Metabolic complications of glucocorticoids - Prevention by metformin.

Abstract

Glucocorticoid treatment is prescribed in 2 to 3% of the population for various diseases. Chronic exposure to excess glucocorticoid can lead to iatrogenic Cushing's syndrome, which is associated with increased morbidity, especially from cardiovascular diseases and infections. While several 'steroid-sparing' drugs have been introduced, glucocorticoid treatment is still applied in a large number of patients. We have previously showed that the enzyme AMPK plays a key role in mediating the metabolic effects of glucocorticoids. While metformin is the most widely used drug for treatment of diabetes mellitus, its mechanism of effect is still debated. Among several effects, it stimulates AMPK in peripheral tissue, affects the mitochondrial electron chain, influences gut bacteria and stimulates GDF15. We have hypothesised that metformin will counteract the metabolic effects of glucocorticoids, even in patients without diabetes. Two double-blind placebo-controlled randomised clinical studies were conducted: in the first, glucocorticoid-naive patients started metformin treatment early together with the glucocorticoid treatment. While in placebo group glycaemic indices worsened, these sequelae were prevented in the metformin group, suggesting a beneficial effect of metformin on glycaemic control in non-diabetic patients receiving glucocorticoid treatment. In the second study, we treated patients already on established glucocorticoid therapy for a longer period with metformin or placebo. In addition to the beneficial effects on glucose metabolism, we observed significant improvement in lipid, liver, fibrinolysis, bone and inflammatory parameters, as well as fat tissue and carotid intima media thickness. Moreover, patients had a lower risk of developing pneumonia and a reduced number of admissions to hospital, representing financial advantage for the health service. We believe that the routine use of metformin for patients on glucocorticoid treatment would represent a key advantage in the care for this patient population.