Summary

Outcomes Studies:

• CREDENCE was a randomized, double-blind, placebo (PBO)-controlled, parallel group trial assessing whether INVOKANA 100 mg has a renal and/or cardiovascular (CV) protective effect compared to PBO in patients with type 2 diabetes mellitus (T2DM) and albuminuric chronic kidney disease (CKD), who were also receiving standard of care.^{1, 2}
• INVOKANA significantly reduced the rates of the primary composite outcome of endstage kidney disease (ESKD), doubling of serum creatinine (dSCr), and renal or CV death (43.2 and 61.2 per 1000 patient years [PYs] in the INVOKANA and PBO arms, respectively), resulting in a 30% relative risk reduction (hazard ratio [HR], 0.70; 95% confidence interval (CI), 0.59-0.82; P=0.00001).¹
  • • Individual components of the primary composite outcome included: ESKD (HR, 0.68; 95% CI, 0.54-0.86; P=0.002); dSCR (HR, 0.60; 95% CI, 0.48-0.76; P<0.001); CV death (HR, 0.78; 95% CI, 0.61-1.00; P=0.0502).¹
  • In the CREDENCE study, INVOKANA significantly reduced the risk of the following:¹
    • The composite of CV death and hospitalized heart failure (HHF; relative risk reduction [RRR], 31%; HR, 0.69; 95% CI, 0.57-0.83; P<0.001); the composite of Major Adverse CV Events (MACE), comprised of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke (RRR, 20%; HR, 0.80; 95% CI, 0.67-0.95; P=0.01); and HHF (RRR, 39%; HR, 0.61; 95% CI, 0.47-0.80; P<0.001).¹
  • INVOKANA treatment was associated with a greater mean reduction in HbA1c, systolic blood pressure (SBP), diastolic pressure, body weight, and lower urinary albumin-to-creatinine ratio compared to PBO.¹
  • INVOKANA treatment resulted in a slower decline of estimated glomerular filtration rate (eGFR) over time, despite a greater initial reduction in eGFR.¹
• In a subgroup analysis of patients from the CANVAS Program with a baseline eGFR of ≥60 or <60 mL/min/1.73 m², INVOKANA was associated with a significant reduction in HbA1c, SBP, and body weight in patients with eGFR ≥60 and <60 mL/min/1.73 m², compared with PBO.³ Effects on HbA1c and body weight were attenuated in the eGFR <60 mL/min/1.73 m² subgroup.
  • Compared with PBO, INVOKANA was associated with an acute decline in eGFR, both in the eGFR ≥60 and <60 mL/min/1.73m² subgroups (P heterogeneity=0.21); however, demonstrated stabilized kidney function thereafter (P heterogeneity=0.58).
  • Effects of INVOKANA on the composite renal outcomes (end-stage renal disease [ESRD], renal death, and 40% reduction in eGFR or dSCr) was consistent between the eGFR ≥60 and <60 mL/min/1.73 m² subgroups (P=0.28 and P=0.21, respectively).³

Glycemic Control Studies:

• In a phase 3 study in patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m²), both INVOKANA 100 and 300 mg reduced HbA1c from baseline compared with PBO at week 26 (-0.33, -0.44 and -0.03%, respectively; P<0.05).⁴ Both doses of INVOKANA continued to show reductions from baseline in A1C levels at week 52 (-0.19% and -0.33% for INVOKANA100 mg and 300 mg groups, respectively).⁵
• In a pooled analysis of 4 randomized, double-blind, PBO-controlled, phase 3 studies^{4, 6-8} in patients with eGFR ≥30 and <60 mL/min/1.73 m², both INVOKANA 100 and 300 mg significantly reduced HbA1c and body weight vs PBO. HbA1c and body weight changes were greater in patients with eGFR ≥45 mL/min/1.73 m² than in those <45 mL/min/1.73 m².⁹

Additional citations identified during a literature search have been included in the REFERENCES section for your review.^{10, 11}

OUtcomes STUDIES

Patients with Mild to Moderate Renal Impairment

CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), was a randomized, double-blind, PBO-controlled, parallel group multicenter, event driven clinical trial to assess the effects of INVOKANA (100 mg) compared with PBO on clinically important renal outcomes in people with T2DM and established CKD (eGFR 30 to <90 mL/min/1.73 m²) and albuminuria (ratio of albumin to creatinine >300 to 5000 mg/g), who were receiving a stable, maximum tolerated or labelled dose (for >4 weeks prior to randomization) of an angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB).^{1, 2, 12-15}

