Short-term metformin protects against glucocorticoid-induced toxicity in healthy subjects: a randomized, double-blind, placebo-controlled trial
Objective: Glucocorticoids are potent anti-inflammatory drugs, but strategies to prevent side effects are lacking. We investigated whether metformin could prevent glucocorticoid-related toxicity and explored the underlying mechanisms.
Research Design and Methods: This single-center randomized, placebo-controlled, double-blind cross-over trial compared metformin to placebo during high-dose glucocorticoid treatment in 18 lean, healthy males. The trial was conducted at the University Hospital Basel, Switzerland. Participants received prednisone 30mg/d in combination with metformin or placebo for two 7-day periods (1:1 randomization). The primary outcome, change in insulin sensitivity, was assessed using a two-sided paired t-test. Before and after each study period, we conducted a mixed meal tolerance test (MMTT), blood metabolomics, and RNAseq of subcutaneous adipose tissue biopsies.
Results: Metformin improved insulin sensitivity as assessed by the Matsuda-index (placebo: mean change -2.73 ±3.55 SD; metformin: 2.21 ±3.95; mean difference of change -4.94 -7.24 to -2.65 95% CI, p<0.001, n=17). Metabolomic and transcriptomic analyses revealed that metformin altered fatty acid flux in the blood and downregulated genes involved in fatty acid synthesis in adipose tissue. Metformin reduced markers of protein breakdown and bone resorption. Furthermore, metformin downregulated genes responsible for AMPK inhibition and impacted GLP1 and bile acid metabolism.
Conclusions: Metformin prevents glucocorticoid-induced insulin resistance and reduces markers of dyslipidemia, myopathy, and possibly bone resorption through AMPK-dependent and -independent pathways.