Lean type 2 diabetes mellitus is an independent predictor of mortality in primary biliary cholangitis

Table 1 Baseline characteristics of primary biliary cholangitis with different diabetes status and lean phenotype status, median (interquartile range)/n (%)

Characteristic	Overall (n = 877)	Lean T2DM (n = 129)	Non-lean T2DM (n = 75)	Lean non-T2DM (n = 415)	Non-lean non-T2DM (n = 258)	P value
Age (years)	57 (50-66)	60 (53-69)	62 (56-70)	57 (49-65)	54 (47.75-64)	< 0.001
Female	716 (81.64)	104 (80.62)	61 (81.33)	344 (82.89)	207 (80.23)	0.833
BMI (kg/m2)	21.88 (19.29-24)	20.29 (18.05-21.65)	25 (24-26)	20 (18-21.08)	25 (24-26)	< 0.001
Combined medical history
Hepatic steatosis	131 (14.94)	13 (10.08)	19 (25.33)	38 (9.16)	61 (23.64)	< 0.001
Hypertension	176 (20.07)	35 (27.13)	31 (41.33)	57 (13.73)	53 (20.54)	< 0.001
Coronary heart disease	37 (4.22)	4 (3.10)	10 (13.33)	9 (2.17)	14 (5.43)	< 0.001
Laboratory parameters
TBil (μmol/L)	25 (14.8-70.75)	35.2 (16.35-109.45)	29.8 (17-63.3)	25.9 (15.3-72.7)	20.55 (13.1-50.03)	< 0.001
TBA (μmol/L)	32 (9.6-122.2)	44.9 (12.35-166.35)	30.8 (9.6-90.6)	38.5 (12.4-134.6)	17.45 (7.8-87.3)	< 0.001
Albumin (g/L)	50 (27-95)	39 (24-89)	48 (25-87)	52 (27-94)	53 (32.75-100.25)	< 0.001
ALT (U/L)	63 (38-106)	60 (32.5-109.5)	48 (32-88)	72 (41-115)	55.5 (37-98.5)	0.015
AST (U/L)	200 (128-339)	199 (112-322)	160 (114-254)	230 (137-411)	181 (119.75-268.75)	0.004
ALP (U/L)	165 (68-367)	131 (68.5-336)	155 (66-330)	196 (67-420)	149.5 (70.75-344)	< 0.001
GGT (U/L)	35.2 (29.85-40.4)	31.5 (27.35-36.75)	32.7 (28.5-38.6)	34.9 (29.4-40.3)	38 (33.78-42.05)	0.267
Platelets (× 109/L)	156 (90-229)	127 (69.5-184)	122 (75-178)	154 (101-230)	185.5 (111.75-246)	< 0.001
INR	1.04 (0.95-1.2)	1.13 (0.97-1.26)	1.16 (0.99-1.28)	1.05 (0.95-1.12)	1 (0.94-1.12)	< 0.001
Immunological markers
AMA-M2 positive	612 (69.78)	103 (79.84)	50 (66.67)	288 (69.40)	171 (66.28)	0.045
Anti-sp100 positive	242 (26.89)	19 (14.73)	8 (10.67)	43 (10.36)	26 (10.08)	0.075
Anti-gp210 positive	233 (26.57)	39 (30.23)	22 (29.33)	119 (28.67)	53 (20.54)	0.524
Outcome (death)	234 (26.68)	66 (51.16)	22 (29.33)	104 (25.06)	42 (16.28)	< 0.001

BMI: Body mass index; TBil: Total bilirubin; TBA: Total bile acid; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyltransferase; INR: International normalized ratio; AMA-M2: Anti-mitochondrial antibody M2; Anti-sp100: Anti-speckled protein 100; Anti-gp210: Anti-glycoprotein 210; T2DM: Type 2 diabetes mellitus.

