GLP-1 Drugs and Cancer Risk

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Glucagon-like peptide-1 receptor agonists (GLP-1s) have transformed the treatment of diabetes and obesity. These medications, including semaglutide (Ozempic, Wegovy), liraglutide (Victoza, Saxenda), and dulaglutide (Trulicity), work by mimicking the GLP-1 hormone, which regulates blood sugar and promotes weight loss. Some studies suggest GLP-1s also have anti-inflammatory and neuroprotective effects.

However, as the popularity of these drugs soars, questions have emerged regarding their potential link to cancer risk. Ahead, a look at GLP-1 receptor agonists and their possible association with various cancers.

Since the introduction of GLP-1s, researchers have investigated whether they could increase cancer risk.

A comprehensive nationwide analysis involving 1.1 million patients with obesity revealed that GLP-1s are associated with a decreased risk of 25 different cancer types, including those affecting the digestive tract, skin (notably melanoma), breast, and female genital organs, particularly uterine cancer. Semaglutide demonstrated the most pronounced protective effects, especially against gastrointestinal cancers like stomach cancer. Conversely, liraglutide was linked to an increased risk of certain cancers, such as breast and thyroid cancers. In general, it appears that the cancer-risk profile may vary among different GLP-1s.

Specific concerns have focused on the pancreas, thyroid, and gastrointestinal tract. Several mechanisms for how GLP-1s affect cancer have been proposed:

• Cell proliferation: GLP-1 receptors are found in various tissues, and prolonged activation of these receptors could lead to abnormal cell growth.
• Hormonal effects: GLP-1 influences insulin and glucagon, possibly indirectly affecting tumor development.
• Chronic inflammation: While GLP-1 RAs reduce inflammation in some conditions, prolonged stimulation could have unexpected consequences.

The most widely debated concern is whether GLP-1 drugs increase the risk of thyroid cancer, particularly medullary thyroid carcinoma (MTC). Animal studies have shown that long-term GLP-1 receptor activation can lead to C-cell hyperplasia, a precursor to MTC.

• Data from the FDA Adverse Event Reporting System (FAERS) showed elevated reporting rates for MTC and papillary thyroid cancer.
• Retrospective analyses associate GLP-1s with a 65% higher thyroid cancer risk in patients with type 2 diabetes compared to metformin, yet large-scale trials like STEP 3-4 found malignancy rates of 0.7–1.1% in semaglutide users vs. 0.4–0.5% in controls.
• A French study analyzing data from the national health insurance system found that current use of GLP-1 RAs was associated with a 46% increased risk of all thyroid cancers and a 78% increased risk of medullary thyroid cancer after one to three years of use. The study suggests that GLP-1 receptors in thyroid tissue may play a role in cancer development.

While these studies have raised questions, a 2024 multinational cohort study of 145,000 patients found no significant increase in thyroid cancer risk (HR 1.19, 95% CI 0.93–1.52) over 3.9 years compared to dipeptidyl peptidase-4 (DPP-4) inhibitors. (DPP-4 drugs treat type 2 diabetes by inhibiting the enzyme that breaks down hormones called incretins that help regulate blood sugar levels. DPP-4 inhibitors include sitagliptin (Januvia), saxagliptin (Onglyza), and linagliptin (Tradjenta), among others.)

Currently, the FDA requires a warning about the risk of MTC on GLP-1 drug labels, but actual cases in humans remain rare. More research is needed to determine if there is any excess risk of cancers associated with long-term use of GLP-1 drugs.

Emerging experimental evidence highlights specific risks:

• Semaglutide stimulated 19–22% growth in neuroendocrine tumor cell lines expressing high GLP-1 receptors.
• Animal models showed 72% tumor growth acceleration with semaglutide.

These findings suggest caution in patients with GLP-1 receptor-positive neuroendocrine tumors, though clinical data remain limited. They also underscore the importance of personalized risk assessment when prescribing semaglutide for patients with neuroendocrine tumors expressing GLP-1 receptors.

The pancreas expresses GLP-1 receptors, leading to concerns that prolonged exposure could contribute to an increased risk of acute pancreatitis and pancreatic cancer. Some key findings:

• FAERS data identified a 9.86-fold increased reporting rate for pancreatic malignancies with GLP-1s, but cohort studies show no elevated risk compared to SGLT2 inhibitor drugs.
• Preclinical models indicate GLP-1 activation may promote pancreatic ductal cancer cell proliferation, though the effects in humans are still unclear.

While some adverse event reporting data suggest an increased rate of pancreatic cancer, large-scale studies and analyses consistently show no significant risk elevation.

GLP-1 drugs may influence gastrointestinal cancer risks due to their ability to slow gastric emptying. Research findings include:

• Reduced risk of gastric and esophageal cancers: A national analysis found that patients on GLP-1 drugs had a 61.5% lower risk of gastric cancer and a 69.1% lower risk of esophageal cancer over seven years compared to those not using these drugs. The mechanisms behind these effects include reduced internal fat deposits deposition, improved insulin sensitivity, and anti-inflammatory properties.
• Colorectal cancer: Emerging evidence suggests a protective role of GLP-1s against colorectal cancer. A large retrospective study presented at the American College of Gastroenterology (ACG) 2024 Annual Meeting found that GLP-1s significantly decreased the risk of early-onset colorectal cancer in patients under 50 with type 2 diabetes
• Obesity-associated cancers: GLP-1 drugs’ weight loss effects could reduce risks for obesity-related cancers, such as those of the liver, pancreas, and gallbladder. Obesity is a known risk factor for many cancers, and weight reduction likely contributes to the protective benefits observed with GLP-1 RAs.

