masmiquel, L.; Kumar, H.; Sargin, M.; Karsbol, J.D.; Jacobsen, S.H.; Chow, F. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 2017, 5, 341–354. [Google Scholar] [CrossRef] [PubMed]
  68. Aroda, V.R.; Bain, S.C.; Cariou, B.; Piletic, M.; Rose, L.; Axelsen, M.; Rowe, E.; DeVries, J.H. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol. 2017, 5, 355–366. [Google Scholar] [CrossRef] [PubMed]
  69. Aroda, V.R.; Frias, J.P.; Ji, L.; Niemoeller, E.; Nguyen-Pascal, M.L.; Denkel, K.; Espinasse, M.; Guo, H.; Baek, S.; Choi, J.; et al. Efficacy and safety of once-weekly efpeglenatide in people with suboptimally controlled type 2 diabetes: The AMPLITUDE-D, AMPLITUDE-L and AMPLITUDE-S randomized controlled trials. Diabetes Obes. Metab. 2023, 25, 2084–2095. [Google Scholar] [CrossRef]
  70. Aroda, V.R.; Rosenstock, J.; Terauchi, Y.; Altuntas, Y.; Lalic, N.M.; Morales Villegas, E.C.; Jeppesen, O.K.; Christiansen, E.; Hertz, C.L.; Haluzik, M.; et al. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison with Placebo in Patients With Type 2 Diabetes. Diabetes Care 2019, 42, 1724–1732. [Google Scholar] [CrossRef]
  71. Aronne, L.J.; Sattar, N.; Horn, D.B.; Bays, H.E.; Wharton, S.; Lin, W.Y.; Ahmad, N.N.; Zhang, S.; Liao, R.; Bunck, M.C.; 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. [Google Scholar] [CrossRef] [PubMed]
  72. Aronson, R.; Frias, J.; Goldman, A.; Darekar, A.; Lauring, B.; Terra, S.G. Long-term efficacy and safety of ertugliflozin monotherapy in patients with inadequately controlled T2DM despite diet and exercise: VERTIS MONO extension study. Diabetes Obes. Metab. 2018, 20, 1453–1460. [Google Scholar] [CrossRef]
  73. Bailey, C.J.; Gross, J.L.; Pieters, A.; Bastien, A.; List, J.F. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: A randomised, double-blind, placebo-controlled trial. Lancet 2010, 375, 2223–2233. [Google Scholar] [CrossRef]
  74. Barnett, A.H.; Mithal, A.; Manassie, J.; Jones, R.; Rattunde, H.; Woerle, H.J.; Broedl, U.C.; EMPA-REG RENAL Trial Investigators. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: A randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014, 2, 369–384. [Google Scholar] [CrossRef]
  75. Bhatt, D.L.; Szarek, M.; Pitt, B.; Cannon, C.P.; Leiter, L.A.; McGuire, D.K.; Lewis, J.B.; Riddle, M.C.; Inzucchi, S.E.; Kosiborod, M.N.; et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N. Engl. J. Med. 2021, 384, 129–139. [Google Scholar] [CrossRef]
  76. Bhatt, D.L.; Szarek, M.; Steg, P.G.; Cannon, C.P.; Leiter, L.A.; McGuire, D.K.; Lewis, J.B.; Riddle, M.C.; Voors, A.A.; Metra, M.; et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N. Engl. J. Med. 2021, 384, 117–128. [Google Scholar] [CrossRef]
  77. Bliddal, H.; Bays, H.; Czernichow, S.; Udden Hemmingsson, J.; Hjelmesaeth, J.; Hoffmann Morville, T.; Koroleva, A.; Skov Neergaard, J.; Velez Sanchez, P.; Wharton, S.; et al. Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis. N. Engl. J. Med. 2024, 391, 1573–1583. [Google Scholar] [CrossRef]
  78. Blonde, L.; Jendle, J.; Gross, J.; Woo, V.; Jiang, H.; Fahrbach, J.L.; Milicevic, Z. Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): A randomised, open-label, phase 3, non-inferiority study. Lancet 2015, 385, 2057–2066. [Google Scholar] [CrossRef] [PubMed]
  79. Buse, J.B.; Garg, S.K.; Rosenstock, J.; Bailey, T.S.; Banks, P.; Bode, B.W.; Danne, T.; Kushner, J.A.; Lane, W.S.; Lapuerta, P.; et al. Sotagliflozin in Combination with Optimized Insulin Therapy in Adults with Type 1 Diabetes: The North American inTandem1 Study. Diabetes Care 2018, 41, 1970–1980. [Google Scholar] [CrossRef]
  80. Buse, J.B.; Nordahl Christensen, H.; Harty, B.J.; Mitchell, J.; Soule, B.P.; Zacherle, E.; Cziraky, M.; Willey, V.J. Study design and baseline profile for adults with type 2 diabetes in the once-weekly subcutaneous SEmaglutide randomized PRAgmatic (SEPRA) trial. BMJ Open Diabetes Res. Care 2023, 11, e003206. [Google Scholar] [CrossRef]
  81. Buse, J.B.; Rosenstock, J.; Sesti, G.; Schmidt, W.E.; Montanya, E.; Brett, J.H.; Zychma, M.; Blonde, L.; Group, L.-S. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: A 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009, 374, 39–47. [Google Scholar] [CrossRef] [PubMed]
  82. Cefalu, W.T.; Leiter, L.A.; de Bruin, T.W.; Gause-Nilsson, I.; Sugg, J.; Parikh, S.J. Dapagliflozin’s Effects on Glycemia and Cardiovascular Risk Factors in High-Risk Patients with Type 2 Diabetes: A 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study with a 28-Week Extension. Diabetes Care 2015, 38, 1218–1227. [Google Scholar] [CrossRef] [PubMed]
  83. Charbonnel, B.; Steinberg, H.; Eymard, E.; Xu, L.; Thakkar, P.; Prabhu, V.; Davies, M.J.; Engel, S.S. Efficacy and safety over 26 weeks of an oral treatment strategy including sitagliptin compared with an injectable treatment strategy with liraglutide in patients with type 2 diabetes mellitus inadequately controlled on metformin: A randomised clinical trial. Diabetologia 2013, 56, 1503–1511. [Google Scholar] [CrossRef]
  84. Cherney, D.Z.I.; Ferrannini, E.; Umpierrez, G.E.; Peters, A.L.; Rosenstock, J.; Powell, D.R.; Davies, M.J.; Banks, P.; Agarwal, R. Efficacy and safety of sotagliflozin in patients with type 2 diabetes and stage 3 chronic kidney disease. Diabetes Obes. Metab. 2023, 25, 1646–1657. [Google Scholar] [CrossRef]
  85. Coskun, T.; Sloop, K.W.; Loghin, C.; Alsina-Fernandez, J.; Urva, S.; Bokvist, K.B.; Cui, X.; Briere, D.A.; Cabrera, O.; Roell, W.C.; et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol. Metab. 2018, 18, 3–14. [Google Scholar] [CrossRef]
  86. Danne, T.; Cariou, B.; Banks, P.; Brandle, M.; Brath, H.; Franek, E.; Kushner, J.A.; Lapuerta, P.; McGuire, D.K.; Peters, A.L.; et al. HbA(1c) and Hypoglycemia Reductions at 24 and 52 Weeks with Sotagliflozin in Combination with Insulin in Adults with Type 1 Diabetes: The European inTandem2 Study. Diabetes Care 2018, 41, 1981–1990. [Google Scholar] [CrossRef]
  87. Davies, M.; Faerch, L.; Jeppesen, O.K.; Pakseresht, A.; Pedersen, S.D.; Perreault, L.; Rosenstock, J.; Shimomura, I.; Viljoen, A.; Wadden, T.A.; et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021, 397, 971–984. [Google Scholar] [CrossRef]
