Characteristics of the study population
A total of 161,937 patients with new-onset T2DM at enrollment were included from the NHIS database. Among them, 51,100 patients were aged ≥ 30 years and had a prescription for antidiabetic medications. Further, 23,229 patients were excluded on the basis of the following exclusion criteria: <2 insurance claims each year (n = 491 patients), took antidiabetic drugs for < 180 days (n = 9,919 patients), and the presence of an end-stage disease (n = 2,083 patients) (Fig. 1).
The final study population comprised 27,871 patients; their mean age was 57.28 years, 15,132 (54.29%) were men, and the mean duration of diabetes was 6.56 ± 2.81 years. The concomitant diseases were hypertension in 66.94% of the patients and dyslipidemia in 72.57%. During the 2-year postdiagnosis period, 70.06% of the patients had taken metformin, 53.62% had taken SU, 15.48% had taken DPP4I, and 2.57% had taken insulin. The compliance of antidiabetic drugs was observed in 77.86% of the patients as per the MPR. The concomitant medication was ACEI/ARB in 47.81% of the patients, DHP-CCB in 40.67%, and statin in 46.52%. Of the 27,871 patients, at the index date of 2 years postdiagnosis, 9,130 patients (32.76%) had no complications, 9,015 patients (32.35%) had one complication, and 9,726 (34.90%) patients had two or more complications. Older patients were found to have more complications than younger patients. The number of women was relatively higher in the patients with complications. The CCI score for coexisting diseases was 1.66 ± 1.00 in the patients with no complications, 2.62 ± 1.35 in the patients with one complication, and 4.12 ± 1.82 in the patients with two or more complications (Table 1).
Total diabetes complications at 2 years postdiagnosis and during the follow-up period
The number of patients with no complications was 9,130 (32.76%) during the 2-year postdiagnosis period and 3,714 (13.33%) during the follow-up period; the numbers of patients with one complication was 9,015 (48.10%) and 5,888 (24.37%) during these periods, respectively. Two or more complications were observed in 9,726 (34.89%) and 18,269 (65.54%) patients during these periods, respectively. The number of patients with complications that occurred during the 2-year postdiagnosis period was total 18,741 and the highest for neuropathy in 8,896 (47.47%) followed by cardiovascular complications in 7,508 (40.06%) and retinopathy in 5,739 (30.62%). A total of 24,157 patients had complications during the follow-up period with the highest for neuropathy in 15,385 (63.69%), followed by cardiovascular complications in 12,652 (52.37%) and retinopathy in 11,698 (48.42%) (Supplement Fig. 1, Supplement Table 3).
Table 3
Relative risk of new onset diabetic complications by patient characteristics
Characteristics | Composite complications RR (95% CI) |
Age | 1.006 (1.005–1.007)* |
Male (Ref. female) | 0.93 (0.92–0.95)* |
CCI | 1.018 (1.013–1.023)* |
Baseline DCSI | 1.26 (1.25–1.27)* |
Insulin | 1.07 (1.03–1.11)* |
Aspirin | 1.07 (1.06–1.09)* |
Clopidogrel | 0.96 (0.94–0.98)* |
Sarpogrelate | 1.00 (0.97–1.02) |
Cilostazol | 0.99 (0.95–1.03) |
ACEI/ARB | 0.99 (0.98–1.01) |
Statin | 0.92 (0.91–0.93)* |
Number of antidiabetics | |
1 | Reference |
2 | 1.01 (1.00-1.03) |
3 + | 1.13 (1.10–1.17)* |
Antidiabetics therapy | |
Mono therapy | |
Metformin | Reference |
DPP4-I | 0.77 (0.70–0.85)* |
Sulfonylurea | 1.29 (1.27–1.32)* |
Glucosidase | 1.25 (1.18–1.33)* |
Dual therapy | |
Metformin + Sulfonylurea | Reference |
Metformin + DPP4-I | 0.71 (0.69–0.73)* |
Abbreviation: CCI, Charlson comorbidity index score; ACEI/ARB, angiotensin-1 converting enzyme Inhibitor/angiotensin-2 receptor blocker, DPP4-I, Dipeptidyl peptidase-4 inhibitor. * statistically significant |
Incidence and relative risk of new-onset diabetes complications during the follow-up period
A total of 18,741 patients developed new complications during the follow-up period with the highest for neuropathy 9,913 (54.05%), followed by cardiovascular complications 7,738 (42.19%) and retinopathy 7,595 (41.41%) (Table 2).
