SUMMARY

• CREDENCE was a randomized, double-blind, placebo (PBO)-controlled, parallel-group, multicenter, event-driven clinical trial designed to assess effects of INVOKANA (100 mg) vs PBO on clinically important renal outcomes in people with type 2 diabetes mellitus (T2DM) and established chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] 30 to <90 mL/min/1.73 m²) and albuminuria (urinary albumin to creatinine ratio [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 (ACEi) or angiotensin II receptor blocker (ARB).^1-5
  • In the CREDENCE study, INVOKANA significantly reduced the rates of the primary  composite outcome of end-stage kidney disease (ESKD), doubling of serum creatinine (dSCr), or renal or CV death (43.2 and 61.2 per 1000 patient-years [PY] in the INVOKANA and PBO arms, respectively), resulting in a 30% relative risk reduction (RRR) (hazard ratio [HR], 0.70; 95% confidence interval (CI), 0.59–0.82; P=0.00001). The effects were consistent across prespecified subgroups.¹
  • INVOKANA significantly reduced the relative risk of the prespecified renal-specific secondary composite outcome of ESKD, dSCr, or renal death by 34% (HR, 0.66; 95% CI, 0.53-0.81; P<0.001).¹
    • The event rate of ESKD was 20.4 and 29.4 per 1000 PY (HR, 0.68; 95% CI, 0.54-0.86) in the INVOKANA and PBO groups, respectively; P=0.002).¹
    • The event rate of dSCr was 20.7 and 33.8 per 1000 PY (HR, 0.60; 95% CI, 0.48-0.76; P<0.001) in the INVOKANA and PBO groups, respectively.¹
    • The event rate of renal death was 0.3 and 0.9 per 1000 PY in the INVOKANA and PBO groups, respectively.¹
  • Effects were consistent for the prespecified exploratory composite of ESKD, renal death, or CV death (HR, 0.73; 95% CI, 0.61-0.87) and the post hoc exploratory outcome of dialysis, kidney transplantation, or renal death (hazard ratio, 0.72; 95% CI, 0.54 to 0.97)
  • The overall decline in eGFR slope over time was attenuated with INVOKANA vs PBO, with a difference of 1.52 mL/min/1.73 m²/year (95% CI, -1.11, -1.93 mL/min/1.73 m²/year).¹
  • In a post hoc analysis evaluating the effect of INVOKANA on kidney-related adverse events (AEs), the overall incidence rate of kidney-related AEs for INVOKANA vs placebo was 6.0 vs 8.4 per 100 PY (HR, 0.71; 95% CI, 0.61-0.82; P<0.001). The reduction in risk of kidney-related AEs associated with randomization to INVOKANA was larger for participants with higher baseline UACR.⁶
• CANVAS Program: In the CANVAS Program,⁷ comprising the prespecified integrated analysis of 2 large cardiovascular outcome trials, CANagliflozin cardioVascular Assessment Study (CANVAS)⁸ and CANVAS-Renal (CANVAS-R)⁹, INVOKANA was associated with reduced progression of albuminuria¹⁰ and lower risk of substantive loss of kidney function.⁷ The progression of albuminuria and the composite outcome of sustained 40% reduction in eGFR, need for renal replacement therapy (RRT), or renal death occurred less frequently in the INVOKANA group vs PBO. In addition, regression of albuminuria was more frequent in patients in the INVOKANA group vs PBO.⁷
  • A post hoc analysis of the CANVAS program demonstrated that the initiation of INVOKANA based on a clinical risk-based assessment was more efficient in preventing kidney and heart failure outcomes compared with the initiation of INVOKANA based on HbA1c or UACR assessment alone.¹¹
  • In a post hoc analysis exploring potential mediators of the beneficial effects of INVOKANA on kidney outcomes in the CANVAS Program, 9 biomarkers were identified as individually significant mediators, with erythrocyte concentration, hematocrit, and hemoglobin having the largest mediating effect.¹²
• UACR and Albuminuria: In 4 PBO- and active-controlled phase 3 studies^13-16 (including 1 INVOKANA monotherapy study), which evaluated efficacy and safety of INVOKANA in patients with normal or mildly impaired baseline renal function, greater mean and median reductions in UACR were reported with INVOKANA 100 and 300 mg relative to PBO or comparator.¹⁷
• Additional citations identified during a literature search in included in the REFERENCES section for your review.^18-22

