Introduction
Methods
Participants and study design
Randomisation and treatments
Endpoints and assessments
Statistical analyses
Results
Participant disposition and baseline characteristics
Characteristic | PBO/SITA (n = 183) | SITA 100 mg (n = 366) | CANA 100 mg (n = 368) | CANA 300 mg (n = 367) | Total (N = 1,284) |
---|---|---|---|---|---|
Sex, n (%) | |||||
Male | 94 (51.4) | 172 (47.0) | 174 (47.3) | 165 (45.0) | 605 (47.1) |
Female | 89 (48.6) | 194 (53.0) | 194 (52.7) | 202 (55.0) | 679 (52.9) |
Age, years | 55.3 ± 9.8 | 55.5 ± 9.6 | 55.5 ± 9.4 | 55.3 ± 9.2 | 55.4 ± 9.4 |
Race, n (%) | |||||
White | 129 (70.5) | 264 (72.1) | 252 (68.5) | 256 (69.8) | 901 (70.2) |
Black or African-American | 3 (1.6) | 13 (3.6) | 16 (4.3) | 13 (3.5) | 45 (3.5) |
Asian | 30 (16.4) | 41 (11.2) | 51 (13.9) | 60 (16.3) | 182 (14.2) |
Othera
| 21 (11.5) | 48 (13.1) | 49 (13.3) | 38 (10.4) | 156 (12.1) |
HbA1c, % (mmol/mol) | 8.0 ± 0.9 (64 ± 9.8) | 7.9 ± 0.9 (63 ± 9.8) | 7.9 ± 0.9 (63 ± 9.8) | 7.9 ± 0.9 (63 ± 9.8) | 7.9 ± 0.9 (63 ± 9.8) |
FPG, mmol/l | 9.1 ± 2.1 | 9.4 ± 2.3 | 9.3 ± 2.3 | 9.6 ± 2.5 | 9.4 ± 2.3 |
Body weight, kg | 86.6 ± 22.4 | 87.7 ± 21.6 | 88.8 ± 22.2 | 85.4 ± 20.9 | 87.2 ± 21.7 |
BMI, kg/m2
| 31.1 ± 6.1 | 32.0 ± 6.1 | 32.4 ± 6.4 | 31.4 ± 6.3 | 31.8 ± 6.2 |
Duration of diabetes, years | 6.8 ± 5.3 | 6.8 ± 5.2 | 6.7 ± 5.4 | 7.1 ± 5.4 | 6.9 ± 5.3 |
Effect on glycaemic variables
Variable | SITA 100 mg (n = 366) | CANA 100 mg (n = 368) | CANA 300 mg (n = 367) |
---|---|---|---|
HbA1c, n
| 354 | 365 | 360 |
Mean ± SD baseline, % (mmol/mol) | 7.9 ± 0.9 (63 ± 9.8) | 7.9 ± 0.9 (63 ± 9.8) | 8.0 ± 0.9 (64 ± 9.8) |
LS mean ± SE change, % (mmol/mol) | −0.73 ± 0.05 (−8.0 ± 0.5) | −0.73 ± 0.05 (−8.0 ± 0.5) | −0.88 ± 0.05 (−9.6 ± 0.5) |
Difference vs SITA (95% CI), % | 0.00 (−0.12, 0.12) | −0.15 (−0.27, –0.03) | |
Difference vs SITA (95% CI), mmol/mol | 0.0 (−1.3, 1.3) | −1.6 (−3.0, –0.3) | |
FPG, n
| 354 | 365 | 360 |
Mean ± SD baseline, mmol/l | 9.4 ± 2.3 | 9.4 ± 2.3 | 9.6 ± 2.5 |
LS mean ± SE change | −1.0 ± 0.1 | −1.5 ± 0.1 | −2.0 ± 0.1 |
Difference vs SITA (95% CI) | −0.5 (−0.7, –0.2)a
| −1.0 (−1.2, –0.7)a
| |
Body weight, n
| 355 | 365 | 360 |
Mean ± SD baseline, kg | 87.6 ± 20.9 | 88.7 ± 22.3 | 85.4 ± 20.7 |
LS mean ± SE change, kg | −1.2 ± 0.2 | −3.3 ± 0.2 | −3.7 ± 0.2 |
LS mean ± SE per cent change | −1.3 ± 0.2 | −3.8 ± 0.2 | −4.2 ± 0.2 |
Difference vs SITA (95% CI) | −2.4 (−3.0, –1.8)a
| −2.9 (−3.4, –2.3)a
| |
Systolic BP, n
