Background
Type 2 diabetes is associated with disabling and potentially life-threatening microvascular and macrovascular complications [
1,
2]. As many as 80% of patients with type 2 diabetes develop cardiovascular complications, which account for approximately 65% of deaths in this group [
3‐
5]. The contribution of microvascular complications to type 2 diabetes morbidity is also substantial [
2,
6]. Large prospective studies have demonstrated that intensive glycemic control decreases the incidence and delays the progression of microvascular complications in patients with type 2 diabetes [
7‐
12]. The benefits of intensive glycemic control in reducing the incidence of macrovascular complications are less clear; however, previous studies have demonstrated that better glycemic control may modestly reduce the long-term risk of some macrovascular events. Furthermore, recent cardiovascular outcome trials [
13,
14] and a large observational study [
15] have suggested that some glucose-lowering agents may substantially improve cardiovascular outcomes in patients with type 2 diabetes.
Previous estimates from observational studies of the prevalence of vascular complications in patients with type 2 diabetes vary greatly [
16‐
21], and a lack of standardization in the assessment methods used renders them difficult to compare. Better understanding of the burden of vascular complications in patients with type 2 diabetes across the globe is of considerable importance, particularly in countries where no data are currently available, because this will provide critically important information for decisions on health policy, including strategies for complication prevention.
There is a paucity in particular regarding global, comparative data on baseline characteristics, treatment pathways and outcomes in patients with type 2 diabetes who are relatively early in the disease process at the time of initiating second-line glucose-lowering therapy. It is particularly important to obtain comparative data, given the plethora of second-line treatment options for patients with type 2 diabetes, compared with the first-line setting in which metformin monotherapy is well established and recommended by major treatment guidelines. To address this important knowledge gap, we initiated DISCOVER (NCT02322762, NCT02226822), a 3-year, prospective, observational study program of patients with type 2 diabetes initiating second-line therapy, conducted in 38 countries across six continents [
22,
23]. Here, we report the baseline data from DISCOVER to describe the prevalence of vascular complications in patients with type 2 diabetes across multiple countries and regions, using standardized methodology.
Discussion
This large, prospective study of close to 16,000 patients with type 2 diabetes initiating second-line glucose-lowering therapy is being conducted in 38 countries across six continents. The burden of both microvascular and macrovascular complications at second-line therapy initiation, assessed using a standardized methodology, was found to be substantial and varied markedly between regions and countries. This study is one of the first to offer a truly global view of the prevalence of vascular complications among patients with type 2 diabetes who are at relatively early stages of their disease. DISCOVER also includes many lower- and upper-middle-income countries, for which no data on the prevalence of diabetes complications were previously available.
When standardized for age and sex, the highest prevalence of microvascular and macrovascular complications was found in Europe, where patients also had the highest mean BMI and blood pressure, which are important cardiovascular risk factors [
26]. These findings could also be explained by rates of screening for complications being higher in Europe than in other regions, or by a greater proportion of patients seen in specialty settings. Across the European countries, Russia had the highest prevalence of microvascular and macrovascular complications. These observations are supported by Russian state diabetes registry data, which show a high prevalence of recorded vascular disease in patients with type 2 diabetes, including 18.6% for diabetic neuropathy and 13.0% for diabetic retinopathy [
27]. When excluding Russia from our analysis, the prevalence in Europe of macrovascular complications, but not that of microvascular complications, remained the highest across all regions.
Our multivariable analysis of factors potentially associated with complication prevalence identified positive correlations between microvascular and macrovascular complications and age, male sex, low level of education, diabetes duration, and history of hypoglycemia. Other research has shown that greater and more prolonged exposure to hyperglycemia, as would occur in patients with a long duration of uncontrolled type 2 diabetes, increases the risk of both microvascular and macrovascular complications [
28]. Of note, a significant association was observed in the current analysis between HbA
1c level and microvascular, but not macrovascular, complications. This is consistent with previous findings that intensive glycemic control decreases the incidence of microvascular complications, with much less certainty in terms of its effects on macrovascular events [
7‐
12,
29].
Large, international, observational studies that have reported the prevalence of vascular complications in patients with type 2 diabetes are rare. The A
1chieve study was a global, prospective, observational study of more than 66,000 patients with type 2 diabetes from 28 countries in Asia, Africa, Europe, and South America, and reported a prevalence of microvascular complications at baseline of 53.5%, and of macrovascular complications of 27.2% [
21]. However, the patients included in that study were initiating insulin analogs, typically administered after failure to achieve target HbA
1c levels with other glucose-lowering drugs. Consequently, the patients in A
1chieve had a much longer duration of diabetes than those in DISCOVER (mean 8.0 vs 5.6 years) and a higher mean baseline HbA
1c level (9.5% vs 8.4%).
The IMPROVE study, conducted in eight countries and involving more than 50,000 patients receiving insulin therapy, also reported a high prevalence of both microvascular and macrovascular complications (45.0% and 28.0%, respectively) [
30]. Again, the mean duration of diabetes (6.9 years) and mean HbA
1c levels (9.4%) were higher in IMPROVE than in the DISCOVER study. The International Diabetes Management Practice Study (IDMPS) was conducted in 18 developing countries across Asia, Eastern Europe, and Latin America. The prevalence estimates reported for microvascular and macrovascular complications were again high at 55.3% and 26.1%, respectively [
31]. In this survey of a general population of patients with type 2 diabetes, the mean diabetes duration was 8.4 years, and 31% of patients were treated with insulin, either on its own or in combination with oral agents.
The differences in patient characteristics between A1chieve, IMPROVE, IDMPS, and DISCOVER are likely to explain the differences in the observed rates of vascular complications. All three of the previous studies included patients with longer-term disease than in DISCOVER. Our study is therefore the first global observational study of its kind, evaluating a population of patients with a much shorter disease duration.
