Dulaglutide (Trulicity): Dosing, Weight Loss, and How It Compares to Semaglutide and Tirzepatide

What is dulaglutide approved for?

Trulicity carries two FDA indications [1]. The first is glycemic control, as an adjunct to diet and exercise, in adults and in pediatric patients 10 years and older with type 2 diabetes [1]. The second is reducing the risk of major adverse cardiovascular events, meaning cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors [1]. A prior heart attack or stroke is not required for that second indication; multiple risk factors are enough [1].

There is no obesity or chronic weight-management indication in the label [1]. Weight change on dulaglutide is a trial result, not an approved use.

Dulaglutide is a human GLP-1 receptor agonist with 90% amino acid sequence homology to endogenous GLP-1(7-37) [1]. It increases intracellular cAMP in pancreatic beta cells, which causes glucose-dependent insulin release, decreases glucagon secretion and slows gastric emptying [1]. Its half-life is about 5 days [1].

How is dulaglutide dosed?

Adults start at 0.75 mg once weekly. After 4 weeks the dose may increase to 1.5 mg if more glycemic control is needed, and further increases are made in 1.5 mg steps after at least 4 weeks on the current dose, to a maximum of 4.5 mg once weekly [1].

Children 10 and older start at 0.75 mg and may increase to 1.5 mg after at least 4 weeks; the pediatric maximum is 1.5 mg, not 4.5 mg [1].

A missed dose is given as soon as possible if at least 3 days (72 hours) remain before the next scheduled dose; otherwise it is skipped [1]. The weekly day can be changed when the last dose was 3 or more days before the new day [1]. Injections go into the abdomen, thigh or upper arm, at any time of day, with or without food, rotating sites [1]. When Trulicity is used with insulin, the injections are administered separately and are not mixed [1].

Dulaglutide pharmacokinetics are not clinically relevantly affected by age, sex, race, body weight, or renal or hepatic impairment [1].

Does dulaglutide cause weight loss?

Yes, but modestly. In SUSTAIN 7, an open-label trial of 1,201 adults with type 2 diabetes on metformin over 40 weeks, dulaglutide 0.75 mg produced 2.3 kg of weight loss and dulaglutide 1.5 mg produced 3.0 kg, against 4.6 kg with semaglutide 0.5 mg and 6.5 kg with semaglutide 1 mg [2]. In AWARD-11, dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks in 1,842 adults on metformin [4].

For scale, the weight-management products have been tested in different populations. STEP 1 found semaglutide 2.4 mg produced 14.9% mean body weight loss over 68 weeks versus 2.4% with placebo in 1,961 adults with obesity or overweight and no diabetes [5]. SURMOUNT-1 found tirzepatide 15 mg produced 20.9% weight loss over 72 weeks versus 3.1% with placebo in 2,539 adults [6]. Neither trial tested dulaglutide.

How well does dulaglutide lower HbA1c?

AWARD-11 compared dulaglutide 1.5, 3 and 4.5 mg directly in 1,842 adults on metformin over 36 weeks. In AWARD-11, the 4.5-mg group had a mean HbA1c reduction of 1.77 points versus 1.54 points with 1.5 mg at 36 weeks; the estimated treatment difference was -0.24 points (P<0.001) [4].

AWARD-6 randomized 599 adults on metformin to dulaglutide 1.5 mg weekly or liraglutide 1.8 mg daily for 26 weeks. HbA1c fell 1.42 points with dulaglutide and 1.36 points with liraglutide, a difference of -0.06 points (95% CI -0.19 to 0.07), meeting the 0.4-point noninferiority margin [8].

AWARD-PEDS, a 26-week double-blind trial in 154 youths aged 10 to under 18, found HbA1c rose 0.6 points on placebo while falling 0.6 points on 0.75 mg and 0.9 points on 1.5 mg (p<0.001 for both), with no difference in BMI change between groups [9].

How does dulaglutide compare with semaglutide?

Both are once-weekly GLP-1 injections for type 2 diabetes, and the head-to-head data favor semaglutide on both glucose and weight. In SUSTAIN 7, semaglutide 0.5 mg lowered HbA1c 1.5 points and semaglutide 1 mg 1.8 points, versus 1.1 and 1.4 points for dulaglutide 0.75 and 1.5 mg; weight loss was 4.6 and 6.5 kg versus 2.3 and 3.0 kg [2]. That trial was open-label and lasted 40 weeks [2].

The two products differ in approved uses. Trulicity is approved only for type 2 diabetes and cardiovascular risk reduction in that population [1]. Semaglutide comes in several FDA-approved forms, including Wegovy injection and Wegovy tablets for weight reduction and for cardiovascular risk reduction in adults with established cardiovascular disease and either obesity or overweight [10].

Cardiovascular results come from different populations. REWIND enrolled adults with type 2 diabetes and either prior cardiovascular disease or risk factors, and 31.5% had established cardiovascular disease [11]. SELECT enrolled 17,604 adults with established cardiovascular disease and a BMI of 27 or more but no diabetes, and found a hazard ratio of 0.80 for cardiovascular death, myocardial infarction or stroke with semaglutide 2.4 mg [12]. Those hazard ratios are not a like-for-like comparison.

