Get your patient on Trulicity (Dulaglutide)

TRULICITY^® is indicated:

• As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus.
• To reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors.

• Recommended starting dosage is 0.75 mg injected subcutaneously once weekly.
• After 4 weeks, the dosage may be increased to 1.5 mg once weekly for additional glycemic control.
• If additional glycemic control is needed, increase dosage in 1.5 mg increments after at least 4 weeks on the current dosage.
• Maximum recommended dosage is 4.5 mg injected subcutaneously once weekly.

• Recommended starting dosage is 0.75 mg injected subcutaneously once weekly.
• If additional glycemic control is needed, increase dosage to the maximum recommended dosage of 1.5 mg once weekly after at least 4 weeks on the 0.75 mg dosage.

• If a dose is missed, administer the missed dose as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose.

• Administer once weekly at any time of day with or without food.
• Inject subcutaneously in the abdomen, thigh, or upper arm.

Injection: TRULICITY is a clear and colorless solution available as:

• 0.75 mg/0.5 mL solution in a single-dose pen
• 1.5 mg/0.5 mL solution in a single-dose pen
• 3 mg/0.5 mL solution in a single-dose pen
• 4.5 mg/0.5 mL solution in a single-dose pen

TRULICITY is contraindicated in patients with:

• Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
  [see Warnings and Precautions (

  5.1 Risk of Thyroid C-cell Tumors

  In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure

  [see Nonclinical Toxicology (13.1)]

  . Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.

  One case of MTC was reported in a patient treated with TRULICITY in a clinical trial. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial (REWIND). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.

  TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

  Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

  )]
  .
• Serious hypersensitivity reaction to dulaglutide or to any of the product components. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with TRULICITY
  [see Warnings and Precautions (

  5.4 Hypersensitivity Reactions

  There have been postmarketing reports of serious hypersensitivity reactions including anaphylactic reactions and angioedema in patients treated with TRULICITY

  [see Adverse Reactions (6.2)]

  . If a hypersensitivity reaction occurs, discontinue TRULICITY; treat promptly per standard of care, and monitor until signs and symptoms resolve. TRULICITY is contraindicated in patients with a previous serious hypersensitivity reaction to dulaglutide or to any of the components of TRULICITY.

  Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with TRULICITY.

  )]
  .

• Thyroid C-cell Tumors:
  See Boxed Warning (
  5.1 Risk of Thyroid C-cell Tumors

  In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure

  [see Nonclinical Toxicology (13.1)]

  . Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.

  One case of MTC was reported in a patient treated with TRULICITY in a clinical trial. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial (REWIND). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.

  TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

  Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
  ).
• Acute Pancreatitis:
  Has been observed in patients treated with GLP-1 receptor agonists, including TRULICITY. Discontinue if pancreatitis is suspected (
  5.2 Acute Pancreatitis

  Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including TRULICITY

  [see Adverse Reactions (6.1)]

  .

  After initiation of TRULICITY, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue TRULICITY and initiate appropriate management.
  ).
• Hypoglycemia:
  Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dose of insulin secretagogue or insulin may be necessary (
  5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

  Patients receiving TRULICITY in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia

  [see Adverse Reactions (6.1) and Drug Interactions (7)].

  The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
  ).
• Hypersensitivity Reactions:
  Serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) have occurred. Discontinue TRULICITY and promptly seek medical advice (
  5.4 Hypersensitivity Reactions

  There have been postmarketing reports of serious hypersensitivity reactions including anaphylactic reactions and angioedema in patients treated with TRULICITY

  [see Adverse Reactions (6.2)]

  . If a hypersensitivity reaction occurs, discontinue TRULICITY; treat promptly per standard of care, and monitor until signs and symptoms resolve. TRULICITY is contraindicated in patients with a previous serious hypersensitivity reaction to dulaglutide or to any of the components of TRULICITY.

  Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with TRULICITY.
  ).
• Acute Kidney Injury Due to Volume Depletion:
  Monitor renal function in patients reporting adverse reactions that could lead to volume depletion (
  5.5 Acute Kidney Injury Due to Volume Depletion

  There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists, including TRULICITY

  [see Adverse Reactions (6.2)]

  . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea

  [see Adverse Reactions (6.1)]

  . Monitor renal function in patients reporting adverse reactions to TRULICITY that could lead to volume depletion, especially during dosage initiation and escalation of TRULICITY.
  ).
• Severe Gastrointestinal Adverse Reactions:
  Use may be associated with gastrointestinal adverse reactions, sometimes severe. TRULICITY is not recommended in patients with severe gastroparesis (
  5.6 Severe Gastrointestinal Adverse Reactions

  Use of TRULICITY has been associated with gastrointestinal adverse reactions, sometimes severe

  [see Adverse Reactions (6)]

  . In the pool of placebo-controlled trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving TRULICITY (0.75 mg 2.2%, 1.5 mg 4.3%) than placebo (1.4%).

  TRULICITY is not recommended in patients with severe gastroparesis.
  ).
• Diabetic Retinopathy Complications:
  Have been reported in a cardiovascular outcomes trial. Monitor patients with a history of diabetic retinopathy (
  5.7 Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy

  In a cardiovascular outcomes trial with a median follow up of 5.4 years involving patients with type 2 diabetes with established cardiovascular disease or multiple cardiovascular risk factors, diabetic retinopathy complications occurred in patients treated with TRULICITY 1.5 mg (1.9%) and placebo (1.5%). These events were prospectively ascertained as a secondary composite endpoint. The proportion of patients with diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (TRULICITY 8.5%, placebo 6.2%) than among patients without a known history of diabetic retinopathy (TRULICITY 1%, placebo 1%).

  Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.
  ).
• Acute Gallbladder Disease:
  If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated (
  5.8 Acute Gallbladder Disease

  Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In a cardiovascular outcomes trial with a median follow up of 5.4 years, cholelithiasis occurred at a rate of 0.62/100 patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy. Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placebo respectively. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.
  ).
• Pulmonary Aspiration During General Anesthesia or Deep Sedation:
  Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures (
  5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation

  TRULICITY delays gastric emptying

  [see Clinical Pharmacology (12.2)]

  . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations.

  Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking TRULICITY, including whether modifying preoperative fasting recommendations or temporarily discontinuing TRULICITY could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking TRULICITY.
  ).

The following serious reactions are described below or elsewhere in the prescribing information:

• Risk of Thyroid C-cell Tumors
  [see Warnings and Precautions (

  5.1 Risk of Thyroid C-cell Tumors

  In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure

  [see Nonclinical Toxicology (13.1)]

  . Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.

