II. Indications

  1. See GLP-1 Agonist
  2. Type II Diabetes Mellitus
    1. Very effective for weight loss in comorbid Obesity
    2. May be used in combination with Basal insulin (e.g. Lantus)
  3. Insulin deficiency and Insulin Resistance
    1. Adjunct to Glucophage, Sulfonylureas, Glitazones
  4. Weight Loss
    1. At least 50% of weight regained on stopping GLP-1 agents

III. Contraindications

  1. See GLP-1 Agonist
  2. Type I Diabetes Mellitus
  3. Medullary Thyroid Carcinoma (personal or Family History)
  4. Multiple Endocrine Neoplasia syndrome type 2 (active)
  5. Concurrent prandial Insulin (Bolus Insulin)
    1. Basal insulin (e.g. Lantus) may be used
  6. Renal Insufficiency (specific for Exenatide in contrast with other GLP-1 Agonists)
    1. Creatinine Clearance <30 ml/min for Exenatide
    2. Creatinine Clearance <45 ml/min for Exenatide XR
  7. Severe Gastrointestinal Diseases or Gastroparesis
    1. Relative contraindication due to the high Incidence of gastrointestinal side effects with GLP-1 Agonists

IV. Mechanism

  1. See GLP-1 Agonist
  2. Glucagon-Like Peptide 1 (GLP-1) Agonist, an Incretin Mimetic, derived from Gila monster Saliva
    1. Increases Glucose dependent Insulin secretion
    2. Inhibits Glucagon secretion
    3. Delays gastric emptying
    4. Decreases food intake (improves satiety and decreases appetite)
      1. Direct effects at the Hypothalamus, Nucleus Accumbens, ventral tegmental areas and Vagus Nerve

V. Medications

  1. Precautions
    1. All GLP-1 Agonists are expensive ($600 to $1300 per month in 2024)
    2. GLP-1 shortages (esp. Semaglutide and Tirzepatide) have resulted in many online resellers
      1. Buy from only licensed pharmacies (U.S.), and appropriately accredited (e.g. compounding pharmacy)
      2. Certificates of analysis confirm active ingredient
    3. Exenatide specific
      1. Protect medication from light exposure
      2. Keep refrigerated before first use
        1. After initial use, keep at room Temperature (above freezing and <78 F (<25 C)
      3. Caution in impaired Renal Function (and monitor)
        1. Exenatide is contraindicated with Creatinine Clearance <30 ml/min
        2. Exenatide ER Weekly is contraindicated with Creatinine Clearance <45 ml/min
  2. Exenatide (Byetta) Immediate Release
    1. Lowers Hemoglobin A1C by 1.0%
    2. Contraindicated in eGFR <30 ml/min
    3. Prefilled pen holds 30 day supply (60 twice daily doses)
      1. Pen 5 mcg/dose holds 1.2 ml of 250 mcg/ml
      2. Pen 10 mcg/dose holds 2.4 ml of 250 mcg/ml
  3. Exenatide ER Weekly (Bydureon, Bydureon BCise pen)
    1. Exenatide extended release available as 2 mg doses in prefilled pen (Bydureon) or autoinjector (Bydureon BCise)
    2. Lowers Hemoglobin A1C by 1.3%
    3. Contraindicated in eGFR <45 ml/min
    4. Injected once weekly
    5. Requires reconstitution from powder before dose
    6. Less Nausea than Byetta or Victoza, but more injection site reactions than Byetta and Victoza
    7. Bydureon BCise does not appear more effective than Bydureon (despite hype of consistent drug levels)

VI. Dosing: Adults

  1. Give subcutaneous doses in the upper arm, Abdomen or thigh (and rotate injection sites)
  2. Exenatide (Byetta)
    1. Contraindicated in eGFR <30 ml/min
    2. Give within 60 minutes of morning and evening meals (with meals at least 6 hours apart)
    3. Start 5 mcg SQ twice daily
    4. May increase to 10 mcg SQ twice daily after 1 month, if Blood Sugars not optimized at lower dose
  3. Exenatide ER Weekly (Bydureon, Bydureon BCise pen)
    1. Contraindicated in eGFR <45 ml/min
    2. Dose 2 mg SQ once weekly (regardless of mealtime)

