Incretin Mimetic

Aka: Incretin Mimetic, GLP-1 Analog, GLP-1 Agonist, GLP1 Agonist, Glucagon-Like Peptide 1, GLP-1, GLP-1 Mimetic, GLP-1 Receptor Agonist, Albiglutide, Tanzeum

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II. Indications

  1. 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. Some agents in this class also reduce Cardiovascular Risk
  2. Insulin deficiency and Insulin Resistance
    1. Adjunct to Glucophage, Sulfonylureas, Glitazones
  3. Weight Loss
    1. At least 50% of weight regained on stopping GLP-1 agents
    2. Semaglutide High Dose (Wegovy)
    3. Liraglutide High Dose (Saxenda)

III. Contraindications

  1. Type I Diabetes Mellitus
  2. Concurrent prandial Insulin (Bolus Insulin)
    1. Basal insulin (e.g. Lantus) may be used with Byetta
  3. Renal Insufficiency
    1. Creatinine Clearance <30 ml/min for Exenatide
    2. Creatinine Clearance <45 ml/min for Exenatide XR
  4. Medullary Thyroid Carcinoma (personal or Family History)
  5. Multiple Endocrine Neoplasia syndrome type 2 (active)

IV. Mechanism

  1. Synthetic form of exendin-4
    1. Originally identified in Gila Monster Saliva
    2. Peptide with 39 Amino Acids
  2. Incretin Mimetic
    1. Incretin analogue that mimics endogenous Hormone
    2. Incretins (GIP and GLP1) are normally released from GI Tract (enteroendocrine cells) following meals
      1. Glucose-Like Peptides (GLP)
      2. Glucose-Dependent Insulinotropic Polypeptides (GIP)
  3. Incretin effects
    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
  4. GLP-1 Receptor Agonists
    1. Increase the activity of endogenous GLP1
    2. Most are SQ Injections (except oral Semaglutide, Orforglipron, Danuglipron)

V. Precautions

  1. Avoid using 2 Incretins (e.g. Byetta with Januvia) in combination (raises cost, risk of Pancreatitis without significant benefit)
    1. (2012) Presc Lett 19(8): 45
  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

