SUMMARY

• The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) study was a phase 4 renal outcomes trial, evaluating whether INVOKANA has a renal and vascular protective effect in reducing the progression of renal impairment compared to placebo (PBO) in patients with type 2 diabetes mellitus (T2DM), stage 2 or 3 chronic kidney disease (CKD), and macroalbuminuria.¹
  • In a post hoc analysis, the proportion of patients with acute kidney injury (AKI) events was similar between treatment groups for the first 12 months of follow-up. After 12 months, numerically fewer events were reported in the INVOKANA group (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.64-1.13; P=0.3).²
• In the CANVAS Program, comprised of 2 large INVOKANA cardiovascular (CV) outcome studies known as CANVAS and CANVAS-R, there was no increased risk of AKI in the INVOKANA group compared with the PBO group.³
• In a pool of 4 phase 3, PBO-controlled studies (N=2313), incidence of renal-related adverse events (AEs; including blood creatinine increased, estimated glomerular filtration rate [eGFR] decreased, oliguria, renal failure, acute renal failure, and renal impairment) was 0.6%, 1.7% and 0.6% with INVOKANA 100, 300 mg, and PBO, respectively.⁴ In the pooled population of patients with stage 3 CKD (N=1085), renal-related AEs were higher with INVOKANA 100 and 300 mg compared with PBO (8.9%, 9.3% and 3.7%, respectively). Few renal-related AEs were deemed serious or led to study discontinuation.^4-6
• Multiple real world evidence studies that evaluated the association between SGLT2is and AKI have been summarized in this letter.^7-11
• A review of the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database from March 29, 2013, to October 19, 2015 identified 101 postmarketing cases of AKI with INVOKANA (n=73) and dapagliflozin (n=28). In approximately half (n=58) of the cases for INVOKANA and dapagliflozin, AKI occurred within 1 month of starting the drug, and most patients improved after discontinuing the drug.¹²

BACKGROUND

Terminology: AKI and Acute Renal Failure

• AKI represents the sudden loss of kidney function, generally occurring over the course of hours to days and resulting in the retention of metabolic waste products and dysregulation of fluid, electrolyte, and acid-base homeostasis.^13,14
• The acute loss of kidney function (previously referred to as acute renal failure), for which the focus generally was limited to the most severe episodes with complete or near-complete loss of kidney function, is now replaced with the current terminology of AKI, with increased focus on smaller decrements in kidney function.^13,14

Postulated Mechanism(s)

• The exact mechanism of AKI is unknown, however transient changes in renal function reported with CANA may be related to a mild osmotic diuretic effect of this agent.¹⁵

CLINICAL DATA

CREDENCE

CREDENCE was a randomized, double-blind, PBO-controlled, parallel group multicenter, event-driven trial (N=4401) to assess the effects of INVOKANA (100 mg) vs PBO on clinically important renal outcomes in people with T2DM and established CKD and albuminuria, who were receiving a stable, maximum tolerated or labelled dose (for ≥4 weeks prior to randomization) of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker.^1,16-19

• Patients who were eligible to participate in the study were ≥30 years with T2DM (A1c ≥6.5% to ≤12.0%; participants in Germany required an A1c range of ≥6.5% to <10.5%), had CKD, and an eGFR 30 to <90 mL/min/1.73m² and albuminuria (urine albumin:creatinine ratio >300 to 5000 mg/g).¹
• 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).
• Use of other therapies for glycemic management and CV risk factor control was recommended in accordance with clinical practice guidelines.
• The primary endpoint was the composite of end-stage kidney disease (ESKD) (defined as chronic dialysis for >30 days, renal transplantation, or eGFR <15 mL/min/1.73m² sustained for >30 days), the doubling of serum creatinine (dSCr) from baseline average sustained for ≥30 days, and death due to renal disease or CV disease (CVD).

