Introduction
Methods
Results
Characteristic | Participants with amputation | Participants without amputation | p value (total with amputation vs total without amputation)b | ||||
---|---|---|---|---|---|---|---|
Canagliflozin (n = 140) | Placebo (n = 47) | Total (n = 187) | Canagliflozin (n = 5650) | Placebo (n = 4297) | Total (n = 9947) | ||
Age, years, mean (SD) | 62.3 (7.1) | 60.9 (6.3) | 62.0 (6.9) | 63.2 (8.3) | 63.5 (8.2) | 63.3 (8.3) | 0.025 |
Female sex, n (%) | 27 (19.3) | 5 (10.6) | 32 (17.1) | 2007 (35.5) | 1592 (37.0) | 3599 (36.2) | <0.001 |
Race, n (%) | 0.008 | ||||||
White | 120 (85.7) | 44 (93.6) | 164 (87.7) | 4385 (77.6) | 3389 (78.9) | 7774 (78.2) | |
Asian | 8 (5.7) | 2 (4.3) | 10 (5.3) | 769 (13.6) | 505 (11.7) | 1274 (12.8) | |
Black or African-American | 2 (1.4) | 1 (2.1) | 3 (1.6) | 173 (3.1) | 159 (3.7) | 332 (3.3) | |
Otherc | 10 (7.1) | 0 (0.0) | 10 (5.3) | 323 (5.7) | 244 (5.7) | 567 (5.7) | |
Current smoker, n (%) | 22 (15.7) | 14 (29.8) | 36 (19.3) | 996 (17.6) | 770 (17.9) | 1766 (17.8) | 0.597 |
History of hypertension, n (%) | 123 (87.9) | 42 (89.4) | 165 (88.2) | 5060 (89.6) | 3893 (90.6) | 8953 (90.0) | 0.424 |
Duration of diabetes, years, mean (SD) | 16.8 (8.6) | 14.8 (8.4) | 16.3 (8.6) | 13.4 (7.7) | 13.7 (7.8) | 13.5 (7.7) | <0.001 |
Microvascular disease history, n (%) | |||||||
Nephropathy | 40 (28.6) | 16 (34.0) | 56 (29.9) | 953 (16.9) | 763 (17.8) | 1716 (17.3) | <0.001 |
Retinopathy | 50 (35.7) | 19 (40.4) | 69 (36.9) | 1152 (20.4) | 906 (21.1) | 2058 (20.7) | <0.001 |
Neuropathy | 84 (60.0) | 27 (57.4) | 111 (59.4) | 1703 (30.1) | 1295 (30.1) | 2998 (30.1) | <0.001 |
Atherosclerotic disease, n (%)d | |||||||
Coronary | 83 (59.3) | 28 (59.6) | 111 (59.4) | 3148 (55.7) | 2458 (57.2) | 5606 (56.4) | 0.413 |
Cerebrovascular | 35 (25.0) | 10 (21.3) | 45 (24.1) | 1076 (19.0) | 835 (19.4) | 1911 (19.2) | 0.111 |
Peripheral | 81 (57.9) | 32 (68.1) | 113 (60.4) | 1094 (19.4) | 904 (21.0) | 1998 (20.1) | <0.001 |
Any | 129 (92.1) | 43 (91.5) | 172 (92.0) | 3994 (70.7) | 3152 (73.4) | 7146 (71.8) | <0.001 |
History of cardiovascular disease, n (%)e | 116 (82.9) | 38 (80.9) | 154 (82.4) | 3636 (64.4) | 2861 (66.6) | 6497 (65.3) | <0.001 |
History of atrial fibrillation, n (%) | 12 (8.6) | 6 (12.8) | 18 (9.6) | 339 (6.0) | 256 (6.0) | 595 (6.0) | 0.038 |
History of heart failure, n (%) | 27 (19.3) | 8 (17.0) | 35 (18.7) | 774 (13.7) | 650 (15.1) | 1424 (14.3) | 0.093 |
