SUMMARY  

• In the CREDENCE study (N=4401), INVOKANA significantly reduced the risk of 2 prespecified adjudicated heart failure (HF) outcomes.¹
  • Incidence rates of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) were 31.5 vs 45.4 per 1000 patient-years (PY) in the INVOKANA vs placebo groups, respectively, resulting in a relative risk reduction (RRR) of 31% (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.57-0.83; P<0.001).
  • Incidence rates of HHF events were 15.7 vs 25.3 per 1000 PY, with an RRR of 39% (HR, 0.61; 95% CI, 0.47-0.80; P<0.001).
  • The treatment effects of INVOKANA on these prespecified secondary HF outcomes were confirmed using a planned sequential hierarchical testing procedure.
  • In a secondary analysis, the effect of INVOKANA on CV death or HHF did not show significant differences when evaluated by baseline age, sex, history of CV disease (CVD), history of HF, estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), or loop diuretic use (all P_interaction>0.2 for HRs).²
• In the CANVAS Program³ (N=10,142), INVOKANA was associated with reduced risk of HF outcomes.
  • Incidence rates of HHF were 5.5 and 8.7 per 1000 PY in the INVOKANA and placebo groups, respectively (HR, 0.67; 95% CI, 0.52-0.87).³ Risk of the composite of CV death or HHF was 16.3 and 20.8 per 1000 PY in INVOKANA and placebo groups, respectively (HR, 0.78; 95% CI, 0.67-0.91).³
  • A subgroup analysis of the CANVAS Program, suggests that the potential benefit of INVOKANA on the composite of CV death or HHF may be greater in patients with prior history of HF (HR, 0.61; 95% CI, 0.46-0.80) compared with those without HF at baseline (HR, 0.87; 95% CI, 0.72-1.06; P_interaction=0.021).⁴
  • A subanalysis from the CANVAS Program showed INVOKANA reduced the overall risk of HF events in patients with type 2 diabetes mellitus (T2DM) and high CV risk, with no clear difference in effects on HF with reduced ejection fraction (HFrEF) vs HF with preserved ejection fraction (HFpEF)events.⁵
• In the CANDLE study (N=245) evaluating a cardiac biomarker, INVOKANA 100 mg did not meet noninferiority to glimepiride in altering N-terminal pro-brain natriuretic peptide (NT-proBNP) levels from baseline to week 24 in patients with New York Heart Association (NYHA) functional class I-III chronic heart failure (CHF; ratio of change with INVOKANA vs glimepiride was 0.48 [95% CI, -0.13 to 1.59; P=0.226). Please see below for full study summary and study limitations.⁶
• In CANA-HF, compared with sitaglipitin, INVOKANA did not significantly improve the coprimary endpoints of peak oxygen consumption (VO₂) and minute ventilation/carbon dioxide production (VE/VCO₂) slope. INVOKANA was associated with significant improvement in additional surrogate endpoints, including lean peak VO₂, ventilatory anaerobic threshold (VAT), respiratory exchange ratio (RER)-matched VO₂, and quality of life.⁷
• The CHIEF-HF^8-12 (Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure) study (N=448) investigated the effects of INVOKANA 100 mg vs placebo on health status across the spectrum of HF, regardless of EF and diabetes status.
  • INVOKANA significantly improved Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at 12 weeks vs placebo with a difference of 4.3 points at week 12 (95% CI, 0.80-7.80; P=0.016).
  • Serious adverse events occurred in 12.1% of patients (n=27) in the INVOKANA treatment group and 7.8% of patients (n=18) in the placebo treatment group.
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^13-19

CLINICAL DATA

CREDENCE

CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) was a randomized, double-blind, placebo-controlled, parallel-group multicenter, event-driven study designed to assess the effects of INVOKANA (100 mg) compared to placebo on clinically important renal and CV outcomes in people with T2DM and established chronic kidney disease (CKD; eGFR 30 to <90 mL/min/1.73 m²) and albuminuria (UACR >300 to 5000 mg/g), who were receiving a stable, maximum tolerated labelled dose (for >4 weeks prior to randomization) of an angiotensin-converting-enzyme inhibitor or angiotensin II receptor blocker.^1,20-23

