Indirect bilirubin is inversely associated with diabetic retinopathy risk and is a potential predictive biomarker

Table 1 Characteristics of the study participants

Variable	Total (n = 6993)	DR (n = 2122)	Non-DR (n = 4871)	P value
Male (%)	64.2	62.7	64.8	0.098
Age (years)	55.9 ± 14.0	58.8 ± 11.3	54.6 ± 14.8	< 0.001c
Duration of diabetes (years)	7.5 (2.5-13.0)	11.0 (6.0-16.0)	5.5 (1.2-11.0)	< 0.001c
Systolic blood pressure (mmHg)	133.2 ± 19.3	137.8 ± 21.1	131.3 ± 18.1	< 0.001c
Diastolic blood pressure (mmHg)	80.0 ± 11.3	80.9 ± 11.7	79.6 ± 11.1	< 0.001c
BMI (kg/m2)	24.6 ± 3.7	24.4 ± 3.5	24.6 ± 3.8	0.015a
Insulin treatment (%)	66.4	77.2	61.8	< 0.001c
Biguanide treatment (%)	44	47.3	36.4	< 0.001c
Sulfonylurea treatment (%)	7.8	6.3	8.4	0.002b
Glinide treatment (%)	3	3.3	2.9	0.450
α-glucosidase inhibitor treatment (%)	25	25.5	24.8	0.525
Thiazolidinedione treatment (%)	0.8	0.7	0.9	0.302
DPP-4 inhibitor treatment (%)	13.5	11.6	14.3	0.003b
GLP-1 analog treatment (%)	3.4	2.5	3.9	0.003b
SGLT-2 inhibitor treatment (%)	0.6	0.1	0.8	0.001b
Lipid-lowering drugs (%)	79.3	85.6	76.6	< 0.001c
FPG (mmol/L)	8.5 (6.1-12.8)	8.6 (6.0-12.7)	8.4 (6.1-12.9)	0.372
HbA1c (%)	8.5 (7.0-10.4)	8.7 (7.2-10.2)	8.4 (6.9-10.5)	0.278
Total cholesterol (mmol/L)	4.2 ± 1.2	4.2 ± 1.3	4.2 ± 1.2	0.949
Triglycerides (mmol/L)	1.4 (1.0-2.2)	1.4 (1.0-2.1)	1.4 (1.0-2.2)	0.190
HDL (mmol/L)	0.98 ± 0.29	1.00 ± 0.30	0.98 ± 0.28	0.004b
LDL (mmol/L)	2.47 ± 0.91	2.48 ± 0.99	2.47 ± 0.88	0.366
ACR (mg/g)	17.4 (8.7-57.3)	43.0 (13.0-361.9)	14.1 (8.0-33.7)	< 0.001c
eGFR (mL/min per 1.73m2)	102.4 ± 24.0	94.8 ± 27.7	105.3 ± 21.7	< 0.001c
AST (IU/L)	18.0 (14.5-24.0)	17.6 (14.0-22.3)	18.3 (15.0-25.0)	< 0.001c
ALT (IU/L)	19.0 (13.1-29.0)	17.0 (12.1-25.0)	20.0 (14.0-31.0)	< 0.001c
GGT (IU/L)	23.2 (16.0-38.0)	21.0 (15.0-34.4)	24.1 (16.0-40.0)	< 0.001c
TBIL (μmol/dL)	1.08 (0.82-1.45)	0.96 (0.72-1.28)	1.14 (0.87-1.52)	< 0.001c
IBIL (μmol/dL)	0.74 (0.55-1.00)	0.65 (0.47-0.88)	0.78 (0.58-1.04)	< 0.001c
DBIL (μmol/dL)	0.34 (0.24-0.47)	0.30 (0.21-0.42)	0.35 (0.25-0.48)	< 0.001c
CRP (> 10 mg/L) (%)	25.4	28.7	24.2	0.079
1,25(OH)2D3 (ng/mL)	12.7 (8.9-17.9)	11.3 (7.3-16.7)	13.1 (9.6-18.4)	< 0.001c

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

Statistical significance was determined at a P value < 0.05. Continuous variables with a normal distribution are presented as the mean ± SD, whereas variables with a skewed distribution are expressed as medians (25^th and 75^th percentiles of the interquartile range). Categorical variables are summarized as frequencies (percentages). Comparisons between groups were performed via Student’s t-test for normally distributed continuous variables, the Mann-Whitney U test for nonnormally distributed continuous variables, and the χ² test for categorical variables. Comparisons are between the diabetic retinopathy group and the non-diabetic retinopathy group. DR: Diabetic retinopathy; BMI: Body mass index; DPP-4: Dipeptidyl peptidase-4; GLP-1: Glucagon-like peptide-1; SGLT-2: Sodium-glucose cotransporter-2; FPG: Fasting plasma glucose; HbA1c: Glycosylated hemoglobin; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; ACR: Albumin/creatinine ratio; eGFR: Estimated glomerular filtration rate; AST: Aspartate transaminase; ALT: Alanine aminotransferase; GGT: Gamma-glutamyl transferase; TBIL: Total bilirubin; IBIL: Indirect bilirubin; DBIL: Direct bilirubin; CRP: C-reactive protein.

Table 2 Multivariate analysis of the association between bilirubin indices and the risk of developing diabetic retinopathy

Variables	Model 1		Model 2		Model 3
	OR (95%CI)	P value	OR (95%CI)	P value	OR (95%CI)	P value
IBIL	0.423 (0.361-0.496)	< 0.001b	0.480 (0.407-0.565)	< 0.001b	0.500 (0.363-0.686)	< 0.001b
DBIL	0.480 (0.365-0.630)	< 0.001b	0.637 (0.486-0.834)	0.001a	1.029 (0.860-1.231)	0.754
TBIL	0.568 (0.507-0.636)	< 0.001b	0.634 (0.565-0.712)	< 0.001b	0.837 (0.693-1.011)	0.837

^aP < 0.01.

^bP < 0.001.

Statistical significance was determined at a P value < 0.05. Multivariate logistic regression analysis was conducted to identify independent risk factors for the development of diabetic retinopathy. Model 1: Adjusted for age. Model 2: Adjusted for age and duration of diabetes. Model 3: Adjusted for age, duration of diabetes, systolic blood pressure, the estimated glomerular filtration rate, the albumin/creatinine ratio, and 1,25(OH)₂D₃. IBIL: Indirect bilirubin; DBIL: Direct bilirubin; TBIL: Total bilirubin; OR: Odds ratio; 95%CI: 95% confidence interval.