Recent data for ertugliflozin [7] suggest an imbalance in atraumatic lower limb amputation, with rates per 1000 participant-years in the 15?mg, 5?mg and comparator groups of 4.4, 1.6 and 0.6 across the development programme (12 events) and 5.0, 6.8 and 4.3 in the individual and ongoing cardiovascular end result trial (61 events). 71%, major 29%); as previously published, rates were 6.30 vs 3.37 per 1000 participant-years with canagliflozin vs placebo (HR 1.97 [95% CI 1.41, 2.75]). Risk was comparable for ischaemic and GSK369796 infective aetiologies and for 100?mg and 300?mg doses. Overall amputation risk was strongly associated with baseline history of prior amputation (major or minor) (HR 21.31 [95% CI 15.40, 29.49]) and other established risk factors. No interactions between randomised treatment and participant characteristics explained the effect of canagliflozin on amputation risk. For every clinical subgroup studied, numbers of amputation events projected were smaller than numbers of major adverse cardiovascular events averted. Conclusions/interpretation The CANVAS Program exhibited that canagliflozin increased the risk of amputation (mainly minor) in this study population. Anticipated risk factors for amputation were identified, such GSK369796 as prior history of amputation, peripheral vascular disease and neuropathy, but no specific aetiological mechanism or at-risk subgroup for canagliflozin was recognized. Electronic supplementary material The online version of this article (10.1007/s00125-019-4839-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users. value (total with amputation vs total without amputation)b(%)27 (19.3)5 (10.6)32 (17.1)2007 (35.5)1592 (37.0)3599 (36.2) 0.001Race, (%)0.008?White120 (85.7)44 (93.6)164 (87.7)4385 (77.6)3389 (78.9)7774 (78.2)?Asian8 (5.7)2 (4.3)10 (5.3)769 (13.6)505 (11.7)1274 (12.8)?Black or African-American2 (1.4)1 (2.1)3 (1.6)173 (3.1)159 (3.7)332 (3.3)?Otherc10 (7.1)0 (0.0)10 (5.3)323 (5.7)244 (5.7)567 (5.7)Current smoker, (%)22 (15.7)14 (29.8)36 (19.3)996 (17.6)770 (17.9)1766 (17.8)0.597History of hypertension, (%)123 (87.9)42 (89.4)165 (88.2)5060 (89.6)3893 (90.6)8953 (90.0)0.424Duration 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) 0.001Microvascular disease history, (%)?Nephropathy40 (28.6)16 (34.0)56 (29.9)953 (16.9)763 (17.8)1716 (17.3) 0.001?Retinopathy50 (35.7)19 (40.4)69 (36.9)1152 (20.4)906 (21.1)2058 GSK369796 (20.7) 0.001?Neuropathy84 (60.0)27 (57.4)111 (59.4)1703 (30.1)1295 (30.1)2998 (30.1) 0.001Atherosclerotic disease, (%)d?Coronary83 (59.3)28 (59.6)111 (59.4)3148 (55.7)2458 (57.2)5606 (56.4)0.413?Cerebrovascular35 (25.0)10 (21.3)45 (24.1)1076 (19.0)835 (19.4)1911 (19.2)0.111?Peripheral81 (57.9)32 (68.1)113 (60.4)1094 (19.4)904 (21.0)1998 (20.1) 0.001?Any129 (92.1)43 (91.5)172 (92.0)3994 (70.7)3152 (73.4)7146 (71.8) 0.001History of cardiovascular disease, (%)e116 (82.9)38 (80.9)154 (82.4)3636 (64.4)2861 (66.6)6497 (65.3) 0.001History of atrial fibrillation, (%)12 (8.6)6 (12.8)18 (9.6)339 (6.0)256 (6.0)595 (6.0)0.038History of heart failure, (%)27 (19.3)8 (17.0)35 (18.7)774 (13.7)650 (15.1)1424 (14.3)0.093History of amputation, (%)38 (27.1)13 (27.7)51 (27.3)98 (1.7)88 (2.0)186 (1.9) 0.001BMI, 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)0.0765Systolic 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)0.3947Diastolic 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)0.7711HbA1c, mmol/mol, mean (SD)69 (9.8)68 (10.9)69 (9.8)66 (9.8)66 (9.8)66 (9.8) 0.001HbA1c, %, 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) 0.001LDL-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)0.3481LDL/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)0.1537eGFR, ml?min?1 [1.73?m]?2, mean (SD)f72.4 (18.2)73.7 (23.5)72.7 (19.7)76.8 (20.3)76.2 (20.8)76.5 (20.5)0.0121Micro- or macroalbuminuria, (%)g69 (49.6)26 (56.5)95 (51.4)1656 (29.6)1272 (30.0)2928 (29.7) 0.001Concomitant drug therapies, (%)?Insulin96 (68.6)35 (74.5)131 (70.1)2793 (49.4)2169 (50.5)4962 (49.9) 0.001?Metformin92 (65.7)37 (78.7)129 Ik3-2 antibody (69.0)4351 (77.0)3340 (77.7)7691 (77.3)0.0071?Sulfonylurea51 (36.4)18 (38.3)69 (36.9)2475 (43.8)1815 (42.2)4290 (43.1)0.0882?GLP-1 receptor agonist8 (5.7)2 (4.3)10 (5.3)214 (3.8)183 (4.3)397 (4.0)0.3493?DPP-4 inhibitor12 (8.6)5 (10.6)17 (9.1)685 (12.1)559 (13.0)1244 (12.5)0.1610?Loop diuretic33 (23.6)8 (17.0)41 (21.9)683 (12.1)584 (13.6)1267 (12.7)0.0002?Non-loop diuretic53 (37.9)17 (36.2)70 (37.4)2030 (35.9)1546 (36.0)3576 (36.0)0.6756?Calcium antagonist52 (37.1)17 (36.2)69 (36.9)1878 (33.2)1496 (34.8)3374 (33.9)0.3942?RAAS inhibitor112 (80.0)36 (76.6)148 (79.1)4530 (80.2)3435 (79.9)7965 (80.1)0.7525?-Blocker79 (56.4)30 (63.8)109 (58.3)2959 (52.4)2352 (54.7)5311 (53.4)0.1836?Statin102 (72.9)35 (74.5)137 (73.3)4224 (74.8)3235 (75.3)7459 (75.0)0.5895?Aspirin67 (47.9)20 (42.6)87 (46.5)1884 (33.3)978 (22.8)2862 (28.8) 0.001?Other antithrombotic41 (29.3)24 (51.1)65 (34.8)2240 (39.6)2213 (51.5)4453 (44.8)0.006 Open in a separate window aOne participant was randomised at two different sites and only the first randomisation is included in the intention-to-treat analysis set bAnalysed with a Wilcoxon two-sample test cIncludes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple, other and unknown dSome participants had 1 type of atherosclerotic disease eAs defined in the protocol fValues for eGFR.