Exenatide

Exenatide is an Anti-diabetic Agent belonging to the pharmacological class of long-acting Glucagon-like peptide-1 receptor agonists (GLP-1 RA).

Exenatide is approved for treating type 2 diabetes mellitus in adults. It is prescribed to help improve blood sugar control in adults with this condition and is often used with diet, exercise, or other antidiabetic medications.

Exenatide is administered subcutaneously with a rapid onset of action, reaching peak plasma concentrations in about 2 hours. Its half-life is approximately 2.4 hours, necessitating twice-daily dosing. Renal elimination plays a significant role in clearance, with approximately 40% excreted unchanged in urine.

The most common side effects are diarrhoea, vomiting, and nausea. Hypoglycemia, or low blood sugar, can result from it as well, especially if you also take other diabetic medications such as sulphonylureas or insulin.

Exenatide is available in the form of injectable solutions (prefilled pen)

The molecule is available in the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.

Exenatide is an Anti-diabetic Agent belonging to the pharmacological class of long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RA)

Following their release into the circulation from the gut, incretins, such as glucagon-like peptide-1 (GLP-1), boost glucose-dependent insulin production and display additional antihyperglycemic effects. Exenatide is a GLP-1 receptor agonist that increases the pancreatic beta-cells ability to secrete insulin in response to glucose levels, inhibits unnecessarily excessive glucagon release, and delays stomach emptying.

Exenatide's amino acid sequence and human GLP-1's partly overlap. In vitro studies have demonstrated that exenatide binds to and activates the human GLP-1 receptor. By means of processes involving cyclic AMP and/or other intracellular signalling pathways, this increases the pancreatic beta cells' in vivo insulin production and their glucose-dependent insulin synthesis.

Data duration of Exenatide action typically lasts about one week after a single subcutaneous injection.

The Data of Tmax of Exenatide occurs approximately 10-12 hours after subcutaneous administration.

The Data of Cmax of Exenatide approximately 2.1 hours after subcutaneous administration.

Exenatide is available in the form of injectable solutions (prefilled pen)

Injectable solutions: To be administered parenterally, as applicable.

Make sure there are no particles or colour changes before using this product. Use the liquid sparingly if either problem is present. Usually, once every seven days, give this medicine. The veins and muscles should not be injected with it. With or without food, it can be taken. Give the insulin and Exenatide separately if you're also taking the former. Maintain them separately. The injection sites should not be close to one another, even if you can inject various drugs in the same area.

Treatment of Type 2 diabetes mellitus

• Exenatide can be used to treat Diabetes mellitus type 2 treatment. It helps regulate glucose levels after meals by stimulating insulin release and reducing the amount of glucose the liver produces.
• It is typically prescribed as an adjunct therapy to diet and exercise for individuals with type 2 diabetes who have not achieved adequate blood sugar control with other oral antidiabetic medications.
• It may be used to lose weight or weight maintenance, making it a favourable choice for those with type 2 diabetes who need to lose or control their weight.

In Treatment of Type 2 diabetes mellitus

Exenatide helps to control high blood glucose (sugar) levels. It reduces the possibility of hyperglycemia by helping in blood sugar regulation. It also encourages moderate weight reduction or weight maintenance, which is beneficial to individuals aiming to control either their weight and their diabetes. Exenatide also promotes the synthesis of insulin, improving glucose regulation after meals.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

• It is indicated as an adjunct to exercise and diet to help individuals improve glycemic control in adults with type 2 diabetes mellitus
• A substitute monotherapy, metformin, thiazolidinediones, or sulfonylureas as adjunctive therapy or addition therapy to insulin glargine (long-acting insulin),
• If patients cannot adequately regulate their blood sugar levels with insulin glargine, they may be given either with or without metformin and/or a thiazolidinedione.

Parenterally: Exenatide is available as an injection solution that can be administered parenterally. It is advised to take within 60 minutes before morning and evening meals, approximately 6 hr or more apart. Exenatide with or without meals once per week, at any time of the day. In the upper arm, thigh, or abdomen, it is injected subcutaneously (SC) and switch up the injection location every time you provide a dosage. Administer SC only; do not administer IM or IV. Never combine the shots when using insulin; always give them separately. The injections of insulin and Exenatide may be administered in the same area of the body, but they shouldn't be close together.

The physician will start the treatment on a low dose to reduce the risk of stomach or abdominal side effects, gradually increasing it as necessary.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Injection solutions: 250mcg/mL (1.2mL vial) or 250mcg/mL (2.4mL vial)

Exenatide is available in the form of injection solutions (prefilled pen)

Dose Adjustment in Adult Patients:

Diabetes Mellitus Type 2

Immediate-release: Initially, 5 mcg SC q12hr within 60 minutes before meals; after 1 month, this dose may be increased to 10 mcg q12hr.

