Efficacy and Safety of Tirzepatide  for the Management of Obesity: A Systematic Review and Meta-analysis of Randomized  Controlled Trials (RCTs)            

Efficacy and Safety of Tirzepatide for the Management of Obesity: A Systematic Review and Meta-analysis of Randomized Controlled Trials (RCTs) | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 24 November 2025 V1 Latest version Share on Efficacy and Safety of Tirzepatide for the Management of Obesity: A Systematic Review and Meta-analysis of Randomized Controlled Trials (RCTs) Authors : Kissan Ghose , David Losier , Paulami Deshmukh , Monica Gaurdian , Maurya Patel , Nadia Ahmed , Mohammed Moazzam Vahora , Sean Ghose , Cara Mohammed , Avni Bhatia , Kebire Gofar , and Muhammad Ayyan 0000-0002-4023-7956 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176402391.10613553/v1 828 views 179 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective: Obesity is a significant risk factor for Type 2 Diabetes and plays a significant role in global morbidity and mortality. While current pharmacological treatments, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA), have demonstrated efficacy in weight loss and glycemic control, Tirzepatide, a dual glucose-dependent insulinotropic polypeptide, has arisen as a viable treatment option. This study aims to investigate the evidence on comparing Tirzepatide to placebo and GLP-1 RAs such as Semaglutide and Dulaglutide Methods: We searched electronic databases to retrieve and include all randomized controlled trials (RCTs) that analyzed the effect of tirzepatide for the management of obesity. The revised Cochrane’s “Risk of Bias" tool for randomized trials (RoB 2.0) was used to assess the risk of bias in the included studies. Using RevMan, risk ratios (RR) along with the 95% confidence intervals (95% CI) were used for dichotomous outcomes, and standard mean differences (SMD) along with the 95% confidence intervals (95% CI) were used for continuous outcomes. Results: A total of fourteen RCTs were included in our meta-analysis, reporting data from 9968 patients. When comparing tirzepatide to placebo, our analysis showed a statistically significant difference favoring Tirzepatide dosages of 5mg, 10mg and 15mg for change in mean body weight (SMD -2.25; 95% CI: -2.62 to -1.88), weight reduction of ≥ 5% (RR 3.76; 95% CI: 3.16-4.47), weight reduction of ≥ 10% (RR 6.40; 95% CI: 5.00-8.19) and weight reduction of ≥ 15% (RR 11.32; 95% CI: 8.34-15.37). When comparing Tirzepatide vs GLP-1 agonists, our meta-analysis showed a statistically significant difference favoring Tirzepatide dosages of 5mg, 10mg and 15mg for Change in mean body weight (SMD -2.18; 95% CI: -2.70 to -1.66), weight reduction of ≥ 5% (RR 2.96; 95% CI: 2.14-4.10), weight reduction of ≥ 10% (RR 3.25; 95% CI: 2.28-4.64), and weight reduction of ≥ 15% (RR 4.72; 95% CI: 2.75, 8.11). Conclusion: This meta-analysis confirms that tirzepatide is an effective pharmacologic option for obesity treatment, demonstrating statistically significant reductions in mean body weight and BMI. Given its recent FDA approval for obesity, tirzepatide represents a promising advancement in obesity treatment, though further long-term studies are needed to assess sustained efficacy and long-term adverse effects. INTRODUCTION Obesity is a global public health crisis associated with significant morbidity and mortality. The global prevalence of ethnic-specific obesity was determined to be 45.1% in 2022. 1 With a steep increase in obesity, there has been a parallel increase in associated non-communicable diseases (NCDs). 2 Current treatment guidelines position weight loss as a primary target in the management of common NCDs such as type 2 diabetes mellitus (T2DM), hypertension, and metabolic syndrome-associated fatty liver disease, and advocate for a minimum weight loss of 5 to 10% to obtain metabolic improvements. 3 Outcomes are often better with greater weight loss, and reductions of higher magnitude (10–15%) have shown disease-modifying effects leading to NCD remission. 