Warning: fopen(/home/virtual/enm-kes/journal/upload/ip_log/ip_log_2025-02.txt): failed to open stream: Permission denied in /home/virtual/lib/view_data.php on line 100 Warning: fwrite() expects parameter 1 to be resource, boolean given in /home/virtual/lib/view_data.php on line 101 Tirzepatide and Cancer Risk in Individuals with and without Diabetes: A Systematic Review and Meta-Analysis
Skip Navigation
Skip to contents

Endocrinol Metab : Endocrinology and Metabolism

clarivate
OPEN ACCESS
SEARCH
Search

Articles

Page Path
HOME > Endocrinol Metab > Ahead-of print > Article
Original Article
Tirzepatide and Cancer Risk in Individuals with and without Diabetes: A Systematic Review and Meta-Analysis
A.B.M. Kamrul-Hasan1orcid, Muhammad Shah Alam2orcid, Deep Dutta3orcid, Thanikai Sasikanth4orcid, Fatema Tuz Zahura Aalpona5orcid, Lakshmi Nagendra6orcid

DOI: https://doi.org/10.3803/EnM.2024.2164
Published online: January 15, 2025

1Department of Endocrinology, Mymensingh Medical College, Mymensingh, Bangladesh

2Department of Medicine, Army Medical College Cumilla, Cumilla, Bangladesh

3Department of Endocrinology, CEDAR Superspeciality Clinics, New Delhi, India

4Department of Endocrinology, National Hospital of Sri Lanka, Colombo, Sri Lanka

5Department of Obstetrics and Gynecology, Atpara Upazila Health Complex, Netrokona, Bangladesh

6Department of Endocrinology, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India

Corresponding author: A.B.M. Kamrul-Hasan Department of Endocrinology, Mymensingh Medical College, Charpara, Mymensingh Sadar, Mymensingh 2200, Bangladesh Tel: +880-1711103905, Fax: +880-9166064, E-mail: rangassmc@gmail.com
• Received: September 29, 2024   • Revised: October 11, 2024   • Accepted: November 14, 2024