History of amputation, n (%) | 38 (27.1) | 13 (27.7) | 51 (27.3) | 98 (1.7) | 88 (2.0) | 186 (1.9) | <0.001 |
BMI, kg/m2, mean (SD) | 32.5 (5.9) | 33.3 (6.9) | 32.7 (6.1) | 31.9 (5.9) | 32.0 (5.9) | 31.9 (5.9) | 0.0765 |
Systolic BP, mmHg, mean (SD) | 138.5 (16.4) | 135.0 (15.7) | 137.6 (16.3) | 136.4 (15.8) | 136.9 (15.8) | 136.6 (15.8) | 0.3947 |
Diastolic BP, mmHg, mean (SD) | 77.3 (9.4) | 78.0 (10.1) | 77.5 (9.6) | 77.6 (9.6) | 77.8 (9.7) | 77.7 (9.7) | 0.7711 |
HbA1c, mmol/mol, mean (SD) | 69 (9.8) | 68 (10.9) | 69 (9.8) | 66 (9.8) | 66 (9.8) | 66 (9.8) | <0.001 |
HbA1c, %, mean (SD) | 8.5 (0.9) | 8.4 (1.0) | 8.5 (0.9) | 8.2 (0.9) | 8.2 (0.9) | 8.2 (0.9) | <0.001 |
LDL-cholesterol, mmol/l, mean (SD) | 2.3 (1.0) | 2.5 (0.9) | 2.4 (1.0) | 2.3 (0.9) | 2.3 (0.9) | 2.3 (0.9) | 0.3481 |
LDL/HDL-cholesterol ratio, mean (SD) | 2.1 (1.0) | 2.3 (0.8) | 2.1 (0.9) | 2.0 (0.9) | 2.0 (0.9) | 2.0 (0.9) | 0.1537 |
eGFR, ml min−1 [1.73 m]−2, mean (SD)f | 72.4 (18.2) | 73.7 (23.5) | 72.7 (19.7) | 76.8 (20.3) | 76.2 (20.8) | 76.5 (20.5) | 0.0121 |
Micro- or macroalbuminuria, n (%)g | 69 (49.6) | 26 (56.5) | 95 (51.4) | 1656 (29.6) | 1272 (30.0) | 2928 (29.7) | <0.001 |
Concomitant drug therapies, n (%) | |||||||
Insulin | 96 (68.6) | 35 (74.5) | 131 (70.1) | 2793 (49.4) | 2169 (50.5) | 4962 (49.9) | <0.001 |
Metformin | 92 (65.7) | 37 (78.7) | 129 (69.0) | 4351 (77.0) | 3340 (77.7) | 7691 (77.3) | 0.0071 |
Sulfonylurea | 51 (36.4) | 18 (38.3) | 69 (36.9) | 2475 (43.8) | 1815 (42.2) | 4290 (43.1) | 0.0882 |
GLP-1 receptor agonist | 8 (5.7) | 2 (4.3) | 10 (5.3) | 214 (3.8) | 183 (4.3) | 397 (4.0) | 0.3493 |
DPP-4 inhibitor | 12 (8.6) | 5 (10.6) | 17 (9.1) | 685 (12.1) | 559 (13.0) | 1244 (12.5) | 0.1610 |
Loop diuretic | 33 (23.6) | 8 (17.0) | 41 (21.9) | 683 (12.1) | 584 (13.6) | 1267 (12.7) | 0.0002 |
Non-loop diuretic | 53 (37.9) | 17 (36.2) | 70 (37.4) | 2030 (35.9) | 1546 (36.0) | 3576 (36.0) | 0.6756 |
Calcium antagonist | 52 (37.1) | 17 (36.2) | 69 (36.9) | 1878 (33.2) | 1496 (34.8) | 3374 (33.9) | 0.3942 |
RAAS inhibitor | 112 (80.0) | 36 (76.6) | 148 (79.1) | 4530 (80.2) | 3435 (79.9) | 7965 (80.1) | 0.7525 |
β-Blocker | 79 (56.4) | 30 (63.8) | 109 (58.3) | 2959 (52.4) | 2352 (54.7) | 5311 (53.4) | 0.1836 |
Statin | 102 (72.9) | 35 (74.5) | 137 (73.3) | 4224 (74.8) | 3235 (75.3) | 7459 (75.0) | 0.5895 |
