Introduction
Canagliflozin and Metformin FDC
Pharmacology and Bioequivalence
Phase 3 Studies of Canagliflozin in Combination with Metformin
Study | Study design | Key inclusion criteria | Background therapy | Patients |
---|---|---|---|---|
Initial combination with CANA + MET [16] | Initial combination therapy with CANA + MET vs each component for 26 weeks | 18–75 years old; HbA1c 7.5–12.0%; eGFR ≥60 mL/min/1.73 m2
| Drug-naïve patients (not on AHA therapy or off for ≥12 weeks before screening) |
N = 1186; CANA 100 mg/MET, n = 237; CANA 300 mg/MET, n = 237; CANA 100 mg, n = 237; CANA 300 mg, n = 238; MET, n = 237 |
Add-on to MET vs PBO/SITA [24] | PBO-controlled, 26-week core period; active-controlled (vs SITA), 26-week extension period | 18–80 years old; HbA1c 7.0–10.5%; eGFR ≥55 mL/min/1.73 m2* | Stable MET dose (≥2000 mg/day [or ≥1500 mg/day if unable to tolerate a higher dose]) for ≥8 weeks |
N = 1284; PBO/SITA, n = 183; SITA 100 mg, n = 366; CANA 100 mg, n = 368; CANA 300 mg, n = 367 |
Active-controlled (vs GLIM) 52-week core period and 52-week extension | 18–80 years old; HbA1c 7.0–9.5%; eGFR ≥55 mL/min/1.73 m2* | Stable MET dose (≥2000 mg/day [or ≥1500 mg/day if unable to tolerate higher dose]) for ≥10 weeks |
N = 1450; GLIM, n = 482; CANA 100 mg, n = 483; CANA 300 mg, n = 485 | |
Add-on to MET + SU vs SITA [28] | Active-controlled (vs SITA), 52-week treatment period | ≥18 years old; HbA1c 7.0–10.5%; eGFR ≥55 mL/min/1.73 m2* | Stable MET dose (≥2000 mg/day [or ≥1500 mg/day if unable to tolerate a higher dose]) and SU (at least half of maximally labeled dose) for ≥8 weeks |
N = 755; CANA 300 mg, n = 377; SITA 100 mg, n = 378 |
Add-on to MET + SU vs PBO [27] | PBO-controlled, 26-week core period and 26-week extension period | 18–80 years old; HbA1c 7.0–10.5%; eGFR ≥55 mL/min/1.73 m2* | Stable MET dose (≥2000 mg/day [or ≥1500 mg/day if unable to tolerate a higher dose]) and SU (at least half of maximally labeled dose) for ≥8 weeks |
N = 469, PBO, n = 156; CANA 100 mg, n = 157; CANA 300 mg, n = 156 |
Add-on to MET + PIO vs PBO/SITA [26] | PBO-controlled, 26-week core period; active-controlled (vs SITA), 26-week extension period | 18–80 years old; HbA1c 7.0–10.5%; eGFR ≥55 mL/min/1.73 m2* | Stable MET dose (≥2000 mg/day [or ≥1500 mg/day if unable to tolerate a higher dose]) and PIO 30 or 45 mg/day for ≥8 weeks |
N = 342; PBO/SITA, n = 115; CANA 100 mg, n = 113; CANA 300 mg, n = 114 |
Add-on to MET + insulin vs PBO [29] | Prespecified 18-week substudy of a subset of patients from the ongoing PBO-controlled CANVAS trial | ≥30 years old with documented, symptomatic, atherosclerotic cardiovascular disease, or ≥50 years old with ≥2 cardiovascular risk factors at screening; HbA1c 7.0–10.5%; eGFR ≥30 mL/min/1.73 m2
| Stable MET dose(≥2000 mg/day) and insulin (≥30 IU/day; basal and/or bolus) |
N = 432; PBO, n = 145; CANA 100 mg, n = 139; CANA 300 mg, n = 148 |
Study | Duration, week | HbA1c, % | Treatment groups | ||||
---|---|---|---|---|---|---|---|
MET | CANA 100 mg | CANA 300 mg | CANA 100 mg/MET | CANA 300 mg/MET | |||
Initial combination with CANA + MET [16] | 26 | Baselinea
| 8.8 | 8.8 | 8.8 | 8.8 | 8.9 |
Changeb
| −1.30 | −1.37c
| −1.42c
| −1.77d,e
| −1.78d,f
|
PBO | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
Add-on to MET vs PBO/SITA [24] | 26 | Baselinea
| 8.0 | 7.9 | 8.0 | – | – |
Changeb
| −0.17 | −0.79g
| −0.94g
| – | – |
SITA 100 mg | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
52 | Baselinea
| 7.9 | 7.9 | 8.0 | – | – | |
Changeb
| −0.73 | −0.73 | −0.88 | – | – |
GLIM | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
52 | Baselinea
| 7.8 | 7.8 | 7.8 | – | – | |
Changeb
| −0.81 | −0.82 | −0.93 | – | – | ||
