Fig. 1Cumulative overall survival and cumulative cardiovascular event-free survival of patients with severe hypoglycemia (SH) estimated by Cox regression analysis. (A) Overall survival after SH. (B) Cardiovascular event-free survival after SH. CI, confidence interval.
Table 1Baseline characteristics of the groups with and without severe hypoglycemia
Characteristic |
SH (–) |
SH (+) |
P value |
Number |
821 |
85 |
|
Female sex |
481 (58.6) |
56 (65.9) |
0.193 |
Age, yr |
55.3±9.8 |
60.2±10.4 |
<0.001 |
Diabetes duration, yr |
7.9±6.5 |
10.8±8.4 |
0.003 |
Hypertension |
398 (48.5) |
49 (57.6) |
0.107 |
BMI, kg/m2
|
24.8±3.4 |
24.1±3.4 |
0.070 |
Smoking |
203 (24.7) |
16 (18.8) |
0.226 |
CVD history |
52 (6.3) |
30 (35.3) |
<0.001 |
Insulin |
209 (25.5) |
42 (49.4) |
<0.001 |
Sulfonylurea |
515 (62.7) |
42 (49.4) |
0.016 |
Metformin |
314 (38.2) |
28 (32.9) |
0.337 |
ACE inhibitor/ARBs |
256 (31.2) |
31 (36.5) |
0.318 |
Statin |
98 (11.9) |
11 (12.9) |
0.786 |
Acetylsalicylic acid |
63 (7.7) |
7 (8.2) |
0.854 |
Diabetic retinopathya
|
168/810 (22.9) |
29/810 (38.7) |
0.002 |
Diabetic nephropathy |
192 (23.4) |
28 (32.9) |
0.050 |
Laboratory finding at baseline |
|
|
|
FPG, mg/dL |
176.8±66.1 |
182.9±85.1 |
0.432 |
eGFR, mL/min/1.73 m2
|
92.9±17.1 |
82.4±21.9 |
<0.001 |
Baseline HbA1c, % |
8.8±2.1 |
9.2±2.1 |
0.094 |
Total cholesterol, mg/dL |
183.2±37.0 |
190.7±39.5 |
0.992 |
Triglyceride, mg/dL |
159.7±103.4 |
150.4±68.6 |
0.414 |
HDL-C, mg/dL |
43.0±10.3 |
43.5±12.1 |
0.659 |
LDL-C, mg/dL |
108.3±32.6 |
117.1±33.2 |
0.018 |
UAE, mg/day |
10.0 (5.7–30.0) |
15.3 (8.0–65.5) |
0.010 |
Table 2Comparison of baseline parameters between the patients who survived and died
Characteristic |
Total |
Survived |
Died |
P value |
Number |
906 |
820 |
86 |
|
Female sex |
537 (59.3) |
493 (60.1) |
44 (51.2) |
0.108 |
Age, yr |
55.7±10.0 |
55.0±9.8 |
62.7±9.2 |
<0.001 |
Diabetes duration, yr |
8.2±6.7 |
7.8±6.4 |
11.9±8.6 |
<0.001 |
Hypertension |
447 (49.3) |
385 (47.0) |
62 (72.1) |
<0.001 |
Body mass index, kg/m2
|
24.7±3.4 |
24.7±3.3 |
24.6±4.1 |
0.829 |
Smoking |
219 (24.2) |
189 (23.0) |
30 (34.9) |
0.015 |
CVD history |
82 (9.1) |
65 (7.9) |
17 (19.8) |
<0.001 |
Severe hypoglycemia |
85 (9.4) |
68 (8.3) |
17 (19.8) |
0.001 |
Insulin |
251 (27.7) |
207 (25.2) |
44 (51.2) |
<0.001 |
ACE inhibitor/ARBs |
287 (31.7) |
255 (31.1) |
32 (37.2) |
0.246 |
Statin |
109 (12.0) |
102 (12.4) |
7 (8.1) |
0.244 |
Acetylsalicylic acid |
70 (7.7) |
58 (7.1) |
12 (14.0) |
0.023 |
Diabetic retinopathy |
197/810 (21.7) |
164/810 (22.0) |
33/810 (50.8) |
<0.001 |
Diabetic nephropathy |
220 (24.3) |
160 (22.0) |
40 (46.5) |
<0.001 |
Laboratory finding at baseline |
|
|
|
|
FPG, mg/dL |
177.4±68.1 |
176.6±65.1 |
184.5±91.9 |
