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

Abstract

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 glucagonlike 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. KEYWORDSGLP-1 receptor agonists, obesity, SGLT2 inhibitors, type 2 diabetes, weight loss | INTRODUCTIONObesity has a critical role in the development and progression of type 2 diabetes (T2DM). With the rising prevalence of obesity, the excess risk of T2DM with even modest weight gain is significant, increasing exponentially relative to body mass index (BMI), in men and women. 1,2 A BMI of 25 kg m −2 is associated with a 2-and 8-fold increased risk of T2DM in males and females, respectively; a BMI of 35 is associated with a 42-and 93-fold increased risk, respectively. 3The pathophysiology of T2DM is thought to be mediated by ectopic fat deposition (in visceral fat, skeletal muscle, liver, pancreatic β-cells, and other organs), as subcutaneous fat expansion becomes ---This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial

“…While indirect comparisons across clinical trials should be interpreted with caution, given the heterogeneity of the study populations, these findings suggest that body composition changes with semaglutide are consistent with those in previous studies of other GLP-1RAs. These changes are supported by the proposed mechanisms of weight loss with GLP-1RAs through appetite modulation via the central nervous system with minimal effect on energy expenditure [42,43], as well as through the increase of natriuresis caused by inhibition of the sodium-hydrogen ion transporter in the proximal tubule, which subsequently reduces sodium retention and extracellular fluid volume expansion [44]. An additional mechanism may be nausea/vomiting, which was Multiple imputation was used where missing data were imputed using observed data from participants within the same group defined by randomised treatment, using a regression model including region and stratification factor as categorical effects and data from baseline and all previous visits as covariates…”

Drug Therapy in Obesity: A Review of Current and Emerging Treatments

“…Interestingly, as a result of the enhanced glycosuria mediated by this class of medications, they are associated with an increased urinary loss of about 60-100 g of glucose (200-300 kcal) per day [59]. One meta-analysis reported a mean weight loss of 2.1-2.7 kg associated with their use from phase III clinical trials in people with T2D [60]. The EMA and FDA have approved several drugs in this class of medication for the treatment of T2D including dapagliflozin, empagliflozin, canagliflozin and ertugliflozin.…”

Glycaemic and non‐glycaemic efficacy of once‐weekly GLP‐1 receptor agonists in people with type 2 diabetes

“…SGLT2is prevent the reabsorption of glucose from the filtrate in the kidney and thus reduce overall blood sugar levels 56,57 . Consequently, this depletion of glucose and its associated calories in people with T2D with increased blood glucose mean that SGLT2is are the only other class of glucose‐lowering drug along with GLP‐1 RAs that routinely result in weight loss 58 …”