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
  2. SGLT2 Inhibitors allow more Glucose to remain in the urine without reabsorption

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. Efficacy

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

VI. 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]

VII. 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

VIII. Contraindications

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

IX. 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 (may result in dehydration)
  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. Presents with Nausea, Vomiting, Fatigue, confusion (as early as first 2 weeks of starting medication)
    2. Occurred in 73 reported cases in 2 years for patients with Serum Glucose <250 mg/dl
    3. Increased risk with renal Impairment (as well as dehydration, acute illness)
      1. Avoid Farxiga (Dapagliflozin) if GFR <60 ml/min
      2. Avoid Invokana (Canagliflozin) and Jardiance (Empagliflozin) if GFR <45 ml/min
    4. FDA
      1. http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm
  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

X. Dosing

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

XI. Resources

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

XII. 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]

Images: Related links to external sites (from Bing)

Related Studies (from Trip Database) Open in New Window

Cost: Medications

invokana (on 3/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
INVOKANA 100 MG TABLET $13.70 each
INVOKANA 300 MG TABLET $13.70 each
farxiga (on 3/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
FARXIGA 10 MG TABLET $13.78 each
FARXIGA 5 MG TABLET $13.79 each
jardiance (on 5/17/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
JARDIANCE 10 MG TABLET $13.78 each
JARDIANCE 25 MG TABLET $13.83 each

Ontology: Sodium-Glucose Transporter 2 (C1565154)

Definition (MSH) A sodium-glucose transporter that is expressed in the luminal membrane of the PROXIMAL KIDNEY TUBULES.
Concepts Amino Acid, Peptide, or Protein (T116) , Biologically Active Substance (T123)
MSH D051297
Italian Trasportatore sodio-glucosio 2
English Sodium-Glucose Transporter 2, SODIUM GLUCOSE TRANSPORTER 002, Sodium-Glucose Transporter 2 [Chemical/Ingredient], SGLT2 Protein, SLC5A2 Protein, Sodium Glucose Transporter 2
Czech transportér 2 pro sodík a glukosu
Finnish Natrium-glukoosin kuljettaja 2
Japanese ナトリウム-グルコーストランスポーター2, ナトリウム-グルコース輸送体2, グルコースナトリウム輸送体2, ナトリウム-グルコース共輸送体2, ナトリウム-ブドウ糖共輸送体2, グルコース-ナトリウム共輸送体2, ナトリウム依存性グルコース共輸送体2, グルコースナトリウムトランスポーター2
French Transporteur-2 sodium-glucose, Cotransporteur de glucose sodium-dépendant de type 2, SGLT2, Protéine SGLT2, Protéine SLC5A2, Transporteur SGLT2, Transporteur SLC5A2
Swedish Sodium-Glucose Transporter 2
Polish Transporter 2 sodowo-glukozowy
Portuguese Transportador de Sódio-Glucose, 2, Transportador 2 de Sódio-Glucose, Transportador de Glucose-Sódio, 2, Transportador 2 de Glucose-Sódio
German Natrium-Glucose-Transporter 2, SGLT2-Protein, SLC5A2-Protein
Spanish Transportador 2 de Sodio-Glucosa

Ontology: canagliflozin (C2974540)

Definition (NCI) A C-glucoside with a thiophene ring that is an orally available inhibitor of sodium-glucose transporter 2 (SGLT2) with antihyperglycemic activity. Canagliflozin is also able to reduce body weight and has a low risk for hypoglycemia.
Concepts Carbohydrate (T118) , Pharmacologic Substance (T121)
MSH C552334
SnomedCT 703676004, 703681008
English canagliflozin, 1-(glucopyranosyl)-4-methyl-3-(5-(4-fluorophenyl)-2-thienylmethyl)benzene, CANAGLIFLOZIN, canagliflozin (medication), antidiabetics canagliflozin, Canagliflozin (substance), Canagliflozin (product), Canagliflozin