Limitations of Use

• TRULICITY has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.2)]. Consider other antidiabetic therapies in patients with a history of pancreatitis.
• TRULICITY should not be used in patients with type 1 diabetes mellitus.
• TRULICITY has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis and is therefore not recommended in these patients [see Warnings and Precautions (5.6)].

2.1 Dosage

• The recommended initiating dose of TRULICITY is 0.75 mg injected subcutaneously once weekly.
• Increase the dose to 1.5 mg once weekly for additional glycemic control.
• If additional glycemic control is needed, increase the dose to 3 mg once weekly after at least 4 weeks on the 1.5 mg dose.
• If additional glycemic control is needed, increase the dose to the maximum dose of 4.5 mg once weekly after at least 4 weeks on the 3 mg dose.
• If a dose is missed, instruct patients to administer as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose. If less than 3 days remain before the next scheduled dose, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.
• The day of weekly administration can be changed if necessary, as long as the last dose was administered 3 or more days before.

2.2 Important Administration Instructions

• Administer TRULICITY once weekly, any time of day, with or without food.
• Inject TRULICITY subcutaneously in the abdomen, thigh, or upper arm.
• Rotate injection sites with each dose.
• Inspect TRULICITY visually before use. It should appear clear and colorless. Do not use TRULICITY if particulate matter or coloration is seen.
• When using TRULICITY with insulin, administer as separate injections and never mix. It is acceptable to inject TRULICITY and insulin in the same body region, but the injections should not be adjacent to each other.

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 study. 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.

5.2 Pancreatitis

In a pooled analysis from the original registration studies, 12 (3.4 cases per 1000 patient years) pancreatitis-related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient years).

Based on an analysis of adjudicated events in a clinical study evaluating Trulicity 1.5 mg, 3 mg, or 4.5 mg once weekly, pancreatitis occurred in 1 patient exposed to TRULICITY 1.5 mg (0.2%), in 2 patients exposed to TRULICITY 3 mg (0.3%), and 3 patients exposed to TRULICITY 4.5 mg (0.5%).

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, promptly discontinue TRULICITY. If pancreatitis is confirmed, TRULICITY should not be restarted. TRULICITY has not been evaluated in patients with a prior history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.

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.

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 (6.3)]. If a hypersensitivity reaction occurs, discontinue TRULICITY; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous hypersensitivity reaction to TRULICITY [see Contraindications (4)].

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.

5.5 Acute Kidney Injury

In patients treated with GLP-1 receptor agonists, including TRULICITY, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Because these reactions may worsen renal function, use caution when initiating or escalating doses of TRULICITY in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions [see Use in Specific Populations (8.6)].

5.6 Severe Gastrointestinal Disease

Use of TRULICITY may be associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6.1)]. TRULICITY has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

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.

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

6.2 Immunogenicity

In clinical studies, 64 (1.6%) TRULICITY-treated patients developed anti-drug antibodies (ADAs) to the active ingredient in TRULICITY (i.e., dulaglutide).

Of the 64 dulaglutide-treated patients that developed dulaglutide ADAs, 34 patients (0.9% of the overall population) had dulaglutide-neutralizing antibodies, and 36 patients (0.9% of the overall population) developed antibodies against native GLP-1.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to dulaglutide cannot be directly compared with the incidence of antibodies of other products.

6.3 Postmarketing Experience

The following additional adverse reactions have been reported during post-approval use of TRULICITY. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Anaphylactic reactions, angioedema.
• Acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis.

7.1 Oral Medications

TRULICITY delays gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. The delay in gastric emptying is dose-dependent but is attenuated with the recommended dose escalation to higher doses of TRULICITY [see Dosage and Administration (2.1)]. The delay is largest after the first dose and diminishes with subsequent doses. In clinical pharmacology studies, TRULICITY 1.5 mg did not affect the absorption of the tested orally administered medications to a clinically relevant degree [see Clinical Pharmacology (12.3)]. There is limited experience with the use of concomitant medications in clinical trials with TRULICITY doses of 3 mg and 4.5 mg.

Monitor drug levels of oral medications with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with TRULICITY.

7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When initiating TRULICITY, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3) and Adverse Reactions (6)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of TRULICITY have not been established in pediatric patients. TRULICITY is not recommended for use in pediatric patients younger than 18 years.