Inclusion Criteria^{1, 13}

• ≥30 years of age with CKD in the setting of T2DM (HbA1c ≥6.5% to ≤12.0%; ≥6.5% to <10.5% in Germany).
• eGFR ≥30 to <90 mL/min/1.73 m²
• Prespecified to enroll ~60% with stage 3 CKD (eGFR 30 to <60 mL/min/1.73 m²)
• eGFR was calculated using the CKD-EPI formula.
• Albuminuria (urine albumin:creatinine ratio [UACR] >300 mg/g and ≤5000 mg/g)

Exclusion Criteria (Select)^{1, 13}

• Nondiabetic kidney disease
• History of kidney disease treated with immunosuppression.
• History of treatment with chronic dialysis or kidney transplantation.

Methodology^{1, 13}

• Patients were randomly assigned in a 1:1 ratio to either INVOKANA 100 mg or matching PBO using randomly permuted blocks with stratification by baseline eGFR categories (30 to <45, 45 to <60, and 60 to <90 mL/min/1.73 m²).
• Patients were instructed to take their study treatment once daily before the first meal of the day, with a log maintained of study capsule counts.²
• Administration was to continue (even if eGFR drops below 30 mL/min/1.73 m²) until the completion of the study, the commencement of dialysis, kidney transplantation, incidence of diabetic ketoacidosis, pregnancy, or receipt of disallowed therapy.

Outcomes^{1, 13}

• The primary outcome was the composite of the following:
  • ESKD (defined as chronic dialysis for >30 days, renal transplantation, or eGFR <15 mL/min/1.73m² sustained for >30 days)
  • Doubling of serum creatinine from baseline average sustained for >30 days.
  • Death due to renal or CV disease
• Secondary outcomes were planned for sequential hierarchical testing. If INVOKANA was superior to PBO 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 in the following order:²
  • Composite of CV death or hospitalized heart failure
  • Composite of MACE, comprised of CV death, nonfatal MI, or nonfatal stroke.
  • HHF
  • Renal-specific composite of ESKD, dSCr, or renal death
  • CV death
  • All-cause mortality
  • Broader CV composite of CV death, nonfatal MI, nonfatal stroke, HHF, or hospitalized unstable angina.
• Prespecified exploratory endpoints included: composite endpoint of ESKD, renal or CV death; ESKD; dSCr; renal death; fatal and nonfatal MI; fatal and nonfatal stroke; hospitalized unstable angina; change in eGFR over time; change in albuminuria over time.² A post hoc exploratory outcome was reported for the composite of dialysis, kidney transplant, or renal death.
• All adverse events (AEs) were collected from randomization through 30 days after the last dose of study drug. AEs of interest to be collected include: all malignancies, fatal pancreatitis, hemorrhagic/necrotizing pancreatitis, nephrotoxicity/acute kidney injury (AKI), venous thromboembolic events, fractures, diabetic ketoacidosis, and amputation.²
• All renal and CV events that are components in the primary and secondary composite endpoints of the study and all key safety outcomes (bone fractures, pancreatitis, ketoacidosis, renal cell carcinoma [RCC]) were adjudicated by independent blinded adjudication committees.²

Baseline Characteristics^{1, 12, 13}

• A total of 4401 participants were randomized from 690 sites across 34 countries between March 2014 and May 2017 in the intention-to-treat (ITT) analysis set. There were 4 participants that were not dosed, leading to 4397 participants in the ontreatment and on-study analysis sets.
• Baseline characteristics were similar between the INVOKANA and PBO groups. These included a mean age of 63 years, 33.9% female participants, mean duration of T2DM of 15.8 years; mean HbA1c of 8.3%, mean eGFR of 56.2 mL/min/1.73m², median UACR of 927 mg/g.²
  • In the total population, 50.4% had prior CV disease, 14.8% had a history of heart failure, and 5.3% had a history of amputation.
• Across both treatment groups, the mean exposure to study drug was 115 weeks.
• For more information related to the CREDENCE baseline characteristics, please refer to Table: CREDENCE: Baseline Characteristics

