VU Research Portal Type 2 diabetes, its pharmacological treatment and associations with cancer Overbeek, J.A. 2019 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Overbeek, J. A. (2019). Type 2 diabetes, its pharmacological treatment and associations with cancer: (Pharmaco)epidemiological studies based on data from the PHARMO DIAMANT cohort. 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Sep. 2021 CHAPTER 1 General introduction, outline and data sources CHAPTER 1 INDEX Diabetes Diabetes mellitus, commonly referred to as diabetes, is one of the largest global health emergencies of the 21st century.1 It is associated with high disability and premature mortality and symptoms of this chronic metabolic disease include increased urination and excessive thirst and hunger. Furthermore, diabetes is characterised by hyperglycaemia (i.e. elevated blood glucose levels) which is associated with both micro- (neuropathy, retinopathy, nephropathy) and macrovascular complications (coronary artery disease, cerebrovascular disease),2, 3 which have a substantial negative influence on a person’s quality of life. Worldwide, the prevalence of diabetes in 2015 is estimated at 415 million.1 Despite better awareness and new developments in treatment of diabetes and prevention of type 2 diabetes (T2D), the number of persons with diabetes increases. In most countries, this increase was alongside cultural and social changes: ageing populations, increasing urbanisation, reduced physical activity and increased overweightness. In the Netherlands, more than 1.1 million persons had diabetes (69.7 per 1,000 men and 62.9 per 1,000 women) in 2017.4 Type 1 diabetes (T1D) and T2D are the major forms of diabetes, T1D accounts for 5-10% of all diabetes cases and T2D for 90-95%. In T2D, there is a relative insulin deficiency resulting from a progressive insulin secretory defect on the background of insulin resistance. Genetic and environmental factors, such as excess body weight and lack of physical activity seem to contribute to onset of the disease. The current thesis mainly focuses on T2D. In the Netherlands, T2D is mainly treated by general practitioners (GPs). Treatment usually starts with lifestyle management by smoking cessation, increase in physical activity, weight control and a healthy diet to decrease hyperglycaemia. As the disease progresses, pharmaceutical treatment is usually required. Since 2006, the Dutch diabetes guideline for GPs, issued by the Dutch College of GPs (NHG guideline T2D)5 recommends a step-wise approach with metformin as the first drug. Addition of a sulfonylurea (SU) derivative is recommended if glycaemic control is not achieved. If persons do not reach the HbA1c target with this combination, insulin should be added. Since July 2018, this step-wise approach was updated and instead of adding insulin to the combination of metformin and SU, there is now also room for the addition of a newer incretin-based therapy (i.e. dipeptidyl-peptidase-4 [DPP-4] inhibitors and glucagon- like peptide-1 [GLP-1] receptor agonists).6 The aim of the guideline is to prevent or delay the occurrence of micro- and macrovascular complications. Cancer Cancer is a group of diseases that are referred to as malignant neoplasms. Malignant neoplasms are characterised by abnormal cell growth and division and have the potential 10 CHAPTER 1 INDEX to invade or spread to other parts of the body. In the Netherlands, the 10-year prevalence of cancer almost doubled from 1.8% in 1999 to 3.3% in 2016 and is expected to increase further.7 In 2016, the most occurring cancer types were prostate, colon and skin (excluding basal cell carcinoma) cancer among men and breast, skin (excluding basal cell carcinoma) and colon cancer among women.8 Association between type 2 diabetes and cancer Because of the increased prevalence of both diabetes and cancer, it is likely that these diseases also occur together more often within the same individual. In the Netherlands, the number of people with both diabetes and cancer doubled in the past 15 years.9 Epidemiological studies suggest that people with diabetes are at significantly higher risk for many forms of cancer. Meta-analyses of cohort studies10-16 show increased risks of cancer ranging from 1.25 for breast cancer to 2.23 for hepatocellular carcinoma. On the contrary, in men with T2D a decreased risk of prostate cancer is observed (RR = 0.84; 95% CI: 0.76-0.93).17 Several mechanisms have been proposed for the increased risk of cancer among people with T2D, such as common risk factors, the specific metabolic derangements of diabetes itself (i.e. hyperglycaemia, hyperinsulinemia and insulin resistance) and the use of glucose lowering drugs. Common risk factors It has been published that diabetes and cancer have several risk factors in common, such as older age, obesity, lack of physical activity and poor diet. Increasing age is associated with diabetes, because of bodily resistance to insulin due to increased adiposity, decreased lean muscle mass, changes in dietary habits, and reduced physical activity.18 Furthermore, the pancreas starts to produce insulin less effectively as age increases.19 For cancer, advancing age is the most important risk factor. Older individuals might be more susceptible to oncogenic mutations or cells might need time to accumulate enough mutations to become cancerous.20 Obesity, mainly due to anthropometric parameters and lifestyle factors, activates different biological mechanisms (e.g. hyperinsulinemia, insulin resistance, vascular growth factors, oxidative stress, and alterations in immune function), resulting in a higher cancer risk.21 Metabolic derangements There are two main hypotheses postulated which might explain the association between diabetes and cancer: the hyperglycaemia hypothesis and the hyperinsulinemia hypothesis. The hyperglycaemia hypothesis22 suggests that tumour cells grow faster in a high glucose environment, because of their glucose-dependence. Hyperinsulinemia (i.e. elevated blood insulin levels) is often both a result and a driver of insulin resistance23 and may promote tumour cell growth directly via insulin receptors, or indirectly via the insulin-like growth 11 CHAPTER 1 INDEX factor-1 (IGF-1) receptor. IGF-1, and subsequently the IGF-1 receptor, could act as a growth stimulus for tumour cells and increase tumour growth, invasion and metastasis.24 Blood glucose lowering drugs Along these aforementioned hypotheses, the use of glucose lowering drugs has also been associated with cancer. These drugs include amongst others metformin, insulin (analogues) and DPP-4 inhibitors. Metformin Evidence from observational studies suggested that some blood glucose lowering drugs are associated with either increased or reduced risk of cancer. One of these medications is the first-line treatment metformin. Since 2005, different epidemiological studies suggested a reduction in the incidence of cancer with metformin use.25-27 However, these studies contained important biases that made the results look ‘protective’.28 The more recent epidemiological studies which avoided these biases reported a less protective effect or no association between metformin and the incidence of different cancer types.29 Currently, many randomised controlled trials (RCTs) are ongoing, investigating whether metformin might be an anti-tumour agent. Insulin (analogues) Because of the hyperinsulinemia hypothesis, insulin is studied as a potential cause to explain the increased risk of cancer among people with T2D. Several epidemiological studies30-32 raised concern that insulin analogues might increase risk of cancer, which lead to a call by the European Medicines Agency (EMA). In 2011, the “Cancer Risk and Insulin analoGues” (CARING) project was initiated to quantify the risk of cancer associated with the use of inulin (analogues). In 2017, they concluded that there was no evidence of a relationship between cancer incidence and use of insulin analogues at follow-up exceeding 5 years.33 Incretin-based drugs: DPP-4 inhibitors & GLP-1 receptor agonists The newer incretin-based drugs are approved by the Food and Drug Administration (FDA) since 2005 and by the EMA since 2006. Studies using the FDA Adverse Event Reporting System (AERS) suggested an increased risk of acute pancreatitis and pancreatic cancer associated with the use of incretin-based drugs.34, 35 However, the FDA AERS database is based on spontaneous adverse events and henceforward causal relationships cannot be established. Therefore, both the FDA and the EMA independently reviewed all clinical and preclinical data, but in 2014 a final conclusion was not yet reached.36