VI. Medications: Single Agent GLP-1

  1. General selection
    1. All agents are expensive ($600 to $1300 per month in 2024)
    2. The most potent agents (Exenatide ER, Dulaglutide, Liraglutide, Semaglutide) lower Hemoglobin A1C 1.5%
    3. The most weight loss (6 pounds) occurs with Exenatide ER, Dulaglutide, Liraglutide
    4. Once weekly dosing is available for Albiglutide, Exenatide ER and Dulaglutide
    5. Most difficult to prepare are Exenatide ER and Albiglutide which both require reconstitution before injection
    6. Dulaglutide and Liraglutide appear to be most potent with greatest weight loss, weekly dosing and easiest to prepare
    7. Cardiovascular Risk is reduced with Liraglutide (strongest evidence), Semaglutide and Dulaglutide
      1. The other GLP-1 agents appear to be cardiovascular neutral
      2. These same agents appear to best GLP-1 agents in reducing CKD progression (but less than SGLT2 Inhibitors)
  2. Exenatide (Byetta)
    1. Glucagon-Like Peptide 1 (GLP-1) Agonist derived from Gila monster Saliva
    2. Associated with weight loss and Nausea
    3. Lowers Hemoglobin A1C by 1.0%
    4. Contraindicated in eGFR <30 ml/min
    5. Dosing
      1. Give within 60 minutes of morning and evening meals
      2. Start Byetta 5 mcg SQ twice daily
      3. Later, if Blood Sugars not optimized at one month, may increase to 10 mcg twice daily
    6. Preparations: Prefilled pen holds 30 day supply
      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. Injected once weekly
    2. More potent than Byetta (lowers Hemoglobin A1C by 1.3%)
    3. Less Nausea than Byetta or Victoza
    4. Requires reconstitution from powder before dose
    5. More injection site reactions than Byetta and Victoza
    6. Contraindicated in eGFR <45 ml/min
    7. Bydureon BCise does not appear more effective than Bydureon (despite hype of consistent drug levels)
  4. Dulaglutide (Trulicity)
    1. Approved in 2022 for use in age 10 years and older with Type 2 Diabetes Mellitus
    2. More potent than Byetta (lowers Hemoglobin A1C by 1.5%)
    3. Once weekly injection
    4. Weight loss of 6 pounds on average
    5. Reduces Cardiovascular Risk at 1.5 mg weekly dose
      1. However, does not decrease overall mortality or cardiovascular mortality (unlike Victoza)
  5. Liraglutide Standard Dose (Victoza)
    1. Single daily injection (as contrasted with twice daily Byetta)
    2. More potent than Byetta (lowers Hemoglobin A1C by 1.5%)
    3. Adverse effects include Nausea (transient) and Headache
    4. Reduces Cardiovascular Risk and death at 1.8 mg daily dose
    5. Approved in 2019 for use in age 10 years and older with Type 2 Diabetes Mellitus
    6. May reduce hypoalbuminuria (NNT 83), but does not delay Dialysis
      1. Mann (2017) N Engl J Med 377(9):839-48 [PubMed]
  6. Liraglutide High Dose (Saxenda)
    1. Indicated only in Obesity
      1. Do not use this dosing for Diabetes Mellitus alone
    2. Dosing
      1. Start at 0.6 mg SQ daily and increase weekly
      2. Saxenda is dosed up to 3 mg daily (contrast with 1.8 mg with Victoza)
    3. FDA approved as an Obesity Medication with release in 2015
    4. Results in weight loss up to 9.7 to 13 lb (4.4 to 5.9 kg) over Placebo
    5. Associated with gastrointestinal side effects (Nausea, Vomiting and Diarrhea)
    6. Consider in Type II Diabetes Mellitus in which an Obesity Medication is being considered
    7. Contraindicated in MEN-2 and Medullary Thyroid Cancer (personal history or Family History)
    8. Reduces Cardiovascular Risk and death
  7. Semaglutide Standard Injection (Ozempic, Diabetes Mellitus)
    1. Once weekly injection (similar to Bydureon)
    2. Start at 0.25 mg injected SQ weekly, and slowly titrate to maximum of 1.0 mg injected weekly
    3. Lowers Hemoglobin A1C 1.5%
    4. Reduces Cardiovascular Risk at 0.5 mg weekly dose
      1. However, does not decrease overall mortality or cardiovascular mortality (unlike Victoza)
    5. Increased risk of Retinopathy complications (esp. if pre-existing Retinopathy)
  8. Semglutide High Dose (Wegovy, weight loss in Obesity only)
    1. Indicated only in Obesity
      1. Do not use this dosing for Diabetes Mellitus alone
    2. Dosing
      1. Start at 0.25 mg injected SQ weekly, and slowly titrate over first 16 weeks to max 2.4 mg weekly
      2. Increase dose monthly (0.5, 1, 1.7, 2.4 mg) over the first 16 weeks, then continue at 2.4 mg
      3. Target dose 2.4 mg/week costs $1400/month in 2021
    3. Efficacy
      1. Mean weight loss 13% body weight (at least 5% in most patients)
      2. Weight loss sustained >1 year while on Semaglutide
      3. Expect 10-12% weight loss at one year (twice the weight loss of Saxenda)
      4. Stop medication if inadequate weight loss (<5% at 12 weeks of 2.5 mg/week)
    4. References
      1. (2021) Presc Lett 28(8): 45
      2. Bald (2023) Am Fam Physician 107(1): 90-1 [PubMed]
      3. Capehorn (2020) Diabetes Metab 46:100-9 +PMID: 31539622 [PubMed]
      4. Garvey (2022) Nat Med 28:2083-91 +PMID: 36216945 [PubMed]
      5. Wilding (2021) N Engl J Med 384:989-1002 +PMID: 33567185 [PubMed]
  9. Semaglutide Oral (Rybelsus)
    1. First oral GLP-1 Agonist
    2. Take once orally daily with NO more than 4 ounces of water
      1. Take at least 30 minutes before first food, water or medication of the day
    3. Associated with short term weight loss <10 pounds
    4. Gastrointestinal adverse effects may be prolonged
    5. Lowers Hemoglobin A1C 1%
  10. Discontinued agents
    1. Lixisenatide (Adlyxin)
      1. Discontinued in the U.S. in 2023 (after having been released only in 2017)
      2. Once daily injection dosing
    2. Albiglutide (Tanzeum)
      1. Withdrawn from global market in 2018
      2. Similar potency to Byetta (lowers Hemoglobin A1C by 1.0%)
      3. Less weight loss than with other agents (1-2 pounds compared with 6 pounds with other agents)
      4. Injected once weekly (similar to Bydureon)
      5. Less Nausea than Byetta and Victoza
      6. More injection site reactions than Byetta and Victoza