  88. Davies, M.J.; Bain, S.C.; Atkin, S.L.; Rossing, P.; Scott, D.; Shamkhalova, M.S.; Bosch-Traberg, H.; Syren, A.; Umpierrez, G.E. Efficacy and Safety of Liraglutide Versus Placebo as Add-on to Glucose-Lowering Therapy in Patients with Type 2 Diabetes and Moderate Renal Impairment (LIRA-RENAL): A Randomized Clinical Trial. Diabetes Care 2016, 39, 222–230. [Google Scholar] [CrossRef] [PubMed]
  89. Davies, M.J.; Bergenstal, R.; Bode, B.; Kushner, R.F.; Lewin, A.; Skjoth, T.V.; Andreasen, A.H.; Jensen, C.B.; DeFronzo, R.A.; NN8022-1922 Study Group. Efficacy of Liraglutide for Weight Loss Among Patients with Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA 2015, 314, 687–699. [Google Scholar] [CrossRef] [PubMed]
  90. Dei Cas, A.; Micheli, M.M.; Aldigeri, R.; Gardini, S.; Ferrari-Pellegrini, F.; Perini, M.; Messa, G.; Antonini, M.; Spigoni, V.; Cinquegrani, G.; et al. Long-acting exenatide does not prevent cognitive decline in mild cognitive impairment: A proof-of-concept clinical trial. J. Endocrinol. Investig. 2024, 47, 2339–2349. [Google Scholar] [CrossRef] [PubMed]
  91. Del Prato, S.; Kahn, S.E.; Pavo, I.; Weerakkody, G.J.; Yang, Z.; Doupis, J.; Aizenberg, D.; Wynne, A.G.; Riesmeyer, J.S.; Heine, R.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, 1811–1824. [Google Scholar] [CrossRef]
  92. Dungan, K.M.; Povedano, S.T.; Forst, T.; Gonzalez, J.G.; Atisso, C.; Sealls, W.; Fahrbach, J.L. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): A randomised, open-label, phase 3, non-inferiority trial. Lancet 2014, 384, 1349–1357. [Google Scholar] [CrossRef]
  93. Dungan, K.M.; Weitgasser, R.; Perez Manghi, F.; Pintilei, E.; Fahrbach, J.L.; Jiang, H.H.; Shell, J.; Robertson, K.E. A 24-week study to evaluate the efficacy and safety of once-weekly dulaglutide added on to glimepiride in type 2 diabetes (AWARD-8). Diabetes Obes. Metab. 2016, 18, 475–482. [Google Scholar] [CrossRef]
  94. Feng, P.; Sheng, X.; Ji, Y.; Urva, S.; Wang, F.; Miller, S.; Qian, C.; An, Z.; Cui, Y. A Phase 1 Multiple Dose Study of Tirzepatide in Chinese Patients with Type 2 Diabetes. Adv. Ther. 2023, 40, 3434–3445. [Google Scholar] [CrossRef]
  95. Ferrannini, E.; Berk, A.; Hantel, S.; Pinnetti, S.; Hach, T.; Woerle, H.J.; Broedl, U.C. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: An active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care 2013, 36, 4015–4021. [Google Scholar] [CrossRef]
  96. Fox, C.K.; Clark, J.M.; Rudser, K.D.; Ryder, J.R.; Gross, A.C.; Nathan, B.M.; Sunni, M.; Dengel, D.R.; Billington, C.J.; Bensignor, M.O.; et al. Exenatide for weight-loss maintenance in adolescents with severe obesity: A randomized, placebo-controlled trial. Obesity 2022, 30, 1105–1115. [Google Scholar] [CrossRef]
  97. Frias, J.P.; Choi, J.; Rosenstock, J.; Popescu, L.; Niemoeller, E.; Muehlen-Bartmer, I.; Baek, S. Efficacy and Safety of Once-Weekly Efpeglenatide Monotherapy Versus Placebo in Type 2 Diabetes: The AMPLITUDE-M Randomized Controlled Trial. Diabetes Care 2022, 45, 1592–1600. [Google Scholar] [CrossRef]
  98. Frias, J.P.; Davies, M.J.; Rosenstock, J.; Perez Manghi, F.C.; Fernandez Lando, L.; Bergman, B.K.; Liu, B.; Cui, X.; Brown, K.; SURPASS-2 Investigators. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N. Engl. J. Med. 2021, 385, 503–515. [Google Scholar] [CrossRef]
  99. Frias, J.P.; Hsia, S.; Eyde, S.; Liu, R.; Ma, X.; Konig, M.; Kazda, C.; Mather, K.J.; Haupt, A.; Pratt, E.; et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: A multicentre, randomised, dose-response, phase 2 study. Lancet 2023, 402, 472–483. [Google Scholar] [CrossRef]
  100. Frias, J.P.; Nauck, M.A.; Van, J.; Kutner, M.E.; Cui, X.; Benson, C.; Urva, S.; Gimeno, R.E.; Milicevic, Z.; Robins, D.; 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, 2180–2193. [Google Scholar] [CrossRef]
  101. Gallwitz, B.; Bohmer, M.; Segiet, T.; Molle, A.; Milek, K.; Becker, B.; Helsberg, K.; Petto, H.; Peters, N.; Bachmann, O. Exenatide twice daily versus premixed insulin aspart 70/30 in metformin-treated patients with type 2 diabetes: A randomized 26-week study on glycemic control and hypoglycemia. Diabetes Care 2011, 34, 604–606. [Google Scholar] [CrossRef]
  102. Gallwitz, B.; Guzman, J.; Dotta, F.; Guerci, B.; Simo, R.; Basson, B.R.; Festa, A.; Kiljanski, J.; Sapin, H.; Trautmann, M.; et al. Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): An open-label, randomised controlled trial. Lancet 2012, 379, 2270–2278. [Google Scholar] [CrossRef]
  103. Gao, L.; Lee, B.W.; Chawla, M.; Kim, J.; Huo, L.; Du, L.; Huang, Y.; Ji, L. 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, 1500–1510. [Google Scholar] [CrossRef]
  104. Garber, A.; Henry, R.; Ratner, R.; Garcia-Hernandez, P.A.; Rodriguez-Pattzi, H.; Olvera-Alvarez, I.; Hale, P.M.; Zdravkovic, M.; Bode, B.; the LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): A randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009, 373, 473–481. [Google Scholar] [CrossRef]
  105. Garvey, W.T.; Batterham, R.L.; Bhatta, M.; Buscemi, S.; Christensen, L.N.; Frias, J.P.; Jodar, E.; Kandler, K.; Rigas, G.; Wadden, T.A.; et al. Two-year effects of semaglutide in adults with overweight or obesity: The STEP 5 trial. Nat. Med. 2022, 28, 2083–2091. [Google Scholar] [CrossRef]
  106. Garvey, W.T.; Frias, J.P.; Jastreboff, A.M.; le Roux, C.W.; Sattar, N.; Aizenberg, D.; Mao, H.; Zhang, S.; Ahmad, N.N.; Bunck, M.C.; 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, 613–626. [Google Scholar] [CrossRef]
  107. Gerstein, H.C.; Lee, S.F.; Pare, G.; Bethel, M.A.; Colhoun, H.M.; Hoover, A.; Lakshmanan, M.; Lin, Y.; Pirro, V.; Qian, H.R.; et al. Biomarker Changes Associated with Both Dulaglutide and Cardiovascular Events in the REWIND Randomized Controlled Trial: A Nested Case-Control Post Hoc Analysis. Diabetes Care 2023, 46, 1046–1051. [Google Scholar] [CrossRef]
  108. Giorgino, F.; Benroubi, M.; Sun, J.H.; Zimmermann, A.G.; Pechtner, V. Efficacy and Safety of Once-Weekly Dulaglutide Versus Insulin Glargine in Patients with Type 2 Diabetes on Metformin and Glimepiride (AWARD-2). Diabetes Care 2015, 38, 2241–2249. [Google Scholar] [CrossRef]
  109. Grunberger, G.; Camp, S.; Johnson, J.; Huyck, S.; Terra, S.G.; Mancuso, J.P.; Jiang, Z.W.; Golm, G.; Engel, S.S.; Lauring, B. Ertugliflozin in Patients with Stage 3 Chronic Kidney Disease and Type 2 Diabetes Mellitus: The VERTIS RENAL Randomized Study. Diabetes Ther. 2018, 9, 49–66. [Google Scholar] [CrossRef]
