long-term assessment of overall and renal safety can help you prescribe confidently1,2

Consider long-term overall and renal safety data when choosing a type 2 diabetes treatment

significantly fewer overall serious adverse events were observed with INVOKANA® over 6.5 years vs placebo (on a background of standard of care*)2

  • Patients had a history of CVD or ≥2 CV risk factors
  • INVOKANA® was associated with an increased risk of lower-limb amputation, primarily of the toe and midfoot3

Safety and adverse event rate per 100 patient-years over 338 weeks2

 

Placebo

INVOKANA® 100 mg and 300 mg

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 cancer

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

*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 adverse events, the annualized incidence rates are reported with data from CANVAS alone through January 7, 2014, because after this time, only serious adverse events or adverse events leading to discontinuation were collected. In CANVAS-R, only serious adverse events or adverse events 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 adverse events is not possible.

CVD=cardiovascular disease.

in the CANVAS Program, after an initial decline, mean eGFR remained stable for up to 6.5 years with INVOKANA® (on a background of standard of care)1

Mean eGFR values from baseline over 338 weeks (mL/min/1.73 m2)1

Mean eGFR values from baseline over 338 weeks with INVOKANA® (canagliflozin) vs. placebo
  • 80% of patients in both the INVOKANA® and placebo groups were receiving angiotensin-converting enzyme inhibitors (ACEi’s) and/or angiotensin receptor blockers (ARBs) at baseline
Systolic blood pressure reductions with canagliflozin + metformin vs. sitagliptin + metformin

patient population in the CANVAS Program2

The CANVAS Program involved 2 trials (CANVAS and CANVAS-R) 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

*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).

Select baseline characteristics2

Mean age 63.3 years
Mean duration of diabetes 13.5 years
Mean A1C 8.2%
Mean BMI 32.0 kg/m2
Mean eGFR 76.5 mL/min/1.73 m2
Current smoker 17.8%
History of hypertension 90.0%
History of heart failure 14.4%
History of cardiovascular disease 65.6%
History of peripheral vascular disease 20.8%
History of retinopathy 21.0%
History of nephropathy 17.5%
History of neuropathy 30.7%
History of amputation 2.3%

Values for eGFR were calculated with data from 5794 patients in the INVOKANA® group, 4346 in the placebo group, and 10,140 in the total population.

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

background therapies in the CANVAS Program2

  • The use of other antihyperglycemic agents during follow-up was 9.3% lower in the INVOKANA® group than in the placebo group (95% CI: –11.0, –7.6)

Baseline background therapies in the CANVAS Program (N=10,142)1,2§

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

§One patient was randomized at 2 different sites and only the first randomization is included in the ITT analysis set.

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

amputation considerations

  • In the CANVAS Program, the amputation rate was 0.63 events/100 patient-years in the pooled INVOKANA® group and 0.34 events/100 patient-years in the placebo group2
    • In other words, the CANVAS Program showed that treating 100 patients with established CVD or CV risk with INVOKANA® for a year led to an additional 0.3 events
  • The highest risk of lower-limb amputation across treatments was seen in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy2
  • 96% (45/47) of the placebo-treated patients and 92% (129/140) of the INVOKANA®-treated patients who experienced an atraumatic lower-limb amputation had ≥1 etiologies—lower-extremity infection, gangrene, diabetic foot ulcer, or acute limb ischemia—and/or had a history of a prior amputation1
  • There was no increase in amputation observed across 12 other completed phase 3 and 4 INVOKANA® trials comprising >8100 patients in the clinical development program1

 

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

The CANVAS Program involved 2 trials (CANVAS and CANVAS-R) 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 outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes planned for sequential conditional hypothesis testing were death from any cause, death from cardiovascular causes, progression of albuminuria, and the composite of death from cardiovascular causes and hospitalization for heart failure.2

*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. Data on file. Janssen Pharmaceuticals, Inc., Titusville, NJ. 2. 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. 3. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.