Diabetes Pharmacotherapy and Cancer Risk

Emerging evidence highlights a complex interplay between treatments for diabetes and the risk of developing malignancies. Metabolic disturbances inherent to diabetes mellitus – notably hyperglycaemia, hyperinsulinaemia and chronic inflammation – can promote cellular proliferation and DNA damage, creating a permissive environment for tumour initiation and progression. Pharmacotherapeutic agents that modulate glucose homeostasis may alter these pathways: for example, metformin activates AMPK and reduces hepatic gluconeogenesis, potentially exerting antineoplastic effects, whereas exogenous insulin or insulin secretagogues may amplify mitogenic signalling through the insulin/IGF-1 axis. Observational studies have reported variable associations with site-specific cancers, complicated by confounding factors such as disease duration, obesity and concomitant therapies. Contemporary molecular and genetic approaches seek to clarify causality, while drug-repurposing strategies aim to exploit off-target anticancer properties of established antidiabetic agents. A nuanced understanding of these interactions is essential to optimise glycaemic management without compromising long-term oncological outcomes, and to harness potential chemopreventive actions in diabetic populations worldwide.

Research from Nature Portfolio

A foundational study using a transgenic mouse model of prostate cancer demonstrated that the sulfonylurea glipizide suppresses tumour growth and metastasis by inhibiting angiogenesis rather than through direct cytotoxicity. In treated tumours, microvessel density was markedly reduced and endothelial tubular formation was impaired, effects linked to modulation of angiopoietin-1 signalling. This work established that a widely used antidiabetic compound can be repurposed to target tumour neovascularisation, illustrating the potential for chronic diabetes medications to influence cancer biology beyond glycaemic control.

Diabetes Pharmacotherapy and Cancer Risk publication trend

The graph below shows the total number of articles in diabetes pharmacotherapy and cancer risk across all publications each year (not limited to Nature Index journals).

Technical terms

Mendelian randomisation: A genetic epidemiology method using inherited variants as proxies for modifiable exposures to infer causal effects on disease outcomes.

Peroxisome proliferator-activated receptor γ (PPARG): A nuclear transcription factor targeted by thiazolidinediones that regulates adipogenesis and insulin sensitivity.

Sulfonylurea receptor (ABCC8/KCNJ11): Components of ATP-sensitive potassium channels in pancreatic β-cells that mediate insulin secretion in response to sulfonylurea drugs.

Dipeptidyl peptidase 4 (DPP4): An enzyme that degrades incretin hormones; its inhibition prolongs insulinotropic effects and modulates immune-inflammatory pathways.

Angiogenesis: The process of new blood vessel formation, exploited by tumours to secure oxygen and nutrient supply for growth and metastasis.

References

1. Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis. Diabetologia (2023).
2. Association of glucose-lowering drug target and risk of gastrointestinal cancer: a mendelian randomization study. Cell & Bioscience (2024).
3. Repurposing of Chronically Used Drugs in Cancer Therapy: A Chance to Grasp. Cancers (2023).
4. Glipizide suppresses prostate cancer progression in the TRAMP model by inhibiting angiogenesis. Scientific Reports (2016).