eTable 3. Characteristics of the persons included in the study

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eTable 1. Operational definition of serious hypoglycemia and performance measure of the ascertainment algorithm

ICD-9-CM code Diagnosis description Diagnosis position and claim type

Performance of algorithm

251.0 Hypoglycemic coma Any position of

discharge diagnosis on ED claim or principal position on inpatient claim

PPV ~78%⁴ (inpatient claim);

~89%⁵ (ED claim) 251.1 Other specific hypoglycemia

251.2 Hypoglycemia, unspecified

250.8X Diabetes with other specified manifestations Exclusionary diagnosis codes in the occurrences of 250.8X^4,5

259.8 Other specified

endocrine disorders

Secondary diabetic glycogenosis

Any position of discharge diagnosis on ED claim or principal position on inpatient claim

272.7 Mixed hyperlipidemia Diabetic lipidosis 681.XX Cellulitis and abscess of

finger and toe

Cellulitis 682.XX Other cellulitis and

abscess

686.9 Unspecified local infection of skin and subcutaneous tissue 707.1X Ulcer of lower limbs,

except decubitus ulcer

Ulcers of the lower extremity

707.2X Pressure ulcer stages 707.8 Chronic ulcer of other

specified sites 707.9 Chronic ulcer of

unspecified site

709.3 Degenerative skin

disorders

Necrobiosis lipoidica diabeticorum 730.0X Acute osteomyelitis Osteomyelitis 730.1X Chronic osteomyelitis

730.2X Unspecified

osteomyelitis

731.8 Other bone involvement in diseases classified elsewhere

ED: emergency department. ICD-9-CM: International Classification of Diseases, 9th Revision, Clinical Modification. PPV: positive predictive value.

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eTable 2. Pre-specified time-varying covariates included in the conditional Poisson regression model

Category Component Description Identification

method Drugs that can

cause hypoglycemia

ACE inhibitors^a benazepril, enalapril, lisinopril, perindopril, ramipril, captopril, fosinopril, moexipril, quinapril, trandolapril

NDC, dispensing date, days’ supply Anti-infectives^b alatrofloxacin, cinoxacin, ciprofloxacin,

chloramphenicol, chloroquine, enoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, pentamidine, quinine, sparfloxacin, sulfamethoxazole, trimethoprim, trovafloxacin

NDC, dispensing date, days’ supply

ARBs^a losartan, candesartan, valsartan, irbesartan, eprosartan, olmesartan, telmisartan, azilsartan

NDC, dispensing date, days’ supply Beta blockers^a acebutolol, atenolol, betaxolol, bisoprolol,

carteolol, carvedilol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, pindolol, propranolol, sotalol, timolol

MAO inhibitors^a isocarboxazid, phenelzine, selegiline, rasagiline, tranylcypromine

NDC, dispensing date, days’ supply Salicylates^a aminosalicylic acid, aspirin, bismuth

subsalicylate, choline salicylate, magnesium salicylate, magnesium salicylate,

magnesium salicylate tetrahydrate, phenyl salicylate, salicylic acid, salsalate, sodium salicylate, sodium thiosalicylate

Others^a haloperidol, quinidine, clofibrate, disopyramide

NDC, dispensing date, days’ supply Drugs that can

cause

hyperglycemia

Atypical antipsychotics^a

aripiprazole, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone

NDC, dispensing date, days’ supply Calcineurin

inhibitors^a

cyclosporine, sirolimus, tacrolimus NDC, dispensing date, days’ supply Corticosteroids^a betamethasone, budesonide, cortisone,

dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone

Protease inhibitors^a amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir

NDC, dispensing date, days’ supply Retinoid^a tretinoin, isotretinoin, acitretin NDC, dispensing

date, days’ supply Furosemide, thiazide,

and thiazide-like diuretics^a

bendroflumethiazide, benzthiazide, chlorothiazide, chlorthalidone, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, methyclothiazide,