  110. Hadjadj, S.; Rosenstock, J.; Meinicke, T.; Woerle, H.J.; Broedl, U.C. Initial Combination of Empagliflozin and Metformin in Patients with Type 2 Diabetes. Diabetes Care 2016, 39, 1718–1728. [Google Scholar] [CrossRef]
  111. Heerspink, H.J.L.; Stefansson, B.V.; Correa-Rotter, R.; Chertow, G.M.; Greene, T.; Hou, F.F.; Mann, J.F.E.; McMurray, J.J.V.; Lindberg, M.; Rossing, P.; et al. Dapagliflozin in Patients with Chronic Kidney Disease. N. Engl. J. Med. 2020, 383, 1436–1446. [Google Scholar] [CrossRef]
  112. Heise, T.; Mari, A.; DeVries, J.H.; Urva, S.; Li, J.; Pratt, E.J.; Coskun, T.; Thomas, M.K.; Mather, K.J.; Haupt, A.; et al. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: A multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol. 2022, 10, 418–429. [Google Scholar] [CrossRef]
  113. Heller, S.R.; Geybels, M.S.; Iqbal, A.; Liu, L.; Wagner, L.; Chow, E. A higher non-severe hypoglycaemia rate is associated with an increased risk of subsequent severe hypoglycaemia and major adverse cardiovascular events in individuals with type 2 diabetes in the LEADER study. Diabetologia 2022, 65, 55–64. [Google Scholar] [CrossRef]
  114. Home, P.D.; Ahren, B.; Reusch, J.E.B.; Rendell, M.; Weissman, P.N.; Cirkel, D.T.; Miller, D.; Ambery, P.; Carr, M.C.; Nauck, M.A. Three-year data from 5 HARMONY phase 3 clinical trials of albiglutide in type 2 diabetes mellitus: Long-term efficacy with or without rescue therapy. Diabetes Res. Clin. Pract. 2017, 131, 49–60. [Google Scholar] [CrossRef]
  115. Husain, M.; Birkenfeld, A.L.; Donsmark, M.; Dungan, K.; Eliaschewitz, F.G.; Franco, D.R.; Jeppesen, O.K.; Lingvay, I.; Mosenzon, O.; Pedersen, S.D.; et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N. Engl. J. Med. 2019, 381, 841–851. [Google Scholar] [CrossRef]
  116. 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, 623–633. [Google Scholar] [CrossRef]
  117. Flat-Sugar Trial Investigators. Glucose Variability in a 26-Week Randomized Comparison of Mealtime Treatment with Rapid-Acting Insulin Versus GLP-1 Agonist in Participants with Type 2 Diabetes at High Cardiovascular Risk. Diabetes Care 2016, 39, 973–981. [Google Scholar] [CrossRef]
  118. Jagomae, T.; Seppa, K.; Reimets, R.; Pastak, M.; Plaas, M.; Hickey, M.A.; Kukker, K.G.; Moons, L.; De Groef, L.; Vasar, E.; et al. Early Intervention and Lifelong Treatment with GLP1 Receptor Agonist Liraglutide in a Wolfram Syndrome Rat Model with an Emphasis on Visual Neurodegeneration, Sensorineural Hearing Loss and Diabetic Phenotype. Cells 2021, 10, 3193. [Google Scholar] [CrossRef]
  119. Januzzi, J.L., Jr.; Butler, J.; Jarolim, P.; Sattar, N.; Vijapurkar, U.; Desai, M.; Davies, M.J. Effects of Canagliflozin on Cardiovascular Biomarkers in Older Adults with Type 2 Diabetes. J. Am. Coll. Cardiol. 2017, 70, 704–712. [Google Scholar] [CrossRef]
  120. Jastreboff, A.M.; Aronne, L.J.; Ahmad, N.N.; Wharton, S.; Connery, L.; Alves, B.; Kiyosue, A.; Zhang, S.; Liu, B.; Bunck, M.C.; et al. Tirzepatide Once Weekly for the Treatment of Obesity. N. Engl. J. Med. 2022, 387, 205–216. [Google Scholar] [CrossRef]
  121. Kadowaki, T.; Isendahl, J.; Khalid, U.; Lee, S.Y.; Nishida, T.; Ogawa, W.; Tobe, K.; Yamauchi, T.; Lim, S.; investigators, S. Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): A randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial. Lancet Diabetes Endocrinol. 2022, 10, 193–206. [Google Scholar] [CrossRef]
  122. Kaku, K.; Yamada, Y.; Watada, H.; Abiko, A.; Nishida, T.; Zacho, J.; Kiyosue, A. Safety and efficacy of once-weekly semaglutide vs additional oral antidiabetic drugs in Japanese people with inadequately controlled type 2 diabetes: A randomized trial. Diabetes Obes. Metab. 2018, 20, 1202–1212. [Google Scholar] [CrossRef]
  123. Kellerer, M.; Kaltoft, M.S.; Lawson, J.; Nielsen, L.L.; Strojek, K.; Tabak, O.; Jacob, S. Effect of once-weekly semaglutide versus thrice-daily insulin aspart, both as add-on to metformin and optimized insulin glargine treatment in participants with type 2 diabetes (SUSTAIN 11): A randomized, open-label, multinational, phase 3b trial. Diabetes Obes. Metab. 2022, 24, 1788–1799. [Google Scholar] [CrossRef]
  124. Kosiborod, M.N.; Esterline, R.; Furtado, R.H.M.; Oscarsson, J.; Gasparyan, S.B.; Koch, G.G.; Martinez, F.; Mukhtar, O.; Verma, S.; Chopra, V.; et al. Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2021, 9, 586–594. [Google Scholar] [CrossRef]
  125. Kovacs, C.S.; Seshiah, V.; Merker, L.; Christiansen, A.V.; Roux, F.; Salsali, A.; Kim, G.; Stella, P.; Woerle, H.J.; Broedl, U.C.; et al. Empagliflozin as Add-on Therapy to Pioglitazone with or Without Metformin in Patients with Type 2 Diabetes Mellitus. Clin. Ther. 2015, 37, 1773–1788.e1. [Google Scholar] [CrossRef] [PubMed]
  126. Koychev, I.; Reid, G.; Nguyen, M.; Mentz, R.J.; Joyce, D.; Shah, S.H.; Holman, R.R. Inflammatory proteins associated with Alzheimer’s disease reduced by a GLP1 receptor agonist: A post hoc analysis of the EXSCEL randomized placebo controlled trial. Alzheimer’s Res. Ther. 2024, 16, 212. [Google Scholar] [CrossRef]
  127. Lavalle-Gonzalez, F.J.; Januszewicz, A.; Davidson, J.; Tong, C.; Qiu, R.; Canovatchel, W.; Meininger, G. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: A randomised trial. Diabetologia 2013, 56, 2582–2592. [Google Scholar] [CrossRef] [PubMed]
  128. Leiter, L.A.; Cefalu, W.T.; de Bruin, T.W.; Xu, J.; Parikh, S.; Johnsson, E.; Gause-Nilsson, I. Long-term maintenance of efficacy of dapagliflozin in patients with type 2 diabetes mellitus and cardiovascular disease. Diabetes Obes. Metab. 2016, 18, 766–774. [Google Scholar] [CrossRef] [PubMed]
  129. Lingvay, I.; Catarig, A.M.; Frias, J.P.; Kumar, H.; Lausvig, N.L.; le Roux, C.W.; Thielke, D.; Viljoen, A.; McCrimmon, R.J. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): A double-blind, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol. 2019, 7, 834–844. [Google Scholar] [CrossRef]
  130. Lock, J.P. Bexagliflozin Efficacy and Safety Trial (BEST). Available online: https://clinicaltrials.gov/study/NCT02558296?cond=NCT02558296&rank=1 (accessed on 28 October 2024).
