GLP-1 Receptor Agonists Special Populations: A Prescriber's Summary

Is pregnancy a contraindication to a GLP-1 drug?

The contraindications section of the Wegovy and Foundayo labels lists a personal or family history of medullary thyroid carcinoma (MTC), MEN 2, and a prior serious hypersensitivity reaction to the drug or an excipient. Pregnancy is not on that list [1][2]. It sits under warnings and use in specific populations instead: the labels say the drugs may cause fetal harm and that weight loss offers no benefit to a pregnant patient; for weight or cardiovascular risk reduction, the Wegovy label says to discontinue when a pregnancy is recognized, and the Foundayo label, which covers weight management and not cardiovascular risk reduction, says to discontinue when pregnancy is recognized [1][2].

Wegovy gives the most specific timing instruction. For patients using it for weight reduction or cardiovascular risk reduction, the label says to discontinue at least 2 months before a planned pregnancy because semaglutide's half-life is about one week [1]. For the MASH indication, the label instead says to use Wegovy during pregnancy only if the potential benefit justifies the potential risk to the fetus [1].

The fetal-risk language comes from animal reproduction studies. In pregnant rats given semaglutide during organogenesis, embryofetal mortality, structural abnormalities and growth alterations occurred at clinically relevant exposures; rabbits and monkeys showed early pregnancy losses and structural abnormalities alongside marked maternal weight loss [1]. The Wegovy label states that human pharmacovigilance and trial data are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, and it maintains a pregnancy exposure registry [1].

What does the label say about breastfeeding?

The Wegovy label states that breastfeeding is not recommended during treatment with Wegovy tablets [1]. For the injection, it states that it is not known whether semaglutide is present in human milk, what effect it would have on a breastfed infant, or how it would affect milk production [1].

Which products are labeled for children?

• Victoza (liraglutide), daily injection: type 2 diabetes in adults and children aged 10 and older [4].
• Trulicity (dulaglutide), weekly injection: type 2 diabetes in adults and children aged 10 and older; the cardiovascular risk-reduction indication applies to adults [5].
• Wegovy injection: weight reduction in adults and children aged 12 and older with obesity [1].
• Saxenda (liraglutide), daily injection: children aged 12 and older who weigh more than 60 kg and have obesity, as well as adults [6].

Wegovy tablets and Foundayo carry adult weight-management indications [1][2].

Gallbladder disease was more frequent in the pediatric Wegovy program than in adults. In the weight-reduction trial in patients aged 12 and older, cholelithiasis was reported by 3.8% of Wegovy-treated patients and 0% of placebo patients, and cholecystitis by 0.8% and 0% [1]. In the adult weight-reduction trials, cholelithiasis was reported by 1.6% versus 0.7% and cholecystitis by 0.6% versus 0.2% [1].

Kidneys: what the labels warn about

The Wegovy and Foundayo labels both warn about acute kidney injury from volume depletion. The Wegovy label says to monitor renal function in patients reporting adverse reactions that could lead to volume depletion [1]. The Foundayo label says most reported cases occurred in patients who had nausea, vomiting or diarrhea leading to dehydration, and advises monitoring renal function especially during dose initiation and escalation [2]. The Ozempic label includes a kidney-outcomes indication in type 2 diabetes with chronic kidney disease [7].

Liver disease

The Foundayo label states it is not recommended in patients with severe hepatic impairment [2]. At the other end of the liver spectrum, Wegovy injection is indicated for noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced fibrosis (F2 to F3), under accelerated approval [1].

Cardiovascular disease

Wegovy is labeled to reduce the risk of CV death, nonfatal myocardial infarction or nonfatal stroke in adults with established CV disease who have obesity or overweight [1]. In SELECT, 17,604 adults with established CV disease and a BMI of 27 or higher, none with diabetes, were assigned semaglutide 2.4 mg or placebo; mean follow-up was 39.8 months and mean treatment exposure was 34.2 months, and the primary composite endpoint occurred in 6.5% versus 8.0% (HR 0.80) [8]. In SUSTAIN-6, 3,297 adults with type 2 diabetes took semaglutide 0.5 or 1 mg or placebo for 104 weeks; the same composite occurred in 6.6% versus 8.9% (HR 0.74, P<0.001 for noninferiority) [9].

