Trulicity (Dulaglutide) FDA Approval History

Original FDA Approval: September 2014

Trulicity received its first FDA approval on September 18, 2014, under NDA 125469 for the treatment of type 2 diabetes mellitus as an adjunct to diet and exercise [1]. The approval covered two dose strengths: 0.75 mg and 1.5 mg administered once weekly via a single-dose prefilled pen (the Trulicity pen).

The agency based this decision on the AWARD clinical trial program, a series of six Phase III studies enrolling more than 3,000 patients with type 2 diabetes. AWARD-1 compared dulaglutide against exenatide twice daily, while AWARD-3 tested it against metformin monotherapy. Across the program, dulaglutide 1.5 mg consistently reduced HbA1c by 0.8% to 1.6% from baseline, depending on comparator and study population [2]. The approval did not include a cardiovascular benefit claim. That would come later.

Eli Lilly submitted the original Biologics License Application (technically processed as an NDA for the drug-device combination) in late 2013. FDA review proceeded under a standard timeline, and the Endocrinologic and Metabolic Drugs Advisory Committee did not convene a separate hearing, as the GLP-1 class safety profile was already well characterized by 2014 [1].

The AWARD Trial Program: Key Efficacy Data

Six randomized controlled trials formed the backbone of the original submission. Each AWARD study targeted a different patient population or comparator to establish dulaglutide's place in the treatment algorithm.

AWARD-1 (N=978) tested dulaglutide 1.5 mg and 0.75 mg against exenatide 10 mcg twice daily and placebo over 52 weeks. The 1.5 mg dose achieved a mean HbA1c reduction of 1.51% versus 0.99% for exenatide, meeting superiority [3]. AWARD-5 (N=1,098) compared both dulaglutide doses against sitagliptin 100 mg over 104 weeks, and dulaglutide 1.5 mg maintained a 0.7% greater HbA1c reduction at two years [4]. AWARD-6 (N=599) demonstrated non-inferiority of dulaglutide 1.5 mg to liraglutide 1.8 mg daily, with similar HbA1c reductions of approximately 1.4% at 26 weeks [5].

These trials also showed consistent weight loss with dulaglutide, though the magnitude was modest: typically 1.5 to 3.0 kg over 26 to 52 weeks, less than what would later be reported with higher-dose semaglutide formulations.

Boxed Warning: Thyroid C-Cell Tumor Risk

Every GLP-1 receptor agonist approved in the United States carries a boxed warning for thyroid C-cell tumors. Dulaglutide is no exception. The warning stems from rodent carcinogenicity studies in which dulaglutide caused dose-dependent and treatment-duration-dependent increases in thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in both rats and mice [1].

The clinical relevance in humans remains uncertain. GLP-1 receptors are expressed on rodent thyroid C-cells at much higher density than on human C-cells, and no causal link between GLP-1 receptor agonists and MTC in humans has been established in over 15 years of post-market surveillance [6]. The boxed warning states that Trulicity is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

FDA requires a medication guide to be dispensed with every prescription. A formal REMS program is not required for dulaglutide, distinguishing it from certain other drug classes with mandatory prescriber certification.

REWIND Trial and the Cardiovascular Label Expansion

The REWIND trial changed dulaglutide's regulatory profile. Published in The Lancet in June 2019, REWIND randomized 9,901 patients with type 2 diabetes and either established cardiovascular disease or cardiovascular risk factors to dulaglutide 1.5 mg weekly or placebo, with a median follow-up of 5.4 years [7].

The primary composite endpoint (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurred in 12.0% of dulaglutide-treated patients versus 13.4% of placebo-treated patients (HR 0.88, 95% CI 0.79 to 0.99; P=0.026) [7]. This 12% relative risk reduction was statistically significant.

REWIND stands apart from other GLP-1 receptor agonist cardiovascular outcomes trials (CVOTs) in two ways. First, its population included a larger proportion of patients without established atherosclerotic cardiovascular disease (approximately 69% were primary prevention). Second, the 5.4-year median follow-up was the longest of any completed GLP-1 CVOT at that time, compared with 2.1 years for LEADER (liraglutide) and 2.0 years for SUSTAIN-6 (semaglutide) [7].

Based on REWIND, the FDA approved a supplemental NDA in January 2020 adding a new indication: reduction of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors [8]. This made Trulicity the third GLP-1 receptor agonist to carry a cardiovascular risk reduction claim, after liraglutide and injectable semaglutide.

Dr. Hertzel Gerstein, REWIND's principal investigator, stated at the time of publication: "These findings indicate that dulaglutide can reduce cardiovascular events in a broad range of people with type 2 diabetes, including those who have not yet had a cardiovascular event" [7].

Higher-Dose Approvals: 3.0 mg and 4.5 mg

The FDA approved two additional dose strengths on September 10, 2020, bringing the available options to 0.75 mg, 1.5 mg, 3.0 mg, and 4.5 mg [9]. The dose escalation data came from the AWARD-11 trial (N=1,842), which compared the higher doses against dulaglutide 1.5 mg over 36 weeks in adults with type 2 diabetes inadequately controlled on metformin [10].

AWARD-11 results were clear. Dulaglutide 4.5 mg reduced HbA1c by 1.87% from a baseline of approximately 8.6%, compared to 1.54% with the 1.5 mg dose. The 3.0 mg dose fell in between at 1.71%. Weight loss was also dose-dependent: 4.7 kg with 4.5 mg versus 3.1 kg with 1.5 mg at 36 weeks [10]. Gastrointestinal side effects (nausea, diarrhea, vomiting) increased modestly with the higher doses but followed the same pattern seen across the GLP-1 class.