  131. Ludvik, B.; Frias, J.P.; Tinahones, F.J.; Wainstein, J.; Jiang, H.; Robertson, K.E.; Garcia-Perez, L.E.; Woodward, D.B.; Milicevic, Z. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): A 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018, 6, 370–381. [Google Scholar] [CrossRef]
  132. Ludvik, B.; Giorgino, F.; Jodar, E.; Frias, J.P.; Fernandez Lando, L.; Brown, K.; Bray, R.; Rodriguez, A. 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, 583–598. [Google Scholar] [CrossRef]
  133. Mathieu, C.; Ranetti, A.E.; Li, D.; Ekholm, E.; Cook, W.; Hirshberg, B.; Chen, H.; Hansen, L.; Iqbal, N. Randomized, Double-Blind, Phase 3 Trial of Triple Therapy with Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes. Diabetes Care 2015, 38, 2009–2017. [Google Scholar] [CrossRef]
  134. McMurray, J.J.V.; Solomon, S.D.; Inzucchi, S.E.; Kober, L.; Kosiborod, M.N.; Martinez, F.A.; Ponikowski, P.; Sabatine, M.S.; Anand, I.S.; Belohlavek, J.; et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N. Engl. J. Med. 2019, 381, 1995–2008. [Google Scholar] [CrossRef] [PubMed]
  135. Mellander, A.; Billger, M.; Johnsson, E.; Traff, A.K.; Yoshida, S.; Johnsson, K. Hypersensitivity Events, Including Potentially Hypersensitivity-Related Skin Events, with Dapagliflozin in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis. Clin. Drug Investig. 2016, 36, 925–933. [Google Scholar] [CrossRef]
  136. Meneilly, G.S.; Roy-Duval, C.; Alawi, H.; Dailey, G.; Bellido, D.; Trescoli, C.; Manrique Hurtado, H.; Guo, H.; Pilorget, V.; Perfetti, R.; et al. Lixisenatide Therapy in Older Patients with Type 2 Diabetes Inadequately Controlled on Their Current Antidiabetic Treatment: The GetGoal-O Randomized Trial. Diabetes Care 2017, 40, 485–493. [Google Scholar] [CrossRef]
  137. Mosenzon, O.; Blicher, T.M.; Rosenlund, S.; Eriksson, J.W.; Heller, S.; Hels, O.H.; Pratley, R.; Sathyapalan, T.; Desouza, C.; PIONEER 5 Investigators. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): A placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019, 7, 515–527. [Google Scholar] [CrossRef]
  138. Mu, Y.; Bao, X.; Eliaschewitz, F.G.; Hansen, M.R.; Kim, B.T.; Koroleva, A.; Ma, R.C.W.; Yang, T.; Zu, N.; Liu, M.; et al. Efficacy and safety of once weekly semaglutide 2.4 mg for weight management in a predominantly east Asian population with overweight or obesity (STEP 7): A double-blind, multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2024, 12, 184–195. [Google Scholar] [CrossRef] [PubMed]
  139. Mullins, R.J.; Mustapic, M.; Chia, C.W.; Carlson, O.; Gulyani, S.; Tran, J.; Li, Y.; Mattson, M.P.; Resnick, S.; Egan, J.M.; et al. A Pilot Study of Exenatide Actions in Alzheimer’s Disease. Curr. Alzheimer Res. 2019, 16, 741–752. [Google Scholar] [CrossRef]
  140. Nauck, M.; Frid, A.; Hermansen, K.; Shah, N.S.; Tankova, T.; Mitha, I.H.; Zdravkovic, M.; During, M.; Matthews, D.R.; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: The LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009, 32, 84–90. [Google Scholar] [CrossRef] [PubMed]
  141. Nauck, M.; Rizzo, M.; Johnson, A.; Bosch-Traberg, H.; Madsen, J.; Cariou, B. Once-Daily Liraglutide Versus Lixisenatide as Add-on to Metformin in Type 2 Diabetes: A 26-Week Randomized Controlled Clinical Trial. Diabetes Care 2016, 39, 1501–1509. [Google Scholar] [CrossRef] [PubMed]
  142. Nauck, M.A.; Stewart, M.W.; Perkins, C.; Jones-Leone, A.; Yang, F.; Perry, C.; Reinhardt, R.R.; Rendell, M. Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetologia 2016, 59, 266–274. [Google Scholar] [CrossRef] [PubMed]
  143. O’Neil, P.M.; Birkenfeld, A.L.; McGowan, B.; Mosenzon, O.; Pedersen, S.D.; Wharton, S.; Carson, C.G.; Jepsen, C.H.; Kabisch, M.; Wilding, J.P.H. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: A randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet 2018, 392, 637–649. [Google Scholar] [CrossRef]
  144. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef] [PubMed]
  145. Perkovic, V.; Jardine, M.J.; Neal, B.; Bompoint, S.; Heerspink, H.J.L.; Charytan, D.M.; Edwards, R.; Agarwal, R.; Bakris, G.; Bull, S.; et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N. Engl. J. Med. 2019, 380, 2295–2306. [Google Scholar] [CrossRef]
  146. Pieber, T.R.; Bode, B.; Mertens, A.; Cho, Y.M.; Christiansen, E.; Hertz, C.L.; Wallenstein, S.O.R.; Buse, J.B.; PIONEER 7 Investigators. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): A multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019, 7, 528–539. [Google Scholar] [CrossRef]
  147. Pi-Sunyer, X.; Astrup, A.; Fujioka, K.; Greenway, F.; Halpern, A.; Krempf, M.; Lau, D.C.; le Roux, C.W.; Violante Ortiz, R.; Jensen, C.B.; et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N. Engl. J. Med. 2015, 373, 11–22. [Google Scholar] [CrossRef]
  148. Polidori, D.; Mari, A.; Ferrannini, E. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia 2014, 57, 891–901. [Google Scholar] [CrossRef]
  149. Pratley, R.; Amod, A.; Hoff, S.T.; Kadowaki, T.; Lingvay, I.; Nauck, M.; Pedersen, K.B.; Saugstrup, T.; Meier, J.J.; PIONEER 4 Investigators. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): A randomised, double-blind, phase 3a trial. Lancet 2019, 394, 39–50. [Google Scholar] [CrossRef] [PubMed]
  150. Pratley, R.E.; Aroda, V.R.; Lingvay, I.; Ludemann, J.; Andreassen, C.; Navarria, A.; Viljoen, A.; SUSTAIN 7 Investigators. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018, 6, 275–286. [Google Scholar] [CrossRef]
  151. Pratley, R.E.; Nauck, M.A.; Barnett, A.H.; Feinglos, M.N.; Ovalle, F.; Harman-Boehm, I.; Ye, J.; Scott, R.; Johnson, S.; Stewart, M.; et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): A randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014, 2, 289–297. [Google Scholar] [CrossRef] [PubMed]
  152. Ridderstrale, M.; Andersen, K.R.; Zeller, C.; Kim, G.; Woerle, H.J.; Broedl, U.C.; EMPA-REG H2H-SU Trial Investigators. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: A 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014, 2, 691–700. [Google Scholar] [CrossRef]
  153. Rodbard, H.W.; Rosenstock, J.; Canani, L.H.; Deerochanawong, C.; Gumprecht, J.; Lindberg, S.O.; Lingvay, I.; Sondergaard, A.L.; Treppendahl, M.B.; Montanya, E.; et al. Oral Semaglutide Versus Empagliflozin in Patients with Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care 2019, 42, 2272–2281. [Google Scholar] [CrossRef]
  154. Roden, M.; Weng, J.; Eilbracht, J.; Delafont, B.; Kim, G.; Woerle, H.J.; Broedl, U.C.; EMPA-REG MONO Trial Investigators. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013, 1, 208–219. [Google Scholar] [CrossRef] [PubMed]
  155. Rodgers, M.; Migdal, A.L.; Rodriguez, T.G.; Chen, Z.Z.; Nath, A.K.; Gerszten, R.E.; Kasid, N.; Toschi, E.; Tripaldi, J.; Heineman, B.; et al. Weight Loss Outcomes Among Early High Responders to Exenatide Treatment: A Randomized, Placebo Controlled Study in Overweight and Obese Women. Front. Endocrinol. 2021, 12, 742873. [Google Scholar] [CrossRef]
  156. Rosenstock, J.; Fonseca, V.A.; Gross, J.L.; Ratner, R.E.; Ahren, B.; Chow, F.C.; Yang, F.; Miller, D.; Johnson, S.L.; Stewart, M.W.; et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: A comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care 2014, 37, 2317–2325. [Google Scholar] [CrossRef]