BACKGROUND

Terminology: Albuminuria and Proteinuria

• One manifestation of CKD is protein in the urine. In diabetic patients with protein in their urine, albumin is the predominant protein based on its small size and abundant quantity.  Urinary albumin is a marker for CKD due to diabetes, glomerular disease, and hypertension.^23-25
• Albuminuria is the presence of albumin in the urine whereas proteinuria is the presence of proteins in the urine.  Some literature sources use the terms proteinuria and albuminuria, interchangeably, but proteinuria is defined as urinary protein excretion that includes albumin and other proteins.²⁵
• The UACR is a ratio between two measured substances: urine albumin (mg/dL) and urine creatinine (g/dL). UACR estimates a 24-hour urine albumin excretion in mg/day.^24,26,27

CLINICAL DATA

CREDENCE

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 designed to assess effects of INVOKANA (100 mg once daily) vs PBO on clinically important renal outcomes in patients with T2DM and established 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 ACEi or ARB.^1,2,4,5,28

Study Design & Methodology

Patients who were eligible to participate in the study:^1,2,28

• ≥30 years of age with CKD in the setting of T2DM (HbA1c ≥6.5% to ≤12.0%; participants in Germany required a HbA1c range of ≥6.5% to <10.5%).
• 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 (UACR >300 mg/g and ≤5000 mg/g)
• On a stable, maximum tolerated or labelled daily dose of an ACEi or ARB for ≥4 weeks prior to randomization.

Patients with type 1 diabetes, nondiabetic kidney disease, or a history of kidney disease treated with immunosuppression, dialysis or kidney transplantation were excluded.  Use of a direct renin inhibitor, a mineralocorticoid receptor antagonist, or dual-agent treatment combining an ACEi with an ARB were not allowed during the study.^1,2,28

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).

CREDENCE was designed to be an event-driven study with a projected duration of ~5.5 years to accrue an estimated occurrence of 844 events required to provide >90% power for a detection of a 20% RRR for the primary composite outcome for an alpha of 0.045.²

Outcomes

• The primary outcome was the composite of:
  • ESKD (defined as chronic dialysis for >30 days, renal transplantation, or eGFR <15 mL/min/1.73 m² sustained for >30 days)
  • Doubling of serum creatinine (dSCr) from baseline average sustained for >30 days
  • Death due to renal or CV causes
• Seven secondary outcomes were planned for sequential hierarchical testing and included the renal-specific composite of ESKD, dSCr, or renal death situated 4^th in the sequence.
• Prespecified exploratory renal outcomes included: composite of ESKD, renal death, or CV death; ESKD; dSCr; renal death; 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 AEs were collected from randomization until 30 days after the last dose of blinded study drug (on-treatment analysis).²
• All renal events that were components of the primary and secondary composite endpoints of the study were adjudicated by independent blinded adjudication committees.²

Baseline Characteristics

• 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 on-treatment and on-study analysis sets.
• Baseline characteristics were similar between the INVOKANA and PBO groups. These included: mean age 63 years, 33.9% female participants, mean duration of T2DM 15.8 years; mean HbA1c 8.3%, mean eGFR 56.2 mL/min/1.73 m², median UACR 927 mg/g.²
• For more information related to the CREDENCE baseline characteristics, please refer to Table: CREDENCE: Select 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.
  • At study completion, the median follow-up duration was 2.62 years (range 0.02-4.53 years).¹
  • A total of 4361 (99.1%) of participants were followed until the study completion for clinical and safety endpoints. Final vital status was collected in 99.9% of participants.
  • The most frequent reason for study discontinuation was an AE (12% and 13% of INVOKANA and PBO groups, respectively)

Primary Composite Outcome and Component Outcomes

• In CREDENCE, INVOKANA significantly reduced the rates of the composite outcome of ESKD, dSCr, or renal or CV death (43.2 and 61.2 per 1000 PY in the INVOKANA and placebo 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 Table: Number Needed to Treat.
  • The effects were consistent across regions and all prespecified subgroups.¹

• The event rate of ESKD was 20.4 and 29.4 per 1000 PY (HR, 0.68; 95% CI, 0.54-0.86) in the INVOKANA and PBO groups, respectively; P=0.002).¹ See Figure: Time to First Occurrence: End-Stage Kidney Disease and Table: Number Needed to Treat.