Results

By July 2018, the number of confirmed primary endpoints to trigger the planned interim analysis had been accrued and the prespecified efficacy criteria for early cessation had been achieved. The independent data monitoring committee advised the Steering Committee to end the CREDENCE study early after a median follow-up duration of 2.62 years (range, 0.02-4.53 years).¹

Primary Composite Outcome

• In the CREDENCE study, INVOKANA significantly reduced the rates of the composite outcome of ESKD, dSCr, and renal or CV death (43.2 and 61.2 per 1000 PYs in the INVOKANA and PBO arms, respectively), resulting in a 30% RRR (HR, 0.70; 95% CI, 0.59-0.82; P=0.00001; number needed to treat [NNT], 22 over 2.5 years for the primary composite endpoint).
• See Figure: Time to First Occurrence: Primary Composite Outcome and Tables: Summary of Efficacy Results and NNT.¹
• The effects were consistent across regions and all prespecified subgroups.¹

Individual Components of the Primary Composite Outcome

• • The event rate of ESKD was 20.4 and 29.4 per 1000 PYs (HR, 0.68; 95% CI, 0.540.86) in the INVOKANA and PBO groups, respectively; P=0.002).¹ See Figure: Time to First Occurrence: End Stage Kidney Disease and Tables: Summary of Efficacy Results and NNT.

• • The event rate of dSCR was 20.7 and 33.8 per 1000 PYs (HR, 0.60; 95% CI, 0.480.76; P<0.001) in the INVOKANA and PBO groups, respectively.¹ See Table: Summary of Efficacy Results.
  • The event rate of renal death was 0.3 and 0.9 per 1000 PYs in the INVOKANA (n=2) and PBO (n=5) groups, respectively. Since there were <10 events of renal death, a HR and 95% CI were not reported. ¹
  • The event rate of CV death was 19.0 and 24.4 per 1000 PYs (HR, 0.78; 95% CI, 0.61-1.00) in the INVOKANA and PBO groups, respectively.¹ See Figure: Time to First Occurrence: Cardiovascular Death and Table: Summary of Efficacy Results.

Secondary and Exploratory Outcomes

• In the CREDENCE study, INVOKANA significantly reduced the risk of the following:¹
  • The composite of CV death and hospitalized heart failure (RRR, 31%; HR, 0.69; 95% CI, 0.57-0.83; P<0.001)
  • MACE (RRR, 20%; HR, 0.80; 95% CI, 0.67-0.95; P=0.01)
  • HHF (RRR, 39%; HR, 0.61; 95% CI, 0.47-0.80; P<0.001)
  • Renal-specific composite of ESKD, dSCr, or renal death (RRR, 34%; HR, 0.66; 95% CI, 0.53-0.81; P<0.001).
• The risk of CV death was not found to be statistically significant (P=0.0502), therefore, due to the hierarchical testing sequence, the remaining 2 secondary endpoints were not formally tested.¹
• See Table: Summary of Efficacy Results.

Subgroup Analyses

A subgroup analysis was conducted to evaluate the primary composite outcome (ESKD, dSCr, or renal or CV death) and the renal-specific composite outcome (ESKD, dSCr, or renal death) according to screening eGFR and UACR at baseline.¹ See Table: Primary and RenalSpecific Composite Outcome Based on Screening eGFR and Baseline UACR.

Safety Outcomes

• • The overall rates of AEs and serious AEs, (on-treatment and on-study analysis sets), were similar between the treatment groups.¹ See Table: Summary of Safety Results.
  • There was no imbalance observed in the risk of lower limb amputation between the INVOKANA vs PBO arms (12.3 vs 11.2 per 1000 PYs; HR, 1.11; 95% CI, 0.79-1.56).¹
  • Rates of fracture were similar between the INVOKANA and PBO treatment arms (11.8 vs 12.1 per 1000 PYs; HR, 0.98; 95% CI, 0.70-1.37).¹
  • All renal-related AEs occurred at a significantly higher rate with PBO compared with INVOKANA (79.1 vs 57.1 per 1000 PYs; HR, 0.71; 95% CI, 0.61-0.82). Hyperkalemia events and acute kidney injury events were reported more in the PBO arm compared with the INVOKANA arm (hyperkalemia: 36.9 vs 29.7 per 1000 PYs,; HR, 0.80; 95% CI, 0.65-1.00; acute kidney injury: 20.0 vs 16.9; HR, 0.85; 95% CI, 0.64-1.13).¹
  • Diabetic ketoacidosis rates were low overall, but higher in participants treated with INVOKANA (2.2 vs 0.2 events per 1000 PYs; HR, 10.8; 95% CI, 1.39-83.65).¹
  • Rates of cancer, including renal cell carcinoma, were similar in both treatment arms.¹

