Is there an increased cancer risk associated with Glucagon-like peptide (GLP)?

From the Guidelines

There is no established link between GLP-1 receptor agonists and increased cancer risk in humans, as evidenced by large clinical trials and post-marketing surveillance, including the EXSCEL trial which found no significant difference in the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events between the exenatide group and the placebo group 1. The current evidence from studies such as the EXSCEL trial, which reported results with the once-weekly GLP-1 receptor agonist extended-release exenatide, found that major adverse cardiovascular events were numerically lower with use of extended-release exenatide compared with placebo, although this difference was not statistically significant 1. Some key points to consider include:

• Early animal studies with some GLP-1 medications showed an increased risk of thyroid C-cell tumors in rodents, which is why these medications carry a boxed warning about medullary thyroid carcinoma 1.
• However, this effect appears to be rodent-specific and has not been observed in humans, as supported by the findings of the EXSCEL trial 1.
• As a precaution, these medications are contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2.
• Some patients may experience concerns about pancreatic cancer risk, but long-term studies, such as the EXSCEL trial, have not confirmed any increased risk 1.
• If you're taking or considering a GLP-1 medication for diabetes or weight management, the benefits typically outweigh theoretical risks, but always discuss any specific concerns with your healthcare provider who can evaluate your individual risk factors. It's also worth noting that the GLP-1 receptor agonists have been shown to have cardiovascular benefits, as demonstrated by the LEADER trial, which found a benefit in cardiovascular outcomes with GLP-1 receptor agonists 1. Overall, the evidence suggests that GLP-1 receptor agonists are safe and effective for the treatment of diabetes and weight management, with no established link to increased cancer risk in humans.

From the FDA Drug Label

A 104-week carcinogenicity study was conducted in male and female CD-1 mice at doses of 0.03,0.2,1.0, and 3.0 mg/kg/day liraglutide administered by bolus subcutaneous injection yielding systemic exposures 0.2-, 2-, 10- and 45-times the human exposure, respectively, at the MRHD of 1. 8 mg/day based on plasma AUC comparison. A dose-related increase in benign thyroid C-cell adenomas was seen in the 1.0 and the 3.0 mg/kg/day groups with incidences of 13% and 19% in males and 6% and 20% in females, respectively. C-cell adenomas did not occur in control groups or 0.03 and 0.2 mg/kg/day groups. Treatment-related malignant C-cell carcinomas occurred in 3% of females in the 3. 0 mg/kg/day group. A 104-week carcinogenicity study was conducted in male and female Sprague Dawley rats at doses of 0.075,0.25 and 0. 75 mg/kg/day liraglutide administered by bolus subcutaneous injection with exposures 0.5-, 2- and 8-times the human exposure, respectively, resulting from the MRHD based on plasma AUC comparison. A treatment-related increase in benign thyroid C-cell adenomas was seen in males in 0.25 and 0. 75 mg/kg/day liraglutide groups with incidences of 12%, 16%, 42%, and 46% and in all female liraglutide-treated groups with incidences of 10%, 27%, 33%, and 56% in 0 (control), 0.075,0.25, and 0. 75 mg/kg/day groups, respectively. A treatment-related increase in malignant thyroid C-cell carcinomas was observed in all male liraglutide-treated groups with incidences of 2%, 8%, 6%, and 14% and in females at 0.25 and 0.75 mg/kg/day with incidences of 0%, 0%, 4%, and 6% in 0 (control), 0.075,0.25, and 0. 75 mg/kg/day groups, respectively.

The GLP-1 receptor agonist liraglutide has been associated with an increased risk of thyroid C-cell tumors in animal studies. Key findings include:

• Benign thyroid C-cell adenomas were seen in mice and rats treated with liraglutide.
• Malignant thyroid C-cell carcinomas were also observed in mice and rats treated with liraglutide. However, the human relevance of these findings is unknown and has not been determined by clinical studies or nonclinical studies 2.

From the Research

Increased Cancer Risk with GLP-1 Receptor Agonists

• The relationship between GLP-1 receptor agonists and cancer risk is complex, with varying effects on different types of cancer 3.
• Some studies suggest that GLP-1 receptor agonists may be associated with a lower risk of certain cancers, such as prostate, lung, and colon cancer 3.
• However, other studies have found that GLP-1 receptor agonists may be associated with a higher risk of thyroid cancer 3.
• A systematic review and meta-analysis found that treatment with GLP-1 receptor agonists does not increase the risk of breast neoplasms 4.
• The evidence suggests that the risk of cancer associated with GLP-1 receptor agonists may depend on the specific type of cancer and the duration of treatment 3.

Specific Cancers and GLP-1 Receptor Agonists

• Prostate cancer: GLP-1 receptor agonists may be associated with a lower risk of prostate cancer, with an adjusted odds ratio (aOR) of 0.81 3.
• Lung cancer: GLP-1 receptor agonists may be associated with a lower risk of lung cancer, with an aOR of 0.81 3.
• Colon cancer: GLP-1 receptor agonists may be associated with a lower risk of colon cancer, with an aOR of 0.85 3.
• Thyroid cancer: GLP-1 receptor agonists may be associated with a higher risk of thyroid cancer, with an aOR of 1.65 3.
• Breast cancer: Treatment with GLP-1 receptor agonists does not increase the risk of breast neoplasms, with a relative risk (RR) of 0.98 4.