Dulaglutide - A Weekly Shot to Improve Blood Sugar

Overview:

Dulaglutide is a once-a-week prescription medicine to improve adult blood sugar (glucose) levels. The antidiabetic drug is injected subcutaneously (under the skin). It decreases the risk of cardiovascular events, including heart attack, stroke (occurs due to blocked blood supply), or death, in people with heart diseases. Dulaglutide is approved as an adjunct therapy to diet and exercise in managing type 2 diabetes.

How Does Dulaglutide Work?

Dulaglutide acts as an incretin mimetic hormone (responsible for stimulating insulin secretion). It works on the glucagon-like peptide-1 receptor (GLP1R). These receptors are found in the beta cells of the pancreas. It can lead to insulin release and subsequent reduction of blood glucose concentration. Dulaglutide reduces fasting glucose and post-meal concentration in patients with type diabetes mellitus through the agonism of the GLP-1 receptor. In addition, Dulaglutide reduces glucagon (a short chain of amino acid hormones produced by the alpha cells of the pancreas) and slows gastric emptying.

Uses of Dulaglutide:

Dulaglutide treats type 2 diabetes mellitus (when the body does not produce the required insulin). It is taken alone or with other medications, along with diet and exercise, to control blood sugar levels.

Dulaglutide is indicated for use in the following conditions:

• Firstly, it is used when Metformin (the first choice to manage blood sugar levels in type 2 diabetes) is not tolerated or contraindicated.

• The drug may be prescribed in addition to other medicinal products to treat diabetes.

• It reduces major adverse cardiovascular events (MACE) in adults having type 2 diabetes mellitus cardiovascular disease or multiple cardiovascular risk factors.

Limitations:

• Dulaglutide is not recommended as first-line therapy for patients with inadequate fasting blood glucose and who do not exercise.

• The drug is available only as an injection.

• Dulaglutide slows stomach emptying. It can affect the absorption of other medications.

• The drug is studied in patients with a history of pancreatitis.

• Dulaglutide must be avoided in patients having type 1 diabetes mellitus or to treat diabetic ketoacidosis (build-up of acids in blood when sugar is too high).

• Using Dulaglutide in patients with the severe gastrointestinal disease is not recommended.

Dosage:

1. Route of Administration - Subcutaneous route.

2. Dosage Strengths

• Available in a single-dose pen.

3. Dosage Forms

Dulaglutide is a liquid solution inside prefilled, single-dose, and disposable pens. The pens are for single use and must be entirely delivered as a subcutaneous solution in:

• 0.75 milligrams / 0.5 milliliters of liquid solution.

• 1.5 milligram / 0.5 milliliters of liquid solution.

• Three milligrams / 0.5 milliliters of liquid solution.

• 4.5 milligram / 0.5 milliliters of liquid solution.

4. Typical Dosage

• Monotherapy - The typical dosage range for Dulaglutide is 0.75 milligrams to 4.5 milligrams, given once a week.

• Add-On Therapy - The recommended dose is 1.5 milligrams once a week.

• The maximum dose of Dulaglutide is 4.5 milligrams, given once a week.

Special Considerations

• Pregnancy - Dulaglutide may cause fetal harm. The drug is taken only if the benefits of the drug outweigh the risk to the fetus.

• Lactation - There is no data on the effect of Dulaglutide on breastfed infants or milk production.

• Pediatric Population - The safety and efficacy of Dulaglutide in children under 18 years have yet to be established.

• Geriatric Patients - No overall difference in safety or efficacy has been detected in older individuals. The drug should be cautiously administered in older adults with varying medical problems.

• Renal Impairment - Patients with mild, moderate, or severe renal impairment do not require any adjustment. There is minimal experience in patients with end-stage renal disease, which is not recommended in this population.

• Hepatic Impairment -.There is limited clinical evidence of Dulaglutide in patients with hepatic impairment. Therefore, therapy with Dulaglutide should be cautiously administered in this population.

Warnings and Contraindications:

• Medullary Thyroid Carcinoma - Dulaglutide is contraindicated in patients with medullary thyroid carcinoma (cancer formed inside the medulla of the thyroid). The use of drugs increases the risk of developing the tumor.