The switch from immediate to delayed release

One day after stopping exenatide (Byetta) with immediate release, begin weekly extended-release SC injections.

Following the beginning of extended-release (Bydureon) medication, blood glucose levels may rise for around two weeks.

Exenatide extended-release administration may begin without a prior dose of the drug's immediate-release dosage form.

Dosing Considerations

Intracranial Hypertension (Orphan)

Orphan designation for idiopathic intracranial hypertension

Exenatide should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.

While taking Exenatide, maintain regular meal schedules with balanced macronutrient content to help stabilize blood sugar levels. Avoid injections after meals and advised to take within 60 minutes of a meal, twice daily.

Limit or avoid the intake of alcohol as it can interfere with blood sugar regulation.

Be cautious with fatty or high-calorie meals, as these may worsen gastrointestinal side effects such as nausea, vomiting, or diarrhoea.

Be cautious about the risk of low blood sugar, particularly when combined with other diabetes medications that can cause hypoglycemia. Always carry a source of fast-acting glucose (like glucose tablets) to raise blood sugar if needed.

It is advised to stay hydrated, maintain a rich, balanced diet with appropriate carbohydrate intake, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Exenatide may be contraindicated in the following conditions:-

• Hypersensitivity
• Severe renal impairment (CrCl 30 mL/min), often known as ESRD.
• Previous history of immune-mediated thrombocytopenia caused by drugs or related goods
• Any past or family history of medullary thyroid cancer

• Consider reducing the insulin dose in individuals with an increased risk of hypoglycemia when combined with long-acting insulin (such as insulin glargine).
• Acute Kidney Injury: Exenatide has been linked to altered renal function, including higher blood creatinine levels, renal impairment, worsening of chronic renal failure, and sporadic acute renal failure necessitating hemodialysis or kidney transplantation. Some incidents happened in people taking other medications known to affect hydration or renal function. With supportive treatment and the cessation of probable causal agents, renal function often improved. Clinical and preclinical research have not revealed any direct nephrotoxicity. Exercise care while starting or increasing dosages, particularly in individuals with mild renal impairment (creatinine clearance 30–50 mL/min), as several side effects, including nausea, vomiting, and temporary hypovolemia, are possible.
• Severe hypersensitivity reactions, like anaphylaxis and angioedema, have been reported. If a hypersensitivity reaction happens, stop therapy and any other suspect medications and seek medical help immediately. Patients who have previously experienced anaphylaxis or angioedema after taking another GLP-1 receptor agonist should also be informed and closely monitored for allergic reactions; it is unknown whether these patients will be more likely to experience it with the specific drug.
• Risk of acute pancreatitis has been reported that include both fatal and nonfatal hemorrhagic or necrotizing pancreatitis; after dose initiation and after dose increases, cautiously monitoring patients for any signs and symptoms of pancreatitis (persistent severe abdominal pain which may sometimes radiate to the back may or may not be accompanied by vomiting); Stop taking the medication right away and start the proper therapy if pancreatitis is suspected; Don't start your therapy again if pancreatitis has been diagnosed; In individuals with a history of pancreatitis, consider using antidiabetic medications besides exenatide.
• Reducing the dosage of sulfonylurea (or another concurrently administered insulin secretagogue) or insulin in patients at increased risk of hypoglycemia may lower that risk. Concurrent use of prandial insulin has yet to be studied and cannot be advised. Other glucose-independent insulin secretagogues (such as meglitinides or sulfonylureas) or insulin could reduce that risk.
• Patients taking these concurrent drugs should be made aware of the risk of hypoglycemia and instructed on the symptoms and indications of hypoglycemia.
• Severe bleeding from drug-induced immune-mediated thrombocytopenia that can be fatal has been reported in a post-marketing setting; this condition is an immune-mediated reaction with exenatide-dependent anti-platelet antibodies that destroy platelets when exenatide is present. If drug-induced thrombocytopenia is suspected, stop the patient's treatment immediately and avoid re-exposing them to exenatide.
• Exenatide antibody development is likely, and up to 4% of patients may experience deteriorating glycemic control and need alternate antidiabetic treatment.

It is unsafe to consume Exenatide with alcohol.

There is no sufficient scientific evidence traceable regarding the use and safety of Exenatide in breastfeeding.

Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus.

Limit Alcohol consumption, and avoid heavy or high-fat meals.

The adverse reactions related to Exenatide can be categorized as:

Common Adverse Effects: Nausea, vomiting, diarrhoea, and injection site reactions.

Less Common Adverse effects: Abdominal pain, headache or dizziness

Rare Adverse Effects: Severe allergic reactions, pancreatitis, or thyroid problems.