VII. Adverse Effects

  1. See GLP-1 Agonist
  2. Adverse effect Prevalence based on original Byetta data
  3. Nausea (44%) or Vomiting (13%)
    1. More with Exenatide than with Exenatide ER Weekly
    2. Less frequent with Bydureon
    3. Eat smaller meals and more slowly, stopping before fullness (satiety)
    4. Consider short-term Ondansetron
    5. Consider dose reduction until tolerated
  4. Diarrhea (13%)
  5. Dizziness (9%)
  6. Headache (9%)
  7. Injection site reactions
    1. More with Exenatide ER Weekly than Exenatide
  8. Hypoglycemia
    1. Alone, GLP-1 Agonists do not significantly increase risk of Hypoglycemia
    2. Avoid combination with Bolus Insulin (Mealtime Insulin) or Insulin Secretagogues (e.g. Sulfonylureas)
    3. With Sulfonylurea: 14.4% at 5 mcg, 35.7% at 10 mcg
    4. With Metformin: 4.5% at 5 mcg, 5.3% at 10 mcg
  9. Pancreatitis (occurs with all GLP-1 Agonists)
    1. Incidence may be as high as 1 in 50 on Byetta for two years
    2. Singh (2013) JAMA Intern Med 173(7):534-9 [PubMed]
  10. Gallbladder disease (Cholelithiasis, Cholecystitis, Choledocholithiasis)
    1. Increased by one in 357 patients over 3 years of medication use
    2. Increased with longer use, higher dose and when GLP-1 Agonist is used for weight loss
    3. Faillie (2016) JAMA Intern Med 176(10): 1474-81 +PMID: 27478902 [PubMed]
  11. Subcutaneous Fat Loss
    1. Desired weight loss (esp. Semaglutide) may result in loose, sagging skin ("Ozempic face")
  12. Other serious but uncommon effects (<1%)
    1. Acute Kidney Injury
    2. Angioedema
    3. Suicidality (case reports, FDA is investigating as of 2024)

VIII. Safety

  1. Unknown safety in Lactation
  2. Most GLP-1 Agonists have unknown safety in pregnancy (avoid)
    1. High dose weight loss GLP-1 Agonists (e.g. Saxena, Wegovy) are considered Pregnancy Category X

IX. Efficacy

  1. No effect on Cardiovascular Risk
  2. Potency
    1. Exenatide (Byetta) lowers Hemoglobin A1C by 1.0%
      1. Contrast with the most potent GLP-1 Agonists that lower A1C 1.5%
    2. Exenatide ER Weekly (Bydureon, Bydureon BCise pen) lowers Hemoglobin A1C by 1.3%
      1. Bydureon BCise does not appear more effective than Bydureon (despite hype of consistent drug levels)

X. Drug Interactions

  1. Avoid using 2 Incretins (e.g. Byetta with Januvia) in combination
    1. Raises cost, risk of Pancreatitis without significant benefit
    2. (2012) Presc Lett 19(8): 45
  2. Concurrent prandial Insulin (Bolus Insulin)
    1. Basal insulin (e.g. Lantus) may be used
  3. Medications that require rapid gastrointestinal absorption
    1. Take at least one hour before Immediate release Exenatide (Byetta)

XII. References

  1. (2024) Presc Lett 31(7): 38
  2. (2024) Presc Lett 31(2): 8-9
  3. (2022) Presc Lett 30(2): 7
  4. (2019) Presc Lett 26(11):62-3
  5. (2019) Presc Lett 26(8):46
  6. (2018) Presc Lett 25(2)
  7. (2014) Presc Lett 21(12): 69
  8. (2012) Presc Lett 19(3): 15
  9. Nordt and Kaucher (2023) EM:Rap 23(9)
  10. Dungan (2005) Clin Diabetes 23: 56-62 [PubMed]
  11. Ezzo (2006) Am Fam Physician 73 [PubMed]
  12. Fineman (2003) Diabetes Care 26:2370-7 [PubMed]
  13. Jones (2007) Am Fam Physician 75:1831-5 [PubMed]
  14. Joy (2005) Ann Pharmacol 39:110-8 [PubMed]
  15. Vaughan (2024) Am Fam Physician 109(4): 333-42 [PubMed]

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Related Studies

Cost: Medications

byetta (on 1/1/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
BYETTA 10 MCG DOSE PEN INJ $320.92 per ml
BYETTA 5 MCG DOSE PEN INJ $641.27 per ml
bydureon (on 1/19/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
BYDUREON 2 MG PEN INJECT $181.57 each
BYDUREON BCISE 2 MG AUTOINJECT $220.25 per ml