GLP-1 RA benefit may branch out into obesity-related cancers

Another feather may have been added in the cap of glucagon-like protein-1 receptor agonists (GLP-1 RAs) – the class of type 2 diabetes (T2D) drugs that has become a blockbuster recently due to their remarkable weight loss benefit – as evidence of their potential to reduce the risk of obesity-associated cancers (OACs) comes to light.

Apart from T2D and obesity, there are data corroborating the cardiorenal protective effect of GLP-1 RA treatment. [Diabetes Care 2023;46:S140-S157; Am J Prev Cardiol 2023;14:100502; Adv Chronic Kidney Dis 2021; 28:337-346] The evidence reflecting the benefits of GLP-1 RAs for OACs highlight its potential to go beyond its initial indications.

GLP-1 RAs vs bariatric surgery, no intervention

“Bariatric surgery [BS] is suggested to reduce the risk of OACs, prompting us to explore whether GLP-1 RAs offer a similar association,” noted the investigators of a study that evaluated the effects of GLP-1 RAs, BS, and no intervention (NI) in individuals with a BMI ≥35 kg/m².

“Our study found that both GLP-1 RA therapy and [BS] reduced the risk of weight-related cancers as compared to NI,” said co-first author Cindy Lin, PGY-2 internal medicine resident from Case Western Reserve University, Cleveland, Ohio, US, who presented the results at ASCO 2024.

Using data from the TriNetX database, Lin and team created three pairwise propensity score-matched comparisons: GLP-1 RAs vs BS (n=14,504), GLP-1 RAs vs NI (n=21,768), and BS vs NI (n=55,798). The average age across groups was about 50 years and roughly two-thirds of participants were women. Participants had a minimum 1 year of continuous GLP-1 RA therapy or follow-up, extending to 3 and 5 years. The team looked at 15 years of follow-up data and evaluated 13 OACs. [ASCO 2024, abstract 10508]

The 13 OACs identified by the International Agency for Research on Cancer Handbook Working Group in 2016 are mostly gastrointestinal (colorectal, gallbladder, liver, pancreatic cancer; oesophageal adenocarcinoma; cancer of the gastric cardia), followed by female reproductive (endometrial, ovarian, postmenopausal breast cancer) and other cancers (meningioma, multiple myeloma [MM], thyroid cancer, renal cell carcinoma). [N Engl J Med 2016;375:794-798]

After at least a year of continuous GLP-1 RA use and follow-up of up to 15 years, the hazard ratio (HR) for GLP-1 RAs vs BS was 1.147 (p=0.319). “For GLP-1 RAs vs NI, the Kaplan-Meier curves diverged around 1,000 days, increasing with time [HR, 0.809], with a significant log-rank test and a p-value of 0.0325,” Lin said. A similar pattern was seen for BS vs NI (HR, 0.809; p=0.0016).

“Both [BS] and GLP-1 RA therapy had superior all-cause mortality compared with NI,” added Lin. These were reflected by the HRs after at least 1 year (HR, 0.684; p<0.0001 [BS] and HR, 0.729; p=0.0011 [GLP-1 RAs]).

Mechanism of cancer risk reduction

Lin noted multiple pathways by which GLP-1 RAs may reduce cancer risk. One is through the weight that participants shed during GLP-1 RA treatment. The effect may also be attributed to glycaemic control or immune modulation and anti-inflammatory effects.

Other mechanisms that may have been responsible for the reduction of cancer risk are independent cellular pathways such as inhibition of growth- and survival-regulating kinases GSK3 and ERK1/2. [Pharmacol Res 2022;182:106320; Endocrinology 2011;152:3362-3372]

Not without caveats

“[The findings are] particularly relevant since GLP-1 RAs had been in clinical use since 2005,” said discussant Dr Onyinye Balogun from Weill Cornell Medicine, New York, New York, US, at ASCO 2024. She noted, however, that while the results are promising, these do raise some questions.

