Weight Loss Advances with GLP-1 Receptor Agonists: Too Good to be True?

May 18, 2023

By Hadley Greenwood

Peer Reviewed

Medications originally developed as agents to treat type 2 diabetes have been making headlines for their use as weight loss drugs, even in individuals without diabetes. The medical community has known for years that some agents used in diabetes can also cause considerable weight loss. Liraglutide, a GLP-1 receptor agonist, was approved by the FDA in 2014 as a weight-loss medication.1 More recently, Wegovy, a higher dose (maximum weight-loss dose 2.4 mg) of the GLP-1 receptor agonist semaglutide Ozempic (maximum diabetes dose 2.0 mg), received FDA approval in 2021.2 The American media and the public are catching on, with high-profile figures and internet influencers touting their anecdotal success with these agents. Consumer demand and the number of physicians prescribing weight-loss medicines have spiked accordingly, with headlines detailing widespread shortages of Ozempic. This increased publicity has coincided with data published in June 2022 from a phase 3 trial that showed substantial weight reduction with tirzepatide, a dual GIP receptor/GLP-1 receptor agonist that holds great promise as a new treatment for individuals with obesity.3

These medications are expected to significantly improve morbidity and mortality outcomes for those with obesity, with corresponding projections that the pharmaceutical weight-loss market will grow markedly. Will these treatments become the standard of care for long-term weight control, or will the momentum of their integration into clinical practice stall? What drawbacks and barriers exist that may discourage a practitioner from prescribing these medications?

In the SURMOUNT-1 trial of tirzepatide, Jastreboff and colleagues studied adults with a body-mass index of 30 or more, or 27 or more with at least one weight-related complication, excluding diabetes. At baseline, the 2539 participants weighed an average of 230.6 pounds, with a body-mass index of 38. The vast majority (91%) of participants who received the 15-mg once-weekly dose achieved body-weight reduction of at least 5% by 72 weeks, the benchmark for clinically significant weight loss, with associated improvement in glycemic measures and triglycerides.3,4 Many lost far more than that, with a mean percentage change in body weight from baseline of -20.9% in the participants on 15-mg weekly subcutaneous tirzepatide at 72 weeks compared to 3.1% weight reduction with placebo. This resulted in a remarkable mean weight reduction of 52 pounds in the 15-mg group over 72 weeks. In comparison, a 2021 study by Wildling and colleagues found that semaglutide was associated with a weight reduction of 14.9% over 68 weeks compared to -2.4% with placebo.5 Tirzepatide treatment also improved physical function scores and cardiometabolic risk factors such as blood pressure, fasting insulin levels, and lipid levels compared with placebo.3 

These findings correspond with the results from the SURPASS-2 trial, which showed tirzepatide treatment to be superior to semaglutide, specifically in patients with type 2 diabetes, based on the primary endpoint of change in glycated hemoglobin level after 40 weeks.6 Their secondary endpoint of weight loss showed that tirzepatide was superior in a head-to-head comparison, with nearly double the weight loss in those receiving 15 mg weekly tirzepatide compared to those receiving 1 mg weekly semaglutide.6

As promising as these findings are, there are considerable barriers to access.  Wegovy, developed by Novo Nordisk, had a list price of $1,349.02 per one month’s supply as of June 2022.7 Some insurance companies will not cover this cost, and Medicare still does not cover obesity medications.8 Off-label use of other prescription medications in those without diabetes is also not covered. The stigma surrounding people living in larger bodies affects insurance coverage, a topic worthy of discussion.

The next point is the indefinite length of time for which these medications need to be taken. When semaglutide was withdrawn after 20 weeks of treatment in the STEP 4 randomized clinical trial, participants who switched to placebo regained a significant amount of the weight they had lost, with a mean weight change of +6.9%  over the next 48 weeks.9 While the implication that the medication needs to be taken for life fits within the recent reframing of obesity as a chronic illness, the cost adds up to over $15,600 a year without insurance coverage.

Conversely, bariatric surgery is covered by Medicare and results in more substantial and durable weight reduction for a lower cost. A systemic review by O’Brien and colleagues in 2019 demonstrated sustained total weight loss of 22.2% at 20 years.10 With this said, the advantages of bariatric surgery do not take away the potential value of these pharmacologic agents. Surgery may not be the answer for many patients.

Finally, a retrospective cohort study published in 2021 by Weiss and colleagues looked at GLP-1 receptor agonist therapy in patients with diabetes. They found that the real-world weight reduction with these medications was notably less than that demonstrated in prior clinical trials.11 This was attributable to suboptimal adherence and higher discontinuation rates. It is likely that both adherence and discontinuation are due to adverse effects, which are primarily gastrointestinal. The SURMOUNT-1 trial reported a 31% rate of nausea at the highest (and most effective) dose of tirzepatide, with diarrhea second at 23%.3 Although the Weiss study participants all had diabetes, it still prompts reflection on the real-world effectiveness of incretin hormones for clinically meaningful and sustained weight loss. The participants studied in the SURMOUNT-1 trial were highly motivated and had adjunctive lifestyle interventions, including dietician support and 150 minutes of physical activity per week. The ability to extrapolate the remarkable weight loss in this trial to the general population who might lack access to healthy foods, dieticians, and facilities for physical activity should also be questioned when considering real-world efficacy. Some questions remain between the findings of suboptimal adherence in the Weiss trial and the debate surrounding the extrapolation of real-world conclusions from the SURMOUNT-1 study.

While the cost, indefinite length of use, and concerns about effectiveness in real-world weight reduction are all worthy of consideration, these new anti-obesity medications nevertheless hold great promise. With pressure to support insurance coverage of anti-obesity medications, one major barrier to access may soon fall. And with that, these medications may become the standard of care for those who qualify.

Hadley Greenwood is a 3rd year medical student at NYU Grossman School of Medicine

Reviewed by Michael Tanner, MD, associate editor, Clinical Correlations

Image courtesy of Wikimedia Commons, source: https://www.flickr.com/photos/alancleaver/sets/72157606825074174/


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