Table 2 Cox regression analysis of lean type 2 diabetes mellitus phenotype as an independent predictor of liver-related mortality in primary biliary cholangitis patients

Variable	Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)1	P value	HR (95%CI)2	P value	HR (95%CI)3	P value
Age (years)	1.028 (1.016-1.039)	< 0.001	1.022 (1.010-1.033)	< 0.001	1.023 (1.011-1.035)	< 0.001	1.017 (1.003-1.031)	0.017
Female (%)	0.942 (0.676-1.311)	0.722	0.892 (0.640-1.242)	0.498	0.897 (0.643-1.250)	0.520	0.888 (0.627-1.257)	0.503
Combined medical history
Hepatic steatosis	0.513 (0.328-0.804)	0.004			0.606 (0.384-0.957)	0.032	0.816 (0.512-1.298)	0.39
Hypertension	0.769 (0.542-1.093)	0.144			0.610 (0.421-0.885)	0.009	0.863 (0.59-1.263)	0.448
Coronary heart disease	1.169 (0.620-2.204)	0.628			1.077 (0.550-2.109)	0.828	1.193 (0.602-2.364)	0.613
Laboratory parameters
TBil (μmol/L)	1.003 (1.002-1.004)	< 0.001					1.002 (1.001-1.003)	< 0.001
TBA (μmol/L)	1.002 (1.002-1.003)	< 0.001					1.001 (1-1.002)	0.118
Albumin (g/L)	0.871 (0.855-0.887)	< 0.001					0.91 (0.888-0.931)	< 0.001
ALT (U/L)	0.998 (0.997-1.000)	0.026					0.997 (0.995-1)	0.047
AST (U/L)	1.001 (1.000-1.001)	0.236					1.002 (1-1.004)	0.025
ALP (U/L)	1.001 (1.000-1.001)	< 0.001					1.001 (1-1.001)	0.008
GGT (U/L)	1.000 (1.000-1.000)	0.803					1 (1-1.001)	0.203
Platelets (× 109/L)	0.993 (0.991-0.995)	< 0.001					0.996 (0.994-0.998)	< 0.001
INR	3.148 (2.581-3.840)	< 0.001					1.549 (1.124-2.136)	0.008
Immunological markers
AMA-M2 positive	1.229 (0.923-1.637)	0.158					0.741 (0.546-1.008)	0.056
Anti-sp100 positive	1.346 (0.922-1.965)	0.123					1.247 (0.936-1.66)	0.132
Anti-gp210 positive	1.535 (1.171-2.012)	0.002					1.359 (0.921-2.007)	0.122
Study groups
Non-lean non-T2DM	Reference	< 0.001	Reference	< 0.001	Reference	< 0.001	Reference	< 0.001
Lean non-T2DM	1.553 (1.086-2.223)	0.016	1.512 (1.056-2.164)	0.024	1.385 (0.964-1.990)	0.078	0.787 (0.534-1.16)	0.227
Non-lean T2DM	2.123 (1.267-3.558)	0.004	1.801 (1.068-3.037)	0.027	2.020 (1.193-3.420)	0.009	0.919 (0.529-1.595)	0.763
Lean T2DM	4.064 (2.759-5.987)	< 0.001	3.596 (2.429-5.323)	< 0.001	3.450 (2.325-5.121)	< 0.001	1.845 (1.219-2.793)	0.004

¹Model A: Adjusted for age, sex, and the study groups.

²Model B: Adjusted for age, sex, hepatic steatosis, coronary heart disease, hypertension, and the study groups.

³Model C: Adjusted for age, sex, hepatic steatosis, coronary heart disease, hypertension, total bilirubin, total bile acids, albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, platelet, international normalized ratio, anti-mitochondrial antibody-M2, anti-sp100 antibody, anti-glycoprotein 210 antibody, and the study groups.

TBil: Total bilirubin; TBA: Total bile acid; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyltransferase; INR: International normalized ratio; AMA-M2: Anti-mitochondrial antibody M2; Anti-sp100: Anti-speckled protein 100; Anti-gp210: Anti-glycoprotein 210; T2DM: Type 2 diabetes mellitus; HR: Hazard ratio; CI: Confidence interval.