| 355 | 365 | 360 |
Mean ± SD baseline, mmHg | 128.0 ± 13.5 | 128.0 ± 12.7 | 128.7 ± 13.0 |
LS mean ± SE change | −0.7 ± 0.6 | −3.5 ± 0.6 | −4.7 ± 0.6 |
Difference vs SITA (95% CI) | −2.9 (−4.5, –1.3)a
| −4.0 (−5.6, –2.4)a
| |
Diastolic BP, n
| 355 | 365 | 360 |
Mean ± SD baseline, mmHg | 77.5 ± 8.0 | 77.7 ± 8.4 | 77.9 ± 8.3 |
LS mean ± SE change | −0.3 ± 0.4 | −1.8 ± 0.4 | −1.8 ± 0.4 |
Difference vs SITA (95% CI) | −1.4 (−2.4, –0.5)b
| −1.5 (−2.5, –0.5)b
| |
Triacylglycerol, n
| 339 | 359 | 343 |
Mean ± SD baseline, mmol/l | 2.0 ± 1.1 | 2.2 ± 1.6 | 2.1 ± 1.5 |
LS mean ± SE change | −0.15 ± 0.05 | −0.12 ± 0.05 | −0.19 ± 0.05 |
Median (IQR) per cent change | −3.3 (−22.8, 16.7) | −2.7 (−28.4, 22.5) | −8.7 (−29.1, 23.3) |
LS mean ± SE per cent change | −0.4 ± 2.5 | 1.9 ± 2.4 | 2.8 ± 2.4 |
Difference vs SITA (95% CI) | 2.3 (−3.9, 8.5)c
| 3.2 (−3.1, 9.5)c
| |
LDL-cholesterol, n
| 338 | 358 | 343 |
Mean ± SD baseline, mmol/l | 2.8 ± 0.9 | 2.8 ± 0.8 | 2.8 ± 0.9 |
LS mean ± SE change | 0.08 ± 0.04 | 0.11 ± 0.04 | 0.11 ± 0.04 |
Median (IQR) per cent change | 0.9 (−9.6, 16.8) | 6.0 (−9.9, 21.8) | 5.3 (−8.8, 22.6) |
LS mean ± SE per cent change | 6.0 ± 1.8 | 7.7 ± 1.7 | 8.8 ± 1.8 |
Difference vs SITA (95% CI) | 1.7 (−2.8, 6.2)b
| 2.8 (−1.8, 7.4)b
| |
HDL-cholesterol, n
| 338 | 359 | 343 |
Mean ± SD baseline, mmol/l | 1.2 ± 0.3 | 1.2 ± 0.3 | 1.2 ± 0.3 |
LS mean ± SE change | 0.06 ± 0.01 | 0.12 ± 0.01 | 0.14 ± 0.01 |
Median (IQR) per cent change | 4.4 (−4.0, 14.8) | 8.0 (0.0, 19.8) | 11.1 (0.0, 22.8) |
LS mean ± SE per cent change | 6.0 ± 1.1 | 11.2 ± 1.0 | 13.2 ± 1.1 |
Difference vs SITA (95% CI) | 5.2 (2.5, 7.9)d
| 7.2 (4.4, 10.0)d
| |
LDL-cholesterol/HDL-cholesterol, n
| 338 | 358 | 343 |
Mean ± SD baseline, mol/mol | 2.6 ± 1.0 | 2.5 ± 0.9 | 2.4 ± 0.9 |
LS mean ± SE change | −0.04 ± 0.04 | −0.13 ± 0.04 | −0.15 ± 0.04 |
Median (IQR) per cent change | −1.7 (−14.1, 14.6) | −5.3 (−19.3, 11.7) | −4.3 (−18.1, 13.2) |
LS mean ± SE per cent change | 1.6 ± 1.8 | −0.8 ± 1.8 | −1.3 ± 1.8 |
Difference vs SITA (95% CI) | −2.4 (−7.1, 2.2)b
| −2.9 (−7.6, 1.8)b
| |
Non-HDL-cholesterol, n
| 337 | 357 | 340 |
Mean ± SD baseline, mmol/l | 3.7 ± 1.0 | 3.8 ± 1.1 | 3.7 ± 1.0 |
LS mean ± SE change | 0.03 ± 0.05 | 0.04 ± 0.05 | 0.05 ± 0.05 |
Median (IQR) per cent change | 1.9 (−9.7, 13.7) | 2.4 (−8.8, 14.8) | 2.8 (−8.3, 18.8) |
LS mean ± SE per cent change | 2.8 ± 1.4 | 3.8 ± 1.3 | 4.0 ± 1.4 |
Difference vs SITA (95% CI) | 0.9 (−2.6, 4.4)b