4 Among pharmacotherapeutics prescribed for obesity, Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RA) have been notably stated. Glucagon-like peptide 1 (GLP-1) is a glucagon incretin hormone released from the gut enteroendocrine L-cells. GLP-1 (and GLP-2) are continuously secreted from enteroendocrine cells at low basal levels in the fasting or interprandial state. Circulating levels of these peptides increase rapidly within minutes of food ingestion. GLP-1 controls glycemic variation during meals by increasing insulin secretion and decreasing glucagon secretion. It additionally slows gastric emptying and reduces food intake, which limits weight gain. 5 Tirzepatide, originally developed for T2DM, has demonstrated significant weight-loss benefits in patients with or without T2DM in RCTs and has emerged as one of the most promising weight-loss drugs on the market. Tirzepatide has shown its weight-loss effects in overweight and obese persons, with multi-targeted action and fewer adverse events. 6 Tirzepatide, a novel dual-agonist of receptors for the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), has shown promising potential for improving glycemic control and decreasing body weight in people with type 2 diabetes. 7 Tirzepatide has been approved for treating obesity at doses of up to 15 mg once weekly. 8 Tirzepatide, being a relatively newer GLP-1 RA, awaits safety and efficacy testing among naive obese patients. Additionally, amidst the pool of available RCTs, the duration of drug therapy has been less than a year in several randomized trials, overlooking the fact that weight loss due to GLP-1 RA can continue beyond the said duration. 9 Several randomized controlled trials (RCTs) have evaluated the efficacy and safety of tirzepatide for the management of obesity, with or without T2DM. We aim to comprehensively synthesize evidence from all the published RCTs on this topic, including the recently published SURMOUNT-5 trial 10 and SURMOUNT-CN trial 11 , which were not studied in previous meta-analyses 6,12 METHODS This meta-analysis was conducted following the Cochrane Handbook for Systematic Reviews of Interventions 13 and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines 14 . This meta-analysis has been registered by the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42025632429). Data Searches and Sources To find relevant articles from commencement to May 2025, the following databases were searched: Cochrane Central Register of Controlled Trials (CENTRAL, via The Cochrane Library), MEDLINE (PubMed), Embase, and ClinicalTrials.gov. The search strategy consisted of identifying relevant keywords and Medical Subject Headings (MeSH) and used a combination of keywords like “Tirzepatide”, “obesity”, “overweight”, and “LY3298176”. In addition, we conducted a grey literature search on sources like Open Grey, and backward citation searching was done using reference lists of relevant articles. Eligibility Criteria Studies were screened, and eligible studies fulfilled the following criteria: Population (Patients with obesity or overweight), Intervention (Tirzepatide irrespective of dose), Comparison (Placebo/GLP-1 RA), and Study Design (Randomized Controlled Studies (RCTs) only). All other study designs, like cross-sectional studies and cohort studies, were excluded. All the RCTs that compared Tirzepatide to insulin only were excluded. Study Selection and Data Extraction We imported all the retrieved studies into Rayyan. Two review authors independently completed the title and abstract screening, where they applied the inclusion/exclusion criteria and retrieved full texts if they were unsure. The remaining studies were screened by reading their full texts. Any disagreements were settled through discussion and by consulting a third author. The data extraction was done by two review authors independently, and they extracted the data into a pre-piloted Excel spreadsheet. The extracted data included study characteristics (trial name, study location, treatment duration, and follow-up period), intervention details (dosage and frequency), patient characteristics (sample size, mean age, gender, baseline characteristics, and baseline glucose-lowering therapy (if any)), and outcomes. Outcomes Primary outcomes measured in this study included mean change in body weight, Weight Reduction of ≥ 5%, Weight Reduction of ≥ 10%, and Weight Reduction of ≥ 15%. Secondary outcomes measured included change in BMI, change in waist circumference, weight reduction of ≥ 20%, and adverse events. The adverse events included