Dulaglutide Subcutaneous

Type 2 Diabetes Mellitus

Dulaglutide is used as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients >=10 years of age with type 2 diabetes mellitus.^[1] Dulaglutide has been used alone or as add-on therapy with metformin, the combination of metformin and a sulfonylurea, the combination of metformin and a thiazolidinedione, a sodium-glucose cotransporter 2 (SGLT2) inhibitor with or without metformin, basal insulin with or without metformin, and prandial insulin with or without metformin.^{[1][2][3][4][5][6][7]}

Dulaglutide also is used to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors.^[1][21]

Glycemic Control

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).^{[698][704][705]} In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a GLP-1 receptor agonist, SGLT2 inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.^[698][704] Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another drug) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.^[698][704] In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic drug classes with complementary mechanisms of action. ^[698]

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.^[698][704] Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.^[704] In addition, early initiation of combination therapy may help to more rapidly attain glycemic goals and extend the time to treatment failure.^[704]

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.^{[698][704][705][706]} When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.^[704] While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.^[698] Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.^[698][704]

Patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure should receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit.^[704][705] Experts state that therapy with a GLP-1 receptor agonist or SGLT2 inhibitor should be considered for patients with the aforementioned comorbidities independently of the patients' HbA_1c.^[704] GLP-1 receptor agonists and SGLT2 inhibitors appear to have effects on the kidneys independent of their glycemic effects, and some experts suggest that an agent from one of these classes of drugs be considered in patients with type 2 diabetes mellitus and chronic kidney disease (CKD). ^{[698][704][706]} In patients without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, the decision regarding the addition of other antidiabetic agents (e.g., GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, thiazolidinedione, sulfonylurea, basal insulin) to metformin therapy should be based on avoidance of adverse effects, cost, and individual patient factors.^[704]

Has not been studiedin patients with a history of pancreatitis;consider other antidiabeticagentsin such patients.^[1]

Data are lacking on the use of dulaglutide in patients with severe GI disease, including severe gastroparesis, and the drug is not recommended for use in patients with preexisting severe GI disease.^[1]

Dulaglutide is_not_ indicated for the treatment of type 1 diabetes mellitus.^[1]

Dulaglutide Monotherapy in Adults

When given as monotherapy for the management of type 2 diabetes mellitus, dulaglutide improves glycemic control as evidenced by reductions from baseline in glycosylated hemoglobin (hemoglobin A_1c; HbA_1c).^[1][2][6] Efficacy and safety of dulaglutide as monotherapy have been established in a 52-week, randomized, double-blind, noninferiority study comparing dulaglutide (0.75 mg or 1.5 mg once weekly throughout the study) with metformin (median initial dosage of 1 g daily with upward titration to 1.5-2 g daily) in patients with type 2 diabetes mellitus.^[1][2][6] The primary study end point was the change in HbA_1c from baseline to week 26.^[1][2]

At week 26, HbA_1c was reduced in all treatment groups; both dosages of dulaglutide were noninferior to metformin at 26 and 52 weeks.^[1][2][6] Mean HbA_1c was reduced by 0.7 and 0.8% in patients receiving dulaglutide 0.75 and 1.5 mg, respectively, and by 0.6% in those receiving metformin.^[1][2] Patients in all 3 treatment groups also had decreased fasting plasma glucose and body weight at 26 and 52 weeks.^[1][2][6] Patients included in this trial had type 2 diabetes mellitus inadequately controlled by diet and exercise or one oral antidiabetic agent, and had a mean baseline HbA_1c of 7.6%.^[1][2] Approximately 75% of patients were taking an oral antidiabetic agent before the study; approximately 90% of these patients were receiving metformin and approximately 10% were receiving a sulfonylurea.^[1][2]

