# Resistant and Refractory Obesity: The Complexity of Anti-Obesity Therapy Failure

## TL;DR

This review explores why some obesity treatments fail in real-world settings, highlighting factors like mental health, environment, and genetics that affect treatment outcomes.

## Contribution

The paper provides a comprehensive analysis of the multifactorial causes of anti-obesity therapy resistance and refractoriness.

## Key findings

- Psychiatric comorbidities and socioeconomic factors significantly impact the effectiveness of anti-obesity medications.
- Genetic and immunological factors, such as pharmacogenomic variants and antidrug antibodies, contribute to therapy resistance.
- Personalized management strategies are needed to improve outcomes for difficult-to-treat patients.

## Abstract

Pharmacotherapy is a key component of obesity management, yet treatment failure remains a prevalent challenge in clinical practice. Such failure may present as insufficient pharmacological response, early discontinuation, or post-treatment weight regain, underscoring the discrepancy between clinical trial efficacy and real-world outcomes. The effectiveness of anti-obesity medications (AOMs) is influenced by psychiatric comorbidities, including depression, anxiety, and disordered eating patterns, as well as environmental and socioeconomic factors such as limited healthcare access, weight-related stigma, and high medication costs. Individual characteristics, including physical activity, body composition, visceral adiposity, and microbiome profile, further modulate treatment outcomes. Pharmacokinetic and pharmacotherapeutic limitations such as drug-phenotype mismatch, route of administration, suboptimal formulations, and exposure to counterfeit products also compromise efficacy. No less important are genetic and immunological factors, comprising pharmacogenomic variants of both incretin and melanocortin receptors along with antidrug antibodies (ADAs), which may constitute therapy resistance. Concomitant medications and comorbid endocrine disorders can additionally attenuate weight-loss effects. The objective of this review is to characterize the multifactorial nature of resistance and refractoriness to anti-obesity therapy, and the importance of identifying pretreatment predictive factors for recognizing individuals at risk of inadequate or lack of response, thereby enabling personalized management strategies and improving long-term clinical outcomes, particularly in “difficult-to-treat” patients.