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
- GFR <45 ml/min: Avoid Farxiga (Dapagliflozin) and Ertuglifozin (Steglatro)
- GFR <30 ml/min: Avoid all SGLT2 Inhibitors
- Efficacy is reduced at low GFR
- Some SGLT2 Inhibitors may be approved down to GFR 20 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
- 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
-
Canagliflozin (Invokana, released 2013)
- Start: 100 mg orally daily
- Maximum: 300 mg orally daily (avoid if GFR <60 ml/min)
- Reduces cardiovascular events (MI, CVA) and progression of Chronic Kidney Disease (see below)
-
Dapagliflozin (Farxiga)
- Dose: 5 to 10 mg/day
-
Empagliflozin (Jardiance)
- FDA approved for age >=10 years as of 2023
- Dose: 10 to 25 mg/day
-
Ertugliflozin (Steglatro)
- Dose: 5 to 15 mg/day
-
Sotagliflozin (Inpefa)
- Released in 2023 approved for CHF, but not yet for Diabetes Mellitus
- Higher Incidence of Diarrhea due to gastrointestinal SGLT1 blockade
- (2023) Presc Lett 30(7): 37
-
Bexagliflozin (Brenzavvy)
- Released in 2023 at $50/month (compared with other SGLT2 Inhibitors costing $600/month)
- FDA approved for Type 2 Diabetes, with similar efficacy to other agents (lowers Hgb A1c 0.5%)
- May not be initially covered by insurance, resulting in cost higher than other agent copays
- (2023) Presc Lett 30(9): 51
- Ipragliflozin (Suglat)
- Not approved for use in U.S.
VI. Dosing
- AM dosing is recommended due to Diuretic effect
- Taken 30 minutes before first meal of day
- Avoid in Dehydration
VII. Pharmacokinetics
- SGLT2 Inhibitors share similar Pharmacokinetics
- Rapid absorption and peak activity within 2 hours
- Half-Life 3-6 hours
- Renal excretion (90%) with minimal metabolism
- Toxic dose >5 g in adults (>100 mg/kg in children)
- Evaluate for Dehydration, Polyuria, Hypotension and initiate fluid Resuscitation
- Evaluate for Ketoacidosis (Anion Gap Metabolic Acidosis, Serum Ketones)
VIII. Efficacy
- Decrease weight 5 lb
- Lowers Hemoglobin A1C 0.5 to 1%
- Glucose lowering effect decreases with lower GFR
- Decrease Cardiovascular Risk
- Decrease Chronic Kidney Disease progression
IX. 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]
- Heart Failure with Preserved Ejection Fraction
- Appears effective in reducing hospitalizations even in non-Diabetic patients with HFpEF
- However, best effect in reduced Ejection Fraction (even mild reduction of 40-50% EF)
- Anker (2021) N Engl J Med [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]
- Reduces progression of Chronic Kidney Disease and its cardiovascular complications (including death)
- 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)
X. 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
XI. 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
- 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
XII. Safety
- Avoid in Lactation
- Pregnancy
- Unknown safety in first trimester
- Avoid in second and third trimester
- Monitoring
XIII. Resources
- Efficacy and safety of Canagliflozin
XIV. 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]