Efficacy of GLP-1 Agonists for Weight Loss in Adults With out Diabetes

Obesity was first recognized by the American Medical Association as a chronic disease requiring medical interventions in 2013.1 Although medications promoting weight loss have been available since the 1930s, few remain on the market because of side effects, including cardiotoxicity, psychiatric disturbances, and dependency.2,3 The US Food and Drug Administration (FDA) has approved 6 agents for the long-term management of obesity: liraglutide, lorcaserin, naltrexone/bupropion, orlistat, phentermine/topiramate, and semaglutide.2

This review will focus on the 2 most recently approved antiobesity medications — liraglutide and semaglutide. These agents are glucagon-like peptide-1 (GLP-1) agonists, which were first approved for the treatment of type 2 diabetes. The new indications include weight loss in adults with obesity (body mass index [BMI] ≥30) without diabetes and adults with a BMI ≥27 and 1 weight-related comorbidity (hypertension, type 2 diabetes, or dyslipidemia).2 The agents were approved based on clinical studies supporting the use of these GLP-1 agonists as targeted antiobesity therapies.2,3

Prevalence of Obesity in the United States

The prevalence of obesity among adults in the United States has been increasing and has reached 41.9%, with the highest rates found among non-Hispanic Black adults (49.9%) followed by Hispanic adults (45.6%), according to data from the 2017-2020 National Health and Nutrition Examination Survey.4,5 Obesity is associated with an increased risk of developing diabetes, heart disease, stroke, and some types of cancer.4 Obesity is also associated with poorer mental health outcomes and reduced quality of life.6

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Pathophysiology of Obesity

While weight gain is commonly thought to be caused by an imbalance of calorie intake to calorie expenditure, the risk of developing obesity is associated with environmental and genetic factors.2 Data from the genome project have identified more than 140 genetic chromosomal regions related to obesity.7 Weight gain is also related to use of certain medications such as antidepressants and corticosteroids as well as certain illnesses, including Cushing disease and hypothyroidism.6 Research into the role of the gastrointestinal (GI) system has found that an altered microbiome also appears to play a role in the development of obesity.2

The Role of Incretin Hormones in Metabolism

The latest agents to fight obesity target GLP-1 receptors, which are concentrated within the pancreas, GI system, central nervous system, heart, lungs, kidneys, blood vessels, and peripheral nervous system.1 Incretin hormones are GI peptides secreted following food intake and an elevation of blood glucose.1 The focus on incretin hormones as an obesity treatment evolved after observing the incretin effect.1 This effect describes the 2- to 3-fold increased insulin stimulation from the pancreas following oral glucose consumption as compared with intravenous infusion.1 Ingestion of oral glucose leads to the secretion of glucose-dependent insulinotropic polypeptide (GIP) and GLP -1 from the specialized cells in the gut.1 K-cells produce GIP in the duodenum and upper jejunum, and L-cells produce GLP-1 in the lower GI system.1 The combined effect of GIP and GLP-1 in healthy adults results in increased insulin secretion and delayed gastric emptying.1 In people with type 2 diabetes, however, this incretin effect is decreased or nonexistent.1

Incretin Effects on Organs

Glucagon-like peptide-1 uptake in the hypothalamus reduces appetite and food intake and increases satiety.7-10 The alpha cells of the pancreas produce glucagon and the beta cells of the pancreas secrete insulin.8 Both cell types have GIP and GLP-1 receptors on their membranes.1 The presence of GLP-1 delays gastric emptying and acid secretion while slowing transit through the gut.8 Uptake of GLP-1 in the liver decreases gluconeogenesis, increases glycogen storage, and decreases lipogenesis.8-10

Mechanism of Action of GLP-1 Agonists

Glucagon-like peptide-1 receptor agonists improve glycemic control by enhancing insulin secretion from the beta-pancreatic cells and inhibiting glucagon release from the alpha-pancreatic cells.9,10 Additionally, the agonists slow gastric emptying, increase satiety, and reduce the appetite, resulting in weight reduction.9,10 Endogenous GLP-1 has a half-life of less than 2 minutes because it is rapidly degraded by dipeptidyl peptidase IV (DPP4).9 Glucagon-like peptide-1 receptor agonists are identified as short- or long-acting agents.10 Short-acting agonists circulate for a few hours, followed by periods of GLP-1 inactivity.10 Long-acting agonists produce a long-lasting drug concentration with little fluctuation in drug levels.10 Short-acting GLP-1 agonists lower glucose levels by slowing gastric emptying, while long-acting GLP-1 agonists lower glucose levels by slowing gastric emptying, increasing insulin production, and inhibiting glucagon.10 Both liraglutide and semaglutide are long-acting agents; no short acting agents are currently approved for weight loss.10-12

