In a robust clinical trial program,
In a robust clinical trial program,
As demonstrated in the landmark CREDENCE trial, INVOKANA® 100 mg has a proven safety profile in patients with DKD* and T2D who have an eGFR as low as 301
| CREDENCE | Placebo | INVOKANA® 100 mg | Hazard ratio (95% CI) |
|---|---|---|---|
| Adverse event† rate per 100 patient-years over 42 months1 | |||
| Any adverse event (AE) | 37.93 | 35.14 | 0.87 (0.82, 0.93) |
| Any serious AE | 16.44 | 14.52 | 0.87 (0.79, 0.97) |
| Serious AEs related to trial drug | 0.86 | 1.22 | 1.45 (0.98, 2.14) |
| Hyperkalemia‡ | 3.69 | 2.97 | 0.80 (0.65, 1.00) |
| Acute kidney injury | 2.00 | 1.69 | 0.85 (0.64, 1.13) |
| Diabetic ketoacidosis§ | 0.02 | 0.22 | 10.80 (1.39, 83.65) |
| Male genital mycotic infection | 0.09 | 0.84 | 9.30 (2.83, 30.60) |
| Female genital mycotic infection | 0.61 | 1.26 | 2.10 (1.00, 4.45) |
| Amputation | 1.12 | 1.23 | 1.11 (0.79, 1.56) |
| Fracture | 1.21 | 1.18 | 0.98 (0.70, 1.37) |
| Renal-cell carcinoma | 0.09 | 0.02 | NA|| |
| Breast cancer¶ | 0.16 | 0.41 | 2.59 (0.69, 9.76) |
| Bladder cancer | 0.16 | 0.17 | 1.10 (0.45, 2.72) |
| Acute pancreatitis | 0.04 | 0.10 | NA|| |
The incidence of hypotension was 2.8% for INVOKANA® and 1.5% for placebo.2 Hypoglycemia incidence was 4.43 vs 4.89 per 100 patient-years, respectively.1
eGFR is measured in mL/min/1.73 m2.
*With albuminuria >300 mg/day.
†Amputation, fracture, and cancer events were determined in the on-study population, whereas the other safety events were determined in the on-treatment population. The analyses for fracture, renal-cell carcinoma, acute pancreatitis, and diabetic ketoacidosis were based on confirmed and adjudicated results.
‡Adverse events of hyperkalemia were spontaneously reported by the investigator. The definition of hyperkalemia includes the preferred terms "hyperkalemia" and "blood potassium increased" in the Medical Dictionary for Regulatory Activities.
§All potential ketone-related events were adjudicated for diabetic ketoacidosis by an independent adjudication committee on the basis of clinical presentation and predefined biochemical measures.
||NA denotes not applicable because hazard ratios and 95% confidence intervals were reported only for outcomes with >10 events.
¶The diagnosis of breast cancer was established only in women.
As demonstrated in a landmark CV outcomes trial, INVOKANA® has a proven safety profile in patients with T2D and CVD3
Rates of events for the primary and secondary prevention cohorts in the CANVAS Program in the active and control groups combined
| CANVAS | Event rate (95% CI) per 1000 patient-years4 | ||
|---|---|---|---|
| Variable | Secondary prevention (n=6656) | Primary prevention (n=3486) | Hazard ratio (95% CI) |
| Safety outcomes | |||
| Male genital infections* | 26.5 (23.7, 29.6) | 29.0 (24.9, 33.7) | 0.87 (0.72, 1.05) |
| Female genital infections† | 59.6 (48.0, 73.2) | 57.1 (46.7, 69.2) | 1.02 (0.77, 1.35) |
| Urinary tract infections† | 38.0 (33.3, 43.1) | 47.1 (40.9, 54.0) | 0.80 (0.67, 0.97) |
| Lower extremity amputation | 6.9 (5.9, 8.1) | 2.4 (1.6, 3.3) | 2.85 (1.95, 4.16) |
| All fracture | 14.1 (12.6, 15.8) | 14.0 (12.1, 16.1) | 1.03 (0.86, 1.24) |
| Low-trauma fracture | 10.8 (9.5, 12.3) | 10.4 (8.7, 12.3) | 1.06 (0.86, 1.31) |
| Diabetic ketoacidosis | 0.4 (0.2, 0.7) | 0.7 (0.3, 1.3) | 0.48 (0.19, 1.22) |
| Acute pancreatitis | 0.5 (0.2, 0.9) | 0.4 (0.1, 0.9) | 1.44 (0.44, 4.72) |
| Volume depletion events† | 28.1 (24.1, 32.5) | 19.6 (15.8, 24.2) | 1.42 (1.10, 1.83) |
| Hypoglycemia† | 57.4 (51.4, 63.9) | 50.7 (44.2, 58.0) | 1.12 (0.94, 1.33) |
| Renal adverse events† | 21.5 (18.0, 25.4) | 16.8 (13.2, 20.9) | 1.28 (0.97, 1.69) |
| Thromboembolism | 1.5 (1.0, 2.2) | 2.1 (1.4, 3.1) | 0.74 (0.43, 1.28) |
| Renal cell cancer | 0.5 (0.3, 0.9) | 0.4 (0.1, 0.8) | 1.70 (0.60, 4.83) |
| Bladder cancer | 1.0 (0.6, 1.5) | 1.1 (0.6, 1.8) | 0.94 (0.49, 1.81) |
| Breast cancer | 2.6 (1.5, 4.2) | 3.2 (2.0, 5.0) | 0.82 (0.43, 1.58) |
*Includes balanitis and phimosis.
