GLP-1 Receptor Agonists: Class Overview Monograph

What is a GLP-1 receptor agonist?

GLP-1 receptor agonists bind and activate the receptor for glucagon-like peptide-1. GLP-1 is a physiological regulator of appetite and caloric intake, and the receptor is present in several areas of the brain involved in appetite regulation [1]. The Ozempic label adds that semaglutide stimulates insulin secretion and lowers glucagon secretion in a glucose-dependent manner, with a minor delay in gastric emptying [3]. The Wegovy, tirzepatide and Foundayo labels also say those drugs delay gastric emptying, which can change the absorption of oral medicines [1][12][2].

All current US products are prescription-only, as injections or tablets [1][2]. Native GLP-1 is degraded within about 2 to 3 minutes in the circulation, so the drugs are built as longer-acting compounds [14]. Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1 and a half-life of about one week [1]; orforglipron is a small molecule with a half-life of about 29 to 49 hours, taken once daily with or without food [2].

Duration divides the class. Short-acting agents such as exenatide twice daily and lixisenatide lower postprandial glucose mainly by slowing gastric emptying, while longer-acting agents such as liraglutide and dulaglutide have a stronger effect on fasting glucose through their insulin and glucagon actions [14].

Tirzepatide is labeled as a GIP receptor and GLP-1 receptor agonist — a dual agonist, not a pure GLP-1 agonist — although it is commonly grouped with GLP-1 drugs [12]. Its label says nonclinical studies suggest the added GIP activity may further contribute to regulation of food intake [12].

Which products are FDA approved, and for what?

• Semaglutide (Novo Nordisk). Ozempic weekly injection is for type 2 diabetes, including cardiovascular risk reduction in type 2 diabetes with established cardiovascular disease and kidney outcomes in type 2 diabetes with chronic kidney disease [3]. Rybelsus and Ozempic tablets are for type 2 diabetes and cardiovascular risk reduction [4]. Wegovy injection is for weight reduction in adults and children 12 and older with obesity, cardiovascular risk reduction, and MASH [1]. Wegovy tablets were approved 2025-12-22 for weight reduction and cardiovascular risk reduction in adults [1].
• Liraglutide (Novo Nordisk). Victoza, a daily injection, is for type 2 diabetes in adults and children 10 and older, with cardiovascular risk reduction in adults with type 2 diabetes and established cardiovascular disease [5]. Saxenda is for weight management in adults with obesity, or overweight plus a comorbidity, and in children 12 and older weighing over 60 kg with obesity [11]. Xultophy 100/3.6 combines insulin degludec with liraglutide for adults with type 2 diabetes [9].
• Dulaglutide. Trulicity is a weekly injection for type 2 diabetes in adults and children 10 and older and for cardiovascular risk reduction in adults with type 2 diabetes who have established cardiovascular disease or multiple risk factors; it has no weight-loss indication [6].
• Exenatide. Byetta is a twice-daily injection for type 2 diabetes in adults [7]. The weekly Bydureon and Bydureon BCise products are listed as discontinued in Drugs@FDA [15].
• Lixisenatide. Adlyxin was approved 2016-07-27, and its Drugs@FDA record lists a supplement label dated March 12, 2026 [16]. Soliqua 100/33 combines insulin glargine with lixisenatide for adults with type 2 diabetes [8].
• Orforglipron. Foundayo, approved 2026-04-01, is an oral once-daily small-molecule GLP-1 receptor agonist for weight reduction and long-term weight maintenance in adults with obesity, or overweight plus a weight-related comorbidity; its label has no diabetes indication [2][17].
• Tirzepatide. Mounjaro is for type 2 diabetes and Zepbound for weight and sleep apnea; both are labeled as GIP and GLP-1 receptor agonists [12][10].

The labels do not treat the class as interchangeable. Wegovy, Saxenda, Zepbound and Foundayo are approved for weight management; Ozempic, Rybelsus, Victoza, Trulicity, Byetta, Mounjaro, Soliqua and Xultophy are not [1][11][12][2].

How much weight do these drugs produce?