incidences of nausea, vomiting, diarrhea, pancreatitis, gallbladder disease, hypersensitivity reactions, injection site reactions, hypertension, Major Cardiovascular Events (MACE), adverse events leading to discontinuation of trial drugs or placebo, hypoglycemia, and serious adverse events. Risk of Bias Assessment To assess the internal validity of the RCTs included in this review, two authors independently applied the revised Cochrane Risk of Bias Tool (RoB 2.0) to assess the risk of bias and assign a rating of low risk of bias, some concerns regarding risk of bias, and high risk of bias. Domains assessed for risk of bias included the randomization process, deviations from intended interventions, missing data outcome, measurement of the outcome, selection of the reported result, and overall bias. Data Synthesis This meta-analysis was conducted using Review Manager (RevMan) 5.4. Dichotomous outcomes for each study arm were synthesized under a random effects model that utilized risk ratio (RR) and 95% confidence intervals (95% CI) as measures of effect. Continuous outcomes for each study arm were synthesized under a random effects model that utilized a Standard Mean Difference (SMD) and 95% confidence intervals (95% CI) as measures of effect. I 2 statistics were used to quantify statistical heterogeneity among included studies. All the individual analyses were stratified according to the dose of Tirzepatide (5 mg or 10 mg, or 15 mg/MTD). RESULTS A total of 756 studies were retrieved after database searching. After title and abstract screening, 70 studies were left. After full-text screening, we included 14 RCTs 11,15–26 in this systematic review, reporting data from 9968 patients in this meta-analysis. Two RCTs were excluded even though they satisfied the inclusion criteria. SURPASS-3 27 and SURPASS-4 28 were excluded as they compared Tirzepatide against insulin only and not against Placebo or Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist groups. The included RCTs took place in the following countries: Argentina, Australia, Brazil, China, the Czech Republic, Germany, India, Israel, Japan, Mexico, Poland, Puerto Rico, Russia, Slovakia, Spain, Taiwan, the United Kingdom, and the USA. A detailed process of the study selection is illustrated in Figure 1. There were some unique characteristics to the studies included in this review. Out of the total 14 RCTs, 11 studies compared Tirzepatide to a placebo, while 4 RCTs compared Tirzepatide to a GLP-1 agonist, either Semaglutide or Dulaglutide (Frias et al. 24 compared Tirzepatide to a placebo and dulaglutide). Frias et al. 24 and SURPASS J-MONO 23 compared Tirzepatide to dulaglutide 1.5mg and 0.75mg, respectively. SURPASS-2 and SURMOUNT-5 compared tirzepatide to semaglutide. Frias et al. 26 , SURMOUNT-1, SURPASS-1, SURPASS-2, SURPASS-5, SURMOUNT-5, and SURPASS-J MONO were the only studies that included 5mg, 10mg, and 15mg dosages of Tirzepatide. Major characteristics for each of the included articles can be seen in Table 1. According to our ROB 2.0 assessment, all 14 RCTs had a low risk of bias. A complete risk of bias assessment can be seen in Supplementary Figure S1. Results of analyses TIRZEPATIDE VS PLACEBO Primary Outcomes Change in mean body weight: The statistical analysis showed that Tirzepatide was associated with a statistically significant decrease in mean body weight (SMD: -2.25; 95%: -2.62 to -1.88; I 2 : 98%). The 10 mg dosage of Tirzepatide had a greater decrease in mean body weight than the 15mg dosage (-2.78 vs -2.11), suggesting that the change in mean body weight was not dose-dependent. [Figure 2] Weight reduction of 5% or More: According to our meta-analysis, Tirzepatide was associated with a statistically significant increase in proportion of patients with weight reduction of ≥ 5% (RR: 3.76; 95%: 3.16, 4.47; I 2 : 85%). The 5mg dosage of Tirzepatide had a greater proportion of patients with weight reduction of ≥ 5% than the 15mg dosage (5.01 vs 4.08), suggesting that a weight reduction of 5% or more was not dose-dependent. [Supplementary Figure S2] Weight reduction of 10% or More: Our analysis showed that the Tirzepatide was associated with a statistically significant increase in proportion of patients with weight reduction of ≥ 10% (RR: 6.40; 95%: 5.00, 8.19; I 2 : 76%). The 5mg