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SGLT2 Inhibitor

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SGLT2 Inhibitor, Sodium-Glucose Co-Transporter-2 Inhibitor, Sodium-Glucose Transporter 2, Invokana, Canagliflozin, Farxiga, Dapagliflozin, Ipragliflozin, Empagliflozin, Jardiance, Flozins, Steglatro, Ertugliflozin

  • 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
  • Mechanism
  1. Sodium-Glucose Transporter 2 (SGLT2) acts in the Kidneys to resorb Glucose
  2. SGLT2 Inhibitors allow more Glucose to remain in the urine without reabsorption
  • 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)
  • Efficacy
  1. Lowers Hemoglobin A1C 0.5 to 1%
  2. Decrease weight 5 lb
  • 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) has a 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]
  5. Empagliflozin (Jardiance) 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]
  6. Invokana (Canagliflozin) 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]
  • Disadvantages
  1. See adverse effects below (UTI, yeast infections, Fractures)
  2. Expensive ($10 per day or more than $250/month) - similar to Januvia costs
  3. Lower efficacy in moderate to severe renal Impairment
  • Contraindications
  1. Renal dysfunction
    1. GFR <60 ml/min: Avoid Farxiga (Dapagliflozin)
    2. GFR <45 ml/min: Avoid both Invokana (Canagliflozin) and Empagliflozin (Jardiance)
  • Adverse Effects
  1. Urinary Tract Infection
  2. Genital yeast infection
    1. Number needed to harm (NNH) 17 in women, 40 in men
  3. Diuretic effect
    1. Risk of dehydration, Orthostatic Hypotension
  4. LDL Cholesterol increase (4-8 mg/dl)
  5. Hyperkalemia
    1. When used in combination with ACE Inhibitors, Angiotensin Receptor Blockers or Potassium Sparing Diuretics
  6. Bladder Cancer increased risk
    1. Associated only with Farxiga
  7. Euglycemic Ketoacidosis
    1. See Euglycemic Ketoacidosis
  8. 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
  9. Acute Kidney Injury
    1. Seen with Canagliflozin (Invokana) and Dapagliflozin (Farxiga)
    2. http://www.fda.gov/Drugs/DrugSafety/ucm505860.htm
  10. Acute Pancreatitis
  11. Fournier's Gangrene
    1. https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm
  12. 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. FDA Drug Safety Communication
      1. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm
  • Dosing
  1. AM dosing is recommended due to Diuretic effect
  2. Taken 30 minutes before first meal of day
  • Resources
  1. Efficacy and safety of Canagliflozin
    1. http://onlinelibrary.wiley.com/doi/10.1111/dom.12054/pdf
  • References
  1. (2018) Presc Lett 25(2)
  2. (2016) Presc Lett 23(2): 8-9
  3. (2014) Presc Lett 21(10): 57
  4. (2013) Presc Lett 20(5): 28
  5. Nisly (2013)Am J Health-Syst Pharm 70 (4):311-9 [PubMed]
  6. Stenlof (2013) Diabetes Obes Metab 15(4): 372-82 [PubMed]