New horizons in the drug treatment of obesity

Summary

Only modest or transient weight loss achieved with most anti-obesity medications available in the past failed to meet expectations of both patients and physicians. Drug combinations and gut hormone analogues represent a new, more efficient and safe approach to the treatment of obesity and related health risks. Initially, gut hormone analogues, e.g. glucagon like peptide-1 (GLP-1) agonist liraglutide, have successfully been applied for the treatment of type 2 diabetes and later on for the treatment of obesity. The paper reports on the phase 3 clinical trials in obesity management with novel gut hormone analogues, GLP-1 agonist semaglutide and dual gut hormone agonist tirzepatide, a single molecule which targets receptors of two gut hormones, GLP1-1 and glucose-dependent insulinotropic polypeptide (GIP). Both semaglutide and tirzepatide are applied subcutaneously once-weekly. Weight loss achieved with these new drugs, particularly with tirzepatide, is comparable to that observed with less invasive bariatric procedures and is accompanied by significant improvements in cardiometabolic risks and favorable safety profile. Observed gastrointestinal adverse events with these medications were usually transient and mild to moderate in severity. Semaglutide has been approved as an anti-obesity drug for long-term weight management by the European Medicines Agency (EMA) while tirzepatide is waiting for its approval. Clinical studies with oral semaglutide, triple incretin agonist retatrutide, non-peptide GLP-1 oral agonist orforglipron and cagrilintide/semaglutide combination also provided promising results in the weight management. On the other hand, setmelanotide is a drug that acts on the melanocortin-4 receptor (MC4R) and is designated for the treatment of very rare monogenic disorders exhibiting severe obesity in early childhood, e.g. deficiency of proopiomelanocortin or leptin receptor. Individually tailored treatment with antiobesity drugs should be an integral part of the comprehensive obesity management which includes diet, exercise and cognitive behavioral intervention. Well educated physicians should ensure the success of treatment by antiobesity drugs. In addition, health authorities and health insurance companies should consider that the cost of new antiobesity drugs prevents such efficient treatment in most of indicated patients and therefore the measures to arrange appropriate availability of these drugs should be adopted.

Keywords:

semaglutide – Weight loss – antiobesity drugs – tirzepatide – setmelanotide – gut hormone analogues – cardiometabolic risks