SUMMARY  

• In the CANVAS Program, INVOKANA did not have a significant effect on serum potassium in the overall population or in key subgroups. Hyperkalemia adverse events (AEs) were not common and occurred at comparable rates among the INVOKANA and placebo (PBO) groups.¹
• In pooled data from 7 phase 3 studies^2-8, INVOKANA was generally associated with small mean percent changes in serum electrolytes.⁹
• In the CREDENCE trial, patients in the INVOKANA group had a reduced incidence of hyperkalemia and initiation of potassium binders versus placebo (hazard ratio [HR]: 0.78; 95% confidence interval [CI]: 0.64-0.95, P=0.014), with no effect on hypokalemia (HR: 0.92; 95% CI: 0.71-1.20, P=0.53).¹⁰
• In a population-based, active-comparator cohort study, patients in the INVOKANA group had reduced risk of hyperkalemia vs dipeptidyl peptidase-4 inhibitors (DPP-4i) (HR: 0.72; 95% CI: 0.63-0.83).^11,12

BACKGROUND - MECHANISM OF ELECTROLYTE CHANGES

Canagliflozin (CANA) is an inhibitor of sodium-glucose co-transporter 2 (SGLT2), which is expressed in the proximal renal tubules of the kidneys. SGLT2 is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. By inhibiting SGLT2, CANA reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion (UGE). Due to increased UGE, CANA treatment results in a mild osmotic diuresis.⁹ It has been suggested that small changes in serum electrolytes seen with CANA may be the result of the mild osmotic diuretic effects of this agent, but the specific mechanism of transient potassium increase observed with CANA 300 mg is unknown. Due to increased UGE, CANA use results in a mild osmotic diuresis and small changes in some serum electrolytes (eg, magnesium, phosphate, potassium) in type 2 diabetes mellitus (T2DM) patients, more often in those with reduced estimated glomerular filtration rate (eGFR) and with CANA 300 mg.⁹

CLINICAL DATA

CANVAS Program

Weir et al (2020)¹ examined the effect of INVOKANA on serum potassium levels and hyperkalemia rates in the CANVAS Program (N=10,142), which was comprised of 2 randomized, double-blind, PBO-controlled studies known as CANVAS and CANVAS-R.

• Patients were randomized 1:1:1 to INVOKANA 100 or 300 mg or PBO.
• Serum potassium measurements were assessed at ~6-month intervals.
• The prespecified limit of change criteria for decreased serum potassium was serum potassium <3.4 mEq/L (lower limit of normal) and >15% decrease from baseline, and for increased serum potassium was serum potassium >5.4 mEq/L (upper limit of normal) and >15% increase from baseline. Analysis of serum potassium measurements ≥6.5 mEq/L was also predefined. Post hoc assessments of serum potassium ≥5.5 and ≥6.0 mEq/L were also evaluated overall and by baseline eGFR (≥60, 45 to <60, and <45 mL/min/1.73 m²). Safety analyses included all investigator-reported AEs of hyperkalemia.
• Mean potassium levels were generally consistent over time among the INVOKANA and PBO groups, both overall and by baseline eGFR (≥60, 45 to <60, and <45 mL/min/1.73 m²).
• The risk of increased or decreased serum potassium was similar among the INVOKANA and PBO groups, overall and by baseline eGFR (all P-heterogeneity ≥0.56) or use of renin-angiotensin-aldosterone system inhibitors (all P-heterogeneity ≥0.71); levels did not appear different by INVOKANA dose.
• Hyperkalemia (6.9 and 4.4 patients per 1000 patient-years with INVOKANA and PBO; HR:1.60; 95% CI: 0.92-2.81) and serious hyperkalemia (0.4 and 0.6 patients per 1000 patient-years with INVOKANA and PBO; HR: 0.75; 95% CI: 0.27-2.11) AEs did not differ between groups.

Weir MR et al (2014)⁹ analyzed data from seven phase 3 studies^2-8 to evaluate effect of INVOKANA on serum electrolytes in 2 pooled populations of T2DM patients based on renal function.