Combination Therapy in Adults

When given as add-on therapy in combination with one or more oral antidiabetic agents (e.g., metformin, a sulfonylurea, a thiazolidinedione), dulaglutide improved glycemic control more than sitagliptin or exenatide.^[1][3][4][6] Dulaglutide was noninferior to insulin glargine in reducing HbA_1c when added to prandial insulin with or without metformin or to other oral antidiabetic agents, and was noninferior to liraglutide when added to metformin.^[1][5][6] Safety and efficacy of dulaglutide as add-on therapy to other antidiabetic agents in the management of type 2 diabetes mellitus have been established in several randomized, active-controlled, double-blind or open-label studies lasting 24-104 weeks in over 4000 patients.^[1][6] In these studies, patients randomized to dulaglutide generally received either 0.75 or 1.5 mg once weekly with no dosage adjustments.^{[1][3][4][5][6]}

In a 24-week, double-blind study, add-on therapy with dulaglutide (1.5 mg once weekly) substantially reduced HbA_1c from baseline compared with placebo at 24 weeks (mean difference in HbA_1c: 1.1%) in patients receiving glimepiride.^[1] An HbA_1c less than 7% was achieved in 50 or 17% of patients receiving dulaglutide or placebo, respectively.^[1]

In a 104-week, randomized, double-blind study, patients who received dulaglutide in addition to existing metformin therapy (at least 1.5 g daily) experienced a substantially greater reduction in HbA_1c at the 52-week primary end point than those who received sitagliptin (100 mg once daily) as add-on therapy to metformin.^[1][3][6] Both 0.75- and 1.5-mg dosages of dulaglutide were superior to placebo and sitagliptin in reducing HbA_1c, with greater reduction in HbA_1c with the higher dulaglutide dosage.^[1][3][6] More patients achieved HbA_1c less than 7% in the dulaglutide groups than in the sitagliptin group; patients who received dulaglutide also had substantially lowered fasting plasma glucose and greater weight loss compared with those who received sitagliptin.^[1][3][6]

In a 52-week study in patients inadequately controlled on pioglitazone (30-45 mg daily) and metformin (at least 1.5 g daily) therapy, add-on therapy with dulaglutide (0.75 or 1.5 mg once weekly) was superior to placebo and add-on exenatide (5 mcg twice daily for 4 weeks, then 10 mcg twice daily) in reducing HbA_1c at the 26-week primary end point.^[1][4][6] Superiority of dulaglutide over exenatide was maintained at 52 weeks.^[4] At 26 weeks, an HbA_1c less than 7% was achieved in 66 or 78% of patients receiving dulaglutide 0.75 or 1.5 mg, respectively, compared with 52% of those receiving exenatide.^[1][4]

In another 24-week, double-blind study, add-on therapy with dulaglutide (0.75 or 1.5 mg once weekly) in patients receiving SGLT2 inhibitor therapy with or without metformin substantially reduced HbA_1c from baseline compared with placebo at 24 weeks (mean difference in HbA_1c of 0.7 or 0.8% in the 0.75- or 1.5-mg group, respectively).^[1] An HbA_1c less than 7% was achieved in 59, 67, or 31% of patients receiving once-weekly dulaglutide 0.75 mg, dulaglutide 1.5 mg, or placebo, respectively.^[1] Mean reductions from baseline in fasting serum glucose at week 24 with dulaglutide 0.75 and 1.5 mg once weekly were 19 and 24 mg/dL, respectively, compared with placebo.^[1]

In a 78-week, randomized, open-label noninferiority study, dulaglutide (0.75 or 1.5 mg once weekly) was compared with insulin glargine (10 units daily initially, titrated to a fasting plasma glucose goal of less than 100 mg/dL) as add-on therapy to maximally tolerated dosages of metformin and glimepiride.^[1][5][6] At the 52-week primary end point, dulaglutide 1.5 mg was superior, and 0.75 mg noninferior to insulin glargine (mean daily dosage 29.4 units) as add-on therapy with regard to HbA_1c reduction.^[1][5] Dulaglutide was associated with mean body weight losses^[1][5] of 1.3 and 1.9 kg for the 0.75- and 1.5-mg dosages, respectively, while insulin glargine treatment resulted in a mean body weight gain^[1][5] of 1.4 kg.^[1]