dosage of Tirzepatide had a greater proportion of patients with weight reduction of ≥ 10% than the 15mg dosage (12.04 vs 7.38), suggesting that a weight reduction of 10% or more was not dose-dependent. [Supplementary Figure S3] Weight reduction of 15% or More: According to our meta-analysis, Tirzepatide group had a statistically significant increase in proportion of patients with weight reduction of ≥ 15% (RR: 11.32; 95%: 8.34, 15.37; I 2 : 56%). This effect was found to be dose-dependent, with the greatest effect shown by the 15 mg dose of Tirzepatide (RR 14.96; 95% CI:8.87- 25.24). [Supplementary Figure S4]. Secondary Outcomes Change in BMI: The decrease in BMI was greater at all doses of tirzepatide compared to placebo (SMD -2.81, 95% CI: -3.36 to -2.27). [Supplementary Table S1] Change in waist circumference: The decrease in waist circumference was greater at all doses of tirzepatide compared to placebo (SMD -1.46, 95% CI: -1.71 to -1.21). [Supplementary Table S1] Adverse events: When compared to placebo, Tirzepatide increased the incidences of nausea, vomiting, and injection site reactions at all doses. A detailed breakdown of all the secondary outcomes can be seen in Supplementary Table S1. TIRZEPATIDE VS GLP-1 AGONISTS Primary Outcomes Change in mean Body weight difference: According to our analysis, tirzepatide was associated with a statistically significant decrease in the body weight (SMD -2.18; 95% CI: -2.70 to -1.66; I 2 : 98%). Tirzepatide 10 mg dose was associated with a greater decrease in body weight as compared to the 5 mg and 15 mg dosages (For 10 mg dose, SMD -2.99; 95% CI: -4.57 to -1.42; I 2 : 99%). [Figure 3] Weight Reduction of 5% or More: Tirzepatide was associated with a statistically significant increase in the proportion of patients with ≥ 5% weight loss (RR 2.96; 95% CI: 2.14, 4.10; I 2 : 97%). It is important to note that the 5mg dosage of Tirzepatide had a greater proportion of patients with weight reduction of ≥ 5% than the 15mg dosage (RR: 4.23 vs 3.22), suggesting that a weight reduction of ≥ 5% was not dose dependent. [Supplementary Figure S5]. Weight Reduction of 10% or More: Tirzepatide was associated with a statistically significant increase in the proportion of patients with ≥ 10% weight loss (RR 3.25; 95% CI: 2.28, 4.64; I 2 : 93%). Tirzepatide 10 mg dose was associated with a greater proportion of patients with ≥ 10% weight loss as compared to the 5 mg and 15 mg dosages (For 10 mg dose, RR 4.84; 95% CI: 1.33 to 17.54; I 2 : 91%). [Supplementary Figure S6]. Weight Reduction of 15% or More: Weight Reduction of 10% or More: Tirzepatide was associated with a statistically significant increase in the proportion of patients with ≥ 15% weight loss (RR 4.72; 95% CI: 2.75, 8.11; I 2 : 88%). Tirzepatide 10 mg dose was associated with a greater proportion of patients with ≥ 15% weight loss as compared to the 5 mg and 15 mg dosages (For 10 mg dose, RR 9.08; 95% CI: 1.71 to 48.18; I 2 : 75%) [Supplementary Figure S7]. Secondary Outcomes Change in BMI: Tirzepatide 15 mg was associated with a statistically significant decrease in BMI as compared to GLP-1 RA (SMD -2.93, 95% CI: -4.05 to -1.80). Tirzepatide 5 mg and 10 mg dosages had similar change in BMI, when compared to GLP-1 RA. [Supplementary Table S2] Change in waist circumference: The decrease in waist circumference was greater at all doses of tirzepatide compared to GLP-1 RA (SMD -1.87, 95% CI: -2.35 to -1.38). [Supplementary Table S2] Adverse events: When compared to GLP-1 RA, Tirzepatide had similar incidences of nausea, vomiting, MACE, and serious adverse events among other adverse events. A detailed breakdown of all the secondary outcomes can be seen in Supplementary Table S2. DISCUSSION This systematic review and meta-analysis of 14 randomized controlled trials (RCTs), encompassing 9968 patients, demonstrates that tirzepatide, administered at doses of 5 mg, 10 mg, and 15 mg, leads to statistically significant and clinically meaningful reductions in body weight compared to both placebo and active GLP-1 receptor agonists (GLP-1 RAs) in individuals with overweight or obesity. According to our meta-analysis, when compared to either placebo or GLP-1 RAs, tirzepatide was associated with statistically significant reductions in mean body weight, BMI, and waist circumference across