Copyright © 2025 Korean Endocrine Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • 1,342 Views
  • 128 Download
  • Background
    Data on the carcinogenic potential of tirzepatide from randomized controlled trials (RCTs) are limited. Furthermore, no meta-analysis has included all relevant RCTs to assess the cancer risk associated with tirzepatide.
  • Methods
    RCTs involving patients receiving tirzepatide in the intervention arm and either a placebo or any active comparator in the control arm were searched through electronic databases. The primary outcome was the overall risk of any cancer, and secondary outcomes were the risks of specific types of cancer in the tirzepatide versus the control groups.
  • Results
    Thirteen RCTs with 13,761 participants were analyzed. Over 26 to 72 weeks, the tirzepatide and pooled control groups had identical risks of any cancer (risk ratio, 0.78; 95% confidence interval, 0.53 to 1.16; P=0.22). The two groups had comparable cancer risks in patients with and without diabetes. In subgroup analyses, the risks were also similar in the tirzepatide versus placebo, insulin, and glucagon-like peptide-1 receptor agonist groups. The overall cancer risk was also comparable for different doses of tirzepatide compared to the control groups; only a 10-mg tirzepatide dose had a lower risk of any cancer than placebo. Furthermore, compared to the control groups (pooled or separately), tirzepatide did not increase the risk of any specific cancer types. Despite greater increments in serum calcitonin with 10- and 15-mg tirzepatide doses than with placebo, the included RCTs reported no cases of papillary thyroid carcinoma.
  • Conclusion
    Tirzepatide use in RCTs over 26 to 72 weeks did not increase overall or specific cancer risk.
Obesity has been recognized as a risk factor for many cancers [1]. Several malignancies have shown increased occurrence in individuals with type 2 diabetes (T2D). It is widely accepted that diabetes is not mutagenic but may be mitogenic, likely due to factors such as hyperglycemia, hyperinsulinemia, or the confounding effects of adiposity. Consequently, individuals predisposed to cancer or those with undiagnosed cancer may experience accelerated disease progression in the presence of uncontrolled hyperglycemia [2]. In this context, anti-obesity and antidiabetic drugs should, at a minimum, not adversely affect cancer risk. Metformin may decrease cancer risk, whereas insulin and sulfonylureas could elevate such risks [3]. Thiazolidinediones have been linked to significant reductions in overall cancer risks; however, the association between pioglitazone and urinary bladder cancer, despite initial findings, remains controversial [4,5]. A recent meta-analysis of 157 randomized controlled trials (RCTs) indicated that dipeptidyl peptidase-4 inhibitors do not affect overall cancer risk and are associated with a significantly reduced risk of colorectal cancer [6]. Hypothetically, antidiabetic drugs that promote weight loss or improve hyperinsulinemia are likely to lower cancer risk. Dicembrini et al. [7], in a recent meta-analysis of 27 RCTs, found no difference in cancer incidence between sodium-glucose cotransporter-2 inhibitors and comparators, including placebo. However, the evidence remains limited and inconclusive regarding the cancer risk associated with emerging anti-diabetic medications such as glucagon-like peptide-1 (GLP-1)-based therapies. The U.S. Food and Drug Administration (FDA) database from 2004 to 2009 reported increased risks of pancreatic and thyroid cancer associated with the GLP-1 receptor agonist (GLP-1RA) exenatide compared to other therapies [8]. Another study using the French National Health Care Insurance System Database also reported increased risks of all thyroid cancers and medullary thyroid cancer with the use of GLP-1RAs (exenatide, liraglutide, and dulaglutide) over 1–3 years [9]. In a recent retrospective study based on a nationwide multicenter database of electronic health records of 113 million United States patients, GLP-1RAs, compared with insulin, were associated with a significant risk reduction in 10 of 13 obesity-associated cancers, including pancreatic and colorectal cancer; however, GLP-1RA had no impact on thyroid cancer [10].
Tirzepatide is the first and only GLP-1 and glucose-dependent insulinotropic peptide (GIP) agonist approved by the FDA for the treatment of diabetes and obesity [11,12]. Its effects on glucose lowering and weight reduction are promising [13,14]. Given its high efficacy in reducing glycemia and weight, tirzepatide may also have potential anti-cancer properties. However, its GLP-1-based mechanism of action could theoretically increase the risk of certain cancers [15]. Data regarding the cancer risk associated with tirzepatide are limited in the published RCTs. Additionally, there is a lack of observational studies providing long-term data on its carcinogenic potential. Given the potentially lifelong nature of such treatment, establishing the carcinogenic safety profile of tirzepatide is crucial. A recent systematic review and meta-analysis (SRM) of nine RCTs that examined the cancer risk associated with tirzepatide has been published. This SRM has several limitations, including the exclusion of some available RCTs, restriction to studies conducted among patients with diabetes, and the absence of subgroup analyses for different tirzepatide doses. Furthermore, it did not compare the cancer risk of tirzepatide with that of GLP-1RAs [16]. Therefore, there was a clear need to conduct an updated SRM that includes all relevant RCTs of tirzepatide reporting on cancer risk.
Ethical compliance
The SRM was registered with PROSPERO (CRD42024574086), and the protocol summary can be accessed online. It adhered to the guidelines specified in the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Appendix 1) [17,18].
Search strategy
A systematic search was conducted across various databases and registers, including MEDLINE (via PubMed), Scopus, Cochrane Central Register, and ClinicalTrials.gov. This search spanned from the inception of each database to June 20, 2024. We employed a Boolean search strategy using the terms ‘tirzepatide’ OR ‘LY3437943,’ applying these terms exclusively to the titles of documents. The aim was to identify both recently published and unpublished clinical trials in English. Additionally, the search involved reviewing references within the clinical trials retrieved for this study, as well as relevant journals.
Study selection
The selection of clinical trials for this meta-analysis adhered to the PICOS criteria for SRM. The patient population (P) included individuals treated with tirzepatide for any clinical indication. The intervention (I) involved the administration of tirzepatide. The control (C) comprised individuals who received either a placebo or another active comparator. The outcomes (O) measured were the proportions of study subjects diagnosed with any form of cancer. The study type (S) was restricted to RCTs. This analysis focused on RCTs that lasted at least 12 weeks and involved study subjects aged 18 years or older. Each trial included at least two treatment arms/groups: one group received tirzepatide either as monotherapy or in combination with other drugs, and the other group was given a placebo or another active comparator, either alone or in combination with other drugs. Excluded from this analysis were clinical trials involving animals or healthy humans, nonrandomized trials, RCTs shorter than 12 weeks, retrospective studies, pooled analyses of clinical trials, conference proceedings, letters to editors, case reports, and articles that lacked relevant data on the outcomes of interest.
Outcomes analyzed
The primary outcome of the study was the overall risk of any cancer in the tirzepatide group compared to the control groups. Secondary outcomes included the risks of specific cancers in the tirzepatide group versus the control groups. Analyses were stratified based on the type of control groups and the dosage of tirzepatide.
Data extraction and dealing with missing data
Four review authors independently extracted data using standardized forms, as detailed elsewhere [19]. The approach to managing missing data is also described in the same source [19].
Risk of bias assessment
Four authors independently assessed the risk of bias (RoB) using version 2 of the Cochrane RoB tool for randomized trials (RoB 2) within the Review Manager (RevMan) computer program, version 7.2.0 (Cochrane Collaboration, London, UK) [20,21]. The specific biases addressed are detailed in the same source [19]. When appropriate (i.e., with at least 10 studies in a forest plot), publication bias was evaluated using funnel plots in the same software [21,22].
Statistical analysis
The results were presented as risk ratios (RRs) for dichotomous variables and standardized mean differences (SMDs) for continuous variables, each with 95% confidence intervals (CIs). Forest plots, created using the RevMan computer program version 7.2.0, illustrated the comparisons of RRs for primary and secondary outcomes. In these plots, the left side indicated a favorable outcome for tirzepatide, while the right side favored the control group(s) [21]. To accommodate the anticipated heterogeneity due to variations in population characteristics and study durations, random effects analysis models were employed. The inverse variance statistical method was utilized consistently across the analyses. The results included forest plots that incorporated data from at least two RCTs. A significance threshold of P<0.05 was established.
Assessment of heterogeneity
The evaluation of heterogeneity began with an analysis of forest plots. Subsequently, the chi-squared test with N-1 degrees of freedom and a significance level of 0.05 was conducted to determine statistical significance. Additionally, the I2 test was employed for further analysis [23]. The interpretation of I2 values has been detailed elsewhere [19].
Grading of the results
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the quality of evidence for each outcome in the meta-analysis [24]. The method for developing the summary of findings (SoF) table and determining the quality of evidence as ‘high,’ ‘moderate,’ ‘low,’ or ‘very low’ has been described elsewhere [19].
Search results
Fig. 1 illustrates the study selection process. Initially, 1,092 articles were identified. After screening titles and abstracts and conducting full-text reviews, the number of studies considered for this meta-analysis was reduced to 30. A detailed evaluation was performed on 13 RCTs involving 13,761 subjects, all of which met the inclusion criteria [25-37]. Seventeen studies were excluded; nine were sub-studies or post hoc analyses of an included trial, while the remaining eight did not report the outcomes of interest (Supplemental Table S1).
Study characteristics
