SUMMARY  

• CREDENCE was a randomized, double-blind, placebo (PBO)-controlled, parallel-group, multicenter study 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
  • Announcement of Early Termination Due to Efficacy: On July 16, 2018, the Janssen Pharmaceutical Companies of Johnson & Johnson announced that the CREDENCE trial was stopping early based on achievement of prespecified efficacy criteria. The study’s Independent Data Monitoring Committee (IDMC) recommended this decision during a planned interim analysis based on demonstration of efficacy, as the trial had achieved prespecified criteria for the primary composite outcome of end-stage kidney disease (ESKD; defined as time to dialysis or kidney transplantation), doubling of serum creatinine (dSCr), and renal or CV death, when used in addition to standard of care.³
  • In patients with T2DM and kidney disease, the risk of kidney failure and CV events was lower in the INVOKANA group vs the PBO group.¹
• DAPA-CKD was a randomized, double-blind, PBO-controlled, multicenter study designed to assess the long-term efficacy (in reducing kidney and CV events) and safety of dapagliflozin 10 mg vs PBO in patients with CKD, with or without T2DM, who were also receiving standard of care.⁴ In contrast to the CREDENCE study described above, the DAPA-CKD study included patients with CKD but without T2DM, in order to assess whether sodium-glucose co-transporter-2 (SGLT2) inhibitors such as dapagliflozin are effective in patients with nondiabetic kidney disease.⁵
  • Announcement of Early Termination Due to Efficacy: Following a regular review meeting on March 26, 2020, the IDMC recommended to the 2 coprincipal investigators that the study be discontinued due to clear efficacy, on the basis of 408 primary outcome events. The study leadership team accepted this recommendation and chose April 3, 2020 as the cutoff date for all efficacy analyses.⁴
  • Among patients with CKD, regardless of the presence or absence of T2DM, dapagliflozin was shown to significantly reduce the risk of a composite of sustained decline in estimated glomerular filtration rate (eGFR) of ≥50%, ESKD, or death from renal or CV causes compared with PBO.⁴
• There are no published phase 2, 3, or 4 clinical studies that directly compare the safety and efficacy outcomes of INVOKANA vs dapagliflozin.  
• Comparisons between trials are complicated by differences in: populations, trial designs, analytic approaches, and drug effects.⁶
  • Comparisons are, therefore, hazardous, subject to bias, and may be confounded by multiple uncontrolled factors.⁶ Additionally, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.⁷

BACKGROUND

• There are no published phase 2, 3, or 4 clinical studies that directly compare the safety and efficacy outcomes of INVOKANA and dapagliflozin.
• Comparison between trials are complicated by differences in⁶:
  • Populations
  • Trial designs
  • Analytic approaches
  • Drug effects
• Comparisons are, therefore, hazardous, subject to bias, and may be confounded by multiple uncontrolled factors.⁶ Additionally, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.⁷
• Nevertheless, there is interest in interpreting renal outcomes trials for INVOKANA and dapagliflozin, specifically CREDENCE study data in the context of DAPA-CKD. As such, a brief overview of the CREDENCE and DAPA-CKD clinical studies, including an overview of study design, baseline characteristics, key outcomes, and overall safety, is provided, and does not imply a head-to-head comparison. For additional information specific to these studies, please refer to the published literature.^1,4

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 study designed to assess the effects of INVOKANA (100 mg) compared to PBO on clinically important renal outcomes in patients with T2DM and established CKD (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 labeled dose (for ≥4 weeks prior to randomization) of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB).^1,2,8-11

Methodology^1,9

• The study consisted of a screening and run-in period, a double-blind treatment period (INVOKANA 100 mg vs PBO), and a 30-day post-treatment (after study completion or permanent discontinuation of study drug) follow-up. The total duration of the study was planned to be approximately 5.5 years.
• Patients meeting eligibility criteria at screening underwent a 2-week, single-blind, PBO run-in period, and were deemed eligible for randomization if they took ≥80% of the run-in study medication.
• 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.
  • INVOKANA 100 mg was selected due to the favorable benefit-to-risk profile compared to INVOKANA 300 mg in patients with CKD in the INVOKANA phase 3 clinical development program.²
• Patients were followed up at weeks 3, 13, and 26, and then with telephone calls and in-clinic visits in 13-week intervals.
• Use of other therapies for glycemic management and CV risk factor control was recommended in accordance with clinical practice guidelines.
• Due to an increased risk of lower limb amputations in another INVOKANA study¹², an amendment was made to the protocol in May 2016, requiring investigators to examine the feet of patients at each visit, and temporarily interrupt treatment in those who develop any active condition associated with amputation (ie, lower-extremity infection, skin ulcer, osteomyelitis, gangrene, or critical limb ischemia) until the condition has resolved. Restarting medication was encouraged after careful consideration of benefits and risks.^1,2,9

