Associations of nontraditional lipoprotein ratios with future cardiovascular events in patients with type 2 diabetes mellitus

Table 1 Baseline characteristics of participants, n (%)

Characteristics	Total (n = 10182)	With MACE (n = 1813)	Without MACE (n = 8369)	P value
TC/HDL-C	4.63 ± 1.51	4.88 ± 1.57	4.58 ± 1.49	< 0.001
LDL-C/HDL-C	2.64 ± 1.00	2.80 ± 1.07	2.60 ± 0.99	< 0.001
Non-HDL-C/HDL-C	3.63 ± 1.51	3.88 ± 1.57	3.58 ± 1.49	< 0.001
RC/HDL-C	0.99 ± 0.85	1.09 ± 0.87	0.97 ± 0.85	< 0.001
Male	6254 (61.42)	1253 (69.11)	5001 (59.76)	< 0.001
White	6362 (62.48)	1256 (69.28)	5106 (61.01)	< 0.001
Age (year), mean ± SD	62.81 ± 6.64	64.12 ± 7.12	62.53 ± 6.50	< 0.001
Educational level				0.001
Less than high school graduate	1500 (14.74)	304 (16.80)	1196 (14.30)	-
High school grad (or GED)	2688 (26.42)	478 (26.41)	2210 (26.42)	-
Some college or technical school	3338 (32.81)	614 (33.92)	2724 (32.56)	-
College graduate or more	2649 (26.03)	414 (22.87)	2235 (26.72)	-
Living alone	8118 (79.74)	1429 (78.82)	6689 (79.95)	0.280
Depression	2410 (23.67)	483 (26.66)	1927 (23.03)	< 0.001
Cigarette-smoking status	1238 (12.16)	252 (13.90)	986 (11.78)	0.012
Alcohol status	2429 (23.87)	427 (23.58)	2002 (23.93)	0.750
Duration of T2DM (years), mean ± SD	10.80 ± 7.60	12.20 ± 8.21	10.50 ± 7.42	< 0.001
Previous cardiovascular events	3580 (35.16)	962 (53.06)	2618 (31.28)	< 0.001
Previous heart failure	489 (4.80)	167 (9.22)	322 (3.85)	< 0.001
Previous hypertension	7674 (75.37)	1416 (78.10)	6258 (74.78)	0.003
Previous hyperlipidemia	7120 (69.93)	1296 (71.48)	5824 (69.59)	0.111
BMI, kg/m2	32.23 ± 5.40	32.30 ± 5.38	32.21 ± 5.41	0.557
Systolic blood pressure, mmHg	136.35 ± 17.10	138.09 ± 18.01	135.98 ± 16.88	< 0.001
Diastolic blood pressure, mmHg	74.88 ± 10.66	73.71 ± 11.38	75.13 ± 10.49	< 0.001
Heart rate, bpm	72.68 ± 11.75	72.31 ± 12.30	72.75 ± 11.62	0.146
HbA1c, %	8.30 ± 1.06	8.41 ± 1.09	8.28 ± 1.05	< 0.001
Fasting blood glucose, mg/dL	175.14 ± 56.11	180.43 ± 59.62	174.00 ± 55.26	< 0.001
Triglycerides, mg/dL	188.45 ± 135.70	199.28 ± 137.11	186.10 ± 135.29	< 0.001
eGFR, mL/minute/1.73 m2	91.05 ± 27.14	87.62 ± 26.95	91.80 ± 27.13	< 0.001
Insulin	1137 (11.17)	277 (15.28)	860 (10.28)	< 0.001
Biguanide	6509 (63.93)	1080 (59.57)	5429 (64.88)	< 0.001
ACEI/ARB	7057 (69.31)	1259 (69.44)	5798 (69.28)	0.891
Beta-blocker	3061 (30.14)	726 (40.13)	2335 (27.98)	< 0.001
Aspirin	5545 (54.72)	1033 (57.23)	4512 (54.17)	0.018
Statin	6463 (63.73)	1180 (65.30)	5283 (63.38)	0.124
Cholesterol absorption inhibitor	205 (2.02)	38 (2.11)	167 (2.01)	0.784

MACE: Major adverse cardiovascular events; TC: Total cholesterol; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; RC: Remnant cholesterol; GED: General education development; T2DM: Type 2 diabetes mellitus; BMI: Body mass index; bpm: Beet per minute; HbA1c: Hemoglobin A1c; eGFR: Estimated glomerular filtration rate; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker.