All but one [25] of the RCTs included in this meta-analysis were phase 3 trials. Ten trials involved individuals with T2D [25,27,30-37], while three focused on obese or overweight subjects without diabetes [26,28,29]. Six RCTs utilized matching placebos [26-29,31,35], four used insulin [33,34,36,37], two employed GLP-1RA [30,32], and one trial included both placebo and GLP-1RA in the control groups [25]. Most RCTs featured three tirzepatide arms with dosages of 5, 10, and 15 mg [26,30-37]; one included an additional 1 mg arm [25], two had two arms of 10 and 15 mg [27,29], and one trial administered a single tirzepatide arm at the maximum tolerated dose (either 10 or 15 mg) [28]. The duration of the trials varied: one lasted 26 weeks [25], four spanned 40 weeks [31,32,35,37], five extended to 52 weeks [29,30,33,34,36], and three covered 72 weeks [26,27,28]. The baseline characteristics of the study subjects were consistent across all trial arms in the included RCTs. Table 1 provides a summary of the included studies.
Risk of bias in the included studies
Supplemental Fig. S1 illustrates the RoB across the 13 RCTs included in the meta-analysis. Seven trials (53.8%) exhibited a low overall RoB. The SURMOUNT-3 study raised ‘some concerns’ regarding attrition bias due to missing outcome data. Five studies (38.7%) demonstrated high risks for overall bias, primarily due to deviations from intended interventions. Publication bias was evaluated using funnel plots for RCTs that provided data on the primary outcome, as shown in Supplemental Fig. S2.
Grading of the results
The SoF table presents the grades for the certainty of the evidence supporting the primary outcome of the meta-analysis (Supplemental Table S2).
Effect of tirzepatide on the primary outcome: risk of any cancer
Overall, tirzepatide use was associated with a similar risk of any cancer to the pooled control (RR, 0.78; 95% CI, 0.53 to 1.16; I2=0%; P=0.22, high certainty of evidence). In the subgroup analysis, the risks were also comparable in the two groups in patients with diabetes (RR, 0.70; 95% CI, 0.44 to 1.12; I2=0%; P=0.14), and without diabetes (RR, 1.02; 95% CI, 0.50 to 2.12; I2=0%; P=0.95) (Fig. 2).
When the control groups were analyzed separately, tirzepatide had indifferent risks of any cancer versus placebo (RR, 0.66; 95% CI, 0.38 to 1.16; I2=0%; P=0.15, high certainty of evidence), insulin (RR, 0.89; 95% CI, 0.49 to 1.60; I2=0%; P=0.69, high certainty of evidence), and GLP-1RA (RR, 0.97; 95% CI, 0.22 to 4.34; I2=17%; P=0.97, high certainty of evidence) (Table 2). In subgroup analysis for different doses of tirzepatide, the 10 mg dose of the drug had a lower risk of any cancer than the placebo (RR, 0.34; 95% CI, 0.13 to 0.86; I2=0%; P=0.02). However, these risks were comparable in other instances with tirzepatide and controls (placebo, insulin, and GLP-1RA) in subgroup analyses according to tirzepatide dose (Table 2).
Effect of tirzepatide on the secondary outcomes: risks of individual cancers
Compared to the pooled control groups, tirzepatide did not increase the risks of breast cancer (RR, 0.59; 95% CI, 0.21 to 1.65; I2=0%; P=0.31), cholangiocarcinoma (RR, 0.33; 95% CI, 0.05 to 2.08; I2=0%; P=0.24), colon cancer (RR, 0.73; 95% CI, 0.26 to 2.04; I2=0%; P=0.54), gastric cancer (RR, 1.24; 95% CI, 0.13 to 11.86; I2=0%; P=0.85), glioblastoma (RR, 0.48; 95% CI, 0.08 to 3.04; I2=0%; P=0.44), lung cancer (RR, 0.39; 95% CI, 0.12 to 1.20; I2=0%; P=0.10), lymphoma (any) (RR, 0.18; 95% CI, 0.03 to 1.17; I2=0%; P=0.07), meningioma (RR, 0.62; 95% CI, 0.121 to 3.20; I2=0%; P=0.57), ovarian cancer (RR, 0.68; 95% CI, 0.11 to 4.32; I2=1%; P=0.68), pancreatic cancer (RR, 0.85; 95% CI, 0.10 to 7.43; I2=30%; P=0.89), prostate cancer (RR, 0.53; 95% CI, 0.14 to 1.91; I2=0%; P=0.33), renal cancer (RR, 1.33; 95% CI, 0.37 to 4.78; I2=0%; P=0.66), skin cancer (RR, 1.52; 95% CI, 0.31 to 7.34; I2=0%; P=0.61), squamous cell carcinoma (RR, 1.45; 95% CI, 0.23 to 9.17; I2=0%; P=0.70), thyroid cancer (papillary) (RR, 1.07; 95% CI, 0.22 to 5.12; I2=0%; P=0.93), urinary bladder cancer (RR, 0.49; 95% CI, 0.07 to 3.27; I2=6%; P=0.46), and uterine cancer (RR, 1.12; 95% CI, 0.23 to 5.53; I2=0%; P=0.89) (Table 3). Moreover, in subgroup analyses of the controls, tirzepatide did not increase the risks of any of these cancers compared to placebo, insulin, or GLP-1RA (Table 3).
Greater percent increases in serum calcitonin were observed with tirzepatide doses of 10 mg (SMD 18.28%; 95% CI, 7.45% to 29.11%; I2=100%; P=0.0009) and 15 mg (SMD 12.67%; 95% CI, 9.44% to 15.10%; I2=99%; P<0.00001) than with placebo (Supplemental Fig. S3). However, the included RCTs reported no cases of medullary thyroid carcinoma in either the tirzepatide or the control groups.
This SRM is the first in-depth analysis of cancer risks in RCTs involving tirzepatide. It includes data from 13 RCTs, which predominantly exhibit a low overall RoB and encompass 13,761 participants. The SRM assessed the cancer risks associated with tirzepatide in comparison to control groups, which included placebo, insulin, or GLP-1RAs. Our findings indicate that the use of tirzepatide was not linked to an increased risk of any cancer when compared to the pooled controls; this was consistent across subgroup analyses of the control groups. Furthermore, the risks of individual cancers did not show an increase in the tirzepatide group compared to either the pooled or individual control groups.
Tirzepatide is a dual agonist that activates both GLP-1 and GIP receptors. GLP-1 receptors are found in non-neoplastic pancreatic islet cells, duodenal glands, stomach, breast tissue, lung and kidney vasculature, and brain tissue. They are also overexpressed in insulinomas and medullary thyroid carcinomas [38]. GIP is typically expressed in the brain, bone, pancreas, and adipose tissues, and its increased expression has been noted in neuroendocrine tumors and colorectal cancer cells [39,40]. The overexpression of GIP receptors observed in obesity may be linked to the heightened risk of colorectal cancer in obese individuals [39]. In patients receiving tirzepatide, the downstream activation of GLP-1 and GIP receptor-mediated molecular pathways, especially in those with chronic pancreatitis, could increase the risk of developing pancreatic cancer [41]. Similarly, the activation of these receptors in target tissues such as the breast, liver, and colon may encourage cellular progression and growth, potentially leading to a higher risk of malignancy [42]. GLP-1 and GIP receptors are also present in thyroid C-cells, and animal studies have indicated an increased risk of medullary thyroid carcinoma with GLP-1RA treatment [43]. However, the direct applicability of these findings to human risk remains uncertain, even though these findings raise concerns [44].
Nonetheless, GLP-1–based therapies have been identified as having several anti-cancer effects. As previously discussed, diabetes and obesity are known to contribute to both the incidence and progression of cancer. The treatment with GLP-1–based therapies, which mediates a decrease in blood glucose and body weight, may inhibit cancer growth and progression [15]. Data from the Look Action for Health in Diabetes (AHEAD) Trial showed that an intensive lifestyle intervention aimed at weight loss reduced the incidence of obesity-related cancers by 16% in adults with overweight or obesity and T2D after a median follow-up of 11 years [45]. In a large recent cohort study, GLP-1RAs were associated with lower risks of specific obesity-associated cancers compared to insulins or metformin in patients with T2D [10]. A recent meta-analysis, which included data from 37 RCTs and 19 real-world studies, reported no increased risk of any cancer with semaglutide use [46]. Tirzepatide is currently the most potent weight-lowering drug approved. It also has the highest glycemic efficacy following insulin [13]. Theoretically, tirzepatide offers the best anti-cancer effects, considering the potential link between weight loss and reduced cancer risk. The current meta-analysis confirms that tirzepatide is not associated with an increased overall cancer risk. Both tirzepatide and the pooled control group showed comparable overall cancer risks in subjects with and without diabetes. Popovic et al. [16], in their previous meta-analysis, found similar cancer risks in patients with diabetes in both groups. By including more RCTs, our meta-analysis strengthens the evidence provided by Popovic et al. [16] and further confirms the carcinogenic safety of tirzepatide in patients with obesity who do not have diabetes. In subgroup analyses based on the drugs used in the control arms, the overall cancer risks were identical in the tirzepatide group compared to the placebo, insulin, and GLP-1RA groups. The lower overall cancer risks observed in the tirzepatide 10 mg arm compared to the placebo arm may be due to chance. However, this finding offers hope that the theoretical oncogenic benefits of tirzepatide could become a reality, a possibility that future trials will need to confirm.
Although, as previously mentioned, GLP-1RAs are theoretically associated with medullary thyroid carcinoma, no cases were reported in the RCTs included in our study, either in the tirzepatide or control groups. However, we did observe higher increases in serum calcitonin levels, a tumor marker for medullary thyroid carcinoma, with increased doses of tirzepatide compared to placebo. To further ensure the safety of the drug, the clinical significance of this rise in calcitonin levels must be clarified in future tirzepatide trials. Additionally, consistent with previous meta-analyses by Popovic et al. [16] on tirzepatide and Nagendra et al. [46] on semaglutide, we found no increased risk of papillary thyroid carcinoma, the most common type of thyroid cancer, associated with tirzepatide [16,36]. Our findings regarding the risks of other specific cancers with tirzepatide are reassuring and align with the results of previous meta-analyses.
This is the first comprehensive SRM to examine the carcinogenic potential of tirzepatide based on published RCTs. The evidence was found to be reasonably robust, adequately addressing this safety concern commonly associated with GLP-1-based therapies. However, we must acknowledge the limitations due to the relatively short follow-up period and the small size of the study populations, especially given the lifelong nature and high prevalence of the conditions treated by the drug (obesity and T2D) worldwide. Additionally, the proportion of participants from ethnically diverse backgrounds was relatively small, as most of the RCTs included in this SRM were conducted in Europe and America. This poses another limitation, casting doubt on the generalizability of our findings. Furthermore, the RCTs included were not specifically designed to assess the incidence of new cancer cases among the study subjects. To address these uncertainties, longer-term studies with larger and more globally diverse participant groups are necessary.
Based on current data, this systematic review provides reassuring insights into the cancer risks associated with short-term use of tirzepatide (ranging from 26 to 72 weeks) as observed in the included RCTs. Future RCTs that are larger and longer-term, along with real-world studies that appropriately involve diverse ethnic groups, are anticipated to enhance our understanding of the oncogenic or anti-oncogenic potential (if any) of tirzepatide. This promising drug molecule, known for its excellent disease-modifying properties, holds potential for managing obesity and T2D more effectively through an evidence-based approach.

