Body weight is determined by a complex regulatory system that is necessary to ensure survival of the species 鈥� too little food reduces body weight but, extreme caloric restriction also decreases fertility and, ultimately, can result in death. Preservation of body weight is, therefore, an imperative of species survival. However, excess body weight contributes to chronic diseases, such as obesity and Type 2 diabetes, as well as fatty liver and cardiovascular diseases.
Body weight is also influenced by social determinants. Food is now abundantly available in many societies and, indeed, portion sizes in restaurants and, most notably, in fast-food chains, have increased by up to 500% since the 1950鈥檚. The perception of wealth also influences body weight, with both extreme thinness and overweight being considered signs of affluence, depending on the culture.
Obesity is classified by the World Health Organization as 鈥渁 chronic complex disease defined by excessive fat deposits that can impair health.鈥� Indeed, with the exception of south-east Asia, the number of individuals who are overweight or obese now exceeds those who are underweight. In Canada, one-in-three adults is now obese, with a body mass index (BMI) of greater than 30 kg of body weight/m2聽of height. Note that a healthy BMI is in the range of 18.5鈥�24.9 kg/m2. The remarkable uptake of glucagon-like peptide-1 (GLP-1)-based drugs, such as Ozempic, is therefore not surprizing given the need to prevent or at least reduce the impact of obesity-associated chronic diseases. Indeed, it has recently been reported that approximately one-million Canadians are currently taking a GLP-1-based pharmaceutical.聽
Ozempic and related pharmaceuticals (i.e., Wegovy, Rybelsus, Trulicity, Victoza and Saxenda) reduce body weight at least in part through actions in the brain to reduce appetite. Indeed, weight loss can reach 10-25% of starting weight, depending upon the drug used. However, these numbers encompass a large range of weight losses, with some individuals losing little-to-no weight and others losing substantially more. Weight loss also reached a plateau after a number of months, leading users to feel that the drug is no longer working. Furthermore, GLP-1-based therapeutics are associated with side-effects such as nausea that can be intolerable for some people. Finally, these drugs are expensive, with costs reaching up to $500 CAD per month depending on the drug and the dose. As a consequence, 50% or more of the individuals using GLP-1-based therapeutics stop their treatment after the first year of use.
So, what happens when one stops using GLP-1-based drugs for weight loss? Well, if you stop taking your blood pressure medication, your pressure rises. If you stop taking your statins, your blood lipid levels rise. Unsurprisingly, the same is true for body weight, which rebounds when the brain is no longer receiving the signal to reduce food intake. However, what was a little unexpected was the finding that amount of weight regain is related to the original weight that was lost.
In a landmark study (Diabetes Obes Metab. 2022; 24:1553-1564), 1961 obese adults were treated with 2.4 mg of semaglutide (i.e., the same drug in Ozempic, Wegovy and Rybelsus) for 68 weeks, with 327 of the participants followed for an additional year following treatment discontinuation. Overall weight loss during treatment averaged 17.3% as compared to 2% in the placebo group. However, the range of weight loss with the treatment varied from less than 5% to greater than 20%. Following withdrawal of the treatment, weight regain averaged only 11.6% in the treatment group, meaning a net weight loss of 5.7% after one year of treatment and one year of discontinuation; the comparable number in the placebo group was 0.1%. In other words, as a whole, not all of the weight lost during treatment was regained. Furthermore, the range of weight regain also varied. Those who lost less than 5% during treatment ended up regaining more weight than they had lost, whereas those who lost more than 20% of their body weight during treatment ended up 12% lighter than they had started.
The mechanisms underlying the variances in treatment responses, as well as why not all weight is regained followed treatment discontinuation are not understood. It must also be recognized that these findings were made during a controlled clinical trial of limited duration and may not be as robust in a real-world setting. However, the authors noted that similar findings have been made previously with other weight loss pharmaceuticals that work through different mechanisms than the GLP-1-based drugs. Ultimately, the findings of this study, as well as of related investigations, confirmed that continued use of GLP-1-based weight loss drugs is required to maintain weight loss.
Finally, is weight regain really a bad thing if you end up weighing less than when you started treatment? It has long been known based on pre-Ozempic studies that repeated weight loss followed by weight regain, or so-called Yoyo dieting, is often associated with a weight regain that can exceed the original weight loss over the ensuing 2-5 years. It has further been suggested the body retains a 鈥榤emory鈥� of the original body weight through alterations in gene expression, and that this may occur due to a biological drive to prevent starvation. Whether these findings apply to the weight regain associated with discontinuation of GLP-1-based pharmaceuticals remains to be determined. However, given that weight loss to reduce obesity and its co-morbidities is one goal of these treatments, it seems reasonable to suggest that maintenance of treatment, when feasible, should be strongly encouraged. 聽
Patricia Brubaker, Ph.D., F.R.S.C., F.C.A.H.S. is a Professor Emerita, Departments of Physiology and Medicine at the University of Toronto, Toronto, ON, Canada. Dr. Brubaker completed both her undergrad and PhD at 黑料不打烊 University.
