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Incretin Mimetic

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Incretin Mimetic, GLP-1 Analog, GLP-1 Agonist, GLP1 Agonist, Glucagon-Like Peptide 1, GLP-1, GLP-1 Mimetic, GLP-1 Receptor Agonist, Byetta, Exenatide, Bydureon, Bydureon BCise, Liraglutide, Victoza, Saxenda, Tanzeum, Albiglutide, Dulaglutide, Trulicity, Adlyxin, Lixisenatide, Soliqua, Xultophy, Semaglutide, Ozempic, Rybelsus, Wegovy, Twincretin, GIP Agonist, Tirzeptatide, Mounjaro

  • See Also
  1. Sitagliptin (Januvia)
  2. Dipeptidyl Peptidase-4 Inhibitor (DPP-4 Inhibitor)
  • Indications
  1. Type II Diabetes Mellitus
    1. Especially in Obesity
    2. May be used in combination with basal Insulin (e.g. Lantus)
    3. Increased cardiovascular risk
  2. Insulin deficiency and Insulin Resistance
    1. Adjunct to Glucophage, Sulfonylureas, Glitazones
  • 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 Failure: Creatinine Clearance <30 ml/min
  • 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. Incretin released from GI Tract following meals
  3. Incretin effects
    1. Increases Glucose dependent Insulin secretion
    2. Inhibits Glucagon
    3. Delays gastric emptying
    4. Decreases food intake (improves satiety)
  • Preparations
  • Single Agent GLP-1
  1. General selection
    1. All agents are expensive ($600 to $900 per month)
    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. 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
    5. 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. Less Nausea than Byetta and Victoza
    6. More injection site reactions than Byetta and Victoza
    7. Bydureon BCise does not appear more effective than Bydureon (despite hype of consistent drug levels)
  4. 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]
  5. Liraglutide High Dose (Saxenda)
    1. 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)
    2. FDA approved as an Obesity Medication with release in 2015
    3. Results in weight loss up to 9.7 to 13 lb (4.4 to 5.9 kg) over Placebo
    4. Associated with gastrointestinal side effects (Nausea, Vomiting and Diarrhea)
    5. Consider in Type II Diabetes Mellitus in which an Obesity Medication is being considered
    6. Contraindicated in MEN-2 and Medullary Thyroid Cancer (personal history or Family History)
    7. Reduces cardiovascular risk and death
  6. Albiglutide (Tanzeum)
    1. Similar potency to Byetta (lowers Hemoglobin A1C by 1.0%)
    2. Less weight loss than with other agents (1-2 pounds compared with 6 pounds with other agents)
    3. Injected once weekly (similar to Bydureon)
    4. Less Nausea than Byetta and Victoza
    5. More injection site reactions than Byetta and Victoza
  7. Dulaglutide (Trulicity)
    1. More potent than Byetta (lowers Hemoglobin A1C by 1.5%)
    2. Once weekly injection
    3. Weight loss of 6 pounds on average
    4. Reduces cardiovascular risk at 1.5 mg weekly dose
      1. However, does not decrease overall mortality or cardiovascular mortality (unlike Victoza)
  8. Lixisenatide (Adlyxin)
    1. Newer agent of the class (released in 2017)
    2. Once daily injection dosing
  9. Semaglutide Injection (Ozempic, Wegovy)
    1. Dosing: Ozempic (Diabetes Mellitus)
      1. Once weekly injection (similar to Bydureon)
      2. Start at 0.25 mg injected 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)
    2. Dosing: Wegovy (weight loss in Obesity only, do not use this dosing for Diabetes Mellitus alone)
      1. Start at 0.25 mg injected weekly, and slowly titrate over first 16 weeks to maximum of 2.4 mg weekly
        1. Increase dose monthly (0.5, 1, 1.7, 2.4 mg) over the first 16 weeks, then continue at 2.4 mg
      2. Mean weight loss 13% body weight (at least 5% in most patients) and sustained >1 year while on Semaglutide
        1. Expect 10-12% weight loss at one year (twice the weight loss of Saxenda)
        2. Stop medication if inadequate weight loss (<5% at 12 weeks of 2.5 mg/week)
      3. Target dose 2.4 mg/week costs $1400/month in 2021
      4. References
        1. (2021) Presc Lett 28(8): 45
        2. Bald (2023) Am Fam Physician 107(1): 90-1 [PubMed]
  10. 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%
  • Preparations
  • 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. Tirzeptatide (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
  • Preparations
  • 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
  • Efficacy
  1. Lowers HBA1C 0.4 to 0.8% (at 5 and 10 mcg doses)
  2. Lowers weight by up to 4-10 pounds
  • Adverse Effects
  1. Adverse effect Prevalence based on original Byetta data
  2. Nausea (44%) or Vomiting (13%)
    1. Less frequent with Bydureon
  3. Diarrhea (13%)
  4. Dizziness (9%)
  5. Headache (9%)
  6. Hypoglycemia
    1. Alone, does not appear to significantly increase risk of Hypoglycemia
    2. With Sulfonylurea: 14.4% at 5 mcg, 35.7% at 10 mcg
    3. With Glucophage: 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. Retinopathy complications
    1. Occurs with Semaglutide (Ozempic)
  11. Other serious but uncommon effects (<1%)
    1. Acute Kidney Injury
    2. Angioedema
  • 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
  • References
  1. (2022) Presc Lett 30(2): 7
  2. (2019) Presc Lett 26(11):62-3
  3. (2019) Presc Lett 26(8):46
  4. (2018) Presc Lett 25(2)
  5. (2014) Presc Lett 21(12): 69
  6. (2012) Presc Lett 19(3): 15
  7. Dungan (2005) Clin Diabetes 23: 56-62 [PubMed]
  8. Ezzo (2006) Am Fam Physician 73 [PubMed]
  9. Fineman (2003) Diabetes Care 26:2370-7 [PubMed]
  10. Jones (2007) Am Fam Physician 75:1831-5 [PubMed]
  11. Joy (2005) Ann Pharmacol 39:110-8 [PubMed]