Influence of Fibrinogen/Albumin Ratio and Fibrinogen/Pre-Albumin Ratio on Cardiac Autonomic Neuropathy in Type 2 Diabetes

Figures & data

Table 1 Comparison of Clinical Characteristics Between T2DM Patients with and without DCAN

Variable	Non-DCAN	DCAN	P-value
Patients (n)	565	150
Male/female (%)	350/215 (62/38)	105/45 (70/30)	0.068
Age (years)	56.13 ± 10.32	57.90 ± 7.91	0.024
Duration (years)	10 (3, 14)	10 (6, 17)	0.001
BMI (kg/m^2)	24.12 ± 3.24	24.34 ± 3.57	0.458
SBP (mmHg)	133.25 ± 17.47	138.65 ± 20.49	0.003
HR (beats/min)	86.45 ± 12.52	89.92 ± 11.56	0.002
FBG (mmol/L)	7.60 (6.05, 11.70)	11.15 (7.35, 14.43)	<0.001
HbA1c (%)	9.17 ± 2.33	9.93 ± 2.53	0.001
TG (mmol/L)	1.45 (0.98, 2.30)	1.47 (1.10, 2.24)	0.496
TC (mmol/L)	4.22 ± 1.20	4.21 ± 1.19	0.896
LDL-C (mmol/L)	2.55 ± 0.97	2.49 ± 1.00	0.513
HDL-C (mmol/L)	1.08 ± 0.34	1.05 ± 0.30	0.324
ALT (U/L)	18 (13, 27)	16 (12.75, 25.25)	0.239
AST (U/L)	16 (13, 21)	16 (13, 22.25)	0.962
GGT (U/L)	23 (16, 38)	27.5 (18.75, 50.50)	0.008
SCr (µmol/L)	65 (53.5, 78)	73 (59.75, 94.25)	<0.001
UA (mmol/L)	321.51 ± 95.20	345.24 ± 101.30	0.008
eGFR (mL/min/1.73 m^2)	108.62 ± 27.53	96.21 ± 34.48	<0.001
Hs-CRP (mg/L)	1.15 (0.52, 2.50)	1.86 (0.68, 3.68)	<0.001
WBC (×10^9/L)	6.51 ± 1.46	6.77 ± 1.55	0.053
NEU (×10^9/L)	4.15 ± 1.19	4.49 ± 1.29	0.002
LY (×10^9/L)	1.78 ± 0.59	1.65 ± 0.60	0.014
MONO (×10^9/L)	0.42 ± 0.14	0.44 ± 0.15	0.091
PLR	124.80 ± 56.66	138.50 ± 65.30	0.011
NLR	2.48 ± 1.31	3.11 ± 1.61	0.001
LMR	4.55 ± 1.68	4.11 ± 2.12	0.008
FIB (g/L)	3.00 ± 0.88	3.89 ± 1.46	<0.001
ALB (g/L)	42.29 ± 3.89	39.49 ± 5.07	<0.001
PALB (mg/L)	231.46 ± 51.20	213.71 ± 57.35	0.001
FAR (g/g)	7.22 ± 2.56	10.29 ± 4.83	<0.001
FPR (g/mg)	1.43 ± 0.93	2.19 ± 1.85	<0.001
Hypertension n (%)	267 (47.3)	91 (60.7)	0.002
DPN n (%)	208 (36.8)	114 (76.0)	<0.001
DN n (%)	116 (20.5)	77 (51.3)	<0.001
DR n (%)	155 (27.4)	95 (63.3)	<0.001

Notes: Data were presented as means ± SD, n (%), or interquartile range. Bolded font indicates P < 0.05.