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Category Component Description Identification

method metolazone, polythiazide,

trichlormethiazide Drugs that interact

with insulin secretagogues

CYP2C9 inhibitors amiodarone^a, capecitabine^a,

cotrimoxazole^b, efavirenz^a, fenofibrate^a, fluconazole^b, isoniazid, lovastatin, metronidazole^b, miconazole^b,

oxandroloneâ, paroxetineâ, probenecidâ, sulfamethoxazole^b, sulfinpyrazoneâ, teniposideâ, tigecyclineâ, voriconazole^b, zafirlukastâ

CYP3A4 inhibitors azithromycin^b, clarithromycin^b,

erythromycin^b, simvastatin^a, gemfibrozil^a

NDC, dispensing date, days’ supply Others^a insulin, other antidiabetes drugs NDC, dispensing

date, days’ supply Major non-chronic

condition that may affect hypoglycemia

Acute infection^b acute infection identified at any position of discharge diagnosis on inpatient or outpatient claims

ICD-9-CM diagnosis codes, admission or service date ACE: angiotensin-converting enzyme. ARB: angiotensin II receptor antagonists. CYP: cytochrome P450 enzyme.

ICD-9-CM: International Classification of Diseases 9th Revision Clinical Modification. MAO: monoamine oxidase.

NDC: National Drug Code. ^aMeasured as a person-day level binary variable indicating being dispensed on the current day (refers to each day during the observation time as current) or any time during the 30 days prior to the current day. ^bMeasured as a person-day level binary variable indicating being diagnosed on the current day or any time during the 15 days prior to the current day. *covariates additionally adjusted in the sensitivity analysis.

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eTable 3. Characteristics of the persons included in the study

Antidiabetes drugs (Object drugs)

glimepiride glipizide glyburide nateglinide repaglinide metformin Number of persons, person-days, and outcome occurrences

Number of persons 7,828 13,509 14,046 982 1,925 24,931

Person-days of observation time, total 2,234,976 3,755,050 3,667,018 188,109 363,141 8,990,281

Median observation time in days per individual (Q1; Q3) 156 (66; 358) 153 (68; 342) 138 (64; 310) 96 (38; 212) 97 (38; 221) 219 (102; 450)

Person-days exposed to a precipitant drug 105,926 148,316 138,065 9,619 25,986 322,902

Person-days unexposed to a precipitant drug 2,129,050 3,606,734 3,528,953 178,490 337,155 8,667,379

Number of outcome occurrences during observation time 9,708 17,188 17,332 1,297 2,535 32,098

Demographic characteristics Category Number (%) of persons, unless otherwise noted

Age in years at start of observation time Median (Q1; Q3)

68.6 (57.7;

77.4)

65.6 (53.4;

75.3)

67.4 (55.3;

76.6)

67.8 (56.5;

77.6)

71.1 (60.8;

79.2)

61.2 (48.6; 72.1)

Sex Female 5,249 (67.1) 8,463 (62.6) 9,033 (64.3) 641 (65.3) 1,254 (65.1) 16,027 (64.3)

Race/Ethnicity White 3,076 (39.3) 4,433 (32.8) 4,488 (32.0) 401 (40.8) 669 (34.8) 9,037 (36.2)

Black 1,346 (17.2) 3,337 (24.7) 3,027 (21.6) 176 (17.9) 414 (21.5) 5,702 (22.9) Hispanic/Latino 1,647 (21.0) 3,059 (22.6) 3,452 (24.6) 195 (19.9) 317 (16.5) 5,591 (22.4) Other/Unknown 1,759 (22.5) 2,680 (19.8) 3,079 (21.9) 210 (21.4) 525 (27.3) 4,601 (18.5) State of residence California 3,971 (50.7) 6,779 (50.2) 7,921 (56.4) 530 (54.0) 807 (41.9) 12,633 (50.7)

