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DARK SHADOW OF TYPE 2 DIABETES More than just blood glucose controlIntroduction 1 Chapter 1: Macrovascular complications of type 2 diabetes 2 Myocardial infarction 2 Stroke 2 Cardiovascular deaths 3 Heart failure 4 Chapter 2: Microvascular complications of type 2 diabetes 6 Kidney disease 6 Amputations 7 Eye disease 7 Chapter 3: Non-traditional complications 9 Cancer 9 Dementia 10 Liver disease 10 Chapter 4: Novel medications for type 2 diabetes 11 Chapter 5: Opportunities for improvement 14 Appendix. Detailed methods for chapter 5 18 References 19 ContentsDiabetes remains one of the greatest contemporary health challenges. The numbers of people with diabetes are measured in the hundreds of millions globally, and the list of organ systems adversely affected by diabetes continues to grow. In 2017, we released The Dark Heart of Type 2 Diabetes report. This report summarized what was known about the various effects of diabetes on the heart, and provided an estimate of how many lives could be saved if the new class of sodium– glucose co-transporter-2 (SGLT2) inhibitor drugs was used more widely. The report sought to highlight aspects of the effects of diabetes that are not always well-recognised and thereby to increase awareness and improve outcomes for people with type 2 diabetes. The success of Dark Heart in raising these issues prompted us to use a similar format to expand into some of the other complications of diabetes. In this Dark Shadow report, we provide up to date information on the impact of diabetes on a broader range of complications. In chapters 1 and 2, we bring the latest information on the major microvascular and macrovascular complications, and, in chapter 3, delve into a number of the other ‘non-traditional’ complications, including cancer, dementia and liver disease. Wherever possible, we provide information directly relevant to Australia. Similar to Dark Heart, we also look at opportunities to improve outcomes. The last few years has seen a flurry of publications of major trials showing benefits of novel glucose-lowering drugs on both cardiovascular and renal outcomes. Importantly, these benefits did not result from lowering blood glucose, but arose from other, as yet inadequately understood, mechanisms. In chapter 4, we summarize the published literature on the benefits of these agents. Finally, in chapter 5, we estimate the potential population-wide benefits of increasing the uptake of these agents among those at highest risk. However, not everything is about the latest discoveries. As has been documented repeatedly in many areas of health, there is underuse of interventions whose benefits have already been established over many years. This implementation gap remains wide in type 2 diabetes, and so chapter 5 also provides estimates for how many cardiovascular and renal events could be prevented if there was better use of statins, ACE inhibitors and angiotensin receptor blockers. Introduction 1BAKER HEART & DIABETES INSTITUTECardiovascular disease Cardiovascular disease (CVD) is the leading cause of death in adults with type 2 diabetes (1) (Table 1). Compared to their non-diabetic counterparts, those with type 2 diabetes are at approximately two fold increased risk of many manifestations of CVD, including myocardial infarction, heart failure, stroke, peripheral arterial disease and sudden cardiac death. Almost two thirds of people with type 2 diabetes self-report having hypertension or other manifestations of CVD (2) (Figure 1). In one Australian study, one third of people with type 2 diabetes visiting their GP had previously had a heart attack, stroke or had peripheral vascular disease (3). The economic burden of CVD combined with type 2 diabetes at both the patient and population level is significant. Treating CVD costs 20-49% of the total direct cost of diabetes at the population level. Among people with type 2 diabetes, the median annual costs per person with CVD, coronary artery disease, heart failure and stroke are 112%, 107%, 59%, and 322% higher respectively, compared to people with type 2 diabetes but without CVD (4). Myocardial infarction In a systematic review including data from 4.5 million people with type 2 diabetes, 10% of the total population had previously had a myocardial infarction (5). In a study of 1.9 million people from the UK of whom 1.8% had type 2 diabetes, diabetes was associated with a 54% increased risk of non-fatal myocardial infarction (6). However, studies from the UK (7) and the USA (8) have shown that the rate of myocardial infarction has declined by approximately a quarter between 1992 and 2012. Studies from Australia have also shown that mortality from CVD among people with type 2 diabetes has been falling (9), although these improvements have not been so clear in younger adults. Stroke In the same systematic review as above, 7.6% of the diabetes population had previously had a stroke (5). The risk of stroke appears greater in women than in men, independent of differences in other cardiovascular risk factors (10). Macrovascular complications of type 2 diabetes Figure 1. The prevalence of self-reported CVD in people with diabetes (2). Table 1. The increased risk of cardiovascular disease in people with type 2 diabetes is thought to reflect changes in cardiovascular pathology including: • Greater plaque burden • Great complexity of lesions • Greater coronary calcification • Greater extent of coronary ischemia • More multi-vessel disease • More significantly affected vessels • Fewer normal vessels • Reduced coronary collateral recruitment • Reduced coronary