Future therapies for obesity

[madman]

Obesity is a chronic disease associated with increased morbidity and mortality. Bariatric surgery can lead to sustained long-term weight loss (WL) and improvement in multiple obesity-related complications, but it is not scalable at the population level. Over the past few years, gut hormone-based pharmacotherapies for obesity and type 2 diabetes mellitus (T2DM) have rapidly evolved, and combinations of glucagon-like peptide 1 (GLP1) with other gut hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) as dual or triple agonists are under investigation to enhance and complement the effects of GLP1 on WL and obesity-related complications. Tirzepatide, a dual agonist of GLP1 and GIP receptors, marks a new era in obesity pharmacotherapy in which a combination of gut hormones could approach the WL achieved with bariatric surgery. In this review, we discuss emerging obesity treatments with a focus on gut hormone combinations and the concept of a multimodal approach for obesity management.




*Oral GLP1 RAs


*Combination of gut hormones




Emerging pharmacotherapies for obesity

*Dual-agonism GLP1 and GIP

*Tirzepatide




Pharmacotherapies in the pipeline based on gut hormone combinations with GLP1

*Dual agonism with amylin

*Dual agonism with glucagon

*Triple agonism (GLP1/GIP/glucagon)

*GIP antagonists in combination with GLP1 RAs




*Other pharmacotherapies in the pipeline not based on gut hormones


*A new era in obesity management and considerations for novel and future pharmacotherapies




Conclusion

Tirzepatide, the first approved dual agonist (GLP1 and GIP receptors) for T2DM management, also marks a new era for obesity pharmacotherapies, where mean WL approaches that of bariatric surgery. Multiple other gut hormone combinations are under investigation as potential future therapies for obesity and metabolic complications. Between them, CagriSema and the triple agonist retatrutide are the furthest advanced in clinical development and have progressed to phase III trials. Additional research assessing the long-term safety, clinical effectiveness and cost-effectiveness of new and future obesity pharmacotherapies will help us understand better their position in treatment algorithms for WL and obesity-related complications, as part of an integrated multimodal approach aiming to support people with obesity achieving and maintaining individualised WL and metabolic targets.

 

[madman]

Fig 1. The mean weight loss achieved at approximately 1 year follow-up with moderate-intensity lifestyle interventions (500 kcal/day deficit diet and advice to exercise for 150 min/week), currently available pharmacotherapies (and tirzepatide) and bariatric surgery in people without diabetes. *Not approved yet for obesity management; **approved in the USA, but not in Europe.

 

[madman]

Fig 2. Pharmacotherapies under investigation based on a combination of glucagon-like peptide 1 (GLP1) with other gut hormones and the actions related to agonism of each gut hormone and antagonism of glucose-dependent insulinotropic polypeptide (GIP). PYY = Peptide YY; *action in preclinical models; **clinical data not available yet.

 

[madman]

Table 1. Efficacy of tirzepatide 5, 10 and 15 mg in phase III global clinical trials for type 2 diabetes mellitus and obesity management

 

[madman]

Table 2. Efficacy in early-phase clinical trials with pharmacotherapies based on combinations of gut hormones

 

[madman]

Key points

*A better understanding of the role of gut hormones in the regulation of appetite and glucose homeostasis has led to the discovery of glucagon-like peptide 1 (GLP1) receptor analogues (RAs), which are established treatments for obesity and type 2 diabetes mellitus (T2DM).

*In the search for the next generation of obesity pharmacotherapies, multiple combinations of GLP1 receptor agonists with other gut hormones (amylin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon) with diverse metabolic actions are under development as dual or triple agonists.

*Tirzepatide 5–15 mg is the first dual GLP1 and GIP receptor agonist approved for T2DM management and, in people with obesity without diabetes, resulted in up to a 20.9% weight loss with good tolerability (phase III trial data).

*The combination of the amylin analogue cagrilintide with the GLP1 RA semaglutide 2.4 mg (CagriSema) as well as the triple agonist (GLP1/GIP/glucagon) retatrutide could bridge further the efficacy gap between bariatric surgery and pharmacotherapies; both drugs have progressed to phase III trials.

*Oral GLP1 receptor analogues (oral semaglutide and danuglipron) are also under investigation as potential obesity treatments.

*The long-term safety, clinical effectiveness and cost-effectiveness of novel and future pharmacotherapies for obesity and T2DM require further evaluation to help us understand better their position in treatment algorithms.

 

[madman]

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