Summary

• A post hoc analysis of the CREDENCE study found that INVOKANA increased the risk of genital mycotic infections (GMIs), but not urinary tract infections (UTIs). INVOKANA did not affect the risk of UTI overall or in any subgroup.¹
• In the CANVAS trial^2,3, one of two trials^2-5 comprising the CANVAS Program, UTI adverse events (AEs) were reported at an incidence rate of 40 and 37 per 1000 patients-years in the INVOKANA and placebo treatment groups, respectively.⁶
• Pooled Phase 3, Placebo-Controlled Studies: In the pool of four 26-week placebo-controlled clinical trials^7-10, UTI was a commonly reported adverse reaction (≥2%): INVOKANA 100 mg (5.9%), INVOKANA 300 mg (4.3%) and placebo (4.0%).¹¹
  • Recurrence: Recurrent symptomatic UTI was similar across INVOKANA and nonINVOKANA treatment groups.¹¹
  • Discontinuation: Discontinuations due to UTIs occurred in 0.2%, 0.1%, and 0% of patients in the placebo, INVOKANA 100 mg, and 300 treatment groups, respectively.¹¹
  • Treatment: A slightly higher proportion of subjects in the placebo group (84.6%) compared to the INVOKANA 100 and 300 mg groups (75.5% and 80.6%, respectively) were treated with antimicrobial therapy.¹¹ The specific antimicrobial agents used to treat the UTIs were not reported.
• Pooled Phase 3, Placebo- and Active-Controlled Studies: In a pooled dataset of eight phase 3 active- and placebo-controlled studies^2,7-10,12-14 with longer mean exposure, the incidence of UTI AEs was 8.2%, 8.1%, and 6.7% with INVOKANA 100 mg, INVOKANA 300 mg, and non-INVOKANA, respectively.¹¹
• Please find in the REFERENCES section: Incidence of UTI with INVOKANA treatment was also reported in other phase 3 and postmarketing studies.^15-19 A published systematic review and meta-analysis support the above phase 2/3 AE data related to INVOKANA use.²⁰ The economic impact of UTI in patients treated with INVOKANA was evaluated in a retrospective cohort study.²¹

BACKGROUND

On December 4, 2015, the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication that reports the SGLT2 inhibitor class of drugs had their Full Prescribing Information updated to include warnings regarding serious UTIs which can lead to hospitalizations.

The FDA review of the FDA Adverse Event Reporting System (FAERS) database from March 2013 through October 2014 identified 19 post marketing cases (INVOKANA (n=10); dapagliflozin (n=9)) of life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis) that started as UTIs with the SGLT2 inhibitor. All 19 patients were hospitalized, and a few required admissions to an intensive care unit or dialysis to treat kidney failure. Discontinuation of the SGLT2 inhibitor was reported in 15 cases. Blood cultures isolated E. coli as the organism in 8 of 19 cases. There were no reports of fungal urosepsis, however 11 cases had no information on culture testing.

The FDA advises Healthcare Professionals to evaluate patients for signs and symptoms of UTIs and treat promptly if indicated. Patients should be counseled about the signs and symptoms of a UTI and seek medical advice should such symptoms occur.

The complete communication can be accessed at the FDA website: www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious.

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 study designed to assess effects of INVOKANA (100 mg once daily) vs placebo on clinically important renal outcomes in patients with T2DM and established chronic kidney disease (estimated glomerular filtration rate 30 to <90 mL/min/1.73 m²) and albuminuria (urinary albumin to creatinine ratio >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.^22-26 In a post hoc analysis of CREDENCE, Kang et al (2020)¹ analyzed the risk of GMI and UTI with INVOKANA compared to placebo, both overall and in subgroups, in addition to predictors of risk for GMIs.

• The primary analysis was conducted in the on-treatment population.
• Overall, 5.7% (166/2905) of men and 20.1% (300/1492) of women experienced 669 UTIs, of which 8.7% (58/669) were reported as serious. The majority of patients continued treatment following their first infection, with similar recurrence rates in the INVOKANA and placebo groups.
• INVOKANA did not affect the risk of UTI (hazard ratio: 1.08 [95% confidence interval (CI): 0.90-1.29]; P=0.42) overall or in any subgroup.

