A Non-Linear Association of High-Density Lipoprotein Cholesterol with All-Cause and Cause-Specific Mortality in Diabetic Patients

Figures & data

Figure 1 Research flow chart.

Table 1 Baseline Characteristics According to High-Density Lipoprotein Cholesterol Levels

	Total	High Density Lipoprotein Cholesterol					P-value
		Q1	Q2	Q3	Q4	Q5
Number	6549	1448	1346	1245	1212	1298
Age, years	60.82 ± 14.36	58.74 ± 14.59	59.79 ± 14.84	60.99 ± 13.75	61.69 ± 13.93	63.21 ± 14.16	<0.001
Gender, n (%)							<0.001
Male	3372 (51.49)	1016 (70.17)	810 (60.18)	634 (50.92)	495 (40.84)	417 (32.13)
Female	3177 (48.51)	432 (29.83)	536 (39.82)	611 (49.08)	717 (59.16)	881 (67.87)
Race, n (%)							<0.001
Non-white	4005 (61.15)	773 (53.38)	819 (60.85)	760 (61.04)	800 (66.01)	853 (65.72)
White	2544 (38.85)	675 (46.62)	527 (39.15)	485 (38.96)	412 (33.99)	445 (34.28)
Smoking, n (%)							<0.001
No	3128 (48.10)	579 (40.18)	622 (46.70)	608 (49.27)	627 (51.95)	692 (53.69)
Yes	3375 (51.90)	862 (59.82)	710 (53.30)	626 (50.73)	580 (48.05)	597 (46.31)
Education level, n (%)							0.059
Less than high school	2576 (39.68)	600 (41.67)	549 (41.15)	479 (38.85)	479 (39.82)	469 (36.58)
High school or above	3916 (60.32)	840 (58.33)	785 (58.85)	754 (61.15)	724 (60.18)	813 (63.42)
Body mass index, kg/m^2	32.01 ± 7.35	33.05 ± 6.92	32.46 ± 7.26	32.38 ± 7.42	31.79 ± 7.29	30.26 ± 7.59	<0.001
Systolic blood pressure, mmHg	132.50 ± 20.82	130.52 ± 19.26	131.84 ± 20.81	132.25 ± 20.60	133.37 ± 21.49	134.80 ± 21.81	<0.001
Diastolic blood pressure, mmHg	68.64 ± 15.32	69.90 ± 15.02	68.85 ± 15.60	68.73 ± 15.19	68.35 ± 15.32	67.20 ± 15.39	<0.001
eGFR, mg/min/1.73m^2	79.65 ± 30.10	80.34 ± 31.38	79.78 ± 30.44	79.04 ± 27.60	80.17 ± 28.04	78.86 ± 32.37	0.636
Glycohemoglobin, %	7.22 ± 1.77	7.43 ± 1.82	7.29 ± 1.73	7.27 ± 1.81	7.14 ± 1.74	6.92 ± 1.72	<0.001
Fasting blood glucose, mg/dL	154.81 ± 64.58	165.32 ± 70.67	158.86 ± 68.06	156.33 ± 62.46	148.38 ± 57.03	145.67 ± 61.69	<0.001
Serum lipid level
Triglycerides							<0.001
mg/dL	179.78 ± 183.04	282.30 ± 259.18	205.00 ± 252.62	166.35 ± 99.26	135.79 ± 69.09	113.06 ± 60.29
mmol/L	2.03 ± 2.07	3.19 ± 2.93	2.31 ± 2.85	1.88 ± 1.12	1.53 ± 0.78	1.28 ± 0.68
Low density lipoprotein							0.002
mg/dL	109.09 ± 37.17	103.10 ± 36.75	111.39 ± 36.95	110.21 ± 36.34	110.41 ± 37.82	109.37 ± 37.45
