Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient efficacy and dubious safety.
Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing obstacles. Recent advances, including increased understanding of the molecular gut-brain communication, are inspiring the pursuit of next-generation AOMs that appear capable of safely achieving sizeable and sustained body weight loss.
…The pursuit of anti-obesity medications (AOMs) has been tremendously challenging for technical and societal reasons. Only in the last 2 decades has the definition of the molecular mechanisms that control appetite (Box 1; Figure 2) advanced to a point where drug discovery can be rationally pursued. Historically, there has been a collection of AOM failures that have occurred after regulatory approval. Most of these pertain to adverse cardiovascular effects (sibutramine, fenfluramine, dexfenfluramine, rainbow pills), increased suicidal risk (rimonabant) or enhanced likelihood of drug dependence and abuse (methamphetamine) (Table 1). As such, certain drugs are recommended only for short-term use, due to addictive potential or emergence of tachyphylaxis (phentermine, amfepramone, cathin hydrochloride). Nonetheless, phentermine has not shown adverse cardiovascular outcomes in real-life studies and remains a commonly prescribed long-term AOM.
…to achieve body weight normalization along with suitable tolerability and safety remained an insurmountable challenge. However, recent clinical trials with advanced therapeutic candidates including glucagon-like peptide 1 receptor (GLP1R) agonism are promoting the belief that breakthrough, drug-based management of obesity may be possible. On 4 June 2021, the US Food and Drug Administration (FDA) approved semaglutide 2.4 mg for chronic weight management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure or cholesterol, or T2D), for use in addition to a reduced-calorie diet and increased physical activity. This now constitutes the second GLP1R agonist registered for body weight management, as liraglutide 3 mg was approved by the FDA in 2014 for treatment of adult obesity and in 2020 for obesity in adolescents aged 12–17 years.
With the exception of semaglutide 2.4 mg, the average percentage body weight reduction for currently registered drug treatments varies in the single-digit range, with only a small fraction of subjects capable of achieving and maintaining >10% loss at tolerable doses (Figure 3). Although such weight loss is clinically meaningful, and serves to improve the severity of comorbid diseases, it is paltry when viewed against the efficacy of bariatric surgery. An ideal AOM should sizeably and sustainably correct excess weight while reducing the risk of CVD and other comorbidities, devoid of the potential for abuse, tachyphylaxis and other adverse effects that have historically plagued this field. It is a lofty goal and, at times, still challenged by the question of whether obesity itself constitutes a disease worthy of chronic drug therapy.
…The recent precedent-setting results with semaglutide and tirzepatide, in which each reported mean weight loss well in excess of 10%, employing a GLP1 mechanism that has separately proven to improve cardiovascular outcomes in T2D studies, inspires confidence for the future.