Abstract
Background
Methods
Results
SUPPLEMENTARY MATERIALS
Notes
CONFLICTS OF INTEREST
Yong-Moon Park was statistical advisors of the Diabetes & Metabolism Journal from 2020 to 2021. Seung-Hyun Ko was editorial board member of the Diabetes & Metabolism Journal from 2020 to 2021. They were not involved in the review process of this article. Otherwise, there was no conflict of interest.
REFERENCES
Table 1
Characteristic | Total participants | Severe hypoglycemia event | P value | |
---|---|---|---|---|
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No | Yes | |||
Number | 181,263 | 169,984 | 11,279 | |
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Age, yr | 64.61±7.87 | 64.33±7.83 | 68.89±7.24 | <0.0001 |
|
||||
Duration of follow-up, yr | 7.87±1.72 | 8.11±1.36 | 4.31±2.44 | <0.0001 |
|
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Income, quartile | <0.0001 | |||
Medical aid+Q1 | 38,971 (21.50) | 36,649 (21.56) | 2,322 (20.59) | |
Q2 | 32,807 (18.10) | 30,803 (18.12) | 2,004 (17.77) | |
Q3 | 46,000 (25.38) | 43,250 (25.44) | 2,750 (24.38) | |
Q4 | 63,485 (35.02) | 59,282 (34.88) | 4,203 (37.26) | |
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Smoking status | 0.0100 | |||
Never | 173,787 (95.88) | 163,035 (95.91) | 10,752 (95.33) | |
Ex-smoker | 2,079 (1.15) | 1,930 (1.14) | 149 (1.32) | |
Current smoker | 5,397 (2.98) | 5,019 (2.95) | 378 (3.35) | |
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Alcohol consumption | <0.0001 | |||
None | 165,468 (91.29) | 154,890 (91.12) | 10,578 (93.78) | |
Mild | 15,005 (8.28) | 14,346 (8.44) | 659 (5.84) | |
Heavy | 790 (0.44) | 748 (0.44) | 42 (0.37) | |
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Regular exercise (yes) | 33,282 (18.36) | 31,752 (18.68) | 1,530 (13.57) | <0.0001 |
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Body mass index, mean, kg/m2 | 25.21±3.4 | 25.23±3.39 | 24.99±3.52 | <0.0001 |
<18.5 | 2,177 (1.20) | 1,953 (1.15) | 224 (1.99) | <0.0001 |
18.5–<23 | 43,796 (24.16) | 40,803 (24.00) | 2,993 (26.54) | <0.0001 |
23–<25 | 44,587 (24.6) | 41,880 (24.64) | 2,707 (24.00) | <0.0001 |
25–<30 | 75,280 (41.53) | 70,846 (41.68) | 4,434 (39.31) | <0.0001 |
≥30 | 15,423 (8.51) | 14,502 (8.53) | 921 (8.17) | <0.0001 |
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Blood pressure, mm Hg | ||||
Systolic | 129.97±16.37 | 129.88±16.32 | 131.41±16.99 | <0.0001 |
Diastolic | 78.09±10.18 | 78.09±10.17 | 78.11±10.39 | 0.8358 |
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Estimated glomerular filtration rate, mL/min/1.73 m2 | 79.23±28.58 | 79.73±28.68 | 71.80±25.82 | <0.0001 |
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Fasting glucose, mg/dL | 138.2±44.08 | 137.96±43.13 | 141.86±56.47 | <0.0001 |
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Total cholesterol, mg/dL | 202.6±49.56 | 202.74±49.14 | 200.50±55.46 | <0.0001 |
