Introduction
Materials and methods
Research database
Study population
Definitions of drug use and comparison groups
Study endpoint
Covariate ascertainment
Statistical analysis
Results
Baseline characteristics
Variables | All patients n = 26,742 | Met+SU users n = 24,277 (%) | Met+AGI users n = 808 (%) | Met+TZD users n = 581 (%) | Met+glinide users n = 962 (%) | Met+DPP-4I users n = 114 (%) | p value (5 groups) |
---|---|---|---|---|---|---|---|
Patient characteristics | |||||||
Age, years | 56.4 (11.8) | 56.3 (11.7) | 56.3 (13.1) | 56.4 (12.0) | 57.8 (12.8) | 56.2 (12.8) | 0.004 |
Male | 14,083 (52.7) | 12,842 (52.9) | 366 (45.3) | 313 (53.9) | 505 (52.5) | 57 (50.0) | 0.0009 |
Diabetes durationa, years | 2.5 (2.9) | 2.4 (2.8) | 3.6 (3.5) | 3.3 (3.5) | 3.1 (3.5) | 4.8 (4.3) | < 0.0001 |
Follow up duration, years | 6.6 (3.4) | 6.8 ± 3.4 | 4.7 ± 2.5 | 4.9 ± 2.6 | 5.6 ± 2.7 | 1.7 ± 0.5 | < 0.0001 |
Co-morbidities | |||||||
COPD | 8641 (32.3) | 7770 (32.0) | 299 (37.0) | 194 (33.4) | 329 (34.2) | 49 (43.0) | 0.0019 |
CKD | 316 (1.2) | 271 (1.1) | 12 (1.5) | 11 (1.9) | 17 (1.8) | 5 (4.4) | 0.002 |
Hypertension | 16,028 (60.0) | 14,393 (59.3) | 563 (69.7) | 395 (68.0) | 599 (62.3) | 78 (68.4) | < 0.0001 |
Hyperlipidemia | 15,443 (57.8) | 13,794 (56.8) | 589 (72.9) | 404 (69.5) | 571 (59.4) | 85 (74.6) | < 0.0001 |
Heart failureb
| 1118 (4.2) | 989 (4.1) | 42 (5.2) | 22 (3.8) | 55 (5.7) | 10 (8.8) | 0.005 |
Medications | |||||||
ACEIs/ARBs | 11,945 (44.7) | 10,609 (43.7) | 452 (55.9) | 334 (57.5) | 482 (50.1) | 68 (59.7) | < 0.0001 |
Alpha blockers | 3396 (12.7) | 2999 (12.4) | 121 (15.0) | 108 (18.6) | 147 (15.3) | 21 (18.4) | < 0.0001 |
Beta blockers | 13,393 (50.1) | 11,966 (49.3) | 516 (63.9) | 326 (56.1) | 513 (53.3) | 72 (63.2) | <0.0001 |
CCB | 13,034 (48.7) | 11,662 (48.0) | 483 (59.8) | 320 (55.1) | 499 (51.9) | 70 (61.4) | < 0.0001 |
Diuretics | 9434 (35.3) | 8428 (34.7) | 352 (43.6) | 229 (39.4) | 378 (39.3) | 47 (41.2) | < 0.0001 |
Aspirin | 8957 (33.5) | 7939 (32.7) | 348 (43.1) | 246 (42.3) | 376 (39.1) | 48 (42.1) | < 0.0001 |
Clopidogrel | 304 (1.1) | 237 (1.0) | 32 (4.0) | 13 (2.2) | 17 (1.8) | 5 (4.4) | < 0.0001 |
Warfarin | 176 (0.7) | 152 (0.6) | 10 (1.2) | 4 (0.7) | 10 (1.0) | 0 | 0.11 |
Statins | 7419 (27.7) | 6408 (26.4) | 359 (44.4) | 270 (46.5) | 325 (33.8) | 57 (50.0) | < 0.0001 |
Fibrates | 6282 (23.5) | 5623 (23.2) | 245 (30.3) | 165 (28.4) | 213 (22.1) | 36 (31.6) | < 0.0001 |
Effects of different second-line anti-diabetic agents on cardiovascular outcomes
Variable | Event | PYs | Rate | Crude HR (95% CI) | Adjusted HR (95% CI) | p value |
---|---|---|---|---|---|---|
MACE | ||||||
Met+SU users | 4512 | 155,459 | 29.0 | Ref. | Ref. | – |
