Association Between Metabolic Dysfunction-Associated Fatty Liver Disease and MACCEs in Patients with Diabetic Foot Ulcers: An Ambispective Longitudinal Cohort Study

Figures & data

Figure 1 Flow chart for selecting patients with DFUs.

Table 1 Baseline Characteristics of the Subjects

	Non-MAFLD (n= 643)	MAFLD (n= 246)	p-value
Gender, n (%)			0.282
Female	198 (30.8)	85 (34.6)
Male	445 (69.2)	161 (65.4)
Age, years	63 (53,72)	63 (56,72)	0.145
Hypertension, n (%)			0.134
No	292 (45.4)	98 (39.8)
Yes	351 (54.6)	148 (60.2)
CHD, n (%)			0.353
No	576 (89.6)	215 (87.4)
Yes	67 (10.4)	31 (12.6)
CVD, n (%)			0.406
No	562 (87.4)	220 (89.4)
Yes	81 (12.6)	26 (10.6)
PAD, n (%)			0.173
No	320 (49.8)	135 (54.9)
Yes	323 (50.2)	111 (45.1)
DR, n (%)			0.495
No	461 (71.7)	182 (74.0)
Yes	182 (28.3)	64 (26.0)
DPN, n (%)			0.735
No	186 (28.9)	74 (30.1)
Yes	457 (71.1)	172 (69.9)
DN, n (%)			0.218
No	376 (58.5)	155 (63.0)
Yes	267 (41.5)	91 (37.0)
Smoking, n (%)			0.789
No	470 (73.1)	182 (74.0)
Yes	173 (26.9)	64 (26.0)
Drinking, n (%)			0.434
No	532 (82.7)	198 (80.5)
Yes	111 (17.3)	48 (19.5)
Duration of diabetes, years	9 (4,13)	10 (4,13)	0.897
SBP, mmHg	139 (124,156)	143 (126,160)	0.039*
DBP, mmHg	72 (65,80)	76 (68,83.25)	<0.001*
WBC, ×10^9/L	8.39 (6.64,11.3)	8.39 (7.035,10.44)	0.629
Hb, g/L	110 (93,125)	120 (108,135)	<0.001*
TC, mmol/L	4.01 (3.24,4.85)	4.30 (3.52,5.13)	<0.001*
TG, mmol/L	1.13 (0.88,1.58)	1.47 (1.1,1.95)	<0.001*
HDL-C, mmol/L	0.94 (0.72,1.13)	0.94 (0.78,1.13)	0.352
LDL-C, mmol/L	2.49 (1.94,3.1)	2.78 (2.21,3.47)	<0.001*
ALB, g/L	33.2 (27.7,36.6)	35.3 (30.98,38.4)	<0.001*
ALT, U/L	15 (10,22)	16 (12,22)	0.022*
AST, U/L	18 (14,25)	19 (15,23)	0.882
Cr, μmol/L	88 (66,119)	78.5 (63.75,106.75)	0.01*
UA, μmol/L	320 (224,397)	346.5 (262,415.5)	0.001*
HbA1c, %	9 (7,11.3)	8.7 (7.38,10.4)	0.172
Infection severity, n (%)			0.628
PEDIS 2 grade/mild	89 (13.8)	31 (12.6)
PEDIS 2 grade above/moderate and severe	554 (86.2)	215 (87.4)
Ischemia severity, n (%)			0.286
TEXAS 1C/mild	138 (21.5)	61 (24.8)
TEXAS 1C above/moderate and severe	505 (78.5)	185 (75.2)

Notes: median (inter-quartile range, IQR) for continuous variables. Percentage (%) for categorical variables. * P < 0.05.

Abbreviations: MAFLD, metabolic dysfunction-associated fatty liver disease; CHD, coronary heart disease; CVD, cerebrovascular disease; PAD, peripheral arterial disease; DR, diabetic retinopathy; DPN, diabetic peripheral neuropathy; DN, diabetic nephropathy; SBP, systolic blood pressure; DBP, diastolic blood pressure; WBC, leukocyte; Hb, hemoglobin; TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ALB, serum albumin; ALT, alanine transaminase; AST, aspartate transaminase; Cr, creatinine; UA, uric acid; HbA1c, glycosylated hemoglobin; PEDIS, perfusion, extent, depth, infection, and sensation; TEXAS, University of Texas System.