Supplemental Table S1.

The Basic Characteristics of the Excluded Randomized Controlled Trials and Participants
enm-2024-2164-Supplemental-Table-S1.pdf

Supplemental Table S2.

Summary of Findings Table
enm-2024-2164-Supplemental-Table-S2.pdf

Supplemental Fig. S1.

(A) Risk of bias summary: review authors’ judgments about each risk of bias item for each included study. (B) Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies.
enm-2024-2164-Supplemental-Fig-S1.pdf

Supplemental Fig. S2.

Funnel plot for the studies that were included in the meta-analysis of the risk of any cancer in tirzepatide versus pooled control groups. SE, standard error; RR, risk ratio.
enm-2024-2164-Supplemental-Fig-S2.pdf

Supplemental Fig. S3.

Forest plot highlighting the percent changes from baseline in serum calcitonin levels in tirzepatide versus placebo groups. SMD, standardized mean difference; SE, standard error; IV, intravenous; CI, confidence interval.
enm-2024-2164-Supplemental-Fig-S3.pdf

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Conception or design: A.B.M.K.H., D.D. Acquisition, analysis, or interpretation of data: A.B.M.K.H., M.S.A., T.S., F.T.Z.A., L.N. Drafting the work or revising: A.B.M.K.H., M.S.A., D.D., T.S., F.T.Z.A., L.N. Final approval of the manuscript: A. B.M.K.H., M.S.A., D.D., T.S., F.T.Z.A., L.N.