Met+AGI users | 70 | 3735 | 18.7 | 0.72 (0.57–0.92) | 0.74 (0.59–0.94) | 0.01 |
Met+TZD users | 50 | 2814 | 17.8 | 0.68 (0.51–0.89) | 0.66 (0.50–0.88) | 0.004 |
Met+glinide users | 141 | 5187 | 27.2 | 1.01 (0.85–1.19) | 0.89 (0.75–1.06) | 0.18 |
Met+DPP-4I users | 2 | 194 | 10.3 | 0.52 (0.13–2.08) | 0.52 (0.13–2.10) | 0.36 |
ACS | ||||||
Met+SU users | 693 | 163,037 | 42.5 | Ref. | Ref. | – |
Met+AGI users | 11 | 3805 | 28.9 | 0.76 (0.42–1.39) | 0.74 (0.41–1.34) | 0.32 |
Met+TZD users | 10 | 2851 | 35.1 | 0.91 (0.49–1.71) | 0.85 (0.45–1.59) | 0.61 |
Met+glinide users | 14 | 5364 | 26.1 | 0.66 (0.39–1.12) | 0.60 (0.35–1.03) | 0.06 |
Met+DPP-4I users | 0 | 194 | 0 | – | – | – |
Stroke | ||||||
Met+SU users | 2206 | 157,529 | 140 | Ref. | Ref. | – |
Met+AGI users | 35 | 3750 | 93.3 | 0.71 (0.51–1.00) | 0.71 (0.51–0.99) | 0.04 |
Met+TZD users | 16 | 2833 | 56.5 | 0.43 (0.26–0.70) | 0.41 (0.25–0.67) | 0.0004 |
Met+glinide users | 75 | 5213 | 144 | 1.07 (0.85–1.35) | 0.95 (0.75–1.20) | 0.66 |
Met+DPP-4I users | 1 | 194 | 51.7 | 0.46 (0.07–3.30) | 0.46 (0.06–3.24) | 0.43 |
Ischemic stroke | ||||||
Met+SU users | 1850 | 158,569 | 117 | Ref. | Ref. | – |
Met+AGI users | 27 | 3765 | 71.7 | 0.66 (0.45–0.96) | 0.65 (0.44–0.95) | 0.02 |
Met+TZD users | 11 | 2845 | 38.7 | 0.35 (0.19–0.64) | 0.34 (0.19–0.61) | 0.0003 |
Met+glinide users | 55 | 5247 | 105 | 0.94 (0.72–1.23) | 0.83 (0.64–1.09) | 0.18 |
Met+DPP-4I users | 1 | 194 | 51.7 | 0.55 (0.08–3.94) | 0.53 (0.07–3.77) | 0.52 |
Hemorrhagic stroke | ||||||
Met+SU users | 303 | 164,609 | 18.4 | Ref. | Ref. | – |
Met+AGI users | 5 | 3813 | 13.1 | 0.77 (0.32–1.88) | 0.82 (0.34–1.99) | 0.66 |
Met+TZD users | 2 | 2863 | 6.98 | 0.41 (0.10–1.64) | 0.41 (0.10–1.64) | 0.21 |
Met+glinide users | 11 | 5378 | 20.5 | 1.16 (0.64–2.12) | 1.08 (0.59–1.98) | 0.80 |
Met+DPP-4I users | 0 | 194 | 0 | – | – | – |
Mortality | ||||||
Met+SU users | 2640 | 165,404 | 160 | Ref. | Ref. | – |
Met+AGI users | 37 | 3824 | 96.8 | 0.78 (0.56–1.08) | 0.83 (0.60–1.15) | 0.26 |
Met+TZD users | 29 | 2872 | 101 | 0.79 (0.55–1.14) | 0.81 (0.56–1.17) | 0.27 |
Met+glinide users | 79 | 5392 | 147 | 1.07 (0.86–1.34) | 0.93 (0.74–1.16) | 0.51 |
Met+DPP-4I users | 1 | 194 | 51.4 | 0.75 (0.11–5.34) | 0.79 (0.11–5.61) | 0.81 |
Subgroup analysis on cardiovascular outcomes in patients receiving different second-line anti-diabetic agents
MACE event | Event | PYs | Rate | Crude HR (95% CI) | Adjusted HR (95% CI) | p value |
---|---|---|---|---|---|---|
< 45 years | ||||||
Met+SU users | 320 | 27,932 | 115 | Ref. | Ref. | – |
Met+AGI users | 6 | 708 | 84.7 | 0.94 (0.42–2.12) | 0.79 (0.35–1.79) | 0.57 |
Met+TZD users | 5 | 479 | 104 | 1.15 (0.47–2.78) | 1.04 (0.43–2.54) | 0.93 |
Met+glinide users | 8 | 878 | 91.1 | 0.91 (0.45–1.84) | 0.99 (0.49–2.01) | 0.98 |