Aspirin | 67 (47.9) | 20 (42.6) | 87 (46.5) | 1884 (33.3) | 978 (22.8) | 2862 (28.8) | <0.001 |
Other antithrombotic | 41 (29.3) | 24 (51.1) | 65 (34.8) | 2240 (39.6) | 2213 (51.5) | 4453 (44.8) | 0.006 |
Characteristic | Univariate | Multivariate |
---|---|---|
Demographics | ||
Male sex | 2.63 (1.80, 3.85) | 2.26 (1.53, 3.35) |
Age (year older) | 0.98 (0.97, 1.00) | |
Current smoker | 1.11 (0.77, 1.59) | |
Race | ||
White vs non-white | 2.18 (1.41, 3.38) | |
Asian vs non-Asian | 0.32 (0.17, 0.61) | 0.44 (0.23, 0.85) |
Black vs non-Black | 0.59 (0.19, 1.86) | |
Region | ||
North America vs others | 1.07 (0.77, 1.48) | |
Central/South America vs others | 1.64 (1.03, 2.62) | |
Europe vs others | 1.13 (0.84, 1.52) | |
Rest of world vs others | 0.68 (0.49, 0.94) | |
Prior amputation (Yes/No) | 21.31 (15.40, 29.49) | 16.27 (10.65, 24.63) |
Peripheral vascular disease (Yes/No)a | 2.51 (1.85, 3.41) | 2.77 (1.93, 3.96) |
Cardiovascular disease (Yes/No) | 2.85 (1.95, 4.16) | |
Microvascular disease history | ||
Neuropathy (Yes/No) | 3.38 (2.52, 4.52) | 1.86 (1.35, 2.56) |
Nephropathy (Yes/No) | 2.18 (1.60, 2.99) | |
Retinopathy (Yes/No) | 2.27 (1.69, 3.06) | |
Any albuminuria (Yes/No) | 2.65 (1.99, 3.54) | 1.63 (1.20, 2.22) |
Hypertension (Yes/No) | 0.91 (0.58, 1.42) | |
Heart failure (Yes/No) | 1.52 (1.05, 2.19) | |
Duration of diabetes (year greater) | 1.04 (1.03, 1.06) | |
Concomitant medications (Yes/No) | ||
Insulin use | 2.37 (1.73, 3.24) | |
Sulfonylurea | 0.72 (0.53, 0.97) | |
Metformin | 0.68 (0.50, 0.93) | |
GLP-1 receptor agonist | 1.59 (0.84, 3.03) | |
DPP-4 inhibitor | 0.83 (0.50, 1.37) | |
Loop diuretic | 1.26 (0.95, 1.68) | |
Non-loop diuretic | 1.04 (0.77, 1.40) | |
Statin | 0.94 (0.68, 1.30) | |
Aspirin | 1.34 (0.89, 2.03) | |
Other antithrombotic | 1.70 (1.04, 2.80) | |
RAAS inhibitor | 0.93 (0.66, 1.33) | |
β-Blocker | 1.28 (0.96, 1.71) | |
Calcium channel blocker | 1.17 (0.87, 1.57) | |
Laboratory and clinical variables | ||
HbA1c (10.9 mmol/mol [1%] greater) | 1.37 (1.18, 1.58) | |
HbA1c (≥64 mmol/mol [8%] vs <64 mmol/mol [8%]) | 2.12 (1.54, 2.93) | 1.99 (1.43, 2.76) |
Haemoglobin (1 g/l greater) | 1.00 (0.99, 1.01) | |
eGFR (1 ml/min greater) | 0.99 (0.98, 1.00) | |
Systolic BP (1 mmHg greater) | 1.00 (1.00, 1.01) | |
Haematocrit (1% greater) | 1.00 (0.97, 1.04) | |
BMI (1 kg/m2 greater) | 1.02 (1.00, 1.04) | |
LDL-cholesterol (0.026 mmol/l greater) | 1.08 (0.93, 1.26) | |