Abbreviations: BMI, body mass index; SBP, systolic blood pressure; HR, heart rate; FBG, fasting blood glucose; HbA1c, glycated hemoglobin A1c; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Hs-CRP, hypersensitive C-reactive protein; WBC, white blood cell; NEU, neutrophil count; LY, lymphocyte count; MONO, monocytes count; PLR, platelet-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio; LMR, neutrophil-to-monocytes ratio; FIB, fibrinogen; ALB, albumin; PALB, prealbumin; FAR, fibrinogen-to-albumin ratio; FPR, fibrinogen-to-prealbumin ratio; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, glutamyl-transferase; SCr, serum creatinine; UA, uric acid; eGFR, estimated glomerular filtration rate; DPN, diabetic peripheral neuropathy; DN, diabetic nephropathy; DR, diabetic retinopathy. DCAN diagnosed diabetic cardiac autonomic neuropathy. No-DCAN diabetic patients without DCAN. Pre-DCAN diabetic patients with subclinical DCAN. Non-DCAN includes No-DCAN and Pre-DCAN.

Table 2 Characteristics of Patients According to FAR and FPR Quartiles

Category	FAR (g/g)				P-value	FPR (mg/g)				P-value
	Q1 (< 5.80)	Q2 (5.80–7.00)	Q3 (7.01–8.67)	Q4 (≥8.68)		Q1 (<1.03)	Q2 (1.03–1.29)	Q3 (1.30–1.67)	Q4 (≥ 1.68)
Patients (n)	179	179	179	178		178	181	180	176
Hs-CRP (mg/L)	0.76 (0.37, 1.98)	0.89 (0.43, 1.93)	1.18 (0.66, 2.89)	2.81 (1.26, 4.20)	<0.001	0.65 (0.35, 1.65)	1.00 (0.50, 2.33)	1.27 (0.68, 2.91)	2.54 (1.24, 4.05)	<0.001
WBC (×10^9/L)	6.28 ± 1.40	6.40 ± 1.42	6.66 ± 1.44	6.91 ± 1.60	<0.001	6.31 ± 1.40	6.48 ± 1.45	6.71 ± 1.45	6.75 ± 1.59	0.014
NEU (×10^9/L)	3.91 ± 1.10	4.05 ± 1.14	4.31 ± 1.11	4.62 ± 1.38	<0.001	3.92 ± 1.14	4.09 ± 1.11	4.34 ± 1.15	4.54 ± 1.37	<0.001
LY (×10^9/L)	1.80 ± 0.59	1.78 ± 0.60	1.78 ± 0.60	1.66 ± 0.59	0.119	1.80 ± 0.56	1.80 ± 0.62	1.78 ± 0.63	1.63 ± 0.55	0.022
MOMO (×10^9/L)	0.39 ± 0.13	0.42 ± 0.12	0.42 ± 0.15	0.45 ± 0.15	0.001	0.40 ± 0.13	0.42 ± 0.14	0.42 ± 0.14	0.44 ± 0.15	0.090
PLR	115.53 ± 46.29	122.26 ± 53.34	124.22 ± 61.78	148.80 ±6 6.72	<0.001	118.63 ± 48.60	121.59 ± 62.36	126.28 ± 52.70	144.50 ± 66.84	<0.001
NLR	2.41 ± 1.17	2.55 ± 1.20	2.75 ± 1.45	3.15 ± 1.59	<0.001	2.41 ± 1.25	2.54 ± 1.10	2.77 ± 1.38	3.14 ± 1.67	<0.001
LMR	4.90 ± 1.78	4.39 ± 1.44	4.58 ± 1.97	3.95 ± 1.81	<0.001	4.79 ± 1.67	4.51 ± 1.66	4.44 ± 1.76	4.08 ± 2.00	0.002
DB (beats/min)	16 (11, 23)	14 (10, 21)	13 (9, 20)	9 (6, 15)	<0.001	15 (11, 22)	14 (9, 20)	13 (7, 16)	9 (7, 16)	<0.001
VAL	1.38 (1.20, 1.50)	1.29 (1.19, 1.48)	1.29 (1.18, 1.44)	1.19 (1.12, 1.38)	<0.001	1.37 (1.22, 1.46)	1.30 (1.17, 1.50)	1.28 (1.17, 1.44)	1.20 (1.12, 1.33)	<0.001
DCAN n (%)	15 (8.4)	29 (16.2)	30 (16.8)	76 (42.7)	<0.001	17 (9.6)	33 (18.2)	31 (17.2)	69 (39.2)	<0.001
DPN n (%)	62 (34.6)	73 (40.8)	70 (39.1)	117 (65.7)	<0.001	66 (37.1)	71 (39.2)	73 (40.6)	112 (63.6)	<0.001
Hypertension n (%)	96 (53.6)	85 (47.5)	84 (46.9)	93 (52.2)	0.490	104 (58.4)	81 (44.8)	87 (48.3)	86 (48.9)	0.062
DN n (%)	35 (19.6)	32 (17.9)	43 (24.0)	83 (46.6)	<0.001	37 (20.8)	39 (21.5)	50 (27.8)	67 (38.1)	0.001
DR n (%)	44 (24.6)	61 (34.1)	57 (31.8)	88 (49.4)	<0.001	44 (24.7)	61 (33.7)	60 (33.3)	85 (48.3)	<0.001

