Use of weekly GLP-1 agonists as anti-obesity medications: challenges about their effective and safe use in clinical practice and their potential therapeutic applications beyond weight loss

Obesity, a chronic, multifactorial, relapsing disease, is associated with an increased risk for multiple medical conditions and is closely linked to excess mortality. The worldwide prevalence of obesity has more than tripled since 1975, with 3 billion people living nowadays with eirher overweight or obesity. Therefore, obesity, a global epidemic, has emerged as one of the most important public health problems facing the world today with a significant impact on healthcare systems and society in general.

To date, lifestyle interventions, encompassing dietary changes and regular physical activity, have been the cornerstone of treatment for obesity, but they have limited long-term efficacy and durability of weight loss for the vast majority of people. Bariatric surgery, albeit highly effective, has remained profoundly underutilised because of several factors. Until recently, the history of pharmacotherapy for weight loss has been marked by withdrawal of numerous medications for safety reasons in combination with limited efficacy, limiting its use to selected cases.

Since 2021, the advent of semaglutide, combing unprecedented efficacy for weight loss with good safety profile, has dramatically changed the landscape of obesity management. It has generated widespread publicity and huge demand, leading to global shortage of supply. In recent years, there has been an exponential rise in prescription of two weekly injectable anti-obesity medications (AOMs), semaglutide and tirzepatide, which produce a greater than 10% placebo-subtracted weight loss in most people. However, several questions remain unanswered about the optimal use of these medications in clinical practice, including uncertainties about predictors of response, optimal duration of treatment and issues about discontinuation, personalizing care, and possible long-term or rare side effects.

In addition, emerging evidence suggests that they can improve clinical outcomes and have direct benefit on weight-related comorbidities, including cardiovascular disease, heart failure, metabolic dysfunction-associated liver disease and obstructive sleep apnea. Numerus studies are also currently their potential application on other medical conditions, such as neurodegenerative diseases and addictions. The impact of these promising agents on the progression and clinical outcomes in a wide variety of conditions remains to be determined.

This research topic aims to explore various aspects of the effectiveness and safety of weekly, injectable AOMs, namely semaglutide and tirzepatide, in day-to-day clinical practice.

This entails numerous questions which have arisen regarding their optimal use, including great heterogeneity of response and factors underlying, duration of use, timing / mode / sequalae of drug discontinuation, different titration/dosing regimens, personalizing use, real-world data, outcomes in subpopulations with specific obesity phenotypes, and long-term safety profile and potential, unknown yet, adverse events.

The other key objectives are to gain further insights
(i) in the impact of these agents on clinical outcomes in patients with obesity and weight-related comorbidities
(ii) in the potential future therapeutic applicability to other medical conditions.

The remit of this research topic would be limited to semaglutide and tirzepatide, without extending neither to other, currently available AOMs nor to novel AOMs in the research pipeline.

We’d welcome articles in the following, but not limited to, subtopics:

- Efficacy for weight loss, including predictors, durability, titration/dosing regimens
- Duration of use and issues related to discontinuation
- Safety profile and adverse events
- Real-world data on the effectiveness and safety of GLP-1 agonists for weight loss
- Challenges and guidance about real-world use of GLP-1 agonists
- Evidence/perspective on personalizing use of GLP-1 agonists for weight loss
- Lifestyle modifications in combination with pharmacotherapy
- Use of GLP-1 agonists as AOMs in specific subpopulations
- Effect of GLP-1 agonists on the clinical outcomes in weight-related comorbidities, ranging from cardiovascular disease and obstructive sleep apnea to osteoarthritis and liver disease
- Potential therapeutic application of GLP-1 agonists to various medical conditions, such as neurological diseases and addictions