Introduction
Methods
Data Source
Study Population
Exposure Definition
Outcome Assessment
Covariates
Statistical Analysis
Results
Baseline Characteristics
Nonuser of ADM | Metformin mono-tx | Metformin combo-tx | Sulfonylurea mono-tx | Sulfonylurea combo-tx | Other ADM mono-tx | Metformin and sulfonylurea combo-tx | |
---|---|---|---|---|---|---|---|
(N = 722) | (N = 374) | (N = 47) | (N = 653) | (N = 108) | (N = 147) | (N = 302) | |
Age (years) | 67.8 (11.1) | 66.6 (11.1) | 68.8 (11.2) | 67.4 (11.2) | 67.1 (11.3) | 67.4 (11.0) | 66.2 (10.4)* |
Male n (%) | 131 (43.4) | 168 (44.9) | 16 (34.0) | 278 (42.6) | 54 (50.0) | 68 (46.3) | 280 (38.8) |
BMI (kg/m2) | 24.2 (3.2) | 24.9 (3.1)* | 24.5 (3.4) | 24.3 (3.0) | 24.1 (3.4) | 24.3 (3.2) | 25.4 (3.4)* |
Waist (cm) | 83.6 (9.5) | 85.1 (9.5)* | 86.0 (10.8) | 84.5 (8.5) | 84.9 (7.4) | 83.6 (9.9) | 87.3 (10.6)* |
SBP (mmHg) | 135.0 (10.4) | 135.3 (9.4) | 138.8 (10.2)* | 135.9 (9.7) | 136.9 (9.6) | 136.7 (9.9) | 137.5 (11.0)* |
DBP (mmHg) | 82.3 (6.2) | 83.0 (5.6) | 84.1 (5.4)* | 83.2 (6.0)* | 83.4 (5.5) | 83.4 (6.9) | 84.5 (6.5)* |
FPG (mmol/L) | 7.1 (1.4) | 7.4 (1.5)* | 7.5 (1.9) | 7.4 (1.4)* | 7.9 (2.0)* | 7.2 (1.1) | 7.9 (2.2)* |
PA (MET × h/day) | 4.0 (2.4) | 3.9 (2.1) | 3.6 (2.2) | 3.9 (2.2) | 4.2 (2.4) | 3.9 (2.6) | 4.0 (2.4) |
Hypertension n (%) | 51 (7.1) | 24 (6.4) | 3 (6.4) | 44 (6.7) | 4 (3.7) | 11 (7.5) | 24 (7.9) |
Overweight n (%) | 362 (50.1)# | 229 (61.2) | 28 (59.6) | 350 (53.6) | 56 (51.9) | 77 (52.4) | 198 (65.6) |
Abdominal obesity n (%) | 269 (37.3)# | 157 (42.0) | 22 (46.8) | 242 (37.1) | 41 (38.0) | 44 (29.9) | 138 (45.7) |
Smoking n (%) | 67 (9.3)# | 36 (9.6) | 6 (12.8) | 49 (7.5) | 19 (17.6) | 16 (10.9) | 39 (12.9) |
Excessive alcohol use n (%) | 33 (4.6)# | 23 (6.1) | 4 (8.5) | 39 (6.0) | 13 (12.0) | 12 (8.2) | 25 (8.3) |
FPG after 12 months (mmol/L) | 6.7 (0.9) | 6.9 (1.2)* | 7.3 (1.4)* | 6.9 (1.2)* | 6.9 (1.0)* | 6.8 (0.9) | 6.7 (0.9)* |
DFPG (mmol/L) | 0.4(1.4) | 0.5 (1.7) | 0.1 (2.2) | 0.5 (1.7) | 1.0 (2.1)* | 0.5 (1.2) | 0.8 (2.2)* |
Incidence of cancer n (%) | 40 (5.5) | 12 (3.2) | 2 (4.3) | 20 (3.1) | 4 (3.7) | 8 (5.4) | 8 (2.6) |