This dose expansion gave clinicians the option to escalate patients who had a partial glycemic response to the original doses. The higher doses did not require a new cardiovascular outcomes trial.

Pediatric Indication: June 2022

On June 16, 2022, the FDA expanded the Trulicity label to include pediatric patients aged 10 years and older with type 2 diabetes [11]. The approval was supported by a 26-week randomized trial comparing dulaglutide 0.75 mg weekly (with optional uptitration to 1.5 mg) against placebo in 154 pediatric patients.

At 26 weeks, dulaglutide-treated patients had an HbA1c reduction of 0.6% versus a 0.6% increase in the placebo group, yielding a treatment difference of approximately 1.2 percentage points [11]. The safety profile in the pediatric population was consistent with findings in adults. This made Trulicity one of a small number of GLP-1 receptor agonists approved for use in children, alongside liraglutide (Victoza).

Post-Market Safety Surveillance

Since its 2014 approval, dulaglutide has accumulated extensive real-world safety data through multiple surveillance systems.

FDA Adverse Event Reporting System (FAERS). The most commonly reported adverse events for dulaglutide in FAERS align with the labeled gastrointestinal effects: nausea, vomiting, diarrhea, and injection site reactions. Reports of acute pancreatitis have been filed, and the prescribing information includes a warning about pancreatitis risk, though controlled trial data have not demonstrated a statistically significant increase [1]. A 2023 signal assessment by the FDA reviewed reports of intestinal obstruction associated with GLP-1 receptor agonists as a class. The agency updated labeling for several GLP-1 drugs to include ileus as an adverse reaction [12].

Sentinel System. The FDA's Sentinel Initiative, which uses claims data from over 100 million covered lives, has been used to monitor GLP-1 receptor agonists for thyroid cancer, pancreatic cancer, and gallbladder events. A Sentinel analysis published in 2024 examined medullary thyroid carcinoma incidence among GLP-1 receptor agonist users and did not find a significant increase compared to other diabetes therapies, though confidence intervals remained wide given the rarity of MTC [13].

Gallbladder events. The Trulicity label includes a precaution regarding cholelithiasis and cholecystitis. In the REWIND trial, gallbladder-related events occurred in 1.5% of dulaglutide-treated patients compared to 1.1% on placebo [7]. A 2022 meta-analysis across all GLP-1 receptor agonist CVOTs estimated a pooled relative risk of 1.27 for cholelithiasis (95% CI 1.10 to 1.47) [14].

Acute kidney injury. The labeling advises caution in patients with renal impairment and recommends monitoring renal function when initiating or escalating dulaglutide in patients reporting severe gastrointestinal reactions that could lead to dehydration. This warning applies to the entire GLP-1 class.

Label Sections and Prescribing Details

The current Trulicity prescribing information, last revised in 2023, spans 37 pages and contains the following notable sections [1]:

Section 5.1 details the thyroid C-cell tumor boxed warning. Section 5.2 covers pancreatitis, instructing prescribers to discontinue dulaglutide if pancreatitis is suspected. Section 5.3 addresses hypoglycemia risk when co-prescribed with insulin or sulfonylureas, recommending dose reduction of the companion agent.

Section 14 summarizes the clinical trial efficacy data from the AWARD program and REWIND. Section 8.4 notes that dulaglutide has not been studied in patients with severe renal impairment (eGFR <15 mL/min/1.73 m²), and no dose adjustment is recommended for mild to moderate renal impairment.

The 2020 label revision added the cardiovascular indication language under Section 1. Specific wording states: "Trulicity is indicated 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" [8].

Trulicity in the GLP-1 Competitive Context

By 2026, Trulicity occupies a different position than it did at launch. Semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) have captured significant market share due to greater weight-loss efficacy. Peak U.S. sales for Trulicity reached approximately $7.4 billion in 2022 before declining as prescribers shifted to newer agents [15].

Eli Lilly has not pursued a weight-management indication for dulaglutide. The 4.5 mg dose produces meaningful glycemic control, but its weight-loss effect (approximately 4.7 kg at 36 weeks) is substantially less than semaglutide 2.4 mg (14.9% body weight at 68 weeks in STEP-1, N=1,961) or tirzepatide 15 mg (22.5% at 72 weeks in SURMOUNT-1, N=2,539) [16][17].

The drug's patent protection is also relevant to its regulatory trajectory. Key patents for Trulicity are expected to expire starting in 2027, and biosimilar developers have begun filing regulatory applications. The FDA's Purple Book lists dulaglutide as a reference product under BLA 125469.

European Regulatory Comparison

For reference, the European Medicines Agency (EMA) granted marketing authorization for Trulicity on November 21, 2014, approximately two months after the FDA approval [18]. The EMA's Committee for Medicinal Products for Human Use (CHMP) based its positive opinion on the same AWARD dataset. The European label includes equivalent warnings about thyroid C-cell tumors and pancreatitis risk.

The cardiovascular indication was added to the European Summary of Product Characteristics following REWIND, consistent with the FDA's timeline. One distinction: the EMA label does not include a pediatric indication for dulaglutide as of early 2026, as the supporting pediatric data were evaluated under a different regulatory framework.