Effect of Antidiabetic Medications on Cancer Risk: Mechanisms and Clinical Evidence

Abstract

Introduction: The increasing body of evidence suggests that antidiabetic drugs have a highly complex and context-specific interrelation with cancer risk, which is affected through the interplay of metabolic dysregulation, pharmacological processes, and oncogenic signalling pathways.

Objectives: This epidemiological, clinical, and mechanistic review combines the available epidemiological, clinical, and mechanistic data to investigate the effect of various classes of antidiabetic drugs on cancer development and progression.

Methods: We reviewed the recent literature to find out effect of antidiabetic medications on cancer risk.

Results: Antidiabetic therapies have a heterogeneous impact, i.e. either protective or promotive based on the drug class, length of exposure, biological context and patient-specific characteristics. Metformin is the most consistently inverse related agent to cancer incidence and mortality of the existing agents. Its ability to induce AMP-activated protein kinase (AMPK), suppress mammalian target of rapamycin (mTOR) signalling and mitigate hyperinsulinemia-induced mitogenic pathways gives it great biological plausibility for these protective actions. Conversely, insulin therapy and insulin secretagogues, including sulfonylureas, could elevate cancer risk in some circumstances by raising insulin levels in the body and stimulating insulin and insulin-like growth factor-1 (IGF-1) receptor signalling, which promotes cell proliferation and suppresses apoptosis. Other drugs such as thiazolidinedione classes, incretin-based therapy and sodium-glucose cotransporter-2 (SGLT2) are in a middle range, there being emerging mechanistic data but inconsistent clinical results. Nevertheless, important gaps are present in heterogeneity in the study design, confounded by the severity of the disease, and insufficient cancer-specific endpoints in the randomized controlled trials. These insights are the reasons for the need for highly powered studies and precision medicines.

Conclusions: The inclusion of cancer risk assessment in diabetes care could enhance efficacy in decision-making in therapeutic settings especially high-risk groups and rational identification and repurposing of antidiabetic drugs with oncological utility.