| 1.1 (−2.4, 4.7)b
|
Effect on body weight, BP and lipids
Safety and tolerability
AE | No. (%) of participants | |||
---|---|---|---|---|
PBO/SITA (n = 183) | SITA 100 mg (n = 366) | CANA 100 mg (n = 368) | CANA 300 mg (n = 367) | |
Any AE | 122 (66.7) | 236 (64.5) | 266 (72.3) | 230 (62.7) |
AEs leading to discontinuation | 8 (4.4) | 16 (4.4) | 19 (5.2) | 12 (3.3) |
AEs related to study druga
| 23 (12.6) | 72 (19.7) | 97 (26.4) | 73 (19.9) |
Serious AEs | 7 (3.8) | 18 (4.9) | 15 (4.1) | 12 (3.3) |
Deaths | 1 (0.5) | 1 (0.3) | 0 | 1 (0.3) |
Selected AEs | ||||
UTI | 12 (6.6) | 23 (6.3) | 29 (7.9) | 18 (4.9) |
Genital mycotic infection | ||||
Menb,c
| 1 (1.1) | 2 (1.2) | 9 (5.2) | 4 (2.4) |
Womend,e
| 1 (1.1) | 5 (2.6) | 22 (11.3) | 20 (9.9) |
Osmotic diuresis-related AEs | ||||
Pollakiuriaf
| 1 (0.5) | 2 (0.5) | 21 (5.7) | 11 (3.0) |
Polyuriag
| 0 | 0 | 2 (0.5) | 2 (0.5) |
Volume-related AEs | ||||
Postural dizziness | 1 (0.5) | 1 (0.3) | 2 (0.5) | 2 (0.5) |
Orthostatic hypotension | 0 | 0 | 0 | 1 (0.3) |
Variable | PBO/SITA | SITA 100 mg | CANA 100 mg | CANA 300 mg |
---|---|---|---|---|
ALT, n
| 137 | 282 | 294 | 293 |
Mean baseline, μkat/l | 0.5 | 0.5 | 0.5 | 0.5 |
Mean ± SD per cent change | 7.1 ± 40.7 | 5.1 ± 41.6 | −2.2 ± 39.9 | −10.2 ± 39.6 |
AST, n
| 137 | 281 | 292 | 293 |
Mean baseline, μkat/l | 0.4 | 0.4 | 0.4 | 0.4 |
Mean ± SD per cent change | 9.8 ± 31.8 | 7.1 ± 36.8 | 2.6 ± 32.6 | −2.4 ± 28.9 |
Bilirubin, n
| 138 | 282 | 296 | 293 |
Mean baseline, μmol/l | 9.1 | 8.7 | 9.0 | 8.5 |
Mean ± SD per cent change | −3.9 ± 31.4 | −1.3 ± 33.4 | 11.6 ± 45.6 | 14.3 ± 41.1 |
BUN, n
| 139 | 282 | 296 | 295 |
Mean baseline, mmol/l | 5.4 | 5.5 | 5.1 | 5.2 |
Mean ± SD per cent change | 5.9 ± 33.8 | 3.5 ± 26.6 | 14.8 ± 26.7 | 16.1 ± 33.4 |
Creatinine, n
| 139 | 282 | 296 | 295 |
Mean baseline, μmol/l | 73.9 | 72.0 | 71.4 | 70.2 |
Mean ± SD per cent change | 3.3 ± 18.0 | 3.4 ± 13.6 | 2.3 ± 11.4 | 2.5 ± 12.4 |
eGFR, n
| 139 | 282 | 296 | 295 |
Mean baseline, ml min−1 (1.73 m2)−1
| 87.7 | 89.1 | 89.7 | 90.2 |
Mean ± SD per cent change | −1.4 ± 18.2 | −2.4 ± 12.8 | −1.4 ± 12.8 | −1.5 ± 12.9 |
Urate, n
| 139 | 282 | 296 | 295 |
Mean baseline, μmol/l | 333.4 | 328.8 | 316.6 | 311.2 |
Mean ± SD per cent change | 5.0 ± 17.4 | 3.9 ± 18.4 | −10.5 ± 18.3 | −11.0 ± 18.8 |
Haemoglobin, n
| 134 | 277 | 292 | 285 |
Mean baseline, g/l | 141.3 | 141.0 | 140.5 | 140.0 |
Mean ± SD per cent change | −1.6 ± 6.0 | −1.6 ± 6.2 | 4.0 ± 7.2 | 3.7 ± 7.1 |