Correlation Between T2DM and Cancer Risk

A recent study suggests strengthening cancer screening recommendations may be beneficial in patients with T2DM.

The relationship between diabetes and cancer risk has been reviewed in several studies throughout the years. Many have suggested that hyperinsulinemia and shared risk factors between the two diseases could be among the mechanisms responsible for the increased risk. Epidemiologic studies have associated T2DM with a lower risk of prostate cancer but a higher risk of kidney, colorectal, liver, breast, and pancreatic cancer, as well as a higher risk for overall cancer; however, studies have been inconsistent.

A recent study sought to evaluate the causal association between T2DM and the risk of overall and site-specific cancer. To assess this relationship, researchers performed a two-sample Mendelian randomization (MR) study evaluating the exposure-outcome association using genetic variants as proxy risk factors. This method reduces the chance of confounding and eliminates the reverse causality seen in other observational studies. This study also evaluated the relationship between cancer risk, fasting glucose, and fasting insulin levels using secondary analysis and a meta-analysis of available MR studies. Researchers collected data from the DIAbetes Genetics Replication And Meta-analysis consortium, the Breast Cancer Association Consortium, the Pancreatic Cancer Case-Control Consortium, UK Biobank, the Meta-Analyses of Glucose and Insulin-related traits Consortium, and the Pancreatic Cancer Cohort Consortium.

The different sources used to collect data included participants from European descent, and most studies reported the number of cancer cases from a cancer registry or hospital data. Researchers used SNPs as instrumental variables for T2DM, fasting glucose, and fasting insulin to control for confounding, and these were selected based on results from previously published studies. This analysis did not include SNPs in or near the FTO gene region due to previous reports that BMI entirely drives the effects of diabetes and fasting insulin-related genetic variants in this gene. The final analysis included a total of 399 SNPs for T2DM, 35 for fasting glucose, and 17 for fasting insulin, as well as 295 SNPs for T2DM that were used in the sensitivity analysis. To reduce BMI’s influence on the results, investigators used a multivariable MR method adjusting for BMI. Researchers used OR, I2, and sensitivity analysis to evaluate the data, and results were interpreted based on the strengths of association and consistency across studies rather than on p values.

Researchers reported the OR per 1 unit increase in genetically predicted log odds of T2DM for pancreatic cancer as 1.13, 1.08 for kidney cancer, 1.08 for uterine cancer, and 1.07 for cervical cancer, suggesting higher odds of association between these and T2DM. In contrast, the OR for melanoma and esophageal cancer was 0.93 and 0.89, respectively. These findings were also consistent among analyses using SNPs for T2DM. Therefore, researchers concluded there was evidence of associations between genetic liability to T2DM and a higher risk of kidney, uterine, cervical, and pancreatic cancer, but a lower risk of melanoma and esophageal cancer. On the other hand, an association with overall cancer risk was not seen in either the primary analysis or the sensitivity analysis. This study also contradicts previously published studies as it found limited evidence supporting a causal relationship between T2DM and a lower risk of prostate cancer. Results from the meta-analysis additionally showed no evidence of an association between fasting glucose and five site-specific cancers. However, there was some evidence that genetically predicted high fasting insulin levels increased the risk of kidney, uterus, lung, and pancreatic cancer.

This study thoroughly evaluated the association between T2DM, overall cancer risk, and 22 site-specific cancers. Other studies have also assessed the relationship between prediabetes and cancer risk and have found similar results. A meta-analysis that included 891,426 participants found that patients with prediabetes were also at increased risk of cancer, mostly attributed to insulin resistance. Therefore, both patients with diabetes and those with prediabetes may benefit from increased surveillance and cancer screening. Special consideration should be given to cancer screening for pancreatic, kidney, uterine, and cervical cancer as these may occur more frequently in these patients. Further studies are needed to establish a clear relationship between diabetes and cancer risk; however, based on this study’s results, glucose control and cancer surveillance could facilitate improved quality of life and survival in these patients.

Practice Pearls: 

• Patients with T2DM have a higher risk of pancreatic, kidney, uterine, and cervical cancer but a lower risk of melanoma and esophageal cancer. 
• High fasting insulin may increase the risk of kidney, uterus, lung, and pancreatic cancer.
• Closer monitoring for certain site-specific cancers may be beneficial in patients with T2DM.

Yuan, et al. “Is Type 2 Diabetes Causally Associated With Cancer Risk? Evidence From a Two-Sample Mendelian Randomization Study”. Diabetes Care, vol 69, issue 7, 2020, pp 1588-1596. doi: 10.2337/db20-0084 

Huang, et al. “Prediabetes and the Risk of Cancer: A Meta-Analysis.” Diabetologia, U.S. National Library of Medicine. doi: 10.1007/s00125-014-3361-2 

Leyany Feijoo Ramos, PharmD. Candidate, LECOM School of Pharmacy