Summary

• In clinical studies, small to moderate increases in hemoglobin (Hb) and hematocrit (Hct) were observed in patients taking INVOKANA.^1-6
• Generally, increases in Hb or Hct were seen by week 12 and remained stable throughout the study period.⁷
• Additional citations identified during a literature search have been included in the REFERENCES section for your review.^8-11

CLINICAL STUDIES

Hb or Hct Changes Over 26 Weeks

In a pool of four, 26-week, phase 3, placebo-controlled studies,^1,12-14 a small-to-moderate increase in Hb from baseline to week 26 was reported in patients treated with INVOKANA 100 mg (3.5%) and 300 mg (3.8%) compared with placebo (-1.1%).¹⁵ Increases in Hct were also observed.⁵ See Table: Mean Change From Baseline to Week 26 in Hb and Hct Laboratory Values With INVOKANA in 4 Pooled, Placebo-Controlled Studies.

At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had Hb above the upper limit of normal.¹⁵ The proportion of patients with increases in Hb of ≥2 g/dL from baseline (any post-baseline value) was higher in patients treated with INVOKANA 100 mg and 300 mg vs placebo (6.0%, 5.5%, and 1.0%, respectively).⁵

In a phase 4, randomized, double-blind, placebo-controlled, parallel-group, 26-week, multicenter study evaluating the efficacy and safety of titrated INVOKANA in type 2 diabetes mellitus (T2DM) patients on stable combination therapy with metformin and sitagliptin (N=218), increases in Hb were reported in the INVOKANA group (4.4%) compared with placebo (0.2%).¹⁶ In addition, a greater proportion of patients met the predefined limits of change criterion of a ≥20 g/L increase from baseline with INVOKANA (6.5% [n=6]) vs placebo (0%).

Hb or Hct Changes Over 52 and 104 Weeks

Several studies^1,3,13,14 observed an increase in Hb, which generally occurred by week 12 and remained stable through week 52.⁷ In a 26-week study of older subjects with a 78-week double-blinded extension,¹⁷ the increase in Hb was maximal at week 52 and remained stable through week 104.⁷

Hb or Hct Changes Over 3 Months and Correlation With Changes in the Septal E/e′ Ratio

Matsutani et al (2018)⁶ conducted a prospective, single-center pilot study to evaluate the effects of additional treatment with INVOKANA on left ventricular diastolic function in patients with T2DM. A total of 37 patients with T2DM (25 males and 12 females) were recruited from outpatient centers in Japan and included in the analysis. The mean age was 64.2 years and 32.4% of patients had existing cardiovascular disease.

• Compared to baseline, statistically significant increases in Hb and Hct were observed after 3 months of treatment (see Table: Comparison of Hemoglobin and Hematocrit Levels Between Baseline and 3 Months After Treatment).
• INVOKANA was associated with significant improvement in left ventricular diastolic function (the early diastolic mitral inflow velocity to early diastolic septal mitral annulus velocity [septal E/e′] ratio of 13.7±3.5 to 12.1±2.8; P=0.001).
• Among the various parameters that changed throughout INVOKANA administration, only changes in Hb significantly correlated with changes in the septal E/e′ ratio (P=0.002).
• In multiple regression analysis, changes in Hb were also revealed to be an independent predictive factor for changes in the septal E/e′ ratio.

Hct and Hb Changes Over 6 Months: A Post Hoc Analysis

Nakatani et al (2023)^18,19 conducted a post hoc analysis of the multicenter, prospective, randomized, open-label, controlled CANDLE trial to assess the impact of INVOKANA vs glimepiride on Hct and Hb levels in patients with T2DM and heart failure (HF). A total of 226 patients (per-protocol population) with T2DM and HF were randomized to receive either INVOKANA 100 mg (n=109) or glimepiride 0.5 mg (n=117) once daily. The mean age was 68.8 years, and 75.2% of patients were male.

• After 24 weeks of randomization, the Hct level was significantly higher in the INVOKANA group than in the glimepiride group (0.434±0.057 vs 0.412±0.046; P=0.002).
• The difference in the Hct level between the INVOKANA vs glimepiride groups was evident at 1 month (0.422±0.048 vs 0.410±0.045; P=0.062) and was statistically significant at 3 months (0.435±0.051 vs 0.411±0.044; P<0.001) and 6 months (0.434±0.057 vs 0.412±0.046; P=0.002) after randomization.
• INVOKANA-treated patients exhibited a significantly greater change in both Hct difference (0.017±0.034 vs -0.002±0.024; P<0.001) and Hct ratio (1.044±0.090 vs 0.997±0.058; P<0.001) than glimepiride-treated patients.

MECHANISM FOR EFFECT ON HB OR HCT

It is postulated that increases in Hb or Hct are likely the result of hemoconcentration associated with the osmotic diuretic effects of canagliflozin.^5,20 Increases in Hct may be related not only to plasma volume reduction, but also tubulointerstitial recovery with erythropoietin production, possibly resulting in better oxygen transport.^8,21

POLYCYTHEMIA

Case Report

Das et al (2018)²² reported on a case of unmasking and aggravation of polycythemia vera by INVOKANA in a 51-year-old obese male patient with T2DM who was prescribed INVOKANA 100 mg for control of glycemia. Six months after INVOKANA initiation, the patient was presented with asymptomatic elevation of hemogram measurements (Hb: 16.9 g/dL, Hct: 55%, red cell number: 8.1 million/mm³, total leukocytes: 23,010/mm³, and platelet count: 9.7*10⁶/mm³). Laboratory testing revealed polycythemia vera-type myeloproliferative neoplasm. INVOKANA was discontinued and the patient was treated with aspirin and hydroxyurea. One month after INVOKANA discontinuation, a remarkable improvement in the patient’s hematological profile was observed, with no other significant intervention required. INVOKANA was subsequently restarted of the patient’s own accord, causing his hematological profile to again worsen. INVOKANA was subsequently stopped.

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 02 December 2024.