Invokana (Canagliflozin)
canagliflozin
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Type 2 diabetes mellitus — glycaemic control | Adults and paediatric patients ≥10 years | Adjunct to diet and exercise; mono- or combination therapy | FDA Approved |
| Cardiovascular risk reduction in T2DM with established CVD | Adults | Adjunctive (MACE reduction) | FDA Approved |
| Renal and cardiovascular outcomes in diabetic nephropathy | Adults with T2DM and albuminuria >300 mg/day | Adjunctive (reduction of ESKD, doubling of SCr, CV death, HF hospitalisation) | FDA Approved |
Canagliflozin was the first SGLT2 inhibitor approved in the United States (March 2013) and remains widely prescribed for type 2 diabetes with cardiorenal comorbidities. The CV indication is supported by the integrated CANVAS Program, while the renal indication is based on the landmark CREDENCE trial demonstrating a 30% relative risk reduction in the primary renal composite endpoint. In December 2024, the glycaemic control indication was expanded to include paediatric patients aged 10 years and older.
Heart failure with reduced or preserved ejection fraction (without diabetes): SGLT2 inhibitors as a class have strong evidence in HFrEF and HFpEF, but canagliflozin specifically does not carry an FDA-approved HF indication independent of diabetes. Evidence quality: Moderate (extrapolated from class-effect data and CANVAS sub-analyses).
Non-diabetic chronic kidney disease: Other SGLT2 inhibitors (dapagliflozin, empagliflozin) are approved for CKD irrespective of diabetes status, but canagliflozin’s CREDENCE data are specific to diabetic nephropathy. Evidence quality: Moderate.
Dosing
Adult and Paediatric (≥10 years) Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| T2DM — glycaemic control, initial therapy or add-on | 100 mg once daily | 100–300 mg once daily | 300 mg/day | Take before the first meal of the day; up-titration to 300 mg requires eGFR ≥60 Applies to adults and paediatric patients ≥10 years (FDA PI 12/2024) |
| CV risk reduction — T2DM with established atherosclerotic CVD | 100 mg once daily | 100 mg once daily | 100 mg/day | Based on CANVAS Program; no proven incremental CV benefit with 300 mg Continue regardless of HbA1c target achievement |
| Diabetic nephropathy — renal and CV outcome protection | 100 mg once daily | 100 mg once daily | 100 mg/day | Requires albuminuria >300 mg/day; may continue even if eGFR falls below 30 (CREDENCE protocol) Do not initiate if eGFR <30 |
| Concomitant UGT inducer use (e.g., rifampin, phenytoin) | 100 mg once daily | 200 mg once daily | 300 mg/day (eGFR ≥60); 200 mg/day (eGFR <60) | Increase dose in patients tolerating 100 mg; rifampin decreases canagliflozin AUC by ~51% |
| Peri-operative management | — | Withhold at least 3 days before surgery or procedures with prolonged fasting; resume when clinically stable and oral intake restored Glucosuria persists ~3 days after last dose (FDA PI) | ||
Renal Impairment Dosing
| eGFR (mL/min/1.73 m²) | Glycaemic Control Dose | Cardiorenal Protection Dose | Notes |
|---|---|---|---|
| ≥60 | 100–300 mg once daily | 100 mg once daily | Full dose range available |
| 30 to <60 | 100 mg once daily (max) | 100 mg once daily | Do not exceed 100 mg; glycaemic efficacy reduced but cardiorenal benefit maintained |
| <30 | Do not initiate | 100 mg once daily (may continue if already on therapy with albuminuria >300 mg/day) | Glycaemic benefit negligible; continue only for nephroprotective indication |
For the CV and renal indications, only the 100 mg dose is recommended. Higher doses do not provide additional cardiorenal benefit and carry incremental risk of volume depletion and amputation. Even as eGFR declines below 30, clinicians may continue canagliflozin 100 mg in patients who were already taking it for nephroprotection, as supported by the CREDENCE protocol. An initial eGFR dip of 10–15% is expected and typically stabilises within weeks; this should not prompt discontinuation.
