Innovation and pharmacological alternatives for use in people living with obesity

Abstract

Pharmacological therapeutics for obesity are undergoing an unprecedented revolution, driven by high neuroendocrine precision in the regulation of energy homeostasis¹. In this context, new pharmacological alternatives are completely redefining the management of this disease.

Among injectable treatments, multireceptor molecules have demonstrated magnitudes of weight loss comparable to bariatric and metabolic surgery, associated with cardiovascular, renal, and hepatic benefits. GLP-1 and glucagon co-agonists (survodutida, pemvidutida, and mazdutida) combine the incretin effect with the capacity of glucagon to increase energy expenditure and hepatic lipid oxidation, positioning themselves as key tools in metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Similarly, retatrutida, a GLP-1, GIP, and glucagon tri-agonist, marks a milestone in weight-loss efficacy with reductions close to 20%, along with metabolic optimization. For its part, maridebart cafraglutida (MariTide), a peptide-antibody conjugate combining GLP-1 agonism with GIP antagonism, introduces an innovative monthly dosing schedule with 16.2% weight loss and robust metabolic protection^1-3.

Likewise, long-acting amylin analogs regulate food intake through circuits independent of incretins. This group ranges from selective (eloralintida) and non-selective (cagrilintida and petrelintida) amylin receptor agonists to unimolecular co-agonists (such as zenagamtide or amicretina, which combines semaglutide with a non-selective amylin analog achieving a weight reduction close to 24%) or bimolecular combinations (cagrilintida with semaglutide)^1-3. 

In the pursuit of high-quality weight loss, preserving lean mass using anabolic or anticatabolic agents becomes particularly valuable. Among them, bimagrumab (an activin type II receptor antagonist) selectively reduces fat mass while promoting muscle accretion and development^1-3.

On the other hand, oral therapies drive a key paradigm shift in adherence and accessibility. Non-peptide small molecules, such as orforgliprón (a high-affinity partial GLP-1 receptor agonist), eliminate the stringent fasting conditions required for peptide molecules (such as oral semaglutide), simplifying daily dosing, optimizing costs, and overcoming manufacturing and distribution barriers^1-3.

However, evidence confirms that treatment discontinuation leads to weight regain and the return of cardiometabolic risk; therefore, the true challenge transcends molecular sophistication and demands ensuring equitable global access, therapeutic sustainability, and articulation from primary care¹.