Florida 776 (9.9) 1,499 (11.1) 1,434 (10.2) 79 (8.0) 154 (8.0) 2,394 (9.6) New York 1,626 (20.8) 3,285 (24.3) 3,011 (21.4) 218 (22.2) 714 (37.1) 5,877 (23.6)

Ohio 991 (12.7) 1,148 (8.5) 1,159 (8.3) 106 (10.8) 88 (4.6) 2,492 (10.0)

Pennsylvania 464 (5.9) 798 (5.9) 521 (3.7) 49 (5.0) 162 (8.4) 1,535 (6.2) Calendar year at start of observation time 1999 238 (3.0) 575 (4.3) 635 (4.5) 0 (0.0) 110 (5.7) 1,293 (5.2)

2000 461 (5.9) 1,134 (8.4) 1,232 (8.8) 0 (0.0) 124 (6.4) 2,519 (10.1)

2001 422 (5.4) 1,116 (8.3) 1,550 (11.0) 82 (8.4) 144 (7.5) 2,459 (9.9)

2002 528 (6.7) 1,084 (8.0) 1,403 (10.0) 103 (10.5) 144 (7.5) 2,035 (8.2)

2003 631 (8.1) 1,092 (8.1) 1,379 (9.8) 99 (10.1) 124 (6.4) 2,099 (8.4)

2004 630 (8.0) 1,014 (7.5) 1,194 (8.5) 117 (11.9) 129 (6.7) 1,916 (7.7)

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glimepiride glipizide glyburide nateglinide repaglinide metformin

2005 616 (7.9) 1,061 (7.9) 1,194 (8.5) 152 (15.5) 131 (6.8) 1,974 (7.9)

2006 858 (11.0) 1,399 (10.4) 1,360 (9.7) 104 (10.6) 212 (11.0) 2,429 (9.7)

2007 755 (9.6) 1,075 (8.0) 935 (6.7) 79 (8.0) 190 (9.9) 1,747 (7.0)

2008 603 (7.7) 918 (6.8) 818 (5.8) 66 (6.7) 174 (9.0) 1,492 (6.0)

2009 634 (8.1) 939 (7.0) 754 (5.4) 61 (6.2) 129 (6.7) 1,627 (6.5)

2010 604 (7.7) 853 (6.3) 709 (5.0) 44 (4.5) 129 (6.7) 1,400 (5.6)

2011 493 (6.3) 691 (5.1) 528 (3.8) 44 (4.5) 120 (6.2) 1,101 (4.4)

2012 355 (4.5) 558 (4.1) 355 (2.5) 31 (3.2) 65 (3.4) 840 (3.4)

Dually-enrolled for Medicare anytime during baseline period

Yes 5,960 (76.1) 9,222 (68.3) 9,648 (68.7) 767 (78.1) 1,582 (82.2) 15,308 (61.4) Nursing home residence at start of

observation time

Yes 40 (0.5) 121 (0.9) 79 (0.6) 12 (1.2) 17 (0.9) 131 (0.5)

Exposure to a precipitant drug Category Number (%) of person-days

donepezil Yes 79,921 (3.6) 112,805 (3.0) 106,968 (2.9) 6,880 (3.7) 19,391 (5.3) 241,574 (2.7)

galantamine Yes 5,471 (0.2) 4,568 (0.1) 6,932 (0.2) 323 (0.2) 1,549 (0.4) 10,386 (0.1)

memantine Yes 29,556 (1.3) 41,764 (1.1) 32,780 (0.9) 2,419 (1.3) 8,309 (2.3) 93,821 (1.0)

rivastigmine Yes 4,913 (0.2) 7,477 (0.2) 9,035 (0.2) 1,429 (0.8) 2,077 (0.6) 18,595 (0.2)

rivastigmine transdermal Yes 4,479 (0.2) 5,031 (0.1) 2,723 (0.1) 89 (0.0) 901 (0.2) 12,860 (0.1)