Results

Efficacy

By July 2018, the number of confirmed primary endpoints to trigger the planned interim analysis had been accrued and prespecified efficacy criteria for early cessation had been achieved. The independent data monitoring committee advised to end the CREDENCE study early after a median follow-up duration of 2.62 years (range, 0.02-4.53 years).¹

• INVOKANA significantly reduced rates of the composite outcome of ESKD, dSCr, and renal or CV death (43.2 and 61.2 per 1000 patient-years [PYs] in INVOKANA and PBO, respectively), resulting in a 30% relative risk reduction (RRR; HR, 0.70; 95% CI, 0.59-0.82; P=0.00001; NNT, 22 over 2.5 years for the primary composite endpoint).
• In the CREDENCE study, INVOKANA significantly reduced the risk of the following¹:
  • The composite of CV death and hospitalization for heart failure (HHF; RRR, 31%; HR, 0.69; 95% CI, 0.57-0.83; P<0.001).
  • Major adverse CV event (CV death, nonfatal myocardial infarction, or nonfatal stroke; 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).
• INVOKANA treatment demonstrated a greater mean change in the systolic blood pressure (-3.30 mmHg; 95% CI, -2.73 to -3.87), diastolic blood pressure (-0.95 mmHg; 95% CI, -0.61 to -1.28), and body weight (-0.80 kg; 95% CI, -0.69 to -0.92).¹

Safety

• In CREDENCE, the overall rates of AEs and serious AEs, (on-treatment and on-study analysis sets) were similar between treatment groups.¹
  • There were no higher risks of hyperkalemia, AKI, acute pancreatitis, fracture, or renal-cell carcinoma with INVOKANA than with PBO.
  • AKI occurred at a rate of 16.9 and 20.0 events per 1000 PYs in the INVOKANA and PBO groups, respectively (HR, 0.85; 95% CI, 0.64-1.13).
  • Renal-related AEs (including AKI) occurred at a rate of 57.1 and 79.1 events per 1000 PYs in the INVOKANA and PBO groups, respectively (HR, 0.71; 95% CI, 0.61-0.82).¹⁷

Heerspink et al (2022)² conducted a post hoc analysis of the CREDENCE trial to further evaluate the effect of INVOKANA on kidney safety outcomes. The primary outcome of this analysis was the first kidney-related AE. Other endpoints included the first kidney-related serious AE (kidney-related AEs that were life threatening or led to unplanned hospitalization, prolonged hospitalization, or death) and the first AKI. In patients who had AKI, recovery of kidney function 30 days after AKI was evaluated as an exploratory outcome. This was assessed by the change in eGFR from the last estimate before AKI to the eGFR 30 days after AKI.

• During a mean follow-up of 2.1±0.9 (standard deviation) years, kidney-related AEs occurred in 678 participants, including 388 (17.7%; event rate, 8.4 per 100 PYs) in the PBO group and 290 (13.2%; event rate, 6.0 per 100 PYs) in the INVOKANA group (HR, 0.71; 95% CI, 0.61-0.82; P<0.001).
  • Across the 3 eGFR strata (30-<45, 45-<60, and 60-<90 mL/min/1.73 m²), INVOKANA was associated with lower rates of kidney-related AEs compared with PBO (HRs: 0.73, 0.60, and 0.81, respectively; P=0.3 for interaction).
• Kidney-related serious AEs occurred for 82 participants (3.7%, event rate, 1.7 per 100 PYs) in the PBO group and 61 participants (2.8%; event rate, 1.2 per 100 PYs) in the INVOKANA group (HR, 0.72; 95% CI, 0.51-1.00; P=0.05).
• AKI events were reported for 98 participants in the PBO group (4.5%, event rate, 2.0 per 100 PYs) and 86 (3.9%; event rate, 1.7 per 100 PYs) in the INVOKANA group (HR, 0.85; 95% CI, 0.64-1.13; P=0.3). In these patients, a total of 212 AKI events were observed, including 114 for the 98 participants in the PBO group and 98 for the 86 participants in the INVOKANA group.
  • The main predisposing factors associated with AKI in both groups were dehydration/hypovolemia and septic shock. In about half of the patients with AKI events in both groups, study medication was continued after AKI. Study medication was interrupted or stopped permanently at the time of the event in 24.5% and 8.2% of patients in the PBO group and 29.1% and 7.0% in the INVOKANA group, respectively.
  • A total of 15 patients had any AE of volume depletion within 30 days before the AKI (11 in the INVOKANA group and 4 in PBO group, P=0.03). Full recovery of kidney function after AKI occurred in 53.1% of patients in the INVOKANA group vs 35.4% in the PBO group (odds ratio, 2.2; 95% CI, 1.0-4.7; P=0.04), and a lack of recovery in kidney function occurred more in the PBO group (35.4%) than in the INVOKANA group (18.4%; odds ratio, 0.46; 95% CI, 0.21-0.97; P=0.04).
  • The proportion of patients who required dialysis within 30 days after the AKI event was 16.3% in the PBO group and 10.5% in the INVOKANA group (P=0.3). The proportion of deaths within 30 days after the AKI event was 10.2% in the PBO group and 7.0% in the INVOKANA group (P=0.5).
• The proportion of patients with kidney-related serious AEs or AKI was similar between treatment groups during the first 12 months of follow-up. After 12 months, there was a separation with fewer events reported in the INVOKANA group.

