Journal Name: Clinical Drug Investigation

Journal name: Clinical Drug Investigation

Article title: Higher risk of sulfonylurea-associated hypoglycemic symptoms in women with type 2 diabetes mellitus

Authors’ names: Ayami Kajiwara, Ayana Kita, Junji Saruwatari, Kentaro Oniki, Kazunori Morita, Masato Yamamura, Motoji Murase, Haruo Koda, Seisuke Hirota, Tadao Ishizuka, Kazuko Nakagawa

Supplemental Table 1. Questionnaire and checklist items for the Japan Pharmaceutical Association Drug Event Monitoring project, 2011

Age (years) / Prescription on the surveillance day a
Sex / As previous prescription/ adjusted dose/
Male/ female / changed into another sulfonylurea/ discontinued
Alcohol consumption / Duration of diabetic pharmacotherapy
Yes/ No / For < 3 months/ ≥ 3, < 12 months/
Smoking habit / ≥ 12, < 24 months/ ≥ 24 months
Yes/ No / Experience of hypoglycemia b
Sulfonylurea currently taking / Yes/ No
Glimepiride/ glibenclamide/ gliclazide/ / Adverse drug reaction a, c
glyclopyramide/ chlorpropamide/ tolbutamide/ / Fatigue/ shaking/ sweating/ hunger/ blurred
acetohexamide / vision/ headache/ palpitation/ unconsciousness/
Previous day of the prescription of sulfonylurea / facial pallor or flushing/ yawning/ nausea/
Daily dose (mg) / seizure/ coma/ diarrhea/ anorexia/ rash/ others/
When to take sulfonylurea / nothing
Before meal/ after meal / Situation or condition when hypoglycemic
Concomitant hypoglycemic agent a / symptoms occurred
Biguanide/ thiazolidinedione/ α-glucosidase / Treatment for hypoglycemic symptoms
inhibitor/ rapid insulin secretagogue/ / Had food or juice including sugar and recovered/
DPP-4 inhibitor/ GLP-1 analog/ insulin/ others/ / had sugar-including product but unrecovered/
nothing / do nothing/ others

a Multiple answers allowed.

b The question was phased, “Have you ever experienced any hypoglycemic symptoms?”

c The question was phased, “Have there been any changes since the previous prescription?” with caution against leading the patient to make a particular response.

DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1

Supplemental Table 2. Distribution of the characteristics of the patients with or without previous experience of hypoglycemia

