Notice of Special Interest (NOSI): Epidemiologic Studies to Assess the Impact of Incretin Mimetics on New and Recurrent Cancer Risk
Notice Number:

Key Dates

Release Date:

March 7, 2024

First Available Due Date:
May 25, 2024
Expiration Date:
May 09, 2026

Related Announcements

  • December 14, 2022 - National Cancer Institute Program Project Applications for the Years 2023, 2024, and 2025 (P01 Clinical Trial Optional). See NOFO PAR-23-059
  • October 12, 2021 - Exploratory Grants in Cancer Control (R21 Clinical Trial Optional). See NOFO PAR-21-341
  • September 10, 2021 - NCI Mentored Clinical Scientist Research Career Development Award to Promote Diversity (K08 Independent Clinical Trial Not Allowed). See NOFO PAR-21-300
  • September 10, 2021 - NCI Transition Career Development Award to Promote Diversity (K22 Independent Clinical Trial Not Allowed). See NOFO PAR-21-301
  • May 05, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-20-185
  • May 05, 2020 - NIH Pathway to Independence Award (Parent K99/R00 – Independent Clinical Trial Not Allowed). See NOFO PA-20-188

Issued by

National Cancer Institute (NCI)


The purpose of this notice of special interest (NOSI) is to solicit submission of innovative epidemiologic research designed and focused on facilitating and enhancing our understanding of the impact of long-term incretin mimetic use on cancer risk and outcomes among individuals with and without comorbid conditions. Cancer types vary in latency after exogenous exposure(s). As such, latency/temporal issues (long term exposure to incretin mimetics and follow-up time) must be critically considered in proposed projects. A minimum latency period for incretin mimetic use of one (1) year is required. In this NOSI we seek applications using large clinical data sets.


Obesity, a global epidemic and public health crisis, is a recognized risk factor for at least 13 types of cancer and is associated with increased cancer-related death. The link between obesity and cancer is complex and multifactorial. Excess body fat can lead to chronic inflammation, insulin resistance, and hormonal imbalances, all of which can promote the development and progression of cancer. Given the alarming rise in obesity rates worldwide and its association with multiple cancers, investigation into effective strategies for obesity management that can potentially reduce the risk of obesity-related cancers is important. Lifestyle modifications should be the first-line treatment. Nevertheless, the high risk of relapse with lifestyle changes has resulted in a growing interest in non-invasive pharmacotherapeutic interventions to achieve and maintain weight loss and mitigate the detrimental impact of obesity on cancer.

Incretin mimetics mimic incretin hormones such as glucagon-like peptide (GLP)-1 by stimulating glucose dependent insulin release, suppressing appetite and inhibiting glucagon secretion. Current FDA approved incretin mimetics for type 2 diabetes mellitus (T2DM) or obesity in the absence of T2DM are receptor agonists (RA)s of GLP-1 and more recently GLP-1/ glucose?dependent insulinotropic polypeptide (GIP)-1. Use of these RAs has demonstrated dramatic weight loss in overweight and obese individuals, with or without T2DM, with newer agents demonstrating on average 15% or more weight loss after approximately one year of use. Agents in the pipeline are evaluating combining hormones that influence food intake with the hope of increasing weight loss. Retatrutide, an agent not yet FDA approved that targets  GLP-1, GIP-1 and glucagon receptors, led to an average 24% loss of body weight after 48 weeks. While most incretin mimetics require a subcutaneous injection due to poor oral bioavailability, pharmaceutical companies are developing agents with better efficacy after oral intake. Daily oral orforglipron, a nonpeptide GLP-1 RA that is not currently FDA approved, demonstrated a mean weight loss of up to 14.7% after 36 weeks of use.

The use of incretin mimetics has increased dramatically since the first agent, exenatide, was approved in 2005. The  approval of three semaglutide drugs [Ozempic (FDA-approved for T2DM in 2017), Rybelsus, an oral agent (FDA-approved for T2DM in 2019) and Wegovy (approved for weight loss in 2021)] catapulted these agents to the public domain. There is wide geographic variation in semaglutide prescriptions across metropolitan areas in the United States (US) that do not correlate with levels of disease status (e.g., T2DM, obesity, or heart disease) suggesting massive off-label usage that will continue to rise. The global GLP-1RA market was estimated to be $12.7 billion in 2021, with an anticipated 6.1% annual growth through 2028.

Impact of Incretin Mimetics on Cancer Risk

The impact of incretin mimetics on cancer risk in humans is unclear, with growing concerns on potential adverse effects. To date, human evidence of cancer risks associated with incretin mimetic use is equivocal and based on studies with considerable methodological issues (e.g., selection bias, limited statistical power, limited follow-up time, and/or inadequate control of confounders). Conversely, the beneficial effects of incretin mimetics in lowering obesity-associated cancer risk, mortality, and recurrence are promising. Hence, investigations into the role of these agents as possible cancer reduction measures are warranted while balancing the potential associated harms.