†For these AEs, the annualized event rates were reported with data from CANVAS alone through January 7, 2014, because after this time, only serious AEs or AEs leading to discontinuation were collected. In CANVAS-R, only serious AEs or AEs leading to discontinuation were collected. Owing to the differences between the 2 trials in methods of collection of the data, an integrated analysis of these AEs is not possible.
In a monotherapy study of patients with T2D who were inadequately controlled on diet and exercise, overall incidence of adverse events and incidence of hypoglycemia were comparable in patients receiving INVOKANA® vs placebo2,5
| Placebo (n=192) | INVOKANA® 100 mg (n=195) | INVOKANA® 300 mg (n=197) | |
|---|---|---|---|
| Overall safety and select adverse events with INVOKANA® monotherapy vs placebo over 26 weeks2,5 | |||
| Any adverse event (AE) | 52.6% | 61.0% | 59.9% |
| AEs related to study drug* | 9.4% | 17.4% | 25.4% |
| Serious AEs related to study drug* | 0% | 1.5% | 0% |
| Urinary tract infection | 4.2% | 7.2% | 5.1% |
| Hypoglycemia | 2.6% | 3.6% | 3.0% |
| Genital mycotic infection | |||
| Male† | 0% | 2.5% | 5.6% |
| Female‡ | 3.8% | 8.8% | 7.4% |
| Osmotic diuresis–related AEs | |||
| Increased urine frequency | 0.5% | 2.6% | 3.0% |
| Increased urine volume | 0% | 0% | 3.0% |
| Volume-related AEs | |||
| Postural dizziness | 0% | 0.5% | 1.0% |
| Orthostatic hypotension | 0% | 0% | 1.0% |
All AEs are reported regardless of rescue medication, except for osmotic diuresis–related and volume-related AEs, which are reported before the start of rescue therapy.
*Possibly, probably, or very likely related to study drug, as assessed by investigators.
†Placebo, n=88; INVOKANA® 100 mg, n=81; INVOKANA® 300 mg, n=89; including balanitis, balanitis Candida, balanoposthitis, and genital infection fungal.
‡Placebo, n=104; INVOKANA® 100 mg, n=114; INVOKANA® 300 mg, n=108; including vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovaginitis.
CANVAS=Canagliflozin Cardiovascular Assessment Study; CREDENCE=Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; CV=cardiovascular; CVD=cardiovascular disease; DKD=diabetic kidney disease; T2D=type 2 diabetes.
CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) was a randomized, double-blind, placebo-controlled, parallel group, multicenter, event-driven clinical trial. The trial compared the effects of INVOKANA® 100 mg vs placebo in 4401 men and women with type 2 diabetes and diabetic kidney disease (described as chronic kidney disease with eGFR 30 to <90 mL/min/1.73 m2 and albuminuria [ratio of albumin to creatinine >300 to 5000 mg/g]) who were already taking a stable, maximum-tolerated, or labeled dose (for ≥4 weeks prior to randomization) of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The mean eGFR of patients was 56.2 mL/min/1.73 m2 and the median urinary albumin-to-creatinine ratio was 927 mg/g. The primary efficacy outcome was the composite of end-stage kidney disease (dialysis, transplant, or eGFR <15 mL/min/1.73 m2), doubling of serum creatinine, or renal or cardiovascular (CV) death. Prespecified secondary outcomes included a composite of CV death or hospitalization for heart failure; a composite of heart attack, stroke, or CV death; hospitalization for heart failure; and a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal death.1
The CANVAS Program was an integrated analysis of 2 trials (the CANVAS trial and the CANVAS-R trial) with a total of 10,142 men and women with type 2 diabetes. Of the participants, 96.0% completed the trial and vital status was confirmed for 99.6%. The mean follow-up for the CANVAS Program was 188.2 weeks, while the length of follow-up was 295.9 weeks and 108.0 weeks in the CANVAS and CANVAS-R trials, respectively. Participants were either ≥30 years of age with a history of symptomatic atherosclerotic cardiovascular disease or ≥50 years of age with ≥2 risk factors* for cardiovascular disease. The primary efficacy outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.3
*≥2 of the following risk factors for CVD: duration of diabetes ≥10 years, systolic blood pressure >140 mm Hg while they were receiving ≥1 antihypertensive agents, currently smoking, microalbuminuria or macroalbuminuria, or HDL cholesterol level <1 mmol/L (38.7 mg/dL).
The efficacy and safety of INVOKANA® monotherapy were assessed in subjects with type 2 diabetes mellitus who were inadequately controlled with diet and exercise. In this 26-week, double-blind, placebo-controlled study, 584 patients were randomized to receive placebo (n=192), INVOKANA® 100 mg (n=195), or INVOKANA® 300 mg (n=197). Mean baseline A1C values were, respectively, 7.97%, 8.06%, and 8.01%. The primary endpoint was the change in A1C from baseline to week 26. Prespecified secondary endpoints included change in fasting plasma glucose, change in percent body weight, and change in systolic blood pressure.2,5