GLP-1 receptor agonists for weight loss management

Key takeaways:

• GLP-1 receptor agonists are associated with significant weight loss in patients with obesity.
• A strategy for minimizing adverse events from these drugs should be followed.

Obesity is one of the most common chronic preventable comorbidities affecting adults and children in the United States.

It is estimated that 42.4% of U.S. adults have obesity, with the rate increasing more than 10 percentage points in the past 2 decades. The prevalence of severe obesity has also doubled during the same period.

Individuals with obesity have increased risk for heart disease, stroke, type 2 diabetes and kidney disease as well as several types of cancer. These are among the leading causes of preventable death in the U.S. In 2019, the estimated health care costs of obesity in the U.S. were $173 billion. It is expected that by 2030, one in two adults will have obesity.

The importance of controlling obesity cannot be overstated in terms of improving patients’ health care outcomes and saving costs.

Pharmacologic options

Eric Smith

Pharmacologic options can be used for the treatment of obesity; however, they should be reserved for inadequate weight loss despite implementing lifestyle interventions, according to the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) 2016 clinical practice guideline. AACE and ACE recommend initiation of weight-loss medications for patients with a BMI of 27 mg/kg² or greater after failing an adequate trial of lifestyle interventions. If patients have a severe obesity-related complication including but not limited to hypertension, type 2 diabetes, CVD, dyslipidemia and a BMI of 27 mg/kg² or greater, then concurrent initiation of weight-loss medication with lifestyle interventions can be considered, according to the guideline. Anti-obesity medications should not be used alone; use is only in addition to lifestyle modifications, according to the guideline.

Erin E. Pauling

This Pharmacology Consult will focus on GLP-1 receptor agonists that are currently FDA approved for weight loss, including semaglutide (Wegovy, Novo Nordisk) and liraglutide (Saxenda, Novo Nordisk), but other FDA-approved options exist, such as orlistat, naltrexone/bupropion and phentermine/topiramate. Although these agents are approved for certain individuals aged 12 years and older, we will discuss evidence related to the use of injectable semaglutide and liraglutide for weight management in adults. Additionally, several agents currently being investigated for obesity management will be highlighted.

Mechanism of action

Sarah Spinler

GLP-1 and glucose-dependent insulinotropic peptide (GIP) are incretin hormones that are released postprandially to increase insulin secretion and decrease glucagon secretion, ultimately lowering blood glucose. Incretin hormones also act to slow gastric emptying, increase satiation, decrease hunger, decrease food cravings and alter food preference and food-reward pathways. Semaglutide and liraglutide are injectable GLP-1 receptor agonists that target these incretin receptors to take advantage of the latter effects to promote weight loss. The agents are administered once weekly and once daily, respectively.

Semaglutide injection

The Semaglutide Treatment Effect in People with Obesity (STEP) trials consisted of five phase 3 clinical trials of injectable semaglutide. These trials were double-blind, randomized, multicenter, international studies. Specifically, STEP 5 was a 2-year trial that included participants with overweight or obesity. The study included 304 participants who were randomly assigned to semaglutide 2.4 mg or placebo; both arms included lifestyle modifications.

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The first coprimary endpoint was weight loss of 5% or greater from baseline, which was achieved in 83.3% of the semaglutide group vs. 34.9% of the placebo group at 104 weeks. The second coprimary endpoint of change in body weight from baseline was –15.2% vs. –2.6% in the semaglutide and placebo groups, respectively. There was no statistical difference in discontinuation between the two groups. The main adverse effects in the semaglutide arm were gastrointestinal (GI) related, which included nausea, vomiting, diarrhea and constipation.

At this time, subcutaneous semaglutide is approved for weight loss; however, there is emerging data for the use of the oral dosage form for this indication. In preliminary results of OASIS 1, a recent 68-week, phase 3a clinical trial that compared once-daily oral semaglutide with placebo in adults with obesity or overweight with one or more underlying comorbidities, the average weight loss from baseline was 15.1% in the semaglutide group and 2.4% in the placebo group.