• Population 1: patients (N=2215) with normal or mildly impaired baseline renal function (eGFR ≥60 mL/min/1.73m²; mean eGFR=89.6 mL/min/1.73m²) and inadequately controlled T2DM from a pool of four phase 3 studies.^2,3,8
• Population 2: patients (N=721) with moderate renal impairment (eGFR ≥45 and <60 mL/min/1.73m²; Stage 3A chronic kidney disease [CKD; mean eGFR=53.3 mL/min/1.73m²]) and inadequately controlled T2DM from a different pool of four phase 3 studies.^4-7
• In each of the seven studies, patients were randomized to receive INVOKANA 100 or 300 mg or PBO once daily.^2-7 All studies included a 26-week core treatment period with the exception of one,⁷ which had a primary assessment time point at week 18.
• There were no exclusion criteria based on serum electrolyte values at screening. Additionally, in these studies, there were no restrictions on use or modification of anti-hypertensive medications, non-steroidal anti-inflammatory drugs, or salt substitutes.
• Assessments of serum electrolytes included mean changes from baseline over time and the proportion of patients meeting outlier criteria. Within each population, outlier analyses were performed to determine the proportion of patients who had an episode of elevated electrolytes meeting pre-defined criteria.
• In Population 1 ~56% of patients and in Population 2 ~86% were taking anti-hypertensive agents that interfere with potassium excretion (renin-angiotensin aldosterone system [RAAS]-acting agents and/or potassium-sparing diuretics).
• Based on the assessment and discretion of each individual investigator, clinically relevant changes in serum electrolytes that occurred during the study were recorded as AEs.

Changes in Serum Electrolytes

Potassium

• In Population 1, the mean percent changes in serum potassium from baseline with INVOKANA 100 mg, 300 mg, and PBO were 0.6%, 1.0%, and 0.5% respectively, and 1.7%, 2.8%, and 0.7%, respectively, in Population 2.⁹ See Table: Changes in Serum Electrolytes: Mean and Mean Percent Change from Baseline in Pooled PBO-Controlled Studies.⁹
• In Population 1, the proportion of patients with an episode of serum potassium outside pre-defined limits of change (>upper limit of normal [ULN] [5.4 mEq/L] and >15% increase from baseline) with INVOKANA 100 mg, 300 mg and PBO was 4.5%, 6.8%, and 4.7% respectively, and 5.2%, 9.1%, and 5.5%, respectively, in Population 2.⁹
• In Population 1, the proportion of patients with serum potassium levels meeting outlier criteria (<lower limit of normal [LLN] [3.4 mEq/L] and >15% decrease from baseline) with INVOKANA 100 and 300 mg and PBO was 0.9%, 0.4% and 0.7%, respectively, and 1.9%, 0.4%, and 0.8%, respectively, in Population 2.⁹

Sodium

• In Population 1, mean percent changes from baseline in serum sodium with INVOKANA 100 mg, 300 mg, and PBO were 0.2%, 0.2%, and 0.1%, respectively, and 0.1%, 0.3%, and -0.1%, respectively, in Population 2. See Table: Changes in Serum Electrolytes: Mean and Mean Percent Change from Baseline in Pooled PBO-Controlled Studies.⁹
• The ULN for serum sodium was 147 mEq/L in patients 18 to 58 years and 145 mEq/L for patients 59 to 150 years of age. The proportion of patients with serum sodium meeting outlier criteria for elevated sodium (>ULN and increase of >5 mEq/L from baseline) in Population 1 was 1.9%, 2.4%, and 1.7% with INVOKANA 100 mg, 300 mg, and PBO, respectively.  In Population 2 the proportion of patients meeting this outlier criteria with INVOKANA 100 mg, 300 mg and PBO was 3.8%, 4.8%, and 2.4%, respectively, with most serum sodium elevations ≤150 mEq/L.⁹
• In each treatment group, one patient had a serum sodium >150 mEq/L (values of 156, 151, and 152 mEq/L with INVOKANA 100 mg, 300 mg, and PBO, respectively) and these values declined over the remainder of the assessment period.⁹
• The LLN for serum sodium was 132 mEq/L in patients 18 to 58 years and 135 mEq/L for patients 59 to 150 years of age. In Population 1, the proportion of patients with serum sodium meeting the outlier criteria (<LLN and decrease of >5 mEq/L from baseline) was 0%, 0.5% and 0.5%, respectively with INVOKANA 100mg, 300 mg, and PBO, respectively and 0.9%, 1.3%, and 2.7%, respectively, in Population 2.⁹

Magnesium (Mg)