Nonuser of ADM | Metformin mono-tx | Metformin combo-tx | Sulfonylurea mono-tx | Sulfonylurea combo-tx | Other ADM mono-tx | Metformin and sulfonylurea combo-tx | |
---|---|---|---|---|---|---|---|
(N = 512) | (N = 167) | (N = 35) | (N = 367) | (N = 96) | (N = 116) | (N = 126) | |
Age (years) | 68.1 (11.3) | 67.3 (11.8) | 66.1 (11.3) | 66.9 (11.3) | 70.0 (10.5) | 67.1 (11.2) | 64.4 (10.3)* |
Male n (%) | 188 (36.7) | 72 (43.1) | 17 (48.6) | 156 (42.5) | 44 (45.8) | 55 (47.4) | 51 (40.5) |
BMI (kg/m2) | 24.5 (3.1) | 24.9 (3.2)* | 24.3 (3.0) | 24.3 (2.9) | 24.5 (3.2) | 24.2 (2.9) | 25.7 (3.7)* |
Waist (cm) | 83.4 (9.6) | 85.5 (10.1)* | 84.2 (8.2) | 84.1 (8.5) | 84.8 (7.6) | 83.2 (9.7) | 88.3 (11.7)* |
SBP (mmHg) | 134.5 (10.2) | 134.8 (9.2) | 135.4 (9.1) | 135.3 (9.1) | 136.5 (8.6) | 136.7 (10.0)* | 136.2 (11.0) |
DBP (mmHg) | 82.1 (6.4) | 83.0 (5.6) | 83.9 (4.8)* | 83.0 (6.1) | 83.5 (6.2) | 83.4 (4.8)* | 84.7 (7.1)* |
FPG (mmol/L) | 6.9 (1.1) | 7.4 (1.5)* | 7.5 (2.0)* | 7.4 (1.5)* | 7.6 (1.6)* | 7.4 (1.6)* | 7.8 (2.0)* |
PA (MET × h/day) | 4.1 (2.1) | 3.8 (2.0) | 4.0 (1.9) | 3.8 (2.1) | 3.7 (2.2) | 3.8 ((2.3) | 4.4 (2.4) |
Hypertension n (%) | 35 (6.8) | 9 (5.4) | 3 (8.6) | 24 (6.5) | 3 (3.1) | 11 (9.5) | 11 (8.7) |
Overweight n (%) | 259 (50.6)# | 101 (60.5) | 20 (57.1) | 194 (52.9) | 54 (56.3) | 51 (52.6) | 87 (69.0) |
Abdominal obesity n (%) | 185 (36.1)# | 71 (42.5) | 16 (45.7) | 132 (36.0) | 39 (40.6) | 34 (29.3) | 63 (50.0) |
Smoking n (%) | 35 (6.8)# | 12 (7.2) | 9 (25.7) | 26 (7.1) | 14 (14.6) | 8 (6.9) | 12 (9.5) |
Excessive alcohol use n (%) | 17 (3.3) | 9 (5.4) | 5 (14.3) | 24 (6.5) | 7 (7.3) | 9 (7.8) | 8 (6.3) |
FPG after 12 months (mmol/L) | 6.6 (0.7) | 6.7 (0.9) | 7.0 (1.4) | 6.9 (1.1)* | 7.2 (1.4)* | 6.8 (1.0) | 7.3 (1.6)* |
DFPG (mmol/L) | 0.4 (1.1) | 0.7 (1.5)* | 0.5 (2.2) | 0.5 (1.7) | 0.4 (2.0) | 0.6 (1.8) | 0.6 (2.0) |
Incidence of cancer n (%) | 30 (5.9) | 3 (1.8) | 1 (2.9) | 11 (3.0) | 4 (4.2) | 8 (6.9) | 3 (2.4) |
Association of Metformin and Sulfonylurea Therapy with Cancer Incidence
Cancer site | ICD10 | ITT cohort | PP cohort | ||
---|---|---|---|---|---|
Number of cancer cases | Rate, % | Number of cancer cases | Rate, % | ||
