SGLT2 Inhibitor

Aka: SGLT2 Inhibitor, Sodium-Glucose Co-Transporter-2 Inhibitor, Sodium-Glucose Transporter 2, Flozins, Ipragliflozin

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II. Indications

  1. Type 2 Diabetes Mellitus Management
    1. Comorbid Chronic Kidney Disease or Microalbuminuria
    2. Comorbid Congestive Heart Failure
  2. Like GLP-1 Agonists, SGLT2 Inhibitors have moved to first-line agents for their effects on conditions comorbid to Diabetes
    1. SGLT2 Inhibitors (as with GLP-1 Agonists) may assist with weight loss in Obesity
    2. SGLT2 Inhibitors (as with GLP-1 Agonists) decrease Cardiovascular Risk
      1. Best evidence for Empagliflozin (Jardiance)
    3. SGLT2 Inhibitors (as with GLP-1 Agonists) decrease Chronic Kidney Disease progression
      1. Best evidence for Empagliflozin (Jardiance), Canagliflozin (Invokana), Dapagliflozin (Farxiga)

III. Contraindications

  1. Type 1 Diabetes Mellitus
  2. Renal dysfunction
    1. GFR <45 ml/min: Avoid Farxiga (Dapagliflozin) and Ertuglifozin (Steglatro)
    2. GFR <30 ml/min: Avoid all SGLT2 Inhibitors
      1. Efficacy is reduced at low GFR
      2. Some SGLT2 Inhibitors may be approved down to GFR 20 ml/min
  3. Other relative contraindications (use with caution)
    1. Diabetic Ketoacidosis (relative contraindication)
    2. Osteoporosis or Osteopenia (low Bone Mineral Density)
    3. Diabetic Foot Wound (Neuropathic Foot Ulcer)
  4. Perioperative status (or prolonged Fasting, Dehydration)
    1. Hold for at least 3 to 4 days before major surgery

IV. Mechanism

  1. Sodium-Glucose Transporter 2 (SGLT2)
    1. SGLT2 acts in the Kidneys to resorb Glucose at the proximal tubules
    2. SGLT2 mediates 90% of renal Glucose reabsorption from the tubules
  2. SGLT2 Inhibitors
    1. Blocks SGLT2, Allowing more Glucose to remain in the urine without reabsorption
    2. Results in osmotic diuresis
    3. Efficacy is lower when GFR is decreased

V. Medications

  1. Canagliflozin (Invokana, released 2013)
    1. Start: 100 mg orally daily
    2. Maximum: 300 mg orally daily (avoid if GFR <60 ml/min)
    3. Reduces cardiovascular events (MI, CVA) and progression of Chronic Kidney Disease (see below)
  2. Dapagliflozin (Farxiga)
    1. Dose: 5 to 10 mg/day
  3. Empagliflozin (Jardiance)
    1. FDA approved for age >=10 years as of 2023
    2. Dose: 10 to 25 mg/day
  4. Ertugliflozin (Steglatro)
    1. Dose: 5 to 15 mg/day
  5. Sotagliflozin (Inpefa)
    1. Released in 2023 approved for CHF, but not yet for Diabetes Mellitus
    2. Higher Incidence of Diarrhea due to gastrointestinal SGLT1 blockade
    3. (2023) Presc Lett 30(7): 37
  6. Bexagliflozin (Brenzavvy)
    1. Released in 2023 at $50/month (compared with other SGLT2 Inhibitors costing $600/month)
    2. FDA approved for Type 2 Diabetes, with similar efficacy to other agents (lowers Hgb A1c 0.5%)
    3. May not be initially covered by insurance, resulting in cost higher than other agent copays
    4. (2023) Presc Lett 30(9): 51
  7. Ipragliflozin (Suglat)
    1. Not approved for use in U.S.

VI. Dosing

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

VII. Pharmacokinetics

  1. SGLT2 Inhibitors share similar Pharmacokinetics
  2. Rapid absorption and peak activity within 2 hours
  3. Half-Life 3-6 hours
  4. Renal excretion (90%) with minimal metabolism
  5. Toxic dose >5 g in adults (>100 mg/kg in children)
    1. Evaluate for Dehydration, Polyuria, Hypotension and initiate fluid Resuscitation
    2. Evaluate for Ketoacidosis (Anion Gap Metabolic Acidosis, Serum Ketones)

VIII. Efficacy

  1. Decrease weight 5 lb
  2. Lowers Hemoglobin A1C 0.5 to 1%
    1. Glucose lowering effect decreases with lower GFR
  3. Decrease Cardiovascular Risk
  4. Decrease Chronic Kidney Disease progression