  157. Rosenstock, J.; Frias, J.P.; Rodbard, H.W.; Tofe, S.; Sears, E.; Huh, R.; Fernandez Lando, L.; Patel, H. Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial. JAMA 2023, 330, 1631–1640. [Google Scholar] [CrossRef]
  158. Rosenstock, J.; Raccah, D.; Koranyi, L.; Maffei, L.; Boka, G.; Miossec, P.; Gerich, J.E. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: A 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care 2013, 36, 2945–2951. [Google Scholar] [CrossRef]
  159. Rosenstock, J.; Wysham, C.; Frias, J.P.; Kaneko, S.; Lee, C.J.; Fernandez Lando, L.; Mao, H.; Cui, X.; Karanikas, C.A.; Thieu, V.T. 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, 143–155. [Google Scholar] [CrossRef]
  160. Rubino, D.; Abrahamsson, N.; Davies, M.; Hesse, D.; Greenway, F.L.; Jensen, C.; Lingvay, I.; Mosenzon, O.; Rosenstock, J.; Rubio, M.A.; et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults with Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA 2021, 325, 1414–1425. [Google Scholar] [CrossRef] [PubMed]
  161. Rubino, D.M.; Greenway, F.L.; Khalid, U.; O’Neil, P.M.; Rosenstock, J.; Sorrig, R.; Wadden, T.A.; Wizert, A.; Garvey, W.T.; STEP 8 Investigators. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults with Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA 2022, 327, 138–150. [Google Scholar] [CrossRef]
  162. Schechter, M.; Wiviott, S.D.; Raz, I.; Goodrich, E.L.; Rozenberg, A.; Yanuv, I.; Murphy, S.A.; Zelniker, T.A.; Fredriksson, M.; Johansson, P.A.; et al. Effects of dapagliflozin on hospitalisations in people with type 2 diabetes: Post-hoc analyses of the DECLARE-TIMI 58 trial. Lancet Diabetes Endocrinol. 2023, 11, 233–241. [Google Scholar] [CrossRef]
  163. Schernthaner, G.; Gross, J.L.; Rosenstock, J.; Guarisco, M.; Fu, M.; Yee, J.; Kawaguchi, M.; Canovatchel, W.; Meininger, G. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: A 52-week randomized trial. Diabetes Care 2013, 36, 2508–2515. [Google Scholar] [CrossRef]
  164. Scully, K.J.; Wolfsdorf, J.I. Efficacy of GLP-1 Agonist Therapy in Autosomal Dominant WFS1-Related Disorder: A Case Report. Horm. Res. Paediatr. 2020, 93, 409–414. [Google Scholar] [CrossRef]
  165. Spertus, J.A.; Birmingham, M.C.; Nassif, M.; Damaraju, C.V.; Abbate, A.; Butler, J.; Lanfear, D.E.; Lingvay, I.; Kosiborod, M.N.; Januzzi, J.L. The SGLT2 inhibitor canagliflozin in heart failure: The CHIEF-HF remote, patient-centered randomized trial. Nat. Med. 2022, 28, 809–813. [Google Scholar] [CrossRef]
  166. Stack, A.G.; Han, D.; Goldwater, R.; Johansson, S.; Dronamraju, N.; Oscarsson, J.; Johnsson, E.; Parkinson, J.; Erlandsson, F. Dapagliflozin Added to Verinurad Plus Febuxostat Further Reduces Serum Uric Acid in Hyperuricemia: The QUARTZ Study. J. Clin. Endocrinol. Metab. 2021, 106, e2347–e2356. [Google Scholar] [CrossRef] [PubMed]
  167. Stenlof, K.; Cefalu, W.T.; Kim, K.A.; Jodar, E.; Alba, M.; Edwards, R.; Tong, C.; Canovatchel, W.; Meininger, G. Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: Findings from the 52-week CANTATA-M study. Curr. Med. Res. Opin. 2014, 30, 163–175. [Google Scholar] [CrossRef] [PubMed]
  168. Tuttle, K.R.; Hauske, S.J.; Canziani, M.E.; Caramori, M.L.; Cherney, D.; Cronin, L.; Heerspink, H.J.L.; Hugo, C.; Nangaku, M.; Rotter, R.C.; et al. Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: A randomised, controlled, phase 2 trial. Lancet 2024, 403, 379–390. [Google Scholar] [CrossRef] [PubMed]
  169. Tuttle, K.R.; Lakshmanan, M.C.; Rayner, B.; Busch, R.S.; Zimmermann, A.G.; Woodward, D.B.; Botros, F.T. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): A multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 2018, 6, 605–617. [Google Scholar] [CrossRef]
  170. Tuttle, K.R.; Levin, A.; Nangaku, M.; Kadowaki, T.; Agarwal, R.; Hauske, S.J.; Elsasser, A.; Ritter, I.; Steubl, D.; Wanner, C.; et al. Safety of Empagliflozin in Patients with Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials. Diabetes Care 2022, 45, 1445–1452. [Google Scholar] [CrossRef]
  171. Umpierrez, G.; Tofe Povedano, S.; Perez Manghi, F.; Shurzinske, L.; Pechtner, V. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care 2014, 37, 2168–2176. [Google Scholar] [CrossRef] [PubMed]
  172. Vardeny, O.; Desai, A.S.; Jhund, P.S.; Fang, J.C.; Claggett, B.; de Boer, R.A.; Hernandez, A.F.; Inzucchi, S.E.; Kosiborod, M.N.; Lam, C.S.P.; et al. Dapagliflozin and Mode of Death in Heart Failure with Improved Ejection Fraction: A Post Hoc Analysis of the DELIVER Trial. JAMA Cardiol. 2024, 9, 283–289. [Google Scholar] [CrossRef] [PubMed]
  173. Wadden, T.A.; Bailey, T.S.; Billings, L.K.; Davies, M.; Frias, J.P.; Koroleva, A.; Lingvay, I.; O’Neil, P.M.; Rubino, D.M.; Skovgaard, D.; et al. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults with Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA 2021, 325, 1403–1413. [Google Scholar] [CrossRef]
  174. Wadden, T.A.; Chao, A.M.; Machineni, S.; Kushner, R.; Ard, J.; Srivastava, G.; Halpern, B.; Zhang, S.; Chen, J.; Bunck, M.C.; et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: The SURMOUNT-3 phase 3 trial. Nat. Med. 2023, 29, 2909–2918. [Google Scholar] [CrossRef] [PubMed]
  175. Wason, S. Efficacy and Safety of Sotagliflozin Versus Placebo in Participants with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control While Taking Insulin Alone or with Other Oral Antidiabetic Agents (SOTA-INS). Available online: https://clinicaltrials.gov/study/NCT03285594?cond=NCT03285594&rank=1 (accessed on 28 October 2024).
  176. Weinstock, R.S.; Guerci, B.; Umpierrez, G.; Nauck, M.A.; Skrivanek, Z.; Milicevic, Z. Safety and efficacy of once-weekly dulaglutide versus sitagliptin after 2 years in metformin-treated patients with type 2 diabetes (AWARD-5): A randomized, phase III study. Diabetes Obes. Metab. 2015, 17, 849–858. [Google Scholar] [CrossRef]
  177. Weissman, P.N.; Carr, M.C.; Ye, J.; Cirkel, D.T.; Stewart, M.; Perry, C.; Pratley, R. HARMONY 4: Randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Diabetologia 2014, 57, 2475–2484. [Google Scholar] [CrossRef]
  178. Wilding, J.P.; Woo, V.; Soler, N.G.; Pahor, A.; Sugg, J.; Rohwedder, K.; Parikh, S.; Dapagliflozin 006 Study Group. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: A randomized trial. Ann. Intern. Med. 2012, 156, 405–415. [Google Scholar] [CrossRef]
  179. Wilding, J.P.H.; Batterham, R.L.; Calanna, S.; Davies, M.; Van Gaal, L.F.; Lingvay, I.; McGowan, B.M.; Rosenstock, J.; Tran, M.T.D.; Wadden, T.A.; et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N. Engl. J. Med. 2021, 384, 989–1002. [Google Scholar] [CrossRef] [PubMed]
  180. Wysham, C.; Blevins, T.; Arakaki, R.; Colon, G.; Garcia, P.; Atisso, C.; Kuhstoss, D.; Lakshmanan, M. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care 2014, 37, 2159–2167. [Google Scholar] [CrossRef] [PubMed]
  181. Yu, M.; Brunt, K.V.; Milicevic, Z.; Varnado, O.; Boye, K.S. Patient-reported Outcomes in Patients with Type 2 Diabetes Treated with Dulaglutide Added to Titrated Insulin Glargine (AWARD-9). Clin. Ther. 2017, 39, 2284–2295. [Google Scholar] [CrossRef] [PubMed]
  182. Zhao, L.; Cheng, Z.; Lu, Y.; Liu, M.; Chen, H.; Zhang, M.; Wang, R.; Yuan, Y.; Li, X. Tirzepatide for Weight Reduction in Chinese Adults with Obesity: The SURMOUNT-CN Randomized Clinical Trial. JAMA 2024, 332, 551–560. [Google Scholar] [CrossRef]
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Figure 1. PRISMA2020 flowchart of current network meta-analysis.