Pharmacology
Mechanism of Action
Canagliflozin selectively inhibits sodium-glucose co-transporter 2 (SGLT2) located in the proximal renal tubule. Under normal physiology, SGLT2 is responsible for reabsorbing approximately 90% of filtered glucose. By blocking this transporter, canagliflozin lowers the renal threshold for glucose excretion (RTG) from approximately 180 mg/dL to 70–90 mg/dL, promoting urinary glucose elimination of roughly 100 g/day at therapeutic doses. This insulin-independent mechanism reduces plasma glucose, provides a modest caloric deficit (approximately 200–300 kcal/day), and induces osmotic diuresis and mild natriuresis. The resulting reduction in intraglomerular pressure—mediated through enhanced delivery of sodium to the macula densa and activation of tubuloglomerular feedback—is believed to underlie the nephroprotective effects observed in clinical trials. Additional cardiorenal benefits are thought to involve improved myocardial energetics, reduced preload, and favourable effects on neurohormonal activation.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax 1–2 h; bioavailability ~65%; food has no effect on AUC | Administer before breakfast to capture postprandial glucose via delayed intestinal absorption of glucose (local SGLT1 inhibition at higher doses) |
| Distribution | Vd 83.5 L; protein binding 99% (primarily albumin) | Extensively tissue-distributed; negligibly removed by haemodialysis due to high protein binding |
| Metabolism | Predominantly O-glucuronidation via UGT1A9 and UGT2B4; CYP3A4 oxidative metabolism ~7% | UGT inducers (rifampin, phenytoin) reduce canagliflozin exposure by ~51%; CYP3A4 interactions are not clinically significant |
| Elimination | Faecal 41.5%, renal 33% (30.5% as glucuronides, <1% unchanged); t½ 10.6 h (100 mg), 13.1 h (300 mg) | Dual elimination supports once-daily dosing; dose-proportional pharmacokinetics across 50–300 mg range |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Female genital mycotic infections | 10.4–11.4% (vs 3.2% placebo) | Vulvovaginal candidiasis most common; higher risk with prior history; most respond to standard topical antifungals |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Urinary tract infection | 4.3–5.9% (vs 4.0% placebo) | No significant increase in CREDENCE (renal population); serious UTIs including urosepsis are uncommon |
| Increased urination (pollakiuria, polyuria) | 4.6–5.3% (vs 0.8% placebo) | Related to osmotic diuresis; often self-limiting within weeks; counsel patients to expect this effect early in therapy |
| Male genital mycotic infections | 3.7–4.2% (vs 0.6% placebo) | Balanitis and balanoposthitis most common; higher risk in uncircumcised males; 22% recurrence rate on canagliflozin |
| Thirst | 2.3–2.8% (vs 0.2% placebo) | Reflects osmotic diuresis-driven volume contraction; encourage adequate fluid intake |
| Nausea | 2.2–2.3% (vs 1.5% placebo) | Usually mild and transient; rarely limits therapy |
| Constipation | 1.8–2.3% (vs 0.9% placebo) | May reflect mild dehydration; responds to increased fluid intake |
| Hypotension-related events (dizziness, orthostasis, syncope) | 2.8% (vs 1.5% placebo; CREDENCE) | Higher incidence in patients ≥65 years, eGFR <60, or on loop diuretics; assess and correct volume status before initiation |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Lower limb amputation | 5.9 per 1,000 pt-yrs (CANVAS) | Median follow-up ~5.7 years; risk present from early treatment | Assess risk factors (prior amputation, PVD, neuropathy, foot ulcers) before initiation; monitor feet regularly; discontinue if lower limb infection, ulcer, or gangrene develops |
| Diabetic ketoacidosis (euglycaemic or hyperglycaemic) | 0.5% (CREDENCE; 0.21/100 pt-yrs) | Any time; higher risk in perioperative settings, illness, reduced caloric intake | Discontinue immediately if suspected; assess ketones regardless of glucose level (may be <250 mg/dL); withhold ≥3 days before surgery |
| Acute kidney injury | Uncommon (<1%) | Typically within first month; often related to volume depletion | Correct volume depletion before starting; hold during acute illness, dehydration, or concurrent nephrotoxin exposure |
| Necrotising fasciitis of the perineum (Fournier’s gangrene) | Very rare (post-marketing; 12 cases across all SGLT2i in 5 years) | Median ~9 months (range 7 days to 25 months) | Urgent surgical assessment; discontinue canagliflozin; initiate broad-spectrum antibiotics; surgical debridement as indicated |
| Bone fracture | Uncommon; increased vs placebo in CANVAS | As early as 12 weeks after initiation | Assess fracture risk factors before initiation; consider BMD if at risk; associated with dose-dependent BMD decline at hip and lower spine |
| Anaphylaxis / angioedema | Rare (post-marketing) | Hours to days after first dose | Discontinue permanently; treat per anaphylaxis protocol; canagliflozin is contraindicated after serious hypersensitivity |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Female genital mycotic infections | 0.7% | Pooled placebo-controlled glycaemic control trials (vs 0% placebo) |
| Male genital mycotic infections | 0.5% | Pooled placebo-controlled trials (vs 0% placebo); phimosis reported in 0.3% of uncircumcised males |
| Renal-related adverse events | 1.2–1.6% | 100 mg and 300 mg groups respectively; vs 1.0% placebo (patients with moderate renal impairment at baseline) |
Genital mycotic infections are the most common reason for SGLT2 inhibitor discontinuation despite being clinically manageable. Risk-reduction strategies include advising patients on genital hygiene, recommending cotton undergarments, and encouraging early treatment with topical azole antifungals. Patients with a history of recurrent candidiasis may benefit from prophylactic single-dose oral fluconazole at treatment initiation (off-label). The absolute risk increase is outweighed by cardiorenal benefits in most clinical scenarios.
