Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: Mechanistic possibilities

We are facing a global epidemic of obesity and type 2 diabetes. Weight loss, in the context of obesity and type 2 diabetes, may improve glycaemic control and weight-related comorbidities, and in some cases, induce diabetes remission. Although lifestyle-based weight loss strategies may be initially successful, most are not effective long-term. There is an increasing need to consider pharmacological approaches to assist weight loss in diabetes-obesity. Older glucose-lowering agents may cause weight gain, whereas the newer drug classes, sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide receptor agonists (GLP-1 RAs), concomitantly target weight loss and glycaemic control. Clinical trial data suggest that both SGLT2i and GLP1 RAs cause a mean weight loss of approximately 2 to 3 kg but real-world evidence and clinical experience suggests a significant heterogeneity in the magnitude of the weight loss (GLP-1 RAs) or the magnitude of the actual weight loss is significantly less than anticipated (SGLT2i). Why do some individuals lose more weight than others in response to these pharmacological treatments? This review will first explore mechanisms by which body weight is regulated through control of energy balance and its dysregulation in obesity, and then consider how these mechanisms may be modulated therapeutically with SGLT2i and GLP1 RAs.