Risk of rapid progression to dialysis in patients with type 2 diabetes mellitus with and without diabetes-related complications at diagnosis

Many adults with diabetes mellitus are unaware worldwide. The study objectives aimed to evaluate the risk of dialysis within 5 years of diagnosis between patients with newly diagnosed diabetes with and without diabetes-related complications. A retrospective longitudinal nationwide cohort study was conducted. Patients diagnosed with diabetes between 2005 and 2013 were followed up until 2018. They were categorized based on the presence or absence of complications, the number of complications, and the diabetes complications severity index (DCSI) scores. Dialysis outcomes were determined through the Registry of Catastrophic Illness from the National Health Insurance Research Database. Among the analyzed patients, 25.38% had complications at diagnosis. Patients with complications at diagnosis had a significantly higher risk of dialysis within 5 years (adjusted hazard ratio: 9.55, 95% confidence interval CI 9.02–10.11). Increasing DCSI scores and the number of complications were associated with higher dialysis risks. Patients with one complication had a 7.26-times higher risk (95% CI 6.83–7.71), while those with ≥ 3 complications had a 36.12-times higher risk (95% CI 32.28–40.41). In conclusion, newly diagnosed diabetes patients with complications face an increased risk of dialysis within 5 years. The severity and number of complications are directly linked to the risk of dialysis within this timeframe.


Bivariate analysis for risk factors of dialysis within 5 years after DM diagnosis
A total of 7185 patients (0.71%) with diabetes needed dialysis within 5 years after their diagnosis.Furthermore, diabetes patients with complications at the time of diagnosis had a significantly higher risk of progressing to requiring dialysis within 5 years compared with those without complications at the time of diagnosis (2.14% versus 0.22%, P < 0.001).Next, a higher DCSI score was associated with a higher 5-year cumulative incidence rate of dialysis after diabetes diagnosis (0.38% when the DCSI score was 1; 12.55% when the DCSI score was ≥ 5).The number of DM-related complications was also associated with the risk of dialysis within 5 years of diagnosis.Of the patients with one DM-related complication at the time of DM diagnosis, 1.54% required dialysis within 5 years.When two or three or more DM-related complications were present at the time of DM diagnosis, the 5-year cumulative incidence rates of dialysis were 4.67 and 8.12, respectively.
Patients who required dialysis within 5 years of their diagnosis were older than those who did not (59.27± 13.87 versus 57.74 ± 13.41, P < 0.001).Additionally, the rate of dialysis within 5 years of diabetes diagnosis increased with age group (0.61% in the 20-44 years group versus 0.97% in the ≧75 years group).Male diabetes patients had a slightly higher risk of requiring dialysis within 5 years compared with female patients (0.81% versus 0.58%, P < 0.001), and the 5-year cumulative incidence rate of dialysis was higher among older DM patients.In addition, DM patients who were married, had a higher education level, had a higher monthly salary, underwent a free adult health examination within 3 years, joined a pay-for-performance diabetes care program, had fewer comorbidities, had a higher primary physician service volume, and underwent care at a primary clinic or from a nonpublic health-care organization were associated with a lower 5-year incidence rate of dialysis.A detailed comparison of the risk factors for the 5-year cumulative incidence of dialysis is provided in Table 2.