CANVAS Program

The CANVAS Program (N=10,142) was comprised of 2 large INVOKANA cardiovascular (CV) outcome studies, including CANVAS and CANVAS-R.⁶ The CANVAS Program includes a pre-specified integrated analysis of the two trials designed to meet FDA post-marketing requirement to determine CV safety, as well as evaluate the potential for CV protection efficacy of INVOKANA in patients with type 2 diabetes mellitus (T2DM).^4,5,27,28 The mean duration of diabetes at baseline was 13.5 years (13.5 years in INVOKANA treatment group; 13.7 years in the placebo group).⁶

• In the CANVAS Program, UTIs were identified as an AE of interest which required the collection of additional information for a more detailed analysis.²⁹
• UTI events in the CANVAS trial were reported at an incidence rate of 40 and 37 per 1000 patients-years in the INVOKANA and placebo treatment groups, respectively (P=0.38).⁶
  • (Note: The annualized incidence rates of UTI are reported with data from CANVAS alone through 7 January 2014, because after this time, only serious AEs or AEs leading to discontinuation were collected. In CANVAS-R, only serious AEs or AEs leading to discontinuation were collected. Owing to the differences between the two trials in methods of collection of the data, an integrated analysis of these AEs is not possible.)⁶

Pooled Analysis of Phase 3, Placebo-Controlled Studies

Nicolle et al (2014)¹¹ conducted a pooled analysis of four 26-week, placebo-controlled clinical studies^7-10 (population 1)^5,6. In one trial, INVOKANA was used as monotherapy⁷ and in three trials^8-10, INVOKANA was used as add-on therapy. These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily.

• The overall incidence of UTI AEs were 5.9%, 4.3%, and 4.0% with INVOKANA 100 mg, 300 mg, and placebo, respectively.¹¹
• The majority (88.3%) of subjects with reported UTIs were women.¹¹
  • Women: The incidence of UTIs in the INVOKANA 300 mg group (6.3%) was slightly lower compared with the placebo group (7.7%), with the highest incidence observed in the INVOKANA 100 mg group (11.1%).
  • Men: A similar incidence of UTIs was seen in the placebo (0.6%) and INVOKANA 100 mg (0.5%) groups, with a higher incidence seen in the INVOKANA 300 mg group (2.2%).
• The median time to the first symptomatic UTI was 70.5 and 76 days in the INVOKANA 100 and 300 treatment groups respectively, and 90 days in the placebo group. The median duration of symptomatic UTIs were similar among patients in each group with duration ranging from 11 to 12.5 days.¹¹
• The proportion of patients with recurrent symptomatic UTI was similar across treatment groups: INVOKANA 100 mg (0.6%), INVOKANA 300 mg (0.2%) and placebo (0.5%).¹¹
• Discontinuations due to UTIs occurred in 1 (0.2%) subject in the placebo group, in 1 (0.1%) subject in the INVOKANA 100 mg group and 0% with INVOKANA 300 mg.¹¹
• Severity: Across treatment groups, few serious UTIs were reported: 0%, 0.2% (n=2), and 0.1% (n=1) in the placebo, INVOKANA 100 mg, and INVOKANA 300 mg groups, respectively. Upper UTIs (ie, kidney infection and urosepsis): Two subjects in the INVOKANA groups and no subjects in the placebo group had upper UTIs. Treatment: A slightly higher proportion of subjects in the placebo group (84.6%) compared to the INVOKANA 100 and 300 mg groups (75.5% and 80.6%, respectively) were treated with antimicrobial therapy. The specific antimicrobial agents used to treat the UTIs were not reported.¹¹

Nicolle et al (2014)¹¹ also evaluated UTIs in a pooled dataset of 8 phase 3, active- and placebo-controlled studies^2,7-10,12-14 with longer mean exposure (population 2).

• This population included four 26-week, placebo-controlled studies (population 1)^7-10, an active-controlled study (glimepiride)¹², placebo-controlled studies in patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 and <50 mL/min/1.73m2),¹³ and in older patients (≥55 to ≤80 years)¹⁴ and data from the CANVAS study⁶ (data cutoff July 1, 2012).¹¹
• The results of this broader population were generally consistent with those described in population 1. The incidence of UTI AEs were higher with INVOKANA 100 (8.2%) and 300 mg (8.1%) compared to the non- INVOKANA (6.7%) group. For additional information, refer to Table: Summary of UTI AEs in Pooled Data of 8 Active- and Placebo-Controlled Studies.¹¹
• The incidence of upper UTIs (kidney infection, acute and chronic pyelonephritis, urosepsis) were 0.6%, 0.3%, and 0.3% in the INVOKANA 100 mg, INVOKANA 300 mg, and non-INVOKANA treatment groups, respectively. The proportion of patients with acute upper UTIs was similar across treatment groups, however chronic pyelonephritis was reported more in INVOKANA-treated patients (0.13%) than in the non-INVOKANA treatment group (0.03%).¹¹

Additional Phase 3 Data

The incidence of UTIs in the phase 3 study extension periods (up to 52 weeks or 104 weeks) is provided in Tables: Incidence of UTIs in Phase 3, Placebo-/Active-Controlled Studies and Incidence of UTIs in Phase 3, Placebo-Controlled Studies. The overall incidences of UTI AEs in phase 3 studies were similar at the end of the core periods (summarized above) and at the end of the extension periods.