Variable / Total / Males / Females
Without symptoms
N = 1,517 / With
symptoms
N = 602 / ORa [95%CI] / Without symptoms
N = 852 / With
symptoms
N = 305 / ORa [95%CI] / Without symptoms
N = 665 / With
symptoms
N = 297 / ORa [95%CI]
Sex
Male (%) / 852 (56.2) / 305 (50.7) / 1 / - / - / - / - / - / -
Female (%) / 665 (43.8) / 297 (49.3) / 1.25 [1.01-1.56] / - / - / - / - / - / -
Concomitant hypoglycemic agent
0 / 572 (37.7) / 150 (24.9) / 1 / 302 (35.4) / 76 (24.9) / 1 / 270 (40.6) / 74 (24.9) / 1
1 / 711 (46.9) / 307 (51.0) / 1.59 [1.26-2.00] / 404 (47.4) / 153 (50.2) / 1.40 [1.02-1.93] / 307 (46.2) / 154 (51.9) / 1.81 [1.30-2.53]
≥ 2 / 234 (15.4) / 145 (24.1) / 2.27 [1.70-3.02] / 146 (17.1) / 76 (24.9) / 1.89 [1.28-2.80] / 88 (13.2) / 69 (23.2) / 2.82 [1.84-4.33]
Duration of diabetes medication
< 3 months (%) / 41 (2.7) / 12 (2.0) / 1 / 24 (2.8) / 7 (2.3) / 1 / 17 (2.6) / 5 (1.7) / 1
≥ 3, < 12 months (%) / 77 (5.1) / 18 (3.0) / 0.84 [0.37-1.94] / 47 (5.5) / 10 (3.3) / 0.84 [0.28-2.51] / 30 (4.5) / 8 (2.7) / 1.12 [0.30-4.16]
≥ 12, < 24 months (%) / 124 (8.2) / 39 (6.5) / 1.12 [0.53-2.36] / 68 (8.0) / 16 (5.2) / 0.91 [0.33-2.50] / 56 (8.4) / 23 (7.7) / 1.53 [0.49-4.85]
≥ 24 months (%) / 1275 (84.0) / 533 (88.5) / 1.37 [0.70-2.67] / 713 (83.7) / 272 (89.2) / 1.35 [0.57-3.23] / 562 (84.5) / 261 (87.9) / 1.67 [0.58-4.86]
Daily dose c
≤ median (%) / 679 (44.8) / 254 (42.2) / 1 / 373 (43.8) / 121 (39.7) / 1 / 306 (46.0) / 133 (44.8) / 1
median (%) / 838 (55.2) / 348 (57.8) / 0.96 [0.78-1.17] / 479 (56.2) / 184 (60.3) / 1.02 [0.77-1.35] / 359 (54.0) / 164 (55.2) / 0.91 [0.68-1.21]
Surveillance period (day) b / 27.4 ± 12.9 / 26.3 ± 12.4 / 0.99 [0.98-1.00] / 28.2 ± 13.3 / 26.7 ± 12.1 / 0.99 [0.98-1.00] / 26.3 ± 12.2 / 26.0 ± 12.7 / 1.00 [0.98-1.01]
Age (years) / 68.7 ± 11.7 / 67.7 ± 11.2 / 0.99 [0.98-1.00] / 67.2 ± 11.5 / 66.4 ± 11.1 / 0.99 [0.98-1.00] / 70.6 ± 11.7 / 69.0 ± 11.1 / 1.00 [0.98-1.01]
Alcohol consumption
Non-drinker (%) / 819 (54.0) / 340 (56.5) / 1 / 269 (31.6) / 120 (39.3) / 1 / 550 (82.7) / 220 (74.1) / 1
Drinker (%) / 540 (35.6) / 186 (30.9) / 0.92 [0.72-1.17] / 484 (56.8) / 145 (47.5) / 0.68 [0.50-0.90] / 56 (8.4) / 41 (13.8) / 1.89 [1.21-2.97]
Unknown (%) / 158 (10.4) / 76 (12.6) / 1.23 [0.90-1.68] / 99 (11.6) / 40 (13.1) / 0.94 [0.61-1.45] / 59 (8.9) / 36 (12.1) / 1.50 [0.95-2.37]

a Adjusted for the factors listed in this table.

b The mean period from the last prescription to the surveillance.

c Median dose of each sulfonylurea was used to create two groups: patients with over median dose and those with median dose or less, in order to assess the daily doses of the three sulfonylureas in the same scale.

Supplemental Table 3. Distribution of the characteristics of the patients with or without non-hypoglycemic symptoms during sulfonylureas use

