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1Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
2Research Institute of National Health Insurance Service Ilsan Hospital, Goyang, Korea
3Division of Endocrinology and Metabolism, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
Copyright © 2022 Korean Endocrine Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTIONS
Conception or design: M.J.K., S.O.S. Acquisition, analysis, or interpretation of data: H.M.K., M.J.K., S.O.S. Drafting the work or revising: H.M.K. Final approval of the manuscript: H.M.K., S.O.S.
Characteristic | Metformin non-users (n=64,756) | Metformin users (n=66,013) |
---|---|---|
Age, yra | 63.9±16.4 | 64.2±13.7 |
0–14 | 269 (0.4) | 212 (0.3) |
15–20 | 163 (0.3) | 226 (0.3) |
20–24 | 333 (0.5) | 295 (0.4) |
25–29 | 1,145 (1.8) | 422 (0.6) |
30–34 | 1,711 (2.6) | 571 (0.9) |
35–39 | 1,593 (2.5) | 1,205 (1.8) |
40–44 | 2,274 (3.5) | 2,050 (3.1) |
45–49 | 3,543 (5.5) | 3,633 (5.5) |
50–54 | 4,890 (7.6) | 5,203 (7.9) |
55–59 | 5,792 (8.9) | 5,534 (8.4) |
60–64 | 7,540 (11.6) | 9,967 (15.1) |
65–69 | 9,960 (15.4) | 11,399 (17.3) |
70–74 | 8,784 (13.6) | 11,979 (18.1) |
75–79 | 7,962 (12.3) | 8,007 (12.1) |
≥80 | 8,797 (13.6) | 5,310 (8.0) |
Year of study enrollmenta | ||
2005 | 15,370 (23.7) | 16,125 (24.4) |
2006 | 14,158 (21.9) | 11,613 (17.6) |
2007 | 12,823 (19.8) | 12,209 (18.5) |
2008 | 11,863 (18.3) | 12,704 (19.2) |
2009 | 10,542 (16.3) | 13,362 (20.2) |
Economic status | ||
1–5 (lowest) | 21,860 (33.8) | 22,175 (33.6) |
6–10 | 11,162 (17.2) | 11,452 (17.3) |
11–15 | 14,349 (22.2) | 14,346 (21.7) |
16–20 (highest) | 17,385 (26.8) | 18,040 (27.3) |
Region of residenceb | ||
Seoul (capital city) | 13,558 (20.9) | 13,510 (20.5) |
Metropolitan cities | 15,690 (24.2) | 16,344 (24.8) |
Rural areas | 35,508 (54.8) | 36,159 (54.8) |
Anti-diabetic drugs | ||
Metformin | ||
Yes | 0 | 66,013 (100.0) |
No | 64,756 (100.0) | 0 |
Sulfonylureasb | ||
Yes | 30,135 (46.5) | 30,155 (45.7) |
No | 34,621 (53.5) | 35,858 (54.3) |
TZD | ||
Yes | 2,190 (3.4) | 2,204 (3.3) |
No | 62,566 (96.6) | 63,809 (96.7) |
DPP4i | ||
Yes | 1,140 (1.8) | 1,138 (1.7) |
No | 63,616 (98.2) | 64,875 (98.3) |
AGIa | ||
Yes | 5,812 (9.0) | 5,534 (8.4) |
No | 58,944 (91.0) | 60,479 (91.6) |
Meglitinide | ||
Yes | 1,968 (3.0) | 1,939 (2.9) |
No | 62,788 (97.0) | 64,074 (97.1) |
Daily metformin dose, mean (range), mg | 519 (148) | |
Cumulative metformin dose, mean (range), mg | 865,999 (547,170) | |
None | 64,756 (100.0) | 0 |
0–239,999 | 0 | 9,611 (14.6) |
240,000–1,200,000 | 0 | 39,900 (60.4) |
>1,200,000 | 0 | 16,502 (25.0) |
Cumulative duration of therapy, mean (range), day | 1,666 (912) | |
None | 64,756 (100.0) | 0 |
0–469 | 0 | 9,161 (13.9) |
470–1,999 | 0 | 30,429 (46.1) |
≥2,000 | 0 | 26,423 (40.0) |
Cervical cancer cases | 274 | 219 |
Cancer cases (%) |
Incidence of cancer, /100,000 person-years |
Hazard ratio (95% CI) |
|||
---|---|---|---|---|---|
Metformin non-user | Metformin user | Metformin non-user | Metformin user | Univariate | Multivariatea |
274 (0.42) | 219 (0.33) | 30.5 | 24.2 | 0.805 (0.674–0.961)b | 0.783 (0.655–0.936)b |
CI, confidence interval.