Competing risk models and adjusted cumulative incidence for dialysis
Table 3 shows the results of the competing risk models for the risk of requiring dialysis within 5 years among patients with newly diagnosed diabetes.Among 1,016,018 patients with type II DM included in this study, there were 110,004 (10.83%) patients died before dialysis within 5 years of DM diagnosis.As mentioned, the multivariable competing risk models included 15 pre-specific prognostic covariates.Model A demonstrated that the patients with DM-related complications at the time of diabetes diagnosis had a 9.55-times higher risk of dialysis within 5 years compared with those without complications at diagnosis (adjusted hazard ratio [HR]: 9.55, 95% confidence interval CI 9.02-10.11,P < 0.001).Model B demonstrated that the risk of dialysis within 5 years significantly increased with the DCSI score.Compared with the patients without DM-related complications, those with DCSI scores of 1, 2, 3, 4, and ≥ 5 had 1.97-, 15.33-, 20.42-, 55.05-, and 67.56-times higher risks of dialysis within 5 years, respectively.Model C indicated that the patients with one DM-related complication at the time of diabetes diagnosis had a 7.26-times higher risk of dialysis within 5 years compared with those without DM-related complications (adjusted HR: 7.26, 95% CI 6.83-7.71,P < 0.001).The patients with 2 and ≥ 3 DM-related complications had even higher risks of dialysis within 5 years, as presented in Table 3 (adjusted HR: 21.66, 95% CI 20.11-23.33,P < 0.001 and adjusted HR: 36.12,95% CI 32.28-40.41,P < 0.001, respectively).Figure 1 presents the multivariate-adjusted 5-year cumulative incidence rates of dialysis for diabetes patients with or without DM-related complications, alongside the corresponding DCSI scores, and with 0, 1, 2 or ≥ 3 www.nature.com/scientificreports/S2 and Fig. S1).

Discussion
This study demonstrated that approximately 25.38% of the analyzed patients had DM-related complications at the time of their diagnosis.Those with complications at the time of DM diagnosis had a higher incidence of dialysis within 5 years.Furthermore, compared with those without complications at DM diagnosis, those with complications had a 9.55 times higher risk of requiring dialysis within 5 years.Next, the risk of requiring dialysis within 5 years increased with the DCSI scores and the number of DM-related complications.Patients with a DCSI score of 1 had a 1.97 times higher risk of dialysis than those without DM-related complications.However, when the DCSI score was more than 5, the risk of dialysis within 5 years was 67.56 times higher.Moreover, patients with three or more DM-related complications had a 36.12 times higher risk of dialysis compared with those without any DM-related complications.To the best of our knowledge, this study was the first to compare the risk of rapid progression to ESRD among diabetic patients with and without complications at the time of diagnosis.
The prevalence of undiagnosed diabetes remained high because patients can be asymptomatic until complications develop.According to an international diabetes federation report published in 2019, half of the global diabetic population is unaware of their condition 1 .In Germany, a nationwide sample of 35,869 primary care patients screened in 2005 revealed that the prevalence of type 2 DM was 12.2%, including 23% undiagnosed subjects 15 .Furthermore, the ESTEBAN Survey, conducted in France between 2014 and 2016, revealed that 23% of all diabetes cases were undiagnosed 16 .Next, according to a 2015 national cross-sectional study involving 19,935 respondents conducted in Malaysia, the overall prevalence of type 2 DM was 17.5%; the prevalence of undiagnosed type 2 DM was 9.2%, suggesting that 52% of all individuals with type 2 DM remain undiagnosed 17 .Similar to previous reports, the present study found that 25.38% of the type 2 DM population had complications at the time of diagnosis.Among the analyzed patients, 21.12% had one DM-related complication, and 3.70% had two DM-related complications.Regarding complication severity, 12.69% of the patients had a DCSI score of 1, and 9.52% had a DCSI score of 2. The mean DCSI score for the patients with complications was 1.69 ± 0.88.
