The burden of type 2 diabetes, chronic kidney disease (CKD) and cardiovascular disease (CVD) has had devastating effects on Indigenous populations of both Australia and Canada, and there appear to be close similarities in the disease presentation and impact between the Indigenous populations of these geographically disparate continents. Both populations have earlier onset of chronic conditions such as diabetes and CVD compared to the non-Indigenous population, and chronic conditions are the greatest single contributor to the premature mortality in both Indigenous populations [1–5].

Despite the high prevalence of diabetes, CVD and CKD among Indigenous populations globally, there is little published data from studies using detailed participant examinations for assessment of complications of diabetes [6, 7]. Diabetic nephropathy has been well described in both Indigenous Australians and Canadians [8, 9], but there are fewer available data on retinopathy, neuropathy and peripheral vascular disease (PVD). CVD is the leading cause of premature mortality among Indigenous Australians and Canadians [1, 4, 5, 10], and rates of CVD and of CVD-related mortality appear to be increasing among these populations, despite a reduction in the non-Indigenous populations of both nations [11–13].

In light of these apparent similarities in early onset and high prevalence of both type 2 diabetes and CVD among the Indigenous populations of Australia and Canada, we aimed to compare cardiovascular risk profile and microvascular complications of diabetes from three recent comprehensive, although small clinical studies of Aboriginal cohorts with diabetes from Australia and Canada: 1) a remote Aboriginal community in Northeast Arnhemland, Northern Territory, Australia; 2) the Darwin Region Urban Indigenous Diabetes (DRUID) Study, Northern Territory, Australia; and 3) the Sandy Lake Diabetes Complications Study, from a remote First Nations community from northwestern Ontario, Canada [14–16].

Remote Canadian participants displayed a significantly lower diastolic blood pressure than urban Indigenous Australians and lower heart rate than both Australian groups (Table 2), with differences remaining significant on stratification by gender (except for male urban Australians compared to remote Canadians).

The remote Australian group had significantly lower HDL-cholesterol and higher urine ACR than both urban Australians and remote Canadians. Of note, compared to each of the Australian groups, the remote Canadian group demonstrated higher HDL-cholesterol and lower triglycerides, C-reactive protein (CRP) and homocysteine. However, compared to urban Indigenous Australians, remote Indigenous Canadians had higher urine ACR (but better kidney function as determined by MDRD formula for eGFR). Differences between urban Australian and remote Canadian participants remained for all biochemical variables on stratification by gender with the exception of ACR for women.

Systematic reviews have drawn attention to the high prevalence of diabetes, CVD and CKD among Indigenous populations globally but studies from detailed clinical examination of participants are limited, and much of the available data stems from medical records or administrative databases [6, 7]. This is an important gap because syntheses of detailed clinical data from even small cohorts may enhance our understanding of the extent and nature of these conditions. We have reported that although these Indigenous cohorts with diabetes from Australia and Canada displayed similarities for some key factors, there were significant differences for both CVD risk factors and microvascular complications of diabetes between groups. Rates of some CVD risk factors were higher in remote Indigenous Australians - central obesity (despite a lower BMI), dyslipidemia and CRP. Although rates of retinopathy and neuropathy were similar across the three groups, rates of nephropathy were higher in both remote groups than in the urban Australian group.

The three population groups reveal similarly common anthropometric, metabolic and lifestyle factors such as young age, mean HbA1c (8-8.7% across the groups), duration of diabetes (median duration 6 to 9 years across groups) and high rates of cigarette smoking (particularly in both remote groups with 50% current smokers). Consistent with previous reports, obesity and related comorbidities were also very common in all groups [10, 26]. Interestingly, all 3 groups displayed relatively well controlled blood pressure, with mean values within each group within the targets of systolic < 130 and diastolic < 80 mmHg. Medication use was similar across the studies, with the exception of insulin, where use was lower in the remote Australian group, and metformin which was used more frequently in both Australian groups than in the Canadian group.

When compared to population-based data for the overall Australian population (from the AusDiab Study), achievement of therapeutic targets by urban Indigenous Australian participants with diabetes from the DRUID study was better for blood pressure and total cholesterol, but worse for glycemic control [15]. Although poor, the proportion of DRUID participants meeting glycemic therapeutic targets (HbA1c < 7%) was similar to that reported in secondary care settings in Australia [27, 28], as well as in remote Northern Australian communities [29, 30]. Possible contributory factors to the lower rate of achieving therapeutic targets for glycemic control (compared to good rates of blood pressure control) in the Indigenous populations of the current study include unmeasured factors such as psychosocial stress, socio-economic disadvantage and access to medical care, including access to diabetes education and support of self-management in the use of insulin. It is possible that more intensive use of insulin therapy could result in improved glycemic control in these populations [31], but an associated increase in culturally-appropriate diabetes education and support would need to be a key component of that management strategy. It is notable that rates of angiotensin converting enzyme inhibitor use were high across all 3 groups in the current study, although use of HMG CoA reductase inhibitors was only moderate. Rates of use of both of these classes of medications were higher in the current study than in the Aboriginal participants of the Fremantle Diabetes Study [32], however that study was performed a decade prior to the current studies. The greater use of angiotension converting enzyme inhibitors than of lipid-lowering medications in the current study may relate to the higher rates of albuminuria than elevated LDL-cholesterol in participants of the current study.