a The comparisons were made using metformin non-users as the reference group. The hazard ratio was adjusted for age, economic status, region of residence, and anti-diabetic medications (sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, alpha-glucosidase inhibitors, and meglitinide);
b P<0.05.
Variable | Hazard ratio (95% CI)a | Hazard ratio (95% CI)b |
---|---|---|
Cumulative duration, day | ||
Non-users | 1.000 | - |
0–469 | 1.603 (1.205–2.131)d | 1.000 |
470–1,999 | 1.140 (0.931–1.396)c | 0.723 (0.530–0.095)d |
≥2,000 | 0.151 (0.093–0.243)c | 0.094 (0.055–0.161)c |
Cumulative dose, mg | ||
Non-users | 1.000 | - |
0–239,999 | 1.798 (1.376–2.349)c | 1.000 |
240,000–1,200,000 | 0.849 (0.692–1.042)c | 0.549 (0.356–0.642)c |
>1,200,000 | 0.141 (0.077–0.258)c | 0.079 (0.042–0.151)c |
Age, yr | ||
Non-users | 1.000 | - |
<50 | 0.763 (0.481–1.252)d | - |
≥50 | 0.791 (0.650–0.961)d | - |
CI, confidence interval.
a The comparisons were made using metformin non-users as the reference group. The hazard ratios were adjusted for age, economic status, region of residence, and anti-diabetic medications (sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, alpha-glucosidase inhibitors, and meglitinide);
b The comparisons were made using a cumulative duration of 0–469 days or a cumulative dose of 0–239,999 mg as the reference groups. The hazard ratios were adjusted for age, economic status, region of residence, and anti-diabetic medications (sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, alpha-glucosidase inhibitors, and meglitinide);
c P<0.001;
d P<0.05.
Characteristic | Metformin non-users (n=64,756) | Metformin users (n=66,013) |
---|---|---|
Age, yr |
63.9±16.4 | 64.2±13.7 |
0–14 | 269 (0.4) | 212 (0.3) |
15–20 | 163 (0.3) | 226 (0.3) |
20–24 | 333 (0.5) | 295 (0.4) |
25–29 | 1,145 (1.8) | 422 (0.6) |
30–34 | 1,711 (2.6) | 571 (0.9) |
35–39 | 1,593 (2.5) | 1,205 (1.8) |
40–44 | 2,274 (3.5) | 2,050 (3.1) |
45–49 | 3,543 (5.5) | 3,633 (5.5) |
50–54 | 4,890 (7.6) | 5,203 (7.9) |
55–59 | 5,792 (8.9) | 5,534 (8.4) |
60–64 | 7,540 (11.6) | 9,967 (15.1) |
65–69 | 9,960 (15.4) | 11,399 (17.3) |
70–74 | 8,784 (13.6) | 11,979 (18.1) |
75–79 | 7,962 (12.3) | 8,007 (12.1) |
≥80 | 8,797 (13.6) | 5,310 (8.0) |
Year of study enrollment |
||
2005 | 15,370 (23.7) | 16,125 (24.4) |
2006 | 14,158 (21.9) | 11,613 (17.6) |
2007 | 12,823 (19.8) | 12,209 (18.5) |
2008 | 11,863 (18.3) | 12,704 (19.2) |
2009 | 10,542 (16.3) | 13,362 (20.2) |
Economic status | ||
1–5 (lowest) | 21,860 (33.8) | 22,175 (33.6) |
6–10 | 11,162 (17.2) | 11,452 (17.3) |
11–15 | 14,349 (22.2) | 14,346 (21.7) |
16–20 (highest) | 17,385 (26.8) | 18,040 (27.3) |
Region of residence |
||
Seoul (capital city) | 13,558 (20.9) | 13,510 (20.5) |
Metropolitan cities | 15,690 (24.2) | 16,344 (24.8) |
Rural areas | 35,508 (54.8) | 36,159 (54.8) |
Anti-diabetic drugs | ||
Metformin | ||
Yes | 0 | 66,013 (100.0) |
No | 64,756 (100.0) | 0 |