• Patients with a history of CV events within the previous 12 weeks or a history of NYHA class IV HF at any time were excluded from the study.²⁰
• Patients were randomly assigned in a 1:1 ratio to either INVOKANA 100 mg or matching placebo.¹

Outcomes

• The primary outcome was the composite of end-stage kidney disease (ESKD), doubling of serum creatinine (dSCr), or death due to renal or CV causes.
• Seven secondary outcomes were planned for sequential hierarchical testing. If INVOKANA was superior to placebo for reducing the risk of the primary efficacy endpoint, the treatment effects in the secondary endpoints would be tested subsequently. Statistical significance was required before testing the next hypothesis in the hierarchical test procedure. The 3 HF outcomes included in the hierarchy were ranked 1, 3, and 7:²⁰
  • 1. Composite of CV death and HHF
  • 3. HHF
  • 7. Expanded CV composite of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, HHF, and hospitalized unstable angina

Results

The CREDENCE study was designed to be an event-driven study with a projected duration of ~5.5 years. In July 2018, Johnson & Johnson announced that the CREDENCE study was stopping early based on demonstration of efficacy, as the study had achieved prespecified criteria for the primary composite endpoint of ESKD, dSCr, or renal or CV death, when used in addition to standard of care.²⁰

• A total of 4401 patients were randomized across 34 countries in the intentiontotreat analysis set. There were 4 patients that were not dosed, leading to 4397 patients in the on-treatment and on-study analysis sets.
• Median (range) follow-up was 2.62 (0.02-4.53) years.

Baseline Characteristics

• Baseline characteristics were similar between the INVOKANA and placebo groups, with a mean age of 63 years, 66% male patients, mean duration of T2DM of 15.8 years; mean glycated hemoglobin (HbA1c) of 8.3%, mean eGFR of 56.2 mL/min/1.73 m², median UACR of 927 mg/g; 50.4% had prior CVD, 14.8% had a history of HF.²⁰
  • The proportion of subjects with a history of HF was similar between the INVOKANA (14.9%; n=329) and placebo (14.7%; n=323) groups.¹

Prespecified and Adjudicated Secondary Outcomes

Since superiority of INVOKANA over placebo in reducing the risk of the primary composite outcome was established (HR, 0.70; 95% CI, 0.59-0.82; P=0.00001), sequential testing of treatment effects on the prespecified secondary outcomes proceeded down the hierarchy.

• In the CREDENCE study, INVOKANA significantly reduced the risk of the composite of CV death or HHF (RRR, 31%; HR, 0.69; 95% CI, 0.57-0.83; P<0.001) compared with placebo. See Figure: Event Rate of CV Death or HHF in CREDENCE. See Table: Summary of HF Outcome Results From CREDENCE.

• INVOKANA treatment was found to significantly reduce the risk of HHF events (RRR, 39%; HR, 0.61; 95% CI, 0.53-0.81; P<0.001) compared with placebo.¹ See Figure: Event Rate of HHF in CREDENCE. See Table: Summary of HF Outcome Results From CREDENCE.
  • The number needed to treat (NNT) over 2.5 years to prevent 1 HHF is 46 (calculated as the reciprocal of the between-group difference in cumulative incidence at 2.5 years on the basis of the Kaplan-Meier curve).¹

• Based on the hierarchical testing being stopped at the fourth secondary outcome which showed no significant between-group difference all subsequent outcomes in the hierarchical testing sequence, including the broader CV composite endpoint was not formally tested.¹
• See Table: Summary of HF Outcome Results From CREDENCE.

Additional Analyses of CREDENCE

Arnott et al (2020)² conducted a secondary analysis of the prespecified, hierarchical, secondary outcome HHF or CV death by patient baseline characteristics including age (>65 or <65), sex (M/F), history of CVD (Y/N), history of HF or corresponding NYHA functional classification (no HF or NYHA I-III), eGFR 30 to <45, 45 to <60, and 60 to <90 mL/min/1.73 m², UACR (>1000 or <1000), and baseline diuretic use (Y/N). In the CREDENCE study, 432 patients experienced an HHF/CV event over a median follow-up of 2.6 years. The effect of INVOKANA on CV death or HHF did not show significant differences by these baseline subgroups (all P_interaction>0.2 for HRs).