Intermediate Outcomes

• • INVOKANA treatment demonstrated a greater least-squares [LS] mean reduction in HbA1c at 13 weeks (-0.31%; 95% CI, -0.26% to -0.37%) and a greater overall mean reduction throughout the study (-0.25%; 95% CI, -0.20% to -0.31%) compared with PBO.¹
  • INVOKANA treatment demonstrated a greater mean change in systolic blood pressure (-3.30 mmHg; 95% CI, -2.73 to -3.87 mmHg), diastolic blood pressure (0.95 mmHg; 95% CI, -0.61 to -1.28 mmHg), and body weight (-0.80 kg; 95% CI, -0.69 to -0.92 kg).¹
  • The geometric mean of UACR was 31% lower on average during follow-up in the INVOKANA arm (95% CI, -26% to -35%).¹
  • The overall decline in eGFR slope over time was attenuated with INVOKANA vs PBO, with a difference of 1.52 mL/min/1.73m²/year (95% CI, -1.11 to 1.93 mL/min/1.73m²/year).¹

The CANVAS Program

The CANVAS Program (N=10,142) comprises 2 large INVOKANA CV outcome studies, CANVAS⁸ and CANVAS-R^16-20 This integrated analysis of CANVAS and CANVAS-R, as part of the CANVAS Program, was conducted to evaluate the effects of INVOKANA on CV, renal, and safety outcomes.²¹

At baseline, 65.6% of patients had a history of atherosclerotic CV disease and 35% had at least 2 risk factors for CV disease.^{18, 21}  Among the participants in the CANVAS Program, 22.6% had microalbuminuria, 7.6% had macroalbuminuria, 17.5% of patients had nephropathy, and the median ACR measured in milligrams of albumin and grams of creatinine was 12.3 at baseline.²¹  At baseline, eGFR ≥45 to <60 ml/min/1.73 m² and eGFR ≥30 to <45 mL/min/1.73 m² was reported in 14.6% and 5.2% of patients, respectively, in the CANVAS program.¹⁸ Mean follow-up was 188.2 weeks.²¹

In the CANVAS Program:

• Progression of albuminuria occurred less frequently in patients in the INVOKANA group compared to PBO (89.4 vs 128.7 per 1000 PYs), corresponding to a HR of 0.73 and 95% CI of 0.67 to 0.79, with a greater effect in CANVAS-R (HR, 0.64; 95% CI, 0.57-0.73) compared with CANVAS (HR, 0.80; 95% CI, 0.72-0.90) (P=0.02 for homogeneity).²¹
• Similarly, regression of albuminuria was more frequent in the INVOKANA group compared with the PBO group (293.4 vs 187.5 per 1000 PYs; HR, 1.70; 95% CI, 1.511.91).²¹
• There were nominal findings for the composite outcome of sustained ≥40% reduction in eGFR, need for RRT, or renal death, which occurred less frequently with INVOKANA vs PBO (5.5 vs 9.0 per 1000 PYs; HR, 0.60; 95% CI, 0.47-0.77), with no difference between the CANVAS and CANVAS-R trials.²¹
• A prespecified subgroup analysis reported an eGFR of 30 to <60 ml/min/1.73 m² at an event rate of 36.4 and 49.3 per 1000 PYs (HR, 0.70, 95% CI, 0.55-0.90) in the INVOKANA and PBO groups, respectively.
• Additionally, eGFR 60 to <90 ml/min/1.73 m² was reported at an event rate of 26.8 and 29 per 1000 PYs, (HR, 0.95; 95% CI, 0.80-1.13 in the INVOKANA and PBO groups, respectively.²¹
• The adverse effects observed in the CANVAS Program were generally consistent with the known safety profile of INVOKANA, except for an increased risk for lower extremity amputation, with the majority at the level of the toe or metatarsal.²¹

Secondary Analyses of the CANVAS Program

Neuen et al (2018)³ conducted a subgroup analysis to determine the effects of INVOKANA on renal and safety outcomes in patients within the CANVAS Program that had a baseline eGFR of ≥60 mL/min/1.73 m² or <60 mL/min/1.73 m².

