worldwide has almost quadrupled [7]. This is in part due to population growth and ageing, but also represents a true increase in prevalence. The epidemic of type 2 diabetes is closely linked to the rising prevalence of obesity and is contributed by numerous factors including globalisation and urbanisation, with increasingly sedentary lifestyles and greater caloric intake [8].
The diabetes epidemic has been characterised by substantial variation between geographic locations, ethnicities and cultural groups. Low- and middle-income countries have seen the greatest increases in diabetes prevalence over recent decades and this disparity is predicted to continue (Fig. 2) [5, 7]. This has been attributed to differences in both genetic and environmental factors, with potential interactions between them. There is evidence that the intrauterine environment and foetal nutrition can impact gene expression via epigenetic changes [9]. Thus, maternal health can potentially impact the chronic disease risk of subsequent generations. Such factors are theorised to have contributed to the dramatic increases in prevalence in resource-poor settings.
Fig. 2. Estimated number of people (aged 20–79 years) with diabetes worldwide and per region in 2017 and 2045. With permission from: IDF Diabetes Atlas Eighth Edition 2017. Brussels, International Diabetes Federation, 2017.
Diabetes and Vascular Disease Mechanisms
Diabetes mellitus is a metabolic disorder characterised by chronic hyperglycaemia as well as disruption to fat, carbohydrate and protein metabolism. Hyperinsulinaemia, insulin resistance and pancreatic β-cell failure are typical of type 2 diabetes. Type 1 diabetes is an immune-mediated condition, usually with detectable autoantibodies, which results in the destruction of β-cells and insulin deficiency. Other rarer forms of diabetes include, among others, monogenic diabetes, drug-induced diabetes and diseases of the exocrine pancreas.
Diabetes complications are traditionally classified into microvascular complications such as neuropathy, retinopathy and nephropathy; and macrovascular complications such as ischaemic heart disease, stroke and peripheral arterial disease. Ischaemic heart disease remains the most common cause of mortality in patients with diabetes, typically presenting at an earlier age, with greater severity and more diffuse atherosclerotic disease than in patients without diabetes [10]. More recently, heart failure has emerged as an important manifestation of heart disease in people with diabetes. While it may be a consequence of coronary artery disease and myocardial infarction, there is strong evidence of a direct metabolic effect on cardiac function, leading to fibrosis and stiffness of the ventricles and reduced filling volumes [11]. Indeed, recent data show that, in diabetes, heart failure frequently presents before there have been any clinical episodes of coronary artery disease [12].
Mechanisms for the development of atherosclerotic cardiovascular disease associated with hyperglycaemia include endothelial dysfunction, hypercoagulability, advanced glycation end product formation, increased platelet reactivity, increased oxidative stress and increased inflammation [10, 13]. Due to shared risk factors, people with diabetes often have concomitant disorders contributing to their cardiovascular risk, such as hypertension, dyslipidaemia, obesity and obstructive sleep apnoea. Furthermore, insulin-resistance, even prior to the onset of hyperglycaemia, may affect lipid metabolism directly, leading to elevated triglycerides, low high-density lipoprotein and small dense low-density lipoproteins (LDL) [10]. This pattern of dyslipidaemia is known to be atherogenic.
Trends in Cardiovascular Risk and Mortality
Over the last 2 decades, there has been a significant decline in rates of cardiovascular mortality globally. However, absolute numbers of premature cardiovascular deaths continue to rise in low- and middle-income countries [14]. Patterns in cardiovascular mortality vary greatly between geographic regions. While globally ischaemic heart disease accounts for the majority of cardiovascular deaths, there are some regions, particularly East and Southeast Asia and Sub-Saharan Africa, where stroke is the dominant cause. This is in part due to higher rates of haemorrhagic stroke. It is unclear how much of the difference in stroke mortality relates to differences in incidence versus differences in case fatality [14].
Falling mortality trends have also been observed among people with diabetes in developed countries. For example, in Australia, both all-cause and cardiovascular mortality risk have declined significantly in both type 1 and 2 diabetes [15]. Figure 3 depicts trends over time in standardised mortality ratios for all-cause mortality in people with type 2 diabetes compared to the non-diabetic population. Despite significant improvements, an excess risk of mortality associated with diabetes remains.
Fig. 3. Standardised mortality ratios for all-cause mortality among men (a) and women (b) with type 2 diabetes between 1997 and 2010 in Australia. Source: Harding et al. [15].
In addition to improvements in mortality rates, data from the United States have shown significant reductions in the incidence of cardiovascular events, including acute myocardial infarction and stroke [16]. Thus, the reduced mortality rates are not solely due to improved survival relating to treatment of complications but are, at least in part, due to the prevention of complications occurring. These improvements in cardiovascular risk have been more pronounced among adults with diabetes than in the general population. There was a 68% reduction in the rate of acute myocardial infarction among people with diabetes, with 141 events per 10,000 people in 1990 and 46 events per 10,000 people in 2010, whereas among people without diabetes, there was a 31% reduction, with 38 events per 10,000 people in 1990 and 26 events per 10,000 people in 2010. Diabetes still infers a greater risk of myocardial infarction, but the magnitude of the risk difference has reduced substantially. Reductions in rates of stroke were less substantial, such that myocardial infarction is now as common as stroke, having previously been significantly more common.
It is not possible from these large population-based studies to explain the determinants of the trends observed. Nevertheless, there are likely to be numerous contributing factors including population-wide risk factor trends, such as the decline in rates of cigarette smoking; improvements in the management of risk factors such as blood pressure and lipids in patients with diabetes; and advances in acute clinical care, such as improved access to and success of coronary revascularisation. In recent decades, numerous randomised control trials have shown the benefits of modifying different cardiovascular risk factors in high risk patients and there has been increasing use of medications such as statins, aspirin and renin-angiotensin system antagonists. Greater focus on improving systems of care and risk factor modification