The CANVAS Program

The CANVAS Program³ (N=10,142) comprises the 2 large INVOKANA CV outcome studies: CANVAS²⁴ and CANVAS-R²⁵ in patients with T2DM and CVD or >2 risk factors for CVD.³ The CANVAS Program includes a prespecified integrated analysis of the 2 studies to meet the Food and Drug Administration (FDA) post-marketing requirement to determine CV safety. This program also evaluated potential for CV efficacy of INVOKANA in T2DM patients, as well as renal and safety outcomes.^25-28

• CANVAS was a randomized, double-blind, placebo-controlled, parallel group, multicentered, phase 3, event-driven study evaluating CV risk for major adverse cardiac events (MACE), including CV death, nonfatal MI, and nonfatal stroke with INVOKANA vs placebo (1:1:1 ratio of INVOKANA 100 mg, INVOKANA 300 mg, or matching placebo) in patients with CVD or at high risk of CVD on background standard of care (including metformin).^24,26,28
• CANVAS-R was a randomized, double-blind, placebo-controlled, parallel group, multicentered, phase 4 study which assessed effect of INVOKANA compared to placebo (1:1 ratio to INVOKANA 100 mg or matching placebo; optional up-titration at week 13 or after to INVOKANA 300 mg) on progression of albuminuria in T2DM patients with CVD or >2 risk factors for CVD.^25,29

Study Design

In the CANVAS Program, HHF and the composite of CV death or HHF were prespecified exploratory outcomes.³ Fatal HF and the composite of fatal HF or HHF were analyzed to explore in further detail the effect of INVOKANA on HF.⁴ CV death included death due to HF (fatal HF). Fatal HF events were those with HF adjudicated as proximate cause of death.^3,4

Baseline Characteristics

Baseline characteristics were similar in the INVOKANA and placebo treatment groups and were comparable across CANVAS and CANVAS-R. See Table: Key Baseline Characteristics for CANVAS, CANVAS-R, and the CANVAS Program.

Results

• Among 10,142 patients randomized in the CANVAS Program, 243 were hospitalized for HF during the study. INVOKANA was associated with lower risk of HHF compared to placebo (annualized incidence rates of 5.5 and 8.7 per 1000 PY, respectively [HR, 0.67; 95% CI, 0.52-0.87; P=0.002] based on the full integrated dataset.^3,4
• INVOKANA was associated with a lower risk of the composite endpoint of CV death or HHF compared to placebo (annualized incidence rates of 16.3 and 20.8 per 1000 PY, respectively [HR, 0.78 95% CI, 0.67-0.91; P=0.002]. Compared with placebo, INVOKANA was also associated with significantly lower risks of the composite of fatal HF or HHF (HR, 0.70; 95% CI, 0.55-0.89; P=0.003). There was no clear separate effect on fatal HF (HR, 0.89; 95% CI, 0.49-1.60; P=0.69) for which there were few events.^3,4
• Adverse events reported in the CANVAS Program were generally consistent with the known safety profile of INVOKANA, with the exception of an increased risk of amputation events.³

Additional Analyses of the CANVAS Program

Figtree et al (2019)³⁰ conducted a retrospective review of medical record data from the CANVAS Program to further categorize HF events that occurred during the studies (CANVAS and CANVAS-R). The analysis evaluated the effects of INVOKANA on HF in patients with HFpEF (defined as EF >50%, with documented HF at admission for the event); HFrEF (defined as EF<50% during HF admission or prior rEF with no evidence of recovery). All other HF events were defined as HF with unknown EF (HFuEF).

