In the US, the prevalence of obesity among adults has reached nearly 42%, according to the latest data from the Centers for Disease Control and Prevention (CDC).¹ The global burden of obesity now affects more than 1 billion individuals. For persons with obesity, lifestyle interventions such as healthy eating and regular physical activity are still important weight management techniques. Lifestyle interventions, however, may not be sufficient for all patients, which is where pharmacotherapy can be helpful. While medications for chronic weight management are not novel, there has been a surge in the development of newer antiobesity agents in recent years with distinct mechanisms of action and improved safety and efficacy profiles.

With the rise in demand for these newer antiobesity medications, primary care clinicians may face more questions regarding their use from patients who struggle to reach a healthy weight.

Background/overview

Medications for weight management have been available for decades. “We’ve had antiobesity medications that are FDA-approved since the late 1950s,” said medical weight management specialist Sandra Christensen, MSN, ARNP, in an interview with Patient Care Online. “We have the old-school phentermine, diethylpropion, phendimetrazine—which was all that I had when I started treating obesity—and then we have a newer generation that came out in the 2010s. These include phentermine/topiramate, naltrexone, bupropion, orlistat, and lorcaserin, which has since been removed from the market. These were also the first medications that were approved for chronic use.”

The third and most recent group of medications include the glucagon-like peptide-1 receptor agonists (GLP-1 RAs), alone and in combination with molecules whose mechanism of action is complementary. GLP-1RAs were originally approved for the treatment of hyperglycemia in patients with type 2 diabetes. More recent research showing their effectiveness in reducing weight among patients with overweight and obesity has led to expanded indications for several agents from the US Food and Drug Administration (FDA).

GLP-1 RAs are “naturally-occurring gut hormones,” said Caroline Apovian, MD, professor of medicine at Harvard Medical School, in an interview with Patient Care Online. “We’ve created analogs for these naturally-occurring gut hormones that your body makes when you eat food. They are secreted in the gut, in your small intestine, and they go to the brain and make you feel full.”

In addition, GLP-1 RAs increase the time it takes for food to travel through the intestine, thus making individuals feel full for a longer period of time, noted Apovian, who is also codirector of the Center for Weight Management and Wellness in the division of endocrinology, diabetes, and hypertension at Brigham and Women's Hospital in Boston, MA.

GLP-1RAs approved

Liraglutide. Liraglutide (Saxenda, Novo Nordisk) is a once-daily GLP-1 RA that was approved in 2014 for chronic weight management in adults with obesity or overweight. In 2020, the FDA approved an updated label for liraglutide for use in the treatment of obesity in adolescents aged 12 to 17 years weighing more than 60 kg and with an initial body mass index (BMI) corresponding to ≥30 kg/m2 for adults, as an adjunct to reduced-calorie meals and increased physical activity. With the updated label, liraglutide became the first FDA-approved therapy for adolescents with obesity in more than a decade.

The safety and efficacy of liraglutide as a treatment for adolescents with obesity was based on the results from a phase 3a trial published in The New England Journal of Medicine.² The double-blind, 56-week study examined the effects of liraglutide vs placebo for weight management in 251 patients aged 12 to 17 years with obesity as an adjunct to lifestyle therapy, defined as counselling in healthy nutrition and physical activity for weight loss. Participants were randomly assigned to receive either 3 mg of liraglutide or placebo subcutaneously once daily, in addition to lifestyle therapy. The primary endpoint was the change from baseline in BMI standard-deviation score (BMI-SDS) at week 56. The results showed a significant reduction in BMI-SDS, as well as reductions in BMI, mean body weight, and other weight-related endpoints among participants who received liraglutide vs placebo.

Semaglutide. On June 4, 2021, the FDA announced the approval of semaglutide 2.4 mg injection (Wegovy,™ Novo Nordisk) for chronic weight management in persons with obesity or overweight with at least 1 weight-related comorbidity (eg, hypertension, type 2 diabetes [T2D]) as an adjunct to diet and exercise, making it the first medication to receive such an approval since liraglutide in 2014. It was also the first once-weekly GLP-1 RA to receive FDA approval for chronic weight management.

The FDA approval was based on results from the phase 3a STEP clinical trial program which examined the effect of gradually titrated doses of semaglutide over 16 to 20 weeks to a therapeutic dose of 2.4 mg. STEP program studies were conducted in patients with and without T2D with the largest enrolling those without. Across all studies, use of semaglutide 2.4 mg among those without diabetes was associated with an average weight loss of 17-18% that was sustained over 68 weeks. In the study of patients free of T2D, the average weight at baseline was 231 lbs and average BMI was 38 kg/m².

