What to Know About the New Obesity Medications

Educational Objectives

The goal of this program is to improve medical management of obesity. After hearing and assimilating this program, the clinician will be better able to:

1. Explain the results of the STEP 1 trial assessing efficacy of semaglutide.
2. Compare the effectiveness of tirzepatide and semaglutide based on evidence.

Summary

Epidemiology: the prevalence of obesity (body mass index [BMI] >30 kg/m²) has rapidly increased; in the United States, the prevalence is >40%; obesity commonly impacts the gastrointestinal system

Indications for antiobesity medication (AOM): patients should have undergone lifestyle modifications for ≥6 mo; AOMs are prescribed in patients with class 1 obesity (BMI >30), or overweight and obesity-related complications (lower cutoffs in patients of Asian descent [significant obesity with lower BMI])

Early AOMs: the drugs approved by the US Food and Drug Administration (FDA) include phentermine, topiramate, and orlistat (weight loss, 5%); additional FDA-approved medications, including phentermine-topiramate (eg, Qsymia), naltrexone-bupropion (eg, Contrave), and liraglutide (eg, Saxenda), produce better weight loss (5%-10%); liraglutide is the first glucagon-like peptide 1 (GLP-1) receptor agonist (RA) approved for obesity

Incretin effect: in healthy individuals, insulin levels rise higher with oral glucose than intravenous glucose; patients with type 2 diabetes mellitus (T2DM) have significantly reduced incretin effect

Incretins: GLP-1 — mainly acts on the central nervous system (CNS; eg, increases satiety, reduces food intake, nausea, decreases body weight), the pancreas (eg, increases insulin, decreases glucagon), and the stomach (eg, reduces gastric emptying); glucose-dependent insulinotropic polypeptide (GIP) — acts on the CNS, the pancreas, and the subcutaneous adipose tissue

GLP-1 receptor agonist: native GLP-1 is released in the gut (half-life, 1-2 min) and rapidly degraded by dipeptidyl peptidase 4; semaglutide is more resistant to degradation (linked to a fatty acid moiety) and can be administered once weekly subcutaneously; semaglutide was approved for T2DM (eg, Ozempic) in 2017 and obesity (eg, Wegovy) in 2021; the STEP 1 trial (Wilding et al [2021]), which randomized overweight patients without diabetes to semaglutide (maximum dose, 2.4 mg) or placebo, reported 15% total body weight loss (TBWL) with semaglutide (vs ≈3% with placebo)

Tirzepatide: binds to GLP-1 and GIP receptors, has a longer half-life, and can be administered once weekly; approved for T2DM (eg, Mounjaro) and obesity (eg, Zepbound); Jastreboff et al (2022) reported 3% TBWL with placebo vs 21% with high-dose tirzepatide (15 mg); the SURPASS-2 trial (Frías et al [2021]) reported higher TBWL with all 3 strengths of tirzepatide (5, 10, and 15 mg) compared with semaglutide (1 mg) and higher reductions in hemoglobin A_1c with tirzepatide

Drug discontinuation: Rubino et al (2021) reported sustainable weight loss with semaglutide, but weight regain in patients who had switched to placebo for >20 wk; Aronne et al (2024) reported weight loss of ≈25% with continued use of tirzepatide and weight regain (10% below baseline) with a switch to placebo

Other uses: Newsome et al (2021) reported resolution of metabolic dysfunction-associated steatohepatitis in 17% of patients in the placebo group vs≈60% in the 0.4-mg once-daily semaglutide group (odds ratio, ≈7); higher doses of semaglutide showed rapid improvement in liver enzymes; cardiovascular disease — study (Lincoff et al [2023]) reported a ≈20% reduction in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke with semaglutide in patients without diabetes; the heart failure composite endpoint and death from any cause (≈20%) improved in the semaglutide group; the US FDA approved the use of semaglutide in patients with cardiovascular disease and overweight or obesity; malignancy — obesity is strongly associated with colorectal cancer; Wang et al (2024) reported a 44% reduction in the colorectal cancer risk with GLP-1 RA vs insulin and a 25% reduction vs metformin

Complications of GLP-1 RA: Sodhi et al (2023) reported a higher risk for pancreatitis, bowel obstruction, and gastroparesis with GLP-1 RA compared with bupropion-naltrexone; Yeo et al (2024) reported a 33% increased risk for aspiration pneumonia with GLP-1 RA; gastroparesis has been reported in patients who received only 1 or 2 doses

Prescribing GLP-1 RA: consider individualized medical assessment with lifestyle counseling and other therapies (eg, bariatric surgery, bariatric endoscopy); rule out absolute contraindications (eg, history of pancreatitis, gastroparesis, thyroid cancer); educate patients on expected side effects, especially sarcopenia; initiate with the lowest dose and uptitrate once a month; switch medications in patients without a good clinical response; closely monitor for adverse events

Novel medications: retatrutide is a triple agonist to GLP-1, GIP, and glucagon; Jastreboff et al (2023) reported 24% TBWL with the highest dose of retatrutide vs 2% with placebo; Knop et al (2023) reported 15% TBWL with oral semaglutide administered once daily at 68 wk; orforglipron, a GLP-1 RA, is under development

Readings

Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024;331(1):38–48. doi:10.1001/jama.2023.24945; Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-515. doi:10.1056/NEJMoa2107519; Idrees Z, Cancarevic I, Huang L. FDA-approved pharmacotherapy for weight loss over the last decade. Cureus. 2022;14(9):e29262. doi:10.7759/cureus.29262; Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038; Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity - A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972; Knop FK, Aroda VR, do Vale RD, et al. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;402(10403):705-719. doi:10.1016/S0140-6736(23)01185-6; Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563; Lisco G, De Tullio A, Disoteo O, et al. Glucagon-like peptide 1 receptor agonists and thyroid cancer: Is it the time to be concerned?. Endocr Connect. 2023;12(11):e230257. doi:10.1530/EC-23-0257; Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384(12):1113-1124. doi:10.1056/NEJMoa2028395; Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021;325(14):1414-1425. doi:10.1001/jama.2021.3224; Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M. Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA. 2023;330(18):1795–1797. doi:10.1001/jama.2023.19574; Wang L, Wang W, Kaelber DC, Xu R, Berger NA. GLP-1 receptor agonists and colorectal cancer risk in drug-naive patients with type 2 diabetes, with and without overweight/obesity. JAMA Oncol. 2024;10(2):256-258. doi:10.1001/jamaoncol.2023.5573; Wharton S, Blevins T, Connery L, et al. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N Engl J Med. 2023;389(10):877-888. doi:10.1056/NEJMoa2302392; Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183; Yeo YH, Gaddam S, Ng WH, et al. Increased risk of aspiration pneumonia associated with endoscopic procedures among patients with glucagon-like peptide 1 receptor agonist use. Gastroenterology. 2024;167(2):402-404.e3. doi:10.1053/j.gastro.2024.03.015.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Yeoh’s lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Yeoh was recorded at the 2nd Annual Updates in Gastroenterology and Hepatology, held April 17-20, 2024, in Sonoma, CA, and presented by Stanford Medicine. For information on future CME activities from this presenter, please visit https://stanford.cloud-cme.com/. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.50 CE contact hours.

Lecture ID:

GE382002

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.