Individuals with undiagnosed diabetes are reportedly at a high risk of developing complications if they remain untreated 18 .In addition, diabetes patients with poor glycemic control reportedly have a relatively high risk of developing DM-related complications 19 .Hyperglycemic states can lead to macrovascular complicationssuch as coronary artery disease, peripheral arterial disease, and stroke-and microvascular complications, including diabetic nephropathy, neuropathy, and retinopathy 20 .The UK Prospective Diabetes Study (UKPDS) revealed that intensive glucose therapy in patients with newly diagnosed type 2 diabetes reduces their risk of developing microvascular complications 13 .Furthermore, a subsequent 10-year follow-up revealed a reduced risk of myocardial infarction and all-cause mortality 21 .Therefore, individuals who are at risk of type 2 diabetes should be screened to initiate patient-centered management and minimize the development and progression of microvascular and macrovascular complications, including the prevention or delay of chronic kidney disease 22,23 .
Next, patients with diabetes reportedly have a 1.75-5-times higher risk of developing chronic kidney disease compared with the general population 24,25 .The incidence of DKD is 2-4% among patients with diabetes, and the median time taken to develop diabetic nephropathy is 94.9 months 26,27 .The UKPDS also reported that 29% of the analyzed patients with newly diagnosed type 2 diabetes developed renal impairment during a median follow-up period of 15 years 28  www.nature.com/scientificreports/chronic low-grade inflammation, advanced glycation end products, and physical inactivity 29 .Early management of these modifiable risk factors may improve the prognosis of DKD in diabetic patients 28 .A study conducted in the United States used the National Health and Nutrition Examination Survey to compare the prevalence rates of chronic kidney disease among people without diabetes, those with prediabetes, those with diagnosed diabetes, and those with undiagnosed diabetes and found the rates of these four groups to be 10.6%, 17.7%, 39.6%, and 41.7%, respectively.These results indicate that the prevalence of chronic kidney disease in patients with undiagnosed diabetes is higher than that in patients with prediabetes and that in diagnosed patients 30 .In the present study, we observed that 19.16% of the patients with DM-related complications at the time of diagnosis had nephropathy.That is, the patients with DM-related complications at the time of diagnosis did not start glycemic control interventions early and thus were at a relatively high risk of requiring dialysis within 5 years.Diabetes is the leading cause of ESRD globally, accounting for 44% of all new ESRD cases 1,31 .In one study, the annual incidence of ESRD ranged from 0.04 to 1.8% 26 .In Japan, the incidence of ESRD is 4.1/1,000 person-years, and renal function deterioration is associated with older age, poor glycemic control, blood pressure, proteinuria, estimated glomerular filtration rate, history of cardiovascular disease, lifestyle factors (e.g.body mass index, low dietary fiber intake, increased high sodium intake, infrequent exercise), and depressive symptoms 32 .In this study, the risk of dialysis within 5 years after a diabetes diagnosis was higher in the older age group than the younger group.In Taiwan, the incidence rate of dialysis was 523 per million population in 2018 8 .In Finland, a report on 421,429 patients with type 2 diabetes revealed that 1516 of these patients developed ESRD and that the cumulative risk rates of ESRD at 10 and 20 years after diabetes diagnosis were 0.29% and 0.74%, respectively 33 .There were 0.71% of patients who needed dialysis within 5 years after the diagnosis of diabetes in this study, which was higher than previous reports.The higher incidence of ESRD in the Western Pacific region, as previously reported, may account for the higher dialysis rates observed in the current study 34 .In addition, patients without diabetic complications at diagnosis had similar dialysis risks compared to previous reports.On the other hand, a higher risk of dialysis was observed in patients with diabetic complications at diagnosis, which may be another reason for the higher rate of dialysis in this study.In addition, previous studies have reported that patients with DM-related complications, such as cardiovascular disease and peripheral arterial disease, are at a relatively high risk of DKD progression 35,36 .Patients with diabetic retinopathy are also at a relatively high risk of DKD 37,38 .Previous studies in Taiwan comparing dialysis risk among diabetic physicians and nurses with the general diabetes population have revealed a higher risk of dialysis among patients with comorbidities 39,40 .Similarly, the results

