II. Indications
-
Type II Diabetes Mellitus
- Especially in Obesity
- May be used in combination with basal Insulin (e.g. Lantus)
- Increased Cardiovascular Risk
-
Insulin deficiency and Insulin Resistance
- Adjunct to Glucophage, Sulfonylureas, Glitazones
- Weight Loss
- Semaglutide High Dose (Wegovy)
- Liraglutide High Dose (Saxenda)
III. Contraindications
- Type I Diabetes Mellitus
- Concurrent prandial Insulin (Bolus Insulin)
- Renal Failure: Creatinine Clearance <30 ml/min
- Medullary Thyroid Carcinoma (personal or Family History)
- Multiple Endocrine Neoplasia syndrome type 2 (personal or Family History)
IV. Mechanism
- Synthetic form of exendin-4
- Originally identified in Gila Monster Saliva
- Peptide with 39 Amino Acids
- Incretin Mimetic
-
Incretin effects
- Increases Glucose dependent Insulin secretion
- Inhibits Glucagon secretion
- Delays gastric emptying
- Decreases food intake (improves satiety and decreases appetite)
- Direct effects at the Hypothalamus, Nucleus Accumbens, ventral tegmental areas and Vagus Nerve
V. Preparations: Single Agent GLP-1
-
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
- These same agents appear to best GLP-1 agents in reducing CKD progression (but less than SGLT2 Inhibitors)
- 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%
- Dosing
- Give within 60 minutes of morning and evening meals
- Start Byetta 5 mcg SQ twice daily
- Later, if Blood Sugars not optimized at one month, may increase to 10 mcg twice daily
- Preparations: Prefilled pen holds 30 day supply
- Pen 5 mcg/dose holds 1.2 ml of 250 mcg/ml
- Pen 10 mcg/dose holds 2.4 ml of 250 mcg/ml
- 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)
- 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)
- Approved in 2022 for use in age 10 years and older with Type 2 Diabetes Mellitus
- 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
- 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)
- Indicated only in Obesity
- Do not use this dosing for Diabetes Mellitus alone
- 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
- Indicated only in Obesity
- Semaglutide Standard Injection (Ozempic, Diabetes Mellitus)
- Once weekly injection (similar to Bydureon)
- Start at 0.25 mg injected SQ weekly, and slowly titrate to maximum of 1.0 mg injected weekly
- Lowers Hemoglobin A1C 1.5%
- Reduces Cardiovascular Risk at 0.5 mg weekly dose
- However, does not decrease overall mortality or cardiovascular mortality (unlike Victoza)
- Increased risk of Retinopathy complications (esp. if pre-existing Retinopathy)
- Samglutide High Dose (Wegovy, weight loss in Obesity only)
- Indicated only in Obesity
- Do not use this dosing for Diabetes Mellitus alone
- Dosing
- Start at 0.25 mg injected SQ weekly, and slowly titrate over first 16 weeks to max 2.4 mg weekly
- Increase dose monthly (0.5, 1, 1.7, 2.4 mg) over the first 16 weeks, then continue at 2.4 mg
- Target dose 2.4 mg/week costs $1400/month in 2021
- Efficacy
- Mean weight loss 13% body weight (at least 5% in most patients)
- Weight loss sustained >1 year while on Semaglutide
- Expect 10-12% weight loss at one year (twice the weight loss of Saxenda)
- Stop medication if inadequate weight loss (<5% at 12 weeks of 2.5 mg/week)
- References
- Indicated only in Obesity
- 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: Single Agent GLP-1 Agonist and GIP Agonist (Twincretin)
- Background
- Glucose-Dependent Insulinoptropic Polypeptide (GIP)
- Some GLP-1 Agonists are also active as GIP Agonists ("Twincretins")
- Tirzeptatide (Mounjaro) is the first drug released in 2022, that is active at both GIP and GLP-1 receptors
-
Tirzepatide (Mounjaro)