The CANVAS Program

• The CANVAS Program (N=10,142) comprises 2 large INVOKANA CV outcome studies, CANVAS and CANVAS-R, in patients with T2DM with a history of or at high risk for CVD.³ The CANVAS Program includes a pre-specified integrated analysis of these studies to meet the FDA postmarketing requirement to determine CV safety, as well as evaluate potential for CV protection with INVOKANA use in patients with T2DM. Renal and safety outcomes were also evaluated.^20-23 At baseline, 65.6% of patients had a history of atherosclerotic CVD and 35% had at least 2 risk factors for CVD.^3,20 In addition, at baseline, 17.2% (n=994/5795) of patients in the INVOKANA group and 17.9% (n=780/4347) in the PBO group had documented nephropathy.

Renal Safety Assessment

• Safety assessments were based on on-treatment analysis, defined as patients who experienced a safety outcome while on study drug or within 30 days of discontinuation.³
• There was no increased risk of AKI in the CANVAS Program for INVOKANA compared to PBO.³
• In the CANVAS trial, AKI occurred at an event rate of 3.0 and 4.1 per 1000 PYs of exposure in the INVOKANA and PBO groups, respectively (P=0.33).³
  • For the CANVAS study, AKI as an AE was collected through January 4, 2014. After this date, only events leading to discontinuation and serious AEs were collected. For CANVAS-R, the collection of AEs was streamlined to include serious AEs, AEs that led to study drug discontinuation, and all AEs of interest.

Pooled Analyses of Phase 3 Studies

Perkovic et al (2015)⁶ reviewed data from analyses of 3 phase 3 studies up to 104 weeks (Weir et al [2015]²⁴), 4 PBO-controlled 26 week-studies (Usiskin et al⁴), and 4 PBO-controlled studies up to 26 weeks in patients with moderate renal impairment (Yamout et al⁵). Qiu et al (2017)²⁵ reviewed data from analysis of 7 PBO- and active-controlled studies of 52-104 weeks in duration.

Long-Term Data - Normal to Moderate Renal Impairment

Weir et al (2015)²⁴ presented results of an analysis of 3 phase 3 studies^26-30 which evaluated effect of INVOKANA on eGFR for up to 2 years (104 weeks) in T2DM patients with various degrees of baseline renal function. This analysis included a phase 3 study in older patients with T2DM (Bode et al³⁰), an add-on to metformin vs glimepiride study (Leiter et al²⁹), and a phase 3 study (Yale et al²⁶) in T2DM patients with moderate renal impairment.⁶

• The observed changes in eGFR were greatest at the first postbaseline visit (3-6 weeks) and generally stabilized or attenuated within 26 weeks and remained unchanged for up to 104 weeks. The eGFR progressively declined with glimepiride but not with PBO (see Figure: Effect of INVOKANA on eGFR Over Time).^6,8

Renal-Related AEs

• In a study²⁹ evaluating efficacy and safety of INVOKANA compared with glimepiride as add-on therapy in adults with T2DM inadequately controlled on metformin monotherapy, the percent of patients with any renal AE (including blood creatinine increased, eGFR decrease, renal failure, acute renal failure, and renal impairment) was similar (3%) across treatment groups at week 104 (N=1452).^24,32
  • The proportions of patients on INVOKANA 100 mg, 300 mg, and glimepiride with a postbaseline eGFR value <80 mL/min/1.73 m² and a decrease of >30% were 6.6%, 8.5%, and 8.7%, respectively.
  • The proportions of patients on INVOKANA 100 mg, 300 mg, and glimepiride with a postbaseline eGFR decrease >50% were 0.8%, 1.3%, and 0.4%, respectively.
  • Regardless of study drug, nearly all patients with an eGFR decrease >50% from baseline had eGFR changes that returned toward baseline values during or after study discontinuation.³²
• In the study³⁰ in older subjects aged 55-80 years, any renal AE occurred in 3% of patients on INVOKANA 300 mg and 5% of patients taking INVOKANA 100 mg and PBO at week 104 (N=714).²⁴
• In the study²⁶ in patients with moderate renal impairment (eGFR ≥30 and <50 mL/min/1.73m²), any renal AE occurred in 7% of patients in the INVOKANA (100 and 300 mg) group and 8% in the PBO group (N=269) at 52 weeks.²⁴