Drug Interactions
Canagliflozin is primarily metabolised by UGT1A9 and UGT2B4 with minimal CYP3A4 involvement. It is a weak inhibitor of P-glycoprotein and a substrate of P-gp. Clinically significant interactions are relatively few but include UGT enzyme inducers and drugs affected by volume shifts.
Monitoring
-
Renal Function (eGFR)
Baseline, then as clinically indicated
Routine Required before initiation to guide dosing. An initial eGFR dip of 10–15% is expected with SGLT2 inhibitors and is haemodynamically mediated; it does not warrant discontinuation. Reassess if clinically indicated (e.g., acute illness, addition of nephrotoxins). -
HbA1c
Every 3–6 months
Routine Monitor glycaemic control. Note that canagliflozin may be continued for cardiorenal indications even if HbA1c is at target; do not discontinue solely on the basis of normalised glucose levels. -
Blood Pressure
Each clinic visit
Routine Canagliflozin produces placebo-adjusted SBP reductions of 3.7–5.4 mmHg. Review antihypertensive regimen and consider dose reduction if symptomatic hypotension develops, especially in elderly patients or those on loop diuretics. -
Volume Status
Baseline and ongoing
Routine Assess for dehydration, orthostatic hypotension, and dizziness. Correct volume depletion before initiation, particularly in patients with eGFR <60, age ≥65, or on concomitant diuretics. -
Serum Potassium
Baseline, then periodically
Trigger-based Monitor in patients with renal impairment or those on ACE inhibitors, ARBs, potassium-sparing diuretics, or finerenone. Severe hyperkalaemia (≥6.5 mEq/L) reported in up to 1.3% with 300 mg in moderate renal impairment. -
Lipid Panel
Periodically
Routine Dose-related increases in LDL (4.5–8.0%) and non-HDL cholesterol (1.5–3.6%) observed. Assess whether statin therapy adjustments are needed. -
Lower Limb Assessment
Each clinic visit
Routine Inspect feet for infection, ulcers, sores, and tenderness. Counsel patients on preventive foot care. Discontinue if infection, gangrene, or diabetic foot ulcer develops. -
Ketones
Clinically indicated
Trigger-based Check blood or urine ketones if patient presents with nausea, vomiting, abdominal pain, malaise, or dyspnoea, regardless of blood glucose level. Maintain high index of suspicion for euglycaemic DKA. -
Haemoglobin / Haematocrit
Periodically
Trigger-based Canagliflozin causes haemoconcentration; mean haemoglobin increases of 3–4%. Monitor if patient has polycythaemia or is receiving erythropoiesis-stimulating agents.
Contraindications & Cautions
Absolute Contraindications
- Serious hypersensitivity to canagliflozin (anaphylaxis, angioedema, or severe cutaneous reactions). Canagliflozin is permanently contraindicated after a documented serious hypersensitivity reaction.
- Type 1 diabetes mellitus for glycaemic control (markedly increased DKA risk without proven benefit).
Relative Contraindications (Specialist Input Recommended)
- eGFR <30 mL/min/1.73 m² (for new initiation) — glycaemic efficacy is negligible. However, patients already established on canagliflozin with albuminuria >300 mg/day may continue for nephroprotective indication under specialist guidance.
- Severe hepatic impairment (Child-Pugh C) — not studied; use is not recommended (FDA PI).
- Active diabetic foot ulcer, gangrene, or osteomyelitis — increased amputation risk (CANVAS data); defer initiation until resolved.
- Pregnancy (2nd and 3rd trimester) — juvenile animal studies showed irreversible renal tubular dilatation at exposures 0.5-times the clinical dose; use appropriate contraception.
- Recurrent DKA or history of ketosis-prone diabetes — canagliflozin exacerbates ketoacidosis risk, particularly with insulin dose reductions or reduced caloric intake.
Use with Caution
- Elderly patients (≥65 years) — higher incidence of volume depletion events, particularly with 300 mg dose and in those ≥75 years.
- Concurrent loop diuretic therapy — additive volume depletion; assess and correct volume status before initiation.
- Patients at high fracture risk — BMD reduction at hip and lumbar spine observed; fractures may occur as early as 12 weeks.
- Recurrent genital mycotic infections — higher infection rates; counsel on hygiene and have treatment plan ready.