all doses (5 mg, 10 mg, and 15 mg). Similarly, it increased the likelihood of attaining ≥5%, ≥10%, and ≥15% weight loss compared to placebo, with dose-dependency only evident for ≥15% reductions. Safety profiles were comparable to GLP-1 agonists, though gastrointestinal adverse events were more frequent than placebo. The findings of this meta-analysis are largely in agreement with previously conducted systematic reviews and meta-analyses evaluating tirzepatide for weight management. Qin et al. 29 reported substantial weight loss with tirzepatide, noting that a significant percentage of participants achieved ≥10% weight loss, which aligns with our results. Similarly, Karagiannis et al. 30 concluded that tirzepatide outperformed selective GLP-1 RAs in weight reduction and glycemic control in patients with type 2 diabetes. Our results further support these conclusions, extending the evidence to a broader obesity-focused population and confirming tirzepatide’s greater efficacy compared to GLP-1 RAs (e.g., dulaglutide and semaglutide). Lin et al. 7 also documented significant improvements in body weight, waist circumference, and glycemic parameters with tirzepatide, consistent with our observations of considerable reductions in these metrics. The network meta-analysis by Liu et al. 31 comparing various incretin drugs found tirzepatide to exhibit superior efficacy in reducing body weight and improving glycemic control, which is corroborated by our results. Additionally, their study 31 highlighted tirzepatide’s favorable efficacy and safety profile, noting gastrointestinal adverse events (e.g., nausea, vomiting, and diarrhea) as more frequent than placebo but comparable to other GLP-1 RAs, a finding corroborated by our analysis. These safety outcomes are further supported by pivotal trials such as SURMOUNT-1 15 . The importance of dose escalation in managing these gastrointestinal side effects was explored in early phase 2 trials; for instance, Frias et al. 2020 26 investigated different dose-escalation regimens and concluded that lower starting doses and smaller dose increments are associated with a more favorable side effect profile, a principle that has informed subsequent phase 3 trial designs and clinical practice recommendations. By incorporating recent randomized controlled trials (RCTs), our meta-analysis offers updated pooled estimates that may account for slight variations, particularly in the exact proportions of patients attaining specific weight loss thresholds, when compared to earlier reviews. Crucially, our meta-analysis includes the recent SURMOUNT-5 trial 25 , which directly compared maximum tolerated doses of tirzepatide (10 mg or 15 mg) with maximum tolerated doses of semaglutide (1.7 mg or 2.4 mg) in adults with obesity but without type 2 diabetes. Aronne et al. reported a significantly greater mean percent change in body weight with tirzepatide (−20.2%) compared to semaglutide (−13.7%) at 72 weeks (p<0.001), and a greater reduction in waist circumference (−18.4 cm vs -13.0 cm, p<0.001). This head-to-head evidence against higher, obesity-indicated doses of semaglutide strongly supports our pooled findings of tirzepatide’s enhanced efficacy. In our study, most of the weight-loss outcomes did not show dose-dependency. This may be due to high heterogeneity among included studies or better tolerability of lower doses of tirzepatide. Several limitations should be considered when interpreting the results of this meta-analysis. Firstly, this analysis relies on published, study-level data from RCTs, not individual patient-level data, which imparts bias associated with our findings. Secondly, although statistical heterogeneity was variable across outcomes (e.g., high for mean body weight change, I²=98% vs placebo; low for nausea with 5mg tirzepatide vs placebo, I²=0%), clinical heterogeneity is a significant consideration. The included trials were conducted in various countries with differing healthcare setups, and enrolled populations with variability in baseline characteristics (e.g., presence of type 2 diabetes, baseline BMI) and study designs (e.g., duration, background lifestyle interventions). Therefore, the findings should be generalized with caution to specific subpopulations. Most of the included trials were also sponsored by the drug