Reports on Postmarketing

Alopecia

allergic response

Angioedema

Pancreatitis

Rash

Kidney problems

Upper respiratory infection

severe hypoglycemia with concurrent usage of insulin or sulfonylurea

Dysgeusia

Somnolence

Cholecystectomy is necessary due to cholecystitis and cholelithiasis

The clinically relevant drug interactions of Exenatide are briefly summarized here.

• Warfarin: Exenatide may alter the effectiveness of warfarin, a blood thinner. Close monitoring of blood clotting parameters is necessary if these drugs are used together.
• Digoxin: Exenatide might decrease the absorption of digoxin, a medication used for heart conditions. Monitor digoxin levels and adjust the dose if necessary.
• Insulin: When used with insulin or insulin secretagogues (e.g., sulfonylureas), Exenatide can increase the risk of hypoglycemia (low blood sugar). Dosage adjustments may be needed.
• Gastrointestinal Medications: Drugs that affect gastrointestinal motility, like metoclopramide, may alter the absorption of Exenatide.
• Beta-Blockers: Beta-blockers can mask the symptoms of hypoglycemia, so patients taking them alongside Exenatide should be cautious and monitor their blood sugar levels closely

The most common side effects of Exenatide include:

• Diarrhea
• Hypoglycaemia (low blood sugar level) in combination with insulin or sulphonylurea
• Nausea
• Vomiting

• Pregnancy

Pregnancy Category C; Use with caution if benefits outweigh risks.

Some risks affect the mother and the foetus associated with poorly managed pregnancy diabetes; however, the limited data on pregnant women do not allow for a determination of a drug-related risk for severe birth abnormalities or miscarriage.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women with poorly managed diabetes have an increased risk of developing diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm birth, stillbirth, and delivery complications. Significant birth abnormalities, stillbirths, and macrosomia-related morbidity are more likely in foetuses with poorly managed diabetes.

Animal Data

Exenatide exposure during pregnancy and breastfeeding has been associated with worse foetal and neonatal outcomes in animal reproduction studies and maternal effects.

Exenatide, given to mice during pregnancy and lactation, increased newborn fatalities at systemic exposure, resulting in a maximum recommended human dosage (MRHD) of 20 mcg/day.

• Nursing mothers:

There is no information on the drug's presence in breast milk, its effects on nursing infants, or milk production. The drug was found in lactating mice's milk, but the clinical relevance of the data could be more evident due to species-specific differences in lactation physiology. The developmental and health benefits of breastfeeding should be considered, along with the mother's clinical need for therapy and any potential adverse effects on the breastfed child from the drug or other medical issues.

Data

Exenatide concentration in milk reached up to 2.5% of the levels in maternal plasma in breastfeeding mice that received subcutaneous injections of the drug twice daily.

• Pediatric Use

As per the FDA, safety and effectiveness in the pediatric population have not been established.

• Geriatric Use

According to a population pharmacokinetic investigation of individuals aged 22 to 73, exenatide's pharmacokinetic characteristics are unaffected by patient age. 16 individuals 75 years of age or older and 282 patients 65 or older participated in the study. These patients and younger patients did not vary in safety or efficacy. Renal function should be considered when choosing a dosage for seniors since they are more likely to have diminished renal function.

No variations in safety or efficacy for Exenatide have been reported between patients 65 and older and younger adult patients.

Dose Adjustment in Kidney Impairment Patients:

Mild (CrCl 50-80 mL/min):No dosage adjustment is necessary

Moderate (CrCl 30-50 mL/min): Use caution while starting or increasing the dose

ESRD or severe (CrCl 30 mL/min): not advised

Renal transplantation: Use with caution

Dose Adjustment in Hepatic Impairment Patients:

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Exenatide.

Overconsumption of Exenatide may lead to severe nausea, vomiting, diarrhoea, and possibly low blood sugar (hypoglycemia).

Management

There is no specific antidote or treatment for excessive intake of Exenatide. However, immediate medical attention is essential. Exenatide should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Activated charcoal or gastric lavage may also be considered if the overdose is detected shortly after ingestion to reduce absorption.

Management typically involves supportive measures like intravenous fluids, fluid replacement to prevent dehydration, and symptomatic treatment such as antiemetic medications for nausea and vomiting.

If severe hypoglycemia occurs, glucose administration (e.g., IV dextrose) may be necessary to raise blood sugar levels.

In severe cases, Intravenous (IV) glucose administration may be required to maintain proper hydration and electrolyte balance.

Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of hypoglycemia.

Pharmacodynamics:

The body's normal response to glucose is altered when people take exenatide. In response to glucose, more insulin and less glucagon are produced, yet in situations of hypoglycemia, a normal quantity of glucagon is released. Exenatide also prolongs the time it takes for the stomach to empty, which delays the flow of glucose into the bloodstream. These outcomes avoid both hyper- and hypoglycemia.

