Metabolic score for insulin resistance is associated with adverse cardiovascular events in patients with type 2 diabetes

Table 1 Baseline characteristics of participants by quartiles of metabolic score for insulin resistance, n (%)

Outcome	Q1 (n = 2548)	Q2 (n = 2547)	Q3 (n = 2548)	Q4 (n = 2548)	P value
METS-IR, mean ± SD	41.19 ± 4.23	50.39 ± 2.09	57.78 ± 2.33	69.71 ± 6.66	< 0.001
Age (years), mean ± SD	64.26 ± 7.12	63.39 ± 6.64	62.47 ± 6.37	61.14 ± 5.98	< 0.001
Sex					0.002
Male	1511 (59.30)	1640 (64.39)	1570 (61.62)	1544 (60.60)
Female	1037 (40.70)	907 (35.61)	978 (38.38)	1004 (39.40)
Race					< 0.001
White	1152 (45.21)	1512 (59.36)	1739 (68.25)	1965 (77.12)
Non-white	1396 (54.79)	1035 (40.64)	809 (31.75)	583 (22.88)
Education					< 0.001
Less than high school graduate	434 (17.05)	413 (16.22)	373 (14.64)	281 (11.04)
High school grad	671 (26.37)	667 (26.19)	673 (26.42)	679 (26.68)
Some college or technical school	690 (27.11)	814 (31.96)	869 (34.12)	968 (38.04)
College graduate or more	750 (29.47)	653 (25.64)	632 (24.81)	617 (24.24)
CVD history	825 (32.38)	898 (35.26)	927 (36.38)	933 (36.62)	0.005
Duration of diabetes (years), mean ± SD	12.05 ± 8.14	11.06 ± 7.76	10.26 ± 7.17	9.83 ± 7.07	< 0.001
Previous hypertension	1861 (73.04)	1901 (74.64)	1925 (75.55)	1993 (78.22)	0.008
Proteinuria	429 (16.84)	483 (18.96)	505 (19.83)	610 (23.94)	< 0.001
Heart failure	81 (3.18)	96 (3.77)	126 (4.95)	184 (7.22)	< 0.001
Depression	425 (16.68)	535 (21.01)	628 (24.66)	824 (32.35)	< 0.001
Living alone	2043 (80.18)	2034 (79.89)	2031 (79.71)	2018 (79.23)	0.861
Smoking					< 0.001
Yes	1325 (52.00)	1513 (59.40)	1549 (60.79)	1547 (60.71)
No	1223 (48.00)	1034 (40.60)	999 (39.21)	1001 (39.29)
Alcohol					< 0.001
Yes	659 (25.86)	661 (25.96)	588 (23.10)	524 (20.58)
No	1889 (74.14)	1885 (74.04)	1958 (76.90)	2022 (79.42)
BMI (kg/m2), mean ± SD	26.36 ± 2.76	30.38 ± 2.67	33.76 ± 3.16	38.41 ± 3.68	< 0.001
SBP (mmHg), mean ± SD	137.20 ± 16.95	136.49 ± 17.25	135.99 ± 17.17	135.73 ± 17.03	0.013
