Summary

• In the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) study, hospitalization of heart failure (HHF) occurred at a rate of 15.7 (n=89/2202) and 25.3 (n=141/2199) events per 1000 patient-years in the INVOKANA and placebo (PBO) groups, respectively (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.47-0.80); P<0.001).¹
• In the CANVAS Program (CANagliflozin cardiovascular Assessment Study), HHF occurred at a rate of 5.5 vs 8.7 events per 1000 patient-years in the INVOKANA and PBO groups, respectively (HR, 0.67; 95% CI, 0.52-0.87).²
• A pooled analysis of the CANVAS program and CREDENCE study revealed that INVOKANA reduced total HHF (mean event ratio, 0.63; 95% CI, 0.54-0.73) across estimated glomerular filtration rate (eGFR) subgroups (P_interaction=0.51).³
• In pooled data from 7 active- and PBO-controlled, phase 3 INVOKANA clinical studies,^4-11 congestive heart failure (HF) was reported in 9 (0.1%) patients in the combined INVOKANA group (including 100 mg and 300 mg groups, n=6177) and in 10 (0.3%) patients in the non-INVOKANA group (n=3262).¹²
• An additional citation identified during a literature search has been included in the REFERENCES section for your review.¹³

CLINICAL STUDIES

CREDENCE was a randomized, double-blind, PBO-controlled, parallel group multicenter, event-driven study (N=4401) designed to assess the effects of INVOKANA 100 mg compared to PBO on clinically important renal outcomes in people with type 2 diabetes mellitus (T2DM) and established chronic kidney disease (eGFR 30 to <90 mL/min/1.73m²) and albuminuria (ratio of albumin to creatinine >300 to 5000 mg/g), who were receiving a stable, maximum tolerated or labeled dose (for ≥4 weeks prior to randomization) of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker.^1,14-16 Median follow-up was ~2.62 years.¹

• Patients with a current or history of HF of New York Heart Association Class IV cardiac disease were excluded from the study.¹
• HHF was included as a stand-alone secondary efficacy outcome, as well as part of a composite with cardiovascular (CV) death, and a broader CV composite with CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalized unstable angina.¹
• At baseline, 14.8% (n=652) of the total population had a history of HF.¹
• Hospitalized HF occurred at a rate of 15.7 (n=89/2202) and 25.3 (n=141/2199) events per 1000 patient-years in the INVOKANA and PBO groups, respectively (HR, 0.61; 95% CI, 0.47-0.80; P<0.001).¹

The CANVAS Program comprised 2 large INVOKANA CV outcome studies, CANVAS^8,17 and CANVAS-R (CANagliflozin cardioVascular Assessment Study-Renal),^18,19 and included a prespecified integrated analysis to meet the Food and Drug Administration postmarketing requirement for CV safety, as well as evaluate potential for CV protection of INVOKANA in T2DM patients with prior history of CV disease or ≥2 CV risk factors.^2,20 Mean follow-up time was 188.2 weeks.²

• HHF was included as a prespecified exploratory CV outcome.²
• At baseline, 14.4% of the total population had a history of HF.²
• HHF occurred at a rate of 5.5 vs 8.7 events per 1000 patient-years in the INVOKANA and PBO groups, respectively (HR, 0.67; 95% CI, 0.52-0.87).²
• Of the 10,142 patients in the CANVAS Program, 276 experienced a fatal or hospitalized HF event during follow-up, with 61 patients having more than 1 event.²¹

A pooled analysis of the CANVAS program (N=10,142) and CREDENCE study (N=4401) evaluated the risk of first and total HHF events as well as response to INVOKANA across different levels of kidney function (eGFR: <45, 45-60, and >60 mL/min/1.73m²) in patients with T2DM who were at a high CV risk or had established chronic kidney disease. The median follow-up was 2.5 years.³

• The 2 key outcomes of this analysis were HHF and the composite of CV death and HHF.
• INVOKANA reduced the time to first HHF (HR, 0.58; 95% CI, 0.48-0.70; P<0.0001) consistently across the baseline eGFR subgroups (P_interaction=0.84).
• INVOKANA reduced total HHF (mean event ratio, 0.63; 95% CI, 0.54-0.73) across the eGFR subgroups (P_interaction=0.51).
• INVOKANA reduced the risk of CV death and total HHF (mean event ratio, 0.72; 95% CI, 0.65-0.80) across the eGFR subgroups (P_interaction=0.82).

In pooled data from 7 active- and PBO-controlled, phase 3 INVOKANA clinical studies,^4-11 congestive HF was reported in 9 (0.1%) patients in the combined INVOKANA group (including 100 mg and 300 mg groups, n=6177) and in 10 (0.3%) patients in the non-INVOKANA group (n=3262).¹²

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 26 February 2025.