Exposure to pre-specified time-varying covariates^a

Category Number (%) of person-days, unless otherwise noted

Acute infection in prior 15 days Yes 245,844 (11.0) 391,282 (10.4) 366,091 (10.0) 26,710 (14.2) 47,731 (13.1) 862,421 (9.6) donepezil-exposed Yes 10,753 (13.5) 15,632 (13.9) 13,776 (12.9) 1,106 (16.1) 2,989 (15.4) 32,499 (13.5)

galantamine-exposed Yes 603 (11.0) 629 (13.8) 1,252 (18.1) 58 (18.0) 210 (13.6) 1,480 (14.2)

memantine-exposed Yes 4,538 (15.4) 6,592 (15.8) 4,962 (15.1) 428 (17.7) 1,718 (20.7) 12,307 (13.1)

rivastigmine-exposed Yes 661 (13.5) 1,135 (15.2) 1,010 (11.2) 271 (19.0) 301 (14.5) 2,371 (12.8)

rivastigmine transdermal-exposed Yes 727 (16.2) 771 (15.3) 430 (15.8) 13 (14.6) 193 (21.4) 1,555 (12.1) Salicylates in prior 30 days Yes 320,816 (14.4) 541,975 (14.4) 524,646 (14.3) 35,559 (18.9) 60,770 (16.7) 1,324,992 (14.7) donepezil-exposed Yes 12,998 (16.3) 21,878 (19.4) 23,096 (21.6) 2,471 (35.9) 4,809 (24.8) 51,192 (21.2)

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galantamine-exposed Yes 822 (15.0) 1,239 (27.1) 1,673 (24.1) 0 (0.0) 47 (3.0) 2,422 (23.3)

memantine-exposed Yes 5,278 (17.9) 8,457 (20.2) 4,726 (14.4) 1,249 (51.6) 1,517 (18.3) 14,512 (15.5)

rivastigmine transdermal-exposed Yes 330 (7.4) 934 (18.6) 206 (7.6) 0 (0.0) 120 (13.3) 2,101 (16.3) MAO inhibitors in prior 30 days Yes 2,100 (0.1) 2,155 (0.1) 1,786 (0.0) 84 (0.0) 306 (0.1) 6,943 (0.1)

donepezil-exposed Yes 211 (0.3) 39 (0.0) 147 (0.1) 0 (0.0) 290 (1.5) 213 (0.1)

galantamine-exposed Yes 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 26 (0.3)

memantine-exposed Yes 0 (0.0) 122 (0.3) 0 (0.0) 0 (0.0) 0 (0.0) 64 (0.1)

rivastigmine-exposed Yes 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

rivastigmine transdermal-exposed Yes 53 (1.2) 0 (0.0) 312 (11.5) 0 (0.0) 0 (0.0) 0 (0.0)

Quinolones in prior 15 days Yes 71,724 (3.2) 106,392 (2.8) 103,808 (2.8) 7,358 (3.9) 13,212 (3.6) 234,591 (2.6)

donepezil-exposed Yes 2,503 (3.1) 3,936 (3.5) 3,940 (3.7) 214 (3.1) 871 (4.5) 7,478 (3.1)

memantine-exposed Yes 1,142 (3.9) 1,514 (3.6) 1,377 (4.2) 58 (2.4) 375 (4.5) 3,049 (3.2)

Sulfamethoxazole/Trimethoprim in prior 15 days

Yes 21,737 (1.0) 45,743 (1.2) 41,468 (1.1) 2,698 (1.4) 3,593 (1.0) 101,664 (1.1)

donepezil-exposed Yes 725 (0.9) 1,101 (1.0) 1,078 (1.0) 167 (2.4) 79 (0.4) 1,868 (0.8)

Other anti-infectives in prior 15 days Yes 190,180 (8.5) 319,783 (8.5) 291,953 (8.0) 18,199 (9.7) 28,703 (7.9) 769,143 (8.6)

rivastigmine-exposed Yes 528 (10.7) 607 (8.1) 607 (6.7) 215 (15.0) 340 (16.4) 1,308 (7.0)