Figure 1. PRISMA2020 flowchart of current network meta-analysis.
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Figure 2. (A) Network structure of the primary outcome: incidence of hearing loss. The overall structure of the network meta-analysis. The lines between nodes represent direct comparisons from various trials, with the numbers over the lines indicating the number of trials providing these comparisons for each specific treatment. The thickness of the lines corresponds to the number of trials linked to the network. (B) Network structure of the primary outcome: incidence of hearing loss in subgroup of dosage. The overall structure of the network meta-analysis. The lines between nodes represent direct comparisons from various trials, with the numbers over the lines indicating the number of trials providing these comparisons for each specific treatment. The thickness of the lines corresponds to the number of trials linked to the network.
Figure 2. (A) Network structure of the primary outcome: incidence of hearing loss. The overall structure of the network meta-analysis. The lines between nodes represent direct comparisons from various trials, with the numbers over the lines indicating the number of trials providing these comparisons for each specific treatment. The thickness of the lines corresponds to the number of trials linked to the network. (B) Network structure of the primary outcome: incidence of hearing loss in subgroup of dosage. The overall structure of the network meta-analysis. The lines between nodes represent direct comparisons from various trials, with the numbers over the lines indicating the number of trials providing these comparisons for each specific treatment. The thickness of the lines corresponds to the number of trials linked to the network.
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Figure 3. (A) Forest plot of primary outcome: incidence of hearing loss. When the effect size (expressed as odds ratio) is less than 1, the specified treatment is associated with fewer hearing loss events compared to placebo/controls. The arrow represents the order of ranking. (B) Forest plot of primary outcome: incidence of hearing loss in subgroup of dosage. When the effect size (expressed as odds ratio) is less than 1, the specified treatment is associated with fewer hearing loss events compared to placebo/controls. The arrow represents the order of ranking.
Figure 3. (A) Forest plot of primary outcome: incidence of hearing loss. When the effect size (expressed as odds ratio) is less than 1, the specified treatment is associated with fewer hearing loss events compared to placebo/controls. The arrow represents the order of ranking. (B) Forest plot of primary outcome: incidence of hearing loss in subgroup of dosage. When the effect size (expressed as odds ratio) is less than 1, the specified treatment is associated with fewer hearing loss events compared to placebo/controls. The arrow represents the order of ranking.
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Figure 4. Schematic diagram of the physiopathology of exendin-4 related micro-platelet-erythrocyte clot formation. (A) The exendin-4 administration leads to matrix metalloproteinase-9 suppression; (B) the suppressed matrix metalloproteinase-9 losses its inhibitor effects on platelet aggregation and activation; (C) the consequent activated platelet aggregation formed micro-platelet-erythrocyte clot with erythrocytes; (D) finally, the upstream micro-platelet-erythrocyte clot migrates and occludes the downstream cochlea, either in stria vascularis (upper allow indicated) or in terminal branches of inner radiating arteriole (low allow indicated). Abbreviation: 95% CIs: 95% confidence intervals; GLP-1 agonist: glucagon-like peptide-1 agonist; NMA: network meta-analysis; OR: odds ratio; RCT: randomized controlled trial; SGLT2 inhibitor: sodium–glucose cotransporter 2 inhibitor.
Figure 4. Schematic diagram of the physiopathology of exendin-4 related micro-platelet-erythrocyte clot formation. (A) The exendin-4 administration leads to matrix metalloproteinase-9 suppression; (B) the suppressed matrix metalloproteinase-9 losses its inhibitor effects on platelet aggregation and activation; (C) the consequent activated platelet aggregation formed micro-platelet-erythrocyte clot with erythrocytes; (D) finally, the upstream micro-platelet-erythrocyte clot migrates and occludes the downstream cochlea, either in stria vascularis (upper allow indicated) or in terminal branches of inner radiating arteriole (low allow indicated). Abbreviation: 95% CIs: 95% confidence intervals; GLP-1 agonist: glucagon-like peptide-1 agonist; NMA: network meta-analysis; OR: odds ratio; RCT: randomized controlled trial; SGLT2 inhibitor: sodium–glucose cotransporter 2 inhibitor.
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Table 1. (A) League table of the primary outcome: incidence of hearing loss. (B) League table of the primary outcome: incidence of hearing loss in subgroup of dosage.
Table 1. (A) League table of the primary outcome: incidence of hearing loss. (B) League table of the primary outcome: incidence of hearing loss in subgroup of dosage.
(A)
01_Sotagliflozin 0.17 [0.01; 4.10]
0.22 (0, 2286941337189.82)02_Albiglutide 0.20 [0.01; 4.16]
0 (0, 2.56)0 (0, 2.39)03_Canagliflozin 0.56 [0.11; 2.90]
0 (0, 1.05)0 (0, 1.16)0.65 (0.04, 7.39)04_Empagliflozin 0.63 [0.32; 1.23]
0 (0, 2.87)0 (0, 3.35)0.81 (0.01, 56.86)1.21 (0.02, 65.45)05_Tirzepatide 0.41 [0.04; 3.98]
0 (0, 1.03)0 (0, 1.15)0.61 (0.02, 10.65)0.96 (0.06, 9.25)0.77 (0.01, 70.74)06_Dulaglutide0.52 [0.12; 2.26]
0 (0, 0.57)0 (0, 0.54)0.38 (0.02, 3.16)0.57 (0.17, 1.58)0.46 (0.01, 21.69)0.59 (0.08, 5.9)07_Placebo_
