Dulaglutide

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

Dulaglutide is approved for treating type 2 diabetes mellitus in adults. It simulates the actions of incretin hormones, which increase insulin release and decrease glucagon production in response to meals, to enhance glycemic control and lower blood sugar levels.

After subcutaneous injection, dulaglutide is slowly absorbed and reaches its peak in around 48 hours. Its extended half-life of elimination, around five days, is significant. Proteolytic breakdown accounts for most of the drug's removal, whereas renal excretion is relatively minor.

The most common side effects of dulaglutide include nausea, diarrhoea, stomach discomfort, and appetite loss. Hypoglycemia (low blood sugar level) can potentially result from it, especially if patients take other blood sugar-lowering medications simultaneously.

Dulaglutide is available in the form of injectable solutions

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

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

Dulaglutide stimulates the pancreatic beta cells' GLP-1 receptor, with 90% of its amino acid sequence with endogenous human GLP-1. In pancreatic beta cells, where it is membrane-bound and connected to adenylyl cyclase, dulaglutide stimulates the GLP-1 receptor. Dulaglutide causes beta cells to produce more intracellular cyclic AMP (cAMP), which triggers glucose-dependent insulin release. Also, dulaglutide delays stomach emptying and reduces glucagon production.

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

The Data of Tmax of Dulaglutide approximately 48 hours post-injection.

The Data of Cmax of Dulaglutide approximately 72 hours (3 days) following injection.

Dulaglutide is available in the form of injectable solutions

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 dulaglutide 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

Dulaglutide can be used to treat Diabetes mellitus type 2 treatment. t helps improve blood sugar control by increasing the levels of incretin hormones in the body that stimulate insulin release and reduce the amount of glucose produced by the liver. Usually, Dulaglutide is used along with a healthy diet and regular exercise.

In Treatment of Type 2 diabetes mellitus

Dulaglutide helps to control high blood glucose (sugar) levels. Lowering blood glucose levels is a crucial part of managing diabetes. It often only causes a single frequent adverse effect and is taken once weekly at any time.

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 with type 2 diabetes mellitus (T2DM) who are under ten years old improve their glycemic control.
• To boost glycemic control in persons with type 2 diabetes mellitus (T2DM), a once-weekly SC injection, diet, and exercise are indicated.
• It is also indicated to lower the risk of significant adverse cardiovascular (CV) events in people with T2DM who have established CV diseases or multiple CV risk factors, such as CV mortality, nonfatal MI, or nonfatal stroke.

Parenterally: Dulaglutide is available as an injection solution that can be administered parenterally. It is possible to take dulaglutide 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. If required, and if the last dose was administered at least three days ago, the day of weekly administration can be adjusted. Never combine the shots when using insulin; always give them separately. The injections of insulin and dulaglutide 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: 0.75mg/0.5mL, 1.5mg/0.5mL, 3mg/0.5mL or 4.5mg/0.5mL

Dulaglutide is available in the form of injection solutions.

Dose Adjustment in Adult Patients:

Diabetes Mellitus Type 2

Initial: 0.75 mg SC once per week

The dose may be increased to 1.5 mg once a week for further glycemic management.

After at least four weeks on the 1.5-mg dosage, increase to 3 mg once weekly if further glycemic control is required.

After at least four weeks on the 3-mg dosage, raise the dose to a maximum of 4.5 mg once weekly if more glycemic control is required.

Dosing Considerations

Not recommended as a first-line treatment for those who cannot be well managed with exercise and diet.

Has not been studied with a history of pancreatitis; consider using a different anti-diabetic medication.

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

While taking Dulaglutide, maintain regular meal schedules with balanced macronutrient content to help stabilize blood sugar levels.

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.

Avoid excessive consumption of grapefruit or its juice, as it may interact with Dulaglutide.

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.

Dulaglutide may be contraindicated in the following conditions:-

• Hypersensitivity reaction to Dulaglutide or any of its excipients,
• Medullary thyroid cancer (MTC) in the individual or the family
• Type 2 Multiple Endocrine Neoplasia (MEN-2)