Liraglutide injection

The Safety and Clinical Adiposity – Liraglutide Evidence (SCALE) trial was a randomized, double-blind, multicenter, international clinical trial that included 3,731 participants who were randomly assigned 2:1 to 3 mg liraglutide or placebo, both including lifestyle modifications. At 56 weeks, the change in body weight was –8% in the liraglutide group and –2.5% in the placebo group, and 63.2% participants in the liraglutide group achieved weight loss of 5% or greater compared with 27.1% of the placebo groups. Weight loss of 10% or greater occurred in 33.1% vs. 10.6% of the liraglutide and placebo groups, respectively. The main adverse events reported in the liraglutide group were GI related, including nausea, vomiting, diarrhea and constipation. Acute pancreatitis was reported in the liraglutide group.

Orforglipron

Orforglipron (Eli Lilly) is a novel oral GLP-1 receptor agonist that is currently in phase 3 clinical trials. Currently, orforglipron does not carry any FDA indication; however, trials are investigating the agent in type 2 diabetes and obesity. If approved, orforglipron would be the first oral GLP-1 receptor agonist approved for weight loss.

A phase 2 randomized, placebo-controlled interventional trial explored weight loss in patients with obesity or overweight with at least one weight-related coexisting condition was recently completed. The orforglipron 45 mg oral daily dose conferred weight change from baseline of –12.6% at 26 weeks and –14.7% at 36 weeks. Weight loss of at least 5% was achieved in 90% of participants, weight loss of at least 10% was achieved in 69% and weight loss of at least 15% was achieved in 48%. The most common adverse events were similar to the injectable GLP-1 receptor agonists.

Tirzepatide

Tirzepatide (Mounjaro, Eli Lilly) is a dual incretin agonist that targets both GLP-1 and GIP receptors. Currently, it is only FDA-approved for the treatment of type 2 diabetes, but is being studied for the treatment of obesity, as it was seen to cause significant weight loss.

The SURMOUNT-1 trial was a 72-week, phase 3, randomized, double-blind, multicenter clinical trial that evaluated three tirzepatide doses vs. placebo (1:1:1:1) for the treatment of obesity. The primary endpoint of weight loss of at least 5% occurred in 85% of the tirzepatide 5 mg group, 89% of the tirzepatide 10 mg group and 91% of participants in the tirzepatide 15 mg group. More than half of the participants in the 10 mg and 15 mg arms experienced a 20% or more reduction in total body weight by week 20. (Figure 1). The mean change in weight at 72 weeks was –35.5 lb with the 5 mg dose, –48.9 lb with the 10 mg dose, and –52 lb with the 15 mg dose.

Although this medication is not yet FDA-approved for the treatment of obesity, it was granted fast track designation for this indication in October 2022 and current results look promising.

A second phase 3 trial, SURMOUNT-2, enrolled patients with obesity or overweight with a comorbid diagnosis of type 2 diabetes. The study evaluated the 10 mg and 15 mg doses of tirzepatide, which led to an average weight loss of 13.4% and 15.7% from baseline, respectively. The observed weight loss was less than in the SURMOUNT-1 trial, but still significant.

Retatrutide

Recently, a 48-week, phase 2, dose-ranging trial evaluating a novel triple-hormone receptor agonist for obesity management was published. Mechanistically, retatrutide (Eli Lilly) is an agonist of the GLP-1, GIP and glucagon receptors.

The TRIUMPH-3 trial included retatrutide doses ranging from 1 mg to 12 mg with difference in the initial dose to be administered subcutaneously once weekly. The primary endpoint was percent change in body weight from baseline to 24 weeks, which resulted in a 17.5% reduction in the 12 mg (2 mg initial dose) group. The same group realized a 24.2% body weight reduction at 48 weeks, a secondary endpoint. All participants achieved weight loss of at least 5%, 93% achieved weight loss of at least 10% and 83% achieved weight loss of at least 15%.

Adverse events

In each GLP-1 receptor agonist trial, the main adverse events were nausea, vomiting, diarrhea and constipation.

To minimize these events, Sean Wharton, MD, director of the Wharton Medical Clinic in Toronto, and colleagues suggest the “three ‘E’s:

• “Education and explanation
• Escalation to an appropriate dose
• Effective management of GI side effects.”

