Providers must go beyond weight reduction when treating obesity
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Key takeaways:
- Many anti-obesity medications are currently in phase 3 trials.
- Adults with obesity can achieve 15% or more weight loss with multiple anti-obesity medications in the pipeline.
Adults with obesity can lose 15% or more of their body weight with nutrient-stimulated hormone-based therapies, but reducing body weight is not the only goal providers should have when treating obesity, according to a speaker.
Ania M. Jastreboff, MD, PhD, associate professor of medicine and pediatrics (endocrinology) at Yale University School of Medicine, director of the Yale Obesity Research Center and co-director of the Yale Center for Weight Management, discussed medications that are currently in development for the treatment of obesity. With newer medications resulting in greater weight loss, Jastreboff said providers need to adjust their approach for treating obesity.
“We need to move beyond just weight reduction,” Jastreboff said during a presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “We need to focus on treating obesity and improving health outcomes.”
Anti-obesity medications in the pipeline
The FDA has approved two nutrient-stimulated hormone-based therapies for chronic weight management: semaglutide (Wegovy, Novo Nordisk) in June 2021 and tirzepatide (Zepbound, Eli Lilly) in November. In addition to those two approvals, a series of other anti-obesity medications are currently in phase 3 trials:
- The combination drug CagriSema (Novo Nordisk) contains both the amylin analog cagrilintide and the GLP-1 receptor agonist semaglutide. In a phase 1b trial, adults with obesity lost a mean 17.1% of their body weight at 20 weeks with cagrilintide/semaglutide.
- Survodutide (Boehringer Ingelheim/Zealand Pharma), a GLP-1/glucagon dual agonist, is currently in phase 3 trials after phase 2 research showed adults with obesity assigned once-weekly survodutide 4.8 mg lost up to 18.7% of their body weight at 46 weeks.
- Retatrutide (Eli Lilly), a glucose-dependent insulinotropic polypeptide (GIP)/GLP-1/glucagon triple agonist, is currently in development for the treatment of obesity. Retatrutide conferred weight loss of up to 24.2% at 48 weeks in a phase 2 trial among adults assigned once-weekly 12 mg treatment. In addition, 63% of adults who received the highest dose lost 20% or more of their body weight.
- Phase 3 data on higher-dose 50 mg oral semaglutide (Novo Nordisk) were presented earlier in 2023. In the OASIS 1 trial, adults assigned oral semaglutide lost a mean 15.1% of their body weight at 68 weeks.
- Orforglipron (Eli Lilly) is another potential oral medication that is moving into phase 3 trials. In a phase 2 study, the agent reduced body weight by 14.7% at 36 weeks, with nearly half of the participants losing 15% or more of their body weight.
Two other oral medications are currently in phase 2 of development. Danuglipron (Pfizer), an oral GLP-1 receptor agonist, remains in phase 2 after concerns emerged regarding tolerability with twice-daily dosing, according to Jastreboff. A dosing change to once daily is being considered for this agent.
Additionally, a monthly GIP receptor antagonist/GLP-1 receptor agonist, maridebart cafraglutide (formerly AMG 133, Amgen), has progressed to phase 2 trials.
Optimizing health in obesity treatment
Treating obesity involves more than just reducing a person’s body weight, according to Jastreboff. She outlined a series of factors that providers need to keep in mind.
“We need to always remember to target the neurometabolic pathophysiology of obesity,” Jastreboff said. “We need to understand this better. We need to consider the heterogeneity of obesity. How do we target these different mechanisms?”
Jastreboff said factors that may affect obesity treatment selection include the severity of a person’s obesity, their obesity-related conditions, their overall health and metabolic profile, and treatment targets. Combination therapies should also be individualized.
To optimize health, Jastreboff said providers should make sure people with obesity are eating nutritious food, prioritizing protein in their diet, including physical activity in their daily schedule as much as possible, reducing stress and improving quality of sleep.
“There’s no medication that we have that can help us eat more healthfully or exercise more,” Jastreboff said. “Maybe one day that’ll be discovered, but not yet.”
It is also important to consider the rate and quality of weight reduction and the potential for bone loss, vitamin deficiencies and loss of muscle that may result from increasing medication dose too quickly, Jastreboff said.
“Start low and go slow,” Jastreboff said. “For most of my patients, I do not titrate up once a month; I titrate based on how they’re tolerating the medication and the rate of the weight reduction that they’re experiencing.”
Providers should acknowledge that weight bias and stigma affect people with obesity, even when they seek treatment. Providers should also advocate for people with obesity to make sure they have access to medications and can afford treatments, Jastreboff said.
“What good are any of these tools that I have just shown you if our patients do not have access to them?” Jastreboff said.
Perspective
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Katherine H. Saunders, MD, DABOM
With GLP-1 receptor agonist media hype and widespread anticipation of other anti-obesity medications in development, many people — including health care providers — are conflating obesity treatment with weight loss.
These medications are called anti-obesity medications, not weight-loss drugs, for good reason — weight loss is only part of the story. Obesity is a complex, heterogenous, chronic disease that goes way beyond excess weight. Physiologic pathways become dysregulated with obesity, and they cause countless weight-related health complications. Therefore, effective treatment of this refractory and relapsing disease is about so much more than just body weight reduction.
Ania Jastreboff provides a beautiful overview of the complexities of the disease state, and the comprehensive, individualized, empathetic and long-term strategies required to treat individuals with obesity.
When patients present to us for obesity treatment, we identify all contributors to weight gain and all barriers to weight loss, and we include each factor in our personalized education and treatment plans. Especially with the highly effective anti-obesity medications, comprehensive evaluations, tailored management strategies and ongoing reinforcement of lifestyle interventions are critical to ensure long-term success. We select patients carefully, teach them to adjust eating behavior to minimize side effects, and support them to identify early warning signs before serious adverse events occur.
Prescribing anti-obesity medications is a responsibility that cannot be taken lightly.
When patients ask the inevitable question about their weight goals, we focus on health outcomes rather than arbitrary numbers. Reduction in HbA1c, discontinuation of an antihypertensive drug and resolution of sleep apnea are better markers of health than a number on the scale.
What’s more important than the initial weight loss period is the oftentimes extremely tricky weight maintenance phase. Patients require considerably more support than they generally realize to continue lifestyle interventions, prevent medication discontinuation, and develop strategies to get back on track each time they hit inevitable bumps in the road.
I’m honored to be a member of the International Obesity Collaborative, a global initiative to address the disease of obesity on an international scale. Composed of 12 leading obesity organizations, the International Obesity Collaborative aims to raise awareness, share best practices and implement effective interventions to treat obesity worldwide. We recently finalized a consensus statement on obesity care vs. weight loss that highlights many of the principles discussed above and ends with a call to action: “Like other serious chronic diseases, support for obesity care must be incorporated into national public health strategies and include standard benefits and coverage for obesity across the lifespan.”
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Jastreboff A. Incretins in diabetes: Nutrient-stimulated hormone-based therapies for obesity treatment – Clinical application and pipeline. Presented at: World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease; Dec. 7-9, 2023; Los Angeles.
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