IX. 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)
    1. Heart Failure with Reduced Ejection Fraction
      1. Jardiance is associated with a decreased hospitalization and CV death rate when taken over 16 months (NNT 14)
      2. Packer (2020) N Engl J Med 383:1413-24 [PubMed]
    2. Heart Failure with Preserved Ejection Fraction
      1. Appears effective in reducing hospitalizations even in non-Diabetic patients with HFpEF
      2. However, best effect in reduced Ejection Fraction (even mild reduction of 40-50% EF)
      3. Anker (2021) N Engl J Med [PubMed]
    3. 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]
    4. 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]
    5. Reduces progression of Chronic Kidney Disease and its cardiovascular complications (including death)
      1. (2023) N Engl J Med 388(2):117-27 +PMID: 36331190 [PubMed]
  5. Invokana (Canagliflozin)
    1. 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]
  6. Dapagliflozin (Farxiga)
    1. Chronic Kidney Disease (CKD)
      1. Slows CKD progression or reduces risk of CV or renal death (NNT 19)
      2. Heerspink (2020) N Engl J Med 383:1436-46 [PubMed]

X. Disadvantages

  1. See adverse effects below (UTI, yeast infections, Fractures)
  2. Expensive ($10 per day or more than $250 to 500 per month)
  3. Lower efficacy in moderate to severe renal Impairment

XI. Adverse Effects

  1. Perioperative Recommendations
    1. See Preoperative Guidelines for Medications Prior to Surgery
    2. Stop SGLT2 Inhibitors 3 days before surgery (due to Euglycemic Ketoacidosis risk)
    3. Restart SGLT2 Inhibitors post-operatively when oral intake returns to normal
  2. Urinary Tract Infection
  3. Genital yeast infection
    1. Number needed to harm (NNH) 17 in women, 40 in men
  4. Fournier's Gangrene
    1. https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm
  5. Euglycemic Ketoacidosis
    1. See Euglycemic Ketoacidosis
    2. Presents with Anion Gap Metabolic Acidosis (Ketoacidosis despite normal Serum Glucose)
  6. Diuretic effect
    1. Risk of Dehydration, Orthostatic Hypotension
    2. Risk of Acute Kidney Injury (see below)
  7. Acute Kidney Injury
    1. Seen with Canagliflozin (Invokana) and Dapagliflozin (Farxiga), but likely a class effect due to diuresis
    2. Higher risk when combined with ACE Inhibitors (and ARBs), NSAIDs and Diuretics and esp. in elderly
    3. Avoid Hypovolemia, and consider lowering Diuretic dose when on SGLT2 Inhibitor
    4. Check Serum Creatinine before initiating agent, 10-14 days later and again with dose increase
      1. Transient increase in Serum Creatinine is common, and typically improves with use
      2. Stop and hold the SGLT2 Inhibitor if Serum Creatinine rises >30%
    5. Resources: FDA
      1. http://www.fda.gov/Drugs/DrugSafety/ucm505860.htm
  8. Hyperkalemia
    1. When used in combination with ACE Inhibitors, Angiotensin Receptor Blockers or Potassium Sparing Diuretics
    2. May also decrease Serum Potassium
  9. LDL Cholesterol increase (4-8 mg/dl)
  10. Bladder Cancer increased risk
    1. Associated only with Farxiga
  11. 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
  12. Acute Pancreatitis
  13. 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. See Amputation Prevention in Diabetes Mellitus
    5. FDA Drug Safety Communication
      1. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm

XII. Safety

  1. Avoid in Lactation
  2. Pregnancy
    1. Unknown safety in first trimester
    2. Avoid in second and third trimester
  3. Monitoring
    1. Renal Function

XIII. Resources

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

XIV. References

  1. (2020) Presc Lett 27(12): 68
  2. (2020) Presc Lett 27(5): 26
  3. (2018) Presc Lett 25(2)
  4. (2016) Presc Lett 23(2): 8-9
  5. (2014) Presc Lett 21(10): 57
  6. (2013) Presc Lett 20(5): 28
  7. Tomaszewski (2022) Crit Dec Emerg Med 36(11): 32
  8. Nisly (2013)Am J Health-Syst Pharm 70 (4):311-9 [PubMed]
  9. Stenlof (2013) Diabetes Obes Metab 15(4): 372-82 [PubMed]
  10. Vaughan (2024) Am Fam Physician 109(4): 333-42 [PubMed]

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