  One case of MTC was reported in a patient treated with TRULICITY in a clinical trial. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial (REWIND). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.

  TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

  Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

  )]
• Acute Pancreatitis
  [see Warnings and Precautions (

  5.2 Acute Pancreatitis

  Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including TRULICITY

  [see Adverse Reactions (6.1)]

  .

  After initiation of TRULICITY, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue TRULICITY and initiate appropriate management.

  )]
• Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
  [see Warnings and Precautions (

  5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

  Patients receiving TRULICITY in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia

  [see Adverse Reactions (6.1) and Drug Interactions (7)].

  The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

  )]
• Hypersensitivity Reactions
  [see Warnings and Precautions (

  5.4 Hypersensitivity Reactions

  There have been postmarketing reports of serious hypersensitivity reactions including anaphylactic reactions and angioedema in patients treated with TRULICITY

  [see Adverse Reactions (6.2)]

  . If a hypersensitivity reaction occurs, discontinue TRULICITY; treat promptly per standard of care, and monitor until signs and symptoms resolve. TRULICITY is contraindicated in patients with a previous serious hypersensitivity reaction to dulaglutide or to any of the components of TRULICITY.

  Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with TRULICITY.

  )]
• Acute Kidney Injury Due to Volume Depletion
  [see Warnings and Precautions (

  5.5 Acute Kidney Injury Due to Volume Depletion

  There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with GLP-1 receptor agonists, including TRULICITY

  [see Adverse Reactions (6.2)]

  . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea

  [see Adverse Reactions (6.1)]

  . Monitor renal function in patients reporting adverse reactions to TRULICITY that could lead to volume depletion, especially during dosage initiation and escalation of TRULICITY.

  )]
• Severe Gastrointestinal Adverse Reactions
  [see Warnings and Precautions (

  5.6 Severe Gastrointestinal Adverse Reactions

  Use of TRULICITY has been associated with gastrointestinal adverse reactions, sometimes severe

  [see Adverse Reactions (6)]

  . In the pool of placebo-controlled trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving TRULICITY (0.75 mg 2.2%, 1.5 mg 4.3%) than placebo (1.4%).

  TRULICITY is not recommended in patients with severe gastroparesis.

  )]
• Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy
  [see Warnings and Precautions (

  5.7 Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy

  In a cardiovascular outcomes trial with a median follow up of 5.4 years involving patients with type 2 diabetes with established cardiovascular disease or multiple cardiovascular risk factors, diabetic retinopathy complications occurred in patients treated with TRULICITY 1.5 mg (1.9%) and placebo (1.5%). These events were prospectively ascertained as a secondary composite endpoint. The proportion of patients with diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (TRULICITY 8.5%, placebo 6.2%) than among patients without a known history of diabetic retinopathy (TRULICITY 1%, placebo 1%).

  Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.

  )]
• Acute Gallbladder Disease
  [see Warnings and Precautions (

  5.8 Acute Gallbladder Disease

  Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In a cardiovascular outcomes trial with a median follow up of 5.4 years, cholelithiasis occurred at a rate of 0.62/100 patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy. Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placebo respectively. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

  )]
• Pulmonary Aspiration During General Anesthesia or Deep Sedation
  [see Warnings and Precautions (

  5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation

  TRULICITY delays gastric emptying

  [see Clinical Pharmacology (12.2)]

  . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations.

  Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking TRULICITY, including whether modifying preoperative fasting recommendations or temporarily discontinuing TRULICITY could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking TRULICITY.

  )]

Dulaglutide is a human GLP-1 receptor agonist. The molecule is a fusion protein that consists of 2 identical, disulfide-linked chains, each containing an N-terminal GLP-1 analog sequence covalently linked to the Fc portion of a modified human immunoglobulin G4 (IgG4) heavy chain by a small peptide linker and is produced using mammalian cell (Chinese hamster ovary) culture. The GLP-1 analog portion of dulaglutide is 90% homologous to native human GLP-1 (7-37). Structural modifications were introduced in the GLP-1 part of the molecule responsible for interaction with the enzyme dipeptidyl-peptidase-IV (DPP-4). Additional modifications were made in an area with a potential T-cell epitope and in the areas of the IgG4 Fc part of the molecule responsible for binding the high-affinity Fc receptors and half-antibody formation. The overall molecular weight of dulaglutide is approximately 63 kilodaltons.

TRULICITY (dulaglutide) injection is a clear, colorless, sterile, preservative-free solution for subcutaneous use. Each single-dose pen contains a 0.5 mL solution of 0.75 mg, 1.5 mg, 3 mg, or 4.5 mg of dulaglutide and the following excipients: citric acid anhydrous (0.07 mg), mannitol (23.2 mg), polysorbate 80 (0.10 mg for 0.75 mg and 1.5 mg; 0.125 mg for 3 mg and 4.5 mg), and trisodium citrate dihydrate (1.37 mg), in water for injection.

TRULICITY contains dulaglutide, which is a human GLP-1 receptor agonist with 90% amino acid sequence homology to endogenous human GLP-1 (7-37). Dulaglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase in pancreatic beta cells. Dulaglutide increases intracellular cyclic AMP (cAMP) in beta cells leading to glucose-dependent insulin release. Dulaglutide also decreases glucagon secretion and slows gastric emptying.

A 2-year carcinogenicity study was conducted with dulaglutide in male and female rats at doses 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 weekly based on AUC) administered by subcutaneous injection twice weekly. In rats, dulaglutide caused a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) compared to controls, at ≥3-fold the MRHD based on AUC. A statistically significant increase in C-cell adenomas was observed in rats receiving dulaglutide at ≥0.5 mg/kg. Numerical increases in thyroid C-cell carcinomas occurred at 5 mg/kg (24 times the MRHD based on AUC) and were considered to be treatment-related despite the absence of statistical significance.

A 6-month carcinogenicity study was conducted with dulaglutide in rasH2 transgenic mice at doses of 0.3, 1, and 3 mg/kg administered by subcutaneous injection twice weekly. Dulaglutide did not produce increased incidences of thyroid C-cell hyperplasia or neoplasia at any dose.

Dulaglutide is a recombinant protein; no genotoxicity studies have been conducted.

Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies

In fertility and early embryonic development studies in male and female rats, no adverse effects of dulaglutide on sperm morphology, mating, fertility, conception, and embryonic survival were observed at up to 16.3 mg/kg (55-fold the MRHD based on AUC). In female rats, an increase in the number of females with prolonged diestrus and a dose-related decrease in the mean number of corpora lutea, implantation sites, and viable embryos were observed at ≥4.9 mg/kg (≥13-fold the MRHD based on AUC), which occurred in the presence of decreased maternal food consumption and body weight gain.

