II. Indications
-
Type 2 Diabetes Mellitus Management
- Comorbid Chronic Kidney Disease or Microalbuminuria
- Comorbid Congestive Heart Failure
- Like GLP-1 Agonists, SGLT2 Inhibitors have moved to first-line agents for their effects on conditions comorbid to Diabetes
- SGLT2 Inhibitors (as with GLP-1 Agonists) may assist with weight loss in Obesity
- SGLT2 Inhibitors (as with GLP-1 Agonists) decrease Cardiovascular Risk
- Best evidence for Empagliflozin (Jardiance)
- SGLT2 Inhibitors (as with GLP-1 Agonists) decrease Chronic Kidney Disease progression
- Best evidence for Empagliflozin (Jardiance), Canagliflozin (Invokana), Dapagliflozin (Farxiga)
III. Contraindications
- Type 1 Diabetes Mellitus
- Renal dysfunction (CKD Stage 4 or 5, GFR <30 ml/min)
- Other relative contraindications (use with caution)
- Diabetic Ketoacidosis (relative contraindication)
- Osteoporosis or Osteopenia (low Bone Mineral Density)
- Diabetic Foot Wound (Neuropathic Foot Ulcer)
- Perioperative status (or prolonged Fasting, Dehydration)
- Hold for at least 3 to 4 days before major surgery
IV. Mechanism
- See SGLT2 Inhibitor
- Sodium-Glucose Transporter 2 (SGLT2)
-
SGLT2 Inhibitors
- Blocks SGLT2, Allowing more Glucose to remain in the urine without reabsorption
- Results in osmotic diuresis
- Efficacy is lower when GFR is decreased
V. Medications
- Bexagliflozin (Brenzavvy)
- Released in 2023 at $50/month (compared with other SGLT2 Inhibitors costing $600/month)
- May not be initially covered by insurance, resulting in cost higher than other agent copays
- (2023) Presc Lett 30(9): 51
- Released in 2023 at $50/month (compared with other SGLT2 Inhibitors costing $600/month)
VI. Dosing
- AM dosing is recommended due to Diuretic effect
- Taken 30 minutes before first meal of day
- Avoid in Dehydration
- Start 20 mg orally once daily in the morning
VII. Pharmacokinetics: Class Effects
- See SGLT2 Inhibitor
- SGLT2 Inhibitors share similar Pharmacokinetics
- Rapid absorption and peak activity within 2-4 hours
- Teminal Half-Life 12 hours
VIII. Efficacy
- Similar efficacy to other agents (lowers Hgb A1c 0.5%)
- All SGLT2 Inhibitors have lower efficacy in moderate to severe renal Impairment
- Other beneficial class effects that may occur
- Decrease weight 5 lb
- May lower weight up to 4 to 7 pounds (mean 5 lb, via diuresis)
- May lower Blood Pressure by 3-5 mmHg (via similar mechanism to weight)
- May decrease Cardiovascular Risk
- May decrease Chronic Kidney Disease progression
- Low risk of Hypoglycemia
IX. Adverse Effects
- See SGLT2 Inhibitor
- 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
- See Euglycemic Ketoacidosis
- Presents with Anion Gap Metabolic Acidosis (Ketoacidosis despite normal Serum Glucose)
-
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
- May also decrease Serum Potassium
- 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. Safety
- Avoid in Lactation
- Pregnancy
- Unknown safety in first trimester
- Avoid in second and third trimester
- Monitoring
XI. Resources
- Bexagliflozin (DailyMed)
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
- Tomaszewski (2022) Crit Dec Emerg Med 36(11): 32
- Nisly (2013)Am J Health-Syst Pharm 70 (4):311-9 [PubMed]
- Stenlof (2013) Diabetes Obes Metab 15(4): 372-82 [PubMed]
- Vaughan (2024) Am Fam Physician 109(4): 333-42 [PubMed]