mmol/L	2.82 ± 0.96	2.67 ± 0.95	2.88 ± 0.96	2.85 ± 0.94	2.86 ± 0.98	2.83 ± 0.97
Total cholesterol							<0.001
mg/dL	193.09 ± 48.10	185.30 ± 50.10	192.35 ± 51.31	193.07 ± 46.68	193.05 ± 43.34	202.58 ± 46.34
mmol/L	4.99 ± 1.24	4.79 ± 1.30	4.97 ± 1.33	4.99 ± 1.21	4.99 ± 1.12	5.24 ± 1.20
High density lipoprotein							<0.001
mg/dL	48.12 ± 14.15	32.28 ± 4.12	40.65 ± 1.65	46.30 ± 1.68	53.69 ± 2.56	70.08 ± 11.27
mmol/L	1.24 ± 0.37	0.84 ± 0.11	1.05 ± 0.04	1.20 ± 0.04	1.39 ± 0.07	1.81 ± 0.29
Comorbidities, n (%)
Hypertension							0.286
No	1457 (22.27)	340 (23.50)	306 (22.78)	288 (23.15)	255 (21.04)	268 (20.66)
Yes	5086 (77.73)	1107 (76.50)	1037 (77.22)	956 (76.85)	957 (78.96)	1029 (79.34)
Cardiovascular disease							<0.001
No	5008 (76.99)	1045 (72.47)	1013 (75.94)	956 (77.35)	967 (80.25)	1027 (79.74)
Yes	1497 (23.01)	397 (27.53)	321 (24.06)	280 (22.65)	238 (19.75)	261 (20.26)
Cancer							0.203
No	5636 (86.77)	1271 (88.26)	1161 (87.10)	1067 (86.61)	1042 (86.54)	1095 (85.15)
Yes	859 (13.23)	169 (11.74)	172 (12.90)	165 (13.39)	162 (13.46)	191 (14.85)
Treatment, n (%)
Antihypertensive drugs							0.331
No	2704 (41.29)	618 (42.68)	562 (41.75)	528 (42.41)	480 (39.60)	516 (39.75)
Yes	3845 (58.71)	830 (57.32)	784 (58.25)	717 (57.59)	732 (60.40)	782 (60.25)
Hypoglycemic agents,							0.145
No	2980 (45.50)	676 (46.69)	612 (45.47)	577 (46.35)	512 (42.24)	603 (46.46)
Yes	3569 (54.50)	772 (53.31)	734 (54.53)	668 (53.65)	700 (57.76)	695 (53.54)
Lipid-lowering drugs							0.361
No	4275 (65.28)	966 (66.71)	893 (66.34)	797 (64.02)	771 (63.61)	848 (65.33)
Yes	2274 (34.72)	482 (33.29)	453 (33.66)	448 (35.98)	441 (36.39)	450 (34.67)
Antiplatelet drugs							0.014
No	6195 (94.59)	1357 (93.72)	1266 (94.06)	1167 (93.73)	1158 (95.54)	1247 (96.07)
Yes	354 (5.41)	91 (6.28)	80 (5.94)	78 (6.27)	54 (4.46)	51 (3.93)
Outcomes, n (%)
Cancer mortality							0.651
No	6287 (96.00)	1382 (95.44)	1296 (96.29)	1193 (95.82)	1170 (96.53)	1246 (95.99)
Yes	262 (4.00)	66 (4.56)	50 (3.71)	52 (4.18)	42 (3.47)	52 (4.01)
Cardiovascular disease mortality							0.417
No	6160 (94.06)	1347 (93.02)	1268 (94.21)	1172 (94.14)	1147 (94.64)	1226 (94.45)
Yes	389 (5.94)	101 (6.98)	78 (5.79)	73 (5.86)	65 (5.36)	72 (5.55)
All-cause mortality							0.003
No	5003 (76.39)	1074 (74.17)	1023 (76.00)	953 (76.55)	975 (80.45)	978 (75.35)
Yes	1546 (23.61)	374 (25.83)	323 (24.00)	292 (23.45)	237 (19.55)	320 (24.65)