Our findings highlight a key opportunity for improved monitoring of complications, and the importance of early and aggressive risk factor modification. This is in line with current practice guidelines; for example, the European Society of Cardiology guidelines for cardiovascular disease prevention consider patients with diabetes to be at very high cardiovascular risk, regardless of other risk factors, and therefore recommend statin treatment in addition to intensive blood pressure management for all patients [
32]. The American Heart Association and American Diabetes Association similarly recommend intensive management of cardiovascular risk factors in patients with diabetes [
33]. As outlined in the American Diabetes Association/European Association for the Study of Diabetes joint position statement, it is also important to consider classes of glucose-lowering medications with positive impacts on cardiovascular risk factors, especially in patients with established cardiovascular disease [
34]. In a recent, large cohort study, patients with type 2 diabetes who had levels of HbA
1c, cholesterol, serum albumin and blood pressure all within target ranges, and who did not smoke, were at similar risk of myocardial infarction or stroke as age-, sex- and country-matched controls [
35]. Risk scores can help clinicians identify patients with type 2 diabetes who are at low or high risk of vascular disease [
36,
37].
The main strengths of the DISCOVER study include its prospective design, the large number of patients enrolled, and the participation of lower- and upper-middle-income countries where patients have rarely, or never, been studied previously. The use of a standardized electronic case report form is another key strength of the study, allowing valid comparisons of results within and across countries and regions worldwide. In addition, sites were selected in a way intended to ensure that the enrolled patient population is as diverse and representative as possible of the general population of patients with type 2 diabetes.
Our findings should, nevertheless, be interpreted in the context of several potential limitations. The ascertainment and diagnosis of diabetes-related vascular complications were based on the judgment of individual physicians, and we could not determine whether the complications occurred before or after the diagnosis of type 2 diabetes. In some countries, rural sites do not have any established infrastructure for data collection, and primary care practitioners may be insufficiently trained, or not permitted, to conduct observational research. In these countries, where rural sites and primary care settings are necessarily under-represented, the quality of healthcare is likely to be overestimated.
The observational nature of the DISCOVER study means that the study protocol does not mandate screening for complications, and that the presence and severity of complications are not adjudicated. The reported prevalence estimates may therefore be underestimates, because physicians may not be aware of complications in some patients. In many lower- and upper-middle-income countries participating in DISCOVER, fundus cameras used for retinopathy screening may be inaccessible to many patients, particularly in rural areas [
38].
In the present analysis, we considered erectile dysfunction to be a microvascular complication, and diabetic foot to be a macrovascular complication. However, no assessment of the underlying pathophysiology of these conditions in individual patients was made. Finally, imputation was required during the multivariable analysis to account for some unreported data, in particular for HbA1c and total cholesterol. This is consistent with the noninterventional nature of the DISCOVER study, whereby laboratory values and other clinical variables are measured according to standard clinical practice at each site. In several countries, measurement of biomarkers including HbA1c and total cholesterol may not be covered by health insurance, and may therefore not be routinely measured for all patients.
Authors’ contributions
All authors contributed to the development of the manuscript, and all authors approved the final version before submission. An AstraZeneca team reviewed the manuscript during its development and was allowed to make suggestions. However, the final content was determined by the authors. MK is the guarantor of this work. All authors read and approved the final manuscript.
Competing interests
MK, MBG, AN, SP, WR, MVS, HW, IS, and KK are members of the DISCOVER Scientific Committee and received support from AstraZeneca to attend DISCOVER planning and update meetings. HC, PF, NH, and FS are employees of AstraZeneca. JC-R is an employee of Evidera. In addition, MK has received honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Glytec Systems, Intarcia, Janssen, Merck, Novo Nordisk, Novartis, Sanofi, and ZS Pharma; and research support from AstraZeneca and Boehringer Ingelheim; MBG has received honoraria from Merck-Serono; AN has received honoraria from AstraZeneca, Eli Lilly, Medtronic, and Novo Nordisk, and research support from Artsana, Dexcom, Novo Nordisk, and Sanofi-Aventis; SP has received honoraria from AstraZeneca; WR has received honoraria from AstraZeneca and research support from Novo Nordisk; MVS has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, and Sanofi, and research support from Sanofi; HW has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Kissei Pharma, Kowa, Kyowa Hakko Kirin, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novo Nordisk, Novartis, Ono Pharmaceutical, Sanofi, Sanwa Kagaku Kenkyusho, and Takeda, and research support from Abbott, Astellas Pharma, AstraZeneca, Bayer, Benefit One Health Care, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Kissei Pharma, Kowa, Kyowa Hakko Kirin, Johnson & Johnson, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nitto Boseki, Novartis, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanofi, Sanwa Kagaku Kenkyusho, Taisho Toyama Pharmaceutical, Takeda, and Terumo Corp; IS has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Kowa, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novo Nordisk, Ono Pharmaceutical, Sanwa Kagaku Kenkyusho, and Takeda Pharmaceutical, and research support from Astellas Pharma, AstraZeneca, Daiichi Sankyo, Eli Lilly, Japan Foundation for Applied Enzymology, Japan Science and Technology Agency, Kowa, Kyowa Hakko Kirin, Midori Health Management Center, Mitsubishi Tanabe Pharma, Novo Nordisk, Ono Pharmaceutical, Sanofi, Suzuken Memorial Foundation, and Takeda Pharmaceutical; FT has received research support from AstraZeneca; and KK has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, and Sanofi, has received research support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, and Sanofi, and is additionally supported by the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care East Midlands.