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Endocrinol Metab 2025;40:112-124
https://doi.org/10.3803/EnM.2024.2164
pISSN 2093-596X · eISSN 2093-5978
Original
Article
Tirzepatide and Cancer Risk in Individuals with and
without Diabetes: A Systematic Review and Meta-Analysis
A.B.M. Kamrul-Hasan1, Muhammad Shah Alam2, Deep Dutta3, Thanikai Sasikanth4, Fatema Tuz Zahura Aalpona5,
Lakshmi Nagendra6
1Department of Endocrinology, Mymensingh Medical College, Mymensingh; 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
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 out-
comes 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 can-
cer risks in patients with and without diabetes. In subgroup analyses, the risks were also similar in the tirzepatide versus placebo, in-
sulin, and glucagon-like peptide-1 receptor agonist groups. The overall cancer risk was also comparable for different doses of tirz-
epatide 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.
Keywords: Tirzepatide; Meta-analysis; Diabetes mellitus, type 2; Obesity; Neoplasms; Thyroid neoplasms; Pancreatic neoplasms
INTRODUCTION
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 con-
founding effects of adiposity. Consequently, individuals predis-
posed to cancer or those with undiagnosed cancer may experi-
ence accelerated disease progression in the presence of uncon-
Received: 29 August 2024, Revised: 11 October 2024,
Accepted: 14 November 2024
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
Copyright © 2025 Korean Endocrine Society
This is an Open Access article distributed under the terms of the Creative Com-
mons Attribution Non-Commercial License (https://creativecommons.org/
licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribu-
tion, and reproduction in any medium, provided the original work is properly
cited.
Tirzepatide and Cancer
Copyright © 2025 Korean Endocrine Society www.e-enm.org 11 3
Endocrinol Metab 2025;40:112-124
https://doi.org/10.3803/EnM.2024.2164
pISSN 2093-596X · eISSN 2093-5978
trolled hyperglycemia [2]. In this context, anti-obesity and anti-
diabetic 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 uri-
nary bladder cancer, despite initial findings, remains controver-
sial [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 signifi-
cantly reduced risk of colorectal cancer [6]. Hypothetically, anti-
diabetic drugs that promote weight loss or improve hyperinsu-
linemia 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 re-
mains limited and inconclusive regarding the cancer risk associ-
ated 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 report-
ed increased risks of pancreatic and thyroid cancer associated
with the GLP-1 receptor agonist (GLP-1RA) exenatide com-
pared to other therapies [8]. Another study using the French Na-
tional Health Care Insurance System Database also reported in-
creased risks of all thyroid cancers and medullary thyroid cancer
with the use of GLP-1RAs (exenatide, liraglutide, and dulaglu-
tide) 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 glu-
cose lowering and weight reduction are promising [13,14]. Giv-
en 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 poten-
tially lifelong nature of such treatment, establishing the carcino-
genic 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]. There-
fore, there was a clear need to conduct an updated SRM that in-
cludes all relevant RCTs of tirzepatide reporting on cancer risk.
METHODS
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 Systemat-
ic Reviews of Interventions and the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) (Appen-
dix 1) [17,18].
Search strategy
A systematic search was conducted across various databases
and registers, including MEDLINE (via PubMed), Scopus, Co-
chrane 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 ‘tirz-
epatide’ 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. Additional-
ly, 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) includ-
ed individuals treated with tirzepatide for any clinical indica-
tion. The intervention (I) involved the administration of tirzepa-
tide. The control (C) comprised individuals who received either
a placebo or another active comparator. The outcomes (O) mea-
sured 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 in-
volved study subjects aged 18 years or older. Each trial included
at least two treatment arms/groups: one group received tirzepa-
tide either as monotherapy or in combination with other drugs,
and the other group was given a placebo or another active com-
Kamrul-Hasan A.B.M, et al.
11 4 www.e-enm.org Copyright © 2025 Korean Endocrine Society
parator, either alone or in combination with other drugs. Ex-
cluded 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 arti-
cles 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 stan-
dardized 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) us-
ing version 2 of the Cochrane RoB tool for randomized trials
(RoB 2) within the Review Manager (RevMan) computer pro-
gram, 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 con-
tinuous variables, each with 95% confidence intervals (CIs).
Forest plots, created using the RevMan computer program ver-
sion 7.2.0, illustrated the comparisons of RRs for primary and
secondary outcomes. In these plots, the left side indicated a fa-
vorable outcome for tirzepatide, while the right side favored the
control group(s) [21]. To accommodate the anticipated hetero-
geneity 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 incor-
porated 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 de-
termine statistical significance. Additionally, the I2 test was em-
ployed 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].
