Diabetes, Antidiabetic Medications and Cancer Risk in Type 2 Diabetes: Focus on SGLT-2 Inhibitors

Abstract

In the last decade, cancer became the leading cause of death in the population under 65 in the European Union. Diabetes is also considered as a factor increasing risk of cancer incidence and mortality. Type 2 diabetes is frequently associated with being overweight and obese, which also plays a role in malignancy. Among biological mechanisms linking diabetes and obesity with cancer hyperglycemia, hyperinsulinemia, insulin resistance, increased levels of growth factors, steroid and peptide hormones, oxidative stress and increased activity of pro-inflammatory cytokines are listed. Antidiabetic medications can modulate cancer risk through directly impacting metabolism of cancer cells as well as indirectly through impact on risk factors of malignancy. Some of them are considered beneficial (metformin and thiazolidinedions-with the exception of bladder cancer); on the other hand, excess of exogenous insulin may be potentially harmful, while other medications seem to have neutral impact on cancer risk. Inhibitors of the sodium-glucose cotransporter-2 (SGLT-2) are increasingly used in the treatment of type 2 diabetes. However, their association with cancer risk is unclear. The aim of this review was to analyze the anticancer potential of this class of drugs, as well as risks of site-specific malignancies associated with their use.

Keywords: DPP-4 inhibitors; GLP-1 receptor agonists; insulin; metformin; sulfonylureas; thiazolidinedions.

Figure 1

Schematic presentation of types of insulin and IGF receptors and post-receptor effects after binding to their ligands (based on [34,35,36,37,38,40]). PI3K—phosphatidylinositol 3-kinase; PKB—protein kinase B; PKC—protein kinase C; Fox—forkhead box protein; PDE3B—phosphodiesterase 3B; GLUT-4—glucose transporter-4; GSK3—glycogen synthase kinase 3; ERK—extracellular signal-regulated kinases; mTOR—mammalian target of rapamycin, p70S6—p70S6kinase. Solid lines: main pathways activated by ligand binding, dotted lines: additional pathways.

Figure 2

A simplified view of the relationship between obesity, diabetes and related metabolic disorders and cancer risk (based on [29,30,31,32,33,34,35,36,37,43,44,45,46,47,48,63,64,65,66]). IGFBP—insulin-like growth factor binding protein; SHBG—sex hormone binding globulin; VEGF—vascular endothelial growth factor; PAI-1—plasminogen activator inhibitor-1; TNF-α—tumor necrosis factor-α; MCP-1—Monocyte Chemoattractive Protein-1, CRP—C-reactive protein; IL-6—interleukin-6; IL-1β—interleukin 1β; IL-32—interleukin-32; IR-A—insulin receptor A; ROS—reactive oxygen species; AGE—advanced glycation end-products; RAGE—receptor for AGE; NF-κB—nuclear factor kappa B.

Figure 3

Forest plot of meta-analysis of the risk of neoplasms incidence for SGLT-2 inhibitors vs. placebo in cardiovascular and renal outcome trials. The size of the square box is proportional to the weight that each study contributes in the meta-analysis. The overall estimate and CI are marked by a diamond.