Table 2 Risk of major adverse cardiovascular events for baseline nontraditional lipoprotein ratios

Characteristics	Crude		Model 1		Model 2		Model 3		Model 4
	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
TC/HDL-C	1.12 (1.09-1.15)	< 0.0001	1.12 (1.09-1.15)	< 0.0001	1.12 (1.09-1.15)	< 0.0001	1.10 (1.07-1.13)	< 0.0001	1.09 (1.06-1.13)	< 0.0001
Q1	Reference	-	Reference	-	Reference	-	Reference	-	Reference	-
Q2	1.16 (1.00-1.33)	0.0439	1.14 (0.99-1.31)	0.0720	1.16 (1.01-1.34)	0.0409	1.14 (0.99-1.32)	0.0727	1.14 (0.98-1.31)	0.0816
Q3	1.36 (1.19-1.56)	< 0.0001	1.34 (1.17-1.54)	< 0.0001	1.35 (1.17-1.55)	< 0.0001	1.31 (1.14-1.51)	0.0002	1.30 (1.13-1.50)	0.0003
Q4	1.61 (1.41-1.84)	< 0.0001	1.58 (1.38-1.81)	< 0.0001	1.64 (1.43-1.88)	< 0.0001	1.53 (1.33-1.76)	< 0.0001	1.50 (1.29-1.73)	< 0.0001
P for trend	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001
Per 1 SD	1.18 (1.13-1.23)	< 0.0001	1.18 (1.13-1.23)	< 0.0001	1.19 (1.14-1.24)	< 0.0001	1.16 (1.11-1.21)	< 0.0001	1.15 (1.09-1.20)	< 0.0001
LDL-C/HDL-C	1.18 (1.13-1.23)	< 0.0001	1.18 (1.12-1.23)	< 0.0001	1.19 (1.14-1.24)	< 0.0001	1.16 (1.11-1.22)	< 0.0001	1.16 (1.10-1.21)	< 0.0001
Q1	Reference	-	Reference	-	Reference	-	Reference	-	Reference	-
Q2	1.20 (1.04-1.38)	0.0116	1.19 (1.03-1.37)	0.0162	1.16 (1.01-1.33)	0.0424	1.13 (0.98-1.30)	0.0904	1.13 (0.98-1.30)	0.0989
Q3	1.31 (1.14-1.50)	0.0001	1.30 (1.13-1.49)	0.0002	1.33 (1.16-1.53)	< 0.0001	1.30 (1.13-1.49)	0.0003	1.29 (1.12-1.48)	0.0004
Q4	1.55 (1.36-1.77)	< 0.0001	1.54 (1.35-1.76)	< 0.0001	1.62 (1.42-1.86)	< 0.0001	1.53 (1.33-1.76)	< 0.0001	1.51 (1.30-1.74)	< 0.0001
P for trend	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001
Per 1 SD	1.18 (1.13-1.23)	< 0.0001	1.18 (1.13-1.23)	< 0.0001	1.19 (1.14-1.24)	< 0.0001	1.16 (1.11-1.22)	< 0.0001	1.16 (1.10-1.21)	< 0.0001
Non-HDL-C/HDL-C	1.12 (1.09-1.15)	< 0.0001	1.12 (1.09-1.15)	< 0.0001	1.12 (1.09-1.15)	< 0.0001	1.10 (1.07-1.13)	< 0.0001	1.09 (1.06-1.13)	< 0.0001
Q1	Reference	-	Reference	-	Reference	-	Reference	-	Reference	-
Q2	1.16 (1.00-1.33)	0.0439	1.14 (0.99-1.31)	0.0720	1.16 (1.01-1.34)	0.0409	1.14 (0.99-1.32)	0.0727	1.14 (0.98-1.31)	0.0816
Q3	1.36 (1.19-1.56)	< 0.0001	1.34 (1.17-1.54)	< 0.0001	1.35 (1.17-1.55)	< 0.0001	1.31 (1.14-1.51)	0.0002	1.30 (1.13-1.50)	0.0003
Q4	1.61 (1.41-1.84)	< 0.0001	1.58 (1.38-1.81)	< 0.0001	1.64 (1.43-1.88)	< 0.0001	1.53 (1.33-1.76)	< 0.0001	1.50 (1.29-1.73)	< 0.0001
P for trend	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001
Per 1 SD	1.18 (1.13-1.23)	< 0.0001	1.18 (1.13-1.23)	< 0.0001	1.19 (1.14-1.24)	< 0.0001	1.16 (1.11-1.21)	< 0.0001	1.15 (1.09-1.20)	< 0.0001
RC/HDL-C	1.12 (1.08-1.17)	< 0.0001	1.12 (1.07-1.17)	< 0.0001	1.11 (1.06-1.16)	< 0.0001	1.09 (1.04-1.14)	< 0.0001	1.08 (1.03-1.14)	< 0.0001
Q1	Reference	-	Reference	-	Reference	-	Reference	-	Reference	-
Q2	1.13 (0.98-1.30)	0.0966	1.08 (0.93-1.24)	0.3024	1.07 (0.93-1.24)	0.3453	1.05 (0.91-1.22)	0.4849	1.05 (0.91-1.21)	0.5090
Q3	1.42 (1.24-1.63)	< 0.0001	1.34 (1.17-1.54)	< 0.0001	1.31 (1.14-1.505)	0.0002	1.26 (1.09-1.45)	0.0014	1.26 (1.09-1.45)	0.0016
Q4	1.49 (1.30-1.70)	< 0.0001	1.44 (1.25-1.65)	< 0.0001	1.40 (1.21-1.61)	< 0.0001	1.32 (1.14-1.52)	0.0002	1.30 (1.12-1.50)	0.0005
P for trend	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001
Per 1 SD	1.10 (1.06-1.14)	< 0.0001	1.10 (1.06-1.14)	< 0.0001	1.09 (1.05-1.14)	< 0.0001	1.07 (1.03-1.12)	0.0005	1.07 (1.03-1.11)	0.0014