In STEP 1, 1,961 adults with obesity or overweight and no diabetes received semaglutide 2.4 mg weekly or placebo for 68 weeks: weight changed by -14.9% versus -2.4% [18]. In SURMOUNT-1, 2,539 adults without diabetes received tirzepatide 5, 10 or 15 mg or placebo for 72 weeks: weight changed by -15.0%, -19.5% and -20.9% versus -3.1% [19]. SURMOUNT-5, an open-label head-to-head trial of 751 adults with obesity and no diabetes over 72 weeks, found -20.2% with tirzepatide at the maximum tolerated dose versus -13.7% with semaglutide, and waist circumference fell 18.4 cm versus 13.0 cm [20]. Whether the extra GIP activity explains that difference is not established by these trials [12][20].

Liraglutide data come from the Saxenda label: over 56 weeks in 3,731 adults with obesity or overweight and a comorbidity, weight changed by -7.4% versus -3.0% with placebo, a difference of 4.5 percentage points, and at least 5% weight loss occurred in 62.3% versus 34.4% [11]. The Foundayo label reports two 72-week placebo-controlled trials: in Trial 1 (3,127 adults with obesity or overweight, no diabetes) weight changed by -7.4%, -8.3% and -11.1% at 5.5, 9 and 17.2 mg versus -2.1% with placebo, and in Trial 2 (1,613 adults with type 2 diabetes and BMI 27 or higher) by -5.1%, -7.0% and -9.6% versus -2.5% [2].

Stopping matters. In STEP 4, 803 adults who reached semaglutide 2.4 mg after a 20-week run-in were randomized to continue or switch to placebo for 48 weeks: weight changed by -7.9% with continued semaglutide versus +6.9% after the switch, a difference of 14.8 points [21].

Do they reduce cardiovascular events?

Large cardiovascular outcome trials include semaglutide and dulaglutide. In SUSTAIN-6, 3,297 adults with type 2 diabetes received semaglutide 0.5 or 1 mg or placebo for 104 weeks: cardiovascular death, nonfatal heart attack or nonfatal stroke occurred in 6.6% versus 8.9% (hazard ratio 0.74) [22]. In REWIND, 9,901 adults with type 2 diabetes and either previous cardiovascular disease or risk factors received dulaglutide 1.5 mg weekly or placebo for a median 5.4 years: the composite occurred in 12.0% versus 13.4% (hazard ratio 0.88) [23]. In SELECT, 17,604 adults with established cardiovascular disease and BMI 27 or higher but no diabetes were followed for a mean of 39.8 months, with a mean exposure to semaglutide 2.4 mg or placebo of 34.2 months: the composite occurred in 6.5% versus 8.0% (hazard ratio 0.80) [24].

How do they compare for blood sugar?

SURPASS-2 (1,879 adults with type 2 diabetes, 40 weeks, open-label) found HbA1c falls of 2.01, 2.24 and 2.30 points with tirzepatide 5, 10 and 15 mg versus 1.86 points with semaglutide 1 mg, with 1.9, 3.6 and 5.5 kg more weight loss [25]. SUSTAIN 7 (1,201 adults, 40 weeks) found HbA1c falls of 1.5 and 1.8 points with semaglutide 0.5 and 1 mg versus 1.1 and 1.4 points with dulaglutide 0.75 and 1.5 mg [26]. In PIONEER 1 (703 adults, 26 weeks), oral semaglutide 14 mg lowered HbA1c by 1.1 points versus placebo on the treatment-policy estimand and 1.4 points on the trial-product estimand [27].

What are the common side effects?

Gastrointestinal effects are the class effect and are worst during dose escalation. In weight-management trials, nausea, vomiting, diarrhea and constipation occurred in 44%, 24%, 30% and 24% with Wegovy 2.4 mg versus 16%, 6%, 16% and 11% with placebo [1]; in 28%, 13%, 23% and 11% with Zepbound 15 mg versus 8%, 2%, 8% and 5% [12]; and in 35%, 24%, 25% and 24% with Foundayo 17.2 mg versus 10%, 4%, 11% and 9% [2]. Rates from different trials and populations are not directly comparable [1][2].