• The effects of INVOKANA on the following outcomes were analyzed in patients with preserved (eGFR ≥60 mL/min/1.73 m²) and reduced (eGFR <60 mL/min/1.73 m²) renal function:
  • Changes from baseline in HbA1c, SBP, body weight, and urinary ACR
  • Adjusted mean eGFR slope difference between INVOKANA and PBO
  • Composite renal outcomes of:
    • 40% reduction in eGFR, ESKD, or renal death
    • dSCr, ESKD, or renal death
  • Serious renal-related, acute kidney injury, and hyperkalemia AEs, and all fracture and amputation outcomes
• At baseline, 8101 (79.9%) patients had eGFR ≥60 mL/min/1.73 m² and 2039 (20.1%) patients had eGFR <60 mL/min/1.73 m².

Efficacy

• INVOKANA was associated with a significant reduction in HbA1c, SBP, body weight, and urinary ACR in patients with eGFR ≥60 and <60 mL/min/1.73 m² vs PBO. ³
  • Effects on HbA1c and body weight were attenuated in the eGFR <60 mL/min/1.73 m² subgroup. ³

Effects on Renal Outcomes

• Compared with PBO, INVOKANA was associated with an acute decline in eGFR at week 6/13 (week 6 for CANVAS and week 13 for CANVAS-R), both in the eGFR ≥60 mL/min/1.73 m² subgroup and the <60 mL/min/1.73 m² subgroup (PBO-subtracted difference of -2.20 and -2.83 mL/min/1.73 m², respectively; P heterogeneity=0.21). ³
• From week 6/13 to the last available measurement, INVOKANA stabilized kidney function in patients with eGFR ≥60 and <60 mL/min/1.73 m² (PBO-subtracted difference of 1.20 and 1.11 mL/min/1.73 m², respectively; P heterogeneity=0.58). ³
• Among patients who were re-evaluated approximately 30 days following treatment discontinuation (as part of the CANVAS-R protocol), change from baseline to offtreatment eGFR levels was higher, on average, with INVOKANA vs PBO in patients with eGFR ≥60 and <60 mL/min/1.73 m² (PBO-subtracted difference of 2.17 and 4.00 mL/min/1.73 m², respectively; P heterogeneity=0.08). ³
• Effects of INVOKANA on the composite renal outcomes of ESRD, renal death, and either 40% reduction in eGFR or dSCr appeared to be consistent between the eGFR ≥60 and <60 mL/min/1.73 m² subgroups (P=0.28 and P=0.21, respectively). ³

Safety

• Rates of serious renal-related AEs, serious acute kidney injury, serious hyperkalemia, amputations, and fracture were consistent among the eGFR ≥60 and <60 mL/min/1.73 m² subgroups (P heterogeneity >0.05 for all outcomes). ³

Neuen et al (2018)²² conducted a secondary analysis of the CANVAS Program to determine the effects of INVOKANA on the primary outcome of composite of MACE comprised of CV mortality, nonfatal MI, or nonfatal stroke as well as other CV and renal outcomes in patients with and without CKD defined as eGFR <60 and >60 mL/min/1.73 m², respectively, as well as baseline kidney function with eGFR subgroups (<45, 45-<60, 60<90, and ≥ 90 mL/min/1.73 m²).²²

• Change in eGFR over time and the difference in treatment arms were assessed from baseline to week 13, and week 13 to last available measurement using ITT.
• In CANVAS-R, the change in eGFR from baseline to off-treatment was assessed by SCr measurements ~30 days after treatment discontinuation.
• The effect of INVOKANA on HbA1c, blood pressure, and body weight were calculated as a mean change from baseline across the entire follow-up period.
• Safety outcomes were assessed by on-treatment analysis, with the exception of amputation and fracture outcomes, which included all subjects who received at least 1 dose of study drug and had an event at any time during follow-up.
• The geometric mean of post-baseline UACR and changes in albuminuria were estimated based on highly skewed distribution of data.

