II. Indications

  1. Type 2 Diabetes Mellitus Management (second-line or third-line agent)
    1. Prefer other second-line agents with longer track record and lesser expense have been exhausted

III. Mechanism

  1. Sodium-Glucose Transporter 2 (SGLT2) acts in the Kidneys to resorb Glucose at the proximal tubules
  2. SGLT2 Inhibitors allow more Glucose to remain in the urine without reabsorption, resulting in osmotic diuresis

IV. Preparations

  1. Invokana (Canagliflozin, released 2013)
    1. Start: 100 mg orally daily
    2. Maximum: 300 mg orally daily (avoid if GFR <60 ml/min)
  2. Farxiga (Dapagliflozin)
  3. Ipragliflozin
  4. Empagliflozin (Jardiance)
  5. Ertugliflozin (Steglatro)

V. Pharmacokinetics

  1. SGLT2 Inhibitors share similar Pharmacokinetics
  2. Rapid absorption and peak activity within 2 hours
  3. Half-Life 3-6 hours
  4. Renal excretion (90%) with minimal metabolism
  5. Toxic dose >5 g in adults (>100 mg/kg in children)
    1. Evaluate for Dehydration, Polyuria, Hypotension and initiate fluid Resuscitation
    2. Evaluate for Ketoacidosis (Anion Gap Metabolic Acidosis, Serum Ketones)

VI. Efficacy

  1. Lowers Hemoglobin A1C 0.5 to 1%
  2. Decrease weight 5 lb

VII. Advantages

  1. May lower weight up to 4 to 7 pounds (via diuresis)
  2. May lower Blood Pressure by 3-5 mmHg (via similar mechanism to weight)
  3. Low risk of Hypoglycemia
  4. Empagliflozin (Jardiance)
    1. Heart Failure with Reduced Ejection Fraction
      1. Jardiance is associated with a decreased hospitalization and CV death rate when taken over 16 months (NNT 14)
      2. Packer (2020) N Engl J Med 383:1413-24 [PubMed]
    2. Heart Failure with Preserved Ejection Fraction
      1. Appears effective in reducing hospitalizations even in non-Diabetic patients with HFpEF
      2. However, best effect in reduced Ejection Fraction (even mild reduction of 40-50% EF)
      3. Anker (2021) N Engl J Med [PubMed]
    3. Modest reduction in overall mortality (NNT 39) and cardiovascular death (NNT 45) over 3 years
      1. Invokana may also lower cardiovascular event risk (NNT 333), but unlike Jardiance does not reduce mortality
      2. Zinman (2015) N Engl J Med 373(22):2117-28 +PMID:26378978 [PubMed]
    4. May slow Diabetic Nephropathy when combined with ACE Inhibitor or ARB
      1. May reduce hypoalbuminuria (NNT 20), but marginal effect on delaying Dialysis (NNT 333)
      2. Wanner (2016) N Engl J Med 375(4):323-34 [PubMed]
  5. Invokana (Canagliflozin)
    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]
  6. Dapagliflozin (Farxiga)
    1. Chronic Kidney Disease (CKD)
      1. Slows CKD progression or reduces risk of CV or renal death (NNT 19)
      2. Heerspink (2020) N Engl J Med 383:1436-46 [PubMed]

VIII. Disadvantages

  1. See adverse effects below (UTI, yeast infections, Fractures)
  2. Expensive ($10 per day or more than $250 to 500 per month)
  3. Lower efficacy in moderate to severe renal Impairment

IX. Contraindications

  1. Renal dysfunction
    1. GFR <60 ml/min: Avoid Farxiga (Dapagliflozin)
    2. GFR <45 ml/min: Avoid both Invokana (Canagliflozin) and Empagliflozin (Jardiance)

X. 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
  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

XI. Dosing

  1. AM dosing is recommended due to Diuretic effect
  2. Taken 30 minutes before first meal of day

XII. Resources

  1. Efficacy and safety of Canagliflozin
    1. http://onlinelibrary.wiley.com/doi/10.1111/dom.12054/pdf

XIII. 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]

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Cost: Medications

invokana (on 4/20/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
INVOKANA 100 MG TABLET Generic $0.00 each
INVOKANA 300 MG TABLET Generic $0.00 each
farxiga (on 1/1/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
FARXIGA 10 MG TABLET Generic $0.00 each
FARXIGA 5 MG TABLET Generic $0.00 each
jardiance (on 1/1/2023 at Medicaid.Gov Survey of pharmacy drug pricing)
JARDIANCE 10 MG TABLET Generic $0.00 each
JARDIANCE 25 MG TABLET Generic $0.00 each
steglatro (on 1/6/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
STEGLATRO 15 MG TABLET Generic $0.00 each
STEGLATRO 5 MG TABLET Generic $0.00 each