Met+DPP-4I users | 0 | 33 | 0 | – | – | – |
45–64 years | ||||||
Met+SU users | 2150 | 93,446 | 230 | Ref. | Ref. | – |
Met+AGI users | 22 | 2193 | 100 | 0.49 (0.32–0.74) | 0.49 (0.32–0.74) | 0.0009 |
Met+TZD users | 22 | 1703 | 129 | 0.63 (0.41–0.95) | 0.61 (0.40–0.94) | 0.02 |
Met+glinide users | 45 | 2890 | 156 | 0.73 (0.54–0.98) | 0.72 (0.54–0.97) | 0.03 |
Met+DPP-4I users | 0 | 114 | 0 | – | – | – |
≥ 65 years | ||||||
Met+SU users | 2042 | 34,081 | 599 | Ref. | Ref. | – |
Met+AGI users | 42 | 833 | 504 | 0.96 (0.71–1.31) | 1.01 (0.74–1.37) | 0.96 |
Met+TZD users | 23 | 632 | 364 | 0.66 (0.44–1.00) | 0.65 (0.43–0.98) | 0.04 |
Met+glinide users | 88 | 1419 | 620 | 1.11 (0.90–1.38) | 1.08 (0.87–1.33) | 0.51 |
Met+DPP-4I users | 2 | 47 | 426 | 0.99 (0.25–3.98) | 1.04 (0.26–4.19) | 0.95 |
Female | ||||||
Met+SU users | 1934 | 75,370 | 257 | Ref. | Ref. | – |
Met+AGI users | 35 | 2073 | 169 | 0.75 (0.54–1.05) | 0.74 (0.53–1.03) | 0.07 |
Met+TZD users | 22 | 1295 | 170 | 0.74 (0.49–1.13) | 0.72 (0.47–1.10) | 0.13 |
Met+glinide users | 58 | 2473 | 235 | 1.00 (0.77–1.30) | 0.86 (0.66–1.12) | 0.26 |
Met+DPP-4I users | 2 | 96 | 208 | 1.23 (0.31–4.95) | 1.20 (0.30–4.81) | 0.80 |
Male | ||||||
Met+SU users | 2578 | 80,089 | 322 | Ref. | Ref. | – |
Met+AGI users | 35 | 1661 | 211 | 0.72 (0.52–1.01) | 0.74 (0.53–1.04) | 0.08 |
Met+TZD users | 28 | 1518 | 184 | 0.63 (0.43–0.91) | 0.61 (0.42–0.89) | 0.01 |
Met+glinide users | 83 | 2714 | 306 | 1.01 (0.81–1.25) | 0.91 (0.73–1.14) | 0.41 |
Met+DPP-4I users | 0 | 97 | 0 | – | – | |
Without COPD | ||||||
Met+SU users | 2783 | 106,567 | 261 | Ref. | Ref. | – |
Met+AGI users | 34 | 2394 | 142 | 0.61 (0.44–0.86) | 0.66 (0.47–0.93) | 0.02 |
Met+TZD users | 27 | 1885 | 143 | 0.61 (0.42–0.89) | 0.61 (0.42–0.89) | 0.01 |
Met+glinide users | 75 | 3535 | 212 | 0.87 (0.69–1.09) | 0.83 (0.66–1.05) | 0.12 |
Met+DPP-4I users | 1 | 110 | 90.8 | 0.52 (0.07–3.72) | 0.50 (0.07–3.59) | 0.49 |
With COPD | ||||||
Met+SU users | 1729 | 48,892 | 354 | Ref. | Ref. | – |
Met+AGI users | 36 | 1340 | 269 | 0.84 (0.61–1.17) | 0.84 (0.60–1.17) | 0.29 |
Met+TZD users | 23 | 929 | 248 | 0.77 (0.51–1.16) | 0.75 (0.49–1.13) | 0.16 |
Met+glinide users | 66 | 1652 | 400 | 1.22 (0.96–1.56) | 0.97 (0.75–1.24) | 0.78 |
Met+DPP-4I users | 1 | 83 | 120 | 0.48 (0.07–3.39) | 0.54 (0.08–3.85) | 0.54 |
Without CKD | ||||||
Met+SU users | 4425 | 153,935 | 287 | Ref. | Ref. | – |
Met+AGI users | 69 | 3672 | 188 | 0.73 (0.58–0.93) | 0.76 (0.60–0.96) | 0.02 |
Met+TZD users | 48 | 2780 | 173 | 0.66 (0.50–0.88) | 0.65 (0.49–0.87) | 0.003 |
Met+glinide users | 135 | 5094 | 265 | 0.99 (0.84–1.18) | 0.88 (0.74–1.05) | 0.16 |
Met+DPP-4I users | 1 | 185 | 54.0 | 0.28 (0.04–1.96) | 0.29 (0.04–2.05) | 0.21 |
