Sensitivity Analyses for the Associations Between Metformin Use and Incident Alzheimer’s Disease With Lookback Period to Assess Metformin Exposure Commencing 10 Years Prior to Index Date for All Cases and Controls
| . | . | . | Unadjusted Analyses . | Adjusted Analysesa . | ||
|---|---|---|---|---|---|---|
| Metformin Exposure . | Individuals With AD (N=9862), n (%) . | Individuals Without AD (N=19 550), n (%) . | OR (95% CI) . | P Value . | OR (95% CI) . | P Value . |
| Any use | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.003 | 1.12 (1.03-1.22) | 0.011 |
| Yes | 7057 (71.6%) | 14233 (72.8%) | 0.98 (0.93-1.04) | 0.514 | 0.98 (0.93-1.04) | 0.489 |
| Cumulative duration of use | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.011 |
| >0 to <1 year | 1421 (14.4%) | 2756 (14.1%) | 1.04 (0.97-1.12) | 0.301 | 1.03 (0.96-1.11) | 0.404 |
| 1 to <5 years | 3026 (30.7%) | 6172 (31.6%) | 0.98 (0.92-1.03) | 0.393 | 0.97 (0.91-1.03) | 0.252 |
| 5 to <10 years | 2610 (26.5%) | 5305 (27.1%) | 0.96 (0.90-1.03) | 0.226 | 0.96 (0.90-1.02) | 0.212 |
| Cumulative dose received c | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.009 |
| >0-365 DDDs | 2118 (21.5%) | 4050 (20.7%) | 1.06 (1.00-1.13) | 0.072 | 1.06 (0.99-1.14) | 0.075 |
| >365-1825 DDDs | 3342 (33.9%) | 6737 (34.5%) | 0.98 (0.93-1.04) | 0.468 | 0.97 (0.91-1.03) | 0.322 |
| >1825 DDDs | 1597 (16.2%) | 3446 (17.6%) | 0.89 (0.83-0.95) | 0.001 | 0.88 (0.82-0.95) | <0.001 |
| Cumulative DDDs/cumulative duration of use c | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.011 |
| >0-0.5 DDDs/day | 1639 (16.6%) | 3010 (15.4%) | 1.08 (1.02-1.16) | 0.017 | 1.08 (1.01-1.16) | 0.022 |
| >0.5-1.0 DDDs/day | 4103 (41.6%) | 8257 (42.2%) | 0.98 (0.93-1.04) | 0.503 | 0.98 (0.92-1.04) | 0.420 |
| >1.0 DDDs/day | 1315 (13.3%) | 2966 (15.2%) | 0.87 (0.81-0.93) | <0.001 | 0.86 (0.80-0.93) | <0.001 |
| . | . | . | Unadjusted Analyses . | Adjusted Analysesa . | ||
|---|---|---|---|---|---|---|
| Metformin Exposure . | Individuals With AD (N=9862), n (%) . | Individuals Without AD (N=19 550), n (%) . | OR (95% CI) . | P Value . | OR (95% CI) . | P Value . |
| Any use | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.003 | 1.12 (1.03-1.22) | 0.011 |
| Yes | 7057 (71.6%) | 14233 (72.8%) | 0.98 (0.93-1.04) | 0.514 | 0.98 (0.93-1.04) | 0.489 |
| Cumulative duration of use | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.011 |
| >0 to <1 year | 1421 (14.4%) | 2756 (14.1%) | 1.04 (0.97-1.12) | 0.301 | 1.03 (0.96-1.11) | 0.404 |
| 1 to <5 years | 3026 (30.7%) | 6172 (31.6%) | 0.98 (0.92-1.03) | 0.393 | 0.97 (0.91-1.03) | 0.252 |
| 5 to <10 years | 2610 (26.5%) | 5305 (27.1%) | 0.96 (0.90-1.03) | 0.226 | 0.96 (0.90-1.02) | 0.212 |
| Cumulative dose received c | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.009 |