• Hypersensitivity - Dulaglutide is contraindicated in patients with a prior reaction to the drug or any of its components.

• Gastroparesis - No studies are available on the effect of Dulaglutide in patients with gastroparesis, which is caused due to delay in emptying of the stomach) and is not recommended for these patients.

Warnings and Precautions:

• Risk of Thyroid C-Cell Tumors - There is an increased chance of thyroid C-cell tumors (adenomas and carcinomas) when taken for a long time. In addition, high doses of Dulaglutide also increase the incidence of the tumor.

• Pancreatitis - Studies have reported pancreas-related adverse effects with Dulaglutide. Patients must observe pancreatitis symptoms, such as continuous and severe abdominal pain.

• Hypoglycemia - Combining Dulaglutide with insulin secretagogues (substances that increase insulin secretion from the pancreas) can increase the risk of hypoglycemia. Insulin secretagogues include glucose-lowering drugs such as Sulfonylureas and Meglitinide.

For Patients

What Is Type 2 Diabetes?

Type 2 diabetes occurs when the blood glucose is too high. It happens when the body fails to produce enough insulin to help enough glucose to get into the cells to be utilized for energy. Insulin is a naturally occurring hormone produced by the pancreas.

Type 2 diabetes makes the body resistant to insulin and forces it to make extra insulin to maintain normal blood sugar levels. It is released by the pancreas when food is taken. The pancreas works hard and gets exhausted. As a result, the blood glucose levels start to rise.

Symptoms of Type 2 Diabetes:

Initially, people with type 2 diabetes may not experience symptoms and often go undiagnosed for years.

The symptoms may include,

• Feeling very thirsty.

• Passing more urine.

• Feeling tired.

• Feeling hungry.

• Slow healing.

• Weight loss.

Extremely high blood sugar levels lead to complications such as hyperosmolar syndrome. The symptoms include confusion, weakness, nausea, and seizure. It is a life-threatening form of dehydration.

Why Is Dulaglutide Prescribed For Type 2 Diabetes?

Dulaglutide is an easy-to-use drug to treat type 2 diabetes mellitus. The drug decreases A1C levels (a blood test of the average blood sugar level of the past two to three months) with a small risk of severe hypoglycemia. When controlled, blood sugar helps prevent kidney damage, blindness, nerve, or sexual function problems. The average weight loss adds an advantage in some patients. In addition, Dulaglutide reduces the incidences of several cardiovascular events, especially in patients with heart diseases or multiple cardiovascular risk factors.

Facts One Should Know About Dulaglutide:

• Dulaglutide causes weight loss. However, it is not FDA-approved for it. In addition, high drug doses may cause weight loss, leading to stomach-related side effects and low blood sugar.

• The Dulaglutide pen has only one dose and is ready to use. Dulaglutide is injected at any time, with or without food.

• Changes in diet and exercise must be combined with the medication.

• Close monitoring of blood sugar levels can avoid the risk of hypoglycemia.

How Should One Take Dulaglutide?

• Dulaglutide injection comes as a solution in a prefilled dosing pen injected subcutaneously in the stomach, thigh, or upper arm.

• The drug is given only once a week and can be taken without food.

• Always look at the injection solution before use. It should be clear, colorless, and free from solid particles.

• The injection is given on the same day of the week. Take the missed dose if a dose is missed and at least three days before the next scheduled dose. Dulaglutide cannot be taken in more than one dose in 72 hours.

• Do not inject into a vein or muscle. Care is taken to avoid injecting the same area next to each other.

• Continue taking Dulaglutide injection even if one feels better. The medicine is to be stopped by talking to the doctor.

• Do not share the dosing pen with anyone.

• Make a list of all the medicines (prescription and nonprescription). Then, show them during doctor visits or in case of admission to a hospital.

Information Be Given to the Doctor Before Taking Dulaglutide Injections:

• Allergies - Inform the doctor if Dulaglutide has caused symptoms like rash, tongue, face, or throat swelling, and other signs of allergic reaction.