DBP (mmHg), mean ± SD	73.20 ± 10.56	74.48 ± 10.58	75.49 ± 10.52	76.38 ± 10.74	< 0.001
Heart rate (bpm), mean ± SD	71.65 ± 11.67	71.78 ± 11.58	73.27 ± 11.66	73.99 ± 11.94	< 0.001
FPG (mg/dL), mean ± SD	157.90 ± 54.45	170.56 ± 52.95	178.76 ± 53.52	193.51 ± 57.66	< 0.001
HbA1C (%), mean ± SD	8.23 ± 1.08	8.23 ± 1.02	8.30 ± 1.02	8.45 ± 1.09	< 0.001
TC (mg/dL), mean ± SD	181.47 ± 39.36	181.10 ± 39.96	183.22 ± 42.08	187.40 ± 45.44	< 0.001
TG (mg/dL), mean ± SD	125.87 ± 72.81	166.08 ± 92.14	201.16 ± 130.08	267.11 ± 215.59	< 0.001
LDL-C (mg/dL), mean ± SD	106.91 ± 33.05	105.91 ± 33.56	104.30 ± 33.92	102.47 ± 34.94	< 0.001
HDL-C (mg/dL), mean ± SD	49.53 ± 13.12	42.51 ± 10.23	39.88 ± 9.46	35.56 ± 8.46	< 0.001
eGFR (mL/minute/1.73 m2), mean ± SD	91.53 ± 30.19	90.70 ± 27.47	90.89 ± 24.57	91.05 ± 26.00	0.727
ALT (mg/dL), mean ± SD	25.12 ± 13.13	27.47 ± 19.14	28.37 ± 15.98	29.38 ± 15.63	< 0.001
Medications
ARB/ACEI	1665 (65.35)	1790 (70.28)	1758 (69.00)	1850 (72.61)	< 0.001
CCB	484 (19.00)	468 (18.37)	484 (19.00)	516 (20.25)	0.382
Bate blockers	604 (23.75)	720 (28.36)	824 (32.44)	917 (36.07)	< 0.001
Biguanides	1563 (61.34)	1646 (64.63)	1686 (66.20)	1623 (63.70)	0.003
Thiazolidinediones	545 (21.39)	507 (19.91)	590 (23.16)	604 (23.70)	0.004
Sulfonylureas	1399 (54.91)	1354 (53.16)	1353 (53.12)	1339 (52.55)	0.363
Insulins	793 (31.12)	882 (34.63)	888 (34.85)	999 (39.21)	< 0.001
Statins	1631 (64.31)	1638 (64.67)	1657 (65.21)	1539 (60.54)	0.002
Aspirin	1326 (52.31)	1381 (54.54)	1440 (56.76)	1402 (55.20)	0.015
Cholesterol absorption inhibitors	51 (2.01)	53 (2.09)	49 (1.93)	54 (2.13)	0.962
MACEs	402 (15.78)	418 (16.41)	482 (18.92)	510 (20.02)	< 0.001
CVD mortality	147 (5.77)	124 (4.87)	176 (6.91)	216 (8.48)	< 0.001
Non-fatal MI	203 (7.97)	228 (8.95)	241 (9.46)	258 (10.13)	0.054
Non-fatal stroke	103 (4.04)	125 (4.91)	130 (5.10)	126 (4.95)	0.276
Total mortality	448 (17.58)	448 (17.59)	491 (19.27)	556 (21.82)	< 0.001
Congestive heart failure	124 (4.87)	132 (5.18)	196 (7.69)	239 (9.38)	< 0.001
Major CHD	379 (14.87)	426 (16.73)	495 (19.43)	544 (21.35)	< 0.001

