Studies demonstrate conflicting findings on the impact of antidiabetic agents on cancer risk

Certain antidiabetic agents (ie, insulin and thiazolidinediones) have been found to be associated with increased cancer risk; however, other studies suggested that metformin may have anticarcinogenic potential, according to a presentation at APSC 2018.

“Cancer risk in patients [with diabetes] who had been using metformin [may be reduced as] metformin can have an anticarcinogenic effect through a lot of potential mechanisms … [However,] there is still some concern with some types of antidiabetic drugs,” said Dr Tseng Chin-Hsiao from the College of Medicine of the National Taiwan University in Taipei, Taiwan.

Insulin and cancer

In breast cancer for instance, breast epithelial cells can express insulin receptors, which are upregulated in breast cancer cells, noted Tseng. “[W]hen a patient has insulin resistance, the [introduction] of insulin would increase the physiological concentration of insulin in the blood,” Tseng explained.

Consequently, the elevated insulin levels may divert insulin from its metabolic to cell-proliferating effects, fostering cell growth and inducing cancer potential, he added.

Conflicting links with thiazolidinediones

Evidence on thiazolidinediones (ie, pioglitazone and rosiglitazone) demonstrates conflicting results.  In one study, a 20-percent increased bladder cancer risk was found with pioglitazone, but not rosiglitazone (adjusted hazard ratio [adjHR], 1.20, 95 percent CI, 0.9–1.5). [Diabetes Care 2011;34:916-922] This was further supported by a Taiwan study, which revealed a higher bladder cancer incidence between pioglitazone ever- vs never-users (1 vs 0.8/1,000 person-years, adjHR, 1.31, 95 percent CI, 0.66–2.58). [Diabetes Care 2012;35:278-280]

In 2013, the International Agency for Research on Cancer agreed that pioglitazone may have carcinogenic potential, noted Tseng. “[However, we couldn’t] say that it really is carcinogenic,” he clarified.

Nonetheless, other studies contradicted these results and found no association between pioglitazone and increased bladder cancer risk. [JAMA 2015;314:265-277; BMJ 2016;354:i3903; Lancet Diabetes Endocrinol 2017;5:887-897]

Tseng highlighted that potential confounders such as kidney or urinary tract disease (ie, infections, stones) should be taken into consideration when establishing a link between bladder cancer and thiazolidinediones.

Metformin potentially anticarcinogenic

On the other hand, metformin has been found to be associated with a reduced risk of pancreatic, hepatocellular, and colorectal cancers, with a 50-percent risk reduction among Taiwanese subjects. [Am J Gastroenterol 2013;108:510-519; Am J Gastroenterol 2013;108:881-891; Cancer Epidemiol Biomarkers Prev 2013;22:2258-2268; Diabetes Metab 2017;43:438-445]

Compared with never-users, metformin ever-users also had a reduced risk of breast and skin cancers (adjHR, 0.63; p<0.0001 and HR, 0.54; p=0.0037, respectively). [Breast Cancer Res Treat 2014;145:785-790; J Am Acad Dermatol 2018;78:694-700]

Thyroid cancer risk also did not increase with metformin (odds ratio, 0.70) which, according to Tseng, could have been brought about by the inhibition of thyroid-stimulating hormone by metformin. [PLoS One 2012;7:e53096]

Given the extensive evidence demonstrating the preventive effect of metformin on various types of cancer, trials are being conducted to investigate the potential usefulness of metformin as a cancer chemotherapeutic adjunct or a cancer preventive agent, said Tseng.

High mortality risk

Patients with diabetes have a 28-percent higher risk of mortality from cancer compared with the general Taiwanese population. [Diabetes Care 2004;27:1605-1609] “The mechanisms are multifactorial and can be related to hyperglycaemia, insulin resistance, hyperinsulinaemia, increased oxidative stress, higher inflammatory status, disturbed metabolism, and [antihyperglycaemic agents],” said Tseng.

Moreover, comorbidities such as obesity and dyslipidaemia could be contributing factors that may influence patients’ predisposition to cancer. Further studies are thus warranted to ascertain the link between cancer risk and antidiabetic agents, he added.