Outcomes^1,9

• 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)
  • dSCr 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 in reducing the risk of the primary efficacy outcome, the treatment effects in the secondary outcomes would be tested subsequently. Statistical significance was required before testing the next hypothesis in the hierarchical test procedure in the following order²:
  • Composite of CV death or hospitalization for heart failure (HHF)
  • Composite of major adverse cardiovascular events (MACE), comprised of CV death, nonfatal myocardial infarction (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 outcomes included: composite of ESKD or death from renal or CV causes; 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 included: all malignancies, fatal pancreatitis, hemorrhagic/necrotizing pancreatitis, nephrotoxicity/acute kidney injury, venous thromboembolic events, fractures, diabetic ketoacidosis, and amputation.²
• All renal and CV events that are components in the primary and secondary composite outcomes of the study and all key safety outcomes (bone fractures, pancreatitis, ketoacidosis, renal cell carcinoma) were adjudicated by independent blinded adjudication committees.²

Statistical Analysis^1,9

• The CREDENCE study 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% relative risk reduction for the primary composite outcome for an alpha level of 0.045.²
• The primary and secondary outcomes were analyzed using a stratified Cox proportional hazard model with stratification of the baseline eGFR based on the intention-to-treat analysis set. Secondary outcomes were tested following a hierarchical sequence.
• A single interim analysis was planned to be conducted by an independent data monitoring committee once 405 confirmed primary efficacy outcomes were accrued. Early termination of the study would be considered if clear evidence of benefit was observed with the primary composite outcome meeting a P<0.01 and the additional composite of ESKD, renal death, and CV death meeting a P<0.025.^2,3
  • If the study was to stop at the interim analysis, the primary outcome would be tested at a two-sided level of 0.022 and the secondary outcomes at a two-sided level of 0.038, to account for type 1 error inflation.
  • Safety analysis used the on-treatment analysis dataset (all treated participants through 30 days after last study drug dose), and selected AEs of interest were also analyzed using the on-study analysis dataset (all treated patients through the end of the trial; ie, global trial end date).
  • The numbers needed to treat to prevent one event over 2.5 years were calculated as the reciprocal of the between-treatment difference in cumulative incidence at 2.5 years based on Kaplan-Meier curve.

DAPA-CKD

DAPA-CKD (DApagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) was a randomized, double-blind, PBO-controlled, multicenter study designed to assess the long-term efficacy (in reducing kidney and CV events) and safety of dapagliflozin vs PBO in patients with CKD, with or without T2DM. Adult patients with or without T2DM who had an eGFR of 25 to 75 mL/min/1.73 m² and a UACR of 200 to 5000 mg/g and were receiving a stable dose of an ACEi or ARB for ≥4 weeks before screening were randomized to receive dapagliflozin 10 mg once daily or PBO.⁴

Outcomes⁴

• Similar to CREDENCE, the primary composite outcome in DAPA-CKD was a kidney disease-related composite. The primary composite outcome, assessed in a time-to-event analysis, was the first occurrence of any of the following:
  • A decline of ≥50% in eGFR (confirmed by a second serum creatinine measurement after ≥28 days)
  • The onset of ESKD (defined as maintenance dialysis for ≥28 days, kidney transplantation, or an eGFR of <15 mL/min/1.73 m² confirmed by a second measurement after ≥28 days)
  • Death from renal or CV causes
• Secondary outcomes (also assessed in time-to-event analyses) included the following, in hierarchical order:
  • Composite kidney outcome of a sustained decline in eGFR of ≥50%, ESKD, or death from renal causes
  • Composite CV outcome, defined as HHF or death from CV causes
  • Death from any cause
• An independent committee whose members were unaware of the trial-group assignments adjudicated all primary and secondary outcomes, except for a sustained decline in eGFR of ≥50% and a sustained eGFR of <15 mL/min/1.73 m².
• Serious AEs, AEs resulting in discontinuation of dapagliflozin or PBO, and AEs of interest (symptoms of volume depletion, renal events, major hypoglycemia, bone fractures, amputations, and potential diabetic ketoacidosis) were assessed.