• Medical History - Inform the doctor of any concurrent illnesses one may be suffering from, especially brain-related damages such as head injury, cancer, seizures, prolonged breathing problems such as asthma, sleep apnea, obstructive pulmonary disease, kidney disease, liver disease, mental disorders such as confusion, depression, suicidal thoughts, or history of substance abuse.

• Drug History - Give the doctor a complete list of the prescription and non-prescription medications one may be taking, including any herbal supplements, nutritional supplements, and vitamins. Ensure to inform the doctor if one is already taking insulin, sulfonylureas, and fluoroquinolones. Severe drug interactions may result in hypoglycemia.

• Pregnancy - Inform the doctor if one is pregnant or planning a pregnancy. Uncontrolled diabetes in pregnancy increases the mother’s risk for diabetic ketoacidosis (excess ketones in the blood), pre-eclampsia, preterm delivery, or spontaneous abortion.

• Lactation - Fewer data is available on Dulaglutide use while breastfeeding. Caution must be taken while nursing a newborn.

• Geriatrics - Older adults have age-related medical problems. Care must be taken while giving Dulaglutide to the elderly.

• Children - The use of Dulaglutide is not recommended in children.

Safety of Dulaglutide:

Dulaglutide does not increase cardiovascular risk compared to other therapies for diabetes, including Metformin, Sitagliptin, and Glargine insulin.

• Safety studies state the safe use of Dulaglutide in patients for one to two years.

• The risk of hypoglycemia with Dulaglutide is about 8 % over one year.

• The biggest concern about Dulaglutide is the risk of pancreatitis.

• Dulaglutide is not recommended for patients with a family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome types 2.

Effectiveness of Dulaglutide:

• Monotherapy with Dulaglutide reduces A1C levels (a blood test that measures blood sugar levels of the past three months) by 0.5 % to 0.7 %.

• When combined with Metformin, Dulaglutide lowers A1C levels by an additional 0.7 % to 1.0 %.

Side Effects Expected With Dulaglutide:

The common side effects that occur with the use of Dulaglutide are as follows:

• Nausea.

• Vomiting.

• Heartburn.

• Decreased appetite.

• Feeling tired.

• Hoarseness.

Serious side effects may include,

• Pain in the stomach's upper left or middle left.

• Vomiting.

• Hives.

• Rash.

• Itching.

• Breathlessness.

• Swelling of lips, tongue, face, and throat.

• Irregular heartbeat.

Can One Stop Taking Dulaglutide Suddenly Without the Doctor's Approval?

• Never stop taking medicines without talking to the doctor. The doctor will probably decrease the dose gradually. It is because stopping the medicines can cause an increase in blood sugar levels.

• Do not take the drug more than advised by the doctor.

Dietary Restrictions to Consider When Taking Dulaglutide Injection:

• Avoid consuming fried or fatty foods. These foods are difficult to digest and cause nausea while taking GLP-1 medication.

• Take food in small amounts. Eat slowly. Eat light and bland food.

• Avoid sugary snacks such as cakes, candy, and ice cream and sugar drinks such as soda pop, colas, sweet tea, or fruit drinks.

• Avoid high-fat and carbohydrates such as bread, potatoes, fast foods, and shakes.

• Maintain a fiber-rich diet, including healthy carbohydrates from fruits, vegetables, and whole grains.

• Limit alcohol consumption, as it can increase the risk of developing low blood sugar.

• Consuming grapefruit increases the blood levels of the medication and may be avoided.

Storage of Dulaglutide Injection:

• Keep the Dulaglutide injection in its original packing in the refrigerator. Keep the prefilled dosing pen at room temperature for up to 14 days. Do not freeze the dosing pen.

• Direct contact with heat, air, and light may damage the medicines. Therefore, keep the medicines away from direct light and heat.

• Keep the Dulaglutide dosing pen out of reach of children and pets. Always lock the safety caps of the medication to protect small children from poisoning themselves.

Disposal of Dulaglutide Injection:

• Do not keep outdated medicines or medicines that are no longer needed.