- In combination with Metformin, reduces Hemoglobin A1C up to 2.3%
- Weight loss in Diabetes Mellitus patients may approach 25 pound loss in 10 months
- Weight loss in patients without Diabetes was 15-21% of total body weight over a 72 week period
- Dose 5 mg/week reduced weight 15%, 10 mg/week reduced weight 19.5%, 15 mg/week reduced weight 20.9%
- Jastreboff (2022) N Engl J Med 387(3): 205-16 [PubMed]
- Same adverse effects and risks as with GLP-1 Agonists
- Also delays gastric emptying and may render Oral Contraceptives less effective
- No available data in 2022 on cardiovascular benefit (unlike some other GLP-1 Agonists)
- Cost in 2022: $1000 per month
- (2022) Presc Lett 29(7): 38-9
VII. 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
VIII. Efficacy
- Lowers HBA1C 0.4 to 0.8% (at 5 and 10 mcg doses)
- Lowers weight by up to 4-10 pounds
IX. 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
- Alone, GLP-1 Agonists do not significantly increase risk of Hypoglycemia
- With Sulfonylurea: 14.4% at 5 mcg, 35.7% at 10 mcg
- With Metformin: 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
- Increased with longer use, higher dose and when GLP-1 Agonist is used for weight loss
- Faillie (2016) JAMA Intern Med 176(10): 1474-81 +PMID: 27478902 [PubMed]
- Increased Heart Rate
- Heart Rate rises in 10-20 bpm in 40% of patients on Semaglutide Injection (Wegovy)
-
Diabetic Retinopathy complications (increased Retinal Hemorrhage)
- Occurs with Semaglutide (Ozempic)
- Paradoxically attributed to better Blood Glucose control
- Subcutaneous Fat Loss
- Desired weight loss (esp. Semaglutide) may result in loose, sagging skin ("Ozempic face")
- Other serious but uncommon effects (<1%)
X. 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
XI. References
- (2022) Presc Lett 30(2): 7
- (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
- Nordt and Kaucher (2023) EM:Rap 23(9)
- 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 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 | |
victoza (on 1/6/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
VICTOZA 2-PAK 18 MG/3 ML PEN | $113.59 per ml | |
VICTOZA 3-PAK 18 MG/3 ML PEN | $113.52 per ml | |
saxenda (on 8/17/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
SAXENDA 18 MG/3 ML PEN | $86.24 per ml | |
trulicity (on 1/1/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
TRULICITY 0.75 MG/0.5 ML PEN | $425.67 per ml | |
TRULICITY 1.5 MG/0.5 ML PEN | $425.63 per ml | |
TRULICITY 3 MG/0.5 ML PEN | $426.02 per ml | |
TRULICITY 4.5 MG/0.5 ML PEN | $426.10 per ml | |
soliqua (on 1/3/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
SOLIQUA 100 UNIT-33 MCG/ML PEN | $51.69 per ml | |
xultophy (on 1/6/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
XULTOPHY 100 UNIT-3.6 MG/ML PEN | $75.69 per ml | |
ozempic (on 1/6/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
OZEMPIC 0.25-0.5 MG/DOSE (2 MG/1.5 ML) PEN | $571.53 per ml | |
OZEMPIC 0.25-0.5 MG/DOSE (2 MG/3 ML) PEN | $300.06 per ml | |
OZEMPIC 1 MG/DOSE (2 MG/1.5 ML) PEN | $285.23 per ml | |
OZEMPIC 1 MG/DOSE (4 MG/3 ML) PEN | $287.01 per ml | |
OZEMPIC 2 MG/DOSE (8 MG/3 ML) PEN | $285.85 per ml | |
rybelsus (on 4/20/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
RYBELSUS 14 MG TABLET | $28.58 each | |
RYBELSUS 3 MG TABLET | $28.58 each | |
RYBELSUS 7 MG TABLET | $28.57 each | |
wegovy (on 2/22/2023 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
WEGOVY 0.25 MG/0.5 ML PEN | $657.38 per ml | |
WEGOVY 0.5 MG/0.5 ML PEN | $644.43 per ml | |
WEGOVY 1 MG/0.5 ML PEN | $644.07 per ml | |
WEGOVY 1.7 MG/0.75 ML PEN | $431.69 per ml | |
WEGOVY 2.4 MG/0.75 ML PEN | $431.80 per ml |