consider the overall safety profile demonstrated for up to 6.5 years, including eGFR over time1,2

significantly fewer overall serious adverse events were observed with INVOKANA® vs placebo + standard of care over 6.5 years1*

 

  • As demonstrated in 10,142 patients in the longest landmark cardiovascular outcomes program for an oral type 2 diabetes therapy
  • Patients had established cardiovascular disease or ≥2 risk factors for CVD

Safety and adverse event rate per 100 patient-years over 338 weeks1

 

Placebo
+ standard of care

INVOKANA® 
100 mg and 300 mg
+ standard of care

P value‡

All serious adverse events (AEs)

12.00

10.43

0.04

AEs leading to discontinuation

3.28

3.55

0.07

Serious and nonserious AEs recorded in the CANVAS Program

Acute pancreatitis (adjudicated)

0.04

0.05

0.63

Renal cell carcinoma

0.02

0.06

0.17

Bladder cancer

0.11

0.10

0.74

Breast cancer

0.26

0.31

0.65

Photosensitivity

0.03

0.10

0.07

Diabetic ketoacidosis (adjudicated)

0.03

0.06

0.14

Amputation

0.34

0.63

<0.001

All fracture (adjudicated)§

1.19

1.54

0.02

Low-trauma fracture (adjudicated)§

0.92

1.16

0.06

Venous thromboembolic events

0.17

0.17

0.63

Male genital mycotic infection||

1.08

3.49

<0.001

Serious and nonserious AEs collected in CANVAS alone

Osmotic diuresis

1.33

3.45

<0.001

Volume depletion

1.85

2.60

0.009

Hypoglycemia

4.64

5.00

0.20

Acute kidney injury

0.41

0.30

0.33

Hyperkalemia

0.44

0.69

0.10

Urinary tract infection

3.70

4.00

0.38

Female genital mycotic infection

1.75

6.88

<0.001

Severe hypersensitivity or cutaneous reaction

0.61

0.85

0.17

Hepatic injury

0.91

0.74

0.35

Renal-related (including acute kidney injury)

1.74

1.97

0.32

mean eGFR remained stable for up to 6.5 years with INVOKANA® after an initial decline2

 

  • Results were achieved on top of standard of care; 80% of patients in both the INVOKANA® and placebo groups were receiving ACEi's and/or ARBs at baseline1
  • The effect on eGFR was observed to reverse after treatment discontinuation, suggesting acute hemodynamic changes may play a role in renal function changes observed with INVOKANA®4
 

 

ACEi's=angiotensin-converting enzyme inhibitors; ARBs=angiotensin receptor blockers.

understanding amputation risk

  • In the CANVAS Program, 1 year of treatment for 100 patients with established CVD or ≥ 2 risk factors for CVD led to 0.63 and 0.34 amputation events with INVOKANA® and placebo, respectively1
  • The highest risk of lower-limb amputation across treatments was seen in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy1
  • Nearly all patients (92% to 96%) who experienced an amputation had one or more of the following identifiable precipitating events3: prior amputation and/or
    – Severe lower-extremity infection
    – Gangrene
    – Diabetic foot ulcer
    – Acute limb ischemia
  • There was no greater increase in precipitating events with INVOKANA® vs placebo3
  • Amputation rates were not dose related1
  • There was no increase in amputation observed across 12 other completed phase 3 and 4 INVOKANA® trials comprising >8100 patients in the clinical development program3
  • Before initiating INVOKANA®, consider the factors in the patient's history that may predispose to the need for amputation and perform routine examination of his or her feet4

*Use of background therapy for glycemic management and other control of risk factors were guided by best practice according to local guidelines.

Analyses were performed on data from the on-treatment data set (patients who had a safety outcome while they were receiving INVOKANA® or placebo or within 30 days after discontinuation of the drug or placebo), except for fracture, amputation, cancer, and diabetic ketoacidosis outcomes, which included all events at any time point in all patients who underwent randomization and received ≥1 dose of INVOKANA® or placebo.

P values were estimated from Cox regression models.

§“Low-trauma fracture” was the prespecified primary fracture outcome, and "all fracture" was a secondary outcome.

||Infection of male genitalia included balanitis, phimosis, and events leading to circumcision.

For these AEs, the annualized incidence rates are 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.

The CANVAS Program was an integrated analysis of 2 trials (the CANVAS trial and the CANVAS-R trial) with a total of 10,142 patients with type 2 diabetes:

  • 65.6% of patients were ≥30 years of age with a history of symptomatic atherosclerotic cardiovascular disease*
  • 34.4% of patients were ≥50 years of age with ≥2 risk factors for cardiovascular disease

Select baseline characteristics1

History  
Hypertension 90.0%
Heart failure 14.4%
Retinopathy 21.0%
Nephropathy 17.5%
Neuropathy 30.7%
Amputation 2.3%
Peripheral vascular disease 20.8%

*A history of cardiovascular disease was defined as a history of symptomatic atherosclerotic vascular disease (coronary, cerebrovascular, or peripheral).

Duration of diabetes ≥10 years, systolic BP >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).

(standard of care for the overall patient population across both treatment arms)

Select baseline background therapies1

Cardioprotective agents  
Statin 74.9%
Antithrombotic 73.6%
RAAS inhibitor (ACEi/ARB) 80.0%
Beta blocker 53.5%
Diuretic 44.3%
Antihyperglycemic agents  
Insulin 50.2%
Sulfonylurea 43.0%
Metformin 77.2%
GLP1 receptor agonist 4.0%
DPP4 inhibitor 12.4%

ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; DPP4=dipeptidyl peptidase-4; GLP1=glucagon-like peptide-1; ITT=intent-to-treat; RAAS=renin-angiotensin-aldosterone system.

Long-term cardiovascular outcomes trial at 338 weeks (Neal et al)

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.1

 

*≥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).

References: 1. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. Supplementary appendix available at: doi:10.1056/NEJMoa1611925. 2. Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018;6(9):691-704. 3. Data on file. Janssen Pharmaceuticals, Inc., Titusville, NJ. 4. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.