Adults: approved drugs and their application in clinical practice

Abstract

Obesity is a chronic, complex, and relapsing disease whose understanding has shifted from a volitional paradigm toward a neuroendocrine and metabolic model. Within this transition, the introduction of GLP-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 receptor agonists has reshaped the therapeutic landscape, raising questions that go beyond prescription alone and challenge both the diabetologist and the observer of contemporary cultural processes.

The pivotal evidence supporting this shift is robust and progressive. The STEP 1 trial showed that once-weekly semaglutide 2.4 mg produced a mean body-weight reduction of 14.9%, compared with 2.4% with placebo, at 68 weeks. Building on this evidence, SURMOUNT-5, the first randomized head-to-head trial, demonstrated the superiority of tirzepatide over semaglutide —20.2% versus 13.7% body-weight reduction at 72 weeks— with a greater decrease in waist circumference, positioning dual GIP/GLP-1 receptor agonism as the most potent pharmacological strategy currently available.

However, this efficacy coexists with a central clinical dilemma: the chronic nature of treatment. STEP 4 documented that discontinuation of semaglutide after dose escalation was associated with a 6.9% weight regain, compared with an additional 7.9% weight loss among those who continued therapy. SURMOUNT-4 replicated this pattern with tirzepatide, and a recent post hoc analysis showed that 82% of patients regained more than 25% of the weight they had lost one year after treatment withdrawal.

This debate is further compounded by concerns regarding body composition. A recent network meta-analysis quantified that lean mass loss accounts for approximately 25% of total weight loss with GLP-1 RAs, with the most potent molecules —tirzepatide and semaglutide— being the least effective in preserving lean mass. This finding underscores the need to integrate adequate protein-based nutritional strategies and resistance training into the therapeutic plan.

Finally, no clinical analysis would be complete without addressing the sociocultural phenomenon surrounding these drugs. In February 2026, the Pan American Health Organization issued an epidemiological alert regarding the increase in adverse events associated with the misuse of GLP-1 RAs, warning about their commercialization through unofficial channels and the circulation of falsified products. Studies analyzing different social media platforms have documented the promotion of cosmetic use, associated global shortages, and emerging signals related to mental health. Together, these phenomena configure a scenario in which the medicalization of weight loss exceeds the boundaries of clinical indication and calls upon diabetologists to adopt a role that is simultaneously that of rigorous prescribers and critical mediators in the face of consumer-driven demand