manufacturer, which introduces a potential for reporting bias, underscoring the need for independent long-term studies. For this reason, positive findings should be interpreted with caution. Furthermore, the follow-up durations of the included RCTs, while up to 72 weeks for some, may not fully capture the very long-term maintenance of weight loss or the incidence of rare, delayed adverse events. Despite these limitations, our study has several strengths. A rigorous search strategy, adhering to Cochrane principles, was employed, and only RCTs were included, thereby enhancing the internal validity of the findings by minimizing the selection bias and confounding associated with the inclusion of observational studies. Crucially, this review incorporates data from the most recent RCTs, providing an up-to-date synthesis of tirzepatide’s efficacy and safety profile for obesity management. A key strength is the inclusion of the latest RCTs, most notably the SURMOUNT-5 trial, which provides head-to-head comparison between higher doses of semaglutide and tirzepatide, making our synthesis highly current. The implications of these findings are significant. The implications of these findings are significant for both clinical practice and future research. For clinical practice, tirzepatide’s robust weight-loss efficacy, including demonstrated superiority over higher doses of semaglutide in the non-diabetic obese population, positions it as a leading therapeutic option, especially for patients requiring substantial weight loss. For research, this study highlights tirzepatide’s superior weight loss outcomes compared to the GLP-1 RAs included in the trials. Further head-to-head RCTs directly comparing tirzepatide with other potent weight loss interventions, including newer GLP-1 RAs at obesity-specific doses (e.g., semaglutide 2.4 mg) and bariatric surgery, are warranted to fully delineate its comparative effectiveness and inform patient selection. CONCLUSION In conclusion, tirzepatide demonstrates substantial and dose-dependent efficacy in promoting weight loss, reducing BMI and waist circumference in individuals with obesity, with or without type 2 diabetes. While its use is associated with an increased incidence of generally mild-to-moderate and transient gastrointestinal adverse events, its overall benefit-risk profile appears favorable for obesity management. More large-scale, long-term RCTs are needed to further ascertain the sustained effects of tirzepatide on weight maintenance, its impact on obesity-related comorbidities such as cardiovascular outcomes and non-alcoholic steatohepatitis, and its comparative effectiveness against other established and emerging obesity treatments across diverse populations. Continued investigation will be crucial in defining tirzepatide’s precise role within the evolving multidisciplinary approach to obesity care. REFERENCES 1. Noubiap JJ, Nansseu JR, Lontchi-Yimagou E, et al. 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Comparative efficacy of incretin drugs on glycemic control, body weight, and blood pressure in adults with overweight or obesity and with/without type 2 diabetes: a systematic review and network meta-analysis. Front Endocrinol (Lausanne) . 2025;16:1513641. doi:10.3389/fendo.2025.1513641 Information & Authors Information Version history V1 Version 1 24 November 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords meta-analysis obesity systematic review tirzepatide weight loss Authors Affiliations Kissan Ghose View all articles by this author David Losier View all articles by this author Paulami Deshmukh View all articles by this author Monica Gaurdian View all articles by this author Maurya Patel View all articles by this author Nadia Ahmed View all articles by this author Mohammed Moazzam Vahora View all articles by this author Sean Ghose View all articles by this author Cara Mohammed View all articles by this author Avni Bhatia View all articles by this author Kebire Gofar View all articles by this author Muhammad Ayyan 0000-0002-4023-7956 [email protected] View all articles by this author Metrics & Citations Metrics Article Usage 828 views 179 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Kissan Ghose, David Losier, Paulami Deshmukh, et al. 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