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High density lipoprotein, mg/dL | 54.86±39.2 | 54.90±39.34 | 54.25±37.05 | 0.0911 |
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Low density lipoprotein, mg/dL | 118.95±82.35 | 119.18±80.25 | 115.45±109.06 | <0.0001 |
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Comorbidities | ||||
Hypertension | 127,977 (70.6) | 118,823 (69.90) | 9,154 (81.16) | <0.0001 |
Dyslipidemia | 96,283 (53.12) | 90,290 (53.12) | 5,993 (53.13) | 0.9714 |
Chronic kidney disease | 33,701(18.59) | 30,057 (17.68) | 3,644 (32.31) | <0.0001 |
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Past history of disease, by questionnaire | ||||
Strokea | <0.0001 | |||
No | 156,541 (97.34) | 146,352 (97.45) | 10,189 (95.80) | |
Yes | 4,271 (2.66) | 3,824 (2.55) | 447 (4.20) | |
Heart diseasea | <0.0001 | |||
No | 148,550 (92.34) | 139,047 (92.55) | 9,503 (89.33) | |
Yes | 12,330 (7.66) | 11,195 (7.45) | 1,135 (10.67) | |
Cardiovascular diseasea | <0.0001 | |||
No | 144,930 (90.06) | 135,804 (90.37) | 9,126 (85.76) | |
Yes | 15,994 (9.94) | 14,479 (9.63) | 1,515 (14.24) | |
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Insulin treatment | 22,409 (12.36) | 19,488 (11.46) | 2,921(25.90) | <0.0001 |
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Insulin secretagogues | ||||
Sulfonylurea | 113,176 (62.44) | 104,011 (61.19) | 9,165 (81.26) | <0.0001 |
Glinide | 6,854 (3.78) | 6,173 (3.63) | 681 (6.04) | <0.0001 |
Oral hypoglycemic agents ≥3 | 46,085(25.42) | 41,335 (24.32) | 4,750 (42.11) | <0.0001 |
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Age at menarche, yr | 16.60±1.81 | 16.58±1.82 | 16.82±1.77 | <0.0001 |
≤12 | 1,362 (0.75) | 1,309 (0.77) | 53 (0.47) | <0.0001 |
13–14 | 19,330 (10.66) | 18,429 (10.84) | 901 (7.99) | <0.0001 |
15–16 | 67,067 (37.00) | 63,182 (37.17) | 3,885 (34.44) | <0.0001 |
≥17 | 93,504 (51.58) | 87,064 (51.22) | 6,440 (57.10) | <0.0001 |
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Age at menopause, yr | 50.05±4.34 | 50.09±4.32 | 49.45±4.61 | <0.0001 |
<40 | 3,917 (2.16) | 3,562 (2.10) | 355 (3.15) | <0.0001 |
40–44 | 11,708 (6.46) | 10,766 (6.33) | 942 (8.35) | <0.0001 |
45–49 | 46,523 (25.67) | 43,449 (25.56) | 3,074 (27.25) | <0.0001 |
50–54 | 95,293 (52.57) | 89,720 (52.78) | 5,573 (49.41) | <0.0001 |
≥55 | 23,822 (13.14) | 22,487 (13.23) | 1,335 (11.84) | <0.0001 |
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Reproductive life span, yr | 33.45±4.74 | 33.51±4.71 | 32.63±4.98 | <0.0001 |
<30 | 28,130 (15.52) | 25,838 (15.20) | 2,292 (20.32) | <0.0001 |
30–34 | 74,110 (40.89) | 69,114 (40.66) | 4,996 (44.29) | <0.0001 |
35–39 | 64,903 (35.81) | 61,623 (36.25) | 3,280 (29.08) | <0.0001 |
≥40 | 14,120 (7.79) | 13,409 (7.89) | 711 (6.30) | <0.0001 |
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Parity | <0.0001 | |||