A study that compared cancer risk among individuals using GLP-1RAs vs. metformin users based on real world data from an electronic health record database, which was validated using data from the FDA Adverse Event Reporting System, found a decreased risk of colon, lung, and prostate cancer (PCa)  compared to metformin, while also observing a 65% significant increase in thyroid cancer risk. A nested case-control analysis of individuals with T2DM in the French national health insurance database observed an increased risk of all thyroid cancer of 58%, with risk of medullary thyroid cancer (MTC) increased by 78% for those treated with GLP-1RAs for 1-3 years. FDA approved GLP-1RA and dual GIP/GLP-1RA agents carry a black box warning prohibiting their use in patients with MTC and multiple endocrine neoplasia type 2 (MEN2) syndrome, which includes tumors of the thyroid, parathyroid, and adrenal gland.  On the other hand, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency concluded that available evidence does not support a link between GLP-1RAs and thyroid cancer ( Comprehensive, long-term epidemiologic studies are critically needed to assess potential associations between incretin mimetic use, especially newer agents, and cancer development.

Analysis of four randomized controlled trials (RCTs) involving patients with T2DM demonstrated a 47% reduction in PCa risk with GLP-1RA administration, and a cohort study using the UK Clinical Practice Research Datalink, a national database representative of the UK population. also showed a lower risk of PCa among men taking GLP-1RAs vs. sulfonylureas, with the benefit starting after 30 months on treatment. An RCT assessing the effect of liraglutide 3 mg daily in the treatment of obesity among individuals without T2DM observed a non-statistically higher incidence of breast cancer in the treatment group among individuals who lost the most weight vs. controls. A second RCT evaluating liraglutide 1.8 mg daily in patients with T2DM had a similar observation among women who lost weight. The cancers were mostly detected within the first year on treatment. On the other hand, neither the UK Clinical Practice Research Datalink, nor a meta-analysis of 50 studies which reported breast cancer events, identified an association between GLP-1RAs and breast cancer risk. These findings suggest that the higher detection of breast cancer in individuals on liraglutide may be related to easier detection after weight loss. Nonetheless, further epidemiologic investigations of the benefit vs. harm of these agents are needed to inform clinical guidance.

In a meta-analysis of 76 RCTs, increases in the risk of gallbladder or biliary diseases after taking GLP-1RAs were reported, both among those with and without T2DM, particularly at higher doses, for longer durations, and for weight loss. The same study reported a non-statistically significant 43% elevated risk in biliary cancer. There was not a significant increase in the risk of cholangiocarcinoma with GLP-1RA use in a nationwide Scandinavian cohort study of data from over 96,000 patients receiving the agents with a median follow-up time of 4.4 years. Recent evidence suggests that liraglutide and semaglutide, in combination with caloric restriction and increased physical activity, may decrease the risk of hepatocellular carcinoma by decreasing liver inflammation, adipose liver content, and liver fibrosis.

There are GLP-1 and GIP-1 receptors in most human organs, suggesting that these agents might provide off-target effects unrelated to hunger suppression. Long-term follow-up after incretin mimetic use is critical to further our understanding of the harm vs. benefit associated with these agents and cancer development.

Adherence to incretin mimetics is essential to understanding their effects on cancer risk. Several factors that impact adherence include regimen complexity and frequency, route of administration, tolerability, and affordability. These factors are important to consider in assessing the potential impact of these agents on cancer prevention and control.   Additionally, agent cost may influence their uptake. A retrospective cohort study of adults with T2DM found that adults with the highest out-of-pocket cost were less likely to initiate GLP-1RA or SGLT2 (define) inhibitor treatment than those with the lowest out-of-pocket costs. Other considerations include understanding the role of social determinants of health, as well as racial and ethnic disparities in adherence to incretin mimetics. For example, an analysis of NHANES data from 2015 to 2020 found that many Americans eligible for semaglutide were unable to afford the medication. Specifically, a larger proportion of African American and Hispanic adults had financial barriers to accessing these treatments than other subgroups.   Studies are needed to better understand the factors that impede or facilitate adherence to incretin mimetics , which can ultimately impact weight loss, cancer risk and treatment related outcomes.

Impact of Incretin Mimetics on Additional Cancers

We are unaware of large scale published findings on incretin mimetics in cancer patients at risk of recurrence and/or second cancers. It is established that that obesity negatively impacts cancer outcomes and survival. A systematic review and meta-analysis of 230 high quality studies reported conclusively that obesity was associated with greater mortality overall in patients with cancer while patients with obesity and lung cancer, renal cell carcinoma, and melanoma had a lower risk of death than patients with the same cancers without obesity. The authors recommended weight-reducing strategies as effective measures for reducing mortality in cancer patients. As obesity represents a modifiable risk factor and is a target for cancer prevention measures and to improve cancer outcomes, including recurrence, mortality and second cancers, incretin mimetics offer a possible solution alone or in addition to other lifestyle modifications and/or surgical interventions.  There is a paucity of reported observational investigations or interventions/trials in this area of research to inform clinical guidance.