Table 3 Cox regression analysis of lean phenotype and type 2 diabetes mellitus status interaction effect in primary biliary cholangitis patients

Variable	Univariate analysis
	HR (95%CI)	P value
Age (years)	1.017 (1.003-1.031)	0.017
Female (%)	0.888 (0.627-1.287)	0.503
Combined medical history
Hepatic steatosis	0.816 (0.512-1.298)	0.39
Hypertension	0.863 (0.590-1.263)	0.448
Coronary heart disease	1.193 (0.602-2.364)	0.613
Laboratory parameters
TBil (μmol/L)	1.002 (1.001-1.003)	< 0.001
TBA (μmol/L)	1.001 (1.000-1.002)	0.118
Albumin (g/L)	0.910 (0.888-0.931)	< 0.001
ALT (U/L)	0.997 (0.995-1.000)	0.047
AST (U/L)	1.002 (1.000-1.004)	0.025
ALP (U/L)	1.001 (1.000-1.001)	0.008
GGT (U/L)	1.000 (1.000-1.001)	0.203
Platelets (× 109/L)	0.996 (0.994-0.998)	< 0.001
INR	1.549 (1.124-2.136)	0.008
Immunological markers
AMA-M2 positive	0.741 (0.546-1.008)	0.056
Anti-sp100 positive	1.359 (0.921-2.007)	0.122
Anti-gp210 positive	1.247 (0.936-1.660)	0.132
Study groups
T2DM	0.919 (0.529-1.595)	0.763
Lean1	0.787 (0.534-1.160)	0.227
T2DM-lean	2.551 (1.344-4.840)	0.004

¹Lean status was defined by a body mass index threshold of < 23 kg/m².

HR: Hazard ratio; CI: Confidence interval; TBil: Total bilirubin; TBA: Total bile acid; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyltransferase; INR: International normalized ratio; AMA-M2: Anti-mitochondrial antibody M2; Anti-sp100: Anti-speckled protein 100; Anti-gp210: Anti-glycoprotein 210; T2DM: Type 2 diabetes mellitus.

Table 4 Baseline characteristics stratified by type 2 diabetes mellitus-lean and non- type 2 diabetes mellitus non-lean phenotypes before and after propensity score matching in primary biliary cholangitis patients, median (interquartile range)/n (%)

Variable	Before propensity score matching				After propensity score matching
	Overall (n = 386)	T2DM lean (n = 129)	Non-T2DM non-lean (n = 257)	P value	Overall (n = 386)	T2DM lean (n = 111)	Non-T2DM non-lean (n = 111)	SMD
Age (years)	57 (49-66)	60 (53-69)	54 (48-64)	< 0.001	60 (53-69)	59 (53-68)	61 (53-69)	0.071
Female	311 (80.57)	104 (80.62)	207 (80.54)	0.986	181 (81.5)	89 (80.18)	92 (82.88)	0.069
Laboratory parameters
TBil (μmol/L)	22.65 (13.98-71.25)	35.2 (16.35-109.45)	20.5 (13.1-50.55)	< 0.001	28.35 (15.48-90.5)	33.9 (15.7-96.4)	25.1 (15.3-71)	0.08
Albumin (g/L)	36 (30.48-40.8)	31.5 (27.35-36.75)	38 (33.75-42.1)	< 0.001	33.75 (28.55-38.3)	32.7 (27.9-38)	34.3 (29.1-38.3)	0.06
ALT (U/L)	47 (28-95)	39 (24-89)	53 (32.5-99)	0.003	46 (26.75-91.25)	38 (23-87)	50 (33-96)	0.046
ALP (U/L)	55.5 (35-103)	60 (32.5-109.5)	55 (37-99)	0.336	199 (130-320.5)	197 (115-339)	201 (152-312)	0.021
Platelets (× 109/L)	166.5 (94-236)	127 (69.5-184)	186 (113-246)	< 0.001	144.5 (75-198.25)	143 (71-188)	150 (79-203)	0.034
INR	1.02 (0.94-1.18)	1.13 (0.97-1.26)	1.0 (0.94-1.12)	< 0.001	1.05 (0.96-1.22)	1.1 (0.95-1.2)	1.01 (0.96-1.2)	0.009
Immunological markers
AMA-M2 positive	274 (70.98)	103 (79.84)	171 (66.54)	0.007	173 (77.9)	86 (77.48)	87 (78.38)	0.022

TBil: Total bilirubin; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; INR: International normalized ratio; AMA-M2: Anti-mitochondrial antibody M2; T2DM: Type 2 diabetes mellitus; SMD: Standardized mean difference.