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Other drugs that can cause hypoglycemia in prior 30 days

Yes 20,491 (0.9) 74,132 (2.0) 54,379 (1.5) 1,165 (0.6) 3,379 (0.9) 164,341 (1.8)

memantine-exposed Yes 395 (1.3) 778 (1.9) 1,411 (4.3) 145 (6.0) 85 (1.0) 2,112 (2.3)

Thiazide diuretics in prior 30 days Yes 380,989 (17.0) 571,106 (15.2) 572,363 (15.6) 30,553 (16.2) 67,047 (18.5) 1,495,505 (16.6) donepezil-exposed Yes 14,661 (18.3) 18,098 (16.0) 21,605 (20.2) 344 (5.0) 3,614 (18.6) 48,844 (20.2) galantamine-exposed Yes 1,329 (24.3) 1,469 (32.2) 1,384 (20.0) 165 (51.1) 378 (24.4) 3,714 (35.8)

memantine-exposed Yes 6,214 (21.0) 7,716 (18.5) 7,223 (22.0) 24 (1.0) 1,632 (19.6) 19,960 (21.3)

rivastigmine transdermal-exposed Yes 1,576 (35.2) 600 (11.9) 388 (14.2) 0 (0.0) 111 (12.3) 3,760 (29.2) Corticosteroids in prior 30 days Yes 122,882 (5.5) 202,427 (5.4) 174,295 (4.8) 13,002 (6.9) 23,130 (6.4) 423,205 (4.7)

donepezil-exposed Yes 3,012 (3.8) 4,371 (3.9) 3,617 (3.4) 107 (1.6) 1,376 (7.1) 8,411 (3.5)

rivastigmine transdermal-exposed Yes 188 (4.2) 184 (3.7) 146 (5.4) 48 (53.9) 10 (1.1) 953 (7.4) Protease inhibitors in prior 30 days Yes 7,368 (0.3) 30,508 (0.8) 15,276 (0.4) 1,404 (0.7) 1,453 (0.4) 62,158 (0.7)

Retinoids in prior 30 days Yes 139 (0.0) 248 (0.0) 41 (0.0) 0 (0.0) 0 (0.0) 2,176 (0.0)

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Atypical antipsychotics in prior 30 days Yes 229,145 (10.3) 523,355 (13.9) 452,940 (12.4) 28,049 (14.9) 39,214 (10.8) 1,524,175 (17.0) donepezil-exposed Yes 14,557 (18.2) 28,217 (25.0) 25,151 (23.5) 3,083 (44.8) 4,719 (24.3) 57,691 (23.9)

memantine-exposed Yes 9,144 (30.9) 15,858 (38.0) 7,158 (21.8) 877 (36.3) 1,774 (21.4) 21,885 (23.3) rivastigmine-exposed Yes 1,393 (28.4) 2,145 (28.7) 1,092 (12.1) 153 (10.7) 208 (10.0) 3,653 (19.6) rivastigmine transdermal-exposed Yes 924 (20.6) 1,765 (35.1) 464 (17.0) 47 (52.8) 90 (10.0) 2,993 (23.3) Calcineurin inhibitors in prior 30 days Yes 5,664 (0.3) 22,823 (0.6) 7,114 (0.2) 2,006 (1.1) 1,874 (0.5) 11,799 (0.1)