The Wegovy cardiovascular indication covers CV death, nonfatal myocardial infarction and nonfatal stroke; heart failure is not a labeled indication for Wegovy, Zepbound or Foundayo [1][2][3]. Resting heart rate rises modestly on these drugs: the Wegovy label reports mean increases of 1 to 4 bpm, the Foundayo label 4 to 5 bpm versus 0.5 bpm on placebo, and the tirzepatide label 1 to 3 bpm [1][2][3].

Eyes

Diabetic retinopathy complications are a labeled warning for semaglutide. In SUSTAIN-6, retinopathy complications occurred in 3% of semaglutide-treated patients versus 1.8% on placebo [1][9]. The Wegovy label says patients with a history of diabetic retinopathy should be monitored [1]. Non-arteritic anterior ischemic optic neuropathy (NAION) is not in the US semaglutide labels; EMA's safety committee describes NAION as a very rare side effect of semaglutide, affecting up to 1 in 10,000 people, and studies in adults with type 2 diabetes suggest about one additional case per 10,000 person-years of treatment [10].

Surgery and sedation

Both the Wegovy and Foundayo labels carry a warning about pulmonary aspiration during general anesthesia or deep sedation, reported in patients taking GLP-1 receptor agonists for elective procedures, and both tell patients to inform their care team about planned surgery [1][2].

Oral medicines, including contraceptives and levothyroxine

The class delays gastric emptying, and labels advise closer clinical or laboratory monitoring for oral drugs with a narrow therapeutic index or that require clinical monitoring [1][2]. The specifics differ by product:

• Oral semaglutide increased levothyroxine exposure by 33% [1].
• The Foundayo label limits simvastatin to 20 mg once daily when taken with Foundayo (simvastatin acid exposure doubled), limits Foundayo to 9 mg daily with a strong CYP3A4 inhibitor, advises avoiding strong CYP3A4 inducers, and advises avoiding strong CYP3A4 inhibitors that also inhibit OATP1B, such as ritonavir [2].
• Contraception: tirzepatide labels advise switching to a non-oral method or adding a barrier method for 4 weeks after starting and for 4 weeks after each dose increase; Foundayo labels advise the same for 30 days after starting and after each dose escalation [3][2]. Semaglutide labels carry no such advice, and a tablet interaction study found no clinically significant change in ethinyl estradiol or levonorgestrel [1].

Insulin and sulfonylureas

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 insulin secretagogue when starting [1][2]. In Foundayo's type 2 diabetes trial, plasma glucose below 54 mg/dL occurred in 7% of patients taking a sulfonylurea versus 0.5% of those not taking one [2].

Thyroid warning and the rest of the class contraindications

The Wegovy, Victoza and Trulicity boxed warnings describe thyroid C-cell tumors seen in rodents, with human relevance unknown, and these products are contraindicated in patients with a personal or family history of MTC or MEN 2 [1][4][5]. Foundayo also carries a boxed warning, but its label says orforglipron is not pharmacologically active in rats or mice and produced no rodent tumors; the human relevance of GLP-1-dependent rodent tumors remains undetermined, and the MTC and MEN 2 contraindication applies [2]. Byetta and Soliqua carry no boxed warning [11][12].

Severe gastrointestinal reactions are a labeled warning, and the labels state these drugs are not recommended in patients with severe gastroparesis; they do not state that GLP-1 drugs cause gastroparesis [1][2]. Foundayo's trials reported severe gastrointestinal reactions in about 3% of treated patients versus 1% on placebo, and 8% of treated patients stopped treatment for adverse reactions versus 3% on placebo [2].