• Likewise, unneeded injection solutions should not be disposed of by flushing or throwing them out with regular garbage.

• The used dosing pen and cartridges are disposed of safely in a sharps container. Drop the sharps container at collection sites, hospitals, or medical waste facilities.

• Dispose of the medicine through the local medicine take-back program, which can be accessed or learned more about through the local pharmacist.

• Some people may not have access to a drug take-back program. Ask the local pharmacist about any other drug disposal options available.

Overdose:

• In case of an overdose, call the poison control helpline.

• Call the emergency services if the person has collapsed or has trouble breathing.

• Overdose symptoms include nausea, vomiting, or symptoms of hypoglycemia. Taking too much Dulaglutide increases the risk of hypoglycemia, which can be severe.

• Supportive treatment is initiated following the patient's clinical signs and symptoms.

For Doctors

Indications:

• The drug is prescribed to lower blood sugar levels. It is indicated as a supplement to diet and exercise in adults with type 2 diabetes.

• It reduces the risk of cardiovascular diseases such as heart attacks or stroke in patients with established heart diseases and multiple cardiovascular risk factors.

What Is the Pharmacology of Dulaglutide?

Description

Dulaglutide is a human GLP-1 receptor agonist. The molecule is a fusion protein consisting of two identical, disulfide-linked chains. It is a clear, colorless, sterile solution. Each 0.5 ml solution of the medicine contains 0.75 mg or 1.5 mg of Dulaglutide.

Components -

1. Active Ingredients

• Dulaglutide.

2. Inactive Ingredients

• Citric acid anhydrous (0.07 mg).

• Mannitol (23.2 mg).

• Polysorbate 80 (0.10 mg).

• Trisodium citrate dihydrate (1.37 mg).

• Water for injection.

Clinical Pharmacology:

Mechanism of Action

Dulaglutide increases insulin secretion when glucose levels are elevated. It helps the pancreas to release the right amount of insulin when blood sugar levels are high. It decreases glucagon secretions and delays gastric emptying.

Pharmacodynamics

The drug reduces fasting and post-meal glucose concentration in type 2 diabetic patients. The drug reduces glucagon secretions and enhances glucose-dependent insulin secretions. It delays gastric emptying, with the most significant delay occurring after the first dose. The effect lessens with successive doses.

Pharmacokinetics

• The mean Cmax- is 114 ng/ml and 14,000 ng/ml.

• Median Tmax- Approximately 24 to 72 hours.

[Cmax- Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose].

[Tmax- Time taken for a drug to reach maximum concentration after administration of a dose].

Pharmacokinetic Changes - Steady-state concentrations are achieved between two and four weeks after once-weekly administration. There is no statistically significant effect based on exposure sites.

A. Distribution

• Steady-state Plasma Levels - 47 % to 65 %.

• Time to Approach Steady-state Levels - 48 hours.

• Mean Volume of Distribution - 19.2 L and 17.4 L.

B. Metabolism

• Metabolic Processes- Dulaglutide is degraded into its component amino acids by general protein metabolism pathways.

C. Elimination:

Elimination of Dulaglutide occurs by degrading individual amino acids.

• Elimination Half-Life - Five days.

• Mean Clearance of Dulaglutide - 0.142 liters per hour.

Special Considerations:

• Renal Impairment - Impaired renal function can result in a reduced rate and decreased excretion of Dulaglutide and its active metabolite.

• Hepatic Impairment - Close monitoring is required while administering Dulaglutide in hepatic dysfunction.

• Alcohol - Taking alcohol can increase the risk of low blood sugar levels and should be avoided.

• Age - Dulaglutide should be avoided in children below 18 years of age.

Drug Interactions:

• Sulfonylureas - Combining Dulaglutide with sulfonylureas increases the risk of hypoglycemia. Dose adjustments may be made to manage the interaction.

• Glinides - The medication stimulates the pancreas to release insulin. Combining the two drugs has a high risk of hypoglycemia.

• Fluoroquinolones - The combination with antibiotics affects blood sugar levels, especially in the elderly. Regular monitoring of blood sugar levels is required during treatment.