In a 52-week, randomized, open-label noninferiority trial in patients with moderate to severe chronic kidney disease, dulaglutide (0.75 or 1.5 mg once weekly) was compared with insulin glargine (initiated at 50% of the prerandomization total daily insulin dosage and titrated to a fasting plasma glucose of less than 100 mg/dL) as add-on therapy to prandial (3 times daily) insulin lispro with or without metformin.^[1][6] At the 26-week primary end point, HbA_1c was reduced in all treatment groups; both dosages of dulaglutide were noninferior to insulin glargine.^[1] Overall estimated glomerular filtration rate (eGFR) in study patients at baseline was 38 mL/minute per 1.73 m²; 30% of patients had an eGFR of less than 30 mL/minute per 1.73 m² and 45% had macroalbuminuria.^[1]

In a 26-week, open-label noninferiority study, dulaglutide (1.5 mg once weekly) was compared with liraglutide (titrated from 0.6 mg daily to 1.8 mg daily by week 3) as add-on therapy in patients with type 2 diabetes not adequately controlled with metformin (at least 1.5 g daily).^[7] At the 26-week primary end point, HbA_1c was reduced in both groups; the dulaglutide 1.5-mg dosage was noninferior to liraglutide.^[7]

In a 28-week, double-blind study, dulaglutide (1.5 mg once weekly) added to therapy with basal insulin glargine with or without metformin was more effective than placebo in reducing HbA_1c (1.4 versus 0.7% change from baseline).^[1] At week 28, HbA_1c was less than 7% in 67 or 33% of patients receiving dulaglutide or placebo, respectively.^[1]

Use in Pediatric Patients

Efficacy and safety of dulaglutide in pediatric patients have been established in a 26-week randomized, double-blind, placebo-controlled trial with an open-label extension for an additional 26 weeks.^[1] In this study, 154 patients >=10 years of age with type 2 diabetes mellitus who had inadequate glycemic control despite diet and exercise were randomized to receive dulaglutide (0.75 or 1.5 mg) or placebo once weekly by subcutaneous injection with or without concomitant metformin and/or basal insulin.^[1] Results at 26 weeks showed that dulaglutide was significantly more effective than placebo in reducing HbA_1c from baseline (difference from placebo of -1.2% with dulaglutide 0.75 mg and -1.5% with dulaglutide 1.5 mg).^[1]

Reduction in Risk of Major Adverse Cardiovascular Events

Dulaglutide is used to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors.^{[1][704][705]} In addition to lowering blood glucose, GLP-1 receptor agonists appear to modify several nonglycemic cardiovascular risk factors such as blood pressure, body weight, and lipid profile.^[80][81] Additionally, GLP-1 receptor agonists may have beneficial endothelial effects.^[80][81]

In a double-blind, placebo-controlled study (REWIND) in 9901 adults with type 2 diabetes mellitus at risk for cardiovascular events or with a history of cardiovascular disease,^[1] add-on therapy with dulaglutide (1.5 mg subcutaneously once weekly for a median of 5.4 years) substantially reduced the primary composite outcome (first occurrence of nonfatal myocardial infarction [MI], nonfatal stroke, or death from cardiovascular causes).^[1][21] The primary composite outcome occurred in 12 or 13.4% of patients receiving dulaglutide or placebo, respectively, representing a 12% risk reduction with dulaglutide therapy.^[1][21] All-cause mortality did not differ between treatment groups.^[1] Patients in the study were at least 50 years of age (mean age: 66 years) and approximately 32% of the patients had established cardiovascular disease.^[1] Approximately 95% of patients were receiving at least one antidiabetic drug (e.g., metformin, sulfonylurea, insulin); most patients were also receiving cardiovascular drugs at baseline (angiotensin-converting enzyme [ACE] inhibitor or angiotensin II receptor antagonist [81.5% of patients], β-adrenergic blocking agent [β-blocker; 45.6% of patients], calcium-channel blocker [34.4% of patients], diuretic [46.5% of patients], statin [66.1% of patients], antithrombotic agent [58.7% of patients], aspirin [51.7% of patients]).^[1]