26-Week Data - Normal to Mild Renal Function

• In a pooled analysis (Usiskin et al⁴) of 4 phase 3 PBO-controlled 26 week studies (N=2313)^33-36 of patients with eGFR ≥50mL/min/1.73 m², the incidence of renal-related AEs (e.g., acute renal failure, renal impairment, blood creatinine increased, and eGFR decreased) were low and generally balanced across treatment groups (see Table: Renal-Related AEs in Patients With and Without Renal Impairment). Few renal-related AEs were deemed serious or led to study discontinuation.^4,6
• The proportion of patients who experienced at least 1 event of significant renal function decline, defined as an eGFR <80 mL/min/1.73 m² and 30% lower than baseline, was 2.1% with PBO, 2.0% with CANA 100 mg, and 4.1% with CANA 300 mg. At the end of treatment, 0.5% with PBO, 0.7% with CANA 100 mg, and 1.4% with CANA 300 mg had a significant renal function decline.^37,4

Up to 26-Week Data - Moderate Renal Impairment

• In a pooled analysis (Yamout et al⁵) of 4 randomized, double-blind, PBO-controlled, phase 3 studies^28,34,15,38 in patients with moderate renal impairment (eGFR ≥30 and <60 mL/min/1.73m²) and inadequately controlled T2DM (N=1085), the incidence of renal-related AEs (including renal failure, acute renal failure, renal impairment blood creatinine, eGFR decreased, and oliguria) was higher with INVOKANA 100 and 300 mg compared with PBO (see Table: Renal-Related AEs in Patients With and Without Renal Impairment).
• Few renal-related AEs were deemed serious or led to study discontinuation.^5,6

Up to 104-Week Data

• In a pooled analysis (Qiu et al 2017²⁵) of 7 active- and PBO-controlled trials (N=5598), incidence rate of renal-related AEs was 2.1, 2.5, and 2.6 per 100 PYs with INVOKANA 100 mg and 300 mg and non-INVOKANA, respectively. Incidence rates of serious renal-related AEs with INVOKANA 100 and 300 mg and non-INVOKANA were 0.15, 0.05, and 0.09 per 100 PYs, respectively).²⁵

In a post hoc analysis of a randomized active-controlled double-blind trial, INVOKANA compared to glimepiride decreases albuminuria and slows the progression of kidney function decline independent of glycemic control.³⁹

A network meta-analysis comparing the associations of individual SGLT2i with adverse renal outcomes in patients with T2DM has also been conducted.⁴⁰ Comment on this meta-analysis is also available for your reference.⁴¹

Real-World Evidence

Chung et al (2023)⁹ conducted a retrospective cohort study using the Taiwan National Health Insurance data set, which evaluated the incidence of AKI and acute kidney injury requiring dialysis (AKI-D) with SGLT2is and dipeptidyl peptidase 4 inhibitors (DPP4is) in patients with T2DM.

• After 1:1 propensity score matching, 104,462 patients (52,231 in each cohort) were included in the study.
• The incidence of AKI and AKI-D was reported in 856 (0.8%) and 102 (<0.1%) patients, respectively (see Table: Incidence and Risk of AKI and AKI-D in Patients Receiving SGLT2is and DPP4is).
• The SGLT2i group had an adjusted HR of 0.66 (95% CI, 0.57-0.75; P<0.001) and 0.56 (95% CI, 0.37-0.84; P=0.005) for AKI and AKI-D, respectively, compared with the DPP4i group.
• SGLT2i use showed significant benefits in patients with AKI who had respiratory failure (HR, 0.42; 95% CI, 0.26-0.69; P<0.001) and shock (HR, 0.48; 95% CI, 0.23-0.99; P=0.048) but not heart disease (HR, 0.79; 95% CI, 0.58-1.07; P=0.13) and sepsis (HR, 0.77; 95% CI, 0.58-1.03; P=0.08).
• According to the 90-day prognosis for the risk of advanced CKD among patients with AKI, there was a 6.53% (23/352) lowered incidence of advanced CKD in SGLT2i vs DPP4i users (P=0.045). The incidence of ESKD and death in SGLT2i vs DPP4i users was similar.