TRULICITY has been studied in adults as monotherapy and in combination with metformin, sulfonylurea, metformin and sulfonylurea, metformin and thiazolidinedione, sodium-glucose co-transporter-2 inhibitors (SGLT2i) with or without metformin, basal insulin with or without metformin, and prandial insulin with or without metformin. TRULICITY has also been studied in patients with type 2 diabetes mellitus and moderate to severe renal impairment.

Dose escalation was performed in one trial in adults with TRULICITY doses up to 4.5 mg added to metformin. All other clinical studies in adults evaluated TRULICITY 0.75 mg and 1.5 mg without dose escalation; patients were initiated and maintained on either 0.75 mg or 1.5 mg for the duration of the trials

[see Clinical Studies (

14.2 Glycemic Control Monotherapy Trials in Adults with Type 2 Diabetes Mellitus

In a double-blind trial with primary endpoint at 26 weeks, 807 adult patients inadequately treated with diet and exercise, or with diet and exercise and one antidiabetic agent used at submaximal dose, were randomized to TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or metformin 1500 to 2000 mg/day following a two-week washout. Seventy-five percent (75%) of the randomized population were treated with one antidiabetic agent at the screening visit. Most patients previously treated with an antidiabetic agent were receiving metformin (~90%) at a median dose of 1000 mg daily and approximately 10% were receiving a sulfonylurea.

Patients had a mean age of 56 years and a mean duration of type 2 diabetes of 3 years. Forty-four percent were male. The White, Black and Asian race accounted for 74%, 7% and 8% of the population, respectively. Twenty-nine percent of the trial population were from the US.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in reduction in HbA1c from baseline at 26-weeks (Table 4). The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and metformin excluded the pre-specified non-inferiority margin of 0.4%.

Table 4: Results at Week 26 in a Trial of TRULICITY as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus^a

Abbreviation: HbA1c = hemoglobin A1c.
aIntent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy was missing for 10%, 12% and 14% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and metformin, respectively.
bLeast-squares mean adjusted for baseline value and other stratification factors.
‡Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 265 individuals in each of the treatment arms.
	26-Week Primary Time Point
	TRULICITY 0.75 mg	TRULICITY 1.5 mg	Metformin 1500-2000 mg
Intent-to-Treat (ITT) Population (N) ‡	270	269	268
HbA1c (%) (Mean)
Baseline	7.6	7.6	7.6
Change from baselineb	-0.7	-0.8	-0.6
Fasting Serum Glucose (mg/dL) (Mean)
Baseline	161	164	161
Change from baselineb	-26	-29	-24
Body Weight (kg) (Mean)
Baseline	91.8	92.7	92.4
Change from baselineb	-1.4	-2.3	-2.2

,

14.3 Glycemic Control Combination Therapy Trials in Adults with Type 2 Diabetes Mellitus

Sitagliptin-Controlled Trial (Add-on to Metformin)

In this placebo-controlled, double-blind trial with primary endpoint at 52 weeks, 972 adult patients were randomized to placebo, TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or sitagliptin 100 mg/day (after 26 weeks, patients in the placebo treatment group received blinded sitagliptin 100 mg/day for the remainder of the trial), all as add-on to metformin. Randomization occurred after an 11-week lead-in period to allow for a metformin titration period, followed by a 6-week glycemic stabilization period. Patients had a mean age of 54 years; mean duration of type 2 diabetes of 7 years; 48% were male; race: White, Black and Asian were 53%, 4% and 27%, respectively; and 24% of the trial population were in the US.

At the 26-week placebo-controlled time point, the HbA1c change was 0.1%, -1.0%, -1.2%, and -0.6% for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. The percentage of patients who achieved HbA1c <7.0% was 22%, 56%, 62% and 39% for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. At 26 weeks, there was a mean weight reduction of 1.4 kg, 2.7 kg, 3.0 kg, and 1.4 kg for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. There was a mean reduction of fasting glucose of 9 mg/dL, 35 mg/dL, 41 mg/dL, and 18 mg/dL for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to sitagliptin (at 26 and 52 weeks), all in combination with metformin (Table 5andFigure 3).

Table 5: Results at Week 52 of TRULICITY Compared to Sitagliptin used as Add-On to Metformin in Adult Patients with Type 2 Diabetes Mellitus^a

Abbreviations: HbA1c = hemoglobin A1c.
aAll ITT patients randomized after the dose-finding portion of the trial. Last observation carried forward (LOCF) was used to impute missing data. At Week 52 primary efficacy was missing for 15%, 19%, and 20% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and sitagliptin, respectively.
bLeast-squares (LS) mean adjusted for baseline value and other stratification factors.
‡Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 276, 277, and 270 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and sitagliptin, respectively.
††Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to sitagliptin, assessed only for HbA1c.
##p<0.001 TRULICITY compared to sitagliptin, assessed only for HbA1c <7.0%.
	52-Week Primary Time Point
	TRULICITY 0.75 mg	TRULICITY 1.5 mg	Sitagliptin 100 mg
Intent-to-Treat (ITT) Population (N) ‡	281	279	273
HbA1c (%) (Mean)
Baseline	8.2	8.1	8.0
Change from baselineb	-0.9	-1.1	-0.4
Difference from sitagliptinb(95% CI)	-0.5 (-0.7, -0.3)††	-0.7 (-0.9, -0.5)††	-
Percentage of patients HbA1c <7.0%	49##	59##	33
Fasting Plasma Glucose (mg/dL) (Mean)
Baseline	174	173	171
Change from baselineb	-30	-41	-14
Difference from sitagliptinb(95% CI)	-15 (-22, -9)	-27 (-33, -20)	-
Body Weight (kg) (Mean)
Baseline	85.5	86.5	85.8
Change from baselineb	-2.7	-3.1	-1.5
Difference from sitagliptinb(95% CI)	-1.2 (-1.8, -0.6)	-1.5 (-2.1, -0.9)	-

Mean HbA1c adjusted for baseline HbA1c and country.
Number of patients with observed data
Placebo	139	108
TRULICITY 0.75 mg	281	258	238
TRULICITY 1.5 mg	279	249	225
Sitagliptin	273	241	219

Figure 3: Adjusted Mean HbA1c at each Time Point (ITT, MMRM) and at Week 52 (ITT, LOCF) in Adult Patients with Type 2 Diabetes Mellitus

Dosage Ranging Trial of TRULICITY 1.5, 3 mg, and 4.5 mg (Add-on to Metformin)

In this parallel-arm, double-blind trial with primary endpoint at 36 weeks, a total of 1842 adult patients were randomized 1:1:1 to TRULICITY 1.5 mg, TRULICITY 3 mg, or TRULICITY 4.5 mg once weekly, all as add-on to metformin (NCT03495102).