Baseline Characteristics

• At baseline, 2039 (20.1%) of the 10,142 patients had CKD, of which 71.6% had a history of CVD; the mean HbA1c was 8.3%; the mean eGFR was 49 mL/min/1.73 m², which included 554 (5.5%) patients with a baseline eGFR <45 mL/min/1.73m².²²
• Patients with lower baseline eGFR were found to be older, more likely female, Caucasian, have a longer duration of diabetes, have established micro- or macrovascular disease, history of heart failure, micro- or macroalbuminuria, treated with insulin and CV protective therapies (all P<0.0001).²²
• Baseline characteristics for patients with and without CKD were well-balanced across groups.²³

Results – Intermediate Outcomes²²

• Compared with placebo, INVOKANA significantly reduced HbA1c across all eGFR categories, however, the effects were attenuated progressively with lower eGFR (P_{heterogeneity}<0.0001). INVOKANA also significantly lowered albuminuria across all eGFR categories (P_{heterogeneity}=0.01).
• Similar intermediate outcome results were observed in patients with and without CKD, apart from the effect of INVOKANA on body weight, which was attenuated in subjects with CKD (-1.32 kg vs -1.67 kg, respectively; P_{heterogeneity}=0.0002).
• See Table: Change in HbA1c, SBP, Body Weight, and UACR with INVOKANA Compared With Placebo Across All Levels of Kidney Function.
• See Table: Change in HbA1c, SBP, Body Weight, and UACR with INVOKANA Compared With Placebo in Subjects With and Without CKD.

Results – Cardiovascular Outcomes²²

• The relative risk reduction of MACE was similar across all the eGFR subgroups and for participants with and without CKD (P_{heterogeneity}=0.33 and 0.08, respectively). Effects on fatal/nonfatal MI, CV death, and HHF were consistent across the eGFR categories P_{heterogeneity}=0.08, >0.50, and >0.50, respectively). Heterogeneity was observed with fatal/nonfatal stroke with a potential greater benefit with lower eGFR and patients with CKD (P_{heterogeneity}=0.01 for both)
• See Table: Effect of INVOKANA on CV, Renal, and Safety Outcomes According to Baseline eGFR.
• See Table: Effect of INVOKANA On CV, Renal, and Safety Outcomes in Subjects With and Without CKD.

Results – Renal Outcomes²²

• Compared with placebo, INVOKANA was associated with an acute decline in eGFR at week 6 for CANVAS and week 13 for CANVAS-R, in the eGFR ≥90, 60-<90, 45-<60, and <45 mL/min/1.73 m² categories (placebo-subtracted differences of -1.89, -2.33, -2.85 and -2.75 mL/min/1.73 m², respectively; P_{heterogeneity}=0.09).
• From week 6/13 to the last available measurement, INVOKANA slowed decline in kidney function in patients in all eGFR categories (placebo-subtracted mean slope difference of 1.47, 1.09, 1.05, and 1.35 mL/min/1.73 m², respectively; P_{heterogeneity}=0.21).
• Change from baseline to off-treatment (~30 days after treatment discontinuation) eGFR levels was higher, on average, with INVOKANA vs placebo across all eGFR categories (placebo-subtracted difference of 1.18, 2.73, 4.63, and 2.69 mL/min/1.73 m², respectively; P_{heterogeneity}=0.047).
• Effects of INVOKANA on the composite renal outcomes of ESKD, renal death, and either 40% reduction in eGFR or doubling of serum creatinine appeared to be consistent between all the eGFR categories (P_{heterogeneity}=0.59).
• See Table: Effect of INVOKANA on CV, Renal, and Safety Outcomes According to Baseline eGFR.