Comparative Review of Study Designs and Baseline Characteristics

• For study design overview of CREDENCE and DAPA-CKD, including baseline characteristics and outcomes, please see Table: Summary of INVOKANA and Dapagliflozin Renal Outcomes Trials Study Design.

Results of CREDENCE and DAPA-CKD

Primary Outcomes

CREDENCE

• In the CREDENCE study, INVOKANA significantly reduced the rates of the primary composite outcome of ESKD, dSCr, or renal or CV death (43.2 and 61.2 per 1000 patient-years 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; number needed to treat [NNT]: 22 over 2.5 years for the primary composite outcome).¹
  • The event rate of ESKD was 20.4 and 29.4 per 1000 patient-years in the INVOKANA and PBO groups, respectively (HR: 0.68; 95% CI: 0.54-0.86; P=0.002).
  • The event rate of dSCr was 20.7 and 33.8 per 1000 patient-years in the INVOKANA and PBO groups, respectively (HR: 0.60; 95% CI: 0.48-0.76; P<0.001).
  • The event rate of renal death was 0.3 and 0.9 per 1000 patient-years 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.
  • The event rate of CV death was 19.0 and 24.4 per 1000 patient-years in the INVOKANA and PBO groups, respectively (HR: 0.78; 95% CI: 0.61-1.00).
• The effect of INVOKANA on the primary composite outcome was consistent across regions and all prespecified subgroups.¹

DAPA-CKD

• In the DAPA-CKD study, the primary composite outcome of a sustained decline in eGFR of ≥50%, ESKD, or death from renal or CV causes occurred in 197 (9.2%) dapagliflozin-treated patients and in 312 (14.5%) PBO-treated patients (HR: 0.61; 95% CI: 0.51-0.72; P<0.001).⁴
  • The event rates for all components of the primary composite outcome favored dapagliflozin. The NNT to prevent 1 primary outcome event was 19 (95% CI: 15-27).
• The effect of dapagliflozin on the primary composite outcome was generally consistent across prespecified subgroups. The HR for the comparison of dapagliflozin and PBO for the primary composite outcome was 0.64 (95% CI: 0.52-0.79) in patients with T2DM vs 0.50 (95% CI: 0.35-0.72) in patients without T2DM.⁴
• In contrast to CREDENCE, DAPA-CKD assessed the effects of an SGLT2 inhibitor (dapagliflozin) in patients with CKD of whom 32.5% did not have T2DM and 14.5% had an eGFR <30 mL/min/1.73 m². The study confirmed dapagliflozin’s kidney-protective effects among the broader population of patients with CKD without T2DM.⁴
• See Table: Overview of the CREDENCE and DAPA-CKD Primary Composite Outcomes.

Secondary and Exploratory Outcomes

CREDENCE

• In the CREDENCE study, INVOKANA significantly reduced the risk of¹:
  • Composite of CV death and HHF (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 outcomes were not formally tested.¹

DAPA-CKD

• The incidence of each secondary outcome was lower in the dapagliflozin group vs the PBO group.⁴
  • The HR for the composite kidney outcome of a sustained decline in eGFR of ≥50%, ESKD, or death from renal causes was 0.56 (95% CI: 0.45-0.68; P<0.001). The HR for the composite of death from CV causes or HHF was 0.71 (95% CI: 0.55-0.92; P=0.009).
• Death from any cause occurred in 101 (4.7%) dapagliflozin-treated patients and in 146 (6.8%) PBO-treated patients (HR: 0.69; 95% CI: 0.53-0.88; P=0.004).⁴

Safety Outcomes

CREDENCE

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

DAPA-CKD

• The overall incidences of AEs and serious AEs were similar among the dapagliflozin and PBO groups.⁴
• Diabetic ketoacidosis was reported in 2 PBO-treated patients and in none of the dapagliflozin-treated patients. Neither diabetic ketoacidosis nor severe hypoglycemia was observed in patients without T2DM.⁴
• There was 1 case of Fournier’s gangrene in the PBO group and none in the dapagliflozin group.⁴

Literature Search

A literature search of MEDLINE^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 28 May 2024.