Impact of micro‐ and macrovascular complications of type 2 diabetes on quality of life: Insights from the DISCOVER prospective cohort study

Abstract Background The key goals of management in patients with type 2 diabetes (T2D) are to prolong life and improve quality of life. Micro‐ and macrovascular complications of T2D not only increase the risk of morbidity and mortality, but cross‐sectional studies indicate they may also worsen quality of life. We prospectively examined the association of complications that developed during the follow‐up with concurrent changes in quality of life. Materials and methods DISCOVER is a multinational, prospective, observational cohort study of T2D patients enrolled at initiation of second‐line glucose‐lowering therapy. Quality of life was assessed with the SF‐36 Physical (PCS) and Mental Components Summary (MCS) scores at baseline, 6 months, and 1, 2 and 3 years. Hierarchical repeated measures regression models for PCS and MCS were constructed with complications included as time‐dependent covariates; first each complication was modelled alone and then second including all interval complications (to account for different complications occurring in the same patient). Results Among 7830 patients with T2D from 30 countries (mean age 56.6 years, 47.6% women, mean duration of T2D 5.6 years), baseline mean SF‐36 PCS was 48.0 ± 7.8 and SF‐36 MCS was 45.5 ± 10.4. At baseline, 1422 (18.2%) patients had a known microvascular complication, and 966 (12.3%) had a macrovascular complication. Over the 3 years of the study, 641 (12.0%) developed a new microvascular complication (most commonly neuropathy) and 372 (5.8%) developed a new macrovascular complication (most commonly coronary disease). New diagnoses of coronary disease, peripheral artery disease, heart failure and neuropathy were each associated with subsequent moderate reductions in SF‐36 PCS (range 0.7 to 1.6 points) and new cerebrovascular disease was associated with a reduction in SF‐36 MCS (2.6 points). Results were consistent when all interval complications were considered in the same model. Conclusion In a prospective, multinational study of patients with T2D, the development of macrovascular complications and neuropathy was associated with decreases in both physical and mental quality of life. Our results provide additional support for clinicians to focus on the prevention, detection and management of the complications of T2D.


| INTRODUC TI ON
While preventing morbidity and prolonging life are key goals of treatment in patients with type 2 diabetes (T2D) and are the focus of many studies, improving or maintaining quality of life may be of equal or even greater importance to patients. Several factors have the potential to adversely impact the quality of life of patients with T2D, including feeling challenged by glycaemic control, dietary restrictions, hypoglycaemia, polypharmacy and medication side effects. Another important aspect of living with diabetes is the development of microvascular and macrovascular complications, which are not only common 1,2 but also increase the risk of additional morbidity 2,3 and mortality. [4][5][6] Beyond survival and hospitalization, complications may also adversely impact the patient's quality of life, with cross-sectional studies indicating that diabetes-related complications are associated with an increased risk of depression or anxiety, 7 lower treatment satisfaction scores 8 and worse quality of life. 9 Complications in patients with type 1 diabetes have also been associated with lower scores on all subscales of the 36-item Short-Form Health Survey (SF-36), with a similar but weaker association in patients with T2D. 10,11 Regarding specific complications, neuropathy, cardiovascular disease and end-stage renal disease have each been found to be associated with decreased scores on the SF-36. 12,13 A key limitation in these prior studies is their cross-sectional design, which has substantial risk of confounding, as patients with particular complications also have other factors that impact quality of life that cannot be fully accounted for with multivariable adjustment. Furthermore, as multiple complications often cluster in the same patients, understanding the true impact of any particular complication requires concurrent adjustment for other complications. As such, we used the DISCOVER prospective global study to examine the association of development of new complications with concurrent changes in quality of life. This longitudinal approach allows each patient to serve as his or her own control, thereby reducing bias due to confounding and more effectively isolating the impact of the new complication on quality of life.

| Study protocol
The DISCOVER study is a multinational, prospective, observational study of individuals with T2D being initiated on second-line glucoselowering medication (either add-on or switching). 14 Between December 2014 and June 2016, consecutive eligible adults were enrolled from 38 countries (Supplemental Table S1) and followed at 6, 12, 24 and 36 months. 15 Patients were excluded who were pregnant, undergoing dialysis, had a history of renal transplant or were treated with an injectable agent or herbal remedy/natural medicine alone as a first-line agent. Patients from China (n = 1292) were excluded from this analysis due to regulations on data privacy released during the study. Data from Canada, Denmark, Japan and Norway (n = 2255) were excluded, as hospitalization data from these countries were incomplete. Data from Bahrain, Kuwait and Oman (n = 152) were excluded, as the SF-36 was not collected in these countries.
Demographics, comorbidities, interval events, laboratory data and medications were prospectively collected using standardized data collection forms. In line with the observational nature of the study, patients were not obliged to attend study visits (data were recorded at clinical follow-up visits), and clinical data were measured and recorded according to routine clinical practice at each site. The study protocol was approved by the appropriate clinical research ethics committees in each participating country and by the institutional review board at each site. All participants provided written informed consent. The data that support the findings of this study are available from the corresponding author or study sponsor upon reasonable request.

| Complications
Microvascular and macrovascular complications were assessed at baseline and each follow-up time point using a combination of outpatient visits, emergency room visits and hospitalizations. Results were consistent when all interval complications were considered in the same model.

