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Glucagon-like peptide-1 (GLP-1) AGONIST - Incretin Mimetics

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Drug Monographs   top of page

Products

exenatide (Byetta ®) Liraglutide (Victoza®)

Typical reductions in A1C values - Incretin Mimetics:

 
0.5 - 1.0%.
Background

Overview

 DPP4 inhibitors - Incretin mimetics


Diabetes:  Drug Class Navigation  top of page

Secretagogues

Insulin sensitizers

Alpha-glucosidase inh

Sulfonylureas Biguanides e.g. Metformin Alpha-glucosidase Inhibitors
 Meglitinides (e.g. Prandin) Glitazones - Thiazolidinediones  

Peptide analogs

AMYLIN AGONISTS - Anti-hyperglycemic Synthetic Analogs DPP-4 INHIBITORS -  Dipeptidyl peptidase-4 inhibitor  –    Gliptins Glucagon-like peptide-1 (GLP-1) AGONIST -Incretin Mimetics 

exenatide (Byetta ®) top of page

These highlights do not include all the information needed to use BYETTA safely and effectively. See full prescribing information for BYETTA.

CLINICAL PHARMACOLOGY
:
Mechanism of Action:
Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. BYETTA is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.

The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide promotes insulin release from pancreatic beta cells in the presence of elevated glucose concentrations.

BYETTA improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.

Glucose-dependent insulin secretion: BYETTA has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, BYETTA does not impair the normal glucagon response to hypoglycemia.

First-phase insulin response: In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of BYETTA at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with BYETTA compared with saline (p <0.001 for both).


Pharmacokinetics:
Absorption:
Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC 0-inf) was 1036 pg·h/mL following SC administration of a 10-mcg dose of BYETTA. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of BYETTA in the abdomen, thigh, or upper arm.

Distribution:
The mean apparent volume of distribution of exenatide following SC administration of a single dose of BYETTA is 28.3 L.

Metabolism and Elimination:
Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 h post-dose.


INDICATIONS AND USAGE:
Type 2 Diabetes Mellitus:
BYETTA is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use
BYETTA is not a substitute for insulin. BYETTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

The concurrent use of BYETTA with insulin has not been studied and cannot be recommended.

Based on postmarketing data BYETTA has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. BYETTA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using BYETTA. Other antidiabetic therapies should be considered in patients with a history of pancreatitis

DOSAGE AND ADMINISTRATION:
Recommended Dosing:
BYETTA should be initiated at 5 mcg administered twice daily at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). BYETTA should not be administered after a meal. Based on clinical response, the dose of BYETTA can be increased to 10 mcg twice daily after 1 month of therapy. Initiation with 5 mcg reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. No data are available on the safety or efficacy of intravenous or intramuscular injection of BYETTA.

Use BYETTA only if it is clear, colorless and contains no particles.

Renal Impairment:
BYETTA is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 mL/min) and should be used with caution in patients with renal transplantation. No dosage adjustment of BYETTA is required in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min). Caution should be applied when initiating or escalating doses of BYETTA from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min)


DOSAGE FORMS AND STRENGTHS:
BYETTA is supplied as 250 mcg/mL exenatide in:
5 mcg per dose, 60 doses, 1.2 mL prefilled pen
10 mcg per dose, 60 doses, 2.4 mL prefilled pen


CONTRAINDICATIONS:
History of severe hypersensitivity to exenatide or any product components .


WARNINGS AND PRECAUTIONS:
Pancreatitis: Postmarketing reports, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Discontinue BYETTA promptly. BYETTA should not be restarted. Consider other antidiabetic therapies in patients with a history of pancreatitis.
Hypoglycemia: Increased risk when BYETTA is used in combination with a sulfonylurea. Consider reducing the sulfonylurea dose.
Renal Impairment: Postmarketing reports, sometimes requiring hemodialysis and kidney transplantation. BYETTA should not be used in patients with severe renal impairment or end-stage renal disease and should be used with caution in patients with renal transplantation. Caution should be applied when initiating BYETTA or escalating the dose of BYETTA in patients with moderate renal failure.
Severe Gastrointestinal Disease: Use of BYETTA is not recommended in patients with severe gastrointestinal disease (e.g., gastroparesis).
Hypersensitivity: Postmarketing reports of hypersensitivity reactions (e.g. anaphylaxis and angioedema). The patient should discontinue BYETTA and other suspect medications and promptly seek medical advice.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYETTA or any other antidiabetic drug.