Results - Safety²²

• Safety outcomes were generally consistent across eGFR categories, including for serious AEs, AEs leading to discontinuation, amputations, and bone fractures (P_{heterogeneity}>0.05 for all safety outcomes).
• For serious renal-related AEs, INVOKANA had a similar event rate compared with placebo in the overall population (2.5 vs 3.3 per 1000 PYs, respectively; HR, 0.76; 95% CI, 0.49-1.19). Serious renal-related AEs were generally consistent across eGFR subgroups (P_{heterogeneity}=0.85).
• For serious AKI events, INVOKANA had a similar event rate compared with placebo (1.6 vs 2.5 per 1000 patient-years, respectively; HR, 0.66; 95% CI, 0.39-1.11). Event rates were generally consistent across eGFR subgroups (P_{heterogeneity}=0.74)
• See Table: Effect of INVOKANA on CV, Renal, and Safety Outcomes According to Baseline eGFR.

Peters et al (2020)²⁴ evaluated the prognostic utility of PromarkerD (a novel blood test that can predict future renal function decline) in patients with T2DM participating in the CANVAS study.

• PromarkerD scores were measured at baseline in 3570 CANVAS study patients (INVOKANA, n=2375; placebo, n=1196).
  • Biomarker concentrations (CD5L, ApoA4, IGFBP3), measured by mass spectrometry, were combined with clinical data (age, serum high-density lipoprotein cholesterol, eGFR) to provide PromarkerD scores.
  • The PromarkerD score ranges from 0 to 100% and is categorized as low-, moderate-, or high-risk.
• Renal function decline was defined as incident diabetic kidney disease during the 4 years following randomization.
• Mean age was 62.7 years, 67% of patients were male, median duration of diabetes was 12.4 years, median PromarkerD score was 2.88%, 70.5% of patients were categorized as low-risk for renal function decline, 13.6% as moderate-risk, and 15.9% as high-risk.
• There was no significant difference in baseline PromarkerD scores by allocated treatment (P=0.58).
• Baseline PromarkerD moderate-risk and high-risk scores were found to be prognostic for clinically significant renal function decline (moderate-risk odds ratio [OR], 5.29; 95% CI, 4.22-6.64 and high-risk OR, 13.52; 95% CI, 10.69-17.11) vs low-risk scores, with P<0.001 for both.

Glycemic Control studies

Moderate Renal Impairment

Yale et al (2013, 2014)^4,5 evaluated the efficacy and safety of INVOKANA 100 mg and 300 mg once daily vs PBO in adult patients with stage 3 CKD; moderate renal impairment and inadequately controlled T2DM; N=269 in a randomized, double-blind, PBO-controlled, phase 3 study with a 26-week core period followed by a 26-week, double-blind extension period (total duration: 52 weeks).

• Inclusion criteria were adults with T2DM, ≥25 years of age, with HbA1C ≥7.0% and ≤10.5%, stage 3 CKD (eGFR ≥30 and <50 mL/min/1.73 m²) and were either not on antihyperglycemic agents (AHAs) or were on a stable AHA regimen (95% of patients on insulin and/or sulfonylurea). Patients were required to have generally stable renal function (≤25% decrease in eGFR from screening to week 2 visits).
• Baseline demographic and disease characteristics were similar across treatment groups. Mean eGFR was 39.4 mL/min/1.73 m² and median ACR was 30.0 μg/mg.

Efficacy

• A summary of prespecified primary and secondary endpoints are shown in Table: Selected Efficacy Endpoints at Weeks 26 and 52 (mITT population).
• INVOKANA 100 mg and 300 mg also demonstrated the following: reductions from baseline in body weight, decreases in SBP and diastolic blood pressure, and increases in high-density lipoprotein cholesterol compared with PBO at 26 and 52 weeks. Increases from baseline in low-density lipoprotein cholesterol were observed across groups, with a larger increase seen with PBO compared to INVOKANA 100 and 300 mg at 52 weeks.

Safety

• Overall, incidences of any AEs, serious AEs, and AEs that led to discontinuation were similar in the INVOKANA 100 mg, 300 mg, and PBO groups. In patients taking background antihyperglycemic therapy, including insulin and sulfonylureas, hypoglycemic episodes were more frequent with INVOKANA 100 mg and 300 mg compared with PBO. See Table: Summary of Overall Safety and Select AEs at Weeks 26 and 52.

