Fig. 1Correlations between clinical variables and heart rate-corrected QT (QTc) interval during severe hypoglycemia (SH) episode. (A) Duration of diabetes (years; r=0.036, P=0.621). (B) Plasma glucose (mg/dL; r=0.108, P=0.120). (C) Glycosylated hemoglobin (HbA1c) level (%; r=−0.098, P=0.251). (D) QTc interval before SH (ms; r=0.333, P<0.001).
Table 1Sex-stratified clinical characteristics of the participants during SH episode
Characteristic |
All participants |
Men |
Women |
P value |
Number |
208 (100) |
81 (38.9) |
127 (61.1) |
|
QTc interval at baseline, ms |
433±33 |
419±29 |
443±33 |
<0.001 |
QTc prolongation at baseline, % |
24.8 |
21.3 |
27.0 |
0.353 |
QTc interval during SH, ms |
460±33 |
450±31 |
467±32 |
0.002 |
QTc prolongation at SH, % |
54.8 |
54.3 |
55.1 |
0.957 |
Age, yr |
68.1±12.1 |
67.2±12.1 |
68.8±12.2 |
0.370 |
Diabetes duration, yr |
14.1±10.1 |
13.8±10.1 |
14.3±10.1 |
0.730 |
BMI, kg/m2
|
23.6±4.0 |
22.3±3.5 |
24.5±4.0 |
<0.001 |
Alcohol, % |
17.8 |
35.8 |
6.3 |
<0.001 |
Smoking, % |
15.9 |
34.6 |
3.9 |
<0.001 |
Hypertension, % |
61.4 |
51.9 |
67.2 |
0.031 |
CKD, % |
35.6 |
42.0 |
31.5 |
0.124 |
Diabetic retinopathy, % |
61.5 |
58.7 |
63.8 |
0.596 |
SBP, mm Hg |
137±27 |
138±30 |
136±26 |
0.717 |
DBP, mm Hg |
81±14 |
82±15 |
81±13 |
0.559 |
Pulse rate, beats/min |
83±13 |
84±13 |
82±13 |
0.200 |
Plasma glucose, mg/dL |
35.9±14.6 |
33.8±15.1 |
37.3±14.2 |
0.094 |
eGFR, mL/min/1.73 m2
|
78.8±37.7 |
81.2±36.9 |
77.2±38.2 |
0.739 |
HbA1c, % |
7.4±1.6 |
7.6±1.9 |
7.2±1.3 |
0.175 |
Microalbuminuria, mg/day |
142.3±329.4 |
145.7±229.2 |
139.9±387.8 |
0.938 |
Potassium, mEq/L |
3.9±0.6 |
3.9±0.7 |
3.9±0.6 |
0.881 |
Calcium, mg/dL |
8.7±0.8 |
8.5±0.7 |
8.8±0.8 |
0.135 |
Magnesium, mg/dL |
2.3±0.6 |
2.3±0.6 |
2.3±0.5 |
0.896 |
TC, mg/dL |
165.9±45.5 |
156.7±38.4 |
172.3±49.1 |
0.071 |
TG, mg/dL |
116.5±72.7 |
113.4±72.3 |
118.5±73.5 |
0.721 |
HDL-C, mg/dL |
45.6±21.1 |
40.5±13.6 |
48.7±24.3 |
0.051 |
LDL-C, mg/dL |
88.6±43.8 |
83.4±29.2 |
92.2±51.3 |
0.360 |
Recurrent SH, % |
|
|
|
0.790 |
First episode |
60.7 |
60.5 |
60.8 |
Second episode |
29.6 |
32.1 |
28.0 |
≥Third episode |
9.7 |
7.4 |
11.2 |
Glucose-lowering treatment, % |
|
|
|
|
Insulin |
39.4 |
44.4 |
36.2 |
0.237 |
Sulfonylure |
45.7 |
45.7 |
45.7 |
0.999 |
Table 2Comparison of clinical characteristics between patients with prolonged QTc and patients without prolonged QTc during the SH episode
Characteristic |
Men |
Women |
QTc <460 ms |
QTc ≥460 ms |
P value |
QTc <460 ms |
QTc ≥460 ms |
P value |
Number |
44 (54.3) |
37 (38.3) |
|
57 (44.9) |
70 (55.1) |
|
QTc interval during SH, ms |
425±18 |
475±20 |
<0.001 |
438±17 |
486±25 |
<0.001 |
Age, yr |
65.1±12.0 |
69.0±12.0 |
0.149 |
68.0±12.2 |
69.3±12.2 |
0.553 |
Diabetes duration, yr |
12.4±9.5 |
14.9±10.6 |
0.296 |
13.0±8.8 |
15.3±11.1 |
0.196 |
BMI, kg/m2
|
22.3±3.1 |
22.4±3.9 |
0.854 |
24.7±4.4 |
24.4±3.8 |
0.762 |
Alcohol, % |
35.1 |
36.4 |
0.909 |
3.5 |
8.6 |
0.245 |
Smoking, % |
43.2 |
27.3 |
0.132 |
3.5 |
4.3 |
0.823 |
Hypertension, % |
45.7 |
50.0 |
0.708 |
66.1 |
68.1 |
0.809 |
CKD, % |
43.2 |
40.9 |
0.832 |
28.1 |
34.3 |
0.453 |
Diabetic retinopathy, % |
52.2 |
65.2 |
0.369 |
53.8 |
71.9 |
0.155 |
