II. 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

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 Failure: Creatinine Clearance <30 ml/min

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. 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)

V. 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. 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%
  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
    2. Dosing: Wegovy (weight loss only, do not use this dosing for Diabetes Mellitus alone)
      1. Start at 0.25 mg injected weekly, and slowly titrate over 16 weeks to maximum of 2.4 mg weekly
      2. Expect 10-12% weight loss at one year (twice the weight loss of Saxenda)
      3. Stop medication if inadequate weight loss (<5% at 12 weeks of 2.5 mg/week)
      4. Costs $1400/month in 2021
      5. (2021) Presc Lett 28(8): 45
    3. Lowers Hemoglobin A1C 1.5%
    4. Lowers body weight 9 lbs
    5. Increased risk of Retinopathy complications (esp. if pre-existing Retinopathy)
    6. Reduces cardiovascular risk at 0.5 mg weekly dose
      1. However, does not decrease overall mortality or cardiovascular mortality (unlike Victoza)
  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%

VI. 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. Same adverse effects and risks as with GLP-1 Agonists
    4. Also delays gastric emptying and may render Oral Contraceptives less effective
    5. No available data in 2022 on cardiovascular benefit (unlike some other GLP-1 Agonists)
    6. Cost in 2022: $1000 per month
    7. (2022) Presc Lett 29(7): 38-9

VII. 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

VIII. Dosing: Byetta

  1. Initial
    1. Byetta 5 mcg SQ twice daily
    2. Give within 60 minutes of morning and evening meals
  2. Later, if Blood Sugars not optimized
    1. May increase to 10 mcg bid after 1 month
  3. Preparations: Prefilled pen holds 30 day supply
    1. 5 mcg/dose pen holds 1.2 ml of 250 mcg/ml
    2. 10 mcg/dose pen holds 2.4 ml of 250 mcg/ml

IX. Efficacy

  1. Lowers HBA1C 0.4 to 0.8% (at 5 and 10 mcg doses)
  2. Lowers weight by up to 4-10 pounds

X. Cost

  1. Tanzeum: $325/month
  2. Bydureon: $400+/month
  3. Byetta: $400+/month
  4. Victoza: $600/month

XI. 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. Faillie (2016) JAMA Intern Med 176(10): 1474-81 +PMID: 27478902 [PubMed]
  9. Retinopathy complications
    1. Occurs with Semaglutide (Ozempic)
  10. Other serious but uncommon effects (<1%)
    1. Acute Kidney Injury
    2. Angioedema

XII. 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

XIII. References

Images: Related links to external sites (from Bing)

Related Studies

Cost: Medications

byetta (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
BYETTA 10 MCG DOSE PEN INJ $267.39 per ml
BYETTA 5 MCG DOSE PEN INJ $533.58 per ml
bydureon (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
BYDUREON 2 MG VIAL $149.42 each
victoza (on 9/2/2016 at Medicaid.Gov Survey of pharmacy drug pricing)
VICTOZA 2-PAK 18 MG/3 ML PEN $80.25 per ml
VICTOZA 3-PAK 18 MG/3 ML PEN $80.05 per ml
saxenda (on 1/18/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
SAXENDA 18 MG/3 ML PEN $73.68 per ml
tanzeum (on 5/17/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
TANZEUM 30 MG PEN INJECT $125.35 each
TANZEUM 50 MG PEN INJECT $125.05 each
trulicity (on 5/2/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
TRULICITY 0.75 MG/0.5 ML PEN $327.61 per ml
TRULICITY 1.5 MG/0.5 ML PEN $326.50 per ml
soliqua (on 5/17/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
SOLIQUA 100 UNIT-33 MCG/ML PEN $40.41 per ml

Ontology: Glucagon-Like Peptide 1 (C0061355)

Definition (MSH) A peptide of 36 or 37 amino acids that is derived from PROGLUCAGON and mainly produced by the INTESTINAL L CELLS. GLP-1(1-37 or 1-36) is further N-terminally truncated resulting in GLP-1(7-37) or GLP-1-(7-36) which can be amidated. These GLP-1 peptides are known to enhance glucose-dependent INSULIN release, suppress GLUCAGON release and gastric emptying, lower BLOOD GLUCOSE, and reduce food intake.
Concepts Amino Acid, Peptide, or Protein (T116)
MSH D052216
SnomedCT 43004008
Portuguese Peptídeo 1 Semelhante ao Glucagon, Peptídeo 1 Similar ao Glucagon, Peptídeo I Semelhante ao Glucagon, Peptídeo Semelhante ao Glucagon 1, Peptídeo Similar ao Glucagon 1, Peptídeo Glucagonoide 1, Peptídeo I Similar ao Glucagon, Peptídeo Semelhante ao Glucagon I, Peptídeo Glucagon-Like I, Peptídeo Glucagon-Like 1, Peptídeo Similar ao Glucagon I, Peptídeo 1 Glucagonoide
Italian Peptide 1 simile al glucagone, GLP-1
German Glucagon-Like-Peptide-1, Glucagon-ähnliches Peptid 1, GLP-1, Glukagon-ähnliches Peptid 1
Swedish Glucagonliknande peptid 1
English GLP1, GLUCAGON-LIKE PEPTIDE 1, Glucagon-Like Peptide 1, GLUCAGON LIKE PEPTIDE 001, Glucagon-Like Peptide 1 [Chemical/Ingredient], glp-1, glp 1, glucagon like peptide 1, Glucagon-like peptide 1, Glucagon-like peptide 1 (substance), GLP-1, GLP 1, Glucagon Like Peptide 1, Glucagon-Like Peptide-1
Czech GLP-1, peptid 1 podobný glukagonu, glukagonu podobný peptid 1
Spanish Péptido 1 Similar al Glucagón, Péptido 1 Glucagonoide, Péptido Similar al Glucagón 1, Péptido Glucagonoide 1, GLP - 1, péptido I similar al glucagón (sustancia), péptido I similar al glucagón
Finnish Glukagonia muistuttava peptidi 1
French Glucagon-like peptide I, GLP-1, Glucagon-like peptide 1, Glucagon-like peptide-1, Proglucagon (78-107)
Polish Peptyd glukagonopodobny 1
Norwegian Glukagonlignende peptid 1, GLP-1

