Research is important to us for many reasons. Sometimes, for example, research results in a new treatment (e.g., Alexander Fleming and penicillin), a new idea (e.g., Einstein’s theory of relativity), or a new way of doing things (e.g., Dr. Doudna’s CRISPR methodology for gene editing). Novelty is a major theme behind what makes research important.
Yet sometimes research is important not because it offers us something new but because it reminds us of something old that we were reluctant to accept. This past week’s research on weight regain after discontinuing tirzepatide (Zepbound) is one such case.1
Zepbound is a potent GLP-1 (glucagon-like peptide 1) medicine that helps many people achieve dramatic weight loss and coincident metabolic health improvements (e.g., diabetes, fatty liver disease, sleep apnea). The Phase 3 clinical trial for Zepbound showed an average weight loss of >50 pounds over a year of treatment.2 This level of weight loss remains unmatched by any treatment short of bariatric surgery. But this latest study asked a different question: what happens when people stop using Zepbound?
The answer seems to be the same thing that happens with all the other weight loss methods studied to date.
- 83% regained significant amounts of weight (>25% of weight lost from treatment)
- Among those regaining weight, participants also experienced health gain reversals in parameters such as waist circumference, blood pressure, and cholesterol
- Weight gain and health reversal trends for many people began almost immediately after stopping their treatment
For decades, seemingly every new diet, exercise program, bariatric surgery, and weight loss medicine has tantalized us with the hope that they could produce permanent weight loss with a short-term treatment. Each time the harsh reality of weight regain shattered these hopes, only for them to miraculously reassemble in time for the next popular treatment. In several longer-term trials, GLP-1 weight loss medicines now show the same pattern of weight regain upon cessation of treatment.
Why is weight regain (mostly) inevitable without long-term treatment?
Although weight regain is a risk with every weight loss treatment, findings from the National Weight Loss Registry3 reveal that it is possible for some people to maintain significant weight loss. For example, people who both lose and maintain significant weight loss tend to:
- Eat regular meals and monitor portion sizes indefinitely, without following any specific diet
- Maintain exercise as a regular part of their lifestyle
- Weigh themselves regularly
- Reduce sedentary activities such as TV and social media
The takeaway from the National Weight Loss Registry for long-term weight loss is this: permanent weight loss requires permanent treatment. Although diet and exercise programs, bariatric surgeries, and GLP-1 medicines produce weight loss through different biopsychosocial mechanisms, their need for treatment (which may consist, for example, of enduring lifestyle changes, ongoing medicine use, or diligent adherence to post-bariatric nutrition) in perpetuity is the same.
For most people, maintaining weight loss requires a lifelong battle with their own biology. This inconvenient truth underlies the necessity for ongoing treatment. Fat cells, for instance, are not mere passive storage vessels for energy as commonly conceived. They are, in fact, miniature organs in themselves, secreting specific hormones (e.g., leptin) to the brain during periods of weight loss that increase appetite and decrease satiety. Remarkably, fat cells even maintain “memories” of their pre-weight loss selves in the form of epigenetic gene expression patterns. These epigenetic memories can compel weight regain long after weight loss has ended.4 Couple these fat cell influences with equally powerful changes in the brain’s reward system pathways that occur during periods of overweight and obesity, and even the best-intentioned person can find their conscious weight loss goals overruled by primordial human biology optimized over millions of years of evolution to prioritize weight regain over weight loss.5
Overweight and obesity as chronic diseases
This latest research on weight regain following GLP-1 medicine treatment suggests a conclusion we already accept in many other areas of our lives. What happens to physical fitness once exercise stops? How long does love last when we stop nurturing our relationships? We maintain our daily brushing and (hopefully) flossing routines because we know that tooth decay begins to set in as soon as we pause these habits. Most of us don’t need a Phase 3 clinical trial study to realize the following: All things we consider good must be defended. Perhaps we can finally add weight loss to this list of goods.
Science and healthcare have only recently acknowledged that excess body fat (i.e., overweight and obesity) is a chronic disease requiring long-term treatment and management. If this seems self-evident to you, consider that it took the American Medical Association until 2013 to officially recognize obesity as a chronic condition. 6 Since its inception in 1847, experts in the world’s most prestigious medical association viewed overweight and obesity much like they did acute diseases and accidents that could be treated with short-term interventions. The tide on obesity took that long to turn.
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The critical next step is conveying this updated understanding to the broader public. As long as we continue to view weight loss as a short-term problem, we will tend towards short-term solutions and suffer the physical and mental toll of short-term results. In contrast, once we collectively embrace healthy weight loss as a life-long journey, long-term treatments supporting weight loss and weight loss maintenance will become the new standard of care. This change has to start somewhere, why not with us?