Renal Parameters and Renal Injury

• INVOKANA 100 mg and 300 mg resulted in decreases in eGFR and increases in blood urea nitrogen (BUN) vs PBO at week 26 and at week 52, with modest decreases in eGFR (-4.3%, -9.4%, and -2.8%, respectively) and increases in BUN with INVOKANA 100 mg and 300 mg vs PBO (12.0%, 17.3%, and 5.4%, respectively). The decrease in eGFR with INVOKANA treatment was largest at week 3 and trended towards baseline during the remainder of the treatment period.
• At week 26, INVOKANA 100 mg and 300 mg resulted in modest decreases in urine albumin to creatinine ratio (ACR) vs PBO. A similar median percent decrease in ACR was seen with INVOKANA 100 mg (-16.4%) and 300 mg (-28.0%) vs PBO (19.7%) at week 52.
• A lower proportion of subjects in the INVOKANA 100 mg and 300 mg groups reported progression of albuminuria (i.e., from normoalbuminuria to micro- or macroalbuminuria, or from micro- to macroalbuminuria) relative to those in the PBO group at week 26. Similarly, a lower proportion of patients in the INVOKANA 100 mg and 300 mg groups reported progression of albuminuria vs PBO (10.3%, 14.7%, and 17.1%, respectively) at week 52.

Laboratory Changes

• There were modest increases in serum magnesium and phosphate with INVOKANA vs PBO at weeks 26 and 52.
• An increase in hemoglobin with INVOKANA 100 mg and 300 mg (6.5% and 4.2%, respectively) vs PBO (-1.4%) at week 52 was observed.
• There was a small decrease in alanine aminotransferase (ALT) with INVOKANA 300 mg (-4.4%) and small increases with INVOKANA 100 mg and PBO (10.1% and 8.2%, respectively) at week 26. Small increases in aspartate aminotransferase (AST) were observed with INVOKANA 100 mg (5.5%) and PBO (4.3%) vs a small decrease observed with INVOKANA 300 mg (-4.3%) at week 26, and similar trends in changes in ALT and AST were reported through week 52.

Yamout et al (2014)⁹ evaluated the efficacy and safety of INVOKANA vs PBO in patients with moderate renal impairment (eGFR ≥30 and <60 mL/min/1.73 m²) and inadequately controlled T2DM (N=1085) in a pool of 4 randomized, double-blind, PBO-controlled, phase 3 studies.^{6, 4, 7, 8} Subgroup results are also reported for patients with eGFR ≥30 and <45 mL/min/1.73 m² (n=364) and eGFR ≥45 and <60 mL/min/1.73 m² (n=721).

Efficacy

• See Table: Efficacy Endpoints in Patients with Moderate Renal Impairment. Additionally, changes in SBP were greater with INVOKANA 100 mg (-4.4) and 300 mg (-6.0) compared to PBO (-1.6) in the overall population.

Safety

• Overall, INVOKANA was generally well tolerated. Serious AEs were more frequent with PBO than with INVOKANA. AE-related discontinuation rates were higher with INVOKANA 300 mg than with INVOKANA 100 mg and PBO.
• Incidence of urinary tract infections (UTIs) was numerically higher with INVOKANA 300 mg vs INVOKANA 100 mg and PBO; rates of serious UTIs and those leading to discontinuation were low across groups.
• Incidence of AEs related to reduced intravascular volume was increased with INVOKANA 100 mg and 300 mg vs PBO and AEs related to osmotic diuresis were similar across groups.

Gilbert et al (2014)²⁵ evaluated a pool of 6 randomized, double-blind, PBO-controlled studies,^{6, 26-30} comparing the change in HbA1C by age and renal function status in T2DM patients receiving INVOKANA 100 mg and 300 mg treatment to PBO at either week 18^{29, 30} or week 26.^{6, 26-28}

• Greater HbA1C reductions were seen in patients with a higher baseline eGFR (eGFR ≥90 and ≥60 to <90 mL/min/1.73 m²) and in younger patients (<65 years). In patients with eGFR ≥45 to <60 mL/min/1.73 m², both INVOKANA 100 mg and 300 mg provided improvements in HbA1C.
• The incidence of any AEs was generally similar across all groups, regardless of baseline age and eGFR.

Other literature^31-34 evaluated the effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of INVOKANA, including a post hoc analysis evaluating the effect of INVOKANA on serum electrolytes in patients with T2DM, based on renal function status.³⁵

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, Derwent Drug File (and other resources, including internal/external databases) was conducted on 18 April 2023 and did not identify any relevant citations pertaining to this topic.