Though GLP-1s are generally considered to be safe, we are still learning about the safety of the long-term use of GLP-1 medications

Although GLP-1 medications like Ozempic, Zepbound, and Saxenda are well-established for managing obesity and type 2 diabetes — and their common gastrointestinal side effects (e.g., nausea, vomiting, diarrhea, constipation) are well-documented — less is known about their long-term safety. Further, data is also shedding a light on rare but serious side effects, such as pancreatitis, gastroparesis, and ileus. While these drugs are generally considered safe and are most effective when paired with lifestyle changes, ongoing research is crucial to fully understand their long-term effects.

Semaglutide: The STEP 5 Trial

The STEP 5 trial¹ evaluated the efficacy and safety of once-weekly subcutaneous 2.4 mg semaglutide for long-term use in adults with obesity. Participants had at least one weight-related comorbidity, but did not have diabetes. A total of 304 participants were randomized 1:1 into either the semaglutide group (n = 152) or the placebo group (n = 152). The study population was predominantly white (77.6%) and female (93.1%). The mean change in body weight from baseline to week 104 was -15.2% in the semaglutide group compared to -2.6% in the placebo group.

 

Mild to moderate gastrointestinal (GI) events were reported more frequently in the semaglutide group. Adverse events leading to treatment discontinuation occurred in nine participants (5.9%) in the semaglutide group and seven participants (4.6%) in the placebo group. The most commonly reported side effects were nausea, diarrhea, vomiting, and constipation, occurring in 82.2% of the semaglutide group versus 53.9% of the placebo group. Most GI events were mild to moderate and transient. Six participants (3.9%) in the semaglutide group discontinued treatment permanently due to GI events, compared to one participant (0.7%) in the placebo group.

 

Serious adverse events were reported in 12 participants (7.9%) in the semaglutide group and 18 participants (11.8%) in the placebo group. One death occurred in the semaglutide group; however, an independent external event adjudication committee determined it was unrelated to the study drug. Gallbladder issues were reported in four participants in the semaglutide group and two in the placebo group. Malignant neoplasms were reported in two participants in the semaglutide group and four in the placebo group. No cases of pancreatitis were reported in either group. The authors noted that the safety profile of semaglutide in the STEP 5 trial was consistent with findings from other STEP trials.

Liraglutide: Satiety and Clinical Adiposity — Liraglutide Evidence (SCALE)

The SCALE trial² investigated the efficacy and safety of once-weekly subcutaneous liraglutide at a dose of 3.0 mg. A total of 3,731 adults with obesity — but without type 2 diabetes — were randomly assigned to either the liraglutide group (n = 2,487) or the placebo group (n = 1,244). After 56 weeks, participants in the liraglutide group lost a mean of 8.0 kg, compared to 2.6 kg in the placebo group.

 

The most commonly reported side effects in the liraglutide group were nausea, diarrhea, constipation, and vomiting. Over 94% of these side effects were mild to moderate in severity. Gastrointestinal (GI) side effects were the most frequent reason for withdrawal in the liraglutide group, with 159 participants (6.4%) discontinuing treatment compared to 9 participants (0.7%) in the placebo group. The authors noted that nausea and vomiting typically occurred within the first four to eight weeks of treatment.

 

The incidence of serious adverse events was higher in the liraglutide group (154 events) than in the placebo group (62 events). Three deaths were reported: one in the liraglutide group, attributed to cardiomegaly and hypertensive heart disease, and two in the placebo group—one from pulmonary fibrosis and one from cardiorespiratory arrest.

 

Gallbladder-related events were more common in the liraglutide group (n = 61; 3.1 events per 100 patient-years) than in the placebo group (n = 12; 1.4 events per 100 patient-years). There were also more cases of cholelithiasis and cholecystitis in the liraglutide group. Pancreatitis was confirmed via adjudication in 10 cases in the liraglutide group, compared to one case in the placebo group. Five of the pancreatitis cases in the liraglutide group were related to gallstones. The incidence of adjudicated and confirmed neoplasms was similar between groups (1.9 per 100 patient-years in the liraglutide group vs. 2.4 per 100 patient-years in the placebo group).

Tirzepatide: SURMOUNT 4

The SURMOUNT-4 trial³ investigated the efficacy and safety of once-weekly subcutaneous tirzepatide at doses of 10.0 mg and 15.0 mg in 670 adults with obesity but without diabetes. This Phase 3 randomized withdrawal trial included a 36-week open-label lead-in period, followed by a 52-week double-blind, placebo-controlled period.

