Perspectives in weight control in diabetes – SGLT2 inhibitors and GLP-1–glucagon dual agonism

Treatment of people with type 2 diabetes mellitus (T2D) and obesity should include glycemic control and sustained weight loss. However, organ protection and/or risk reduction for co-morbidities have also emerged as important goals. Here, we define this combined treatment approach as ‘weight loss plus’ and describe it as a metabolic concept where increased energy expenditure is central to outcomes. We suggest there are currently two drug classes – sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1)–glucagon dual agonists – that can facilitate this ‘weight loss plus’ approach. We describe evidence supporting that both classes address the underlying pathophysiology of T2D and facilitate normalization of metabolism through increased periods of energy expenditure, which effect other organ systems and may facilitate long-term cardio-renal benefits. These benefits have been demonstrated in trials of SGLT2is, and appear, to some degree, to be independent of glycemia and substantial weight loss. The combined effect of caloric restriction and metabolic correction facilitated by SGLT2i and GLP-1–glucagon dual agonists can be conceptualized as mimicking dietary restriction and physical activity, a phenomenon not previously observed with drugs whose benefits predominantly arise from absolute weight loss, and which may be key to achieving a ‘weight loss plus’ approach to treatment