SUMMARY

• In the CREDENCE study (N=4401), designed to assess the effects of INVOKANA vs placebo on renal outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), no increased risk of acute pancreatitis was reported in the INVOKANA group compared to the placebo group.¹
• In the CANVAS Program^2,3 (N=10,142) comprised of 2 large INVOKANA cardiovascular (CV) outcome studies, CANVAS^4,5 and CANVAS-R^6,7, no increased risk of pancreatitis was detected in patients taking INVOKANA compared to placebo.²
• An observational study designed to evaluate the risk of acute pancreatitis among new users of INVOKANA vs 6 classes of other antihyperglycemic agents (AHAs) found that the risk of acute pancreatitis in patients newly treated with INVOKANA was similar to that observed in patients treated with other AHAs.⁸
• An additional reference was identified by a literature search for your review.⁹
• For complete information, please refer to the Full Prescribing Information.

CLINICAL DATA

Phase 3 Studies

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 clinical trial designed to assess the effects of INVOKANA (100 mg) vs matching placebo (1:1) on clinically important renal outcomes in people with T2DM and established CKD (estimated glomerular filtration rate [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 labelled dose (for >4 weeks prior to randomization) of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker.^1,10-14

• All adverse events (AEs) were collected from randomization through 30 days after the last dose of study drug. Pancreatitis was identified as an AE of interest to be reported within 24 hours and to be recorded using a designated electronic case report form.¹¹ All events were adjudicated by independent blinded adjudication committees.¹⁰
  • Safety analyses 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]).¹

Results

• A total of 4401 participants were randomized between March 2014 and May 2017 in the intention-to-treat analysis set. There were 4 participants that were not dosed, leading to 4397 participants in the on-treatment and on-study analysis sets.¹
• Baseline characteristics were similar between the INVOKANA and placebo groups.¹⁰
• Acute pancreatitis occurred at a rate of 1.0 (n=5/2200) and 0.4 (n=2/2197) events per 1000 patient-years in the INVOKANA and placebo groups, respectively.¹
  • Hazard ratios and 95% confidence intervals were calculated for outcomes with >10 events.
  • The analysis of acute pancreatitis events was based on confirmed and adjudicated results.

The CANVAS Program

The CV safety of INVOKANA was evaluated in 2 CV outcome studies, CANVAS (CANagliflozin cardioVascular Assessment Study)^4,5 and CANVAS-R (Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM) to determine CV safety of as well as the potential for CV protection in patients with T2DM who had either a prior history of CV disease or at least two CV risk factors.^2,3,6,7 The efficacy and safety information from CANVAS^4,5 was combined with the data from CANVAS-R^6,7 in a pre-specified integrated analysis of CV safety outcomes, as well as renal and safety outcomes.^2,3

Selected safety outcomes, including pancreatitis, were adjudicated by an identical independent Endpoint Adjudication Committee that was shared across the two trials and operated to the same Charter.^2,4,6 Likewise, CANVAS and CANVAS-R shared the same Independent Data Monitoring Committee that provided interim monitoring of unblinded safety and efficacy data throughout the course of the trials.^3,4

• In the CANVAS Program, the adjudicated incidence of pancreatitis was 0.49 and 0.35 events per 1000 patient-years in the INVOKANA and placebo treatment groups, respectively.²
• Case-level details of these pancreatitis events were not reported.

Pooled Data

• In pooled data from eight active- and placebo-controlled phase 3 studies^4,15-21 an increase in the general incidence of pancreatitis, as well as incidence of acute and chronic was noted with INVOKANA (see Table: Incidence of Pancreatitis in Pooled Eight Phase 3 Studies).²² This dataset includes data through the core periods (up to 26^{15,17,18,19-21} or 52¹⁶ weeks) for the phase 3 studies and through 15 September 2011 for the CANVAS⁴ study.
  • In the long term exposure data (through 31 January 2012) of the same phase 3 study data set,^4,15-21 one death due to hemorrhagic pancreatitis was reported with INVOKANA100 mg (n=3092).²²

AEs of Pancreatitis in Additional Phase 3 Study Data

• A search of the clinicaltrials.gov registry identified pancreatitis AEs in additional phase 3 study data including study extension periods.^23-25 A summary of these AEs is provided in Table: Adverse Events of Pancreatitis in Additional Phase 3 Study Data.

Published Postmarketing Case Reports

Few case reports of pancreatitis associated with INVOKANA treatment have been published.^29-34

real-world evidence

Yuan et al (2019)⁸ conducted an observational study to evaluate the risk of acute pancreatitis among new users of INVOKANA vs 6 classes of other AHAs (glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sulfonylureas, thiazolidinediones, insulin, and other AHAs). Three US claims databases were analyzed based on a prespecified protocol approved by the European Medicines Agency. Propensity scores were adjusted to control for imbalances in baseline covariates. Across the 3 claims databases, there were between 12,023 to 80,986 new users of INVOKANA, with crude incidence rates of acute pancreatitis (events/1000 person-years) between 1.5 to 2.2 for INVOKANA and 1.1 to 6.6 for other AHAs. Risk of acute pancreatitis in patients newly treated with INVOKANA was similar to that observed in patients treated with other AHAs.

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 05 November 2024.