GLP-1 Agonists May Reduce Cancer Risk for Patients With Diabetes

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) were linked to a significantly reduced risk of 10 of 13 common obesity-associated cancers for patients with type 2 diabetes, according to new research published in JAMA Network Open.¹

Compared with insulin, patients who received GLP-1 treatment had significantly reduced risks of:

Long-term studies are needed to explore whether GLP-1 receptor agonists can directly prevent obesity-related cancers | Image credit: Halfpoint – stock.adobe.com

• Gallbladder cancer by 65%
• Meningioma by 63%
• Pancreatic cancer by 59%
• Hepatocellular carcinoma by 53%
• Ovarian cancer by 48%
• Colorectal cancer by 46%
• Multiple myeloma by 41%
• Esophageal cancer by 40%
• Endometrial cancer by 26%
• Kidney cancer by 24%

Use of the drug class was also linked to a 27% lower risk of stomach cancer compared with insulin use, although this was not deemed significant by the research authors. The study was not able to demonstrate a reduction in postmenopausal breast cancer (HR, 1.07; 95% CI, 0.93-1.23) or thyroid cancer (HR, 0.99; 95% CI, 0.79-1.24). Additionally, there was no significant decrease in cancer risk associated with GLP-1 RAs when compared with metformin.

“Of those cancers that showed a decreased risk among patients taking GLP-1 RAs compared with those taking insulin, HRs for patients taking GLP-1 RAs vs those taking metformin for colorectal and gallbladder cancer were less than 1, but the risk reduction was not statistically significant,” the authors noted. “Compared with metformin, GLP-1 RAs were not associated with a decreased risk of any cancers, but were associated with an increased risk of kidney cancer (HR, 1.54; 95% CI, 1.27-1.87).”

It should also be noted that there were varying amounts of patients in each treatment arm for the different cancer outcomes. For example, fewer than 30 patients total were assessed for stomach cancer and 40 patients for meningioma, while there were more than 600 patients assessed for colorectal cancer and more than 800 for breast cancer. This may have swayed these percentage reduced risks, especially for the smaller cohorts.

To come to these findings, the authors of the retrospective cohort study utilized a nationwide multicenter database with electronic health records (EHRs) of 113 million patients in the US. The study focused on more than 1.6 million patients with type 2 diabetes (T2D) who had no prior diagnosis of obesity-associated cancers and were prescribed GLP-1 RAs, insulin, or metformin between 2005 and 2018. The occurrence of first-time diagnoses for each of the 13 cancers was examined over a 15-year follow-up period after initial exposure.

The study authors mentioned several limitations. As a retrospective observational study based on patient EHRs, it faces inherent issues such as overdiagnosis, underdiagnosis, misdiagnosis, unmeasured or uncontrolled confounders, and biases, making it impossible to draw causal inferences despite extensive variable control. They also said the accuracy of cancer diagnoses captured in patient EHRs is uncertain, although the relative risk analysis should remain unaffected by diagnostic inconsistencies as all patients were from the same health care organizations.

Additionally, while both the exposure and comparison groups were derived from the same EHR database within the same time frame, the authors said these results need validation in other databases and platforms. The study also could not control for postindex event variables such as weight loss, which limits the ability to correlate risk reduction with weight loss, and it lacked control over health care utilization and insurance types. Lastly, due to the absence of medication adherence data in EHRs, the study used an intention-to-treat approach based on medication prescriptions, without accounting for adherence and duration of use.

The authors emphasized the need for further long-term studies to explore the potential cancer-preventive effects of GLP-1 RAs on obesity-related cancers, along with investigations into newer and potentially more effective antidiabetic and weight loss agents, including those with multihormone agonist activities. Research should also assess the preventive effects of these agents on cancers not related to obesity.

“In addition, the associations of the GLP-1 RA targeted pharmacologic agents with cancer risk should be compared with the use of ILI [intensive lifestyle intervention] and metabolic-bariatric surgery for the control of obesity and diabetes,” the authors said. “As noted previously, it will be important to correlate these associations with the control of T2D [type 2 diabetes] and obesity. Moreover, given that T2D and overweight or obesity have negative impacts on patients during cancer therapy, GLP-1 RAs should be evaluated for control of these comorbid conditions during cancer therapy as well as for secondary prevention to delay cancer recurrence.”

Outside of cancer outcomes, semaglutide—a popular GLP-1 RA—has been shown to significantly reduce the risk of major kidney outcomes, cardiovascular events, and death in patients with type 2 diabetes and chronic kidney disease.² In a study published in The New England Journal of Medicine, patients who received weekly semaglutide injections had a 24% lower risk of primary outcome events, a 21% reduced risk of kidney-related outcomes, and a 29% lower risk of death due to cardiovascular causes compared with those given a placebo.

It’s also important to note that, despite health insurance coverage, many adults still struggle to afford GLP-1 drugs, with over half of the users finding it difficult to cover the costs.³ According to the May 2024 Kaiser Family Foundation Health Tracking Poll, most adults use GLP-1 drugs to treat chronic conditions like diabetes or heart disease, but there is a growing trend of using these medications primarily for weight loss. The high cost of GLP-1 drugs remains a significant barrier, with many insured patients having to pay part or all of the cost themselves. If a causal link is found between GLP-1 RA use and obesity-related cancer reduction, it will be important to make sure patients can access the treatment.

References

1. 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. Published online July 5, 2024. doi:10.1001/jamanetworkopen.2024.21305
2. Klein HE. Semaglutide lowers risk of major kidney outcomes, cardiovascular events, death in patients with diabetes and CKD. AJMC®. May 24, 2024. Accessed July 3, 2024. https://www.ajmc.com/view/semaglutide-lowers-risk-of-major-kidney-outcomes-cardiovascular-events-death-in-patients-with-diabetes-and-ckd
3. Klein HE. Most insured adults still have to pay at least part of the cost of GLP-1 drugs. AJMC. May 16, 2024. Accessed July 3, 2024. https://www.ajmc.com/view/most-insured-adults-still-have-to-pay-at-least-part-of-the-cost-of-glp-1-drugs