vasodilatory reserve Total population 57 % 66 % 63 % Chapter 1 2THE DARK SHADOW OF TYPE 2 DIABETESCardiovascular deaths Adults with type 2 diabetes have a two to four fold increased risk of cardiovascular related death compared to those without diabetes (11). Living with type 2 diabetes shortens life expectancy, with the impact being greater with earlier onset diabetes. On average, a 45 year old person with diabetes can expect to live 6 years less than a person free of diabetes, with many of these earlier deaths being due to CVD (12). In the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, a population based study including 11,247 adults aged 25 years and older, across Australia, approximately 34% of all deaths were attributable to CVD across a 5-year period (13) – two thirds of these deaths occurred in people who had either type 2 diabetes or prediabetes. Nevertheless, there is evidence of some improvement. Data in over 1 million Australian adults with diabetes on our National Diabetes registry, showed that the cardiovascular death rate fell from 2002-2011 in both men and women (9). Unfortunately, the declines in mortality were not consistent across all ages, with people at younger ages (0-40 years) experiencing lesser declines than older adults. Indigenous Australians are nearly four times more likely to have type 2 diabetes compared to non-Indigenous Australians (14). In 2013–14, hospitalisations in which type 2 diabetes was the principal or additional diagnosis were four times more frequent in Indigenous Australians compared to non-Indigenous Australians. Rates of hospitalisation of Indigenous people for diabetes increased with age. However the greatest gap between Indigenous and non-Indigenous Australians occurs at younger ages. Between the ages of 25 and 44 years, hospitalisation rates were 14 times higher in Indigenous than non-Indigenous Australians (14). Ischemic heart disease is the leading cause of death in Indigenous Australians with a population rate 1.8 times higher than that of non-Indigenous Australians (15). The excess relative risk is even greater in people of younger ages, with 12% of deaths in Indigenous Australians aged 30-39 years being attributable to CVD compared to 4% in non-Indigenous Australians. Figure 2. Percentage of deaths attributable to CVD in Indigenous Australians aged 30-39 years compared to non-Indigenous Australians of the same age (15). 12 % 4 % Indigenous Australians Non-Indigenous Australians 3BAKER HEART & DIABETES INSTITUTEHeart failure Heart failure is a complex syndrome characterized by symptoms easily confused with diabetes itself or other co-morbidities such as obesity (i.e. dyspnea and fatigue, Table 2). Type 2 diabetes and heart failure often occur in conjunction with each other, as each disease independently increases the risk of the other. Heart failure has been reported in 12-57% of those with type 2 diabetes (16) and occurs up to 8 times more frequently in people with diabetes, compared to those without. Heart failure has typically been viewed as the final stage of structural heart disease, most commonly resulting from previous infarction or from valvular disease. However, it has become increasingly recognized that heart failure can be the very first presentation of heart disease, and may occur in the absence of either coronary artery or valvular heart disease, especially among people with diabetes. Indeed, in a study of nearly two million people in the UK, heart failure was the second most common initial manifestation of CVD (after peripheral arterial disease) in people with type 2 diabetes (6). Thus, in many people, heart failure was not preceded by coronary artery disease, and can arise directly from the metabolic effects of diabetes on the myocardium. Heart failure is emerging as a leading cause of death in type 2 diabetes (17), the 5-year survival rate being worse than that of many cancers. Studies have also demonstrated that even mild elevations in blood glucose levels or abnormalities in insulin sensitivity are associated with increased risk of heart failure (18, 19). Furthermore, the Framingham Heart Study showed in 5881 participants, that the increased risk of heart failure per one unit increase in body mass index was 5% in men and 7% in women, even after adjusting for demographics and known risk factors (20). The continuous relationship between higher body mass index and risk of heart failure has also been shown in other large studies (21, 22). Among people with heart failure, type 2 diabetes is associated with reduced quality of life, more hospital admissions, longer admissions and more readmissions. An Table 2. Common signs and symptoms of heart failure. Shortness of breath (dyspnea) Impaired ability to exercise Swelling (oedema) in lower limbs Persistent cough Fatigue and weakness Rapid or irregular heartbeat 4THE DARK SHADOW OF TYPE 2 DIABETESAustralian study showed that more than a third of acute admissions for heart failure were in people with type 2 diabetes (23) (Figure 3). In a study of Australian Veterans, nearly one in four older patients hospitalised for diabetes, were re-admitted within 30 days, with heart failure being one of the strongest predictive factors of readmission (24). Importantly, the average cost per hospitalisation for any admission in Australia for people with type 2 diabetes is $8755 (25), thereby posing a significant economic burden. Figure 3. The percentage of admissions with acute heart failure in which diabetes was or was not present (23) Practice Point Think of heart failure as a potential cause of breathlessness or exercise intolerance, even when there has been no prior cardiac disease. 