Background
Methods
Study design and patient population
Inclusion criteria | Patients contributing to pooled analysis, n | ||||||||
---|---|---|---|---|---|---|---|---|---|
Study | Duration*
| Age, y | HbA1c, % | eGFR, | PBO | CANA | CANA | Total | Aged |
mL/min/1.73 m2
| 100 mg | 300 mg | ≥65 y | ||||||
Monotherapy | 26 weeks | ≥18 to ≤80 | ≥7.0 and ≤10.0 | ≥50 | 192 | 195 | 197 | 584 | 118 |
Add-on to MET | 26 weeks | ≥18 to ≤80 | ≥7.0 and ≤10.5 | ≥55 | 183 | 368 | 367 | 918 | 149 |
Add-on to MET + SU | 26 weeks | ≥18 to ≤80 | ≥7.0 and ≤10.5 | ≥55 | 156 | 157 | 156 | 469 | 85 |
Add-on to MET + PIO | 26 weeks | ≥18 to ≤80 | ≥7.0 and ≤10.5 | ≥55 | 115 | 113 | 114 | 342 | 93 |
Overall total, n
|
646
|
833
|
834
|
2,313
|
445
|
Endpoints and assessments
Statistical analyses
Results
Patient disposition and baseline characteristics
Patients <65 y | Patients ≥65 y | |||||
---|---|---|---|---|---|---|
Characteristic | PBO | CANA 100 mg | CANA 300 mg | PBO | CANA 100 mg | CANA 300 mg |
(n = 509) | (n = 674) | (n = 685) | (n = 137) | (n = 159) | (n = 149) | |
Sex, n (%) | ||||||
Male | 263 (51.7) | 327 (48.5) | 327 (47.7) | 71 (51.8) | 81 (50.9) | 77 (51.7) |
Female | 246 (48.3) | 347 (51.5) | 358 (52.3) | 66 (48.2) | 78 (49.1) | 72 (48.3) |
Age, y | 53.0 ± 8.1 | 52.6 ± 8.1 | 52.8 ± 7.8 | 68.7 ± 3.5 | 70.0 ± 3.6 | 69.1 ± 3.5 |
Race, n (%)†
| ||||||
White | 358 (70.3) | 455 (67.5) | 482 (70.4) | 112 (81.8) | 136 (85.5) | 128 (85.9) |
Black or African American | 23 (4.5) | 40 (5.9) | 43 (6.3) | 5 (3.6) | 3 (1.9) | 5 (3.4) |
Asian | 75 (14.7) | 99 (14.7) | 92 (13.4) | 7 (5.1) | 4 (2.5) | 8 (5.4) |
Other‡
| 53 (10.4) | 80 (11.9) | 68 (9.9) | 13 (9.5) | 16 (10.1) | 8 (5.4) |
HbA1c, % | 8.1 ± 1.0 | 8.0 ± 0.9 | 8.0 ± 1.0 | 7.8 ± 0.8 | 7.9 ± 0.9 | 7.9 ± 0.9 |
FPG, mmol/L | 9.3 ± 2.2 | 9.4 ± 2.3 | 9.4 ± 2.3 | 9.0 ± 2.1 | 9.6 ± 2.4 | 9.6 ± 2.6 |
Body weight, kg | 90.1 ± 22.3 | 91.0 ± 22.7 | 89.3 ± 22.8 | 86.3 ± 19.4 | 84.6 ± 19.7 | 84.6 ± 17.7 |
BMI, kg/m2
| 32.2 ± 6.7 | 32.7 ± 6.6 | 32.3 ± 6.7 | 30.8 ± 5.0 | 30.8 ± 5.2 | 30.5 ± 5.2 |
Systolic BP, mmHg | 127.4 ± 13.2 | 126.9 ± 12.6 | 127.6 ± 12.6 | 132.7 ± 13.1 | 132.5 ± 12.8 | 134.3 ± 12.5 |
eGFR, mL/min/1.73 m2
| 90.0 ± 19.9 | 90.9 ± 19.0 | 91.3 ± 18.9 | 75.9 ± 15.1 | 77.3 ± 14.6 | 77.4 ± 13.5 |
Duration of diabetes, y | 6.7 ± 5.4 | 6.4 ± 5.2 | 6.7 ± 5.4 | 10.2 ± 7.9 | 10.5 ± 7.0 | 10.8 ± 8.1 |
Patients with cardiac disorders, n (%)§