104 | Baselinea
| 7.8 | 7.8 | 7.8 | – | – | |
Changeb
| −0.55 | −0.65 | −0.74 | – | – |
SITA 100 mg | CANA 300 mg | ||||||
---|---|---|---|---|---|---|---|
Add-on to MET + SU vs SITA [28] | 52 | Baselinea
| 8.1 | – | 8.1 | – | – |
Changeb
| −0.66 | – | −1.03 | – | – |
PBO | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
Add-on to MET + SU vs PBO [27] | 26 | Baselinea
| 8.1 | 8.1 | 8.1 | – | – |
Changeb
| −0.13 | −0.85g
| −1.06g
| – | – | ||
52 | Baselinea
| 8.1 | 8.1 | 8.1 | – | – | |
Changeb
| 0.01 | −0.74 | −0.96 | – | – | ||
Add-on to MET + PIO vs PBO/SITA [26] | 26 | Baselinea
| 8.0 | 8.0 | 7.8 | – | – |
Changeb
| −0.26 | −0.89g
| −1.03g
| – | – | ||
52 | Baselinea
| – | 8.0 | 7.8 | – | – | |
Changeb
| – | −0.92 | −1.03 | – | – | ||
Add-on to MET + insulin vs PBO [29] | 18 | Baselinea
| 8.2 | 8.2 | 8.2 | – | – |
Changeb
| −0.03 | −0.64g
| −0.79g
| – | – |
Study | Duration, week | Body weight, kg | Treatment group | ||||
---|---|---|---|---|---|---|---|
MET | CANA 100 mg | CANA 300 mg | CANA 100 mg/MET | CANA 300 mg/MET | |||
Initial combination with CANA + MET [16] | 26 | Baselinea
| 92.1 | 90.3 | 93.0 | 88.3 | 91.5 |
Changeb
| −2.1 | −3.0c
| −3.9d
| −3.5e
| −4.2e
|
PBO | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
Add-on to MET vs PBO/SITA [24] | 26 | Baselinea
| 86.7 | 88.7 | 85.4 | – | – |
Changeb
| −1.2 | −3.7f
| −4.2f
| – | – |
SITA 100 mg | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
52 | Baselinea
| 87.6 | 88.7 | 85.4 | – | – | |
Changeb
| −1.3 | −3.8g
| −4.2g
| – | – |
GLIM | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
52 | Baselinea
| 86.6 | 86.8 | 86.6 | – | – | |
Changeb
| 1.0 | −4.2h
| −4.7h
| – | – | ||
104 | Baselinea
| 86.6 | 86.8 | 86.6 | – | – | |
Changeb
| 0.9 | −4.1 | −4.2 | – | – |
SITA 100 mg | CANA 300 mg | ||||||
---|---|---|---|---|---|---|---|
Add-on to MET + SU vs SITA [28] | 52 | Baselinea
| 89.6 | – | 87.6 | – | – |
Changeb
| 0.3 | – | −2.5g
| – | – |
PBO | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
Add-on to MET + SU vs PBO [27] | 26 | Baselinea
| 90.8 | 93.5 | 93.5 | – | – |
Changeb
| −0.7 | −2.1f
| −2.6f
| – | – | ||
52 | Baselinea
| 90.8 | 93.5 | 93.5 | – | – | |
Changeb
| −0.9 | −2.2 | −3.2 | – | – | ||
Add-on to MET + PIO vs PBO/SITA [26] | 26 | Baselinea
| 94.0 | 94.2 | 94.4 | – | – |
Changeb
| −0.1 | −2.8f
| −3.8f
| – | – | ||
52 | Baselinea
| – | 94.2 | 94.4 | – | – | |
Changeb
| – | −2.7 | −3.7 | – | – | ||
Add-on to MET + insulin vs PBO [29] | 18 | Baselinea
| 102.3 | 99.7 | 101.1 | – | – |
Changeb
| 0.0 | −1.7f
| −2.7f
| – | – |
Study | Duration, week | Systolic BP, mmHg | Treatment group | ||||
---|---|---|---|---|---|---|---|
MET | CANA 100 mg | CANA 300 mg | CANA 100 mg/MET | CANA 300 mg/MET | |||
Initial combination with CANA + MET [16] | 26 | Baselinea
| 129.4 | 128.9 | 130.1 | 127.6 | 128.1 |
Changeb
| −0.3 | −2.2 | −2.4 | −2.2c
| −1.7c
|
PBO | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
Add-on to MET vs PBO/SITA [24] | 26 | Baselinea
| 128.0 | 128.0 | 128.7 | – | – |
Changeb
| 1.5 | −3.8d
| −5.1d
| – | – |
SITA 100 mg | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
52 | Baselinea
| 128.0 | 128.0 | 128.7 | – | – | |
Changeb
| −0.7 | −3.5e
| −4.7e
| – | – |
GLIM | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
52 | Baselinea
| 129.5 | 130.0 | 130.0 | – | – | |
Changeb
| 0.2 | −3.3 | −4.6 | – | – | ||
104 | Baselinea
| 129.5 | 130.0 | 130.0 | – | – | |
Changeb
| 1.7 | −2.0 | −3.1 | – | – |
SITA 100 mg | CANA 300 mg | ||||||
---|---|---|---|---|---|---|---|
Add-on to MET + SU vs SITA [28] | 52 | Baselinea
| 130.1 | – | 131.2 | – | – |
Changeb
| 0.9 | – | −5.1e
| – | – |
PBO | CANA 100 mg | CANA 300 mg | |||||