Notes: Data were presented as means ± SD, n (%), or interquartile range. Bolded font indicates P < 0.05. The FAR and FPR quartiles were recorded as low quartile (Q1), middle quartile (Q2), high quartile (Q3), and the highest quartile (Q4).

Abbreviations: FAR, fibrinogen-to-albumin ratio; FPR, fibrinogen-to-prealbumin ratio; Hs-CRP, hypersensitive C-reactive protein; WBC, white blood cell; NEU, neutrophil count; LY, lymphocyte count; MONO, monocytes count; PLR, platelet-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio; LMR, neutrophil-to-monocytes ratio; DB, the difference between the maximum and minimum heart rates during deep breathing; VAL, the ratio of the longest to shortest R-R interval during the Valsalva maneuver; DCAN, diabetic cardiac autonomic neuropathy; DPN, diabetic peripheral neuropathy; DN, diabetic nephropathy; DR, diabetic retinopathy.

Table 3 Odds Ratio for Diabetic Cardiac Autonomic Neuropathy

Model	FAR	P-value	FPR	P-value
	OR (95% CI)		OR (95% CI)
M1	1.26 (1.19, 1.33)	<0.001	1.57 (1.34, 1.85)	<0.001
M2	1.26 (1.18, 1.33)	<0.001	1.53 (1.29, 1.82)	<0.001
M3	1.23 (1.15, 1.30)	<0.001	1.44 (1.21, 1.70)	<0.001
M4	1.22 (1.14, 1.31)	<0.001	1.36 (1.14, 1.61)	0.001
M5	1.16 (1.08, 1.25)	<0.001	1.22 (1.03, 1.44)	0.021

Notes: Bolded font indicates P < 0.05. M1 unadjusted. M2 includes age, sex, BMI, duration, FBG, HbA1c, SBP and HR in addition to the predictors of M1. M3 includes ALT, AST, GGT, UA and SCr in addition to the predictors of M2. M4 includes Hs-CRP, NLR, PLR and LMR in addition to the predictors of M3. M5 includes hypertension, DPN, DN and DR in addition to the predictors of M4.

Abbreviations: FAR, fibrinogen-to-albumin ratio; FPR, fibrinogen-to-prealbumin ratio.

