Other therapies and cancer
The relationship between type 2 diabetes and some types of cancer is complex, and there has been considerable interest in the possibility that therapies used for diabetes might modulate this relationship for better or worse. In general, metformin has been associated with a better outcome in observational studies, and insulin with a worse outcome; in neither case has a clear causal relationship been established. These are discussed separately. Of the remaining therapies, sulfonylureas may be associated with increased cancer risk and a worse prognosis, possibly mediated by hyperinsulinaemia. Both positive and negative effects have been reported with the thiazolidinediones (TZDs) but pioglitazone, the only member of the class in routine use, has been associated with an increased risk of bladder cancer. The GLP-1 agonists have come under suspicion with respect to thyroid medullary cancer and pancreatic adenocarcinoma, and the DPP4 inhibitors might also be implicated. It should be emphasised that most of the postulated effects have yet to be proved beyond doubt, and this remains an area of considerable methodological difficulty and controversy. This article provides an overview, and the TZDs and GLP-1 based therapies are considered in greater detail in daughter sections.
The sulfonylureas (SUs) have in general attracted relatively little interest in relation to cancer, as compared with other agents. A Canadian study reported an increased cancer mortality in patients with type 2 diabetes treated with sulfonylureas or insulin, as compared with metformin, but could not distinguish between a protective effect of metformin or a deleterious effect of the other therapies. Similar findings came from a study in the UK, which once again found a similar pattern of risk for both therapies in relation to the same cancers. Both insulin and SUs are associated with increased insulin levelswhich might potentially explain the difference. See Hyperinsulinemia and cancer.
The thiazolidinediones, otherwise known as the TZDs or glitazones, have had a troubled history. Troglitazone, the first agent in the class, was launched in 1997 and withdrawn in 2000. Rosiglitazone and pioglitazone were launched in 2000, but rosiglitazone was withdrawn in many countries in 2010 because of adverse cardiovascular effects, and pioglitazone was withdrawn in France and Germany in 2012 because of an increased rate of bladder cancer in men. The TZDs are agonists acting upon the nuclear PPAR-gamma receptor, and modulate expression of a large number of genes with metabolic and other actions. This pleiotropic range of actions may help to explain the wide range of unwanted effects associated with their use. These consequences do however include potentially useful effects upon some types of cancer, and (like metformin) TZDs are currently in clinical trial as adjuvants to cancer therapy. See TZDs and cancer
The GLP-1 based therapies
An innovative approach to the therapy of diabetes has been based upon the properties of the gut hormone Glucagon-Like Peptide-1 (GLP-1). GLP-1 has a range of actions that are potentially useful in type 2 diabetes, including potentiation of insulin release in response to food, inhibition of glucagon secretion, delayed gastric emptying and central effects upon appetite. GLP-1 itself has a very short half-life, and is thus of limited therapeutic value. This limitation has been overcome by inhibition of the dipeptidyl peptidase-4 (DPP-4) enyzmes that normally inactivate GLP-1. An alternative approach has been the development of GLP-1 analogues resistant to enzymatic degradation. GLP-1 receptors are widely distributed in the body, establishing the potential for off-target effects impacting upon the exocrine pancreas, thyroid, cardiovascular system, kidneys and other tissues. DPP-4 inhibition might also have unpredictable consequences for other regulatory pathways. Animal studies have identified an increased risk of C-cell thyroid tumours in rats, and a signal for human pancreatic adenocarcinoma has been detected in two regulatory databases. See GLP-1 based therapies and cancer