Research Objectives

This proposed NOSI complements the molecular focus of PAR-23-279 and PAR-23-280 “Mechanisms that Impact Cancer Risk with Use of Incretin Mimetics” which solicit mechanistic investigations related to incretin mimetics. Investigations in response to the proposed NOSI align with three domains across the cancer continuum (Etiology, Prevention, and Survivorship).

Investigators are strongly encouraged to use one of various epidemiologic study designs in response to this NOSI. These may include leveraging existing population-based data sources, such as cohorts and registries, and data from available randomized clinical trials. Applicants are also encouraged to incorporate real-world data (e.g., electronic health records) when possible, or may propose new data collection as warranted. Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the requirements as outlined in the NIH Grants Policy Statement. Upon approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

Several responsive approaches include, but are not limited to:

  • Investigate the association between incretin mimetic usage and cancer risk across diverse populations.
  • Analyze cancer types, incidence, and risk factors associated with incretin mimetic use.
  • Identify potential biologic, environmental, lifestyle (e.g., alcohol consumption, smoking) and behavioral (psychological and social) factors that may interact with incretin mimetics in cancer etiology.
  • Leverage real-world data sources (e.g., electronic health records) to explore the role of incretin mimetics and long-term outcomes, including the development of second cancers and cancer recurrence.
  • Identify factors that may influence cancer recurrence among survivors who take or have taken incretin mimetics, such as treatment adherence or comorbidities.
  • Understanding the potential for exacerbation of health disparities through use of high cost therapeutic agents.

Questions that could be addressed include, but are not limited to:

  • Which cancers (or cancer subtypes) are impacted by these agents, either favorably or unfavorably?
  • Does diet quality influence the impact of incretin mimetics on cancer or cancer biomarkers?
  • Which individuals (gender, age, ethnicity or race) are more (or less) are most likely to benefit from the use of incretin mimetics after long-term use?
  • Which behavioral factors influence long-term benefit of incretin mimetics?   
  • Does short-term use of incretin mimetics influence long-term behavioral changes (lifestyle modifications) to impact cancer reduction?
  • Are there off-target effects that alter cancer or cancer biomarker risk?  Are these off-target effects impacted by dose?
  • Does the specific incretin mimetic (GLP-1, GIP-1, or combination agent) influence the cancer or cancer biomarker impact?
  • Do incretin mimetics impact cancer risk differently among individuals with vs. those without T2DM?
  • Is the impact of these agents on cancer or cancer biomarkers directly linked to weight loss, or are there weight loss-independent effects as well?
  • Among patients with T2DM, do these agents impact cancer or cancer biomarkers independent of glucose control?

Non-responsive Studies

  • Applications that focus on preclinical investigations.
  • Studies that are primarily laboratory focused, although laboratory studies may comprise a component of the project.
  • Newly proposed clinical trials.
  • Studies that do not investigate human populations who have taken incretin mimetics for at least 1 year.
  • Studies that do not have primary endpoints relevant to incident cancer, second cancer risk or cancer recurrence.

Application and Submission Information

Submit applications for this initiative using one of the following notices of funding opportunity (NOFO) or any reissues of these announcements through the expiration date of this notice. This NOSI expires May 09, 2026.

Activity CodeNOFOFirst Available Due Date
PA-20-185NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)June 5, 2024
PA-20-188NIH Pathway to Independence Award (Parent K99/R00-Independent Clinical Trial Not Allowed)July 12, 2024
PAR-21-300NCI Mentored Clinical Scientist Research Career Development Award to Promote Diversity (K08 Independent Clinical Trial Not Allowed)July 12, 2024
PAR-21-301NCI Transition Career Development Award to Promote Diversity (K22 Independent Clinical Trial Not Allowed)July 12, 2024
PAR-21-341Exploratory Grants in Cancer Control (R21 clinical trial optional)June 16, 2024
PAR-23-059National Cancer Institute Program Project Applications for the Years 2023, 2024, and 2025 (P01 Clinical Trial Optional)May 25, 2024

All instructions in the SF424 (R&R) Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include “NOT-CA-24-037” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.


Scientific/Research Contact(s)

For inquiries related to general information about the NOSI and incretin mimetics:

Edward Sauter, MD, PhD
Division of Cancer Prevention
National Cancer Institute (NCI)
Telephone: 240-276-7657

For inquiries related to epidemiologic study designs:

Naoko Ishibe, ScD
Division of Cancer Control and Population Sciences
National Cancer Institute (NCI)
Telephone: 301-825-4579

For inquiries related to impact on cancer patients:

Kelly Filipski, PhD, MPH
Division of Cancer Control and Population Sciences
National Cancer Institute (NCI)
Telephone: 240-276-6841

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277