HDL-cholesterol (0.026 mmol/l greater) | 0.74 (0.45, 1.19) | |
Triacylglycerols (0.011 mmol/l greater) | 1.07 (1.00, 1.15) | |
Canagliflozin treatment | 1.97 (1.41, 2.75) | 1.82 (1.29, 2.56) |
Risk factor | Participants excluded n (%) | Participants with an amputation n events per 1000 participant-years | Amputations among 1000 participants treated for 5 years n (95% CI) | Major adverse cardiovascular events prevented among 1000 participants treated for 5 years n (95% CI) | ||
---|---|---|---|---|---|---|
Canagliflozin | Placebo | All | Major | |||
All participants | 0 (0) | 6.3 | 3.4 | 15 (8, 22) | 4 (1, 8) | 23 (4, 41) |
Excluding those with baseline risks identified as independent in multivariate modelling | ||||||
Amputation | 237 (2) | 4.7 | 2.5 | 11 (5, 17) | 5 (2, 8) | 21 (3, 40) |
Macroalbuminuria | 865 (9) | 5.5 | 2.9 | 13 (6, 20) | 4 (1, 8) | 17 (–2, 35) |
Male sex | 6503 (64) | 3.5 | 1.0 | 13 (5, 20) | 4 (–1, 9) | 17 (–11, 45) |
Non-Asian ethnicity | 8850 (87) | 2.3 | 1.0 | 6 (–4, 17) | 4 (–1, 9) | –2 (–39, 36) |
PVDa | 1874 (18) | 5.2 | 2.4 | 14 (7, 21) | 3 (–1, 7) | 19 (0, 39) |
Neuropathy | 3109 (31) | 3.6 | 2.0 | 8 (1, 14) | 3 (–1, 6) | 28 (7, 49) |
HbA1c ≥64 mmol/mol (8%) | 5729 (57) | 3.6 | 2.5 | 5 (–3, 14) | 3 (–2, 7) | 11 (–14, 37) |
Excluding those with baseline risk combinations | ||||||
Amputation or macroalbuminuria | 937 (9) | 4.2 | 2.3 | 10 (4, 16) | 5 (2, 8) | 15 (–4, 33) |
PVD or macroalbuminuria | 2467 (24) | 4.5 | 2.0 | 13 (6, 19) | 3 (–1, 6) | 13 (–7, 33) |
Amputation or PVD | 2111 (21) | 3.2 | 1.3 | 10 (4, 15) | 3 (0, 6) | 17 (–2, 37) |
Neuropathy or macroalbuminuria | 3588 (35) | 3.1 | 1.4 | 8 (2, 14) | 3 (0, 7) | 12 (0, 24) |
Amputation or neuropathy | 3211 (32) | 2.7 | 1.6 | 6 (0, 12) | 3 (0, 6) | 26 (5, 47) |
PVD or neuropathy | 4037 (40) | 3.0 | 1.2 | 9 (3, 15) | 2 (–1, 4) | 23 (1, 44) |
Amputation, PVD or macroalbuminuria | 2644 (26) | 2.9 | 1.2 | 9 (3, 14) | 3 (0, 6) | 11 (–8, 310) |
Amputation, neuropathy or macroalbuminuria | 3664 (36) | 2.3 | 1.3 | 5 (0, 10) | 3 (0, 6) | 19 (–2, 40) |
PVD, neuropathy or macroalbuminuria | 4438 (44) | 2.5 | 0.7 | 9 (4, 14) | 2 (0, 5) | 18 (–4, 39) |
Amputation, PVD or neuropathy | 4139 (41) | 2.0 | 0.6 | 7 (2, 12) | 2 (0, 4) | 21 (–1, 43) |
Amputation, PVD, neuropathy or macroalbuminuria | 4512 (45) | 1.7 | 0.6 | 5 (1, 10) | 2 (–1, 4) | 16 (–6, 38) |