The risk of new complications during the follow-up period increased with age, female sex, and a higher CCI score. As DCSI increased, the risk of new complications increased by 26% [relative risk (RR) 1.26, 95% CI 1.28–1.27]. The use of more than three antidiabetics increased the risk of new complications by 13% (RR 1.13, 95% CI 1.10–1.17); the risk was relatively higher in patients treated with insulin (RR 1.07, 95% CI 1.03–1.11) and relatively lower in patients treated with statins (RR 0.71, 95% CI 0.69–0.73) as the concomitant medication. On comparing monotherapy with reference metformin, the risk of new complications was higher in patients treated with sulfonylurea (RR 1.29, 95% CI 1.27–1.32) than in patients treated with DPP4-I (RR 0.77, 95% CI 0.70–0.85). On comparing dual therapy [metformin + SU] with combination therapy [metformin + DPP4-I], patients treated with combination therapy had a 29% (RR 0.71, 95% CI 0.69–0.73) lower risk of new complications (Table 3).
All-cause hospitalization
A total of 14,297 (51.30%) of the 27,871 patients were admitted to the hospital for all causes. The mean frequency of hospitalization during the follow-up period increased 2.96 times in the patients without complications, 3.15 times in the patients with one complication, and 3.59 times in the patients with two or more complications. The average duration of hospitalization was 54.94 days in the patients without complications, 76.40 days in the patients with one complication, and 106 days in the patients with two or more complications (Supplement Table 4).
Table 4
Poisson regression model of relative risk of hospitalization and Cox proportional hazard model of mortality
Characteristics | Hospitalization adjusted RR (95%CI) | Mortality adjusted HR (95%CI) |
Age | 1.009 (1.008–1.011) | 1.093 (1.088–1.097) |
Male (Ref. female) | 0.94 (0.90–0.97) | 1.80 (1.65–1.96) |
Insulin use | 1.91 (1.81–2.02) | 2.83 (2.52–3.17) |
Diabetic complications severity index (linear) | 1.04 (1.03–1.06) | 1.13 (1.11–1.16) |
DCSI (categorical) | | |
0 | Reference | Reference |
1 | 1.06 (1.01–1.11) | 1.05 (0.93–1.19) |
2 | 1.10 (1.04–1.16) | 1.12 (0.98–1.27) |
3 | 1.11 (1.03–1.18) | 1.34 (1.17–1.54) |
4 | 1.21 (1.12–1.32) | 1.76 (1.51–2.05) |
5+ | 1.34 (1.23–1.47) | 1.87 (1.60–2.19) |
Number of complications (categorical) | | |
0 | Reference | Reference |
1 | 1.06 (1.01–1.11) | 1.10 (0.98–1.24) |
2 | 1.10 (1.04–1.16) | 1.29 (1.14–1.46) |
3 | 1.16 (1.08–1.24) | 1.45 (1.26–1.66) |
4 | 1.22 (1.11–1.34) | 1.57 (1.31–1.89) |
5+ | 1.36 (1.18–1.57) | 1.65 (1.24–2.20) |
adjust - age, sex, insulin use | | |
The adjusted RR of hospitalization was 1.06 (95% CI 1.01–1.11) when DCSI was 1, and it increased to 1.34 (95% CI 1.23–1.47) when DCSI was ≥ 5 compared with when DCSI was 0 as the reference (Table 4, Supplement table 5).
All-cause mortality
Among the 27,871 patients, 2,302 (8.26%) died because of all causes. Overall, 490 (5.37%) of the 9,130 patients without complications, 659 (7.31%) of the 9,015 patients with one complication, and 1,153 (11.85%) of the 9,726 patients with two or more complications died (Supplement Table 4). The ROC curve showed that DCSI was a useful indicator of mortality (Supplement Fig. 2). As the number of diabetes complications increased, the survival rate of patients decreased significantly (Fig. 2). The adjusted hazard ratio of mortality increased to 1.05 (95% CI 0.93–1.19) when DCSI was 1 and 1.87 (95% CI 1.60–2.19) when DCSI was ≥ 5 compared with when DCSI was 0 as the reference (Table 4, Supplement table 6).