Patients should be counseled on means to decrease adverse event risk such as reducing meal size; avoiding overeating; and limiting fatty/spicy food, alcohol and carbonated beverages. GLP-1 receptor agonists should be prescribed at a low dose and titrated with slower increases individualized based on patient response. Clinicians should manage GI adverse events in a stepwise approach based on severity. For short-term or mild adverse events, dietary modifications are warranted and, for constipation, increased fiber/water intake can be recommended. If symptoms persist or become more severe, halting the GLP-1 receptor agonist dose titration and assessing the patient for the presence of underlying conditions may be advised. Should a patient be unable to tolerate GI adverse events, a lower dose or alternative GLP-1 receptor agonist can be considered.

A promising future

GLP-1 receptor agonists offer a promising future for the treatment of patients with obesity. Both semaglutide and liraglutide were shown to significantly increase weight loss in this patient population due to slower gastric emptying time, increased satiety, decreased hunger and food cravings, as well as alteration of the food reward pathway. Although subcutaneous semaglutide was shown to have better weight-loss results when compared with liraglutide, both medications are well tolerated with only minor GI adverse events.

The weight-loss efficacy of these medications has led to significant media coverage and increased use by the general public. Subsequently, these agents have been sparsely available, complicating the treatment of obesity. In particular, drug shortages have affected the availability of semaglutide. This trend questions the appropriateness of prescribing these medications for short-term use as it is not recommended based on lack of scientific evidence.

Further efforts should be made to educate providers and the public at large about the effects of GLP-1 receptor agonists and guideline recommendations for their use.

References:

• American Society of Health-System Pharmacists. https://www.ashp.org/drug-shortages/current-shortages/drug-shortage-detail.aspx?id=813&loginreturnUrl=SSOCheckOnly. Updated July 26, 2023. Accessed Aug. 16, 2023.
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• Clinicaltrials.gov. A study of orforglipron (LY3502970) in adult participants with obesity or overweight with weight-related comorbidities (ATTAIN-1). https://classic.clinicaltrials.gov/ct2/show/NCT05869903. Updated July 21, 2023. Accessed Aug. 16, 2023.
• Clinicaltrials.gov. A study of tirzepatide (LY3298176) in participants with type 2 diabetes who have obesity or are overweight (SURMOUNT-2). https://clinicaltrials.gov/ct2/show/NCT04657003. Updated April 13, 2023. Accessed Aug. 16, 2023.
• Garvey WT, et al. Endocr Pract. 2016;doi:10.4157.EP161365.GL.
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• Lilly’s tirzepatide achieved up to 15.7% weight loss in adults with obesity or overweight and type 2 diabetes in SURMOUNT-2. https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-achieved-157-weight-loss-adults-obesity-or. Published April 27, 2023. Accessed Aug. 16, 2023.
• Mounjaro [package insert]. Indianapolis, Indiana: Eli Lilly & Co.; 2022.
• Novo Nordisk A/S: Oral semaglutide 50 mg achieved 15.1% weight loss (17.4% if all people adhered to treatment) in adults with obesity or overweight in the OASIS 1 trial. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=166110. Published May 22, 2023. Accessed Aug. 16, 2023.
• Pi-Sunyer X, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1411892.
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• Saxenda [package insert]. Bagsvard, Denmark: Novo Nordisk A/S; 2022.
• Ward ZJ, et al. N Engl J Med. 2019;doi:10.1056/NEJMsa1909301.
• Ward ZJ, et al. PLoS One. 2021;doi:10.1371/journal.pone.0247307.
• Wegovy [package insert]. Bagsvard, Denmark: Novo Nordisk A/S; 2022.
• Wharton S, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2302392.
• Wharton S, et al. Postgrad Med. 2022;doi:10.1080/00325481.2021.2002616.

For more information:

Zachary Abe, BS, is a PharmD candidate at Binghamton University School of Pharmacy and Pharmaceutical Sciences.

Eric Smith, BS, is a PharmD candidate at Binghamton University School of Pharmacy and Pharmaceutical Sciences.

Erin E. Pauling, PharmD, BCACP, is clinical associate professor and assistant dean for academic affairs at Binghamton University School of Pharmacy and Pharmaceutical Sciences.

Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Healio | Cardiology Today Pharmacology Consult column editor. Spinler is professor and chair of the department of pharmacy services in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. Spinler can be reached at [email protected].

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