- Patients on insulin or sulfonylureas — increased hypoglycaemia risk; consider pre-emptive dose reduction of the insulin or secretagogue.
An approximately 2-fold increased risk of lower limb amputations was observed with canagliflozin compared to placebo in the CANVAS and CANVAS-R trials (5.9 vs 2.8 and 7.5 vs 4.2 events per 1,000 patient-years, respectively). Toe and midfoot amputations were most common, but below-knee and above-knee amputations also occurred. The FDA boxed warning for amputation was added in 2017 and subsequently removed in August 2020; however, the risk remains documented in the Warnings and Precautions section of the current label. Clinicians should assess amputation risk factors before prescribing and ensure ongoing foot surveillance.
DKA, including fatal cases, has been reported in patients with type 2 diabetes receiving SGLT2 inhibitors. Blood glucose at presentation may be below 250 mg/dL (euglycaemic DKA). Urinary glucose excretion persists for approximately 3 days after the last dose, but post-marketing reports describe ketoacidosis persisting beyond 6 days and up to 2 weeks after discontinuation. Withhold canagliflozin at least 3 days before scheduled surgery.
Patient Counselling
Purpose of Therapy
Canagliflozin works by helping the kidneys remove excess sugar through the urine, which lowers blood sugar levels and provides additional protection for the heart and kidneys. In patients with diabetes-related kidney disease or cardiovascular disease, canagliflozin can reduce the risk of kidney failure, heart attacks, strokes, and hospitalisations for heart failure. It is taken as a tablet once daily before the first meal of the day.
How to Take
Take canagliflozin once daily before your first meal of the day. Swallow the tablet whole. If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Do not double up. Stay well hydrated throughout the day. Do not stop taking canagliflozin without discussing with your prescriber, even if your blood sugar levels are well controlled, as the heart and kidney benefits continue independently of glucose lowering.
Sources
- INVOKANA (canagliflozin) tablets prescribing information. Janssen Pharmaceuticals, Inc. Revised 12/2024. DailyMed Label Primary source for all dosing, indications, adverse reactions, pharmacokinetic parameters, and contraindications cited in this monograph.
- FDA Supplemental Approval for Pediatric Indication. NDA 204042. December 2024. FDA Review Document Supporting evidence for the paediatric expansion to patients aged 10 years and older, including Study DIA3018 efficacy data.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925 Integrated CANVAS Program analysis establishing cardiovascular benefit (MACE reduction) and identifying the amputation safety signal.
- Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi:10.1056/NEJMoa1811744 CREDENCE trial demonstrating 30% relative risk reduction in the primary renal composite endpoint, stopped early for efficacy.
- Mahaffey KW, Neal B, Perkovic V, et al. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program. Circulation. 2018;137(4):323-334. doi:10.1161/CIRCULATIONAHA.117.032038 Subgroup analysis of CANVAS demonstrating consistent CV benefit across primary and secondary prevention populations.
- American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes — 2025. Diabetes Care. 2025;48(Suppl 1). doi:10.2337/dc25-SINT Positions SGLT2 inhibitors as preferred agents in T2DM with established CVD, heart failure, or CKD, independent of HbA1c.
- KDIGO 2024 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2024;106(5S):S1-S127. doi:10.1016/j.kint.2024.06.024 Recommends SGLT2 inhibitors as first-line cardiorenal therapy in T2DM with CKD alongside metformin and RAS blockade.
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063 Provides class I recommendation for SGLT2 inhibitors in HFrEF and HFpEF with comorbid T2DM.
- Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017;60(2):215-225. doi:10.1007/s00125-016-4157-3 Comprehensive review of tubuloglomerular feedback and haemodynamic mechanisms underlying SGLT2 inhibitor nephroprotection.
- Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108-2117. doi:10.1007/s00125-018-4670-7 Explores proposed cardiorenal benefit pathways including natriuresis, ketone body utilisation, and reduction in epicardial fat.
- Devineni D, Curtin CR, Polidori D, et al. Pharmacokinetics and Pharmacodynamics of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, in Subjects With Type 2 Diabetes Mellitus. J Clin Pharmacol. 2013;53(6):601-610. doi:10.1002/jcph.88 Phase I PK/PD study establishing dose-proportional pharmacokinetics, renal threshold suppression, and urinary glucose excretion profiles.
- Devineni D, Vaccaro N, Murphy J, et al. Effects of Rifampin, Cyclosporine A, and Probenecid on the Pharmacokinetic Profile of Canagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Healthy Participants. Int J Clin Pharmacol Ther. 2015;53(2):115-128. doi:10.5414/CP202158 Drug interaction study quantifying the 51% AUC reduction with rifampin co-administration and guiding UGT inducer dose adjustments.