A new era in obesity management

Abstract

2023 was the most memorable year on record for obesity. The American Academy of Pediatrics recognized the complex, multifactorial nature of obesity and the broad range of treatments necessary to care for pediatric patients. The first-ever triple agonist and high-potency oral GLP1 agonist was introduced with unprecedented results.

Obesity, a global pandemic, is pervasive in adult and paediatric patients and necessitates innovative and effective therapeutic strategies^1,2. Yet, only in current years have we seen a shift in the scientific and public discourse towards the consideration of treatment beyond behavioural techniques to address obesity to the current consideration of anti-obesity medications, mainly owing to the marked interest in glucagon-like peptide 1 (GLP1) agonists. It has been well established that weight stigma, defined as pervasive misconceptions and stereotypes associated with higher body weight, is both a social determinant of health and a human rights issue that has been a barrier that prevents persons with the most prevalent chronic disease in human history from receiving adequate care³. Still, current studies have shed light on the potential of multi-target hormone agonists and GLP1 receptor agonists in managing obesity. These studies have offered groundbreaking insights, presenting a hopeful future for obesity research and treatment.

At the beginning of 2023, the American Academy of Pediatrics published its highly anticipated clinical practice guideline (CPG)⁴. This critical paper was their first updated guideline since 2007, underscoring the complexity of obesity as a chronic disease, particularly in the paediatric population. The research highlighted the multifaceted aetiology of obesity, which extends beyond personal lifestyle choices to encompass genetic, physiological, socioeconomic and environmental factors. Furthermore, it emphasized the profound influence of social determinants of health on obesity risk and treatment. This comprehensive understanding of obesity’s intricate nature is vital to the field as it shifts the perspective from a simplistic to a more nuanced view of this pervasive condition.

These findings have substantial implications for practical patient care and research. The resultant CPG is designed to guide paediatricians and other paediatric health-care providers in evaluating and treating children with overweight or obesity considering their health status, family system, community context and treatment resources. This child-centric, multi-faceted approach, supported by robust evidence from controlled and comparative effectiveness trials and high-quality longitudinal and epidemiological studies, can potentially improve the standard of care for this patient population. The CPG’s key action statements and consensus recommendations, informed by expert opinion and an extensive literature review, provide a valuable resource for health-care professionals. This guideline not only influences clinical practice but also paves the way for further research into obesity’s complex nature and effective management.

In the era of GLP1 receptor agonists, there had previously not been an oral option that rivals injectable options for treating obesity. However, Wharton et al. published a study that demonstrated the potential efficacy and safety of orforglipron, a nonpeptide GLP1 receptor agonist, as a daily oral therapy for weight reduction in adults with obesity⁵. In a phase II, randomized, double-blind trial involving 272 participants, the researchers found that the mean change in body weight from baseline at week 26 ranged from −8.6% to −12.6% across the orforglipron dose cohorts, compared with −2.0% in the placebo group. At week 36, the mean change ranged from −9.4% to −14.7% in the orforglipron groups and was −2.3% in the placebo group. This weight reduction was associated with improvements in all prespecified weight-related and cardiometabolic measures.

This study is essential to the field as it provides compelling evidence for using orforglipron as an oral treatment for obesity. Until now, the management of obesity has been a substantial challenge due to the limited availability of effective, safe and easy-to-use therapeutic interventions. Introducing an oral GLP1 receptor agonist like orforglipron could represent a transformative step in obesity treatment, offering a more convenient alternative to injectable therapies. However, it should be noted that the most common adverse events reported with orforglipron were gastrointestinal events, leading to treatment discontinuation in 10–17% of participants across dose cohorts. Overall, these findings not only affect clinical practice by expanding treatment options for obesity but also pave the way for future research exploring similar therapeutic strategies (Fig. 1).

Fig. 1∣. Triple agonism mechanism for glucagon-like peptide 1 agonists.

This figure demonstrates the complexity of single, dual and triple agonism. Single agonism: glucagon-like peptide 1 (GLP1) agonism improves satiety and decreases appetite and food intake, increases lipolysis, slows gastric emptying, reduces hepatic steatosis and lipid content, and increases insulin secretion. Double agonism: GLP1 and glucagon agonism improves body weight, glycaemic control and energy expenditure and reduces cholesterol. GLP1 and glucose insulinotropic polypeptide (GIP) agonism improves glycaemic control, body weight loss and lipolysis. Triple agonism: GLP1, GIP and glucagon agonism reduces body weight, liver fat and fibrosis, and improves glycaemic control, energy expenditure, lipolysis and neuroprotection.

Finally, we saw the introduction of the first-ever triple agonist for treating obesity. The key findings of this study revolved around the efficacy and safety of retatrutide (LY3437943), an agonist of the glucose-dependent insulinotropic polypeptide, GLP1 and glucagon receptors⁶ (Fig. 1). In a phase II, double-blind, randomized, placebo-controlled trial involving 338 adults, Jastreboff et al. observed that the least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups ranged from −7.2% to −17.5%, compared with −1.6% in the placebo group. At 48 weeks, these changes ranged from −8.7% to −24.2% in the retatrutide groups, as opposed to −2.1% in the placebo group. Notably, at 48 weeks, weight reductions of 5% or more, 10% or more and 15% or more had occurred in a marked proportion of the participants who received retatrutide, with the most common adverse events gastrointestinal and dose-related.

This study is particularly substantial as it provides valuable insights into the dose–response relationships of retatrutide concerning side effects, safety and efficacy for treating obesity. Obesity has been identified as a major risk factor for a variety of chronic diseases, and the development of effective therapeutic interventions is of paramount importance. The findings from this study suggest that retatrutide could offer a potent option for weight reduction, potentially affecting patient care and clinical practice markedly. Furthermore, these results could guide future research efforts to optimize the dosing and administration of retatrutide to maximize its therapeutic benefits while minimizing adverse events.

Current advancements in obesity treatment have led to substantial improvements in patient outcomes. However, there is an urgent need to address the disparities in access and quality of obesity care⁷. Disparities in access and quality of care could negate the benefits of innovative obesity treatments worldwide^8,9. The disparities are particularly pronounced in paediatric populations, in which racial inequities in obesity treatment are evident¹⁰. There is a need for concerted efforts to address disparities in obesity care, particularly in the light of current advances in treatment modalities.

Key advances.

• The American Academy of Pediatrics published its first updated clinical practice guideline in 15 years, recognizing the complex, multifactorial nature of paediatric obesity and embracing the full range of treatment modalities, including lifestyle, pharmacotherapy, and metabolic and bariatric surgery⁴.

• High-potency GLP1 agonism could only be delivered in injectable form until the oral GLP1 orforglipron study demonstrated similar efficacy to its injectable counterparts⁵.

• For the first time, phase II clinical trial results demonstrated that triple-agonist, an agonist of the glucose-dependent insulinotropic polypeptide, GLP1 and glucagon receptors, retatrutide showed higher total body weight loss than any agent prior⁶.