New Approaches to Obesity Treatment

Obesity is a chronic systemic relapsing disease associated with multiple physical and mental complications, including coronary heart disease, heart failure, hypertension, atrial fibrillation, diabetes mellitus, sleep apnea, nonalcoholic fatty liver disease, depression, and many others.

Obesity is based on an imbalance between energy intake and expenditure. This interaction is regulated by a complex network of hormones, brain centers, and environmental influences. All approaches to obesity management aim to restore this balance.

Recommendations regarding lifestyle, nutrition, and physical activity have a limited effect in many patients and often do not allow the desired weight to be maintained over the long term.

Obesity is becoming increasingly prevalent and, in many countries, represents a serious challenge for the healthcare system as a whole. Today, there are approximately 650 million patients with obesity worldwide. Because of its complex constellation of metabolic disorders, obesity leads to reduced life expectancy and premature death.

Recent studies of the pathophysiology of obesity have led to the development of a range of promising pharmacological agents that guarantee effective and sustained weight loss while also treating comorbidities associated with obesity. At the same time, expanding knowledge of obesity metabolism and the emergence of a range of medications are contributing to the development of a precision-medicine approach.

The purpose of this review is to provide additional information on approved centrally acting anti-obesity medications, considering not only metabolic and cardiovascular effects but also less-studied clinical benefits and disadvantages of their use, in order to expand the pharmacological options for chronic weight management.

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Current Anti-Obesity Medications

Anti-obesity medications (AOMs) are prescribed in combination with a low-calorie diet and increased physical activity in people with a body mass index (BMI) ≥30 kg/m2 and with obesity-related comorbidities such as type 2 diabetes, hypertension, and dyslipidemia.

Currently, five AOMs are approved in the United States for chronic weight management:

• liraglutide;
• orlistat;
• naltrexone/bupropion;
• phentermine/topiramate;
• semaglutide/Ozempic.

In Europe, liraglutide, orlistat, and naltrexone/bupropion are approved. One medication is approved in China (orlistat). All of the listed medications have different mechanisms of action leading to weight loss.

One of the mechanisms of weight reduction involves the incretin hormone system. The principal representative of this group is glucagon-like peptide 1 (GLP-1). GLP-1 combines a unique set of properties: it regulates blood glucose levels, slows digestion, prolongs satiety, and reduces food cravings. GLP-1 is a hormone released from the proglucagon gene in L-cells of the distal small intestine and colon in response to oral nutrient intake. GLP-1 binds to GLP-1 receptors expressed in pancreatic beta cells, gastric mucosa, kidneys, heart, and hypothalamus. GLP-1 stimulates insulin release and secretion in hyperglycemic states, slows gastric emptying, and reduces food intake.

Liraglutide and semaglutide were the first medications with this mechanism of action to be approved for use.

Semaglutide is a GLP-1 receptor agonist. The medication was recently approved by the US Food and Drug Administration (FDA) for weight management.

The STEP (Semaglutide Treatment Effect in People with obesity) clinical trial program evaluated once-weekly subcutaneous semaglutide 2.4 mg in patients with overweight or obesity. Among the other analogues, semaglutide demonstrated the greatest weight-loss efficacy — approximately 15% of initial body weight over 68 weeks. In addition, reductions in cardiovascular risk factors and improvements in overall physical functioning were observed. The most common adverse effects were transient mild-to-moderate gastrointestinal events that generally resolved without treatment discontinuation. Semaglutide has a long half-life, requiring injection only once weekly, which makes its use convenient for patients.

Tirzepatide deserves separate attention as a dual agonist acting on two polypeptide pathways of metabolism. It is a synthetic analogue of GLP-1 and gastric inhibitory polypeptide (Glucose Dependent Insulinotropic Peptide — GIP). By influencing appetite regulation and energy balance, tirzepatide provides greater efficacy compared with single-target treatment approaches. In addition, in clinical trials tirzepatide demonstrated high efficacy in blood glucose regulation and the treatment of nonalcoholic fatty liver disease.

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Conclusion

It should be taken into account that obesity harms not only somatic but also mental health, aggravating conditions such as depression and anxiety. By reducing food cravings and stabilizing mood, AOMs demonstrate broad potential for improving mental health as well. A number of studies also support a protective effect of AOMs in the development of neurodegenerative diseases such as Alzheimer disease and parkinsonism.

Obesity is a more complex problem than simply excess weight. A comprehensive approach to treating this multifactorial disease draws attention to a new group of centrally acting AOMs with multitarget effects on the metabolic system as a whole.

References

1. Chao AM, Tronieri JS, Amaro A, Wadden TA. Semaglutide for the treatment of obesity. Trends Cardiovasc Med. 2023;33(3):159-166. https://doi.org/10.1016/j.tcm.2021.12.008

2. Bergmann NC, Davies MJ, Lingvay I, Knop FK. Semaglutide for the treatment of overweight and obesity: A review. Diabetes Obes Metab. 2023;25(1):18-35. doi:10.1111/dom.14863

3. Guglielmi V, Bettini S, Sbraccia P, et al. Beyond Weight Loss: Added Benefits Could Guide the Choice of Anti-Obesity Medications. Curr Obes Rep. 2023;12(2):127-146. doi:10.1007/s13679-023-00502-7