This is an innovative and original study proposal due to the following aspects:
1) The contribution of long-term GLP-1 receptor agonism, alone or combined with intensive personalized nutrition and physical activity interventions, acting on the GLP-1 system, to metabolic benefits and body weight reduction in people with obesity and type 2 diabetes mellitus (T2DM), is novel and has not been studied previously;
2) This approach has major clinical implications, as pharmacotherapy is effective only when combined with dietary interventions, given the biology of obesity and its redundant mechanisms, as a chronic disease;
3) The study is designed as randomized, controlled and statistically powered to detect clinically relevant changes in the primary outcomes;
4) The study will evaluate the efficacy of once-weekly subcutaneous administration of semaglutide in a real-world setting, when added to current standard antidiabetic therapy for patients with T2DM;
5) The data from this study can provide evidence to support decision-making by clinicians, payers, and policymakers in routine clinical practice;
6) Strategies used to mitigate operational challenges encountered due to the pragmatic nature of the study can inform the design of future pragmatic clinical trials in diabetes and other chronic diseases;
7) Will demonstrate that intensive personalized and structured nutritional advice, in combination with standard care, will produce clinically meaningful weight loss, similar to that produced by semaglutide.
The proposed DiaBEZ project is timely, utilizes novel technologies and integrated approaches not used in previous studies, accumulating expertise in nutrition, physiology, metagenomics, and bioinformatics, and will help highlight the translational potential of personalized medicine as an attractive tool or target for the development of more effective therapeutic interventions for obesity and diabetes.
Potential impact of the project. This project will have a significant scientific impact on our understanding of the effects of the GLP-1RA semaglutide on obesity and diabetes. Second, the data will improve our understanding of how specific diets and exercise can be used to effectively modulate the GLP-1 system to improve metabolic parameters associated with obesity and diabetes. Third, the project will generate knowledge about specific bacterial strains that mediate physiological processes and gut hormones with a major role in satiety, energy regulation, glucose and lipid metabolism. It will have a societal impact by providing evidence from clinical trials showing that manipulation of gut hormones such as GLP-1 and microbiota, through GLP-1 agonism, diet and exercise, can influence host metabolism and improve parameters associated with obesity and type 2 diabetes.