METS-IR: Metabolic score for insulin resistance; CVD: Cardiovascular disease; BMI: Body mass index; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; FPG: Fasting plasma glucose; HbA1C: Hemoglobin A1c; TC: Total cholesterol; TG: Triglycerides; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; eGFR: Estimated glomerular filtration rate; ALT: Alanine aminotransferase; ARB: Angiotensin receptor blocker; ACEI: Angiotensin converting enzyme inhibitors; CCB: Calcium channel blockers; MACEs: Major adverse cardiovascular events; MI: Myocardial infarction; CHD: Coronary heart disease.

Table 2 Risk of primary and secondary outcomes based on metabolic score for insulin resistance in type 2 diabetes patient

Outcome	Events/n	Non-adjusted		Model 1		Model 2		Model 3
		HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
MACEs
METS-IR	-	1.01 (1.01-1.01)	< 0.00001	1.01 (1.01-1.02)	< 0.00001	1.01 (1.01-1.01)	< 0.00001	1.01 (1.00-1.01)	0.0004
Q1	402/2548	Reference	-	Reference	-	Reference	-	Reference	-
Q2	418/2547	1.05 (0.92-1.20)	0.4837	1.07 (0.94-1.23)	0.3044	1.02 (0.89-1.17)	0.7661	1.00 (0.87-1.15)	0.9647
Q3	482/2548	1.22 (1.07-1.39)	0.0036	1.31 (1.14-1.49)	< 0.0001	1.23 (1.07-1.41)	0.0035	1.20 (1.05-1.38)	0.0090
Q4	510/2548	1.32 (1.15-1.50)	< 0.0001	1.50 (1.31-1.71)	< 0.00001	1.31 (1.14-1.52)	0.0002	1.25 (1.08-1.45)	0.0024
Per 1 SD	-	1.12 (1.07-1.17)	< 0.00001	1.18 (1.12-1.23)	< 0.00001	1.12 (1.06-1.18)	< 0.00001	1.10 (1.04-1.16)	0.0004
P for trend	-	-	< 0.00001	-	< 0.00001	-	< 0.00001	-	0.0003
CVD mortality
METS-IR	-	1.02 (1.01-1.02)	< 0.0001	1.02 (1.02-1.03)	< 0.00001	1.02 (1.01-1.03)	< 0.0001	1.02 (1.01-1.03)	< 0.0001
Q1	147/2548	Reference	-	Reference	-	Reference	-	Reference
Q2	124/2547	0.85 (0.67-1.08)	0.1790	0.88 (0.70-1.12)	0.3102	0.83 (0.65-1.06)	0.1382	0.80 (0.63-1.02)	0.0778
Q3	176/2548	1.22 (0.98-1.52)	0.0764	1.38 (1.10-1.72)	0.0045	1.28 (1.02-1.60)	0.0361	1.23 (0.98-1.54)	0.0808
Q4	216/2548	1.54 (1.25-1.90)	< 0.0001	1.92 (1.55-2.38)	< 0.0001	1.66 (1.32-2.09)	< 0.0001	1.55 (1.23-1.96)	0.0003
Per 1 SD	-	1.20 (1.12-1.29)	< 0.0001	1.32 (1.22-1.42)	< 0.00001	1.25 (1.15-1.36)	< 0.0001	1.22 (1.12-1.32)	< 0.0001
P for trend	-	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001
Non-fatal MI
METS-IR	-	1.01 (1.00-1.01)	0.0020	1.01 (1.01-1.02)	< 0.00001	1.01 (1.00-1.01)	0.0466	1.00 (1.00-1.01)	0.1933
Q1	203/2548	Reference	-	Reference	-	Reference	-	Reference	-
Q2	228/2547	1.13 (0.94-1.37)	0.1978	1.14 (0.95-1.38)	0.1633	1.09 (0.90-1.32)	0.3753	1.07 (0.88-1.30)	0.4836
Q3	241/2548	1.20 (0.99-1.44)	0.0597	1.25 (1.04-1.51)	0.0178	1.17 (0.96-1.42)	0.1152	1.13 (0.93-1.38)	0.2198
Q4	258/2548	1.31 (1.09-1.57)	0.0043	1.43 (1.18-1.72)	0.0002	1.24 (1.01-1.51)	0.0385	1.16 (0.94-1.42)	0.1588
Per 1 SD	-	1.10 (1.04-1.18)	0.0020	1.14 (1.07-1.22)	< 0.00001	1.08 (1.00-1.15)	0.0466	1.05 (0.98-1.13)	0.1933
