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Glucagon-like peptide-1 (GLP1) and GLP1/glucose-dependent insulinotropic polypeptide medications have proven to be the most effective anti-obesity medications (AOMs) available on the market today. Access to these medications, though, is still extremely limited due to either lack of insurance coverage or a drug supply shortage.

With the expectation that over the next several years newer AOMs become available, the hope is that access to liraglutide (Saxenda), semaglutide (Wegovy), and tirzepatide (Zepbound) will continue to improve.

In a study in , Ghusn and Hurtado conducted a review of various databases to study the tolerability, side effects, and risks of these medications. We now have 10 years of experience using liraglutide, 3 years of using semaglutide, and about 1.5 years of use of tirzepatide. Regarding efficacy, tirzepatide has proven to be superior at each time point, with mean weight loss at 12 months of 20% compared with 15% for semaglutide and 9% for liraglutide.

Regardless of the achieved weight loss, each of these AOMs has been found to improve glycemic control, lower systolic and diastolic blood pressure, and improve fasting lipids. Semaglutide stands out in also offering up to a 20% risk reduction of nonfatal myocardial infarction, stroke, or death from other cardiovascular causes, as demonstrated in the SELECT trial.

With regards to tolerability, gastrointestinal side effects were most commonly seen in all three medications, with the majority labeled mild to moderate in severity and transient. Nausea, diarrhea, vomiting and constipation were the most common reported side effects.

In patients taking liraglutide, there was a 6.4% discontinuation rate due to side effects. In most patients taking semaglutide and tirzepatide, the mild and transient gastrointestinal side effects did not result in discontinuation of the medication.

In randomized controlled studies, serious adverse events were more common in patients taking any of these three AOMs compared with the placebo group of patients -- these toxicities included cholelethiasis, acute cholecystitis, and pancreatitis.

Hepatobiliary disease was more commonly seen in patients who used these AOMs at higher doses and for a longer duration. Most patients underwent elective cholecystectomy and were able to resume the AOM.

Unlike the initial randomized controlled studies, multiple recent systematic reviews and meta-analyses demonstrated that despite a statistically significant risk of elevation of pancreatic enzymes in patients taking these AOMs, there is no significant difference in development of acute pancreatitis or pancreatic cancer in these patients.

With regards to mood, there was no clinically significant difference in mental health assessments, and some patients showed improvement in mood while taking these AOMs.

There are certain case reports, however, of a deterioration in mood with these medications. Recent studies showed no causal relationship between these agents and suicidality.

Hypoglycemia with these agents was not serious and largely seen only in patients taking insulin or other insulin secretagogues. Notably, there was no increase in the rate of neoplasms in patients taking these AOMs.

The authors note that patients in the liraglutide group who had above average rates of weight loss had a slightly higher rate of breast cancer. One meta-analysis showed an 11% decrease in all-cause mortality in patients taking these AOMs.

Overall, Ghusn and Hurtado provide reassurance that these AOMs are safe and effective with rare serious adverse events and usually mild/moderate gastrointestinal side effects that are generally transient.

Our goal is to provide effective treatment for patients with obesity via an individualized approach with the goal of using the lowest effective doses of AOMs and providing counseling support if adverse effects arise.

Shared decision-making is crucial in treating obesity as it is for all diseases. These authors note that we will continue to monitor these medications closely and learn about any new side effects not yet reported.

There is research ongoing in determining ideal medication interruption time before anesthesia or endoscopic procedures to avoid complications of delayed gastric emptying. Thus far, the benefits of these highly effective AOMs outweigh the potential risks as observed both by clinicians and patients.

Alina Elperin, MD, DABOM, an Internist and Obesity Medicine specialist in Evanston, Illinois, is a Clinical Assistant Professor at the University of Chicago Pritzker School of Medicine.

Read the study here and an interview about it here.

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