Other research has reported that GLP-1 receptors are expressed throughout the gastrointestinal tract, promoting intestinal lining healing and regulating the gut microbiome, which may counteract inflammation and dysbiosis linked to colorectal cancer CRC.

These findings suggest that GLP-1 drugs may offer protective benefits against certain gastrointestinal cancers, though further research is needed to confirm these associations and understand the underlying mechanisms.

Breast cancer has emerged as an area of interest, given GLP-1s impact on insulin regulation and metabolism. Research to date suggests a neutral or potentially protective effect of GLP-1 RAs on breast cancer risk.

• A 2022 review in Diabetes & Metabolism found no evidence of an increased risk of breast cancer among GLP-1 users. This research has found that weight loss and improved insulin sensitivity associated with GLP-1 drugs may reduce the risk of estrogen-receptor-positive (ER+) breast cancer incidence, as obesity and insulin resistance are known risk factors for this type of cancer.
• Other studies have even suggested that GLP-1s might inhibit cancer cell growth in laboratory settings, although these findings require further study.

While the current evidence is reassuring, long-term studies are necessary to confirm these findings and fully understand the relationship between GLP-1s and breast cancer risk.

GLP-1s are emerging as a promising therapeutic option for managing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), both of which are significant risk factors for liver cancer.

• Research has found that GLP-1s can reduce fat accumulation and inflammation of the liver, key contributors to NAFLD and NASH progression. Liver fat content was reduced by up to 42% in clinical trials.
• GLP-1 treatment significantly lowers liver enzyme levels, improving liver function.

Overall, GLP-1 receptor agonists offer multifaceted benefits for patients with NAFLD and NASH by reducing liver fat, improving enzyme profiles, and potentially lowering the risk of liver cancer through liver protection and reduced inflammation. Further research is needed to study their role in liver cancer prevention thoroughly.

While concerns about cancer risks exist, the overall benefits of GLP-1 drugs in managing diabetes and obesity are substantial. Important considerations include:

• Individual risk factors: Those with a personal or family history of thyroid or pancreatic cancer should discuss risks with their doctor.
• Monitoring: Regular check-ups, including thyroid ultrasounds and pancreatic enzyme tests, may be warranted for long-term users.
• Alternative treatments: For those at higher cancer risk, other diabetes and weight-loss therapies might be preferable.

If you choose to take GLP-1s, experts have the following clinical recommendations:

• High-risk screening: Patients with personal/family history of MTC or multiple endocrine neoplasia (MEN2) should avoid GLP-1s.
• Monitoring: Regular thyroid ultrasounds and calcitonin checks should be done in long-term GLP-1 users.
• Balanced risk-benefit: For most patients, the cardiovascular and metabolic benefits of GLP-1 drugs outweigh cancer risks.

Research on GLP-1 medications and cancer risk shows that the connection is complicated and requires careful evaluation for each patient. Some GLP-1 drugs, like semaglutide, may help protect against certain cancers, while others, such as liraglutide, could increase the risk of specific types of cancer. For most people, the benefits of better metabolic health likely outweigh these potential risks. However, healthcare providers and patients should consider individual factors, like personal and family medical history, and work together to make informed decisions about treatment to achieve the best results. 

If you’re considering GLP-1 therapy, discuss the risks and benefits with your doctor, especially if you have a history of endocrine or gastrointestinal cancers. The future of GLP-1 drugs remains promising, but ongoing research will be key to fully understanding their long-term effects and potential adverse events.

Paloma Health’s weight loss treatments prioritize a personalized approach to ensure the safest and most effective outcomes when considering GLP-1 drugs. Paloma’s process involves working closely with patients to evaluate individual risks and benefits, particularly in light of emerging research on the potential cancer risks and protective effects of GLP-1 receptor agonists. For example, while some studies suggest short-term elevated vigilance for thyroid cancer risk during initial treatment phases, others highlight significant reductions in obesity-related cancer risks, such as gastrointestinal and pancreatic cancers, with specific GLP-1 medications like semaglutide. At Paloma Health, the focus is on comprehensive risk assessment, tailored dosing strategies, and ongoing monitoring to optimize treatment outcomes while addressing any concerns about long-term safety. Learn more about Paloma’s personalized weight loss treatments now.

• GLP-1 receptor agonists (Ozempic, Wegovy, Victoza, Saxenda, Trulicity) help regulate blood sugar and promote weight loss, with potential anti-inflammatory and neuroprotective benefits.
• Cancer risk concerns vary by drug type; semaglutide may protect against cancers like gastrointestinal and uterine cancers, while liraglutide has been linked to higher breast and thyroid cancer risks.
• Thyroid cancer risks are debated, with some studies suggesting an increased risk, particularly of medullary thyroid carcinoma (MTC), but large-scale analyses show no significant association.
• Pancreatic and neuroendocrine cancer risks remain unclear; while some experimental studies show increased tumor growth, real-world data do not confirm an elevated risk.
• Gastrointestinal and obesity-related cancers may see reduced risks with GLP-1 use, possibly due to weight loss, improved insulin sensitivity, and anti-inflammatory properties.
• Clinical recommendations emphasize personalized risk assessments, high-risk patient screening, and regular monitoring for those on long-term GLP-1 therapy.