Nulliparity | 3,518 (1.94) | 3,355 (1.97) | 163 (1.45) | |
1 | 7,915 (4.37) | 7,555 (4.44) | 360 (3.19) | |
≥2 | 169,830 (93.69) | 159,074 (93.58) | 10,756 (95.36) | |
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Duration of breastfeeding, mo | <0.0001 | |||
Never | 9,079 (5.01) | 8,673 (5.10) | 406 (3.60) | |
<6 | 7,408 (4.09) | 7,123 (4.19) | 285 (2.53) | |
6–11 | 24,786 (13.67) | 23,514 (13.83) | 1,272 (11.28) | |
≥12 | 139,990 (77.23) | 130,674 (76.87) | 9,316 (82.6) | |
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Duration of HRT, yr | <0.0001 | |||
Never | 159,628 (88.06) | 149,138 (87.74) | 10,490 (93.00) | |
<2 | 12,764 (7.04) | 12,310 (7.24) | 454 (4.03) | |
2–4 | 4,819 (2.66) | 4,645 (2.73) | 174 (1.54) | |
≥5 | 4,052 (2.24) | 3,891 (2.29) | 161 (1.43) | |
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Duration of OC use, yr | <0.0001 | |||
Never | 150,657 (83.12) | 141,046 (82.98) | 9,611 (85.21) | |
<1 | 17,012 (9.39) | 16,137 (9.49) | 875 (7.76) | |
≥1 | 13,594 (7.50) | 12,801 (7.53) | 793 (7.03) |
Table 2
Variable | No. of subjects | No. of SH events | Follow-up duration, person-year | Incidence rate, /1,000 person-year | HR (95% confidence intervals) | ||
---|---|---|---|---|---|---|---|
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Model 1 | Model 2 | Model 3 | |||||
Age at menarche, yr | |||||||
≤12 | 1,362 | 53 | 10,986.6 | 4.8 | 0.83 (0.63–1.09) | 0.94 (0.71–1.24) | |
13–14 | 19,330 | 901 | 154,159.2 | 5.8 | 1 (Ref) | 1 (Ref) | |
15–16 | 67,067 | 3,885 | 529,316.0 | 7.3 | 1.26a (1.17–1.35) | 1.09b (1.02–1.17) | |
≥17 | 93,504 | 6,440 | 732,587.2 | 8.8 | 1.50a (1.40–1.61) | 1.15a (1.07–1.23) | |
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Age at menopause, yr | |||||||
<40 | 3,917 | 355 | 29,908.9 | 11.9 | 1 (Ref) | 1 (Ref) | |
40–44 | 11,708 | 942 | 90,413.7 | 10.4 | 0.88b (0.78–0.99) | 0.89b (0.79–1.00) | |
45–49 | 46,523 | 3,074 | 365,296.6 | 8.4 | 0.71a (0.64–0.79) | 0.84b (0.75–0.94) | |
50–54 | 95,293 | 5,573 | 752,279.6 | 7.4 | 0.62a (0.56–0.70) | 0.78a (0.70–0.87) | |
≥55 | 23,822 | 1,335 | 189,150.2 | 7.1 | 0.60a (0.53–0.67) | 0.73a (0.65–0.83) | |
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Reproductive life span, yr | |||||||
<30 | 28,130 | 2,292 | 217,040.3 | 10.6 | 1 (Ref) | 1 (Ref) | |
30–34 | 74,110 | 4,996 | 580,426.7 | 8.6 | 0.82a (0.78–0.86) | 0.91a (0.86–0.95) | |
35–39 | 64,903 | 3,280 | 517,309.5 | 6.3 | 0.6a (0.57–0.63) | 0.80a (0.76–0.84) | |
≥40 | 14,120 | 711 | 112,272.5 | 6.3 | 0.6a (0.55–0.65) | 0.74a (0.68–0.81) | |
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Parity | |||||||
Nulliparity | 3,518 | 163 | 27,940.8 | 5.8 | 1 (Ref) | 1 (Ref) | 1 (Ref) |
1 | 7,915 | 360 | 63,267.0 | 5.7 | 0.98 (0.81–1.17) | 1.05 (0.87–1.27) | 1.05 (0.87–1.27) |
≥2 | 169,830 | 10,756 | 1,335,841.2 | 8.1 | 1.38 (1.18–1.61) | 1.06 (0.90–1.26) | 1.06 (0.90–1.26) |