• In Population 1, the mean percent changes from baseline in serum Mg with INVOKANA 100 mg, 300 mg, and PBO were 8.1%, 9.3%, and -0.4%, respectively, and 8.8%, 12.6%, and -0.2%, respectively, in Population 2. Please refer to Table: Changes in Serum Electrolytes: Mean and Mean Percent Change from Baseline in Pooled PBO-Controlled Studies.⁹ Increases in serum Mg were reported at Week 6 for Population 1 and Week 3 or 6 for Population 2 and remained elevated throughout the treatment period without further increase.⁹
• The ULN for serum Mg was 3.1 mg/dL in patients 18 to 79 years and 2.0 mg/dL for patients 80 to 150 years of age. No patients had elevations in serum Mg meeting outlier criteria (>ULN and >25% increase from baseline) in Population 1 and 1.4%, 0.9%, and 0% patients had elevations in Mg meeting outlier criteria with INVOKANA 100 mg, 300 mg, and PBO, respectively in Population 2.⁹
• In Population 1, the proportion of patients with serum Mg meeting the outlier criteria levels (<LLN [1.5 mg/dL] and >25% decrease from baseline) was 0.5% in the PBO group and no patients taking INVOKANA 100 mg and 300 mg. In Population 2, the proportion of patients meeting outlier criteria was 0%, 0.4% and 0.8% with INVOKANA 100 mg, 300 mg, and PBO, respectively.⁹

Bicarbonate

• In Population 1, mean percent changes from baseline in serum bicarbonate with INVOKANA 100 mg, 300 mg, and PBO were 1.6%, 1.1%, and 3.3%, respectively and
  -0.7%, 1.0%, and 2.6%, respectively, in Population 2. Please refer to Table: Changes in Serum Electrolytes: Mean and Mean Percent Change from Baseline in Pooled PBO-Controlled Studies.⁹
• In Population 1, the proportion of patients who had bicarbonate values meeting outlier criterion (<16 mEq/L) was 2.7%, 3.0%, and 1.9% with INVOKANA 100 mg, 300 mg, and PBO, respectively and in Population 2, the proportion of patients meeting this outlier was 2.8%, 6.1%, and 2.4% with INVOKANA 100 mg, 300 mg and PBO, respectively.⁹

Phosphate

• In Population 1, mean percent changes from baseline in serum phosphate with INVOKANA 100 mg, 300 mg, and PBO were 3.5%, 5.2%, and 1.4%, respectively and 2.9%, 4.7%, and 0.8%, respectively, in Population 2. Please refer to Table: Changes in Serum Electrolytes: Mean and Mean Percent Change from Baseline in Pooled PBO-Controlled Studies.⁹
• In Population 1, the proportion of patients who had elevations in serum phosphate meeting outlier criteria (>ULN [5.1 mg/dL] and >25% increase from baseline) was 0.6%, 1.7%, and 1.2% with INVOKANA 100 mg, 300 mg, and PBO, respectively. In Population 2, 1.4%, 1.3%, and 0.4% patients met these criteria with INVOKANA 100 mg, 300 mg, and PBO, respectively.⁹
• In Population 1, the proportion of patients who had reductions in serum phosphate meeting outlier criteria (<LLN [2.2 mg/dL] and >25% decrease from baseline) was 0.1%, 0.3% and 0% with INVOKANA 100 mg, 300 mg, and PBO, respectively. In Population 2, 0%, 0.4%, and 0% patients met these criteria with INVOKANA 100 mg, 300 mg, and PBO, respectively.⁹

Calcium

• In Population 1 mean percent changes from baseline in serum calcium with INVOKANA 100 mg, 300 mg, and PBO were 0.8%, 1.2%, and 0.2%, respectively and -0.1%, 0.6%, and 0.1%, respectively in Population 2. Please refer to Table: Changes in Serum Electrolytes: Mean and Mean Percent Change from Baseline in Pooled PBO-Controlled Studies.⁹
• In Population 1, the proportion of patients who had elevations in serum calcium meeting outlier criteria (>ULN [10.6 mg/dL] and >10% increase from baseline) was 1.0%, 1.5%, and 0.7% with INVOKANA 100 mg, 300 mg, and PBO, respectively. In Population 2, 0.9%, 0.9%, and 2.0% patients met these criteria with INVOKANA 100 mg, 300 mg, and PBO, respectively.⁹

CREDENCE

Neuen et al (2021)¹⁰ assessed the effects of INVOKANA on serum potassium in a post-hoc analysis of the CREDENCE trial. CREDENCE was a double blind, event-driven, randomized, placebo-controlled trial in patients with T2DM and CKD. Patients were randomized to receive either INVOKANA 100 mg or placebo once daily.