Data are expressed as hazard ratio and 95% confidence interval (reported in parentheses) as assessed by multivariable-adjusted Cox proportional hazards regression analysis. Model 1 adjusted for sex, age, race, and educational level. Model 2 adjusted for model 1 covariables plus depression, cigarette-smoking status, duration of type 2 diabetes mellitus, previous cardiovascular events, previous heart failure, and previous hypertension. Model 3 adjusted for model 2 covariables plus body mass index, systolic blood pressure, diastolic blood pressure, hemoglobin A1c, fasting blood glucose, and estimated glomerular filtration rate. Model 4 adjusted for model 3 covariables plus insulin use, biguanide use, beta-blocker use, and statin use. TC: Total cholesterol; HDL-C: High-density lipoprotein cholesterol; SD: Standard deviation; LDL-C: Low-density lipoprotein cholesterol; RC: Remnant cholesterol; HR: Hazard ratio; CI: Confidence interval.

Table 3 Threshold effect analyses of nontraditional lipoprotein ratios on major adverse cardiovascular events

Characteristics	One linear-regression model	Inflection point (K)	< K, effect 1	> K, effect 2	P value for LRT
TC/HDL-C	1.09 (1.06-1.13), P < 0.0001	7.29	1.14 (1.09-1.19), P < 0.0001	0.97 (0.88-1.07), P = 0.4915	0.003
LDL-C/HDL-C	1.16 (1.10-1.21), P < 0.0001	1.35	0.64 (0.30-1.36), P = 0.2453	0.97 (0.88-1.08), P = 0.5786	0.140
Non-HDL-C/HDL-C	1.09 (1.06-1.13), P < 0.0001	6.29	1.14 (1.09-1.19), P < 0.0001	0.97 (0.88-1.07), P = 0.4915	0.003
RC/HDL-C	1.08 (1.03-1.14), P = 0.0014	2.15	1.24 (1.13-1.36), P < 0.0001	0.95 (0.86-1.05), P = 0.3543	< 0.001

The effects shown are adjusted for Model 4, including sex, age, race, educational level, depression, cigarette-smoking status, duration of type 2 diabetes mellitus, previous cardiovascular events, previous heart failure, previous hypertension, body mass index, systolic blood pressure, diastolic blood pressure, hemoglobin A1c, fasting blood glucose, estimated glomerular filtration rate, insulin use, biguanide use, beta-blocker use, and statin use. TC: Total cholesterol; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; RC: Remnant cholesterol; LRT: Likelihood ratio test.