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Duration of breastfeeding, mo | |||||||
Never | 9,079 | 406 | 72,648.3 | 5.6 | 1 (Ref) | 1 (Ref) | 1 (Ref) |
<6 | 7,408 | 285 | 59,689.5 | 4.8 | 0.85 (0.73–0.99) | 0.86 (0.73–1.00) | 0.86 (0.73–1.00) |
6–11 | 24,786 | 1,272 | 197,014.4 | 6.5 | 1.16 (1.03–1.29) | 0.97 (0.86–1.09) | 0.97 (0.86–1.10) |
≥12 | 139,990 | 9,316 | 1,097,696.8 | 8.5 | 1.52 (1.37–1.68) | 1.00 (0.90–1.12) | 1.00 (0.90–1.12) |
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Duration of HRT, yr | |||||||
Never | 159,628 | 10,490 | 1,250,819.9 | 8.4 | 1 (Ref) | 1 (Ref) | 1 (Ref) |
<2 | 12,764 | 454 | 104,141.8 | 4.4 | 0.52a (0.47–0.57) | 0.76a (0.69–0.83) | 0.76a (0.69–0.83) |
2–4 | 4,819 | 174 | 39,103.8 | 4.5 | 0.53a (0.46–0.62) | 0.79b (0.68–0.92) | 0.79b (0.68–0.92) |
≥5 | 4,052 | 161 | 32,983.5 | 4.9 | 0.58a (0.50–0.68) | 0.78b (0.67–0.91) | 0.78b (0.67–0.92) |
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Duration of OC use, yr | |||||||
Never | 150,657 | 9,611 | 1,182,741.3 | 8.1 | 1 (Ref) | 1 (Ref) | 1 (Ref) |
<1 | 17,012 | 875 | 136,097.6 | 6.4 | 0.79 (0.74–0.85) | 0.94 (0.88–1.01) | 0.94 (0.88–1.01) |
≥1 | 13,594 | 793 | 108,210.1 | 7.3 | 0.90 (0.84–0.97) | 1.02 (0.94–1.09) | 1.02 (0.95–1.10) |
Model 1: non-adjusted; Model 2: adjusted for age at menarche, age at menopause, number of parities, duration of breastfeeding, duration of HRT, duration of oral contraceptive use, alcohol consumption, smoking, regular exercise, income, body mass index, hypertension, dyslipidemia, use of three or more oral hypoglycemic agents, insulin treatment, use of insulin secretagogues such as sulfonylureas and glinides; Model 3: adjusted for reproductive life span instead of age at menarche and menopause in Model 2.
Table 3
Subgroup | RLS, yr | No. of subjects | No. of SH event | Follow-up duration, person-year | Incidence rate, /1,000 person-year | HR (95% CI)a | P for interaction |
---|---|---|---|---|---|---|---|
Age, yr | 0.0032 | ||||||
<65 | <30 | 10,490 | 455 | 85,499.5 | 5.3 | 1 (Ref) | |
30–34 | 34,372 | 1,199 | 281,346.4 | 4.3 | 0.83 (0.74–0.92) | ||
35–39 | 38,296 | 1,078 | 313,943.3 | 3.4 | 0.69 (0.62–0.77) | ||
≥40 | 7,490 | 221 | 61,229.0 | 3.6 | 0.64 (0.54–0.75) | ||
≥65 | <30 | 17,640 | 1,837 | 131,540.8 | 14.0 | 1 (Ref) | |
30–34 | 39,738 | 3,797 | 299,080.3 | 12.7 | 0.93 (0.88–0.99) | ||
35–39 | 26,607 | 2,202 | 203,366.2 | 10.8 | 0.85 (0.80–0.90) | ||
≥40 | 6,630 | 490 | 51,043.5 | 9.6 | 0.79 (0.71–0.87) |
a Adjusted for age, fasting glucose level, RLS, number of parities, duration of breastfeeding, duration of hormone replacement therapy, duration of oral contraceptives use, alcohol consumption, smoking, regular exercise, income, body mass index, hypertension, dyslipidemia, chronic kidney disease, use of three or more oral hypoglycemic agents, use of insulin secretagogues such as sulfonylureas and glinides, insulin treatment.