Short-term Metformin Protects Against Glucocorticoid-Induced Toxicity in Healthy Individuals: A Randomized, Double-Blind, Placebo-Controlled Trial.

Summary

In a double-blind crossover RCT in healthy men receiving high-dose prednisone, metformin significantly improved insulin sensitivity (Matsuda index) and favorably modulated lipid flux and adipose transcriptional programs. Multi-omics indicated AMPK-linked and independent pathways, with reductions in markers of myopathy and bone resorption.

Key Findings

• Metformin improved insulin sensitivity vs placebo during prednisone therapy (Matsuda index mean difference −4.94; P<0.001).
• Metabolomics/transcriptomics showed reduced fatty acid synthesis gene expression and altered lipid flux in blood and adipose tissue.
• Markers of protein breakdown and bone resorption decreased, and genes inhibiting AMPK were downregulated; GLP‑1 and bile acid pathways were affected.

Clinical Implications

Consider metformin co-therapy to mitigate short-term glucocorticoid-induced insulin resistance and metabolic derangements in at-risk patients; confirm efficacy and safety in patient populations and longer durations before routine adoption.

Limitations

• Small sample size (n=18; 17 for primary analysis) and short exposure (two 7‑day periods)
• Healthy lean males only; generalizability to patients on chronic glucocorticoids is uncertain

Future Directions

Test metformin prophylaxis in diverse patient populations on glucocorticoids (e.g., rheumatology, oncology), longer durations, and evaluate hard outcomes (hyperglycemia, fractures, myopathy).