Table 5 Sensitivity analysis: Impact of lean type 2 diabetes mellitus phenotype on adverse outcomes in primary biliary cholangitis patients

Variable	Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)1	P value	HR (95%CI)2	P value	HR (95%CI)3	P value
Age (years)	1.028 (1.016-1.039)	< 0.001	1.022 (1.010-1.033)	< 0.001	1.022 (1.010-1.033)	< 0.001	1.017 (1.003-1.030)	0.014
Female (%)	0.942 (0.676-1.311)	0.722	0.892 (0.640-1.242)	0.498	0.892 (0.640-1.242)	0.498	0.895 (0.632-1.267)	0.532
Laboratory parameters
TBil (μmol/L)	1.003 (1.002-1.004)	< 0.001					1.002 (1.001-1.003)	< 0.001
TBA (μmol/L)	1.002 (1.002-1.003)	< 0.001					1.001 (1.000-1.002)	0.119
Albumin (g/L)	0.871 (0.855-0.887)	< 0.001					0.909 (0.888-0.931)	< 0.001
ALT (U/L)	0.998 (0.997-1.000)	0.026					0.997 (0.994-1.000)	0.043
AST (U/L)	1.001 (1.000-1.001)	0.236					1.002 (1.000-1.004)	0.023
ALP (U/L)	1.001 (1.000-1.001)	< 0.001					1.001 (1.000-1.001)	0.005
GGT (U/L)	1.000 (1.000-1.000)	0.803					1.000 (1.000-1.001)	0.217
Platelets (× 109/L)	0.993 (0.991-0.995)	< 0.001					0.996 (0.994-0.998)	< 0.001
INR	3.148 (2.581-3.840)	< 0.001					1.533 (1.109-2.119)	0.01
Immunological markers
AMA-M2 positive	1.229 (0.923-1.637)	0.158					0.749 (0.552-1.016)	0.064
Anti-sp100 positive	1.346 (0.922-1.965)	0.123					1.237 (0.932-1.642)	0.141
Anti-gp210 positive	1.535 (1.171-2.012)	0.002					1.371 (0.930-2.021)	0.111
Study groups
Non-lean non-T2DM	Reference	< 0.001	Reference	< 0.001	Reference	< 0.001	Reference	< 0.001
Lean non-T2DM	1.5553 (1.086-2.223)	0.016	1.512 (1.056-2.164)	0.024	1.512 (1.056-2.164)	0.024	0.811 (0.554-1.188)	0.283
Non-lean T2DM	2.123 (1.267-3.558)	0.004	1.801 (1.068-3.037)	0.027	1.801 (1.068-3.037)	0.027	0.912 (0.528-1.573)	0.74
Lean T2DM	4.064 (2.759-5.987)	< 0.001	3.596 (2.429-5.323)	< 0.001	3.596 (2.429-5.323)	< 0.001	1.872 (1.243-2.818)	0.003

¹Model A: Adjusted for age, sex, and the study groups.

²Model B: Adjusted for age, sex, hepatic steatosis, coronary heart disease, hypertension, and the study groups.

³Model C: Adjusted for age, sex, hepatic steatosis, coronary heart disease, hypertension, total bilirubin, total bile acids, albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, platelet, international normalized ratio, anti-mitochondrial antibody-M2, anti-sp100 antibody, anti-glycoprotein 210 antibody, and the study groups.

TBil: Total bilirubin; TBA: Total bile acid; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyltransferase; INR: International normalized ratio; AMA-M2: Anti-mitochondrial antibody M2; Anti-sp100: Anti-speckled protein 100; Anti-gp210: Anti-glycoprotein 210; T2DM: Type 2 diabetes mellitus; HR: Hazard ratio; CI: Confidence interval.