| >0-365 DDDs | 2118 (21.5%) | 4050 (20.7%) | 1.06 (1.00-1.13) | 0.072 | 1.06 (0.99-1.14) | 0.075 |
| >365-1825 DDDs | 3342 (33.9%) | 6737 (34.5%) | 0.98 (0.93-1.04) | 0.468 | 0.97 (0.91-1.03) | 0.322 |
| >1825 DDDs | 1597 (16.2%) | 3446 (17.6%) | 0.89 (0.83-0.95) | 0.001 | 0.88 (0.82-0.95) | <0.001 |
| Cumulative DDDs/cumulative duration of use c | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.011 |
| >0-0.5 DDDs/day | 1639 (16.6%) | 3010 (15.4%) | 1.08 (1.02-1.16) | 0.017 | 1.08 (1.01-1.16) | 0.022 |
| >0.5-1.0 DDDs/day | 4103 (41.6%) | 8257 (42.2%) | 0.98 (0.93-1.04) | 0.503 | 0.98 (0.92-1.04) | 0.420 |
| >1.0 DDDs/day | 1315 (13.3%) | 2966 (15.2%) | 0.87 (0.81-0.93) | <0.001 | 0.86 (0.80-0.93) | <0.001 |
Abbreviations: AD, Alzheimer’s disease; CI, confidence interval; DDD, defined daily dose; OR, odds ratio.
a Adjusted for region of residence, occupational social class, cardiovascular disease (stroke, hypertension, coronary artery disease, chronic heart failure, atrial fibrillation, peripheral arterial disease), psychiatric disorders (bipolar, schizophrenia, depression), renal disease, statin use, antihypertensive use, and use of sulfonylureas, insulin and other diabetes medications.
b Individuals who were only exposed to metformin during the 3-year lag period
c Metformin defined daily dose (DDD) is 2 g
Sensitivity Analyses for the Associations Between Metformin Use and Incident Alzheimer’s Disease With Lookback Period to Assess Metformin Exposure Commencing 10 Years Prior to Index Date for All Cases and Controls
| . | . | . | Unadjusted Analyses . | Adjusted Analysesa . | ||
|---|---|---|---|---|---|---|
| Metformin Exposure . | Individuals With AD (N=9862), n (%) . | Individuals Without AD (N=19 550), n (%) . | OR (95% CI) . | P Value . | OR (95% CI) . | P Value . |
| Any use | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.003 | 1.12 (1.03-1.22) | 0.011 |
| Yes | 7057 (71.6%) | 14233 (72.8%) | 0.98 (0.93-1.04) | 0.514 | 0.98 (0.93-1.04) | 0.489 |
| Cumulative duration of use | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.011 |
| >0 to <1 year | 1421 (14.4%) | 2756 (14.1%) | 1.04 (0.97-1.12) | 0.301 | 1.03 (0.96-1.11) | 0.404 |
| 1 to <5 years | 3026 (30.7%) | 6172 (31.6%) | 0.98 (0.92-1.03) | 0.393 | 0.97 (0.91-1.03) | 0.252 |
| 5 to <10 years | 2610 (26.5%) | 5305 (27.1%) | 0.96 (0.90-1.03) | 0.226 | 0.96 (0.90-1.02) | 0.212 |
| Cumulative dose received c | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.009 |
| >0-365 DDDs | 2118 (21.5%) | 4050 (20.7%) | 1.06 (1.00-1.13) | 0.072 | 1.06 (0.99-1.14) | 0.075 |
| >365-1825 DDDs | 3342 (33.9%) | 6737 (34.5%) | 0.98 (0.93-1.04) | 0.468 | 0.97 (0.91-1.03) | 0.322 |
| >1825 DDDs | 1597 (16.2%) | 3446 (17.6%) | 0.89 (0.83-0.95) | 0.001 | 0.88 (0.82-0.95) | <0.001 |
