Baseline characteristics of the study population
A total of 420 subjects with 688 lesions, with a mean follow-up period of 12.8±1.3 months, were included in the analysis. The male-to-female ratio was 74:26 and the mean age was 64.5±9.0 years. Among these subjects, 73.8% were with hypertension and 77.6% of the subjects were with multivessel disease. The mean HbA1c during follow-up was 7.4±1.2%, and CV, SD, VIM of HbA1c during follow-up were 0.061 [IQR 0.038~0.107], 0.402 [IQR 0.252~0.839] and 0.209 [IQR 0.127~0.297], respectively. CV (Pearson’s r = 0.325, P<0.001) and SD (Pearson’s r = 0.445, P<0.001) were correlated to the mean HbA1c while there was no significant correlation between VIM and the mean HbA1c level (Pearson’s r=0.070, P=0.169). To analyze the effect of HbA1c variability on ISR, we divided the population based on tertiles of CV of HbA1c (Table 1). There was no significant difference in age, sex, history of hypertension, admission blood pressure, smoking status and duration of diabetes between the three tertiles. At admission, subjects with the highest tertile of CV of HbA1c had higher levels of HbA1c, fasting and 2 h postprandial glucose, but lower 2 h postparandial insulin level than those with the lowest tertile. Fasting insulin level was similar between the three groups. Meanwhile, HDL-C was lower, whereas serum creatine and hsCRP were higher in subjects with the highest tertile. OHA and insulin were more frequently used in subjects with higher CV of HbA1c.
Table 1. Baseline Characteristics.
Tertiles of CV of HbA1c
|
T1
(0.005~0.045)
|
T2
(0.045~0.086)
|
T3
(0.086~0.397)
|
P
|
n
|
141
|
139
|
140
|
|
Demographic characteristics & clinical measures
|
|
|
|
Male sex
|
102 (72.3)
|
110 (79.1)
|
97 (69.3)
|
0.161
|
Age, years
|
64.79±8.80
|
63.99±8.87
|
64.74±9.33
|
0.705
|
BMI, kg/m2
|
25.61±3.47
|
25.14±2.83
|
25.59±3.14
|
0.375
|
Systolic BP, mmHg
|
139.34±20.09
|
137.43±19.68
|
137.24±23.39
|
0.657
|
Diastolic BP, mmHg
|
78.42±13.57
|
75.96±11.71
|
75.41±11.18
|
0.091
|
Medical history
|
|
|
|
|
Hypertension
|
101 (71.6)
|
105 (75.5)
|
104 (74.3)
|
0.749
|
Duration of diabetes, years
|
11.8±9.8
|
8.9±5.7
|
11.1±8.0
|
0.078
|
Current smoker
|
59 (41.8)
|
76 (54.7)
|
60 (42.9)
|
0.058
|
Laboratory values
|
|
|
|
|
HbA1C, %
|
7.0±1.6
|
7.1±1.0
|
8.4±1.5
|
<0.001
|
Fasting glucose, mmol/L
|
6.97±2.61
|
6.85±2.31
|
9.17±3.86
|
<0.001
|
Postparandial glucose (2h),
mmol/L
|
12.05±3.87
|
12.57±4.41
|
14.98±5.04
|
<0.001
|
Fasting insulin, µU/mL
|
11.03 (8.26~16.99)
|
9.97 (6.66~16.05)
|
11.04 (7.39~18.85)
|
0.451
|
Postparandial insulin (2 h),
µU/mL
|
46.53 (35.88~75.78)
|
44.50 (26.59~83.72)
|
37.61 (24.18~63.65)
|
0.009
|
HOMA-IR
|
3.28 (2.18~5.57)
|
3.18 (1.73~5.16)
|
4.62 (2.29~6.68)
|
0.005
|
Hemoglobin, g/L
|
133.99±16.10
|
131.82±17.46
|
131.66±20.73
|
0.489
|
Triglyceride, mmol/L
|
1.50 (1.15~2.35)
|
1.28 (0.98~2.04)
|
1.70 (1.15~2.13)
|
0.008
|
Total cholesterol, mmol/L
|
4.20±1.17
|
3.96±1.08
|
4.10±1.27
|
0.243
|
HDL cholesterol, mmol/L
|
1.06±0.24
|
1.08±0.28
|
0.98±0.20
|
0.002
|
LDL cholesterol, mmol/L
|
2.44±0.92
|
2.30±0.88
|
2.46±0.93
|
0.295
|
Non-HDL cholesterol,
mmol/L