• • The event rate of dSCR was 20.7 and 33.8 per 1000 PY (HR, 0.60; 95% CI, 0.48-0.76; P<0.001) in the INVOKANA and PBO groups, respectively.¹
  • The event rate of renal death was 0.3 and 0.9 per 1000 PY in the INVOKANA (n=2) and PBO (n=5) groups, respectively. Since there were <10 events, a HR, and 95% CI were not reported.¹
• See Table: Summary of Efficacy Results for Renal Outcomes.

Secondary and Exploratory Outcomes

• In CREDENCE, INVOKANA significantly reduced the risk of the renal-specific composite, comprised of ESKD, dSCr, or renal death by 34% (HR, 0.66; 95% CI, 0.53-0.81; P<0.001). See Table: Summary of Efficacy Results for Renal Outcomes, Figure: Rates of Renal Composite in CREDENCE, and Table: Number Needed to Treat.

Subgroup Analyses

• A subgroup analysis evaluated the primary composite (ESKD, dSCR, renal/CV death) and renal specific composite (ESKD, dSCr, renal death) based on select baseline characteristics.¹ See Tables: Subgroup analysis of primary composite outcome among selected baseline characteristics and Renal specific composite outcome of ESKD, dSCr, or renal death by screening eGFR and baseline albuminuria.

Safety Outcomes

• In CREDENCE, rates of AEs and serious AEs, using the on-treatment analysis, were similar overall in the INVOKANA and PBO arms. See Table: Summary of Safety Results.

Intermediate Outcomes

• In the INVOKANA arm, the geometric mean of UACR was 31% lower on average during follow-up compared to PBO (95% CI, -26%, -35%).
• The overall decline in eGFR slope over time was attenuated with INVOKANA vs PBO, with a difference of 1.52 mL/min/1.73 m²/year (95% CI, -1.11, -1.93).¹
  • During the first 3 weeks of the study, patients treated with INVOKANA had a greater acute reduction in eGFR (3.72+0.25 vs 0.55+0.25 mL/min/1.73 m²/year; difference of -3.17 mL/min/1.73 m²/year; 95% CI, 2.47-3.87).
  • After the initial acute decline, patients treated with INVOKANA had a slower chronic decline in eGFR (-1.85+0.13 vs -4.59+0.14 m/min/1.73 m²/year; difference of 2.74 mL/min/1.73 m²/year) compared to PBO. See Figure: Effects on eGFR.

Post Hoc Analysis

Heerspink et al (2022)⁶ conducted a post hoc analysis of the CREDENCE trial to evaluate the effect of INVOKANA (100 mg/day) on kidney-related AEs in comparison to placebo.

