II. Indications
- Type II Diabetes Mellitus
-
Insulin deficiency and Insulin Resistance
- Adjunct to Glucophage, Sulfonylureas, Glitazones
III. Contraindications
- Type I Diabetes Mellitus
- Concurrent prandial Insulin (Bolus Insulin)
- Renal Failure: Creatinine Clearance <30 ml/min
IV. Mechanism
- Synthetic form of exendin-4
- Originally identified in Gila Monster Saliva
- Peptide with 39 amino acids
- Incretin Mimetic
- Incretin analogue that mimics endogenous hormone
- Incretin released from GI tract following meals
- Incretin effects
V. Preparations: Single Agent
-
General selection
- All agents are expensive ($600 to $900 per month)
- The most potent agents (Exenatide ER, Dulaglutide, Liraglutide, Semaglutide) lower Hemoglobin A1C 1.5%
- The most weight loss (6 pounds) occurs with Exenatide ER, Dulaglutide, Liraglutide
- Once weekly dosing is available for Albiglutide, Exenatide ER and Dulaglutide
- Most difficult to prepare are Exenatide ER and Albiglutide which both require reconstitution before injection
- Dulaglutide and Liraglutide appear to be most potent with greatest weight loss, weekly dosing and easiest to prepare
- Cardiovascular risk is reduced with Liraglutide (strongest evidence), Semaglutide and Dulaglutide
- The other GLP-1 agents appear to be cardiovascular neutral
- Exenatide (Byetta)
- Glucagon-Like Peptide 1 (GLP-1) agonist derived from Gila monster Saliva
- Associated with weight loss and Nausea
- Lowers Hemoglobin A1C by 1.0%
- Exenatide ER Weekly (Bydureon, Bydureon BCise pen)
- Injected once weekly
- More potent than Byetta (lowers Hemoglobin A1C by 1.3%)
- Less Nausea than Byetta or Victoza
- Requires reconstitution from powder before dose
- Less Nausea than Byetta and Victoza
- More injection site reactions than Byetta and Victoza
- Bydureon BCise does not appear more effective than Bydureon (despite hype of consistent drug levels)
- Liraglutide Standard Dose (Victoza)
- Single daily injection (as contrasted with twice daily Byetta)
- More potent than Byetta (lowers Hemoglobin A1C by 1.5%)
- Adverse effects include Nausea (transient) and Headache
- Reduces cardiovascular risk and death at 1.8 mg daily dose
- Approved in 2019 for use in age 10 years and older with Type 2 Diabetes Mellitus
- May reduce hypoalbuminuria (NNT 83), but does not delay Dialysis
- Liraglutide High Dose (Saxenda)
- Dosing
- Start at 0.6 mg SQ daily and increase weekly
- Saxenda is dosed up to 3 mg daily (contrast with 1.8 mg with Victoza)
- FDA approved as an Obesity Medication with release in 2015
- Results in weight loss up to 9.7 to 13 lb (4.4 to 5.9 kg) over Placebo
- Associated with gastrointestinal side effects (Nausea, Vomiting and Diarrhea)
- Consider in Type II Diabetes Mellitus in which an Obesity Medication is being considered
- Contraindicated in MEN-2 and Medullary Thyroid Cancer (personal history or Family History)
- Reduces cardiovascular risk and death
- Dosing
- Albiglutide (Tanzeum)
- Similar potency to Byetta (lowers Hemoglobin A1C by 1.0%)
- Less weight loss than with other agents (1-2 pounds compared with 6 pounds with other agents)
- Injected once weekly (similar to Bydureon)
- Less Nausea than Byetta and Victoza
- More injection site reactions than Byetta and Victoza
- Dulaglutide (Trulicity)
- More potent than Byetta (lowers Hemoglobin A1C by 1.5%)
- Once weekly injection
- Weight loss of 6 pounds on average
- Reduces cardiovascular risk at 1.5 mg weekly dose