Ontology: exenatide (C0167117)

Definition (NCI) A 39 amino acid peptide and synthetic version of exendin-4, a hormone found in the saliva of the venomous lizard Gila monster, with insulin secretagogue and antihyperglycemic activity. Exenatide is administered subcutaneously and mimics human glucagon-like peptide-1 (GLP-1). Compared to GLP-1, exenatide has a longer half-life of 2.4 hours.
Concepts Amino Acid, Peptide, or Protein (T116) , Pharmacologic Substance (T121)
MSH C074031
SnomedCT 416859008, 417734003
English exendin-4, EXENATIDE, exenatide (medication), exenatide [Chemical/Ingredient], Ex4 peptide, exendin 4, exenatide, Exendin 4, Exenatide (product), Exenatide (substance), Exenatide
Spanish exenatida (producto), exenatida (sustancia), exenatida

Ontology: liraglutide (C1456408)

Definition (NCI) A long-acting, fatty acylated glucagon-like peptide-1 (GLP-1) analog administered subcutaneously, with antihyperglycemic activity. Liraglutide's prolonged action and half-life of 11-15 hours are attributed to the attachment of the fatty acid palmitic acid to GLP-1 that reversibly binds to albumin. Albumin binding protects liraglutide from immediate degradation and elimination and causes GLP-1 to be released from abumin in a slow and consistent manner. This agent may cause thyroid C-cell tumors and increases the risk of acute pancreatitis.
Concepts Pharmacologic Substance (T121) , Amino Acid, Peptide, or Protein (T116) , Hormone (T125)
MSH C439759
SnomedCT 444828003, 444907006
English LIRAGLUTIDE, Liraglutide (substance), Liraglutide (product), Liraglutide, N26-(Hexadecanoyl-gamma-glutamyle)-(34-arginine)glucagon-like-peptide-1-(7-37)-peptide, liraglutide
Spanish liraglutida, liraglutida (sustancia), liraglutida (producto)

Ontology: Incretin mimetic product (C1562104)

Concepts Hormone (T125) , Pharmacologic Substance (T121)
SnomedCT 416171004, 416636000
Spanish incretinomimético, agente mimético de la incretina (sustancia), agente mimético de la incretina, producto mimético de la incretina (producto), producto mimético de la incretina
English Incretin mimetic agent (substance), Incretin mimetic agent, Incretin mimetic product (product), Incretin mimetic product

Ontology: Byetta (C1636686)

Concepts Amino Acid, Peptide, or Protein (T116) , Pharmacologic Substance (T121)
MSH C074031
English Byetta

Ontology: albiglutide (C2607479)

Definition (NCI) A long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, with antihyperglycemic activity. Albiglutide is composed of a GLP-1 (7-36) dimer fused to recombinant human albumin. Upon subcutaneous administration, this agent has a half-life of 4-7 days and resists degradation by dipeptidyl peptidase-4 (DPP-4).
Concepts Amino Acid, Peptide, or Protein (T116) , Biologically Active Substance (T123)
MSH C534611
SnomedCT 703129009
English albiglutide, ALBIGLUTIDE, Albiglutide (substance), Albiglutide

Ontology: Victoza (C2732208)

Concepts Amino Acid, Peptide, or Protein (T116) , Pharmacologic Substance (T121)
MSH C439759
English Victoza, victoza

Ontology: GLP-1 Receptor Agonist [EPC] (C2917359)

Concepts Pharmacologic Substance (T121)
English GLP-1 Receptor Agonist, Glucagon-like Peptide 1 Receptor Agonist, Glucagon-like Peptide-1 Receptor Agonist, GLP-1 Receptor Agonist [EPC]

Ontology: dulaglutide (C3179549)

Concepts Amino Acid, Peptide, or Protein (T116) , Pharmacologic Substance (T121)
MSH C555680
English dulaglutide

Ontology: Bydureon (C3257792)

Concepts Amino Acid, Peptide, or Protein (T116) , Pharmacologic Substance (T121)
MSH C074031
English Bydureon, bydureon, Amylin Pharmaceuticals brand of exenatide

Ontology: GLP-1 Mimetics (C3273809)

Definition (NCI) Any of the analogues of the endogenous gastrointestinal hormone glucagon-like peptide-1 (GLP-1) with antihyperglycemic activity. GLP-1 mimetics mimic the activity of GLP-1 and thereby stimulate glucose-dependent secretion of insulin from pancreatic beta cells, suppress glucagon secretion from alpha cells, increase insulin sensitivity and inhibit gastric emptying thereby slowing absorption of nutrients and creating a satiating effect. Altogether, this lowers blood glucose levels. GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).
Concepts Chemical Viewed Functionally (T120)
English GLP-1 Analogue, GLP-1 Mimetics

Ontology: Tanzeum (C3819089)

Concepts Pharmacologic Substance (T121)
English Tanzeum