Summary

• In the CREDENCE study¹ (N=4,401), evaluating the efficacy and safety of INVOKANA in albuminuric diabetic kidney disease, hepatic injury rates were captured as an adverse event of interest.
  • Hepatic injuries in CREDENCE occurred at a rate of 5.5 and 6.5 per 1000 patient-years (PY) in INVOKANA and PBO groups, respectively (HR 0.86, 95% CI [0.52-1.43]).²
• In the CANVAS Program^3,4 (N=10,142), comprised of 2 large INVOKANA cardiovascular (CV) outcome studies, CANVAS^5,6 and CANVAS-R,^7,8 hepatic injury events were captured in the CANVAS study alone.
  • Hepatic injury events occurred at a rate of 7.4 and 9.1 per 1000 (PY) in INVOKANA and PBO groups, respectively (P=0.35).
• Two pooled analyses of phase 3 data from 4 placebo-controlled studies^9-12 and 2 active-controlled studies^11,13 reported reductions in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (AP), and increases in bilirubin with INVOKANA compared to PBO over 26 weeks and compared to sitagliptin over 52 weeks.^14,15

Clinical studies

CREDENCE Study

CREDENCE¹ (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), was a randomized, double-blind, placebo (PBO)-controlled, parallel group multicenter clinical 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.

• Adverse events of interest included serious adverse events of hepatic injury. Adverse events were collected and coded using the Medical Dictionary for Regulatory Activities (MedDRA) from randomization until 30 days after the last date of blinded study medication.²
• Hepatic injuries in CREDENCE occurred at a rate of 5.5 and 6.5 per 1000 PY in INVOKANA and PBO groups, respectively (HR 0.86, 95% CI [0.52-1.43]).²

CANVAS Program

In order to meet requirements of Food and Drug Administration (FDA) Guidance¹⁶  and the FDA Approval Letter¹⁷, INVOKANA CV safety was evaluated in 2 CV outcome studies, CANVAS (CANagliflozin cardioVascular Assessment Study)^5,6 and CANVAS-R (Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM).^3,4,7,8 Efficacy and safety information from CANVAS^5,6 was combined with CANVAS-R^7,8 in a prespecified integrated analysis of CV safety outcomes.^3,4 This integrated analysis met the FDA post-marketing requirement to determine INVOKANA CV safety and evaluated potential for CV protection in T2DM patients who had either a prior history of CV disease (CVD) or ≥2 CV risk factors. The integrated analysis of CANVAS and CANVAS-R also evaluated effects of INVOKANA on renal and safety outcomes.

• Hepatic injury was considered a serious and non-serious adverse event (AE) of interest and collected only in CANVAS. Events were collected through January 7, 2014, after which only serious AEs or those which led to drug discontinuation were collected.³
  • Preferred terms for hepatic injury (e.g., acute hepatic failure, allergic hepatitis, etc.) can be found in the study protocol.¹⁸
• Hepatic injury events in CANVAS occurred at a rate of 7.4 and 9.1 per 1000 PY in INVOKANA and PBO groups, respectively (P=0.35). Case-level details were not reported.³

HEPATIC SAFETY EVALUATION

Liver Function Tests (LFTs)

LFTs were conducted at baseline and periodically thereafter throughout the INVOKANA program. Not all patients in the safety population had baseline and follow-up liver enzymes.

Pooled Analysis - Phase 3 Studies

In pooled, phase 3 clinical studies^9-12, a consistent decrease was observed in mean change from baseline at week 26 in AST, ALT, and GGT, with smaller decreases observed for AP. For bilirubin, higher mean % increases were observed in both INVOKANA groups relative to PBO (see Table: Mean % Changes From Baseline at Week 26 in 4 Pooled, PBO-Controlled, Phase 3 Studies).¹⁴

In another pooled analysis of 52-week data from 2 phase 3 studies^11,13, mean % changes of INVOKANA 300 mg compared with sitagliptin 100 mg were -3.6% and 10.6%, respectively, for ALT (P<0.001), and -6.6% and 6.8%, respectively, for GGT (P<0.001). Changes in AP were -2.8% and -4.1% with INVOKANA 300 mg and sitagliptin 100 mg, respectively. INVOKANA 300 mg was associated with increased AST (1.1%), although smaller than sitagliptin 100 mg (11.7%) (P<0.01). Greater increases in bilirubin were seen with INVOKANA 300 mg compared with sitagliptin 100 mg (13.8% and 0.8%, respectively; P<0.001).¹⁵

Phase 3 Studies

Mean % change of LFTs at the end of the core period for select phase 3 studies are shown in Table: Mean % Changes from Baseline in LFTs of Phase 3 Studies - Core Period.

LFT changes were also reported in extension periods of phase 3 studies.^{9,11,12,19-23}

Predefined Limits of Change (PDLC) for LFTs

• PDLC for ALT or AST elevations were based on any postbaseline double-blind treatment period and last on-treatment value (up to 2 days after last dose of study drug) meeting PDLC criterion. See Table: Number of Patients with LFTs Outside PDLC Criteria.
  • In pooled data from 4 phase 3, PBO-controlled studies^9-12, few patients met PDLC for increases in ALT, AST, and bilirubin over 26 weeks.¹⁵
  • In pooled data from 2 phase 3 studies of INVOKANA 300 mg vs sitagliptin^11,13, few patients met PDLC criteria for increases in ALT, AST, and bilirubin over 52 weeks.¹⁵
• No patients met Hy’s law criteria (i.e., greater incidence of ALT or AST ≥3x upper limit of normal [ULN] vs PBO and total bilirubin >2x ULN without elevated AP, and without history of hepatitis or pre-existing/acute liver disease, or use of another drug capable of causing liver injury³³).¹⁵

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 31 January 2024.