- However, does not decrease overall mortality or cardiovascular mortality (unlike Victoza)
- Lixisenatide (Adlyxin)
- Newer agent of the class (released in 2017)
- Once daily injection dosing
- Semaglutide Injection (Ozempic)
- Once weekly injection (similar to Bydureon)
- Lowers Hemoglobin A1C 1.5%
- Lowers body weight 9 lbs
- Increased risk of Retinopathy complications (esp. if pre-existing Retinopathy)
- Reduces cardiovascular risk at 0.5 mg weekly dose
- However, does not decrease overall mortality or cardiovascular mortality (unlike Victoza)
- Semaglutide Oral (Rybelsus)
- First oral GLP-1 Agonist
- Take once orally daily with NO more than 4 ounces of water
- Take at least 30 minutes before first food, water or medication of the day
- Associated with short term weight loss <10 pounds
- Gastrointestinal adverse effects may be prolonged
- Lowers Hemoglobin A1C 1%
VI. Preparations: Combination
- Advantages
- May spare basal Insulin Dosing
- Disadvantages
- Very expensive ($760 to 950 per month)
- Limits titration of basal Insulin Dosing (fixed dose combinations)
- Agents
- Xultophy (Insulin Degludec with Liraglutide)
- Soliqua (Insulin Glargine with Lixisenatide)
- References
- (2017) Presc Lett 24(6): 35
VII. Dosing: Byetta
- Initial
- Byetta 5 mcg SQ twice daily
- Give within 60 minutes of morning and evening meals
- Later, if Blood Sugars not optimized
- May increase to 10 mcg bid after 1 month
- Preparations: Prefilled pen holds 30 day supply
- 5 mcg/dose pen holds 1.2 ml of 250 mcg/ml
- 10 mcg/dose pen holds 2.4 ml of 250 mcg/ml
VIII. Efficacy
- Lowers HBA1C 0.4 to 0.8% (at 5 and 10 mcg doses)
- Lowers weight by up to 4-10 pounds
IX. Cost
- Tanzeum: $325/month
- Bydureon: $400+/month
- Byetta: $400+/month
- Victoza: $600/month
X. Adverse Effects
- Adverse effect Prevalence based on original Byetta data
-
Nausea (44%) or Vomiting (13%)
- Less frequent with Bydureon
- Diarrhea (13%)
- Dizziness (9%)
- Headache (9%)
-
Hypoglycemia
- With Sulfonylurea: 14.4% at 5 mcg, 35.7% at 10 mcg
- With Glucophage: 4.5% at 5 mcg, 5.3% at 10 mcg
-
Pancreatitis (occurs with all GLP-1 Agonists)
- Incidence may be as high as 1 in 50 on Byetta for two years
- Singh (2013) JAMA Intern Med 173(7):534-9 [PubMed]
- Gallbladder disease (Cholelithiasis, Cholecystitis, Choledocholithiasis)
- Increased by one in 357 patients over 3 years of medication use
- Faillie (2016) JAMA Intern Med 176(10): 1474-81 +PMID: 27478902 [PubMed]
-
Retinopathy complications
- Occurs with Semaglutide (Ozempic)
- Other serious but uncommon effects (<1%)
XI. Precautions
- Avoid using 2 Incretins (e.g. Byetta with Januvia) in combination (raises cost, risk of Pancreatitis without significant benefit)
- (2012) Presc Lett 19(8): 45
XII. References
- (2019) Presc Lett 26(11):62-3
- (2019) Presc Lett 26(8):46
- (2018) Presc Lett 25(2)
- (2014) Presc Lett 21(12): 69
- (2012) Presc Lett 19(3): 15
- Dungan (2005) Clin Diabetes 23: 56-62 [PubMed]
- Ezzo (2006) Am Fam Physician 73 [PubMed]
- Fineman (2003) Diabetes Care 26:2370-7 [PubMed]
- Jones (2007) Am Fam Physician 75:1831-5 [PubMed]
- Joy (2005) Ann Pharmacol 39:110-8 [PubMed]
Images: Related links to external sites (from Bing)
Related Studies
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 PEN INJECT | $149.65 each | |
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) |
Russian | GLIUKAGON-PODOBNYI PEPTID 1, ГЛЮКАГОН-ПОДОБНЫЙ ПЕПТИД 1 |
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 |