SBP, mm Hg |
135±24 |
140±34 |
0.494 |
138±28 |
135±25 |
0.549 |
DBP, mm Hg |
81±14 |
82±16 |
0.705 |
82±15 |
80±11 |
0.334 |
Pulse rate, beats/min |
81±12 |
87±13 |
0.026 |
84±12 |
80±14 |
0.058 |
Plasma glucose, mg/dL |
33.2±14.3 |
34.3±15.8 |
0.738 |
36.3±14.4 |
38.1±14.1 |
0.465 |
eGFR, mL/min/1.73 m2
|
73.4±37.5 |
87.8±35.5 |
0.080 |
82.8±36.6 |
72.8±39.1 |
0.146 |
HbA1c, % |
7.6±1.9 |
7.7±2.0 |
0.882 |
7.2±1.2 |
7.3±1.4 |
0.736 |
Microalbuminuria, mg/day |
43.8±49.0 |
241.9±287.4 |
0.010 |
220.8±545.8 |
74.0±164.3 |
0.235 |
Potassium, mEq/L |
3.9±0.8 |
3.8±0.6 |
0.365 |
3.9±0.6 |
3.9±0.7 |
0.713 |
Calcium, mg/dL |
8.7±0.8 |
8.2±0.4 |
0.077 |
9.0±0.9 |
8.6±0.7 |
0.142 |
Magnesium, mg/dL |
2.4±0.8 |
2.2±0.3 |
0.563 |
2.5±0.5 |
2.2±0.5 |
0.117 |
TC, mg/dL |
149.7±36.3 |
163.3±39.9 |
0.228 |
165.7±50.8 |
180.6±46.5 |
0.215 |
TG, mg/dL |
115.4±73.9 |
111.2±72.3 |
0.849 |
112.7±46.5 |
122.9±73.3 |
0.577 |
HDL-C, mg/dL |
38.3±12.8 |
43.1±14.4 |
0.267 |
54.3±32.4 |
44.6±14.8 |
0.112 |
LDL-C, mg/dL |
73.1±27.2 |
95.6±27.4 |
0.020 |
101.9±63.4 |
85.6±40.1 |
0.267 |
Recurrent SH, % |
|
|
0.476 |
|
|
0.608 |
First episode |
51.4 |
68.2 |
56.4 |
64.3 |
Second episode |
40.5 |
25.0 |
32.7 |
24.3 |
≥Third episode |
8.1 |
6.8 |
10.9 |
11.4 |
Glucose-lowering treatment, % |
|
|
|
|
|
|
Insulin |
43.2 |
45.5 |
0.842 |
36.5 |
40.9 |
0.629 |
Sulfonylurea |
54.1 |
38.6 |
0.165 |
50.0 |
53.0 |
0.744 |
Table 3Prolongation of QTc interval during SH compared with baseline QTc interval and recovery after SH
Variable |
Baseline |
During SH event |
After SH |
P value |
QTc interval, ms |
|
|
|
|
Total |
433±33 |
460±33 |
442±29 |
<0.001 |
Men |
419±29 |
450±31 |
434±28 |
<0.001 |
Women |
443±33 |
467±32 |
447±28 |
<0.001 |
QTc interval prolongation, % |
|
|
|
|
Total |
24.8 |
54.8 |
33.8 |
<0.001 |
Men |
21.3 |
54.3 |
18.2 |
<0.001 |
Women |
27.0 |
55.1 |
28.3 |
<0.001 |
Group without prolonged QTc interval, ms |
|
|
|
|
Total |
424±26 |
432±18 |
432±22 |
0.019 |
Men |
413±24 |
425±18 |
428±21 |
0.003 |
Women |
434±24 |
438±17 |
435±23 |
0.509 |
Group with prolonged QTc interval, ms |
|
|
|
|
Total |
441±37 |
482±24 |
450±31 |
<0.001 |
Men |
425±33 |
475±20 |
441±34 |
<0.001 |
Women |
450±37 |
486±25 |
456±29 |
<0.001 |
Table 4Univariable and multivariable logistic regression analysis for QTc prolongation during SH episode
Variable |
Unadjusted |
Adjusted |
|
Odds ratio (95% CI) |
P value |
Odds ratio (95% CI) |
P value |
Age, yr |
1.02 (0.99–1.04) |
0.171 |
1.02 (0.99–1.06) |
0.215 |
Diabetes duration, yr |
1.39 (0.98–1.97) |
0.067 |
1.45 (0.92–2.30) |
0.110 |
Female sex |
1.03 (0.59–1.81) |
0.910 |
1.15 (0.51–2.62) |
0.736 |
BMI, kg/m2
|
1.01 (0.93–1.09) |
0.885 |
1.01 (0.92–1.12) |
0.772 |
Smoking, % |
0.64 (0.30–1.35) |
0.242 |
0.64 (0.22–1.88) |
0.415 |
Hypertension |
0.99 (0.56–1.75) |
0.968 |
0.58 (0.26–1.30) |
0.185 |
CKD |
1.13 (0.64–2.002) |
0.675 |
1.23 (0.59–2.56) |
0.587 |
Previous SH |
0.82 (0.54–1.24) |
0.351 |
0.59 (0.29–1.21) |
0.152 |
Insulin |
1.24 (0.71–2.17) |
0.457 |
0.55 (0.20–1.54) |
0.258 |
Sulfonylurea |
0.75 (0.43–1.30) |
0.301 |
0.51 (0.20–1.32) |
0.165 |
Baseline QTc prolongation |
2.22 (1.13–4.33) |
0.020 |
2.92 (1.22–6.96) |
0.016 |