8.5 Geriatric Use

In the glycemic control trials [see Clinical Studies (14.1)], 620 (18.6%) TRULICITY-treated patients were 65 years of age or older and 65 (1.9%) TRULICITY-treated patients were 75 years of age or older at baseline. In the TRULICITY 1.5 mg treatment arm of the REWIND trial [see Clinical Studies (14.2)], a total of 2619 (52.9%) patients were 65 years of age or older, and 484 (9.8%) patients were 75 years of age or older at baseline.

No overall differences in safety or efficacy were detected between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

TRULICITY has been studied in patients with varying degrees of renal function, including a dedicated study in patients with moderate to severe chronic kidney disease. No overall differences in safety or effectiveness were observed in these studies according to renal function [see Clinical Studies (14)].

In a clinical pharmacology study in subjects with renal impairment, including end-stage renal disease (ESRD), no clinically relevant change in dulaglutide pharmacokinetics (PK) was observed. In the 52-week study in patients with type 2 diabetes and moderate to severe renal impairment, the PK behavior of TRULICITY 0.75 mg and 1.5 mg once weekly was similar to that demonstrated in previous clinical studies [see Clinical Pharmacology (12.3)].

No dose adjustment is recommended in patients with renal impairment including end-stage renal disease (ESRD). Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions. Use TRULICITY with caution in patients with ESRD [see Warning and Precautions (5.5), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no clinically relevant change in dulaglutide PK was observed [see Clinical Pharmacology (12.3)]. However, there is limited clinical experience in patients with mild, moderate, or severe hepatic impairment; therefore, use TRULICITY with caution in these patient populations.

8.8 Gastroparesis

Dulaglutide slows gastric emptying. TRULICITY has not been studied in patients with preexisting gastroparesis. Use TRULICITY with caution in patients with gastroparesis.

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

TRULICITY lowers fasting glucose and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus. The reduction in fasting and postprandial glucose can be observed after a single dose.

12.3 Pharmacokinetics

The pharmacokinetics of dulaglutide is similar between healthy subjects and patients with type 2 diabetes mellitus. Following subcutaneous administration, the time to maximum plasma concentration of dulaglutide at steady state ranges from 24 to 72 hours, with a median of 48 hours. After reaching steady state, the accumulation ratio was approximately 1.56. Steady-state plasma dulaglutide concentrations were achieved between 2 and 4 weeks following once weekly administration. Site of subcutaneous administration (abdomen, upper arm, and thigh) had no statistically significant effect on the exposure to dulaglutide.

Specific Populations

The intrinsic factors of age, gender, race, ethnicity, body weight, or renal or hepatic impairment do not have a clinically relevant effect on the PK of dulaglutide as shown in Figure 1.

Abbreviations: AUC = area under the time-concentration curve; CI = confidence interval; Cmax = maximum concentration; ESRD = end-stage renal disease; PK = pharmacokinetics.

Note: Reference values for weight, age, gender, and race comparisons are 93 kg, 56 years old, male, and white, respectively; reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function from the respective clinical pharmacology studies. The weight values shown in the plot (70 and 120 kg) are the 10th and 90th percentiles of weight in the PK population.

Figure 1: Impact of intrinsic factors on dulaglutide pharmacokinetics.

Potential for Dulaglutide to Influence the Pharmacokinetics of Other Drugs

Dulaglutide slows gastric emptying and, as a result, may reduce the extent and rate of absorption of orally co-administered medications. In clinical pharmacology studies, dulaglutide at a dose of 1.5 mg did not affect the absorption of the tested orally administered medications to any clinically relevant degree. The delay in gastric emptying is dose-dependent but is attenuated with the recommended dose escalation to higher doses of TRULICITY [see Dosage and Administration (2.1), Drug Interactions (7.1)]. The delay is largest after the first dose and diminishes with subsequent doses. PK measures indicating the magnitude of these interactions are presented in Figure 2.

Abbreviations: AUC = area under the time-concentration curve; CI = confidence interval; Cmax = maximum concentration; PK = pharmacokinetics.

Note: Reference group is co-administered medication given alone.

Figure 2: Impact of dulaglutide 1.5 mg on the pharmacokinetics of co-administered medications.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

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 [see Boxed Warning and Warnings and Precautions (5.1)].

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.

13.2 Animal Toxicology and/or Pharmacology

Zucker diabetic fatty (ZDF) rats were given 0.5, 1.5, or 5 mg/kg/twice weekly of dulaglutide (1-, 3-, and 13-fold the MRHD based on AUC) for 3 months. Increases of 12% to 33% in total and pancreatic amylase, but not lipase, were observed at all doses without microscopic pancreatic inflammatory correlates in individual animals. Other changes in the dulaglutide-treated animals included increased interlobular ductal epithelium without active ductal cell proliferation (≥0.5 mg/kg), increased acinar atrophy with/without inflammation (≥1.5 mg/kg), and increased neutrophilic inflammation of the acinar pancreas (5 mg/kg).