With CKD | ||||||
Met+SU users | 87 | 1524 | 571 | Ref. | Ref. | – |
Met+AGI users | 1 | 63 | 160 | 0.28 (0.04–2.05) | 0.31 (0.04–2.31) | 0.25 |
Met+TZD users | 2 | 34 | 594 | 1.28 (0.31–5.27) | 1.32 (0.30–5.83) | 0.72 |
Met+glinide users | 6 | 93 | 647 | 1.11 (0.48–2.54) | 1.06 (0.44–2.54) | 0.90 |
Met+DPP-4I users | 1 | 9 | 1175 | 2.60 (0.35–19.1) | 2.77 (0.35–21.7) | 0.33 |
Without hypertension | ||||||
Met+SU users | 1333 | 67,523 | 197 | Ref. | Ref. | – |
Met+AGI users | 11 | 1172 | 93.8 | 0.56 (0.31–1.01) | 0.63 (0.34–1.14) | 0.13 |
Met+TZD users | 10 | 918 | 109 | 0.64 (0.34–1.19) | 0.65 (0.35–1.21) | 0.17 |
Met+glinide users | 33 | 2106 | 157 | 0.87 (0.62–1.23) | 0.85 (0.60–1.21) | 0.37 |
Met+DPP-4I users | 0 | 61 | 0 | – | – | – |
With hypertension | ||||||
Met+SU users | 3179 | 87,936 | 362 | Ref. | Ref. | – |
Met+AGI users | 59 | 2562 | 230 | 0.70 (0.54–0.91) | 0.77 (0.59–1.00) | 0.04 |
Met+TZD users | 40 | 1896 | 211 | 0.64 (0.46–0.87) | 0.66 (0.48–0.90) | 0.009 |
Met+glinide users | 108 | 3081 | 351 | 1.04 (0.85–1.25) | 0.91 (0.75–1.10) | 0.33 |
Met+DPP-4I users | 2 | 132 | 151 | 0.59 (0.15–2.37) | 0.63 (0.16–2.54) | 0.52 |
Without hyperlipidemia | ||||||
Met+SU users | 2321 | 71,328 | 325 | Ref. | Ref. | – |
Met+AGI users | 23 | 1063 | 216 | 0.74 (0.49–1.11) | 0.70 (0.46–1.05) | 0.09 |
Met+TZD users | 21 | 900 | 233 | 0.79 (0.51–1.21) | 0.70 (0.46–1.08) | 0.11 |
Met+glinide users | 61 | 2249 | 271 | 0.89 (0.69–1.15) | 0.83 (0.64–1.07) | 0.14 |
Met+DPP-4I users | 1 | 52 | 192 | 0.83 (0.12–5.87) | 0.95 (0.13–6.75) | 0.96 |
With hyperlipidemia | ||||||
Met+SU users | 2191 | 84,131 | 260 | Ref. | Ref. | – |
Met+AGI users | 47 | 2671 | 176 | 0.76 (0.57–1.01) | 0.77 (0.58–1.03) | 0.08 |
Met+TZD users | 29 | 1914 | 152 | 0.64 (0.44–0.92) | 0.63 (0.44–0.91) | 0.01 |
Met+glinide users | 80 | 2938 | 272 | 1.12 (0.90–1.40) | 0.94 (0.75–1.18) | 0.60 |
Met+DPP-4I users | 1 | 142 | 70.7 | 0.41 (0.06–2.88) | 0.37 (0.05–2.63) | 0.32 |
Without HF | ||||||
Met+SU users | 4196 | 150,199 | 279 | Ref. | Ref. | – |
Met+AGI users | 61 | 3570 | 171 | 0.69 (0.54–0.89) | 0.72 (0.56–0.93) | 0.01 |
Met+TZD users | 43 | 2732 | 157 | 0.63 (0.46–0.85) | 0.61 (0.45–0.82) | 0.001 |
Met+glinide users | 128 | 4923 | 260 | 1.00 (0.84–1.20) | 0.90 (0.75–1.07) | 0.22 |
Met+DPP-4I users | 2 | 174 | 115 | 0.62 (0.16–2.50) | 0.67 (0.17–2.68) | 0.57 |
With HF | ||||||
Met+SU users | 316 | 5260 | 601 | Ref. | Ref. | – |
Met+AGI users | 9 | 164 | 548 | 0.96 (0.50–1.87) | 0.91 (0.46–1.79) | 0.79 |
Met+TZD users | 7 | 82 | 853 | 1.53 (0.72–3.24) | 1.43 (0.67–3.04) | 0.36 |
Met+glinide users | 13 | 264 | 493 | 0.86 (0.49–1.50) | 0.89 (0.51–1.56) | 0.69 |
Met+DPP-4I users | 0 | 19 | 0 | – | – |