Cluster-based metabolic subphenotypes and projected cross-organ risk in Chinese adults with prediabetes

Table 1 Baseline characteristics and organ risk measures across cluster-defined metabolic subtypes, mean ± SD/median (interquartile range)/n (%)

Characteristic	Overall	MARD	MOD	SID	SIR	P value
	(n = 621)	(n = 190)	(n = 177)	(n = 159)	(n = 95)
Female sex	319 (51.4)	100 (52.6)	81 (45.8)	91 (57.2)	47 (49.5)	0.197
Age (years)	51.08 ± 10.14	57.85 ± 6.82	44.04 ± 7.84	55.42 ± 7.90	43.39 ± 9.33	< 0.001
BMI (kg/m2)	25.20 (23.40, 27.40)	25.90 (24.49, 27.38)	25.09 (23.70, 26.50)	23.20 (21.40, 24.60)	29.30 (27.38, 31.90)	< 0.001
Waist circumference (cm)	88.92 ± 9.69	91.03 ± 8.29	87.25 ± 7.79	82.50 ± 7.78	98.57 ± 9.39	< 0.001
SBP (mmHg)	124.04 ± 15.53	127.47 ± 14.45	120.68 ± 13.91	121.93 ± 17.85	126.81 ± 14.75	< 0.001
Diastolic blood pressure (mmHg)	77.91 ± 9.95	77.66 ± 9.32	77.83 ± 10.02	75.81 ± 9.80	81.82 ± 10.25	< 0.001
Fasting glucose (mmol/L)	5.96 ± 0.62	6.00 ± 0.56	5.81 ± 0.66	6.07 ± 0.60	5.95 ± 0.65	0.002
2-hour glucose (mmol/L)	8.73 ± 1.38	8.79 ± 1.38	8.61 ± 1.36	8.55 ± 1.45	9.15 ± 1.21	0.013
1-hour glucose (mmol/L)	11.28 ± 2.20	11.54 ± 2.06	10.63 ± 2.16	11.36 ± 2.42	11.83 ± 1.93	< 0.001
HbA1c (%)	5.80 ± 0.34	5.97 ± 0.23	5.51 ± 0.31	5.91 ± 0.27	5.84 ± 0.33	< 0.001
Fasting insulin (0 minute)	10.20 (7.21, 14.43)	12.84 (10.12, 15.72)	9.53 (7.50, 11.44)	6.29 (4.84, 7.44)	21.99 (16.79, 27.87)	< 0.001
Insulin (1 hour)	74.77 (47.34, 116.47)	95.61 (65.53, 135.60)	63.24 (45.91, 89.81)	45.57 (32.63, 67.96)	144.85 (99.99, 180.48)	< 0.001
Insulin (2 hours)	72.96 (46.57, 113.40)	91.33 (61.30, 131.45)	65.01 (46.50, 101.10)	45.31 (31.41, 68.39)	154.40 (101.35, 215.55)	< 0.001
HOMA-IR	2.68 (1.86, 3.89)	3.44 (2.63, 4.32)	2.50 (1.82, 3.06)	1.67 (1.29, 2.08)	5.62 (4.13, 7.56)	< 0.001
HOMA-β cell function	85.71 (58.59, 126.32)	104.34 (83.28, 128.07)	81.12 (64.17, 106.39)	48.66 (37.37, 58.26)	165.29 (134.71, 238.79)	< 0.001
TG (mmol/L)	1.44 (1.04, 2.06)	1.59 (1.19, 2.23)	1.31 (0.96, 2.01)	1.17 (0.90, 1.54)	1.81 (1.32, 2.51)	< 0.001
TC (mmol/L)	4.81 (4.20, 5.51)	4.78 (4.10, 5.45)	4.75 (4.20, 5.33)	4.90 (4.31, 5.74)	4.78 (4.29, 5.47)	0.248
LDL-C (mmol/L)	3.09 (2.54, 3.59)	3.07 (2.54, 3.58)	3.05 (2.49, 3.55)	3.12 (2.56, 3.73)	3.12 (2.67, 3.45)	0.601
AST (U/L)	20.00 (17.00, 24.00)	21.00 (18.00, 25.00)	19.00 (17.00, 23.00)	20.00 (17.00, 22.00)	22.00 (18.00, 28.00)	< 0.001
ALT (U/L)	22.00 (16.00, 30.00)	24.00 (18.00, 32.00)	21.00 (16.00, 29.00)	18.00 (15.00, 23.00)	30.57 (20.00, 44.00)	< 0.001
PLT count (× 109/L)	236.00 (206.00, 273.00)	229.34 (199.25, 260.88)	241.00 (212.00, 281.00)	229.62 (196.50, 258.50)	259.00 (218.50, 296.50)	< 0.001
HDL cholesterol (mmol/L)	1.27 (1.08, 1.50)	1.24 (1.07, 1.42)	1.25 (1.09, 1.50)	1.42 (1.23, 1.62)	1.13 (1.00, 1.29)	< 0.001
10-year CVD risk (%)	6.13 (3.17, 11.26)	10.28 (5.68, 16.55)	3.39 (2.02, 7.61)	6.13 (3.97, 10.16)	5.46 (2.64, 8.23)	< 0.001
FIB-4 index	0.97 (0.69, 1.29)	1.11 (0.90, 1.41)	0.77 (0.59, 1.01)	1.15 (0.96, 1.40)	0.67 (0.47, 0.89)	< 0.001
Cr (μmol/L)	69.00 (59.20, 80.20)	71.00 (59.90, 81.40)	70.00 (59.40, 80.20)	66.10 (58.35, 77.70)	69.20 (59.85, 78.85)	0.290
Measured ACR (mg/g)	5.59 (3.19, 10.57)	6.68 (3.36, 12.63)	4.76 (3.00, 9.24)	5.23 (2.82, 9.81)	7.35 (3.72, 16.95)	0.018
eGFR (mL/minute/1.73 m2)	97.76 (88.75, 105.56)	92.55 (83.14, 98.64)	104.11 (96.86, 111.23)	94.97 (85.42, 102.37)	102.59 (93.61, 112.72)	< 0.001
CKD-PC projected CKD risk (5 years) (%)	2.32 (0.97, 5.26)	4.86 (2.77, 8.43)	0.95 (0.49, 1.89)	3.60 (1.72, 6.15)	1.11 (0.63, 2.69)	< 0.001