ADVERSE REACTIONS:
Most common (geq5%) and occurring more frequently than placebo in clinical trials: nausea, hypoglycemia, vomiting, diarrhea, feeling jittery, dizziness, headache, dyspepsia. Nausea usually decreases over time.

Postmarketing reports of increased international normalized ratio (INR) with concomitant use of warfarin, sometimes with bleeding.

To report SUSPECTED ADVERSE REACTIONS contact Amylin Pharmaceuticals, Inc. and Eli Lilly and Company at 1-800-868-1190 and www.byetta.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS:
Warfarin: Postmarketing reports of increased INR sometimes associated with bleeding. Monitor INR frequently until stable upon initiation or alteration of BYETTA therapy.


USE IN SPECIFIC POPULATIONS:
Pregnancy: Based on animal data, BYETTA may cause fetal harm. BYETTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To report drug exposure during pregnancy call 1-800-633-9081.
Nursing Mothers: Caution should be exercised when BYETTA is administered to a nursing woman (8.3).

Liraglutide (Victoza®)  top of page

These highlights do not include all the information needed to use Victoza safely and effectively. See full prescribing information for Victoza.

Victoza® (liraglutide (rDNA origin) injection), solution for subcutaneous use -
Initial U.S. Approval: 2010

WARNING: RISK OF THYROID C-CELL TUMORS

See full prescribing information for complete boxed warning.

Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in rodents. It is unknown whether Victoza causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies.
Victoza is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

INDICATIONS AND USAGE:
Victoza is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use:
[1] Not recommended as first-line therapy for patients inadequately controlled on diet and exercise.
[2] Has not been studied sufficiently in patients with a history of pancreatitis. Use caution.
[3] Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
[4] Has not been studied in combination with insulin.


DOSAGE AND ADMINISTRATION:
Administer once daily at any time of day, independently of meals.
Inject subcutaneously in the abdomen, thigh or upper arm.
The injection site and timing can be changed without dose adjustment.
Initiate at 0.6 mg per day for one week. This dose is intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control. After one week, increase the dose to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg.
When initiating Victoza, consider reducing the dose of concomitantly-administered insulin secretagogues to reduce the risk of hypoglycemia.
Victoza solution should be inspected prior to each injection, and the solution should be used only if it is clear, colorless, and contains no particles.



DOSAGE FORMS AND STRENGTHS:

Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg,
or 1.8 mg (6 mg/mL, 3 mL)



CONTRAINDICATIONS:
Do not use in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.

WARNINGS AND PRECAUTIONS:
Thyroid C-cell tumors in animals: Human relevance unknown. Counsel patients regarding the risk of medullary thyroid carcinoma and the symptoms of thyroid tumors.

Pancreatitis: In clinical trials, there were more cases of pancreatitis among Victoza-treated patients than among comparator-treated patients. If pancreatitis is suspected, Victoza and other potentially suspect drugs should be discontinued. Victoza should not be restarted if pancreatitis is confirmed. Use with caution in patients with a history of pancreatitis.

Serious hypoglycemia: Can occur when Victoza is used with an insulin secretagogue (e.g. a sulfonylurea). Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia.

Macrovascular outcomes: There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza or any other antidiabetic drug.


ADVERSE REACTIONS:
The most common adverse reactions, reported in geq5% of patients treated with Victoza and more commonly than in patients treated with placebo, are: headache, nausea, diarrhea and anti-liraglutide antibody formation.
Immunogenicity-related events, including urticaria, were more common among Victoza-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials.

To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-877-484-2869 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS:
Victoza delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use caution.


USE IN SPECIFIC POPULATIONS:
There are no data in patients below 18 years of age.
Use with caution in patients with renal or hepatic impairment.


CLINICAL PHARMACOLOGY:
Mechanism of Action:
Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). GLP-1(7-37) represents <20% of total circulating endogenous GLP-1. Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying.

GLP-1(7-37) has a half-life of 1.5-2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once daily administration, is a result of self-association that delays absorption, plasma protein binding and stability against metabolic degradation by DPP-IV and NEP.

Pharmacodynamics:
Victoza’s pharmacodynamic profile is consistent with its pharmacokinetic profile observed after single subcutaneous administration as Victoza lowered fasting, premeal and postprandial glucose throughout the day.

Fasting and postprandial glucose was measured before and up to 5 hours after a standardized meal after treatment to steady state with 0.6, 1.2 and 1.8 mg Victoza or placebo. Compared to placebo, the postprandial plasma glucose AUC 0-300min was 35% lower after Victoza 1.2 mg and 38% lower after Victoza 1.8 mg.