• Acetazolamide - The drug interferes with blood glucose control and reduces the effectiveness of Dulaglutide and other diabetic drugs.

• Bexarotene - Taking Dulaglutide with Bexarotene increases the risk of pancreatitis or inflammation of the pancreas.

• Gatifloxacin - The drug affects the blood glucose levels in patients with diabetes and should be avoided.

• Gymnema - Combining Gymnema with Dulaglutide may lower the blood sugar levels too low and should be avoided.

What Have Clinical Trials Shown About Dulaglutide?

Trial 1:

Objective - To study once-weekly Dulaglutide for treating youths with type 2 diabetes.

• A double-blind, placebo-controlled 26-week trial was conducted on 154 participants.

• Random participants (10 to 18 years of age) were treated with lifestyle modifications alone or with Metformin and received once-weekly subcutaneous injections of placebo, Dulaglutide 0.75 mg.

Primary End Point - change from baseline in the glycated hemoglobin level at 26 weeks.

Secondary End Point - The glycated hemoglobin level changed from the fasting glucose Concentration baseline to less than 7.0 %.

Result - The mean glycated hemoglobin level had increased in the placebo group and decreased in the Dulaglutide group. The fasting glucose concentration increased in the placebo group and decreased in the Liraglutide group. Treatment with Dulaglutide at a once-weekly dose of 0.75 milligrams was superior to a placebo in improving glycemic control among youths with type 2 diabetes.

Trial 2:

Objective - To evaluate the real-world efficacy, durability, and side effects profile of once-a-week GLP 1 RA Dulaglutide in Indian type 2 diabetes mellitus patients.

• A retrospective observational study for efficacy, including HbA1c and weight, on 117 patients who were prescribed Dulagutide.

Primary End Point - Six-month follow-up of 74 patients showed a mean reduction of HbA1c by 0.87 % and weight by 3.8 %.

Final End Point - Subjects with poor glycemic control or greater weight had a fall in HbA1c or had a weight reduction at the end of the study. 25 % of the subjects discontinued the treatment because of gastrointestinal side effects.

Result - Hb1Ac is linearly related and proportional to baseline HbA1c levels. Subjects having higher baseline HbA1c at the initiation of therapy with Dulaglutide showed a more significant reduction in HbA1c levels. Also, the weight difference observed significantly correlated with the subject's baseline weight.

Patient Counseling Information:

Administration Instructions

• Dulaglutide is injected weekly without regard to meals.

• The medicine is given as a shot under the skin of the stomach, thigh, or upper arm.

• Ensure the injection is used on the same day each week at any time.

• Never reuse or share dosing pens and dispose of them in a puncture-proof container.

• Use a new needle each time.

• Do not use the medicine if the color has changed and looks cloudy.

• Exercise regularly and test blood sugar or urine to see results.

• Do not keep outdated medicines or medicines that are no longer needed.

• Family members must be counseled about diabetes, dosing, lifestyle changes, and diet.

Complications or Side Effects:

• Allergic Reactions - Dulaglutide causes severe allergic reactions, including anaphylaxis and angioedema, which may be life-threatening. Patients may complain of chest tightness, cough, difficulty swallowing, fast heartbeat, hives, or swelling of the face or around the eyes.

• Thyroid Cancer - Dulaglutide has a boxed warning for the risk of thyroid cancer. A boxed warning is a severe warning from the Food and Drug Administration.

• Diabetic Retinopathy - Using Dulaglutide in patients with a history of eye problems, including diabetic retinopathy (a complication of diabetes causing damage to the eyes), can worsen the condition.

• Children - Dulaglutide is not used in children under 18 years.

• Avoid Driving - Avoid driving or using machinery if there are any signs of low blood sugar.

• Alcohol - Drinking alcohol causes severe low blood sugar and may be avoided.

• Other Medicines - Do not mix other medicines, such as insulin or Metformin, with Dulaglutide. In addition, caution must be taken while administering non-prescription drugs, such as for colds, coughs, headaches, or sinus problems.

• Digestive Problems - Dulaglutide causes digestive problems with symptoms including nausea, vomiting, and abdominal pain.