Weighing the Evidence on New Weight Loss Drugs – Five Takeaways

The prevalence of overweight and obesity keeps worsening in America despite our enormous collective effort to lose weight. The U.S. Centers for Disease Control and Prevention estimates that overweight and obesity now affect over 70% of Americans and add over $170 billion to annual U.S. healthcare costs. About half of Americans try to lose weight each year, and social trends constantly shift around a myriad of weight loss interventions and products. Among these, weight-loss-inducing medications have historically received limited attention. However, public interest and demand for weight loss drugs has spiked since the introduction of two new drugs: semaglutide (Wegovy) in 2022 and tirzepatide (Zepbound) in 2023. 

Semaglutide, tirzepatide, and liraglutide (Saxenda)–another weight loss drug introduced in 2014–are glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a type of antidiabetic drug that improves glycemic control by modulating insulin and glucagon secretion. GLP-1 RAs also induce satiety by delaying gastric emptying and modulating appetite and may thus help patients reduce their food intake and lose weight. Three other weight loss drugs are available with U.S. Food and Drug Administration (FDA) approval: Orlistat (Xenical, Alli), a drug that suppresses fat absorption in the intestine, and phentermine-topiramate (Qsymia) and naltrexone-bupropion (Contrave), two neuromodulator combinations that suppress appetite. FDA has also approved liraglutide (Victoza), semaglutide (Ozempic, Rybelsus), and tirzepatide (Mounjaro) for treating diabetes, alongside GLP-1 RAs dulaglutide (Trulicity) and exenatide (Bydureon BCise, Byetta).

A large body of evidence, including many high-quality studies, has established the safety and effectiveness of FDA-approved GLP-1 RAs for promoting weight loss. However, prescribing information may not cover all questions that physicians and patients may have about how to use the drugs, which may create barriers to treatment. Furthermore, longstanding misconceptions and misinformation spreading through social media may also interfere with optimal utilization of these novel drugs.

ECRI’s Clinical Evidence Assessment service recently published a special report on clinical best practices for managing obesity and overweight with GLP-1 receptor agonists. The report reviews available clinical evidence, clinical practice guidelines, and other resources to provide context on GLP-1 RA use for overweight and obesity treatment and support prescriber decisions on patient selection, treatment initiation and dosing, treatment duration and discontinuation, adverse event monitoring, and supporting lifestyle changes in these patients.

Here are five key takeaways from ECRI’s clinical evidence research:

1. GLP-1 RAs are effective to achieve additional, clinically significant weight loss in adolescents and adults with obesity or overweight, as indicated by FDA-approved labeling, and who are committed to achieving weight loss through lifestyle changes (i.e., diet, exercise). Evidence suggests that mental illness is not an absolute contraindication for GLP-1 RA therapy and that GLP-1 RAs may be useful as a bridge to bariatric surgery.
2. Intensive behavioral therapy consisting of recommendations on diet (with a goal of achieving a 500 kcal/day deficit) and physical activity (with a goal of 150 min/week of moderate-intensity exercise) delivered by a dietitian or similarly qualified care provider at least once a month is an effective approach to lifestyle intervention for patients considering GLP-1RA therapy. Meal replacement programs meeting similar criteria may be an appropriate alternative or supplement to dietary recommendations.
3. GLP-1 RAs can provide clinically significant benefits at submaximal doses and should be taken at the maximal tolerated dose but should be discontinued if patients fail to achieve significant weight loss on this dose after six months. Tirzepatide and semaglutide are more effective than liraglutide, but the benefit may not be clinically significant and some patients may experience worse side effects with these drugs than with liraglutide.
4. Weight regain is likely after discontinuing GLP-1 RA therapy; therefore, the drugs are intended for chronic use. The need for weaning regimens is not anticipated in patients discontinuing treatment.
5. Patients can expect mild and transient side effects on treatment initiation, including nausea, vomiting, constipation, diarrhea, and headaches. Rare but serious side effects that warrant monitoring and patient education include pancreatitis, gastroparesis, bowel obstruction, and cholestasis. The association of GLP-1 RA and thyroid cancer risk remains unclear.
   

ECRI members may access this report in its entirety here. Non-members may register to receive a copy of the report.