Balogun called for more studies exploring GLP-1 RA use in cancer survivors since these patients were excluded from the study. “Weight management has significant benefits for individuals with OACs, notably breast and endometrial cancer. When we manage an individual’s weight, it decreases the risk of cancer recurrence and cancer mortality.”

Also, as the study only included participants with continuous GLP-1 RA use, future studies should examine if the benefits would accrue on an intermittent basis, considering patients who are taking these drugs intermittently due to cost and shortage driven by the demand that may have snowballed into “sometimes inappropriate prescriptions”, Balogun pointed out.

The effect of prolonged exposure to GLP-1 RAs should also be evaluated, Balogun said, adding that it remains to be seen if undergoing both GLP-1 RA treatment and BS offers better control of OACs.

Breast cancer recurrence

In a retrospective analysis by researchers from Yale University, semaglutide/tirzepatide-treated and untreated individuals had similar rates of local breast cancer recurrence (1.5 percent vs 1.3 percent). Still, the former group had lower incidences of locoregional (0 percent vs 4.7 percent) and distant breast cancer recurrence (1.5 percent vs 3.3 percent) than the latter.

Though the between-group differences failed to achieve statistical significance, the findings imply that breast cancer recurrence risk did not appear to be influenced by GLP-1 RA treatment. [ASCO 2024, abstract e24140]

This analysis included stage I–III breast cancer patients receiving semaglutide or tirzepatide for weight loss. Of the 5,430 evaluable participants with nonmetastatic disease (mean age 58 years), 70 (1.3 percent) were prescribed semaglutide or tirzepatide.

Supporting data in T2D patients

In another retrospective study involving nearly 1.7 million T2D patients (mean age 59.8 years, 50.1 percent men, 4 percent Asian), GLP-1 RAs were tied to a significant risk reduction in 10 of 13 OACs compared with insulin. [JAMA Network Open 2024;7:e2421305]

These included gallbladder cancer (HR, 0.35), meningioma (HR, 0.37), pancreatic cancer (HR, 0.41), hepatocellular carcinoma (HR, 0.47), ovarian cancer (HR, 0.52), colorectal cancer (HR, 0.54), MM (HR, 0.59), oesophageal cancer (HR, 0.60), endometrial cancer (HR, 0.74), and kidney cancer (HR, 0.76).

Although not statistically significant, the HR for stomach cancer was <1 in individuals who were on GLP-1 RA vs those on insulin (HR, 0.73).

Compared with metformin, GLP-1 RAs were not associated with the risk reduction of any cancers. However, GLP-1 RA use was tied to an increased risk of kidney cancer (HR, 1.54), contrary to what was observed in the comparison between GLP-1 RAs and insulin.

“These divergent risks require further clinical and mechanistic studies for a full evaluation. Nonetheless, they suggest the need for continued monitoring in patients being treated with GLP-1 RAs,” according to the researchers, who were also from Case Western Reserve University.

Overall, this study showed that GLP-1 RAs may reduce the risk of specific OACs vs insulin or metformin in T2D patients. The investigators noted that the results “provide preliminary evidence of the potential benefit of GLP-1 RAs for cancer prevention in high-risk populations and support further preclinical and clinical studies for the prevention of certain OACs.”

Increased thyroid cancer risk?

Collectively, these data support the role of GLP-1 RAs in preventing OACs, but further studies are warranted to add weight to evidence substantiating the potential of this class of drugs to expand their indications and revolutionize the cancer treatment landscape.

Another important issue to note is the boxed warning cautioning GLP-1 RA use in individuals with a family history of thyroid cancers (specifically medullary thyroid cancers) following trials in rodents. [https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf, accessed August 12, 2024]

While the association between GLP-1 RA use and thyroid cancers remains inconclusive, it stands to reason that individuals on GLP-1 RA therapy should be counselled comprehensively on the probable risk of thyroid cancer and symptoms of thyroid tumours. [Nutrients 2023;15:3737]