VII. Medications: Single Agent GLP-1 Agonist and GIP Agonist (Twincretin)

  1. Background
    1. Glucose-Dependent Insulinoptropic Polypeptide (GIP)
      1. Like GLP-1, GIP is another Incretin secreted in the intestinal tract in response to food
      2. Also like GLP-1, GIP stimulates Insulin release, decreases Glucose synthesis and increases satiety
    2. Some GLP-1 Agonists are also active as GIP Agonists ("Twincretins")
      1. Tirzeptatide (Mounjaro) is the first drug released in 2022, that is active at both GIP and GLP-1 receptors
  2. Tirzepatide (Mounjaro)
    1. In combination with Metformin, reduces Hemoglobin A1C up to 2.3%
    2. Weight loss in Diabetes Mellitus patients may approach 25 pound loss in 10 months
    3. Weight loss in patients without Diabetes was 15-21% of total body weight over a 72 week period
      1. Dose 5 mg/week reduced weight 15%, 10 mg/week reduced weight 19.5%, 15 mg/week reduced weight 20.9%
      2. Jastreboff (2022) N Engl J Med 387(3): 205-16 [PubMed]
    4. Same adverse effects and risks as with GLP-1 Agonists
    5. Also delays gastric emptying and may render Oral Contraceptives less effective
    6. No available data in 2022 on cardiovascular benefit (unlike some other GLP-1 Agonists)
    7. Cost in 2022: $1000 per month
    8. (2022) Presc Lett 29(7): 38-9

VIII. Medications: Combination

  1. Advantages
    1. May spare basal Insulin Dosing
  2. Disadvantages
    1. Very expensive ($760 to 950 per month)
    2. Limits titration of basal Insulin Dosing (fixed dose combinations)
  3. Agents
    1. Xultophy (Insulin Degludec with Liraglutide)
    2. Soliqua (Insulin Glargine with Lixisenatide)
  4. References
    1. (2017) Presc Lett 24(6): 35

IX. Adverse Effects

  1. Adverse effect Prevalence based on original Byetta data
  2. Nausea (44%) or Vomiting (13%)
    1. Less frequent with Bydureon
    2. Eat smaller meals and more slowly, stopping before fullness (satiety)
    3. Consider short-term Ondansetron
    4. Consider dose reduction until tolerated
  3. Diarrhea (13%)
  4. Dizziness (9%)
  5. Headache (9%)
  6. 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
  7. 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]
  8. 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]
  9. Increased Heart Rate
    1. Heart Rate rises in 10-20 bpm in 40% of patients on Semaglutide Injection (Wegovy)
  10. Diabetic Retinopathy complications (increased Retinal Hemorrhage)
    1. Occurs with Semaglutide, Liraglutide, Dulaglutide
    2. Paradoxically attributed to better Blood Glucose control
  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)

X. 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

XI. Efficacy

  1. Lowers HBA1C 0.8 to 2% (potent agents typically lower A1C by 1.5%)
  2. Lowers weight by up to 4-10 pounds (up to 5 to 13% for some agents)
  3. Some GLP-1 Agonists reduce Cardiovascular Risk
    1. Liraglutide (strongest evidence)
    2. Semaglutide
    3. Dulaglutide

XII. 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

XIII. 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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