Chen et al (2022)¹⁰ conducted a pharmacovigilance study using data from the FAERS database (from January 2004 to December 2020), which evaluated the association between SGLT2is and AKI in patients with T2DM. The onset times of SGLT2i-associated AKI and the fatality rates after AKI were also examined.

• The mean age of patients with SGLT2i-associated AKI was 57.90 (±11.84) years, with 58.46% and 28.67% of patients in the age groups of 45-64 years and >65 years, respectively. Excluding the unspecified data, 56.68% of patients were male.
• Of the 2483 cases of suspected SGLT2i-associated AKI, 1650 (66.45%), 325 (13.09%), and 374 (15.06%) cases were related to INVOKANA, dapagliflozin, and empagliflozin, respectively (see Table: Association Between SGLT2is and AKI Signals).
• The median time from SGLT2i administration to the onset of AKI was 72.0 (interquartile range [IQR], 21.0-266.0) days, with a significant difference found among SGLT2is (P<0.01). The longest median time was noted for INVOKANA (98.0 [IQR, 27.0-295.0] days), and the shortest median time was noted for ertugliflozin (23.0 [IQR, 18.0-28.0] days).
• A quick onset (as soon as the initiation of the drug) of AKI was observed in 5.63% of all SGLT2i-associated AKI cases and 4.97%, 8.96%, and 5.00% of patients on INVOKANA, dapagliflozin, and empagliflozin, respectively.
• SGLT2i-associated AKI led to initial or prolonged hospitalization in 63.50% of patients. The fatality rate among all AKI cases was 1.59%, with no significant difference found among SGLT2is (P=0.553). The highest fatality rate was noted for dapagliflozin (2.12%).

Horii et al (2022)¹¹ conducted a retrospective cohort study using the Medical Data Vision administrative claims database, which evaluated the association between SGLT2is and AKI in Japanese patients with T2DM.

• Of the 171,622 patients with T2DM who were treated with SGLT2is, 476 developed AKI (see Table: HR for AKI in Patients with T2DM Treated with SGLT2is).
• The mean duration from SGLT2i initiation to the onset of AKI was 146.3±104.4 days. The first 30 days of SGLT2i initiation showed the highest AKI incidence, after which there was a general downward trend.

Ueda et al (2018)⁷ conducted a register-based cohort study in Sweden and Denmark, utilizing a non-parsimonious propensity score model, which evaluated the association between new users of SGLT2is or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) use and AEs of concern, including AKI.

• After propensity score matching, 34,426 patients (17,213 in each cohort) were included in the study. Of the SGLT2is, 1% used INVOKANA, 61% used dapagliflozin, and 38% used empagliflozin.
• New users of SGLT2is did not have an increased risk of AKI compared to new users of GLP-1 RAs (HR, 0.69; 95% CI, 0.45-1.05). Additional analysis using data truncated at 6 months after initiation of study drug showed a similar HR to the primary analysis.

A retrospective analysis by Nadkarni et al (2017)⁸ of 2 large health system databases was conducted in patients with T2DM, with and without baseline reduced eGFR, using propensity score matching. Longitudinal data was analyzed from the Mount Sinai Chronic Kidney Disease Registry (between January 1, 2014, and December 30, 2016, N=12,704) and the Geisinger Health System (between January 1, 2013, and February 10, 2017, N=56,163). Propensity matching was performed with a 1:1 match for case and control subjects.

Results: Mount Sinai Cohort

• A total of 377 patients on an SGLT2i were matched with 377 patients not on an SGLT2i. Of the SGLT2i patients included, 71.8% were on INVOKANA, 19.4% were on dapagliflozin and 8.9% were on empagliflozin.
• The incidence rate of an AKI event was 3 (3.8%) and 8 (9.7%) per 100 PYs in SGLT2i patients and non-SGLT2i patients, respectively (P=0.002).
• The adjusted HR for AKI was 0.2 (95% CI, 0.1-0.5) for the INVOKANA group and 1.1 (95% CI, 0.5-2.7) for the dapagliflozin group. Results for empagliflozin in this cohort are not available because of the small sample size and lack of model convergence.

