GLP-1 Side Effects: Hypoglycemia, Nausea, Constipation, and Sulfur Burps Explained

Which GLP-1 side effects are most common?

Nausea is the most frequently reported reaction in the Wegovy and Foundayo adverse reaction tables [1][2]. In the Wegovy 2.4 mg injection trials, which ran up to 68 weeks, nausea occurred in 44%, diarrhea in 30%, vomiting in 24% and constipation in 24%, against 16%, 16%, 6% and 11% with placebo [1]. In the two pooled 72-week orforglipron (Foundayo) trials, the 17.2 mg dose produced nausea in 35%, diarrhea in 25%, vomiting in 24% and constipation in 24%, against 10%, 11%, 4% and 9% [2]. For tirzepatide 15 mg, pooled across trials of up to 72 weeks, the rates were nausea 28%, vomiting 13%, diarrhea 23% and constipation 11%, against 8%, 2%, 8% and 5% [3]. The Wegovy label cautions that rates from different trials cannot be compared directly [1].

Adverse reactions led to permanent discontinuation in 6.8% on Wegovy 2.4 mg versus 3.2% on placebo, 6.7% on tirzepatide 15 mg versus 3.4%, and 8% on Foundayo overall (10% at 17.2 mg) versus 3% [1][3][2]. In the Wegovy label the most common reasons were nausea (1.8% versus 0.2%), vomiting (1.2% versus 0%) and diarrhea (0.7% versus 0.1%) [1]. The Foundayo label says most patients who discontinued because of adverse reactions did so because of gastrointestinal reactions (5%) [2].

How often do GLP-1 drugs cause hypoglycemia?

The labels address hypoglycemia first as a combination risk. The Wegovy label states that the risk of hypoglycemia is increased when semaglutide is used with insulin or an insulin secretagogue such as a sulfonylurea, and that reducing the dose of the insulin or secretagogue may be necessary [1]. The Foundayo label says the same and explains that orforglipron stimulates insulin release when blood glucose is already elevated, which could increase the risk when it is paired with insulin or an insulin secretagogue [2].

The clearest signal in the labels comes from people with type 2 diabetes who were also taking a sulfonylurea. In the Foundayo type 2 diabetes trial, glucose below 54 mg/dL was reported in 7% of patients taking a sulfonylurea versus 0.5% of those who were not [2]. Across that trial, hypoglycemia occurred in 2% of orforglipron-treated patients versus 0.2% on placebo, with one severe episode in the orforglipron group and none on placebo [2].

Wegovy's label reports the same pattern. In its weight-management trial in adults with type 2 diabetes and a BMI of at least 27, hypoglycemia below 54 mg/dL was reported in more patients on Wegovy than on placebo, and one Wegovy-treated patient had an episode of severe hypoglycemia requiring help from another person [1]. The label's adverse reaction table lists hypoglycemia in patients with type 2 diabetes who were not taking insulin at 6% versus 2% on placebo [1].

In adults without diabetes, Foundayo Trial 1 did not systematically capture hypoglycemia, but glucose below 54 mg/dL was reported in 0.6% of orforglipron-treated patients and no placebo patients, with no severe episodes [2]. The Foundayo label states that hypoglycemia has also been associated with the drug and with GLP-1 receptor agonists in adults without type 2 diabetes [2]. The Wegovy label states that use in type 1 diabetes, or in combination with insulin, has not been evaluated [1].

Both labels say to consider lowering the dose of the insulin or sulfonylurea at initiation, and to monitor blood glucose before and during treatment in people with diabetes [1][2].

Nausea and the dose schedule

Nausea sits at the top of the adverse reaction tables for semaglutide 2.4 mg and orforglipron 17.2 mg, and it is the most common reaction listed for tirzepatide 15 mg [1][2][3].

The labels build a slow start into the schedule. Wegovy injection begins at 0.25 mg once weekly for 4 weeks and titrates every 4 weeks toward the maintenance dose [1]. Foundayo begins at 0.8 mg once daily, moves to 2.5 mg and then 5.5 mg after at least 30 days on each, and only then to 9, 14.5 or 17.2 mg based on response and tolerability [2]. The Foundayo label says to follow this escalation to reduce the risk of gastrointestinal adverse reactions [2].

What about constipation?

Constipation is among the most common adverse reactions for the weight-management GLP-1 drugs: 24% versus 11% with Wegovy 2.4 mg, 24% versus 9% with Foundayo 17.2 mg, and 11% versus 5% with tirzepatide 15 mg [1][2][3].

The labels group it with the other gastrointestinal reactions. Wegovy describes severe gastrointestinal adverse reactions and states that it is not recommended in patients with severe gastroparesis [1]. Foundayo reports severe gastrointestinal reactions in about 3% of treated patients versus 1% on placebo and carries the same gastroparesis statement [2]. The labels do not say that GLP-1 drugs cause gastroparesis [1][2].

Burping and sulfur burps

Burping, listed as eructation, appears in the adverse reaction tables: 7% with Wegovy 2.4 mg versus less than 1% on placebo, and 8% with Foundayo 17.2 mg versus 1% [1][2]. The tables list the burping without describing an odor [1][2].

Serious risks the labels attach to GI symptoms

Acute pancreatitis has been reported with GLP-1 receptor agonists; the labels describe persistent or severe abdominal pain, sometimes radiating to the back, with or without nausea or vomiting, and say to discontinue the drug if pancreatitis is suspected [1][2]. Acute gallbladder disease, including cholelithiasis and cholecystitis, occurred more often with Wegovy than placebo in adult weight-management trials: cholelithiasis 1.6% versus 0.7%, and cholecystitis 0.6% versus 0.2% [1].

Acute kidney injury from volume depletion is another labeled risk, and the Foundayo label notes that most reported cases followed nausea, vomiting or diarrhea that led to dehydration [2]. Serious hypersensitivity, including anaphylaxis and angioedema, is listed on the Wegovy label [1]. The Wegovy label also describes pulmonary aspiration during general anesthesia or deep sedation and says to instruct patients to inform healthcare providers of any planned surgeries or procedures [1].