---|---|---|---|---|---|---|---|
Add-on to MET + SU vs PBO [27] | 26 | Baselinea
| 130.1 | 130.4 | 130.8 | – | – |
Changeb
| −2.7 | −4.9 | −4.3 | – | – | ||
52 | Baselinea
| 130.1 | 130.4 | 130.8 | – | – | |
Changeb
| 0.1 | −3.7 | −2.9 | – | – | ||
Add-on to MET + PIO vs PBO/SITA [26] | 26 | Baselinea
| 128.2 | 126.4 | 126.7 | – | – |
Changeb
| −1.2 | −5.3f
| −4.7g
| – | – | ||
52 | Baselinea
| – | 126.4 | 126.7 | – | – | |
Changeb
| – | −3.4 | −3.7 | – | – | ||
Add-on to MET + insulin vs PBO [29] | 18 | Baselinea
| 138.3 | 136.2 | 141.7 | – | – |
Changeb
| −1.7 | −5.2 | −7.7d
| – | – |
Efficacy
Initial Combination Therapy with Canagliflozin and Metformin
Canagliflozin as Dual Therapy with Metformin
Canagliflozin in Combination with Metformin Plus Other AHAs
Safety and Tolerability
Parameter | Combination of CANA + MET |
---|---|
Overall safety and tolerability | Generally well tolerated; low incidence of AEs leading to study discontinuation and serious AEs |
Genital mycotic infections | Higher incidence versus PBO, SITA, and GLIM; low incidence with CANA/MET in initial combination therapy Generally mild or moderate in intensity; few led to study discontinuation Generally higher incidence in women than in men; more likely to occur in patients with a history of genital mycotic infections and in uncircumcised males |
UTIs | Low incidence across studies; higher incidence versus GLIM and PBO; similar incidence compared with SITA Generally mild to moderate in intensity and few led to discontinuation; low incidence of serious or upper UTIs |
Osmotic diuresis–related AEs (e.g., pollakiuria, polyuria, thirst) | Generally low incidence Higher incidence versus PBO, SITA, and GLIM; few led to study discontinuation |
Volume depletion–related AEs (e.g., orthostatic hypotension, dizziness postural) | Generally low incidence; dose-dependent increase in incidence seen across studies Incidence was higher in patients taking loop diuretics, in patients with moderate renal impairment (i.e., eGFR ≥30 to <60 mL/min/1.73 m2), and in patients aged ≥75 years |
Gastrointestinal-related AEs (i.e., diarrhea, nausea, vomiting) | No increase in incidence with CANA as add-on to MET ± other AHAs versus PBO, SITA, or GLIM; incidence was low with CANA/MET as initial combination therapy |
Hypoglycemia | Low incidence when not used in combination with background AHAs associated with hypoglycemia (e.g., SU or insulin) Significantly lower incidence versus GLIM Slightly higher incidence with CANA as add-on to MET versus SITA; similar incidence with CANA as add-on to MET + SU versus SITA with greater HbA1c lowering with CANA; incidence with CANA/MET was similar to MET in initial combination therapy Low incidence across studies of severe hypoglycemia episodes |
Diabetic ketoacidosis AEs | Low incidence across studies No serious AEs of diabetic ketoacidosis with CANA as add-on to MET, MET + PIO, or in the MET + insulin subset of CANVAS 1 serious event each with CANA 100 mg as add-on to MET + SU and with CANA 300 mg as initial combination therapy |
Fractures | Incidence low and similar across studies in non-CANVAS studies |
Fasting plasma lipids | Triglycerides were generally reduced across studies High-density lipoprotein cholesterol and low-density lipoprotein cholesterol were generally increased across studies |
Clinical laboratory parameters | Transient reduction in eGFR early in treatment that attenuated over time No clinically meaningful changes in alanine aminotransferase, aspartate aminotransferase, bilirubin, blood urea nitrogen, creatinine, urate, and hemoglobin Small changes in serum electrolytes (i.e., potassium, magnesium, phosphate) |