Endocrine Abstracts

Excess adiposity, especially in visceral depots, is a major driver of insulin resistance, fatty liver and hyperglycaemia in type 2 diabetes mellitus (T2DM). Treatment guidelines for T2DM emphasise lifestyle measures (principally diet and exercise) with pharmacotherapy as additionally required to achieve glycaemic control. Therapeutic strategies ideally assist weight control, avoid hypoglycaemia and address cardiovascular, renal and other risks. Metformin (weight neutral), which counters insulin resistance and offers several of these requirements is usually initial pharmacotherapy. Dipeptidyl peptidase-4 inhibitors (weight neutral), which prevent the rapid breakdown of endogenous incretin hormones and potentiate nutrient-induced insulin release are often introduced next. However, the weight-lowering properties of sodium/glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) encourage use of these agents for obese patients. SGLT2 inhibitors reduce reabsorption of filtered glucose by the proximal tubules of the kidney, creating a therapeutic glucosuria of 50–90 g/day (200–360 kcal) often enabling >5% weight loss. Since the mechanism is independent of insulin, SGLT2 inhibitors can be combined with other agents at most stages of T2DM provided glomerular filtration is adequate. The osmotic diuresis generated by SGLT2 inhibitors may improve blood pressure control, and large outcome trials have identified cardio-protective and reno-protective benefits. GLP-1RAs increase meal-related insulin secretion, suppress prandial glucagon secretion, slow gastric emptying and exert a satiety effect which promotes weight loss, often >5%. Currently available GLP-1RAs are administered by daily or once weekly subcutaneous injection, and an orally administered GLP-1RA is advanced in development. Fixed-ratio combinations of insulin with a GLP-1RA can reduce/prevent the weight gain associated with insulin therapy, and hybrid and chimeric peptide sequences that activate receptors for GLP-1, gastric inhibitory peptide, glucagon, gastrin, oxyntomodulin and peptide YY are advancing in development.