• In the CANVAS Program, 14.4% (n=1461) of patients had a history of HF at baseline.
• During follow-up, 276 of the 10,142 patients had a fatal HF event or HHF event, of which 61 had >1 HF event. See Table: Effects of INVOKANA vs PBO on Fatal HF or HHF, HFpEF, HFrEF, and HFuEF in the CANVAS Program.

Radholm et al (2018)⁴ reported subgroup analyses of the CANVAS Program comparing INVOKANA vs placebo among 14.4% (n=1461) of patients with and 85.6% (n=8681) without HF at baseline. See Table: Select Baseline Characteristics of Patients With and Without HF at Baseline in the CANVAS Program. The primary composite outcome for this subgroup analyses of patients with or without HF was adjudicated CV death or HHF. Patients with NYHA class IV HF were excluded.

CV Death/HHF

• Among 1461 patients with HF at baseline, 203 had CV death or HHF events. INVOKANA was associated with lower risk of CV death or HHF vs to placebo (annualized incidence rates 35.4 and 56.8 per 1000 PY, respectively [HR, 0.61; 95% CI, 0.46-0.80]).⁴
• Among 8681 patients without HF at baseline, 449 had CV death or HHF events (13.6 and 15.2 events per 1000 PY, respectively [HR, 0.87; 95% CI, 0.72-1.06]).⁴
• Benefit on CV death or HHF was significantly greater in patients with a prior history of HF compared to those without HF at baseline (P_interaction=0.021).

HHF Alone

• In patients with HF at baseline (n=1461), INVOKANA was associated with lower risk of HHF vs to placebo (annualized incidence rates 14.1 and 28.1 per 1000 PY, respectively [HR, 0.51; 95% CI, 0.33-0.78]).
• In patients without HF at baseline (n=8681), rates of HHF were 4.3 and 5.7 per 1000 PY in INVOKANA and placebo groups, respectively (HR, 0.79; 95% CI, 0.57-1.09).
• The NNT based on annualized incidences rates reported above to prevent 1 HHF event in 5 years was substantially fewer in patients with prior history of HHF (1 in 14) compared with those without HF history (1 in 144).⁵

Mahaffey et al (2017)³¹ reported prespecified subgroup analyses of the CANVAS Program comparing the effect of INVOKANA vs placebo on HHF among the 66% of patients with a history of atherosclerotic CVD (n=6656) and the 34% of patients without prior history of atherosclerotic CVD but with ≥2 CV risk factors (n=3486) at baseline. See Table: Select Baseline Characteristics of Patients With CVD or Patients at Risk for CVD in the CANVAS Program. The study was not designed with appropriate statistical power to show definitive treatment differences in the outcomes in patients with CVD and in patients at risk for CVD.

Results

• Among 6656 patients with history of CVD at baseline in the CANVAS Program, 198 were hospitalized for HF during the study. INVOKANA was associated with lower risk of HHF compared with placebo (annualized incidence rates 7.3 and 11.3 per 1000 PY, respectively [HR 0.68; 95% CI, 0.51-0.90; log-rank P=0.007]. ³¹
• Among 3486 patients without history of CVD but with ≥2 risk factors at baseline in the CANVAS Program, 45 were hospitalized for HF during the study. INVOKANA was associated with lower risk of HHF compared with placebo (event rate of 2.6 and 4.2 per 1000 PY, respectively [HR 0.64; 95% CI, 0.35-1.15; log-rank P= 0.13].³¹
• Compared with placebo, INVOKANA was associated with similar proportional reductions in HHF in patients with or without CVD, with no statistical evidence of heterogeneity found between these subgroups (P_interaction=0.91).

Post Hoc Analysis of CREDENCE Study and CANVAS Program

Ang et al (2022)³² conducted a post hoc analysis using the pooled, individual patient data from the CREDENCE study and CANVAS Program to investigate the effects of INVOKANA on CV and kidney outcomes and all-cause mortality in patients with and without a history of CVD (secondary and primary prevention, respectively; N=14,543).