| 64 (12.6) | 85 (12.6) | 87 (12.7) | 39 (28.5) | 46 (28.9) | 45 (30.2) |
Patients on antihypertensive medications, n (%)||
| 305 (59.9) | 415 (61.6) | 408 (59.6) | 110 (80.3) | 120 (75.5) | 115 (77.2) |
Efficacy
Glycaemic parameters
Body weight and BP
Safety and tolerability
Overall safety and tolerability
Patients <65 y, n (%) | Patients ≥65 y, n (%) | |||||
---|---|---|---|---|---|---|
PBO | CANA 100 mg | CANA 300 mg | PBO | CANA 100 mg | CANA 300 mg | |
(n = 509) | (n = 674) | (n = 685) | (n = 137) | (n = 159) | (n = 149) | |
Any AE | 300 (58.9) | 404 (59.9) | 404 (59.0) | 84 (61.3) | 97 (61.0) | 90 (60.4) |
AEs leading to discontinuation | 14 (2.8) | 22 (3.3) | 22 (3.2) | 6 (4.4) | 14 (8.8) | 8 (5.4) |
AEs related to study drug†
| 66 (13.0) | 136 (20.2) | 155 (22.6) | 19 (13.9) | 35 (22.0) | 36 (24.2) |
Serious AEs | 17 (3.3) | 17 (2.5) | 17 (2.5) | 5 (3.6) | 11 (6.9) | 5 (3.4) |
Deaths | 1 (0.2) | 1 (0.1) | 1 (0.1) | 1 (0.7) | 0 | 0 |
Selected AEs | ||||||
UTI | 20 (3.9) | 41 (6.1) | 29 (4.2) | 6 (4.4) | 8 (5.0) | 7 (4.7) |
Genital mycotic infection | ||||||
Male‡,§
| 2 (0.8) | 14 (4.3) | 11 (3.4) | 0 | 3 (3.7) | 4 (5.2) |
Female||,¶
| 10 (4.1) | 37 (10.7) | 44 (12.3) | 0 | 7 (9.0) | 5 (6.9) |
Osmotic diuresis-related AEs#
| 4 (0.8) | 44 (6.5) | 39 (5.7) | 1 (0.7) | 12 (7.5) | 8 (5.4) |
Volume depletion-related AEs**
| 5 (1.0) | 6 (0.9) | 8 (1.2) | 2 (1.5) | 4 (2.5) | 3 (2.0) |
Renal-related AEs††
| 2 (0.4) | 2 (0.3) | 12 (1.8) | 2 (1.5) | 3 (1.9) | 2 (1.3) |
Fasting plasma lipids
Patients <65 y | Patients ≥65 y | |||||
---|---|---|---|---|---|---|
PBO | CANA 100 mg | CANA 300 mg | PBO | CANA 100 mg | CANA 300 mg | |
Triglycerides, n | 446 | 614 | 610 | 118 | 139 | 131 |
Mean ± SD baseline, mmol/L | 2.2 ± 1.4 | 2.1 ± 1.5 | 2.1 ± 1.5 | 1.8 ± 0.8 | 1.9 ± 1.1 | 1.7 ± 0.9 |
LS mean ± SE change | 0.01 ± 0.05 | -0.10 ± 0.04 | -0.23 ± 0.04 | -0.05 ± 0.05 | -0.14 ± 0.05 | -0.16 ± 0.05 |
Median (IQR) percent change | -1.6 | -6.0 | -9.3 | -3.2 | -7.4 | -9.2 |
(-22.1, 28.8) | (-26.4, 24.4) | (-28.6, 19.8) | (-20.4, 16.3) | (-21.9, 10.6) | (-25.8, 10.2) | |
LS mean ± SE percent change | 9.1 ± 2.2 | 3.7 ± 2.0 | 0.6 ± 2.0 | 2.6 ± 3.0 | -2.4 ± 2.8 | -2.5 ± 2.9 |
Difference versus PBO (95% CI) | -5.4 (-11.1, 0.3) | -8.5 (-14.2, -2.8) | -5.0 (-13.0, 3.1) | -5.1 (-13.3, 3.1) | ||
LDL-C, n | 444 | 609 | 601 | 118 | 137 | 129 |
Mean ± SD baseline, mmol/L | 2.9 ± 1.0 | 2.8 ± 0.9 | 2.7 ± 0.9 | 2.7 ± 1.0 | 2.6 ± 0.9 | 2.7 ± 1.0 |