P for trend	-	-	0.0037	-	0.0001	-	0.0307	-	0.1388
Non-fatal stroke
METS-IR	-	1.01 (1.00-1.01)	0.1472	1.01 (1.00-1.02)	0.0119	1.01 (1.00-1.02)	0.1492	1.01 (1.00-1.02)	0.1576
Q1	103/2548	Reference	-	Reference	-	Reference	-	Reference	-
Q2	125/2547	1.23 (0.94-1.59)	0.1255	1.26 (0.97-1.64)	0.0836	1.20 (0.92-1.56)	0.1818	1.19 (0.91-1.56)	0.1980
Q3	139/2548	1.28 (0.99-1.66)	0.0618	1.37 (1.06-1.78)	0.0169	1.31 (1.00-1.71)	0.0489	1.32 (1.01-1.73)	0.0443
Q4	126/2548	1.27 (0.98-1.65)	0.0703	1.45 (1.11-1.88)	0.0064	1.29 (0.97-1.72)	0.0751	1.29 (0.97-1.72)	0.0835
Per 1 SD	-	1.07 (0.98-1.17)	0.1472	1.12 (1.03-1.23)	0.0119	1.08 (0.97-1.19)	0.1492	1.07 (0.97-1.19)	0.1576
P for trend	-	-	0.0720	-	0.0052	-	0.0620	-	0.0645
Total mortality
METS-IR	-	1.01 (1.00-1.01)	< 0.0001	1.02 (1.01-1.02)	< 0.0001	1.01 (1.01-1.02)	< 0.0001	1.01 (1.01-1.02)	< 0.0001
Q1	448/2548	Reference	-	Reference	-	Reference	-	Reference
Q2	448/2547	1.01 (0.88-1.15)	0.9213	1.07 (0.93-1.22)	0.3417	1.01 (0.88-1.15)	0.909	0.99 (0.87-1.13)	0.8556
Q3	491/2548	1.12 (0.98-1.27)	0.0891	1.30 (1.14-1.47)	< 0.0001	1.20 (1.05-1.37)	0.0082	1.17 (1.02-1.34)	0.0233
Q4	556/2548	1.31 (1.15-1.48)	< 0.0001	1.70 (1.50-1.93)	< 0.0001	1.47 (1.28-1.68)	< 0.0001	1.39 (1.21-1.59)	< 0.0001
Per 1 SD	-	1.10 (1.05-1.15)	< 0.0001	1.22 (1.17-1.28)	< 0.0001	1.15 (1.10-1.21)	< 0.0001	1.13 (1.08-1.19)	< 0.0001
P for trend	-	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001
CHF
METS-IR	-	1.03 (1.02-1.03)	< 0.0001	1.04 (1.03-1.04)	< 0.0001	1.03 (1.02-1.04)	< 0.0001	1.03 (1.02-1.04)	< 0.0001
Q1	124/2548	Reference	-	Reference	-	Reference	-	Reference	-
Q2	132/2547	1.07 (0.84-1.37)	0.5656	1.13 (0.89-1.45)	0.3203	1.06 (0.83-1.36)	0.6457	1.04 (0.80-1.34)	0.7809
Q3	196/2548	1.62 (1.30-2.03)	< 0.0001	1.86 (1.48-2.33)	< 0.0001	1.82 (1.44-2.30)	< 0.0001	1.76 (1.39-2.23)	< 0.0001
Q4	239/2548	2.09 (1.69-2.60)	< 0.0001	2.65 (2.13-3.31)	< 0.0001	2.31 (1.82-2.92)	< 0.0001	2.22 (1.74-2.82)	< 0.0001
Per 1 SD	-	1.35 (1.26-1.44)	< 0.0001	1.48 (1.38-1.59)	< 0.0001	1.42 (1.31-1.53)	< 0.0001	1.40 (1.29-1.52)	< 0.0001
P for trend	-	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001
Major CHD
METS-IR	-	1.01 (1.01-1.02)	< 0.0001	1.02 (1.01-1.02)	< 0.0001	1.01 (1.01-1.02)	< 0.0001	1.01 (1.01-1.02)	< 0.0001
Q1	379/2548	Reference	-	Reference	-	Reference	-	Reference	-
Q2	426/2547	1.14 (0.99-1.31)	0.0596	1.16 (1.01-1.33)	0.0410	1.10 (0.95-1.27)	0.1887	1.07 (0.93-1.24)	0.3298
Q3	495/2548	1.34 (1.17-1.53)	< 0.0001	1.41 (1.23-1.61)	< 0.0001	1.31 (1.14-1.51)	0.0001	1.26 (1.10-1.45)	0.0012
Q4	544/2548	1.50 (1.32-1.72)	< 0.0001	1.65 (1.44-1.89)	< 0.0001	1.43 (1.24-1.66)	< 0.0001	1.35 (1.17-1.56)	< 0.0001
Per 1 SD	-	1.17 (1.12-1.23)	< 0.0001	1.22 (1.17-1.28)	< 0.0001	1.16 (1.10-1.22)	< 0.0001	1.13 (1.08-1.19)	< 0.0001
P for trend	-	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	< 0.0001