• Patients were categorized into 2 groups: 5667 (39%) in the primary prevention group (INVOKANA, n=3128; placebo, n=2539) and 8876 (61%) in the secondary prevention group (INVOKANA, n=4869; placebo, n=4007).
• Baseline characteristics were generally similar across both the groups.
• No heterogeneity was observed in the RRR of CV and kidney outcomes and all-cause mortality with INVOKANA vs placebo across both the groups (all P_interaction>0.624). See Table: HHF and CV Death or HHF Rates in Primary and Secondary Prevention Groups.

Li et al (2022)³³ conducted a post hoc analysis of the CREDENCE study to investigate the effects of INVOKANA on total (first and subsequent) CV events in patients with T2DM and CKD.

• Total CV composite events per 1000 PY were 71.4 and 100.6 in the INVOKANA (n=372) and placebo (n=511) groups, respectively (HR/IRR, 0.71; 95% CI, 0.590.86; P<0.001).
  • Total events per 1000 PY of HF resulting in death or hospitalization were 24.7 and 42.2 in the INVOKANA and placebo groups, respectively (HR/IRR, 0.59; 95% CI, 0.430.80; P=0.001).
  • The risk difference of expected events (HF resulting in death or hospitalization) in every 1000 patients treated with INVOKANA for 2.5 years was -44 (-69 to -18).

Sarraju et al (2022)³⁴ conducted a study using an individual patient data meta-analysis from the CREDENCE study and CANVAS Program to investigate the effects of INVOKANA on CV outcomes according to baseline eGFR and UACR in patients with T2DM (N=14,543).

• Rates of HHF were examined in subgroups defined by baseline eGFR (<45, 45-60, and >60 mL/min/1.73 m²) and UACR (<30, 30-300, and >300 mg/g).
• Mean age was 63 years; 35% were female; 75% were White; of the 14,540 patients, 1919 (13.2%), 2972 (20.4%), and 9649 (66.4%) patients had baseline eGFR <45, 45-60, and >60 mL/min/1.73 m², respectively.
• Median (interquartile range [IQR]) UACR within the eGFR subgroups <45, 45-60, and >60 mL/min/1.73 m² was 687.0 (229.0-1745.0), 233.6 (13.8964.0), and 15.9 (7.2133.8), respectively, and 1352 (70%), 1380 (46%), and 1901 (20%) patients had baseline UACR >300 mg/g.
• INVOKANA treatment reduced HHF and CV death or HHF rates compared with placebo across the eGFR (all P_{heterogeneity}>0.50) and UACR (all P_{heterogeneity}>0.40) subgroups. See Table: HHF and CV Death or HHF Rates According to Baseline eGFR and UACR.
• INVOKANA treatment reduced HHF and CV death or HHF rates compared with placebo across UACR subgroups within eGFR categories. See Table: HHF and CV Death or HHF Rates According to Baseline eGFR/UACR.  

Perkovic et al (2020)³⁵ conducted a post hoc analysis using integrated, pooled, patientlevel data from the CREDENCE study and CANVAS Program to investigate the combined effects of eGFR and UACR on the risk of HHF, and to determine the effect of INVOKANA on reducing HHF risk in patients with T2DM (N=14,543).

• Risk of HHF was examined in subgroups defined by baseline eGFR (<45, 45-50, and >60 mL/min/1.73 m²) and UACR (<30, 30-300, and >300 mg/g).
• Mean age was 63 years; 35% were female; 75% were White; mean eGFR was 70.3 mL/min/1.73 m² and median UACR (IQR) was 501.0 (8.4-523.6) mg/g.
• Rates of HHF increased as eGFR declined, and INVOKANA reduced the risk of HHF compared with placebo, with consistent effects observed across eGFR subgroups (P_interaction=0.84). Rates of HHF increased with increasing UACR, and INVOKANA reduced the risk of HHF compared with placebo, with consistent effects observed across baseline UACR categories (P_interaction=0.38).
• In placebo-treated patients, the risk of HHF was generally lowest in those with UACR <30 mg/g and eGFR >60 mL/min/1.73 m², and highest in those with UACR >300 mg/g and eGFR <45 mL/min/1.73 m².

