Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial

Abstract

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.

Metformin and COVID-19: From cellular mechanisms to reduced mortality

“…Finally, in a recent randomized, double-blind, placebo-controlled, proof-of-concept phase-II trial, metformin reduced metabolic complications and inflammation in non-diabetes patients receiving systemic glucocorticoid therapy for inflammatory diseases. The results of this study further emphasize the anti-inflammatory effects of metformin independently of glucose control [15] .…”

“…Thus, it is of major importance to know the effect of metformin on the clinical outcomes of patients with T2DM during the COVID-19 outbreak. Inflammation due to cytokine storms is recognized to play a crucial role in the poor prognosis of patients infected with the SARS-CoV-2 [13] and, as metformin has been shown to exert some anti-inflammatory effects irrespective of diabetes status [14] , [15] , it may be speculated that this glucose-lowering agent could favourably influence the clinical outcomes of patients with T2DM hospitalized for COVID-19 beyond its effects on glucose control [16] , [17] , [18] .…”

Hyperglycaemia‐associated macrophage pyroptosis accelerates periodontal inflamm‐aging

“…Despite its hypoglycaemic effect, metformin exerts anti‐inflammatory and anti‐ageing activities (Pryor et al, 2019; Pernicova et al, 2020). In diabetic mice, metformin could decrease pyroptotic macrophages and down‐regulate surrounding senescent cells and systematic SASP.…”

Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy

“…3). Metformin counteracts this effect and hence might be beneficial for metabolic complications induced by glucocorticoid excess, especially the accumulation of visceral adiposity (Christ-Crain et al 2008, Seelig et al 2017, even in non-diabetic patients (Pernicova et al 2020). Since most of the drugs described in Table 1 are commonly given to patients with glucocorticoid excess or deficiency, clarifying their impact on clock molecular pathways could expand the available options for chrono-pharmacological treatment.…”