Adverse reactions led to discontinuation in 6.8% on Wegovy 2.4 mg versus 3.2% on placebo [1], 6.7% on Zepbound 15 mg versus 3.4% [12], and 8% pooled on Foundayo versus 3%, rising to 10% at 17.2 mg [2]. Hair loss, linked to weight reduction and more common in women, was reported by 3% versus 1% on Wegovy [1], 4% to 5% versus 1% on Zepbound [12], and 5% versus 2% at Foundayo 17.2 mg, including 7% of women versus 0.9% of men [2]. Mean resting heart rate rose 1 to 4 bpm with Wegovy [1], 1 to 3 bpm with tirzepatide [12], and 4 to 5 bpm with Foundayo versus 0.5 bpm on placebo [2].

Labels also warn about acute pancreatitis, severe gastrointestinal reactions, acute kidney injury from dehydration, acute gallbladder disease and serious hypersensitivity, and they state the drugs are not recommended in severe gastroparesis [1][2]. The Wegovy label reports cholelithiasis in 1.6% of injection-treated patients versus 0.7% on placebo [1]. Diabetic retinopathy complications are a labeled warning in type 2 diabetes; in SUSTAIN-6 they occurred in 3% versus 1.8% on placebo [1].

What does the boxed warning say?

Ozempic [3], oral Ozempic and Rybelsus [4], Wegovy injection and tablets [1], Victoza [5], Saxenda [11], Trulicity [6], Mounjaro [10], Zepbound [12] and Xultophy [9] carry a boxed warning about thyroid C-cell tumors seen in rodents, with human relevance unknown. Byetta and Soliqua carry no boxed warning [7][8]. Foundayo's boxed warning uses different wording: orforglipron is not pharmacologically active in rats or mice and caused no rodent tumors, but the human relevance of GLP-1-receptor-dependent rodent tumors is undetermined [2].

The products that carry that boxed warning are contraindicated in people with a personal or family history of medullary thyroid carcinoma or MEN 2 [1][2]. Across the labels, a prior serious hypersensitivity reaction to the drug or its ingredients is also a contraindication [1][2].

How do they interact with other drugs?

The class delays gastric emptying and may change the absorption of oral medicines, so labels advise closer monitoring for drugs with a narrow therapeutic index [1][2]. Advice on oral hormonal contraceptives differs by product: tirzepatide labels advise switching to a non-oral method or adding a barrier method for 4 weeks after starting and after each dose increase [12], and Foundayo for 30 days after starting and after each dose increase [2]. Semaglutide labels carry no such advice, and a tablet interaction study found no clinically significant change in ethinyl estradiol or levonorgestrel [1].

All GLP-1 drugs raise hypoglycemia risk when combined with insulin or a sulfonylurea, and labels advise considering a lower dose of the insulin or sulfonylurea when starting [1][2]. In the Foundayo type 2 diabetes trial, glucose below 54 mg/dL occurred in 7% of patients taking a sulfonylurea versus 0.5% of those not [2]. The Foundayo label adds product-specific rules: a maximum of 9 mg daily with a strong CYP3A4 inhibitor, avoiding strong CYP3A4 inducers, avoiding strong CYP3A4 inhibitors that also inhibit OATP1B such as ritonavir, and no more than simvastatin 20 mg daily because simvastatin acid exposure doubled [2]. Oral semaglutide increased levothyroxine exposure by 33% [1].

Pregnancy

Weight-loss use offers no benefit in pregnancy, and labels advise stopping the drug when pregnancy is recognized [1][2]. The Wegovy label advises stopping at least 2 months before a planned pregnancy because of semaglutide's long half-life [1].

Compounded and unapproved versions

Compounded drugs are not FDA approved and are not reviewed by FDA for safety, effectiveness or quality [13]. Retatrutide and cagrilintide cannot be used in compounding under federal law, are not components of any FDA-approved drug, and have not been found safe and effective for any condition [13]. On 2026-04-30 FDA proposed to exclude semaglutide, tirzepatide and liraglutide from the list of bulk substances outsourcing facilities may compound with, finding no clinical need; comments were due 2026-06-29 and FDA said no final decision had been made [28].

FDA concluded on 2026-01-13 that GLP-1 receptor agonists show no increased risk of suicidal behavior or ideation and asked makers to remove that warning from Saxenda, Wegovy and Zepbound, the only GLP-1 labels that had it; those labels now list the section as removed [29][11][1][12].