Results: Geisinger Cohort

• A total of 1207 patients on an SGLT2i were matched with 1207 non-FDA SGLT2i patients. Of the SGLT2i patients included in the analysis, 60.6% were on INVOKANA, 10.8% were on dapagliflozin, and 28.6% were on empagliflozin.
• The incidence rate of an AKI event was 1.7 (2.2%) and 3.8 (4.6%) per 100 PY in SGLT2i patients and non-SGLT2i patients, respectively (P<0.01).
• The adjusted HR for AKI was 0.61 (95% CI: 0.33-1.12) for the INVOKANA group, 0.32 (95% CI: 0.02-5.18) for the dapagliflozin group, and 0.96 (95% CI: 0.21-4.35) for the empagliflozin group.

POSTMARKETING CASE REPORTS IN THE PUBLIC DOMAIN

Please refer to the drug safety communication on the FDA website for more details: https://www.fda.gov/Drugs/DrugSafety/ucm505860.htm.

The FDA review of the FAERS database from March 29, 2013, to October 19, 2015, identified 101 postmarketing cases of AKI with INVOKANA (n=73) and dapagliflozin (n=28).¹² This number includes only reports submitted to FDA, so there are likely additional cases about which we are unaware. In approximately half of the cases, the events of AKI occurred within 1 month of starting the drug, and most patients improved after stopping it. Some cases occurred in patients who were younger than 65 years. Some patients were dehydrated, had low blood pressure, or were taking other medicines that can affect the kidneys.

In an extension of the analysis of FAERS reports up to the end of 2015, 125 cases of AKI were identified with INVOKANA, 50 with dapagliflozin and 15 with empagliflozin.³² There were 3 cases with INVOKANA plus metformin, 6 with dapagliflozin plus metformin extended release and 2 with empagliflozin plus linagliptin.

In an additional study of FAERs data, cases of acute renal failure with SGLT2is between January 2013 and September 2016 were analyzed.⁴² Of the total 1224 SGLT2i-related postmarketing cases of acute renal failure identified, 928 occurred with INVOKANA, 177 with dapagliflozin, and 124 with empagliflozin.

Hassani-Ardakania et al (2019)⁴³ reported on a case of severe AKI exacerbated by INVOKANA in a 72-year-old female patient with T2DM. The patient, who had no known chronic renal insufficiency, was presented to the emergency room with a 3-day history of nausea, vomiting, and increased somnolence. Medications included valsartan, metoprolol, rosuvastatin, aspirin, INVOKANA, sitagliptin, metformin, insulin degludec and aspart, donepezil, citalopram, gabapentin, and pantoprazole. INVOKANA 300 mg once daily was initiated approximately 18 months prior to presentation. Testing revealed a potassium level of 7.4 (normal: 3.5-5.5) mmol/L, an elevated creatinine level of 1154 (normal: 45-95) µmol/L, and granular casts in the urine; imaging of the abdomen and pelvis did not reveal any findings of obstruction. The patient was diagnosed with AKI secondary to ischemic acute tubular necrosis, with INVOKANA use considered as a contributing factor. The patient started on renal replacement therapy, receiving continuous veno-venous hemofiltration and subsequent intermittent hemodialysis (IHD), leading to hemodynamic stability. Renal function recovered gradually following 8 weeks of IHD.

Phadke et al (2020)⁴⁴ reported on the case of a 66-year-old, T2DM patient who developed AKI-D following INVOKANA use. The patient was started on INVOKANA 300 mg orally once daily and was admitted with oliguric AKI 5 days after starting INVOKANA. INVOKANA was discontinued upon hospital admission. The patient was presented with hematuria, nonnephrotic-range proteinuria, and a serum creatinine level of 6.8 (baseline, 1.1-1.3) mg/dL, and subsequently required hemodialysis. Acute interstitial nephritis was considered in the differential diagnosis due to recent antibiotic use (ampicillin-sulbactam). Kidney biopsy confirmed the presence of osmotic nephropathy. The patient’s kidney function returned to baseline after 2 weeks of hemodialysis.

Additional case reports identified during a literature search are referenced.^45,46

RECOMMENDATIONS AND MANAGEMENT

The updated CANA product labeling³⁷ provides recommendations to Health Care Professionals, including the following:

1. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKANA in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.
2. Encourage patients to read the Medication Guide that they receive with their INVOKANA prescriptions.

Please refer to the full Prescribing Information and Medication Guide for additional management recommendations.³⁷

Additional real-world evidence studies have reported AKI in included patients.⁴⁷

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, Derwent Drug File (and other resources, including internal/external databases) was conducted on 18 April 2023.