How does dulaglutide compare with tirzepatide?

Tirzepatide activates both GIP and GLP-1 receptors, and its label calls it a GIP and GLP-1 receptor agonist; it is not a pure GLP-1 drug like dulaglutide [13].

The two have been compared head to head in SURPASS-CVOT: 13,165 adults with type 2 diabetes and atherosclerotic cardiovascular disease received tirzepatide up to 15 mg or dulaglutide 1.5 mg weekly. The composite of cardiovascular death, myocardial infarction or stroke occurred in 12.2% on tirzepatide and 13.1% on dulaglutide (hazard ratio 0.92, 95.3% CI 0.83 to 1.01), so tirzepatide was noninferior to dulaglutide and did not show superiority [3].

SURPASS-CVOT compared the drugs on cardiovascular events [3]. The tirzepatide weight and HbA1c figures cited here come from trials against semaglutide rather than dulaglutide: SURMOUNT-5 found 20.2% weight loss with tirzepatide against 13.7% with semaglutide over 72 weeks in 751 adults with obesity and no diabetes [15], and SURPASS-2 in 1,879 adults with type 2 diabetes over 40 weeks found HbA1c reductions of 2.01, 2.24 and 2.30 points for tirzepatide 5, 10 and 15 mg versus 1.86 points for semaglutide 1 mg [16].

What did REWIND show?

REWIND was a double-blind, placebo-controlled trial in 9,901 adults aged 50 or older with type 2 diabetes and either cardiovascular disease or risk factors, with a median follow-up of 5.4 years [11]. The primary composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death occurred in 12.0% on dulaglutide 1.5 mg versus 13.4% on placebo (hazard ratio 0.88, 95% CI 0.79 to 0.99; p=0.026) [11]. All-cause death was 10.8% versus 12.0%, which was not significant [11]. Fatal or non-fatal stroke occurred in 3.2% versus 4.1% (hazard ratio 0.76) [11]. Gastrointestinal adverse events were reported by 47.4% of dulaglutide patients and 34.1% of placebo patients during follow-up [11].

What side effects does dulaglutide cause?

Gastrointestinal effects dominate. In the adult placebo-controlled pool (placebo N=568, 0.75 mg N=836, 1.5 mg N=834; mean exposure 23.8 weeks), the label reports nausea in 5.3%, 12.4% and 21.1%; diarrhea in 6.7%, 8.9% and 12.6%; vomiting in 2.3%, 6.0% and 12.7%; abdominal pain in 4.9%, 6.5% and 9.4%; and decreased appetite in 1.6%, 4.9% and 8.6% [1]. Any GI reaction occurred in 21%, 32% and 41%, and treatment stopped for GI reasons in 0.2%, 1.3% and 3.5% [1]. Most nausea and GI events were mild to moderate [1].

At the higher doses (AWARD-11, 36 weeks, add-on to metformin), nausea occurred in 13.4% on 1.5 mg, 15.6% on 3 mg and 16.4% on 4.5 mg; diarrhea in 7.0%, 11.4% and 10.7%; and vomiting in 5.6%, 8.3% and 9.3% [1].

Hypoglycemia depends on what else is taken. With insulin glargine, glucose below 54 mg/dL occurred in 14.7% on dulaglutide 1.5 mg versus 9.3% on placebo; with glimepiride, 3.3% versus 0% [1].

What does the Trulicity label warn about?

The boxed warning covers thyroid C-cell tumors: dulaglutide caused dose-related, treatment-duration-dependent thyroid C-cell adenomas and carcinomas in rats after lifetime exposure, and human relevance is unknown [1]. The drug is contraindicated in people with a personal or family history of medullary thyroid carcinoma or MEN 2, and in people with a serious hypersensitivity to dulaglutide or a product component [1]. Routine calcitonin or thyroid ultrasound monitoring is of uncertain value [1].

Other warnings cover acute pancreatitis, hypoglycemia with insulin or an insulin secretagogue, serious hypersensitivity including anaphylaxis and angioedema, acute kidney injury from volume depletion, severe gastrointestinal reactions (with no recommendation for use in severe gastroparesis), diabetic retinopathy complications, acute gallbladder disease, and pulmonary aspiration during general anesthesia or deep sedation [1].

The current label contains no mention of alcohol, so it carries no alcohol warning or restriction [1].

The label says Trulicity should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, and human data are limited [1].

On oral drugs, dulaglutide delays gastric emptying and can reduce the absorption rate of oral medicines; the delay is dose-dependent, largest after the first dose, and attenuated with the recommended escalation [1]. Trulicity 1.5 mg did not affect absorption of tested oral drugs to a clinically relevant degree, and experience at 3 and 4.5 mg is limited; the label advises monitoring levels of narrow-therapeutic-index oral drugs such as warfarin [1]. When Trulicity is started alongside insulin or a sulfonylurea, the label advises considering a lower dose of the insulin or sulfonylurea to reduce hypoglycemia risk [1].