II. Indications
-
Type 2 Diabetes Mellitus Management (second-line or third-line agent)
- Prefer other second-line agents with longer track record and lesser expense have been exhausted
III. Mechanism
IV. Preparations
- Invokana (Canagliflozin, released 2013)
- Start: 100 mg orally daily
- Maximum: 300 mg orally daily (avoid if GFR <60 ml/min)
- Farxiga (Dapagliflozin)
- Ipragliflozin
- Empagliflozin (Jardiance)
- Ertugliflozin (Steglatro)
V. Efficacy
- Lowers Hemoglobin A1C 0.5 to 1%
- Decrease weight 5 lb
VI. Advantages
- May lower weight up to 4 to 7 pounds (via diuresis)
- May lower Blood Pressure by 3-5 mmHg (via similar mechanism to weight)
- Low risk of Hypoglycemia
- Empagliflozin (Jardiance)
- Heart Failure with Reduced Ejection Fraction
- Jardiance is associated with a decreased hospitalization and CV death rate when taken over 16 months (NNT 14)
- Packer (2020) N Engl J Med 383:1413-24 [PubMed]
- Modest reduction in overall mortality (NNT 39) and cardiovascular death (NNT 45) over 3 years
- Invokana may also lower cardiovascular event risk (NNT 333), but unlike Jardiance does not reduce mortality
- Zinman (2015) N Engl J Med 373(22):2117-28 +PMID:26378978 [PubMed]
- May slow Diabetic Nephropathy when combined with ACE Inhibitor or ARB
- May reduce hypoalbuminuria (NNT 20), but marginal effect on delaying Dialysis (NNT 333)
- Wanner (2016) N Engl J Med 375(4):323-34 [PubMed]
- Heart Failure with Reduced Ejection Fraction
- Invokana (Canagliflozin)
- Delays Chronic Kidney Disease progression (likely a class effect)
- When taken for 2.5 years, delays Serum Creatinine doubling in those with GFR <60 ml/min (NNT 31)
- Balance with the risk of Acute Kidney Injury in those dehydrated while taking SGLT2 Inhibitors
- Perkovic (2019) N Engl J Med +PMID: 30990260 [PubMed]
- Delays Chronic Kidney Disease progression (likely a class effect)
- Dapagliflozin (Farxiga)
- Chronic Kidney Disease (CKD)
- Slows CKD progression or reduces risk of CV or renal death (NNT 19)
- Heerspink (2020) N Engl J Med 383:1436-46 [PubMed]
- Chronic Kidney Disease (CKD)
VII. Disadvantages
- See adverse effects below (UTI, yeast infections, Fractures)
- Expensive ($10 per day or more than $250 to 500 per month)
- Lower efficacy in moderate to severe renal Impairment
VIII. Contraindications
- Renal dysfunction
- GFR <60 ml/min: Avoid Farxiga (Dapagliflozin)
- GFR <45 ml/min: Avoid both Invokana (Canagliflozin) and Empagliflozin (Jardiance)
IX. Adverse Effects
- Perioperative Recommendations
- See Preoperative Guidelines for Medications Prior to Surgery
- Stop SGLT2 Inhibitors 3 days before surgery (due to Euglycemic Ketoacidosis risk)
- Restart SGLT2 Inhibitors post-operatively when oral intake returns to normal
- Urinary Tract Infection
- Genital yeast infection
- Number needed to harm (NNH) 17 in women, 40 in men
- Fournier's Gangrene
- Euglycemic Ketoacidosis
-
Diuretic effect
- Risk of dehydration, Orthostatic Hypotension
- Risk of Acute Kidney Injury (see below)
-
Acute Kidney Injury
- Seen with Canagliflozin (Invokana) and Dapagliflozin (Farxiga), but likely a class effect due to diuresis
- Higher risk when combined with ACE Inhibitors (and ARBs), NSAIDs and Diuretics and esp. in elderly
- Avoid hypovolemia, and consider lowering Diuretic dose when on SGLT2 Inhibitor
- Check Serum Creatinine before initiating agent, 10-14 days later and again with dose increase
- Stop and hold the SGLT2 Inhibitor Serum Creatinine rises >30%
- http://www.fda.gov/Drugs/DrugSafety/ucm505860.htm
-
Hyperkalemia
- When used in combination with ACE Inhibitors, Angiotensin Receptor Blockers or Potassium Sparing Diuretics
- LDL Cholesterol increase (4-8 mg/dl)
-
Bladder Cancer increased risk
- Associated only with Farxiga
-
Fractures
- Upper extremity Fractures most common (and not caused by major Trauma)
- Number needed to harm 125 for one additional Fracture with Invokana over 18 months of use
- Invokana and for those with Renal Insufficiency, Farxiga, have been associated with increased risk
- Unknown mechanism (possibly decreased Bone Mineral Density, increased fall risk)
- http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm
- Acute Pancreatitis
- Amputation Risk
- Canagliflozin associated with increased risk of amputations
- Relative Risk: 2.0 (risk of 6 amputations per 1000 on Canagliflozin)
- May be a SGLT2 Inhibitor class effect (unclear mechanism)
- See Amputation Prevention in Diabetes Mellitus
- FDA Drug Safety Communication
X. Dosing
- AM dosing is recommended due to Diuretic effect
- Taken 30 minutes before first meal of day
XI. Resources
- Efficacy and safety of Canagliflozin
XII. References
- (2020) Presc Lett 27(12): 68
- (2020) Presc Lett 27(5): 26
- (2018) Presc Lett 25(2)
- (2016) Presc Lett 23(2): 8-9
- (2014) Presc Lett 21(10): 57
- (2013) Presc Lett 20(5): 28
- Nisly (2013)Am J Health-Syst Pharm 70 (4):311-9 [PubMed]
- Stenlof (2013) Diabetes Obes Metab 15(4): 372-82 [PubMed]
Images: Related links to external sites (from Bing)
Related Studies
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 |
Russian | НАТРИЙ-ГЛЮКОЗНЫЙ ТРАНСПОРТЕР 2, NATRII-GLIUKOZNYI TRANSPORTER 2, NATRII-GLIUKOZY TRANSPORTER 2, НАТРИЙ-ГЛЮКОЗЫ ТРАНСПОРТЕР 2 |
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 |