Study participants
Patients with a history of at least one hospitalization and a diagnosis of diabetes (ICD-9-CM code 250.x or A181) or a history of three outpatient clinic visits within 365 consecutive days with concurrent use of diabetes medication were defined as diabetic patients [46][47][48] .Patients older than 20 years with type 2 diabetes newly diagnosed between 2005 and 2013 were also included in this study.Patients were excluded according to the following criteria: (1) A diagnosis of type I DM, which is defined as a catastrophic illness, a history of hospitalization for diabetes ketone acidosis (DKA; ICD-9-CM code 250.1x) with outpatient visit diagnosis of insulin-dependent diabetes (ICD-9-CM code 250.× 1 or 250.× 3), or a history of three outpatient clinic visits for insulin-dependent diabetes within 365 consecutive days without DKA hospitalization; (2) those with a diagnosis of gestational diabetes (ICD-9-CM code 648.0 or 648.8); (3) receipt of kidney transplant surgery before DM diagnosis; (4) receipt of renal replacement therapy before DM diagnosis; and (5) incomplete data (Fig. 2).

Relevant variables
According to the DCSI developed by Young et al. in 2008 49 , DM-related complications can be categorized into seven major categories, namely retinopathy, nephropathy, neuropathy, cerebrovascular disease, cardiovascular disease, peripheral vascular disease, and metabolic disease.In this study, patients who had DM-related complications within 1 year before DM diagnosis were classified as the diabetic complication group, whereas patients without DM-related complications were classified as the nondiabetic complication group.We calculated the DCSI score, a score between 0 and 13 based on the corresponding ICD-9-CM code, of each patient in the diabetic complication group.This group was further divided into five subgroups according to DCSI scores of 1, 2, 3, 4, and ≥ 5. We also recorded the number of DM-related complications and further divided the diabetic complication subgroups based on 1, 2, and ≥ 3 complications at diagnosis.The distribution of DM-related complications at the time of DM diagnosis was recorded.
To better understand the study participants' personal characteristics, we retrieved information regarding their age, sex, marital status (unmarried, married, divorced, or widowed), and highest education level (elementary school or lower, junior high school, senior high school, or university or higher) from the database.The economic status of the research participants was divided into six groups according to their monthly salaries: ≤ NT$17,280, NT$17,281-NT$22,800, NT$22,801-NT$28,800, NT$28,801-NT$36,300, NT$36,301-NT$45,800, and ≥ NT$45,801.We also analyzed the urbanization level of residential areas (seven levels, with level 1 being the most urbanized 50 ) as an environmental factor.Information of mortality after diabetes diagnosis were obtained from the Cause of Death File from the Ministry of Health and Welfare.
Patients with a history of cancer in the Registry of Catastrophic Illness were considered to have a history of malignancy.Patients were considered to have comorbidities, such as hypertension, stroke and diseases listed in the Charlson Comorbidity Index (CCI) 51 if they had received a primary or secondary diagnosis based on an ICD-9-CM code either twice during outpatient visits or once during hospitalization.CCI scores were calculated for all the participants.To avoid the dual calculation of CCI scores with DCSI scores, diabetes-related diagnoses, strokerelated diagnoses, and cancer-related diagnoses were not included in the calculation of CCI scores.Information about whether diabetes patients had participated in diabetes pay-for-performance care programs (with or without code E4, the specific treatment code for pay-for-performance programs during outpatient visits) was also collected from the database 48 .The diabetes pay-for-performance program launched by the NHI administration in Taiwan provides a financial incentive to facilitate comprehensive assessment and continuous care for patients with diabetes since 2001.According to previous report, the pay-for-performance program increased proportions of patients with HbA1c < 7% (34.5% vs. 32.4%),blood pressure < 130/80 mmHg (37.7% vs. 30.9%),and lowdensity lipoprotein cholesterol < 100 mg/dL or total cholesterol < 160 mg/dL 52 .We also determined from the database whether individuals had received a free adult health examination (with or without code 21 or 24, the specific codes at outpatient visits) within 3 years prior to their diabetes diagnosis to represent the health belief factor in this study 53 .Finally, this study examined the characteristics of health-care providers, including each primary physician's service volume (defined as their annual diabetes patient service volume, calculated using the quartile method 47 ), health-care organizational level (medical center, regional hospital, district hospital, or primary clinic), and ownership of their health-care organization (public or nonpublic).

Outcome measurement
The primary endpoint of this study was the determination of whether patients with newly diagnosed DM required dialysis within 5 years.Information regarding dialysis was obtained from the Registry of Catastrophic Illness.Patients with any one of the aforementioned 30 catastrophic diseases, including ESRD requiring dialysis, can apply for a certificate of catastrophic illness.Patients can then be exempted from copayments of medical expenses if their catastrophic illness is acknowledged by a physician and registered in the NHI program.In Taiwan, patients can only apply for catastrophic illness of dialysis after receiving consecutive dialysis for three months.The application form must be completed by a nephrologist, and the certification of catastrophic illness of dialysis will only be issued after rigorous review.The definition of chronic dialysis was consistent with previous studies 54,55 .The time intervals between DM diagnosis and catastrophic illness registration for the patients in this study were recorded to analyze the cumulative incidence of dialysis.Both 5-year and long term (followed until December 31, 2018) cumulative incidence of dialysis were calculated to realize the influence of diabetes complications of risk of dialysis.