P values were derived from the χ² test or Fisher’s exact test for categorical variables and the Kruskal-Wallis test for continuous variables, as appropriate. Score-derived organ-risk measures were calculated in outcome-specific analytic samples: (1) Framingham-estimated 10-year cardiovascular disease risk, n = 452; (2) Chronic kidney disease prognosis consortium-projected 5-year chronic kidney disease risk, n = 448; and (3) Fibrosis-4 index, n = 621. Albumin-to-creatinine ratio was summarized from measured urinary albumin and urinary creatinine values. ACR: Albumin-to-creatinine ratio; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; CKD: Chronic kidney disease; CKD-PC: Chronic kidney disease prognosis consortium; CVD: Cardiovascular disease; eGFR: Estimated glomerular filtration rate; FIB-4: Fibrosis-4; HDL: High-density lipoprotein; HOMA-IR: Homeostasis model assessment of insulin resistance; HOMA-β: Homeostasis model assessment of β-cell function; LDL-C: Low-density lipoprotein cholesterol; TC: Total cholesterol; TG: Triglyceride; Cr: Creatinine; MARD: Mild age-related dysmetabolism; MOD: Mild obesity-related dysmetabolism; SID: Severe insulin deficiency; SIR: Severe insulin resistance; BMI: Body mass index; SBP: Systolic blood pressure; HbA1c: Glycated hemoglobin; PLT: Platelet.

Table 2 Exploratory Poisson regression analyses of threshold-defined intermediate/high-risk outcomes across organ domains, n (%)

Subtype	Model	n	Participants meeting threshold	PR	95%CI (PR)	P value
Framingham-estimated 10-year CVD risk ≥ 10%
MOD (Ref)	Model 1	132	22 (16.7)	Ref	-	-
MARD	Model 1	138	71 (51.4)	3.087	2.040-4.672	< 0.001
SID	Model 1	108	28 (25.9)	1.556	0.946-2.557	0.082
SIR	Model 1	74	10 (13.5)	0.811	0.406-1.618	0.552
MOD (Ref)	Model 2	132	22 (16.7)	Ref	-	-
MARD	Model 2	138	71 (51.4)	1.942	1.283-2.940	0.002
SID	Model 2	108	28 (25.9)	1.805	1.116-2.921	0.016
SIR	Model 2	74	10 (13.5)	0.399	0.206-0.772	0.006
CKD-PC-estimated projected 5-year CKD risk ≥ 5%
MOD (Ref)	Model 1	133	7 (5.3)	Ref	-	-
MARD	Model 1	133	65 (48.9)	9.286	4.423-19.495	< 0.001
SID	Model 1	107	36 (33.6)	6.393	2.964-13.787	< 0.001
SIR	Model 1	75	9 (12.0)	2.280	0.885-5.874	0.088
MOD (Ref)	Model 2	133	7 (5.3)	Ref	-	-
MARD	Model 2	133	65 (48.9)	8.748	4.123-18.560	< 0.001
SID	Model 2	107	36 (33.6)	6.407	2.990-13.728	< 0.001
SIR	Model 2	75	9 (12.0)	2.095	0.790-5.555	0.137
FIB-4 ≥ 1.30
MOD (Ref)	Model 1	177	17 (9.6)	Ref	-	-
MARD	Model 1	190	68 (35.8)	3.726	2.282-6.085	< 0.001
SID	Model 1	159	58 (36.5)	3.798	2.312-6.239	< 0.001
SIR	Model 1	95	9 (9.5)	0.986	0.457-2.127	0.972
MOD (Ref)	Model 2	165	16 (9.7)	Ref	-	-
MARD	Model 2	177	67 (37.9)	3.002	1.758-5.127	< 0.001
SID	Model 2	149	58 (38.9)	3.505	2.100-5.849	< 0.001
SIR	Model 2	94	9 (9.6)	0.912	0.410-2.028	0.821

The n column gives the subtype-specific denominator in the corresponding model sample. Participants meeting threshold are presented as n (%), with percentages calculated using the subtype-specific denominator; these values represent score-defined risk classifications rather than observed clinical outcomes. Poisson regression with HC3 robust standard errors was used to estimate prevalence ratios and 95%CI, with mild obesity-related dysmetabolism as the reference group. Model 1 was unadjusted. Revised model 2 included waist circumference, aspartate aminotransferase, platelet count, estimated glomerular filtration rate, triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) for the cardiovascular disease analysis; waist circumference, LDL-C, TG, aspartate aminotransferase, and platelet count for the chronic kidney disease analysis; and waist circumference, sex, systolic blood pressure, estimated glomerular filtration rate, TG, and LDL-C for the fibrosis-4 analysis. Covariates were aligned by participant identifier before model fitting. CKD: Chronic kidney disease; CKD-PC: Chronic kidney disease prognosis consortium; CVD: Cardiovascular disease; FIB-4: Fibrosis-4; MARD: Mild age-related dysmetabolism; MOD: Mild obesity-related dysmetabolism; PR: Prevalence ratio; SID: Severe insulin deficiency; SIR: Severe insulin resistance; Ref: Reference.