Additional Studies

Tanaka et al (2019)^6,36 conducted the CANDLE (Safety of Canagliflozin in Diabetic Patients with Chronic Heart Failure: Randomized, Non-Inferiority Trial) study, a multicenter, prospective, randomized, open-label, blinded-endpoint, investigator-initiated, Japanese study assessing INVOKANA compared with glimepiride in T2DM patients with chronic HF, using NT-proBNP as an HF biomarker.

• A total of 245 patients with T2DM and NYHA class I-III chronic HF were randomized to receive INVOKANA 100 mg daily or glimepiride (starting dose: 0.5 or 1.0 mg daily). Patients were excluded if their eGFR was <45 mL/min/1.73 m², NYHA class IV, or had a history of CVD requiring revascularization.
• The primary outcome was the percent change in NT-proBNP from baseline to week 24. Several prespecified, adjudicated clinical safety endpoints were analyzed, including HHF.
• The majority of patients were elderly (68.6±10.1 years) and male (75%), with wellcontrolled blood pressure, NYHA functional class I (64%) or II (34%), left ventricular ejection fraction of 57.6±14.6%, and HbA1c of 7.0±0.8%.⁶
• The mean percent change of NT-proBNP at 24 weeks from baseline was 10.4% (95% CI, -7.18 to 35.77) in the INVOKANA group and 21.5% (95% CI, -7.18 to 35.77 in the glimepiride group; the ratio of change with INVOKANA vs glimepiride was 0.48 (95% CI, -0.13 to 1.59; P=0.226). This did not meet the prespecified noninferiority margin of 1.1 in the upper limit of the 2-sided 95% CI.
• A greater reduction in NT-proBNP levels was observed in all patients treated with INVOKANA; however, there was no significant difference in baseline-adjusted mean changes in NT-proBNP levels (-78.7 pg/mL [95% CI, -139.9 to -17.5] vs -4.5 pg/mL [95% CI, -63.4 to 54.4], INVOKANA vs glimepiride, respectively)
• Any adverse event was reported in 9 and 13 patients in the INVOKANA and glimepiride groups, respectively. Two patients had a prespecified and adjudicated clinical event in the INVOKANA group, 1 nonfatal stroke and 1 investigator-reported worsening of HF. Five patients in the glimepiride group had a prespecified adjudicated clinical event; 3 investigator-reported worsening of HF and 2 all-cause deaths were reported.
• There were several study limitations such as single-center, open-label study design, small sample size, study duration, 1 study visit, natural variation of naturetic peptide levels, CHF diagnosed locally by clinical symptoms and history only, inclusion of patients with low mean NT-proBNP levels, higher percentage of patients with mild CHF and higher percentage with HFpEF.

Carbone et al (2020)⁷ conducted a randomized, double-blind, controlled study to investigate the effects of INVOKANA 100 mg daily compared to sitagliptin 100 mg daily on cardiorespiratory fitness (CRF) in patients with T2DM and stable chronic established HF with HFrEF. The study, known as CANA-HF, evaluated whether INVOKANA improved peak VO₂ and ventilatory efficiency in patients with T2DM and HFrEF compared to sitagliptin.

• Stable patients with symptomatic HF (NYHA class II-III) with a left ventricular ejection fraction of ≤40%, T2DM, and reduced CRF were enrolled in the study.
• Peak VO₂ and VE/VCO₂ slope (coprimary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO₂ (additional CRF variable), VAT (additional CRF variable), cardiac function, quality of life (using Minnesota Living with Heart Failure Questionnaire [MLHFQ]), and biomarkers (HbA1c, NT-proBNP, and GFR) were all measured at baseline and at 12-week follow-up.
• The study was terminated early due to new guidelines recommending INVOKANA over sitagliptin in HF. A total of 36 patients had been enrolled (INVOKANA, n=17; sitagliptin, n=19); baseline characteristics were similar between groups.
• Statistically significant improvements in the coprimary endpoints were not observed in either group. There were no significant changes in peak VO₂ and VE/VCO₂ slope between groups (P=0.083 and P=0.98, respectively) or within groups (INVOKANA: P=0.23 and P=0.66, respectively; sitagliptin: P=0.16 and P=0.65, respectively).
• Compared with sitagliptin, INVOKANA significantly improved lean peak VO₂ (+2.4 mL•kg_LM^-1•min^-1, P=0.036), VAT (+1.5 mL•kg^-1•min^-1, P=0.012), and VO₂ matched for RER (+2.4 mL•kg^-1•min^-1, P=0.002). INVOKANA reduced MLHFQ score compared to sitagliptin (-12.1, P=0.018), which correlated with improvement in quality of life.
• INVOKANA improved cardiac function vs sitagliptin. No significant changes in biomarkers were observed. The overall number of adverse events was low, with 1 event of worsening HF reported with sitagliptin.