PHASE 2 STUDIES

Rosenstock et al (2012)³⁵ evaluated the efficacy and safety of INVOKANA in a 12-week, phase 2b, dose-ranging study in adult subjects with T2DM with inadequate glycemic control while on existing metformin monotherapy (N=451).

• Patients were randomized to 1 of 7 groups: INVOKANA 50, 100, 200, or 300 mg once daily, 300 mg twice daily, sitagliptin 100 mg once daily, or placebo.
• Similar rates of UTIs were observed between the INVOKANA (3% to 9%), placebo (6%), and sitagliptin (2%) groups. None of the UTIs led to study discontinuation; they were mild or moderate in severity.
• Additional safety analyses were conducted to determine the prevalence of bacteriuria and frequency of UTIs.³⁶
  • At baseline and at week 12, a midstream, clean-catch urine specimen was used for dipstick analysis and culture. Self-administered vaginal swabs were also obtained.
  • Subjects with a history of a UTI within 3 months prior to screening were excluded.
  • The prevalence of bacteriuria at baseline was 6.4% in the pooled INVOKANA group and 6.5% in the pooled placebo/sitagliptin group (control). This prevalence was higher in women. The number of patients with bacteriuria at week 12 did not differ between the INVOKANA group (7.7%) and the control group (6.3%).
  • Among subjects with negative cultures at baseline, 3 out of 82 (3.7%) control subjects and 10 out of 207 (4.8%) INVOKANA subjects became bacteriuric at week 12, without evidence for dose-dependency in the INVOKANA group. Escherichia coli was the most common organism isolated at baseline and at study end.
  • INVOKANA treatment, relative to placebo/sitagliptin treatment, was not a significant predictor of UTI (after adjusting for other possible risk factors)
    • Adjusted Odds Ratio (OR)=2.39 (95% CI, 0.58-9.94; P=0.23).

Retrospective analysis

A retrospective analysis utilizing the FDA FAERS was conducted to compare UTI and genital fungal infection cases reported between March 2013 and November 2015 for 6 SGLT2 inhibitors and combination products, including INVOKANA and INVOKANA/metformin.³⁷

• UTI cases were captured with preferred terms: UTI, genitourinary tract infection, kidney infection, cystitis, and pyelonephritis.
• A total of 727 UTI cases were reported across the SGLT2 inhibitor class. INVOKANA as a single agent was associated with the greatest number of reports of UTI (n=503), however, there was a larger number of INVOKANA cases in total due to its time on the market. See Table: Number of UTI Cases Reported for INVOKANA and INVOKANA/Metformin.
  • Of the combination products, INVOKANA/metformin had the most UTI cases reported (n=8).

Mechanism of development of utis

• People with diabetes are at higher risk for developing UTIs and their increased susceptibility is associated with increased duration and severity of diabetes. Clinical epidemiological data identifying mechanisms of increased UTI susceptibility in diabetes patients are lacking. The etiology of UTI in these patients may be multifactorial (e.g, bacterial growth with glucose in urine) and is not fully established.^38,39
• Increase in urinary glucose excretion may increase bacterial growth in the perineum. Therefore, in the clinical development program, the effect of INVOKANA treatment on bacteriuria was examined in phase 2 studies.³⁶ In addition, the incidence of AEs of UTI was evaluated in phase 2 and phase 3 studies and these results are summarized above.

PH EFFECTS

• In INVOKANA clinical studies, pH effects or acidification of urine and its impact on the incidence of UTI were not studied.

PREVENTATIVE THERAPY

• In INVOKANA clinical studies, pharmacologic prophylactic therapy was not administered for the prevention of UTIs.
• Please refer to the following website for information on non-pharmacological preventative methods:
  • National Center for Biotechnology Information, U.S. National Library of Medicine: www.ncbi.nlm.nih.gov/

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 13 August 2024.