Abstract
According to the International Diabetes Federation, there are currently 382 million people affected by diabetes, and it is estimated that this will increase to 592 million by 2035. 1 At the same time, a recent World Health Organization (WHO) fact sheet reported that worldwide cancer incidence will increase from 14 million today to 22 million in 2032, 2 and there is a developing concern that a link between diabetes and some cancers may be fuelling this latter increase.
As reviewed by Joost and Lutz et al. in this issue, the relative risk of developing different cancer types is increased in patients with type 2 diabetes mellitus (T2DM), for example, breast cancer by ~20%, colon cancer by 30%–40% and pancreatic cancer by 70%–90%. As outlined in these excellent reviews, numerous studies have indicated that hyperinsulinaemia, either endogenous as a response to insulin resistance, or by the use of secretagogues, such as sulphonl yureas, or excessive use of exogenous insulin, is associated with an increase cancer risk. 3 Possible pathophysiological mechanisms include the activation of mitogenic pathways via the insulin receptor and/or the receptor for insulin-like growth factor I by increased insulin levels. 3
The global use of sulphonylureas is related to its low cost, but this group of drugs are associated with increased, occasionally severe, hypoglycaemia, which in rare cases may be associated with a fatal outcome, and there is mounting evidence that their use is associated with increased cardiovascular and total mortality. 4 Thus, together with the increased cancer risk in T2DM treated with sulphonylureas, the benefit–risk ratio is not in favour of indiscriminate widespread use of this class of drug. Moreover, with the increased worldwide access to other therapeutic options, such as dipeptidyl peptidase 4 (DPP-4) and sodium-glucose linked transporter 2 (SGLT2) inhibitors, which do not cause these side effects, there are effective alternatives available when metformin as monotherapy no longer achieves the desired HbA1c target.
The chronic progressive nature of T2DM is associated with a gradual decline in insulin secretion of approximately 4% per year. This frequently leads to a requirement for insulin therapy to achieve an adequate level of glycaemic control. To avoid unnecessary high doses of insulin, which may lead to increased hypoglycaemia, weight gain and a potential for an increased cancer risk, there are important recommendations to follow, which can be summarised in the following principles.
Fix fasting first. If fasting plasma glucose is not at the target using current therapy, initiate insulin therapy by adding basal insulin before the night to achieve fasting plasma glucose values at the target, while avoiding nocturnal hypoglycaemia.
Combine insulin therapy with co-medications known to have beneficial effects to reduce insulin requirements, for example, metformin, SGLT2 inhibitors, glucagon-like peptide 1 (GLP1) receptor agonists, if there are no contraindications/intolerances.
Use as much insulin as needed, but as little as possible.
If we follow this guidance by avoiding treatment with sulfonylureas and the use of unnecessarily high dosages of insulin in our treatment algorithms for patients with T2DM, we should be able to reduce the risks associated with insulin, providing therapies including increased cancer risk.