Following randomization, all patients received TRULICITY 0.75 mg once weekly. The dose was increased every 4 weeks to the next higher dose until the patients reached their assigned dose (1.5 mg, 3 mg, or 4.5 mg). Patients were to remain on the assigned study dose for the duration of the trial.

Patients had a mean age of 57.1 years; a mean duration of type 2 diabetes of 7.6 years; 51.2% were male; race: White, Black, and Asian were 85.8%, 4.5%, and 2.4%, respectively; and 27.6% of the trial population was in the US.

At 36 weeks, treatment with TRULICITY 4.5 mg resulted in a statistically significant reduction in HbA1c and in body weight compared to TRULICITY 1.5 mg (Table 6andFigure 4).

Table 6. Results at Week 36 of TRULICITY 1.5 mg Compared to 3 mg and 4.5 mg as Add-On to Metformin in Adult Patients with Type 2 Diabetes Mellitus^a

Abbreviations: HbA1c = hemoglobin A1c
aIntent-to-treat population. At Week 36, primary efficacy was missing for 7%, 7%, and 6% of individuals treated with TRULICITY 1.5 mg, TRULICITY 3 mg, and TRULICITY 4.5 mg, respectively.
bLeast-squares mean adjusted for baseline value and other stratification factors. Missing data were imputed using multiple imputation.
cPatients with missing HbA1c data at Week 36 were considered as not achieving HbA1c target.
^ p=0.0001 for superiority compared to TRULICITY 1.5 mg, overall type I error controlled.
^^ p<0.0001 for superiority compared to TRULICITY 1.5 mg, overall type I error controlled.
	36-Week Primary Time Point
	TRULICITY 1.5 mg	TRULICITY 3 mg	TRULICITY 4.5 mg
Intent-to-Treat (ITT) Population (N)	612	616	614
HbA1c (%) (Mean)
Baseline	8.6	8.6	8.6
Change from baselineb	-1.5	-1.6	-1.8
Difference from 1.5 mgb(95% CI)		-0.1 (-0.2, 0.0)	-0.2 (-0.4, -0.1) ^
Percentage of patients HbA1c <7.0% c	50	56	62
Fasting Serum Glucose (mg/dL) (Mean)
Baseline	185	184	183
Change from baselineb	-45	-46	-51
Difference from 1.5 mgb(95% CI)		- 2 (-7, 3)	-6 (-11, -2)
Body Weight (kg) (Mean)
Baseline	95.5	96.3	95.4
Change from baselineb	-3.0	-3.8	-4.6
Difference from 1.5 mgb(95% CI)		-0.9 (-1.4, -0.4)	-1.6 (-2.2, -1.1) ^^

Number of patients with observed data
TRULICITY 1.5 mg	612		567
TRULICITY 3 mg	616		572
TRULICITY 4.5 mg	614		575

Observed mean HbA1c at scheduled visits and retrieved dropout multiple imputation (MI) based estimate at week 36.

Figure 4: Mean HbA1c at each Time Point (ITT) and at Week 36 (ITT, MI)

Placebo-Controlled Trial (Add-on to Sulfonylurea)

In this 24-week placebo-controlled, double-blind trial, 299 adult patients were randomized to and received placebo or once weekly TRULICITY 1.5 mg, both as add-on to glimepiride. Patients had a mean age of 58 years; mean duration of type 2 diabetes of 8 years; 44% were male; race: White, Black, and Asian were 83%, 4%, and 2%, respectively; and 24% of the trial population were in the US.

At 24 weeks, treatment with once weekly TRULICITY 1.5 mg resulted in a statistically significant reduction in HbA1c compared to placebo (Table 7).

Table 7: Results at Week 24 of TRULICITY Compared to Placebo as Add-On to Glimepiride in Adult Patients with Type 2 Diabetes Mellitus^a

Abbreviations: HbA1c = hemoglobin A1c.
aIntent-to-treat population. Data post-onset of rescue therapy are treated as missing. At Week 24 primary efficacy was missing for 10% and 12% of individuals randomized to TRULICITY 1.5 mg and placebo, respectively.
bLeast-squares mean from ANCOVA adjusted for baseline value and other stratification factors. Placebo multiple imputation, with respect to the baseline values, was used to model a wash-out of the treatment effect for patients having missing Week 24 data.
cPatients with missing HbA1c data at Week 24 were considered as non-responders.
††p<0.001 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled.
	24-Week Primary Time Point
	Placebo	TRULICITY 1.5 mg
Intent-to-Treat (ITT) Population (N)	60	239
HbA1c (%) (Mean)
Baseline	8.4	8.4
Change from baselineb	-0.3	-1.3
Difference from placebob(95% CI)		-1.1 (-1.4, -0.7)††
Percentage of patients HbA1c <7.0% c	17	50††
Fasting Serum Glucose (mg/dL) (Mean)
Baseline	175	178
Change from baselineb	2	-28
Difference from placebob(95% CI)		-30 (-44, -15)††
Body Weight (kg) (Mean)
Baseline	89.5	84.5
Change from baselineb	-0.2	-0.5
Difference from placebob(95% CI)		-0.4 (-1.2, 0.5)

Placebo- and Exenatide-Controlled Trial (Add-on to Metformin and Thiazolidinedione)

In this placebo-controlled trial with primary endpoint at 26 weeks, 976 adult patients were randomized to and received placebo, TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or exenatide 10 mcg BID, all as add-on to maximally tolerated doses of metformin (≥1500 mg per day) and pioglitazone (up to 45 mg per day). Exenatide treatment group assignment was open-label while the treatment assignments to placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg were blinded. After 26 weeks, patients in the placebo treatment group were randomized to either TRULICITY 0.75 mg once weekly or TRULICITY 1.5 mg once weekly to maintain blinding. Randomization occurred after a 12-week lead-in period; during the initial 4 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and pioglitazone; this was followed by an 8-week glycemic stabilization period prior to randomization. Patients randomized to exenatide started at a dose of 5 mcg BID for 4 weeks and then were escalated to 10 mcg BID. Patients had a mean age of 56 years; mean duration of type 2 diabetes of 9 years; 58% were male; race: White, Black and Asian were 74%, 8% and 3%, respectively; and 81% of the trial population were in the US.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to exenatide at 26 weeks (Table 8andFigure 5). Over the 52-week trial period, the percentage of patients who required glycemic rescue was 8.9% in the TRULICITY 0.75 mg once weekly + metformin and pioglitazone treatment group, 3.2% in the TRULICITY 1.5 mg once weekly + metformin and pioglitazone treatment group, and 8.7% in the exenatide BID + metformin and pioglitazone treatment group.