or_Control		0.89 [0.22; 3.62]0.66 [0.11; 3.98]0.80 [0.19; 3.36]0.66 [0.10; 4.21]0.25 [0.03; 2.23]0.60 [0.03; 12.47]0.34 [0.01; 8.30]0.40 [0.02; 8.35]0.11 [0.01; 2.06]
0 (0, 0.5)0 (0, 0.62)0.3 (0.01, 5.56)0.48 (0.04, 4.22)0.4 (0.01, 31.86)0.48 (0.03, 10.47)0.84 (0.11, 5.84)08_Inject_
semaglutide
0 (0, 0.53)0 (0, 0.57)0.24 (0.01, 5.69)0.37 (0.02, 5.35)0.29 (0, 33.06)0.38 (0.02, 11.35)0.66 (0.05, 7.81)0.8 (0.03, 20.52)09_Exenatide
0 (0, 0.5)0 (0, 0.52)0.24 (0.01, 4.26)0.37 (0.02, 3.22)0.3 (0, 21.2)0.38 (0.02, 7.12)0.65 (0.06, 4.68)0.8 (0.03, 11.95)0.99 (0.03, 23.27)10_Dapagliflozin
0 (0, 0.28)0 (0, 0.33)0.12 (0, 2.92)0.18 (0, 2.72)0.15 (0, 14.28)0.19 (0, 5.45)0.33 (0.01, 3.85)0.39 (0.01, 9.76)0.49 (0.01, 17.46)0.52 (0.01, 15.02)11_Ertugliflozin
0 (0, 0.14)0 (0, 0.16)0.06 (0, 1.78)0.1 (0, 1.72)0.07 (0, 9.52)0.1 (0, 3.85)0.18 (0, 2.6)0.2 (0, 6.43)0.25 (0, 11.63)0.26 (0, 10.68)0.51 (0.01, 45.3)12_Liraglutide
0 (0, 0)0 (0, 0)0 (0, 0.33)0 (0, 0.53)0 (0, 0.73)0 (0, 0.44)0 (0, 0.93)0 (0, 1.29)0 (0, 2.04)0 (0, 1.92)0 (0, 4.23)0 (0, 5.95)13_Oral_
semaglutide
0 (0, 0)0 (0, 0)0 (0, 0.41)0 (0, 0.57)0 (0, 1.03)0 (0, 0.75)0 (0, 0.95)0 (0, 1.62)0 (0, 1.89)0 (0, 1.97)0 (0, 5.04)0 (0, 10.18)145.21 (0, 15638204434817468416)14_Bexagliflozin
0 (0, 0)0 (0, 0)0 (0, 0.29)0 (0, 0.27)0 (0, 0.49)0 (0, 0.39)0 (0, 0.49)0 (0, 0.7)0 (0, 0.88)0 (0, 1.03)0 (0, 3.33)0 (0, 5.35)1.53 (0, 39759673530850082816)0.02 (0, 642665163278770)15_Efpeglenatide
0 (0, 0)0 (0, 0)0 (0, 0.05)0 (0, 0.06)0 (0, 0.07)0 (0, 0.07)0 (0, 0.1)0 (0, 0.18)0 (0, 0.2)0 (0, 0.21)0 (0, 0.38)0 (0, 1.4)0.52 (0, 41443130473760)0 (0, 174818703323.2)0.02 (0, 16044177798929.8)16_Lixisenatide
(B)
01_Tirzepatide_
low_dosage		 0.33 [0.01; 8.14] 0.34 [0.01; 8.48]
174.27 (0, 10463610754211418112)02_Sotagliflozin 0.17 [0.01; 4.10]
0.94 (0, 23865462628940.6)0.02 (0, 83814535670.54)03_Albiglutide 0.20 [0.01; 4.16]
7.18 (0, 10384045242332)0.02 (0, 76625689170891.9)2.79 (0, 226025279542229)04_Dulaglutide_
low_dosage		 0.33 [0.01; 8.22]
1.17 (0, 93257222307134.8)0 (0, 592940298063597)1.01 (0, 131811533539368)0.7 (0, 181440300040.18)05_Inject_
semaglutide_
low_dosage		 0.66 [0.03; 16.34] 0.34 [0.01; 8.27]
0 (0, 0.79)0 (0, 8.45)0 (0, 25.84)0 (0, 27.45)0 (0, 10.56)06_Tirzepatide_
medium_
dosage		 1.01 [0.10; 9.75] 0.34 [0.01; 8.43]
0 (0, 2.37)0 (0, 5.31)0 (0, 16.31)0 (0, 16.7)0 (0, 6.32)0.68 (0, 146.15)07_Canagliflozin_
high_dosage		1.00 [0.06; 15.96] 0.62 [0.08; 5.08]
0 (0, 2.2)0 (0, 5.17)0 (0, 4.46)0 (0, 17.79)0 (0, 6.1)0.63 (0, 154.69)0.94 (0.01, 59.33)08_Canagliflozin_
low_dosage		 0.62 [0.08; 5.07]
0 (0, 1.31)0 (0, 6.04)0 (0, 4.16)0 (0, 12.78)0 (0, 4.37)0.53 (0, 117.71)0.76 (0.01, 103.71)0.79 (0.01, 100.39)09_Empagliflozin
_high_dosage		1.00 [0.06; 15.98] 0.62 [0.08; 5.07]
0 (0, 0.57)0 (0, 1.87)0 (0, 1.29)0 (0, 4.23)0 (0, 1.53)0.34 (0, 24.29)0.51 (0.01, 14.49)0.53 (0.01, 14.92)0.69 (0.01, 13.22)10_Empagliflozin
_low_dosage		 0.64 [0.33; 1.26]
0 (0, 0.4)0 (0, 3.6)0 (0, 3.88)0 (0, 8.59)0 (0, 3.25)0.43 (0.01, 11.28)0.6 (0, 81.02)0.69 (0, 99.71)0.87 (0, 102.78)1.33 (0.03, 103.38)11_Tirzepatide_
high_dosage		 0.99 [0.10; 9.57]
0 (0, 0.44)0 (0, 1.44)0 (0, 0.94)0 (0, 1.32)0 (0, 1.14)0.21 (0, 20.54)0.33 (0, 16.23)0.34 (0, 14.65)0.45 (0, 15.63)0.72 (0.02, 9.31)0.48 (0, 31.08)12_Dulaglutide_
high_dosage		0.61 [0.14; 2.61]
0 (0, 0.24)0 (0, 0.83)0 (0, 0.55)0 (0, 1.82)0 (0, 0.68)0.17 (0, 8.7)0.26 (0.01, 4.88)0.27 (0.01, 5.23)0.35 (0.01, 5.42)0.53 (0.1, 1.84)0.39 (0.01, 12.01)0.73 (0.07, 15.56)13_Placebo_
or_Control		 0.71 [0.07; 6.80]0.67 [0.11; 3.99]0.66 [0.11; 3.98]0.80 [0.19; 3.36]0.99 [0.10; 9.54]0.43 [0.06; 2.90]0.25 [0.03; 2.23]0.34 [0.01; 8.30]0.60 [0.03; 12.47]0.20 [0.01; 4.17]0.11 [0.01; 2.06]
0 (0, 2749665048400134)0 (0, 13835349680732138)0 (0, 4106605056265394)0 (0, 416046115627.38)0 (0, 247794060699236)3.36 (0, 1747509744556715776)4.57 (0, 3863746537860638720)4.97 (0, 5275996480618600448)5.3 (0, 4429532891571235840)8.65 (0, 7964217336657846272)8.04 (0, 6558691788735834112)14.84 (0, 11731741958374318080)17.51 (0, 17741192217616175104)14_Efpeglenatide
_low_dosage		 0.20 [0.01; 4.16]
0 (0, 0.44)0 (0, 1.6)0 (0, 0.88)0 (0, 2.9)0 (0, 0.57)0.1 (0, 38.54)0.16 (0, 29.55)0.17 (0, 26.76)0.23 (0, 30.52)0.38 (0, 25.55)0.25 (0, 60.04)0.52 (0, 78.93)0.75 (0.01, 40.49)0.04 (0, 80325932675121217536)15_Inject_
semaglutide_
medium_dosage
0 (0, 0.24)0 (0, 0.64)0 (0, 0.54)0 (0, 1.75)0 (0, 0.65)0.1 (0, 14.57)0.15 (0, 10.53)0.16 (0, 11.04)0.2 (0, 12.12)0.3 (0.01, 8.21)0.22 (0, 24.01)0.41 (0.01, 38.67)0.57 (0.02, 13.68)0.03 (0, 2.01122131702702e+20)0.8 (0, 147.22)16_Inject_
semaglutide_
high_dosage
0 (0, 0.26)0 (0, 0.88)0 (0, 0.58)0 (0, 1.74)0 (0, 0.72)0.09 (0, 15.53)0.15 (0, 12.22)0.15 (0, 11.81)0.2 (0, 12.92)0.32 (0.01, 8.36)0.23 (0, 23.58)0.46 (0.01, 39.17)0.62 (0.03, 14.08)0.03 (0, 1.7925843597753e+20)0.89 (0.01, 179.63)1.06 (0.01, 84.22)17_Exenatide
0 (0, 0.2)0 (0, 0.64)0 (0, 0.47)0 (0, 1.19)0 (0, 0.56)0.09 (0, 9.19)0.14 (0, 6.29)0.15 (0, 6.62)0.18 (0, 7.19)0.31 (0.01, 3.84)0.2 (0, 13.5)0.43 (0.01, 19.45)0.59 (0.03, 6.15)0.03 (0, 1.01388022129584e+20)0.81 (0.01, 84.95)1.01 (0.01, 46.22)0.96 (0.01, 45.76)18_Dapagliflozin
0 (0, 0.18)0 (0, 0.63)0 (0, 0.37)0 (0, 1.15)0 (0, 0.54)0.06 (0, 13.86)0.1 (0, 8.88)0.1 (0, 9.66)0.13 (0, 10.34)0.23 (0, 6.78)0.15 (0, 18.82)0.29 (0, 27.46)0.44 (0.01, 10.54)0.02 (0, 54300857840542908416)0.55 (0, 99.78)0.74 (0, 63.75)0.65 (0, 62.92)0.73 (0.01, 60.62)19_Ertugliflozin_
high_dosage		0.58 [0.07; 5.15]
0 (0, 0.09)0 (0, 0.33)0 (0, 0.21)0 (0, 0.76)0 (0, 0.27)0.03 (0, 6.65)0.05 (0, 4.94)0.05 (0, 5.09)0.07 (0, 6.1)0.11 (0, 3.75)0.08 (0, 10.64)0.17 (0, 17.44)0.23 (0, 6.33)0.01 (0, 27862512272519688192)0.29 (0, 67.19)0.37 (0, 40.33)0.35 (0, 41.08)0.37 (0, 39.43)0.53 (0.03, 12.71)20_Ertugliflozin_
