When should they be used?
The new incretin-based medications are a class of antidiabetic drugs that stabilize blood glucose by stimulating insulin secretion and suppressing glucagon production in the body in response to energy intake. In addition to hypoglycemic effects, some of these drugs (i.e., liraglutide, semaglutide, and tirzepatide) combined with lifestyle changes have shown themselves to be highly effective in facilitating weight control and have been approved by the Food and Drug Administration (FDA) for the chronic management of obesity.
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In people with obesity or overweight with weight-related comorbidities (but not with diabetes), liraglutide 3 mg, a glucagon-like peptide-1 receptor agonist (GLP-1RAs), reduced baseline body weight by 8% up to 56 weeks, while semaglutide 2,4 mg, another GLP-1RAs, produced a weight loss of 15% up to 2 years. The two drugs decrease energy intake mainly by modifying hunger and satiety signals in specific neural regions and slowing gastric emptying. Tirzepatide 15 mg, a dual agonist for glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors,which has synergistic effects on appetite, energy intake, and fat mass, produced an average weight loss of 20.9% after 72 weeks.
Semaglutide 2,4 has also been shown to produce a reduction of the 20% risk of heart attack or stroke in non-diabetic patients who are overweight or obese with established cardiovascular disease. Furthermore, it has been shown to improve symptoms, physical limitations, and exercise function and reduce inflammation and body weight in patients with obesity and heart failure with preserved ejection fraction.
Despite these important positive clinical effects, some problems are associated with the use of the new weight loss drugs:
Side effects. Common medication side effects include nausea, abdominal pain, vomiting, diarrhea, and constipation. These side effects can sometimes get better over time, but at least 10% of patients who start these drugs have to be taken off of them because the side effects do not improve. It is also worth underlining that these drugs can also be associated with rare but more serious side effects (e.g., pancreatitis, hypoglycemia, diabetic retinopathy complications, gastroparesis, and bowel obstruction. Research on the long-term use of these drugs is ongoing, and additional side effects may continue to be discovered.
Weigh regain. The weight loss with semaglutide reaches a plateau after 62 weeks, and two-thirds of the weight is regained if the drug is discontinued. A similar rate of weight regain has also been observed after the discontinuation of tirzepatide. These data indicate that for the management of clinical obesity, they should be used as “lifetime drugs.” However, no data on the long-term effects of weight loss and health are available.
High cost. The drugs are costly (up to $1300/month in the US) and are not usually reimbursed by health insurance. The use of these drugs, therefore, is an expensive therapy that’s unaffordable for many people with higher weight.
Potential development and worsening of eating disorders and negative impact on their treatment. The use of new weight loss drugs, increasing satiety, decreasing hunger, and producing in some persons nausea, vomiting, and diarrhea can exacerbate extreme and rigid dietary restriction and the development or worsening of eating disorder psychopathology. Furthermore, the effects of these drugs on satiety/hunger could also negatively impact the treatment of an eating disorder that requires the intake of regular meals and snacks. GLP-1ARs have not been approved for the treatment of any eating disorder symptoms and, to date, misuse of these drugs has not yet been published. However, some authors have observed problematic use in their clinical practices, and warnings and calls to action have already been made regarding their potential misuse in adolescents with eating disorders. The current parenteral administration of these weight loss drugs discourages their misuse, but when oral formulations are available, their unsupervised use is almost inevitable. On the other side, these drugs seem to reduce binge eating in patients with obesity without diabetes. However, the results of the only randomized control trial in patients with binge-eating disorder using liraglutide were limited by an incorrect randomization of some participants.
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The above data and considerations suggest some clinical guidelines for using GLP-1ARs drugs in the treatment of patients with binge-eating disorder and obesity.
GLP-1ARs should not be indicated for the treatment of binge-eating disorder or for reducing binge-eating episodes. Indeed, their prescription in the initial phase of recommended treatment for eating disorders could exacerbate dysfunctional dieting and hinder the implementation of the regular eating procedure, a key strategy to address binge-eating episodes. The only exception is for patients with binge-eating disorder who are already taking these drugs for the management of type 2 diabetes and who will need to continue their use.
A more complex decision to make is with patients who are using GLP-1AR drugs to lose weight. Indeed, the suspension of these drugs could determine an increase in body weight. At the same time, its continuing use will prevent the learning of specific psychological strategies and procedures for addressing binge-eating episodes and other eating disorder psychopathology. The pros and cons of interrupting the drug should be discussed with the patient in these cases. If the patients decide to continue using the drugs, their decision should be respected. However, it must be underlined that their use should not be an obstacle to adopting regular eating procedures and other procedures to address dysfunctional dieting. On the contrary, patients who decide to suspend the weight loss drugs should be helped to address the binge-eating episodes, dysregulated eating, and overeating with habitual cognitive behavior strategies and procedures.
After the remission of binge-eating episodes, if the patient wishes to lose a reasonable amount of weight (i.e., the patient has a presence of obesity and absence of overvaluation of shape and weight) and has difficulties in adhering to the flexible and moderate dietary restriction, it should be evaluated with them what the pros and cons are for using the GLP-1AR drugs, as they are effective in the management of clinical obesity and their cardiometabolic complications. In these cases, patients need to receive detailed information on the side effects of these drugs, their cost, the need for lifetime use, and the risks of adopting extreme dieting that could promote the reactivation of binge-eating episodes and other eating disorder psychopathology. It is also important to recommend that patients be periodically followed by a physician who is an expert in managing clinical obesity, GLP-1AR drugs, and binge-eating disorder.
References
Bartel S, McElroy SL, Levangie D, Keshen A. Use of glucagon-like peptide-1 receptor agonists in eating disorder populations. Int J Eat Disord. 2023. doi: 10.1002/eat.24109.
Cooper DM, Rothstein MA, Amin A, Hirsch JD, Cooper E. Unintended consequences of glucagon-like peptide-1 receptor agonists medications in children and adolescents: A call to action. J Clin Transl Sci. 2023;7(1):e184. doi: 10.1017/cts.2023.612.
Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022. doi: 10.1056/NEJMoa2206038.
Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-32. doi: 10.1056/NEJMoa2307563.
Wharton S, Batterham RL, Bhatta M, Buscemi S, Christensen LN, Frias JP, et al. Two-year effect of semaglutide 2.4 mg on control of eating in adults with overweight/obesity: STEP 5. Obesity. 2023;31(3):703-15. doi: 10.1002/oby.23673.
Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553-64. doi: 10.1111/dom.14725.