• Hypersensitivity Reactions: Use caution when administering a drug to a patient who has previously experienced angioedema or anaphylaxis with another GLP-1 receptor agonist; it is unclear whether such patients will be predisposed to anaphylaxis with the drug; discontinue if such reactions occur. Systemic hypersensitivity reactions have been reported, as well as anaphylaxis and angioedema.
• Acute Kidney Injury: Treatment with glucagonlike peptide-1 (GLP-1) receptor agonists has been linked to acute and chronic renal failure, some requiring hemodialysis.
• Severe Gastrointestinal Disease: GI adverse effects that might be severe may be related; encourage patients to prevent fluid loss; has not been researched in individuals with severe gastrointestinal disorders, such as gastroparesis.
• Acute Gallbladder Disease: In GLP-1 receptor agonist trials and postmarketing, acute gallbladder disease symptoms like cholelithiasis or cholecystitis have been documented. Severe acute cholecystitis symptoms have also been reported. Investigations and the proper clinical follow-up are recommended if cholelithiasis is suspected.
• Diabetic retinopathy complications: Patients with known cardiovascular disease or multiple risk factors were examined in the REWIND CV outcomes study, which included 9901 individuals and had a median follow-up of 5.4 years. According to secondary composite endpoints, 1.9% of people using dulaglutide for diabetic retinopathy problems encountered them, compared to 1.5% of people taking a placebo. Compared to patients without such a history, individuals with baseline histories of diabetic retinopathy noted rates (dulaglutide 8.5%, placebo 6.2%). It is significant to highlight that temporary worsening of diabetic retinopathy can occur when glucose control improves quickly. As a result, people with a history of diabetic retinopathy must be continually monitored for development.
• Medullary thyroid carcinoma (MTC): In individuals on dulaglutide, there are no proven advantages to routinely checking blood calcitonin levels or thyroid ultrasounds for medullary thyroid cancer (MTC). The presence of MTC may be indicated by elevated blood calcitonin levels, often >50 ng/L; additional assessment is required in such situations. Evaluate patients with thyroid nodules seen on neck imaging or during physical examinations.
• Pancreatitis: Rare cases of acute pancreatitis have been reported after initiating therapy. Carefully monitor for pancreatitis symptoms, such as persistent severe pain in the abdomen that may radiate to the back, with or without vomiting. If pancreatitis is suspected, discontinue treatment and do not resume if confirmed. Patients with a history of pancreatitis may need alternative anti-diabetic therapies.

It is unsafe to consume Dulaglutide with alcohol.

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

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

Limit Alcohol or grapefruit juice consumption, and avoid fatty or high-calorie meals.

The adverse reactions related to Dulaglutide can be categorized as:

• Common Adverse Effects: Nausea, increased amylase, increased lipase, diarrhoea
• Less Common Adverse effects: Abdominal pain, vomiting, decreased appetite, fatigue, dyspepsia, constipation, severe hypoglycemia with prandial insulin, flatulence, sinus tachycardia, abdominal distension, gastroesophageal reflux disease, AV block, eructation.
• Rare Adverse Effects: Hypersensitivity, sometimes severe (e.g., severe urticaria, systemic rash, facial oedema, lip swelling), injection-site reactions, pancreatitis, cholelithiasis and cholecystitis

Reports on Postmarketing

Ileus: Gastrointestinal

Cholecystitis, cholelithiasis necessitating a cholecystectomy, cholestasis, increased liver enzymes, and hepatitis are among the hepatobiliary conditions.

Anaphylactic responses and angioedema are signs of hypersensitivity

Renal: Hemodialysis may be required in acute or worsening chronic renal failure.

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

• Oral Medications for GI Disorders: Drugs that affect gastrointestinal motility, such as metoclopramide, may alter the absorption of dulaglutide. Administering these drugs at the same time as dulaglutide should be avoided.
• Insulin: When used alongside insulin, especially in patients with type 1 diabetes, there may be an increased risk of hypoglycemia. Dosage adjustments for insulin may be required.
• Warfarin: Warfarin's ability to prevent clotting may be affected by dulaglutide. When these medications are combined, careful monitoring of prothrombin time and international normalised ratio (INR) is required.
• Use with Insulin or an Insulin Secretagogue (such as Sulfonylurea) concurrently: Consider lowering the dosage of concurrently provided insulin secretagogues (such as sulfonylureas) or insulin before starting Dulaglutide to lessen the risk of hypoglycemia.
• Oral Contraceptives: Dulaglutide can slow down the absorption of oral contraceptives. It's essential to use additional contraceptive methods or adjust the timing of your contraceptive dose if necessary.

The most common side effects of Dulaglutide include:

• Nausea
• Diarrhea
• Vomiting
• Abdominal pain
• Loss of appetite

• Pregnancy

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

There is inadequate knowledge of the effects of drugs on significant birth abnormalities and miscarriages in pregnant women.

The risks of poorly managed diabetes during pregnancy are considered clinically (e.g., diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery difficulties).

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

According to a comparison of plasma area under the time-concentration curves (AUC), systemic exposures of pregnant rats given subcutaneous doses of dulaglutide of 0.49, 1.63, or 4.89 mg/kg every three days during organogenesis were 2, 6, and 18 times higher than those of people given the MRHD of 4.5 mg/week. Dulaglutide harmed maternal weight increase and food intake, which led to smaller foetal weights being seen at dosages of less than 1.63 mg/kg. A higher post-implantation loss rate of 4.89 mg/kg was also seen, along with abnormal skeletal ossifications.

