Dynamic glycemic exposure and trajectory profiling for incident diabetic kidney disease: A longitudinal cohort study

Table 1 Baseline and clinical characteristics of participants according to diabetic kidney disease status, n (%)/median (interquartile range)

Variables	No-DKD (n = 813)	DKD (n = 244)	P value
Age (years)	53.8 (45.0, 62.0)	58.6 (48.8, 67.0)	< 0.001
Male sex (%)	488 (59.9)	131 (53.7)	0.099
BMI (kg/m2)	24.0 (22.1, 26.2)	24.1 (22.0, 26.1)	0.475
Hypertension (%)	352 (43.2)	119 (48.8)	0.143
MACCE (%)1	105 (12.9)	46 (18.9)	0.026
Hyperlipidemia (%)	315 (38.7)	88 (36.1)	0.513
ACEI/ARB treatment (%)	101 (12.4)	43 (17.7)	0.047
Diabetes duration (years)	3.5 (1.0, 6.5)	12.0 (4.5, 19.0)	< 0.001
HbA1c (%)	7.6 (6.5, 10.2)	9.7 (7.5, 11.9)	< 0.001
FPG (mmol/L)	8.0 (6.5, 11.4)	9.6 (7.2, 14.0)	< 0.001
BUN (mmol/L)	5.2 (4.3, 6.1)	5.2 (4.4, 6.2)	0.463
CREAT (μmol/L)	67.0 (56.0, 79.0)	66.0 (55.0, 79.8)	0.374
UA (μmol/L)	343.0 (278.0, 415.5)	337.0 (271.0, 429.0)	0.884
eGFR (mL/minute/1.73 m2)	99.3 (88.8, 108.7)	96.2 (82.9, 107.2)	0.009
TC (mmol/L)	4.8 (4.2, 5.6)	4.9 (4.3, 5.8)	0.054
TG (mmol/L)	1.4 (1.0, 2.2)	1.5 (1.1, 2.3)	0.062
HDL-C (mmol/L)	1.1 (0.9, 1.4)	1.1 (0.9, 1.3)	0.481
LDL-C (mmol/L)	3.0 (2.4, 3.7)	3.2 (2.5, 3.9)	0.179
Lp(a) (mg/L)	108.0 (54.5, 205.5)	113.3 (63.8, 218.5)	0.369
UACR (mg/g)	10.0 (6.5, 15.0)	15.8 (10.1, 25.6)	< 0.001
Total HbA1c measurement (n)	7.0 (5.0, 9.0)	7.0 (4.0, 9.0)	0.400
Measurement intensity (n/year)	1.0 (0.8, 1.3)	1.0 (0.7, 1.3)	0.027
Median measurement interval (years)	1.0 (0.6, 1.8)	1.2 (0.6, 2.1)	0.300
Follow-up time (years)	7.1 (5.0, 9.3)	6.5 (4.4, 9.1)	0.040

¹Major adverse cardiovascular and cerebrovascular events includes coronary heart disease and stroke.

BMI: Body mass index; DKD: Diabetic kidney disease; MACCE: Major adverse cardiovascular and cerebrovascular events; ACEI: Angiotensin-converting enzyme inhibitors; ARB: Angiotensin II receptor blockers; HbA1c: Glycated hemoglobin; BUN: Blood urea nitrogen; FPG: Fasting plasma glucose; CREAT: Creatinine; UA: Uric acid; eGFR: Estimated glomerular filtration rate; TC: Total cholesterol; TG: Triglycerides; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; Lp(a): Lipoprotein(a); UACR: Urinary albumin-to-creatinine ratio.

Table 2 The association of baseline and time-weighted average glycated hemoglobin with incident diabetic kidney disease