Nasopharynx | C11 | 2 | 2.13 | 1 | 1.67 |
Stomach | C16 | 7 | 7.45 | 4 | 6.67 |
Small intestine | C17 | 1 | 1.06 | 1 | 1.67 |
Colorectum | C18–20 | 19 | 20.21 | 9 | 15.00 |
Liver | C22 | 5 | 5.32 | 4 | 6.67 |
Gallbladder | C23–24 | 3 | 3.19 | 1 | 1.67 |
Pancreas | C25 | 4 | 4.26 | 2 | 3.33 |
Trachea, bronchus, and lung | C34 | 22 | 23.40 | 16 | 26.67 |
Other skin | C44 | 1 | 1.06 | 1 | 1.67 |
Breast | C50 | 7 | 7.45 | 7 | 11.67 |
Corpus uteri | C54 | 1 | 1.06 | 1 | 1.67 |
Prostate | C61 | 7 | 7.45 | 3 | 5.00 |
Bladder | C67 | 1 | 1.06 | 0 | 0.00 |
Brain, central nervous system | C70–72 | 4 | 4.26 | 2 | 3.33 |
Thyroid | C73 | 7 | 7.45 | 5 | 8.33 |
Leukemia | C92–95 | 3 | 3.19 | 3 | 5.00 |
All sites | C00–97 | 94 | 100.00 | 60 | 100.00 |
Exposure | Incidence rate (1000/Pys) | Crude HR | Adjusted HRa | ||||
---|---|---|---|---|---|---|---|
HR | 95% CI |
P
| HR | 95% CI |
P
| ||
ITT cohort | |||||||
Nonuser of ADM | 11.53 | 1.0 (Reference) | 1.0 (Reference) | ||||
Metformin mono-tx | 6.61 | 0.58 | 0.30–1.10 | 0.09 | 0.51 | 0.27–0.99 | 0.045 |
Metformin combo-tx | 8.62 | 0.75 | 0.18–3.10 | 0.69 | 0.60 | 0.15–2.49 | 0.48 |
Sulfonylurea mono-tx | 6.27 | 0.55 | 0.32–0.93 | 0.03 | 0.50 | 0.29–0.85 | 0.01 |
Sulfonylurea combo-tx | 7.59 | 0.66 | 0.25–1.85 | 0.43 | 0.59 | 0.21–1.65 | 0.31 |
Other ADM mono-tx | 11.48 | 1 | 0.47–2.13 | 0.99 | 0.98 | 0.46–2.10 | 0.96 |
Metformin and sulfonylurea combo-tx | 5.5 | 0.48 | 0.22–1.02 | 0.06 | 0.39 | 0.18–0.84 | 0.02 |
PP cohort | |||||||
Nonuser of ADM | 12.27 | 1.0 (Reference) | 1.0 (Reference) | ||||
Metformin mono-tx | 3.73 | 0.31 | 0.09–1.00 | 0.05 | 0.29 | 0.09–0.96 | 0.04 |
Metformin combo-tx | 5.78 | 0.48 | 0.06–3.49 | 0.47 | 0.41 | 0.06–3.02 | 0.38 |
Sulfonylurea mono-tx | 6.15 | 0.51 | 0.25–1.01 | 0.05 | 0.45 | 0.22–0.91 | 0.03 |
Sulfonylurea combo-tx | 8.62 | 0.71 | 0.25–2.00 | 0.51 | 0.53 | 0.19–1.55 | 0.25 |
Other ADM mono-tx | 14.81 | 1.2 | 0.55–2.62 | 0.65 | 1.14 | 0.52–2.49 | 0.75 |
Metformin and sulfonylurea combo-tx | 4.94 | 0.41 | 0.12–1.33 | 0.14 | 0.32 | 0.09–1.09 | 0.07 |
Sensitivity Analyses
ITT cohort | PP cohort | |||||
---|---|---|---|---|---|---|
Adjusted HRa | Adjusted HRa | |||||
HR | 95% CI |
P