62 % 38 % No Diabetes Diabetes 5BAKER HEART & DIABETES INSTITUTEKidney disease People with type 2 diabetes are nearly two times more likely to have chronic kidney disease (CKD) compared to those without diabetes. Data from an Australian study (AusDiab) found that among adults aged 25 years and older with type 2 diabetes, 27% had evidence of CKD. These data suggest that a quarter of a million Australians have CKD and are at risk of end stage renal disease, cardiovascular events and premature death. By comparison in the US, the prevalence of CKD in type 2 diabetes is 44% in the overall population (mean age 64 years) according to results from the NHANES 1999–2012 data (26). Diabetes is the most common cause of end-stage kidney disease (ESKD, i.e. dialysis or kidney transplant). For example, in Australia, diabetes is the primary cause of 37% of all cases of ESKD (27). In most other countries around the world, diabetes is also the most common cause of ESKD, with a number of Asian countries reporting that diabetes accounts for 40-50% of all ESKD. Among Indigenous Australians, the burden Microvascular complications of type 2 diabetes Figure 4. Percentage of new end stage kidney disease cases with a primary diagnosis of diabetes in 1991 and 2012. of ESKD is even greater. The overall risk is four times greater than among non-Indigenous Australians, and 70% is due to diabetes (28). Compared to those without type 2 diabetes, the incidence of ESKD is as much as 10 times higher in those with diabetes. In Australia in 1991, 13% of new ESKD cases had a primary diagnosis of diabetes, compared to 38% in 2012 (29) (Figure 4). The growth in ESKD is predominantly due to increased prevalence of type 2 diabetes, improved survival in this population and greater willingness to treat sicker and older patients with ESKD (30). Recent national Australian data from the Australian and New Zealand Dialysis and Transplant Registry showed that while the incidence of ESKD was slowly falling in those with type 2 diabetes aged 50-80, it was rising in those aged under 50 years (31). It is possible that this rise is being driven by the younger age of onset of type 2 diabetes, and perhaps less aggressive risk factor management in younger adults with type 2 diabetes. This study also confirmed the much higher incidence of ESKD in the Indigenous population. Practice Point Aggressive risk factor management is vital in younger adults with type 2 diabetes to reduce the very high risk of complications. 38 % 13 % due to diabetes 2012 due to diabetes 1991 Chapter 2 6THE DARK SHADOW OF TYPE 2 DIABETESAmputations Lower extremity amputations are a major complication of type 2 diabetes, as they pose a significant physical, economic and psychosocial burden. Indeed, diabetes is responsible for the majority of non-traumatic lower-limb amputations. There were 4,402 lower-limb amputations in people with diabetes in Australia between 2012-13 (32). They typically result from foot ulceration, which, in turn, is usually due to peripheral arterial disease, peripheral neuropathy, or a combination of the two. Lower-limb amputations are more common in males (75% of all lower-limb amputations) and in those aged 65 years and over (58% of all lower-limb amputations) (32). However, there have been reductions in lower extremity amputations since 1982 worldwide. In Australia, lower extremity amputations rates fell by 2.4% per year between 2000 and 2010, driven primarily by a decline in major amputations (i.e. those above the foot) (33). Globally, the decline in amputations appears to have been driven by a reduction in major amputations, with smaller declines, and in some cases increases, in minor amputations (34). Regular screening for neuropathy and peripheral arterial disease, aggressive management of early foot problems and the ready availability of multi-disciplinary foot clinics have been the reason for these improvements in amputation rates. It is noteworthy that even within a single health service in England, rates of amputation varied 5-10-fold across geographic districts, with variation in care likely to account for much of this (35). In people with diabetes, those of Indigenous descent are at an increased risk for amputation. Among those with diabetes aged 25-49 years, Indigenous people are 27 times more likely to have a minor amputation (toe or foot) and 38 times more likely to have a major amputation (above the knee) compared to non-Indigenous people (36). Furthermore, nearly all (98%) non-traumatic amputations in Indigenous people are related to diabetes. Eye disease Diabetic eye disease is a leading cause of irreversible vision loss and blindness in working age adults worldwide. A study involving 33 countries globally found that approximately one third of people with type 2 diabetes have diabetic retinopathy and one in 20 have diabetic macular oedema (37). Diabetic retinopathy is the main cause of vision loss in non-Indigenous and Indigenous Australian adults with known diabetes. The National Eye Health Survey (NEHS) showed that the prevalence of any diabetic retinopathy in Australia is 29% among non-Indigenous adults with diabetes and 44% among Indigenous adults with diabetes (38) (Figure 5). The NEHS also showed that the prevalence of macular oedema is higher in Indigenous Australians compared to non-Indigenous Australians (15% vs 6%) (38). The expected increase in the number of those people living with type 2 diabetes in Australia in the coming decades will lead to an increased number of people with diabetic eye disease or vison loss. 7BAKER HEART & DIABETES INSTITUTENext >