low_dosage
0 (0, 0.09)0 (0, 0.2)0 (0, 0.19)0 (0, 0.59)0 (0, 0.23)0.03 (0, 5.33)0.04 (0, 3.56)0.04 (0, 3.63)0.06 (0, 4.11)0.09 (0, 2.84)0.07 (0, 8.4)0.13 (0, 13.58)0.17 (0, 4.7)0.01 (0, 17672406927695316992)0.23 (0, 47.84)0.29 (0, 29.33)0.28 (0, 29.45)0.3 (0, 29.33)0.4 (0, 73.46)0.74 (0, 141.71)21_Liraglutide
0 (0, 0)0 (0, 0)0 (0, 0.01)0 (0, 0.01)0 (0, 0)0 (0, 0.53)0 (0, 0.89)0 (0, 0.63)0 (0, 0.58)0 (0, 0.89)0 (0, 0.98)0 (0, 1.67)0 (0, 1.67)0 (0, 12286429074044.5)0 (0, 3.79)0 (0, 4.67)0 (0, 4.48)0 (0, 4.1)0 (0, 6.99)0 (0, 14.67)0 (0, 19.44)22_Bexagliflozin
0 (0, 0)0 (0, 0)0 (0, 0)0 (0, 0)0 (0, 0)0 (0, 0.35)0 (0, 0.35)0 (0, 0.33)0 (0, 0.51)0 (0, 0.46)0 (0, 0.56)0 (0, 0.93)0 (0, 0.86)0 (0, 120950538640435856)0 (0, 4.43)0 (0, 2.1)0 (0, 2.36)0 (0, 2.02)0 (0, 7.57)0 (0, 12.28)0 (0, 8.89)1.21 (0, 1747737841683757)23_Oral_
semaglutide
0 (0, 0)0 (0, 0)0 (0, 0)0 (0, 0)0 (0, 0.01)0 (0, 0.22)0 (0, 0.21)0 (0, 0.2)0 (0, 0.18)0 (0, 0.2)0 (0, 0.33)0 (0, 0.46)0 (0, 0.39)0 (0, 0.43)0 (0, 1.86)0 (0, 0.98)0 (0, 1.04)0 (0, 0.99)0 (0, 1.9)0 (0, 4)0 (0, 5.11)0.09 (0, 25965618197430972)0.92 (0, 466713242374613)24_Efpeglenatide
_high_dosage
0 (0, 0)0 (0, 0)0 (0, 0)0 (0, 0)0 (0, 0)0 (0, 0.09)0 (0, 0.1)0 (0, 0.09)0 (0, 0.11)0 (0, 0.11)0 (0, 0.2)0 (0, 0.25)0 (0, 0.21)0 (0, 20563509532733)0 (0, 0.82)0 (0, 0.56)0 (0, 0.68)0 (0, 0.61)0 (0, 1.08)0 (0, 2.14)0 (0, 2.52)2.06 (0, 6625401557077732)6.09 (0, 2608743386738966)8.01 (0, 65039373111329704)25_Lixisenatide
(A) Data presented as OR [95% CIs]. Pairwise (upper-right portion) and network (lower-left portion) meta-analysis results are presented as estimate effect sizes for the outcome of overall events of hearing loss. The gray-background indicated the interventions. Interventions are reported in order of mean ranking of beneficial prophylactic effects on overall events of hearing loss, and outcomes are expressed as odds ratio (OR) (95% confidence intervals) (95% CIs). For the pairwise meta-analyses, OR of less than 1 indicates that the treatment specified in the row achieved a more beneficial effect than that specified in the column. For the network meta-analysis (NMA), OR of less than 1 indicates that the treatment specified in the column achieved a more beneficial effect than that specified in the row. Bold results indicate statistical significance. (B) Data presented as OR [95% CIs]. Pairwise (upper-right portion) and network (lower-left portion) meta-analysis results are presented as estimated effect sizes for the outcome of hearing loss events in a subgroup of dosage. The gray-background indicated the interventions. Interventions are reported in order of mean ranking of beneficial prophylactic effect on events of hearing loss in a subgroup of dosage, and outcomes are expressed as odds ratio (OR) (95% confidence intervals) (95% CIs). For the pairwise meta-analyses, OR of less than 1 indicates that the treatment specified in the row achieved a more beneficial effect than that specified in the column. For the network meta-analysis (NMA), OR of less than 1 indicates that the treatment specified in the column achieved a more beneficial effect than that specified in the row. Bold results indicate statistical significance. Abbreviation: 95% CIs: 95% confidence intervals; GLP-1 agonist: glucagon-like peptide-1 agonist; NMA: network meta-analysis; OR: odds ratio; RCT: randomized controlled trial; SGLT2 inhibitor: sodium–glucose cotransporter 2 inhibitor.
Table 2. Summary of main findings in this network meta-analysis.
Table 2. Summary of main findings in this network meta-analysis.
MedicationsOverallSubgroup of Dosage
LixisenatideSignificantly increased events of hearing loss/highest riskSignificantly increased events of hearing loss/highest risk
EfpeglenatideNot significantHigh-dose efpeglenatide (i.e., 6 mg/week) significantly increased events of hearing loss
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MDPI and ACS Style

Chen, J.-J.; Hsu, C.-W.; Hung, C.-M.; Liang, C.-S.; Su, K.-P.; Carvalho, A.F.; Stubbs, B.; Chen, Y.-W.; Chen, T.-Y.; Lei, W.-T.; et al. Risk of Hearing Loss in Patients Treated with Exendin-4 Derivatives: A Network Meta-Analysis of Glucagon-like Peptide-1 Receptor Agonists and Sodium–Glucose Cotransporter 2 Inhibitors. Pharmaceuticals 2025, 18, 735. https://doi.org/10.3390/ph18050735

AMA Style

Chen J-J, Hsu C-W, Hung C-M, Liang C-S, Su K-P, Carvalho AF, Stubbs B, Chen Y-W, Chen T-Y, Lei W-T, et al. Risk of Hearing Loss in Patients Treated with Exendin-4 Derivatives: A Network Meta-Analysis of Glucagon-like Peptide-1 Receptor Agonists and Sodium–Glucose Cotransporter 2 Inhibitors. Pharmaceuticals. 2025; 18(5):735. https://doi.org/10.3390/ph18050735

Chicago/Turabian Style

Chen, Jiann-Jy, Chih-Wei Hsu, Chao-Ming Hung, Chih-Sung Liang, Kuan-Pin Su, Andre F. Carvalho, Brendon Stubbs, Yen-Wen Chen, Tien-Yu Chen, Wei-Te Lei, and et al. 2025. "Risk of Hearing Loss in Patients Treated with Exendin-4 Derivatives: A Network Meta-Analysis of Glucagon-like Peptide-1 Receptor Agonists and Sodium–Glucose Cotransporter 2 Inhibitors" Pharmaceuticals 18, no. 5: 735. https://doi.org/10.3390/ph18050735

APA Style

Chen, J.-J., Hsu, C.-W., Hung, C.-M., Liang, C.-S., Su, K.-P., Carvalho, A. F., Stubbs, B., Chen, Y.-W., Chen, T.-Y., Lei, W.-T., Zeng, B.-Y., & Tseng, P.-T. (2025). Risk of Hearing Loss in Patients Treated with Exendin-4 Derivatives: A Network Meta-Analysis of Glucagon-like Peptide-1 Receptor Agonists and Sodium–Glucose Cotransporter 2 Inhibitors. Pharmaceuticals, 18(5), 735. https://doi.org/10.3390/ph18050735

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