Treatment of monkeys for 12 months with 8.15 mg/kg/twice weekly of dulaglutide (nearly 200-fold the MRHD based on AUC) demonstrated no evidence of pancreatic inflammation or pancreatic intraepithelial neoplasia. In 4 of 19 monkeys on dulaglutide treatment, there was an increase in goblet cells within the pancreatic ducts, but no differences from the control group in total amylase or lipase at study termination. There were no proliferative changes in the thyroid C-cells.

14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus

TRULICITY has been studied 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 study with TRULICITY doses up to 4.5 mg added to metformin. All other clinical studies 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.

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).

Combination Therapy

Add-on to Metformin

In this placebo-controlled, double-blind study with primary endpoint at 52 weeks, 972 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 study), 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 study 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 5 and Figure 3).

Table 5: Results at Week 52 of TRULICITY Compared to Sitagliptin used as Add-On to Metformina

Abbreviations: HbA1c = hemoglobin A1c.
a All ITT patients randomized after the dose-finding portion of the study. 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.
b Least-squares (LS) mean adjusted for baseline value and other stratification factors.
‡ Subjects 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)	-

Figure 3: Adjusted Mean HbA1c at each Time Point (ITT, MMRM) and at Week 52 (ITT, LOCF)

TRULICITY 3 mg and 4.5 mg Add-on to Metformin

In this parallel-arm, double-blind study with primary endpoint at 36 weeks, a total of 1842 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 the assigned study dose (1.5 mg, 3 mg, or 4.5 mg). Patients were to remain on the assigned study dose for the duration of the study.

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 study 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 6 and Figure 4).

Table 6. Results at Week 36 of TRULICITY 1.5 mg Compared to 3 mg and 4.5 mg as Add-On to Metformina

Abbreviations: HbA1c = hemoglobin A1c
a Intent-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.
b Least-squares mean adjusted for baseline value and other stratification factors. Missing data were imputed using multiple imputation.
c Patients 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) ^^

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

Add-on to Sulfonylurea

In this 24-week placebo-controlled, double-blind study, 299 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 study 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 Glimepiridea

Abbreviations: HbA1c = hemoglobin A1c.
a Intent-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.
b Least-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 subjects having missing Week 24 data.
c Patients 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)

Add-on to Metformin and Thiazolidinedione

In this placebo-controlled study with primary endpoint at 26 weeks, 976 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 study blind. 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 study 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 8 and Figure 5). Over the 52-week study 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 Thiazolidinedionea

Abbreviations: BID = twice daily; HbA1c = hemoglobin A1c.
a Intent-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.
b Least-squares (LS) mean adjusted for baseline value and other stratification factors.
‡ Subjects 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)	-

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

Combination Therapy with SGLT2i, with or without Metformin

In this 24-week placebo-controlled, double-blind study, 423 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 study 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 SGLT2ia

Abbreviations: HbA1c = hemoglobin A1c; SGLT2i = sodium-glucose co-transporter-2 inhibitors.
a Intent-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.
b Least-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).
c Patients 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)††

Add-on to Metformin and Sulfonylurea

In this open-label comparator study (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 52 weeks, 807 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 study 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 study 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 Sulfonylureaa

Abbreviations: HbA1c = hemoglobin A1c.
a Intent-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.
b Least-squares (LS) mean adjusted for baseline value and other stratification factors.
‡ Subjects 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)	-

Combination Therapy with Basal Insulin, with or without Metformin

In this 28-week placebo-controlled, double-blind study, 300 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 study 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 Insulina

Abbreviations: HbA1c = hemoglobin A1c.
a Intent-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.
b Least-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 subjects having missing Week 28 data.
c Patients 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)††

Combination Therapy with Prandial Insulin, with or without Metformin

In this open-label comparator study (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26 weeks, 884 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-study 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-study 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 study 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 Lisproa

Abbreviation: HbA1c = hemoglobin A1c
a Intent-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.
b Least-squares (LS) mean adjusted for baseline value and other stratification factors.
‡ Subjects 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)	-

14.2 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 study, 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 to Figure 6 and Table 14.

Vital status was available for 99.7% of subjects 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.

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