Empagliflozin

Aka: Empagliflozin, Jardiance

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II. Indications

  1. Type 2 Diabetes Mellitus Management
    1. FDA approved for age 10 years and older
    2. Comorbid Chronic Kidney Disease or Microalbuminuria
    3. 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 with GFR <30 ml/min (previously <45 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. Other contraindications due to lack of efficacy (from Empagliflozin labeling)
    1. Polycystic Kidney Disease
    2. Chronic Kidney Disease requiring IV Immunosuppression (or equivalent to Prednisone 45 mg/day)
  5. 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. Empagliflozin (Jardiance)

VI. Dosing

  1. Empagliflozin is FDA approved for age 10 years and older (as of 2023)
  2. AM dosing is recommended due to Diuretic effect
  3. Avoid in Dehydration
  4. Taken 30 minutes before first meal of day
  5. Start: 10 mg orally daily
  6. Next: May increase to 25 mg orally daily

VII. Pharmacokinetics

  1. SGLT2 Inhibitors share similar Pharmacokinetics
  2. Rapid absorption and peak activity within 2 hours

VIII. Efficacy

  1. Lower efficacy in moderate to severe renal Impairment
  2. Class Effects
    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. Lowers Hemoglobin A1C 0.5 to 1%
      1. Glucose lowering effect decreases with lower GFR
      2. Low risk of Hypoglycemia
    4. Decreases Cardiovascular Risk
    5. Decreases Chronic Kidney Disease progression
  3. Empagliflozin (Jardiance) specific effects
    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]

IX. 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. Stop and hold the SGLT2 Inhibitor Serum Creatinine rises >30%
    5. Resources
      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

X. 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

XI. Resources

  1. Empagliflozin
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=faf3dd6a-9cd0-39c2-0d2e-232cb3f67565

XII. 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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Related Studies

Cost: Medications

jardiance (on 1/1/2023 at Medicaid.Gov Survey of pharmacy drug pricing)
JARDIANCE 10 MG TABLET $18.96 each
JARDIANCE 25 MG TABLET $18.96 each
FPNotebook does not benefit financially from showing this medication data or their pharmacy links. This information is provided only to help medical providers and their patients see relative costs. Insurance plans negotiate lower medication prices with suppliers. Prices shown here are out of pocket, non-negotiated rates. See Needy Meds for financial assistance information. GoodRx is another tool for finding lower drug prices.

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