• The primary outcome was the first kidney-related AE defined as the composite of investigator-reported AEs that were coded as primarily renal according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Other outcomes included the first serious kidney-related AE (kidney-related AE that was life-threatening, led to unplanned hospitalization, prolonged hospitalization, or death) and the first acute kidney injury (AKI).
• The rates of kidney-related AEs were determined using Cox models stratified by screening eGFR levels of 60 to <90, 45 to <60, and 30 to <45 mL/min/1.73 m².
• Of the 4397 participants in the on-treatment analysis, conducted from baseline until 30 days after the last date of study drug, kidney-related AEs occurred in 678 participants (INVOKANA, n=290; placebo; n=388) at a mean follow-up of 2.1±0.9 years.
• The overall incidence rate of kidney-related AEs for INVOKANA vs placebo was 6.0 vs 8.4 per 100 PY (HR, 0.71; 95% CI, 0.61-0.82; P<0.001).
  • The incidence rate of serious kidney-related AEs for INVOKANA vs placebo was 1.2 vs 1.7 per 100 PY (HR, 0.72; 95% CI, 0.51-1.00; P=0.05), and the incidence rate of AKI for INVOKANA vs placebo was 1.7 vs 2.0 per 100 PY (HR, 0.85; 95% CI, 0.64-1.13; P=0.3).
• The effect of INVOKANA on kidney-related AEs did not vary by any baseline participant characteristic, except baseline UACR, for which the reduction in risk associated with randomization to INVOKANA correlated with higher baseline UACR. A similar effect was observed for both kidney-related serious AEs and AKI.
• Among the participants who developed AKI, full recovery of kidney function occurred in 53.1% in the INVOKANA group vs 35.4% in the placebo group (OR, 2.2; 95% CI, 1.0-4.7; P=0.04). A lack of recovery of kidney function was more frequently observed in the placebo group (35.4%) compared with the INVOKANA group (18.4%; OR, 0.46; 95% CI, 0.21-0.97; P=0.04).
• The proportion of participants who required dialysis within 30 days after the AKI event in the INVOKANA group vs placebo group was 10.5% vs 16.3% (P=0.3). The proportion of participants who died within 30 days after an AKI event in the INVOKANA group vs placebo group was 7.0% vs 10.2% (P=0.5).
• For the screening eGFR strata of 60 to <90, 45 to <60, and 30 to <45 mL/min/1.73 m², HRs for INVOKANA vs placebo were 0.73, 0.60, and 0.81, respectively (P=0.3 for interaction).

CANVAS Program

The CANVAS Program (N=10,142) comprises the two large INVOKANA CV outcome studies CANVAS⁸ and CANVAS-R⁹ in patients with T2DM and a history of or at high risk of CV disease.⁷ The CANVAS Program included a pre-specified integrated analysis of these two studies to meet the FDA postmarketing requirement to determine CV safety, as well as evaluate potential for CV protection efficacy of INVOKANA in T2DM patients, in addition to renal and safety outcomes.^29-32 At baseline, 65.6% of patients had a history of symptomatic atherosclerotic CV disease and 35% with ≥2 risk factors for CV disease.^7,29

• The progression of albuminuria was a primary endpoint for CANVAS-R.³¹ Key prespecified exploratory renal outcomes for the integrated CANVAS Program included progression of albuminuria, regression of albuminuria, and a renal composite, including: 40% reduction in eGFR sustained for >2 consecutive measures, need for RRT, and renal death.⁷
  • Albuminuria progression was defined as the development of micro- or macroalbuminuria in a patient with baseline normoalbuminuria or the development of macroalbuminuria in a patient with baseline microalbuminuria, accompanied by a UACR increase ≥30% from baseline.⁷
  • Albuminuria regression was defined as the development of normoalbuminuria in a patient with baseline micro- or macroalbuminuria or the development or microalbuminuria in a patient with baseline macroalbuminuria, accompanied by a decrease in UACR ≥30% from baseline.⁷
  • Need for RRT is defined as the need for dialysis or transplantation. Renal death is defined as death with a proximate renal cause.⁷
• Baseline characteristics were balanced across both groups. See Table: Renal-Related Baseline Characteristics. Mean follow-up was 188.2 weeks in the CANVAS Program, with a mean follow-up of 295.9 weeks and 108 weeks for CANVAS and CANVAS-R, respectively.⁷

Renal-Related Outcomes

Based on the analysis of the full integrated data set in the CANVAS Program, INVOKANA was associated with protection against progression of albuminuria and substantive loss of kidney function.⁷ All renal outcomes were adjudicated by the Endpoint Adjudication Committee.

• See Table: Effects of INVOKANA vs PBO on Renal Outcomes in CANVAS, CANVAS-R, and the CANVAS Program for the nominal effect estimates for renal outcomes since hypothesis testing was not performed.⁷