Notes: Values are mean ± standardized differences or n (%). Continuous variables were tested using a one-way ANOVA, and count variables were tested using a Chi-square.

Abbreviations: Q, quintiles; n, number; eGFR, estimated glomerular filtration rate.

Figure 2 Kaplan-Meier survival curves for all-cause (A), cardiovascular (B), and cancer (C) mortality by high density lipoprotein cholesterol groups.

Table 2 Multivariate Cox Regression Analysis of HDL-C Levels with Cause-Specific Mortality

	Model I HR (95% CI), P	Model II HR (95% CI), P	Model III HR (95% CI), P
All-cause mortality
HDL-C (per 1mmol/L increment)	1.07 (0.94, 1.23) 0.3116	0.92 (0.79, 1.06) 0.2376	1.01 (0.86, 1.19) 0.8903
HDL-C groups
Q1	1.30 (1.11, 1.53) 0.0015	1.43 (1.21, 1.70) <0.0001	1.30 (1.09, 1.56) 0.0046
Q2	1.20 (1.02, 1.42) 0.0322	1.26 (1.06, 1.49) 0.0084	1.19 (0.99, 1.43) 0.0612
Q3	1.22 (1.03, 1.45) 0.0218	1.20 (1.01, 1.42) 0.0380	1.14 (0.95, 1.37) 0.1628
Q4	1.0	1.0	1.0
Q5	1.30 (1.10, 1.54) 0.0020	1.20 (1.01, 1.42) 0.0370	1.20 (1.00, 1.44) 0.0481
P for trend	0.334	0.002	0.113
Cardiovascular mortality
HDL-C (per 1mmol/L increment)	0.94 (0.71, 1.25) 0.6716	0.83 (0.61, 1.12) 0.2130	0.97 (0.70, 1.34) 0.8408
HDL-C groups
Q1	1.28 (0.94, 1.75) 0.1207	1.38 (1.00, 1.89) 0.0503	1.22 (0.86, 1.74) 0.2686
Q2	1.06 (0.76, 1.47) 0.7445	1.08 (0.78, 1.51) 0.6438	1.02 (0.71, 1.45) 0.9347
Q3	1.11 (0.80, 1.56) 0.5259	1.08 (0.77, 1.51) 0.6608	0.99 (0.69, 1.43) 0.9746
Q4	1.0	1.0	1.0
Q5	1.07 (0.77, 1.50) 0.6892	1.00 (0.71, 1.39) 0.9802	1.01 (0.70, 1.46) 0.9460
P for trend	0.212	0.043	0.327
Cancer mortality
HDL-C (per 1mmol/L increment)	1.13 (0.82, 1.58) 0.4542	1.11 (0.79, 1.57) 0.5465	1.18 (0.81, 1.72) 0.3955
HDL-C groups
Q1	1.31 (0.89, 1.92) 0.1770	1.32 (0.89, 1.96) 0.1710	1.15 (0.76, 1.75) 0.5021
Q2	1.06 (0.70, 1.59) 0.7980	1.05 (0.69, 1.59) 0.8253	0.97 (0.63, 1.48) 0.8849
Q3	1.23 (0.82, 1.85) 0.3212	1.19 (0.79, 1.79) 0.4066	1.02 (0.67, 1.56) 0.9345
Q4	1.0	1.0	1.0
Q5	1.19 (0.79, 1.79) 0.4024	1.15 (0.77, 1.73) 0.4938	1.05 (0.69, 1.61) 0.8227
P for trend	0.550	0.459	0.722

Notes: Data are HR (95% CI). Model I adjust for none. Model II adjust for age, gender, and body mass index. Model III adjust for age, gender, body mass index, race, education level, smoking, systolic blood pressure, estimated glomerular filtration rate, glycohemoglobin, total cholesterol, comorbidities (hypertension, cardiovascular disease, and cancer), and medicine use (antihypertensive drugs, hypoglycemic agents, lipid-lowering drugs, and antiplatelet drugs). Multivariate Cox regression was performed.

Abbreviations: HDL-C, high density lipoprotein cholesterol; HR, hazard ratio; CI, confidence interval; Q, quintiles.

Table 3 The Results of Two-Piecewise Linear Regression Model Between High-Density Lipoprotein Cholesterol and Cause-Specific Mortality

	All-Cause Mortality HR (95% CI) P-value	Cardiovascular Disease Mortality HR (95% CI) P-value	Cancer Mortality HR (95% CI) P-value
Cutoff value, mmol/L	1.36 (53 mg/dL)	1.28 (49 mg/dL)	1.89 (73 mg/dL)
<Cut-off value	0.62 (0.46, 0.85) 0.0025	0.66 (0.33, 1.31) 0.2319	0.83 (0.53, 1.30) 0.4159
≥Cut-off value	1.50 (1.16, 1.94) 0.0018	1.23 (0.76, 2.01) 0.4036	3.83 (1.76, 8.34) 0.0007
P for log likelihood ratio test	<0.001	0.218	0.009

Notes: Data are HR (95% CI). Age, gender, body mass index, race, education level, smoking, systolic blood pressure, estimated glomerular filtration rate, glycohemoglobin, total cholesterol, comorbidities (hypertension, cardiovascular disease, and cancer), and medicine use (antihypertensive drugs, hypoglycemic agents, lipid-lowering drugs, and antiplatelet drugs) were adjusted. Generalized additive model was performed.

Abbreviations: HR, hazard ratio; CI, confidence interval.

Figure 3 Adjusted spline curves analyze for the association of high density lipoprotein cholesterol with all-cause (A), cardiovascular (B), and cancer (C) mortality. Age, gender, body mass index, race, education level, smoking, systolic blood pressure, estimated glomerular filtration rate, glycohemoglobin, total cholesterol, comorbidities (hypertension, cardiovascular disease, and cancer), and medicine use (antihypertensive drugs, hypoglycemic agents, lipid-lowering drugs, and antiplatelet drugs) were adjusted.