Fig. 1.
Flowchart on study retrieval and inclusion in the meta-analysis.
enm-2024-2164f1.jpg
Fig. 2.
Forest plot highlighting the risk of any cancer in the tirzepatide versus pooled control groups. IV, intravenous; CI, confidence interval.
enm-2024-2164f2.jpg
Table 1.
Baseline Characteristics of the Included Randomized Controlled Trials and Participants
Registration no., Phase, Place of the trial Trial ID (name), Study Major characteristics of the study subjects Study arms Number Age, yr, mean±SD Female sex, % Duration, wk
NCT03131687, Phase 2, Multicenter in Poland, Puerto Rico, Slovakia, and USA Frias et al. (2018) [25] Adults with T2D on diet and exercise (±metformin), HbA1c 7%–10.5%, BMI 23–50 kg/m2 Tirzepatide 1 mg 52 57.4±8.9 44 26
Tirzepatide 5 mg 55 57.9±8.2 38
Tirzepatide 10 mg 51 56.5±9.9 41
Tirzepatide 15 mg 53 56.0±7.6 59
Placebo 51 56.6±8.9 56
Dulaglutide 1.5 mg 54 58.7±7.8 43
NCT04184622, Phase 3, Multicenter in multiple countries SURMOUNT-1, Jastreboff et al. (2022) [26] Adults with BMI 30 or 27 kg/m2 and at least one weight-related complication, excluding diabetes Tirzepatide 5 mg 630 45.6±12.7 67.6 72
Tirzepatide 10 mg 636 44.7±12.4 67.1
Tirzepatide 15 mg 630 44.9±12.3 67.5
Placebo 642 44.4±12.5 67.8
NCT04657003, Phase 3, Multicenter in multiple countries SURMOUNT-2, Garvey et al. (2023) [27] Adults with T2D, BMI 27 kg/m2, HbA1c 7%–10% Tirzepatide 10 mg 312 54.3±10.7 51 72
Tirzepatide 15 mg 311 53.6±10.6 51
Placebo 315 54.7±10.5 50
NCT04657016, Phase 3, Multicenter in USA, Argentina, and Brazi l SURMOUNT-3, Wadden et al. (2023) [28] Adults with BMI 30 or 27 kg/m2 and at least one weight-related complication, excluding diabetes Tirzepatide MTD (10 or 15 mg)a 287 45.4±12.6 63.1 72
Placebo 292 45.7±11.8 62.7
NCT05024032, Phase 3, Multicenter in China SURMOUNT-CN, Zhao et al. (2024) [29] Adults with BMI 28 or 24 kg/m2 and at least one weight-related comorbidity, excluding diabetes Tirzepatide 10 mg 70 34.7±7.2 50 52
Tirzepatide 15 mg 71 35.8±9.3 49.3
Placebo 69 37.8±10.2 47.8
NCT03861052, NCT04093752, Phase 3, Multicenter in Japan SURPASS J-mono, Inagaki et al. (2022) [30] Age 20 years with T2D on diet and exercise or discontinued OAD monotherapy, HbA1c 7%–10%, BMI 23 kg/m2 Tirzepatide 5 mg 159 56.8±10.1 29 52
Tirzepatide 10 mg 158 56.2±10.3 25
Tirzepatide 15 mg 160 56.0±10.7 18
Dulaglutide 0.75 mg 159 57.5±10.2 26
NCT03954834, Phase 3, Multicenter in India, Japan, Mexico, and USA SURPASS-1, Rosenstock et al. (2021) [31] Adults with T2D inadequately controlled with diet and exercise alone and who were naive to injectable diabetes therapy, HbA1c 7%–9.5%, BMI 23 kg/m2 Tirzepatide 5 mg 121 54.1±11.9 54 40
Tirzepatide 10 mg 121 55.8±10.4 40
Tirzepatide 15 mg 121 52.9±12.3 48
Placebo 115 53.6±12.8 51
NCT03987919, Phase 3, Multicenter in multiple countries SURPASS-2, Frias et al. (2021) [32] Adults with T2D inadequately controlled with metformin, HbA1c 7%–10.5%, BMI 25 kg/m2 Tirzepatide 5 mg 470 56.3±10.0 56.4 40
Tirzepatide 10 mg 469 57.2±10.5 49.3
Tirzepatide 15 mg 470 55.9±10.4 54.5
Semaglutide 469 56.9±10.8 52.0
NCT03882970, Phase 3, Multicenter in multiple countries SURPASS-3, Ludvik et al. (2021) [33] Adults with T2D treated with any combination of metformin, SU, or SGLT2i, HbA1c 7%–10.5%, BMI 25 kg/m2 Tirzepatide 5 mg 358 57.2±10.1 44 52
Tirzepatide 10 mg 360 57.4±9.7 46
Tirzepatide 15 mg 359 57.5±10.2 46
Insulin degludec 360 57.5±10.1 41
NCT03730662, Phase 3, Multicenter in multiple countries SURPASS-4, Del Prato et al. (2021) [34] Adults with T2D inadequately controlled with metformin ±an SGLT2i, HbA1c 7%–10.5%, BMI 25 kg/m2 Tirzepatide 5 mg 329 62.9±8.6 40 52
Tirzepatide 10 mg 328 63.7±8.7 36
Tirzepatide 15 mg 338 63.7±8.6 40
Insulin glargine 1,000 63.8±8.5 36
NCT04039503, Phase 3, Multicenter in multiple countries SURPASS-5, Dahl et al. (2022) [35] Adults with T2D receiving stable doses of once-daily insulin glargine ±metformin, HbA1c 7%–10.5%, BMI 23 kg/m2 Tirzepatide 5 mg 116 62±10 47 40
Tirzepatide 10 mg 119 60±10 39
Tirzepatide 15 mg 120 61±10 46
Placebo 120 60±10 45
NCT04537923, Phase 3b, Multicenter in multiple countries SURPASS-6, Rosenstock et al. (2023) [36] Adults with T2D inadequately controlled with basal insulin ±up to two OADs, HbA1c 7.5%–11%, BMI 23–45 kg/m2 Tirzepatide 5 mg 243 58.0±10.2 56.4 52
Tirzepatide 10 mg 238 59.6±9.4 62.6
Tirzepatide 15 mg 236 58.2±9.6 59.3
Insulin lispro 708 59.0±9.7 55.9
NCT04093752, Phase 3, Multicenter in China, South Korea, Australia, and India SURPASS-AP-Combo, Gao et al. (2023) [37] Adults with T2D inadequately controlled with metformin ±SU, HbA1c 7.5%–11%, BMI 23 kg/m2 Tirzepatide 5 mg 230 53.1±11.2 41.7 40
Tirzepatide 10 mg 228 53.5±11.1 44.7
Tirzepatide 15 mg 229 54.3±11.6 43.7
Insulin glargine 220 55.6±11.4 46.4

SD, standard deviation; T2D, type 2 diabetes; HbA1c, glycated hemoglobin; BMI, body mass index; MTD, maximum tolerated dose; OAD, oral anti-diabetic drugs; SU, sulfonylureas; SGLT2i, sodium-glucose cotransporter-2 inhibitor.

a Tirzepatide MTD was analyzed as tirzepatide 15 mg.