• The main outcome of this post-hoc analysis was a composite of investigator-reported hyperkalemia events or the initiation of potassium binders. Other potassium related outcomes included investigator reported hyperkalemia alone, initiation of potassium binders alone, hyperkalemia defined as a serum potassium ≥6.0 mmol/L, investigator reported hypokalemia, hypokalemia defined as serum potassium <3.5 mmol/L, and mean difference in serum potassium over time.
• In the CREDENCE trial, 4401 patients were randomized and a total of 4397 (99.9%) had serum potassium levels available at baseline. At baseline, the mean serum potassium was 4.5 mmol/L in both arms.  
• Over a median follow up of 2.6 years, 179 (8.1%) patients in the INVOKANA arm and 226 (10.3%) in the placebo arm experienced the composite of investigator reported hyperkalemia or initiation of potassium binders. INVOKANA reduced the relative risk of the composite by 22% (32.7 vs. 41.9 participants per 1000 patient years; HR: 0.78; 95% CI: 0.64-0.95, P=0.014). Patients in the INVOKANA arm had a lower incidence of investigator reported hyperkalemia alone (HR: 0.82; 95% CI: 0.67-1.01, P=0.063), and initiation of potassium binders alone (HR: 0.66; 95% CI: 0.46-0.95, P=0.027).
• INVOKANA reduced the incidence of hyperkalemia defined as serum potassium ≥6 mmol/L (HR: 0.77; 95% CI: 0.61-0.98, P=0.031)
• Mean serum potassium levels increased for both the INVOKANA and placebo arms. Over the duration of the trial, no significant difference in mean serum potassium levels was observed between both treatment arms (placebo-subtracted difference 0.00039 mmol/L; 95% CI: 0.018 to 0.019, P=0.97).
• The incidence of investigator reported hypokalemia (HR: 1.20; 95% CI: 0.71-2.04, P=0.50), and hypokalemia defined as serum potassium <3.5mmol/L (HR: 0.92; 95% CI: 0.71-1.20, P=0.53) was low.

Gilbert et al (2016)¹³ conducted a post hoc analysis of pooled 26-week data from 4 randomized, double-blind, PBO-controlled, phase 3 studies (N=2,313)^2,3,6,8 to evaluate effects of INVOKANA on serum Mg in patients with T2DM and hypomagnesemia (defined as Mg <1.8 mg/dL). At baseline, 18.3% of patients had hypomagnesemia, 80.7% had serum Mg 1.8-2.3 mg/dL (normal Mg), and 1.0% had serum Mg >2.3 mg/dL (hypermagnesemia); the proportions were similar across groups in each category. The mean baseline serum Mg was 1.9 mg/dL. At week 26, increases in serum Mg were seen with INVOKANA 100 mg and 300 mg vs PBO in patients with baseline serum Mg <1.8 mg/dL and ≥1.8 mg/dL. A greater proportion of patients with baseline hypomagnesemia had serum Mg ≥1.8 mg/dL at week 26 with INVOKANA 100 mg and 300 mg vs PBO.

AEs Related to Electrolyte Changes

AEs associated with elevations in serum potassium were reported in 6 (0.8%), 6 (0.7%), and 1 (0.2%) patients in the INVOKANA 100 mg, 300 mg, and PBO groups, respectively, in Population 1, and in 3 (1.4%), 5 (2.1%), and 4 patients (1.5%) in Population 2.⁹ The incidence of AEs related to changes in serum bicarbonate, calcium, Mg, phosphate, potassium, or sodium was low and generally similar across groups in both populations.⁹

REAL-WORLD DATA

Fu et al (2024)^11,12 conducted a population-based, active-comparator, new-user cohort study using claims data from Optum’s deidentified Clinformatics Data Mart Database, IBM MarketScan, and Medicare from April 2013 to April 2022 to evaluate the comparative risk of hyperkalemia with sodium-glucose cotransporter-2 inhibitor (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and DPP-4i in patients with T2DM and CKD. Three separate cohorts were included in this study: SGLT-2i versus DPP-4i (cohort 1), GLP1RA versus DPP-4i (cohort 2), and SGLT-2i versus GLP-1RA (cohort 3). INVOKANA was the SGLT-2i used in 32.9% of patients in cohort 1 and 34.4% of patients in cohort 3. At baseline, the mean serum potassium level was 4.5 mmol/L across the different cohorts.

• Subgroup analyses of individual agents in the SGLT-2i vs DPP-4i cohort found that INVOKANA was associated with lower risk of hyperkalemia vs DPP-4i.¹² See Table: Subgroup Analyses of INVOKANA vs DPP-4i for Risk of Hyperkalemia After 1:1 PSM.

In addition to the above summarized data, other relevant literature which reports serum electrolyte changes with INVOKANA was identified.^3-5,8,14-28

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 16 May 2024.