LS mean ± SE change | -0.05 ± 0.03 | 0.06 ± 0.03 | 0.17 ± 0.03 | -0.07 ± 0.06 | 0.04 ± 0.05 | 0.07 ± 0.06 |
Median (IQR) percent change | -2.3 | 2.0 | 6.5 | -1.5 | 1.9 | 2.0 |
(-16.9, 11.3) | (-10.7, 19.4) | (-7.8, 23.9) | (-9.8, 12.2) | (-7.1, 15.5) | (-10.5, 17.9) | |
LS mean ± SE percent change | 1.5 ± 1.4 | 6.3 ± 1.2 | 9.8 ± 1.2 | 0.7 ± 2.1 | 3.5 ± 1.9 | 6.8 ± 2.0 |
Difference versus PBO (95% CI) | 4.8 (1.2, 8.4) | 8.3 (4.7, 11.9) | 2.7 (-2.9, 8.4) | 6.1 (0.4, 11.8) | ||
HDL-C, n | 446 | 612 | 606 | 118 | 138 | 129 |
Mean ± SD baseline, mmol/L | 1.2 ± 0.3 | 1.2 ± 0.3 | 1.2 ± 0.3 | 1.2 ± 0.3 | 1.3 ± 0.3 | 1.3 ± 0.3 |
LS mean ± SE change | 0.03 ± 0.01 | 0.09 ± 0.01 | 0.10 ± 0.01 | 0.03 ± 0.02 | 0.12 ± 0.02 | 0.12 ± 0.02 |
Median (IQR) percent change | 3.2 | 7.3 | 9.5 | 3.9 | 9.2 | 9.7 |
(-6.0, 13.6) | (-2.6, 19.6) | (-0.7, 20.0) | (-4.7, 11.8) | (0.0, 17.6) | (-0.8, 21.2) | |
LS mean ± SE percent change | 4.0 ± 0.8 | 9.2 ± 0.7 | 10.2 ± 0.7 | 3.6 ± 1.4 | 9.8 ± 1.3 | 10.8 ± 1.4 |
Difference versus PBO (95% CI) | 5.2 (3.1, 7.3) | 6.1 (4.1, 8.2) | 6.2 (2.4, 9.9) | 7.2 (3.4, 11.0) | ||
LDL-C/HDL-C, n | 444 | 609 | 601 | 118 | 137 | 129 |
Mean ± SD baseline, mol/mol | 2.6 ± 1.1 | 2.5 ± 1.0 | 2.4 ± 0.9 | 2.3 ± 1.0 | 2.2 ± 0.9 | 2.2 ± 0.8 |
LS mean ± SE change | -0.13 ± 0.03 | -0.12 ± 0.03 | -0.07 ± 0.03 | -0.10 ± 0.05 | -0.15 ± 0.05 | -0.11 ± 0.05 |
Median (IQR) percent change | -6.8 | -5.4 | -1.5 | -4.4 | -3.3 | -7.3 |
(-19.3, 9.3) | (-19.0, 10.9) | (-16.3, 14.1) | (-19.8, 12.8) | (-17.4, 7.8) | (-21.9, 11.8) | |
LS mean ± SE percent change | -0.5 ± 1.4 | -0.7 ± 1.2 | 1.3 ± 1.2 | -1.4 ± 2.3 | -4.2 ± 2.2 | -1.2 ± 2.3 |
Difference versus PBO (95% CI) | -0.2 (-3.8, 3.4) | 1.8 (-1.8, 5.4) | -2.8 (-9.1, 3.4) | 0.2 (-6.2, 6.5) | ||
Non–HDL-C, n | 446 | 609 | 602 | 117 | 138 | 127 |
Mean ± SD baseline, mmol/L | 3.9 ± 1.1 | 3.8 ± 1.1 | 3.6 ± 1.0 | 3.5 ± 1.2 | 3.5 ± 1.1 | 3.5 ± 1.1 |
LS mean ± SE change | -0.04 ± 0.04 | 0.00 ± 0.03 | 0.10 ± 0.03 | -0.09 ± 0.07 | -0.02 ± 0.06 | -0.02 ± 0.06 |
Median (IQR) percent change | -2.3 | -0.7 | 2.4 | -2.6 | 0.0 | 0.0 |
(-13.6, 9.7) | (-10.2, 13.1) | (-8.6, 14.9) | (-10.6, 9.5) | (-6.3, 11.5) | (-12.6, 13.5) | |
LS mean ± SE percent change | 1.1 ± 1.0 | 2.6 ± 0.9 | 4.7 ± 0.9 | -0.5 ± 1.8 | 0.8 ± 1.7 | 2.8 ± 1.8 |
Difference versus PBO (95% CI) | 1.4 (-1.3, 4.1) | 3.6 (0.8, 6.3) | 1.3 (-3.6, 6.2) | 3.3 (-1.7, 8.3) |