Table 4 Odds Ratio for DCAN According to FAR and FRP Quartiles

Model	Quartile	FAR	P-value	P for trend	FPR	P-value	P for trend
		OR (95% CI)			OR (95% CI)
M 1	Per SD increase	2.21 (1.83, 2.67)	<0.001	<0.001	1.74 (1.42, 2.12)	<0.001	<0.001
	Q1	1 (reference)	-		1 (reference)	-
	Q2	2.11 (1.09, 4.10)	0.027		2.11 (1.13, 3.95)	0.019
	Q3	2.20 (1.14, 4.25)	0.019		1.97 (1.05, 3.71)	0.035
	Q4	8.15 (4.44, 14.94)	<0.001		6.11 (3.41, 10.96)	<0.001
M 2	Per SD increase	2.17 (1.78, 2.66)	<0.001	<0.001	1.68 (1.36, 2.07)	<0.001	<0.001
	Q1	1 (reference)	-		1 (reference)	-
	Q2	1.81 (0.91, 3.58)	0.089		2.08 (1.87, 3.98)	0.027
	Q3	1.90 (0.95, 3.76)	0.068		1.90 (0.98, 3.69)	0.056
	Q4	6.76 (3.59, 12.74)	<0.001		6.13 (3.27, 11.52)	<0.001
M 3	Per SD increase	2.00 (1.62, 2.47)	<0.001	<0.001	1.56 (1.27, 1.91)	<0.001	<0.001
	Q1	1 (reference)	-		1 (reference)	-
	Q2	1.84 (0.92, 3.67)	0.086		1.78 (0.92, 3.45)	0.086
	Q3	1.69 (0.84, 3.39)	0.143		1.53 (0.78, 3.02)	0.217
	Q4	5.09 (2.64, 9.81)	<0.001		4.29 (2.23, 8.24)	<0.001
M 4	Per SD increase	1.97 (1.56, 2.48)	<0.001	<0.001	1.45 (1.18, 1.78)	0.001	0.001
	Q1	1 (reference)	-		1 (reference)	-
	Q2	1.81 (0.90, 3.64)	0.096		1.71 (0.88, 3.33)	0.114
	Q3	1.60 (0.79, 3.23)	0.192		1.43 (0.72, 2.84)	0.305
	Q4	4.48 (2.23, 8.98)	<0.001		3.60 (1.79, 7.21)	<0.001
M 5	Per SD increase	1.65 (1.29, 2.11)	<0.001	0.001	1.27 (1.04, 1.56)	0.021	0.006
	Q1	1 (reference)	-		1 (reference)	-
	Q2	1.65 (0.80, 3.42)	0.177		1.88 (0.94, 3.78)	0.076
	Q3	1.55 (0.74, 3.23)	0.242		1.41 (0.68, 2.91)	0.355
	Q4	3.06 (1.46, 6.40)	0.003		2.76 (1.32, 5.77)	0.007

Notes: Bolded font indicates P < 0.05. The FAR and FPR quartiles were recorded as low quartile (Q1), middle quartile (Q2), high quartile (Q3), and the highest quartile (Q4). M1 unadjusted. M2 includes age, sex, BMI, duration, FBG, HbA1c, SBP and HR in addition to the predictors of M1. M3 includes ALT, AST, GGT, UA and SCr in addition to the predictors of M2. M4 includes Hs-CRP, NLR, PLR and LMR in addition to the predictors of M3. M5 includes hypertension, DPN, DN and DR in addition to the predictors of M4.

Abbreviations: FAR, fibrinogen-to-albumin ratio; FPR, fibrinogen-to-prealbumin ratio.

Figure 1 Evaluate the levels of FAR and FPR in different subgroups (median with 95% CI).

Notes: ns P > 0.05; * P < 0.05; ** P < 0.01; *** P < 0.001. FAR levels in different subgroups (A). FPR levels in different subgroups (B). DB: the difference between the maximum and minimum heart rates during deep breathing. DB ≥ 15 as normal (db1), between 10–15 as critical (db2), DB ≤ 10 as abnormal (db3). VAL: the ratio of the longest to shortest R-R interval during the Valsalva maneuver. VAL ≥ 1.21 as normal (val1), between 1.10–1.21 as crucial (val2), VAL ≤ 1.10 as abnormal (val3). DCAN: diagnosed DCAN. No-DCAN: diabetic patients without DCAN. Pre-DCAN: diabetic patients with subclinical DCAN. Non-DCAN includes No-DCAN and Pre-DCAN.

Abbreviations: FAR, fibrinogen-to-albumin ratio; FPR, fibrinogen-to-prealbumin ratio.

Data Sharing Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.