Conclusion:
In a prospective, multinational study of patients with T2D, the development of macrovascular complications and neuropathy was associated with decreases in both physical and mental quality of life. Our results provide additional support for clinicians to focus on the prevention, detection and management of the complications of T2D.

| Quality of life assessment
Quality of life was assessed using the SF-36, which is a generic health status measure that consists of 36 questions across eight domains: physical functioning, role physical, bodily pain, general health, vitality, role emotional, social functioning and mental health. 16 The SF-36 also provides a physical component summary (PCS) and mental component summary (MCS), which were the primary outcomes of interest for the current study. Scores for the PCS and MCS are scaled to an overall US population mean of 50 and standard deviation of 10; higher scores indicate better health status, and the minimal clinically important change is ~2.5 points. 17 Patients with baseline SF-36 and at least one follow-up assessment were included.

| Statistical analysis
Baseline characteristics of patients who were eligible but missing follow-up data were compared with those in the analytic cohort using standardized differences (>10% difference is considered clinically relevant). Within the analytic cohort, for descriptive purposes, we compared the characteristics of patients with versus without complications at enrolment, including baseline PCS and MCS scores.

To examine the unadjusted association of interval complications
with changes in quality of life, we compared the percentage of patients who had a ≥2.5-point decrease in PCS or MCS from baseline to last available follow-up between those with versus without each of the interval complications using chi-square tests.
Our primary analysis involved construction of hierarchical repeated measures linear models for (1) PCS and (2) MCS with each interval complication entered as a time-dependent covariate and adjusted for baseline PCS or MCS, respectively. These models were first done with each complication separately (ie one model for each complication) and then as a single model with all interval complications included (as patients could experience more than one complication during follow-up). Patients were considered to serve as their own control, with baseline PCS or MCS included in the models, and thus, no additional adjustment was made for patient factors. All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, North Carolina), with statistical significance determined by p < 0.05.
As these analyses were considered exploratory, there was no statistical adjustment for multiple testing.

| Patient population
A total of 15,983 people with T2D from 38 countries who were initiating 2nd-line glucose-lowering therapy were enrolled in DISCOVER between 2014 and 2016. We excluded 3699 from eight countries due to complete data being unavailable at the time of the analysis for administrative reasons (China), incomplete data on hospitalizations (Canada, Denmark, Japan, Norway) or lack of SF-36 collection (Bahrain, Kuwait, Oman). We also excluded 50 patients with missing data on baseline complications, 3978 patients with missing baseline SF-36 scores and 426 additional patients with no follow-up SF-36 data. As such, our analytic cohort included 7830 participants from 30 countries. Patients excluded due to missing data on complications during follow-up or SF-36 data were more likely to be nonsmokers, had higher body mass indices and higher blood pressure; otherwise were similar to those in the analytic cohort in terms of demographics, laboratory data, comorbidities, medications and baseline complication burden (Supplemental Table S2). Mean age (±SD) of the analytic cohort was 56.6 ± 11.6 years, 47.6% were women, 10.8% were current smokers, mean HbA1c was 8.4 ± 1.7% and mean duration of T2D at time of enrolment was 5.6 ± 5.1 years.
There were 2076 patients (26.5%) who had a vascular complication at enrolment, and these patients were more likely to be older age, current or former smokers, and have a longer duration of T2D (Table 1). Neuropathy was the most common baseline complication at 9.3%, followed by coronary artery disease in 8.6% and chronic kidney disease in 7.1% of patients (Table 2). There were 1397 participants (17.8%) who developed at least one new microvascular complication over the course of the study (most commonly, neuropathy) and 596 (7.6%) who developed at least one new macrovascular complication (most commonly, coronary artery disease; Figure 1).    Table 4).

| Quality of life
In the repeated measures models that examined each interval complication in isolation, a new diagnosis of coronary artery disease, peripheral artery disease, heart failure and neuropathy was each associated with a small decrement in SF-36 PCS score (Table 3) whereas a new cerebrovascular event was associated with a decrement in SF-36 MCS score and a new retinopathy was associated with a better SF-36 MCS score (Table 4). When all interval complications were considered in the same model, to account for different complications occurring in the same patient, results were similar, although the associations of interval coronary disease and heart failure with worse SF-36 scores were no longer statistically significant (point estimates were similar).

| DISCUSS ION
In a prospective global cohort of patients with T2D initiating second-line glucose-lowering therapy, several T2D-related com-  Note: Data are presented as mean ± SD (number of patients with data) or n (%).

| Prior studies
There are few studies that have examined the impact of complications  Furthermore, these data could be used to inform models to estimate the potential benefit or cost-effectiveness of interventions for T2D that reduce the risk of complications.

| Limitations
First, it is important to note that DISCOVER is an observational study designed to describe processes of care in real-world clinical F I G U R E 2 Short-form 36 physical and mental components summary score over 3 years of follow-up

| CON CLUS ION
In a prospective global study of patients with T2D, we found that