| Cumulative DDDs/cumulative duration of use c | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.011 |
| >0-0.5 DDDs/day | 1639 (16.6%) | 3010 (15.4%) | 1.08 (1.02-1.16) | 0.017 | 1.08 (1.01-1.16) | 0.022 |
| >0.5-1.0 DDDs/day | 4103 (41.6%) | 8257 (42.2%) | 0.98 (0.93-1.04) | 0.503 | 0.98 (0.92-1.04) | 0.420 |
| >1.0 DDDs/day | 1315 (13.3%) | 2966 (15.2%) | 0.87 (0.81-0.93) | <0.001 | 0.86 (0.80-0.93) | <0.001 |
| . | . | . | Unadjusted Analyses . | Adjusted Analysesa . | ||
|---|---|---|---|---|---|---|
| Metformin Exposure . | Individuals With AD (N=9862), n (%) . | Individuals Without AD (N=19 550), n (%) . | OR (95% CI) . | P Value . | OR (95% CI) . | P Value . |
| Any use | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.003 | 1.12 (1.03-1.22) | 0.011 |
| Yes | 7057 (71.6%) | 14233 (72.8%) | 0.98 (0.93-1.04) | 0.514 | 0.98 (0.93-1.04) | 0.489 |
| Cumulative duration of use | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.011 |
| >0 to <1 year | 1421 (14.4%) | 2756 (14.1%) | 1.04 (0.97-1.12) | 0.301 | 1.03 (0.96-1.11) | 0.404 |
| 1 to <5 years | 3026 (30.7%) | 6172 (31.6%) | 0.98 (0.92-1.03) | 0.393 | 0.97 (0.91-1.03) | 0.252 |
| 5 to <10 years | 2610 (26.5%) | 5305 (27.1%) | 0.96 (0.90-1.03) | 0.226 | 0.96 (0.90-1.02) | 0.212 |
| Cumulative dose received c | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.009 |
| >0-365 DDDs | 2118 (21.5%) | 4050 (20.7%) | 1.06 (1.00-1.13) | 0.072 | 1.06 (0.99-1.14) | 0.075 |
| >365-1825 DDDs | 3342 (33.9%) | 6737 (34.5%) | 0.98 (0.93-1.04) | 0.468 | 0.97 (0.91-1.03) | 0.322 |
| >1825 DDDs | 1597 (16.2%) | 3446 (17.6%) | 0.89 (0.83-0.95) | 0.001 | 0.88 (0.82-0.95) | <0.001 |
| Cumulative DDDs/cumulative duration of use c | ||||||
| No use | 1977 (20.1%) | 3871 (19.8%) | Reference | Reference | ||
| Use only during lag periodb | 828 (8.4%) | 1446 (7.4%) | 1.14 (1.05-1.24) | 0.002 | 1.12 (1.03-1.22) | 0.011 |
| >0-0.5 DDDs/day | 1639 (16.6%) | 3010 (15.4%) | 1.08 (1.02-1.16) | 0.017 | 1.08 (1.01-1.16) | 0.022 |
| >0.5-1.0 DDDs/day | 4103 (41.6%) | 8257 (42.2%) | 0.98 (0.93-1.04) | 0.503 | 0.98 (0.92-1.04) | 0.420 |
| >1.0 DDDs/day | 1315 (13.3%) | 2966 (15.2%) | 0.87 (0.81-0.93) | <0.001 | 0.86 (0.80-0.93) | <0.001 |
Abbreviations: AD, Alzheimer’s disease; CI, confidence interval; DDD, defined daily dose; OR, odds ratio.
a Adjusted for region of residence, occupational social class, cardiovascular disease (stroke, hypertension, coronary artery disease, chronic heart failure, atrial fibrillation, peripheral arterial disease), psychiatric disorders (bipolar, schizophrenia, depression), renal disease, statin use, antihypertensive use, and use of sulfonylureas, insulin and other diabetes medications.
b Individuals who were only exposed to metformin during the 3-year lag period
c Metformin defined daily dose (DDD) is 2 g
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