RESULTS
Search results
Fig. 1 illustrates the study selection process. Initially, 1,092 arti-
cles 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 in-
cluded trial, while the remaining eight did not report the out-
comes 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 sub-
jects 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 place-
bo and GLP-1RA in the control groups [25]. Most RCTs fea-
tured 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-
28]. The baseline characteristics of the study subjects were con-
sistent across all trial arms in the included RCTs. Table 1 pro-
Tirzepatide and Cancer
Copyright © 2025 Korean Endocrine Society www.e-enm.org 11 5
Fig. 1. Flowchart on study retrieval and inclusion in the meta-analysis.
Identification of studies via databases and registers
Identification
Screening
Included
Records identified from:
Databases (n=988)
PubMed (n=317)
Scopus (n=350)
Cochrane (n=321)
Registers (n=104)
ClinicalTrials.gov (n=104)
Total (n=1,092)
Studies included in the review
(n=13)
Reports of included studies
(n=13)
Records removed before screening:
Duplicate records removed (n=84)
Records marked as ineligible by automation tools (n=0)
Records removed for other reasons (n=0)
Records screened (n=1,008)
Reports sought for retrieval (n=30)
Reports assessed for eligibility (n=30)
Reports excluded (n=17)
Substudy or post hoc analysis of an included trial (n=9)
Not reported the outcome(s) of interest (n=8)
Records excluded (n=978)
Reports not retrieved (n=0)
vides a summary of the included studies.
Risk of bias in the included studies
Supplemental Fig. S1 illustrates the RoB across the 13 RCTs in-
cluded in the meta-analysis. Seven trials (53.8%) exhibited a
low overall RoB. The SURMOUNT-3 study raised ‘some con-
cerns’ regarding attrition bias due to missing outcome data. Five
studies (38.7%) demonstrated high risks for overall bias, primar-
ily 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 evi-
dence 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 evi-
dence), 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 evi-
dence) (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).
Kamrul-Hasan A.B.M, et al.
11 6 www.e-enm.org Copyright © 2025 Korean Endocrine Society
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
Tirzepatide 5 mg
Tirzepatide 10 mg
Tirzepatide 15 mg
Placebo
Dulaglutide 1.5 mg
52
55
51
53
51
54
57.4±8.9
57.9±8.2
56.5±9.9
56.0±7.6
56.6±8.9
58.7±7.8
44
38
41
59
56
43
26
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
Tirzepatide 10 mg
Tirzepatide 15 mg
Placebo
630
636
630
642
45.6±12.7
44.7±12.4
44.9±12.3
44.4±12.5
67.6
67.1
67.5
67.8
72
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
Tirzepatide 15 mg
Placebo
312
311
315
54.3±10.7
53.6±10.6
54.7±10.5
51
51
50
72
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
Placebo
287
292
45.4±12.6
45.7±11.8
63.1
62.7
72
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
Tirzepatide 15 mg
Placebo
70
71
69
34.7±7.2
35.8±9.3
37.8±10.2
50
49.3
47.8
52
NCT03861052,
NCT04093752, Phase 3,
Multicenter in Japan
SURPASS J-mo-
no, 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
Tirzepatide 10 mg
Tirzepatide 15 mg
Dulaglutide 0.75 mg
159
158
160
159
56.8±10.1
56.2±10.3
56.0±10.7
57.5±10.2
29
25
18
26
52
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
Tirzepatide 10 mg
Tirzepatide 15 mg
Placebo
121
121
121
115
54.1±11.9
55.8±10.4
52.9±12.3
53.6±12.8
54
40
48
51
40
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
Tirzepatide 10 mg
Tirzepatide 15 mg
Semaglutide
470
469
470
469
56.3±10.0
57.2±10.5
55.9±10.4
56.9±10.8
56.4
49.3
54.5
52.0
40
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
Tirzepatide 10 mg
Tirzepatide 15 mg
Insulin degludec
358
360
359
360
57.2±10.1
57.4±9.7
57.5±10.2
57.5±10.1
44
46
46
41
52
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
Tirzepatide 10 mg
Tirzepatide 15 mg
Insulin glargine
329
328
338
1,000
62.9±8.6
63.7±8.7
63.7±8.6
63.8±8.5
40
36
40
36
52
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
Tirzepatide 10 mg
Tirzepatide 15 mg
Placebo
116
119
120
120
62±10
60±10
61±10
60±10
47
39
46
45
40
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
Tirzepatide 10 mg
Tirzepatide 15 mg
Insulin lispro
243
238
236
708
58.0±10.2
59.6±9.4
58.2±9.6
59.0±9.7
56.4
62.6
59.3
55.9
52
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
Tirzepatide 10 mg
Tirzepatide 15 mg
Insulin glargine
230
228
229
220
53.1±11.2
53.5±11.1
54.3±11.6
55.6±11.4
41.7
44.7
43.7
46.4
40
SD, standard deviation; T2D, type 2 diabetes; HbA1c, glycated hemoglobin; BMI, body mass index; MTD, maximum tolerated dose; OAD, oral anti-di-
abetic drugs; SU, sulfonylureas; SGLT2i, sodium-glucose cotransporter-2 inhibitor.
