Milestones in the journey towards addressing obesity; Past trials and triumphs, recent breakthroughs, and an exciting future in the era of emerging effective medical therapies and integration of effective medical therapies with metabolic surgery

Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies

“…The so far ubiquitous failure of phase 3 agents has been suggested to be irrespective of the endpoint, whether clinical, histological, or HVPG outcome-driven (Chalasani et al, 2020;Garcia-Tsao et al, 2020;Harrison et al, 2020b;Harrison et al, 2022a). We speculate that adding cardiometabolic outcomes and pronounced BW loss (>10%) to the spectrum of requirements for MASLD/MASH pharmacological interventions could provide extrahepatic benefits and improve overall clinical outcomes Vuppalanchi et al, 2021;Kokkorakis et al, 2023c).…”

“…Therefore, medical or surgical interventions should be considered if the desired weight loss cannot be achieved with lifestyle. Bariatric surgery, although typically reserved for patients with prevalent metabolic comorbidities, has proven a very effective treatment option for MASLD/MASH, associated with risk reduction for major adverse CV events (Fakhry et al, 2019;Aminian et al, 2021;Seeberg et al, 2022;Kokkorakis et al, 2023c;Verrastro et al, 2023) (Table 2). The need for specific pharmacological treatment for MASLD is supported by the fact that BW loss is a very elusive target, which is also difficult to sustain (Evert and Franz, 2017;Muzurović et al, 2020;Yan et al, 2022).…”

“…Leptin is a targeted pharmacotherapy for situations of lipoatrophy with leptin deficiency and requiring leptin replacement therapy (Kokkorakis et al, 2023c). Specifically, leptin therapy in the form of recombinant-human-methionyl-leptin metreleptin, administered by subcutaneous injections for 12 months, was examined in common forms of MASLD (NCT01679197), on the basis that recombinant leptin therapy reverses MASH in leptin-deficient lipodystrophy (Akinci et al, 2021).…”

“…There is a current paradoxical lack of national MASLD clinical guidelines and a pronounced lack of inclusion of MASLD in the treatment strategies for related cardiometabolic conditions such as T2DM (Lazarus et al, 2022b). Documenting all burdens associated with SLD could raise public awareness regarding the link between obesity and MASLD (Polyzos et al, 2019a;Kokkorakis et al, 2023c).…”

Effective questionnaire-based prediction models for type 2 diabetes across several ethnicities: a model development and validation study

“…The number of individuals living with type 2 diabetes mellitus (T2D) is rapidly increasing globally, driven by factors such as ageing, urbanisation, sedentarism, and the increasing prevalence of obesity. 1 , 2 In 2019, diabetes accounted for 66.3 million disability-adjusted life years (DALYs) and 4.2 million deaths among adults worldwide, 3 with disproportionately steep prevalence and complications among non-White ethnic minorities in low-income and middle-income countries. 4 …”