Sulfonylureas |
||
Yes | 30,135 (46.5) | 30,155 (45.7) |
No | 34,621 (53.5) | 35,858 (54.3) |
TZD | ||
Yes | 2,190 (3.4) | 2,204 (3.3) |
No | 62,566 (96.6) | 63,809 (96.7) |
DPP4i | ||
Yes | 1,140 (1.8) | 1,138 (1.7) |
No | 63,616 (98.2) | 64,875 (98.3) |
AGI |
||
Yes | 5,812 (9.0) | 5,534 (8.4) |
No | 58,944 (91.0) | 60,479 (91.6) |
Meglitinide | ||
Yes | 1,968 (3.0) | 1,939 (2.9) |
No | 62,788 (97.0) | 64,074 (97.1) |
Daily metformin dose, mean (range), mg | 519 (148) | |
Cumulative metformin dose, mean (range), mg | 865,999 (547,170) | |
None | 64,756 (100.0) | 0 |
0–239,999 | 0 | 9,611 (14.6) |
240,000–1,200,000 | 0 | 39,900 (60.4) |
>1,200,000 | 0 | 16,502 (25.0) |
Cumulative duration of therapy, mean (range), day | 1,666 (912) | |
None | 64,756 (100.0) | 0 |
0–469 | 0 | 9,161 (13.9) |
470–1,999 | 0 | 30,429 (46.1) |
≥2,000 | 0 | 26,423 (40.0) |
Cervical cancer cases | 274 | 219 |
Cancer cases (%) |
Incidence of cancer, /100,000 person-years |
Hazard ratio (95% CI) |
|||
---|---|---|---|---|---|
Metformin non-user | Metformin user | Metformin non-user | Metformin user | Univariate | Multivariate |
274 (0.42) | 219 (0.33) | 30.5 | 24.2 | 0.805 (0.674–0.961) |
0.783 (0.655–0.936) |
Variable | Hazard ratio (95% CI) |
Hazard ratio (95% CI) |
---|---|---|
Cumulative duration, day | ||
Non-users | 1.000 | - |
0–469 | 1.603 (1.205–2.131) |
1.000 |
470–1,999 | 1.140 (0.931–1.396) |
0.723 (0.530–0.095) |
≥2,000 | 0.151 (0.093–0.243) |
0.094 (0.055–0.161) |
Cumulative dose, mg | ||
Non-users | 1.000 | - |
0–239,999 | 1.798 (1.376–2.349) |
1.000 |
240,000–1,200,000 | 0.849 (0.692–1.042) |
0.549 (0.356–0.642) |
>1,200,000 | 0.141 (0.077–0.258) |
0.079 (0.042–0.151) |
Age, yr | ||
Non-users | 1.000 | - |
<50 | 0.763 (0.481–1.252) |
- |
≥50 | 0.791 (0.650–0.961) |
- |
Values are expressed as mean±standard deviation or number (%) unless otherwise indicated. TZD, thiazolidinedione; DPP4i, dipeptidyl peptidase-4 inhibitor; AGI, alpha-glucosidase inhibitor.
CI, confidence interval. The comparisons were made using metformin non-users as the reference group. The hazard ratio was adjusted for age, economic status, region of residence, and anti-diabetic medications (sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, alpha-glucosidase inhibitors, and meglitinide);
CI, confidence interval. The comparisons were made using metformin non-users as the reference group. The hazard ratios were adjusted for age, economic status, region of residence, and anti-diabetic medications (sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, alpha-glucosidase inhibitors, and meglitinide); The comparisons were made using a cumulative duration of 0–469 days or a cumulative dose of 0–239,999 mg as the reference groups. The hazard ratios were adjusted for age, economic status, region of residence, and anti-diabetic medications (sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, alpha-glucosidase inhibitors, and meglitinide);