Table 8: Results at Week 26 of TRULICITY Compared to Placebo and Exenatide, All as Add-On to Metformin and Thiazolidinedione in Adult Patients with Type 2 Diabetes Mellitus^a

Abbreviations: BID = twice daily; HbA1c = hemoglobin A1c.
aIntent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy was missing for 23%, 10%, 7% and 12% of individuals randomized to placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and exenatide, respectively.
bLeast-squares (LS) mean adjusted for baseline value and other stratification factors.
‡Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 119, 269, 271 and 266 individuals randomized to placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and exenatide, respectively.
‡‡Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to placebo, assessed only for HbA1c.
††Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to exenatide, assessed only for HbA1c.
** p<0.001 TRULICITY compared to placebo, assessed only for HbA1c <7.0%.
##p<0.001 TRULICITY compared to exenatide, assessed only for HbA1c <7.0%.
	26-Week Primary Time Point
	Placebo	TRULICITY 0.75 mg	TRULICITY 1.5 mg	Exenatide 10 mcg BID
Intent-to-Treat (ITT) Population (N) ‡	141	280	279	276
HbA1c (%) (Mean)
Baseline	8.1	8.1	8.1	8.1
Change from baselineb	-0.5	-1.3	-1.5	-1.0
Difference from placebob(95% CI)	-	-0.8 (-1.0, -0.7)‡‡	-1.1 (-1.2, -0.9)‡‡	-
Difference from exenatideb(95% CI)	-	-0.3 (-0.4, -0.2)††	-0.5 (-0.7, -0.4)††	-
Percentage of patients HbA1c <7.0%	43	66**, ##	78**, ##	52
Fasting Serum Glucose (mg/dL) (Mean)
Baseline	166	159	162	164
Change from baselineb	-5	-34	-42	-24
Difference from placebob(95% CI)	-	-30 (-36, -23)	-38 (-45, -31)	-
Difference from exenatideb(95% CI)	-	-10 (-15, -5)	-18 (-24, -13)	-
Body Weight (kg) (Mean)
Baseline	94.1	95.5	96.2	97.4
Change from baselineb	1.2	0.2	-1.3	-1.1
Difference from placebob(95% CI)	-	-1.0 (-1.8, -0.3)	-2.5 (-3.3, -1.8)	-
Difference from exenatideb(95% CI)	-	1.3 (0.6, 1.9)	-0.2 (-0.9, 0.4)	-

Mean HbA1c adjusted for baseline HbA1c and country.
Number of patients with observed data
Placebo	141		108
TRULICITY 0.75 mg	280		251
TRULICITY 1.5 mg	279		259
Exenatide	276		242

Figure 5: Adjusted Mean HbA1c at Each Time Point (ITT, MMRM) and at Week 26 (ITT, LOCF)

Placebo-Controlled Trial (Add-on to SGLT2i, with or without Metformin)

In this 24-week placebo-controlled, double-blind trial, 423 adult patients were randomized to and received TRULICITY 0.75 mg, TRULICITY 1.5 mg, or placebo, as add-on to sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy (96% with and 4% without metformin). Trulicity was administered once weekly, and SGLT2i was administered according to the local country label. Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9.4 years; 50% were male; race: White, Black, and Asian were 89%, 3%, and 0.2%, respectively; and 21% of the trial population was in the US.

At 24 weeks, treatment with once weekly TRULICITY 0.75 mg and 1.5 mg resulted in a statistically significant reduction from baseline in HbA1c compared to placebo (Table 9).

The mean baseline body weight was 90.5, 91.1, and 92.9 kg in the placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg groups, respectively. The mean changes from baseline in body weight at Week 24 were -2.0, -2.5, and -2.9 kg for placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively. The difference from placebo (95% CI) was -0.9 kg (-1.7, -0.1) for TRULICITY 1.5 mg.

Table 9: Results at Week 24 of TRULICITY as Add-on to SGLT2i in Adult Patients with Type 2 Diabetes Mellitus^a

Abbreviations: HbA1c = hemoglobin A1c; SGLT2i = sodium-glucose co-transporter-2 inhibitors.
aIntent-to-treat population. At Week 24, primary efficacy was missing for 3%, 4%, and 6% of individuals treated with placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively.
bLeast-squares mean adjusted for baseline value and other stratification factors. Placebo multiple imputation, using baseline and 24-week values from the placebo arm, was applied to model a washout of the treatment effect for patients missing 24-week values (HbA1c, fasting serum glucose, and body weight).
cPatients with missing HbA1c data at Week 24 were considered as non-responders.
††p<0.001 for superiority of TRULICITY compared to placebo, overall type I error controlled.
	24-Week Primary Time Point
	Placebo	TRULICITY 0.75 mg	TRULICITY 1.5 mg
Intent-to-Treat (ITT) Population (N)	140	141	142
HbA1c (%) (Mean)
Baseline	8.1	8.1	8.0
Change from baselineb	-0.6	-1.2	-1.3
Difference from placebob(95% CI)	-	-0.7 (-0.8, -0.5)††	-0.8 (-0.9, -0.6)††
Percentage of patients HbA1c <7.0% c	31	59††	67††
Fasting Serum Glucose (mg/dL) (Mean)
Baseline	153	162	161
Change from baselineb	-6	-25	-30
Difference from placebob(95% CI)	-	-19 (-25, -13)	-24 (-30, -18)††

Insulin Glargine Controlled Trial (Add-on to Metformin and Sulfonylurea)

In this open-label comparator trial (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 52 weeks, 807 adult patients were randomized to and received TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all as add-on to maximally tolerated doses of metformin and glimepiride. Randomization occurred after a 10-week lead-in period; during the initial 2 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and glimepiride. This was followed by a 6- to 8-week glycemic stabilization period prior to randomization.

Patients randomized to insulin glargine were started on a dose of 10 units once daily. Insulin glargine dose adjustments occurred twice weekly for the first 4 weeks of treatment based on self-measured fasting plasma glucose (FPG), followed by once weekly titration through Week 8 of treatment, utilizing an algorithm that targeted a fasting plasma glucose of <100 mg/dL. Only 24% of patients were titrated to goal at the 52-week primary endpoint. The dose of glimepiride could be reduced or discontinued after randomization (at the discretion of the investigator) in the event of persistent hypoglycemia. The dose of glimepiride was reduced or discontinued in 28%, 32%, and 29% of patients randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine.

Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9 years; 51% were male; race: White, Black and Asian were 71%, 1% and 17%, respectively; and 0% of the trial population were in the US.

Treatment with TRULICITY once weekly resulted in a reduction in HbA1c from baseline at 52 weeks when used in combination with metformin and sulfonylurea (Table 10). The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%.

Table 10: Results at Week 52 of TRULICITY Compared to Insulin Glargine, Both as Add-on to Metformin and Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitus^a

Abbreviations: HbA1c = hemoglobin A1c.
aIntent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy was missing for 17%, 13% and 12% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and glargine, respectively.
bLeast-squares (LS) mean adjusted for baseline value and other stratification factors.
‡Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 267, 263 and 259 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine, respectively.
	52-Week Primary Time Point
	TRULICITY 0.75 mg	TRULICITY 1.5 mg	Insulin Glargine
Intent-to-Treat (ITT) Population (N) ‡	272	273	262
HbA1c (%) (Mean)
Baseline	8.1	8.2	8.1
Change from baselineb	-0.8	-1.1	-0.6
Fasting Serum Glucose (mg/dL) (Mean)
Baseline	161	165	163
Change from baselineb	-16	-27	-32
Difference from insulin glargineb(95% CI)	16 (9, 23)	5 (-2, 12)	-
Body Weight (kg) (Mean)
Baseline	86.4	85.2	87.6
Change from baselineb	-1.3	-1.9	1.4
Difference from insulinb(95% CI)	-2.8 (-3.4, -2.2)	-3.3 (-3.9, -2.7)	-

Placebo-Controlled Trial (Add-on to Basal Insulin, with or without Metformin)

In this 28-week placebo-controlled, double-blind trial, 300 adult patients were randomized to placebo or once weekly TRULICITY 1.5 mg, as add-on to titrated basal insulin glargine (with or without metformin). Patients had a mean age of 60 years; mean duration of type 2 diabetes of 13 years; 58% were male; race: White, Black, and Asian were 94%, 4%, and 0.3%, respectively; and 20% of the trial population was in the US.

The mean starting dose of insulin glargine was 37 units/day for patients receiving placebo and 41 units/day for patients receiving TRULICITY 1.5 mg. At randomization, the initial insulin glargine dose in patients with HbA1c <8.0% was reduced by 20%.

At 28 weeks, treatment with once weekly TRULICITY 1.5 mg resulted in a statistically significant reduction in HbA1c compared to placebo (Table 11).

Table 11: Results at Week 28 of TRULICITY Compared to Placebo as Add-On to Basal Insulin in Adult Patients with Type 2 Diabetes Mellitus^a

Abbreviations: HbA1c = hemoglobin A1c.
aIntent-to-treat population. At Week 28, primary efficacy was missing for 12% and 8% of individuals randomized to placebo and TRULICITY 1.5 mg, respectively.
bLeast-squares mean from ANCOVA adjusted for baseline value and other stratification factors. Placebo multiple imputation, with respect to baseline values, was used to model a wash-out of the treatment effect for patients having missing Week 28 data.
cPatients with missing HbA1c data at Week 28 were considered as non-responders.
††p<0.001 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled.
†p≤0.005 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled.
	28-Week Primary Time Point
	Placebo	TRULICITY 1.5 mg
Intent-to-Treat (ITT) Population (N)	150	150
HbA1c (%) (Mean)
Baseline	8.3	8.4
Change from baselineb	-0.7	-1.4
Difference from placebob(95% CI)		-0.7 (-0.9, -0.5)††
Percentage of patients HbA1c <7.0% c	33	67††
Fasting Serum Glucose (mg/dL) (Mean)
Baseline	156	157
Change from baselineb	-30	-44
Difference from placebob(95% CI)		-14 (-23, -4)†
Body Weight (kg) (Mean)
Baseline	92.6	93.3
Change from baselineb	0.8	-1.3
Difference from placebob(95% CI)		-2.1 (-2.9, -1.4)††

Insulin Glargine-Controlled Trial (Combination with Prandial Insulin, with or without

Metformin)

In this open-label comparator trial (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26 weeks, 884 adult patients on 1 or 2 insulin injections per day were enrolled. Randomization occurred after a 9-week lead-in period; during the initial 2 weeks of the lead-in period, patients continued their pre-trial insulin regimen but could be initiated and/or up-titrated on metformin, based on investigator discretion; this was followed by a 7-week glycemic stabilization period prior to randomization.

At randomization, patients discontinued their pre-trial insulin regimen and were randomized to TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro 3 times daily, with or without metformin. Insulin lispro was titrated in each arm based on preprandial and bedtime glucose, and insulin glargine was titrated to a fasting plasma glucose goal of <100 mg/dL. Only 36% of patients randomized to glargine were titrated to the fasting glucose goal at the 26-week primary timepoint.

Patients had a mean age of 59 years; mean duration of type 2 diabetes of 13 years; 54% were male; race: White, Black and Asian were 79%, 10% and 4%, respectively; and 33% of the trial population were in the US.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c from baseline. The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4% (Table 12).

Table 12: Results at Week 26 of TRULICITY Compared to Insulin Glargine, Both in Combination with Insulin Lispro in Adult Patients with Type 2 Diabetes Mellitus^a

Abbreviation: HbA1c = hemoglobin A1c
aIntent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy was missing for 14%, 15%, and 14% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and glargine, respectively.
bLeast-squares (LS) mean adjusted for baseline value and other stratification factors.
‡Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 275, 273 and 276 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine, respectively.
	26-Week Primary Time Point
	TRULICITY 0.75 mg	TRULICITY 1.5 mg	Insulin Glargine
Intent-to-Treat (ITT) Population (N) ‡	293	295	296
HbA1c (%) (Mean)
Baseline	8.4	8.5	8.5
Change from baselineb	-1.6	-1.6	-1.4
Fasting Serum Glucose (mg/dL) (Mean)
Baseline	150	157	154
Change from baselineb	4	-5	-28
Difference from insulin glargineb(95% CI)	32 (24, 41)	24 (15, 32)	-
Body Weight (kg) (Mean)
Baseline	91.7	91.0	90.8
Change from baselineb	0.2	-0.9	2.3
Difference from insulin glargineb(95% CI)	-2.2 (-2.8, -1.5)	-3.2 (-3.8, -2.6)	-

,

14.4 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus and Moderate to Severe Chronic Kidney Disease

In this open-label comparator trial (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26 weeks, a total of 576 adult patients with type 2 diabetes were randomized and treated to compare TRULICITY 0.75 mg and 1.5 mg with insulin glargine (NCT01621178).