Table 2 Risk of MACCEs in Subjects with DFUs Between Two Groups Through Multivariate Cox Regression Analyses

	HR, 95% CI and P -value
	Model I			Model II			Model III
	HR	95%Cl	p-value	HR	95%Cl	p-value	HR	95%Cl	p-value
MACCEs
Non-MAFLD	Ref	-	-	Ref	-	-	Ref	-	-
MAFLD	1.993	1.518–2.615	<0.001*	1.977	1.506–2.596	<0.001*	1.94	1.474–2.553	<0.001*
All-cause mortality
Non-MAFLD	Ref	-	-	Ref	-	-	Ref	-	-
MAFLD	1.856	1.086–3.172	0.024*	1.822	1.066–3.116	0.028*	1.902	1.103–3.279	0.021*
Non-fatal myocardial infarction
Non-MAFLD	Ref	-	-	Ref	-	-	Ref	-	-
MAFLD	2.215	1.081–4.54	0.03*	2.165	1.056–4.442	0.035*	2.148	1.036–4.452	0.04*
Revascularization
Non-MAFLD	Ref	-	-	Ref	-	-	Ref	-	-
MAFLD	2.868	1.541–5.335	0.001*	2.846	1.527–5.303	0.001*	2.73	1.46–5.104	0.002*
Non-fatal stroke
Non-MAFLD	Ref	-	-	Ref	-	-	Ref	-	-
MAFLD	1.59	1.082–2.336	0.018*	1.564	1.064–2.298	0.023*	1.487	1.006–2.199	0.047*
Heart failure
Non-MAFLD	Ref	-	-	Ref	-	-	Ref	-	-
MAFLD	2.223	1.11–4.451	0.024*	2.196	1.095–4.403	0.027*	2.197	1.085–4.452	0.029*

Notes: Model I: adjusted for none. Model II: with Model I adjusted for gender, age. Model III was further adjusted for hyperlipidemia, hypertension, PAD, CHD, CVD, DN, duration of diabetes, SBP, and TC with Model II. * P < 0.05.

Abbreviations: MACCEs, major adverse cardio-cerebral events; MAFLD, metabolic dysfunction-associated fatty liver disease; HR, hazard ratio; CI, confidence interval; DFUs, diabetic foot ulcers; PAD, peripheral arterial disease; CHD, coronary heart disease; CVD, cerebrovascular disease; DN, diabetic nephropathy; SBP, systolic blood pressure; TC, total cholesterol.

Figure 2 The incidence of MACCEs in patients with DFUs between MAFLD and non-MAFLD groups.

Notes: During the follow-up period with a median of 63 months for 10.9 years, the incidence rate of MACCEs, including non-fatal myocardial infarction, coronary artery revascularization, heart failure, non-fatal stroke, and all-cause mortality, was listed in detail between the MAFLD and non-MAFLD groups.

Abbreviations: MACCEs, major adverse cardiac and cerebral events; MAFLD, metabolic dysfunction-associated fatty liver disease.

Figure 3 Subgroup stratified analysis for the association between MAFLD and MACCEs in the forest plots.

Notes: Except for the stratification factors themselves, each stratification was adjusted for all factors, including all independent variables in the Cox regression analysis. *P < 0.05.

Abbreviations: MAFLD, metabolic dysfunction-associated fatty liver disease; MACCEs, major adverse cardiac and cerebral events; HR, hazard ratio; CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; CHD, coronary heart disease; PAD, peripheral arterial disease; DN, diabetic nephropathy.

Figure 4 The cumulative incidence of MACCEs between MAFLD and non-MAFLD groups.

Notes: Kaplan‒Meier analysis showed that compared with the non-MAFLD group, the MAFLD group had a higher cumulative incidence of MACCEs consisting of all-cause mortality (A), non-fatal myocardial infarction (B), coronary artery revascularization (C), and non-fatal stroke (D), and heart failure (E) in patients with DFUs (log-rank, p < 0.05).

Abbreviations: MACCEs, major adverse cardiac and cerebral events; MAFLD, metabolic dysfunction-associated fatty liver disease.