GLP-1 Receptor Agonists Approved for Treating Obesity

Liraglutide (Victoza) and semaglutide (Ozempic) are long-acting GLP-1 agonists are made by the same manufacturer (Novo Nordisk) and currently approved in the treatment of type 2 diabetes.3 Both medications are also approved as adjuncts to a reduced-calorie diet and increased exercise for chronic weight management at different doses and under the brand names of Saxenda and Wegovy, respectively.3,11,12 


In 2015, the Food and Drug Administration approved liraglutide (3 mg) as the first GLP-1 agonist for chronic weight management in adults with obesity and overweight.11 In December, 2020, the FDA approved an updated label for use of liraglutide in the treatment of obesity in adolescents (12-17 years).13 The initial dose is 0.6 mg once daily for 1 week to be increased weekly to a target dose of 3 mg once daily.11 Liraglutide is long-acting and administered by daily subcutaneous injections and has a half-life of 12.6 to 14.3 hours.3


In June 2021, the FDA approved semaglutide for chronic weight management in adults with obesity and overweight.12 With a starting dose of 0.25 mg, the once-weekly subcutaneous injection should be increased in 4-week intervals to 2.4 mg.12 Semaglutide has an extended half-life of approximately 1 week, making it suitable for once-weekly administration.9,12,14  

Safety Profiles and Side/Adverse Effects

The most common side effects of GLP-1 agonists reported in clinical trials for weight management were nausea, diarrhea, vomiting, constipation, abdominal pain, headache, fatigue, dyspepsia, dizziness, abdominal distension/pain, injection site reactions (liraglutide), increased lipase (liraglutide), pyrexia (liraglutide), eructation (semaglutide), flatulence (semaglutide), hypoglycemia in patients with type 2 diabetes, gastroenteritis, and gastroesophageal reflux disease (semaglutide).11,12

Most adverse events reported were mild (69%) and severe adverse events were rare.3 Few patients stopped the medications because of drug-related adverse events, and those that did cited GI-related events.3,11,12 The discontinuations occurred during escalating doses of semaglutide rather than after reaching the final dose.3 Both acute pancreatitis and acute gallbladder disease have been observed in patients treated with GLP-1 receptor agonists, including semaglutide and liraglutide.3,11,12 Reports of cholelithiasis and cholecystitis increased across the semaglutide dosing range (2%-7%).3 An increased risk for developing upper respiratory infections has been reported with the use of GLP-1 agonists.14 The increased risk is listed as an adverse reaction in some package inserts of this class but is not a contraindication to use and is not listed as a warning or precaution.14

Efficacy of Liraglutide and Semaglutide

O’Neil and colleagues compared liraglutide with semaglutide in adults without diabetes and with a BMI ≥30 (mean BMI, 39.3). The authors, who disclosed that the study was funded by the drug’s manufacturer, reported that liraglutide 3.0 daily was associated with an estimated mean weight loss of 7.8% at week 52, while semaglutide 0.2 mg, 0.3 mg, and 0.4 mg resulted in an 11.6%, 11.2%, and 13.8% weight reduction. Estimated mean weight loss was 2.3% for the placebo group.3

The weight loss observed with semaglutide is greater than that reported for other approved antiobesity medications: orlistat (6%), lorcaserin (6%), phentermine-topiramate (8%-10%), and naltrexone-bupropion (5%).3 Most established guidelines define meaningful weight loss as 5% to 10% of initial weight at which point an improvement in cardiovascular risk factors is observed.2

Once-weekly administration may improve patient compliance and quality of life over once-daily dosing as has been demonstrated in management of GLP-1 receptor agonists in the management of type 2 diabetes as well as administration of medications for other chronic diseases.15,16

Insurance Coverage of Antiobesity Medications

Many health insurance companies do not cover the cost of GLP-1 receptor agonists when used for weight loss or other antiobesity medications. Patients may be counseled that coupons and patient assistance programs may be able to assist them in getting access to these GLP-1 receptor agonists in the near future. Semaglutide manufacturing problems have also limited the supply of this agent; this issue is expected to be resolved later this year, according to a recent article in The New York Times.


Glucagon-like peptide-1 receptor agonists access specific brain areas important for appetite regulation, resulting in weight loss.17 These mechanisms may help explain how treatment with GLP-1 agonists led to reduced appetite and food cravings and better control of eating.3,17 Evidence supports both GLP-1 agonists liraglutide and semaglutide as effective agents for weight loss in patients with obesity without diabetes, with semaglutide data providing a more significant weight loss in clinical trials. Although GLP-1 agonists have side effects, the weight loss benefits may outweigh their risks.

Disclosure: Dr Sanders has no relevant financial disclosures.

Darlene M. Sanders, DMSc, MPAS, PA-C, is a family practice PA in rural Montana.


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