Furosemide in prior 30 days Yes 508,822 (22.8) 745,232 (19.8) 637,958 (17.4) 42,957 (22.8) 90,526 (24.9) 1,303,406 (14.5) donepezil-exposed Yes 17,140 (21.4) 28,672 (25.4) 21,963 (20.5) 1,468 (21.3) 5,910 (30.5) 43,467 (18.0)

memantine-exposed Yes 6,115 (20.7) 9,868 (23.6) 7,857 (24.0) 240 (9.9) 2,215 (26.7) 16,240 (17.3) rivastigmine-exposed Yes 1,358 (27.6) 1,352 (18.1) 1,172 (13.0) 674 (47.2) 118 (5.7) 2,483 (13.4) rivastigmine transdermal-exposed Yes 647 (14.4) 1,204 (23.9) 487 (17.9) 0 (0.0) 37 (4.1) 2,458 (19.1) CYP2C9 inhibitors in prior 30 days Yes 291,615 (13.0) 455,334 (12.1) 419,924 (11.5) 28,538 (15.2) 44,899 (12.4) 1,061,013 (11.8) donepezil-exposed Yes 10,468 (13.1) 12,792 (11.3) 10,991 (10.3) 711 (10.3) 2,704 (13.9) 28,325 (11.7)

galantamine-exposed Yes 227 (4.1) 923 (20.2) 1,125 (16.2) 0 (0.0) 338 (21.8) 2,049 (19.7)

memantine-exposed Yes 4,754 (16.1) 5,014 (12.0) 3,889 (11.9) 450 (18.6) 1,207 (14.5) 12,577 (13.4) rivastigmine-exposed Yes 1,088 (22.1) 1,386 (18.5) 1,540 (17.0) 136 (9.5) 399 (19.2) 3,776 (20.3)

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glimepiride glipizide glyburide nateglinide repaglinide metformin rivastigmine transdermal-exposed Yes 485 (10.8) 431 (8.6) 481 (17.7) 27 (30.3) 36 (4.0) 1,740 (13.5) CYP3A4 inhibitors in prior 30 days Yes 465,976 (20.8) 767,169 (20.4) 681,703 (18.6) 37,903 (20.1) 82,462 (22.7) 1,854,906 (20.6) donepezil-exposed Yes 18,842 (23.6) 29,497 (26.1) 25,964 (24.3) 617 (9.0) 4,731 (24.4) 69,695 (28.9)

galantamine-exposed Yes 2,053 (37.5) 1,018 (22.3) 1,998 (28.8) 161 (49.8) 32 (2.1) 2,590 (24.9)

memantine-exposed Yes 7,287 (24.7) 12,863 (30.8) 9,449 (28.8) 522 (21.6) 2,581 (31.1) 27,201 (29.0) rivastigmine-exposed Yes 1,159 (23.6) 2,323 (31.1) 1,203 (13.3) 242 (16.9) 390 (18.8) 5,131 (27.6) rivastigmine transdermal-exposed Yes 682 (15.2) 1,552 (30.8) 1,006 (36.9) 57 (64.0) 83 (9.2) 2,910 (22.6) Insulin in prior 30 days Yes 436,162 (19.5) 646,565 (17.2) 478,312 (13.0) 64,556 (34.3) 130,598 (36.0) 2,096,193 (23.3) donepezil-exposed Yes 16,889 (21.1) 22,121 (19.6) 13,748 (12.9) 3,609 (52.5) 7,902 (40.8) 54,479 (22.6)

galantamine-exposed Yes 1,045 (19.1) 587 (12.9) 990 (14.3) 147 (45.5) 836 (54.0) 2,569 (24.7)

memantine-exposed Yes 7,555 (25.6) 9,115 (21.8) 6,448 (19.7) 1,222 (50.5) 3,306 (39.8) 22,956 (24.5)

rivastigmine-exposed Yes 486 (9.9) 855 (11.4) 383 (4.2) 248 (17.4) 893 (43.0) 2,269 (12.2)

rivastigmine transdermal-exposed Yes 1,075 (24.0) 1,140 (22.7) 317 (11.6) 62 (69.7) 210 (23.3) 3,468 (27.0) Non-insulin other anti-diabetics in prior 30

