By Dr. Liji Thomas, MD Jul 25 2023 Reviewed by Danielle Ellis, B.Sc.

Type 2 diabetes melllitus (T2DM) is a common disease, the prevalence of which is increasing exponentially. It is estimated that by 2030, almost 440 million adults below the age of 80 will have diabetes. The consequences of T2DM on health and mortality have long been a focus of study. However, the medications used to control this dreaded disease have their effects on the body, causing specific adverse effects. Study: Diabetes medications and cancer risk associations: a systematic review and meta-analysis of evidence over the past 10 years. Image Credit: fizkes/Shutterstock.com

Cancer is found to occur at higher rates in people with diabetes, probably because both are associated with common risk factors. Diabetes drugs may also contribute to the risk of cancer.

In an attempt to discern the risk of cancer posed by certain diabetic drugs as well, the authors of a recent paper performed a systematic review and meta-analysis of all studies over the past ten years dealing with this topic. The research was published in Scientific Reports. Introduction

Cancer risk factors among people with diabetes include smoking, lack of physical exercise, overweight, and poor dietary quality. These reflect a state of inflammation, high blood sugar levels, and excessive amounts of insulin in the blood. Several studies have also shown that certain cancers occur more often among those who use specific diabetes drug categories.

The current review aimed to bring together the risk of multiple cancer types at various sites with the different types of medication used to treat diabetes. Earlier studies have looked mostly at how one class of medication affects cancer risk at different sites or, conversely, how all diabetes drugs affect cancer risk overall. The main focus remained on cancers of the breast, lung, liver, and pancreas, as well as CRCs.

The various drug classes explored were biguanides, those based on incretins, alpha-glucosidase inhibitors (AGIs), insulin secretagogues, thiazolidinediones, and insulins. What did the study show?

The review included 92 studies, of which three were randomized controlled trials (RCTs), while the majority (64) were cohort studies. The remaining comprised case-control studies. All three RCTs suffered from poor design, leading to a high risk of bias. Related StoriesUSC study reveals key details about how cancer cells metastasizeUnderstanding the impact of HPV on the vaginal microbiome and its role in cervical cancerWhat is the relative burden of oncologic and nononcologic mortality among long-term survivors of cancer in the US?

The cohort studies were mostly at low risk of bias, as were the case-control studies. The most studied cancers were CRCs and pancreatic cancers. Breast and lung cancers were mostly studied in cohort studies. Lung and liver cancers, and CRCs, were studied in both Asian and Western regions, whereas most research on breast, prostate, and pancreatic cancer was carried out in Western populations.

The results showed that colorectal cancer (CRC) and liver cancer occurred at lower rates among diabetic patients who used biguanides to control their blood sugar levels. The risk of liver cancer was reduced by an impressive 45% and that of CRC by 15%. In case-control studies alone, biguanide use was linked to an increase in pancreatic cancer odds by 25%.

Biguanides regulate energy and cellular metabolism, reducing the levels of oxidative stress, inflammation, and apoptosis, along with reduced body fat formation.

Similarly, breast cancer and liver cancer risk were reduced by about 15% with thiazolidinedione use, while the odds of lung cancer were lowered by 44%. These medications reduce the rates of breast cancer cell division and promote apoptosis while restricting neovascularization of tumors. In the liver, these agents cause the protein p27Kip1 to accumulate, limiting liver cell growth and, thus, perhaps, preventing cancerous changes.

Insulin use was linked to a 25% reduction in the odds of prostate cancer and a 10% drop in breast cancer odds. However, insulins were associated with massive increases in the risk of two cancers; pancreatic cancer risk went up by 240%, while there was a 74% increase in the risk of liver cancer.

The raised liver cancer risk was only among Western populations using insulin, with an increase of 250% in this subgroup. Insulin-resistant patients have high insulin levels in the portal circulation, which reaches the liver, and this might account for some of the risks.

Pancreatic cancers might form or grow faster when exposed to insulin, which promotes growth and cell division. However, severe diabetes is itself a risk factor of pancreatic cancer, adding a confounding factor to the etiology.

With insulin secretagogues, the risk of pancreatic cancer went up by 26%. Cohort studies, but not case-control series, showed a 20% rise in associated CRC following insulin secretagogue use. These agents promote insulin secretion by the pancreas, thus raising insulin-like growth factor 1 levels. Enhancing the rate of cell division may promote pancreatic cancer. What are the implications?

Overall, biguanide and thiazolidinedione use carried no risk, or potentially lower risk of some cancers, while insulin secretagogue and insulin use were associated with increased pancreatic cancer risk.”

The benefits of several medications used to treat diabetes extend to a reduction in the associated risk of cancer. At the same time, the risk of pancreatic and liver cancer shot up in association with the use of insulin and of pancreatic cancer with insulin secretagogues, though to a much lesser extent.

While showing associations between medication classes and cancer risk, the study also emphasizes regional differences as well as discrepancies between different study designs. Other confounding factors may have been at work, such as differences in nutritional status.

These findings suggest that it may be important to weigh the potential harms of insulin among patients with diabetes who are at high risk of liver or pancreatic cancers due to family history or other risk factors.” Journal reference: Chen, Y. et al. (2023) "Diabetes medications and cancer risk associations: a systematic review and meta-analysis of evidence over the past 10 years", Scientific Reports, 13(1). doi: 10.1038/s41598-023-38431-z. https://www.nature.com/articles/s41598-023-38431-z