Variable / Total / Males / Females
Without symptoms
N = 2,094 / With
symptoms
N = 25 / ORa [95%CI] / Without symptoms
N = 1,143 / With
symptoms
N = 14 / ORa [95%CI] / Without symptoms
N = 951 / With
symptoms
N = 11 / ORa [95%CI]
Sex
Male (%) / 1,143 (54.6) / 14 (56.0) / 1 / - / - / - / - / - / -
Female (%) / 951 (45.4) / 11 (44.0) / 0.97 [0.40-2.38] / - / - / - / - / - / -
Concomitant hypoglycemic agent
0 / 719 (34.3) / 3 (12.0) / 1 / 375 (32.8) / 3 (21.4) / 1 / 344 (36.2) / 0 (0.0) / -
1 / 1,001 (47.8) / 17 (68.0) / 3.74 [1.07-13.02] / 549 (48.0) / 8 (57.1) / 1.57 [0.40-6.15] / 452 (47.5) / 9 (81.8) / -
≥ 2 / 374 (17.9) / 5 (20.0) / 2.86 [0.65-12.48] / 219 (19.2) / 3 (21.4) / 1.35 [0.26-7.15] / 155 (16.3) / 2 (18.2) / -
Duration of diabetes medication
< 3 months (%) / 52 (2.5) / 1 (4.0) / 1 / 31 (2.7) / 0 (0.0) / - / 21 (2.2) / 1 (9.1) / 1
≥ 3, < 12 months (%) / 95 (4.5) / 0 (0.0) / - / 57 (5.0) / 0 (0.0) / - / 38 (4.0) / 0 (0.0) / -
≥ 12, < 24 months (%) / 162 (7.7) / 1 (4.0) / 0.28 [0.02-4.66] / 84 (7.3) / 0 (0.0) / - / 78 (8.2) / 1 (9.1) / 0.17 [0.01-3.33]
≥ 24 months (%) / 1,785 (85.2) / 23 (92.0) / 0.49 [0.06-3.89] / 971 (85.0) / 14 (100.0) / - / 814 (85.6) / 9 (81.8) / 0.10 [0.01-.1.17]
Daily dose c
≤ median (%) / 925 (44.2) / 8 (32.0) / 1 / 489 (42.8) / 5 (35.7) / 1 / 436 (45.8) / 3 (27.3) / 1
median (%) / 1,169 (55.8) / 17 (68.0) / 1.38 [0.58-3.26] / 654 (57.2) / 9 (64.3) / 1.12 [0.36-3.47] / 515 (54.2) / 8 (72.7) / 2.01 [0.52-7.83]
Surveillance period (day) b / 27.1 ± 12.8 / 25.8 ± 10.7 / 0.99 [0.96-1.03] / 27.8 ± 13.1 / 28.1 ± 11.0 / 1.00 [0.96-1.04] / 26.3 ± 12.3 / 22.8 ± 10.1 / 0.98 [0.92-1.04]
Age (years) / 68.4 ± 11.5 / 68.6 ± 15.6 / 1.01 [0.97-1.04] / 67.0 ± 11.3 / 65.6 ± 17.8 / 0.98 [0.94-1.03] / 70.1 ± 11.6 / 72.5 ± 11.9 / 1.04 [0.98-1.11]
Alcohol consumption
Non-drinker (%) / 1,146 (54.7) / 13 (52.0) / 1 / 385 (33.7) / 4 (28.6) / 1 / 761 (80.0) / 9 (81.8) / 1
Drinker (%) / 718 (34.3) / 8 (32.0) / 1.00 [0.36-2.76] / 623 (54.5) / 6 (42.9) / 0.91 [0.25-3.27] / 95 (10.0) / 2 (18.2) / 1.78 [0.34-9.42]
Unknown (%) / 230 (11.0) / 4 (16.0) / 1.62 [0.51-5.19] / 135 (11.8) / 4 (28.6) / 2.88 [0.70-11.78] / 95 (10.0) / 0 (0.0) / -

a Adjusted for the factors listed in this table.

b The mean period from the last prescription to the surveillance.

Supplemental Table 4. Prevalence of adverse symptoms in each sulfonylurea therapy

Hypoglycemic adverse symptoms / Non-hypoglycemic adverse symptoms
Total
84/2,119 (4.0) / Males
35/1,157 (3.0) / Females
49/962 (5.1) / Total
25/2,119 (1.2) / Males
14/1,157 (1.2) / Females
11/962 (1.1)
Glimepiride / 57/1,545 (3.7) / 23/850 (2.7)b / 34/695 (4.9)b / 16/1,545 (1.0) / 8/850 (0.9) / 8/695 (1.2)
Glibenclamide / 17/338 (5.0) / 7/190 (3.7) / 10/148 (6.8) / 3/338 (0.9) / 2/190 (1.1) / 1/148 (0.7)
Gliclazide / 10/236 (4.2) / 5/117 (4.3) / 5/119 (4.2) / 6/236 (2.5) / 4/117 (3.4) / 2/119 (1.7)

a The values are presented as the number of cases with adverse symptoms/total subjects (percentage).

b There was a significant difference (p 0.05) in prevalence of adverse symptoms between males and females.