|
3.14±1.16
|
2.88±1.04
|
3.11±1.24
|
0.119
|
Alanine aminotransferase,
IU/L
|
26.97±16.97
|
27.03±17.47
|
28.76±20.16
|
0.647
|
Serum creatinine, μmol/L
|
80.57±18.76
|
87.34±40.13
|
103.68±100.37
|
0.008
|
Blood urea nitrogen,
mmol/L
|
5.69±1.74
|
5.66±2.37
|
6.29±3.05
|
0.052
|
eGFR, mL/min/1.73m2
|
81.80±16.73
|
82.19±17.54
|
80.66±20.46
|
0.775
|
hsCRP, mg/L
|
1.21 (0.55~4.24)
|
1.19 (0.42~4.09)
|
1.96 (0.91~8.55)
|
0.009
|
Cardiac function
|
|
|
|
|
LVEF, %
|
63.3±8.6
|
62.6±8.8
|
62.2±9.7
|
0.619
|
Medication use
|
|
|
|
|
Aspirin
|
136 (96.5)
|
129 (92.8)
|
132 (94.3)
|
0.402
|
P2Y12 inhibitor
|
129 (91.5)
|
129 (92.8)
|
128 (91.4)
|
0.893
|
Beta blocker
|
113 (80.1)
|
108 (77.7)
|
100 (71.4)
|
0.207
|
ACEI
|
49 (34.8)
|
42 (30.2)
|
56 (40.0)
|
0.230
|
ARB
|
47 (33.3)
|
65 (46.8)
|
57 (40.7)
|
0.072
|
CCB
|
45 (31.9)
|
53 (38.1)
|
39 (27.9)
|
0.183
|
Statin
|
136 (96.5)
|
133 (95.7)
|
136 (97.1)
|
0.806
|
OHA
|
66 (46.8)
|
57 (41.0)
|
79 (56.4)
|
0.034
|
Biguanides
|
30 (21.3)
|
30 (21.6)
|
42 (30.0)
|
0.155
|
Sulfonylureas
|
22 (15.6)
|
28 (20.1)
|
36 (25.7)
|
0.109
|
Meglitinides
|
4 (2.8)
|
6 (4.3)
|
8 (5.7)
|
0.492
|
Thiazolidinediones
|
2 (1.4)
|
2 (1.4)
|
8 (5.7)
|
0.046
|
Insulin
|
23 (16.3)
|
21 (15.1)
|
46 (32.9)
|
<0.001
|
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; BP, blood pressure; CCB, calcium-channel blacker; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin A1c; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment-insulin resistance; hsCRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction.
Angiographic findings
There were no significant differences in the target vessels, stent counts, stented length, angiographic pre-and post-PCI RD, DS and MLD between the three groups (Table 2). In the overall population, follow-up coronary angiography showed the prevalence of binary angiographic ISR, defined as ≥50% DS, was 8.6%. The mean DS was 22.9±16.8%, and the mean net luminal loss and net luminal gain was 0.42±0.88 mm and 1.66±0.83 mm, respectively.
Table 2. Lesion and Procedural Characteristics.
Tertiles of CV of HbA1c
|
T1
(0.005~0.045)
|
T2
(0.045~0.086)
|
T3
(0.086~0.397)
|
P
|
Left mainstem lesion
|
4 (1.82)
|
4 (1.73)
|
8 (3.38)
|
0.363
|
Left anterior descending lesion
|
104 (47.27)
|
96 (41.56)
|
92 (38.82)
|
Circumflex lesion
|
65 (29.55)
|
65 (28.14)
|
71 (29.96)
|
Right coronary lesion
|
47 (21.36)
|
66 (28.57)
|
66 (27.85)
|
Multivessel disease
|
109 (77.3)
|
103 (74.1)
|
114 (81.4)
|
0.338
|
RD, pre-PCI, mm
|
2.96±0.51
|
2.91±0.43
|
2.88±0.44
|
0.176
|
%DS pre-PCI
|
81.82±18.21
|
78.66±24.75
|
81.52±24.79
|
0.278
|
MLD pre-PCI, mm
|
0.54±0.55
|
0.62±0.72
|
0.55±0.77
|
0.385
|
RD, post-PCI, mm
|
3.17±0.81
|
3.14±0.94
|
3.13±0.91
|
0.858
|
%DS post-PCI
|
12.89±13.27
|
14.69±13.44
|
13.42±15.06
|
0.370
|
MLD post-PCI, mm
|
2.78±0.87
|
2.70±0.98
|
2.73±0.98
|
0.696
|
Stent count
|
1.45±0.64
|
1.53±0.71
|
1.48±0.72
|
0.409
|
Stented length, mm
|
36.76±17.88
|
38.24±20.72
|
37.11±18.98
|
0.692
|
CV, coefficient of variation; DS, diameter stenosis; MLD, minimal luminal diameter; RD, reference diameter; PCI, percutaneous coronary intervention.