In pregnant rabbits receiving subcutaneous doses of 0.04, 0.12, or 0.41 mg/kg dulaglutide every three days during organogenesis, their systemic exposures were 0.5-, 2-, and five times higher than human exposure at the MRHD, based on plasma AUC comparison. Fetal abnormalities included lung lobular agenesis and skeletal malformations of vertebrae and ribs, which were observed at 0.41 mg/kg, accompanied by reduced maternal food intake and weight gain attributed to dulaglutide's pharmacology.

There is no data regarding the presence of dulaglutide in human milk, its effects on breastfed infants, or its impact on milk production. It was impossible to detect dulaglutide in the milk of nursing animals treated with it. Along with the mother's clinical requirement for Dulaglutide and any potential adverse effects on the breastfed newborn from Dulaglutide or the underlying maternal disease, it is essential to consider the developmental and health benefits of nursing.

• Pediatric Use

Dulaglutide has been proven safe and effective as an adjunct to diet and exercise in paediatric patients with type 2 diabetes mellitus ten years and older to enhance glycemic control. A 26-week, multicenter, randomized, double-blind, parallel-arm, placebo-controlled study in 154 paediatric patients with type 2 diabetes mellitus aged ten years and older supports using dulaglutide for this indication.

Compared to Dulaglutide-treated adults, paediatric patients reported a greater prevalence of injection site-related responses.

Paediatric children under 10 have not been studied for Dulaglutide's safety and efficacy.

Dose Adjustment in Pediatric Patients:

Type 2 diabetes

Initial dose: 0.75 mg SC once per week

After at least four weeks on the 0.75-mg dosage, increase to 1.5 mg once weekly if more glycemic control is required.

Not more than 1.5 mg per week.

• Geriatric Use

At baseline, 620 (19%) of the Dulaglutide-treated patients in the adult glycemic control studies [see Clinical Studies (14.2, 14.3)] were 65 years of age or older, and 65 (2%) were 75 years of age or older. 2,619 (53%) and 484 (10%) patients were 65 years of age or older at baseline in the Dulaglutide 1.5 mg treatment arm of the REWIND trial (cardiovascular outcomes trial in the adults with type 2 diabetes mellitus and cardiovascular disease or several cardiovascular risk factors).

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

Dose Adjustment in Kidney Impairment Patients:

Renal impairment (any severity): No dosage adjustment is required.

Dose Adjustment in Hepatic Impairment Patients:

Hepatic impairment (any severity): No dose adjustment is necessary for hepatic impairment. However, concern is recommended due to limited data.

Signs and Symptoms

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

Overconsumption of Dulaglutide may include non-severe hypoglycemia and mild to moderate gastrointestinal events (e.g., nausea, vomiting).

Management

There is no specific antidote or treatment for excessive intake of Dulaglutide. However, immediate medical attention is essential. Dulaglutide should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

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 hypoglycemia (low blood sugar) occurs, appropriate measures should be taken to raise blood glucose levels, such as administering glucose or high-sugar foods and beverages.

Hospitalization and intravenous (IV) glucose administration may be required in severe cases.

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:

Through the antagonism of the GLP-1 receptor, dulaglutide lowers postprandial glucose (PPG) and fasting glucose levels in people with type 2 diabetes mellitus.7 This medication simulates the effects of human glucagon-like peptide-1, which generally activates the GLP-1 receptor.

Cardiac Electrophysiology

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

Pharmacokinetics:

Absorption

Following subcutaneous injection, dulaglutide is gradually absorbed. Cmax occurred 24 to 48 hours after dose in a pharmacokinetic study involving 20 healthy people. After subcutaneous injections of a single dosage of 0.75 mg and 1.5 mg of dulaglutide, the average absolute bioavailability was 65% and 47%, respectively.

Distribution

The apparent population mean distribution volume in the centre was 3.09 L, whereas the evident population mean distribution volume in the peripheral region was 5.98 L.

Vd: 3.09 L (central); 5.98 L (peripheral)

Metabolism

Typical protein catabolism mechanisms are presumed to break down dulaglutide into its amino acids.

Excretion

Dulaglutide was eliminated at a mean apparent rate of 0.142 L/h. Dulaglutide has an estimated 5-day elimination half-life.