Patients on insulin and other antidiabetic therapy (e.g., oral antidiabetic drugs, pramlintide) had non-insulin therapies discontinued and had their insulin dose adjusted for 12 weeks prior to randomization. Patients on insulin therapy alone maintained a stable insulin dose for 3 weeks prior to randomization. At randomization, patients discontinued their pre-trial insulin regimen and patients were randomized to TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro. For patients randomized to insulin glargine, the initial insulin glargine dose was based on the basal insulin dose prior to randomization. Insulin glargine was allowed to be titrated with a fasting plasma glucose goal of ≤150 mg/dL. Insulin lispro was allowed to be titrated with a preprandial and bedtime glucose goal of ≤180 mg/dL.

Patients had a mean age of 65 years; a mean duration of type 2 diabetes of 18 years; 52% were male; race: White, Black, and Asian were 69%, 16%, and 3%, respectively; and 32% of the trial population were in the US. At baseline, overall mean eGFR was 38 mL/min/1.73 m², 30% of patients had eGFR <30 mL/min/1.73 m², and 45% of patients had macroalbuminuria. Patients on over 70 units/day of basal insulin were excluded from the trial.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c at 26-weeks from baseline. The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%. Mean fasting plasma glucose increased in the TRULICITY arms (Table 13).

Mean baseline body weight was 90.9 kg, 88.1 kg, and 88.2 kg in the TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine arms, respectively. The mean changes from baseline at Week 26 were -1.1, -2, and 1.9 kg in the TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine arms, respectively.

Table 13: Results at Week 26 of TRULICITY Compared to Insulin Glargine, Both in Combination with Insulin Lispro, in Patients with Moderate to Severe Chronic Kidney Disease in Adult Patients with Type 2 Diabetes Mellitus^a

Abbreviation: HbA1c = hemoglobin A1c
aIntent-to-treat population (all randomized and treated patients) was used in the analysis regardless of discontinuation of study drug or initiation of rescue therapy. At Week 26, primary efficacy was missing for 12%, 15%, and 9% of individuals randomized to and treated with TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine, respectively. Missing data were imputed using multiple imputation within treatment group.
bLeast-squares (LS) mean from ANCOVA pattern mixture model adjusted for baseline value and other stratification factors.
	26-Week Primary Time Point
	TRULICITY 0.75 mg	TRULICITY 1.5 mg	Insulin Glargine
Intent-to-Treat Population (N)	190	192	194
HbA1c (%) (Mean)
Baseline	8.6	8.6	8.6
Change from baselineb	-0.9	-1.0	-1.0
Difference from insulin glargineb(95% CI)	0.0 (-0.2, 0.3)	-0.1 (-0.3, 0.2)
Percentage of patients HbA1c <8.0%	73	75	74
Fasting Serum Glucose (mg/dL) (Mean)
Baseline	167	161	170
Change from baselineb	6	14	-23
Difference from insulin glargineb(95% CI)	30 (16, 43)	37 (24, 50)

)]

TRULICITY 0.75 mg and 1.5 mg was studied in pediatric patients 10 years of age and older with type 2 diabetes in combination with or without metformin and/or basal insulin treatment

In patients with type 2 diabetes mellitus, TRULICITY produced reductions from baseline in HbA1c compared to placebo. No overall differences in glycemic effectiveness were observed across demographic subgroups (age, gender, race/ethnicity, duration of diabetes).

A cardiovascular outcomes trial was conducted in adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors. Patients were randomized to TRULICITY 1.5 mg or placebo both added to standard of care. TRULICITY significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal MI, or non-fatal stroke

[see Clinical Studies (

14.5 Cardiovascular Outcomes Trial in Adults with Type 2 Diabetes Mellitus and Cardiovascular Disease or Multiple Cardiovascular Risk Factors

The REWIND trial (NCT01394952) was a multi-national, multi-center, randomized, placebo-controlled, double-blind trial. In this trial, 9901 adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors were randomized to TRULICITY 1.5 mg or placebo both added to standard of care. The median follow-up duration was 5.4 years. The primary endpoint was the time to the first occurrence of a composite 3-component Major Adverse Cardiovascular Events (MACE) outcome, which included CV death, non-fatal myocardial infarction (MI), and non-fatal stroke.

Patients eligible to enter the trial were 50 years of age or older who had type 2 diabetes mellitus, had an HbA1c value ≤9.5% with no lower limit at screening, and had either established CV disease, or did not have established CV disease but had multiple CV risk factors. Patients who were confirmed to have established CV disease (31.5% of randomized patients) had a history of at least one of the following: MI (16.2%); myocardial ischemia by a stress test or with cardiac imaging (9.3%); ischemic stroke (5.3%); coronary, carotid, or peripheral artery revascularization (18.0%); unstable angina (5.9%); or hospitalization for unstable angina with at least one of the following: ECG changes, myocardial ischemia on imaging, or a need for percutaneous coronary intervention (12.0%). Patients confirmed to be without established CV disease, but with multiple CV risk factors, comprised 62.8% of the randomized trial population.

At baseline, demographic and disease characteristics were balanced between treatment groups. Patients had a mean age of 66 years; 46% were female; race: White, Black, and Asian were 76%, 7%, and 4%, respectively.

The median baseline HbA1c was 7.2%. The mean duration of type 2 diabetes was 10.5 years and the mean BMI was 32.3 kg/m².

At baseline, 50.5% of patients had mild renal impairment (eGFR ≥60 but <90 mL/min/1.73m²), 21.6% had moderate renal impairment (eGFR ≥30 but <60 mL/min/1.73m²), and 1.1% of patients had severe renal impairment (eGFR <30 mL/min/1.73m²) out of 9713 patients whose eGFR were available.

At baseline, 94.7% of patients were taking antidiabetic medication, with 10.5% of patients taking three or more antidiabetic drugs. The most common background antidiabetic drugs used at baseline were metformin (81.2%), sulfonylurea (46.0%), and insulin (23.9%). At baseline, CV disease and risk factors were managed with ACE inhibitors or angiotensin receptor blockers (81.5%), beta blockers (45.6%), calcium channel blockers (34.4%), diuretics (46.5%), statin therapy (66.1%), antithrombotic agents (58.7%), and aspirin (51.7%). During the trial, investigators were to modify anti-diabetic and cardiovascular medications to achieve local standard of care treatment targets with respect to blood glucose, lipids, and blood pressure, and manage patients recovering from an acute coronary syndrome or stroke event per local treatment guidelines.