• Progression of albuminuria occurred less frequently in patients in the INVOKANA group compared to PBO, (89.4 vs 128.7 per 1000 patient-years) corresponding to a HR, of 0.73 (95% CI, 0.67 to 0.79) with a greater effect in CANVAS-R (HR, 0.64; 95% CI, 0.57 to 0.73) compared to CANVAS (HR, 0.80; 95% CI, 0.72 to 0.90) (P=0.02 for homogeneity).⁷
• Similarly regression of albuminuria was more frequent in the INVOKANA group compared to PBO (293.4 vs 187.5 per 1000 PY; HR, 1.70, 95% CI, 1.51 to 1.91).⁷
• The renal composite of sustained 40% reduction in eGFR, need for RRT, or renal death occurred less frequently in the INVOKANA group compared to PBO (5.5 vs 9.0 per 1000 patient-years; HR, 0.60; 95% CI, 0.47 to 0.77), with no difference between CANVAS and CANVAS-R.⁷
• In an additional analysis of renal outcomes in the intent-to-treat (ITT) population, INVOKANA was associated with a greater reduction in eGFR compared with PBO from baseline to week 13. From week 13 to the last available measurement, there was a mean annual decline in eGFR with PBO compared with a mean annual increase with INVOKANA.³³ See Figure: Effects of INVOKANA on eGFR Over Time Across the CANVAS Program.

• Among patients who were re-evaluated ~30 days after treatment discontinuation (as part of the CANVAS-R protocol), the change from baseline to the off-treatment eGFR levels was higher, on average, with INVOKANA vs PBO (difference [95% CI] of 2.6 [1.8-3.4] mL/min/1.73 m²).³³ See Figure: Effects of INVOKANA on eGFR 30 Days Off-Treatment in CANVAS-R.

Safety

• 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.⁷

Post Hoc Analyses of the CANVAS Program

Tye et al (2022)¹¹ conducted a post hoc analysis of the CANVAS program to assess whether the initiation of INVOKANA using multivariable predicted risk of kidney outcome guided by clinical risk markers (clinical characteristics and novel biomarkers) was more efficient in preventing clinical outcomes in comparison to an initiation strategy based on HbA1c or UACR alone.

• The analysis used Cox proportional hazards regression models to predict the 5-year risk and treatment effect of INVOKANA on the composite kidney outcome (defined as a sustained 40% eGFR decline, ESKD with eGFR <15 mL/min/1.73 m², or the need of dialysis, kidney transplantation, or kidney death) and the composite heart failure outcome (defined as heart failure hospitalization or CV death).
• The final risk prediction models used were:
  • Clinical markers model (age, previous history of atherosclerotic CV disease, systolic blood pressure [SBP], UACR, hemoglobin, body weight, albumin, eGFR, and the treatment variable)
  • Clinical/novel biomarkers model (tumor necrosis factor receptor-1 [TNFR-1], kidney injury molecule-1 [KIM-1], matrix metalloproteinase-7 [MMP-7], and interleukin-6 [IL-6] in addition to the clinical markers model predictors)
• The performance of each treatment strategy at a given risk threshold was evaluated by comparing the number of events prevented per 1000 patients treated for 5 years using chi-squared statistics.
• Of the 3713 patients in the CANVAS program who had biomarkers measured at baseline, 144 (3.9%) reported a composite kidney outcome and 371 (10.0%) reported a composite heart failure outcome at a median follow-up of 6.1 years.
• The number of composite kidney outcomes and the number of composite heart failure outcomes prevented based on treatment strategy are summarized in the table: Number of Kidney and Heart Failure Events Prevented by Treatment Strategy in Patients With HbA1c ≥7.5% (n=2809).

• The NNT to prevent one composite kidney outcome according to HbA1c ≥7.5%, UACR, clinical markers, and clinical/novel biomarkers approaches were 86.0 (95% CI, 64.9-149.5), 134 (95% CI, 100.9-233.8), 49.0 (95% CI, 37.3-85.9), and 47.0 (95% CI, 35.7-82.2), respectively.
  • This corresponded to 9.6 (95% CI, 5.5-12.6), 5.8 (95% CI, 3.4-7.9), 16.6 (95% CI, 9.5-22.0) (P<0.001 vs HbA1c or UACR approach), and 17.5 (95% CI, 10.0-23.0) (P<0.001 vs HbA1c or UACR approach; P=0.54 vs clinical markers approach) events prevented per 1000 patients treated for 5 years, respectively.
• The NNT to prevent one composite heart failure outcome according to HbA1c ≥7.5%, UACR, clinical markers, and clinical/novel biomarkers approaches were 51.0 (95% CI, 34.2-125.3), 47.0 (95% CI, 31.0-115.5), 39.0 (95% CI, 26.1-95.7), and 39.0 (95% CI, 25.7-94.2), respectively.
  • This corresponded to 16.0 (95% CI, 6.5-24.0), 16.9 (95% CI, 6.9-25.5), 21.0 (95% CI, 8.5-31.4) (P<0.01 vs HbA1c or UACR approach), and 21.3 (95% CI, 8.7-31.9) (P<0.01 vs HbA1c or UACR approach; P=0.85 vs clinical markers approach) events prevented per 1000 patients treated for 5 years, respectively.