Data are expressed as hazard ratio and 95% confidence intervals (reported in parentheses) as assessed by multivariable Cox regression analysis. Model 1 adjusted for age, sex. Model 2 adjusted for model 1 covariables plus race, cardiovascular disease history, previous hypertension, duration of diabetes, proteinuria, heart failure, depression, education, smoke, systolic blood pressure, diastolic blood pressure, glycated hemoglobin, total cholesterol, low-density lipoprotein, estimated glomerular filtration rate, alanine aminotransferase. Model 3 Adjusted for model 2 covariables plus the medications use, calcium channel blockers, beta-blockers, biguanides, thiazolidinediones, insulins, aspirin, statins, cholesterol absorption inhibitors. MACEs: Major adverse cardiovascular events; CVD: Cardiovascular disease; MI: Myocardial infarction; CHF: Congestive heart failure; CHD: Coronary heart disease; METS-IR: Metabolic score for insulin resistance; CI: Confidence interval; HR: Hazard ratio; SD: Standard deviation.

Table 3 Additional predictive value of metabolic score for insulin resistance for outcome

Outcome	C-statistic (95%CI)	P value	NRI (95%CI)	P value	IDI (95%CI)	P value
MACEs
Conventional model	0.669 (0.660-0.679)	-	Reference	-	Reference	-
Conventional model + METS-IR	0.674 (0.664-0.683)	0.0170	0.054 (0.019-0.084)	0.0070	0.003 (0.001-0.005)	< 0.0001
CVD mortality
Conventional model	0.706 (0.697-0.715)	-	Reference	-	Reference	-
Conventional model + METS-IR	0.716 (0.708-0.725)	0.0050	0.104 (0.047-0.145)	< 0.0001	0.004 (0.002-0.008)	< 0.0001
Non-fatal MI
Conventional model	0.661 (0.652-0.670)	-	Reference	-	Reference	-
Conventional model + METS-IR	0.663 (0.654-0.672)	0.2705	0.025 (-0.018 to 0.067)	0.1930	0.001 (0.000-0.003)	0.0130
Non-fatal stroke
Conventional model	0.632 (0.623-0.642)	-	Reference	-	Reference	-
Conventional model + METS-IR	0.634 (0.624-0.643)	0.6054	0.052 (-0.015 to 0.102)	0.1660	0.001 (0.000-0.002)	0.0860
Total mortality
Conventional model	0.693 (0.684-0.702)	-	Reference	-	Reference	-
Conventional model + METS-IR	0.701 (0.692-0.710)	0.0001	0.078 (0.048-0.108)	< 0.0001	0.004 (0.002-0.007)	< 0.0001
Congestive heart failure
Conventional model	0.707 (0.698-0.716)	-	Reference	-	Reference	-
Conventional model + METS-IR	0.732 (0.723-0.741)	< 0.0001	0.211 (0.149-0.254)	< 0.0001	0.016 (0.009-0.025)	< 0.0001
Major CHD
Conventional model	0.677 (0.668-0.686)	-	Reference	-	Reference	-
Conventional model + METS-IR	0.684 (0.674-0.693)	0.0018	0.055 (0.024-0.081)	< 0.0001	0.004 (0.002-0.006)	< 0.0001

The conventional model was adjusted for age, sex, race, cardiovascular disease history, duration of diabetes, systolic blood pressure, diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, smoke, statin, aspirin. CI: Confidence interval; NRI: Net reclassification index; DI: Integrated discrimination improvement; CVD: Cardiovascular disease; IMACEs: Major adverse cardiovascular events; MI: Myocardial infarction; METS-IR: Metabolic score for insulin resistance.