| HR | 95% CI |
P
| |
Age (years) | 1.02 | 1.00–1.04 | 0.03 | 1.02 | 1.0–1.05 | 0.06 |
Gender | ||||||
Male | 1.0 (Reference) | 1.0 (Reference) | ||||
Female | 0.97 | 0.62–1.50 | 0.87 | 1.27 | 0.73–2.22 | 0.4 |
BMI (kg/m2) | 1.01 | 0.95–1.07 | 0.42 | 1.03 | 0.95–1.12 | 0.48 |
Baseline FPG (mmol/L) | 1.35 | 1.19–1.54 | <0.001 | 1.3 | 1.07–1.58 | 0.01 |
DFPG (mmol/L) | 0.8 | 0.72–0.90 | <0.001 | 0.77 | 0.67–0.87 | < 0.001 |
PA (MET × h/day) | 0.99 | 0.90–1.09 | 0.88 | 1.01 | 0.89–1.14 | 0.92 |
Smoking status | ||||||
Never | 1.0 (Reference) | 1.0 (Reference) | ||||
Ever | 1.3 | 0.69–2.46 | 0.42 | 1.42 | 0.61–3.31 | 0.42 |
Excess alcohol assumption | ||||||
Never | 1.0 (Reference) | 1.0 (Reference) | ||||
Ever | 1.01 | 0.40–2.54 | 0.99 | 0.95 | 0.27–3.36 | 0.93 |
ADM | ||||||
Nonuser of ADM | 1.0 (Reference) | 1.0 (Reference) | ||||
Metformin mono-tx | 0.51 | 0.27–0.99 | 0.045 | 0.29 | 0.09–0.96 | 0.04 |
Metformin combo-tx | 0.6 | 0.15–2.49 | 0.48 | 0.41 | 0.06–3.02 | 0.38 |
Sulfonylurea mono-tx | 0.5 | 0.29–0.85 | 0.01 | 0.45 | 0.22–0.91 | 0.03 |
Sulfonylurea combo-tx | 0.59 | 0.21–1.65 | 0.31 | 0.53 | 0.19–1.55 | 0.25 |
Other ADM mono-tx | 0.98 | 0.46–2.10 | 0.96 | 1.14 | 0.52–2.49 | 0.75 |
Metformin and sulfonylurea combo-tx | 0.39 | 0.18–0.84 | 0.02 | 0.32 | 0.09–1.09 | 0.07 |
HR | 95% CI |
P
| |
---|---|---|---|
Gender | |||
Male | 1.0 (Reference) | ||
Female | 0.94 | 0.57–1.55 | 0.8 |
Age (years) | |||
< 65 | 1.0 (Reference) | ||
≥ 65 | 1.73 | 1.05–2.84 | 0.03 |
FPG (mmol/L) | |||
< 7.2 | 1.0 (Reference) | ||
≥ 7.2 | 1.45 | 0.90–2.32 | 0.13 |
BMI (kg/m2) | |||
< 24 | 1.0 (Reference) | ||
≥ 24 | 0.93 | 0.55–1.56 | 0.78 |
Waist circumstance (cm) | |||
Male < 90 or female < 80 | 1.0 (Reference) | ||
Male ≥ 90 or female ≥ 80 | 1.14 | 0.67–1.92 | 0.63 |
Smoking status | |||
Never | 1.0 (Reference) | ||
Ever | 1.64 | 0.74–3.61 | 0.22 |
Excess alcohol assumption | |||
Never | 1.0 (Reference) | ||
Ever | 0.61 | 0.18–2.10 | 0.43 |
Adherence | |||
Non-switch | 1.0 (Reference) | ||
Switch | 1.07 | 0.66–1.74 | 0.78 |
ADM | |||
Nonuser | 1.0 (Reference) | ||
Metformin mono-tx | 0.55 | 0.29–1.07 | 0.08 |
Sulfonylurea mono-tx | 0.52 | 0.30–0.90 | 0.02 |