CHIEF-HF^8-12 was a randomized, double-blind, placebo-controlled, parallel-group, interventional, decentralized, patient-centered, superiority study designed to investigate the effects of INVOKANA 100 mg vs placebo on health status across the spectrum of HF, regardless of EF and diabetes status. Patients were randomized in a 1:1 ratio to either INVOKANA 100 mg (n=222) or placebo (n=226) for a period of 12 weeks.

• Key inclusion criteria included patients with confirmed HF of any type, sole access to smartphone compatible with Fitbit device, willingness to wear a Fitbit (Versa 2), and a KCCQ Overall Summary (KCCQ-OS) >40 to <80.
  • The KCCQ is a 23-item, self-administered questionnaire developed to independently measure the patient's perception of their health status over eight domains:
    • Physical Limitation
    • Symptoms Stability
    • Symptom Frequency
    • Symptom Burden
    • Total Symptom
    • Social Limitation
    • Self-Efficacy
    • Quality of Life
  • Patients were stratified based on their baseline EF (HF with reduced EF [HFrEF] or HF with preserved EF [HFpEF]).
    • HFrEF is defined as: (a) EF <40%; or (b) a primary diagnosis of HF or 2 out patient visits for HF in the past 18 months.  
    • HFpEF is defined as: (a) EF >40%; or (b) a primary diagnosis of HF or 2 out patient visits for HF; or (c) on a loop diuretic or aldosterone receptor blocker in the past 18 months.
• The primary outcome for the study was the change from baseline to week 12 in TSS of the KCCQ.
• Secondary outcomes include:
  • A comparison of daily step counts acquired from the Fitbit,
  • Individual domain scores of the KCCQ: Physical Limitation, Quality of Life, Clinical Summary (the average of Physical Limitation and TSSs), and Overall Summary (the average of the Physical Limitation, TS, Social Functioning, and Quality of Life domains) scores.
• INVOKANA significantly improved KCCQ-TSS at 12 weeks vs placebo with a difference of 4.3 points at week 12 (95% CI, 0.80-7.80; P=0.016). Improvement in KCCQ-TSS with INVOKANA was observed as early as 2 weeks.
• These benefits were consistent across the key pre-specified subgroups listed below:
  • HFrEF: difference of 4.0 points (95% CI, -1.0 to 9.0) and HFpEF: difference of 4.5 points (95% CI, -0.3 to 9.4)
    • P_interaction=0.35
  • T2DM: difference of 6.5 points (95% CI, -0.2, 13.2) and non T2DM: difference of 3.6 points (95% CI, -0.5 to 7.8)
    • P_interaction=0.90
• Improvements in mean scores were also observed in the INVOKANA treatment group for most other KCCQ domains (Overall summary score, Clinical summary score, Physical limitations score, Quality of life score, Social Limitations score) but not for changes in step counts, which did not change over 12 weeks in either group (mean difference favoring INVOKANA of 29.8 steps (95% CI, -284 to 344). No P values are reported for the secondary analyses because a smaller-than planned sample size left no room for additional analyses.
• Serious adverse events occurred in 12.1% of patients (n=27) in the INVOKANA treatment group and 7.8% of patients (n=18) in the placebo treatment group.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT Drug File (and/or other resources, including internal/external databases) was conducted on 21 April 2025. Real-world evidence studies were excluded.