HbA1c parameter	Model 1		Model 2		Model 3
	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
Baseline HbA1c
Per 1% increment	1.21 (1.16-1.27)	< 0.001	1.22 (1.16-1.27)	< 0.001	1.20 (1.14-1.27)	< 0.001
Class 1 (< 7%)	Reference		Reference		Reference
Class 2 (7%-8%)	1.76 (1.12-2.76)	0.014	1.72 (1.09-2.69)	0.019	1.74 (1.1-2.77)	0.018
Class 3 (> 8%)	3.25 (2.28-4.63)	< 0.001	3.44 (2.41-4.90)	< 0.001	3.10 (2.09-4.59)	0.013
P value for trend		< 0.001		< 0.001		< 0.001
TWA-HbA1c1
Per 1% increment	1.39 (1.32-1.46)	< 0.001	1.38 (1.31-1.46)	< 0.001	1.37 (1.29-1.45)	< 0.001
Class 1 (< 7%)	Reference		Reference		Reference
Class 2 (7%-8%)	2.07 (1.32-3.24)	0.002	1.99 (1.27-3.13)	0.003	1.99 (1.26-3.14)	0.003
Class 3 (> 8%)	5.62 (3.90-8.08)	< 0.001	5.52 (3.84-7.94)	< 0.001	4.86 (3.34-7.10)	< 0.001
P value for trend		< 0.001		< 0.001		< 0.001

¹Time-weighted average glycated hemoglobin was included as a time-varying covariate to compute risk estimates for diabetic kidney disease events.

Model 1 unadjusted model; model 2 adjusted for age and sex; model 3 adjusted for age, sex, body mass index, hypertension, major adverse cardiovascular and cerebrovascular events, hyperlipidemia, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment, diabetes duration, blood urea nitrogen, serum creatinine, uric acid, low-density lipoprotein cholesterol, lipoprotein(a), urine albumin-to-creatinine ratio and measurement intensity. HbA1c: Glycated hemoglobin; CI: Confidence interval; HR: Hazard ratio; TWA-HbA1c: Time-weighted average glycated hemoglobin.

Table 3 Predictive performance of baseline glycated hemoglobin vs time-weighted average glycated hemoglobin for incident diabetic kidney disease, median (interquartile range)

Evaluation metric	Baseline HbA1c	TWA-HbA1c1	P value	IDI (95%CI)	P value	NRI (95%CI)	P value
Overall C-index	0.651 (0.613, 0.689)	0.724 (0.687, 0.760)	0.007
Time-dependent AUC
3 years	0.617 (0.516, 0.718)	0.692 (0.595, 0.790)	< 0.001	0.021 (0.011, 0.032)	< 0.001	0.268 (0.129, 0.407)	< 0.001
5 years	0.662 (0.601, 0.724)	0.730 (0.672, 0.788)	< 0.001	0.037 (0.012, 0.062)	< 0.001	0.297 (0.014, 0.580)	< 0.001
7 years	0.653 (0.602, 0.704)	0.726 (0.677, 0.775)	< 0.001	0.058 (0.017, 0.099)	< 0.001	0.301 (0.046, 0.557)	< 0.001

¹Baseline glycated hemoglobin refers to the single measurement at enrollment, whereas time-weighted average-glycated hemoglobin was incorporated into the models as a time-varying covariate. The P values indicate the statistical significance of the improvement in predictive performance when time-weighted average-glycated hemoglobin is used compared to baseline glycated hemoglobin.

HbA1c: Glycated hemoglobin; TWA-HbA1c: Time-weighted average glycated hemoglobin; CI: Confidence interval; IDI: Integrated discrimination improvement; NRI: Net reclassification improvement; AUC: Area under the receiver operating characteristic curve.

Table 4 Association between glycated hemoglobin trajectories and the risk of incident diabetic kidney disease

HbA1c trajectory	Model 1		Model 2		Model 3
	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
Low-stable (group 1)	Reference		Reference		Reference
Quickly declining-stable (group 2)	1.73 (1.09-2.73)	0.020	1.79 (1.13-2.84)	0.013	1.57 (0.95-2.58)	0.076
Quickly increasing-stable (group 3)	3.83 (2.62-5.60)	< 0.001	3.92 (2.68-5.73)	< 0.001	3.62 (2.41-5.43)	< 0.001
High-slow decline (group 4)	6.02 (4.48-8.09)	< 0.001	5.69 (4.22-7.67)	< 0.001	4.72 (3.29-6.77)	< 0.001

Model 1 unadjusted model; model 2 adjusted for age and sex; model 3 adjusted for age, sex, body mass index, hypertension, major adverse cardiovascular and cerebrovascular events, hyperlipidemia, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment, diabetes duration, blood urea nitrogen, serum creatinine, uric acid, low-density lipoprotein cholesterol, lipoprotein(a), urine albumin-to-creatinine ratio and measurement intensity. HbA1c: Glycated hemoglobin; CI: Confidence interval; HR: Hazard ratio.