 

The trial initially enrolled 783 participants, all of whom received once-weekly tirzepatide at their maximum tolerated dose (either 10.0 mg or 15.0 mg) during the 36-week lead-in period. At week 36, 670 participants were randomized 1:1 to continue receiving tirzepatide or switch to placebo for 52 weeks. Of the 783 original participants, 113 withdrew during the lead-in phase due to adverse events, voluntary withdrawal, or other non-treatment-related reasons.

 

Among the 670 participants who continued past the lead-in period, 92.7% achieved a maximum tolerated dose of 15.0 mg, and 7.3% reached 10.0 mg. These participants were then randomized to either continue their maximum tolerated dose or to receive placebo.

 

During the lead-in period, 81% of participants reported at least one treatment-emergent adverse event. The most common were gastrointestinal (GI) events, including nausea (35.5%), diarrhea (21.1%), constipation (20.7%), and vomiting (16.3%). In the double-blind period, 60.3% of participants in the tirzepatide group and 55.8% in the placebo group reported at least one treatment-emergent adverse event. The most frequently reported events during this period were COVID-19 and GI issues. GI events were more common in the tirzepatide group compared to placebo, including diarrhea (10.7% vs. 4.8%), nausea (8.1% vs. 2.7%), and vomiting (5.7% vs. 1.2%). Most GI events were mild to moderate.

 

Discontinuation due to adverse events occurred in 7.0% of participants during the lead-in period and 1.8% during the double-blind period. Sixteen participants reported serious adverse events in the lead-in phase, while ten participants reported serious adverse events during the double-blind period, with similar rates in both tirzepatide and placebo groups.

 

Three deaths were reported during the trial: one due to COVID-19 pneumonia during the lead-in period, one in the tirzepatide group (congestive heart failure), and one in the placebo group (adenocarcinoma of the colon). None of the deaths were deemed related to tirzepatide.

 

Unlike the SCALE trial, no adjudicated cases of pancreatitis were reported. However, cholelithiasis was observed in seven participants during the lead-in period and in one participant in each group during the double-blind period.

Meal Replacements as a Nutritional Strategy for GLP-1 Users

As research continues to explore the long-term safety of GLP-1 medications, one point is already clear: individuals on these medications must be especially mindful of their nutrition. Common side effects such as nausea, reduced appetite, and early satiety can make it challenging to consume balanced, nutrient-rich meals. This is where scientifically designed meal replacements, like those used in the New Direction Advanced and Numetra programs, become a vital tool. These medical-grade formulas ensure that essential proteins, vitamins, and minerals are delivered in optimal ratios, helping to preserve lean muscle mass, support metabolic function, and fill nutritional gaps. Unlike consumer-grade shakes, New Direction Advanced meal replacements are developed to complement medically supervised weight loss efforts and are ideal for those managing the nutritional demands of a GLP-1 regimen — offering consistency, safety, and clinical-grade support when it matters most. Follow this link to learn more about using meal replacements in conjunction with GLP-1 weight loss medications.

 

To further support patients using GLP-1 medications, Robard’s Biocare product is a scientifically formulated nutritional beverage designed to address the common challenges of reduced appetite, digestive discomfort, and nutritional deficiencies. With 30 grams of high-quality protein, 26 essential vitamins and minerals, and a proprietary blend of digestive enzymes and probiotics, Biocare helps preserve lean muscle mass, ease gastrointestinal side effects, and promote treatment compliance. Available in four flavors, Biocare is an ideal daily companion to optimize GLP-1 outcomes and support long-term success.

 

Source(s):

1 Two-year effects of semaglutide in adults with overweight or obesity: The STEP  trial

2  A randomized, controlled trial of 3.0 mg of liraglutide in weight management

3 Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity

 

About the Author: Dr. Dawn M. Sweet has over 20 years of experience in the field of communication. Dr. Sweet has given several invited talks to and workshops for academic and private sector audiences on the role of nonverbal and verbal communication in achieving positive outcomes and mitigating bias. Her research has been published in several top ranked peer-review journals, and it has been featured on NPR’s River to River / All Things Considered, Buzzfeed, and Science Daily. Her research has also been used to inform expert testimony.

About Robard: Robard Corporation’s medical obesity treatment programs and scientifically-designed nutrition products have been utilized by physicians, surgeons and hospitals across the United States to successfully treat patients living with obesity. To learn more about us and how we can help your practice and patients, visit us online www.Robard.com, email us at info@robard.com, or call (800) 222-9201.