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Canagliflozin

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Canagliflozin, Invokana

  • See Also
  1. SGLT2 Inhibitor
  2. Type II Diabetes Medications
  3. Dapagliflozin
  4. Empagliflozin
  5. Ertugliflozin
  6. Sotagliflozin
  7. Bexagliflozin
  • Indications
  1. Type 2 Diabetes Mellitus Management
    1. Comorbid Chronic Kidney Disease or Microalbuminuria
    2. Comorbid Congestive Heart Failure
  2. Like GLP-1 Agonists, SGLT2 Inhibitors have moved to first-line agents for their effects on conditions comorbid to Diabetes
    1. SGLT2 Inhibitors (as with GLP-1 Agonists) may assist with weight loss in Obesity
    2. SGLT2 Inhibitors (as with GLP-1 Agonists) decrease Cardiovascular Risk
      1. Best evidence for Empagliflozin (Jardiance)
    3. SGLT2 Inhibitors (as with GLP-1 Agonists) decrease Chronic Kidney Disease progression
      1. Best evidence for Empagliflozin (Jardiance), Canagliflozin (Invokana), Dapagliflozin (Farxiga)
  • Contraindications
  1. Type 1 Diabetes Mellitus
  2. Renal dysfunction: GFR <30 ml/min
    1. Originally not recommended if GFR <45 ml/min
  3. Other relative contraindications (use with caution)
    1. Diabetic Ketoacidosis (relative contraindication)
    2. Osteoporosis or Osteopenia (low Bone Mineral Density)
    3. Diabetic Foot Wound (Neuropathic Foot Ulcer)
  4. Perioperative status (or prolonged Fasting, Dehydration)
    1. Hold for at least 3 to 4 days before major surgery
  • Mechanism
  1. Sodium-Glucose Transporter 2 (SGLT2)
    1. SGLT2 acts in the Kidneys to resorb Glucose at the proximal tubules
    2. SGLT2 mediates 90% of renal Glucose reabsorption from the tubules
  2. SGLT2 Inhibitors
    1. Blocks SGLT2, Allowing more Glucose to remain in the urine without reabsorption
    2. Results in osmotic diuresis
    3. Efficacy is lower when GFR is decreased
  • Medications
  1. Canagliflozin (Invokana)
  • Dosing
  1. AM dosing is recommended due to Diuretic effect
  2. Taken 30 minutes before first meal of day
  3. Avoid in Dehydration
  4. Start: 100 mg orally daily
  5. Maximum: 300 mg orally daily
    1. Avoid 300 mg dose if GFR <60 ml/min
  • Pharmacokinetics
  1. See SGLT2 Inhibitor
  2. SGLT2 Inhibitors share similar Pharmacokinetics
  3. Rapid absorption and peak activity within 1-2 hours
  4. Half-Life 10 hours (100 mg dose) to 13 hours (300 mg dose)
  • Efficacy
  1. Class Effects
    1. Lower efficacy in moderate to severe renal Impairment
    2. May lower Blood Pressure by 3-5 mmHg (via similar mechanism to weight)
    3. May lower weight up to 4 to 7 pounds (via diuresis)
    4. Decrease Cardiovascular Risk
    5. Decrease Chronic Kidney Disease progression
    6. Lowers Hemoglobin A1C 0.5 to 1%
      1. Glucose lowering effect decreases with lower GFR
      2. Low risk of Hypoglycemia
  2. Invokana (Canagliflozin) specific effects
    1. Delays Chronic Kidney Disease progression (likely a class effect)
      1. When taken for 2.5 years, delays Serum Creatinine doubling in those with GFR <60 ml/min (NNT 31)
      2. Balance with the risk of Acute Kidney Injury in those dehydrated while taking SGLT2 Inhibitors
      3. Perkovic (2019) N Engl J Med +PMID: 30990260 [PubMed]
  • Adverse Effects
  1. Perioperative Recommendations
    1. See Preoperative Guidelines for Medications Prior to Surgery
    2. Stop SGLT2 Inhibitors 3 days before surgery (due to Euglycemic Ketoacidosis risk)
    3. Restart SGLT2 Inhibitors post-operatively when oral intake returns to normal
  2. Urinary Tract Infection
  3. Genital yeast infection
    1. Number needed to harm (NNH) 17 in women, 40 in men
  4. Fournier's Gangrene
    1. https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm
  5. Euglycemic Ketoacidosis
    1. See Euglycemic Ketoacidosis
    2. Presents with Anion Gap Metabolic Acidosis (Ketoacidosis despite normal Serum Glucose)
  6. Diuretic effect
    1. Risk of Dehydration, Orthostatic Hypotension
    2. Risk of Acute Kidney Injury (see below)
  7. Acute Kidney Injury
    1. Seen with Canagliflozin (Invokana) and Dapagliflozin (Farxiga), but likely a class effect due to diuresis
    2. Higher risk when combined with ACE Inhibitors (and ARBs), NSAIDs and Diuretics and esp. in elderly
    3. Avoid Hypovolemia, and consider lowering Diuretic dose when on SGLT2 Inhibitor
    4. Check Serum Creatinine before initiating agent, 10-14 days later and again with dose increase
      1. Stop and hold the SGLT2 Inhibitor Serum Creatinine rises >30%
    5. http://www.fda.gov/Drugs/DrugSafety/ucm505860.htm
  8. Hyperkalemia
    1. When used in combination with ACE Inhibitors, Angiotensin Receptor Blockers or Potassium Sparing Diuretics
    2. May also decrease Serum Potassium
  9. LDL Cholesterol increase (4-8 mg/dl)
  10. Bladder Cancer increased risk
    1. Associated only with Farxiga
  11. Fractures
    1. Upper extremity Fractures most common (and not caused by major Trauma)
    2. Number needed to harm 125 for one additional Fracture with Invokana over 18 months of use
    3. Invokana and for those with Renal Insufficiency, Farxiga, have been associated with increased risk
    4. Unknown mechanism (possibly decreased Bone Mineral Density, increased Fall Risk)
    5. http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm
  12. Acute Pancreatitis
  13. Amputation Risk
    1. Canagliflozin associated with increased risk of amputations
    2. Relative Risk: 2.0 (risk of 6 amputations per 1000 on Canagliflozin)
    3. May be a SGLT2 Inhibitor class effect (unclear mechanism)
    4. See Amputation Prevention in Diabetes Mellitus
    5. FDA Drug Safety Communication
      1. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm
  • Safety
  1. Avoid in Lactation
  2. Pregnancy
    1. Unknown safety in first trimester
    2. Avoid in second and third trimester
  3. Monitoring
    1. Renal Function
  • Resources
  1. Canagliflozin (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3
  2. Efficacy and safety of Canagliflozin
    1. http://onlinelibrary.wiley.com/doi/10.1111/dom.12054/pdf
    2. Stenlöf (2013 )Diabetes Obes Metab 15(4):372-82 +PMID: 23279307 [PubMed]
  • References
  1. (2020) Presc Lett 27(12): 68
  2. (2020) Presc Lett 27(5): 26
  3. (2018) Presc Lett 25(2)
  4. (2016) Presc Lett 23(2): 8-9
  5. (2014) Presc Lett 21(10): 57
  6. (2013) Presc Lett 20(5): 28
  7. Tomaszewski (2022) Crit Dec Emerg Med 36(11): 32
  8. Nisly (2013)Am J Health-Syst Pharm 70 (4):311-9 [PubMed]
  9. Stenlof (2013) Diabetes Obes Metab 15(4): 372-82 [PubMed]
  10. Vaughan (2024) Am Fam Physician 109(4): 333-42 [PubMed]