Cardiac Electrophysiology

In a randomised, placebo- and active-controlled crossover comprehensive QTc research involving 62 healthy volunteers, the impact of exenatide 10 g subcutaneously on QTc interval was assessed. The greatest placebo-adjusted, baseline-corrected QTc in this trial, which has shown ability to identify modest effects, has an upper bound of the 90% confidence interval < 10 msec. Exenatide (10 mcg single dosage) was thus not linked to a clinically significant lengthening of the QTc interval.

An extensive QTc research was conducted to examine the impact of Exenatide on cardiac repolarization. At dosages of 4 and 7 mg, Exenatide had no effect in QTc prolongation. The maximum recommended dosage is 4.5 mg, administered once per week.

Pharmacokinetics:

Absorption

In 2.1 hours, exenatide's plasma concentration reaches its optimum level. Exenatide's bioavailability is 1 because it is administered subcutaneously.

Peak plasma time: 2.1 hr

Peak plasma concentration: 211 pg/mL

AUC: 1036 pg·hr/mL

Distribution

Following SC administration of a single dosage of exenatide, the mean apparent volume of distribution of exenatide is 28.3 L.

Vd: 28.3 L

Metabolism

Dipeptidyl peptidase-4, metalloproteases, endopeptidase 24-11, amino proteases, and serine proteases break down exenatide into smaller peptides and amino acids before the glomerulus filters it. Currently, most exenatide's deterioration is thought to be caused by metalloproteases. Enzymes in the kidney break down exenatides to produce tiny peptides with a length of three amino acids.

Proteolytic degradation following glomerular filtration

Elimination

Exenatide is primarily eliminated through glomerular filtration, then proteolysis, and then excreted in the urine.

Half-life: 2.4 hr (immediate release); 2 weeks (extended-release)

Renal clearance: 9.1 L/hr

Excretion: Urine (primarily)

• Fayfman, Maya et al. “A Randomized Controlled Trial on the Safety and Efficacy of Exenatide Therapy for the Inpatient Management of General Medicine and Surgery Patients With Type 2 Diabetes.” Diabetes care vol. 42,3 (2019): 450-456. doi:10.2337/dc18-1760
• Lønborg, Jacob & Kelbæk, Henning & Vejlstrup, Niels & Bøtker, Hans & Kim, Won & Holmvang, Lene & Jørgensen, Erik & Helqvist, Steffen & Saunamäki, Kari & Terkelsen, Christian & Schoos, Mikkel & Køber, Lars & Clemmensen, Peter & Treiman, Marek & Engstrøm, Thomas. (2012). Exenatide Reduces Final Infarct Size in Patients With ST-Segment-Elevation Myocardial Infarction and Short-Duration of Ischemia. Circulation. Cardiovascular interventions. 5. 288-95. 10.1161/CIRCINTERVENTIONS.112.968388.
• Athauda, Dilan et al. “Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial.” Lancet (London, England) vol. 390,10103 (2017): 1664-1675. doi:10.1016/S0140-6736(17)31585-4
• Doggrell A. Sheila, Is Exenatide Improving the Treatment of Type 2 Diabetes? Analysis of the Individual Clinical Trials with Exenatide, Reviews on Recent Clinical Trials 2007; 2(1) . https://dx.doi.org/10.2174/157488707779318053

• Inform patients that sharing an Exenatide pen with another person is harmful, even if the needle has been replaced, due to the possibility of spreading blood-borne diseases.
• Warn patients that the defining sign of acute pancreatitis is persistent, intense abdominal pain that may extend to the back and may or may not be followed by vomiting. Instruct patients to stop taking Exenatide immediately and call their doctor if they have severe stomach discomfort.
• Remind patients that using Exenatide alongside a substance that causes hypoglycemia, such as sulfonylurea or insulin, increases the risk of hypoglycemia. Inform patients about the symptoms and indicators of hypoglycemia.
• Explain to patients on Exenatide the potential risk of deteriorating renal function and other relevant information.
• Patients using Exenatide should be made aware of the likelihood of deteriorating renal function, the accompanying signs and symptoms of renal dysfunction, and the possibility of dialysis as a medical intervention for renal failure.
• Inform patients know that exenatide usage has been associated with immune-mediated thrombocytopenia. Remind patients to discontinue taking Exenatide and seek immediate medical attention if they experience signs of thrombocytopenia.
• Inform patients that exenatide has been used post-marketing without any documented hypersensitivity reactions. Patients should be told to cease taking Exenatide if they have signs of an allergic reaction and to contact their doctor immediately.
• The possibility of cholelithiasis or cholecystitis should be explained to patients. Patients should be urged to consult their doctor if they suspect they may have cholelithiasis or cholecystitis to receive the proper clinical follow-up.

https://www.ncbi.nlm.nih.gov/books/NBK518981/

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm

https://www.ncbi.nlm.nih.gov/books/NBK548665/

https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021773s9s11s18s22s25lbl.pdf