There was a significant increase in DS across tertiles of CV of HbA1c (Figure 2A, P=0.001). Compared with subjects with the lowest tertile, a higher percentage of DS was found in the highest tertile (26.63±19.08 vs. 19.29±14.47%, P<0.001). Accordingly, net luminal gain (P<0.001) was step-wisely decreased in subjects with higher HbA1c variability as grouped by all the three measures (Figure 2B). Although there was no difference in net luminal loss between tertiles of CV (Figure 2C; P=0.124), it differed significantly between subjects with different tertiles of SD (P=0.023) or VIM (P=0.014) of HbA1c (Supplementary figure I and II). In addition, comparison of HbA1c variability between subjects with and without ISR also showed significantly higher HbA1c variability in ISR patients as analyzed by all the three measures (Supplementary figure III).
The rate of binary angiographic restenosis was substantially elevated with increasing tertiles of CV of HbA1c (lowest tertile: 5.0%, intermediate tertile: 6.5%, highest tertile: 14.3%; P=0.011). Similar findings were observed when grouping the population based on other measures of HbA1c variability. Meanwhile, increased ISR rate was also observed in patients with higher pre-procedural (baseline HbA1c>7%: 10.20% vs. HbA1c≤7%: 6.86%, P<0.001) and post-procedural (mean HbA1c>7%: 11.50% vs. HbA1c≤7%: 4.52%, P<0.001) HbA1c levels.
The impact of HbA1c variability on ISR was analyzed across subgroups of sex, age, dichotomized baseline BMI, eGFR and HbA1c (Figure 3). Since the rate of binary ISR was relatively low, DS at follow-up angiography was compared between subgroups. We found DS was increased across tertiles of CV of HbA1c in male but not female subjects. A trend towards higher percentage of DS across the tertiles was more prominent in subjects with higher BMI and poorer renal function, and was similar between two age groups. Interestingly, compared with subjects with higher HbA1c at the time of PCI (HbA1c>7%), those with lower HbA1c (≤7%) appeared to have more severe restenosis when having higher CV of HbA1c. There was no significant interaction term between tertiles of CV of HbA1c and these grouping variables, with the solo exception of basal HbA1c level (P=0.010). Dividing subjects by tertiles of SD or VIM yielded similar findings with a little variation (Supplementary figure IV and V).
Multivariate analysis
Multivariate analysis was performed to analyze the association between the incidence of ISR and different measures of HbA1c variability (Table 3). The age- and sex- adjusted HR for ISR in subjects with the highest tertile versus the lowest tertile was 3.26 [95% CI 1.37~7.76]. After multivariate adjustment (model 3), the highest tertile conferred a higher risk of ISR as compared to the lowest tertile (2.92 [95% CI 1.18~7.20]). After additional adjustment for baseline HbA1c (model 4) or the mean HbA1c during follow-up (model 5), the corresponding HR for ISR in the highest tertile versus the lowest tertile remained significant (model 4: 3.28 [95% CI 1.25~8.55]; model 5: 3.00 [95% CI 1.14~7.92]). Similar findings were observed by inclusion of other measures of HbA1c variability into these models. In the full adjustment model (model 5), the highest tertile of SD and VIM were significantly associated with 3.69- and 2.82-fold increased risk (all P<0.05) of ISR compared with the lowest tertile, respectively.
Table 3. Multivariate Analysis.