aTirzepatide MTD was analyzed as tirzepatide 15 mg.
Tirzepatide and Cancer
Copyright © 2025 Korean Endocrine Society www.e-enm.org 11 7
Effect of tirzepatide on the secondary outcomes: risks of
individual cancers
Compared to the pooled control groups, tirzepatide did not in-
crease 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,
Fig. 2. Forest plot highlighting the risk of any cancer in the tirzepatide versus pooled control groups. IV, intravenous; CI, confidence interval.
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) 00.15
5 mg 13/922 11/929 1.20 (0.54–2.66) 00.65
10 mg 5/1,309 18/1,313 0.34 (0.13–0.86) 00.02
15 mg 14/1,593 21/1,605 0.72 (0.37–1.40) 00.33
Insulin All doses (pooled) 32/3,476 24/2,288 0.89 (0.49–1.60) 00.69
5 mg 10/1,160 24/2,288 1.00 (0.45–2.24) 01.00
10 mg 13/1,154 24/2,288 1.23 (0.57–2.65) 00.59
15 mg 9/1,162 24/2,288 0.89 (0.38–2.10) 00.79
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) 00.72
15 mg 1/683 3/682 0.48 (0.06–3.69) 00.48
RR, risk ratio; CI, confidence interval; GLP-1RA, glucagon-like peptide-1 receptor agonist.
Kamrul-Hasan A.B.M, et al.
11 8 www.e-enm.org Copyright © 2025 Korean Endocrine Society
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
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) 00.31
Placebo 2/3,161 4/1,370 0.30 (0.07–1.30) 00.11
Insulin 5/3,185 2/1,976 1.13 (0.27–4.81) 00.87
Cholangiocarcinoma All (pooled) 1/2,435 2/1,475 0.33 (0.05–2.08) 00.24
Insulin 1/2,072 1/1,360 0.58 (0.06–5.57) 00.64
Colon cancer All (pooled) 8/5,871 5/3,187 0.73 (0.26–2.04) 00.54
Placebo 2/986 2/430 0.41 (0.06–2.78) 00.36
Insulin 3/3,476 3/2,288 0.91 (0.24–3.43) 00.89
Gastric cancer All (pooled) 2/1,700 0/675 1.24 (0.13–11.86) 00.85
Glioblastoma All (pooled) 1/3,131 2/2,177 0.48 (0.08–3.04) 00.44
Insulin 0/1,712 2/1,708 0.33 (0.03–3.19) 00.34
Lung cancer All (pooled) 4/6,730 8/3,444 0.39 (0.12–1.20) 00.10
Placebo 1/2,055 1/694 0.33 (0.03–3.16) 00.34
Insulin 2/2,789 6/2,068 0.38 (0.08–1.87) 00.23
GLP-1RA 1/2,045 1/682 0.33 (0.03–3.20) 00.34
Lymphoma (any) All (pooled) 0/3,027 3/1,784 0.18 (0.03–1.17) 00.07
Meningioma All (pooled) 3/3,578 2/1,863 0.62 (0.12–3.20) 00.57
Insulin 1/1,682 1/1,220 0.57 (0.06–5.46) 00.62
Ovarian cancer All (pooled) 2/2,350 1/1,020 0.68 (0.11–4.32) 10.68
Insulin 2/1,072 0/584 1.65 (0.17–15.86) 00.66
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) 00.34
Prostate cancer All (pooled) 5/1,898 5/1,116 0.53 (0.14–1.91) 00.33
Placebo 2/924 1/363 0.64 (0.08–5.21) 00.68
Renal cancer All (pooled) 8/5,419 1/2,683 1.33 (0.37–4.78) 00.66
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) 01.00
Skin cancer All (pooled) 5/4,669 0/1,764 1.52 (0.31–7.34) 00.61
Placebo 3/2,183 0/935 2.24 (0.25–20.25) 00.47
Squamous cell carcinoma All (pooled) 3/3,481 0/1,829 1.45 (0.23–9.17) 00.70
Insulin 2/2,072 0/1,360 1.74 (0.18–16.71) 00.63
Thyroid cancer (papillary) All (pooled) 5/3,011 1/1,224 1.07 (0.22–5.12) 00.93
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) 60.46
Insulin 0/2,072 2/1,360 0.19 (0.02–1.86) 00.15
Uterine cancer All (pooled) 4/2,504 0/893 1.12 (0.23–5.53) 00.89
Placebo 3/1,752 0/649 1.17 (0.19–7.41) 00.87
RR, risk ratio; CI, confidence interval; GLP-1RA, glucagon-like peptide-1 receptor agonist.