Table 4 Association between metabolic score for insulin resistance and major adverse cardiovascular events in patients with glycated hemoglobin < 8.0

Outcome	Events/n	Non-adjusted		Model 4		Model 5		Model 6
		HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
MACEs	-	1.02 (1.01-1.02)	< 0.0001	1.02 (1.02-1.03)	< 0.0001	1.02 (1.01-1.02)	< 0.0001	1.01 (1.01-1.02)	0.0005
METS-IR
Q1	160/1219	Reference	-	Reference	-	Reference	-	Reference	-
Q2	168/1154	1.12 (0.90-1.39)	0.2985	1.16 (0.93-1.44)	0.1907	1.08 (0.87-1.36)	0.4755	1.04 (0.83-1.30)	0.7139
Q3	172/1043	1.29 (1.04-1.60)	0.0212	1.43 (1.15-1.78)	0.0013	1.28 (1.02-1.60)	0.0361	1.22 (0.97-1.54)	0.0848
Q4	192/942	1.62 (1.31-2.00)	< 0.0001	1.90 (1.54-2.36)	< 0.0001	1.61 (1.28-2.03)	< 0.0001	1.47 (1.16-1.86)	0.0012
Per 1 SD	-	1.20 (1.11-1.29)	< 0.0001	1.28 (1.19-1.39)	< 0.0001	1.20 (1.11-1.31)	< 0.0001	1.17 (1.07-1.27)	0.0005
P for trend	-	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	0.0005

Data are expressed as hazard ratio and 95% confidence intervals (reported in parentheses) as assessed by multivariable Cox regression analysis. Model 4 adjusted for age, sex. Model 5 adjusted for model 4 covariables plus race, cardiovascular disease history, previous hypertension, duration of diabetes, proteinuria, heart failure, depression, living alone, education, smoke, alcohol, systolic blood pressure, diastolic blood pressure, hazard ratio, glycated hemoglobin, total cholesterol, low-density lipoprotein, estimated glomerular filtration rate, alanine aminotransferase. Model 6 adjusted for model 5 covariables plus the medications use, calcium channel blockers, beta-blockers, biguanides, insulins, aspirin, statins, cholesterol absorption inhibitors. MACEs: Major adverse cardiovascular events; METS-IR: Metabolic score for insulin resistance; CI: Confidence interval; HR: Hazard ratio; SD: Standard deviation.

Table 5 Association between metabolic score for insulin resistance and major adverse cardiovascular events in aspirin-free patients

Outcome	Events/n	Non-adjusted		Model 7		Model 8		Model 9
		HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
MACEs	-	1.01 (1.01-1.01)	< 0.0001	1.01 (1.01-1.02)	< 0.0001	1.01 (1.01-1.01)	< 0.0001	1.01 (1.00, 1.01)	0.0008
METS-IR
Q1	171/1209	Reference	-	Reference	-	Reference	-	Reference	-
Q2	168/1151	1.05 (0.92-1.20)	0.4837	1.07 (0.94-1.23)	0.3044	1.02 (0.89-1.17)	0.7661	1.00 (0.87-1.15)	0.9627
Q3	202/1097	1.22 (1.07-1.39)	0.0036	1.31 (1.14-1.49)	< 0.0001	1.23 (1.07-1.41)	0.0035	1.19 (1.04-1.37)	0.0123
Q4	232/1138	1.32 (1.15-1.50)	< 0.0001	1.50 (1.31-1.71)	< 0.0001	1.31 (1.14-1.52)	0.0002	1.24 (1.07-1.43)	0.004
Per 1 SD	-	1.12 (1.07-1.17)	< 0.0001	1.18 (1.12-1.23)	< 0.0001	1.12 (1.06-1.18)	< 0.0001	1.09 (1.04-1.15)	0.0008
P for trend	-	-	< 0.0001	-	< 0.0001	-	< 0.0001	-	0.0005

Data are expressed as hazard ratio and 95% confidence intervals (reported in parentheses) as assessed by multivariable Cox regression analysis. Model 7 adjusted for age, sex. Model 8 adjusted for model 7 covariables plus race, cardiovascular disease history, previous hypertension, duration of diabetes, proteinuria, heart failure, depression, education, smoke, systolic blood pressure, diastolic blood pressure, glycated hemoglobin, total cholesterol, low-density lipoprotein, estimated glomerular filtration rate, alanine aminotransferase. Model 9 adjusted for model 8 covariables plus the medications use, calcium channel blockers, beta-blockers, biguanides, insulins, statins, cholesterol absorption inhibitors. MACEs: Major adverse cardiovascular events; METS-IR: Metabolic score for insulin resistance; CI: Confidence interval; HR: Hazard ratio; SD: Standard deviation.