Tirzepatide. In 2023, the FDA approved tirzepatide (Zepbound, Eli Lilly), a novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 hormone mimetic, for use in adults requiring chronic weight management. Tirzepatide was previously approved in 2022 (as Mounjaro) for the treatment of hyperglycemia in adults with T2D.

The FDA based its approval on findings from 2 phase 3 randomized placebo-controlled clinical trials, SURMOUNT-1 and SURMOUNT-2.

In the SURMOUNT-1 trial, researchers compared tirzepatide with placebo in 2539 adults with obesity or overweight plus 1 weight-related medical problem, excluding T2D. At 72 weeks, participants taking the highest dose of 15 mg lost an average of 48 lbs; those taking the lowest dose of 5 mg lost an average of 34 lbs, compared with a loss of 7 lbs in the placebo group. Half of patients receiving 10 mg and 47% of those receiving 15 mg of tirzepatide lost 20% or more of their baseline body weight compared with 3% in those receiving placebo. SURMOUNT-1 participants had an average baseline weight of 231 lbs and average BMI 38 kg/m2; weight loss at all 3 dose levels was statistically significant.

In the SURMOUNT-2 study, investigators randomly assigned 938 adults with obesity or overweight who also had T2D to receive tirzepatide 10 mg or 15 mg or placebo. They reported average baseline weight among the cohort of 222 lbs and BMI of 36 kg/m2. Investigators reported mean weight changes among tirzepatide-treated participants of -13.4% for those receiving 10 mg and of -15.7% for those on 15 mg compared to a change of -3.3% in participants receiving placebo.

Drawbacks

The unprecedented efficacy of the GLP-1 RA-based antiobesity medications has triggered an outsized media response and driven widespread off-label prescribing for cosmetic weight loss. The demand, driven in large part by viral online promotion by celebrities and social media influencers, has also led to an illegal market of counterfeit products including potentially dangerous formulations prepared by compounding pharmacies.

For example, in January 2024, Eli Lilly released an open letter to the public warning against the use of 2 formulations of its dual incretin mimetic tirzepatide—marketed as Zepbound for chronic weight management and as Mounjaro to reduce hyperglycemia in persons with T2D—for cosmetic weight loss purposes.

The 2 formulations “are indicated for the treatment of serious diseases; they are not approved for – and should not be used for – cosmetic weight loss,” stated the manufacturer. “Lilly does not promote or encourage use of Mounjaro, Zepbound, or any Lilly medicines outside of a medicine’s FDA-approved indication.”³

Eli Lilly also stated that health care professionals should review the Instructions for Use for both Mounjaro and Zepbound and consider carefully the information on risks associated with tirzepatide detailed in the Full Prescribing Information and Medication Guide for both products.

In addition, in September 2023, the FDA updated the warnings on the label for the semaglutide formulation marketed as Ozempic to include the potential for ileus, which is also a potential side effect for Wegovy (semaglutide for weight management) and Mounjaro (tirzepatide for T2D).

A note to primary care

How can primary care clinicians incorporate antiobesity medication into a treatment plan for patients with obesity? "I encourage primary care providers to learn about obesity and prescribe [antiobesity] medications when they are appropriate," said Sandra Christensen, MSN, ARNP, in an interview with Patient Care Online. “Antiobesity medications work best when they are part of a comprehensive plan, so when you are also giving people nutritional guidance, physical activity, behavioral counseling, they are going to work the best.”

In addition, Christensen says that antiobesity medications should be prescribed for patients with obesity that clinicians can follow up with “because if you get them started on something and they have problematic side effects, then they will just stop taking them and then they can get lost. So, you really want to follow up and have a way to help them manage.”

References:

1. Adult obesity facts. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/obesity/data/adult.html. Updated May 17, 2022. Accessed April 17, 2024.
2. Kelly AS, Auerbach P, Barrientos-Perez M, et al. A randomized, controlled trial of liraglutide for adolescents with obesity. N Engl J Med. 2020;382:2117-2128. doi:10.1056/NEJMoa1916038
3. Open letter regarding the use of Mounjaro® (tirzepatide) and Zepbound® (tirzepatide). News release. Eli Lilly and Company. March 7, 2024. Accessed April 17, 2024. https://lilly.gcs-web.com/node/50471