Statistical analysis
All statistical analyses in this study were performed using SAS (version 9.1; SAS Institute, Cary, NC, USA), and a P value of < 0.05 was considered statistically significant.The demographic data of patients with newly diagnosed DM were presented alongside descriptive data according to the presence or absence of DM-related complications at the time of DM diagnosis.Categorical characteristics are presented as numbers and percentages, and differences among these characteristics were analyzed using the chi-square test.Continuous variables are presented as means and standard deviations.Finally, differences among the study groups and subgroups were tested using Student's t test for two groups and analyses of variance (ANOVA) for three or more groups.
The follow-up period began at the time of DM diagnosis and continued until the date of dialysis commencement, death, or the end of the observation period (December 31, 2018).The study patients were divided into two groups based on whether they required dialysis within 5 years of DM diagnosis.Crude case numbers and the cumulative incidence of dialysis within 5 years are presented according to the patients' characteristics.The log-rank test was conducted to examine differences in the 5-year cumulative incidence rates of dialysis among the subgroups.
For the analysis of dialysis risk among DM patients, death was considered a competing event.To further analyze the risk of dialysis within 5 years among patients with and without DM-related complications and with complications of varying severity, multivariate Cox proportional hazards regression models accounting for competing risk were used with adjustment for 15 prespecified risk covariates (i.e.age; sex; marital status; education level; monthly salary; urbanization level of residential area; CCI score; history of cancer; history of hypertension; history of stroke; enrollment in a pay-for-performance diabetes care program; free adult health exam within 3 years; and primary physician's service volume, health-care organizational level, and ownership of health-care organization).Three competing risk models-namely those for the presence or absence of DM-related complications, DCSI scores, and the number of DM-related complications-were used to calculate the adjusted hazard ratios (HRs) for the risk of dialysis within 5 years after DM diagnosis.After multivariate adjustment, the adjusted HR for dialysis was calculated for each of the three models.Next, we conducted sensitivity tests.The adjusted cumulative incidence of dialysis until December 31, 2018, was plotted.Three competing risk models with adjustment for the same covariates were used to evaluate differences in the risk of dialysis among patients with and without DM-related complications at diagnosis until December 31, 2018.All data in this study were anonymized, and personal data could not be identified.The informed consent was waived by the Research Ethics Committee of the Taichung Jen-Ai Hospital.The research was conducted in

Figure 1 .
Figure 1.Adjusted 5-year cumulative incidence rates of dialysis after diabetes diagnosis.Adjusted for age, sex, marital status, education level, monthly salary, urbanization of household residential area, Charlson Comorbidity Index score, history of cancer, history of hypertension, history of stroke, enrollment in pay-forperformance diabetes care program, receipt of free adult health examination within 3 years, primary physician's service volume, primary physician's level of health-care organization, and primary physician's ownership of health-care organization.(a) shows the adjusted 5-year cumulative incidence rates of dialysis of patients with and without diabetes-related complications at diagnosis.(b) shows the adjusted 5-year cumulative incidence rates of patients with varying Diabetes Complications Severity Index (DCSI) scores.(c) shows the adjusted 5-year cumulative incidence rates of patients with varying numbers of diabetes-related complications.

Table 1 .
Demographic characteristics of patients with newly diagnosed type 2 diabetes with and without complications at diagnosis.SD standard deviation, DCSI diabetes complications severity index, CCI Charlson comorbidity index.a chi-square test, b t test and ANOVA.

Table 2 .
Comparison of 5-year cumulative incidence rates of dialysis between type 2 diabetes patients with and without complications at diagnosis.a log-rank test.

Table 3 .
Competing risk models for risk of dialysis within 5 years among patients with newly diagnosed diabetes.The above models were adjusted for age, sex, marital status, education level, monthly salary, urbanization of household residential area, Charlson Comorbidity Index score, history of cancer, history of hypertension, history of stroke, enrollment in pay-for-performance diabetes care program, receipt of free adult health examination within 3 years, primary physician's service volume, primary physician's level of health-care organization, and primary physician's ownership of health-care organization.