Table 2.
Risks of Any Cancer in the Tirzepatide versus Control Groups
Control Group Tirzepatide dose No. of participants with outcome/participants analyzed
Pooled effect size, RR (95% CI) I2, % P value
Tirzepatide arm Control arm
Placebo All doses (pooled) 32/3,824 21/1,605 0.66 (0.38–1.16) 0 0.15
5 mg 13/922 11/929 1.20 (0.54–2.66) 0 0.65
10 mg 5/1,309 18/1,313 0.34 (0.13–0.86) 0 0.02
15 mg 14/1,593 21/1,605 0.72 (0.37–1.40) 0 0.33
Insulin All doses (pooled) 32/3,476 24/2,288 0.89 (0.49–1.60) 0 0.69
5 mg 10/1,160 24/2,288 1.00 (0.45–2.24) 0 1.00
10 mg 13/1,154 24/2,288 1.23 (0.57–2.65) 0 0.59
15 mg 9/1,162 24/2,288 0.89 (0.38–2.10) 0 0.79
GLP-1RA All doses (pooled) 10/2,045 3/682 0.97 (0.22–4.34) 17 0.97
5 mg 5/684 3/682 1.50 (0.20–11.43) 37 0.70
10 mg 4/678 3/682 1.32 (0.29–6.00) 0 0.72
15 mg 1/683 3/682 0.48 (0.06–3.69) 0 0.48

RR, risk ratio; CI, confidence interval; GLP-1RA, glucagon-like peptide-1 receptor agonist.

Table 3.
Risks of Individual Cancers in the Pooled Tirzepatide versus Control (Pooled and Individual) Groups
Outcome variable Control group No. of participants with outcome/participants analyzed
Pooled effect size, RR (95% CI) I2, % P value
Tirzepatide arm Control arm
Breast cancer All (pooled) 7/6,346 6/3,346 0.59 (0.21–1.65) 0 0.31
Placebo 2/3,161 4/1,370 0.30 (0.07–1.30) 0 0.11
Insulin 5/3,185 2/1,976 1.13 (0.27–4.81) 0 0.87
Cholangiocarcinoma All (pooled) 1/2,435 2/1,475 0.33 (0.05–2.08) 0 0.24
Insulin 1/2,072 1/1,360 0.58 (0.06–5.57) 0 0.64
Colon cancer All (pooled) 8/5,871 5/3,187 0.73 (0.26–2.04) 0 0.54
Placebo 2/986 2/430 0.41 (0.06–2.78) 0 0.36
Insulin 3/3,476 3/2,288 0.91 (0.24–3.43) 0 0.89
Gastric cancer All (pooled) 2/1,700 0/675 1.24 (0.13–11.86) 0 0.85
Glioblastoma All (pooled) 1/3,131 2/2,177 0.48 (0.08–3.04) 0 0.44
Insulin 0/1,712 2/1,708 0.33 (0.03–3.19) 0 0.34
Lung cancer All (pooled) 4/6,730 8/3,444 0.39 (0.12–1.20) 0 0.10
Placebo 1/2,055 1/694 0.33 (0.03–3.16) 0 0.34
Insulin 2/2,789 6/2,068 0.38 (0.08–1.87) 0 0.23
GLP-1RA 1/2,045 1/682 0.33 (0.03–3.20) 0 0.34
Lymphoma (any) All (pooled) 0/3,027 3/1,784 0.18 (0.03–1.17) 0 0.07
Meningioma All (pooled) 3/3,578 2/1,863 0.62 (0.12–3.20) 0 0.57
Insulin 1/1,682 1/1,220 0.57 (0.06–5.46) 0 0.62
Ovarian cancer All (pooled) 2/2,350 1/1,020 0.68 (0.11–4.32) 1 0.68
Insulin 2/1,072 0/584 1.65 (0.17–15.86) 0 0.66
Pancreatic cancer All (pooled) 3/3,731 1/1,917 0.85 (0.10–7.43) 30 0.89
Placebo 1/2,259 1/758 0.33 (0.03–3.16) 0 0.34
Prostate cancer All (pooled) 5/1,898 5/1,116 0.53 (0.14–1.91) 0 0.33
Placebo 2/924 1/363 0.64 (0.08–5.21) 0 0.68
Renal cancer All (pooled) 8/5,419 1/2,683 1.33 (0.37–4.78) 0 0.66
Placebo 3/2,538 1/1,055 0.86 (0.12–6.09) 15 0.88
GLP-1RA 2/1,886 0/628 1.00 (0.10–9.61) 0 1.00
Skin cancer All (pooled) 5/4,669 0/1,764 1.52 (0.31–7.34) 0 0.61
Placebo 3/2,183 0/935 2.24 (0.25–20.25) 0 0.47
Squamous cell carcinoma All (pooled) 3/3,481 0/1,829 1.45 (0.23–9.17) 0 0.70
Insulin 2/2,072 0/1,360 1.74 (0.18–16.71) 0 0.63
Thyroid cancer (papillary) All (pooled) 5/3,011 1/1,224 1.07 (0.22–5.12) 0 0.93
Placebo 2/2,324 1/1,004 0.80 (0.11–5.67) 11 0.82
Urinary bladder cancer All (pooled) 1/2,359 2/1,652 0.49 (0.07–3.27) 6 0.46
Insulin 0/2,072 2/1,360 0.19 (0.02–1.86) 0 0.15
Uterine cancer All (pooled) 4/2,504 0/893 1.12 (0.23–5.53) 0 0.89
Placebo 3/1,752 0/649 1.17 (0.19–7.41) 0 0.87

RR, risk ratio; CI, confidence interval; GLP-1RA, glucagon-like peptide-1 receptor agonist.