Half-life: ~5 days

Clearance: 0.142 L/hr

• Smith, Lillian L et al. "Dulaglutide (Trulicity): The Third Once-Weekly GLP-1 Agonist." P & T : a peer-reviewed journal for formulary management vol. 41,6 (2016): 357-60.
• Jendle, Johan et al. "Efficacy and safety of dulaglutide in treating type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program." Diabetes/metabolism research and reviews vol. 32,8 (2016): 776-790. doi:10.1002/dmrr.2810
• Juan P. Frias, Enzo Bonora, et al; The Efficacy and Safety of the Dulaglutide 3.0 mg and 4.5 mg Versus Dulaglutide 1.5 mg in Metformin-Treated Patients With Type 2 Diabetes in a Randomized Controlled Trial (AWARD-11). Diabetes Care 1 March 2021; 44 (3): 765–773.
• Zhang, L., Zhang, M., Zhang, Y. et al. Efficacy and safety of dulaglutide in the patients with type 2 diabetes: a meta-analysis and systematic review. Sci Rep 6, 18904 (2016). https://doi.org/10.1038/srep18904

Carcinogenesis, Mutagenesis, Impairment of Fertility

Dulaglutide was investigated for its carcinogenic potential over two years in male and female rats at dosages of 0.05, 0.5, 1.5, and 5 mg/kg (0.2, 3-, 8-, and 24-fold the MRHD of 4.5 mg once per week based on AUC), delivered by subcutaneous injection twice per week. In rats, dulaglutide increased the risk of thyroid C-cell tumours (adenomas and/or carcinomas) at a dose- and treatment-dependent rate, at a rate of around three times the MRHD based on AUC, compared to controls. A statistically significant rise in C-cell adenomas was seen in rats given dulaglutide at 0.5 mg/kg. Even though there was no statistically significant difference, numerical increases in thyroid C-cell carcinomas started to appear at 5 mg per kg (24 times the MRHD based on AUC), considering it to be treatment-related.

Using dulaglutide at dosages of 0.3, 1, and 3 mg/kg given by subcutaneous injection twice weekly, 6-month carcinogenicity research was carried out in rasH2 transgenic mice. No matter what dosage was used, dulaglutide did not increase thyroid C-cell hyperplasia or neoplasia.

No research on genotoxicity has been conducted with the recombinant protein dulaglutide.

Thyroid C-cell tumours in rats may or may not be relevant to humans; this cannot be determined by clinical or nonclinical research.

No adverse effects of dulaglutide on mating, fertility, sperm morphology, conception, or embryonic survival were seen in trials on fertility and early embryonic development in male and female rats at doses up to 16.3 mg per kg (55-fold the MRHD based on AUC). In female rats, a dose-related reduce in the mean number of corpora lutea, implantation sites, and viable embryos, as well as an increase in the proportion of females with protracted diestrus were seen at 4.9 mg/kg (13-fold the MRHD based on AUC). Reduced maternal food consumption and weight growth were the causes of this.

• Inform patients that dulaglutide promotes benign and malignant thyroid C-cell tumours in rats, while the relation to humans has not been shown. Encourage patients to inform the doctor about any signs of thyroid tumours, such as a lump in the neck, chronic hoarseness, dysphagia, or dyspnea.
• Acute pancreatitis is characterized by continuous, severe stomach pain that might extend to the back and may or may not be followed by vomiting if patients have chronic, severe stomach discomfort, instruct patients to stop taking Dulaglutide immediately and to consult a physician.
• Explain to patients that consuming Dulaglutide with either insulin or an insulin secretagogue (such as Sulfonylurea) may increase the risk of hypoglycemia. Inform patients about the symptoms and indicators of hypoglycemia.
• Inform patients of the chance of dehydration caused by gastrointestinal side effects and take measures to prevent fluid loss. Inform Dulaglutide patients of the potential risk of deteriorating renal function, the signs and symptoms of renal impairment and the potential for dialysis as a medical intervention for renal failure.
• Inform patients that taking Dulaglutide has been associated with significant hypersensitivity responses. Inform patients of the signs of hypersensitivity responses and tell them to stop taking Dulaglutide and get help immediately if they appear.
• Instruct patients to contact a physician if they suffer changes in eyesight while taking Dulaglutide.
• Inform patients about the possibility of developing cholecystitis or cholelithiasis. Instruct people to consult the physician if they feel they may have cholelithiasis or cholecystitis so they may receive the proper clinical follow-up.
• Encourage individuals to inform the physician if they are pregnant or plan to become pregnant.
• Inform patients that if a dosage is missed and there are at least three days (72 hours) until the next planned dose, they should deliver it as soon as feasible and continue their regular once-weekly dosing schedule. Inform the patient to skip the missed dosage and restart Dulaglutide with the regularly following the scheduled dose if any dose is missed and the next one is due in one or two days.

• https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125469orig1s000medredt.pdf
• https://dailymed.nlm.nih.gov/dailymed/drugInfo.
• https://www.ncbi.nlm.nih.gov/books/NBK547979/
• https://pubmed.ncbi.nlm.nih.gov/26423061/