0.441 |
eGFR, mL/min/1.73 m2
|
91.9±17.8 |
93.5±16.5 |
76.5±22.4 |
<0.001 |
Baseline HbA1c, % |
8.9±2.1 |
8.8±2.1 |
9.3±2.2 |
0.058 |
Total cholesterol, mg/dL |
183.9±37.3 |
184.0±37.1 |
183.2±39.1 |
0.841 |
Triglyceride, mg/dL |
158.8±100.6 |
160.7±103.5 |
141.5±65.0 |
0.016 |
HDL-C, mg/dL |
43.1±10.5 |
43.3±10.3 |
40.6±12.2 |
0.023 |
LDL-C, mg/dL |
109.1±32.8 |
108.6±32.8 |
114.2±32.3 |
0.130 |
UAE, mg/day |
10.0 (5.8–30.0) |
10.0 (5.6–28.1) |
21.6 (9.1–344.8) |
<0.001 |
Table 3Univariable Cox proportional hazards model of severe hypoglycemia for predicting cardiovascular mortality and all-cause mortality
Characteristic |
CV mortality |
All-cause mortality |
Hazard ratio (95% CI) |
P value |
Hazard ratio (95% CI) |
P value |
Female sex |
0.74 (0.31–1.91) |
0.453 |
0.70 (0.46–1.07) |
0.099 |
Age (per 10 years) |
3.75 (2.07–6.80) |
<0.001 |
2.51 (1.93–3.26) |
<0.001 |
Diabetes duration, yr |
|
0.012 |
|
0.012 |
|
1.00 |
|
1.00 |
|
5 to <10 |
0.71 (0.13–3.90) |
0.714 |
1.04 (0.54–2.03) |
0.899 |
≥10 |
4.13 (1.37–12.46) |
0.012 |
2.63 (1.58–4.38) |
<0.001 |
Hypertension (yes vs. no) |
2.83 (1.10–7.30) |
0.032 |
2.88 (1.80–4.62) |
<0.001 |
Body mass index, kg/m2
|
1.11 (0.98–1.25) |
0.099 |
0.99 (0.92–1.05) |
0.656 |
Smoking (yes vs. no) |
0.54 (0.16–1.83) |
0.323 |
1.72 (1.10–2.68) |
0.016 |
CVD history (yes vs. no) |
3.85 (1.28–11.62) |
0.017 |
3.97 (2.32–6.78) |
<0.001 |
Insulin use (yes vs. no) |
3.21 (1.36–7.55) |
0.008 |
3.07 (2.01–4.69) |
<0.001 |
ACEi/ARB (yes vs. no) |
1.70 (0.72–4.03) |
0.23 |
1.32 (0.86–2.05) |
0.208 |
Statin (yes vs. no) |
0.76 (0.18–3.27) |
0.713 |
0.65 (0.30–1.40) |
0.267 |
Acetylsalicylic acid (yes vs. no) |
3.17 (1.07–9.45) |
0.038 |
2.17 (1.18–3.99) |
0.013 |
FPG (per 10 mg/dL) |
1.03 (0.97–1.09) |
0.367 |
1.02 (0.99–1.05) |
0.277 |
LDL-C (per mg/dL) |
1.01 (0.99–1.02) |
0.475 |
1.01 (0.99–1.01) |
0.114 |
eGFR, mL/min/1.73 m2
|
0.94 (0.92–0.96) |
<0.001 |
0.95 (0.94–0.96) |
<0.001 |
Mean HbA1c (per 1% increment) |
1.20 (0.88–1.65) |
0.245 |
1.18 (1.01–1.38) |
0.044 |
Diabetic nephropathy (yes vs. no) |
3.32 (1.41–7.83) |
0.006 |
3.13 (2.05–4.78) |
<0.001 |
SH (yes vs. no) |
16.4 (5.94–45.07) |
<0.001 |
7.52 (4.29–13.20) |
<0.001 |
Table 4Multivariable Cox proportional hazards model of severe hypoglycemia for cardiovascular mortality and all-cause mortality
Variable |
Hazard ratio (95% CI) |
Model 1 |
Model 2 |
Model 3 |
Model 4 |
CV mortality |
|
|
|
|
SH history |
9.16 (3.24–25.94) |
8.86 (2.93–26.80) |
6.56 (2.14–20.08) |
6.34 (2.02–19.87) |
P for trend |
<0.001 |
<0.001 |
0.001 |
0.002 |
All-cause mortality |
|
|
|
|
SH history |
4.92 (2.76–8.77) |
4.18 (2.25–7.77) |
3.09 (1.67–5.76) |
2.64 (1.39–5.02) |
P for trend |
<0.001 |
<0.001 |
<0.001 |
0.003 |