INVOKANA (Page 7 of 9)

14.2 Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease

The CANVAS and CANVAS-R trials were multicenter, multi-national, randomized, double-blind parallel group, with similar inclusion and exclusion criteria. Patients eligible for enrollment in both CANVAS and CANVAS-R trials were: 30 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease (66% of the enrolled population) or were 50 years of age or older and had two or more other specified risk factors for cardiovascular disease (34% of the enrolled population).

The integrated analysis of the CANVAS and CANVAS-R trials compared the risk of Major Adverse Cardiovascular Event (MACE) between canagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.

In CANVAS, patients were randomly assigned 1:1:1 to canagliflozin 100 mg, canagliflozin 300 mg, or matching placebo. In CANVAS-R, patients were randomly assigned 1:1 to canagliflozin 100 mg or matching placebo, and titration to 300 mg was permitted at the investigator’s discretion (based on tolerability and glycemic needs) after Week 13. Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

A total of 10,134 patients were treated (4,327 in CANVAS and 5,807 in CANVAS-R; total of 4,344 randomly assigned to placebo and 5,790 to canagliflozin) for a mean exposure duration of 149 weeks (223 weeks [4.3 years] in CANVAS and 94 weeks [1.8 years] in CANVAS-R). Approximately 78% of the trial population was Caucasian, 13% was Asian, and 3% was Black. The mean age was 63 years and approximately 64% were male.

The mean HbA1C at baseline was 8.2% and mean duration of diabetes was 13.5 years with 70% of patients having had diabetes for 10 years or more. Approximately 31%, 21% and 17% reported a past history of neuropathy, retinopathy and nephropathy, respectively, and the mean eGFR 76 mL/min/1.73 m2. At baseline, patients were treated with one (19%) or more (80%) antidiabetic medications including metformin (77%), insulin (50%), and sulfonylurea (43%).

At baseline, the mean systolic blood pressure was 137 mmHg, the mean diastolic blood pressure was 78 mmHg, the mean LDL was 89 mg/dL, the mean HDL was 46 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 115 mg/g. At baseline, approximately 80% of patients were treated with renin angiotensin system inhibitors, 53% with beta-blockers, 13% with loop diuretics, 36% with non-loop diuretics, 75% with statins, and 74% with antiplatelet agents (mostly aspirin). During the trial, investigators could modify anti-diabetic and cardiovascular therapies to achieve local standard of care treatment targets with respect to blood glucose, lipid, and blood pressure. More patients receiving canagliflozin compared to placebo initiated anti-thrombotics (5.2% vs 4.2%) and statins (5.8% vs 4.8%) during the trial.

For the primary analysis, a stratified Cox proportional hazards model was used to test for non-inferiority against a pre-specified risk margin of 1.3 for the hazard ratio of MACE.

In the integrated analysis of CANVAS and CANVAS-R trials, canagliflozin reduced the risk of first occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.86 (0.75, 0.97). Refer to Table 19. Vital status was obtained for 99.6% of patients across the trials. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 3.

Table 19: Treatment Effect for the Primary Composite Endpoint, MACE, and its Components in the Integrated Analysis of CANVAS and CANVAS-R studies *
Placebo N=4347(%) Canagliflozin N=5795 (%) Hazard ratio (95% C.I.)
Intent-To-Treat Analysis Set
Stratified Cox-proportional hazards model with treatment as a factor and stratified by study and by prior CV disease
P-value for superiority (2-sided) = 0.0158
Number and percentage of first events
Due to pooling of unequal randomization ratios, Cochran-Mantel-Haenszel weights were applied to calculate percentages

Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke(time to first occurrence), §, ,

426 (10.4)

585 (9.2)

0.86 (0.75, 0.97)

Non-fatal myocardial infarction §,

159 (3.9)

215 (3.4)

0.85 (0.69, 1.05)

Non-fatal Stroke §,

116 (2.8)

158 (2.5)

0.90 (0.71, 1.15)

Cardiovascular Death §,

185 (4.6)

268 (4.1)

0.87 (0.72, 1.06)

Figure 3: Time to First Occurrence of MACE

Figure 3
(click image for full-size original)

14.3 Renal and Cardiovascular Outcomes in Patients with Diabetic Nephropathy and Albuminuria

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial (CREDENCE) was a multinational, randomized, double-blind, placebo-controlled trial comparing canagliflozin with placebo in patients with type 2 diabetes mellitus, an eGFR ≥ 30 to < 90 mL/min/1.73 m2 and albuminuria (urine albumin/creatinine > 300 to ≤ 5000 mg/g) who were receiving standard of care including a maximum-tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

The primary objective of CREDENCE was to assess the efficacy of canagliflozin relative to placebo in reducing the composite endpoint of end stage kidney disease (ESKD), doubling of serum creatinine, and renal or CV death.