days

Yes 606,190 (27.1) 675,755 (18.0) 682,503 (18.6) 56,725 (30.2) 83,309 (22.9) 1,845,458 (20.5) donepezil-exposed Yes 24,742 (31.0) 18,189 (16.1) 21,705 (20.3) 1,987 (28.9) 4,342 (22.4) 56,647 (23.4)

galantamine-exposed Yes 2,050 (37.5) 753 (16.5) 1,645 (23.7) 0 (0.0) 158 (10.2) 2,292 (22.1)

memantine-exposed Yes 11,219 (38.0) 6,955 (16.7) 5,282 (16.1) 144 (6.0) 1,368 (16.5) 18,541 (19.8) rivastigmine-exposed Yes 1,520 (30.9) 1,535 (20.5) 2,257 (25.0) 860 (60.2) 176 (8.5) 6,054 (32.6) rivastigmine transdermal-exposed Yes 375 (8.4) 748 (14.9) 803 (29.5) 0 (0.0) 317 (35.2) 1,773 (13.8) MAO: monoamine oxidase. CYP: cytochrome P450 enzyme. ^aExposure to pre-specified time-varying covariates: assessed at the person-day level during the observation time. Detailed information on each of the time-varying covariates is presented in eTable 2.

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eTable 4. Sensitivity analysis: serious hypoglycemia occurrence rate ratios from the concomitant use of insulin secretagogues or metformin (object drugs) and Alzheimer’s disease drugs (precipitant drugs) vs. the use of the object drugs without the precipitant drugs, including observation time during which death occurred

Object drug Precipitant drug Rate ratio^a 95% Confidence Interval

glimepiride donepezil 1.07 0.84‒1.37

galantamine 0.69 0.30‒1.62

memantine 0.77 0.53‒1.12

rivastigmine 1.19 0.55‒2.60

rivastigmine transdermal 0.77 0.31‒1.88

glipizide donepezil 1.14 0.94‒1.38

memantine 0.78 0.59‒1.04

glyburide donepezil 1.02 0.85‒1.23

memantine 0.78 0.57‒1.06

nateglinide donepezil 2.32 1.04‒5.16

galantamine ^b ^b

memantine 0.71 0.23‒2.20

rivastigmine transdermal ^b ^b

repaglinide donepezil 0.77 0.47‒1.28

memantine 0.43 0.22‒0.86

metformin donepezil 0.96 0.84‒1.10

memantine 0.83 0.68‒1.02

aRate ratio: [(outcome occurrence rate during precipitant-exposed time)/(outcome occurrence rate during precipitant-unexposed time)], for each object-precipitant drug pair. Confounder-adjusted. ^b: No estimates due to a small number of outcome occurrences (n<5).

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eTable 5. Sensitivity analysis: serious hypoglycemia occurrence rate ratios from the concomitant use of insulin secretagogues or metformin (object drugs) and Alzheimer’s disease drugs (precipitant drugs) vs. the use of the object drugs without the precipitant drugs, excluding observation time with

potentially incomplete data

Object drug Precipitant drug Rate ratio^a 95% Confidence Interval

glimepiride donepezil 1.19 0.86‒1.67

memantine 0.76 0.46‒1.28

glipizide donepezil 1.05 0.79‒1.40

memantine 0.52 0.33‒0.84

glyburide donepezil 0.91 0.71‒1.18

memantine 0.68 0.46‒1.02

nateglinide donepezil 3.36 1.17‒9.62

galantamine ^b ^b

memantine 0.59 0.14‒2.38

rivastigmine transdermal ^b ^b

repaglinide donepezil 0.73 0.39‒1.37

galantamine ^b ^b

memantine 0.57 0.24‒1.38

metformin donepezil 0.96 0.79‒1.17

memantine 0.74 0.55‒0.98

aRate ratio: [(outcome occurrence rate during precipitant-exposed time)/(outcome occurrence rate during precipitant-unexposed time)], for each object-precipitant drug pair. Confounder-adjusted. ^b: No estimates due to a small number of outcome occurrences (n<5).