Beneficial Effects on Renal Function

In several cardiovascular outcomes trials involving the use of GLP-1 receptor agonists (e.g., dulaglutide, liraglutide, semaglutide) in patients with type 2 diabetes mellitus at high risk for cardiovascular disease or with existing cardiovascular disease, beneficial effects on renal function have been observed as a secondary outcome.^{[82][704][706]} Some experts suggest that in patients with type 2 diabetes mellitus and CKD who are at increased risk for cardiovascular events, use of a GLP-1 receptor agonist may reduce risk of progression of albuminuria, cardiovascular events, or both^† .^[706]

General

Patient Monitoring

Perform regular monitoring (e.g., blood glucose determinations, HbA_1c) to determine therapeutic response.^[1]

Administration

Dulaglutide is administered by subcutaneous injection; the drug should not be administered IV or IM.^[1] Dulaglutide is administered once weekly, on the same day each week, at any time of day without regard to meals.^[1] The day of weekly administration may be changed if necessary; however, at least 3 days should elapse between doses.^[1]

If a dose is missed, the missed dose should be administered as soon as possible if there are at least 3 days (72 hours) remaining before the next scheduled dose; the regular weekly schedule should then be resumed.^[1] If less than 3 days remain before the next scheduled dose, the missed dose should be skipped and the next dose should be administered on the usual weekly day, followed by resumption of the regular weekly schedule.^[1]

Dulaglutide is administered by subcutaneous injection into the abdomen, thigh, or upper arm using a single-dose, prefilled injection pen.^[1][19] Rotate injection sites with each dose.^[1]

When using dulaglutide in combination with insulin, the drugs should be administered as separate injections; insulin and dulaglutide injections should never be mixed.^[1] Dulaglutide and insulin may be injected into the same body regions; however, the injections should not be adjacent to each other.^[1]

Dosage

Type 2 Diabetes Mellitus in Adults

The recommended initial dosage of dulaglutide for the management of type 2 diabetes mellitus in adults is 0.75 mg subcutaneously once weekly.^[1] Increase the dosage to 1.5 mg once weekly for additional glycemic control.^[1] If further glycemic control is needed, dosage may be increased in 1.5-mg increments after at least 4 weeks on the current dosage.^[1] The maximum recommended dosage is 4.5 mg once weekly.^[1]

Type 2 Diabetes Mellitus in Pediatric Patients

The recommended initial dosage of dulaglutide for the management of type 2 diabetes mellitus in pediatric patients >=10 years of age is 0.75 mg subcutaneously once weekly.^[1] If additional glycemic control is needed, the dosage may be increased to the maximum recommended dosage of 1.5 mg once weekly after at least 4 weeks on the 0.75mg dosage.^[1]

Special Populations

No dosage adjustment is necessary in patients with renal or hepatic impairment, including end-stage renal disease.^[1] However, clinicians should use caution in patients with end-stage renal disease.^[1]

Contraindications

Dulaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).^[1]

Dulaglutide is also contraindicated in patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the product components.^[1]

Warnings/Precautions

Warnings

Risk of Thyroid C-Cell Tumors

Glucagon-like peptide-1 (GLP-1) receptor agonists such as dulaglutide cause dose- and treatment duration-dependent thyroid C-cell tumors (adenomas and carcinomas) in rats and mice.^[1] It is unknown whether dulaglutide causes thyroid C-cell tumors, including MTC, in humans.^[1]

At least 1 case of MTC has been reported in a patient treated with dulaglutide.^[1] This patient had serum calcitonin concentrations approximately 8 times the upper limit of normal (ULN) prior to treatment.^[1] Very elevated serum calcitonin values may be indicative of MTC; patients with MTC usually have serum calcitonin values exceeding 50 ng/mL.^[1] Although routine monitoring of serum calcitonin is of uncertain value in patients treated with dulaglutide, patients should also be referred to an endocrinologist for further evaluation if serum calcitonin is found to be elevated.^[1]