Patients were randomized to receive canagliflozin 100 mg (N=2,202) or placebo (N=2,199) and treatment was continued until the initiation of dialysis or renal transplantation.

The median follow-up duration for the 4,401 randomized subjects was 137 weeks. Vital status was obtained for 99.9% of subjects.

The population was 67% White, 20% Asian, and 5% Black; 32% were of Hispanic or Latino ethnicity. The mean age was 63 years and 66% were male.

At randomization, the mean HbA1c was 8.3%, the median urine albumin/creatinine was 927 mg/g, the mean eGFR was 56.2 mL/min/1.73 m2 , 50% had prior CV disease, and 15% reported a history of heart failure. The most frequent antihyperglycemic agents (AHA) medications used at baseline were insulin (66%), biguanides (58%), and sulfonylureas (29%). Nearly all subjects (99.9%) were on ACEi or ARB at randomization, approximately 60% were taking an anti-thrombotic agent (including aspirin), and 69% were on a statin.

The primary composite endpoint in the CREDENCE study was the time to first occurrence of ESKD (defined as an eGFR < 15 mL/min/1.73 m2 , initiation of chronic dialysis or renal transplant), doubling of serum creatinine, and renal or CV death. Canagliflozin 100 mg significantly reduced the risk of the primary composite endpoint based on a time-to-event analysis [HR: 0.70; 95% CI: 0.59, 0.82; p<0.0001] (see Figure 4). The treatment effect reflected a reduction in progression to ESKD, doubling of serum creatinine and cardiovascular death as shown in Table 20 and Figure 4. There were few renal deaths during the trial. Canagliflozin 100 mg also significantly reduced the risk of hospitalization for heart failure [HR: 0.61; 95% CI: 0.47 to 0.80; p<0.001].

Table 20: Analysis of Primary Endpoint (including the Individual Components) and Secondary Endpoints from the CREDENCE Study
Placebo canagliflozin
Endpoint N=2,199 (%) Event Rate *N=2,202 (%) Event Rate *HR (95% CI)
Intent-To-Treat Analysis Set (time to first occurrence)
The individual components do not represent a breakdown of the composite outcomes, but rather the total number of subjects experiencing an event during the course of the study.
Event rate per 100 patient-years.
Hazard ratio (canagliflozin compared to placebo), 95% CI and p-value are estimated using a stratified Cox proportional hazards model including treatment as the explanatory variable and stratified by screening eGFR (≥ 30 to < 45, ≥ 45 to < 60, ≥ 60 to < 90 mL/min/1.73 m 2 ). HR is not presented for renal death due to the small number of events in each group.
P-value <0.0001
P-value <0.001
P-value <0.02

Primary Composite Endpoint (ESKD, doubling of serum creatinine, renal death, or CV death)

340 (15.5)


245 (11.1)


0.70(0.59, 0.82)


165 (7.5)


116 (5.3)


0.68(0.54, 0.86)

Doubling of serum creatinine

188 (8.5)


118 (5.4)


0.60(0.48, 0.76)

Renal death

5 (0.2)


2 (0.1)


CV death

140 (6.4)


110 (5.0)


0.78(0.61, 1.00)

CV death or hospitalization for heart failure

253 (11.5)


179 (8.1)


0.69(0.57, 0.83) §

CV death, non-fatal myocardial infarction or non-fatal stroke

269 (12.2)


217 (9.9)


0.80(0.67, 0.95)

Non-fatal myocardial infarction

87 (4.0)


71 (3.2)


0.81(0.59, 1.10)

Non-fatal stroke

66 (3.0)


53 (2.4)


0.80(0.56, 1.15)

Hospitalization for heart failure

141 (6.4)


89 (4.0)


0.61(0.47, 0.80) §

ESKD, doubling of serum creatinine or renal death

224 (10.2)


153 (6.9)


0.66(0.53, 0.81)

The Kaplan-Meier curve (Figure 4) shows time to first occurrence of the primary composite endpoint of ESKD, doubling of serum creatinine, renal death, or CV death. The curves begin to separate by Week 52 and continue to diverge thereafter.

Figure 4: CREDENCE: Time to First Occurrence of the Primary Composite Endpoint

Figure 4
(click image for full-size original)

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