  • 1. Watts EL, Moore SC, Gunter MJ, Chatterjee N. Adiposity and cancer: meta-analysis, mechanisms, and future perspectives. medRxiv [Preprint] 2024 Feb 18 https://doi.org/10.1101/2024.02.16.24302944.Article
  • 2. Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE, Ioannidis JP. Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ 2015;350:g7607.ArticlePubMed
  • 3. Platts J. Insulin therapy and cancer risk in diabetes mellitus. Clin Med (Lond) 2010;10:509–12.ArticlePubMedPMC
  • 4. Tang H, Shi W, Fu S, Wang T, Zhai S, Song Y, et al. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer Med 2018;7:1070–80.ArticlePubMedPMCPDF
  • 5. Dąbrowski M. Diabetes, antidiabetic medications and cancer risk in type 2 diabetes: focus on SGLT-2 inhibitors. Int J Mol Sci 2021;22:1680.ArticlePubMedPMC
  • 6. Dicembrini I, Nreu B, Montereggi C, Mannucci E, Monami M. Risk of cancer in patients treated with dipeptidyl peptidase-4 inhibitors: an extensive meta-analysis of randomized controlled trials. Acta Diabetol 2020;57:689–96.ArticlePubMedPDF
  • 7. Dicembrini I, Nreu B, Mannucci E, Monami M. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors and cancer: a meta-analysis of randomized controlled trials. Diabetes Obes Metab 2019;21:1871–7.ArticlePubMedPDF
  • 8. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011;141:150–6.ArticlePubMed
  • 9. Bezin J, Gouverneur A, Penichon M, Mathieu C, Garrel R, Hillaire-Buys D, et al. GLP-1 receptor agonists and the risk of thyroid cancer. Diabetes Care 2023;46:384–90.PubMed
  • 10. Wang L, Xu R, Kaelber DC, Berger NA. Glucagon-like peptide 1 receptor agonists and 13 obesity-associated cancers in patients with type 2 diabetes. JAMA Netw Open 2024;7:e2421305.ArticlePubMedPMC
  • 11. U.S. Food and Drug Administration. New drug therapy approvals 2022: advancing health through innovation [Internet]. Silver Spring: FDA; 2023 [cited 2025 Jan 6]. Available from: https://www.fda.gov/drugs/novel-drug-approvals-fda/new-drug-therapy-approvals-2022.
  • 12. U.S. Food and Drug Administration. FDA news release: FDA approves new medication for chronic weight management [Internet]. Silver Spring: FDA; 2023 [cited 2025 Jan 6]. Available from https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management.
  • 13. Permana H, Yanto TA, Hariyanto TI. Efficacy and safety of tirzepatide as novel treatment for type 2 diabetes: a systematic review and meta-analysis of randomized clinical trials. Diabetes Metab Syndr 2022;16:102640.ArticlePubMed
  • 14. Dutta D, Kamrul-Hasan AB, Nagendra L, Bhattacharya S. Efficacy and safety of novel twincretin tirzepatide, a dual GIP/GLP-1 receptor agonist, as an anti-obesity medicine in individuals without diabetes: a systematic review and meta-analysis. touchREV Endocrinol 2024;20:72–80.ArticlePubMedPMC
  • 15. Samuel SM, Varghese E, Kubatka P, Busselberg D. Tirzepatide-friend or foe in diabetic cancer patients? Biomolecules 2022;12:1580.ArticlePubMedPMC
  • 16. Popovic DS, Patoulias D, Popovic LS, Karakasis P, Papanas N, Mantzoros CS. Tirzepatide use and the risk of cancer among individuals with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials. Diabetes Res Clin Pract 2024;213:111758.ArticlePubMed
  • 17. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.4 [Internet]. London: Cochrane Collaboration; 2023 [cited 2025 Jan 6]. Available from: www.training.cochrane.org/handbook.
  • 18. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71.ArticlePubMedPMC
  • 19. Kamrul-Hasan AB, Alam MS, Talukder SK, Dutta D, Selim S. Efficacy and safety of omarigliptin, a novel once-weekly dipeptidyl peptidase-4 inhibitor, in type 2 diabetes mellitus: a systematic review and meta-analysis. Endocrinol Metab (Seoul) 2024;39:109–26.ArticlePubMedPMCPDF
  • 20. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.4 [Internet]. London: Cochrane Collaboration; 2023 Chapter 8, Assessing risk of bias in a randomized trial [cited 2025 Jan 6]. Available from https://training.cochrane.org/handbook/archive/v6.4/chapter-08.
  • 21. Review Manager (RevMan) [Computer program] version 7.2.0 [Internet]. London: Cochrane Collaboration; 2024 [cited 2025 Jan 6]. Available from: https://revman.cochrane.org.
  • 22. Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ. Publication and related biases. Health Technol Assess 2000;4:1–115.ArticlePMCPDF
  • 23. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.ArticlePubMedPMC
  • 24. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines. 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011;64:383–94.ArticlePubMed
  • 25. Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 2018;392:2180–93.ArticlePubMed
  • 26. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022;387:205–16.ArticlePubMed
  • 27. Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2023;402:613–26.PubMed
  • 28. Wadden TA, Chao AM, Machineni S, Kushner R, Ard J, Srivastava G, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med 2023;29:2909–18.ArticlePubMedPMCPDF
  • 29. Zhao L, Cheng Z, Lu Y, Liu M, Chen H, Zhang M, et al. Tirzepatide for weight reduction in Chinese adults with obesity: the SURMOUNT-CN randomized clinical trial. JAMA 2024;332:551–60.PubMedPMC
  • 30. Inagaki N, Takeuchi M, Oura T, Imaoka T, Seino Y. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol 2022;10:623–33.ArticlePubMed
  • 31. Rosenstock J, Wysham C, Frias JP, Kaneko S, Lee CJ, Fernandez Lando L, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet 2021;398:143–55.ArticlePubMed
  • 32. Frias JP, Davies MJ, Rosenstock J, Perez Manghi FC, Fernandez Lando L, Bergman BK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 2021;385:503–15.ArticlePubMed
  • 33. Ludvik B, Giorgino F, Jodar E, Frias JP, Fernandez Lando L, Brown K, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet 2021;398:583–98.ArticlePubMed
  • 34. Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 2021;398:1811–24.PubMed
  • 35. Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA 2022;327:534–45.ArticlePubMedPMC
  • 36. Rosenstock J, Frias JP, Rodbard HW, Tofe S, Sears E, Huh R, et al. Tirzepatide vs insulin lispro added to basal insulin in type 2 diabetes: the SURPASS-6 randomized clinical trial. JAMA 2023;330:1631–40.ArticlePubMedPMC
  • 37. Gao L, Lee BW, Chawla M, Kim J, Huo L, Du L, et al. Tirzepatide versus insulin glargine as second-line or third-line therapy in type 2 diabetes in the Asia-Pacific region: the SURPASS-AP-Combo trial. Nat Med 2023;29:1500–10.ArticlePubMedPDF
  • 38. Korner M, Christ E, Wild D, Reubi JC. Glucagon-like peptide-1 receptor overexpression in cancer and its impact on clinical applications. Front Endocrinol (Lausanne) 2012;3:158.PubMedPMC
  • 39. Sen S, He Y, Koya D, Kanasaki K. Cancer biology in diabetes. J Diabetes Investig 2014;5:251–64.ArticlePubMedPMCPDF
  • 40. Gasbjerg LS, Gabe MB, Hartmann B, Christensen MB, Knop FK, Holst JJ, et al. Glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists as anti-diabetic agents. Peptides 2018;100:173–81.ArticlePubMed
  • 41. Mortazavi M, Moosavi F, Martini M, Giovannetti E, Firuzi O. Prospects of targeting PI3K/AKT/mTOR pathway in pancreatic cancer. Crit Rev Oncol Hematol 2022;176:103749.ArticlePubMed
  • 42. Vigneri PG, Tirro E, Pennisi MS, Massimino M, Stella S, Romano C, et al. The insulin/IGF system in colorectal cancer development and resistance to therapy. Front Oncol 2015;5:230.ArticlePubMedPMC
  • 43. Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 2010;151:1473–86.ArticlePubMedPDF
  • 44. Thompson CA, Sturmer T. Putting GLP-1 RAs and thyroid cancer in context: additional evidence and remaining doubts. Diabetes Care 2023;46:249–51.ArticlePubMedPDF
  • 45. Look AHEAD Research Group, Yeh HC, Bantle JP, Cassidy-Begay M, Blackburn G, Bray GA, et al. Intensive weight loss intervention and cancer risk in adults with type 2 diabetes: analysis of the Look AHEAD randomized clinical trial. Obesity (Silver Spring) 2020;28:1678–86.PubMedPMC
  • 46. Nagendra L, Bg H, Sharma M, Dutta D. Semaglutide and cancer: a systematic review and meta-analysis. Diabetes Metab Syndr 2023;17:102834.ArticlePubMed
Appendix 1.
PRISMA 2020 Checklist
Section and topic Item # Checklist item Location where item is reported
Title
 Title 1 Identify the report as a systematic review. Page 1
Abstract
 Abstract 2 See the PRISMA 2020 for abstracts checklist. Page 3
Introduction
 Rationale 3 Describe the rationale for the review in the context of existing knowledge. Page 5,6
 Objectives 4 Provide an explicit statement of the objective(s) or question(s) the review addresses. Page 6
Methods
 Eligibility criteria 5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses. Page 7,8
 Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted. Page 7
 Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used. Page 7
 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process. Page 7,8
 Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process. Page 8
 Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g., for all measures, time points, analyses), and if not, the methods used to decide which results to collect. Page 8
10b List and define all other variables for which data were sought (e.g., participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information. Page 8
 Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process. Page 8
 Effect measures 12 Specify for each outcome the effect measure(s) (e.g., risk ratio, mean difference) used in the synthesis or presentation of results. Page 8
 Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g., tabulating the study intervention characteristics and comparing against the planned groups for each synthesis [item #5]). Page 8,9
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions. Page 8
13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. Page 9
13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used Page 9
13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g., subgroup analysis, meta-regression). Page 9
13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. Page 9
 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases). Page 8
 Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. Page 9
Results
 Study selection 16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram. Page 10
16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. Page 10
 Study characteristics 17 Cite each included study and present its characteristics. Page 10
 Risk of bias in studies 18 Present assessments of risk of bias for each included study. Page 11
 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots. Pages 11,12,13
 Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. Pages 11,12,13
20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g., confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect. Pages 11,12,13
20c Present results of all investigations of possible causes of heterogeneity among study results. Pages 11,12,13
20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. Pages 11,12,13
 Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed. Pages 11,12,13
 Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed. Pages 11,12,13
Discussion
 Discussion 23a Provide a general interpretation of the results in the context of other evidence. Pages 13,14,15
23b Discuss any limitations of the evidence included in the review. Page 15,16
23c Discuss any limitations of the review processes used. Page 15,16
23d Discuss implications of the results for practice, policy, and future research. Page 15,16
Other information
 Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered. Page 7
24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. Page 7
24c Describe and explain any amendments to information provided at registration or in the protocol. Not applicable
 Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review. Title page
 Competing interests 26 Declare any competing interests of review authors. Title page
 Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review. Title page

PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure & Data

References

    Citations

    Citations to this article as recorded by  

      Figure
      • 0
      • 1
      Related articles
      Tirzepatide and Cancer Risk in Individuals with and without Diabetes: A Systematic Review and Meta-Analysis
      Image Image
      Fig. 1. Flowchart on study retrieval and inclusion in the meta-analysis.
      Fig. 2. Forest plot highlighting the risk of any cancer in the tirzepatide versus pooled control groups. IV, intravenous; CI, confidence interval.
      Tirzepatide and Cancer Risk in Individuals with and without Diabetes: A Systematic Review and Meta-Analysis
      Registration no., Phase, Place of the trial Trial ID (name), Study Major characteristics of the study subjects Study arms Number Age, yr, mean±SD Female sex, % Duration, wk
      NCT03131687, Phase 2, Multicenter in Poland, Puerto Rico, Slovakia, and USA Frias et al. (2018) [25] Adults with T2D on diet and exercise (±metformin), HbA1c 7%–10.5%, BMI 23–50 kg/m2 Tirzepatide 1 mg 52 57.4±8.9 44 26
      Tirzepatide 5 mg 55 57.9±8.2 38
      Tirzepatide 10 mg 51 56.5±9.9 41
      Tirzepatide 15 mg 53 56.0±7.6 59
      Placebo 51 56.6±8.9 56
      Dulaglutide 1.5 mg 54 58.7±7.8 43
      NCT04184622, Phase 3, Multicenter in multiple countries SURMOUNT-1, Jastreboff et al. (2022) [26] Adults with BMI 30 or 27 kg/m2 and at least one weight-related complication, excluding diabetes Tirzepatide 5 mg 630 45.6±12.7 67.6 72
      Tirzepatide 10 mg 636 44.7±12.4 67.1
      Tirzepatide 15 mg 630 44.9±12.3 67.5
      Placebo 642 44.4±12.5 67.8
      NCT04657003, Phase 3, Multicenter in multiple countries SURMOUNT-2, Garvey et al. (2023) [27] Adults with T2D, BMI 27 kg/m2, HbA1c 7%–10% Tirzepatide 10 mg 312 54.3±10.7 51 72
      Tirzepatide 15 mg 311 53.6±10.6 51
      Placebo 315 54.7±10.5 50
      NCT04657016, Phase 3, Multicenter in USA, Argentina, and Brazi l SURMOUNT-3, Wadden et al. (2023) [28] Adults with BMI 30 or 27 kg/m2 and at least one weight-related complication, excluding diabetes Tirzepatide MTD (10 or 15 mg)a 287 45.4±12.6 63.1 72
      Placebo 292 45.7±11.8 62.7
      NCT05024032, Phase 3, Multicenter in China SURMOUNT-CN, Zhao et al. (2024) [29] Adults with BMI 28 or 24 kg/m2 and at least one weight-related comorbidity, excluding diabetes Tirzepatide 10 mg 70 34.7±7.2 50 52
      Tirzepatide 15 mg 71 35.8±9.3 49.3
      Placebo 69 37.8±10.2 47.8
      NCT03861052, NCT04093752, Phase 3, Multicenter in Japan SURPASS J-mono, Inagaki et al. (2022) [30] Age 20 years with T2D on diet and exercise or discontinued OAD monotherapy, HbA1c 7%–10%, BMI 23 kg/m2 Tirzepatide 5 mg 159 56.8±10.1 29 52
      Tirzepatide 10 mg 158 56.2±10.3 25
      Tirzepatide 15 mg 160 56.0±10.7 18
      Dulaglutide 0.75 mg 159 57.5±10.2 26
      NCT03954834, Phase 3, Multicenter in India, Japan, Mexico, and USA SURPASS-1, Rosenstock et al. (2021) [31] Adults with T2D inadequately controlled with diet and exercise alone and who were naive to injectable diabetes therapy, HbA1c 7%–9.5%, BMI 23 kg/m2 Tirzepatide 5 mg 121 54.1±11.9 54 40
      Tirzepatide 10 mg 121 55.8±10.4 40
      Tirzepatide 15 mg 121 52.9±12.3 48
      Placebo 115 53.6±12.8 51
      NCT03987919, Phase 3, Multicenter in multiple countries SURPASS-2, Frias et al. (2021) [32] Adults with T2D inadequately controlled with metformin, HbA1c 7%–10.5%, BMI 25 kg/m2 Tirzepatide 5 mg 470 56.3±10.0 56.4 40
      Tirzepatide 10 mg 469 57.2±10.5 49.3
      Tirzepatide 15 mg 470 55.9±10.4 54.5
      Semaglutide 469 56.9±10.8 52.0
      NCT03882970, Phase 3, Multicenter in multiple countries SURPASS-3, Ludvik et al. (2021) [33] Adults with T2D treated with any combination of metformin, SU, or SGLT2i, HbA1c 7%–10.5%, BMI 25 kg/m2 Tirzepatide 5 mg 358 57.2±10.1 44 52
      Tirzepatide 10 mg 360 57.4±9.7 46
      Tirzepatide 15 mg 359 57.5±10.2 46
      Insulin degludec 360 57.5±10.1 41
      NCT03730662, Phase 3, Multicenter in multiple countries SURPASS-4, Del Prato et al. (2021) [34] Adults with T2D inadequately controlled with metformin ±an SGLT2i, HbA1c 7%–10.5%, BMI 25 kg/m2 Tirzepatide 5 mg 329 62.9±8.6 40 52
      Tirzepatide 10 mg 328 63.7±8.7 36
      Tirzepatide 15 mg 338 63.7±8.6 40
      Insulin glargine 1,000 63.8±8.5 36
      NCT04039503, Phase 3, Multicenter in multiple countries SURPASS-5, Dahl et al. (2022) [35] Adults with T2D receiving stable doses of once-daily insulin glargine ±metformin, HbA1c 7%–10.5%, BMI 23 kg/m2 Tirzepatide 5 mg 116 62±10 47 40
      Tirzepatide 10 mg 119 60±10 39
      Tirzepatide 15 mg 120 61±10 46
      Placebo 120 60±10 45
      NCT04537923, Phase 3b, Multicenter in multiple countries SURPASS-6, Rosenstock et al. (2023) [36] Adults with T2D inadequately controlled with basal insulin ±up to two OADs, HbA1c 7.5%–11%, BMI 23–45 kg/m2 Tirzepatide 5 mg 243 58.0±10.2 56.4 52
      Tirzepatide 10 mg 238 59.6±9.4 62.6
      Tirzepatide 15 mg 236 58.2±9.6 59.3
      Insulin lispro 708 59.0±9.7 55.9
      NCT04093752, Phase 3, Multicenter in China, South Korea, Australia, and India SURPASS-AP-Combo, Gao et al. (2023) [37] Adults with T2D inadequately controlled with metformin ±SU, HbA1c 7.5%–11%, BMI 23 kg/m2 Tirzepatide 5 mg 230 53.1±11.2 41.7 40
      Tirzepatide 10 mg 228 53.5±11.1 44.7
      Tirzepatide 15 mg 229 54.3±11.6 43.7
      Insulin glargine 220 55.6±11.4 46.4
      Control Group Tirzepatide dose No. of participants with outcome/participants analyzed
      Pooled effect size, RR (95% CI) I2, % P value
      Tirzepatide arm Control arm
      Placebo All doses (pooled) 32/3,824 21/1,605 0.66 (0.38–1.16) 0 0.15
      5 mg 13/922 11/929 1.20 (0.54–2.66) 0 0.65
      10 mg 5/1,309 18/1,313 0.34 (0.13–0.86) 0 0.02
      15 mg 14/1,593 21/1,605 0.72 (0.37–1.40) 0 0.33
      Insulin All doses (pooled) 32/3,476 24/2,288 0.89 (0.49–1.60) 0 0.69
      5 mg 10/1,160 24/2,288 1.00 (0.45–2.24) 0 1.00
      10 mg 13/1,154 24/2,288 1.23 (0.57–2.65) 0 0.59
      15 mg 9/1,162 24/2,288 0.89 (0.38–2.10) 0 0.79
      GLP-1RA All doses (pooled) 10/2,045 3/682 0.97 (0.22–4.34) 17 0.97
      5 mg 5/684 3/682 1.50 (0.20–11.43) 37 0.70
      10 mg 4/678 3/682 1.32 (0.29–6.00) 0 0.72
      15 mg 1/683 3/682 0.48 (0.06–3.69) 0 0.48
      Outcome variable Control group No. of participants with outcome/participants analyzed
      Pooled effect size, RR (95% CI) I2, % P value
      Tirzepatide arm Control arm
      Breast cancer All (pooled) 7/6,346 6/3,346 0.59 (0.21–1.65) 0 0.31
      Placebo 2/3,161 4/1,370 0.30 (0.07–1.30) 0 0.11
      Insulin 5/3,185 2/1,976 1.13 (0.27–4.81) 0 0.87
      Cholangiocarcinoma All (pooled) 1/2,435 2/1,475 0.33 (0.05–2.08) 0 0.24
      Insulin 1/2,072 1/1,360 0.58 (0.06–5.57) 0 0.64
      Colon cancer All (pooled) 8/5,871 5/3,187 0.73 (0.26–2.04) 0 0.54
      Placebo 2/986 2/430 0.41 (0.06–2.78) 0 0.36
      Insulin 3/3,476 3/2,288 0.91 (0.24–3.43) 0 0.89
      Gastric cancer All (pooled) 2/1,700 0/675 1.24 (0.13–11.86) 0 0.85
      Glioblastoma All (pooled) 1/3,131 2/2,177 0.48 (0.08–3.04) 0 0.44
      Insulin 0/1,712 2/1,708 0.33 (0.03–3.19) 0 0.34
      Lung cancer All (pooled) 4/6,730 8/3,444 0.39 (0.12–1.20) 0 0.10
      Placebo 1/2,055 1/694 0.33 (0.03–3.16) 0 0.34
      Insulin 2/2,789 6/2,068 0.38 (0.08–1.87) 0 0.23
      GLP-1RA 1/2,045 1/682 0.33 (0.03–3.20) 0 0.34
      Lymphoma (any) All (pooled) 0/3,027 3/1,784 0.18 (0.03–1.17) 0 0.07
      Meningioma All (pooled) 3/3,578 2/1,863 0.62 (0.12–3.20) 0 0.57
      Insulin 1/1,682 1/1,220 0.57 (0.06–5.46) 0 0.62
      Ovarian cancer All (pooled) 2/2,350 1/1,020 0.68 (0.11–4.32) 1 0.68
      Insulin 2/1,072 0/584 1.65 (0.17–15.86) 0 0.66
      Pancreatic cancer All (pooled) 3/3,731 1/1,917 0.85 (0.10–7.43) 30 0.89
      Placebo 1/2,259 1/758 0.33 (0.03–3.16) 0 0.34
      Prostate cancer All (pooled) 5/1,898 5/1,116 0.53 (0.14–1.91) 0 0.33
      Placebo 2/924 1/363 0.64 (0.08–5.21) 0 0.68
      Renal cancer All (pooled) 8/5,419 1/2,683 1.33 (0.37–4.78) 0 0.66
      Placebo 3/2,538 1/1,055 0.86 (0.12–6.09) 15 0.88
      GLP-1RA 2/1,886 0/628 1.00 (0.10–9.61) 0 1.00
      Skin cancer All (pooled) 5/4,669 0/1,764 1.52 (0.31–7.34) 0 0.61
      Placebo 3/2,183 0/935 2.24 (0.25–20.25) 0 0.47
      Squamous cell carcinoma All (pooled) 3/3,481 0/1,829 1.45 (0.23–9.17) 0 0.70
      Insulin 2/2,072 0/1,360 1.74 (0.18–16.71) 0 0.63
      Thyroid cancer (papillary) All (pooled) 5/3,011 1/1,224 1.07 (0.22–5.12) 0 0.93
      Placebo 2/2,324 1/1,004 0.80 (0.11–5.67) 11 0.82
      Urinary bladder cancer All (pooled) 1/2,359 2/1,652 0.49 (0.07–3.27) 6 0.46
      Insulin 0/2,072 2/1,360 0.19 (0.02–1.86) 0 0.15
      Uterine cancer All (pooled) 4/2,504 0/893 1.12 (0.23–5.53) 0 0.89
      Placebo 3/1,752 0/649 1.17 (0.19–7.41) 0 0.87
      Section and topic Item # Checklist item Location where item is reported
      Title
       Title 1 Identify the report as a systematic review. Page 1
      Abstract
       Abstract 2 See the PRISMA 2020 for abstracts checklist. Page 3
      Introduction
       Rationale 3 Describe the rationale for the review in the context of existing knowledge. Page 5,6
       Objectives 4 Provide an explicit statement of the objective(s) or question(s) the review addresses. Page 6
      Methods
       Eligibility criteria 5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses. Page 7,8
       Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted. Page 7
       Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used. Page 7
       Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process. Page 7,8
       Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process. Page 8
       Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g., for all measures, time points, analyses), and if not, the methods used to decide which results to collect. Page 8
      10b List and define all other variables for which data were sought (e.g., participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information. Page 8
       Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process. Page 8
       Effect measures 12 Specify for each outcome the effect measure(s) (e.g., risk ratio, mean difference) used in the synthesis or presentation of results. Page 8
       Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g., tabulating the study intervention characteristics and comparing against the planned groups for each synthesis [item #5]). Page 8,9
      13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions. Page 8
      13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. Page 9
      13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used Page 9
      13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g., subgroup analysis, meta-regression). Page 9
      13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. Page 9
       Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases). Page 8
       Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. Page 9
      Results
       Study selection 16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram. Page 10
      16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. Page 10
       Study characteristics 17 Cite each included study and present its characteristics. Page 10
       Risk of bias in studies 18 Present assessments of risk of bias for each included study. Page 11
       Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots. Pages 11,12,13
       Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. Pages 11,12,13
      20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g., confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect. Pages 11,12,13
      20c Present results of all investigations of possible causes of heterogeneity among study results. Pages 11,12,13
      20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. Pages 11,12,13
       Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed. Pages 11,12,13
       Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed. Pages 11,12,13
      Discussion
       Discussion 23a Provide a general interpretation of the results in the context of other evidence. Pages 13,14,15
      23b Discuss any limitations of the evidence included in the review. Page 15,16
      23c Discuss any limitations of the review processes used. Page 15,16
      23d Discuss implications of the results for practice, policy, and future research. Page 15,16
      Other information
       Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered. Page 7
      24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. Page 7
      24c Describe and explain any amendments to information provided at registration or in the protocol. Not applicable
       Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review. Title page
       Competing interests 26 Declare any competing interests of review authors. Title page
       Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review. Title page
      Table 1. Baseline Characteristics of the Included Randomized Controlled Trials and Participants

      SD, standard deviation; T2D, type 2 diabetes; HbA1c, glycated hemoglobin; BMI, body mass index; MTD, maximum tolerated dose; OAD, oral anti-diabetic drugs; SU, sulfonylureas; SGLT2i, sodium-glucose cotransporter-2 inhibitor.

      Tirzepatide MTD was analyzed as tirzepatide 15 mg.

      Table 2. Risks of Any Cancer in the Tirzepatide versus Control Groups

      RR, risk ratio; CI, confidence interval; GLP-1RA, glucagon-like peptide-1 receptor agonist.

      Table 3. Risks of Individual Cancers in the Pooled Tirzepatide versus Control (Pooled and Individual) Groups

      RR, risk ratio; CI, confidence interval; GLP-1RA, glucagon-like peptide-1 receptor agonist.

      PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.


      Endocrinol Metab : Endocrinology and Metabolism
      TOP