Patients should be counseled about potential risk of MTC and informed about symptoms of thyroid tumors.^[1] Patients with thyroid nodules noted on physical examination or neck imaging also should be referred to an endocrinologist.^[1] The role of monitoring serum calcitonin concentrations or thyroid ultrasounds for the purpose of early detection of MTC in patients receiving dulaglutide is unknown.^[1]

Sensitivity Reactions

Serious hypersensitivity reactions (severe urticaria, systemic rash, facial edema, lip swelling), including anaphylactic reactions and angioedema, have been reported in patients receiving dulaglutide.^[1] If a hypersensitivity reaction occurs, the patient should discontinue dulaglutide, be treated promptly according to the standard of care, and be monitored until signs and symptoms have resolved.^[1] Caution should be exercised in patients with a history of anaphylaxis or angioedema to other GLP-1 receptor agonists, as it is unknown whether such patients will be predisposed to anaphylaxis with dulaglutide.^[1]

Other Warnings and Precautions

Risks During General Anesthesia and Deep Sedation

GLP-1 agonists are associated with adverse GI effects such as nausea, vomiting, and delayed gastric emptying; such effects are likely a result of rapid tachyphlaxis at the level of vagal nerve activation.^[90] Delayed gastric emptying from GLP-1 agonists can increase the risk of regurgitation and pulmonary aspiration of gastric contents during general anesthesia and deep sedation.^[90] Given these concerns, the American Society of Anesthesiologists (ASA) Task Force on Preoperative Fasting has issued a consensus-based guidance for the management of GLP-1 receptor agonists prior to elective surgery.^[90] The task force suggests that for patients on daily GLP-1 agonist dosing (irrespective of indication, dose, or type of surgery), consider holding the drug on the day of the procedure/surgery.^[90] For patients on weekly dosing (irrespective of indication, dose, or type of surgery), consider holding the GLP-1 agonist a week prior to the procedure/surgery.^[90]

If GLP-1 agonists prescribed for diabetes management are held for longer than the dosing schedule, consider consulting an endocrinologist for bridging the antidiabetic therapy to avoid hyperglycemia.^[90] These recommendations are based on limited evidence only (case reports).^[90] For patients requiring urgent or emergent procedures, the task force states to proceed and treat the patient as 'full stomach' and manage accordingly.^[90]

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis has been reported in association with dulaglutide.^[1]

In clinical trials, 5 cases of confirmed pancreatitis occurred among dulaglutide-treated patients compared with 1 case in patients treated with a non-incretin comparator drug (1.4 versus 0.88 cases per 1000 patient years, respectively).^[1]

Observe patients carefully for signs and symptoms of pancreatitis, including persistent severe abdominal pain, sometimesradiating to the back, which may or may not be accompanied by vomiting; if pancreatitis is suspected, dulaglutide should be discontinued promptly.^[1] If pancreatitis is confirmed, dulaglutide should not be restarted.^[1]

Efficacy and safety of dulaglutide have not been established in patients with a history of pancreatitis.^[1] Alternative antidiabetic therapy should be considered in such patients.^[1]

Use with Drugs Known to Cause Hypoglycemia

Patients receiving dulaglutide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin have an increased risk of hypoglycemia.^[1] A lower dosage of the concomitant insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.^[1]

Renal Effects

During postmarketing experience, acute renal failure and worsening of chronic renal failure (which sometimes required hemodialysis) have been reported with GLP-1 receptor agonists.^[1] Some of these events have occurred in patients without known underlying renal disease.^[1] Most of these events have occurred in patients experiencing nausea, vomiting, diarrhea, or dehydration.^[1] Because these GI effects may worsen renal function, clinicians should use caution when initiating dulaglutide or escalating dosage in patients with renal impairment.^[1]

GI Effects

Use of dulaglutide may be associated with adverse GI effects, sometimes severe.^[1] In clinical trials, more patients receiving dulaglutide (1.3-3.5%) discontinued treatment because of adverse GI effects than patients receiving placebo (0.2%).^[1] In a cardiovascular outcomes trial with a median follow-up of 5.4 years, cholelithiasis occurred at rates of 0.62 or 0.56 per 100 patient-years in patients receiving dulaglutide or placebo, respectively; serious acute cholecystitis occurred in 0.5 or 0.3%, respectively, of such patients.^[1] Data are lacking on the use of dulaglutide in patients with severe GI disease, including severe gastroparesis; the manufacturer states that the drug is not recommended in such patients.^[1]