Tertiles
|
Model 1
|
|
Model 2
|
|
Model 3
|
|
Model 4
|
|
Model 5
|
HR (95% CI)
|
P
|
|
HR (95% CI)
|
P
|
|
HR (95% CI)
|
P
|
|
HR (95% CI)
|
P
|
|
HR (95% CI)
|
P
|
CV
|
|
0.004*
|
|
|
0.008*
|
|
|
0.015*
|
|
|
0.013*
|
|
|
0.023*
|
T1
|
reference
|
-
|
|
reference
|
-
|
|
reference
|
-
|
|
reference
|
-
|
|
reference
|
-
|
T2
|
1.22 (0.45~3.27)
|
0.698
|
|
1.03 (0.38~2.79)
|
0.958
|
|
0.96 (0.34~2.74)
|
0.946
|
|
1.00 (0.35~2.86)
|
1.000
|
|
0.97 (0.34~2.75)
|
0.950
|
T3
|
3.26 (1.37~7.76)
|
0.008
|
|
3.06 (1.26~7.45)
|
0.014
|
|
2.92 (1.18~7.20)
|
0.020
|
|
3.28 (1.25~8.55)
|
0.015
|
|
3.00 (1.14~7.92)
|
0.026
|
SD
|
|
0.002*
|
|
|
0.004*
|
|
|
0.008*
|
|
|
0.006*
|
|
|
0.013*
|
T1
|
reference
|
-
|
|
reference
|
-
|
|
reference
|
-
|
|
reference
|
-
|
|
reference
|
-
|
T2
|
1.60 (0.58~4.40)
|
0.364
|
|
1.27 (0.45~3.59)
|
0.648
|
|
1.11 (0.38~3.20)
|
0.848
|
|
1.21 (0.41~3.55)
|
0.727
|
|
1.15 (0.40~3.37)
|
0.792
|
T3
|
3.88 (1.54~9.77)
|
0.004
|
|
3.53 (1.38~9.06)
|
0.009
|
|
3.28 (1.25~8.65)
|
0.016
|
|
4.02 (1.39~11.61)
|
0.010
|
|
3.69 (1.23~11.05)
|
0.020
|
VIM
|
|
0.020*
|
|
|
0.042*
|
|
|
0.029*
|
|
|
0.030*
|
|
|
0.032*
|
T1
|
reference
|
-
|
|
reference
|
-
|
|
reference
|
-
|
|
reference
|
-
|
|
reference
|
-
|
T2
|
1.85 (0.73~4.70)
|
0.196
|
|
1.78 (0.69~4.54)
|
0.230
|
|
1.74 (0.66~4.58)
|
0.265
|
|
1.74 (0.66~4.60)
|
0.267
|
|
1.67 (0.63~4.43)
|
0.304
|
T3
|
2.82 (1.16~6.85)
|
0.022
|
|
2.53 (1.02~6.26)
|
0.045
|
|
2.86 (1.11~7.38)
|
0.030
|
|
2.86 (1.10~7.42)
|
0.031
|
|
2.82 (1.09~7.29)
|
0.032
|
Model 1, includes adjustment for age and sex; Model 2: additional adjustment for systolic and diastolic blood pressure, body mass index, non-HDL cholesterol and eGFR; Model 3, additional adjustment for the post-PCI reference diameter of target vessel, total stented length and medication use including oral hypoglycemic agent and insulin; Model 4, model 3 with additional adjustment for baseline HbA1c; Model 5, model 3 with additional adjustment for the mean HbA1c during follow-up. * P for trend. CI, confidence interval; CV, coefficient of variation; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin A1c; HDL, high-density lipoprotein; HR, hazard ratios; PCI, percutaneous coronary intervention; SD, standard deviation; VIM, variability independent of the mean.
Inclusion of HbA1c variability led to better risk stratification accuracy. After entering tertiles of CV of HbA1c in the model, 29.4% of subjects with ISR were correctly reclassified to a higher risk category and none was reclassified to a lower category. In patients without ISR, 10.8% were correctly reclassified to a lower risk category and 9.4% were reclassified to a higher category (categories of restenosis: <10%, 10~20%, ≥20%). Accordingly, the categorical NRI was 30.76% ([95% CI 14.78~46.74%], P<0.001), and IDI was 2.81% ([95% CI 0.81~4.82%], P=0.006).