Background: There is an urgent need to limit the metabolic side-effects of glucocorticoid overexposure as these can lead to Cushing's syndrome, associated with high morbidity. We have explored the potential for metformin to ameliorate such effects whilst sparing the anti-inflammatory benefits of glucocorticoids. Methods: In this double-blind, phase 2 proof-of-concept trial, 53 patients without known diabetes established on mid-to-high doses of glucocorticoids, administered as treatment for a chronic inflammatory disease, were randomised to receive 2550mg/day metformin (n=26) or an identical placebo (n=27) for 12 weeks. The primary endpoint was the change in visceral to truncal subcutaneous fat ratio assessed by computed tomography; secondary endpoints involved metabolic, bone, cardiovascular and inflammatory parameters. Findings: Nineteen patients on metformin and 21 on placebo completed the study. The groups received equivalent cumulative dose of glucocorticoids (1860mg (IQR 1060 to 2810) vs. 1770mg (IQR 1020-2356) prednisolone equivalent; p=0.76). There was no change in the visceral-to-subcutaneous fat ratio (0.11 (95%CI-0.02 to 0.24); p=0.09) between the treatment groups but metformin-treated patients lost truncal subcutaneous fat (-3835mm 2 (95%CI-6781 to-888); p=0.01) compared to placebo. Improvements in markers of carbohydrate, lipid, liver and bone metabolism were observed on metformin. Additionally, metformin-treated patients had improved fibrinolysis, carotid intima-media thickness, inflammatory parameters and clinical markers of disease activity. The frequency of pneumonia (1 vs. 7 events; p=0.01), overall rate of moderate-to-severe infections (2 vs. 11; p=0.001), and all-cause hospital admissions due to adverse events (1 vs. 9; p=0.001) were lower in the metformin group compared with placebo. Metformin-treated patients experienced more diarrhoea initially. Interpretation: Metformin administration improved the metabolic profile of glucocorticoid-treated patients with inflammatory disease, favourably modifying cardiovascular risk surrogates, reducing inflammation and hospitalisation.

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