Diabetic Retinopathy Complications

In a clinical study involving patients with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors (REWIND), a higher incidence of diabetic retinopathy complications was observed among patients who received dulaglutide compared with those who received placebo (1.9 versus 1.5%, respectively).^[1] Patients with a history of diabetic retinopathy at baseline had a greater absolute increase in risk for diabetic retinopathy complications compared with those without a known history of diabetic retinopathy.^[1] Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy.^[1] Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy while receiving dulaglutide.^[1]

Acute Gallbladder Disease

Acute events of gallbladder disease have been reported with GLP-1 receptor agonists, including dulaglutide, during clinical studies and postmarketing experience.^[1] If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.^[1]

Immunogenicity

In adult clinical trials of dulaglutide for the treatment of type 2 diabetes mellitus, anti-drug antibodies were detected in 1.6% of dulaglutide-treated patients; 0.9% of patients developed neutralizing antibodies and 0.9% of patients developed antibodies to native GLP-1.^[1] Such antibodies did not appear to have any clinically significant effects on the pharmacokinetics, pharmacodynamics, safety, or effectiveness of dulaglutide.^[1]

In the controlled clinical trial of dulaglutide for the treatment of type 2 diabetes mellitus in pediatric patients, 4% of dulaglutide-treated patients developed anti-drug antibodies; 1% of patients developed neutralizing antibodies and 3% developed antibodies against native GLP-1.^[1] Because of the low incidence, the effect of these antibodies on the pharmacokinetics,pharmacodynamics, safety, and/or effectiveness of dulaglutide is not known.^[1]

Specific Populations

Pregnancy

Data on the use of dulaglutide in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage.^[1] Poorly controlled diabetes mellitus during pregnancy increases maternal risks for diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, and delivery complications, and also increases the risk of major birth defects, stillbirth, and macrosomia-related morbidity in the fetus.^[1]

Based on studies in animals, there may be risks to the fetus from exposure to dulaglutide during pregnancy.^[1] Dulaglutide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.^[1]

Lactation

Data are lacking regarding the distribution of dulaglutide into milk in humans, the effects on the breast-fed infant, or the effects on milk production.^[1] The developmental and health effects of breast-feeding should be considered along with the mother's clinical need for dulaglutide and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.^[1]

Pediatric Use

Use of dulaglutidein pediatric patients >=10 years of age with type 2 diabetes mellitus is supported by a 26-week multicenter, randomized, double-blind, placebo-controlled trial.^[1] A higher incidence of injection site reactions have been reported in pediatric patients compared with adults receiving the drug.^[1] Efficacyand safety of dulaglutide have not been established in pediatric patients <10 years of age.^[1]

Geriatric Use

In adult clinical trials, 19% of dulaglutide-treated patients were 65 years of age and older and 2% were 75 years of age and older.^[1] No substantial differences in safety and efficacy relative to younger adults were observed in these patients.^[1]

Hepatic Impairment

Because of the limited clinical experience of dulaglutide in patients with hepatic impairment, the drug should be used with caution in such patients.^[1][10] In a single-dose pharmacokinetic study, systemic exposure of dulaglutide decreased by 23, 33, and 21% in patients with mild, moderate, and severe hepatic impairment, respectively, compared with that in patients with normal hepatic function.^[1][10] These findings were not considered clinically important, and no dosage adjustment is considered necessary in patients with hepatic impairment.^[1][10]

Renal Impairment

In clinical trials of dulaglutide, nooverall differences in safety or efficacy were observed in patients with varying degrees of renal impairment.^[1][10]