Glucose-dependent insulin secretion
The effect of a single dose of 7.5 mcg/kg (~ 0.7 mg) Victoza on insulin secretion rates (ISR) was investigated in 10 patients with type 2 diabetes during graded glucose infusion. In these patients, on average, the ISR response was increased in a glucose-dependent manner (Figure 2).


Figure 2: Mean Insulin Secretion Rate (ISR) versus Glucose Concentration Following Single-Dose Victoza 7.5 mcg/kg (~ 0.7 mg) or Placebo in Patients with Type 2 Diabetes (N=10) During Graded Glucose Infusion

victoza

Glucagon secretion:
Victoza lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. A single dose of Victoza 7.5 mcg/kg (~ 0.7 mg) did not impair glucagon response to low glucose concentrations.

Gastric emptying:
Victoza causes a delay of gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.

Cardiac Electrophysiology (QTc):
The effect of Victoza on cardiac repolarization was tested in a QTc study. Victoza at steady state concentrations with daily doses up to 1.8 mg did not produce QTc prolongation.

Pharmacokinetics:
Absorption - Following subcutaneous administration, maximum concentrations of liraglutide are achieved at 8-12 hours post dosing. The mean peak (Cmax) and total (AUC) exposures of liraglutide were 35 ng/mL and 960 ng·h/mL, respectively, for a subcutaneous single dose of 0.6 mg. After subcutaneous single dose administrations, Cmax and AUC of liraglutide increased proportionally over the therapeutic dose range of 0.6 mg to 1.8 mg. At 1.8 mg Victoza, the average steady state concentration of liraglutide over 24 hours was approximately 128 ng/mL. AUC0-infinity was equivalent between upper arm and abdomen, and between upper arm and thigh. AUC0-infinity from thigh was 22% lower than that from abdomen. However, liraglutide exposures were considered comparable among these three subcutaneous injection sites. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%.

Distribution - The mean apparent volume of distribution after subcutaneous administration of Victoza 0.6 mg is approximately 13 L. The mean volume of distribution after intravenous administration of Victoza is 0.07 L/kg. Liraglutide is extensively bound to plasma protein (>98%).

Metabolism - During the initial 24 hours following administration of a single [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.

Elimination - Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6% and 5%, respectively). The majority of urine and feces radioactivity was excreted during the first 6-8 days. The mean apparent clearance following subcutaneous administration of a single dose of liraglutide is approximately 1.2 L/h with an elimination half-life of approximately 13 hours, making Victoza suitable for once daily administration.



Recommended Storage:
Prior to first use, Victoza should be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze Victoza and do not use Victoza if it has been frozen.

After initial use of the Victoza pen, the pen can be stored for 30 days at controlled room temperature (59°F to 86°F; 15°C to 30°C) or in a refrigerator (36°F to 46°F; 2°C to 8°C). Keep the pen cap on when not in use. Victoza should be protected from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the Victoza pen without an injection needle attached. This will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy.

Background   top of page

Incretins are insulin secretagogues. The two main candidate molecules that fulfill criteria for being an incretin are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic peptide, GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).

Glucagon-like peptide analogs and agonists
"Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor. As a consequence, insulin release from the pancreatic beta cells is increased. Endogenous GLP has a half life of only a few minutes, thus an analogue of GLP would not be practical.

Exenatide (also Exendin-4, marketed as Byetta) is the first GLP-1 agonist approved for the treatment of type 2 diabetes. Exenatide is not an analogue of GLP, but rather a GLP agonist. Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life. Typical reductions in A1C values are 0.5-1.0%.

Liraglutide, a once daily human analogue (97% homology), has been developed by Novo Nordisk under the brand name Victoza.

Taspoglutide is presently in Phase III clinical trials with Hoffman-La Roche.

These agents may also cause a decrease in gastric motility, responsible for the common side effect of nausea, and is probably the mechanism by which weight loss occurs."  [source]

References

Package insert data.

Disclaimer

Listed dosages are for - Adult patients ONLY. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER. GlobalRPH does not directly or indirectly practice medicine or provide medical services and therefore assumes no liability whatsoever of any kind for the information and data accessed through the Service or for any diagnosis or treatment made in reliance thereon.
David F. McAuley, Pharm.D., R.Ph.  GlobalRPh Inc.
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