Li et al (2020)¹² conducted a post hoc analysis to explore potential mediators of the beneficial effects of INVOKANA on major kidney outcomes in the CANVAS Program.

• The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the HRs for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average postrandomization level of each biomarker.
• The kidney outcome was defined as a composite of 40% eGFR decline, ESKD, or death due to kidney disease.
• For 10/18 potential mediators assessed in the CANVAS Program (SBP, triglycerides, UACR, gamma glutamyl transferase [GGT], hematocrit, hemoglobin, serum albumin, erythrocytes, serum bicarbonate, and serum urate), there was significant association of the average postrandomization level with the risk of kidney outcomes in the Cox proportional hazard regression models (all P<0.05). For all 10, biomarker changes were also associated with subsequent risk of the kidney outcome.
  • Nine of these biomarkers (serum erythrocytes [56.7% of effect explained], hematocrit [51.1%], hemoglobin [41.3%], serum urate [35.4%], UACR [23.9%], albumin [19.5%], SBP [8.9%], urine pH [7.5%], and GGT [4.1%]) individually and significantly mediated the effect of INVOKANA on the kidney outcome.
• Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses (erythrocyte concentration, serum urate, and SBP; estimated cumulative mediation of 115%).
• In subgroup analyses, it was found that the mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR. UACR mediated 42.3% and 7.4% of the effect in those with baseline UACR ≥30 mg/g and <30 mg/g, respectively.

Other Clinical Studies

UACR and Albuminuria

The UACR was examined in four^13-16 (including one INVOKANA monotherapy¹⁶ study) PBO- and active-controlled phase 3 studies which evaluated efficacy and safety of INVOKANA in patients with normal or mildly impaired baseline renal function. In three of these studies^13-15, the coadministration of INVOKANA and metformin was permitted. In the fourth study¹⁶, patients were not on baseline metformin.

• In all four studies, greater mean and median reductions in UACR were reported with INVOKANA 100 and 300 mg relative to PBO or comparator.¹⁷

In the active-controlled study (N=1450) of INVOKANA as add-on to metformin vs glimepiride, which enrolled patients with normal or mildly impaired renal function, mean reductions in UACR were seen with INVOKANA 100 (-0.1 g/mol) and 300 mg (-0.9 g/mol), whereas an increase was seen with glimepiride (0.7 g/mol) at week 52.¹³ Mean changes from baseline in UACR at week 104 were -0.02, -0.27, and 1.55 g/mol, respectively, with INVOKANA 100, 300 mg, and glimepiride.³⁴

• In a separate post hoc analysis of the 104-week data, compared to glimepiride, INVOKANA 100 mg decreased UACR by 5.7% (95% CI, 22.3 to 13.1; P=0.16) and INVOKANA 300 mg decreased UACR by 11.2% (95% CI, 3.6 to 18.3; P<0.01). In a subgroup of patients with UACR ≥30 mg/g at baseline, INVOKANA 100 and 300 mg significantly decreased UACR over time, by 31.7% (95% CI, 8.6 to 48.9; P=0.01) and 49.3% (95% CI, 31.9 to 62.2; P<0.001), respectively, relative to glimepiride.³⁵

Weir et al (2015)³⁶ presented results of an analysis of three phase 3 studies^13,34,37-39  which evaluated effect of INVOKANA on eGFR for up to 2 years (104 weeks) in T2DM patients with various degrees of baseline renal function. Median change in UACR in the add-on to metformin vs glimepiride study (Leiter et al³⁴[Study A]), and a phase 3 study (Yale et al³⁹ [Study C]) in T2DM patients with moderate renal impairment⁴⁰ are summarized in Figure: Median Change in Urine ACR from Baseline After Extension Period.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 23 December 2024.