In a single-dose pharmacokinetic study in individuals with renal impairment, systemic exposure to dulaglutide was increased by 20, 28, and 14% in patients with mild, moderate, and severe renal impairment, respectively, and by 12% in patients with end-stage renal disease compared with patients with normal renal function.^[1][10] Corresponding increases in peak plasma concentrations were 13, 23, and 20% in patients with mild, moderate, and severe renal impairment, respectively, and 11% in patients with end-stage renal disease.^[1] In addition, in a 52-week study in patients with type 2 diabetes mellitus and moderate to severe renal impairment, the pharmacokinetics of dulaglutide 0.75 and 1.5 mg once weekly were similar to those reported in prior clinical studies.^[1]

The manufacturer states that no dosage adjustment is necessary in patients with renal impairment including end-stage renal disease.^[1][10] However, caution is advised when the drug is used in patients with end-stage renal disease.^[1] Monitor renal function in patients with renal impairment reporting severe GI reactions.^[1]

Common Adverse Effects

Adverse effects reported in at least 5% of patients receiving dulaglutide include nausea, diarrhea, vomiting, abdominal pain, and decreased appetite.^[1]

Effects on GI Absorption of Other Drugs

Dulaglutide delays gastric emptying and has the potential to reduce the rate of absorption of concomitantly administered oral drugs; the delay in gastric emptying is dose-dependent.^[1] Concentrations of orally administered drugs with a narrow therapeutic index (e.g., warfarin) should be monitored when such drugs are administered concomitantly with dulaglutide.^[1]

Acetaminophen

Concomitant administration of dulaglutide and acetaminophen did not meaningfully alter the peak plasma concentration or area under the concentration-time curve (AUC) of acetaminophen.^[1] The manufacturer states that no adjustment of concomitant acetaminophen dosage is necessary.^[1]

Atorvastatin

Concomitant administration of dulaglutide 1.5 mg and atorvastatin 40 mg decreased the AUC of atorvastatin by 21%, which is not considered clinically important.^[1][10] Peak plasma concentration of atorvastatin was reduced by 70%; the clinical importance of this is not known.^[1][10] The manufacturer states that no adjustment of concomitant atorvastatin dosage is necessary.^[1]

Digoxin

Concomitant administration of dulaglutide and digoxin did not meaningfully alter the peak plasma concentration or AUC of digoxin.^[1] The manufacturer states that no adjustment of concomitant digoxin dosage is necessary.^[1]

Insulin or Insulin Secretagogues

When initiating dulaglutide, consider reducing the dose of concomitantly administered insulin secretagogues (e.g., sulfonylureas) or insulin to reducethe risk of hypoglycemia.^[1]

Lisinopril

Concomitant administration of dulaglutide and lisinopril did not meaningfully alter the peak plasma concentration or AUC of lisinopril.^[1][10] The manufacturer states that no adjustment of concomitant lisinopril dosage is necessary.^[1]

Metformin

Concomitant administration of dulaglutide and metformin did not meaningfully alter the peak plasma concentration or AUC of metformin.^[1][10] The manufacturer states that no adjustment of concomitant metformin dosage is necessary.^[1]

Metoprolol

Concomitant administration of dulaglutide and metoprolol did not meaningfully alter the peak plasma concentration or AUC of metoprolol.^[1][10] The manufacturer states that no adjustment of concomitant metoprolol dosage is necessary.^[1]

Oral Contraceptives

Concomitant administration of dulaglutide and an oral contraceptive containing ethinyl estradiol and norgestimate did not substantially alter the AUC or peak plasma concentration of ethinyl estradiol or norelgestromin (a major metabolite of norgestimate);^[1][10] no adjustment of the concomitant oral contraceptive containing ethinyl estradiol and norgestimate dosage is necessary.^[1]

Sitagliptin

Administration of single doses of dulaglutide 1.5 mg with sitagliptin 100 mg at steady state resulted in increases of approximately 38 and 27% in dulaglutide AUC and peak plasma concentration, respectively, which was not considered clinically important; no dosage adjustment of either drug is necessary.^[1][10]

Warfarin

Concomitant administration of dulaglutide 1.5 mg and single 10-mg doses of warfarin sodium did not meaningfully alter the AUC of R- or S-warfarin; the manufacturer states that no adjustment of concomitant warfarin dosage is necessary.^[1][10]

Dulaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist prepared from mammalian cell culture.^{[1][2][3][4][9]} The drug is a recombinant fusion protein that consists of 2 identical disulfide-linked chains, each containing an N-terminal GLP-1 analog covalently linked to the Fc portion of a modified human immunoglobulin G₄ (IgG₄) heavy chain by a small peptide linker.^[1][2][9] Each GLP-1 analog is 90% homologous to human GLP-1 (7-37) with structural modifications conferring resistance to degradation by dipeptidyl peptidase-4 (DPP-4).^[1][2] Both resistance to DPP-4 degradation and large molecule size (approximately 63 kilodaltons) extend the half-life of dulaglutide, allowing for weekly dosing.^[1][2][9]

Activation of GLP-1 receptors by dulaglutide stimulates insulin release in the presence of elevated glucose concentrations, suppresses glucagon release, and slows gastric emptying, resulting in lower fasting and postprandial blood glucose concentrations in patients with type 2 diabetes mellitus.^[1][2] The delay in gastric emptying produced by dulaglutide is largest after the first dose and diminishes with subsequent dosing.^[1]

Peak plasma dulaglutide concentrations are achieved 24-72 hours following subcutaneous administration.^[1] Steady-state concentrations are achieved 2-4 weeks following weekly administration.^[1] Absolute bioavailability following subcutaneous administration of single doses of 0.75 and 1.5 mg are 65 and 47%, respectively.^[1] Dulaglutide is thought to be degraded into its component amino acids by general protein catabolism pathways.^[1] The elimination half-life of dulaglutide is approximately 5 days.^[1]

Importance of informing patients that dulaglutide causes benign and malignant thyroid C-cell tumors in rats and that relevance of this finding to humans is unknown.^[1] Patients should report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, dyspnea) to their clinician.^[1]

Importance of informing patients about the possibility of acute pancreatitis with dulaglutide therapy.^[1] Importance of patients informing clinicians if they have a history of pancreatitis.^[1] Importance of informing patients about signs and symptoms of pancreatitis, including persistent severe abdominal pain sometimes radiating to the back that may or may not be accompanied by vomiting; importance of patient discontinuing dulaglutide and promptly notifying clinician if such signs or symptoms occur.^[1]

Importance of informing patients of risk of hypoglycemia, particularly if concomitant therapy with an insulin secretagogue (e.g., sulfonylurea) or insulin is used.^[1] Importance of reviewing signs, symptoms, and management of hypoglycemia.^[1]

Importance of informing patients of possibility of hypersensitivity reactions.^[1] Patients should be instructed to discontinue dulaglutide and promptly seek medical advice if symptoms of hypersensitivity occur.^[1]

Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis issuspected for appropriate clinical follow-up.^[1]

Importance of informing patients of potential risk of adverse GI effects and possibility of dehydration due to such adverse effects; patients should be advised to take precautions to avoid fluid depletion.^[1] Importance of informing patients of potential risk of worsening renal function, which may require dialysis in some cases.^[1]

Importance of informing patients to contact their clinician if they experience changes in vision during treatment with dulaglutide.^[1]

Importance of patients reading the manufacturer's instructions for use before starting dulaglutide therapy.^[1] Importance of instructing patients regarding proper use, storage, and disposal of injection pen.^[1] After dispensing, pens should be stored in the refrigerator or may be stored at room temperature for up to 14 days; injection pens should be protected from light and not frozen.^[1]

Importance of informing patients not to take an extra dose of dulaglutide to make up for a missed dose.^[1] If a dose is missed, patients should take the dose as soon as possible if there are at least 3 days (72 hours) until the next dose; the next dose can be taken on their usual weekly day.^[1] If there are less than 3 days until the next dose, the missed dose should be skipped and patient should take the next dose on their usual weekly day.^[1]

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^[1]

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., pancreatitis, diabetic retinopathy, GI disease).^[1]

Importance of informing patients of other important precautionary information.^[1]

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

†Use is not currently included in the labeling approved by the US Food and Drug Administration.

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