Table 4 Subgroups Analysis

	N	All-Cause Mortality HR (95% CI) P-value		P for Log Likelihood Ratio Test	Cardiovascular Disease Mortality HR (95% CI) P-value		P for Log Likelihood Ratio Test	Cancer Mortality HR (95% CI) P-value		P for Log Likelihood Ratio Test
Cutoff value, mmol/L		<1.36	≥1.36		<1.28	≥1.28		<1.89	≥1.89
Age
≥65	2605	0.59 (0.41, 0.84) 0.0036	1.59 (1.19, 2.12) 0.0018	<0.001	0.53 (0.24, 1.17) 0.1157	1.34 (0.77, 2.31) 0.2977	0.114	0.84 (0.48, 1.48) 0.5477	5.32 (2.39, 11.86) <0.0001	0.004
<65	3356	1.06 (0.61, 1.87) 0.8301	1.54 (0.88, 2.71) 0.1332	0.443	2.70 (0.72, 10.15) 0.1418	1.09 (0.34, 3.45) 0.8883	0.374	1.06 (0.49, 2.28) 0.8832	0.64 (0.02, 17.98) 0.7962	0.779
Gender
Male	3082	0.72 (0.49, 1.06) 0.0997	2.08 (1.39, 3.12) 0.0004	0.002	0.53 (0.23, 1.22) 0.1336	1.90 (0.91, 3.95) 0.0853	0.063	1.04 (0.56, 1.92) 0.8956	8.83 (2.27, 34.29) 0.0016	0.025
Female	2879	0.46 (0.28, 0.76) 0.0021	1.34 (0.77, 2.31) 0.2977	0.114	1.09 (0.28, 4.31) 0.9025	0.89 (0.45, 1.77) 0.7405	0.823	0.59 (0.29, 1.17) 0.1314	2.83 (0.93, 8.62) 0.0678	0.066
Race
Non-white	3633	0.61 (0.39, 0.95) 0.0286	1.50 (1.07, 2.10) 0.0174	0.009	0.99 (0.33, 2.91) 0.9799	0.95 (0.48, 1.86) 0.8791	0.960	0.81 (0.44, 1.50) 0.5102	3.07 (1.15, 8.17) 0.0252	0.072
White	2328	0.66 (0.43, 1.01) 0.0546	1.48 (1.00, 2.19) 0.0486	0.022	0.50 (0.20, 1.26) 0.1432	1.53 (0.74, 3.18) 0.2530	0.120	0.83 (0.42, 1.64) 0.5849	5.64 (1.33, 23.90) 0.0189	0.056
Lipid-lowering drugs
No	3844	0.61 (0.40, 0.95) 0.0283	1.57 (1.19, 2.07) 0.0013	0.003	0.75 (0.30, 1.89) 0.5401	1.45 (0.82, 2.57) 0.2060	0.313	0.89 (0.52, 1.53) 0.6653	3.89 (1.72, 8.80) 0.0011	0.019
Yes	2117	0.60 (0.34, 1.06) 0.0783	0.98 (0.63, 1.53) 0.9260	0.265	0.65 (0.23, 1.88) 0.4289	0.65 (0.26, 1.63) 0.3559	0.991	0.70 (0.30, 1.64) 0.4178	3.14 (0.23, 43.43) 0.3939	0.373
Hypoglycemic agents
No	2980	0.70 (0.45, 1.10) 0.1190	1.55 (1.10, 2.18) 0.0120	0.021	1.02 (0.37, 2.79) 0.9760	0.84 (0.40, 1.74) 0.6360	0.796	1.47 (0.79, 2.74) 0.2180	4.48 (2.03, 9.89) <0.001	0.071
Yes	3569	0.59 (0.39, 0.90) 0.0140	1.38 (0.93, 2.04) 0.1080	0.017	0.45 (0.17, 1.16) 0.0969	1.74 (0.87, 3.45) 0.1146	0.059	0.52 (0.26, 1.03) 0.0619	0.39 (0.01, 21.29) 0.6440	0.892

Notes: When analyzing a subgroup variable, age, gender, body mass index, race, education level, smoking, systolic blood pressure, estimated glomerular filtration rate, glycohemoglobin, total cholesterol, comorbidities (hypertension, cardiovascular disease, and cancer), and medicine use (antihypertensive drugs, hypoglycemic agents, lipid-lowering drugs, and antiplatelet drugs) were all adjusted except the variable itself.