For the primary analysis, a Cox proportional hazards model was used to test for superiority. Type I error was controlled across multiple tests. TRULICITY significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal MI, or non-fatal stroke (HR: 0.88, 95% CI 0.79, 0.99). Refer toFigure 6andTable 14.

Vital status was available for 99.7% of patients in the trial. A total of 1128 deaths were recorded during the REWIND trial. A majority of the deaths in the trial were adjudicated as CV deaths, and non-CV deaths were comparable between the treatment groups (4.4% in patients treated with TRULICITY and 5.0% in patients treated with placebo). There were 536 all-cause deaths (10.8%) in the dulaglutide group compared to 592 deaths (12.0%) in the placebo group.

Number of patients at risk
Placebo	4952	4791	4625	4437	4275	3575	742
Dulaglutide	4949	4815	4670	4521	4369	3686	741

Figure 6. KAPLAN MEIER CURVE: Time to First Occurrence of MACE in the REWIND Trial

Table 14: Treatment Effect for MACE and the Individual Components in the REWIND Trial, Median Trial Observation Time of 5.4 years in Adult Patients with Type 2 Diabetes Mellitus^a

aAll randomized patients.
bCox-proportional hazards model with treatment as a factor. Type I error was controlled for the primary and secondary endpoints.
cp=0.026 for superiority (2-sided).
dNumber and percentage of patients with events.
eResults for components of MACE, fatal and non-fatal stroke, and fatal and non-fatal MI are listed descriptively for supportive purposes. No statistical significance should be inferred since these CIs are not adjusted for multiplicity.
Time to First Occurrence of:	TRULICITY N=4949	Placebo N=4952	Hazard Ratio (95% CI) b
Composite of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death (MACE)d	594 (12.0%)	663 (13.4%)	0.88 (0.79, 0.99)c
Cardiovascular deathd,e	317 (6.4%)	346 (7.0%)	0.91 (0.78, 1.06)
Non-fatal myocardial infarctiond,e	205 (4.1%)	212 (4.3%)	0.96 (0.79, 1.16)
Non-fatal stroked,e	135 (2.7%)	175 (3.5%)	0.76 (0.61, 0.95)
Fatal or non-fatal myocardial infarctiond,e	223 (4.5%)	231 (4.7%)	0.96 (0.79, 1.15)
Fatal or non-fatal stroked,e	158 (3.2%)	205 (4.1%)	0.76 (0.62, 0.94)

)]

TRULICITY (dulaglutide) injection is a clear and colorless solution supplied in single-dose pens. TRULICITY is packaged in a cardboard outer carton containing 4 single-dose TRULICITY pens and is supplied as follows:

	Instructions for Use
	TRULICITY ® (TRU-li-si-tee) (dulaglutide) injection, for subcutaneous use 4.5 mg/0.5 mL Single-Dose Pen use 1 time each week (once weekly)

• TRULICITY Single-Dose Pen (Pen) is a disposable, prefilled medicine delivery device. Each Pen contains 1 dose of TRULICITY (4.5 mg/0.5 mL). Each Pen should only be used 1 time.
• TRULICITY is used 1 time each week.
  You may want to mark your calendar to remind you when to take your next dose.

Remove	Check	Inspect	Prepare
Remove the Pen from the refrigerator. Leave the Base Cap on until you are ready to inject.	Check the Pen label to make sure you have the right medicine and it has not expired. Expiration Date	Check the Pen to make sure that it is not damaged and inspect the medicine to make sure it is not cloudy, discolored or has particles in it.	Wash your hands.

Your healthcare provider can help you choose the injection site that is best for you.

	Change (rotate) your injection site each week. You may use the same area of your body, but be sure to choose a different injection site in that area. You may inject the medicine into your stomach (abdomen) or thigh.
	Another person should give you the injection in the back of your upper arm.

Step 1 Uncap the Pen Make sure the Pen is locked . Pull the Base Cap straight off and throw it away in your household trash. Do not put the Base Cap back on — this could damage the needle. Do not touch the needle.
Step 2 Place and Unlock Place the Clear Base flat and firmly against your skin at the injection site . Unlock by turning the Lock Ring.

Step 3 Press and Hold Press and hold the green Injection Button. You will hear a loud click. Continue holding the Clear Base firmly against your skin until you hear a second click. This happens when the needle starts retracting in about 5-10 seconds. Remove the Pen from your skin.

Disposal of Pen

Storage and Handling

Commonly Asked Questions

Other Information

Where to Learn More

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Disposing of Your Used Pens Put your used Pens in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) Pens in your household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:

• Store your Pen in the refrigerator between 36°F to 46°F (2°C to 8°C).
• You may store your Pen at room temperature below 86°F (30°C) for a total of 14 days.
• Do not freeze your Pen. If the Pen has been frozen, throw the Pen away and use a new Pen.
• Storage of your Pen in the original carton is recommended. Protect your Pen from direct heat and light.
• The Pen has glass parts. Handle it carefully. If you drop it on a hard surface, do not use it. Use a new Pen for your injection.
• Keep your TRULICITY Pen and all medicines out of the reach of children.

Air bubbles are normal.

Do not remove the Base Cap. Throw away the Pen and get a new Pen.

A drop of liquid on the tip of the needle is normal.

This is not necessary, but it may help you keep the Pen steady and firm against your skin.

Some people may hear a soft click right before the second loud click. That is the normal operation of the Pen. Do not remove the Pen from your skin until you hear the second louder click.

This is normal.

Check to see if you have received your dose. Your dose was delivered the right way if the gray plunger is visible

• If you have vision problems, do not use your Pen without help from a person trained to use the TRULICITY Pen.

• If you have any questions or problems with your TRULICITY Single-Dose Pen, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider.
• For more information about TRULICITY Single-Dose Pen, visit our website at: www.trulicity.com.

Scan this code to launch www.trulicity.com

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Eli Lilly and Company

Indianapolis, IN 46285, USA

US License Number 1891

TRULICITY is a registered trademark of Eli Lilly and Company.

Copyright © 2020, 2023, Eli Lilly and Company. All rights reserved.

The TRULICITY Pen meets the current dose accuracy and functional requirements of ISO 11608-1:2012 and 11608-5:2012.

Implemented: 04/2023

TRU4.5MG-0002-IFU-20230407

TRULICITY contains dulaglutide, which is a human GLP-1 receptor agonist with 90% amino acid sequence homology to endogenous human GLP-1 (7-37). Dulaglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase in pancreatic beta cells. Dulaglutide increases intracellular cyclic AMP (cAMP) in beta cells leading to glucose-dependent insulin release. Dulaglutide also decreases glucagon secretion and slows gastric emptying.