Tirzepatide and Cancer
Copyright © 2025 Korean Endocrine Society www.e-enm.org 11 9
(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 pla-
cebo (Supplemental Fig. S3). However, the included RCTs re-
ported no cases of medullary thyroid carcinoma in either the
tirzepatide or the control groups.
DISCUSSION
This SRM is the first in-depth analysis of cancer risks in RCTs
involving tirzepatide. It includes data from 13 RCTs, which pre-
dominantly 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 pla-
cebo, 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 carcino-
mas [38]. GIP is typically expressed in the brain, bone, pancre-
as, 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 obesi-
ty 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 pancreati-
tis, 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 progres-
sion and growth, potentially leading to a higher risk of malig-
nancy [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, dia-
betes 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 fol-
low-up of 11 years [45]. In a large recent cohort study, GLP-
1RAs were associated with lower risks of specific obesity-asso-
ciated 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 cur-
rently the most potent weight-lowering drug approved. It also
has the highest glycemic efficacy following insulin [13]. Theo-
retically, tirzepatide offers the best anti-cancer effects, consider-
ing 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 tirzepa-
tide 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. How-
Kamrul-Hasan A.B.M, et al.
120 www.e-enm.org Copyright © 2025 Korean Endocrine Society
ever, this finding offers hope that the theoretical oncogenic ben-
efits of tirzepatide could become a reality, a possibility that fu-
ture trials will need to confirm.
Although, as previously mentioned, GLP-1RAs are theoreti-
cally 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 medul-
lary thyroid carcinoma, with increased doses of tirzepatide com-
pared to placebo. To further ensure the safety of the drug, the
clinical significance of this rise in calcitonin levels must be clar-
ified 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 thy-
roid cancer, associated with tirzepatide [16,36]. Our findings re-
garding 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 carcino-
genic potential of tirzepatide based on published RCTs. The evi-
dence 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 Eu-
rope 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 reas-
suring 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.
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was re-
ported.
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.
ORCID
A.B.M. Kamrul-Hasan https://orcid.org/0000-0002-5681-6522
Muhammad Shah Alam https://orcid.org/0000-0002-9541-5641
Deep Dutta https://orcid.org/0000-0003-4915-8805
Thanikai Sasikanth https://orcid.org/0000-0002-0575-4982
Fatema Tuz Zahura Aalpona
https://orcid.org/0000-0003-1500-818X
Lakshmi Nagendra https://orcid.org/0000-0001-6865-5554
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Appendix 1. PRISMA 2020 Checklist
Section and topic Item # Checklist item Location where
item is reported
Title
Title 1Identify the report as a systematic review. Page 1
Abstract
Abstract 2See the PRISMA 2020 for abstracts checklist. Page 3
Introduction
Rationale 3Describe the rationale for the review in the context of existing knowledge. Page 5,6
Objectives 4Provide an explicit statement of the objective(s) or question(s) the review addresses. Page 6
Methods
Eligibility criteria 5Specify the inclusion and exclusion criteria for the review and how studies were grouped for
the syntheses.
Page 7,8
Information sources 6Specify 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 7Present the full search strategies for all databases, registers and websites, including any filters
and limits used.
Page 7
Selection process 8Specify 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 9Specify 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
Kamrul-Hasan A.B.M, et al.
124 www.e-enm.org Copyright © 2025 Korean Endocrine Society
Appendix 1. Continued
Section and topic Item # Checklist item Location where
item is reported
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; ana-
lytic code; any other materials used in the review.
Title page
PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