We reported a gradient of CVD and metabolic risk factors across the three groups with respect to central obesity, dyslipidemia and inflammatory markers with the most abnormal values being among remote Australians. The greater risk seen in remote compared to urban Indigenous Australians is consistent with previous reports relating to both CVD and end-stage kidney disease (ESKD). Cass et al. described a 20-30 fold gradient in rates of ESKD in Indigenous Australians across different regions of Australia [33], with higher rates in remote than urban regions, associated with greater socioeconomic disadvantage in remote communities [34]. The high levels of CRP in remote Indigenous Australians is consistent with previous reports^{30, 31}; similar findings of higher inflammatory markers in urban India were postulated to relate to high rates of socioeconomic disadvantage [35–37]. Although CRP levels were lower in remote Canadians than both Australian groups, mean CRP was relatively high in all three groups. We have reported that CRP levels were independently elevated in participants with diabetes from the remote Canadian study, with no difference in CRP levels between carriers and non-carriers of the private polymorphism associated with increased prevalence of diabetes in that population (HNF1A G319S) in participants with diabetes [38]. We have previously reported very high fibrinogen levels among urban Indigenous Australian participants of the current study, and that fibrinogen levels were independently associated with CRP and HbA1c in that group [39]. There were also differences in body build and body composition across these population groups, with the striking difference in anthropometric indices for remote Indigenous Australians relating to lack of peripheral adiposity, demonstrated by significantly lower hip circumferences than both urban Australians and remote Canadians. To our knowledge, there are no published data comparing Indigenous Australian and Canadian communities for diabetes complications and CVD risk factors, although there have been previous reports relating to ESKD and HbA1c in these populations [40, 41].

A striking finding of the current study relates to albuminuria - an exception to the above described gradient of risk from remote Indigenous Canadians to urban Indigenous Australians to remote Indigenous Australians. Rates of albuminuria were higher in both remote groups compared to the urban Australian group, with risk of albuminuria remaining independently higher in both remote groups after adjustment for other risk factors. This is consistent with previous reports of high rates of ESKD among Indigenous Australians and Canadians and the remote-urban gradient for ESKD among Indigenous Australians [34]. Of note, there were methodological differences between the studies for ACR, which was measured at the point-of-care in the Canadian study but in the laboratory in the Australian studies, however the remote Australian study did report good agreement between point-of-care and laboratory methods, consistent with previous reports [24, 42].

Rates of microvascular complications other than albuminuria were similar across the three groups. There was no difference in neuropathy (by 10 gm monofilament), PVD or retinopathy rates. The trend to lower retinopathy rates among remote Australians could be explained by methodological differences (data were collected by chart review in that study compared to the use of retinal photography in other groups). There was a difference between the Australian groups in that a lower rate of wearing footwear was evident in the remote compared to the urban group, perhaps reflecting the relatively recent European contact for the remote group and different lifestyles between these groups. However rates of current foot ulcers did not differ between the three groups. The similar rates of microvascular complications of retinopathy and peripheral vascular disease across the three population groups may relate to similarities in HbA1c, but CVD risk factors show prominent differences between population groups. These differences may translate to different CVD outcomes and thus further study is required.

A limitation of this study is that the relatively small sample size of the cohorts which represent three distinct communities within Australia and Canada. It is fully appreciated that although there are many similarities in metabolic and CVD risks described here to those previously reported for other Indigenous groups within Australia and Canada, the results of this study may not reflect those of the general Indigenous populations of Australia and Canada. The urban Indigenous group were a volunteer cohort who represent only 14% of the target population, thus we are unable to comment as to whether they are representative of this population. Nevertheless, the DRUID Study is the largest and most comprehensive dataset on diabetes and related conditions in an urban Indigenous population in Australia. This is of importance as 73% of the Indigenous Australian population live in urban centres [43]. There is a similar paucity of data among urban Canadian Aboriginal people for diabetes complications, thus the Australian data may be of international importance. There were methodological differences between the three studies, particularly for assessment of blood pressure, neuropathy, retinopathy and biochemical variables. We have not assessed genetic factors, socioeconomic disadvantage, psychosocial stress or access to medical care. These factors likely play a role in the urban-remote differences reported between the Australian groups: the remote Australian group had less genetic admixture than the urban Australian group and although Indigenous Australians overall have lower incomes than non-Indigenous Australians, incomes decrease with increasing remoteness [1]. A recent review highlighted that even in countries where a universal health system is in place (such as Australia and Canada), socioeconomic and ethnic inequalities have been reported in the provision of health-care to those with diabetes [44]. Although health services are more likely to exist in urban than remote Australia, there may still be important barriers for Indigenous Australians accessing these services, as evident by reported delays for Indigenous Australians accessing thrombolysis to a similar extent in both urban and remote settings (compared to non-Indigenous Australians) [45]. However the strength of this report is the comprehensive clinical assessment of CVD risks and diabetes complications using standardized techniques, which was a feature of all three studies.

Despite similarly high rates of diabetes, associated complications and premature CVD in these Indigenous populations, several key CVD risk factors were higher in the remote Australian group (central obesity, dyslipidemia, CRP) while albuminuria was notable for higher rates in both remote Indigenous Australians and Canadians than urban Indigenous Australians. In order to address the increased risk of diabetes and CVD in Indigenous communities, action is required from a young age both to prevent diabetes, and to improve management once it is established. As there are important differences in risk profile between Indigenous populations, including within the one country, this action needs to be designed and performed in partnership with communities and tailored to both community and individual needs.